Mechanistic research at York

Mechanisms in molecular interactions and self-assemblies

Victor Chechik Dave Smith

Victor ChechikMechanistic chemistry of free radicals (+ EPR spectroscopy) and nanostructures

• Free radical detection

• Harnessing free radicals for applications

• Organic magnetic materials

Latest raw data\pinene silica X data: +MS, 1.2min #148

0

200

400

600

Intens.

287.0 287.5 288.0 288.5 289.0 289.5 290.0 290.5 m/z

simulation

20 G

experiment

Methodology developing for the detection of free radical intermediates, e.g., based on spin trapping and EPR spectroscopy or MS (with Andrew Rickard).J. Am. Chem. Soc. 2009, 131, 7189; Science 2015, 349, 1072.

New approaches to synthetically-useful radical chemistry, e.g., radical initiation based on non-thermal plasmas or electrochemistry (with Deborah O’Connell, Peter O’Brien and Alison Parkin).Chem. Comm. 2017, 53, 3685; Chem. Eur. J. 2016, 22, 3496.

New chemistry of stable free radicals (with AnnMarie O’Donoghue) and applications to magnetic materialsNat. Comm. 2017, 15088.

• Understanding molecular structure/dynamics

in supramolecular/nanostructures by EPR spectroscopy

• Magnetic nanoparticles

• Nanoparticles in photocatalysis

10 G

Spin labels and EPR spectroscopy for characterisation of nanostructures (with Dave Smith).Soft Matter 2015, 11, 8968; Langmuir 2014, 30, 9210.

Iron and iron oxide micro and nanoparticles, e.g., for drug delivery applications (with Dept. Phys., Electronics and Biol at York).

Understanding the mechanisms of photocatalysis at the semiconductor nanoparticle surface, e.g., EPR spectroscopy to characterise charge carrier trapping at the surface (with Richard Douthwaite).

Dave SmithSupramolecular Nanomaterials

• Self-Assembled Hierarchical Multi-Component Materials

• Physical organic methods to understand & direct performance on multiple length-scales (molecular, nano, micro, macro)

• Applications: Tissue Engineering, Drug Formulation, Environmental Remediation, Soft Nano-Electronics

D. K. Smith and co-workers, J. Am. Chem. Soc. 2015, 137, 15486D. K. Smith and co-workers, Angew. Chem. Int. Ed. 2016, 55, 183

Supramolecular Nanomedicine

• Self-Assembled Multivalent (SAMul) Molecular Recognition

• Physical organic methods used to characterize and optimize binding in highly competitive biological environments

• Applications: Gene Delivery, Heparin Rescue for Coagulation Control, Cell-Surface Binding, Anti-viral Agents

SelfAssembly

BiomolecularRecognition

D. K. Smith and co-workers, Chem. Sci. 2014, 5, 1484D. K. Smith and co-workers, J. Am. Chem. Soc. 2015, 137, 10056

Mechanisms in metal catalysis, kinetics, photochemistry, in operando measurements

Simon Duckett Ian Fairlamb Jason Lynam Robin Perutz

John Slattery Alison Parkin Caroline Dessent

Ian Fairlamb

Mn catalysis (homogeneous) & C-H bond activation

Angewandte Chemie 2016 & 2015Full EPSRC Ind. CASE funding with

Syngenta (Mn catalysis)Full BBSRC Ind. CASE funding with

GSK (Biocatalysis)

Fairlamb group

Catalysis & Mechanism

Automation & Robotics

Biocatalysis & MetalCatalysis

Sustainable Synthesis

http://www-users.york.ac.uk/~ijsf1/index.html

Working with Jason Lynam and Rutherford Appleton Laboratories

Homogeneous-heterogeneous catalysts for cross-coupling reactions; C-H bond activation chemistry

• Nitrite/nitrate redox chem. at PdII/PdIV, C-H bond activation catalysis and functionalisation (J. Am. Chem. Soc. 2017)

• Mechanistic C-H bond activation in fluorinated organic –organometallic systems (Organometallics 2015)

• C-H bond functionalisation at Pd: use of robotic reaction screening and statistical analysis (new – supported by UoY/Wellcome Trust funding).

