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Metal Catalyzed Redox Reactions
Nathan Jui
MacMillan Group Meeting
January 27, 2010
Metal Catalyzed Redox Reactions
! Many metal-catalyzed reactions involve redox processes
Cross-Coupling Chemistry
X
MR
catalyst R
Heck-Type Chemistry
Ar X
R
catalystAr
R
Reduction Chemistry
R
catalystMe
X
H2Me
R
X
DG catalyst DG
[O] R
Oxidation Chemstry
! These reactions and their mechanisms will not be addressed
Metal Catalyzed Redox Reactions
! Many metal-catalyzed reactions involve redox processes
Constraints Applied
1. Catalytic in metal
2. Single electron transfer processes
3. Net redox neutral (no terminal oxidant)
4. No light (purely chemical activation)
5. Selective generation of organic radicals
If electron transfer is accompanied occurs via inner-sphere mechanism
Atom Transfer Radical Chemistry
S X
Mn+1X S
R
Mn+1XRS
RS
ATRA
Cycle
Mn
X
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' as observed by Kharasch and co-workers (1933)
Meroom temp
HBr H3C Me
Brsole product
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
"The presence of benzoyl peroxide or ascaridole modified profoundly the course of the
addition and the product of the reaction was largely, if not all, normal propyl bromide"
-Morris Kharasch
Kharasch, M. S. J. Am. Chem. Soc. 1933, 55, 2531.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' as observed by Kharasch and co-workers (1933)
Meroom temp
HBr H3C Me
Brsole product
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
"The presence of benzoyl peroxide or ascaridole modified profoundly the course of the
addition and the product of the reaction was largely, if not all, normal propyl bromide"
-Morris Kharasch
Kharasch, M. S. J. Am. Chem. Soc. 1933, 55, 2531.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' as observed by Kharasch and co-workers (1933)
Meroom temp
HBr H3C Me
Brsole product
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
"The presence of benzoyl peroxide or ascaridole modified profoundly the course of the
addition and the product of the reaction was largely, if not all, normal propyl bromide"
-Morris Kharasch
Kharasch, M. S. J. Am. Chem. Soc. 1933, 55, 2531.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
"...it may be suggested that the addition process is one requiring the transient
production of neutal atoms of hydrogen and broming from hydrogen bromide"
-Hey and Waters
Hey, D.; Waters, W. Chem. Rev. 1937, 21, 1969.
BzO H Br Br MeMe
Br H Br
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
Kharasch, M. S. et al. Science, 1945 122, 108.
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
! Kharasch later reported the radical addition of halomethanes to olefins (1945)
CCl4 Cl3CCl
MeMe
> 60% yield
(BzO)2, heat
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
"...it may be suggested that the addition process is one requiring the transient
production of neutal atoms of hydrogen and broming from hydrogen bromide"
-Hey and Waters
Hey, D.; Waters, W. Chem. Rev. 1937, 21, 1969.
BzO H Br Br MeMe
Br H Br
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
Meroom temp
HBr, ROORH3C Me
BrMe
Br
minor major
Kharasch, M. S. et al. Science, 1945 122, 108.
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
! Kharasch later reported the radical addition of halomethanes to olefins (1945)
CCl4 Cl3CCl
MeMe
> 60% yield
(BzO)2, heat
The Kharasch Addition Reaction of Halomethanes to Olefins
! Kharasch reported the radical addition of carbon-based radicals to olefins (1945)
Kharasch, M. S. Science 1945, 122, 108.
CCl4Cl3C
ClMe
MeAcO OAc
!
