mechanistic insights into homogeneous and asymmetric iron ......evolution and the formation of b‐n...
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Mechanistic Insights into Homogeneous and
Heterogeneous Asymmetric Iron Catalysis
by
Jessica Sonnenberg
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Department of Chemistry
University of Toronto
© Copyright by Jessica Sonnenberg 2014
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Mechanistic Insights into Homogeneous and Heterogeneous Asymmetric Iron Catalysis
Jessica Sonnenberg
Doctor of Philosophy
Department of Chemistry
University of Toronto
2014
Abstract
Our group has been focused on replacing toxic and expensive precious metal catalysts with iron for the
synthesis of enantiopure compounds for industrial applications. During an investigation into the
mechanism of asymmetric transfer hydrogenation with our first generation iron‐(P‐N‐N‐P) catalysts we
found substantial evidence for zero‐valent iron nanoparticles coated in chiral ligand acting as the active
site. Extensive experimental and computational experiments were undertaken which included NMR,
DFT, reaction profile analysis, substoichiometric poisoning, electron microscope imaging, XPS and
multiphasic analysis, all of which supported the fact that NPs were the active species in catalysis.
Reversibility of this asymmetric reaction on the nanoparticle surface was then probed using oxidative
kinetic resolution of racemic alcohols, yielding modest enantiopurity and high turnover frequencies
(TOF) for a range of aromatic alcohols. Efficient dehydrogenation of ammonia‐borane for hydrogen
evolution and the formation of B‐N oligomers was also shown using the NP system, yielding highly active
systems, with a maximum TOF of 3.66 H2/s‐1.
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We have also begun to focus on the development of iron catalysts for asymmetric direct hydrogenation
of ketones using hydrogen gas. New chiral iron‐(P‐N‐P) catalysts were developed and shown to be quite
active and selective for a wide range of substrates. Mechanistic investigations primarily using NMR and
DFT indicated that a highly active trans‐dihydride species was being formed during catalyst activation.
Lastly, a new library of chiral P‐N‐P and P‐NH‐P ligands were developed, as well as their corresponding
iron complexes, some of which show promise for the development of future generations of active
asymmetric direct hydrogenation catalysts.
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Acknowledgements
I would like to start by thanking my supervisor, Professor Robert Morris for all of his guidance and
support throughout the past four years, as well for his encouragement to pursue new directions with my
research. My research project took many unexpected turns and he supported my choice to explore new
areas of chemistry, and has encouraged me to really push the research to its limits through which I have
grown greatly, both as a chemist and as a person. I would also like to extend a huge thank you to the
Morris group members, past and present, for fruitful discussions, suggestions and friendships.
Most importantly, I would like to thank the love of my life and my best friend, my husband, Chris, for his
relentless support and encouragement. He has kept me focussed and on track in all aspects of my life,
and has been patient and understanding throughout all of my research and extra‐curricular endeavors.
He has always been my most enthusiastic and proud supporter throughout all of my milestones both in
life and in research, and has been there to pull me back up again during the lows. He has kept me
grounded and motivated no matter what chemistry or life threw at me and I would not be where I am
today without his love, patience and support. I love you baby
I would also like to thank my parents, Darren and Elaine, for being my unyielding support system and
mentors for so many years. They have always encouraged me to be the absolute best that I can be and
have been there to guide and help me every step of the way. They celebrated every accomplishment, no
matter how small, and were always proud and encouraging of everything I did. Since I was very young
they have always been exceptional mentors that taught by example; they taught me to work hard, try
my best, be strong, and always believe in myself, no matter what. More importantly, they taught me
that life is all about balance – no matter how successful you are, life is nothing without family, friends,
love, and a cold beer around a campfire with the people you care about. My parents have always been
my heroes and I owe them everything.
And then there is my little brother, Steven. Normally it is the older sibling that is supposed to be wise,
but I have learned more from Steven than I ever could have taught him. Through friendly competition, in
both games and academics, he always kept me at my best. Even with moving away for school,
relationships and friendships that did or didn’t last, and starting our own lives he has always been my
best friend and role model. My brother has taught me how to trust, both others and myself, always be
proud of who I am and what I have accomplished, be compassionate and kind, and to always be myself.
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I would also like to thank my grandma, Eleanor, my Aunt Isabell, my grandparents Phyllis and Ernie, my
Aunt Diane and my friend Marnie for always being there for me and helping me every step of the way.
Thank‐you also to my best friends, Susan, Kerstin, Jessica and Vanessa – you have always kept life fun
and exciting.
Lastly, I would like to dedicate this thesis to my grandpa, Joseph Frost. He was always my number one
fan and cheerleader and I wish he could be here to celebrate this milestone with me.
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Table of Contents
Contents Abstract ......................................................................................................................................................... ii
Acknowledgements ...................................................................................................................................... iv
Table of Contents ......................................................................................................................................... vi
List of Figures ............................................................................................................................................... xi
List of Schemes............................................................................................................................................ xv
List of Tables .............................................................................................................................................. xvii
List of Abbreviations ................................................................................................................................. xviii
Summary of Numbered Compounds .......................................................................................................... xxi
Chapter 1: Introduction – Mechanistic Approaches and Iron‐Based Catalysis ...................................... 1
1.1 Overview ................................................................................................................................................. 1
1.2 The Importance of Identifying the True Catalyst .................................................................................... 1
1.3 Ex Situ Techniques .................................................................................................................................. 3
1.3.1 Electron Microscopy and Energy Dispersive X‐ray Spectroscopy ................................................ 3
1.3.2 X‐ray Photoelectron Spectroscopy .............................................................................................. 5
1.3.3 X‐ray Diffraction and Mössbauer Spectroscopy .......................................................................... 6
1.4 In Operando Techniques ......................................................................................................................... 6
1.4.1 Reaction Profiles and Kinetic Investigations ................................................................................ 7
1.4.2 Poisoning Experiments ................................................................................................................. 8
1.4.3 Extended X‐ray Absorption Fine Structure ................................................................................ 10
1.4.4 Magnetometry ........................................................................................................................... 11
1.4.5 Dynamic Light Scattering ........................................................................................................... 12
1.4.6 NMR Experiments ...................................................................................................................... 13
1.4.7 Chirality ...................................................................................................................................... 15
1.4.8 Polymer‐Bound Substrates ........................................................................................................ 16
1.5 Going Green – Iron‐Based Catalysis ...................................................................................................... 17
1.6 Summary ............................................................................................................................................... 21
1.7 Thesis Outline ........................................................................................................................................ 22
Chapter 2: Iron Nanoparticles Catalysing the Asymmetric Transfer Hydrogenation of Ketones ....... 22
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Chapter 3: Oxidative Kinetic Resolution of Aromatic Alcohols using Iron Nanoparticles .................. 23
Chapter 4: Evidence for Iron Nanoparticles Catalysing the Rapid Dehydrogenation of Ammonia‐
Borane ................................................................................................................................................. 24
Chapter 5: Synthesis and Mechanistic Studies of Iron P‐N‐P’ and P‐NH‐P Asymmetric Hydrogenation
Catalysts .............................................................................................................................................. 24
1.8 References ............................................................................................................................................ 26
Chapter 2: Iron Nanoparticles Catalysing the Asymmetric Transfer Hydrogenation of Ketones ......... 34
2.1 Abstract ................................................................................................................................................. 34
2.2 Introduction .......................................................................................................................................... 35
2.3 Results and Discussion .......................................................................................................................... 37
2.3.1 Spectroscopic Investigation of Catalysis .................................................................................... 37
2.3.2 Studying Reactive Intermediates ............................................................................................... 39
2.3.3 Mass Balance Experiment .......................................................................................................... 42
2.3.4 Mechanistic Evaluations with DFT ............................................................................................. 43
2.3.5 Probes for Heterogeneity........................................................................................................... 44
2.3.6 Reaction Profile .......................................................................................................................... 45
2.3.7 Poisoning Experiments ............................................................................................................... 45
2.3.8 X‐ray Photoelectron Spectroscopy ............................................................................................ 48
2.3.9 Electron Microscopy .................................................................................................................. 49
2.3.10 Superconducting Quantum Interference Device Magnetometry ............................................ 50
2.3.11 Polymer‐bound Substrate Experiments ................................................................................... 51
2.3.12 STEM/EDX/Poisoning Experiments .......................................................................................... 53
2.3.13 Description of Fe NPs ............................................................................................................... 55
2.4 Case Study ............................................................................................................................................. 56
2.5 Conclusions ........................................................................................................................................... 60
2.8 Experimental ......................................................................................................................................... 61
2.8.1 General Procedures ................................................................................................................... 61
2.8.2 Syntheses ................................................................................................................................... 62
2.8.3 Catalysis – Standard Run ............................................................................................................ 63
2.8.4 Catalysis – Poisoning Experiments ............................................................................................. 63
2.8.5 Catalysis – NMR Scale Reactions ................................................................................................ 63
2.8.6 Mass Balance Experiments ........................................................................................................ 64
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2.8.7 Experimental for Polymer‐bound Substrate Experiments ......................................................... 64
2.8.8 Determining the Ratio of Fe on the Surface of Fe NP ................................................................ 66
2.8.9 Catalysis – HCl Addition Experiments ........................................................................................ 67
2.7 References ............................................................................................................................................ 69
Chapter 3: Oxidative Kinetic Resolution of Aromatic Alcohols using Iron Nanoparticles .................... 74
3.1 Abstract ................................................................................................................................................. 74
3.2 Introduction .......................................................................................................................................... 75
3.3 Results and Discussion .......................................................................................................................... 76
3.3.1 Catalytic Runs ............................................................................................................................. 76
3.3.2 Evidence for Nanoparticles ........................................................................................................ 81
3.4 Conclusions ........................................................................................................................................... 88
3.5.1 General Procedures ................................................................................................................... 89
3.5.2 Gas Chromatography ................................................................................................................. 89
3.5.3 Synthesis .................................................................................................................................... 90
3.5.4 Microscopy ................................................................................................................................. 90
3.5.5 Solid State NMR ......................................................................................................................... 91
3.5.6 Catalysis – Standard Run ............................................................................................................ 93
3.5.7 Catalysis – Poisoned Run............................................................................................................ 93
3.6.8 Polymer‐bound Substrate Experiments ..................................................................................... 93
Chapter 4: Evidence for Iron Nanoparticles Catalysing the Rapid Dehydrogenation of Ammonia‐
Borane 97
4.1 Abstract ................................................................................................................................................. 97
4.2 Introduction .......................................................................................................................................... 98
4.3 Experimental ....................................................................................................................................... 100
4.3.1 General Procedures ................................................................................................................. 100
4.3.2 Syntheses ................................................................................................................................. 100
4.3.3 Catalysis ................................................................................................................................... 100
4.4 Results and Discussion ........................................................................................................................ 103
4.4.1 AB Dehydrogenation with Precatalysts (1, 2, 5 and 6) in Protic Solvents ................................ 103
4.4.2 AB Dehydrogenation with Precatalysts (1, 2, 5‐7) in Non‐Protic Solvents .............................. 104
4.4.3 Effect of Varying Conditions of AB Dehydrogenation with Precatalyst (5) .............................. 107
4.4.4 AB Dehydrogenation with In Situ Generated Catalysts ........................................................... 110
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4.4.5 Dimethylamine‐borane (DMAB) Dehydrogenation with Precatalysts (1) and (5) ................... 113
4.4.6 Electron Microscopy Imaging ................................................................................................... 115
4.5 Conclusions ......................................................................................................................................... 118
4.6 References .......................................................................................................................................... 119
Chapter 5: Synthesis and Mechanistic Studies of Iron P‐N‐P’ and P‐NH‐P Asymmetric Hydrogenation
Catalysts 122
5.1 Abstract ............................................................................................................................................... 122
5.2 Introduction ........................................................................................................................................ 123
5.3 Results and Discussion ........................................................................................................................ 126
5.3.1 NMR Investigation of the Mechanism ..................................................................................... 126
5.3.2 Modifying the Catalyst Chirality ............................................................................................... 132
5.3.3 Catalytic Asymmetric Hydrogenation of Acetophenone ......................................................... 136
5.3.4 Synthesis of Fe Complexes Bearing Multiple Stereogenic Centres .......................................... 137
5.3.5 Changing the Catalyst Structure Using 6,5‐(P‐N‐P) Ligands ..................................................... 141
5.4 Conclusions ......................................................................................................................................... 151
5.5. Experimental ...................................................................................................................................... 152
5.5.1 General Considerations ............................................................................................................ 152
5.5.2 Synthesis of Precatalysts for NMR Studies .............................................................................. 152
5.5.3 Synthesis of trans‐dihydride complex (13) .............................................................................. 153
5.5.4 Hydrogenation Studies ............................................................................................................. 157
5.5.5 Synthesis of PN Precursors (14defg) ........................................................................................ 157
5.5.6 Synthesis of mer‐trans‐[Fe(Br)(CO)2(P‐N‐P′)][BF4] precatalysts (10d‐f) ................................... 160
5.5.7 Synthesis of [Fe(PN)2(CO)(Br)][BPh4] (15) ................................................................................ 162
5.5.8 Synthesis of P‐N‐P Ligands (16a,c‐g) ........................................................................................ 162
5.5.9 Synthesis of P‐NH‐P Ligands (17a,c‐f) ...................................................................................... 165
5.5.10 Synthesis of [Fe(P‐N‐P)(NCMe)3][BF4]2 (18a,c‐g).................................................................... 168
5.5.11 Synthesis of [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19a,c‐f) .................................................................. 170
5.5.12 Synthesis of Fe(P‐N‐P)(CO)Br2 (20) ........................................................................................ 172
5.5.13 Transfer Hydrogenation Catalysis .......................................................................................... 173
5.5.14 Ammonia‐Borane Dehydrogenation Catalysis ....................................................................... 173
5.6 References .......................................................................................................................................... 174
Chapter 6: Conclusions and Future Directions ................................................................................... 178
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6.1 Conclusions ......................................................................................................................................... 178
6.2 Future Directions ................................................................................................................................ 184
6.2.1 Investigating the True Nature of the Catalyst .............................................................................. 184
6.2.2 Broadening the Scope of the P‐N‐P System ................................................................................. 185
6.2.3 New Catalytic Directions .............................................................................................................. 187
6.2.4 The Iron Age ................................................................................................................................. 188
6.3 References .......................................................................................................................................... 189
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List of Figures
Figure 1.1: Prototype solution phase cell for electron microscopy analysis. Reprinted with permission of
Reference 47. Copyright 2013 American Chemical Society. ......................................................................... 5
Figure 1.2: Sigmoidal reaction curve depicting the hydrogenation of cyclohexene over time. Curve shows
all three phases (nucleation, catalysis and completion) of the reaction profile. Also shown is the
predicted curve using F‐W Kinetics. Reprinted with permission from Reference 63. Copyright 2009
American Chemical Society. .......................................................................................................................... 8
Figure 1.3: Distinguishing homogeneous from heterogeneous Fe catalysis for the dehydrogenation of
amine‐boranes. Reprinted with permission from Reference 37. Copyright 2014 American Chemical
Society. ........................................................................................................................................................ 10
Figure 1.4: Standard plots obtained using SQUID Magnetometry analysis. Top ‐ hysteresis loops through
varying magnetic fields at two set temperatures (3 K and 40 K). Bottom ‐ ZFC‐FC experiment depicting a
blocking temperature. Reproduced from Reference 74 with permission from The Royal Society of
Chemistry. ................................................................................................................................................... 12
Figure 1.5: Space‐filling model depicting Ru NPs selectively coated by NHC ligands as determined by 13C
solid state NMR spectroscopy. Two NHC ligands tested are also shown for clarity. Reprinted with
permission of Reference 38. Copyright 2011 Wiley‐VCH. .......................................................................... 14
Figure 1.6: Illustrative examples of iron catalysts developed for a wide range of catalytic
transformations. ......................................................................................................................................... 20
Figure 2.7: 31P {1H} spectrum (161 MHz, iPrOH, C6D6 internal reference) of a TH run in 0.65 mL
isopropanol for the production of 1‐phenylethanol from acetophenone (0.60 M) by use of (1) (0.025 M)
and KOtBu (0.14 M) at 26°C. ....................................................................................................................... 38
Figure 2.8: Molecular structure of (3). ........................................................................................................ 40
Figure 2.9: Complete energetics profile and structures depicting the favourable formation of Fe(0). ..... 44
Figure 2.10: Standard catalytic runs using (1) and (2), and poisoning runs using (1) and (2) and 10% PMe3
added at t = 10min. ..................................................................................................................................... 46
Figure 2.11: Conversion profiles for the TH of acetophenone to phenylethanol using (2) at ambient
temperature (28 0C) in the presence of various poisons at the given amounts relative to catalyst,
introduced at the given times. .................................................................................................................... 48
Figure 2.12: STEM images of TH with (1) (left) and (2) (right). ................................................................... 49
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Figure 2.13: Temperature dependence of the Zero Field Cooling‐Field Cooling (ZFC‐FC) SQUID
experiment with (2). ................................................................................................................................... 51
Figure 2.14: Reaction profiles for the conversion of acetophenone to 1‐phenylethanol over time using
the 6,5,6‐system (a) and the 5,5,5‐system (b). Plots depict the effect of adding HCl following by
reactivation with KOtBu. ............................................................................................................................. 59
Figure 3.15: STEM image taken at ‐100oC of activated catalyst; a) [left] solution prepared using (2) and
NaOiPr at room temperature (28oC) in acetone, using iPrOH as the substrate (C:B:S = 1:8:230); b) [right]
solution prepared using (2) and KOtBu at room temperature (28oC) in benzophenone/THF, using iPrOH
as the substrate (C:B:S = 1:8:230). .............................................................................................................. 82
Figure 3.16: Reaction profiles for the catalytic oxidation of racemic 1‐phenylethanol (2.2 mmol) to
acetophenone at 45oC in THF with benzophenone (7.7 mmol), and runs in which the solvent
(THF/benzophenone) or substrate (1‐phenylethanol) were added at 45oC 10 minutes prior to reaction
commencement. ......................................................................................................................................... 83
Figure 3.17: Corresponding enantiopurity in (R)‐phenylethanol over time profile to Figure 3.16. ........... 84
Figure 3.18: Standard and poisoned catalytic runs for the oxidation of 1‐phenylethanol in acetone using
NaOiPr at 28oC and in benzophenone/THF using KOtBu at 45oC, with C:B:S = 1:8:400. ............................ 85
Figure 3.19: 13C {1H} solid state NMR spectrum of phenylethanol‐bound Wang Resin (Wang‐PE) swollen
in CD2Cl2, spun at 10 kHz. ............................................................................................................................ 92
Figure 3.20: 13C {1H} solid state NMR spectrum of acetophenone‐bound Wang Resin (Wang‐B) swollen in
CD2Cl2, spun at 10 kHz. ................................................................................................................................ 92
Figure 4.21: Precatalyst structures for systems investigated for ammonia‐borane dehydrogenation
reactions including ligands tested. ............................................................................................................. 99
Figure 4.22: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL iPrOH at 22oC using 2.5 mol%
Fe and 20 mol% KOtBu. Fe:AB:KOtBu = 1:40:8. ........................................................................................ 104
Figure 4.23: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 2.5 mol% Fe
and 20 mol% KOtBu. ................................................................................................................................. 106
Figure 4.24: Catalytic dehydrogenation of AB. Standard Run: AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC
using 2.5 mol% Precatalyst (5) and 20 mol% KOtBu, Fe:AB:KOtBu = 1:40:8. Variations from standard
conditions as listed in legend. ................................................................................................................... 108
Figure 4.25: Catalytic dehydrogenation of AB. Standard Run: AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC
using 2.5 mol% Precatalyst (5) and base. ................................................................................................. 109
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Figure 4.26: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 4 or 2.5
mol% Fe, 2.6 or 1.6 mol% ligand and 32 or 20 mol% KOtBu. Fe:Ligand:AB:KOtBu = 1:0.6:25:8 or
1:0.6:40:8. Where Fe‐H20 = [Fe(H2O)6][BF4]2. ........................................................................................... 111
Figure 4.27: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 4 mol%
FeBr2, ligand (8) and 32 mol% KOtBu (relative to AB). Fe:AB:KOtBu = 1:25:8. ......................................... 113
Figure 4.28: In situ 11B NMR (128 MHz) spectrum of catalytic dehydrogenation of Me2NHBH3 (entry 24 of
Table 4.6) after 30min. Fe:B:KOtBu = 1:45:8. ........................................................................................... 115
Figure 4.29: TEM images of entry 33 [left] and entry 32 [right]. .............................................................. 116
Figure 5.30: Catalysts used for the direct hydrogenation of polar double bonds. ................................... 124
Figure 5.31: Free energy profile of the amino metal hydride catalytic pathway. .................................... 132
Figure 5.32: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (10d). Hydrogen
atoms of Ph and Cy groups removed for clarity, as is the BF4 counterion. Selected bond lengths (Å) and
angles (deg): Fe(1)‐P(1): 2.245(2); Fe(1)‐P(2): 2.277(2); Fe(1)‐N(1): 1.998(5); Fe(1)‐Br(1): 2.473(1); N(1)‐
C(2): 1.286(8); N(1)‐C(3): 1.511(7): O(1)‐C(11): 1.13(1); O(2)‐C(12): 1.044(8); P(2)‐Fe(1)‐P(1):
170.25(7); C(11)‐Fe(1)‐C(12): 172.5(4). .................................................................................................... 135
Figure 5.33: Molecular structure (thermal ellipsoids at 30% probability) of [Fe(PN)2(CO)Br][BF4] (15).
Hydrogen atoms of Ph groups and the BF4 anion are removed for clarity. Selected bond lengths (Å) and
angles (deg): Fe(1)‐P(1): 2.2701(9); Fe(1)‐P(1a): 2.2702(9); Fe(1)‐N(1): 2.045(3); Fe(1)‐N(1a): 2.045(3);
Fe(1)‐Br(1): 2.451(2); Fe(1)‐C(3): 1.76(1); O(1)‐C(3): 1.17(1); P(1)‐Fe(1)‐P(1a): 172.20(5); N(1)‐Fe(1)‐
N(1a): 92.1(2); P(1)‐Fe(1)‐N(1): 83.3(1). ................................................................................................... 139
Figure 5.34: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (18a). Hydrogen
atoms of Ph groups and BF4 anion are removed for clarity. Selected bond lengths (Å) and angles (deg):
Fe(1)‐P(1): 2.2732(8); Fe(1)‐P(2): 2.3044(8); Fe(1)‐N(1): 1.972(2); Fe(1)‐N(2): 1.922(2); Fe(1)‐N(3):
1.932(2); Fe(1)‐N(4): 1.907(2); N(1)‐C(7): 1.279(3); N(1)‐C(8): 1.485(3): P(2)‐Fe(1)‐P(1): 173.82(3); N(1)‐
Fe(1)‐P(1): 89.82(6); N(1)‐Fe(1)‐P(2): 84.76(6). ....................................................................................... 145
Figure 5.35: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (18e). Hydrogen
atoms of Ph groups and BF4 anion are removed for clarity. Selected bond lengths (Å) and angles (deg):
Fe(1)‐P(1): 2.287(1); Fe(1)‐P(2): 2.256(1); Fe(1)‐N(1): 1.976(3); Fe(1)‐N(2): 1.896(4); Fe(1)‐N(3):
1.928(4); Fe(1)‐N(4): 1.925(3); N(1)‐C(3): 1.291(5); N(1)‐C(2): 1.495(5): P(2)‐Fe(1)‐P(1): 173.44(4); N(1)‐
Fe(1)‐P(1): 84.32(9); N(1)‐Fe(1)‐P(2): 89.12(9). ....................................................................................... 146
Figure 5.36: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (20). Hydrogen
atoms of Ph groups removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1):
2.2668(8); Fe(1)‐P(2): 2.2653(8); Fe(1)‐N(1): 1.987(2); Fe(1)‐Br(1): 2.4821(5); Fe(1)‐Br(2): 2.4787(5);
xiv
Fe(1)‐C(10): 1.776(4); N(1)‐C(2): 1.489(3); N(1)‐C(3): 1.283(3): O(1)‐C(10): 1.097(5); P(2)‐Fe(1)‐P(1):
174.36(3); C(10)‐Fe(1)‐Br(1): 178.2(1); Br(2)‐Fe(1)‐Br(1): 96.52(2). ........................................................ 148
Figure 5.37: Molecular structure (thermal ellipsoids at 30% probability) of Fe(P‐N‐P)Br2 (iPr). Hydrogen
atoms of Ph groups removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.620(4);
Fe(1)‐P(2): 2.500(3); Fe(1)‐N(1): 2.25(1); Fe(1)‐Br(1): 2.453(2); Fe(1)‐Br(2): 2.377(2); N(1)‐C(2): 1.48(2);
N(1)‐C(6): 1.30(2): P(2)‐Fe(1)‐P(1): 158.8(1); Br(2)‐Fe(1)‐Br(1): 122.3(1); N(1)‐Fe(1)‐P(1): 78.1(3); N(1)‐
Fe(1)‐P(2): 80.8(3). .................................................................................................................................... 150
Figure 5.38: 1H NMR spectrum (600 MHz, THF‐d8) of methoxide‐hydride (11a). Peaks: ‐21.6 (dd) and ‐
22.7 (dd) ppm, 2JPH = 52.0 and 56.4 Hz. .................................................................................................... 153
Figure 5.39: 1H NMR spectrum (500 MHz, THF‐d8) of trans‐dihydride (13).............................................. 154
Figure 5.40: 1H NMR {31P‐fully decoupled} spectrum (500 MHz, THF‐d8) of trans‐dihydride (13). Peaks: ‐
9.05 (d) and ‐9.16 (d) ppm, 2JHH = 9.8 Hz. .................................................................................................. 154
Figure 5.41: Simulated 1H NMR spectrum of trans‐dihydride (13). Simulated using hydride shifts ‐9.05
and ‐9.16 ppm, 2JHH = 9.8 Hz, 2JPP = 118.0 Hz, and
2JHP = 42.0, 42.0, 43.0, and 43.0 Hz. ............................ 155
Figure 5.42:31P {1H} NMR spectrum (202 MHz, THF‐d8) of trans‐dihydride (13) doublets at 118.0 and 95.8
ppm (2JPP = 118 Hz), cis‐dihydride doublets at 114.6 and 93.0 ppm (2JPP = 72.5 Hz) and Fe0 complex (12) at
102.8 and 81.5 ppm. ................................................................................................................................. 155
Figure 5.43: 1H NMR spectrum (500 MHz, THF‐d8) of trans‐dihydride (13) at ‐9.1 ppm and cis‐dihydride at
‐8.1 and ‐20.6 ppm. ................................................................................................................................... 156
Figure 5.44: 1H NMR spectrum (600 MHz, THF‐d8) of trans‐dihydride (13c) at ‐8.56 (ddd) and ‐8.94 (td)
ppm and cis‐dihydride at ‐7.31 (ddd) and ‐21.0 (td) ppm. ..................................................................... 156
Figure 6.45: Potential chiral PN ligands for use in the synthesis of new Fe(P‐N‐P)(CO)2Br[BF4]
precatalysts. .............................................................................................................................................. 186
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List of Schemes
Scheme 1.1: Asymmetric transfer hydrogenation of acetophenone using Fe NPs modified with chiral P‐
N‐N‐P ligands............................................................................................................................................... 22
Scheme 1.2: Oxidative kinetic resolution of racemic 1‐phenylethanol using Fe NPs modified with chiral P‐
N‐N‐P ligand. ............................................................................................................................................... 23
Scheme 1.3: The dehydrogenation of ammonia borane to form H2 and B‐N compounds using Fe NPs. .. 24
Scheme 1.4: Direct hydrogenation of ketones to chiral alcohols using Fe‐(P‐N‐P’) precatalysts. .............. 25
Scheme 2.5: Typical reaction scheme for TH, and pre‐catalyst (1) and ((R,R)‐2) structures. **Note this
shows the (R,R) catalyst giving the (S) alcohol** ........................................................................................ 36
Scheme 2.6: Synthesis of ferraaziridine complex (3). ................................................................................. 39
Scheme 2.7: Observation of (4) and proposed structure. .......................................................................... 42
Scheme 2.8: Polymer‐bound substrate experimental overview. ............................................................... 52
Scheme 2.9: Iron‐(P‐N‐N‐P) transfer hydrogenation catalysts developed by our group. Left: First
Generation, 6,5,6‐system and proposed formation of active species. Right: Second Generation, 5,5,5‐
system and proposed formation of active species. .................................................................................... 57
Scheme 3.10: Precatalyst structure and reaction schemes for transfer hydrogenation (TH) [Top] and
oxidative kinetic resolution [Bottom]. ........................................................................................................ 76
Scheme 3.11: Polymer‐bound substrate experimental overview and peaks of interest from 13C {1H} solid
state NMR spectra. ..................................................................................................................................... 87
Scheme 4.12: Generalized reaction scheme and product distribution for optimized catalytic system. .. 100
Scheme 5.13: Activation of [Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts (10a‐c) with LiAlH4 and alcohol. ........ 126
Scheme 5.14: Activation of iron‐alkoxide (11) with base and hydrogen to generate active dihydride (13)
and iron (0) dicarbonyl (12). ..................................................................................................................... 128
Scheme 5.15: Synthesis of [Fe(P‐N‐P)(CO)2Br][BF4] catalysts (10a‐f). ...................................................... 133
Scheme 5.16: Synthetic pathway for the formation of chiral PN complexes (14d‐f). .............................. 134
Scheme 5.17: Synthetic pathway for the formation of the chiral PN compound (S,S)‐(14g). .................. 138
xvi
Scheme 5.18: Synthesis of [Fe(PN)2(CO)Br][BPh4] (15). ............................................................................ 140
Scheme 5.19: Condensation reaction of phosphine aldehyde with (14) to generate enantiopure P‐N‐P
ligands (16). ............................................................................................................................................... 142
Scheme 5.20: Reduction of P‐N‐P ligands (16) to form chiral P‐NH‐P ligands (17). ................................. 143
Scheme 5.21: Synthesis of [Fe(P‐N‐P)(NCMe)3][BF4]2 (18) and [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19) from P‐N‐P
(16) and P‐NH‐P (17), respectively. ........................................................................................................... 144
Scheme 6.22: Synthesis of new Fe(P‐N‐P')(CO)2Br[BF4] precatalysts bearing different groups on
phosphorus. .............................................................................................................................................. 186
Scheme 6.23: Synthesis of phosphine aldehydes bearing PR2 functionality. ........................................... 187
Scheme 6.24: Synthesis of chiral P‐N‐O ligands using previously developed methodologies. ................. 187
xvii
List of Tables
Table 2.1. Relative weight percent of Fe:S on grids (A) and (B) determined using EDX at ‐100oC on a
STEM. .......................................................................................................................................................... 54
Table 2.2: IR peaks for modified resin experiments ................................................................................... 66
Table 3.3: Kinetic Resolution of racemic 1‐phenylethanol (2.2 mmol) using (2) (0.0056 mmol) and base
(0.045 mmol) [C:B:S = 1:8:400]. .................................................................................................................. 78
Table 3.4: Kinetic Resolution of various racemic alcohols using (2) (0.0056 mmol) and KOtBu (0.045
mmol) at 45oC in a stock solution of benzophenone (1.4 g, 7.7 mmol) in THF (4.7 mL, 58 mmol). ........... 80
Table 3.5: GC temperatures and retention times for substrates tested .................................................... 90
Table 4.6: Reaction conditions for all catalytic hydrogen evolution reactions using iron catalysts. ........ 101
Table 5.7: Comparative 31P {1H} NMR shifts, 2JPP coupling constants and IR v(CO) stretches for
Precatalysts (10b‐f). .................................................................................................................................. 136
Table 5.8: Catalytic activity and selectivity for the ADH of acetophenone to 1‐phenylethanol at 50oC.. 137
xviii
List of Abbreviations
AB ammonia‐borane
ADH asymmetric direct hydrogenation
ATH asymmetric transfer hydrogenation
atm atmosphere
BF4 tetrafluoroborate
BT blocking temperature
Bu butyl
C:B:S catalyst to base to substrate
CO carbon monoxide
COSY correlation spectroscopy
DCM dichloromethane
DFT Density Functional Theory
DH direct hydrogenation
DLS dynamic light scattering
dpen 1,2‐diphenylethylenediamine
e.e. enantiomeric excess
EA elemental analysis
EDX energy dispersive X‐ray
equiv. equivalent
Et ethyl
EXAFS extended X‐ray absorption fine structure
fac facial
GC gas chromatography
HMBC heteronuclear multiple‐bond correlation
HSQC heteronuclear single‐quantum correlation
iPr iso‐propyl
iPrOH iso‐propanol
IR infrared
KBr potassium bromide
xix
KOtBu potassium tert‐butoxide
LiAlH4 lithium aluminum hydride
MAS magic angle spinning
Me methyl
MeCN acetonitrile
MeOH methanol
mer meridional
MgSO4 magnesium sulfate
MHz megahertz
MS mass spectrometry
Na2SO4 sodium sulfate
NaBH4 sodium borohydride
NaOiPr sodium isopropoxide
NaOMe sodium methoxide
NaOtBu sodium tert‐butoxide
NEt3 triethylamine
NH4Cl ammonium chloride
NHC N‐heterocyclic carbene
NMR nuclear magnetic resonance
NOESY nuclear Overhauser effect spectroscopy
NP nanoparticle
ORTEP Oak Ridge Thermal Ellipsoid Plot
PCC pyridinium chlorochromate
PCy2 dicyclohexylphosphino
PF6 hexafluorophosphate
PiPr2 diisopropylphosphino
PMe3 trimethyl phosphine
P‐NH‐NH‐P tetradentate diphosphinediamine ligand
P‐NH‐P tridentate diphosphineamine ligand
P‐N‐N‐P tetradentate diphosphinediimine ligand
P‐N‐P tridentate diphosphineimine ligand
PPh2 diphenylphosphino
xx
ppm parts per million
RT room temperature
SEM scanning electron microscope
SQUID super conducting quantum interference device
STEM scanning transmission electron microscopy
tAm tert‐amyl
tAmOH tert‐amyl alcohol
tBu tert‐butyl
TEM transmission electron microscopy
TH transfer hydrogenation
THF tetrahydrofuran
TOF turnover frequency
UV‐Vis ultraviolet visible
XPS X‐ray photoelectron spectroscopy
ZFC‐FC zero‐field‐cooled field‐cooled
xxi
Summary of Numbered Compounds
xxii
xxiii
H2N
PPh2R1
R2
Fe
NH2
BrPh2P
CO
NH2
Ph2P
Ph
Ph
[BPh4]
(15)
PPh2
N PPh2
R1R2
(16a) R1 = R2 = H
(S,S)-(16c) R1 = Me, R2 = Ph
(S)-(16d) R1 = Ph, R2 = H
(S)-(16e) R1 = CH2Ph, R2 = H
(S)-(16f) R1 = iPr, R2 = H
(S,S)-(16g) R1 = R2 = Ph
(14a) R1 = R2 = H
(S,S)-(14c) R1 = Me, R2 = Ph
(S)-(14d) R1 = Ph, R2 = H
(S)-(14e) R1 = CH2Ph, R2 = H
(S)-(14f) R1 = iPr, R2 = H
(S,S)-(14g) R1 = R2 = Ph
PPh2
NH PPh2
R1R2
(17a) R1 = R2 = H
(S,S)-(17c) R1 = Me, R2 = Ph
(S)-(17d) R1 = Ph, R2 = H
(S)-(17e) R1 = CH2Ph, R2 = H
(S)-(17f) R1 = iPr, R2 = H
(S,S)-(17g) R1 = R2 = Ph
Ph
Ph
xxiv
PPh2
N PPh2Fe
NCMe
NCMe
NCMe
R1R2
[BF4]2
PPh2
NH
PPh2Fe
NCMe
NCMe
NCMe
R1R2
[BF4]2
(18a) R1 = R2 = H
(S,S)-(18c) R1 = Me, R2 = Ph
(S)-(18d) R1 = Ph, R2 = H
(S)-(18e) R1 = CH2Ph, R2 = H
(S)-(18f) R1 = iPr, R2 = H
(S,S)-(18g) R1 = R2 = Ph
(19a) R1 = R2 = H
(S,S)-(19c) R1 = Me, R2 = Ph
(S)-(19d) R1 = Ph, R2 = H
(S)-(19e) R1 = CH2Ph, R2 = H
(S)-(19f) R1 = iPr, R2 = H
PPh2
N PPh2Fe
CO
Br
Br
H H BF4
(20)
1
Chapter 1: Introduction – Mechanistic
Approaches and Iron‐Based Catalysis
Partially adapted from Sonnenberg, J.F., Morris, R.H. Catal. Sci. Tech. 2014, 4, 3426‐3438
1.1 Overview
The focus of this introductory chapter is two‐fold; first is to highlight why it is important to understand
the true mechanism of catalysis. This will include an overview of the existing and commonly employed
methodologies for distinguishing homogeneous from heterogeneous systems. To highlight the difficulty
in truly identifying the active species in catalysis, this chapter will examine ex‐situ and in operando
techniques that have been employed to distinguish homogeneous from nanoparticle catalysis involving
transition metal systems. The ex‐situ techniques include electron microscopy and energy dispersive X‐
ray spectroscopy, X‐ray photoelectron spectroscopy, Mössbauer spectroscopy and X‐ray diffraction. The
in operando techniques involve reaction profile and kinetic investigations, poisoning experiments,
EXAFS, magnetometry, dynamic light scattering, NMR experiments, asymmetric induction and polymer
coordination. The second goal of this chapter is to emphasize the importance of transitioning to more
sustainable catalysts based on non‐precious metals, both in the lab and in industry. The use of iron in
catalysis will then be briefly discussed.
1.2 The Importance of Identifying the True Catalyst
What is the true nature of an active catalyst? Answering this question traditionally involved an
investigation into whether a catalyst was homogeneous or bulk metal, but as nanoparticle catalysis
becomes more prevalent this question becomes increasingly difficult and more important to answer.
Determining whether a catalyst is homogeneous or heterogeneous is not straightforward, especially in
the case of nanoparticle (NP) or cluster catalysis, and there is no single test that can conclusively prove
what the true nature of a catalyst is. There have been several noteworthy reviews on how to distinguish
homogeneous from heterogeneous catalysis,1‐10 and this chapter will be focussed primarily on methods
specific to soluble transition metal NPs, as they relate more directly to the topics of this thesis. Many
2
conventional heterogeneous and nanoparticle catalysts are supported systems, and although very
important and versatile,11 these will also not be the focus of this thesis. Critical to this field is the work of
Finke, whose 2003 and 2014 reviews suggested using a suite of tests and experiments, that each provide
evidence for heterogeneity or homogeneity which, when combined together, provide more valuable
insights.1,10 In his 2003 review he refers to the suite of potential tests as the ‘toolkit’, and we will focus
on reviewing, further expanding, and adding to this toolkit. It is also important to address the advice
detailed by Platt in his 1964 article entitled ‘Strong Inference’ where he details the importance of
disproof‐based science.12 In his article he discusses the importance of devising alternative hypotheses,
and executing experiments to test these alternative hypotheses, followed by repeating this process
(asking, ‘what test could disprove your hypothesis?’). This disproof based experimentation and problem
solving must be applied to answering the title question, whereby a series of tests must be undertaken,
each guiding the next, much like a knowledge tree, to build a fact‐based assessment of the catalyst
mechanism. The application of this methodology has been recently detailed extensively as it applies to
the question of homogeneity versus heterogeneity by Stracke and Finke.10
It is important to first consider why such a strong emphasis has been placed on determining the true
nature of a catalytic system: it is only through a complete understanding of the catalytic mechanism that
we can start to make significant improvements to catalytic activity, recyclability, selectivity and stability.
For NP systems, reaction conditions such as temperature, concentration, pressure and the nature of the
reagents, as well as the synthetic methods used to generate the NPs (type of reductants, solvents, time,
temperature, pressure, concentration, etc.) can all affect the size, shape, morphology, crystallinity and
dispersity of the NPs.13,14 The type, binding nature and concentration of stabilizers or ligands can also
have a large influence on the NP structure and behaviour.11,13,15‐17 All of these factors will, in turn, affect
the catalyst’s performance.9 For NPs, many of these factors can be sequentially modified to properly
monitor and tailor the catalyst to better suit the desired catalytic application, making it critical to first
understand how the catalyst operates. Homogeneous systems, much like NPs, are strongly influenced by
their environments, and therefore understanding the mechanism and energies of transition states can
allow for rational modifications to the catalyst structure or reaction conditions for improved
performance. This type of sequential modification and analysis methodology has been recently used by
our group for a homogeneous asymmetric transfer hydrogenation (TH) catalyst which is now the most
efficient catalyst in its field.18‐20 This process would not have been successful without first determining
the true nature of the catalyst, and by understanding the structure, energetics and behaviour of the
active site in the catalytic environment, further improvements to the precatalyst structure were logically
3
implemented. For further details, the importance of distinguishing homogeneous from heterogeneous
catalysis is reviewed elsewhere.1,2
In the following two sections, we provide a detailed list of potential experiments and tests separated
into ex situ and in operando techniques, which can be undertaken to investigate the true nature of a
catalyst. We emphasize how each technique can apply to mechanism elucidation, and give examples of
catalysts that have been studied using those methods. It is critical to remember that no single technique
can provide conclusive proof of heterogeneity, but rather a combination of multiple ex situ and in
operando studies is necessary to draw strong conclusions about the true nature of the catalyst.
1.3 Ex Situ Techniques
For our purposes, ex situ techniques refer to experiments that require the catalytic solutions to be dried
as powders or films to allow for analysis of the metal containing species. These techniques are often
able to provide evidence for the presence of nanoparticles during catalysis (different from proving that
NPs are the active catalyst), and are therefore commonly employed as initial probing experiments to
determine if a more rigorous analysis is needed.
1.3.1 Electron Microscopy and Energy Dispersive X‐ray Spectroscopy
Electron microscopy is a well‐studied, advanced technique,21 that is one of the most common methods
of probing and analysing nanoparticle samples. Transmission (TEM), Scanning (SEM) and Scanning
Transmission (STEM) electron microscopes can be used to visually detect the presence (or lack) of
nanoparticles, as well as examine their size, shape and distributions.22 It is important to first address the
shortfalls of this technique as an analytical tool. First, the presence of nanoparticles does not prove they
are the active catalytic species because 1) nanoparticles may form as an inactive side reaction or an
active homogeneous catalyst may gradually deactivate into nanoparticles23 or 2) the electron beam may
induce nanoparticle formation from a homogeneous sample.24‐27 One must also be aware that reports
do exist of the electron beam inducing phase changes on a heterogeneous surface, which can influence
the resultant structure observed by EM.28 The lack of nanoparticles also cannot be used to prove
homogeneous catalysis as these instruments do have lower levels of detection and the characterization
of particles below 1 nm in diameter is not often possible.2,29 Another complicating issue on the use of
EM for catalytic solution analysis arises from the potential high concentration of non‐volatile organic
contaminants present. We encountered this problem while studying iron NPs contaminated with
4
substrate. During analysis, the organics were rapidly decomposed by the electron beam, making imaging
difficult, and resulting in the need to lower the temperature of the instrument to ‐100 0C, as discussed in
further detail in Chapters 2 and 3.30,31
There are countless examples of nanoparticle catalysts being analysed using electron microscopy for
both base metal32‐37 and precious metal16,38‐43 systems. Select examples include the detection of small (2
nm) monodisperse iron nanoparticles for C‐C bond hydrogenation by Kelsen et. al.,32 the breakthrough
iridium nanocluster analysis work by Lin and Finke showing the time sensitive nature of Ir~300
nanoclusters as the monodisperse particles agglomerate over time,40 and the detection of 0.5‐2 nm
platinum nanoparticles coated onto TiO2 single crystal thin films for CO2 photoreduction by Biswas and
coworkers.44 TEM can also be used to monitor how a NP catalyst changes before and after catalysis,
which can provide useful mechanistic insights.45
In addition to standard imaging capabilities, many electron microscopes are also capable of running
Energy‐Dispersive X‐ray Spectroscopy (EDX) which allows for elemental analysis in selective windows, in
conjunction with imaging.46 Our group took this methodology one step further by using EDX to analyse
samples from activated catalytic solutions and poisoned catalyst solutions, pioneering a new field of
applications using this technique.30 As detailed in Chapter 2, we were able to use EDX analysis to
conclusively show that the poison was only bound to the Fe NPs, providing strong evidence (using a
combination of ex situ and in operando techniques) that the NPs were the active species during
catalysis.
Recently, Miller and co‐workers published the first example of in situ liquid sample analysis with
electron microscopy.47 Their newly developed TEM cell allowed for the continuous passage of liquid
through the cell during microscope imaging as shown in Figure 1.1, eliminating the need for freezing or
drying liquid samples prior to analysis. This has the potential to completely change the way catalytic
chemists answer the title question. Using this technology, it may be possible, in the future, to monitor
the formation of nanoparticles in real time using electron microscopy, and monitor changes as
substrates, poisoning agents and more precatalyst are added. This would also eliminate any doubts
about the effect of drying on NP formation, size and shape. Although these applications have not yet
been realized, Miller et.al. were able to successfully image discrete gold nanorods and polymer particles,
indicating that catalytic analysis may be feasible.
5
Figure 1.1: Prototype solution phase cell for electron microscopy analysis. Reprinted with permission of Reference 47.
Copyright 2013 American Chemical Society.
1.3.2 X‐ray Photoelectron Spectroscopy
X‐ray Photoelectron Spectroscopy (XPS) is a useful technique for determining the valency of metals and
the binding state of organic ligands by comparing spectra to literature values.48 Samples are run in a
similar fashion to those for electron microscopy where the sample is typically dried and analysed as a
powder or film, and therefore the same concerns must also be addressed, as discussed previously. The
window, or area examined, is large, and XPS is therefore useful for indicating the valencies of all metal
species present during catalysis (both homogeneous and heterogeneous). This method was used by Cho
et. al. to analyse their Au NP catalysts which were active for cyanosilylation.49 They found that during
catalysis there was both homogeneous (leached gold) and heterogeneous (Au NP) species that were
active for catalysis that were present in a ~4:1 ratio, respectively. Grosvenor et. al. used this technique
for the study ferrous (Fe2+) and ferric (Fe3+) compounds, which allowed for a detailed analysis of the
spectra of the multiple oxidation states of iron in Fe3O4.50 XPS analyses can be selectively run on
individual elements, and is not limited to metals, which we were able to take advantage of by probing
phosphorus excitation peaks of our catalytic solutions, as detailed in Chapter 2. Also taking advantage of
this capability was Manners and coworkers51 who were able to show the binding of phosphine poisoning
agents onto a Rh(0) NP surface by analysing the phosphorus spectra. During the dehydrocoupling of
amine‐boranes they found that their catalysts were deactivating, and confirmed that small phosphine
6
poisoning agents, such as PMe3, could poison catalysis. They confirmed that this was going through
phosphine ligation on the NP surface using XPS analysis.
1.3.3 X‐ray Diffraction and Mössbauer Spectroscopy
Both of these techniques, much like those discussed in 1.3.1 and 1.3.2, are typically done on dried
samples, diminishing their ability to determine the identity of the active catalytic species. However, they
are both very powerful tools for detecting and characterizing NPs. The complete characterization of a
confirmed NP catalyst can be immensely valuable in evaluating the influence of changing reaction
conditions and synthetic methodologies. In addition, monitoring how a catalyst changes over time to
determine its deactivation pathways is also of great interest, and is feasible using both techniques.40
Similar to XPS, spectral data can be obtained and compared to literature values to determine both the
valency and structure of the metal centre.13,52,53 The detection of zero‐valent metal centres, such as the
iron NPs characterized using both methods by Linn et. al.54 provided strong evidence for the presence of
a nanoparticle or heterogeneous species. Although Mössbauer is typically run on dried samples, single
crystals and polycrystalline samples, this technique can also be applied to solutions, however they are
typically frozen.55 The use of rapidly frozen solution samples has been applied to monitoring the kinetics
of biological reactions containing reactive iron species of varying oxidation states to monitor the
changes in iron species over time.56‐58 A major limitation of Mössbauer is that it is typically only run on
57Fe, as most other common metals used in catalysis are not Mössbauer active.55
1.4 In Operando Techniques
Studying a catalyst in its reactive state can be very informative. Unlike the ex situ techniques discussed
in section 1.3 where the catalytic mixture needed to be dried to allow for analysis, the following
techniques allow one to observe and study the catalyst in solution. Studying the catalyst in the solution
state allows it to be observed in its ‘natural habitat’. By studying dried powders one can only determine
whether nanoparticles are present, but not whether they are the active species, with limited
exceptions.30 With solution techniques, one need not be concerned about the effect of drying on the
active species,23 and it is possible to directly observe the catalyst interacting with a substrate.59
7
1.4.1 Reaction Profiles and Kinetic Investigations
The most common identifiers of NP catalysis come from directly monitoring the reaction. A common
early indicator is a dark or non‐transparent reaction solution. This is indicative of zero‐valent metal
centres and colloidal suspensions which are often generated under strongly reducing reaction
conditions, such as the presence of strong base, reductants, and hydrogen gas.1 Dark or non‐transparent
solutions by no means prove NP formation, but the observation of a resultant dark solution should
prompt further investigations into the true nature of the system.