• Electrochemical activation of waste Pd (Newton Fund)

Internal collaborations: Duckett, Lynam, Perutz, Slattery and Wilson (Maths)External collaborations: Lin (HKUST), Ariafard (Tasmania), Eisenstein (Montpellier), Doherty (Newcastle), Willans (Leeds), Lee (Aston), Johnston (B’ham), EU + Pharma Ind., iPRD / Blacker & Bourne (Leeds)

C-H bond activation EU-COST action – CHAOS (catalysis-focus)EU-IMI-4 (Chem21), BayerCropScience (CASE Award) and Bruker (CASE Award); Chemspeed Robotics

• New cross-coupling Pd catalysts, including bimetallic complexes, Pdn clusters and Pd nanoparticles

• Natural product synthesis and peptide C-H bond functionalisation (Chem. Commun. 2015; Chem. Eur. J. 2015)

http://www-users.york.ac.uk/~ijsf1/index.html (Fairlamb)

Jason LynamUltrafast Spectroscopy as a Mechanistic Probe

Studying mechanism on a ps-ms timescale.Quantitative insight into the processes underpinning Mn-catalysis.Key intermediates in C-C bond formation observed.Effects of substrate and ligands quantified.

Fairlamb, Lynam and Towrie (RAL)

Mechanistic Insight into Organometallic Catalysis

Catalyst DeactivationProduct Isolated

New easily prepared catalyst precursor identified

MethodsIn situ spectroscopyIsotopic labellingKinetics(Organometallic) product isolationDensity Functional Theory

Informed by experiment, DFT identifies novel mechanistic steps

EPSRC Grant EP/H011455/1 J. Am. Chem. Soc., 2013, 135, 2222. Dalton Trans., 2014, 43, 4565. Lynam and Slattery

John SlatteryOuter-sphere electrophilic fluorination (OSEF)

Slattery and Lynam

Patent Appl. WO2016/087879A1J. Am. Chem. Soc., 2015, 137, 10753. Dalton Trans., 2016, 45, 1717.Angew. Chem. Int. Ed., 2017, DOI: 10.1002/anie.201702401R1

OSEF – A novel mechanism for metal-mediated C-F bond formation

Metal-mediated alkyne functionalization via OSEF

Mechanistic details – from NMR, UV/Vis and comprehensive DFT studies probing closed-shell and SET-based mechanisms

Slattery and collaborators

e.g. Chem. Eur. J., 2016, 22, 3414.Dalton Trans., 2015, 44, 110.Dalton Trans., 2014, 43, 11277.J. Am. Chem. Soc., 2013, 135, 2222.

Computational mechanistic studiesDFT and ab initio methods for mechanistic studies in a range of areas

MGD

model

MGD

model

Trp179

Asp13

Ile142

Cys141

Arg606

Trp472

Trp293

Metalloenzymes:Acetylene hydratase

Self-assembled ligand systems

Main group chemistry

Ligand design

Tungsten-containing enzyme

Catalytic alkyne hydration facilitated by ligand-assisted proton shuttle (LAPS) steps

Ligand-exchange mechanism at PhE+ cations (E = S, Se)

Weak C-H…N H-bonds in solution

Alison ParkinExpanding and utilising the electrochemical toolkit

Expansion

• FT voltammetry: simultaneous measurement of electron-hopping and catalytic turnover

PNAS, FTV of Mo enzyme, 2015; Anal Chem, FTV of disulfide protein, 2016; JACS submitted, FTV of H2 biocatalysis

• Conductive surface chemistry to “wire” any redox-catalyst to any electrode

Angewandte, Conductive gels, 2016; Nat Comm, Si-Echem+photonics, 2016

Utilisation

• Redox-tagging drug molecules for triggered activation and monitoring

Inorg Chem, Fc-tagged CO-releasing molecules (with IJSF and JML), 2017

• Electro-synthesis

– late stage functionalisation (with PAOB and VC)