2 H3C 2 CO2AcO OAc
H3C CCl4 CH3Cl Cl3C
Cl3C R RCl3C
RCl3C CCl4
RCl3C
ClCl3C
RCl3C R Cl3C
R
R
Initiation
Propagation
PolymerizationR = Ar
The Kharasch Addition Reaction of Halomethanes to Olefins
! Kharasch reported the use of several radical electrophiles in his new radical reaction
OMehex
Cl
JACS, 1945, 1626
(AcO)2, 40% yield
hex
BrCBr3
h!, 88% yield
JACS, 1946, 154
hex
BrCCl3
(AcO)2, 78% yield
JACS, 1947, 1105
O
ClClOEt
hex
Br
JACS, 1948, 1055
(AcO)2, 54% yield
O
Halogen was used in excess (3- or 4-fold) for optimum yields
Higher order products made up mass balances
Highly activated bromomethanes were the best substrates
Ph
BrCBr3 Cl
PhCCl3Ph
CCl4, (AcO)2CBr4, light
quant96% n
The Failed Polymerizations of Minisci
! Surprisingly, substantial monoadduct formation was observed with carbon tetrachloride
Cl
CNCCl3
NC
nautoclave, 160 °C
CCl4, ROOR NC
ClCCl3
'significant amount'
H
CNCCl3
NC
nautoclave, 160 °C
CHCl3, ROOR NC
ClCHCl2
new regioisomer
! Standard peroxide initiated radical mechanisms occur via hydrogen abstraction
RO H CCl3NC
CCl3NC
CCl3H
Cl3C
Cl3C
NC
H CCl3
Minisci, F. Chem. Ind. (Milan), 1956, 122, 371.
Complete selectivity for opposite regioisomer suggested a new mechanism
Radical Chain Termination by Metal Halide Salts (Jay Kochi)
! Also in 1956, Kochi was studying the oxidation of alkyl radicals by metal salts
Kochi, J. J. Am. Chem. Soc. 1956, 78, 4815.
PhN2Cl CuCl or FeCl2
acetone
Ph
Cl
CuCl
Ph CuCl2
Ph
Cl CuCl
!CuCl
RR
Meerwein Arylation
1. The rate of benzylic radical oxidation by CuCl2 (or FeCl3) is much faster than styrene addition
2. Oxidation occurs through a 'ligand transfer' mechanism (inner-sphere electron transfer)
good yields
0% polymer
Minisci's reaction could have contained metal halides
Accidental Discovery of Catalytic Atom Transfer Radical Chemstry
! Minisci's steel autoclave was corroded and had likely leached iron into the reaction
Asscher, M. et al. J. Chem. Soc. 1963, 1887.
2 CCl4 Fe (s) 2 Cl3C FeCl2
CCl4 FeCl2 Cl3C FeCl3
! Minisci's group and Vofsi and Asscher first describe catalytic atom transfer radical addition
and could have been oxidized to FeCl3 by chlorine radicals
Cl
Cl
ClCl R
1 equiv 2 equiv
1 mol% CuCl (or FeCl2)
2 equiv solvent, 80!120 °C
RCl3C
Cl
46-89% yield
Ph CN CO2Et C6H13
Minisci, F. et al. Gazzeta 1961, 91, 1030.
Proposed Mechanism of Atom Transfer Radical Addition (ATRA)
! Metal catalyst participates in both initiation and termination steps, relative rates dictate selectivity
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
CuIX
CuIIX2R
R R'
RR'
R
RR'
R
RR'
X
R'
RR'
R'n
R R
R X
RR'
RR'
R'R
telomer
polymer
ka1 kd2
kadd
kt kt
kt
kp
Selective ATRA Requires:
1. Low radical concentration
kd1 and kd2 >> ka1 and ka2
kd1 ka2
2. Slow product activation (vs sm)
ka1 >> ka2
3. Oxidation must be fast vs prop.
kd2 >> kp
monoadduct! Red. halogen abstraction
generates radical
! Oxid. halogen abstraction
terminates radical
Catalytic Redox Mechanism:
So Many Different Catalysts...
Y XR
Y R
XYYY Y MLnXn
(cat.)
! The many metals that catalyze CHCl3, CHBr3, CCl4, and/or CBr4 radical addition
! The most commonly used catalysts for ATRA reactions are CuIX and RuIIX2 derivatives
! Exact nature of free radical intermediates is not known
Evaluation of the Proposed Radical Mechanism
! Kharasch systems likely proceed via radical intermediates (Ru, Cu, Fe, Mo, Cr)
Matsumoto, H. et al. Tetrahedron Lett. 1975, 15, 899.
! Metal catalyst impacts diastereoselectivity of CCl4 addition to cyclohexene
CCl4 hex
RuCl2(PPh3)3
galvinoxyl hex
ClCl3C
80 °C, 4 h
0% yield
(76%, no spintrap)
Matsumoto, H. et al. Tetrahedron Lett. 1973, 14, 5147.