Next is the characteristic sigmoidal reaction curve, as depicted in Figure 1.2. The three main sections of
the curve are 1) initiation, 2) catalysis and 3) completion. Initiation refers to the formation of the active
sites, and this process has been studied in detail by Finke and co‐workers, who suggest that to truly
understand how a catalyst operates, one must study the kinetics in detail to determine the rate law,
including running all relevant control experiments, to fully understand where the precatalyst mass
goes.10,60‐63 Depending on the mechanism of catalyst activation, this initiation phase can encompass a
wide range of transformations, often including some kind of nucleation and growth phase, although the
process is exceptionally more complex and must often be studied on a case‐by‐case basis. The size of
the final, active nanoclusters can also be predicted based on low energy conformations containing
specific numbers of metal atoms, or ‘magic numbers’.62,64 Following the formation of the active species
is phase 2, rapid catalytic activity, followed by the completion of the reaction (phase 3). A thorough
kinetic investigation, if done correctly, can provide strong evidence for nanoparticle catalysis; however
this is not always feasible depending on the catalytic system under investigation. For our iron system
discussed in Chapter 2, due to how air sensitive and fast reacting the system was, as well as the fact that
several side reactions were taking place yielding inactive and partially unidentified species, we were not
able to monitor the consumption of precatalyst mass during the reaction.30 This prevented a detailed
kinetic investigation of the activation of our system, inhibiting effective modelling of NP formation and
catalysis. To fully understand the intricacies of catalyst formation, kinetic studies to determine the rate
constants and product formation are crucial, and this has been studied in detail by Finke and co‐
workers, and we direct any interested reader to their work.1,7,10,27,60‐62,65 To give an example of the power
of kinetic analysis, using the Finke‐Watzky (F‐W) Kinetic model, which they derived for their system,
Finke and co‐workers were able to accurately predict reaction profiles based on rate constants and
equations specific to NP nucleation and growth, as depicted in Figure 1.2.61,63
8
Figure 1.2: Sigmoidal reaction curve depicting the hydrogenation of cyclohexene over time. Curve shows all three phases
(nucleation, catalysis and completion) of the reaction profile. Also shown is the predicted curve using F‐W Kinetics. Reprinted
with permission from Reference 63. Copyright 2009 American Chemical Society.
As a caveat, the presence of a sigmoidal reaction curve does not guarantee that a catalyst is
heterogeneous, as has been demonstrated by our group.19 Also, the lack of a sigmoidal reaction curve
does not disprove NP catalysis, but rather suggests the NP activation is much faster than catalysis.33,36
1.4.2 Poisoning Experiments
Following the sigmoidal reaction profile, the next most common test for a NP catalyst is poisoning. There
are two main types of poisoning tests commonly employed: mercury and substoichiometric. Mercury
poisoning is a well‐established tool, commonly used for bulk heterogeneous and some NP catalytic
systems. To successfully use this test, one should add an excess of mercury after the commencement of
catalysis to ensure that it is reacting with the activated catalyst, not the catalyst precursor, by forming
an amalgam with the exposed surface and inhibiting catalysis.1,27,49,51,66‐69 This methodology has been
widely used for nearly 100 years68 and its applications have been thoroughly reviewed previously.1,2 It is
important, however, to draw attention to the potential false‐positive and false‐negative results that are
possible with this method. First is that mercury can poison homogeneous catalysts, and this has been
shown by Dyson.70 In his article he discusses the difficulties associated with distinguishing homogeneous
from heterogeneous catalysis as it pertains to arene hydrogenation, and suggests that mercury may
react with metals and ligands, deactivating homogeneous systems. This would provide a ‘false‐positive’
result for heterogeneous catalysis. Mercury reacting with metal precursors deactivating homogeneous
9
pathways has also been shown with Pt (0) species.23,71 Secondly, mercury is not able to form a stable
amalgam with all metals72 and therefore successful catalysis (not poisoned) cannot act as proof of
homogeneity. There have been many recent examples of this issue, particularly with iron, where the
active catalyst was tolerant to an excess of mercury and was shown to be NPs.30,73,74
The next type of NP poisoning test involves the use of substoichiometric amounts of small poisoning
agents such as phosphines, thiols, amines and alcohols.1,2,7,75 For a homogeneous catalyst system, one
would expect to need one or more equivalents of poison to inhibit catalysis (every metal centre
represents an active site). In a NP system, much of the metal introduced as the precatalyst forms the
core of the active species, whereas the remaining metal makes up the reactive NP surface, resulting in
proportionately fewer active sites. This would indicate that much less than one equivalent of poison
(relative to metal) is needed to inhibit NP catalysis. The difficulty with this technique is choosing the
correct poison that will bind to and block the active sites of the catalyst, keeping in mind the issue of
stoichiometry (can a single poison block more than one active site?).7,76 This method of testing is widely
used and studied and is extensively used in the study of Fe NP catalysts in our group, as discussed in
Chapters 2 and 3. We have significantly expanded the breadth of tests that can be done using this
technique, as discussed in Section 1.3.1 for the use of poisoning jointly with TEM and EDX analysis to
probe the true nature of a catalyst. To further elaborate on the wide applicability of this technique, we
would like to highlight a single example out of the Manners group. Manners and coworkers have
recently published the use of two similar iron catalysts for the dehydrogenation of amine‐boranes,
[CpFe(CO)2]2 (A) and CpFe(CO)2I (B) (Cp = η‐C5H5) both of which require photo‐irradiation to activate.
During studies to further understand the mechanism, they observed different reactive intermediates in
the case of (A) versus (B).37 Following activation of either (A) or (B), they allowed catalysis to reach 50%
conversion before splitting the reaction into two batches. One batch was allowed to react normally, and
10% PMe3 was added to the other batch. The batches that were not treated with PMe3 proceeded
normally, whereas the batches with PMe3 were affected: (A) was completely stopped, and (B) was
slowed. Addition of 1 equivalent of PMe3 instead of 10% (relative to Fe) completely stopped catalysis.
This series of tests provided strong evidence that (A) formed a heterogeneous NP catalyst when
activated, whereas (B) was homogeneous in nature. This was further probed using a wide variety of
techniques including TEM, EDX, DLS (vide supra) and computational (DFT) studies, to provide a strong
collection of evidence for the true nature of the catalyst in both cases, as outlined by Figure 1.3.
10
Figure 1.3: Distinguishing homogeneous from heterogeneous Fe catalysis for the dehydrogenation of amine‐boranes. Reprinted with permission from Reference 37. Copyright 2014 American Chemical Society.
1.4.3 Extended X‐ray Absorption Fine Structure
EXAFS is gaining wide popularity as a powerful technique capable of identifying and characterizing metal
species in the solution state during catalysis.77,78 Lamberti and coworkers have recently published an
extensive review on the use of various EXAFS experiments as they apply to in operando and in situ
studies of heterogeneous catalysis, and we strongly recommend their review article (and references
therein) for further details on the wide applicability of this technique.77
To illustrate how this technique can be used to probe the true identity of an active catalyst, consider the
puzzling case of rhodium catalysed benzene hydrogenation using [RhCp*Cl2]2 precatalyst recently
explored by Bayram et. al.79 For their investigation, they built a pressure reactor with a specialised
window that allowed for the transmission of an X‐ray beam. Using this setup they were able to monitor
the consumption of the [RhCp*Cl2]2 precursor, and the selective formation of a new rhodium species
which was responsible for catalytic activity. This new species was identified as a Rh4 ligated cluster using
theoretical and literature analyses.80 Detailed kinetic studies and quantitative poisoning experiments
were then undertaken to identify Rh4 clusters as the true active species in catalysis, lending tremendous
support to the power of this in operando technique. It is also important to note that although EXAFS
identified the main metal species present, it is not stand‐alone proof of cluster catalysis; for this a suite
of tests were required.
11
Similar EXAFS experiments were done on zero‐valent iron NPs by von Wangelin and coworkers who
were studying alkene hydrogenation from in situ prepared zero‐valent iron NPs. They were able to
quantitatively determine the environment surrounding the iron atoms in both the metal halide
precursor and within the NP,34 confirming the previously hypothesized formation and structure of a THF‐
ligated iron cluster upon activation.81 Stein et. al. have also used EXAFS and small‐angle X‐ray scattering
(SAXS) to study the true active species in Pt catalysed hydrosilation using Karstedt’s Pt (0) precatalyst.23
This system was long believed to operate via a colloidal Pt (0) mechanism,5,71 but was shown to in fact be
monomeric, homogeneous species acting as the active catalyst, which was determined using a wide
range of tests.
1.4.4 Magnetometry
Much like EXAFS analysis, magnetic measurements, particularly Superconducting Quantum Interference
Device (SQUID) Magnetometry, are capable of analysing catalytic solutions of first row transition metals,
in situ. The use of this technique to identify NPs relies heavily on the diverse range of magnetic
properties of metals in different states, particularly diamagnetic, paramagnetic and superparamagnetic
species.82,83 The two standard SQUID experiments typically run are zero field cool‐field cool (ZFC‐FC) and
hysteresis runs.74 The first is a ZFC‐FC experiment, where samples are first supercooled to ~2 K in zero
field, then warmed gradually under the influence of a set magnetic field to ~100 K, and then cooled back
to 2 K under the same field yielding a plot like the one in obtained by de Vries and coworkers in Figure
1.4 (bottom). For a diamagnetic sample, one would expect a slightly negative and flat (constant) plot,
whereas for a paramagnetic sample, one would expect a complete overlay of the FC plot. Figure 1.4
(bottom) instead demonstrates a broad peak around 10‐12 K. This is the blocking temperature (BT) and
indicates the point at which the nanoparticles break out of their blocked regime and begin to become
ferromagnetic, indicative of metal nanoparticles.30,74,84 The second set of experiments typically run are
hysteresis loops, such as those in Figure 1.4 (top). At set temperatures, the instrument scans forward
and backward through a range of magnetic fields. At temperatures above the BT, such as 40 K in Figure
1.4, the plots exactly overlap each other, but at temperatures below the BT (3 K) hysteresis is observed,
and the width of separation of the traces is referred to as the coercive field.
12
Figure 1.4: Standard plots obtained using SQUID Magnetometry analysis. Top ‐ hysteresis loops through varying magnetic
fields at two set temperatures (3 K and 40 K). Bottom ‐ ZFC‐FC experiment depicting a blocking temperature. Reproduced
from Reference 74 with permission from The Royal Society of Chemistry.
These experiments are not as common as they require fairly specialized equipment, but have begun to
see widespread use in the characterization of iron NPs in the 2‐3 nm range,85,86 the 3‐4 nm range30,74 and
the 7 nm range.84
1.4.5 Dynamic Light Scattering
Dynamic Light Scattering (DLS) is a very powerful technique for determining the various sizes of metal
species in solution, allowing for facile in operando studies of catalytic solutions.87 In his review, Crabtree
explains that unlike electron microscopy, which is limited to dry, ex‐situ analysis, DLS gives a much more
realistic picture of the species present during catalysis.2 He also emphasizes the versatility of DLS in that
it can often detect particles smaller than the detection limit of traditional microscopy, yielding the same
sizing information. Historically this technique has seen much more widespread use to either confirm or
13
disprove the presence of NPs,5,23,71,88 but has not been exploited by catalytic chemists in recent years,
with few exceptions.37 It is once again important to point out that although this technique can
demonstrate the presence of NPs, it cannot act as stand‐alone proof of a heterogeneous mechanism;
further in operando studies are needed in conjunction with DLS. It becomes important to point out that
data analysis is not always straightforward. For real life samples there is often a distribution of particle
sizes and the experimentally determined particle radius is actually a weighted average, called the ‘z‐
average size’.87 Therefore it is critical to ensure that disproportionately large agglomerates or organics
such as polymers and dust are not included in analysis as they can drastically skew the average. Another
important note with this technique is that the signal scales with the size of the particles.89 This indicates
that very small particles may be below the detection limits of the instrument, indicating that although
an experiment may suggest that there are no NPs present, it is possible that the catalyst is in fact very
small heterogeneous particles or clusters.
1.4.6 NMR Experiments
No longer only useful for characterizing starting materials and metal precursors, NMR spectroscopy is
one of the most powerful tools for garnering mechanistic insights and identifying reactive intermediates
in catalysis. NMR spectroscopy has been used extensively in homogeneous catalysis to identify and
characterize reactive intermediates, commonly metal hydrides, fluxional species and isotopically
enriched intermediates.20,90‐96 Although the use of NMR experiments to determine the mechanism of
homogeneous catalysis is enormous, the use of it to study NP systems is fairly limited. Many catalytically
active NP solutions contain paramagnetic and superparamagnetic species which can complicate NMR
analysis for heterogeneous systems, but a messy NMR spectrum is by no means evidence for NP
catalysis. NMR spectroscopy is an incredibly powerful technique that allows for the sequential analysis
of a large number of different atoms that may be present in the NP itself, or in the ligand, for example
31P, 29Si, 11B, 19F, 7Li and 195Pt NMR experiments.10 During the analysis of our iron TH catalyst system we
attempted to analyse the catalytic mixtures by NMR spectroscopy.97 Conveniently, our systems have a
phosphorus containing ligand, which enabled the use of 31P NMR spectroscopy. As detailed further in
Chapter 2, analysis indicated the presence of free ligand, indicating that some ligand had become de‐
coordinated from iron during activation, lending support for the formation of zero‐valent NPs. The other
compound present was identified as an electron rich ferraaziridinido complex where one side of the
ligand arm folded upwards to coordinate to the metal centre.97 Initially, assuming this was the active
species, it was independently synthesized and tested for catalysis but found to be completely inactive.
14
This indicated that our true active species was NMR silent, and rigorous computational studies were
undertaken to determine the role of the ferraaziridine complex in catalysis. DFT indicated that it was an
intermediate to a very stable, low energy Fe(0)‐(P‐N‐N‐P) species, supporting the formation of iron NPs
during catalysis and providing a potential pathway to NP formation. This example illustrates the
importance of independently synthesizing and testing potential intermediates determined by NMR
spectroscopy, and demonstrates the power of combining multiple techniques to determine an
activation mechanism.
Another application of NMR experiments for NP catalysis is the use of solid state NMR as shown by
Chaudret and coworkers to probe the surface chemistry and reactivity of ruthenium NPs.38,98 Using 2 nm
Ru NPs formed in the presence of polymer (polyvinylpyrrolidone ‐ PVP) or ligand (bis‐
(diphenylphosphino)butane ‐ dppb), the location and dynamics of 13CO on the surface of the particles
could be directly monitored in the solid state using magic‐angle spinning (MAS) 13C NMR spectroscopy.
Using the NMR data, they were able to determine the location (face, edge or vertex) of the CO as well as
its bonding geometry (bridging or linear) as a function of the type of ligand/stabilizer and CO exposure
conditions.98 Chaudret and coworkers took this one step further and characterized N‐heterocyclic
carbene (NHC) stabilized Ru NPs, and were similarly able to determine location and dynamics of CO,
NHC and hydride ligands on the surface as a function of NHC sterics, as depicted in Figure 1.5. These
results were then analysed in conjunction with catalytic behaviour, allowing for in depth mechanistic
information to be determined correlating ligand sterics with surface/active site effects and catalytic
activity.38
Figure 1.5: Space‐filling model depicting Ru NPs selectively coated by NHC ligands as determined by 13C solid state NMR
spectroscopy. Two NHC ligands tested are also shown for clarity. Reprinted with permission of Reference 38. Copyright 2011
Wiley‐VCH.
15
1.4.7 Chirality
The observation of asymmetric induction is no longer a valid proof for homogeneity as well‐defined and
enantioselective NP catalysts are becoming more widely reported. Well‐defined NP catalysts coated in
chiral ligands have been shown to perform asymmetric catalysis to yield chiral products.11 We recently
published the use of chiral tetradentate P‐N‐N‐P ligands on iron NPs for the asymmetric TH of ketones to
chiral alcohols with modest enantioselectivities of 65% for acetophenone conversion.30 Using the achiral
variant of the P‐N‐N‐P ligand we saw no enantioselectivity, indicating that the ligand was responsible for
inducing chirality, as opposed to an inherently chiral metal surface.99 We then took these systems a step
further and tested our chiral iron NP system for the reverse reaction, oxidative kinetic resolution of
racemic alcohols to generate enantioenriched alcohols. Although rates were moderate, we successfully
showed the first application of chiral NPs for this type of catalysis.31 The use of chiral ligands to induce
asymmetric transformations on NP surfaces has been employed recently by Gao for iron NPs coated
with macrocyclic P‐N‐N‐P‐N‐N ligands for direct asymmetric hydrogenation100 and by Chaudret and
coworkers for asymmetric TH using ruthenium NPs coated in chiral N‐donor ligands.101 Knoppe et. al.
have also shown that a chiral gold cluster can be formed using achiral thiolate ligands (intrinsically chiral
cluster), and the Au38(SR)24 cluster is capable of racemizing in solution under modest conditions.102‐104
Initial discoveries in this field came from Osawa105 who used tartaric acid on Raney nickel for ketone
hydrogenation and from Orito et. al. who used platinum on carbon with cinchonidine (CD) for
hydrogenation.106,107 The Orito reaction has since been built upon by Bönnemann and Braun108 who used
palladium and platinum colloids treated with cinchonidine to hydrogenate ketones, and more recently
by Baiker et. al.109‐111 who bound cinchonidine coated platinum colloids to magnetite particles to allow
for facile separation and reuse. The Orito Reaction has been studied and improved upon significantly
over the past couple decades, and those interested in more information are encouraged to read recent
reviews.112‐114
To round out our discussion of chirality and NPs for asymmetric induction, we would like to address a
recent article by McBreen and coworkers who described the use of a scanning tunneling microscope
(STM) to visually analyse the orientation of chiral modifiers and prochiral substrates on a platinum [111]
surface.59 Using STM they could map out the most common orientations of ligand relative to substrate
and run catalysis to determine the product enantiopurity. Then, using DFT calculations, they could
separately predict the lowest energy conformations (orientations of ligand relative to substrate) and
16
resulting product ee, which was consistent with experimental data. This not only proves the applicability
of NPs to asymmetric catalysis, but demonstrates that much like homogeneous systems, chirality on a
surface can be predictable.
1.4.8 Polymer‐Bound Substrates
The use of multiphasic systems to test heterogeneity is a highly useful and underutilized qualitative tool.
The general concept of this type of test is that a substrate is bound within the pores of porous polymer,
such as a commercially available resin, and catalysis is run using the resin as the substrate.
Homogeneous catalysts are small enough to permeate the pores and do catalysis, yielding product,
whereas heterogeneous catalysts are too large and the polymer remains unchanged.2 This was
conventionally used to determine if homogeneous catalysts were leaching from heterogeneous
catalysts, such as the work done by Davies et. al. who showed that palladium was leaching from Pd/C
yielding active homogeneous species.115 This was done by coordinating the aryl iodide substrate inside a
porous polymer, and supporting the cross‐coupling Pd catalyst separately; catalysis took place, which
indicated that Pd was leaching into solution, entering the polymer and doing cross‐coupling. In his
review, Crabtree also emphasizes the importance of this test as it can indicate whether metal species
have leached into solution, which can cause product contamination, an important issue in the
pharmaceutical industry.2
Collman et. al. reported the use of a C=C cross‐linked Merrifield resin to distinguish homogeneous from
heterogeneous hydrogenation using the resin directly as the substrate.116 These resins were used for a
series of precious metal catalysts and proved highly effective at distinguishing homogeneous from
heterogeneous systems. We also recently applied this technique for our iron NP TH system30 and
oxidative kinetic resolution systems,31 as detailed in Chapters 2 and 3 respectively. For our systems, we
were able to tether substrates within the pores of a polymer and demonstrate that small reagents and
homogeneous catalysts could permeate the pores, whereas no conversion was seen using our Fe
systems, supporting our proposition that the active species were Fe NPs. These systems were analysed
using semi‐solid state 13C NMR spectroscopy on pre‐swollen polymer beads117 to indicate the presence
of C=O versus C‐OH bonding states.118 Other useful analysis methods for the functionalized beads
include the use of IR spectroscopy,30 or selectively untethering the functional group from the polymer
post‐catalysis and running standard analysis techniques (NMR, GC, etc.).119 Although there are several
limitations to this methodology, specifically the types of substrates that can be assembled within the
17
pores of the polymer, it has proven to be a powerful tool for a variety of applications. A few points to
keep in mind with the application of this technique: 1) the catalyst being tested must be active towards
the substrate incorporated into the polymer, 2) the polymer cannot act as a poison to catalysis, 3) the
catalyst must be active on the timescale of polymer catalysis (permeating the pore and catalysing a
reaction inside a polymer will take longer than for free substrate and the catalyst must remain active for
the test to be accurate), and 4) an accurate method of polymer analysis must be designed/devised. For
our studies, this technique was best viewed as a more qualitative mechanistic probe, as opposed to a
quantitative, kinetic probe; however it still yielded highly valuable information.
1.5 Going Green – Iron‐Based Catalysis
So far we have focussed on the importance of distinguishing homogeneous from heterogeneous
catalysis, and a wide variety of techniques to do so. The majority of these techniques are applicable to
all transition metal catalysts, and so we would like to focus one step further and look at iron‐based
catalytic systems.
Catalysis is ubiquitous in academia and industry; it yields most of the pharmaceutical products people
take every day, generates the plastics and materials that go into most commercial products, and is at
the forefront of the energy sector. The problem with this ubiquity is the compounds with which this
catalysis is run. The majority of catalytic reactions are done using precious metal catalysts, specifically
rhodium, iridium, ruthenium, platinum and palladium. Not only are these metals very expensive, but
their availability is rapidly diminishing and cannot sustain our growing needs. Research groups all over
the world have begun to redirect their focus towards the development of more sustainable base metal
catalysts to address this issue. Complexes based on iron, cobalt, copper and nickel have begun to
emerge in the literature as potential green alternatives.120‐122 Not only are these metals significantly
cheaper and more earth abundant, but they are also much less toxic, which is important when
evaluating allowable trace metal impurities in final products for consumer use. In 2008 US
Pharmacopeia released a document outlining the allowable daily levels of various elements in the
human body.123 Precious metals such as Ir, Os, Pt, Pd, Rh and Ru all scored 100 μg/day/50 kg person,
whereas Cu scored 500, Ni and Co 1000, and iron at 15,000 μg/day/50 kg person. Not only does this
show how much less toxic iron is than it’s precious metal counterparts, but also how much more
rigorous (and expensive) of a clean‐up process is required to remove any trace metal impurities with
18
precious metals versus iron.124,125 This therefore provides metrics on how important it is to start moving
towards base metals in catalysis, particularly iron.
In order to make a real impact on industry, new catalysts need to be equally efficient, selective and
stable compared to the well‐established precious metal catalysts already in use, and this has proven to
be quite problematic. Base metals are much smaller and have different reactivities than larger precious
metals, and hence interact differently with the organic ligands typically used with precious metals to
induce specific reactions. Regardless of these many roadblocks, significant progress has been made in
the development of iron based catalysts.20,122,126‐129 As we proceed through our discussions of transfer
hydrogenation, oxidative kinetic resolution, ammonia‐borane dehydrogenation and direct
hydrogenation in Chapters 2‐5 respectively, we will highlight significant iron systems developed in each
area of catalysis. Here, we would like to briefly highlight some of the key iron catalyst discoveries that
have been made in recent years that have set the standards for these types of sustainable
transformations.
We would be remiss to not mention the tremendous influence heterogeneous iron catalysts have had in
industry. Both the Haber‐Bosch Process for the synthesis of ammonia (fertilizer industry)130,131 and the
Fischer‐Tropsch Process for the conversion of hydrogen and carbon monoxide into useful liquid
hydrocarbons for the fuels and energy sector132,133 use heterogeneous iron catalysts under immensely
high pressures and temperatures. Magnetite (Fe3O4) NPs are becoming ubiquitous as catalyst supports,
as they are magnetically recoverable, allowing for easily recycled catalysts to be developed.11,134,135
Magnetite particles are also commonly used in the high tech field for magnetic memory,13 although that
is far beyond the scope of this thesis.
In the area of homogeneous catalysis countless reviews detail the broad applicability of iron as both an
efficient and selective catalyst.120‐122,126,127,136 Much of this work has been inspired by nature; namely,
mimicking the active sites of hydrogenases and nitrogenases in an effort to reproduce the high catalytic
turnover exhibited by naturally occurring enzymes.137‐142 Namely, [FeFe], [NiFe] and [Fe]‐ hydrogenases
are incredibly efficient at forming and releasing H2 gas from protons and electrons, and the FeMo‐
cofactor of the nitrogenase enzyme is able to direct the eight electron conversion of N2 gas and protons
to ammonia. Although there has been tremendous success and breakthroughs in this area, they are
beyond the scope of this thesis and will not be discussed further.
19
Major breakthroughs in the area of homogeneous iron catalysis have been made by the groups of
Morris, Milstein, Casey, Chirik, Peters, Beller and many others, as illustrated in Figure 1.6. Our group has
been heavily involved in the area of ketone hydrogenation using iron‐(P‐N‐N‐P) catalysts, as depicted by
our first, second and third generation systems in Figure 1.6. The first generation system is the focus of
Chapters 2‐4, and was originally published as a direct hydrogenation catalyst,143,144 and later as a more
efficient transfer hydrogenation system capable of achieving turnover frequencies (TOF) of 2600 h‐1 and
enantioselectivities of 65% for acetophenone.145 Our second generation with the smaller coordinating P‐
N‐N‐P rings showed a marked improvement, yielding TOF of up to 30,000 h‐1 and enantioselectivities up
to 90% for acetophenone.18,146,147 By further evaluating the mechanism19,91,148 our third generation of
iron catalysts were developed with a P‐N‐NH‐P ligand scaffold capable of achieving TOF up to 720,000 h‐
1 and comparable enantioselectivities to the second generation.20 Moving away from transfer
hydrogenation and looking at direct hydrogenation, which will be the focus of Chapter 5, Casey and
Guan developed a Shvo‐type system using iron capable of hydrogenating aldehydes and ketones at
modest temperatures and pressures that was shown to operate via an outer sphere (bifunctional)
mechanism.149,150 Beller and coworkers then used the Casey & Guan iron catalyst in conjunction with a
chiral phosphoric acid co‐catalyst to achieve enantioselectivities of up to 96% for imine hydrogenation
under harsh conditions.151 Concurrently, Milstein and coworkers developed a tridentate P‐N‐P pincer
complex on iron with pendant hydride and carbon monoxide functionality which was able to
hydrogenate ketones under much milder conditions, achieving TOFs of 430 h‐1, but without the presence
of a chiral functionality.152,153 Employing a similar P‐N‐P ligand scaffold, Beller et. al. recently published
an iron complex capable of releasing H2 gas from methanol and water with TOFs up to 600 h‐1,154 the
mechanism for which is a major area of discussion in Chapter 5. Lastly are the olefin hydrogenation
catalysts developed by Chirik and coworkers155‐160 and by Peters and coworkers,161,162 which both contain
highly reactive Fe‐N bonds and pincer ligands, and take advantage of the multitude of accessible stable
oxidation states of iron. Also taking advantage of these highly reactive Fe‐N bonds was Yuki et. al. who
were able to transform dinitrogen into silylamine using iron pentacarbonyl and ferrocene precursors.163
These examples represent only a small sector of the wide range of applications of iron in homogeneous
catalysis, but they illustrate the power of using base metals in the place of precious metal systems.
20
N
PiPr2
PiPr2
FeHCO
BrN
PiPr2
PiPr2
FeHBH3CO
HFe
TMS
TMS
OH
OCOC
H
O
O
OPFe
TMS
TMS
OH
OCOC
H
O
OHiPr
iPr iPr
iPr
iPr
iPr
Milstein
Beller
N N
PPh2
PPh2
Fe
L
N
RR
Morris
[BF4]2
Direct Hydrogenation 2008 (L = NCMe)Transfer Hydrogenation 2009 (L = CO)
N N
PPh2
PPh2
Fe
CO
Br
RR [BPh4]
Transfer Hydrogenation 2009
N N
PPh2
PPh2
Fe
CO
Cl
RR [BF4]
Transfer Hydrogenation 2013
Direct Hydrogenation 2011, 2012 Direct Hydrogenation 2007
Casey
Direct Hydrogenation 2011
ChirikN
N NFeAr ArN2 N2
Olefin Hydrogenation 2004Hydrosilation 2012
Peters
Olefin Hydrogenation 2004
N
PiPr2
PiPr2
FeBrCO
HH
Hydrogen Generation (MeOH) 2013Ester Hydrogenation 2014
H
Figure 1.6: Illustrative examples of iron catalysts developed for a wide range of catalytic transformations.
21
1.6 Summary
Determining whether a catalyst is homogeneous or heterogeneous can be quite challenging, and it
requires a combination of many techniques to determine the true nature of a catalytic system. By
employing both ex situ and in operando techniques, with an emphasis on the importance of kinetic
investigations, one can begin to piece together a catalytic mechanism, enabling rational modifications to
be made to improve catalyst activity, selectivity, stability and recyclability. Common ex situ techniques
include electron microscopy with energy dispersive X‐ray spectroscopy, X‐ray photoelectron
spectroscopy, Mössbauer and X‐ray diffraction. These techniques are very useful for characterizing NPs
and for determining whether there are NPs present in a catalytic mixture. Once NPs are identified, the
determination of whether they are the active species in catalysis is necessary, and this requires the use
of in operando studies. Magnetometry and dynamic light scattering are useful techniques for probing
NPs, but once again provide minimal insights into the true nature of the active species. Much more
powerful techniques include investigating the reaction profile and kinetics for the presence of an
induction period and sigmoidal reaction curve, as well as elucidation of the rate law, which is ultimately
quite telling. The use of poisons and substoichiometric poisoning agents in particular, often provide the
strongest evidence for NP catalysis because the poisoning agents bind directly to the active sites during
catalysis. Analytical tools such as NMR spectroscopy and extended X‐ray absorption fine structure have
proven quite valuable for monitoring reactions throughout the activation and catalytic phases and for
observing the changes in the species formed, which is useful for both homogeneous and heterogeneous
catalysis. With the development of discrete and well defined NP catalysts, highly structured systems that
give rise to asymmetric and reproducible catalysis are becoming reliably reported, indicating that
chirality is no longer proof of homogeneity. The use of porous polymers containing substrates is also
growing in popularity as an effective method for determining catalyst size range, which can often
provide strong evidence for mono‐ versus multi‐metallic catalytic systems. With more and more
publications appearing in the literature on NP catalysts and methods for determining the mechanism of
catalysis, we predict that new and more creative techniques will begin to appear to answer this very
important question. Also significant for the future of sustainable catalysis is the replacement of precious
metals with base metals, particularly iron, in the pharmaceutical, fine chemical, fragrance and food
flavouring industries. Significant progress has been made towards the development of new, sustainable
iron catalysts, many of which are now beginning to rival their precious metal counterparts in both
efficiency and selectivity.
22
1.7 Thesis Outline
The ultimate goals of the four‐year project outlined in this thesis were to explore existing catalysts
developed in our group and attempt to elucidate a mechanism, explore other areas of catalysis using the
previously studied catalyst system to determine its applicability, and develop new iron‐based catalysts
capable of directly employing H2 gas in hydrogenation.
Chapter 2: Iron Nanoparticles Catalysing the Asymmetric Transfer Hydrogenation of Ketones
The initial project goal was to investigate the first generation Fe‐(P‐N‐N‐P) catalyst depicted in Figure 1.6
(top left) to determine its mechanism for transfer hydrogenation of ketones in the presence of basic
isopropanol. This was done using a series of NMR and DFT experiments which suggested that the
catalyst may be heterogeneous in nature. The system was then tested using a wide series of
experiments to provide strong evidence that the true catalyst was 4 nm zero‐valent iron nanoparticles
as depicted in Scheme 1.1. The results that are described in this chapter were published in
Organometallics97 and the Journal of the American Chemical Society.30 We would like to acknowledge
Demyan Prokopchuk for running the DFT experiments described therein, Dr. Nils Meyer for growing the
crystal of (3) that initiated this project and Dr. Alan Lough for solving the crystal structure of (3). We
would also like to acknowledge Dr. Neil Coombs for his help in running and characterizing the Fe(0) NPs
by STEM, and Dr. Paul Dube for running SQUID experiments.
Scheme 1.1: Asymmetric transfer hydrogenation of acetophenone using Fe NPs modified with chiral P‐N‐N‐P ligands.
23
Chapter 3: Oxidative Kinetic Resolution of Aromatic Alcohols using Iron Nanoparticles
Following the successful characterization of the Fe(0) NPs in transfer hydrogenation, we tested the
catalyst for the reverse reaction, oxidative kinetic resolution. Racemic 1‐phenylethanol was selectively
converted into acetophenone and R‐alcohol under mild conditions, as depicted in Scheme 1.2. This
methodology was then applied to a wide substrate scope to determine the broad applicability of the
system. The results that are described in this chapter were published by invitation in Topics in Catalysis
in a special themed issue.31 We would like to acknowledge Dmitry Pichugin for his help in running and
analysing solid state NMR data, and Dr. Neil Coombs for his help in running and characterizing the Fe(0)
NPs by STEM.
Scheme 1.2: Oxidative kinetic resolution of racemic 1‐phenylethanol using Fe NPs modified with chiral P‐N‐N‐P ligand.
24
Chapter 4: Evidence for Iron Nanoparticles Catalysing the Rapid Dehydrogenation of Ammonia‐Borane
Chapter 4 outlines the further application of these Fe NPs to the dehydrogenation of ammonia boranes
to form hydrogen gas, as depicted in Scheme 1.3. We studied a broader scope of iron catalysts under a
wider array of conditions to fully investigate how the catalysts operate, and determine their mechanism.
We also studied the resultant B‐N compounds formed to further aid in mechanistic investigations. The
results that are described in this chapter were published in ACS Catalysis.36 We would like to
acknowledge Dr. Doug Holmyard for his help in running and characterizing the Fe(0) NPs by TEM.
Scheme 1.3: The dehydrogenation of ammonia borane to form H2 and B‐N compounds using Fe NPs.
Chapter 5: Synthesis and Mechanistic Studies of Iron P‐N‐P’ and P‐NH‐P Asymmetric Hydrogenation
Catalysts
Following the successful development of asymmetric transfer hydrogenation catalysts in our lab, we
were interested in developing highly efficient and enantioselective direct hydrogenation catalysts based
on iron using P‐N‐P pincer ligands. In depth mechanistic NMR and DFT studies suggested the presence of
an N‐H moiety forming during catalysis as well as an iron‐dihydride. We then investigated the effect of
modifying the chirality of the ligand backbone, the structural flexibility and size of the ligand, and the
attempted incorporation of an N‐H into the precatalyst structure. The results that are described in this
chapter were published in the Journal of the American Chemical Society,90 or were recently submitted.
We would like to acknowledge Dr. Paraskevi Lagaditis for pioneering this project, making the initial
catalysts (10abc), and running the substrate scope all detailed in the J. Am. Chem. Soc. article just
referenced. We would like to acknowledge Dr. Alan Lough for solving all crystal structures, and Dr. Peter
Sues and Kai Wan for running all DFT calculations discussed in Chapter 5.
25
Scheme 1.4: Direct hydrogenation of ketones to chiral alcohols using Fe‐(P‐N‐P’) precatalysts.
26
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34
Chapter 2: Iron Nanoparticles Catalysing
the Asymmetric Transfer Hydrogenation
of Ketones
Adapted from Sonnenberg, J. F., Coombs, N., Dube, P. A., Morris, R. H. J. Am. Chem. Soc. 2012, 134,
5893‐5899 and Prokopchuk, D. E., Sonnenberg, J. F., Meyer, N., Zimmer‐De Iuliis, M., Lough, A. J., Morris,
R. H. Organometallics 2012, 31, 3056‐3064.
2.1 Abstract
Investigation into the mechanism of transfer hydrogenation using trans‐
[Fe(NCMe)CO(PPh2C6H4CH=NCHR‐)2][BF4]2, where R = H (1) or R = Ph (2) (R,R‐dpen), has led to strong
evidence that the active species in catalysis are zero‐valent iron nanoparticles (Fe NPs) functionalized
with achiral (in 1) and chiral (in 2) (P‐N‐N‐P)‐type tetradentate ligands. This is first investigated using
extensive NMR and mass‐balance experiments, followed by analysis of experimentally observed
ferraaziridine and ferraaziridinido species. The P‐N‐N‐P ligand arm is folded upwards on one side,
allowing for a ‐2CN group to bind to iron. This species then allows for a low energy pathway to the
formation of electron rich Fe(0) species, which we suggest lead to Fe NPs. Support for this proposition is
given in terms of in operando techniques such as a kinetic investigation of the induction period during
catalysis as well as poisoning experiments using sub‐stoichiometric amounts of various poisoning
agents. Further support for the presence of Fe NPs includes STEM microscopy imaging with EDX analysis,
XPS analysis, and SQUID magnetometry analysis of catalytic solutions. Further evidence of Fe NPs acting
as the active catalyst is given in terms of a polymer‐supported substrate experiment whereby the NPs
are too large to permeate the pores of a functionalized polymer. Final support is given in terms of a
combined poisoning/STEM/EDX experiment whereby the poisoning agent is shown to be bound to the
Fe NPs. These techniques are then applied in a direct comparison of our first and second generations of
iron catalysts to further expand on the limitations of these techniques and their applicability to both
homogeneous and heterogeneous catalyst systems. These studies provide strong evidence of a rare
example of asymmetric catalysis with non‐precious metal, zero‐valent nanoparticles.
35
2.2 Introduction
The synthesis of enantiopure alcohols is of vital importance in the pharmaceutical, fragrance and food
flavouring industries.1‐3 These alcohols are commonly made in industry via the selective hydrogenation
of carbonyl groups by direct H2‐hydrogenation (DH) or transfer hydrogenation (TH)4 using isopropanol as
the hydrogen source. Catalysts used for these types of conversions are typically based on precious
metals such as iridium, rhodium and ruthenium.5‐7 It has therefore become very attractive to replace
these precious metals with iron,8‐11 as it is significantly cheaper, more abundant, and less toxic.12
We began investigating the use of tetradentate P‐N‐N‐P ligands on iron following the successful
synthesis of the 6,5,6‐(P‐N‐N‐P) ligands by Jeffery et. al.13 and their corresponding ruthenium
compounds by Gao et. al.14‐17 They were able to modify the chirality of the ligand using a wide range of
commercially available chiral diamines, and they could generate both the diimine and diamine P‐N‐N‐P
and P‐NH‐NH‐P systems respectively by NaBH4 reduction. The ruthenium systems with the diamine
backbone were shown to be fairly active and selective for the TH of ketones to chiral alcohols, where the
diimine system was inactive. Exploration of iron catalysts for the hydrogenation of ketones first began
with work by Jothimony et al.18,19 whose catalytic systems were small iron carbonyl cluster compounds.
Gao et al.20 found that adding a tetradentate ligand (S,S)‐PPh2C6H4CH2NHC6H10NHCH2C6H4PPh2 to the
iron(0) carbonyl cluster [NEt3H][Fe3H(CO)11] resulted in a system for the asymmetric TH of ketones.
Following their success, we were interested in testing the effectiveness of the P‐N‐N‐P ligand system on
iron, and successfully synthesized and tested a series of [Fe(P‐N‐N‐P)(NCMe)L]2+ (L = NCMe or CO)
complexes for both DH (L = NCMe) and TH (L = CO).21‐23 Systems of the type trans‐[Fe(NCMe)CO(P‐N‐N‐
P)][BF4]2 (as depicted in Scheme 2.5) with the diphenylethylene diimine backbone achieved turnover
frequencies (TOF) of up to 2600 h‐1 and enantioselectivities of 65% for the TH of acetophenone.23
36
Scheme 2.5: Typical reaction scheme for TH, and pre‐catalyst (1) and ((R,R)‐2) structures. **Note this shows the (R,R) catalyst giving the (S) alcohol**
Previous studies using pre‐catalysts (1) and (2)23 showed an induction period during catalysis, followed
by a rapid increase in rate, and eventual equilibration. Sigmoidal curves such as these are often seen in
heterogeneous systems, where an active catalyst must first form24,25 before any measurable activity is
observed. Given the strongly reducing conditions for catalysis, the resultant dark colour during catalysis,
and our kinetic observations, we asked the question, ‘Could the active species be a heterogeneous
catalyst?’. The Fischer‐Tropsch process26,27 and the Haber‐Bosch synthesis28 are the two most common
examples of using iron in heterogeneous catalysis, however a limited number of other examples do exist
as olefin hydrogenation catalysts.29‐31 Iron nanoparticles are also common catalysts for the formation of
carbon nanotubes,32‐36 are known to catalyse the reduction of peroxides37 and CO2,38 and have also
shown activity for the hydrolytic dehydrogenation of ammonia boranes.39,40 Iron oxides have been used
as nanoparticle supports for heterogeneous catalysis with other metals as the active sites,41‐43 but the
use of zero‐valent iron as an active site for asymmetric catalysis had not been reported prior to our
work.
Nanoparticles (NPs) have been studied extensively in the past decades as possible catalysts for a variety
of reactions due to the fact that they have much higher surface areas than bulk heterogeneous catalysts,
and can therefore be as reactive and reproducible44 as homogeneous catalysts, but with the benefit that
they are often recyclable and separable.45 Nanoparticles are often difficult to detect as they appear
homogeneous in solution,24,25 but there are several reports of transition metal nanoparticles being well
characterized and used for catalysis.44,46‐49 Iron magnetite nanoparticles have been used as supports for
precious metal asymmetric catalysis,50,51 which are often convenient in that they are magnetically
separable.52 Palladium(0) nanoparticles 4 nm in diameter have been modified with chiral ligands to
37
perform asymmetric alkylations,53 demonstrating that an enantioselective reaction is possible using
colloidal metal catalysts.45 Nickel (0) nanoparticles have also been used for the transfer hydrogenation
of ketones in isopropanol,54 demonstrating the use of non‐precious metal NP catalysts for TH. Herein we
provide evidence for the first example of asymmetric catalysis using colloidal iron (0), with no precious
metals present for the TH of ketones.
In the present chapter we will be laying the groundwork for all experimental mechanistic explorations
discussed within this thesis. To do so, we discuss the species observable by NMR and IR spectroscopy
during the TH of acetophenone to 1‐phenylethanol using the iron complex trans‐
[Fe(CO)(MeCN)(PPh2C6H4CH=NCH2‐)2‐4P,N,N,P][(BF4)2] (1)23 as the precatalyst, isopropanol as the
hydrogen source, and potassium tert‐butoxide (KOtBu) as the base. We then elaborate on a wide series
of tests and experiments to probe the true nature of the catalyst, and finish with a case study showing
the true power of these techniques in mechanism elucidation.
2.3 Results and Discussion
2.3.1 Spectroscopic Investigation of Catalysis
To initiate catalysis, (1) or (2) is dissolved in a solution of acetophenone in basic isopropanol, resulting in
a dramatic colour change from clear and bright orange, to clear and dark brown or green respectively.
The activated catalyst mixture is highly air sensitive and exposure to air results in an immediate colour
change to pale yellow, rendering it inactive for TH. The reaction mixture of a typical TH experiment using
(1) as a pre‐catalyst was analysed by NMR and IR techniques. 1H and 31P{1H} NMR spectra were recorded
when the TH was carried out using relatively high catalyst loadings (catalyst:substrate = 1:43). 31P{1H}
NMR spectra were recorded for reaction mixtures in isopropanol using C6D6 as an internal NMR
reference for locking. 1H NMR spectra were carried out in deuterated isopropanol and showed only
poorly resolved peaks. No hydride signals were observed in the region between 0 and ‐30 ppm;
however, a hydride mechanism cannot be dismissed as such a hydride species may be only transient or
in low concentration. The formation of iron hydrides as intermediates was proposed earlier for TH with
the pre‐catalysts [(PP3)Fe(H)(H2)](BPh4) (PP3 = P(CH2CH2PPh2)3)55 and Fe3(CO)12
20 but hydride species
were not isolated or observed spectroscopically.
38
31P{1H} NMR spectra recorded during TH have a number of interesting features. Two related doublets at
84.1 and 68.7 ppm (JPP = 29 Hz), various singlets around ‐13.0 ppm, and two singlets at 32.2 and 31.7
ppm were observed (Figure 2.7). The peak at 32.2 ppm is due to oxidized free P‐N‐N‐P ligand. This was
confirmed by a 31P{1H} NMR spectrum of an independently prepared sample of P‐N‐N‐P ligand oxidized
at phosphorus using hydrogen peroxide. The peak at 31.7 ppm is likely the mono‐oxidized P‐N‐N‐P
ligand, partially overlapped by the peak at 32.2 ppm. The peaks at ‐13.0 are due to the free P‐N‐N‐P
ligand and unidentified PPh2(aryl) species, possibly produced by ligand isomerization and fragmentation,
as well as the phosphine of the mono‐oxidized P‐N‐N‐P. Pre‐catalyst (1) shows a singlet in the
phosphorus spectrum at 50.8 ppm, and is therefore completely consumed during the TH process.
Figure 2.7: 31P {1H} spectrum (161 MHz, iPrOH, C6D6 internal reference) of a TH run in 0.65 mL isopropanol for the production
of 1‐phenylethanol from acetophenone (0.60 M) by use of (1) (0.025 M) and KOtBu (0.14 M) at 26°C.
To investigate the vibrational spectra of the catalytic mixture, the reaction was concentrated under
vacuum to dryness and the IR spectrum of the residue was taken as a KBr disk. The spectrum revealed
weak, broad, absorptions for C=O vibrations at 1960 and 1946 cm‐1, and intense broad absorptions from
39
1835‐1890, with small distinct peaks at 1870 and 1846 cm‐1, indicating that a carbonyl ligand is still
coordinated to a metal center during catalysis, possibly to the active species. The broadness of the
<1900 cm‐1 peak is likely due to the presence of multiple, similar species in solution, with two major
species giving peaks at 1870 and 1846 cm‐1. While 1960 and 1946 cm‐1 are typical values for a
monocarbonyl iron(II) compound, signals below 1900 cm‐1 are usually indicative of iron(0) complexes or
bridging carbonyl ligands.56,57 Assignment of these two peaks was done in conjunction with Density
Functional Theory (DFT) calculations (vide infra).
2.3.2 Studying Reactive Intermediates
With the goal of isolating the intermediates observed by 31P NMR and IR spectroscopy, we investigated
the reaction of precatalyst (1) with two equivalents of sodium isopropoxide in neat benzene without
acetophenone present. Surprisingly, we did not observe the formation of an octahedral iron alkoxide
complex. Instead, a cationic ferraaziridine complex [Fe(CO)(PPh2C6H4CH=NCH2CH2NHCHC6H4PPh2)‐
5P,N,C,N,P][BF4] (3) was isolated in 65% yield, as depicted in Scheme 2.6.
Scheme 2.6: Synthesis of ferraaziridine complex (3).
The single crystal X‐ray diffraction structure (Figure 2.8) revealed a distorted geometry where the C(10)
carbon of the ferraaziridine moiety is bound approximately trans to the carbonyl ligand, with a C(10)‐Fe‐
C(17) angle of 158.3(2) degrees. The complex appears to adopt a distorted octahedral geometry, with a
strained C(10)‐Fe‐N(2) angle of 42.0(1) degrees and obtuse P(1)‐Fe‐C(10) and C(17)‐Fe‐N(2) angles of
106.1(1) and 116.6(1) degrees, respectively. The complex is best viewed as an iron(II) κ2‐ferraaziridine
complex instead of an iron(0) η2‐iminium complex, given the N(2)‐C(10) bond distance of 1.435(5) Å,
characteristic for an N‐C single bond. The bond distances from iron to the imine, amine, and alkyl
functions are 1.980(3) (Fe‐N(1)), 1.988(3) (Fe‐N(2)) and 2.012(2) (Fe‐C(10)) Å, respectively. The metal‐
40
carbonyl distance Fe‐C(17) (1.781(4) Å) is typical for an iron carbonyl bond and is similar to that of
complex (1).23 In the 13C {1H} NMR spectrum, the FeCH carbon is observed at 68 ppm as a doublet of
doublets (2JCP = 5 and 11 Hz). The 31P{1H} NMR spectrum has two sharp doublets at 84.3 and 70.1 ppm
(JP,P = 43 Hz), consistent with the lack of a mirror plane of symmetry of the ligand. The 31P NMR spectrum
of the crude product by the reaction of Scheme 2.6 also shows a singlet at ‐13.4 ppm, consistent with
free ligand being released.
Figure 2.8: Molecular structure of (3).
Since we were able to measure clean and well‐resolved NMR spectra, we expect that the electronic
state of the iron is low spin iron(II) and the complex is diamagnetic. The IR spectrum shows a
characteristic CO vibration band at 1940 cm‐1, similar to signals for six‐coordinate, octahedral Fe(II)
complexes with one CO ligand that have already been reported.58‐61 The CO stretch is observed at lower
wavenumbers than that of the starting material (1) (2002 cm‐1) as expected for a reduction in positive
charge and increase in π‐backbonding from Fe to CO in going from (1) to (3). This increase in bonding to
the carbonyl is reflected in the relative reactivity of the complexes when stirred in acetonitrile: there is
ligand exchange of acetonitrile for CO in (1) but not (3).
To the best of our knowledge, there are only two other examples of a similar ferraaziridine iron
coordination described in the literature. Siebenlist et al. reported that the reaction of an ‐imine ester
(iPrN=CHC(OEt)=O) with Fe2(CO)9 in THF leads mainly to binuclear products with a small amount of the
complex trans‐Fe(CO)2(iPrNHCHC(OEt)=O)‐(κNC))2.
62 Evidence supported that the imine group was
hydrogenated by hydrogen atom extraction from THF in an electron transfer process. As in (3), this
ligand is coordinated to iron via both the amine nitrogen and the adjacent carbon atom, thus forming a
41
three‐membered azametallacycle. In addition, a photochemical reaction of (EtO2C)(NMe2)C=N‐CPh=S
with Fe2(CO)9 produced, among other products, Fe(CO)3(Me2NC(CO2Et)(N=C(Ph)S‐(κNCS)), where the
azametallacycle has geminal methyl groups on nitrogen.63
Complex (3) displays certain spectral features similar to the TH reaction mixture (Figure 2.7). It has an IR
absorption at 1940 cm‐1 and doublets in the 31P{1H} NMR spectrum at 84 and 69 ppm. However, the
signal of the latter spectrum has JP,P coupling constants of 43 Hz while the doublets of the TH solution
have a JP,P of 30 Hz, thus indicating that the complexes are not the same. Complex (3) does not catalyse
the TH of acetophenone in neat isopropanol without base at 26 oC. Based on the coupling constant
mismatch between (3) and the TH mixture, it is not the species present during TH, albeit it is quite
similar.