– CO2 mineralisation

Alison ParkinExpanding and utilising the electrochemical toolkit

Monitoring Reaction Mechanisms with Mass Spectrometry Interfaced with Laser

Spectroscopy

Dr Caroline Dessent

● Instrumentation unique in UK

● Commercial electrospray mass spectrometers custom-adapted to allow laser spectroscopy of mass-selected ions

● Bruker AmaZon and Bruker Esquire ESI-MS

Fig: Schematic of apparatus

(---laser UV/VIS OPO)

Current Capabilities

• Solution-phase reaction mechanisms probed via ESI-MS (reactants/products/intermediates)

• Solution-phase photochemical mechanisms probed via ESI-MS

• Products/intermediates identified via UV/VIS laser spectroscopy

• Direct monitoring of photochemical reaction mechanisms of isolated (gas-phase) systems (e.g. sunscreen photodegradation, Flavin photodegradation)

Planned Future Capabilities• IR-fingerprint detection

• Chiral molecule detection

References1. Locating the Proton in Nicotinamide Protomers via Low-Resolution UV Action

Spectroscopy of Electrosprayed Solutions, Edward Matthews and Caroline E. H. Dessent, JPC A, 46, 9209-9216, 2016.

2. UV laser photoactivation of hexachloroplatinate bound to individual nucleobases in vacuo as molecular level probes of a model photopharmaceutical, Edward Matthews,

Ananya Sen, Naruo Yoshikawa, Caroline E. H. Dessent, PCCP, 18, 15143, 2016.

Mechanisms in sustainable and applied chemistry

James Clark Mike North Peter O’Brien

Will Unsworth Paul Clarke

Levoglucosenone as a Bio-based Platform molecule

J H Clark et al; see for example Chem Comm., 2014, 9650

James Clark

Designing new bio-based solvents to match polarity gaps

J H Clark, et al, ChemSusChem,2016, 3503 ; Green Chem., 2017, DOI: 10.1039/C7GC00112F.

Mike North: Unprecedented Carbonato

Intermediates in Cyclic Carbonates Synthesis

• Complex 2 was subsequently detected when complex 1 was

treated with CO2 at 50 bar carbon dioxide pressure by m/z, IR, 1H NMR and 13C NMR spectra.

• Formation of carbonate complex predicted by DFT calculation.

• complex 1 is not Lewis acidic, complex 2 is Lewis acidic.

• Enantiomerically pure epoxides and deuterated epoxides were

employed in the study of the mechanism.

Adduct state Transition state Product state

M. North et al., Chem. Eur. J., 2014, 20, 15005; ChemSusChem 2016, 9, 791.

HSPiP for Greener Solid Phase

Organic Synthesis (SPOS)

• The ability of various green

solvents to swell common

SPOS resins has recently

been investigated.[1]

• Initial swelling results have

been used to predict

additional green solvents

using HSPiP software.

[1]. S. B. Lawrenson, M. North, F. Peigneguy, A. Routledge, Green Chem., 2017, 19, 952-962.

O’Brien Group Mechanistic Research

Mechanistic Interrogation of Organolithium Chemistry

DFTModelling

Mechanisticblack box

?N

Boc

+ R–Li

+

NNMe

New SyntheticMethodology

6Li/13C NMR Spectroscopyof RLi/diamine Complexes

In situ React IR Spectroscopy

y = -0.0237 ± 0.0011x - 3.4005R² = 0.9842

-7

-6.5

-6

-5.5

-5

-4.5

-4

-3.5

-3

0 30 60 90 120 150

ln[p

relith

iati

on

co

mp

lex A

]

time / sec

t1/2 = 29.2 (± 1.3) sec

y = -0.0079x ± 9.7x10-5 - 2.9465R² = 0.9964

-6

-5.5

-5

-4.5

-4

-3.5

-3

-2.5

0 50 100 150 200 250 300 350 400

ln[L

ihit

hia

ted

In

term

ed

iate

]