RuCl2(PPh3)3
80 °C, 4 h
(BzO)2
80 °C, 4 h
CCl4CCl3
Cl
CCl3
Cl
77% yield96:4 (trans:cis)
low yield53:47 (trans:cis)
Effect not seen with Cu: Asscher, M. et al. J. Chem. Soc. Perkin Trans. 2 1973, 1000.
CCl4
Intermediate radical species likely exist as coordinated radical pairs (Ru system)
Attempts at Enantioselective Kharasch Addition
! Chiral ligands could potentially induce enantioselectivity
Similar result with RhCl-diop system: Murai, S. et al. Angew. Chem. Int. Ed. Eng. 1981, 20, 475.
CCl4Ru2Cl4(diop)3
Ph
Cl
100 °C, 6 hPh CCl3
73% yield
13% ee
Kamigata, N. et al. Bull. Chem. Soc. Jpn. 1987, 60, 3687.
RuL*nCl2
RuIIICl3Cl3CRuIIICl3Cl3CCH2CHPh
CCl4
Ph
Ph
ClCl3C
L* = (!)-diop
O
OMe
Me
CH2PPh2
CH2PPh2
H
H
! Coordinated metal-radical pair should participate in enantiodetermining chlorination
ATRA
Cycle
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Reactions (ATRC)
X
X
ML2Xn
(cat.)FG
FG
! Area 2. Intermolecular Kharasch Type Haloalkylation Reactions
FG X RML2Xn
(cat.)
R
X
FG
Selected Intramolecular ATRA: 5-Exo Trig Cyclizations
! A variety of cyclization substrates and catalytic systems have been developed over 35+ years
Weinreb, S. et al. J. Org. Chem. 1990, 55, 1281.
Cl ClCl RuCl2(PPh3)3
PhH, 155 °C79% yield
MeO2C ClCl RuCl2(PPh3)3
PhH, 165 °C77%, 1:1 dr
MeO2C ClMe RuCl2(PPh3)3
PhH, 165 °C71%, 2:1 dr
MeO2C HMe
Cl
MeO2C HCl
Cl
ClCl
Cl
O
Cl ClCl CuCl
MeCN, 110 °C95% yield O
ClCl
Cl
OO
NH
Cl ClCl CuCl
MeCN, 140 °C57% yield N
H
ClCl
Cl
OO
NH
F BrF CuBr
MeCN, 80 °C84% yield N
H
FF
Br
OO
Clark, A. Chem. Soc. Rev. 2002, 31, 1.
1-10% typical loadings, > 80°C temperatures ~30% typical loading, > 100°C temperatures
RuCl2(PR3)3 catalysts: 1973 (Nagai) CuX catalysts: 1963 (Asscher & Vofsi)
Intramolecular Atom Transfer Radical Cyclization Ligand Effects
! 5-Exo trig cyclization of unsaturated !-haloamide substrates yields lactam scaffolds
Clark, A. Tetrahdron Lett. 1999, 40, 4885.
N
X ClCl
OTs
NTs
O
ClCl Cl30 mol% catalyst
solvent, temp
Catalyst Solvent Temp. Time Yield
CuCl MeCN 80 °C 24 h 97%
CuCl-bipy (5%) CH2Cl2 23 °C 0.2 h 91%
CuCl-bipy CH2Cl2 23 °C 24 h 0%
X
Cl
Cl
H
CuCl-NPMI CH2Cl2 23 °C 72 h 15%H
CuCl-tren-Me6 CH2Cl2 23 °C 2 h 90%H
NN
bipy
NN
NPMI
Me
N
Me2N
NMe2 NMe2
tren-Me6
Radical-Polar Crossover Mechanism: Addition to Enamides
! Electrophilic radicals add to acyl enamines, terminate via radical-polar crossover mechanism
Clark, A. Tetrahdron Lett. 1999, 40, 4885.