Compound (3) could also be observed (along with signals for free/oxidized ligand) by 31P{1H} NMR
techniques via an NMR‐scale reaction in isopropanol with two equivalents of sodium isopropoxide,
suggesting that it could be an intermediate towards the formation of the species with a similar JP,P in the
TH mixture as described above. An isolated, pure sample of (3) was reacted with a stoichiometric
amount of KOtBu in isopropanol to give the postulated ferraaziridinido complex
Fe(CO)(PPh2C6H4CH=NCH2CH2NCHC6H4PPh2)‐5P,N,C,N,P (4) (Scheme 2.7), which only differs from (3) in
that the ferraaziridine nitrogen atom is deprotonated. This structure is proposed on the basis of NMR/IR
spectra and DFT calculations (vide infra). Complex (4) could not be isolated as a pure product, and
therefore analysis was done on the crude solution after removal of excess base. The 31P{1H} NMR
spectrum of the resulting solution shows two doublets at 84.1 and 68.7 ppm (JP,P = 29 Hz) (along with
singlets at ‐12 and ‐13.4 ppm for various isomers of free ligand) which now matches the coupling
constant of the phosphorus‐containing species in the TH mixture. The IR spectrum shows absorptions
associated with carbonyl ligands at 1862 and 1870, as well as broad peaks at 1934 and 1957 cm‐1. From
the similarities of the 31P{1H} NMR spectra and IR spectra between this reaction and the TH solutions, we
reason that (4) is present during TH.
42
Scheme 2.7: Observation of (4) and proposed structure.
Interestingly, when dissolved in neat isopropanol, the crude mixture of (4) is only minimally catalytically
active (0.5% conversion of 3.85 mmol of acetophenone to 1‐phenethanol at 26oC in 1 hour, 40% in 24
hours). This supports that although (4) is the species seen by IR and in the 31P{1H} NMR spectrum, it is
not the catalytically active species during TH. This ‘non‐innocent’ behaviour of the ligand is reminiscent
of the P‐N‐P systems designed by Milstein64 and Schneider65 and P‐N‐N‐P complexes developed in our
group66 whereby the ligand exhibits reversible protonation‐deprotonation behavior. However, our
system is flexible and preferentially adopts a folded/distorted geometry, which is not observed for these
other structurally rigid ligands.
2.3.3 Mass Balance Experiment
Line broadening techniques were required for all 31P{1H} NMR spectra due to very poor signal‐to‐noise,
indicating that several species were likely not being detected by NMR experiments, possibly even the
active species. For that reason, mass balance NMR experiments were carried out. Triphenylphosphine
oxide (OPPh3) is inert to catalysis and was therefore chosen as an internal standard to compare to other
phosphorus integrations. A mixture of two equivalents of OPPh3 and one equivalent of (1) was reacted
with base and substrate in isopropanol, as per standard procedures. NMR experimental conditions were
optimized for accurate integration data. The doublets for (4) account for approximately 25% of the
phosphorus introduced, and ligand and oxidized ligand account for approximately 18%. Therefore, only
43% of the phosphorus introduced for TH is detectable, leaving 57% of all phosphorus‐containing
species unaccounted for and therefore NMR inactive. This is significant because it shows that a
maximum of 75% of the iron is either catalytically active and NMR inactive or is catalytically active and
found in extremely low concentrations.
43
2.3.4 Mechanistic Evaluations with DFT
Extensive computational DFT studies were undertaken to understand the mechanism for the formation
of (3) and (4) from (1), as well as the energetics of the overall system. This work was done
collaboratively with Demyan Prokopchuk, of the Morris group, and will not be the focus of this thesis
chapter, however key structures and energetics are shown in Figure 2.9. To summarize, DFT supports
the formation of both the ferraaziridine (3) and ferraaziridinido (4) species through favourable, low
energy pathways involving deprotonation and simultaneous folding of the ligand arm. This is feasible
due to the structural flexibility of the P‐N‐N‐P ligand system, which is not the case with the 5,5,5‐second
generation catalysts discussed vide infra, which are structurally too rigid to ‘fold’. DFT also indicated the
highly energetically favourable formation of an electron rich, square pyramidal Fe(0) complex, shown in
the bottom right corner of Figure 2.9. The high favourability of (1) to form an Fe(0) complex suggests a
potential route to the formation of heterogeneous or nanoparticulate iron. As discussed previously, the
active species is not NMR active, and therefore using these DFT results we began to investigate the true
nature of our catalytic system, as the question of homogeneity versus heterogeneity became less clear.
44
Figure 2.9: Complete energetics profile and structures depicting the favourable formation of Fe(0).
2.3.5 Probes for Heterogeneity
The most commonly employed method for determining whether a catalyst is heterogeneous is the
mercury poisoning test, however it has been previously reported by our group21 that addition of Hg(0)
has no effect on catalysis. This is likely due to the fact that iron does not form a stable amalgam with
mercury.67 As discussed in detail in Chapter 1, other well‐known methods for determining whether a
catalyst is heterogeneous include filtration, small molecule poisoning experiments, electron microscopy
imaging, magnetometry and X‐ray photoelectron spectroscopy (XPS).24,25,30,47,68,69 The most valuable of
these experiments are those done in operando,70 that is, while the experiment is in progress, such as
kinetic and poisoning experiments, as well as multi‐phase experiments. Filtration of the catalytic mixture
revealed no precipitate, allowing bulk metal to be ruled out as a possible active catalyst, leaving iron (0)
nanoparticles (Fe NPs) as the potential active species.
45
2.3.6 Reaction Profile
Preliminary experiments to determine the true nature of the active catalyst involved studying the
kinetics of the reaction, and the resultant reaction profile for TH of acetophenone to 1‐phenylethanol.
Both catalytic systems (1) and (2) showed a sigmoidal curve, with an induction period of 6‐8 minutes
followed by rapid catalytic activity, and a levelling off of the curve once the reaction reached
equilibrium, as depicted in Figure 2.10. Throughout catalysis with ((R,R)‐2), an enantiomeric excess (e.e.)
of approximately 64% (S) is achieved in the product, and, unlike other iron‐based catalysts developed in
our group,71,72 it is only minimally diminished due to racemization with prolonged exposure to the
reaction medium. This shape of curve is often indicative of heterogeneous catalysis involving colloid
formation,24,25 or autocatalysis, where the product alcohol is involved in catalysis, and therefore catalysis
is slow before enough product is formed. To disprove that the system is autocatalytic due to the
influence of the product alcohol, 0.2 equivalents of 1‐phenylethanol (relative to acetophenone) was
added to the catalytic mixture with the acetophenone during catalysis with (1) and (2). 0.2 equivalents
was used because conversion to product alcohol after 10 minutes (after the induction period), is
typically 18‐20%. The conversion curves exhibited the same sigmoidal shape and the same induction
period; however catalysis slowed down and equilibrium is reached sooner, due to Le Châtelier’s
Principle. To further probe the cause of the induction period, reactions were done where pre‐catalyst (1)
or (2) were reacted with potassium tert‐butoxide in isopropanol for 10 minutes prior to the addition of
substrate. Reaction curves with (1) showed no induction period, indicating that the reaction of the iron
pre‐catalyst with base to form an active species is responsible for the induction period, not the uptake
of substrate. Reaction curves with (2) showed an increase in initial rates and a decrease in the induction
period, also indicating that reduction of the iron species is necessary before the catalyst can become
active. What was also interesting was the subtle increase in the enantioselectivity from 64% to 70%
when the catalyst was allowed to pre‐activate before substrate addition. This is possibly due to the
unencumbered, complete formation of the ligand‐coated nanoparticles without the interference of
substrate, allowing for more optimized coating of the chiral ligand on the surface.
2.3.7 Poisoning Experiments
It is well reported that the use of sub‐stoichiometric amounts of small phosphines and sulphides such as
PPh3 and CS2 as poisoning agents for catalysis is strong evidence for the formation of NPs.24,25,30,47,68,73
Varying amounts of PMe3 in toluene, PPh3 in benzene, PCy3 in toluene, P(OMe)3 in benzene, P(OPh)3 in
toluene, PPhMe2 in toluene, 1,4‐diazabicyclo[2.2.2]octane (DABCO) in isopropanol, ethylene diamine in
46
isopropanol, pentanethiol in pentane and 2‐(dimethylamino)ethanethiol in isopropanol were tested as
potential poisoning agents for catalysis with both (1) and (2). Control experiments were run by adding
toluene, benzene or pentane to the reaction mixture, to ensure no negative mixed solvent effects were
observed. Amine additives, such as DABCO and ethylene diamine had no effect on catalysis, suggesting
that nitrogen donors are not suitable poisoning agents. PMe3, when introduced as catalysis was started,
prevented all conversion of ketone to alcohol. It was then added to an active catalytic mixture after the
induction period in varying concentrations. Percentages of PMe3 (50, 20 and 10%) relative to pre‐
catalyst (1) or (2) were able to completely stop conversion of ketone to alcohol, as shown in Figure 2.10
whereas 5 and 7% only slowed down catalysis. A minimum of 10% PMe3 is required to stop catalysis,
suggesting not only that the active species are NPs but that 10% of the total iron is present as active
sites on the surface of the NP. Alternatively, this could indicate that, if the active catalyst is
homogeneous, only 10% of the iron (relative to the starting iron) is active. To disprove potential
coordination of PMe3 to the precatalyst, which would also prevent catalysis, a large excess of PMe3 was
reacted with (1) in isopropanol and studied by NMR spectroscopy. The 31P {1H} spectrum showed a large,
broad peak for PMe3 and a sharp, small peak for (1), and no peaks for coordinated product.
Figure 2.10: Standard catalytic runs using (1) and (2), and poisoning runs using (1) and (2) and 10% PMe3 added at t = 10min.
To expand the range of possible phosphine poisons, various electronically and sterically varied poisons
were tested, as depicted in Figure 2.11. 20% P(OMe)3 was able to completely stop catalysis with (1), and
47
drastically slowed down catalysis with (2), suggesting minimal effect of changing the electronics of the
poisoning agent, possibly due to the fact that both are able to bind strongly enough to iron. PPh3 and
PCy3 were also tested as potential poisoning agents. To our surprise, when 20% PCy3 was added to
active catalytic mixtures of (1) or (2), conversion rates increased and overall ee was unaffected for
catalysis with (2), at 64% (S). Addition of PPh3 appeared to have no effect on catalysis with (1), but
increased conversion rates slightly with (2). These results suggest a strong dependence on the steric bulk
of the phosphine used, and that poisoning effects could be explained based on Tolman cone angles.74 To
further study the effects of the sterics of the poisoning agent, PPhMe2 was tested, which is slightly
bulkier than the effective PMe3. Similarly to PMe3, catalysis was completely stopped with both (1) and
(2), indicating that sterics does play a significant role in the phosphines’ poisoning ability. We are still
investigating why the conversion rates increase when bulky phosphine groups are added; they may
space themselves out near the surface leaving access to catalytically active sites, unlike PMe3, yet
preventing agglomeration of the NPs. This phenomenon is difficult to explain from a homogeneous
catalyst point of view; the displacement of part of the P‐N‐N‐P ligand by PCy3 may be feasible but would
likely change the enantioselectivity of the reaction. Small phosphines such as PMe3 may be able to
penetrate into the NP shell and bind directly to the Fe active sites, preventing catalysis. As discussed in
detail in Chapter 1, the use of small phosphine poisons has been recently exploited by Manners and
coworkers to compare homogeneity versus heterogeneity of two of their highly active amine‐borane
dehydrogenation catalysts based on iron.40
The last type of poisoning agent we were interested in studying the effects of were sulfur donors, as it is
well reported that carbon disulfide24,73 is a well‐known poison for heterogeneous catalysts. The thiol, 2‐
(dimethylamino)ethanethiol, at 20% relative to iron, drastically slowed down catalysis with (1), and
partially slowed down catalysis with (2), as shown in Figure 2.11, suggesting that the active species is
sensitive to sulfur containing compounds. Pentanethiol, at 15% relative to iron, was also tested, as it is
slightly less bulky than 2‐(dimethylamino)ethanethiol, and sterics had already proven to be very
important in terms of poisoning effects. 15% pentanethiol was as effective as PMe3 at poisoning (2),
showing that the subtle steric change was effective. Interestingly, when 15% pentanethiol was used as a
poison with (1), the rate decreased considerably, however catalysis was not as completely poisoned as it
was with PMe3, but rather was very similar to poisoning with 2‐(dimethylamino)ethanethiol. Poisoning
experiments therefore demonstrate that the ethylenediamine and R,R‐diphenyl‐ethylenediamine
backbones of (1) and (2) play a significant role in catalysis, which results in differences in the poisoning
behaviour for the catalysis with (1) and (2). Catalysis with (2) seems to be more sensitive to steric
48
changes in the poisoning agents, likely because its backbone is much bulkier,74 whereas (1) is poisoned
more completely by a wide range of reagents, and is not as sterically sensitive as (2).
Figure 2.11: Conversion profiles for the TH of acetophenone to phenylethanol using (2) at ambient temperature (28 0C) in the presence of various poisons at the given amounts relative to catalyst, introduced at the given times.
2.3.8 X‐ray Photoelectron Spectroscopy
X‐ray Photoelectron Spectroscopy (XPS) was run on a catalytically active sample with (1) and sodium
isopropoxide as the base. Solutions were dried on a sample grid and briefly exposed to air before
analysis. Initial survey scans allowed for the identification of all elements present, which was followed
by high resolution scans on the P 2p, N 1s, O 1s, Fe 2p, Ag 3d and C 1s. Phosphorus was present in two
different bonding states, likely caused by phosphorus present in both tri‐ and penta‐ valent states. 31P
{1H} NMR studies during catalysis with (1) shows that both free ligand (trivalent P) and oxidized free
ligand (pentavalent P) are present, which could account for two binding states present in the XPS
spectrum. Iron was found to be present in three bonding states, the largest of which corresponds to Fe
(0), and the remaining two corresponding to Fe2O3 and a shake‐up satellite peak.75,76 During analysis,
since the sample is briefly exposed to air, the formation of surface iron oxides is inevitable, resulting in
the additional peaks seen in the XPS.
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0 10 20 30 40 50 60
[phenylethan
ol] (M)
Time (min)
20% PCy3, 8mindelay
20% PPh3, 8mindelay
Standard Run
20% Me2NC2H4SH,8min delay
20% P(OMe)3, 8mindelay
15% C5H11SH,11min delay
10% PMe3, 8mindelay
10% PPhMe2,11min delay
49
2.3.9 Electron Microscopy
Scanning Transmission Electron Microscopy (STEM) imaging was carried out on catalytically active
samples of (1) and of (2) with sodium isopropoxide as the base, acetone as the substrate, and
isopropanol as the TH solvent. Sodium isopropoxide was chosen as the base because the sodium cations
formed crystals with tetrafluroroborate anions which were more easily distinguished than potassium
from the iron samples during analysis. Acetone was used as the reacting ketone due to its low boiling
point and rapid evaporation from the EM grids before analysis. Imaging of both samples revealed
clusters of varying sizes, identified as agglomerated iron nanoparticles. Agglomeration is possibly caused
by drying effects on the EM grids before analysis, or the presence of agglomerated species in solution
caused by catalyst degradation. The NPs were measured to be 4.5 ± 1.2 nm in diameter, similar to those
previously reported.29 Typical images for solutions from catalysis with (1) and (2) are shown in Figure
2.12.
Figure 2.12: STEM images of TH with (1) (left) and (2) (right).
To confirm that the nanoparticle clusters were in fact Fe NPs, Energy‐Dispersive X‐Ray Spectroscopy
(EDX) linescans were collected on several clusters formed from both (1) and (2). Individual linescan
profiles for titanium, iron, carbon, oxygen, phosphorus and nitrogen were acquired and analysed.
Titanium was used as a background marker, and showed minimal signal, which was used to determine
the amount of background in the other profiles. Iron scans showed an intense Fe signal through the
sample clusters with negligible amounts of iron present on the adjacent carbon support film. This
50
indicates that the clusters are in fact Fe NPs, and there is a negligible amount of homogeneously
dispersed iron in the remaining solution. Carbon signals were strong throughout due to the fact that
copper grids coated with a carbon were used for analysis. Nitrogen and phosphorus both showed
significantly weaker signals through the cluster, consistent with a solid iron core and a ligand
functionalized shell. Nitrogen and phosphorus were also present outside of the clusters, indicating that
there is some free ligand isomers, along with oxidized free ligand in solution, consistent with NMR
spectra of TH experiments, which showed free ligand and various isomers of free ligand in the 31P {1H}
NMR spectrum of the TH solution, along with oxidized free ligand. Oxygen showed a relatively strong
signal through the clusters, likely due to some surface CO, residual alkoxides, and inevitable surface
oxidation forming Fe2O3 due to exposure to air prior to analysis.
2.3.10 Superconducting Quantum Interference Device Magnetometry
Superconducting Quantum Interference Device (SQUID) Magnetometry was used to determine the
magnetic properties of TH solutions formed using both (1) and (2). TH solutions were concentrated
under reduced pressure to 0.15 mL in standard NMR tubes and flame sealed under vacuum to prepare
samples. Two sets of experiments were run on each sample.
The first is a zero field cool – field cool (ZFC‐FC) experiment, where samples were cooled in zero field to
2K, and warmed gradually under the influence of a magnetic field to 100K, then cooled back to 2K under
the same field. Samples with both (1) and (2) show a deviation between the plots of the ZFC versus the
FC experiments, indicating that the samples are not paramagnetic. Paramagnetic samples, or samples
with paramagnetic impurities, do not show this type of behaviour.77 Both ZFC plots show an increase in
signal with increasing temperature up to the blocking temperature of 6K (1) and 7K (2), as depicted in
Figure 2.13, where the signal reaches a maximum. This behaviour is consistent with superparamagnetic
particles, which is to be expected for Fe NPs, as was seen for similarly sized Fe NPs previously reported.30
Control samples containing solely isopropanol and small amounts of potassium tert‐butoxide showed a
weak diamagnetic response. In the ZFC‐FC run for (2), the plot drops to a negative (diamagnetic) signal
beyond 38K, due to a more dilute sample (in iron) and solvent dominating the overall signal.
51
Figure 2.13: Temperature dependence of the Zero Field Cooling‐Field Cooling (ZFC‐FC) SQUID experiment with (2).
The second experiment involves raising and lowering the magnetic field under a constant, set
temperature, and analysing the resultant hysteresis loops. The spectrum using (1) shows a coercive field
of 400 Oe at 2K, 175 Oe at 10K, and 0 Oe at 50K. This is again consistent with superparamagnetic
behaviour30,77. This change from the ‘blocked’ regime to the superparamagnetic regime is governed by
temperature, and particle size and composition. The active species formed from (2), similar to the active
species formed from (1), shows no coercive field at higher temperatures, but a coercive field of 32 Oe at
2K. The lower value can likely be attributed to a lower concentration of iron in the sample, and a
different composition of the nanoparticles due to the varied ligand.
2.3.11 Polymer‐bound Substrate Experiments
‘Ex‐Situ’ techniques such as STEM and SQUID, along with XPS confirmed the presence of Fe(0) NPs in the
catalytic reaction mixture, but these techniques alone do not provide proof that the NPs are the
catalytically active species. Kinetic and poisoning experiments are powerful in operando techniques that
provide strong evidence of this, but they cannot completely rule out trace amounts of a homogeneous
species as the active catalyst. For this, we first turned to porous polymer supported substrates, and
using a similar technique employed by Witham,78 tested the relative size of our catalysts compared to
known reductants. Using a commercially available Wang resin, pyridinium chlorochromate (PCC) was
used to selectively oxidize the –OH functionality to form a benzaldehyde‐like substrate within the pores
‐2.0E‐5
‐1.0E‐5
0.0E+0
1.0E‐5
2.0E‐5
3.0E‐5
4.0E‐5
5.0E‐5
6.0E‐5
7.0E‐5
8.0E‐5
0 20 40 60 80 100
Magnetic Moment (emu)
Temperature (K)
52
of the polymer. The polymer was then reacted with catalytically activated (2) and other well‐known
reductants such as the Meerwein‐Pondorf‐Verley catalyst (AlMe3)79 and sodium borohydride, to reduce
the C=O back to C‐OH. Complex (2) provides an active catalyst for the reduction of free benzaldehyde, as
has been previously reported.21 The polymers were analysed by infrared spectroscopy, however the –OH
region was strongly affected by solvents used, and therefore modifications to the polymer were
necessary to gauge the extent of conversion back to –OH. Acetic anhydride was reacted with the
resultant polymer, to selectively react with the –OH and not the C=O, yielding an easily distinguished O‐
C=O peak in the IR. These reactions are summarized in Scheme 2.8. Unfortunately, isopropanol is an
inadequate swelling solvent for Wang resins,80 and therefore a 1:1 solvent mixture of tetrahydrofuran
and isopropanol was necessary for the TH reaction with (2) and the NaBH4 reduction. Toluene is an
adequate swelling solvent for the Wang resin, and therefore no modifications were needed for catalysis
with AlMe3 from the previously reported method.
[Note: Relative swelling of Wang resin in isopropanol:toluene:tetrahydrofuran = 1:2:3]80
Scheme 2.8: Polymer‐bound substrate experimental overview.
NaBH4 was able to completely reduce the benzaldehyde‐modified resin, determined by the
disappearance of the C=O (benzaldehyde) peak at 1685 cm‐1 in the IR, as well as a drastic increase in the
–OH peak at 3436 cm‐1. This was confirmed by the appearance of an O‐C=O peak at 1740 cm‐1 upon
reaction with acetic anhydride. Even at very high catalyst to substrate ratios (1:50 where typical catalysis
is with 1:600), the species derived from (2) was not able to reduce the aldehyde to alcohol, determined
53
by no disappearance of the C=O (benzaldehyde) peak, as well as negligible appearance of the O‐C=O
peak at 1750 cm‐1 for an acetic anhydride reacted alcohol. Further experiments showed that three
sequential additions of catalyst over nine hours (12mg; 0.0114 mmol each for ~0.6 mmol C=O) yielded
the same negative result as a single addition of catalyst, strongly suggesting that the catalyst is unable to
get within the pores of the polymer beads. AlMe3 has been previously reported to catalyse the TH of
benzaldehyde to benzyl alcohol at fairly high catalyst loadings of 1:10 (catalyst:substrate).79 Similarly to
catalysis with (2), three sequential additions of AlMe3 (0.042 mmol each for ~0.42 mmol C=O) over nine
hours were used. IR showed a significant decrease of the C=O (benzaldehyde) peak, and reaction with
acetic anhydride showed the appearance of an O‐C=O peak at 1738 cm‐1, proving that the catalyst was
able to get into the pores and reduce the aldehyde. These results are significant as they show that well
known homogeneous catalysts and reagents are able to get into the pores, but the active species
derived from (2) cannot, suggesting that it is much larger, and therefore supporting that the active
species are Fe (0) NPs.
To ensure that the PCC reaction is high yielding, the benzaldehyde‐modified resin was reacted with
acetic anhydride, and IR showed negligible appearance of the O‐C=O peak. To ensure that the acetic
anhydride reaction is high yielding, the acetic anhydride modified resin was reacted with PCC, and IR
showed negligible appearance of the C=O (benzaldehyde) peak. It is well reported that NaBH4 is able to
reduce benzaldehyde,81 and AlMe3 is also reported to effectively reduce benzaldehyde to benzyl alcohol
at 90% yield in 2 hours with a substrate to catalyst loading of 10:1. (2) was tested as a catalyst for the
hydrogenation of benzaldehyde under standard TH conditions using potassium tert‐butoxide in
isopropanol and yielded 55% conversion in 1 hour with a substrate to catalyst loading of 430:1.
2.3.12 STEM/EDX/Poisoning Experiments
In order to further support that the active species during TH are Fe NPs, we combined poisoning
experiments with STEM/EDX techniques to ‘capture’ the active species. 10% PMe3 and 15% CH3(CH2)4SH
relative to (2) both completely poison catalysis, indicating that ‘P’ of PMe3 and ‘S’ of CH3(CH2)4SH bind to
the active sites of the catalyst, blocking the substrate from being hydrogenated. Therefore, the active
species will show an increase in the amount of ‘P’ or ‘S’ relative to Fe after a sample has been poisoned.
To visually analyse and quantify this we analysed two separate STEM grids; one grid was coated with a
standard TH solution (A), and the second (B) was coated with a poisoned TH solution. (B) was prepared
by poisoning solution (A) at t = 15min with 15% CH3(CH2)4SH then allowing the poison to bind to the
active species for 10 minutes before preparing the grid for analysis. 24 agglomerated clusters on each
54
grid were analysed using EDX to determine relative weight % of Fe:S, and the results are summarized in
Table 2.1.
Table 2.1. Relative weight percent of Fe:S on grids (A) and (B) determined using EDX at ‐100oC on a STEM.
Standard Add 15% S
Weight% Fe Weight% S Weight% Fe Weight% S
Average 94.4 5.6 Average 86.1 13.9
Std. Dev. 3.3 3.3 Std. Dev. 5.2 5.2
Variance 10.6 10.6 Variance 26.7 26.7
**Note: Average, Standard Deviation and Variance have been calculated based on 23 values; one outlier
from each series has been omitted.
In order to determine whether the results are statistically relevant, we calculated the Student’s t‐value
for two samples with unequal variances to yield t = 6.525:
Tabulation of Student’s t‐Test:
6.525
Where: x1 = 13.92261
x2 = 5.616957
n1 = n2 = 23
s12 = 26.70365
s22 = 10.56757
This value of ‘t’ indicates that the average weight % S on the two grids is statistically different at the
99.95% confidence interval, calculated based on 39 degrees of freedom (t40 = 3.551 at 99.95% C.I.)
To get reference t we need to tabulate the degrees of freedom (df):
1 1
2 38.4
Note: t40 = 3.551 (99.95% Confidence)
55
Overall, this experiment demonstrates that when 15% pentanethiol is added to an active TH solution,
the sulfur binds to the Fe NPs and stops catalysis, strongly suggesting that the iron nanoparticles are the
active species in solution. The molar ratio of sulfur to iron that is calculated from the weight percent
values of Table 1 is approximately 0.22:1.0 or 0.13:1.0 if the background signal is subtracted. A 4 nm iron
particle has about half of the iron on the surface (as calculated in the Experimental section below), not
all of which will form active sites. Thus this ratio is reasonable. It is also supported by similar values seen
for other poisoned NPs in the literature such as 0.12 for Rh(0) NPs,70 0.2 PPh3 for Ir~300 clusters44 and
many more.24,25,47,73
CH3(CH2)4SH was chosen for this experiment series instead of PMe3 because the standard TH solutions
do not contain sulfur, but there is a fairly strong phosphorus signal in the background due to the P‐N‐N‐P
ligand present. This background created too much error for the results to be statistically relevant.
2.3.13 Description of Fe NPs
We hypothesize that upon reaction with base the Fe‐(P‐N‐N‐P) complex loses its acetonitrile ligand, and
is reduced to an Fe(0) species, which, according to previous DFT studies is energetically favourable.
Some P‐N‐N‐P ligand then dissociates, as seen in the STEM EDX linescans and 31P {1H} NMR spectrum,
and the Fe(0) –CO NPs then form. Enantioselectivity is thought to be caused by the chiral (P‐N‐N‐P)‐dpen
backbone, which likely coordinates onto the surface of the formed NP, similar to the binding of
cinchonidine on zero‐valent platinum nanoparticles.52,82 Selective binding of the (R,R)‐(P‐N‐N‐P) ligand
would thus affect the environment of the active centre for catalysis, yielding alcohols with reasonably
high e.e. (64% (S)‐1‐phenylethanol from acetophenone). The exact mechanism responsible for the
unprecedentedly high e.e. is still under investigation however we postulate that the surface of the NP
must be very regular for the ligands to bind in such a way as to produce such high enantioselectivities. A
thorough DFT and STM study was recently published by McBreen and coworkers83 outlining the specific
binding of chiral modifiers to a platinum surface whereby the ligands and activated acetophenone
substrate were shown to have preferred binding sites on the surface, giving further support that
asymmetric catalysis is feasible on a NP surface.
One possible explanation for this regularity is outlined by Wang,84 who discovered that at room
temperature, Fe NPs favour a cubic structure, whereby most of the particles are confined only to the six
{100} planes, and not truncated by the {110} planes. This would force most of the Fe atoms to be in
regular intervals, and all active sites along the ‘faces of the cubes’ to be identical, leaving only a small
56
fraction of the atoms along the edges of the cubes to negatively affect the regularity. This phenomenon
was primarily seen for Fe NPs coated in iron oxide, giving a total diameter > 8 nm, which is larger than
the particles we report, however this favourability towards the cubic Fe bcc structure may still dominate
in the case of our catalysis.
Several attempts have been made to synthesize Fe NPs independently using well reported techniques
and functionalize them with our P‐N‐N‐P ligands. Bedford,85 Phua29 and Rangheard30 have described
syntheses and characterizations of Fe (0) NPs formed by the reduction of iron (II) and iron (III) halides
using aryl and alkyl Grignard reagents, often in the presence of stabilizing reagents such as polyethylene
glycol (PEG). We tested NPs formed using this method for the TH of ketones and found that they were
not active, nor were NPs formed using several variations of this method in the presence of P‐N‐N‐P
ligands or P‐N‐N‐P ligand precursors as a template technique. This remained the case whether the ligand
was added during synthesis or to the pre‐formed NPs, and whether synthesis was carried out under an
atmosphere of CO or not. Other reported methods for the synthesis of well‐defined Fe (0) NPs involve
the carbothermal reduction of iron salts on carbon black, as reported by Hoch et. al.86 These NPs were
not catalytically active for the TH of ketones, nor were they upon reaction with P‐N‐N‐P ligand. Attempts
were also made to immobilize iron salts onto carbon and reduce using Grignard reagents to make
carbon supported Fe (0) NPs of a smaller diameter than those reported by Hoch. These were treated
with P‐N‐N‐P ligands, either during or post‐synthesis, and both with and without CO present, however
no catalytic activity for the TH of ketones was observed. Iron (0) powders described by Kavaliunas et.
al.87 were also synthesized and tested for catalysis with P‐N‐N‐P ligand, however were also found to be
inactive. All of these attempts to synthesize Fe (0) NPs using different methods did not yield active
catalysts, thus showing that a very intricate balance of starting materials and conditions are required to
generate the NPs formed during our catalysis.
2.4 Case Study
We first became interested in this question of heterogeneity versus homogeneity when we were
investigating the mechanism of two of our iron TH catalysts, the 6,5,6 and 5,5,5‐systems, both shown at
the top of Scheme 2.9. This case study will detail our investigation and comparison of the two systems,
explaining how the techniques and experiments discussed vide supra can be directly applied.
57
The 6,5,6‐Fe(P‐N‐N‐P) system discussed throughout this chapter, and shown in Scheme 2.9 (left) with
the diphenylethylene diimine backbone, achieved turnover frequencies (TOF) of up to 2600 h‐1 and
enantioselectivities of 65% for the TH of acetophenone.23 To improve these results, we designed a new
series, or second generation, of iron catalysts with a smaller chelating ring that would allow for more
modifications to be made. The 5,5,5‐Fe(P‐N‐N‐P) systems, shown in Scheme 2.9 (top right), are formed
using protected phosphonium dimers,71 which allows for extensive modification of the phosphorous
substituents, including both alkyl72 and aryl groups.88 These systems proved to be exceptionally active,
yielding TOFs of up to 30,000 h‐1 and enantioselectivities up to 90% for acetophenone.88 Given the
successful catalysis with both generations of precatalysts, we set out to determine the catalyst
mechanism in the hopes of being able to generate even more active and selective systems.
N N
PPh2
PPh2
Ph Ph
Fe (0)Nanoparticle N
NPh2P
Ph2P Ph
PhN
N PPh2
PPh2Ph
Ph
NN
PPh2
PPh2
PhPh
Fe
Br
OBPh4
NN
PPh2
PPh2
PhPh
Fe
H
O
H
N N
PPh2
PPh2
Ph Ph
Fe
O
NCMe
[BF4]2
VERSUS
First Generation (6,5,6) Second Generation (5,5,5)
6 65
55
5
Scheme 2.9: Iron‐(P‐N‐N‐P) transfer hydrogenation catalysts developed by our group. Left: First Generation, 6,5,6‐system and proposed formation of active species. Right: Second Generation, 5,5,5‐system and proposed formation of active species.
When we first began our investigation, we assumed both generations would follow the same general
mechanism, and therefore set about probing both simultaneously. Initial experiments with the 6,5,6‐
system showed that some ligand was de‐coordinating during catalysis (31P NMR spectrum), and that the
reaction profile showed the presence of an induction period and sigmoidal curve.89,90 With suspicions
58
that the catalyst may in fact be NPs, we used STEM and SQUID to show that NPs were present during
catalysis, and successfully showed the substoichiometric poisoning of the catalytic system with 10%
PMe3. With strong evidence in hand for NP catalysis, we conducted the polymer coordinated substrate
experiments previously outlined, and were able to strongly support our hypothesis using the thiol
poisoning/EDX experiment detailed above. Given the strong support for heterogeneity for the 6,5,6‐
system, we were still hesitant as investigations into the 5,5,5‐system’s mechanism provided strong
evidence for homogeneity.66,91 For the 5,5,5‐system, initial investigations into the role of base showed
that a highly reactive bis‐ene‐amido species could be isolated, and that this species could be used
directly in catalysis without base.66 An interesting curiosity was the presence of an induction period and
sigmoidal reaction profile with the 5,5,5‐systems. However, isolation of the bis‐ene‐amido species after
treatment with base, when used in catalysis, exhibited no induction period.66 This suggests that unlike
the 6,5,6‐system where the induction period and role of base were to reduce the metal centre to iron
NPs, the 5,5,5‐system’s induction period was due to the formation of this reactive intermediate.
Detailed kinetic studies on the activation and catalytic activity of the 5,5,5‐system provided valuable
insights into the mechanism of the system which were supported by DFT calculations.90,91 It was
determined that activation was dependent on catalyst and base concentrations and inversely dependent
on substrate concentration. Catalysis, on the other hand, was not dependent on base concentration;
once the catalyst becomes activated by base in isopropanol, additional base is no longer needed. The
inverse dependence on the substrate acetophenone was explained by the formation of an enolate
which binds to the iron centre, slowing activation. Kinetic profiles were also successfully and accurately
simulated using experimentally determined rate constants and equations, all of which supported a
homogeneous mechanism. The 5,5,5‐system was also minimally affected by PMe3 poisoning and NPs
were not detected using STEM of activated solutions.
Given the striking difference between the apparent activation modes of the two structurally similar
systems we turned to DFT. As previously discussed, we hypothesized that the 6,5,6‐system is reduced to
zero‐valent iron by a mechanism that involves one side of the ligand arm folding up to form an electron
rich ferraaziridine complex.90 Using DFT we studied the 5,5,5‐system and determined that the folding
mechanism was energetically unlikely due to the rigidity of the ligand scaffold. Instead, low energy
pathways were determined for the reduction of the ligand to form amides, followed by stepwise proton
and hydride transfers to generate the active NH‐FeH species,90 as shown in Scheme 2.9 (bottom right).
This ligand flexibility in the 6,5,6 and rigidity in the 5,5,5‐systems explains why the systems activate in
such different ways. An important discovery in the study of the 5,5,5‐system was the isolation of an
59
imine‐amine iron species upon quenching the bis‐ene‐amido species with HCl. This species, shown in
Figure 2.14b, was shown to catalyse TH with a TOF of 50,000 h‐1, nearly double the rate of the original
5,5,5‐precatalyst, in the presence of base. This eventually led to the development of our third
generation catalyst, capable of achieving TOFs up to 200 s‐1.92 Returning to this concept of catalytic
quenching using acid, followed by reactivation with base, as a final piece of evidence that the two
systems were, in fact, completely different mechanistically, we applied this concept to our 6,5,6‐system.
Both systems were individually activated using base in isopropanol in the presence of substrate, and
allowed to react to ~15% conversion before an excess of HCl was added to quench the reaction. This was
then allowed to stir for a short period of time before a fresh batch of base (KOtBu) was added to
reactivate the solution. The conversion of acetophenone to product was monitored throughout the
process, as depicted in Figure 2.14. Upon the addition of HCl, both systems deactivate, indicated by the
lack of conversion. After the addition of further base, only the 5,5,5‐system regains its activity, whereas
the 6,5,6‐system cannot be reactivated. This test provided the final piece of evidence that the two
systems, although structurally quite similar, were in fact completely different.
Figure 2.14: Reaction profiles for the conversion of acetophenone to 1‐phenylethanol over time using the 6,5,6‐system (a)
and the 5,5,5‐system (b). Plots depict the effect of adding HCl following by reactivation with KOtBu.
This comparison of the first and second generation of catalysts developed in our lab is an important
example of why it is so critical to study the reaction mechanism of every catalyst system, regardless of
how similar they may seem. It also highlights the value of applying a wide range of techniques to piece
together evidence, and ultimately postulate a mechanism.
60
2.5 Conclusions
Upon reaction of our trans‐[Fe(NCMe)CO(PPh2C6H4CH=NCHR‐)2 ][BF4]2 (R = H, Ph) precatalyst (1) with
two equivalents of sodium iso‐propoxide in benzene, an unusual folded ferraaziridine complex
[Fe(CO)(PPh2C6H4CH=NCH2CH2NHCHC6H4PPh2)‐5P,N,C,N,P][BF4] (3) could be isolated, but was found to
not be catalytically active. Upon reaction of the ferraaziridine complex with potassium tert‐butoxide in
isopropanol, a deprotonated ferraaziridinido complex Fe(CO)(PPh2C6H4CH=NCH2CH2NCHC6H4PPh2)‐
5P,N,C,N,P (4) could be observed. (4) matched the species observed by 31P {1H} NMR experiments
during TH, but was also found to not be catalytically active. DFT calculations showed that formation of
(4) was highly energetically favourable, as was the further reduction to the Fe (0), square pyramidal
species Fe(CO)(PPh2C6H4CH=NCH2‐)2‐4P,N,N,P. This favourable reduction to an Fe (0) species provided
support for the potential formation of Fe NPs in solution during catalysis. Upon further investigating the
mechanism with our precatalysts (1) and (2) we discovered by STEM, SQUID and XPS analyses that Fe
NPs were being formed during catalysis. STEM showed that the NPs are approximately 4.5 nm in
diameter, SQUID showed that the catalytic mixture contained primarily a superparamagnetic species,
and XPS analysis confirmed the formation of an Fe (0) species. Reaction profile analysis confirmed that
activation of the Fe precatalyst with base and isopropanol was responsible for the induction period,
resulting in a sigmoidally shaped reaction profile. Several poisoning agents were tested, and PMe3
proved the most effective poison, completely stopping catalysis with only 10% loading relative to the
precatalyst. Functionalization of a porous Wang resin with a benzaldehyde‐like functionality, and
subsequent reaction with various hydrogenation catalysts and reagents proved that well defined
homogeneous species were able to get within the pores, but that the catalyst derived from (2) is too
large, thereby providing further evidence that the active species are NPs. Pentanethiol was shown to be
an effective substoichiometric poisoning agent, and using STEM/EDX techniques it was demonstrated to
bind to the Fe NPs, further supporting that NPs are the active species in catalysis. Lastly, we
demonstrated the use of this wide range of techniques in a comparative case study between our 6,5,6‐
first generation nanoparticle catalysts and our homogeneous 5,5,5‐second generation catalyst system.
This chapter details the extensive mechanistic story of our iron catalysts, and provides a rare example of
highly active asymmetric catalysis using zero‐valent nanoparticles based on non‐precious metals.
61
2.8 Experimental
2.8.1 General Procedures
All preparations, manipulations and catalysis were carried out under an argon or nitrogen atmosphere
using standard Schlenk line and drybox techniques. Dry and oxygen‐free solvents, acetophenone and
ethylene diamine were distilled and dried using the appropriate drying agents. NMR solvents were
purchased from Aldrich and degassed and dried over activated 3 Å molecular sieves. All other reagents
were purchased from various commercial sources and used without further purification. NMR spectra
were recorded using a Bruker 400 and Varian 300 and 400 spectrometers to determine 1H (400 and 300
MHz) and 31P {1H} (121 MHz) shifts. 1H shifts are referenced to deuterated solvents, and 31P peaks are
externally referenced to 85% phosphoric acid.
Gas Chromatography was done on a Perkin Elmer Clarus 400 Chromatograph equipped with a chiral
column (CP chirasil‐Dex CB 25 m x 2.5 mm) and auto‐sampling capabilities. Hydrogen gas was used as
the mobile phase, and the oven temperature was set at 130 0C. Retention times for 1‐phenylethanol are
7.58 and 8.03 minutes, and for acetophenone is 4.56 minutes.
X‐Ray Photoelectron Spectroscopy (XPS) was done at the University of Toronto by Dr. Rana Sodhi and
‘Surface Interface Ontario’ on a Thermo Scientific K‐Alpha XPS spectrometer. The samples were run at a
take‐off angle (relative to the surface) of 90°. A monochromatic Al Kα X‐ray source was used, with a spot
area (on a 90° sample) of 400 μm. No charge compensation was needed. Position of the energy scale
was adjusted to place the main C 1s feature (C‐C) at 284.6 eV. An initial survey spectrum was obtained
and the identified elements were obtained in a snapshot mode at low resolution (pass‐ energy = 150 eV)
for quantification purposes. High resolution spectra (pass energy = 25 eV) were obtained for the P 2p, N
1s, O 1s, Fe 2p, Ag 3d and C 1s regions. The latter two were collected for an internal energy calibration.
The instrument and all data processing were performed using the software (Avantage) provided with
the instrument.
Electron microscopy images were carried out at the ‘Centre for Nanostructure Imaging’ (University of
Toronto) in collaboration with Dr. Neil Coombs, on a Hitachi HD‐2000 STEM operating at ‐100 0C. Low
temperatures were required to minimize contamination and specimen damage by the electron beam.
Samples were placed on an ultrathin carbon film supported by a lacey carbon film on a 400 mesh copper
grid. Energy‐Dispersive X‐Ray Spectroscopy (EDX) was run concurrently using INCA software and the
62
STEM. Linescans were used to analyse iron, oxygen, phosphorus, nitrogen, carbon and titanium. The
latter was collected as a background. Sample preparation: to a vial containing pre‐catalyst (5 mg, 0.006
mmol of (1), or 6 mg, 0.006 mmol of (2)) and NaOtBu (4 mg, 0.042mmol), isopropanol (6 mL, 78 mmol)
and acetone (0.1 mL, 1.4 mmol) were added at the desired temperature, in an argon filled glovebox.
Magnetic measurements were done at McMaster University at the Brockhouse Institute for Materials
Research in collaboration with Dr. Paul Dube, on a Quantum Design MPMS SQUID magnetometer with a
5.5 T magnet. Zero Field Cooling‐Field Cooling (ZFC‐FC) experiments brought the sample down to 2 K in
the absence of a magnetic field, warmed the sample to 100 K under a constant applied field and cooled
back down to 2 K under the same applied field. Hysteresis curves were done at constant temperatures
under fields varying from ‐30000 to 30000 Oe. Sample preparation: to a vial containing pre‐catalyst (5
mg, 0.006 mmol of (1), or 6 mg, 0.006 mmol of (2)) and KOtBu (5 mg, 0.045mmol), 2‐propanol (3 mL, 39
mmol) and acetone (0.05 mL, 0.7 mmol) were added at the desired temperature, in an argon filled
glovebox. The solution was stirred for 8 min, and then concentrated under reduced pressure to 0.15 mL
in an NMR tube. The solution was frozen, put under vacuum, and flame‐sealed.
2.8.2 Syntheses
Precatalysts [Fe(CO)(NCMe)(P2N2en)][BF4]2 (1) and [Fe(CO)(NCMe)(P2N2dpen)][BF4]2 (2) have both been
prepared and characterised previously.23
Preparation of (3): In a nitrogen‐filled glove box, 3 mL of benzene was added to a solid mixture of (1) (56
mg, 0.093 mmol) and NaiOPr (15 mg, 0.18 mmol). The reaction mixture turned dark brown after ca. 15
minutes and was stirred for 12 h at ambient temperature. The solution was filtered off and was allowed
to slowly evaporate for several days, to give the product as dark brown crystals. Crystals for X‐ray
analysis were selected directly from this crop. After washing with ether and pentane the pure product
was obtained. Yield: 31 mg, 0.06 mmol, 65%. 1H NMR (400 MHz, CD3CN): δ = 8.76 (d, JH,P = 3.1 Hz, 1 H,
CH=N), 8.03 (m, 2 H, Ar), 7.75‐6.74 (several m, 22 H, Ph), 6.42 (m, 2 H, Ar), 6.23 (m, 2 H Ar), 4.32 (m, 1 H,
CH2), 4.21 (br s, 1 H, NH), 3.80 (m, 1 H, CH2), 3.61 (m, 1 H, CH), 2.55 (m, 1 H, CH2). 31P{1H} NMR (121 MHz,
CD3CN): δ = 84.3 (d, JP,P = 43.4 Hz), 70.1 (d, JP,P = 43.3 Hz). 13C{1H} NMR (100 MHz, CD3CN): δ = 213.3 (dd,
JC,P = 3.1 Hz, JC,P = 24.2 Hz, CH=N), 170.0 (d, JC,P = 4.6 Hz, Ar), 154.7 (d, JC,P = 32.1 Hz, Ar), 136.9‐128.1
(several m, Ar), 70.1 (d, JC,P = 4.5 Hz,. CH2), 68.1 (dd, JC,P = 5.5 Hz, JC,P = 10.8 Hz, CH), 48.6 (d, JC,P = 1.8 Hz,
CH2). 19F NMR (CD3CN): δ = 152.3 (s). IR(KBr): νCO = 1940 cm
‐1. MS (ESI+, MeOH): for [M‐BF4]+ (m/z =
63
689.2). Analysis calcd for C41H36BF4FeN2OP2∙C6H6: C, 65.99; H, 5.30; N, 3.27. Found: C, 65.82; H, 5.30; N,
3.61.
Observation of (4): In a nitrogen‐filled glove box, 3 mL of isopropanol was added to a solid mixture of (3)
(25 mg, 0.031 mmol) and KOtBu (5 mg, 0.044 mmol). The reaction mixture turned dark brown
immediately and was stirred for 1 h at ambient temperature. The solution was filtered to remove excess
base and NMR and IR spectra of the crude solution were obtained. 31P{1H} NMR (121 MHz, iPrOH, C6D6
insert): δ = 84.1 (d, JP,P = 30.7 Hz), 68.7 (d, JP,P = 30.7 Hz). IR(KBr): νCO = 1862 and 1870 cm‐1, as well as
broad peaks at 1934 and 1957 cm‐1.
2.8.3 Catalysis – Standard Run
To a vial containing pre‐catalyst (5 mg, 0.006 mmol of (1), or 6 mg, 0.006 mmol of (2)) and KOtBu (5 mg,
0.045mmol), isopropanol (6 mL, 78 mmol) and acetophenone (0.35 mL, 3 mmol) were added at the
desired temperature, in an argon filled glovebox. Immediately a dark brown solution was formed for (1)
or a dark green solution for (2). Solutions were stirred vigorously, and samples were taken from the
mixture, quenched by exposure to air and analysed by gas chromatography. When the samples are
exposed to air the solution turns yellow and the reaction stops immediately. The alcohol/ketone
concentration does not change in these solutions, even after several days. All of the catalytic results
were reproduced in triplicate to ensure consistency.
2.8.4 Catalysis – Poisoning Experiments
Solutions were prepared as outlined for a standard run, and sub‐stoichiometric amounts of poisoning
reagents were added to the solution after a set amount of time, typically 8 or 11 minutes. Poisoning
reagents were prepared as dilute stock solutions in toluene, benzene or isopropanol, based on solubility.
Addition of blank stock solutions, either toluene or benzene, had no effect on catalysis. Tested poisoning
agents include: PMe3 in toluene, PPh3 in benzene, PCy3 in toluene, P(OMe)3 in benzene, P(OPh)3 in
toluene, PPhMe2 in toluene, OPPh3 in toluene, DABCO in isopropanol, ethylene diamine in isopropanol,
pentanethiol in pentane and 2‐(dimethylamino)ethanethiol in isopropanol.
2.8.5 Catalysis – NMR Scale Reactions
To a vial containing pre‐catalyst (1) (18 mg, 0.020 mmol)and KOtBu (10 mg, 0.088 mmol), isopropanol
(0.6 mL, 7.8 mmol) and acetophenone (0.1 mL, 0.86 mmol) were added at room temperature, in an
64
argon filled glovebox. Immediately a dark brown solution was formed, which was stirred vigorously for
10 minutes before being transferred to a J‐Young NMR tube containing a D2O insert, and 31P {1H} was run
immediately on a Varian 400 MHz spectrometer. All results were reproduced in triplicate to ensure
consistency.
2.8.6 Mass Balance Experiments
Prior to addition of solvent, OPPh3 (11 mg, 0.040mmol) was added to a vial prepared as outlined above.
The dark brown solution was stirred for 10 minutes and transferred to a J‐Young NMR tube containing a
D2O insert. 31P NMR spectroscopy was run immediately on a Varian 400 MHz spectrometer, with a 90°
pulse, decoupled‐NOE and a relaxation decay of 3.7 seconds. Parameters were optimized by
determining the T1 relaxation times of all species present in the 31P NMR spectrum. All results were
reproduced to ensure consistency.
2.8.7 Experimental for Polymer‐bound Substrate Experiments
Synthesis of Polymer‐supported Substrate (WangPCC): StratoSpheres™ PL‐Wang resin (1.7 mmol –OH/g,
50‐100 mesh, 1% crosslinked) (1.3 g, 2.21 mmol –OH), was stirred with pyridinium chlorochromate (PCC)
(500 mg, 2.32 mmol) in 20 mL dichloromethane for 6 hours at room temperature in a nitrogen filled
glovebox. The resin was then filtered under air, washed extensively with dichloromethane and
isopropanol, and dried overnight under reduced pressure.
Catalysis on Resin with (2): To a vial containing pre‐catalyst (2) (12 mg, 0.0114 mmol), KOtBu (10 mg,
0.09mmol), and WangPCC (~350 mg, ~ 0.6 mmol C=O), isopropanol (3 mL, 39 mmol) and
tetrahydrofuran (3 mL, 37 mmol) were added at room temperature, in an argon filled glovebox. The
solution was stirred for 24hrs, and then the resin was filtered under air, washed with isopropanol and
dichloromethane, and dried overnight under reduced pressure.