time / sec

t1/2 = 86.9 (± 1.1) sec

KineticAnalysis

ReactionConditions

O’Brien Group Mechanistic Research

Mechanistic Interrogation of Organolithium Chemistry

J. Am. Chem. Soc. 2010, 132, 15445

In situ IR and NMR Spectroscopy: Rotamers

J. Am. Chem. Soc. 2012, 134, 5300

6Li/13C NMR Spectroscopyof RLi/diamine Complexes

y = -0.0237 ± 0.0011x - 3.4005R² = 0.9842

-7

-6.5

-6

-5.5

-5

-4.5

-4

-3.5

-3

0 30 60 90 120 150

ln[p

relith

iati

on

co

mp

lex A

]

time / sec

t1/2 = 29.2 (± 1.3) sec

y = -0.0079x ± 9.7x10-5 - 2.9465R² = 0.9964

-6

-5.5

-5

-4.5

-4

-3.5

-3

-2.5

0 50 100 150 200 250 300 350 400

ln[L

ihit

hia

ted

In

term

ed

iate

]

time / sec

t1/2 = 86.9 (± 1.1) sec

In situ React IR Spectroscopy

J. Am. Chem. Soc. 2010, 132, 7260J. Am. Chem. Soc. 2016, 138, 651

LithiationRates

Correlating Theory with Experiment:Using DFT to Predict Reactivity

TrappingRates

Unsworth group published work

Unsworth and Taylor et al. Org. Lett. 2013, 15, 258

React IR- detection of N-acyliminium ions

React IR- Mechanistic/kinetic details• Ag-nanoparticle involvement• Synergistic Ag/silica relationship uncovered

Unsworth and Taylor et al. Angew. Chem. Int. Ed. 2016, 55, 13798

Unsworth group ongoing/future work

For background see: Chem. Eur. J. 2016, 22, 8777.

Successive Ring Expansion (SuRE) reactions in supramolecular chemistry

(e.g. catenanes, rotaxanes).

[Potential links to Durham ECRs, e.g. Avestro, Kitching, Mcgonigal

For background, see: Angew. Chem. Int. Ed. 2015, 54, 15794

Vinyl metal reactive intermediates

Understanding Stereodivergent Heterocycle SynthesisPaul A. Clarke

TBAF/AcOH gives the 2,6-trans-THP.

TFA gives the 2,6-cis-THP.

DFT and synthetic studies show that the 4-hydroxyl group essential for stereodivergence.

Chem. Sci. 2017, 8, 482

Prebiotic “Protocell” Mediated Carbohydrate SynthesisPaul A. Clarke and David K. Smith

Amino esters or amino nitriles embedded in “Protocells” made of simple dipeptide hydrogels or agarose are

catalytically active and promote the formation of 2-deoxy-D-ribose as well as other carbohydrates of prebiotic relevance.

Catalytically active hydrogels are also under investigation.

Mechanisms in enzyme catalysis and metalloproteins

Gideon Davies Martin Fascione Paul Walton

M. A. Fascione et al, Chem. Eur. J., 2012, 18, 321-333 “Do glycosyl sulfonium ions engage in neighboring group participation? A study of oxathiane glycosyl donors and the basis for their selectivity”

Martin Fascione: glycosylation mechanisms

M. A. Fascione et al, Chem. Eur. J., 2012, 18, 2987-2997 “Mechanistic studies on a sulfoxide transfer reaction mediated by diphenyl sulfoxide”

mechanistic carbohydrate chemistry

O

O

S

Ph

OMe

O

O

O

S

Ph

OMe

dr: 96:4

O[18O, 87%]

S

48%

Tf2OOSOTf S OTf

DCM2 equiv.

1 equiv.

-60°C ® rt

-60°C ® rt

DCM

"2:1 premix"

O i)

ii)S

O

O

S

Ph

OO

O

S

Ph

dr: 93:7

52%

-60°C ® rt

DCMO

i)

ii)S

"2:1 premix"

O

O

S

Ph

OSR

LPMO

CBM CBM

endo-G

exo-G

Cu

O2

e

CAZy classification AA9, AA10, AA11, AA13

Quinlan et al, Proc Nat Acad Sci 2011, 15079–15084. Frandsen et al, Nature Chem. Biol. 2016, 298–303.