N
Me BrMe
OBn
NBn
O
MeMe30 mol% CuBr•L
CH2Cl2, rt, 20 minN
Me2N
NMe2 NMe2
82%, 1:1 ratio
= L
N
MeMe
OBn
NBn
O
MeMeCuLBr
!CuLBr2 NBn
O
MeMe
!H+CuLBr2
!CuLBr
N
Cl ClCl
OBn
NBn
O
ClCl30 mol% CuBr•L
CH2Cl2, rt
! While this triethylenetetramine ligand is highly active, the perfect Cu system remains unknown
0% yieldcomplex mixture
Cascade Cyclization Using Copper Redox Catalyst
! Radical mono- and bicyclization utilizing copper-bipy as catalyst (Dan Yang)
Yang, D. et al. Org. Lett. 2006, 8, 5757.
OEt
OO
ClClMe
Me
O
MeCl
CO2Et
ClMe
OEt
OO
ClCl
OCO2Et
Cl
Me MeCl
OEt
OO
ClCl
OCl
CO2Et
Me Me
Cl
CuCl•bipy
DCE, 80 °C21 h
61%
2:1 dr
33%
3:2 dr
! Bicyclization under the conditions outlined above give modest yields and diastereocontrol
79% yield
3:1 dr
Intramolecular Atom Transfer Radical Cyclization
! Medium ring heterocycle formation via redox reaction affords 8 and 9 membered lactones
Clark, A. et al. J. Chem. Soc. Perkin Trans. 1, 2000, 671.
O Cl3
O
30 mol% CuCl-bipy
0.1 M DCE80 °C, 18 h
O O
Cl
ClCl
nn
n = 1: 60% yield
n = 2: 59% yield
! Macrocyclization reactions were also accomplished using a tridentate ligand
Pirrung, F. et al. Synlett. 1993, 50, 739.
OO
O
OO
OO
O
OO CCl3
OClCl
Cl
10 mol% CuCl-ligand
0.2 M DCE, 80 °C70% yield
O
NN N
N
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
X
ML2Xn
(cat.)FG
FG
! Successful radical precursors in ATRC reactions so far are highly activated
n nn= 0-13
RO
O
R2N
O
R2N
O
RO
ONR2
ClRO
OOR
ClCl
ClCl
Cl
ClCl
F
IF
R2N
O
Cl
RCl
R2N
O
Cl
HCl
R2N
O
Cl
MeMe
R Cl
ClCl
RO
O
R
ClCl
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
X
ML2Xn
(cat.)FG
FG
! Successful radical precursors in ATRC reactions so far are highly activated
n nn= 0-13
RO
O
R2N
O
R2N
O
RO
ONR2
ClRO
OOR
ClCl
ClCl
Cl
ClCl
F
IF
R2N
O
Cl
RCl
R2N
O
Cl
HCl
R2N
O
Cl
MeMe
R Cl
ClCl
RO
O
R
ClCl
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
X
ML2Xn
(cat.)FG
FG
! Area 2. Intermolecular Kharasch Addition Reactions of Polyhaloalkanes
n nn= 0-13
ML2Xn
(cat.)R
R'
R
R'
Y Y
X
Y
Y
X
Perfluoroalkylation of Olefins Using ATRA
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. J. Chem. Soc. Perkin Trans. 1. 1991, 627.
RF3C
SCl
O O
RCF3
Cl
1 equiv 2 equiv
! The reaction works well with highly activated olefins but is sensitive to sterics (1,2-substitution)
CF3
Cl
79% yield
41% yield
CF3
Cl
87% yield
CF3
Cl
66% yield
O2N
CF3
Cl
46% yield
CF3
Cl
23% yield
Me
Me
CF3
ClO
OEt
RuL*nCl2
RuIIICl3CF3RuIIICl3
F3CSO2Cl
R
Ph
ClF3C
ATRA
Cycle
SO2
R
CF3
Perfluoroalkylation of Olefins Using ATRA
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. J. Chem. Soc. Perkin Trans. 1. 1991, 627.
RF3C
SCl
O O
RCF3
Cl
1 equiv 2 equiv
! The reaction works well with highly activated olefins but is sensitive to sterics (1,2-substitution)
CF3
Cl
79% yield
41% yield
CF3
Cl
87% yield
CF3
Cl
66% yield
O2N
CF3
Cl
46% yield
CF3
Cl
23% yield
Me
Me
CF3
ClO
OEt
Arene Perfluoroalkylation Using Sulfonyl Chloride Reagents
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. N. J. Chem. Soc. Perkin Trans. 1. 1994, 1339.