Testing Resin as a Poison to Catalysis with (2): (To ensure that the conditions of resin experiments were
not poisonous to the standard TH of acetophenone). To a vial containing pre‐catalyst (2) (6 mg, 0.0057
mmol), KOtBu (5 mg, 0.045mmol), and Wang PCC (~65mg), isopropanol (6 mL, 78 mmol) and
acetophenone (0.35 mL, 3 mmol) were added at room temperature, in an argon filled glovebox. A dark
green solution formed immediately. Solutions were stirred vigorously, and samples were taken from the
mixture, quenched by exposure to air and analysed by gas chromatography. No decrease in catalytic
activity or enantioselectivity was seen, indicating that the resin is not a poison.
65
Catalysis on Resin with AlMe3: To a vial containing WangPCC (~250 mg, ~ 0.42 mmol C=O), isopropanol
(0.06 mL, 0.78 mmol) and toluene (1 mL, 9.4 mmol), AlMe3 (0.042 mmol in 0.2 mL toluene) was added at
room temperature, in a nitrogen filled glovebox. The solution was stirred for 24hrs, and then the resin
was filtered under air, washed with toluene, isopropanol and dichloromethane, and dried overnight
under reduced pressure.
Reduction of Resin with Sodium Borohydride: To a vial containing NaBH4 (23 mg, 0.61 mmol) and
WangPCC (~350 mg, ~ 0.6 mmol C=O), isopropanol (3 mL, 39 mmol) and tetrahydrofuran (3 mL, 37
mmol) were added at room temperature, in an argon filled glovebox. The solution was stirred for 24hrs,
and then the resin was filtered under air, washed with isopropanol and dichloromethane, and dried
overnight under reduced pressure.
Reaction of Resin with Acetic Anhydride (Wang + aa): To a vial containing resin (as prepared in steps 1‐4)
(~250 mg, ~ 0.4 mmol C‐OH/C=O) and iodine (I2) (20 mg, 0.08 mmol) dichloromethane (4 mL, 62 mmol)
and acetic anhydride (0.25 mL, 2.6 mmol) were added at room temperature under air. The solution was
stirred for 22hrs, water (1 mL, 55 mmol) was added, and the solution was stirred for 1 hour. The resin
was then filtered, washed with dichloromethane, and dried overnight under reduced pressure.
66
Table 2.2: IR peaks for modified resin experiments
Resin Sample Relevant IR peaks (cm‐1)
Wang – OH 1612 (strong)
Wang + aa 1615 (strong) – resin
1740 (strong) – O‐C=O (aa)
WangPCC 1612 (strong) – resin
1690 (strong) – C=O (benzaldehyde)
WangPCC + aa 1615 (strong) – resin
1684 (strong) – C=O (benzaldehyde)
1750 (very small) – O‐C=O (aa)
WangPCC – TH with (2) 1615 (strong) – resin
1690 (strong) – C=O (benzaldehyde)
WangPCC – TH with (2) + aa 1612 (strong) – resin
1688 (strong) – C=O (benzaldehyde)
1750 (very small) –O‐ C=O (aa)
WangPCC – TH with AlMe3 1615 (strong) – resin
1688 (small shoulder peak off of 1615 peak) – C=O
(benzaldehyde)
Note: 3447 (very strong) – C‐OH peak has grown
significantly
WangPCC – TH with AlMe3 + aa 1617 (strong) – resin
1693 (weak) – C=O (benzaldehyde)
1738 (fairly strong) – O‐C=O (aa)
WangPCC – NaBH4 1617 (strong) – resin
Note: 3436 (very strong) – C‐OH peak has grown
significantly
WangPCC – NaBH4 + aa 1614 (strong) – resin
1740 (strong) – O‐C=O (aa)
** aa = Acetic Anhydride reactions, TH = Transfer Hydrogenation Reaction
2.8.8 Determining the Ratio of Fe on the Surface of Fe NP
Known:
ΡFe, bulk = 7.87E6 g/m3
Atomic Radii Fe = dFe = 126 pm = 1.26E‐10 m
Assume Iron = body centred cubic 2 Fe atoms / unit cell
MWFe = 55.85 g/mol
Diameter of NP = 4nm r = 2 nm
For Total Fe/NP:
67
, 43
3.351 10
2.637 10 4.722 10 2844
For Surface Fe/NP:
Distance from A B 4 5.04 10
Therefore 4 45 3.564 10
Surface Area of a Circle : 4 5.0266 10
Volume on Surface = 1.7914 10
Mass on Surface = 1.410 10 2.524 10 1520
15202843
53.5%
Similarly, the relative amount of iron on the surface of the nanoparticle can be calculated assuming a
cubic particle with a facial diameter of 4 nm and assuming bcc iron. This yields a final equation of:
30237483
40.4%
2.8.9 Catalysis – HCl Addition Experiments
For 6,5,6‐Catalyst: To a vial containing (2) (6 mg, 0.006 mmol) and KOtBu (5 mg, 0.045 mmol),
isopropanol (6 mL, 78 mmol) and acetophenone (0.35 mL, 3 mmol) were added at the desired
temperature, in an argon filled glovebox. The solution became dark green in colour immediately. The
solution was stirred vigorously for 20 minutes, then 1 M HCl in ether (0.050 mL, 0.05 mmol) was added.
The solution immediately turned bright orange in colour. The solution was stirred vigorously for 5
minutes, then KOtBu (7 mg, 0.062 mmol) was added. The solution turned murky, dark brownish orange,
and was stirred vigorously for one hour. Samples were taken from the starting reaction mixture, the HCl‐
poisoned solution, and several after attempted re‐reduction. Samples were quenched by exposure to air
and analysed by gas chromatography. When the samples are exposed to air the solution turns yellow
68
and the reaction stops immediately. The alcohol/ketone concentration does not change in these
solutions, even after several days.
For 5,5,5‐Catalyst: To a vial containing isopropanol (3 mL, 39 mmol) and acetophenone (0.6 mL, 5.1
mmol), KOtBu (2 mg, 0.018 mmol in 0.4 mL isopropanol) and 5,5,5‐catalyst (2 mg, 0.002 mmol in 0.4 mL
acetophenone) were added at the desired temperature, in an argon filled glovebox. The solution
became dark green in colour immediately. The solution was stirred vigorously for 7 minutes, then 1 M
HCl in ether (0.020 mL, 0.02 mmol) was added. The solution immediately turned yellow in colour. The
solution was stirred vigorously for 5 minutes, then KOtBu (3 mg, 0.027 mmol) was added. The solution
turned yellowy‐green, and was stirred vigorously for 30 minutes. Samples were taken from the starting
reaction mixture, the HCl‐poisoned solution, and several after attempted re‐reduction. Samples were
quenched by exposure to air and analysed by gas chromatography. When the samples are exposed to air
the solution turns yellow and the reaction stops immediately. The alcohol/ketone concentration does
not change in these solutions, even after several days.
69
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74
Chapter 3: Oxidative Kinetic Resolution
of Aromatic Alcohols using Iron
Nanoparticles
Adapted from Sonnenberg, J.F., Pichugin, D., Coombs, N., Morris, R.H. Top. Catal. 2013, 56, 1199‐1207.
3.1 Abstract
Using our chiral transfer hydrogenation (TH) pre‐catalyst trans‐(R,R)‐
[Fe(NCMe)(CO)(PPh2C6H4CH=NCHPh‐)2][BF4]2 (2) we investigated the reverse reaction, oxidative kinetic
resolution (OKR), and were able to achieve turn‐over frequencies up to 335 h‐1 and s‐values in favour of
the (R)‐alcohol up to 10.2. Using racemic 1‐phenylethanol we optimized reaction conditions to maximize
enantioselectivity and turn‐over frequency (TOF) and studied the effect of different proton/hydride
acceptors, temperatures, and bases. Using KOtBu as the base and benzophenone in THF as the solvent
and acceptor at 45 oC, we tested a series of substrates with varying electronic and steric factors. By
increasing the steric bulk at the alcohol, the enantioselectivity increased, however the TOF decreased
dramatically. Varying the electronics of the substrates using electron withdrawing and donating
substituents showed a less significant effect. We propose that the active species in catalysis is zero‐
valent iron nanoparticles (Fe NPs), a postulate that we support with microscopy imaging, sub‐
stoichiometric poisoning experiments, and analysis of the reaction profile. Further support is given in
terms of a polymer‐supported substrate experiment whereby the active species in catalysis is too large
to permeate the pores of a functionalized polymer. To the best of our knowledge, we propose that this
is the first reported example of using a nanoparticle surface for oxidative kinetic resolution.
75
3.2 Introduction
The synthesis of enantiopure alcohols is of vital importance in the pharmaceutical, fragrance and food
flavouring industries.1‐3 These alcohols are commonly made in industry via the selective hydrogenation
of carbonyl groups by direct H2‐hydrogenation or transfer hydrogenation (TH)4 which uses isopropanol
as the hydrogen source. Both types of hydrogenation typically employ homogeneous precious metal
catalysts based on iridium, rhodium and ruthenium.5‐7 A newly expanding methodology for this type of
transformation is the oxidative kinetic resolution of racemic alcohols to yield enantio‐enriched alcohols
and their corresponding ketones.8,9 These reactions were first pioneered by Noyori and coworkers10 who
used their homogeneous chiral diamine RuII TH catalyst as an oxidation catalyst for kinetic resolution.
This is feasible because of the inherent reversibility of transfer hydrogenation catalysis, an approach to
equilibrium process. For TH a proton and hydride are transferred from a donor, such as 2‐propanol, to a
ketone of interest, and is driven by the presence of an excess of 2‐propanol. Therefore, in the presence
of an appropriate acceptor, the reverse reaction is theoretically feasible with all TH catalysts.
An important current area of research is the use of ‘greener’ metal centres such as iron to replace toxic
and expensive precious‐metal catalysts.11‐13 Our group has developed several highly efficient transfer
hydrogenation catalysts based on iron using PNNP tetradentate ligands.14‐17 As outlined in Chapter 2,
and recently published by our group, the active species in one of our catalytic systems is suspected to be
zero‐valent iron nanoparticles (Fe NPs) coated in chiral P‐N‐N‐P ligand, with an overall diameter of 4.5 ±
1.2 nm.18 The precatalyst structure of trans‐(R,R)‐[Fe(NCMe)(CO)(PPh2C6H4CH=NCHPh‐)2][BF4]2 (2) and
reaction scheme for this transformation and the reverse kinetic resolution oxidation reaction are
depicted in Scheme 3.10. An interesting aspect of this system was that it did not racemize enantiopure
products during TH after prolonged exposure, which is often a problem with highly active systems both
on iron15,19 and on other precious‐metal catalysts.20‐23 Given the reversibility of TH and this maintenance
of enantiopurity over prolonged periods of time, we decided to test our suspected nanoparticle catalyst
system for oxidative kinetic resolution of various substrates, and compare these results to known TH
results for the same substrate series already developed.14
76
Scheme 3.10: Precatalyst structure and reaction schemes for transfer hydrogenation (TH) [Top] and oxidative kinetic resolution [Bottom].
Different proton/hydride acceptors have also been explored, but the most common is acetone,9 and
recent progress has been made using oxygen/air as the acceptor (aerobic oxidative kinetic resolution
AOKR).24,25 Several highly efficient catalytic systems have been developed previously for the kinetic
resolution of alcohols using catalysts based on precious metals,24‐26 cobalt,27 copper28 and many more.
However, the use of iron complexes for this transformation is rare,29,30 and the use of nanoparticles or
other heterogeneous catalysts have not yet been reported, to our knowledge.
3.3 Results and Discussion
3.3.1 Catalytic Runs
Acetophenone was used as the standard substrate to test TH with the iron catalysts in our lab,14,18 so we
first sought to explore the kinetic resolution and oxidation of racemic 1‐phenylethanol into
acetophenone and the enantio‐enriched alcohol. We have also reported that our active species for TH
deactivates in the presence of oxygen,18 and therefore we chose to use ketones as the proton/hydride
acceptors instead of air. The results for tests with 1‐phenylethanol are depicted in Table 3.3.
Nanoparticle solutions for TH were typically formed by activating our iron precatalyst (2) with KOtBu in
isopropanol at 28 oC, before the addition of substrate. Therefore, paradoxically, base was employed to
77
produce reactive alkoxides in order to reduce the iron centres and to allow for catalytic oxidations.
Using acetone at 28 oC and KOtBu as the base yields only modest enantiomeric excess (e.e.) and a low
relative rate of consumption of R versus S (‘s’ factor),31 as shown in Entry 1. Selectivity for the (R)‐
alcohol is in keeping with TH results where the (S)‐alcohol is preferentially produced. Enantiomeric
excess in favour of (R)‐phenylethanol was significantly improved by using benzophenone in THF as the
acceptor as shown in Entry 2. It should be noted that in changing the conditions from Entry 1 to 2, the
concentration of acceptor also changes significantly; when acetone is used as the acceptor, it is also the
solvent and is present at 82 mmol (14000:1 relative to catalyst), whereas when benzophenone is used, it
is present in much lower amounts of 7.7 mmol (1000:1 relative to catalyst). The other very important
reason for this change is the fact that acetone readily forms an enolate in the presence of strong base,
but benzophenone does not as it has no enolizable protons. This would indicate that the formation of
acetone enolates is potentially a deactivation pathway; the base may be consumed more rapidly by
acetone and therefore is present in a lower concentration and cannot assist in the reduction of iron as
readily. Alternatively, the enolate competitively binds to the active species in the place of acetone,
preventing the iron species from accepting the proton and hydride from the substrate to propagate the
oxidation reaction.
The turn‐over frequency (TOF) of reactions employing benzophenone as the acceptor was still low, so to
improve the rate of the reaction, we increased the temperature from 28 oC to 45 oC (Entry 3). We were
pleased when the e.e. remained at 59%, and the value of ‘s’ remained unaffected, but the TOF increased
significantly from 46 to 171 h‐1. This indicates that the catalyst structure and mode of action in terms of
selectivity is unchanged at higher temperatures, while greater reaction rates are obtained.
Lastly, we were interested in the effect of the base on the e.e., s‐value and TOF of catalysis and
therefore explored using the milder base sodium isopropoxide (NaOiPr) for catalysis. We hypothesized
that using the strong base KOtBu in acetone was causing the formation of enolates, and therefore we
wanted to test the use of a milder base with acetone, as depicted in entry 4. The TOF increased
significantly from 38 to 203, indicating that the same deactivation by enolates was not occurring.
Although we were successful in increasing the reaction rate, the e.e. and s‐value were significantly lower
than the oxidation done using KOtBu, indicating a severely diminished selectivity. To test whether this
decrease in e.e. was an effect of changing the base, we also tested oxidation in benzophenone/THF at
45oC with NaOiPr (Entry 5). The TOF, e.e. and s‐value were all slightly lower, indicating that the
78
diminished e.e. and s‐value in acetone were likely an effect of the base. The isopropoxide is more
nucleophilic and may affect the selective binding of the substrate, thus diminishing the e.e.
Table 3.3: Kinetic Resolution of racemic 1‐phenylethanol (2.2 mmol) using (2) (0.0056 mmol) and base (0.045 mmol) [C:B:S =
1:8:400].
Entry Temp
(oC)
Solvent Base Time
(hours)
Conversion (%
C=O)
TOFc
(h‐1)
e.e. (R)
(%)
Relative
Rate (s)
1 28 Acetoneb KOtBu 5 43 38 40 4.6
2 28 THFa KOtBu 5 51 46 59 (5 h)
70 (6 h)
6.2
3 45 THFa KOtBu 1.5 52 171 59 6.0
4 28 Acetoneb NaOiPr 1 49 203 33 (1 h)
86 (3 h)
2.8
5 45 THFa NaOiPr 1.5 51 130 51 4.9 a Reaction done in stock solution of benzophenone (1.4 g, 7.7 mmol) in THF (4.7 mL, 58 mmol). b Reaction done in acetone (6 mL, 82 mmol). c TOF calculated based on slope of linear portion of conversion plot relative to catalyst concentration.
Having optimized the reaction conditions for our system using 1‐phenylethanol as the substrate, we
were interested in exploring sterically and electronically different substrates, as depicted in
79
Table 3.4. We first examined the effect of increasing the sterics of the substrate, in an attempt to
increase the e.e. as had been seen previously for TH.14 Starting with the most bulky substrate 2,2‐
dimethyl‐1‐phenylpropanol (Entry 2) there was no conversion to the corresponding ketone even at
lower substrate loadings and prolonged reaction times. Decreasing the steric bulk slightly we tested 2‐
methyl‐1‐phenylpropanol (Entry 3) for oxidative kinetic resolution and were able to achieve an s‐value
of 10.2; however the reaction required lower substrate loadings, prolonged reaction times, and gave a
very low TOF of 13 h‐1. Completing the series of substrates, we tested 1‐phenylpropanol (Entry 4) which
is only slightly bulkier than 1‐phenylethanol, and were able to achieve an s‐value of 8.9 and a TOF of
123. This series very clearly shows that with increasing steric bulk the e.e. (and therefore s‐value)
increases and the TOF (and therefore rate of reaction) decreases. This behaviour closely mimics that
seen for TH with this system,14 supporting the truly reversible nature of these reactions.
We were also interested in the effect of changing the electronics of the substrate on catalysis. We
studied 1‐phenylethanol substrates with electron withdrawing chloro‐ substituents in the para (Entry 5)
and meta (Entry 6) positions. Both showed similar TOF of ~90 h‐1, lower than that observed for the
unsubstituted 1‐phenylethanol (TOF = 171), with s‐values of 4.0‐4.5, also lower than the unsubstituted
substrate (s = 6.0). A similar trend of decreasing rate and e.e. was observed for TH with the meta‐
substituted chloro substrate; however the para‐substitution had a negligible effect on TH.14 To explore
electron donating effects, we studied the para‐methyl substituted substrate (Entry 7). The TOF was the
highest of our series of substrates at 335 h‐1, with an s‐value of 5.3, comparable to 1‐phenylethanol.
Electron donation from the para position can be delocalized through the phenyl ring making the alcohol
more reducing and therefore more rapidly oxidized, increasing the observed rate. The trend for the
series of electron withdrawing through electron donating groups is less clear than with the steric
modifications, but it is clear that the effect of changing the electronics is less significant than the effect
of changing the sterics.
The last substrate of interest was 4‐phenyl‐2‐butanol (Entry 8), which does not have the C‐O bond in
conjugation with the phenyl ring. Catalysis with prolonged reaction times and low substrate loading
yielded very low TOF and poor selectivity, indicating that some steric bulk is required around the C‐O
bond to allow for enantioselectivity, and that electronics are important for influencing reaction rates.
80
Table 3.4: Kinetic Resolution of various racemic alcohols using (2) (0.0056 mmol) and KOtBu (0.045 mmol) at 45oC in a stock
solution of benzophenone (1.4 g, 7.7 mmol) in THF (4.7 mL, 58 mmol).
Entry Product/Substrate Substrate
Loading
Time
(h)
Conversion %
C=O
TOF
(h‐1)
e.e. (R)
(%)
Relative
Rate (s)
1
400
1.5
52
171
59
6.0
2
110
12
0
0
0
N/A
3
300
8
29
13
31 (8 h)
40 (24h)
10.2
4
400
3
52
123
71
8.9
5
400
3
57
91
56
4.0
6
400
2.5
50
91
48
4.5
7
400
0.75
51
335
54 (0.75 h)
68 (1 h)
5.3
8
110
6
18
3.3
5
1.7
81
3.3.2 Evidence for Nanoparticles
Previously we reported an in‐depth series of experiments to examine the potential heterogeneity of the
TH catalytic system using (2),18 and we were interested in whether iron (0) nanoparticles (Fe NPs) were
also the active species for the oxidative kinetic resolution detailed here. Scanning Transmission Electron
Microscopy (STEM) is a powerful imaging tool for determining whether nanoparticles are present during
catalysis.32,33 STEM imaging for the present work was done at ‐100 oC using a Hitachi HD‐2000 STEM on
carbon/copper grids coated with activated catalytic solutions. Low temperatures were needed for
analysis to minimize organic contamination by the electron beam.
The first experiment was done on a sample prepared by activating precatalyst (2) with NaOiPr in
acetone, and using isopropanol as the substrate for 12 minutes with a C:B:S loading of 1:8:230.
Isopropanol was used as the substrate as it has a much lower boiling point than 1‐phenylethanol, and it
could therefore be evaporated off the grid prior to analysis. Imaging showed reasonably well dispersed
nanoparticles with an average diameter of 4‐5 nm, as shown in Figure 3.15 [left]. These are similar in
size and distribution to the nanoparticles previously reported,18 as well as other Fe(0) NPs in the
literature.34
We were also interested in whether the other modes of activation involving other acceptor molecules
would yield similarly dispersed nanoparticles. The second experiment was done on a sample prepared
by activating precatalyst (2) with KOtBu in a benzophenone/THF solution, using isopropanol as the
substrate for 20 minutes, with a C:B:S loading of 1:8:230. Imaging was not as clear as it was for solutions
activated in acetone because the benzophenone cannot be removed from the grids under vacuum prior
to imaging. This resulted in large organic masses being present during analysis as depicted in Figure 3.15
[right]. The images do still show that there are small nanoparticles on the grid behind the organics, and
that they are also 4‐5 nm in diameter. Another interesting feature of the images using benzophenone is
the texture that can be observed encircling the organic masses; several of the benzophenone clouds
appear to have bright rings around them, identified as being salts (KBF4) which dried surrounding the
organic masses.
82
Figure 3.15: STEM image taken at ‐100oC of activated catalyst; a) [left] solution prepared using (2) and NaOiPr at room temperature (28oC) in acetone, using iPrOH as the substrate (C:B:S = 1:8:230); b) [right] solution prepared using (2) and KOtBu at room temperature (28oC) in benzophenone/THF, using iPrOH as the substrate (C:B:S = 1:8:230).
STEM, although a powerful tool for studying the structure of nanoparticles and determining whether
they are present during catalysis, does not prove whether the nanoparticles are the active species in
catalysis. For this, in operando experiments are needed to probe the activation process and the identity
of the active species.18,32,33 Similar to the analysis of the active species for TH, we were interested in
studying the reaction profile for clues as to the mode of activation of the iron precursor. Similar to what
was observed for TH, the reaction profile for oxidation of 1‐phenylethanol at 45 oC in
benzophenone/THF is sigmoidally shaped, as depicted by the blue curve of Figure 3.16. This ‘S’ shape of
the reaction curve with an induction period, followed by rapid catalytic activity, then equilibration is
indicative of colloid catalysis whereby the iron (II) complex first needs to be reduced and form the active
nanoparticles.32,33 Studying the induction period is a useful way of determining the mode of activation.
Reactions were done where the precatalyst (2) was reacted with KOtBu in either 1‐phenylethanol at 45
oC for 10 minutes prior to THF/benzophenone addition [purple plot] or in THF/benzophenone at 45 oC
for 10 minutes prior to substrate addition [red plot]. In the case of pre‐mixing with THF/benzophenone,
no induction period is observed, as is shown in Figure 3.16 [red]. Subsequently, we tested the effect of
pre‐mixing the iron and KOtBu with 1‐phenylethanol prior to addition of THF/benzophenone. No
induction period is observed, and the reaction initiates much more rapidly as seen in Figure 3.16
[purple]. An alcohol solution containing base is going to be significantly more reducing than a
THF/benzophenone solution containing base, supporting the results that the active species forms much
more rapidly when it is pre‐activated in alcohol than when it is pre‐activated in solvent/acceptor, as
would be expected for zero‐valent nanoparticles. These results also show that the induction period is
83
caused by the reaction of iron with base, and that the substrate alcohol does not form unwanted species
like enolates when pre‐mixed with the active species, as we have observed with other iron catalysts in
our group.35
Figure 3.16: Reaction profiles for the catalytic oxidation of racemic 1‐phenylethanol (2.2 mmol) to acetophenone at 45oC in THF with benzophenone (7.7 mmol), and runs in which the solvent (THF/benzophenone) or substrate (1‐phenylethanol) were added at 45oC 10 minutes prior to reaction commencement.
We were also interested in the effect this order of addition had on the resultant e.e. of the alcohols. The
e.e. versus time plot that corresponds with Figure 3.16 is shown in Figure 3.17, and has several
interesting features. The curve for the standard oxidation run [blue] shows a sigmoidal shape very
similar to the conversion profile, and has a resultant e.e. of 62% at 90 min and 69% after 2 h. The profile
for pre‐activating iron complex (2) and base in THF/benzophenone [red] once again shows no induction
period, with a monatomic increase, but has the identical resultant e.e. This indicates that during the
reaction of iron and base without substrate present, the same asymmetric active species is formed. The
main difference in the two plots is that the active species is either allowed to preform and is therefore
immediately active when substrate is added (red), or to slowly form in the presence of substrate yielding
the induction period (blue). This also provides further support that uptake of substrate is not
responsible for the induction period, but rather the reduction of the iron (II) complex to zero valent
nanoparticles coated in chiral ligand. The last curve in Figure 3.17 [purple] shows the effect of pre‐
mixing the iron complex and base in 1‐phenylethanol before the addition of THF/benzophenone. This
0
0.05
0.1
0.15
0.2
0.25
0 20 40 60 80
[Ace
top
hen
on
e] (
M)
Time (min)
Standard Ox at 45 C
Stir with Solvent at45 C for 10 min first
Stir with PE at 45 Cfor 10 min first
84
once again yields no induction period; however the resultant e.e. is significantly lower, at only 36% after
90 min, and 39% after 2 h. The use of KOtBu in 1‐phenylethanol yields much more reducing conditions,
allowing for a more facile formation of zero‐valent iron species, which would cause the increased
activity in this case. This will also form a racemic mixture of phenyl‐alkoxides, which, if the reaction
proceeds via an inner‐sphere type mechanism, could coat a nanoparticle surface before the
THF/benzophenone is added. This increase in racemic alkoxide binding could result in less order, causing
the decreased e.e. observed. A homogeneous explanation of this behaviour could be given in terms of
an iron species (potentially a dimer or cluster compound) with multiple alkoxide binding sites.
Figure 3.17: Corresponding enantiopurity in (R)‐phenylethanol over time profile to Figure 3.16.
It is commonly reported that the use of sub‐stoichiometric amounts of small phosphines and sulphides
such as PPh3 and CS2 as poisoning agents for catalysis is evidence for nanoparticle catalysis.32,33,36‐39 We
previously studied a large series of potential poisoning agents for Fe(0) NPs and determined that
trimethylphosphine (PMe3) in toluene at only 10% loading relative to pre‐catalyst could stop or
significantly impede TH catalysis.18 OKR experiments were run by initiating catalysis of 1‐phenylethanol
by standard methods, followed by addition of 15% PMe3 relative to complex (2) after a set period of
time. Poisoning was tested for catalysis with both types of acceptor molecules (acetone and
benzophenone) under their optimized reaction conditions as depicted in Figure 3.18. Using (2), NaOiPr,
acetone, 1‐phenylethanol and poisoning with PMe3 at t = 11 min, the profile [purple] when compared to
the non‐poisoned run [green], shows a significant decrease in activity. The profile does not completely
plateau, and therefore the active species is not fully poisoned, but this does show that with only 15%
0
10
20
30
40
50
60
70
80
0 20 40 60 80 100 120
e.e. (%)
Time (min)
Standard Ox at 45 C
Stir with Solvent at45 C for 10 min first
Stir with PE at 45 Cfor 10 min first
85
PMe3 relative to Fe the majority of active sites have become bound and inactive, indicative of
nanoparticle catalysis. Similarly, for the oxidation of 1‐phenylethanol in benzophenone/THF using KOtBu
as the base at 45 oC, 15% PMe3 was added to the reaction mixture at t = 21 min. When comparing the
poisoned profile [red] to the non‐poisoned profile [blue] the same trend of a significant decrease, but
not complete cessation in activity is observed, once again supporting Fe (0) NP catalysis.
Figure 3.18: Standard and poisoned catalytic runs for the oxidation of 1‐phenylethanol in acetone using NaOiPr at 28oC and in benzophenone/THF using KOtBu at 45oC, with C:B:S = 1:8:400.
Following from the effect the poison had on the rate of the reaction, we were interested in the poison’s
effect on the e.e. as we have previously reported that poisons have no effect on the e.e. for TH.18 To
study this effect, we compared the e.e. of the alcohols to the concentration of acetophenone formed
throughout the reaction for both non‐poisoned and poisoned runs. To make an accurate comparison,
the poisoned catalytic systems needed to be run for ≥ 6 h and only achieved an average of 32%
conversion. Plotting the [acetophenone] (M) versus the e.e. (%) for poisoned and non‐poisoned
experiments for both types of solvent/acceptors (acetone and THF/benzophenone) yielded the same
trend. The poisoned and non‐poisoned profiles (for both sets of oxidation experiments) showed the
same slope and shape of curve indicating that the e.e. is not affected by the addition of a poisoning
agent. This is significant as it shows that the poisoning agents simply bind to the active sites, blocking
substrate from binding, and do not alter the structure or functionality of the active site in the process.
This type of behaviour would also be expected for nanoparticle catalysis.
0
0.05
0.1
0.15
0.2
0.25
0 20 40 60 80
[Ace
top
hen
on
e] (
M)
Time (min)
Standard Ox, 28 C,Acetone/NaOiPr
Standard Ox, 45 C,THF/Benz.
Ox, 28 C,Acetone/NaOiPr, +15%PMe3 at t=11 min
Ox, 45 C, THF/Benz.+15% PMe3 at t=21 min
86
Our last series of experiments to probe the potential heterogeneity of the active species involved
tethering our standard substrate, 1‐phenylethanol, to the interior of a porous polymer resin and
investigating the catalytic behaviour. The goal of this experiment was to use the porous polymer as a
type of ‘size‐exclusion sieve’ to gauge the overall size of the active catalytic species. The experiment
involved using organic reactions to tether a substrate that the active species can oxidize within a
polymer, then compare catalysis using (2) with another small, well‐known reagent (pyridinium
chlorochromate‐PCC) on the polymer, and analyse whether the substrate was oxidized. Small reagents
such as PCC should be able to fit within the pores of the polymer and oxidize the 1‐phenylethanol to
acetophenone, whereas nanoparticles would be too large to fit within the pores, resulting in no
conversion to ketone. This concept has been used in the past by our lab18 and by other research
groups.40 To analyse the polymers and to determine their functionality, the polymer beads were swollen
using deuterated dichloromethane and proton‐decoupled carbon NMR spectroscopy was run on an
Agilent DD2 600MHz spectrometer using a 3.2 mm narrow bore HXY solid state probe. The polymers
needed to be swollen prior to running NMR experiments in order to get adequate signal strength and
resolution of peaks.41 The desired functionality was installed using the commercially available Wang
resin with a 1.0‐1.5 mmol –OH/g polymer of benzyl alcohol functionality. This was converted to a
benzaldehyde functionality (Wang‐B) using pyridinium chlorochromate in dichloromethane, which could
then be converted into the desired 1‐phenylethanol functionality (Wang‐PE) using an excess of
methylmagnesium chloride in tetrahydrofuran, as depicted in Scheme 3.11.
87
Scheme 3.11: Polymer‐bound substrate experimental overview and peaks of interest from 13C {1H} solid state NMR spectra.
To probe whether known reagents could penetrate the pores of the polymer, Wang‐PE was treated with
PCC in dichloromethane for 16 h. NMR spectra showed the appearance of a ketone carbonyl carbon
resonance at 196.2 ppm and the corresponding –CH3 resonance at 26.2 ppm as the major species, and
Wang‐PE’s C‐OH and –CH3 peaks as the minor species, indicating that an acetophenone functionalized
polymer had formed, proving that small metal complexes can permeate the polymer. The highest TOF
we achieved using (2) for the oxidation of 1‐phenylethanol involved using acetone and NaOiPr at 28 oC,
and hence were the conditions we used for Wang‐PE. The reaction was done at a much higher catalyst
loading (1:35 catalyst to C‐OH, versus 1:400 as typically employed), for 24 h instead of 2 h, and in the
presence of THF to maximize pore swelling and potential reactivity.18,42 NMR spectra showed no change
in 13C signals from the original Wang‐PE and no appearance of ketone signals as had been seen for
oxidation with PCC, indicating that oxidation did not occur using (2). This implies that the active species
during oxidative kinetic resolution is too large to permeate the pores of the polymer, further suggesting
that the active species during catalysis are zero‐valent nanoparticles. Similar to the TH case, it is never
possible to conclusively prove that nanoparticles are the active species in catalysis. However we present
substantial evidence that supports that Fe(0) NPs are the active species in the oxidative kinetic
resolution of aromatic alcohols using (2) as the pre‐catalyst.
88
3.4 Conclusions
Using our trans‐[Fe(NCMe)CO(PPh2C6H4CH=NCHPh‐)2 ][BF4]2 precatalyst, we studied the reversibility of
asymmetric TH in terms of oxidative kinetic resolution of racemic aromatic alcohols. Initially studying 1‐
phenylethanol as our substrate, we probed different bases, sacrificial proton/hydride acceptors and
temperatures and were able to achieve high TOF (> 200 h‐1) using acetone and NaOiPr as well as
reasonable e.e. and s‐values (59% and 6.0, respectively) at 50% conversion to acetophenone using
THF/benzophenone and KOtBu at 45oC (TOF = 171). Using these optimized conditions we tested a wide
range of sterically and electronically varied substrates. By increasing the steric bulk at the alcohol, the
rates of oxidation decreased dramatically, however the e.e. and s‐value increased significantly. Varying
the electronics of the substrate did not give such a linear relationship; by adding electron donating
groups into the para position, the rate increased significantly, and by adding electron withdrawing
chloro groups at either the meta or para positions, the rate and selectivity decreased slightly. We
analysed the reaction mixtures by STEM and were able to image small 4‐5 nm nanoparticles, proving
that they are formed during catalysis. To test whether nanoparticles are the active species, we were
able to demonstrate that the reaction profile is sigmoidal in shape and that the induction period is
caused by the reaction of iron with base, not the uptake of substrate. This supports the claim that the
iron precursor must first be reduced to Fe(0) to form nanoparticles, which presumably are coated with
chiral P‐N‐N‐P ligand, as we hypothesized for the reverse TH active species.18 We also explored PMe3 as
a sub‐stoichiometric poisoning agent. At 15% loading of poison relative to iron, we were able to show
that the catalysis is significantly diminished, further supporting that nanoparticles coated in chiral ligand
are the active species for catalysis. Lastly, we probed the size of the active species using polymer‐
supported substrate experiments to show that the active species is too large to fit within the pores of a
polymer resin. To the best of our knowledge, this is the first example of oxidative kinetic resolution
occurring on the surface of a nanoparticle. It is also an interesting example of a reversible asymmetric
reaction being shown to operate in both the forward and reverse direction on the surface of a
nanoparticle.
89
3.5 Experimental
3.5.1 General Procedures
All preparations, manipulations and catalysis were carried out under argon or nitrogen atmosphere
using standard Schlenk line and drybox techniques. Dry and oxygen‐free solvents and substrates were
distilled and dried using the appropriate drying agents. NMR solvents were purchased from Aldrich and
degassed and dried over activated molecular sieves. All other reagents were purchased from various
commercial sources and used without further purification. NMR spectra were recorded using a Bruker
400 and Varian 300 and 400 spectrometers to determine 1H (400 and 300 MHz) and 31P {1H} (121 MHz)
shifts. 1H shifts are referenced to deuterated solvents, and 31P peaks are externally referenced to 85%
phosphoric acid. Solid state MAS NMR setup parameters are outlined in the ‘Polymer‐Supported
Substrate Experiments’ section.
3.5.2 Gas Chromatography
Gas Chromatography was done on a Perkin Elmer Clarus 400 Chromatograph equipped with a chiral
column (CP chirasil‐Dex CB 25 m x 2.5 mm) and auto‐sampling capabilities. Hydrogen gas was used as
the mobile phase, and the oven temperature was varied dependent on the substrate, as shown in Table
3.5.
90
Table 3.5: GC temperatures and retention times for substrates tested
3.5.3 Synthesis
Precatalyst (R,R)‐[Fe(CO)(NCMe)(P2N2dpen)][BF4]2 (2) has been prepared and characterised previously.14
3.5.4 Microscopy
Electron microscopy images were carried out at the ‘Centre for Nanostructure Imaging’ (University of
Toronto) in collaboration with Dr. Neil Coombs, on a Hitachi HD‐2000 STEM operating at ‐1000C. Low
temperatures were required to minimize contamination and specimen damage by the electron beam.
91
Samples were placed on an ultrathin carbon film supported by a lacey carbon film on a 400 mesh copper
grid. Energy‐Dispersive X‐Ray Spectroscopy (EDX) was run concurrently using INCA software and the
STEM. Sample preparation: to a vial containing pre‐catalyst (6 mg, 0.006 mmol) and base, solvent and
substrate were added at the desired temperature, in an argon filled glovebox. The substrate used was
iPrOH (0.1 mL, 1.3 mmol) as it has a low boiling point and could be easily evaporated off the grids under
vacuum before analysis. For reactions employing benzophenone as the sacrificial oxidant,
benzophenone (1.4 g, 7.7 mmol) was dissolved in THF (4.7 mL, 58 mmol) and KOtBu (5 mg, 0.045 mmol)
was used as the base. Alternatively, acetone (6 mL, 82 mmol) was used as the solvent with NaOiPr (4
mg, 0.049 mmol) as the base.
3.5.5 Solid State NMR
Solid State NMR experiments were conducted at the ‘Centre for Spectroscopic Investigation of Complex
Organic Molecules and Polymers’ (University of Toronto) in collaboration with Dmitry Pichugin. Carbon
spectra were acquired on Agilent DD2 600‐MHz spectrometer with an Agilent 3.2‐mm narrow bore HXY
solids probe. The probe was used in double‐resonance mode; proton and carbon. Spectra were acquired
using magic angle spinning (MAS) at 10‐12 kHz spinning using 'onepul' pulse sequence with calibrated 90
degree pulse, 2 second recycle delay, 50.8 ms acquisition time (2048 points), and spin decoupling.
Experiment time was 4 hours with 7000 scans. 3.2 mm rotors were packed under air with 26.7 mg of
pre‐swollen polymer beads (swollen using CD2Cl2), and pre‐spun at 10kHz outside of the probe for 20
minutes prior to spinning in the NMR probe. Figure 3.19 and Figure 3.20 depict the applicability of this
technique to detecting the lack of and presence of the carbonyl carbon, respectively.
92
Figure 3.19: 13C {1H} solid state NMR spectrum of phenylethanol‐bound Wang Resin (Wang‐PE) swollen in CD2Cl2, spun at 10 kHz.
Figure 3.20: 13C {1H} solid state NMR spectrum of acetophenone‐bound Wang Resin (Wang‐B) swollen in CD2Cl2, spun at 10 kHz.
93
3.5.6 Catalysis – Standard Run
To a vial containing pre‐catalyst (6 mg, 0.006 mmol) and KOtBu (5 mg, 0.045mmol), solvent and
substrate were added at the desired temperature, in an argon filled glovebox. For reactions employing
benzophenone as the sacrificial oxidant, benzophenone (1.4 g, 7.7 mmol) was dissolved in THF (4.7 mL,
58 mmol). Alternatively, acetone (6 mL, 82 mmol) was used as the solvent. Immediately upon addition
of solvent and substrate to the vial, a dark brown solution was formed. Solutions were stirred
vigorously, and samples were taken from the mixture, quenched by exposure to air and analysed by gas
chromatography. When the samples are exposed to air the solution turns yellow and the reaction stops
immediately. The alcohol/ketone concentration does not change in these solutions, even after several
days. All of the catalytic results were reproduced to ensure consistency.
3.5.7 Catalysis – Poisoned Run
Solutions were prepared, initiated and monitored as outlined above. PMe3 in toluene (0.85 μmol in 0.15
mL / 1.4 mmol toluene) was added to the reaction when conversion to ketone was ~10% (varies
dependent on substrate and conditions employed). This is similar to techniques employed for transfer
hydrogenation previously reported.18
3.6.8 Polymer‐bound Substrate Experiments
Synthesis of Polymer‐supported Aldehyde (Wang‐Benzaldehyde, Wang‐B): StratoSpheres™ PL‐Wang resin
(1.0‐1.5 mmol –OH/g, 50‐100 mesh, 1% crosslinked with divinylbenzene) (1.3 g, 1.95 mmol –OH), was
stirred with Pyridinium chlorochromate (PCC) (420 mg, 1.95 mmol) in 20 mL dichloromethane for 6
hours at room temperature in a nitrogen filled glovebox. The resin was then filtered under air, washed
extensively with dichloromethane and isopropanol, and dried overnight under reduced pressure.
Synthesis of Polymer‐supported Alcohol (Wang‐Phenylethanol, Wang‐PE) Wang‐B (600 mg, 0.90 mmol‐
aldehyde) was swelled in 10 mL of dry tetrahydrofuran (THF) for 2 hours at room temperature under
argon. A 3.0 M stock solution of methylmagnesiumchloride (MeMgCl) in ether (0.48 mL, 1.44 mmol) was
added slowly at 0 oC under a constant flow of argon. The mixture was stirred at room temperature
under argon for 20 hours, and then 2 mL of distilled water and 2 mL of isopropanol were added and
stirred for another 30 minutes under air. The resin was then filtered under air, washed extensively with
THF, water and isopropanol, and dried overnight under reduced pressure.
94
Catalysis on Resin with (2): To a vial containing pre‐catalyst (2) (12 mg, 0.011 mmol), NaOiPr (8 mg,
0.097 mmol), and Wang‐PE (~260 mg, ~ 0.39 mmol‐OH), acetone (4 mL, 54 mmol) and tetrahydrofuran
(2 mL, 25 mmol) were added at room temperature, in an argon filled glovebox. The solution was stirred
for 24 hours, and then the resin was filtered under air, washed with isopropanol, THF and
dichloromethane, and dried overnight under reduced pressure.
Catalysis on Resin with PCC: To a vial containing PCC (70 mg, 0.32 mmol) and Wang‐PE (~220 mg, ~ 0.33
mmol‐OH), dichloromethane (6 mL, 94 mmol) was added at room temperature, in an argon filled
glovebox. The solution was stirred for 16 hours, and then the resin was filtered under air, washed with
isopropanol and dichloromethane, and dried overnight under reduced pressure.
95
3.6 References
(1) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal.
2003, 345, 103.
(2) Naud, F.; Spindler, F.; Rueggeberg, C. J.; Schmidt, A. T.; Blaser, H. U. Org. Process Res.
Dev. 2007, 11, 519.
(3) Pugin, B.; Blaser, H. U. Top. Catal. 2010, 53, 953.
(4) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393.
(5) Samec, J. S. M.; Bäckvall, J. E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35,
237.
(6) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40.
(7) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.
(8) Vedejs, E.; Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974.
(9) Pellissier, H. Adv. Syn. & Catal. 2011, 353, 1613.
(10) Hashiguchi, S.; Fujii, A.; Haack, K.‐J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem.
Int. Ed. 1997, 36, 288.
(11) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282.
(12) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217.
(13) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317.
(14) Meyer, N.; Lough, A. J.; Morris, R. H. Chem. Eur. J. 2009, 15, 5605.
(15) Mikhailine, A.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2009, 131, 1394.
(16) Lagaditis, P. O.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2011, 133, 9662.
(17) Sues, P. E.; Lough, A. J.; Morris, R. H. Organometallics 2011, 30, 4418.
(18) Sonnenberg, J. F.; Coombs, N.; Dube, P. A.; Morris, R. H. J. Am. Chem. Soc. 2012, 134,
5893.
(19) Lagaditis, P. O.; Lough, A. J.; Morris, R. H. Inorg. Chem. 2010, 49, 10057.
(20) Gao, J.‐X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087.
(21) Koike, T.; Murata, K.; Ikariya, T. Org. Lett. 2000, 2, 3833.
(22) Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa, M.; Ikariya, T. Tetrahedron Lett. 2003, 44,
7521.
(23) Csjernyik, G.; Bogár, K.; Bäckvall, J.‐E. Tetrahedron Lett. 2004, 45, 6799.
(24) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem. Int. Ed. 2008, 47, 2447.
96
(25) Wills, M. Angew. Chem. Int. Ed. 2008, 47, 4264.
(26) Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem. Int. Ed. 2004, 43, 353.
(27) Kumar Alamsetti, S.; Muthupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15, 5424.
(28) Alamsetti, S. K.; Mannam, S.; Mutupandi, P.; Sekar, G. Chem. Eur. J. 2009, 15, 1086.
(29) Muthupandi, P.; Alamsetti, S. K.; Sekar, G. Chem. Commun. 2009, 3288.
(30) Kunisu, T.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2011, 133, 12937.
(31) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am.
Chem. Soc. 1981, 103, 6237.
(32) Crabtree, R. H. Chem. Rev. 2012, 112, 1536.
(33) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198, 317.
(34) Phua, P. H.; Lefort, L.; Boogers, J. A. F.; Tristany, M.; de Vries, J. G. Chem. Comm. 2009,
3747.
(35) Mikhailine, A. A.; Maishan, M. I.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2012, 134,
12266.
(36) Rangheard, C.; de Julian Fernandez, C.; Phua, P. H.; Hoorn, J.; Lefort, L.; de Vries, J. G.
Dalton Trans. 2010, 39, 8464.
(37) Clark, T. J.; Jaska, C. A.; Turak, A.; Lough, A. J.; Lu, Z. H.; Manners, I. Inorg. Chem. 2007,
46, 7394.
(38) Jaska, C. A.; Temple, K.; Lough, A. J.; Manners, I. J. Am. Chem. Soc. 2003, 125, 9424.
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97
Chapter 4: Evidence for Iron
Nanoparticles Catalysing the Rapid
Dehydrogenation of Ammonia‐Borane
Adapted from Sonnenberg, J.F., Morris, R.H. ACS Catal. 2013, 3, 1092‐1102.
4.1 Abstract
A series of precatalysts of the general formula [Fe(NCMe)(L)(PPh2C6H4CH=NCHR‐)2][BF4]2 (where L = CO
or NCMe, and R = Ph or H) were tested for the dehydrogenation of amine‐boranes. They have already
been used in our lab for the transfer hydrogenation (TH) or direct hydrogenation of ketones and the
oxidative kinetic resolution of alcohols. We compared a series of sterically‐ (R = H or Ph) and
electronically‐ (L = NCMe or CO) varied precatalysts in both protic and aprotic solvents for the release of
hydrogen from ammonia‐borane (AB) and studied the products by NMR spectroscopy. At room
temperature in THF we optimized our systems, and achieved maximum turn‐over frequencies (TOF) of
up to 3.66 H2/s and 1.8 total H2 equivalents, and in isopropanol we were able to release a maximum of
2.9 equivalents H2 and reuse some of our catalytic systems. In previous mechanistic studies we provided
strong evidence that the active species during TH and oxidation catalysis are zero‐valent iron
nanoparticles formed by the reduction of the Fe‐(P‐N‐N‐P) precatalysts with base. To probe the
dehydrogenation active species we successfully show comparable activity between preformed catalysts,
and those generated in situ using commercially available Fe2+ sources and sub‐stoichiometric amounts
of P‐N‐N‐P ligand. This result, when paired with transmission electron microscope (TEM) images of ~4
nm iron nanoparticles of reaction solutions provide evidence that the highly active systems studied are
heterogeneous in nature. This would be the first report of iron nanoparticles catalysing H2 evolution
from AB in non‐protic solvents. We also report the evolution of hydrogen from dimethylamine‐borane
and the resultant product mixtures using the same catalyst series.
98
4.2 Introduction
The transition from high carbon content liquid‐ and solid‐based fuels into gas‐based fuels for energy
applications is of growing economic importance.1 Emerging as the ideal candidate, as a clean,
lightweight and high energy density fuel, is hydrogen gas.2 Among the major challenges in the use of
hydrogen is its storage and production in an efficient and ‘green’ way.3 A potential candidate to solve
this problem is ammonia borane, NH3∙BH3 (AB), which has a total hydrogen content of 19.6 wt %, or 6.5
and 13.1 wt % for the first and second equivalent of hydrogen released.4,5 When analysing catalysts for
such a transformation it is important to study not only the number of equivalents of H2 released, but
also the reaction conditions and type of B/N containing products formed.4,6,7 There are a significant
number of catalytic systems in the literature employing water and protic solvents for the
dehydrogenation/hydrolysis of AB,4 and although larger numbers of equivalents of H2 are evolved, the
formation of strong B‐O bonds precludes their use in industry as the wastes are not recyclable.8 It is
therefore important to generate catalysts that operate in non‐protic solvents such as THF, aromatic
solvents or glyme, as the typical products contain B‐N bonds which can be used to regenerate AB.8
There are several homogeneous systems in the literature based on precious metal catalysts,9‐18 as well
as more abundant metals such as titanium,19 nickel20,21 and iron,7,22,23 and group 6 metal carbonyls24 that
have been used as dehydrogenation catalysts. Heterogeneous catalysts have also been studied,
primarily using precious metal catalysts,25‐29 although there are reports using nickel heterogeneous
catalysts30 for the dehydrogenation of amine‐boranes, including ammonia‐borane. In the field of iron
catalysts for this transformation a few key discoveries stand out as stepping stones. First was the work
by Xu et. al.31 who reduced Fe(SO4) to generate stable, 3 nm, zero‐valent iron nanoparticles (Fe NPs) that
were able to evolve three equivalents of hydrogen from ammonia‐borane in water at room
temperature. Their catalyst was stable under air and magnetically recyclable, however it was only used
for hydrolysis of AB to generate borates, not B‐N polymers or oligomers. The next key example was the
use of [{CpFe(CO)2}2] under photoirradiation to dehydrogenate amine‐boranes by Manners et. al.22,23
wherein they also determined the identity of several of the products and intermediates during the
reaction. Baker et. al.7 used iron systems with phosphine and amido ligands to evolve 1‐2 equivalents of
H2 and generate (BH2NH2)n and (BHNH)n oligomers. Their active systems are hypothesized to be based
on zero‐valent iron systems stabilized by ligands. There is therefore a vacancy in the literature in terms
99
of using defined heterogeneous iron catalyst for the dehydrogenation of amine‐boranes to yield B‐N
polymers and oligomers.