Mechanisms of Cu-containing LPMOs(Walton and Davies)

Methods

MO #163

(β-LUMO 1)

MO #164

(β-LUMO 2)

Spectroscopy Theory

StructuresKinetics

Mechanisms in complex chemical processes and analysis of rich data

Lucy Carpenter Terry Dillon Mat Evans

Andrew Rickard Julie Wilson (Maths)

Terry Dillon - gas-phase organic oxidation

OH + RH (+ O2) H2O + RO2

RO2 = key intermediates - difficult to detect & budgets uncertainFurther RO2 chemistry terminates (1) or recycles key radicals (2)

RO2 + HO2 ROOH + O2 (1) OH + RO + O2 (2)

Experiments lasers generate RO2 & detect OH

Mechanistic info: rate constants; products;

isotope effects; speciated radical recycling info.

Applications: atmospheric / indoor air chem.;

biofuel combustion; autoignition...

Winiberg et al. , Atmos. Chem. Phys. 2016, 16, 4023-4042

Gross et al., J. Phys. Chem. A, 2014, 118 (6), 974–985

Taraborrelli et al., Nature Geos., 2012, 5, 190–193, 2012

Terry Dillon - mechanism validation

1. Reaction rates - experiments on multicomponent RH mixtures

X + RH products (X = OH, Cl,...)

• RH depletion by GC-TOF-MS

• ensemble relative rate analysis

rapid validation of kinetic database & SAR

new data for aromatics, large alkenes

2. Radical reactivity = k1[CH4] + k2[C5H8] + k3[NO2] + ...

Comparative Rate Method for OH &

Cl radicals (with York Plasma Institute)

test atmospheric models / measurements

Shaw et al. , Atmos. Chem. Phys. 2017 (in prep)

Sinha et al., Atmos. Chem. Phys. 2008, 8, 2213

SocietyKnowledge

EconomyTraining

AQ and Climate ResearchUnderpinned by detailed mechanistic understanding

Mechanism Development and

Evaluation

Field Observations

diagnostics and analysis tools

Modelling on a range of scales

Fundamental laboratory data

Chamber Evaluation £6M investment in buildings,

laboratories and equipment

Impact and translation

Master Chemical Mechanism

GEOS-ChemGlobal and

Regional Model

Fundamental chemistry

Field observations

Chamber Evaluationhttp://wacl.org.uk@AtmosChemYork

http://wacl.org.uk

Twitter: @AtmosChemYork

Case Studies• Evidence for renoxification in

the tropical marine boundary layer

• Halogens are an important NOx sink

• Potentially major impact on our understanding of oxidation chemistry Reed et al., Atmos. Chem. Phys., 17, 4081, 2017

HNO3 + aerosol → pNO3- + H+

pNO3 + hv → xHONO + yNO2

HONO + hv → OH + NO

NO NO2 NOx O3 HONO PAN

York’s Cape Verde observatory

• Atmospheric iodine levels influenced by sea surface emissions of inorganic iodine

• HOI and I2 production following the reaction of O3 with I− at the air–sea interface

• Microlayer enchantment

Carpenter et al., Nature Geoscience, 6, 108, 2013

http://wacl.org.uk

Twitter: @AtmosChemYork

Case Studies

• Iodine’s impact on tropospheric oxidants: a global model study in GEOS-Chem

• Newly implemented I chemistry + Br chemistry yield a tropospheric O3 burden decrease of 14.4 % and a small increase in OH (1.8 %) Sherwen et al., Atmos. Chem. Phys., 16, 1161, 2016

• Halogen chemistry reduces O3 radiative forcing• More active halogen chemistry in present day vs. preindustrial

Sherwen et al., Atmos. Chem. Phys., 17, 1557, 2017

length

of drought

Julie Wilson: data processing method development and statistical pattern recognition e.g. multivariate analysis applied in metabolomics and proteomics

Multivariate analysis applied to chemical synthesis

Synthesis of 5-phenylphenanthridin-6(5H)-one