F3CS
Cl
O O
1 equiv 2-5 equiv
! Benzene substrates react but are completely regio-permiscuous
53% yield
trace
41% yield
63% yield
RR
CF3
CF3
CF3 CF3
OMe
CF3
2:1:1 (o:m:p)36% yieldCF3
Me1:1:1 (o:m:p)
CN Me
Me39% yieldCF3
Br1:1:1 (o:m:p)
Arene Perfluoroalkylation Using Sulfonyl Chloride Reagents
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. N. J. Chem. Soc. Perkin Trans. 1. 1994, 1339.
F3CS
Cl
O O
1 equiv 2-5 equiv
! Five-membered heterocyclic compounds work with increased regiocontrol
R RCF3
O CF3 S CF3 S CF3 S CF3Me OHC
N CF3 N CF3
BnN CF3
AcN CF3
COPh
30% 77% 73% 26%
0% 53% 61% 92%
H
Arene Perfluoroalkylation Using Sulfonyl Chloride Reagents
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. N. J. Chem. Soc. Perkin Trans. 1. 1994, 1339.
F3CS
Cl
O O
1 equiv 2-5 equiv
! Benzene substrates react but are completely regio-permiscuous
53% yield
trace
41% yield
63% yield
RR
CF3
CF3
CF3 CF3
OMe
CF3
2:1:1 (o:m:p)36% yieldCF3
Me1:1:1 (o:m:p)
CN Me
Me39% yieldCF3
Br1:1:1 (o:m:p)
Trifluoromethylation of Electron-Poor Enolsilane Substrates
! Ruthenium catalyzed sulfonyl chloride decomposition also works on silyl enol ethers
1 mol% RuCl2(PPh3)2
benzene, 120 °C
Kamigata. N. Phosporus, Sulphur, and Silicon 1997, 155.
F3CS
Cl
O O
1 equiv 2 equiv
R
OTMSR
OCF3R'
R'
OCF3
OCF3
O2N Cl
OCF3
OCF3
MeO
55% yield 51% yield 58% yield 0% yield
Ph
OCF3 H
OCF3
OCF3 O
CF3
28% yield 35% yield 43% yield 0% yield
Me BntBu
Ph
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
O N
O
PhR
R
OR'
TiCl4
O N
O
PhR
R
OR'
O N
O
PhR
R
OR'
CCl3
TiCl4, i-Pr2NEt, CH2Cl2BrCCl3 (3 equiv)
7 mol% RuCl2(PPh3)3
45 °C, 12 h
O N
O
PhR
R
OR'
TiCl4
RuIIRuIII + Br
BrCCl3CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
O N
O
PhR
R
OR'
TiCl4
O N
O
PhR
R
OR'
O N
O
PhR
R
OR'
CCl3
TiCl4, i-Pr2NEt, CH2Cl2BrCCl3 (3 equiv)
7 mol% RuCl2(PPh3)3
45 °C, 12 h
O N
O
PhR
R
OR'
TiCl4
RuIIRuIII + Br
BrCCl3CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
Bn
OMe
CCl3
O N
O
BnMeMe
O
CCl3O N
O
BnMeMe
O
CCl3
O N
O
BnMeMe
OC4H9
CCl3O N
O
BnMeMe
O
CCl3O N
O
BnMeMe
O
CCl3
TsN
6
4OBn
89%, >98:2 dr
99%, >98:2 dr
63%, >98:2 dr
87%, >98:2 dr
91%, >98:2 dr
61%, >98:2 dr
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
O N
O
PhR
R
OR'
TiCl4
O N
O
PhR
R
OR'
O N
O
PhR
R
OR'
CCl3
TiCl4, i-Pr2NEt, CH2Cl2BrCCl3 (3 equiv)
7 mol% RuCl2(PPh3)3
45 °C, 12 h
O N
O
PhR
R
OR'
TiCl4
RuIIRuIII + Br
BrCCl3CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
PhR
R
OR'
TiCl4
CCl3
O N
O
BnMeMe
O
MeO N
O
BnMeMe
O
Me
O N
O
BnMeMe
O
MeO N
O
BnMeMe
O
MeO N
O
BnMeMe
O
Me
64%, >98:2 dr
71%, 1.6:1 dr
83%, >98:2 dr
76%, >98:2 dr
71%, >98:2 dr
75%, 1.3:1 dr
O N
O
BnMeMe
O
MeCl
Cl
CF3
Cl
Me
Cl Cl
ClOMe
O
Cl Cl
OEt
O
OCO2Bn
Cl Cl
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
MatyjaszewskiSawamoto
Carnegie MellonKyoto University
! They independantly reported a new method (ATRP or living radical polymerization)
submitted September 6, 1994 submitted February 16, 1995
'Living Radical Polymerization' 'Atom Transfer Radical Polymerization'
Macromolecules, 1995, 28, 1721. J. Am. Chem. Soc., 1995, 117, 5614.