Figure 4.21: Precatalyst structures for systems investigated for ammonia‐borane dehydrogenation reactions including ligands
tested.
Our group has reported the synthesis of iron complexes of the general formula [Fe(NCMe)(L)(P‐N‐N‐
P)][BF4]2 where L = NCMe or CO and P‐N‐N‐P = (PPh2C6H4CH=NCHR‐)2, as depicted in Figure 4.21, which
have been shown to be highly active for direct H2‐hydrogenation of ketones32 (L = NCMe) and for the TH
of ketones using isopropanol (iPrOH) as the hydrogen source33 (L = CO). Upon further investigation of
the catalyst during TH we proposed that the active catalytic species are zero‐valent Fe NPs. This
proposition was based on DFT support for a low energy pathway for the formation of iron(0)34 as well as
extensive poisoning, imaging and in operando experiments.35 The Fe NPs are proposed to be a zero‐
valent iron core, coated in P‐N‐N‐P ligand, able to bind substrate to active sites and transfer a proton
and hydride equivalent. These nanoparticle catalysts were further probed and shown to be active for
the reverse process; oxidative kinetic resolution of aromatic alcohols to enantio‐enriched alcohols and
ketones, and their heterogeneity was similarly probed.36 These precatalysts with the general formula
[Fe(NCMe)(L)(P‐N‐N‐P)][BF4]2 have therefore proven themselves to be quite versatile in terms of their
chemistry with hydrogen, and we were therefore interested in probing their ability to act as hydrogen
evolving catalysts in the dehydrogenation of ammonia‐borane, as depicted in Scheme 4.12 for our
optimized reaction conditions. The use of alcohol oxidation/reduction catalysts for amine‐borane
dehydrogenation has been previously reported using Ru(PN)2 catalysts11 and were found to be quite
active in terms of rate H2 release.
100
Scheme 4.12: Generalized reaction scheme and product distribution for optimized catalytic system.
4.3 Experimental
4.3.1 General Procedures
All preparations, manipulations and catalysis were carried out under argon or nitrogen atmosphere
using standard Schlenk line and drybox techniques. Dry and oxygen‐free solvents were distilled and
dried using the appropriate drying agents. NMR solvents were purchased from Aldrich and degassed and
dried over activated molecular sieves. All other reagents were purchased from various commercial
sources and used without further purification. NMR spectra were recorded using a Bruker 400 and a
Varian 400 spectrometer to determine 1H (400 MHz), 11B (128 MHz) and 31P {1H} (161 MHz) shifts.
Electron microscopy imaging was carried out at the Department of Pathology & Laboratory Medicine in
the Joseph & Wolf Lebovic Health Complex at Mount Sinai Hospital in collaboration with Dr. Doug
Holmyard on a Tecnai‐20 using a GIF2000 energy filter. Samples were placed on an ultrathin carbon film
supported by a lacey carbon film on a 400 mesh copper grid.
4.3.2 Syntheses
Precatalysts [Fe(CO)(NCMe)(P2N2en)][BF4]2 (1), [Fe(CO)(NCMe)(P2N2dpen)][BF4]2 (R,R‐2),
[Fe(NCMe)2(P2N2en)][BF4]2 (5), and [Fe(NCMe)2(P2N2dpen)][BF4]2 (R,R‐6) and ligands {(PPh2(o‐
C6H4)CH=NHCH2‐)2}: (P2N2en) (8) and (R,R)‐{(PPh2(o‐C6H4)CH=NH(C6H10)NH=CH(o‐C6H4)PPh2)}: (P2N2cy)
(R,R‐9) have been prepared and characterised previously.32,33,37,38 Precatalyst (S,S)‐
[Fe(CO)(Br)(PPh2CH2CH=NHCHPh‐)2][BPh4] (S,S‐7) has been prepared and characterized previously.39
4.3.3 Catalysis
In an argon filled glovebox, precatalyst and ammonia‐borane (AB) were added to a 25 mL two‐neck
round‐bottom flask which was sealed with a rubber septum and a 10 mL dry‐addition flask containing
KOtBu. The sealed system was removed from the glovebox and submerged in a bath at a set, regulated
101
temperature before solvent was added to the flask and stirred for 10 minutes. A cannula needle was
used to pierce the septum and an upturned 50 mL burette filled with water was used to measure the
evolution of gas. To start the reaction, the dry‐addition flask was tilted, and base was added to the
reaction, which was stirred vigorously. Hydrogen production was measured in terms of volume
displacement of water in the burette as a measure of time. All catalytic results were reproduced in
triplicate to ensure consistency.
Table 4.6: Reaction conditions for all catalytic hydrogen evolution reactions using iron catalysts.
Entr
y Catalyst
(mg, mmol) Other
(mg, mmol) H2 Source
(mg, mmol) KOtBu
(mg, mmol)
C:B:Sb Solvent
(mL, mmol)
T
(oC)
Equiv. H2
1 min/1 h
1 (5) (7, 0.0076) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 iPrOH (5, 65) 22 0.93/2.50
2 (1) (7, 0.0077) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 iPrOH (5, 65) 22 0.15/2.58
3 (R,R‐6)
(9, 0.0084)
N/A AB (10, 0.32) (8, 0.071)a 1:8:38 iPrOH (5, 65) 22 0.59/2.89
4 (R,R‐2)
(9, 0.0085)
N/A AB (10, 0.32) (8, 0.071)a 1:8:38 iPrOH (5, 65) 22 0.20/2.90
5 [Fe(H2O)6][BF4]2
(5, 0.015)
(8)
(5, 0.0083)
AB (10, 0.32) (10, 0.089)a 1:6:21 iPrOH (5, 65) 22 0.17/1.02
6 (5) (7, 0.0076) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 THF (5, 62) 22 1.13/1.60
7 (5) (7, 0.0076) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 THF (5, 62) 2 0.95/1.40
8 (5) (7, 0.0076) CO
headspace
AB (10, 0.32) (8, 0.071)a 1:9:42 THF (5, 62) 22 0.05/0.09
9 (5) (5, 0.0055) N/A AB (20, 0.64) (6, 0.053)a 1:9:42 THF (5, 62) 22 1.0/1.22
10 (1) (7, 0.0077) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 THF (5, 62) 22 0.48/1.26
11 (R,R‐6)
(9, 0.0084)
N/A AB (10, 0.32) (8, 0.071)a 1:8:38 THF (5, 62) 22 1.14/1.71
12 (R,R‐2)
(9, 0.0085)
N/A AB (10, 0.32) (8, 0.071)a 1:8:38 THF (5, 62) 22 0.80/1.44
13 [Fe(H2O)6][BF4]2
(5, 0.015)
(8)
(5, 0.0083)
AB (10, 0.32) (10, 0.089)a 1:6:21 THF (5, 62) 22 0.62/1.61
14 [Fe(H2O)6][BF4]2
(5, 0.015)
(R,R‐9)
(5, 0.0083)
AB (10, 0.32) (10, 0.089)a 1:6:21 THF (5, 62) 22 1.08/1.43
15 (S,S‐7)
(9, 0.0081)
N/A AB (10, 0.32) (8, 0.071)a 1:9:40 THF (5, 62) 22 0.28/0.71
102
16 FeBr2
(2.75, 0.013)
N/A
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 22 0.24/0.67
17 FeBr2
(2.75, 0.013)
(8)
(5, 0.0083)
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 22 1.01/1.59
18 FeBr2
(2.75, 0.013)
(8)
(10, 0.016)
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 22 1.03/1.53
19 FeBr2
(2.75, 0.013)
(8)
(2.5, 0.004)
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 22 1.06/1.50
20 FeBr2
(2.75, 0.013)
(8)
(1, 0.002)
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 22 1.11/1.58
21 FeBr2
(2.75, 0.013)
(8)
(5, 0.0083)
AB (10, 0.32) (10, 0.089)a 1:7:25 THF (5, 62) 2 0.87/1.24
22 (5) (7, 0.0076) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 Diglyme
(5, 35)
22 1.06/1.44
23 (1) (7, 0.0077) N/A AB (10, 0.32) (8, 0.071)a 1:9:42 Diglyme
(5, 35)
22 0.43/1.11
24 (5) (7, 0.0076) N/A Me2AB (20,
0.34)
(8, 0.071)a 1:9:45 THF (5, 62) 22 0.63/0.98
25 (1) (7, 0.0077) N/A Me2AB (20,
0.34)
(8, 0.071)a 1:9:45 THF (5, 62) 22 0.44/0.96
26 (5) (7, 0.0076) N/A AB (10, 0.32) (16, 0.14)a 1:18:42 THF (5, 62) 22 1.33/1.83
27 (5) (7, 0.0077) N/A AB (10, 0.32) (4, 0.035)a 1:5:42 THF (5, 62) 22 1.00/1.25
28 (5) (7, 0.0077) N/A AB (10, 0.32) (37, 0.33)a 1:43:42 THF (5, 62) 22 1.17/1.66
29 (5) (7, 0.0077) N/A AB (10, 0.32) 0c 1:10c:4
2
THF (5, 62) 22 0.99/1.22
30 FeBr2
(1.75, 0.008)
(8)
(3.0, 0.005)
AB (10, 0.32) (8, 0.071)a 1:9:40 THF (5, 62) 22 0.98/1.43
31 FeBr2
(1.75, 0.008)
(8)
(3.0, 0.005)
AB (10, 0.32) (8, 0.071)a 1:9:40 Diglyme
(5, 35)
22 1.11/1.39
32 (5) (7, 0.0077) N/A AB (5, 0.16) (6, 0.053) 1:7:21 THF (5, 62) 28d N/A
33 FeBr2
(2.75, 0.013)
(8)
(2.5, 0.04)
AB (7, 0.22) (7, 0.062) 1:5:17 THF (5, 62) 28d N/A
aWhen the dry‐addition flask is tilted and base added, ~1 mg of KOtBu remains trapped in the flask,
hence why an excess was always added. bC:B:S = molar ratio of catalyst:base:substrate/H2 source. cUsed NaOiPr (6 mg, 0.073 mmol). dReactions done in a vial in an argon glovebox ‐ solutions used for TEM imaging.
103
4.4 Results and Discussion
4.4.1 AB Dehydrogenation with Precatalysts (1, 2, 5 and 6) in Protic Solvents
Following Xu et.al.’s work31 on the hydrolysis of AB using 3 nm Fe NPs, we were interested in applying
our Fe NP TH precatalysts (1) and (2) to the dehydrogenation of AB. The optimized method for the
formation of Fe NPs for our previously reported TH catalysis was the reaction of an excess of KOtBu in
iPrOH with precatalyst (1) or (2) before the addition of substrate. Therefore, for the dehydrogenation of
AB we first tested our precatalysts in protic solvents using a slightly modified technique as outlined in
the experimental section. Using 2.5 mol% precatalyst at 22oC (1, 2, 5 and 6) were tested as outlined in
entries 1‐4 of Table 4.6, yielding the results shown in Figure 4.22. Several observations can be made
from the plot; all four precatalysts are active and yield >2.5 equivalents of H2 in an hour. For TH, a 6‐8
minute induction period was observed for the formation of the Fe NPs, whereas none of the reaction
profiles in Figure 4.22 show this. An induction period is often indicative of heterogeneous catalysis,40,41
however, Xu et. al. also reported no induction period for their in situ generated system. Also of note, the
bis‐MeCN complexes (5) and (6) show a more rapid initial rate and a more rapid deactivation (plots level
off at a lower number of equivalents of H2) than the corresponding MeCN‐trans‐CO complexes (1) and
(2). The reason for this difference is unclear but it would suggest that the catalysts derived from the bis‐
MeCN precatalysts have more active sites available due to the increased lability of MeCN versus CO. This
increased lability would result in more rapid initial rates, and more ready deactivation. (2) and (6) are
slightly more active than (1) and (5) indicating that the bulkier phenyl groups in the P‐N‐N‐P ligand are
better stabilizers of the active species than the achiral complex with protons in the P‐N‐N‐P backbone of
the ligand. 11B NMR spectra of active solutions show a singlet at 18.2 ppm, corresponding to B(OiPr)3 as
would be expected for reactions in iPrOH.
104
Figure 4.22: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL iPrOH at 22oC using 2.5 mol% Fe and 20 mol%
KOtBu. Fe:AB:KOtBu = 1:40:8.
To test the reuse of our catalytic systems we added another 40 equivalents of AB to the reaction
mixtures after 30 min. Upon addition, (1), (5), and (6) released ~1 equivalent H2 within 2 hours,
indicating that the catalyst was significantly deactivated. Interestingly, addition of a second batch of AB
to catalysis with (2) resulted in 2.4 equivalents of H2 released in 40 minutes before deactivation
occurred, and further recycling by addition of more AB was unsuccessful. This would suggest that the
active species derived from (2) is slightly better stabilized than the species derived from (1), (5), and (6)
but that all species are not good candidates for multiple recycles, unlike the species studied by Xu et.
al.31
We also explored the use of water and methanol as potential solvents. Only minimal activity was
observed using (1) and (2) with MeOH as the solvent, and no activity was observed using (1, 2, 5 and 6)
with water as the solvent. There is no hydrogen evolution if any component (Fe, base, AB) is missing.
4.4.2 AB Dehydrogenation with Precatalysts (1, 2, 5‐7) in Non‐Protic Solvents
We were interested in using our catalysts to generate B‐N polymers and oligomers from AB using non‐
protic solvents such as THF and glyme. Using the same catalytic conditions as outlined with iPrOH, we
tested THF as a solvent with (1, 2, 5 and 6) as outlined by entries 6, 10‐12 of Table 4.6, and the results
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
Precatalyst 2
Precatalyst 6
Precatalyst 1
Precatalyst 5
105
are shown in Figure 4.23. All four systems are highly active, releasing half an equivalent of H2 within
seconds and a full equivalent in under a minute in the case of (5) and (6) and in less than 20 minutes for
(1) and (2). Similar to the case in iPrOH, the bis‐MeCN catalysts are faster at H2 evolution than their
MeCN‐trans‐CO counterparts. MeCN may be a more labile ligand than CO on Fe NPs, yielding a less
stable species. This might yield a larger number of active sites in either a homogeneous or
heterogeneous catalyst, and thus increase catalytic activity. This was not the case for TH as the one
carbonyl ligand was necessary to promote catalytic activity.33 (2) and (6) are slightly more active than (1)
and (5) respectively, again suggesting the added stabilization of the catalysts containing the bulkier
diphenyl backbone in the P‐N‐N‐P ligand versus the achiral P‐N‐N‐P which contains only protons in the
backbone. All of the catalytic systems also show a similar reaction profile, whereby there is very rapid
catalytic activity in the first 3 minutes, followed by a significant decrease in rate resulting in very slow H2
evolution for the proceeding hour. This reaction profile for dehydrogenation of amine‐boranes is fairly
common, as has been seen for both heterogeneous NP catalysis26 as well as homogeneous catalysis,
specifically the Ru(PN)2 alcohol oxidation/reduction catalysts tested by Blaquiere et.al.11 There are two
possible explanations for this rapid decrease in activity; first, that all of the AB has been consumed and
converted into the most stable product. This is not the case because AB is still present according to 11B
NMR spectroscopy (vide infra) and because addition of more AB yields no further H2 evolution. This
therefore indicates that the cause for the rate decrease is deactivation of the catalyst. Baker et. al.
observed that, upon catalyst deactivation with their system, a black residue of bulk iron was formed;7
however this is not observed with our systems. They also observed protonation of their amide ligands
and formation of P‐B adducts with their phosphine ligands, which we did not observe in the 11B NMR
spectrum. Instead the primary species observed with 31P {1H} NMR spectrum is de‐coordinated P‐N‐N‐P
ligand at ‐16 ppm. A similar spectrum was observed with the activated solution in TH34 when some of
the P‐N‐N‐P ligand de‐coordinated to allow for formation of Fe NPs. The release of P‐N‐N‐P ligand and
the observation that no bulk iron is released supports that Fe NPs are forming during catalysis and that
deactivation involves blocking of active sites on the NP surface, potentially by reactive B‐N compounds.
Further discussion of deactivation modes on iron will be discussed vide infra. Also depicted in Figure
4.23 is the reaction profile using precatalyst (S,S)‐[Fe(CO)(Br)(PPh2CH2CH=NHCHPh‐)2][BPh4] (7) (entry 15
of Table 4.6). This precatalyst is a highly active TH system also developed in our group39,42 that was
recently studied mechanistically43 and determined to likely operate via a homogeneous mechanism, as
there are no low energy pathways leading to Fe(0).44 This system is much less active than systems (1, 2,
106
5 and 6), supporting that the systems operate via different mechanisms for the dehydrogenation of AB,
also suggesting that precatalysts (1, 2, 5 and 6) may generate Fe NPs during catalysis.
Figure 4.23: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 2.5 mol% Fe and 20 mol% KOtBu.
11B {1H} NMR spectrum of the activated solutions using (5) contained peaks for some unreacted AB and
four major species at 20.3, 24.3, 27.8 and 30.9 ppm. Upon coupling to protons, the peaks at 27.8 and
30.9 split into doublets with coupling constants of 137 Hz and 132 Hz respectively, indicating two
different B‐H groups and two different unprotonated boron sites are present. The peak at 30.9 ppm is
assigned to be borazine,9 and the remaining coupled and uncoupled boron species are tentatively
assigned as polyborazylene (PB) and short chain B‐N oligomers or partially cross‐linked PB which could
not be isolated or identified further. 11B NMR spectrum of the activated solutions using (1) also
contained unreacted AB, a triplet at ‐10 ppm for cyclotriborazane (CTB)7,9 and two doublets at 30.9 and
27.9 as observed with (1). This correlates with the fact that (5) generates more H2 than (1), in agreement
with the formation of some PB versus CTB.
The difference in activity of (1) and (5) versus (2) and (6) was small, and therefore the use of the more
expensive, chiral catalysts bearing the diphenyl backbone was discontinued and further experiments
were only conducted using (1) and (5).
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
Precatalyst 6
Precatalyst 5
Precatalyst 2
Precatalyst 1
Precatalyst 7
107
Due to the highly solvent dependent nature of these systems whereby there is no hydrogen evolution in
water, slow but continuous evolution in iPrOH and rapid activity in THF, we also tested diglyme as a
dehydrogenation solvent (Entries 22‐23, Table 4.6). Reaction profiles using both (1) and (5) in THF were
compared to profiles of reactions done in diglyme and the plots were the same, within error. This
suggests that the same active species is generated in both solvents.
4.4.3 Effect of Varying Conditions of AB Dehydrogenation with Precatalyst (5)
Following optimizations of the solvent and precatalyst, we chose to further evaluate (5) under varying
conditions to probe its robustness. We first probed the catalytic system for its temperature dependence.
Standard reactions are run at 22 oC, so we tested the activity of the system when it was pre‐cooled using
an ice bath (entry 7, Table 4.6). The reaction profile is depicted in Figure 4.24 and shows that although
the activity is decreased slightly when compared to runs at 22 oC, the system is still quite active, evolving
one equivalent H2 in 2 minutes, and 1.4 equivalents in an hour before deactivating, compared to one
equivalent H2 in less than 30 seconds and 1.6 equivalents in an hour for the reaction at 22 oC. The
decrease in initial rate can be attributed to slower activation at lower temperatures, but the overall high
efficiency of the system at 2 oC reflects how unique these systems are when compared to the majority of
other AB dehydrogenation catalysts that require high temperatures.10,14,26 Due to the difference in
activity observed between the bis‐MeCN and MeCN‐trans‐CO precatalysts, we were interested in the
effect CO gas would have on the activity of the catalysts (entry 8, Table 4.6). When reactions were run
under a CO headspace instead of an argon headspace, minimal H2 evolution was observed, as shown in
Figure 4.24. This would suggest that either active species are forming and are immediately poisoned by
CO, or CO inhibits the formation of active species. Due to the fact that there is no initial activity
observed, it is likely that the active species do not form under these conditions. To further probe this,
we attempted to poison the system after activation with a known amount of CO; however the results
were inconclusive because the reaction setup employs an open system and the CO gas was rapidly
purged by the evolving hydrogen.
We were also interested in testing the limits of the catalyst at much higher AB loadings to see if our
systems could compare to the highly rapid ruthenium systems developed by Schneider15 and Fagnou11.
Using 0.83 mol% (5) (Fe:AB = 1:120 instead of Fe:AB = 1:40) (entry 9, Table 4.6) we observed the same
general reaction profile, releasing one equivalent of H2 in under one minute, as shown in Figure 4.24.
Using the linear portion of the plot (the first 30 seconds) the turnover frequency (TOF) can be
calculated:
108
3.66
Although the TOF is exceptionally high, the overall turnover number (TON) is only 154 H2 per Fe due to
catalyst deactivation.
Figure 4.24: Catalytic dehydrogenation of AB. Standard Run: AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 2.5 mol% Precatalyst (5) and 20 mol% KOtBu, Fe:AB:KOtBu = 1:40:8. Variations from standard conditions as listed in legend.
Standard experiments were done using 8 equivalents of KOtBu as the base, relative to iron, and we were
interested in probing the dependence of catalytic activity on base and therefore ran experiments using
both double (16 equivalents – entry 26) and half (4 equivalents – entry 27, Table 4.6) the amount of
base, and the reaction profiles are depicted in Figure 4.25. As would be expected, all three profiles
(standard run, and half and double KOtBu) show the same general shape with rapid initial activity
followed by a significant rate decrease as the catalyst deactivates; however the initial rate with half base
is slower and the overall H2 production varies between all three sets of experiments. The slower initial
rate with 4 equivalents of base versus 8 or 16 (1 equivalent H2 in 45 seconds for half base versus 10
seconds for both 8 and 16 equivalents) can be attributed to slower activation with a lower concentration
of base. More surprisingly was the overall yield of H2 achieved by varying the concentration of base;
1.83, 1.60 and 1.25 H2 in one hour for 16, 8 and 4 equivalents of base (relative to (5)) respectively. Given
the similar reaction profiles and same initial rates for 8 and 16 equivalents KOtBu, it would appear as
though catalyst activation is occurring in all cases. It is possible that deactivation of the catalyst is
minimized under the more basic conditions, as alkoxides could protect the active sites; however the
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
Standard Run
T = 2degC
Fe:AB = 1:120
CO Atmosphere
109
exact reason is still unclear. To probe this, we thought that perhaps the base was reacting
stoichiometrically with boron‐containing intermediates, allowing for more equivalents to be released
when more base was present. We were able to rule this out, as running the reaction with equimolar
amounts of KOtBu and AB (entry 28, Table 4.6), we did not evolve more H2 than with 40 mol% KOtBu.
Rather, we saw a decrease in overall yield (1.66 equivalents H2 in 1 hour in comparison to 1.83),
indicating that too much base has the opposite effect, and that the base dependence of this system is
much more complicated. To complete our base dependence studies, we tested the use of NaOiPr, as it is
both reducing and basic, albeit less basic than KOtBu. KOtBu is a very strong base but is not reducing,
whereas NaOiPr is a weaker base but is a moderately strong reductant. Using the standard 20 mol%
NaOiPr (entry 29, Table 4.6), we observed that the system was much less active, both in terms of initial
rates and overall H2 evolution, as depicted by the green triangles in Figure 4.25. Therefore reduction of
iron occurs most rapidly in the presence of AB and the stronger base.
Figure 4.25: Catalytic dehydrogenation of AB. Standard Run: AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 2.5 mol% Precatalyst (5) and base.
Finke has reported that the formation of NPs for use in catalysis can be viewed as an autocatalytic
process45 whereby precatalyst forms active NP catalyst, which then auto‐catalyses the formation of
more active catalyst. From this we would expect that at very low precatalyst concentrations formation
of NPs would be significantly slower and that an induction period might occur. To test the dependence
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
40 mol% KOtBu
100 mol% KOtBu
20 mol% KOtBu,Standard Run
20 mol% NaOiPr
10 mol% KOtBu
110
of catalysis on iron concentration, we varied the concentration of (5) in otherwise identical reaction
conditions. Precatalyst concentrations of 1.5, 0.65 and 0.15 mM were tested. 1.5 and 0.65 mM yielded
similar reaction profiles with rapid initial activity followed by deactivation, however the initial rate using
0.65 mM precatalyst was approximately 75% that of the standard 1.5 mM run. Dropping the
concentration of precatalyst lower to 0.15 mM yielded a completely different profile exhibiting a 10
second induction period, followed by rapid catalytic activity then deactivation. This non‐first order
kinetics is to be expected for NP formation as at very low iron concentrations nucleation and growth of
NPs is expected to be significantly slower.
4.4.4 AB Dehydrogenation with In Situ Generated Catalysts
Further optimization of our catalytic systems led to an investigation of in situ generated catalysts that
would preclude the necessity to first generate our Fe(P‐N‐N‐P) precatalysts. This involved using a one
pot reaction of commercially available Fe(II) precursors, KOtBu, AB, P‐N‐N‐P ligand and solvent. We
previously calculated that for the 4 nm Fe NPs derived from (1) and (2) for TH that approximately 50% of
the iron would be on the surface,35 indicating that less than half of the ligand was being used. We
therefore ran initial tests using Fe(II) precursors and 0.6 equivalents of P‐N‐N‐P ligand. [Fe(H2O)6][BF4]2
was tested with ligand (8) from Figure 4.21, the same P‐N‐N‐P ligand of (1) and (5), in iPrOH (entry 5)
and THF (entry 13, Table 4.6) for AB dehydrogenation using 4 mol% Fe (relative to AB). In iPrOH the
reaction rate was much slower than the preformed catalysts, yielding only one equivalent of H2 in just
under an hour before the system deactivated. In THF, the in situ generated catalyst showed comparable
activity in terms of initial rates and overall H2 generation to reactions using (5), at a lower AB loading,
suggesting that the same active species is being formed. To further investigate ligand effects we
synthesized bulkier and more basic P‐N‐N‐P ligand (9) as shown in Figure 4.21 which contains a
cyclohexyl diamine backbone (entry 14, Table 4.6) and compared activity with ligand (8) and the
reaction profiles are shown in Figure 4.26. Reaction profiles with both ligands are the same in terms of
initial rates and extent of H2 evolution indicating that making this steric and electronic change had a
negligible effect. This was to be expected as catalysis with (5) versus (6) is also similar in THF. We were
also interested in the effect of different Fe(II) precursors and therefore tested FeBr2 (entry 17, Table
4.6). The overall reaction profile in Figure 4.26 is the same for both [Fe(H2O)6][BF4]2 and FeBr2 metal
precursors, once again suggesting that the same active species is being formed. Both yield the same final
amount of H2 (1.6 equivalents in 1 hr) although FeBr2 shows a slightly more rapid initial activation,
potentially due to improved solubility or more rapid reduction to NPs. To confirm that the activity of
111
FeBr2 with (8) can be compared to reactions with (5), we also ran reactions using the same substrate
loading (Fe:AB = 1:40) as outlined in entry 30 of Table 4.6 and depicted in Figure 4.26. Similar initial rates
and extent of H2 evolution at both 1:25 and 1:40 was observed, allowing direct comparisons to be made
with (5); (5) yields 1.1 equivalents H2 in 30 seconds, and 1.6 in 1 hr, whereas FeBr2 with (8) yields 1
equivalent in 30 seconds and 1.4 in 1 hr, strongly suggesting the same active site is present in both.
Experiments in diglyme (entry 31, Table 4.6) gave the same results as catalysis in THF for the FeBr2 with
(8) system, as was observed with (1) and (5). Manners et. al. recently reported the use of skeletal nickel
heterogeneous catalysts derived from the selective leaching of aluminum out of a 50/50 Ni/Al alloy for
the dehydrogenation of amine‐boranes.30 Although the nickel systems were quite active, similarly
prepared iron systems were inactive, suggesting the subtle interplay of metal and stabilizing ligand in
our systems which allow them to be so active.
Figure 4.26: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 4 or 2.5 mol% Fe, 2.6 or 1.6 mol% ligand and 32 or 20 mol% KOtBu. Fe:Ligand:AB:KOtBu = 1:0.6:25:8 or 1:0.6:40:8. Where Fe‐H20 = [Fe(H2O)6][BF4]2.
11B NMR spectral analysis of in situ solutions of catalysis with [Fe(H2O)6][BF4]2 and 0.5 equivalents of
ligand showed two doublets at 30.9 and 27.8 with coupling constants of 127 Hz and 138 Hz respectively.
The major species is the doublet at 27.8 ppm, and it appears to have a broad shoulder from 27 to 24
ppm. These peaks correspond closely with those previously observed using (5), although the singlets at
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
Fe‐H2O + Ligand 8,1:25 Fe:AB
FeBr2 + Ligand 8,1:25 Fe:AB
FeBr2 + Ligand 8,1:40 Fe:AB
Fe‐H2O + Ligand 9,1:25 Fe:AB
112
20.3 and 24.3 ppm were not distinguishable. No peaks for free AB were observed, therefore one would
predict from the distribution of products that more than 1.6 equivalents of H2 should have been
produced, supporting the theory that deactivation may be caused by binding of reactive B‐N
intermediates to the active sites of Fe NPs, thereby poisoning the catalyst surface. This deactivation
mechanism has been previously postulated by Manners et.al. on colloidal nickel catalysts.30 Binding of
these species to the surface would make them undetectable by 11B NMR spectroscopy as the NPs would
be superparamagnetic.35
Using FeBr2 and ligand (8), we further probed the temperature dependence of the system by running
the reaction at 2 oC as we had done previously with (5) (entry 21, Table 4.6). Similar to the behaviour
reported with (5), the plot at 2 oC shows a similar overall shape as the plot at 22 oC with a slightly slower
initial rate, and a deactivation after fewer equivalents H2 released (1.2 equivalents H2 at 2 oC instead of
1.6 at 22 oC). As a second probe to compare the in situ generated catalyst to preformed catalyst we
tested FeBr2 and ligand (8) for dehydrogenation of AB under an atmosphere of CO. As was observed
with (5), no hydrogen evolution was observed when the catalyst was generated under a CO atmosphere,
indicating that CO impedes catalyst formation in both cases.
Chaudret and coworkers previously reported a dependence on metal to ligand ratio using their Ru0 NPs
stabilized by 3‐aminopropyltriethoxysilane on the initial rates of dehydrogenation of
dimethylamineborane (DMAB).27 We therefore investigated our FeBr2 system with different ratios of
ligand (8) to determine the effect on stability (extent of conversion prior to deactivation) and initial
rates. Figure 4.27 shows plots of experiments run using 1.2, 0.6, 0.3 and 0.15 equivalents of ligand (8),
relative to FeBr2 (Entries 17‐20, Table 4.6)). Plots of 1.2, 0.6, 0.3 and 0.15 equivalents of ligand all show
the same initial rates of overall conversion, and identical plot shape, yielding 1 equivalent of H2 in 1
minute and 1.6 equivalents in 1 hour. In contrast, the plot shown in green (triangles) represents the
addition of no ligand (entry 16, Table 4.6), and exhibits significantly different behaviour. When there is
no ligand present, activation is much slower and deactivation occurs much more rapidly, indicating that
the ligand provides stabilization on the NP surface preventing agglomeration and active site poisoning.
This also suggests that as little as 0.15 equivalents of ligand is required to give the needed stabilization
to maximize efficiency of the catalyst. If the catalyst was homogeneous, one would expect to need
equimolar amounts of iron and ligand, and that activity would decrease with decreasing ligand amount,
however this is not the case. Further reduction of the amount of ligand yielded irreproducible results
and overall decreased activity, indicating that 0.15 equivalents is the minimum amount of ligand
113
necessary for this system. It is interesting that with changing ligand concentration there is no observable
effect on the rate of catalysis. Chaudret and coworkers27 observed that with too little ligand present
larger, less active NPs formed, and this is likely the case with our system, which supports that when
<0.15 equivalents of ligand are used irreproducible results are obtained. Chaudret also observed that
with more ligand present the rate also decreased due to the excess of ligands binding to the active sites.
In our system no rate decrease is observed with excess ligand, suggesting that the ligand does not act as
an active site poisoning agent, likely because it is fairly bulky. This provides very strong evidence for a
heterogeneous system as the active catalyst.
Figure 4.27: Catalytic dehydrogenation of AB (10 mg, 0.32 mmol) in 5 mL THF at 22oC using 4 mol% FeBr2, ligand (8) and 32 mol% KOtBu (relative to AB). Fe:AB:KOtBu = 1:25:8.
4.4.5 Dimethylamine‐borane (DMAB) Dehydrogenation with Precatalysts (1) and (5)
Many heterogeneous precious metal catalysts reported focus primarily on the dehydrogenation of
DMAB instead of AB,16,25,27,29,30,46 and thus we sought to test our systems using (1) and (5) with KOtBu in
THF (Entries 24‐25, Table 4.6). Using the same reaction conditions as employed with AB, and with similar
catalyst loading (Fe:KOtBu:DMAB = 1:8:45) hydrogen evolution was measured at 22 oC. (1) and (5)
yielded similar results with (5) achieving faster initial rates (0.62 equivalents H2 in 1 minute for (5) and
0
0.5
1
1.5
2
2.5
3
0 10 20 30 40 50 60
Equivalents H2
Time (min)
1.2 Equiv. Ligand 8
0.6 Equiv. Ligand 8
0.3 Equiv. Ligand 8
0.15 Equiv. Ligand 8
0.6 Equiv. Ligand 8, T= 2degC
No Ligand
114
0.44 for (1)) but both catalysts yielded 0.97 equivalents H2 in 1 hour and 1.1 equivalents in 2 hours
before deactivation. Similar to the AB plots, dehydrogenation of DMAB shows a rapid initial H2
evolution, followed by a significant decrease in rate, before complete deactivation of the active species.
Addition of more DMAB yielded no further H2 evolution indicating that catalyst deactivation had
occurred, similar to the case with AB. 11B NMR analysis of the reaction solutions proved to be much
more complicated than the AB case and results are depicted in Figure 4.28. There is a sharp quartet
at ‐13.3 for unreacted DMAB, a triplet at 2.8 and a quartet at ‐9.7 for the adduct Me2NHBH2NMe2∙BH3, a
small triplet at 5.5 for the (Me2N‐BH2)2 heterocycle, which is typically the most common product formed
during these reactions as it is the rapid decomposition product of the postulated Me2N=BH2
intermediate.16,21,30 The NMR spectrum also shows two doublets at 27 and 28.9 with couplings of 140
and 131 Hz respectively identified as BH(NMe2)2 and a second BH complex.22 Given the formation of
BH(NMe2)2 it is likely that BH3 release occurs, which could interact with –OtBu in solution to generate
BH(OtBu)2,47,48 resulting in the doublet found at 28.9 ppm. Given the product distribution, one would
surmise that evolution of a full equivalent of H2 would be unlikely, suggesting that some boron
containing products may be insoluble or bound to a superparamagnetic NP, making them undetectable
by NMR spectroscopy. This wide range of products and modest yields would suggest that the catalyst is
not selective upon reaction with DMAB, nor is it competitive with other reported catalysts, but it is a
useful proof of concept for these iron systems and their versatility.
115
Figure 4.28: In situ 11B NMR (128 MHz) spectrum of catalytic dehydrogenation of Me2NHBH3 (entry 24 of Table 4.6) after 30min. Fe:B:KOtBu = 1:45:8.
4.4.6 Electron Microscopy Imaging
To further probe the nature of our iron catalytic systems we investigated reaction solutions by
transmission electron microscopy (TEM). We analysed reaction solutions of catalysis with (5) and of
catalysis with FeBr2 with 0.3 equivalents of (8) as outlined in entries 32 and 33 respectively of Table 4.6.
Figure 4.29 [left] is a standard image observed for catalysis with FeBr2 and ligand (8) and shows large
dense masses with very small dense particles dispersed on the surface. Using energy dispersive X‐ray
spectroscopy the large masses were identified as KBr, and the small particles were composed of iron.
The KBr is formed as a result of deco‐ordination of Br from FeBr2 in the presence of KOtBu. The particles
reacted with the electron beam and therefore high magnification imaging was not possible. This
indicates that the particles were likely bound to volatile solvent molecules such as THF which were
liberated upon exposure to the electron beam. Coordination of THF to Fe NPs has been previously
reported and supported by extended X‐ray absorption fine structure experiments.49 This would suggest
that the Fe NPs generated in situ are stabilized by P‐N‐N‐P ligand and THF as a labile ligand, which also
supports why the in situ generated catalyst has comparable activity to (5) in THF but is more rapidly
deactivated in iPrOH. A similar analysis was conducted on catalytic solutions using (5). TEM showed
116
dense clusters also identified as potassium salts and dense areas depicted in Figure 4.29 [right]
identified as ~4 nm Fe NPs. Also scattered across the grid were larger (8‐12 nm), poorly defined
structures of widely varying sizes that were much less dense than the potassium and iron sections of the
grid. Using a GIF‐2000 energy filter these areas were analysed for select elements50 and were
determined to be primarily composed of boron. This suggests that the PB identified by 11B NMR
experiments is coating the grids, and can be roughly characterized by TEM. Applying a similar energy
filter and focusing on phosphorus, it could be shown that phosphorus was primarily bound to the NPs,
as would be expected for the ligand. Size distribution analysis using ImageJ software of the Fe NPs in
Figure 4.29 [right] indicate that the NPs are 4.1 + 0.7 nm in diameter, and they appear to be fairly round
in shape and moderately well dispersed. This fits within the size range observed for catalysis with (1) and
(2) for TH35 and also matches closely with the AB dehydrogenation Fe NPs reported by Xu et. al.31
Figure 4.29: TEM images of entry 33 [left] and entry 32 [right].
To complete our analysis of these new systems, we were interested in comparing them to our previously
explored TH systems.35 To do this, we generated active catalyst for AB dehydrogenation using our iron
precatalysts with AB and KOtBu in THF and then injected these activated solutions into iPrOH solutions
containing acetophenone and monitored the conversion to 1‐phenylethanol using gas chromatography
(GC). Using the GC it is possible to monitor both overall conversion as well as product enantiopurity, so
117
to get the most information out of our catalysis we chose to analyse our two chiral precatalysts (2) and
(6). We previously explained (vide supra) that catalyst deactivation likely occurs during AB
dehydrogenation due to the binding of reactive boron compounds to the surface of the NPs. To
minimize this deactivation before the catalysts could be used for TH we used less AB for the formation
of the active species. A precatalyst to base to AB ratio (Fe:KOtBu:AB) of 1:7:8 in THF was used to reduce
the iron and generate the active species and this activated solution was injected directly into a vial
containing iPrOH and acetophenone, yielding a Fe to ketone ratio of 1:300. Typical TH employing (2) and
a catalyst to substrate loading (Fe:acetophenone) of 1:600 yielded 64% e.e. and 50% conversion in 30
minutes.35 Using the systems described herein we achieved 79% e.e. albeit catalysis took 4 hours to
reach 50% conversion using (2), and no conversion was observed using (6). The high enantiopurity
indicates that similar to the standard TH case, the chiral ligand must be bound to the surface to induce
this level of selectivity.51,52 The increase in enantiopurity can be attributed to a selectivity enhancement
induced by the preference of the system towards preformed catalyst versus in situ generated catalyst,
as was observed previously for TH.35 We hypothesized that the increase in selectivity was due to the
unencumbered, complete formation of the ligand‐coated NPs without the interference of substrate,
allowing for a more optimized coating of the chiral ligand on the surface. The fact that (2) and not (6)
gave active catalysts for TH would indicate that the CO ligand present in precatalyst (2) must remain
bound to the active species, and that it is necessary for TH. We observed this previously as (2) was active
for TH and (6) was only active for direct hydrogenation.32 The presence of CO on the active surface
therefore plays a critical but not well understood role in catalysis as it slows down AB dehydrogenation,
but is crucial for TH. Lastly, it is worth noting the significant decrease in rate on going to the catalysts
prepared in THF using KOtBu and AB versus the systems prepared with KOtBu in iPrOH. This rate
reduction can likely be attributed to a decrease in catalytic sites caused by the binding of reactive boron
containing species to the surface, thereby acting as a catalyst poison. These studies further support that
the active species during AB dehydrogenation are Fe NPs, similar to those previously investigated.
118
4.5 Conclusions
We have demonstrated the wide versatility of the series of iron complexes generally described as
[Fe(NCMe)(L)(PPh2C6H4CH=NCHR‐)2][BF4]2 for their use in the dehydrogenation of amine‐boranes,
particularly for ammonia‐borane, on top of their efficient previous use as hydrogenation32,33,35 and
oxidation36 catalysts. In iPrOH, 2.9 equivalents of H2 could be released in under an hour, yielding
B(OiPr)3, whereas in non‐protic solvents such as THF and diglyme B‐N polymers and oligomers could be
formed, and very rapid initial rates were observed yielding TOFs of up to 3.66 H2/second. Catalysts were
shown to be efficient at low temperatures, a quality not previously thoroughly investigated, and were
shown to be completely poisoned by carbon monoxide. Electron microscopy imaging showed that Fe
NPs were forming during catalysis, but could not confirm whether the true catalyst was heterogeneous,
or if Fe NPs are simply a deactivation product. To probe this property we tested hydrogen evolution
using commercially available Fe2+ precursors in the presence of varying amounts of P‐N‐N‐P ligand. For a
homogeneous catalyst we would expect to need a full equivalent of ligand to achieve comparable
activity, however, we have shown that 1.2, 0.6, 0.3 and 0.15 equivalents of ligand all achieve the same
activity, supporting that the active species are likely to be zero‐valent Fe NPs coated in, and stabilized
by, P‐N‐N‐P ligand, similar to what we observed previously for TH and oxidation with (1) and (2).35,36
Although these iron systems still hold many secrets, they have proven themselves to be quite versatile
catalysts for a wide range of hydrogen reactions. Given the very rapid initial rates of catalysis it has
proven to be quite difficult to run in operando studies to determine the true nature of the catalyst,53 and
we can therefore only propose that the active species are zero‐valent Fe NPs.
119
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122
Chapter 5: Synthesis and Mechanistic
Studies of Iron P‐N‐P’ and P‐NH‐P
Asymmetric Hydrogenation Catalysts
Adapted from Lagaditis, P.O., Sues, P.E., Sonnenberg, J.F., Wan, K.Y., Lough, A.J., Morris, R. H. J. Am.
Chem. Soc. 2014, 136, 1367‐1380, Sonnenberg, J.F., Sues, P.E., Wan, K.Y., Morris, R.H. Submitted, 2014
and Sonnenberg, J.F., Lough, A.J., Morris, R.H. Submitted, 2014.
5.1 Abstract
Pre‐catalysts mer‐trans‐[Fe(P‐N‐P’)(CO)2Br][BF4] (10) were successfully developed for the asymmetric
direct hydrogenation of ketones and imines upon activation with LiAlH4, then alcohol ROH (R = Me,
tAmyl, tBu), followed by base and H2 (g). Previous mechanistic investigations determined that reactive
Fe(P‐NH‐P’)(CO)(H)(OR) (11) complexes were initially produced during activation. Here we provide
strong NMR and experimental evidence that the role of base and H2 in the activation of the isomers of
the complex Fe(P‐NH‐P’)(OR)(H)(CO) (where P‐NH‐P’ = PPh2CH2CH2NHCHMeCHPhPCy2 or (S,S)‐
PPh2CH2CH2NHCH2CH2PiPr2, is to generate the trans‐dihydridoamino complexes, Fe(P‐NH‐P’)(CO)(H)2
(13). This complex can then react with a ketone within the catalytic cycle. Employing related ligand
scaffolds, we successfully generated and tested a series of three new chiral precatalysts (10d‐f) with
chirality derived from amino acids, yielding fairly active and selective systems; turnover frequencies up
to 920 h‐1 and up to 74% enantiomeric excess at 50 oC and 5‐20 atm H2. Extending the scope of the
ligand structure, we then developed a series of chiral P‐N‐P (16) and P‐NH‐P (17) systems starting with
ortho‐diphenylphosphinobenzaldehyde to incorporate a phenylene linker, as well as their corresponding
[Fe(P‐N‐P)(NCMe)3][BF4]2 (18) and [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19) complexes, which were not
catalytically active. Lastly, we made a new achiral iron complex mer‐cis‐Fe(PPh2(o‐
C6H4)CHNCH2CH2PPh2)(CO)Br2 (20) which was active for the direct hydrogenation of acetophenone,
achieving turnover frequencies of 800 h‐1 at 50 oC and 25 atm H2.
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5.2 Introduction
The synthesis of enantiopure alcohols and amines is of significant importance to the pharmaceutical,
fragrance and fine chemical industries, and is typically achieved via the hydrogenation of ketones and
imines, respectively, using precious metal catalysts.1,2 There has been tremendous interest recently in
developing greener catalysts based on early transition metals, to replace iridium, ruthenium and
rhodium catalysts, as they are much cheaper, more earth abundant and less toxic, as was detailed in
Chapter 1.3‐5 Our group has been primarily focused on the development and mechanistic investigation of
iron carbonyl P‐N‐N‐P catalysts for asymmetric transfer hydrogenation (ATH),6‐17 as was discussed in
detail in Chapter 2; however we often encountered problems with product racemization due to
equilibration. We therefore sought to develop asymmetric direct hydrogenation systems that could use
hydrogen gas to prevent reversibility.
Recently, Milstein and coworkers reported iron systems with tridentate P‐N‐P ligands capable of directly
hydrogenating polar double bonds.18,19 These complexes, shown in Figure 5.30, achieved turnover
frequencies (TOF) up to 430 h‐1 at 40 oC and 4.1 atm H2. Beller and coworkers also used a similar ligand
system on iron for the release of H2 gas from methanol and water with TOFs up to 600 h‐1.20 He also
recently detailed the use of the same system for the hydrogenation of esters,21 as did Chakraborty et. al.
who characterized a reactive dihydride intermediate.22 In their hydrogen evolution paper, Beller and
coworkers hypothesized that the system goes through reactive amide‐hydride species, which can be
generated from a Fe(P‐NH‐P)(CO)(H)(OR) complex using base. This type of Fe(P‐N‐P)H(CO) amide
structure has been recently crystallographically characterized by Chakraborty et. al. in their study of the
dehydrogenation and hydrogenation of N‐heterocycles.23 This structure is similar to the proposed
reactive intermediates discussed in detail vide infra.
Prior to the work with the P‐N‐P systems, Casey and Guan developed a Shvo‐type system using iron
capable of hydrogenating aldehydes and ketones, via an outer sphere (bifunctional) mechanism, at
modest temperatures and pressures.24,25 This ligand scaffold was then used by Berkessel et. al. in
conjunction with a chiral phosphorus ligand26 and by Beller and coworkers in conjunction with a chiral
phosphonic acid27 to yield alcohols and amines in modest enantiomeric excess (e.e.), respectively. Our
group has also developed a series of iron‐(P‐N‐N‐P) systems, also shown in Figure 5.30, capable of
hydrogenating ketones with TOFs up to 1000 h‐1 and e.e. up to 76% at 50 oC and 25 atm H2.11 The most
efficient direct hydrogenation catalyst known to date was developed by Noyori and coworkers, and is a
124
ruthenium based catalyst containing a chiral, bidentate phosphorus ligand (BINAP) and a chiral diamine
ligand.28,29 The catalyst, upon activation with base to generate a reactive hydride complex, is capable of
achieving a total turnover number (TON) of up to 100,000 and an e.e. of 99% at ambient temperature
and 8 atm H2. The catalyst operates via a bifunctional, outer‐sphere mechanism that takes advantage of
the “N‐H effect”, whereby the Ru‐hydride and ligand N‐H add directly to the substrate polar double
bond, resulting in a metal amido intermediate that then heterolytically splits H2.30‐33 We were therefore
interested in developing a new series of direct hydrogenation catalysts based on iron that would be
chiral, able to potentially take advantage of the N‐H effect, and employ pincer ligands.34
N
PiPr2
PiPr2
FeHCO
BrN
PiPr2
PiPr2
FeHBH3CO
H
Fe
TMS
TMS
OH
OCOC
H
O O
OPFe
TMS
TMS
OH
OCOC
H
O
OHiPr
iPr iPr
iPr
iPr
iPr
Milstein 2011 and 2012
Beller 2011
N N
PPh2
PPh2
Fe
N
RR
Morris 2008
[BF4]2
Casey 2007
N
PiPr2
PiPr2
FeBrCO
HH
N
Beller 2013 and 2014Jones 2014
Fe
TMS
TMS
OH
OCL*
CO
O
O
OP NMe2
R
R
L* =
Berkessel 2011
Ru
Cl
ClN
N
H H
PPh2
Ph2P
HH
OMe
OMe
R-BINAP R-DAIPEN
Noyori 1998
Figure 5.30: Catalysts used for the direct hydrogenation of polar double bonds.
Combining these key structural features, we developed a P‐N‐P’ ligand scaffold that incorporated chiral
centres, yielding highly active and enantioselective direct hydrogenation catalysts based on iron that
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could operate under mild conditions.35 The precatalysts could be generated using a template method
employing air‐stable phosphonium dimers,10 chiral PN ligands and FeBr2 under a CO (g) atmosphere,
followed by silver‐assisted ligand exchange36 to cleanly generate mer‐trans‐[Fe(Br)(CO)2(P‐CH=N‐
P′)][BF4] (where P‐CH=N‐P′ = R2PCH2CH=NCH2CH2PPh2 and R = iPr (10a) or Cy (10b) or P‐CH=N‐P′ = (S,S)‐
Cy2PCH2CH=NCH(Me)CH(Ph)PPh2 (10c)), the synthesis of which is discussed in detail below. These
systems were found to be quite active for the direct hydrogenation of both ketones and activated
imines under mild conditions; yielding moderate to high e.e.’s when the chiral ligand backbone (Me/Ph)
was employed. Activation of these precatalysts was found to first require reduction with LiAlH4 and then
quenching with excess alcohol to yield hydride species which could be further activated by base for
catalysis (see Scheme 5.13). Extensive NMR experiments followed by detailed DFT calculations allowed
for the identification of the hydride and aluminum‐hydride species formed during the LiAlH4 and alcohol
activation steps. In this chapter, we will first outline further experimentally determined mechanistic
investigations, followed by an account of new iron species developed to probe the applicability of a
modified ligand scaffold. For the mechanistic studies, specific emphasis was placed on determining the
role of base and its importance during activation of the precatalyst, as well as during the catalytic cycle.
Given the success of these catalysts, we then explored the effect of changing the ligand sterics and
chirality (number and type of chiral centres) using alternative PN ligands, the effect of changing the
ligand structure and flexibility using o‐phenylene linkers on the achiral side of the ligand, and the effects
of incorporating an N‐H functionality into the ligand backbone.
126
N
PPh2
PR2
FeHCO
HH2Al
HFe
N
CO
PR2
PPh2
HH3Al
Li
N
PPh2
PR2
FeCOBr
OC
BF4
6 equivLiAlH4
THF
xs R'OH
N
PPh2
PR2
FeH
CO
O
H
+isomers
THF
R'
where R = iPr or Cy
11
12
+
10
N
PPh2
PR2
FeCO
COH
R' = Me, tAmyl, tButyl
Scheme 5.13: Activation of [Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts (10a‐c) with LiAlH4 and alcohol.
5.3 Results and Discussion
5.3.1 NMR Investigation of the Mechanism
Following our successful application of NMR spectroscopy and DFT calculations to determining the initial
activation of our mer‐trans‐[Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts (10a‐c),35 we sought to further apply
these methods to elucidate the complete activation process and catalytic mechanism of these systems.
For ease of analysis, we used our achiral catalyst (R’ = R” = H), bearing iPr groups on one of the
phosphorus donors (R = iPr), (10a) for all NMR studies. Activation of (10a) with LiAlH4 followed by
quenching with alcohol, then reaction with 12‐crown‐4 and filtration to remove residual cations, was
shown to yield a hydride‐alkoxide iron complex, (11) as shown in Scheme 5.13. For catalysis, this
complex is further activated with base under hydrogen to achieve catalytic turnover. To probe this
activation we used NMR spectroscopy to sequentially study this process. Addition of several equivalents
of base without hydrogen present was previously shown to generate the zero‐valent iron species Fe(P‐
NH‐P’)(CO)2 (12), as shown in Scheme 5.14,35 which was inactive towards catalysis, even in the presence
of hydrogen gas. Treatment of (11) with 1 atm H2 yielded no change, even over prolonged periods of
127
exposure (24 hours). Addition of approximately 8 equivalents of base (relative to Fe), either KOtBu,
NaOtBu or NaOMe, in the presence of 1 atm H2 yielded an immediate colour change from bright orange
to dark pink, and then rapidly to deep brown. NMR analysis of the resultant solution indicated the
complete consumption of (11) and the formation of a new species (13) with 31P {1H} doublets at 118.0
and 95.8 ppm and 2JPP = 118 Hz, as well as a new hydride signal centred at ‐9.10 ppm. Selective
decoupling of both the 118.0 and 95.8 ppm 31P signals allowed for resolution of the ‐9.10 ppm signal as
two hydride doublets at ‐9.05 and ‐9.16 ppm with JHH = 9.8 Hz, indicating a dihydride species. The value
of 9.8 Hz for the hydride‐hydride coupling constant supports the formation of a trans‐dihydride,19,37‐40
and the 118 Hz phosphorus‐phosphorus coupling is large and similar to (11) (JPP = 136 Hz),35 indicating
that the phosphorus donors are trans, yielding a mer‐conformation of the P‐N‐P’ ligand. This leads to an
assignment of the structure of (13), which is hypothesized in Scheme 5.14. To complete the
characterization, we ran simulations of the hydride peaks using MestReNova Simulation Software. Using
known coupling constants we were able to exactly simulate the 31P‐coupled 1H spectrum of the hydrides,
as well as determine that JPH = 42 Hz. This value is lower than the 50‐60 Hz splitting observed for (11),
likely due to the high trans influence of the hydrides, producing weak Fe‐H bonds, and thus small 2JPH
splitting, as observed. It is also worth noting that the 31P‐coupled 1H NMR spectra of the hydrides of (13)
are highly symmetrical, supporting that the hydrides are chemically inequivalent but in quite similar
chemical environments. The P‐N‐P’ ligand is not chiral, and therefore to explain the inequivalency of the
hydrides we suggest that the ligand has an amino group (P‐NH‐P’), as drawn in Scheme 5.14.
Unfortunately, we were unable to detect an N‐H signal in the NMR spectrum using a wide range of 2‐D
techniques (COSY, TOCSY, NOESY and ROESY NMR experiments); however there are several equivalents
of alcohol in excess of the iron concentration in solution that may affect the fluxionality of the N‐H
moiety. During the NOESY analysis, we did notice an out of phase correlation between the hydrides and
what appears to be free H2 at 4.55 ppm, indicating some kind of interaction (NOE would be out of
phase), however further analysis was not possible due to the timescale of exchange. A single crystal X‐
ray determination of the iron (0) dicarbonyl complex (12) allowed confirmation of the presence of an N‐
H,35 supporting the postulated structure of (13) with an amine functionality. Lastly, we were also able to
identify a second species in much smaller concentrations present using 31P and 1H NMR spectroscopy,
which we tentatively assigned as the corresponding dihydride species mer‐cis‐Fe(P‐NH‐P’)(CO)(H)2. 31P
doublets at 114.6 and 93.0 with JPP = 106 Hz and poorly resolved hydrides at ‐8.1 and ‐20.6 ppm which
correspond to each other by 31P‐1H HMBC, suggest the presence of a cis‐dihydride and trans‐P (mer‐P‐N‐
P’). Due to very low concentration and peak resolution, no further analysis was possible on this species.
128
Scheme 5.14: Activation of iron‐alkoxide (11) with base and hydrogen to generate active dihydride (13) and iron (0)
dicarbonyl (12).
We similarly analysed our chiral system (10c) via NMR spectroscopy for the formation of dihydride
species. Following the same activation steps used to generate (13), we were able to detect a new
dihydride complex (13c). Following the same logic for identifying the trans dihydride in (13), (13c) has
two doublets in the 31P NMR spectrum at 110.2 and 106.5 ppm with 2JPP = 113.6 Hz for the trans
phosphorus nuclei, yielding the mer‐(P‐N‐P’) ligand. Two sets of hydride signals were detected in the 1H
NMR spectrum at ‐8.56 and ‐8.94 ppm with 2JHH = 9.3 Hz. The ‐8.56 signal was a doublet of doublets of
doublets with 2JPH = 39.0 and 44.2 Hz and the ‐8.94 hydride was a doublet of triplets with 2JPH = 41.9 Hz.
The two hydrides were correlated with one another via 1H‐1H COSY, and were both correlated to the
major 31P signals through 1H‐31P HMBC. Unlike (13) the hydride signals are more well‐defined and
129
separated due to the chirality of the backbone, which allowed for the direct observation of the COSY
correlation and all of the coupling constants without the need for 31P decoupling. Also similar to the
achiral case, we were able to observe a second species in both the 31P and 1H (hydride) NMR spectra,
albeit in comparable concentrations to the trans‐dihydride. 31P NMR spectroscopy exhibited two
doublets at 102.5 and 109.7 ppm with 2JPP = 116.4 Hz and the hydride peaks appeared at ‐7.31 and ‐
21.00 ppm in the 1H NMR spectrum, with 2JHH = 15.5 Hz and 2JPH = 52.0 and 58.0 Hz for the ‐7.31 ppm
hydride and 2JPH = 51.9 Hz for the ‐21.00 ppm hydride. The signals were similarly correlated using 1H‐1H
COSY to confirm that the new species was a dihydride, and using 1H‐31P HMBC. Similar to the achiral case
we once again suggest that this second isomer is the cis‐dihydride.
To probe whether the dihydride (13) was the active species in catalysis we tested it with acetophenone
to gauge conversion to 1‐phenylethanol under H2. We directly injected the THF‐d8 solutions from the
NMR studies which contained (13a), excess base, excess alcohol, and residual 12‐crown‐4, into a
pressurized Parr reactor set at 50 oC and 5 bar H2 along with 0.3 mL acetophenone (Catalyst:Substrate ~
1:500) and 6 mL THF. We saw complete conversion to 1‐phenylethanol in under 15 minutes, which was
comparable to our in situ generated catalysts under the same conditions, that achieved complete
conversion in 15 minutes as well.35 This indicates that the dihydride species is likely the active catalyst
during direct hydrogenation, or an entry point into the catalytic cycle. This was also the case with our
chiral system, (13c), which similarly achieved complete conversion in 15 minutes and yielded an e.e. of
83%, comparable to our in situ generated systems. This product enantiopurity further supports that the
dihydride is the active species, and that the enantiodifferentiating step is unaffected. Interestingly, if we
injected 0.05 mL of acetophenone into the J‐Young NMR tube containing (13a) or (13c) and maintained
a pressure of 1 atm H2 at 30 oC, we saw very little conversion to 1‐phenylethanol and NMR spectra
indicated that the dihydride decomposed into an intractable mixture. The catalyst system is known to be
active, albeit slower, at lower temperatures, indicating that it was the lower H2 pressure that caused
catalyst deactivation, and that higher pressures are required for catalyst turnover. Dihydride (13) can be
generated under 1 atm of H2, however catalytic turnover and conversion of the ketone to product is not
possible and requires at least 5 atm H2. This pressure dependence was therefore an area of interest for
further mechanistic investigations.
Generation of the dihydride (13a) was feasible using either KOtBu or NaOMe, and we were interested in
the effect of the alkali cation and the effect of the strength or basicity of the alkoxide used in catalysis.
As discussed previously, generation of the dihydride requires base. By drying the dihydride solution and
130
redissolving the residue in benzene we were able to filter off the majority of the excess base, and then
inject the dihydride directly into a pressurized reactor. Interestingly, minimal catalytic turnover was
observed, indicating that not only is base required to generate the dihydride, but it is also required for
catalysis. A possible explanation for the continual need for base is that during catalysis there is an excess
of alcohol present which allows the iron complex to be converted back to the alkoxide complex (11). The
excess base is required to prevent this. This was later confirmed using DFT (vide infra) which indicated a
low energy deactivation pathway to form (11).
1H NMR analysis of the dihydride indicated that the trans‐hydrides were inequivalent, which suggested
that there was an N‐H present in the ligand backbone. Alternatively, this inequivalence could arise from
an iron‐amide and a tightly bound cation. To probe the influence of the cation, we ran catalysis with in
situ generated catalysts activated with either NaOtBu or KOtBu. The procedure involved reacting (10a)
with LiAlH4, addition of t‐amyl alcohol until hydrogen evolution ceased, and then injecting the mixture
directly into a Parr reactor containing either NaOtBu or KOtBu and acetophenone under H2. Both yielded
complete conversion of acetophenone to 1‐phenylethanol in 15 minutes, indicating that the identity of
the cation does not play a significant role in catalysis. For our NMR studies we were able to generate the
dihydride species (13a) with either KOtBu or NaOMe, however, when we ran catalysis with either KOtBu
or NaOMe for acetophenone conversion, only the system with KOtBu was active. Turning to our in situ
generated systems, we saw complete conversion of acetophenone in the presence of KOtBu, NaOtBu
and potassium phenylethoxide, but no conversion using NaOMe. This shows that base is required not
only to form the dihydride, but also for catalytic turnover. It also suggested that the basicity of the
alkoxide used plays a key role, as potassium phenylethoxide, the alkoxide of the product alcohol, is
strong enough for catalytic turnover, whereas methoxide, a weaker base, is not. This indicates that the
added base must be stronger than the phenylethoxide product for catalytic turnover.
Similar to the studies discussed in Chapter 2,16 and preliminary mechanistic studies with (10),35 we then
turned to DFT to calculate the energetics of potential pathways for both catalyst activation and catalytic
turnover. This work is beyond the scope of this thesis, and therefore will not be discussed in detail, but
to summarize, two energetically viable pathways were identified as potential mechanisms for catalysis.
One mechanism involved a cation (K+ or Na+) assisted pathway, whereby the cation was closely within
the coordination sphere of the iron‐amide and assisted in H2 splitting. The second mechanism did not
involve any cation assistance, but rather involved the splitting of H2 across a metal‐amide bond and
step‐wise, outersphere reduction of the ketone. It was also determined that the splitting of H2 was the
131
most energetically intensive step, indicating that H2 splitting is the rate‐determining step (RDS) in both
calculated mechanisms.
With two energetically viable mechanisms in hand, we once again turned to NMR spectroscopy and
catalysis to determine which mechanism was taking place. 1H NMR spectroscopy indicated that the
trans‐hydrides were inequivalent, which supports either the presence of an NH or an iron‐amide with a
tightly bound cation, found in the two pathways investigated by DFT. Cryptands are widely used for the
sequestration of metal cations from reaction solutions,41 and we therefore hypothesized that if the first
mechanism was occurring, the addition of a cryptand would pull the metal cation away from the active
catalyst and catalysis would be significantly slowed or stopped. To test this, we used our in situ
generated catalysts activated by KOtBu and added 1.1 equivalents of 2,2,2‐cryptand42 with respect to
KOtBu, to the reaction solution following activation. Conversion of acetophenone was complete in 15
minutes, indicating that the cryptand had no effect on catalysis, and providing evidence that the cation‐
assisted mechanism calculated by DFT is not occurring in this system. To further support this, we also
tested our pre‐synthesized methoxide complex (11) (which has most metal salts removed from filtration
and 12‐crown‐4 workup) for catalysis with base and 2,2,2‐cryptand. Once again, catalysis was complete
in less than 15 minutes, indicating that a cation‐based mechanism was not occurring.
Therefore, we propose that the mechanism shown in Figure 5.31 is most likely to be occurring with
these systems. This mechanism indicates that H2 splitting is the RDS, which is consistent with the fact
that higher pressures than 1 atm H2 (g) is needed for catalytic turnover. We were able to show
experimentally that dihydride formation can occur with NaOMe (and therefore H2 splitting) but catalytic
turnover does not, which seems contradictory to the results that the RDS is H2 splitting. This suggests
that solution hydrogen ion activity (pKa) plays a role in catalytic turnover, as well as catalyst activation,
however the exact role of basicity is still unknown and under active investigation in our group. The
presence of a reactive 5‐coordinate amide in this mechanism is also supported by a recent development
by Jones and coworkers who were able to crystallographically characterize a highly reactive
Fe(PNP)(CO)H amide complex during the dehydrogenation and hydrogenation of N‐heterocycles,
supporting that this route is experimentally viable.23
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Figure 5.31: Free energy profile of the amino metal hydride catalytic pathway.
5.3.2 Modifying the Catalyst Chirality
Following the successful synthesis, mechanistic investigation, and catalytic testing of the [Fe(P‐N‐
P’)(CO)2Br][BF4] systems originally developed, we were interested in broadening the scope of the
catalyst architecture and probing the effect of ligand chirality (both number of chiral sites and sterics of
chiral groups), size and flexibility. We were also interested in introducing an N‐H into the ligand
backbone as DFT and NMR studies suggested that an N‐H was likely involved in catalysis. As outlined in
Scheme 5.15, the precatalysts are formed using an iron‐assisted template reaction of a phosphonium
dimer10,43 and a chiral PN‐ligand under a CO (g) headspace,13 followed by halide abstraction and carbonyl
ligand substitution using AgBF4 also under CO (g)36 to yield the trans‐[Fe(P‐N‐P’)(CO)2Br][BF4] catalysts.
Unlike the Milstein system discussed previously18 where a trans‐Fe(P‐N‐P)(CO)Br2 complex could be
isolated and used to form the reactive iron‐hydride species, a mixture of cis‐ and trans‐bromide species
were isolated using our P‐N‐P’ template approach. To avoid the two isomer problem, we applied the
approach developed by Kirchner and co‐workers.36 His group also isolated a mixture of isomers using his
pincer ligands on iron,44,45 but found that the use of AgBF4 allowed for the clean formation of a trans‐CO
dicarbonyl complex as the sole isomer. This selectivity was shown to arise from the addition of CO to the
133
coordinatively unsaturated [Fe(P‐N‐P)(CO)Br]+ complex (formed from the loss of one Br‐ to Ag+) to
selectively form the trans‐carbonyl complex. In Kirchner and coworkers’ report, the yields of these
reactions are significantly improved when done under a CO (g) atmosphere, suggesting that the
resultant transient Fe(P‐N‐P)Br+ is able to rapidly bind another CO ligand and continue the cycle of
intermolecular transfer. We propose that this same reaction selectivity is taking place with our Fe(P‐N‐
P’)(CO)Br2 isomers, resulting in the clean formation of precatalysts mer‐trans‐Fe(P‐N‐P’)(CO)2Br+, as
shown in Scheme 5.15.
H2NPPh2
R'
+PR2
R2P OH
HO
[Br]21) FeBr2, THF
CO, 5 h2) AgBF4, DCM
CO, 30 min
0.5
PR2
N PPh2
Fe
BrCO
CO
R'[BF4]
R''
R''
(10a) R = iPr, R' = R" = H, 83% yield(10b) R = Cy, R' = R" = H, 89% yield(S,S)-(10c) R = Cy, R' = Me, R" = Ph, 82% yield(S)-(10d) R = Cy, R' = Ph, R" = H, 86% yield(S)-(10e) R = Cy, R' = CH2Ph, R" = H, 84% yield(S)-(10f) R = Cy, R' = iPr, R" = H, 78% yield
Scheme 5.15: Synthesis of [Fe(P‐N‐P)(CO)2Br][BF4] catalysts (10a‐f).
During previous studies35 phosphonium dimers bearing either iPr, Cy or Ph substituents, and PN‐ligands
(achiral R’ = R” = H or chiral R’ = Me, R” = Ph) were used to develop a series of iron complexes, which
were then tested. It was found that either iPr or Cy substituents on the initial phosphonium dimer
species yielded comparably active catalysts, while complexes with Ph substituents were inactive.
Therefore, further studies employed the phosphonium dimer bearing cyclohexyl groups on phosphorus
as this is significantly cheaper than the iPr variant. For the direct hydrogenation of acetophenone at
50oC and 5 atm H2, achiral catalysts (10a) and (10b) achieved turnover frequencies (TOF) of 1980 h‐1, and
the chiral catalyst (S,S)‐(10c) achieved TOF of 1980 h‐1 with an e.e. of 80% (S). As discussed previously,
the precatalysts must be activated prior to use in catalysis. To do this, precatalysts are first treated with
LiAlH4 in THF under an inert atmosphere, followed by addition of alcohol, typically tert‐amyl alcohol
(tAmOH). These activated iron solutions, containing Fe(P‐NH‐P’)(H)(OR)(CO) as discussed previously, are
injected into a pre‐heated and pressurized Parr reactor with base and substrate, to yield an active trans‐
134
Fe(P‐NH‐P’)(H)2(CO) complex. Keeping this activation process in mind, we were interested in developing
a new series of catalysts that employed a cheaper and more variable chiral centre(s).
The chirality in the previously developed system was derived from phenylpropanolamine, or
norephedrine, which is a controlled substance, and very expensive. We therefore turned our attention
to amino acids as a potential source of chirality, as they are more cost efficient. The synthesis of chiral‐
PN ligands from amino acids is well known,46‐51 and we chose to study valine, phenylglycine, and
phenylalanine as sources of iPr, Ph and CH2Ph chiral groups, respectively. The steps for the formation of
chiral PN‐ligands from amino acids are shown in Scheme 5.16 and given in detail in the experimental
section. The amino acid is first reduced with LiAlH4 to yield the amino alcohol, followed by protection of
the nitrogen with a BOC group to prevent unwanted side reactions. The alcohol is then tosylated to
allow for a facile substitution with potassium diphenylphosphide. The last step involves the removal of
the BOC protecting group with strong acid to yield the chiral PN compound with overall yields of 20‐30%
from the amino alcohol.
Scheme 5.16: Synthetic pathway for the formation of chiral PN complexes (14d‐f).
With three new chiral PN‐ligands (S)‐(14d‐f) in hand, we followed the procedure outlined in Scheme
5.15 to generate precatalysts (S)‐(10d‐f). All three new complexes were fully characterized by NMR, MS,
EA and IR, and in the case of (10d), by single crystal X‐ray diffraction (Figure 5.32). The new complexes
are structurally similar to the previously reported precatalysts (10b) and (10c), with 31P {1H} NMR shifts,
2JPP coupling constants, and IR ν(CO) stretching frequencies, in wavenumbers, shown in Table 5.7. All
carbonyl IR stretching frequencies are within the range of 2000‐2010 cm‐1 for the trans‐CO ligands, and
all 2JPP couplings are within the range of 81‐85 Hz for the trans‐31P nuclei of the P‐N‐P ligand, indicative
of the mer‐conformation of the pincer ligand about the catalyst, as observed in the crystal structures of
(10a‐c)35 and (10d). Relevant bond lengths and angles for (10d) are given in Figure 5.32, and are quite
similar to the values obtained in previous systems. In the pincer ligand, N(1)‐C(2) and N(1)‐C(3) bond
135
lengths of 1.286(11) and 1.511(7) Å, respectively, demonstrate that the ligand does contain an imine
group. The P‐Fe‐P bond angle is 170.25(7)o and the CO‐Fe‐CO bond angle is 172.5(4)o, indicative of a
slightly distorted octahedral complex.
Figure 5.32: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (10d). Hydrogen atoms of Ph and Cy
groups removed for clarity, as is the BF4 counterion. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.245(2); Fe(1)‐
P(2): 2.277(2); Fe(1)‐N(1): 1.998(5); Fe(1)‐Br(1): 2.473(1); N(1)‐C(2): 1.286(8); N(1)‐C(3): 1.511(7): O(1)‐C(11): 1.13(1); O(2)‐
C(12): 1.044(8); P(2)‐Fe(1)‐P(1): 170.25(7); C(11)‐Fe(1)‐C(12): 172.5(4).
136
Table 5.7: Comparative 31P {1H} NMR shifts, 2JPP coupling constants and IR v(CO) stretches for Precatalysts (10b‐f).
Precatalyst 31P {1H} NMR Shifts
(ppm)a
2JPP Coupling
Constants (Hz)
IR ν(CO)
(cm‐1)b
(10b) 70.8 (d) and 45.7 (d) 85.0 2005
(10c) 69.2 (d) and 67.8 (d) 81.0 2000
(10d) 66.8 (d) and 39.4 (d) 81.6 2009
(10e) 64.2 (d) and 42.6 (d) 82.1 2004
(10f) 63.3 (d) and 46.3 (d) 81.6 2006
a Solvent = THF‐d8; b KBr disk
5.3.3 Catalytic Asymmetric Hydrogenation of Acetophenone
With new precatalysts in hand, we were interested in testing their catalytic activity for the direct
hydrogenation of acetophenone to chiral 1‐phenylethanol using the previously established activation
methodology (LiAlH4, tAmOH, base). (10b) and (10c) both achieved TOFs of 1980 h‐1 and (10c) achieved
an e.e. of 80% at 50oC and 5 atm H2. Under the same conditions, (10d) achieved a TOF of 920 h‐1 and an
e.e. of 55%, whereas (10e) was slower and less selective achieving TOF of 460 h‐1 and an e.e. of 13%.
(10f) was significantly less active achieving TOF of 250 and an e.e. of 74%, however 20 atm H2 was
required for reproducible results. We are currently unsure as to why the activity drops so significantly on
going from (10b) (achiral) or (10c) (two chiral centres) to (10d‐f) (one chiral centre). We postulate that it
may have to do with PN‐backbone flexibility; in (10c) the two centres lock the orientation of the PN due
to interactions and steric repulsions of the Me and Ph groups, whereas in (10d‐f) with the single chiral
site, the backbone is not as rigid. In addition, the Ph, CH2Ph and iPr groups may induce structural
changes (puckering, folding, etc.) away from the optimal catalytic structure due to repulsion from the
rest of the P‐N‐P’ ligand (or P‐NH‐P’ ligand that forms after the activation of the catalyst). In the achiral
case (10b), there are no chiral centres to lock the ring, however there also aren’t functional groups
disrupting the structure, therefore it is less rigid, but also less likely to pucker. This also supports the
activity trend that (10d) is more active than (10f), whereby the bulkier ‐iPr side group has a more
pronounced, negative effect on the activity of the catalysts than the less bulky and more rigid –Ph group
of (10d). The rigidity argument also supports that (10d) is more active than (10e), which contains a
floppier –CH2Ph group. The next point to address is the effect of changing the chiral centres on the e.e.
of the reaction. As would be expected, on changing from two chiral centres in (10c) to one in (10d‐f) we
137
saw a fairly large drop in e.e., likely caused by the less rigid backbone structure. Also as would be
predicted, the e.e. is higher for the more sterically bulky system for the –iPr group (10f) than in the –Ph
and –CH2Ph systems.
Table 5.8: Catalytic activity and selectivity for the ADH of acetophenone to 1‐phenylethanol at 50oC.
Ph
O
Ph
OH
0.2 mol % Precatalyst
1.2 mol % LiAlH4
xs tAmOH
2.0 mol % KOtBu
THF, 50oC, H2
Precatalyst Pressure H2 (atm) TOF (h‐1) e.e. (%)
(10a) 5 1980 n/a
(10b) 5 1980 n/a
(S,S)‐(10c) 5 1980 80 (S)
(S)‐(10d) 5 920 55 (S)
(S)‐(10e) 5 460 13 (S)
(S)‐(10f) 25 250 74 (S)
(20) 25 800 n/a
5.3.4 Synthesis of Fe Complexes Bearing Multiple Stereogenic Centres
This significant influence on both activity and selectivity seen on going from two chiral centres to one
prompted us to investigate other possible PN‐ligands bearing two chiral centres. Given our tremendous
success with the diphenylethylene diamine (dpen) backbone in our ATH Fe‐(P‐N‐N‐P) catalysts,6,15,52 we
were interested in developing PN‐ligands bearing this type of functionality. Using commercially available
(1R,2S)‐2‐amino‐1,2‐diphenylethanol, the aminophosphine compound (1S,2S)‐2‐(diphenylphosphino)‐
1,2‐diphenylethanamine (14g), can be synthesized in an overall 37% yield employing the process
previously developed by Guo et. al.53 and depicted in Scheme 5.17. To summarize, the amine is first
protected with a BOC group to prevent unwanted side reactions with the primary amine functionality,
followed by cyclisation using thionyl chloride to form a sulfamidite. This could then be oxidized to the
sulfamidate using a catalytic amount of RuCl3‐nH2O and sodium periodate. Then, using potassium
diphenylphosphide, the sulfamidate can be ring opened in an SN2 fashion, reversing the chirality of the
nearest chiral centre, to yield the BOC‐protected PN‐ligand, which can be readily deprotected under
strongly acidic conditions.
138
Scheme 5.17: Synthetic pathway for the formation of the chiral PN compound (S,S)‐(14g).
With (S,S)‐(14g) in hand, we attempted to synthesize the corresponding trans‐[Fe(P‐N‐P’)(CO)2Br]+
complex using the method detailed in Scheme 5.15. Unfortunately, the synthesis was not as
straightforward as was previously described, likely due to significant steric and electronic changes when
the diphenyl backbone is used. Using a wide range of reaction solvents (THF, MeOH, acetone),
temperatures (0oC, room temperature and reflux (70oC)) and orders of reagent addition, we were not
able to synthesize the desired complex, but rather isolated brown powders. Upon crystallization and
analysis using single crystal X‐ray diffraction, we were able to identify the major product of our reaction
attempts as [Fe(PN)2(CO)Br][BF4] (15), as shown in Figure 5.33.
139
Figure 5.33: Molecular structure (thermal ellipsoids at 30% probability) of [Fe(PN)2(CO)Br][BF4] (15). Hydrogen atoms of Ph
groups and the BF4 anion are removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.2701(9); Fe(1)‐
P(1a): 2.2702(9); Fe(1)‐N(1): 2.045(3); Fe(1)‐N(1a): 2.045(3); Fe(1)‐Br(1): 2.451(2); Fe(1)‐C(3): 1.76(1); O(1)‐C(3): 1.17(1);
P(1)‐Fe(1)‐P(1a): 172.20(5); N(1)‐Fe(1)‐N(1a): 92.1(2); P(1)‐Fe(1)‐N(1): 83.3(1).
Interested in the potential reactivity of this complex, we devised an alternative route to the clean and
efficient synthesis of (15), depicted in Scheme 5.18. Using two equivalents of (14g) with FeBr2 under a
CO (g) atmosphere, followed by salt metathesis with NaBPh4, we were able to isolate the BPh4 salt of
(15) as a clean brown powder that could be characterized by NMR, MS, IR and, upon recrystallization, by
single crystal X‐ray diffraction. Complex (15) exhibited a much lower ν(CO) than (10) at 1944 cm‐1 versus
2000‐2010 cm‐1, indicative of a more electron donating trans N‐group versus the trans‐CO in (10). The
31P {1H} NMR spectrum exhibited two doublets at 84.6 and 76.6 ppm with 2JPP = 145.8 Hz, larger than the
81‐85 Hz observed for (10), but still indicative of trans‐phosphorus donors and therefore mer‐P‐N‐P’.
The P‐Fe‐P bond angle is 172.20(5)o, slightly greater than the ~170o angle in (10), while the Fe‐P and Fe‐
N bond lengths are similar. As would be expected from the IR ν(CO) difference, the C‐O bond of the
carbonyl in (15) is longer than that of (10); 1.169(12) Å in (15) versus 1.126(11) and 1.044(8) Å in (10),
indicative of more electronic back donation into the carbonyl antibonding orbital in the new system.
140
Scheme 5.18: Synthesis of [Fe(PN)2(CO)Br][BPh4] (15).
Still intent on generating the corresponding [Fe(P‐N‐P)(CO)2Br]+ complex with the 1,2‐diphenylethylene
backbone, we attempted to react (15) with phosphine‐aldehyde and CO (g) under varying conditions to
synthesize the desired complex. We were still unable, however, to generate the target precatalyst.
Given the presence of two chiral centres, potential structural rigidity due to steric repulsion of the two
chiral centres, and varied electronics of (14g), we hypothesize that if such a precatalyst could be formed,
it is likely that it would be both quite active and selective for direct hydrogenation of polar double
bonds, and therefore further attempts to synthesize this elusive complex are still underway.
Although (15) does not possess the initially desired structure, we were interested in whether it could be
catalytically active. Unfortunately, under pressures of up to 25 atm H2 and temperatures of up to 50oC
we saw no conversion of ketones or imines to their corresponding alcohols or amines. Given the
structural similarities of our new iron system to our [Fe(P‐N‐N‐P)(CO)Br]+ TH catalysts,6,10,12 we were also
interested in the hydrogenation of ketones or imines using isopropanol as the proton and hydride
source. Unfortunately, the system was once again inactive for TH catalysis. In our previous iron catalysts,
the P‐N‐N‐P ligand was always planar, whereas the two PN‐ligands of (15) are not in a plane, which may
block access to catalytically active states or sites. It is also worth pointing out, that with the tetradentate
system, a variant of the catalyst was made where there were amine linkages, [Fe(P‐NH‐NH‐P)(CO)Br]+.
This system was found to be significantly less active than its diimine counterpart.8 This may help explain
why our system, which contains NH2 groups, was not catalytically active.
141
5.3.5 Changing the Catalyst Structure Using 6,5‐(P‐N‐P) Ligands
Given that catalysis and enantioselectivity appeared to be strongly influenced by the structure and
flexibility of the P‐N‐P pincer ligand, we chose to explore a new class of ligands on iron with a larger
ligand architecture. As discussed in previous chapters, our group has developed three generations of
iron‐(P‐N‐N‐P) catalysts for use in hydrogenation.6,10,11 All catalyst ligands are formed via the
condensation of a diamine with phosphine‐aldehydes, much like the formation of the P‐N‐P ligands
previously discussed. In the first generation TH systems, o‐phenylene linkers were utilized, making a
6,5,6‐ ring system around iron, as discussed in Chapter 2, which gave the ligand the flexibility to bend up
and form the ferraaziridine and ferraaziridinido species (3) and (4) respectively.7,16 In the second and
third generation P‐N‐N‐P catalysts, much like the P‐N‐P systems discussed here, phosphonium dimers
were used to generate smaller phosphine‐aldehydes in situ, that gave rise to 5,5,5‐ ring systems on
iron.6,10 These 5,5,5‐systems were rigid and prevented the folding of the ligand during TH catalysis.8,54
Another interesting feature of the ligands in the different generations was the fact that the 6,5,6‐(P‐N‐N‐
P) ligands could be made without the presence of iron, unlike the 5,5,5‐systems that required iron as a
template. This made the reduction of the imine functionalities to amines feasible with the 6,5,6‐system,
allowing for the introduction of an N‐H functionality.55‐57
Combining these concepts, we sought to develop a new generation of P‐N‐P ligands using larger, and
more flexible o‐phenylene linkers, as well as a related series of P‐NH‐P ligands, all of which were to be
tested for hydrogenation as iron catalysts. To synthesize the 6,5‐(P‐N‐P) ligands, we applied a similar
methodology to that previously developed for the synthesis of P‐N‐N‐P ligands;11,55‐58 the condensation
of o‐(diphenylphosphino)benzaldehyde with PN‐ligands (14) in the presence of a drying agent, as shown
in Scheme 5.19. Upon workup, this preparation yielded a wide variety of chiral P‐N‐P ligands (16), in
yields varying from 46‐75%. All of the compounds were characterized by NMR, MS and EA. In the NMR
spectra, 1H chemical shifts for the imine ranged from 8.4‐9.0 ppm, and all species showed two sharp
singlets in the 31P NMR spectrum. (16a) has peaks at ‐13.2 and ‐19.5, (16c) at ‐8.1 and ‐14.5, (16d) at ‐
12.8 and ‐22.9, (16e) at ‐14.1 and ‐23.1, (16f) at ‐13.3 and ‐22.0 and (16g) at ‐7.2 and ‐15.4 ppm. The
achiral ligand (16a) was synthesized and characterized previously by Bluhm et. al.59 who also made a
large series of structurally similar achiral ligands containing P, N, S, and O donor groups. All of these
pincer ligands were used in the synthesis of Cr(‘Y’N‘Z’)Cl3 systems, such as Cr(P‐N‐P)Cl3; these complexes
in turn were used for the oligomerization and polymerization of ethylene, as well as for the selective
formation of 1‐hexene. Similar achiral P‐N‐N ligands have also been developed, where in the place of the
142
diphenylphosphine moiety of the PN‐ligand, Wehman et. al. used a pyridine group, that allowed for the
synthesis of stable Pd(II) and Pd(0) P‐N‐N complexes.60 Kawamura et. al. published the synthesis of a
chiral P‐N‐P ligand derived from valine that is similar to (16f) that contained a 3,5‐di‐tert‐butyl‐
phenylene linker in the place of our unfunctionalized phenylene‐linker.61 They used this ligand with
copper in the asymmetric 1,4‐addition of diethylzinc to 2‐cyclohexen‐1‐one, however, the e.e. of the
resulting ketone was only moderate and activity was quite low.
H
O
PPh2H2N
PPh2R1
Na2SO4
DCM, 24 hPPh2
N PPh2
R1R2
R2
(16a) R1 = R2 = H
(S,S)-(16c) R1 = Me, R2 = Ph
(S)-(16d) R1 = Ph, R2 = H
(S)-(16e) R1 = CH2Ph, R2 = H
(S)-(16f) R1 = iPr, R2 = H
(S,S)-(16g) R1 = R2 = Ph
+
Scheme 5.19: Condensation reaction of phosphine aldehyde with (14) to generate enantiopure P‐N‐P ligands (16).
The next stage of our investigation was the synthesis of the corresponding series of P‐NH‐P ligands (17)
as depicted in Scheme 5.20. It was previously reported that the P‐N‐N‐P ligands could be reduced in the
presence of NaBH4 to yield the corresponding P‐NH‐NH‐P ligands, and we therefore tested this
methodology first.8,55‐57 This was effective for the achiral system (17a), as was also reported by Bluhm,59
who tested the chromium complex as discussed previously. The use of NaBH4 was also effective for the
generation of (17c), with the Me/Ph PN‐backbone, however (17d‐f) could not be effectively reduced.
Under similar reaction conditions and times, (16d‐f) were less than half reduced to (17d‐f), and
prolonged exposure gradually led to decomposition and some ligand oxidation (some phosphine oxides
were detected). To cleanly form (17d‐f), LiAlH4 was used, which allowed for the complete reduction of
the imine bond in those cases. Therefore, the imine bonds of the ligands with a single chiral centre are
more difficult to reduce, once again supporting the observation that these systems have significantly
different behaviour than the achiral and norphedrine derivatives. The P‐NH‐P ligands were fully
characterized by NMR, MS and EA. 1H NMR spectroscopy showed the disappearance of the imine
proton, and 31P {1H} spectra once again exhibited two sharp singlets for the inequivalent phosphorus
143
atoms. (17a) has peaks at ‐16.1 and ‐20.6, (17c) at ‐11.2 and ‐16.2, (17d) at ‐16.4 and ‐23.5, (17e) at ‐
16.0 and ‐23.4 and (17f) at ‐16.1 and ‐22.2 ppm. With the exception of the achiral P‐NH‐P ligand
developed by Bluhm,59 this is a new, and novel series of ligands. Structurally similar P‐N‐N ligands
bearing an N‐H group have been developed and studied extensively by Clarke and coworkers for the
direct and transfer hydrogenation of ketones using ruthenium.62‐64 They have also investigated the effect
of varying the substituents on phosphorus,65 much like our group has done with our P‐N‐N‐P ligands,13,14
to improve the e.e. of the hydrogenation reactions. Furthermore, they explored the role of the N‐H in
catalysis by designing a series of P‐NR‐NR’2 ligands66 and found these to be less active in ketone
hydrogenation than their P‐NH‐NH2 counterparts, indicating the importance of the N‐H in the ligand
structure.
Scheme 5.20: Reduction of P‐N‐P ligands (16) to form chiral P‐NH‐P ligands (17).
Following the successful synthesis and characterization of a new library of P‐N‐P and P‐NH‐P ligands, we
then investigated their coordination to iron. This was initially probed using [Fe(H2O)6][BF4]2 in MeCN
under ambient conditions under an inert atmosphere to generate the corresponding [Fe(P‐N‐
P)(NCMe)3][BF4]2 (18) and [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19) complexes, as depicted in Scheme 5.21. The
reactions were very clean and most were nearly quantitative, with yields ranging from 83‐99%. The
complexes with imine functionalities (18) were isolated as deep red powders and the complexes with
the N‐H ligand (19) were isolated as bright pink‐purple powders.
144
Scheme 5.21: Synthesis of [Fe(P‐N‐P)(NCMe)3][BF4]2 (18) and [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19) from P‐N‐P (16) and P‐NH‐P
(17), respectively.
All of the new complexes were characterized using NMR, MS and EA techniques, and (18a) and (18e)
were characterized crystallographically as depicted in Figure 5.34 and Figure 5.35, respectively. The 1H
NMR spectra of (18) have singlets for the imine proton in the range of 7.9‐8.8 ppm, which are no longer
present in (19), indicating that the imine has been reduced. 31P {1H} NMR spectra of these species
proved to be quite useful for their characterization, as they exhibited two doublets in the 40‐70 ppm
range with 2JPP in the range of 138‐152 Hz. Complex (18) had slightly larger 2JPP in the range of 149‐152
Hz, versus (19), which were in the range of 138‐142 Hz. In the 31P NMR spectra, complexes with two
chiral centres exhibited distinctly different doublets, whereas the doublets for the complexes with a
single chiral centre exhibited a slight roofing effect (2nd order patterning). The achiral complexes, on the
other hand, demonstrated extreme second order patterns. Crystal structures of (18a) and (18e) were
quite similar in terms of common bond lengths and angles. The imine C=N bond for both was 1.279‐
1.291 Å long, indicative of a C‐N double bond, in comparison to the other side of the ligand which had C‐
N bonds with lengths of 1.485‐1.495 Å, indicative of a C‐N single bond.
145
Figure 5.34: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (18a). Hydrogen atoms of Ph groups
and BF4 anion are removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.2732(8); Fe(1)‐P(2):
2.3044(8); Fe(1)‐N(1): 1.972(2); Fe(1)‐N(2): 1.922(2); Fe(1)‐N(3): 1.932(2); Fe(1)‐N(4): 1.907(2); N(1)‐C(7): 1.279(3); N(1)‐C(8):
1.485(3): P(2)‐Fe(1)‐P(1): 173.82(3); N(1)‐Fe(1)‐P(1): 89.82(6); N(1)‐Fe(1)‐P(2): 84.76(6).
146
Figure 5.35: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (18e). Hydrogen atoms of Ph groups
and BF4 anion are removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.287(1); Fe(1)‐P(2): 2.256(1);
Fe(1)‐N(1): 1.976(3); Fe(1)‐N(2): 1.896(4); Fe(1)‐N(3): 1.928(4); Fe(1)‐N(4): 1.925(3); N(1)‐C(3): 1.291(5); N(1)‐C(2): 1.495(5):
P(2)‐Fe(1)‐P(1): 173.44(4); N(1)‐Fe(1)‐P(1): 84.32(9); N(1)‐Fe(1)‐P(2): 89.12(9).
Following the development of a new library of chiral and achiral iron‐P‐N‐P and iron‐P‐NH‐P complexes,
we tested (18) and (19) for various types of catalysis. Unfortunately, neither the P‐N‐P or P‐NH‐P
complexes were active for the direct or transfer hydrogenation of ketones or activated imines. Direct
hydrogenation trials were conducted at 50 oC and 25 atm H2, employing the previously developed
LiAlH4/tAmOH/KOtBu activation process. A simplified process employing only KOtBu was tested as well.
Transfer hydrogenation was tested in an argon glovebox at 28 oC in iPrOH using KOtBu. Unfortunately,
the hydrogenation of ketones to alcohols and imines to amines was not successful under any of the
conditions explored. Given the success of our previously developed [Fe(P‐N‐N‐P)(NCMe)2][BF4]2 systems
to dehydrogenate AB,67 as discussed in Chapter 4, we also tested the achiral complexes (18a) and (19a)
for the catalytic release of H2. Unfortunately, these systems were once again inactive in the presence of
base. Although straightforward to synthesize and handle, these systems appear to be too stable to be
147
catalytically active for the transformations we have explored, and a more complete investigation into
potential applications of these systems is still required.
The next phase of our investigation was to explore the newly developed ligand scaffolds using FeBr2 and
CO (g) as has been previously discussed. Beginning with the achiral imine ligand (16a) we investigated
potential routes for synthesizing Fe(P‐N‐P)(CO)Br2 complexes. Stirring (16a) and one equivalent of FeBr2
under N2 for 45 minutes, followed by rapid freezing of the reaction solution with liquid nitrogen and
atmosphere evacuation, along with subsequent introduction of CO (g) and thawing, led to the clean
formation of Fe(P‐N‐P)(CO)Br2 (20a) in 85% yield as a red‐orange powder. The complex (20a) could also
be synthesized using a template reaction with FeBr2, (14a) and o‐(diphenylphosphino)benzaldehyde,
however, the product was more difficult to extract and purify because unidentified side products were
also forming. The structure of (20a) was confirmed by X‐ray crystallography, as shown in Figure 5.36,
and the complex was fully characterized using NMR, IR, MS and EA. The imine proton was seen in the 1H
NMR spectrum at 8.36 ppm, and this was also confirmed by the crystal structure which had C(2)‐N(1)
and C(3)‐N(1) bond lengths of 1.489(3) and 1.283(3) Å corresponding to the C‐N and C=N bonds of the
ligand backbone, respectively. In the IR spectrum of (20a), the carbonyl stretching wavenumber was
1961 cm‐1, much lower than that of (10a‐f) (2004‐2010 cm‐1) indicating a more electron rich iron centre
than the trans‐dicarbonyl species. The inequivalent phosphorus atoms of the ligand appear as doublets
in the 31P {1H} NMR spectrum at 44.0 and 39.6 ppm with a 2JPP = 216.9 Hz, indicative of trans‐phosphorus
donors. This implies a mer‐ geometry for the ligand, as observed in the crystal structure, yielding the
overall geometry of mer‐cis‐Fe(P‐N‐P)(CO)Br2 (bromides cis). Also observed in the 31P {1H} NMR
spectrum was a second set of doublets at 64.8 and 57.8 ppm with a 2JPP = 184 Hz. This was identified as
the trans‐Br species from the crystal structure, present in 8% based on the cis Br/CO disorder in the
molecular structure.
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Figure 5.36: Molecular structure (thermal ellipsoids at 30% probability) of precatalyst (20). Hydrogen atoms of Ph groups
removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.2668(8); Fe(1)‐P(2): 2.2653(8); Fe(1)‐N(1):
1.987(2); Fe(1)‐Br(1): 2.4821(5); Fe(1)‐Br(2): 2.4787(5); Fe(1)‐C(10): 1.776(4); N(1)‐C(2): 1.489(3); N(1)‐C(3): 1.283(3): O(1)‐
C(10): 1.097(5); P(2)‐Fe(1)‐P(1): 174.36(3); C(10)‐Fe(1)‐Br(1): 178.2(1); Br(2)‐Fe(1)‐Br(1): 96.52(2).
With (20a) in hand, we tested the direct hydrogenation of ketones using the LiAlH4/tAmOH/KOtBu
process previously developed. At 50 oC and 5 atm H2 catalysis was slow and irreproducible. At 50 oC and
25 atm H2, catalysis with a ratio of (20a):KOtBu:acetophenone = 1:13:500 was 80% complete in 30
minutes, and 98% complete in an hour, yielding a TOF of 800 h‐1. This is lower than the corresponding
precatalysts (10a) and (10b), which exhibited TOFs of 1980 h‐1 under the milder H2 pressure of 5 atm.
However, (20a) has diphenylphosphine groups on both sides of the P‐N‐P ligand, unlike (10a) and (10b)
which have a diphenylphosphine group on one side and an alkyl substituted phosphorus donor on the
other side. For the achiral 5,5‐(P‐N‐P) iron complex, when both phosphorus donors were
diphenylphosphine groups, the pre‐catalyst was completely inactive,35 indicating that the incorporation
of the o‐phenylene linker to generate a 6,5‐(P‐N‐P) system may have positively influenced reactivity as
targeted.
Although previous investigations demonstrated that the various complexes (10d‐f) with one stereogenic
centre yielded lower e.e. than the one with two (10c), we were interested in synthesizing and testing the
149
complete series with the o‐phenylene linker, as was done with (20a), to determine whether the same
trends were maintained on changing the ligand structure and flexibility. Unfortunately, we ran into
difficulties attempting to coordinate our pre‐synthesized chiral P‐N‐P and P‐NH‐P ligands to FeBr2.
Following various methodologies we were unable to isolate Fe(P‐N‐P)(CO)Br2 or [Fe(P‐N‐P)(CO)2Br]+
complexes bearing the new chiral ligands developed. Using in situ 31P NMR spectroscopy of reaction
solutions under a CO (g) headspace we were able to detect a pair of doublets, indicating that a single
iron species was forming, however, upon workup, decomposition occurred. Investigating this
decomposition we learned that the iron species were unstable when no longer under a CO (g)
atmosphere, leading to the formation of several species, some of which were paramagnetic, as
evidenced by the highly broadened NMR spectra. Confirming the presence of paramagnetic species,
Fe(PPh2C6H4CHNCHiPrCH2PPh2)Br2 crystallized out of the reaction mixture while attempting to
synthesize (20f) and was characterized crystallographically, as shown in Figure 5.37. The complex is
trigonal bipyramidal with a much narrower P‐Fe‐P angle of 158.78(13)o versus the 170‐175o range seen
with the previously characterized octahedral Fe(P‐N‐P) complexes. The Fe‐Br bonds are of comparable
length to the previous complexes, however, the Fe‐N and two Fe‐P bonds are much longer: Fe(1)‐N(1) of
2.249(10) versus 1.97‐2.04 Å and Fe(1)‐P(1) and Fe(1)‐P(2) of 2.620(4) and 2.500(3) versus 2.25‐2.30 Å.
This indicates a more weakly and loosely bound ligand in this case, explaining why they decompose so
readily. The imine moiety is maintained in the complex with C(6)‐N(1) and C(2)‐N(1) bonds of 1.298(17)
and 1.482(16) Å for the C=N and C‐N bonds respectively.
150
Figure 5.37: Molecular structure (thermal ellipsoids at 30% probability) of Fe(P‐N‐P)Br2 (iPr). Hydrogen atoms of Ph groups
removed for clarity. Selected bond lengths (Å) and angles (deg): Fe(1)‐P(1): 2.620(4); Fe(1)‐P(2): 2.500(3); Fe(1)‐N(1): 2.25(1);
Fe(1)‐Br(1): 2.453(2); Fe(1)‐Br(2): 2.377(2); N(1)‐C(2): 1.48(2); N(1)‐C(6): 1.30(2): P(2)‐Fe(1)‐P(1): 158.8(1); Br(2)‐Fe(1)‐Br(1):
122.3(1); N(1)‐Fe(1)‐P(1): 78.1(3); N(1)‐Fe(1)‐P(2): 80.8(3).
The results discussed in this chapter raise more questions about what structural features are required to
generate highly active and selective iron catalysts for direct hydrogenation. More work is currently
underway to further probe these systems, but is beyond the scope of this thesis chapter. For example,
analogues of the commercially available o‐(diphenylphosphino)benzaldehyde with PR2 groups (R = Cy,
iPr) are known, and can be used to generate systems like (20a). New methodologies need to be
developed to synthesize a wider range of more rigid P‐N‐P and P‐NH‐P ligands and their iron complexes
in order to apply these in catalytic processes. These ideas will be further detailed in Chapter 6 in the
Future Work section.