cited 2,374 timescited 1,571 times
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
MatyjaszewskiSawamoto
Carnegie MellonKyoto University
! They independantly reported a new method (ATRP or living radical polymerization)
submitted September 6, 1994 submitted February 16, 1995
'Living Radical Polymerization' 'Atom Transfer Radical Polymerization'
Macromolecules, 1995, 28, 1721. J. Am. Chem. Soc., 1995, 117, 5614.
cited 2,374 timescited 1,571 times
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
MatyjaszewskiSawamoto
Carnegie MellonKyoto University
! They independantly reported a new method (ATRP or living radical polymerization)
submitted September 6, 1994 submitted February 16, 1995
'Living Radical Polymerization' 'Atom Transfer Radical Polymerization'
Macromolecules, 1995, 28, 1721. J. Am. Chem. Soc., 1995, 117, 5614.
cited 2,374 timescited 1,571 times
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
CuIX
CuIIX2R
R R'
RR'
R
RR'
R
RR'
X
R'
RR'
R'n
R R
R X
RR'
RR'
R'R
teleomer
polymer
ka1 kd2
kadd
kt kt
kt
kp
Selective ATRA Requires:
1. Low radical concentration
kd1 and kd2 >> ka1 and ka2 kd1 ka2
2. Slow product activation (vs sm)
ka1 >> ka2
3. Oxidation must be fast vs prop.
kd2 >> kp
monoadduct
Polymerization Can Occur If:
1. Above requirements are met
2. Starting Halogen is consumed
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
CuIX
CuIIX2R
R R'
RR'
R
RR'
R
RR'
X
R'
RR'
R'n
R R
R X
RR'
RR'
R'R
teleomer
polymer
ka1 kd2
kadd
kt kt
kt
kp
Selective ATRA Requires:
1. Low radical concentration
kd1 and kd2 >> ka1 and ka2 kd1 ka2
2. Slow product activation (vs sm)
ka1 >> ka2
3. Oxidation must be fast vs prop.
kd2 >> kp
monoadduct
Polymerization Can Occur If:
1. Above requirements are met
2. Starting Halogen is consumed
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
CuIX
CuIIX2R
R'
RR'
RR'
X
R'
RR'
R'n
R X
polymer
ka1 kd2
kadd
kp
Selective ATRA Requires:
1. Low radical concentration
kd1 and kd2 >> ka1 and ka2 kd1 ka2
2. Slow product activation (vs sm)
ka1 >> ka2
3. Oxidation must be fast vs prop.
kd2 >> kp
monoadduct
Polymerization Can Occur If:
1. Above requirements are met
2. Starting Halogen is consumed
P X MnXn P MnXn
+m
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhMe Ph
Cl
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
n PDI = 1.3!1.4595% consumption
! PDI = polydispersity index, a measure of how consistent chain growth is
! PDI equal to one: all of the chains in a given sample are of the same length
! Good PDI values are typically > 1.5
PDI = Mn / Mw
Mn = number average molecular weight
Mw = weight average molecular weight
total weight / number of molecules
average weight of average molecule
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhCl Ph
Me
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
PDI = 1.3!1.4595% consumption
! Sawamoto system utilized some well-developed ruthenium phosphine conditions
CO2Me
1 equiv 0.01 equiv
0.5 mol% RuCl2(PPh3)3
2.0 mol% MeAl(OAr)2toluene, 60 °C, 4 h
ClCCl3
n PDI = 1.3!1.490% consumption
Me
CCl4
n
Me CO2Me
! Upon complete conversion, more monomer was added and completely incorporated
! Radical scavengers completely inhibited / stopped reactions
! Addition of different monomers allowed for 'Block polymers' (""""####)
Sawamoto, M. et al. Macromolecules 1995, 28, 1721.
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhCl Ph
Me
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
PDI = 1.3!1.4595% consumption
! Sawamoto system utilized some well-developed ruthenium phosphine conditions
CO2Me
1 equiv 0.01 equiv
0.5 mol% RuCl2(PPh3)3
2.0 mol% MeAl(OAr)2toluene, 60 °C, 4 h
ClCCl3
n PDI = 1.3!1.490% consumption
Me
CCl4
n
Me CO2Me
! Upon complete conversion, more monomer was added and completely incorporated
! Radical scavengers completely inhibited / stopped reactions
! Addition of different monomers allowed for 'Block polymers' (""""####)
Sawamoto, M. et al. Macromolecules 1995, 28, 1721.
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhMe Ph
Cl
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
n PDI = 1.3!1.4595% consumption
! PDI = polydispersity index, a measure of how consistent chain growth is
! PDI equal to one: all of the chains in a given sample are of the same length
! Good PDI values are typically > 1.5
PDI = Mn / Mw
Mn = number average molecular weight
Mw = weight average molecular weight
total weight / number of molecules
average weight of average molecule
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhMe Ph
Cl
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
n PDI = 1.3!1.4595% consumption
! PDI = polydispersity index, a measure of how consistent chain growth is
! PDI equal to one: all of the chains in a given sample are of the same length
! Good PDI values are typically > 1.5
PDI = Mn / Mw
Mn = number average molecular weight
Mw = weight average molecular weight
total weight / number of molecules
average weight of average molecule
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
PhCl Ph
Me
1 equiv 0.01 equiv
1 mol% CuCl
3 mol% bipy130 °C, 3 h
Cl
Ph
Ph
Me
PDI = 1.3!1.4595% consumption
! Sawamoto system utilized some well-developed ruthenium phosphine conditions
CO2Me
1 equiv 0.01 equiv
0.5 mol% RuCl2(PPh3)3
2.0 mol% MeAl(OAr)2toluene, 60 °C, 4 h
ClCCl3
n PDI = 1.3!1.490% consumption
Me
CCl4
n
Me CO2Me
! Upon complete conversion, more monomer was added and completely incorporated
! Radical scavengers completely inhibited / stopped reactions
! Addition of different monomers allowed for 'Block polymers' (""""####)
Sawamoto, M. et al. Macromolecules 1995, 28, 1721.
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
I X Initiator (Alkyl Halide)
MnX / Ligand Catalyst
m monomer
redox potential
unique ATRP keq
solubilities, redox potentials
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Only copper catalysts have been successful in polymerizing all of the above classes
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Only copper catalysts have been successful in polymerizing all of the above classes
P
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Only copper catalysts have been successful in polymerizing all of the above classes
P
M X
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Only copper catalysts have been successful in polymerizing all of the above classes
PX
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
PX X X X X
Atom Transfer Radical Polymerization (ATRP)
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O R
X
NN
PX X X X
CuX CuX, RuX2, NiX2 NiX2, RuX2 FeX2, CuX CuX
! Metals typically used to initiate each indicated monomer class (ligands play huge role)
Atom Transfer Radical Polymerization (ATRP)
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O R
X