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5.4 Conclusions
The activation process and mechanism of catalysis of our recently developed [Fe(P‐N‐P’)(CO)2Br][BF4]
complexes was studied further. The alkoxide‐monohydride complex (11a), previously identified as an
intermediate in the activation of the catalyst was treated with base and H2 and shown by NMR
spectroscopy to form a trans‐dihydride complex (13) that was catalytically active towards the direct
hydrogenation of ketones. To further expand the range of available pre‐catalysts, we synthesized a
series of enantiopure PN‐ligands derived from amino acids. These were condensed with phosphonium
dimers and used to synthesize mer‐trans‐[Fe(P‐N‐P)(CO)2Br][BF4] complexes (10d‐f) derived from (S)‐
phenylglycine, (S)‐phenylalanine and (S)‐valine, respectively, which were shown to be catalytically active
for the direct hydrogenation of ketones under mild conditions. The new systems were slower and less
enantioselective than the original catalyst, which contained a PN moiety derived from (S,S)‐
norephedrine (10c). This is likely due to increased flexibility of the ligand, and a reduction in the number
of stereogenic substituents. Under comparable conditions the TOF for acetophenone hydrogenation
decreased as (10a‐c) (1980 h‐1) > (10d) (920 h‐`1) > (10e) (460 h‐1) > (10f) (250 h‐1) while the e.e of the (S)‐
1‐phenylethanol produced decreased as (10c) (80%) > (10f) (74%) > (10d) (55%) > (10e) (13%).
Given the subtle interplay of ligand rigidity, and the involvement of an N‐H in the ligand backbone in the
reaction mechanism, we developed a new series of P‐N‐P and P‐NH‐P ligands with an o‐phenylene linker
on one side of the ligand to significantly increase ligand flexibility. This new library of ligands was
coordinated to iron to make a series of [Fe(P‐N‐P)(NCMe)3][BF4]2 (18) and [Fe(P‐NH‐P)(NCMe)3][BF4]2
(19) complexes that were shown to be quite stable, but inactive towards hydrogenation (direct or
transfer) and AB dehydrogenation. Lastly, we coordinated our achiral P‐N‐P ligand (16a) to FeBr2 under
CO (g) to generate a new precatalyst mer‐cis‐Fe(P‐N‐P)(CO)Br2 which was active for the direct
hydrogenation of acetophenone with a TOF of 800 h‐1 at 50 oC and 25 atm H2. Unfortunately the chiral
variants of this system decomposed when removed from a CO (g) atmosphere.
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5.5. Experimental
5.5.1 General Considerations
All procedures and manipulations were performed under an argon or nitrogen atmosphere using
standard Schlenk‐line and glove box techniques unless stated otherwise. All solvents were degassed and
dried using standard procedures prior to all manipulations and reactions unless stated otherwise.
Deuterated solvents were purchased from Cambridge Isotope Laboratories or Sigma Aldrich, degassed,
and dried over activated molecular sieves prior to use. All other reagents were purchased from
commercial sources and utilized without further purification. NMR spectra were recorded at ambient
temperature and pressure using a Varian Gemini 400 MHz spectrometer (400 MHz for 1H, 100 MHz for
13C, 376 MHz for 19F, and 161 MHz for 31P), or an Agilent DD2‐600 MHz spectrometer (600 MHz for 1H,
151 MHz for 13C, 564 MHz for 19F, and 243 MHz for 31P) unless stated otherwise. The 1H and 13C NMR
chemical shifts were measured relative to partially deuterated solvent peaks but are reported relative to
tetramethylsilane (TMS). All 31P chemical shifts were measured relative to 85% phosphoric acid as an
external reference. Gas Chromatography was done on a Perkin Elmer Clarus 400 Chromatograph
equipped with a chiral column (CP chirasil‐Dex CB 25 m x 2.5 mm) to determine substrate conversion
and enantiopurity. Hydrogen gas was used as the mobile phase, and the oven temperature was set at
130°C. Retention times for phenylethanol are 7.58 and 8.03 minutes, and for acetophenone is 4.56
minutes. All of the hydrogenation reactions were performed in a 50 mL stainless steel Parr
Hydrogenation reactor at constant temperatures and pressures. The temperature was maintained at
50°C using a constant temperature water bath and was purged of oxygen by flushing the reactor several
times with 5 atm of H2 (g). The elemental analyses were performed on a Perkin‐Elmer 2400 CHN
elemental analyzer. Some complexes gave unsatisfactory carbon analyses but acceptable hydrogen and
nitrogen content because of a combustion problem due to the tetrafluoroborate, hexafluorophosphate
and tetraphenylborate anions, as previously reported in the literature.68 These complexes are denoted
with ** following the EA results.
5.5.2 Synthesis of Precatalysts for NMR Studies
Iron precatalysts (10a,b,c) were generated according to the reported literature procedure, as were the
alkoxide mono‐hydride complexes FeH(OR’)(CO)(P‐CH2NH‐P′) (11), as shown in Figure 5.38.35
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Figure 5.38: 1H NMR spectrum (600 MHz, THF‐d8) of methoxide‐hydride (11a). Peaks: ‐21.6 (dd) and ‐22.7 (dd) ppm, 2JPH =
52.0 and 56.4 Hz.
5.5.3 Synthesis of trans‐dihydride complex (13)
Following the same procedure as outlined for the alkoxide mono‐hydride complexes FeH(OR’)(CO)(P‐
CH2NH‐P′) (11a)35 a THF‐d8 solution (0.6 mL) of the complex was transferred to a Schlenk flask and
exposed to hydrogen. After stirring under H2 (g) for 5 minutes, base (approx. 8 mg) was added in THF‐d8
(0.3 mL) and stirred under H2 (g) for 30 minutes. Upon addition of base, the bright orange solution
rapidly turned bright pink, then dark green/brown. The solution was then injected into an NMR tube
filled with H2 (g) and analysed. Key NMR spectra are depicted in Figure 5.39, Figure 5.40, Figure 5.41,
Figure 5.42 and Figure 5.43.
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Figure 5.39: 1H NMR spectrum (500 MHz, THF‐d8) of trans‐dihydride (13).
Figure 5.40: 1H NMR {31P‐fully decoupled} spectrum (500 MHz, THF‐d8) of trans‐dihydride (13). Peaks: ‐9.05 (d) and ‐9.16 (d)
ppm, 2JHH = 9.8 Hz.
155
Figure 5.41: Simulated 1H NMR spectrum of trans‐dihydride (13). Simulated using hydride shifts ‐9.05 and ‐9.16 ppm, 2JHH =
9.8 Hz, 2JPP = 118.0 Hz, and
2JHP = 42.0, 42.0, 43.0, and 43.0 Hz.
Figure 5.42:31P {1H} NMR spectrum (202 MHz, THF‐d8) of trans‐dihydride (13) doublets at 118.0 and 95.8 ppm (2JPP = 118 Hz),
cis‐dihydride doublets at 114.6 and 93.0 ppm (2JPP = 72.5 Hz) and Fe0 complex (12) at 102.8 and 81.5 ppm.
156
Figure 5.43: 1H NMR spectrum (500 MHz, THF‐d8) of trans‐dihydride (13) at ‐9.1 ppm and cis‐dihydride at ‐8.1 and ‐20.6 ppm.
To further remove the excess base, solutions were dried under reduced pressure, then benzene (3 mL)
was added to the solution in a vial in a nitrogen filled glovebox. The solution was then filtered through
Celite, dried, and put under H2 (g). To the dried solution, THF‐d8 (0.7 mL) was added and further stirred
under H2 (g) for 10 minutes and analysed.
For the chiral system (13c), a similar workup was undertaken starting from (10c). Key NMR spectra are
depicted in Figure 5.44.
Figure 5.44: 1H NMR spectrum (600 MHz, THF‐d8) of trans‐dihydride (13c) at ‐8.56 (ddd) and ‐8.94 (td) ppm and cis‐dihydride at ‐7.31 (ddd) and ‐21.0 (td) ppm.
157
5.5.4 Hydrogenation Studies
For preformed catalyst systems: Stock solutions of acetophenone (0.3 mL, 2.6 mmol) in THF (7 mL) were
injected into Parr reactors heated to 50 0C and pressurized to 5 atm H2 (g) against a flow of hydrogen.
12‐inch needles equipped with 1 mL syringes were used to remove THF‐d8 solutions from rubber‐
septum capped NMR tubes prepared above, and injected into the reactors against a flow of hydrogen.
At set times, small amounts of sample were removed from the reactor using a needle and syringe under
a flow of hydrogen and injected into the Gas Chromatograph for analysis.
For in situ generated systems: In an argon filled glovebox, a vial was charged with [Fe(CO)2(Br)(P‐N‐
P′)][BF4] (5 mg, 0.006 mmol) and 3 mL THF. To this solution, 0.05 mL of LiAlH4 (1.0 M in THF) was added
and the color of the solution immediately changed from pink to dark brown. After stirring for 5 minutes,
2‐methyl‐2‐butanol (0.5 mL) was added and the solution was allowed to stir for an additional 10
minutes. The solution was transferred to a syringe equipped with a 12 inch needle. The same vial was
then charged with acetophenone (0.35 mL, 3.0 mmol) and 3 mL THF. The solution was taken up into the
same syringe that already contained the precatalyst solution and stoppered. In a second syringe
equipped with a 12 inch needle, a solution of base (0.08 mmol) in 3 mL THF was taken up and
stoppered. Both syringes were removed from the glovebox and injected into Parr reactors heated to 50
0C and pressurized to 5 atm H2 (g) against a flow of hydrogen. At set times, small amounts of sample
were removed from the reactor using a needle and syringe under a flow of hydrogen and injected into
the Gas Chromatograph for analysis.
For cryptand addition experiments: a third syringe equipped with a 12‐inch needle was charged with
2,2,2‐cryptand (36 mg, 0.095 mmol) in 0.8 mL THF and stoppered. This solution was injected into the
Parr reactor 2 minutes after the addition of the catalyst/acetophenone and base solutions, and run the
same as discussed above.
5.5.5 Synthesis of PN Precursors (14defg)
Many of these individual steps are published elsewhere,46‐51,53 so the series of steps required for the
generation of the various PN‐ligands illustrated in Scheme 5.16 and Scheme 5.17 are briefly summarized
here:
For (14d‐f), illustrated with (14d):
158
BOC‐Protection: Following a LiAlH4 reduction of commercially available amino acids,69 the corresponding
amino alcohols were purified using a short silica plug to remove alumina‐containing impurities.
Phenylglycinol (2.7 g, 20 mmol) was dissolved in 60 mL DCM and NEt3 (2.8 mL, 21 mmol), then cooled to
0oC. To the cooled solution, (Boc)2O (4.6 g, 21 mmol) in 10 mL DCM was added and stirred for 18 h,
being allowed to slowly warm to RT. 80 mL H2O was added and allowed to stir for a further 0.5 h and
then the organics were collected, and the aqueous phase was washed with DCM (2 x 50 mL). The
organics were combined, washed with brine (2 x 70 mL) and H2O (70 mL), then dried with Na2SO4,
filtered and dried under reduced pressure to yield a white solid.
Tosylation: The white solid (BOC‐protected) (5.0 g, 21.5 mmol) was dissolved in 120 mL DCM and NEt3 (7
mL, 54 mmol), then cooled to 0oC. To the cooled solution, TsCl (5.0 g, 26 mmol) was added and stirred
for 18 h, being allowed to slowly warm to RT. 100 mL H2O was added and allowed to stir for a further 1 h
and then the organics were collected, and the aqueous phase was washed with DCM (2 x 70 mL). The
organics were combined, washed with brine (2 x 70 mL), aqueous NH4Cl (2 x 70 mL) and H2O (2 x 70 mL),
then dried with Na2SO4, filtered and dried under reduced pressure to yield a white solid.
Phosphide Reaction: All steps of this synthesis were conducted using an inert argon atmosphere. In a
flask KPPh2 (from 2 g HPPh2 and 450 mg KH – 10 mmol) was dissolved in 70 mL THF and transferred to a
Schlenk line. The solution was cooled to ‐40oC and the white solid (tosylated product) (2 g, 5 mmol) in 25
mL dry THF was added dropwise to the cooled solution. The solution was stirred at ‐40oC for 6 h, then
warmed to RT and stirred for 10 h, then dried under reduced pressure to yield a bright orange residue.
In a nitrogen filled glovebox, the residue was quickly dissolved in 70 mL pentane, and the excess
phosphide was quenched dropwise with ~3 mL MeOH. The white KOMe by‐product was filtered off and
the solution was concentrated to half volume. The solution was then placed in a freezer for 0.5 h, and a
white powder was collected and dried.
BOC Deprotection: (*inert atmosphere) The white solid (from phosphide reaction) (0.68 g, 1.7 mmol)
was dissolved in 30 mL distilled DCM and cooled to 0oC. To the cooled solution, CF3CO2H (5.5 mL) was
added dropwise and the solution was stirred at 0oC for 1 h then RT for 14 h, before being quenched with
40 mL degassed H2O. Then, the organics were collected and the aqueous phase was extracted with DCM
(2 x 20 mL). The organics were combined and washed with NaHCO3 (30 mL) and water (50 mL). The
solution was dried with Na2SO4, filtered, and dried under reduced pressure, to yield an off‐white solid.
Overall Yield from phenylglycinol = 27%. Characteristic 31P {1H} NMR peaks at ‐22.0 (14d), ‐22.5 (14e)
and ‐21.7 (14f) ppm.
159
For (14g):
BOC‐Protection: To a flask containing commercially available (1R,2S)‐(‐)‐2‐amino‐1,2‐diphenylethanol (3
g, 14 mmol) and sodium carbonate (3.5 g, 33 mmol), 60 mL THF and 30 mL H2O were added and the
solution was cooled to 0oC under air. To the cooled solution, (Boc)2O (3.5 g, 16 mmol) in 15 mL THF was
added. The solution was stirred at 0oC for 1 h, then RT for 3 h, before 60 mL H2O was added and stirred
for an additional 0.5 h. The organics were collected, and the aqueous phase was washed with ethyl
acetate (2 x 50 mL). The organics were combined, washed with brine (2 x 70 mL) and H2O (70 mL), then
dried with MgSO4, filtered and dried under reduced pressure. To the residue, 18 mL of DCM was added
to partially dissolve the residue, followed by 150 mL of hexanes. The slurry was stirred for 18 h and the
white solid was collected by filtration and dried under reduced pressure to yield a pure, white solid.
Cyclisation: The resultant white powder (3.9 g, 12 mmol) was dissolved in 110 mL of DCM and NEt3 (5.2
mL, 51 mmol), and the solution was cooled to ‐40oC. To the cooled solution, SOCl2 (1.5 mL, 13 mmol) in 9
mL DCM was added and the cooled solution was stirred for 1.5 h. It was then quenched with 8 mL H2O,
warmed to RT, and the organics were extracted. The aqueous phase was washed with DCM (2 x 30 mL),
then the organics were combined and washed with brine (2 x 70 mL) and water (70mL). The solution
was then dried with MgSO4, filtered and dried under reduced pressure to yield the crude residue.
Oxidation: The crude residue from cyclisation (4.4 g, 12 mmol) was dissolved in 25 mL DCM, 40 mL
MeCN and 50 mL H2O then cooled to 0oC before RuCl3‐nH2O (26 mg) was added. NaIO4 (4 g, 19 mmol)
was added in portions and the solution was stirred at 0oC for 1 h, then RT for 1.5 h. The organics were
collected, and the aqueous phase was washed with ether (2 x 40 mL). The combined organics were
washed with brine (2 x 70 mL) and water (30mL), then the solution was dried with MgSO4, filtered and
the solvent was removed under reduced pressure. The residue was dissolved in 8 mL of DCM and stirred
with 100 mL of hexanes for 5 hours, to yield a white solid that was collected by filtration and dried under
reduced pressure to yield a pure, white solid.
Phosphide Reaction: All steps of this synthesis were conducted using an inert argon atmosphere. The
white solid (from oxidation) (3 g, 8 mmol) was dissolved in 40 mL dry THF and cooled to ‐78oC. To the
cooled solution, KPPh2 (from 1.7 g HPPh2 and 400 mg KH – 8.5 mmol) in 20 mL THF was added dropwise,
and the solution was stirred at ‐78oC for 1.5 h, then RT for 18 h. To quench the excess phosphide, 25 mL
degassed brine and 2.5 mL 2N H2SO4 (degassed) were added and the solution was stirred for 1 h.
Degassed aqueous Na2CO3 (~10 mL) was added to make the solution slightly basic, and then the organics
160
were collected. The aqueous phase was extracted with 15 mL DCM, and then the organics were
combined and washed with brine (2 x 30 mL) and water (20 mL). The solution was dried with MgSO4,
filtered, and the solvent removed under reduced pressure. To the residue, 10 mL MeOH and 10 mL
MeCN were added and stirred for 4 h. The slurry was cooled in the freezer for 1 h, then the white solid
was collected and dried under reduced pressure.
BOC Deprotection: (*inert atmosphere) The white solid (from phosphide reaction) (3 g, 6.2 mmol) was
dissolved in 25 mL distilled DCM and cooled to 0oC. To the cooled solution, CF3CO2H (7 mL) was added
dropwise and the solution was stirred at 0oC for 1 h then RT for 4 h, before the solvent was removed
under reduced pressure. The residue was dissolved in 25 mL DCM, neutralized with degassed aqueous
Na2CO3 (~25 mL), and the organics were collected. The aqueous phase was extracted with 15 mL DCM,
and then the organics were combined and washed with brine (2 x 25 mL) and water (25 mL). The
solution was dried with MgSO4, filtered, and the solvent was removed reduced pressure, to yield an oily
solution that solidified to a white solid upon standing. Yield = 2 g = 37% overall (from (1R,2S)‐(‐)‐2‐
amino‐1,2‐diphenylethanol). Characteristic 31P {1H} NMR peak at ‐8.3 ppm.
5.5.6 Synthesis of mer‐trans‐[Fe(Br)(CO)2(P‐N‐P′)][BF4] precatalysts (10d‐f)
General Synthesis: In a nitrogen filled glovebox, dicyclohexylphosphonium dimer (0.05 g, 0.078 mmol)
and potassium tert‐butoxide (0.018 g, 0.16 mmol) were stirred in 8 mL THF for 10 minutes to yield a
cloudy white solution. To this solution PN‐ligand (14d‐f) (0.16 mmol) and FeBr2 (0.05 g, 0.23 mmol) were
added, yielding a pale yellow solution, and the flask was transferred to a Schlenk line and put under a CO
(g) atmosphere. Immediately upon exposure the solution turned purple. The solution was stirred under
CO (g) (~2 atm) for 5 hours to yield a deep red‐purple solution. The solvent was removed under reduced
pressure, and the residue was transferred to a nitrogen filled glovebox, and redissolved in 8 mL of DCM.
The solution was filtered through Celite, transferred back to the Schlenk line and exposed to a CO (g)
atmosphere. AgBF4 (0.033 g, 17 mmol) in 2 mL of THF was injected into the solution and stirred for 30
minutes. The solvent was removed under reduced pressure, and the flask transferred back into a
nitrogen filled glovebox. The residue was redissolved in 5 mL of DCM, filtered through Celite and
concentrated to ~1 mL under reduced pressure. 5 mL of pentane was added to crash out the product as
a deep purple powder, which was subsequently washed with diethyl ether and dried under reduced
pressure.
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For R1 = Ph, R2 = H (10d): Yield = 110 mg = 86%
1H NMR (400MHz, THF‐d8) δ: 8.15 (m, 2H, Ar‐CH and P‐Ar‐CH), 8.01 (m, 2H, Ar‐CH and P‐Ar‐CH), 7.1‐7.6
(m, Ar‐CH and P‐Ar‐CH), 7.21 (N=CH, determined indirectly from 1H‐1H COSY), 4.51 (t, 1H, N‐CH, J = 11.6
Hz), 3.63 (CH2‐PPh2, determined indirectly from 1H‐1H COSY), 3.58 (CH2‐PCy2, determined indirectly from
1H‐1H COSY), 3.39 (CH2‐PCy2, determined indirectly from 1H‐1H COSY), 3.13 (dd, 1H, CH2‐PPh2, J = 5.1 and
13.1 Hz) and 0.9‐2.6 (m, PCy‐H) ppm. 31P {1H} (161 MHz, THF‐d8) δ: 66.76 (d, J = 81.9 Hz) and 39.35 (d, J =
81.6 Hz) ppm. 13C {1H} (100 MHz, THF‐d8) δ: 181.6 (N=CH), 128‐133 (Ar‐CH and P‐Ar‐CH), 74.1 (N‐CH),
38.5 (PCy‐C), 36.1 (PCy2‐CH2), 34.5 (PPh2‐CH2), 25‐29 (PCy‐C) and 13.3 (PCy2‐C) ppm. 19F {1H} (356 MHz,
THF‐d8) δ: ‐153 ppm. Anal. Calcd. For [FeC36H43P2NO2Br][BF4]: C 53.6, H 5.40, N 1.70, Found: C 41.93, H
4.98, N 1.40.** MS (ESI, m/z+): 720.1 [FeC36H43P2NO2Br]+. IR: v(CO) = 2009.2 cm‐1.
For R1 = CH2Ph, R2 = H (10e): Yield = 110 mg = 84%
1H NMR (400MHz, THF‐d8) δ: 8.13 (m, 1H, N=CH), 7.74 (m, 1H, Ar‐CH and P‐Ar‐CH), 6.9‐7.5 (m, 14H, Ar‐
CH and P‐Ar‐CH), 3.61 (N‐CH, determined indirectly from 1H‐1H COSY), 3.30 (CH2‐PCy2, determined
indirectly from 1H‐1H COSY), 3.03 (CH2‐PPh2, determined indirectly from 1H‐1H COSY), 2.86 ((CH2‐PPh2,
determined indirectly from 1H‐1H COSY), 1.33 (CH2‐Ph, determined indirectly from 1H‐1H COSY) and 0.8‐
2.5 (m, PCy‐H) ppm. 31P {1H} (161 MHz, THF‐d8) δ: 64.20 (d, J = 82.1 Hz) and 42.55 (d, J = 82.1 Hz) ppm.
13C {1H} (100 MHz, THF‐d8) δ: 146.7 (N=CH), 127‐133 (Ar‐CH and P‐Ar‐CH), 66.5 (N‐CH), 41.1 (CH2‐PPh2),
38.6 (CH2‐PCy2), 26.9 (CH2‐Ph) and 22‐28 (PCy‐C) and 13.6 (PCy2‐C) ppm. 19F {1H} (356 MHz, THF‐d8) δ: ‐
153.3 ppm. Anal. Calcd. For [FeC37H45P2NO2Br][BF4]: C 54.2, H 5.5, N 1.7, Found: C 47.35, H 5.39, N
1.83.** MS (ESI, m/z+): 734.1 [FeC37H45P2NO2Br]+and 676.1 [FeC35H45P2NBr]
+ (loss of two ‐CO). IR: v(CO) =
2004.4 cm‐1.
For R1 = iPr, R2 = H (Used AgPF6 instead of AgBF4) (10f): Yield = 120 mg = 78%
1H NMR (400MHz, THF‐d8) δ: 8.16 (m, 1H, Ph‐CH), 7.92 (m, 1H, Ph‐CH), 7.05‐7.68 (m, 9H, Ph‐CH and
N=CH at 7.58 – determined indirectly for 1H‐13C HSQC), 3.26 (m, 1H, N‐C(iPr)H), 2.98 (m, 2H, CH2‐PPh),
2.35 (m, 2H, CH2‐PCy), 1.21 (iPr‐CH, determined indirectly for 1H‐1H COSY), 0.75 (m, 6H, iPr‐CH3) and 0.6‐
2.1 (m, PCy‐H) ppm. 31P {1H} (161 MHz, THF‐d8) δ: 63.28 (d, J = 81.6 Hz), 46.26 (d, J = 81.6 Hz) and ‐
137.56 (m, PF6‐) ppm. 13C {1H} (100 MHz, THF‐d8) δ: 163.19 (N=CH), 129‐135 (Ph‐CH), 67.02 (N‐C(iPr)H),
42.70 (CH2‐PPh), 35.80 (PCy2‐C), 32.52 (CH2‐PCy), 20‐30 (PCy2‐C), 24.07 (iPr‐CH) and 15.23 (iPr‐CH3) ppm.
19F {1H} (356 MHz, THF‐d8) δ: ‐64.13 (d, PF6‐, J = 790 Hz) ppm. Anal. Calcd. For [FeC37H45P2NO2Br][PF6]: C
47.73, H 5.46, N 1.69, Found: C 40.09, H 6.17, N 1.80.** MS (ESI, m/z+): 686.1 [FeC33H45P2NO2Br]+and
628.2 [FeC31H45P2NBr]+ (loss of two ‐CO). IR: v(CO) = 2005.8 cm‐1.
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5.5.7 Synthesis of [Fe(PN)2(CO)(Br)][BPh4] (15)
In a nitrogen filled glovebox, (14g) (0.074 g, 0.19 mmol) and FeBr2 (0.028 g, 0.13 mmol) were stirred in 4
mL of THF for 30 minutes, then transferred to a Schlenk line and stirred under CO (g) (~2 atm) for 2.5
hours to yield a deep brown solution. The solvent was removed under reduced pressure and transferred
to a nitrogen filled glovebox. The residue was dissolved in ~5 mL of DCM and filtered through Celite to
remove salts. The DCM solution was concentrated under reduced pressure to ~1 mL, and NaBPh4 (0.033
g, 0.096 mmol) in 5 mL of methanol was added and stirred for 15 minutes to precipitate a pale purple
solid. The solid was collected, washed with cold methanol, and dried under reduced pressure. Yield =
100 mg = 87%.
1H NMR (400MHz, THF‐d8) δ: 6.6‐8.1 (m, 40 H, Ph‐CH), 5.23 (m, 1H, C(Ph)H), 5.00 (m, 1H, C(Ph)H,
correlates to 5.23 proton), 4.85 (m, 1H, C(Ph)H), 3.43 (m, 1H, C(Ph)H, correlates to 4.85 proton), 3.43
(broad s, 1H (should be 2H, likely solvent exchange), NH2) and 2.66 broad s, 2H, NH2) ppm. 31P {1H} (161
MHz, THF‐d8) δ: 84.62 (d, J = 145.8 Hz) and 76.58 (d, J = 145.8 Hz) ppm. 13C {1H} (100 MHz, THF‐d8) δ:
126‐137 (Ph‐C), 68.5 (C(Ph)H, correlates to 3.43 proton), 64.4 (C(Ph)H, correlates to 5.00 proton), 50.0
(C(Ph)H, correlates to 5.23 proton), 49.3 (C(Ph)H, correlates to 4.85 proton),ppm. Anal. Calcd. For
[FeC53H48P2NOBr][BPh4]: C 74.23, H 5.50, N 2.25, Found: C 64.66, H 5.43, N 2.36.** MS (ESI, m/z+): 927.2
[FeC53H48P2N2OBr]+, IR: v(CO) = 1943.6 cm‐1.
5.5.8 Synthesis of P‐N‐P Ligands (16a,c‐g)
R1 = R2 = H (16a): In a nitrogen filled glovebox, (14a) (0.6 g, 2.6 mmol) was added to a solution of o‐
(diphenylphosphino)benzaldehyde (0.76 g, 2.6 mmol) and Na2SO4 (5 g, 35 mmol) in 30 mL of DCM. The
mixture was stirred for 24 hours, then filtered through a frit and concentrated to 2 mL. With rigorous
stirring, 8 mL of cold ethanol was added and the flask was sealed and stored at ‐30 oC for 48 hours to
yield a white powder. The powder was filtered and washed with cold ethanol, then dried under reduced
pressure to yield pure P‐N‐P ligand. Yield = 980 mg =75%.
1H NMR (400MHz, CD2Cl2) δ: 8.77 (d, 1H, HC=N, J = 4.7 Hz), 7.8 (dd, 1H, Ar‐CH, J = 3.9, 7.5 Hz), 7.1‐7.4 (m,
22H, Ar‐CH, P‐Ar‐CH), 6.8 (dd, 1H, Ar‐CH, J = 7.4, 4.6 Hz), 3.5 (t, 2H, N‐CH2, J = 7.8 Hz), and 2.1 (t, 2H, P‐
CH2, J = 7.8 Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐13.2 (s), ‐19.5 (s) ppm. 13C {1H} (100 MHz, CD2Cl2) δ:
159.5 (d, HC=N, J = 20 Hz), 137‐139 (Ar‐C, P‐Ar‐C), 127‐134 (Ar‐C, P‐Ar‐C), 57.8 (d, N‐CH2, J = 21.1 Hz) and
29.5 (d, P‐CH2, J = 12.8 Hz) ppm. Anal. Calcd. For [C33H29P2N]: C 79.0, H 5.82, N 2.79, Found: C 77.83, ̾ H
5.59, N 2.81. MS (TOF‐DART, m/z+): 502.185 [C33H30P2N]+. ̾Complex was made multiple times in an
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attempt to synthesize pure compound (acceptable EA) however silica grease impurities (observed in 1H
NMR spectroscopy) caused the carbon analyses to be low.
R1 = Me, R2 = Ph (16c): In a nitrogen filled glovebox, (14c) (0.1 g, 0.31 mmol) was added to a solution of
o‐(diphenylphosphino)benzaldehyde (0.091 g, 0.31 mmol) and Na2SO4 (1 g, 7 mmol) in 5 mL of DCM. The
mixture was stirred for 24 hours, then filtered through a frit and concentrated to 1 mL. With rigorous
stirring, 8 mL of cold pentane was added and the flask was sealed and stored at ‐30 oC for 24 hours to
yield a white powder. The powder was filtered and washed with cold pentane, then dried under reduced
pressure to yield pure P‐N‐P ligand. Yield = 120 mg = 65%.
1H NMR (400MHz, CD2Cl2) δ: 8.80 (d, 1H, HC=N, J = 4.90 Hz), 7.6 (m, 2H, Ar‐CH), 7.0‐7.4 (m, 26H, Ar‐CH,
P‐Ar‐CH), 6.8 (m, 1H, Ar‐CH), 3.72 (d, 1H, CH(Ph), J = 5.6 Hz), 3.63 (dq, 1H, CH(CH3) J = 5.6 and 6.1Hz),
and 0.95 (d, 1H, CH3, J = 6.1 Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐8.1 (s), ‐14.5 (s) ppm. 13C {1H} (100
MHz, CD2Cl2) δ: 157.7 (C=N), 132‐134 (Ar‐C, P‐Ar‐C), 126‐130 (Ar‐C, P‐Ar‐C), 68.6 (CH‐Me), 51.3 (CH‐Ph)
and 19.8 (CH3) ppm. Anal. Calcd. For [C40H35P2N]: C 81.19, H 5.96, N 2.37, Found: C 80.75, H 5.10, N 1.93.
MS (TOF‐DART, m/z+): 592.232 [C40H36P2N]+.
R1 = Ph, R2 = H (16d): In a nitrogen filled glovebox, (14d) (0.15 g, 0.49 mmol) was added to a solution of
o‐(diphenylphosphino)benzaldehyde (0.14 g, 0.48 mmol) and Na2SO4 (2 g, 14 mmol) in 8 mL of DCM. The
mixture was stirred for 24 hours, then filtered through a frit and concentrated to 1 mL. With rigorous
stirring, 8 mL of cold ethanol was added and the flask was sealed and stored at ‐30 oC for 48 hours to
yield a white solid. The solid was filtered and washed with cold ethanol, then dried under reduced
pressure to yield pure P‐N‐P ligand. Yield = 150 mg = 55%.
1H NMR (400MHz, CD2Cl2) δ: 8.68 (d, 1H, N=CH, J = 4.6 Hz), 7.76 (ddd, 1H, Ar‐CH, J = 1.5, 3.9 and 7.8 Hz),
7.05‐7.32 (m, 27H, Ar‐CH), 6.78 (ddd, 1H, Ar‐CH, J = 1.3, 4.6 and 7.7 Hz), 4.16 (quart., 1H, C(Ph)H, J = 7.8
Hz) and 2.41 (qd, 2H, CH2, J = 13.6 and 7.1 Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐12.8 (s), ‐22.9 (s) ppm.
13C {1H} (100 MHz, CD2Cl2) δ: 158.8 (d, C=N, J = 19.8 Hz), 126‐135 (Ar‐C and P‐Ar‐C), 72.5 (d, CH, J = 16.4
Hz) and 53.4 (quint, CH2, J = 27.2 Hz) ppm. Anal. Calcd. For [C39H33P2N]: C 81.1, H 5.76, N 2.43, Found: C
79.07, ̾ H 5.79, N 2.36. MS (ESI, m/z+): 578.2 [C39H34P2N]+. ̾Complex was made multiple times in an
attempt to synthesize pure compound (acceptable EA) however silica grease impurities (observed in 1H
NMR spectroscopy) caused the carbon analyses to be low.
R1 = CH2Ph, R2 = H (16e): In a nitrogen filled glovebox, (14e) (0.27 g, 0.85 mmol) was added to a solution
of o‐(diphenylphosphino)benzaldehyde (0.25 g, 0.85 mmol) and Na2SO4 (2 g, 14 mmol) in 10 mL of DCM.
The mixture was stirred for 24 hours, then filtered through a frit and concentrated to 2 mL, sealed and
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stored at ‐30 oC for 48 hours to yield a pale yellow solid. The solution was decanted off and the solid was
dried under reduced pressure to yield pure P‐N‐P ligand. Yield = 230 mg = 46%.
1H NMR (400MHz, CD2Cl2) δ: 8.37 (d, 1H, N=CH, J = 4.7 Hz), 7.71 (ddd, 1H, Ar‐CH, J = 1.6, 3.9 and 7.6 Hz),
7.15‐7.45 (m, 25H, Ar‐CH), 7.01 (dd, 2H, Ar‐CH, J = 1.7 and 7.9 Hz), 6.86 (ddd, 1H, Ar‐CH, J = 1.5, 4.5 and
7.6 Hz) 3.28 (m, 1H, CH) 2.99 (dd, 1H, CH‐P, J = 4.9 and 13.3 Hz), 2.74 (dd, 1H, CH‐P, J = 8.1 and 13.3 Hz),
2.33 (dd, 1H, CH‐Ph, J = 5.1 and 13.6 Hz) and 2.13 (dd, 1H, CH‐Ph, J = 8.1 and 13.6 Hz) ppm. 31P {1H} (161
MHz, CD2Cl2) δ: ‐14.1 (s), ‐23.1 (s) ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 158.1 (d, C=N, J = 19.3 Hz), 125‐140
(Ar‐C and P‐Ar‐C), 70.3 (d, CH, J = 14.1 Hz) 43.5 (d, CH2‐P, J = 9.0 Hz) and 34.5 (d, CH2‐Ph, J = 12.8 Hz)
ppm. Anal. Calcd. For [C40H35P2N]: C 80.2, H 5.96, N 2.37, Found: C 79.29, H 6.18, N 2.27. MS (ESI, m/z+):
592.2 [C40H36P2N]+.
R1 = iPr, R2 = H (16f): In a nitrogen filled glovebox, (14f) (0.1 g, 0.37 mmol) was added to a solution of o‐
(diphenylphosphino)benzaldehyde (0.11 g, 0.37 mmol) and Na2SO4 (2 g, 14 mmol) in 8 mL of DCM. The
mixture was stirred for 24 hours, then filtered through a frit and concentrated to 1 mL. With rigorous
stirring, 8 mL of cold pentane was added and the flask was sealed and stored at ‐30 oC for 24 hours to
yield a pale yellow solution and a pale grey residue. The residue was discarded and the solvent was
removed under reduced pressure to yield pure P‐N‐P ligand as a pale yellow oily solid. Yield = 100 mg =
50%.
1H NMR (400 MHz, CD2Cl2) δ: 8.65 (d, 1H, HC=N, J = 4.77 Hz), 7.75 (ddd, 1H, Ar‐CH, J = 1.4, 3.9 and 7.7
Hz), 7.70 (dd, 1H, Ar‐CH, J = 3.3 and 5.7 Hz), 7.55 (dd, 1H, Ar‐CH, J = 3.3 and 5.7 Hz), 7.2‐7.4 (m, 20H, P‐
Ar‐CH), 6.85 (ddd, 1H, Ar‐CH, J = 1.4, 4.6 and 7.7 Hz), 2.88 (m, 1H, N‐C‐H), 2.31(dd, 1H, CH2, J = 4.3 and
13.8 Hz), 2.15 (dd, 1H, CH2, J = 8.9 and 13.8 Hz), 1.82 (m, 1H, iPr‐CH), and 0.73 (dd, 6H, iPr‐CH3, J = 5.0,
6.7 Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐13.3 (s), ‐22.0 (s) ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 158.5 (d,
C=N, J = 19.8 Hz), 128‐140 (Ar‐C and P‐Ar‐C), 74.3 (d, N‐C, J = 13 Hz), 33.6 (d, iPr‐CH, J = 8.6 Hz), 32.7 (d,
CH2, J = 13 Hz), 19.3 (s, iPr‐CH3) and 17.6 (s, iPr‐CH3) ppm. Anal. Calcd. For [C36H35P2N]: C 79.5, H 6.49, N
2.58, Found: C 78.6, H 7.04, N 2.19. MS (ESI, m/z+): 544.23 [C36H36P2N]+.
R1 = R2 = Ph (16g): In a nitrogen filled glovebox, (14g) (0.15 g, 0.41 mmol) was added to a solution of o‐
(diphenylphosphino)benzaldehyde (0.12 g, 0.41 mmol) and Na2SO4 (2 g, 14 mmol) in 10 mL of
dichloromethane. The mixture was stirred for 24 hours, then filtered through a frit and concentrated to
1 mL. With rigorous stirring, 8 mL of cold ethanol was added, the solution was concentrated to half
volume, and the vial was sealed and stored at ‐30 oC for 2 hours to yield a pale yellow solid. The solid
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was filtered and washed with cold ethanol, then dried under reduced pressure to yield pure P‐N‐P
ligand. Yield = 151 mg = 58%.
1H NMR (400MHz, CD2Cl2) δ: 8.99 (d, 1H, N=CH, J = 5.6 Hz), 7.68 (td, 2H, Ar‐CH, J = 1.7 and 7.7 Hz), 6.85‐
7.45 (m, 31H, Ar‐CH), 6.81 (ddd, 1H, Ar‐CH, J = 1.4, 4.8 and 7.6 Hz), 4.83 (dd, 1H, N‐CHPh, J = 5.8 and 8.2
Hz) and 4.22 (dd, 1H, P‐CHPh, J = 5.5 and 8.2 Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐7.17 (s), ‐15.36 (s)
ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 158.4 (C=N), 133‐135 (Ar‐C and P‐Ar‐C), 126‐131 (Ar‐C and P‐Ar‐C),
78.9 (d, N‐CHPh, J = 21.0 Hz) and 52.0 (d, P‐CHPh, J = 16.1 Hz) ppm. Anal. Calcd. For [C45H37P2N]: C 82.68,
H 5.70, N 2.14, Found: C 82.50, H 6.16, N 2.14. MS (ESI, m/z+): 654.2 [C45H38P2N]+.
5.5.9 Synthesis of P‐NH‐P Ligands (17a,c‐f)
R1 = R2 = H (17a): In a nitrogen filled glovebox, (16a) (0.055 g, 0.11 mmol) and NaBH4 (0.012 g, 0.31
mmol) were dissolved in 5 mL ethanol, sealed, and transferred to a Schlenk line. The solution was
refluxed under argon for 24 hours, then 8 mL of distilled water was added to neutralize the excess
NaBH4. The flask was then opened to air, and the product was extracted with 20 mL DCM. The aqueous
phase was further extracted with DCM (2x15 mL), and the combined organics were washed with
saturated NH4Cl solution (3x15 mL) and water (3x15 mL), dried with Na2SO4, and the solvent was
removed under reduced pressure to yield a clean, white powder. Yield = 54 mg = 97%.
1H NMR (400MHz, CD2Cl2) δ: 7.2‐7.4 (m, 22H, Ar‐CH), 7.15 (td, 1H, Ar‐CH, J = 1.4 and 7.4 Hz), 6.78 (ddd,
1H, Ar‐CH, J = 1.4, 4.5 and 7.7 Hz), 3.8 (d, 2H, N‐CH2‐Ph, J = 1.8 Hz), 2.51 (quart., 2H, N‐CH2, J = 8.1 Hz),
1.94 (t, 2H, P‐CH2, J = 8.1 Hz), 1.28 (br‐s, 1H, NH) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐16.1 (s), ‐20.6 (s)
ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 128‐135 (Ar‐C and P‐Ar‐C), 52.0 (N‐CH2‐Ph), 45.8 (N‐CH2‐CH2) and 28.7
(P‐CH2) ppm. Anal. Calcd. For [C33H31P2N]: C 78.71, H 6.21, N 2.78, Found: C 78.82, H 6.66, N 2.40. MS
(ESI, m/z+): 504.2 [C33H32P2N]+.
R1 = Me, R2 = Ph (17c): In a nitrogen filled glovebox, (16c) (0.052 g, 0.088 mmol) and NaBH4 (0.010 g,
0.26 mmol) were dissolved in 4 mL of ethanol, sealed, and transferred to a Schlenk line. The solution
was refluxed under argon for 24 hours, then 6 mL of distilled water was added to neutralize the excess
NaBH4. The flask was then opened to air, and the product was extracted with 15 mL of DCM. The
aqueous phase was further extracted with DCM (2x10 mL), and the combined organics were washed
with saturated NH4Cl solution (10 mL), brine (10 mL) and water (10 mL), dried with MgSO4, and the
solvent was removed under reduced pressure to yield a clean, white powder. Yield = 37 mg = 71%.
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1H NMR (600MHz, CD2Cl2) δ: 7.57 (m, 2H, Ph‐CH), 7.10‐7.42 (m, 26H, Ph‐CH), 6.85 (ddd, 1H, Ph‐CH, J =
1.4, 4.5 and 7.7 Hz), 3.96 (dd, 1H, N‐CH2, J = 2.2 and 13.7 Hz), 3.87 (dd, 1H, N‐CH2, J = 2.4 and 13.7 Hz),
3.83 (m, 1H, P‐C(Ph)H), 2.77 (m, 1H, N‐C(Me)H), 1.29 (br‐s, 1H, NH) and 1.00 (d, 3H, CH3, J = 6.7 Hz) ppm.
31P {1H} (161 MHz, CD2Cl2) δ: ‐11.15 (s), ‐16.15 (s) ppm. 13C {1H} (150 MHz, CD2Cl2) δ: 126‐135 (Ph‐C),
53.39 (N‐C(Me)H), 49.22 (N‐CH2), 48.36 (P‐C(Ph)H) and 17.16 (‐CH3) ppm. Anal. Calcd. For [C33H31P2N]: C
80.92, H 6.28, N 2.36 Found: C 80.62, H 6.31, N 2.34. MS (ESI, m/z+): 594.2 [C40H38P2N]+.
R1 = Ph, R2 = H (17d): In a nitrogen filled glovebox, (16d) (0.13 g, 0.23 mmol) was dissolved in 3 mL of THF
and brought up in a syringe and stoppered. In a separate flask in the nitrogen filled glovebox, LiAlH4
(0.018 g, 0.47 mmol) was dissolved in 5 mL of THF, sealed, and transferred to a Schlenk line. The solution
was cooled using an ice bath to 0oC, and the solution of P‐N‐P ligand was slowly added. The solution was
stirred at 0oC for 30 minutes, room temperature for 1 hour and then refluxed under argon for 18 hours.
The solution was cooled in an ice bath and 0.5 mL of water was added to quench any excess LiAlH4, then
the solution was filtered under air through a frit to remove any lithium salts, and washed with 3 mL of
THF. 10 mL of water was added to wash the solution, and the aqueous phase was further washed with
10 mL of DCM. The combined organics were washed with saturated NH4Cl solution (10 mL), brine (10
mL) and water (10 mL), dried with MgSO4, filtered, and the solvent was removed under reduced
pressure to yield a clear oil that solidified on standing. Yield = 120 mg = 92%.
1H NMR (400MHz, CD2Cl2) δ: 7.15‐7.45 (m, 28H, Ar‐CH), 6.89 (m, 1H, Ar‐CH), 3.71 (s, 2H, N‐CH2‐Ph), 3.62
(m, 1H, N‐CH), 2.33 (d, 2H, CH2‐PPh2, J = 7.1 Hz) and 1.29 (br‐s, 1H, NH) ppm. 31P {1H} (161 MHz, CD2Cl2)
δ: ‐16.4 (s), ‐23.5 (s) ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 132‐134 (Ar‐C and P‐Ar‐C), 127‐129 (Ar‐C and P‐
Ar‐C), 60.0 (d, N‐CH J = 15.9 Hz), 50.1 (d, N‐CH2‐Ph, J = 20.7 Hz) and 38.2 (d, CH2‐PPh2, J = 14.3 Hz) ppm.
Anal. Calcd. For [C39H35P2N]: C 80.81, H 6.09, N 2.42, Found: C 79.19, ̾ H 6.80, N 2.26. MS (ESI, m/z+):
580.2 [C39H36P2N]+. ̾Complex was made multiple times in an attempt to synthesize pure compound
(acceptable EA) however silica grease impurities (observed in 1H NMR) caused the carbon analyses to be
low.
R1 = CH2Ph, R2 = H (17e): In a nitrogen filled glovebox, (16e) (0.075 g, 0.13 mmol) was dissolved in 2 mL
of THF and brought up in a syringe and stoppered. In a separate flask in the nitrogen filled glovebox,
LiAlH4 (0.010 g, 0.26 mmol) was dissolved in 4 mL of THF, sealed, and transferred to a Schlenk line. The
solution was cooled using an ice bath to 0oC, and the solution of P‐N‐P ligand was slowly added. The
solution was stirred at 0oC for 30 minutes, room temperature for 1 hour and then refluxed under argon
for 18 hours. The solution was cooled in an ice bath and 0.5 mL of water was added to quench any
167
excess LiAlH4, then the solution was filtered under air through a frit to remove any lithium salts, and
washed with 3 mL of THF. 10 mL of water was added to wash the solution, and the aqueous phase was
further washed with 10 mL of DCM. The combined organics were washed with saturated NH4Cl solution
(10 mL), brine (10 mL) and water (10 mL), dried with MgSO4, filtered, and the solvent was removed
under reduced pressure to yield a clear oil that solidified on standing. Yield = 66 mg = 89%.
1H NMR (400MHz, CD2Cl2) δ: 7.0‐7.3 (m, 26H, Ar‐CH), 6.97 (m, 2H, Ar‐CH), 6.74 (m, 1H, Ar‐CH), 3.80 (d,
2H, N‐CH2‐Ph, J = 2.0 Hz), 2.76 (m, 1H, N‐CH), 2.70 (m, 2H, CH2‐P), 2.03 (d, 2H, CH2‐Ph, J = 6.1 Hz) and
1.20 (br‐s, 1H, NH) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐16.0 (s), ‐23.4 (s) ppm. 13C {1H} (100 MHz, CD2Cl2)
δ: 132‐134 (Ar‐C and P‐Ar‐C), 126‐129 (Ar‐C and P‐Ar‐C), 56.2 (N‐CH), 49.0 (N‐CH2‐Ph) 41.2 (CH2‐P) and
33.3 (CH2‐Ph) ppm. Anal. Calcd. For [C40H37P2N]: C 80.92, H 6.28, N 2.36, Found: Due to nature of
compound, sample could not be extracted for EA. MS (ESI, m/z+): 594.2 [C40H38P2N]+.
R1 = iPr, R2 = H (17f): In a nitrogen filled glovebox, (16f) (0.133 g, 0.24 mmol) was dissolved in 2 mL of
THF and brought up in a syringe and stoppered. In a separate flask in the nitrogen filled glovebox, LiAlH4
(0.020 g, 0.52 mmol) was dissolved in 6 mL of THF, sealed, and transferred to a Schlenk line. The solution
was cooled using an ice bath to 0oC, and the solution of P‐N‐P ligand was slowly added. The solution was
stirred at 0oC for 30 minutes, room temperature for 1 hour and then refluxed under argon for 18 hours.
The solution was cooled in an ice bath and 0.5 mL of water was added to quench any excess LiAlH4, then
the solution was filtered under air through a frit to remove any lithium salts, and washed with 4 mL of
THF. 15 mL of water was added to wash the solution, and the aqueous phase was further washed with
3x10 mL of DCM. The combined organics were washed with saturated NH4Cl solution (15 mL), brine (15
mL) and water (15 mL), dried with MgSO4, filtered, and the solvent was removed under reduced
pressure to yield a clear oil. Yield = 120 mg = 90%.
1H NMR (400MHz, CD2Cl2) δ: 7.21‐7.45 (m, 22H, Ph‐CH), 7.15 (td, 1H, Ph‐CH, J = 1.4 and 7.5 Hz), 6.86
(ddd, 1H, Ph‐CH, J = 1.3, 4.5 and 7.7 Hz), 4.28 (m, 1H, N‐CH2), 4.17 (m, 1H, N‐CH2), 3.88 (m, 2H, CH2‐P),
2.40 (m, 1H, N‐CH), 1.95 (m, 1H, iPr‐CH), 1.62 (br‐m, 1H, NH) and 0.79 (dd, 6H, iPr‐CH3, J = 6.8 and 37.1
Hz) ppm. 31P {1H} (161 MHz, CD2Cl2) δ: ‐16.09 (s), ‐22.15 (s) ppm. 13C {1H} (100 MHz, CD2Cl2) δ: 127‐134
(Ph‐C), 62.07 (N‐CH2), 59.80 (N‐CH), 49.89 (CH2‐P) 20.31 (iPr‐CH) and 17.10 (iPr‐CH3) ppm. Anal. Calcd.
For [C36H37P2N]: C 79.24, H 6.84, N 2.57, Anal. Calcd. For [C36H37P2N]‐2H2O (observed in 1H NMR
spectroscopy, from aqueous workup steps): C 74.30, H 7.10, N 2.40, Found: C 74.69, H 7.81, N 1.58. MS
(ESI, m/z+): 546.2 [C36H38P2N]+.
168
5.5.10 Synthesis of [Fe(P‐N‐P)(NCMe)3][BF4]2 (18a,c‐g)
R1 = R2 = H (18a): In a nitrogen filled glovebox, (16a) (0.097 g, 0.19 mmol) and [Fe(H2O)6][BF4]2 (0.065 g,
0.19 mmol) were stirred in 12 mL of acetonitrile for 16 hours. The solution was then concentrated to 1.5
mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a deep red solid. Yield = 160 mg = 98%.
1H NMR (400MHz, CD3CN) δ: 8.75 (s, 1H, N=CH), 7.45‐7.93 (m, 23H, Ph‐CH), 7.40 (m, 1H, Ph‐CH), 3.84
(dt, 2H, N‐CH2, J = 14.0 and 6.8 Hz), 3.02 (dt, 2H, CH2‐PPh2, J = 6.4 and 2.9 Hz) and 1.99 (s, NC‐CH3/NC‐
CD3) ppm. 31P {1H} (161 MHz, CD3CN) δ: Extreme second order doublets centered at 54.94 ppm,
apparent coupling J = 151.7 Hz). 13C {1H} (100 MHz, CD3CN) δ: 176.9 (N=CH), 129‐137 (Ar‐C and P‐Ar‐C),
117.3 (NCMe), 67.8 (N‐CH2), 22.7 (CH2‐PPh2) and 0.77 (NC‐CH3) ppm. Anal. Calcd. For
[FeC39H38P2N4][BF4]2: C 54.8, H 4.5, N 6.6, Found: C 54.22, H 4.48, N 6.59. MS (ESI, m/z+): 278.6 [Fe
C33H29P2N]+2 (loss of three MeCN).
R1 = Me, R2 = Ph (18c): In a nitrogen filled glovebox, (16c) (0.038 g, 0.063 mmol) and [Fe(H2O)6][BF4]2
(0.021 g, 0.063 mmol) were stirred in 4 mL of acetonitrile for 16 hours. The solution was then
concentrated to 0.5 mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated
in vacuo to yield pure product as a deep red solid. Yield = 58 mg = 97%.
1H NMR (400MHz, CD3CN) δ: 8.67 (s, 1HN=CH), 7.16‐7.92 (m, 27H, Ar‐CH and P‐Ar‐CH), 7.00 (d, 2H, Ar‐
CH and P‐Ar‐CH, J = 7.45 Hz), 4.14 (1H, C(Me)H, overlapping – determined indirectly using 1H‐13C HSQC),
4.10 (1H, C(Ph)H, overlapping – determined indirectly using 1H‐13C HSQC), 1.29 (d, 3H, ‐CH3, J = 4.71 Hz),
1.99 (s, 9H, CH3CN) ppm. 31P {1H} (161 MHz, CD3CN) δ: 72.31 (d, J = 149.4 Hz) and 54.31 (d, J = 149.4 Hz)
ppm. 13C {1H} (100 MHz, CD3CN) δ: 175.5 (N=CH), 127‐137 (Ar‐C and P‐Ar‐C), 119.8 (NCMe), 73.38
(C(Me)H), 49.07 (C(Ph)H), 19.22 (‐CH3) and 0.49 (NCCH3) ppm. Anal. Calcd. For [FeC46H44P2N4][BF4]2: C
58.51, H 4.70, N 5.93, Found: C 55.19, H 4.53, N 4.93.** MS (DART, m/z+): 388.3 [FeC46H44P2N4]2+.
R1 = Ph, R2 = H (18d): In a nitrogen filled glovebox, (16d) (0.238 g, 0.41 mmol) and [Fe(H2O)6][BF4]2 (0.139
g, 0.41 mmol) were stirred in 18 mL of acetonitrile for 16 hours. The solution was then concentrated to 3
mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a deep red solid. Yield = 365 mg = 97%.
1H NMR (400MHz, CD3CN) δ: 7.92 (N=CH, determined indirectly via 1H‐13C HSQC), 7.96 (m, 3H, Ar‐CH and
P‐Ar‐CH), 7.84 (m, 2H, Ar‐CH and P‐Ar‐CH), 7.23‐7.77 (m, 22H, Ar‐CH and P‐Ar‐CH), 7.16 (m, 2H, Ar‐CH
and P‐Ar‐CH), 4.72 (td, 1H, C(Ph)H, J = 3.4 and 11.5 Hz), 3.66 (ddd, 1H, CH2, J = 4.0, 13.0 and 14.7 Hz),
169
3.26 (ddd, 1H, CH2, J = 7.0, 12.5 and 14.6 Hz), 1.99 (s, 9H, CH3CN) ppm. 31P {1H} (161 MHz, CD3CN) δ: 54.8
(d, J = 151 Hz) and 50.5 (d, J = 151 Hz) ppm (roofing doublets). 13C {1H} (100 MHz, CD3CN) δ: 176.8
(N=CH), 129‐137 (Ar‐C and P‐Ar‐C), 120.8 (NCMe), 77.4 (N‐C(Ph)H), 27.4 (CH2) and 1.0 (NCCH3) ppm.
Anal. Calcd. For [FeC45H42P2N4][BF4]2: C 58.1, H 4.6, N 6.0, Found: C 55.01, H 4.26, N 5.35.** MS (ESI,
m/z+): 337 [C41H36P2N2]2+ (loss of two MeCN) and 316.6 [C39H33P2N]
2+ (loss of three MeCN).
R1 = CH2Ph, R2 = H (18e): In a nitrogen filled glovebox, (16e) (0.086 g, 0.15 mmol) and [Fe(H2O)6][BF4]2
(0.049 g, 0.15 mmol) were stirred in 8 mL of acetonitrile for 16 hours. The solution was then
concentrated to 1.5 mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated
in vacuo to yield pure product as a deep red solid. Yield = 136 mg = 96%.
1H NMR (400MHz, CD3CN) δ: 8.33 (d, 1H, N=CH, J = 5.4 Hz), 7.92 (t, 2H, Ph‐CH, J = 8.0 Hz), 7.2‐7.8 (m,
25H, Ph‐CH), 6.95 (d, 2H, Ph‐CH, J = 4.8 Hz), 4.00 (m, 1H, N‐CH), 3.27 (CH2‐Ph, 1H, overlapping with 3.20 ‐
determined indirectly from 1H‐1H COSY), 3.20 (CH2‐PPh2, 1H, overlapping with 3.27 – determined
indirectly from 1H‐1H COSY), 3.08 (dd, 1H, CH2‐PPh2, J = 7.7 and 14.0 Hz), 2.80 (m, 1H, CH2‐Ph) and 2.00
(s, NC‐CH3/NC‐CD3) ppm. 31P {1H} (161 MHz, CD3CN) δ: 54.7 (d, J = 151 Hz) and 51.7 (d, J = 151 Hz) ppm
(roofing doublets). 13C {1H} (100 MHz, CD3CN) δ: 176.1 (d, N=CH, J = 5.4 Hz), 127‐137 (Ar‐C and P‐Ar‐C),
118.6 (NCMe), 76.1 (N‐CH), 39.3 (CH2‐PPh2), 27.8 (CH2‐Ph) and 0.5 (NC‐CH3) ppm. Anal. Calcd. For
[FeC46H44P2N4][BF4]2: C 58.5, H 4.7, N 5.9, Found: C 56.39, H 5.0, N 5.49.** MS (ESI, m/z+): 606.2
[FeC36H35P2N]Li+ (loss of three MeCN).
R1 = iPr, R2 = H (18f): In a nitrogen filled glovebox, (16f) (0.099 g, 0.18 mmol) and [Fe(H2O)6][BF4]2 (0.061
g, 0.18 mmol) were stirred in 10 mL of acetonitrile for 16 hours. The solution was then concentrated to
1.5 mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a deep red solid. Yield = 152 mg = 94%.
1H NMR (400MHz, CD3CN) δ: 8.58 (s, 1H, N=CH), 7.96 (m, 2H, Ph‐CH), 7.4‐7.8 (m, 18H, Ph‐CH), 7.30 (m,
4H, Ph‐CH), 3.74 (dm, 1H, N‐CH, J = 29.7 Hz), 3.32 (m, 1H, CH2‐PPh2), 2.84 (dd, 1H, CH2‐PPh2, J = 7.8 and
14.7 Hz), 1.94 (s, NC‐CH3/NC‐CD3), 1.25 (m, 1H, iPr‐CH), 0.87 (d, 3H, iPr‐CH3, J = 6.2 Hz) and 0.00 (d, 3H,
iPr‐CH3, J = 6.5 Hz) ppm. 31P {1H} (161 MHz, CD3CN) δ: 53.8 (d, J = 151.6 Hz) and 57.3 (d, J = 151.6 Hz)
ppm. 13C {1H} (100 MHz, CD3CN) δ: 177.9 (N=CH), 129‐138 (Ar‐C and P‐Ar‐C), 121.0 (NCMe), 87.5 (N‐CH),
30.0 (iPr‐CH), 24.4 (CH2‐PPh2), 19.2 (iPr‐CH3), 18.1 (iPr‐CH3) and 1.2 (NC‐CH3) ppm. Anal. Calcd. For
[FeC42H44P2N4][BF4]2: C 58.9, H 4.7, N 5.9, Found: C 47.08, H 4.44, N 4.87.** MS (ESI, m/z+): 606.2
[FeC36H35P2N]Li+ (loss of three MeCN).
170
R1 = R2 = Ph (18g): In a nitrogen filled glovebox, (16g) (0.038 g, 0.058 mmol) and [Fe(H2O)6][BF4]2 (0.019
g, 0.057 mmol) were stirred in 5 mL of acetonitrile for 16 hours. The solution was then concentrated to 1
mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a deep red solid. Yield = 55 mg = 96%.
1H NMR (400MHz, CD3CN) δ: 8.15 (s, 1H, N=CH), 6.95‐7.80 (m, 34H, Ph‐CH), 5.17 (dd, 1H, N‐CH(Ph), J =
13.0 and 7.3 Hz), 4.88 (dd, 1H, CH(Ph)‐PPh2, J = 7.7 and 13.0 Hz) and 2.00 (s, 9H, NC‐CH3) ppm. 31P {1H}
(161 MHz, CD3CN) δ: 69.79 (d, J = 148.5 Hz) and 53.34 (d, J = 148.5 Hz). 13C {1H} (100 MHz, CD3CN) δ:
177.9 (N=CH), 127‐137 (Ar‐C and P‐Ar‐C), 117.6 (NCMe), 81.7 (N‐CH(Ph)), 46.6 (CH(Ph)‐PPh2) and 0.34
(NC‐CH3) ppm. Anal. Calcd. For [FeC51H46P2N4][BF4]2: C 60.87, H 4.61, N 5.57, Found: C 59.57, H 4.67, N
5.07. MS (ESI, m/z+): 415.2 [FeC51H46P2N4]+2.
5.5.11 Synthesis of [Fe(P‐NH‐P)(NCMe)3][BF4]2 (19a,c‐f)
R1 = R2 = H (19a): In a nitrogen filled glovebox, (17a) (0.103 g, 0.20 mmol) and [Fe(H2O)6][BF4]2 (0.069 g,
0.20 mmol) were stirred in 14 mL of acetonitrile for 16 hours. The solution was then concentrated to 1.5
mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a deep red solid. Yield = 167 mg = 98%.
1H NMR (400MHz, CD3CN) δ: 7.90 (m, 2H, Ph‐CH), 7.80 (m, 2H, Ph‐CH), 7.45‐7.75 (m, 17H, Ph‐CH), 7.37
(t, 1H, Ph‐CH, J = 8.3 Hz), 7.28 (m, 2H, Ph‐CH), 3.54 (dd, 1H, Ph‐CH2‐NH, J = 13.0 and 3.8 Hz), 3.44 (t, 1H,
CH2‐PPh2, J = 14.6 Hz), 3.19 (m, 1H, Ph‐CH2‐NH), 3.10 (m, 1H, NH‐CH2‐CH2), 2.49 (m, 1H, CH2‐PPh2), 2.38
(m, 1H, NH), 2.32 (m, 1H, NH‐CH2‐CH2) and 1.99 (s, NC‐CH3/NC‐CD3) ppm. 31P {1H} (161 MHz, CD3CN) δ:
58.69 (d, J = 141.9 Hz) and 43.74 (d, J = 141.9 Hz) ppm. 13C {1H} (100 MHz, CD3CN) δ: 127‐141 (Ar‐C and
P‐Ar‐C), 119.1 (NCMe), 57.3 (Ph‐CH2‐NH), 53.8 (HN‐CH2‐CH2), 24.2 (CH2‐PPh2) and 0.49 (NC‐CH3) ppm.
Anal. Calcd. For [FeC39H40P2N4][BF4]2: C 54.7, H 4.7, N 6.5, Found: C 53.22, H 4.96, N 6.27.** MS (ESI,
m/z+): 339.3 [FeC39H40P2N4]2+, 318.1 (loss of MeCN), 300.1 (loss of two MeCN) and 279.6 (loss of three
MeCN).
R1 = Me, R2 = Ph (19c): In a nitrogen filled glovebox, (17c) (0.030 g, 0.050 mmol) and [Fe(H2O)6][BF4]2
(0.017 g, 0.50 mmol) were stirred in 5 mL of acetonitrile for 16 hours. The solution was then
concentrated to 1 mL and washed with pentane (2 x 4 mL). The acetonitrile layer was then evaporated in
vacuo to yield pure product as a bright pink solid. Yield = 47 mg = 99%.
1H NMR (500MHz, CD3CN) δ: 7.00‐7.68 (m, 29H, Ph‐CH), 3.99 (dd, 1H, P‐C(Ph)H, J = 7.7 and 12.2 Hz), 3.82
(dd, 1H, N‐CH2, J = 5.1 and 13.1 Hz), 3.04 (m, 1H, N‐CH2), 2.88 (m, 1H, N‐C(Me)H), 1.99 (s, NC‐CH3/NC‐
171
CD3), 1.92 (NH, determined indirectly using 1H‐1H‐COSY) and 1.17 (d, 3H, CH3, J = 5.8 Hz) ppm. 31P {1H}
(202 MHz, CD3CN) δ: 74.30 (d, J = 138.4 Hz) and 43.31 (d, J = 138.4 Hz) ppm. 13C {1H} (125 MHz, CD3CN) δ:
126‐137 (Ph‐C), 122.0 (NCMe), 62.50 (N‐C(Me)H), 52.78 (N‐CH2), 50.50 (P‐C(Ph)H), 17.11 (‐CH3) and 1.31
(NC‐CH3) ppm. Anal. Calcd. For [FeC46H46P2N4][BF4]2(extra MeCN in solution, verified by NMR
spectroscopy): C 58.39, H 5.00, N 7.09, Found: C 48.80, H 4.58, N 7.85.** MS (ESI, m/z+): 656.2
[FeC40H37P2N][Li]+ (loss of three MeCN).
R1 = Ph, R2 = H (19d): In a nitrogen filled glovebox, (17d) (0.075 g, 0.13 mmol) and [Fe(H2O)6][BF4]2 (0.044
g, 0.13 mmol) were stirred in 10 mL of acetonitrile for 16 hours. The solution was then concentrated to
1.5 mL and washed with pentane (2 x 6 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a bright purple solid. Yield = 114 mg = 99%.
1H NMR (600MHz, CD3CN) δ: 7.25‐7.88 (m, 28H, Ph‐CH), 6.76 (s, 1H, Ph‐CH), 3.63 (t, 1H, P‐CH2, J = 13.8
Hz), 3.46 (m, 1H, N‐C(Ph)H), 3.15 (m, 1H, N‐CH2), 2.94 (t, 1H, N‐CH2), 2.77 (m, 1H, P‐CH2), 2.00 (NH,
determined indirectly using 1H‐1H‐COSY) and 1.98 (s, NC‐CH3/NC‐CD3) ppm. 31P {1H} (242 MHz, CD3CN) δ:
49.07 (d, J = 139.1 Hz) and 41.22 (d, J = 139.1 Hz) ppm. 13C {1H} (150 MHz, CD3CN) δ: 126‐133 (Ph‐C),
120.4 (NCMe), 67.24 (N‐C(Ph)H), 53.84 (N‐CH2), 32.92 (P‐CH2) and 0.68 (NC‐CH3) ppm. Anal. Calcd. For
[FeC45H44P2N4][BF4]2: C 57.98, H 4.76, N 6.01, Found: C 54.66, H 4.92, N 6.04.** MS (DART, m/z+): 380.2
[FeC45H44P2N4]2+.
R1 = CH2Ph, R2 = H (19e): In a nitrogen filled glovebox, (17e) (0.025 g, 0.042 mmol) and [Fe(H2O)6][BF4]2
(0.014 g, 0.42 mmol) were stirred in 5 mL of acetonitrile for 16 hours. The solution was then
concentrated to 1 mL and washed with pentane (2 x 4 mL). The acetonitrile layer was then evaporated in
vacuo to yield pure product as a bright pink solid. Yield = 38 mg = 95%.
1H NMR (600MHz, CD3CN) δ: 7.06‐7.83 (m, 29H, Ph‐CH), 3.90 (m, 1H, N‐CH2), 3.73 (m, 1H, P‐CH2), 3.13
(m, 1H, CH2‐Ph), 3.02 (m, 1H, N‐CH2), 2.71 (m, 1H, N‐C(Bn)H), 2.60 (m, 1H, P‐CH2), 2.23 (m, 1H, Ph‐CH2),
1.98 (s, NC‐CH3/NC‐CD3), 1.97 (NH, determined indirectly using 1H‐1H‐COSY) ppm. 31P {1H} (242 MHz,
CD3CN) δ: 48.82 (d, J = 139.9 Hz) and 41.38 (d, J = 139.9 Hz) ppm. 13C {1H} (150 MHz, CD3CN) δ: 126‐133
(Ph‐C), 123.0 (NCMe), 63.78 (N‐C(Bn)H), 52.72 (N‐CH2), 37.87 (P‐CH2), 30.1 (Ph‐CH2) and 1.06 (NC‐CH3)
ppm. Anal. Calcd. For [FeC46H46P2N4][BF4]2: C 58.39, H 4.90, N 5.92, Found: C 49.34, H 4.78, N 5.56.** MS
(ESI, m/z+): 656.2 [FeC40H37P2N][Li]+ (loss of three MeCN).
R1 = iPr, R2 = H (19f): In a nitrogen filled glovebox, (17f) (0.063 g, 0.12 mmol) and [Fe(H2O)6][BF4]2 (0.039
g, 0.12 mmol) were stirred in 12 mL of acetonitrile for 16 hours. The solution was then concentrated to 2
172
mL and washed with pentane (2 x 5 mL). The acetonitrile layer was then evaporated in vacuo to yield
pure product as a bright pink solid. Yield = 88 mg = 83%.
1H NMR (400MHz, CD3CN) δ: 7.22‐7.86 (m, 24H, Ph‐CH), 4.12 (m, 1H, N‐CH(iPr)), 3.66 (m, 1H, N‐CH2),
3.44 (m, 1H, P‐CH2), 2.84 (m, 1H, N‐CH2), 2.13 (P‐CH2, determined indirectly from 13C‐1H HSQC), 1.99 (s,
NC‐CH3/NC‐CD3), 1.43 (br s, 1H, NH), 1.19 (m, 1H, iPr‐CH) and 0.77 (br m, 6H, iPr‐CH3) ppm. 31P {1H} (161
MHz, CD3CN) δ: 49.55 (d, J = 139.8 Hz) and 41.25 (d, J = 139.8 Hz) ppm. 13C {1H} (100 MHz, CD3CN) δ: 128‐
135 (Ar‐C and P‐Ar‐C), 121.90 (NCMe), 62.01 (N‐CH(iPr)) 51.69 (N‐CH2), 23.95 (P‐CH2), 20.64 (iPr‐CH),
12.55 (iPr‐CH3) and 0.83 (NC‐CH3) ppm. Anal. Calcd. For [FeC42H46P2N4][BF4]2: C 56.16, H 5.16, N 6.23,
Found: C 47.42, H 4.38, N 6.23.** MS (ESI, m/z+): 362.2 [FeC42H46P2N4]2+and 608.2 [FeC36H37P2N]Li
+.
5.5.12 Synthesis of Fe(P‐N‐P)(CO)Br2 (20)
In a nitrogen filled glovebox, (16a) (0.05 g, 0.1 mmol) was added to a solution of FeBr2 (0.22 g, 0.1 mmol)
in 5 mL THF and stirred at room temperature for 45 minutes. The solution was then frozen using liquid
nitrogen and the gases removed under reduced pressure. A carbon monoxide headspace was
introduced and the solution was allowed to warm to room temperature and stirred for an additional 2
hours. The solvent was removed under reduced pressure and the crude product was washed with ether
and hexanes. The residue was dissolved in minimal amounts of DCM and the product was precipitated
out with cold pentane. The powder was filtered and washed with cold pentane, then dried under
reduced pressure to yield pure Fe‐P‐N‐P product. Yield = 63 mg = 85%.
1H NMR (600 MHz, CD2Cl2) δ: 8.36 (s, 1H, N=CH), 8.25 (dd, 2H, Ph‐CH, J = 7.7 and 10.0 Hz), 8.08 (m, 2H,
Ph‐CH), 8.03 (m, 2H, Ph‐CH), 7.31‐7.65 (m, 17H, Ph‐CH), 7.26 (t, 1H, Ph‐CH, J = 8.1 Hz), 4.00 (m, 1H, N‐
CH2), 3.43 (m, 1H, N‐CH2),3.02 (m, 1H, P‐CH2) and 2.55 (m, 1H, P‐CH2) ppm. 31P {1H} (242 MHz, CD2Cl2) δ:
44.01 (d, J = 216.9 Hz), 39.55 (d, J = 216.9 Hz) ppm. 13C {1H} (150 MHz, CD2Cl2) δ: 173.7 (N=CH),126‐137
(Ph‐C), 71.5 (N‐CH2) and 24.1 (P‐CH2) ppm. Anal. Calcd. For [C34H29NP2OFeBr2]: C 54.8, H 3.92, N 1.88,
Found: C 54.93, H 4.19, N 2.74. MS (TOF‐ESI, m/z+): 636.0 [C33H29NP2FeBr]+ (Loss of CO, Br). IR: v(CO) =
1960.6 cm‐1.
Note: Synthesis yields a mixture of cis/trans with a ratio of 8% trans based on the cis Br/CO disorder in
the crystal structure. Minor trans species also observable by 31P NMR spectroscopy at 64.8 and 57.8 ppm
(doublets, J = 184 Hz).
173
5.5.13 Transfer Hydrogenation Catalysis
To a vial containing pre‐catalyst (6 mg, 0.007 mmol) and KOtBu (6 mg, 0.054 mmol), isopropanol (6 mL,
78 mmol) and acetophenone (0.5 mL, 4.3 mmol) were added at 28oC, in an argon filled glovebox.
Solutions were stirred vigorously, and samples were taken from the mixture, quenched by exposure to
air and analysed by gas chromatography. All of the catalytic results were reproduced to ensure
consistency.
5.5.14 Ammonia‐Borane Dehydrogenation Catalysis
In an argon filled glovebox, pre‐catalyst (6 mg, 0.007 mmol) and ammonia‐borane (AB) (10 mg, 0.32
mmol) were added to a 25 mL two‐neck round‐bottom flask which was sealed with a rubber septum and
a 10 mL dry‐addition flask containing KOtBu (8 mg, 0.071 mmol). The sealed system was removed from
the glovebox and submerged in a 24oC water bath before 5 mL THF was added to the flask and stirred
for 10 minutes. A cannula needle was used to pierce the septum and an upturned 50 mL burette filled
with water was used to measure the evolution of gas. To start the reaction, the dry‐addition flask was
tilted, and base was added to the reaction, which was stirred vigorously. Hydrogen production was
measured in terms of volume displacement of water in the burette as a measure of time. All catalytic
results were reproduced to ensure consistency. [C:B:S = 1:10:45]
174
5.6 References
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(12) Meyer, N.; Lough, A. J.; Morris, R. H. Chem. Eur. J. 2009, 15, 5605.
(13) Lagaditis, P. O.; Lough, A. J.; Morris, R. H. Inorg. Chem. 2010, 49, 10057.
(14) Sues, P. E.; Lough, A. J.; Morris, R. H. Organometallics 2011, 30, 4418.
(15) Mikhailine, A. A.; Morris, R. H. Inorg. Chem. 2010, 49, 11039.
(16) Prokopchuk, D. E.; Sonnenberg, J. F.; Meyer, N.; Zimmer‐De Iuliis, M.; Lough, A. J.;
Morris, R. H. Organometallics 2012, 31, 3056.
(17) Mikhailine, A. A.; Maishan, M. I.; Morris, R. H. Org. Lett. 2012, 14, 4638.
(18) Langer, R.; Leitus, G.; Ben‐David, Y.; Milstein, D. Angew. Chem. Int. Ed. 2011, 50, 2120.
(19) Langer, R.; Iron, M. A.; Konstantinovski, L.; Diskin‐Posner, Y.; Leitus, G.; Ben‐David, Y.;
Milstein, D. Chem. Eur. J. 2012, 18, 7196.
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Beller, M. Angew. Chem. Int. Ed. 2013, 125, 14412.
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Gallou, F.; Beller, M. Angew. Chem. Int. Ed. 2014, 10.1002/anie.201402542.
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Guan, H. J. Am. Chem. Soc. 2014, 136, 7869.
(23) Chakraborty, S.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2014, 136, 8564.
(24) Casey, C. P.; Guan, H. J. Am. Chem. Soc. 2007, 129, 5816.
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Organometallics 2011, 30, 3880.
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(31) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393.
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Chem. Soc. 2014, 136, 1367.
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2008, 47, 9142.
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178
Chapter 6: Conclusions and Future
Directions
6.1 Conclusions
In 2008 the Morris group published breakthrough research on the use of chiral P‐N‐N‐P tetradentate
ligands on iron for the asymmetric transfer and direct hydrogenation (TH and DH) of ketones to chiral
alcohols.1 Using the ligand systems developed by Jeffery et. al.2 and later extended by Gao et. al.3‐6 a
series of [Fe(P‐N‐N‐P)(NCMe)2][BF4]2 and [Fe(P‐N‐N‐P)(CO)(NCMe)][BF4]2 precatalysts were tested for DH
and TH respectively, yielding promising turnover frequencies (TOF) and enantiomeric excesses (e.e.),
especially for TH.1,7,8 Given that the ligands were initially developed for ruthenium, it was proposed that
a new generation of Fe(P‐N‐N‐P) catalysts bearing smaller chelating rings would improve both activity
and selectivity, as the ligand would provide a better ‘fit’ around the smaller iron atom. This led to the
development of a highly active and selective second generation catalyst bearing all 5‐membered rings
(the 5,5,5‐system).9 These new [Fe(P‐N‐N‐P)(CO)Br][BPh4] precatalysts could be synthesized using a
template reaction of phosphonium dimers, base, chiral diamine and iron, allowing for facile modification
of the groups on phosphorus and the N‐N backbone.10‐12 The new system proved to be much more
active and selective than the first generation 6,5,6‐system, achieving TOFs up to 30,000 h‐1 and e.e. up
to 90%, versus the 2600 h‐1 and 65% of the 6,5,6‐system. This was surpassed further by our subsequent
third generation system which achieved TOFs of up to 200 s‐1.13
The initial project goal of my work was to investigate the first generation (6,5,6‐) catalyst and attempt to
elucidate a reaction mechanism. At the time, it was predicted that the 6,5,6‐ and 5,5,5‐systems would
operate via the same mechanism, and therefore a separate investigation was undertaken to confirm the
mechanism with the more active system.14,15 Initial investigations of the 6,5,6‐system involved the use of
spectroscopic (NMR) and computational (DFT) techniques.16 31P {1H} NMR spectra of activated catalytic
solutions showed the presence of free ligand and oxidized free ligand, as well as a pair of doublets at
84.1 and 68.7 with 2JPP = 29 Hz. Treatment of the [Fe(P‐N‐N‐P)(CO)(NCMe)][BF4]2 precatalyst with base
allowed for the growth of crystals of a ferraaziridine complex suitable for single‐crystal X‐ray
crystallography. One side of the ligand arm was folded upwards in this complex. Further reduction with
base led to the proposed formation of a ferraaziridinido species, which matched with the experimentally
179
observed NMR data of the activated solutions. This species was found to not be catalytically active, and
therefore NMR mass‐balance experiments were undertaken. Using OPPh3 as an internal standard, it was
determined that only 43% of the phosphorus containing species could be observed, indicating that the
active species was likely NMR silent. The mechanism of formation of the ferraaziridine and
ferraaziridinido species was then studied using DFT, and demonstrated that ligand folding and the
formation of the unsymmetrical complexes was highly energetically favourable. DFT also indicated that
reduction of these species to zero‐valent Fe(P‐N‐N‐P)(CO) was thermodynamically favourable, and likely
occurring during catalysis.
Given that the active species may be derived from zero‐valent iron, a more detailed mechanistic
investigation was undertaken to probe whether the true catalyst could be heterogeneous iron
nanoparticles (Fe NPs).17 We began by investigating the reaction profile, which was sigmoidal in shape;
the induction period was found to be due to the reaction of the precatalyst with base, followed by rapid
catalytic activity and eventual equilibration. We were then able to completely stop catalysis with 10%
PMe3 poison relative to iron, as well as 15% PMe2Ph or 15% pentanethiol. This type of sub‐
stoichiometric poisoning provided strong evidence for a NP catalyst, which was further supported by
scanning transmission electron microscopy (STEM) imaging which showed the presence of 3‐4 nm Fe
particles. Superconducting quantum interference device (SQUID) magnetometry demonstrated the
presence of a blocking temperature in the zero‐field‐cooled field‐cooled (ZFC‐FC) experiment, providing
further evidence that superparamagnetic Fe NPs were present during catalysis. To probe whether the Fe
NPs were the actual active species, we first employed a porous polymer supported benzaldehyde
substrate in catalysis to demonstrate that the active species was too large to permeate the pores of the
polymer. Next, we combined the 15% pentanethiol poisoning experiments with EDX and STEM analysis
to prove that the sulfur of the poison was binding to the surface of the Fe NP and inhibiting catalysis,
providing the final piece of evidence to strongly support that the active species in asymmetric TH was in
fact Fe NPs coated in chiral P‐N‐N‐P ligand.
Upon transitioning to iron‐based asymmetric catalysis, the primary expense is no longer the metal but
the chiral ligand used. In homogeneous catalysis, a one‐to‐one ratio of ligand and metal are required for
activity, whereas in a NP catalyst, only the surface metal atoms require bound ligand. This means that it
is hypothetically feasible to use a substoichiometric amount of ligand to induce the same
transformations, which, in the case of iron systems, can significantly reduce the associated costs. We
attempted to take advantage of this concept by independently synthesizing Fe NPs using a wide variety
180
of known techniques18‐22 and adding ligand; unfortunately we were unable to reproduce the catalytic
behaviour of our original system. We hypothesized that this is likely due to specific interactions that
require the particular activation process of the precatalyst, as well as the fact that the ligand is already
bound to iron in the precatalyst. Although we were not successful at applying this concept with our TH
system, we continued to think about it as we studied other areas of catalysis with Fe NPs.
TH is an equilibrium process due to the inherent reversibility of the proton/hydride transfer, making it
feasible to catalyse the reverse reaction, the oxidation of alcohols to ketones using a proton/hydride
acceptor. If a chiral catalyst is used, it becomes feasible to selectively oxidize only one enantiomer of a
racemic alcohol to ketone, leaving the other enantiomer unaffected, yielding an enantioenriched
solution in up to 50% yield. This process is called oxidative kinetic resolution,23 and we tested our Fe NP
system for this transformation on racemic aromatic alcohols.24 Initial explorations were done using 1‐
phenylethanol (PE), our chiral Fe(P‐N‐N‐P)(CO)(NCMe)[BF4]2 precatalyst, and activation with strong base,
KOtBu. We tested both acetone and benzophenone/THF as the proton/hydride acceptors and solvents
and found that activity and selectivity was lower using acetone, likely due to the formation of enolates
in the presence of strong base. The use of NaOiPr confirmed this, as activity using the weaker base was
significantly improved, at the expense of selectivity. Further optimization indicated that the use of
benzophenone/THF at elevated temperatures of 45 oC provided optimal activity and selectivity,
achieving TOFs of 171 h‐1 and relative rate (s) of 6.0 (measure of the relative conversion of one
enantiomer over the other) for PE to acetophenone. Using the optimized conditions, we conducted a
substrate scope to explore the effect of changing the electronics and sterics of the system. Upon going
to bulkier substrates, activity decreased significantly, but selectivity was greatly improved, achieving s =
10.2 for 2‐methyl‐1‐phenylpropanol. For the non‐conjugated system, 4‐phenyl‐2‐butanol, very low TOFs
and relative selectivities of 3.3 h‐1 and 1.7, respectively, were achieved. Lastly, we studied the influence
of varying electronics using chloro and methyl substituents on the aromatic ring, and found varied
results; chloro substitution had a negligible effect on selectivity and slightly decreased activity, whereas
para‐methyl substitution improved the activity (TOF = 335 h‐1), but had a negligible effect on selectivity
(s = 5.3). To probe the heterogeneity of the system, we employed a similar series of tests to those
previously used for TH; substoichiometric poisoning with PMe3, STEM imaging and induction period
analysis all suggested a similar Fe NP system as the active species. Porous polymer‐bound PE was also
tested for catalysis, and using magic angle spinning (MAS) 13C {1H} semi‐solid state NMR spectra of the
resultant polymer resins, we were able to show that oxidation to acetophenone did not occur within the
181
pore of the polymer using our Fe catalyst, further supporting Fe NP catalysis by the same reasoning
previously discussed.
Given the propensity of our Fe NP systems for a wide range of catalysis involving proton and hydride
transfers, we were interested in testing it for the dehydrogenation of ammonia‐borane (AB). For these
studies we broadened our precatalyst scope, using both [Fe(P‐N‐N‐P)(CO)(NCMe)][BF4]2 and [Fe(P‐N‐N‐
P)(NCMe)2][BF4]2 precatalysts with either a bulkier 1,2‐diphenylethylenediamine (dpen) backbone or the
less bulky, achiral, ethylene variant.25 Initial tests were done in iPrOH for the dehydrogenation of AB to
form borates, B(OiPr)3, and up to 2.9 equivalents of H2, with limited recyclability. Bis‐MeCN catalysts
were more active, but deactivated more rapidly than the CO‐trans‐MeCN systems, indicating the more
rapid formation of active species which, as a result, are poorly stabilized. Also of interest was that the
system bearing the bulkier dpen backbone was slightly more active than the achiral system; however
none of the systems tested were active in H2O as a solvent. Using protic solvents results in the formation
of borates, and we were interested in generating recyclable B‐N containing polymers and oligomers,26
and therefore tested our systems in aprotic solvents. In THF, our systems were immensely active,
releasing over one equivalent of H2 in less than 30 seconds. Our dpen system was slightly more active
than the achiral system, and the bis‐MeCN systems showed more rapid initial activity, as had been
observed in iPrOH. We were able to achieve maximum TOFs of up to 3.66 s‐1, observed high catalytic
activity at 0 oC, and generated primarily borazine, polyborazylene and short B‐N oligomers. STEM
indicated that the active species were likely Fe NPs, however further studies into the true nature of the
catalyst were not conclusive due to the high activity of the system. We also found a dependence of rate
of H2 release on the concentration of base; catalysis was slower with lower loadings of base.
As discussed previously, our ultimate goal behind employing NP catalysts was to use less of the
expensive ligands to achieve the same levels of catalytic activity. We therefore tested Fe2+ sources such
as FeBr2 and [Fe(H2O)6][BF4]2 without ligand in catalysis, and observed the slow release of 0.6
equivalents of H2 over one hour. The addition of one equivalent of achiral P‐N‐N‐P ligand improved the
activity, yielding comparable results to the pre‐synthesized [Fe(P‐N‐N‐P)(NCMe)2]2+ systems. We then
tested the addition of substoichiometric amounts of P‐N‐N‐P ligand, and observed comparable activity
when as little as 0.15 equivalents P‐N‐N‐P (relative to iron) was added as had been observed with the
addition of equimolar amounts. Also, the use of bulkier P‐N‐N‐P ligands improved catalysis relative to
the achiral system, as would be expected from the previous studies. Lastly, we studied the
182
dehydrogenation of dimethylamine‐borane and achieved modest activity, however a wide variety of B‐N
products were observed, indicative of low catalyst selectivity.
Following the successful development of three highly active and selective iron‐P‐N‐N‐P catalyst
generations for TH, our group became interested in studying DH, as it is a much more atom economical
process. Learning from the literature, we sought to develop new iron‐based catalysts for the DH of polar
double bonds that would contain P‐N‐P pincer ligands, chirality, carbonyl group(s) and would allow for
the use of the N‐H Effect.27‐33 This was accomplished with the development of a new series of mer‐trans‐
[Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts that could be generated by the template reaction of a chiral PN
ligand with a phosphine‐aldehyde derived from a phosphonium dimer on FeBr2 under a CO (g)
atmosphere, followed by silver‐mediated carbonyl ligand exchange.34 A variety of these systems could
be developed by changing the PR2 groups (using different phosphonium dimers) as well as changing the
PN ligands used. It was found that for PR2 with R = Cy or iPr highly active systems could be developed
(TOF = 1980 h‐1 for the achiral variant), however with R = Ph no activity was detected. Catalysts with PN
derived from norephedrine (and R = Cy) were highly active and selective (TOF = 1980 h‐1, e.e. = 80%),
whereas catalysts with PN ligands derived from amino acids with only one stereogenic centre were less
active (TOF ranging from 250‐800 h‐1 and e.e. ranging from 13‐74%), at 50 oC and 5 atm H2 in a Parr
reactor. These results indicated that two chiral stereogenic centres were needed to optimize the
substrate directing capabilities of the ligand by maintaining ligand rigidity and structure.
Given how active and selective many of these catalysts were, we were interested in investigating their
mechanism of action using experimental and computational methods. For simplicity, we focussed on the
activation process and catalysis of the achiral system with P‐N‐P’ = PPh2CH2CH2N=CHCH2PiPr2. To achieve
catalytic activity, the [Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts needed to first be activated with LiAlH4,
followed by excess alcohol. Using NMR spectroscopy, we were determined that the species formed
during these activation steps was a Fe(P‐NH‐P’)(CO)(H)(OR) complex, which could be analysed as a
mixture of two isomers (N‐H up and down relative to hydride). For catalysis, the solution then needed to
be injected into a reactor pressurized with H2 and base added. By NMR spectroscopy, the alkoxide
complex is converted into a trans‐dihydride complex, mer‐trans‐Fe(P‐NH‐P’)(CO)(H)2, when exposed to
KOtBu and H2, which is equally as active for the DH of ketones as the in situ prepared system. No
reaction occurs without base, and the formation of zero‐valent Fe(P‐NH‐P’)(CO)2 occurs under basic
conditions without the presence of H2; the dicarbonyl is not catalytically active. The two hydrides of
trans‐Fe(P‐NH‐P’)(CO)(H)2 are similar, but inequivalent, based on 1H NMR data, which indicated the
183
presence of an N‐H or K+ bound amide species. The cation‐assisted mechanism was disproven based on
2,2,2‐cryptand addition experiments, leaving a likely N‐H based mechanism for the catalytic cycle. DFT
calculations provided evidence that the formation of an N‐H, dihydride species was likely occurring and
was the entry point into the catalytic cycle. DFT also suggested that H2 splitting between the iron and
amide was the highest energy step of the cycle, but that under catalytic conditions the reaction was
quite reasonable. Lastly, we experimentally probed the base dependence of the system and determined
that A) both Na+ and K+ bases functioned effectively in catalysis, B) weak bases such as NaOMe were not
effective, and C) base is required during the catalytic cycle (not just for activation). A) Supports the
contention that the cation is not involved in catalysis, as was shown with the cryptand experiment. B)
Suggests that strong base is needed to protect the catalytic amide (potential pKa dependence), because
DFT indicated that H2 splitting at the amide was the rate determining step. C) Supports the argument in
B) that strong base is somehow required to keep the iron system within the catalytic cycle, potentially
preventing unwanted side reactions, although this is still under investigation.
To further expand our work with Fe(P‐N‐P) DH systems, we were interested in developing a new library
of systems that would vary the ligand chirality, flexibility and structure, as well as introduce an N‐H
functionality. Given the successful development of 6,5,6‐(P‐N‐N‐P) ligands and iron complexes, we
investigated the use of o‐phenylene linkers in the phosphine aldehyde to develop a new series of P‐N‐P
ligands using the PN ligands previously studied. The P‐N‐P ligands could also be reduced to P‐NH‐P
ligands using either NaBH4 or LiAlH4 to expand the ligand library and introduce the desired N‐H
functionality. Using this new library of chiral P‐N‐P and P‐NH‐P ligands we synthesized and characterized
the corresponding [Fe(P‐N‐P)(NCMe)3][BF4]2 and [Fe(P‐NH‐P)(NCMe)3][BF4]2 complexes which were
inactive for TH, DH and AB dehydrogenation. Lastly, we investigated the applicability of the P‐N‐P and P‐
NH‐P ligands with FeBr2 and CO (g) for the synthesis of precatalysts that would be similar to the [Fe(P‐N‐
P’)(CO)2Br][BF4] systems previously discussed. Unfortunately the systems were highly unstable, and only
the achiral variant could be cleanly synthesized and tested, yielding TOF of 900 h‐1 at 50 oC and 25 atm
H2.
To conclude, we have explored several areas of catalysis from TH and DH to oxidative kinetic resolution
and the dehydrogenation of AB to generate H2 using iron systems, both heterogeneous and likely
homogeneous. We have developed a series of key tests to probe the heterogeneity of catalysts and
detailed its applicability for several of our catalytic systems. We have also developed a new series of
chiral DH catalysts using Fe(P‐N‐P) systems that show tremendous promise, and open many new
184
potential avenues of investigation into the wider applicability of iron to replace precious metal catalytic
systems.
6.2 Future Directions
The use of iron in catalysis is a rapidly growing and developing field as it holds promise for much more
benign, cheap and earth abundant replacements to the toxic and expensive precious metals currently in
use in industry. Following the discoveries and advancements detailed in this dissertation, there are
several areas of investigation that warrant further studies. These have been broken into several main
avenues of investigation, and are as follows:
6.2.1 Investigating the True Nature of the Catalyst
Given the difficulty in evaluating the true nature of our iron catalysts, as well as the strong evidence that
the structurally similar 5,5,5‐systems were homogeneous in nature, we posit that there are many iron
systems reported in the literature that are erroneously identified as homogeneous. Determining the
true nature of an active catalyst can be immensely valuable as it allows for more rational catalyst design
and insightful modifications to be made. Although there is no way of conclusively proving whether a
catalyst is homogeneous or heterogeneous, we have outlined a series of tests that would be valuable to
apply to newly developed iron systems to provide preliminary insights into a catalysts’ true nature.
There are many iron catalysts in the literature that we suspect may operate via a heterogeneous
mechanism that warrant further investigation. Herein we will highlight a few recent systems in the
literature as well as why we are suspicious of the catalyst’s true nature. First is the AB dehydrogenation
system developed by Baker and coworkers35 who report the use of highly reducing conditions, labile
ligands, and the ready detection of zero‐valent bulk iron in many cases as well as the postulated
involvement of Fe(0). Next is the free radical hydrofluorination of unactivated alkenes using Selectfluor
reported by Barker and Boger36 This system is highly suspicious as they report the use of Fe(III) with
NaBH4 in aqueous conditions without the use of protective ligands, conditions quite similar to those
employed by Xu and coworkers for the hydrolytic dehydrogenation of AB in H2O using 3 nm Fe NPs.37
Beller and coworkers have recently published the use of a tandem iron system employing
[Et3NH][HFe3(CO)11] and Fe(OAc)2 for the reduction of amides.38 Once again, the conditions are strongly
reducing and they are able to add ligand in situ to the reaction systems, much like our AB
185
dehydrogenation system previously discussed.25 This system would be quite interesting to investigate as
the activity may be derived from the need for both metal precursors to develop a highly active and
specific NP structure; the presence of one Fe source may initiate the structure‐specific morphology
required to garner the high activity observed when the metals are used in tandem. Next is the
regioselective synthesis of α‐aryl carboxylic acids from styrene derivatives and CO2 developed by
Greenhalgh and Thomas.39 They report the use of iron halides with Grignard reagents for catalysis,
which has been previously reported to generate small (3‐4 nm) Fe NPs by both Bedford and de Vries.21,22
Similarly, Hatakeyama et. al. reported the use of iron halides with LiBr and magnesium amides (ArRN‐
MgBr) to generate non‐symmetrical triarylamines at elevated temperatures.40 Lastly, is the use of zero
valent iron carbonyls and ferrocenes under strongly reducing conditions to catalytically convert N2 (g)
into N(SiMe3)3 recently reported by Yuki et. al.41
Not only would it be valuable to explore systems developed by other groups, but the Fe(P‐N‐P) system
developed within our group34 and discussed in detail previously also warrants close investigation.
Although we were able to detect reactive hydride species by NMR spectroscopy, the formation of Fe (0)
species does occur during activation and strongly reducing conditions are also employed, indicating that
some investigations into whether Fe NPs are present during catalysis should be undertaken.
6.2.2 Broadening the Scope of the P‐N‐P System
Another area that warrants further investigation is broadening the scope of the P‐N‐P ligands to include
variability at both of the phosphorus groups as well as introducing more chiral centres into the ligand.
The methodology for developing the [Fe(P‐N‐P’)(CO)2Br][BF4] precatalysts has been detailed for a variety
of PN ligands including the achiral variant, the norphedrine‐derived system, and three amino acid
derived systems, and we found that optimal activity and selectivity was achieved using the more rigid
system which contained two chiral centres (norephedrine – Me/Ph). Therefore, we predict that the
development of other systems that contain two chiral groups would also be worthwhile to investigate,
as would systems with varied flexibility, functionality and structure such as those shown in Figure 6.45.
The three PN systems depicted have been recently developed by a potential collaborator at the
University of Toronto and hold promise for the development of a new series of highly active systems.
186
PAr2
NH2
NH2 PAr2 PAr2
NH2
PR2
N PAr2
Fe
BrCO
CO
R'
[BF4]R''
Figure 6.45: Potential chiral PN ligands for use in the synthesis of new Fe(P‐N‐P)(CO)2Br[BF4] precatalysts.
Also of interest in the development and modification of the functional groups of the P‐N‐P catalyst is
changing the groups on phosphorus. As depicted in Figure 6.45, it is feasible to modify the groups on P
(of the PN) in these systems to other aryl groups (not just Ph) which could significantly change the
electronics around Fe. For the norephedrine‐derived system, when both phosphorus donors are
diphenylphosphine, the system is inactive, but with PiPr2 or PCy2 on one side the activity is dramatically
improved. This suggests that replacing diphenylphosphine with dialkylphosphine donors significantly
improves activity, and this follows from Milstein and Beller who have both developed highly active P‐N‐P
systems where both phosphorus donors were PiPr2.28,42 This is feasible if phosphonium dimers bearing
PR2 groups are used in the template reaction with PN ligands bearing PR’2 groups, as depicted in Scheme
6.22. This would allow for in depth exploration into the effects of sterics and electronics of the catalyst
on both activity and selectivity, as well as open up a new library of available P‐N‐P’ ligands, much like
what was previously done by our group with our P‐N‐N‐P systems.10,12
Scheme 6.22: Synthesis of new Fe(P‐N‐P')(CO)2Br[BF4] precatalysts bearing different groups on phosphorus.
Transitioning to the 6,5‐ligand system also developed, a similar exploration into the effect of changing
both the chirality of the PN, as well as the groups on phosphorus would be worthwhile to undertake.
Many of the changes could be done as already detailed for the 5,5 system, requiring the development of
new chiral PN ligands bearing PR2 groups. In the 6,5‐system, however, the phosphine aldehyde
employed in previous investigations, o‐(diphenylphosphino)benzaldehyde, is commercially available and
187
contains a PPh2 functionality. The synthesis of ‐PR2 functionalized phosphine aldehydes of this type has
been previously developed,43,44 and is shown in Scheme 6.23.
Br
H
O
HO OH
p-TsOH Br
H
OO
1. n-BuLi, -78 oC
2. PR2Cl, -78 oCPR2
H
OO
p-TsOH
PR2
H
O
Scheme 6.23: Synthesis of phosphine aldehydes bearing PR2 functionality.
6.2.3 New Catalytic Directions
The next area of investigation we would like to address is the application of our PN and P‐N‐P ligands
with other metals in catalysis, and the use of other metals in templating reactions. When we were
attempting to synthesize the [Fe(P‐N‐P’)(CO)2Br][BF4] catalyst with the diphenyl backbone we were
unable to template and form the P‐N‐P ligand, and rather ended up synthesizing [Fe(PN)2(CO)Br][BF4].
Based on the activity achieved by Noyori with his DH system27 which contained a chiral diamine and a
chiral diphosphine on ruthenium, we predict that the Ru(PN)2HCl complex may be quite active for DH.
This may also hold true for any bulkier PN ligands employed in the synthesis of Fe‐(P‐N‐P’) complexes
detailed previously, and would be an interesting area of research. Also of interest would be the use of
other first row transition metals such as cobalt or nickel with the P‐N‐P and P‐NH‐P ligands developed
for applications in hydrogenation,45‐48 hydrosilation,49 and dehydrogenation.50,51 Preliminary work also
suggests that the synthesis of a library of chiral P‐N‐O ligands is straightforward using methodologies
developed within this dissertation, as depicted in Scheme 6.24, which could also be applied to the
synthesis of new M(PNO)X systems with M = Cr, Co or Ni. Lastly is the potential applicability of other
metals as templating agents for the synthesis of a wide library of multi‐dentate ligand systems. Our
group has shown using multiple systems the power of templating ligands using metal centres, including
iron9 and nickel,52 and we propose that this methodology has the potential to allow for the synthesis of
an enormous library of new ligands.
Scheme 6.24: Synthesis of chiral P‐N‐O ligands using previously developed methodologies.
188
6.2.4 The Iron Age
The use of iron in catalysis is an ever growing and expanding field. Although there has been tremendous
progress so far, there is still much work left to be done. Improvements need to be made to existing iron
systems so that they can rival the precious metal systems currently in use; industry is averse to change,
especially as it pertains to increases in price or decreases in quality. What this means for catalytic
chemists is that the new iron systems being developed must be as active and selective as the precious
metal systems, operate under equal or milder conditions, and be as versatile, recyclable, and easy to
remove from product mixtures as their precious metal counterparts. In the area of iron catalysis, not
only do improvements need to be made for existing systems, but new systems need to be developed in
several areas of catalysis that have experienced limited progress in terms of potential iron replacements.
These areas include the reduction of CO2 and biomass as potential energy sources, alkene
hydrogenation, polymerization and much more.
189
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