NN
PX X X X
CuX CuX, RuX2, NiX2 NiX2, RuX2 FeX2, CuX CuX
! Metals typically used to initiate each indicated monomer class (ligands play huge role)
+1 V -1 V0
FeIII(phen)3 RuCl2(PPh3)3 CuCl(bipy)2 CuCl(Me6-tren)
0.5 -0.5 (vs SCE)
N NN
Me2N
NMe2 NMe2
N
N
N N
CuCl(TPA)RuClCp*PPh3
RuBrCp*PPh3
more stable cations
faster ATRP catalysts
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
PX X X X X
Atom Transfer Radical Polymerization (ATRP)
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O R
X
NN
PX X X X
CuX CuX, RuX2, NiX2 NiX2, RuX2 FeX2, CuX CuX
! Metals typically used to initiate each indicated monomer class (ligands play huge role)
+1 V -1 V0
FeIII(phen)3 RuCl2(PPh3)3 CuCl(bipy)2 CuCl(Me6-tren)
0.5 -0.5 (vs SCE)
N NN
Me2N
NMe2 NMe2
N
N
N N
CuCl(TPA)RuClCp*PPh3
RuBrCp*PPh3
more stable cations
faster ATRP catalysts
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
PX X X X X
Atom Transfer Radical Polymerization (ATRP)
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O R
X
NN
PX X X X
CuX CuX, RuX2, NiX2 NiX2, RuX2 FeX2, CuX CuX
! Metals typically used to initiate each indicated monomer class (ligands play huge role)
+1 V -1 V0
FeIII(phen)3 RuCl2(PPh3)3 CuCl(bipy)2 CuCl(Me6-tren)
0.5 -0.5 (vs SCE)
N NN
Me2N
NMe2 NMe2
N
N
N N
CuCl(TPA)RuClCp*PPh3
RuBrCp*PPh3
more stable cations
faster ATRP catalysts
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
PX X X X X
Atom Transfer Radical Polymerization (ATRP)
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O R
X
NN
PX X X X
CuX CuX, RuX2, NiX2 NiX2, RuX2 FeX2, CuX CuX
! Metals typically used to initiate each indicated monomer class (ligands play huge role)
+1 V -1 V0
FeIII(phen)3 RuCl2(PPh3)3 CuCl(bipy)2 CuCl(Me6-tren)
0.5 -0.5 (vs SCE)
N NN
Me2N
NMe2 NMe2
N
N
N N
CuCl(TPA)RuClCp*PPh3
RuBrCp*PPh3
more stable cations
faster ATRP catalysts
Atom Transfer Radical Polymerization (ATRP)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
P X MnX / Ligand P Mn+1X2 / Ligand+m
I X MnX / Ligand I Mn+1X2 / Ligand
m
termination
kact
kdeact
kp
kt
! Different ATRP systems possess discrete rate properties based on the following! Each monomer has a specific keq (kact/kdeact) and requires specific conditions for ATRP
R
O OR O OR
Me
NN
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
PX X X X X
New Catalyst Systems Allow for ATRA Reactions Under Mild Conditions
! Newer highly active ruthenium catalysts initiate rapidly at room temperature
Severin, K. Chem. Eur. J. 2007, 6899.
RuPh3P Cl
Cl
Mg powder
0.1 mol% catalyst EtO
O
HCl
Ph
Cl
24 h, 97% yield
PhEtO
OCl
Cl
toluene, rt2 equiv 1 equiv
5% RuCl2(PPh3)3: 155 °C, 16 h: 71% yield
New Catalyst Systems Allow for ATRA Reactions Under Mild Conditions
! Newer highly active ruthenium catalysts initiate rapidly at room temperature
Severin, K. Chem. Eur. J. 2007, 6899.
RuPh3P Cl
Cl
Mg powder
0.1 mol% catalyst EtO
O
HCl
Ph
Cl
24 h, 97% yield
PhEtO
OCl
Cl
toluene, rt2 equiv 1 equiv
5% RuCl2(PPh3)3: 155 °C, 16 h: 71% yield
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
X
ML2Xn
(cat.)FG
FG
! Successful radical precursors in ATRC reactions so far are highly activated
n nn= 0-13
RO
O
R2N
O
R2N
O
RO
ONR2
ClRO
OOR
ClCl
ClCl
Cl
ClCl
F
IF
R2N
O
Cl
RCl
R2N
O
Cl
HCl
R2N
O
Cl
MeMe
R Cl
ClCl
RO
O
R
ClCl
Potential Future Atom Transfer Radical Chemistry
R
R'
O OR
R'
O R
Br R'
N
R'
N
Br Br Br BrMe
Potential Future Atom Transfer Radical Chemistry
R
R'
O OR
R'
O R
Br R'
N
R'
N
Br Br Br BrMe