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
Reduction Chemistry
X
M
R
R
Heck-Type Chemistry
Ar
X
catalyst
X
catalyst
catalyst
Me
R
Me
R
Oxidation Chemstry
DG
Ar
H2
X
R
R
! These reactions and their mechanisms will not be addressed
catalyst
[O]
DG
R
Metal Catalyzed Redox Reactions
! Many metal-catalyzed reactions involve redox processes
X
Constraints Applied
S
Mn
R
1. Catalytic in metal
S
X
2. Single electron transfer processes
ATRA
3. Net redox neutral (no terminal oxidant)
Cycle
S
4. No light (purely chemical activation)
R
Mn+1X
Mn+1X
5. Selective generation of organic radicals
R
If electron transfer is accompanied occurs via inner-sphere mechanism
Atom Transfer Radical Chemistry
S
Radical
Radical Addition
Addition Mechanism
Mechanism as
as First
First Defined
Defined
!
! The
The 'Peroxide
'Peroxide Effect'
Effect' as
as observed
observed by
by Kharasch
Kharasch and
and co-workers
co-workers (1933)
(1933)
Me
Me
Me
Me
HBr
HBr
H3C
H3C
room temp
room temp
HBr, ROOR
HBr, ROOR
room temp
room temp
Me
Me
Br
Br
H3C
H3C
sole product
sole product
Me
Me
Br
Br
minor
minor
Me
Me
Br
Br
major
major
"The
"The presence
presence of
of benzoyl
benzoyl peroxide
peroxide or
or ascaridole
ascaridole modified
modified profoundly
profoundly the
the course
course of
of the
the
addition
addition and
and the
the product
product of
of the
the reaction
reaction was
was largely,
largely, ifif not
not all,
all, normal
normal propyl
propyl bromide"
bromide"
-Morris Kharasch
-Morris Kharasch
Kharasch, M. S. J. Am. Chem. Soc. 1933, 55, 2531.
Kharasch, M. S. J. Am. Chem. Soc. 1933, 55, 2531.
Radical Addition Mechanism as First Defined
Radical Addition Mechanism as First Defined
!
! The
The 'Peroxide
'Peroxide Effect'
Effect' independantly
independantly defined
defined by
by Kharash
Kharash et
et al.
al. as
as well
well as
as Hey
Hey and
and Waters
Waters (1937)
(1937)
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
H3C
H C
H33C
HBr, ROOR
HBr, ROOR
ROOR
HBr,
room temp
room temp
temp
room
Me
Me
Me
Me
Me
Me
Br
Br
Br
Br
Br
Br
minor
minor
minor
Me
Me
Me
major
major
major
"...it may be suggested that the addition process is one
requiring
transient
Kharasch,
M. S.the
J. Org.
Chem. 1937, 2, 288.
"...it may be suggested that the addition process is one requiring the transient
production of neutal atoms of hydrogen and broming from hydrogen bromide"
! Kharasch
later reported
the radical
of halomethanes
to olefins
(1945)bromide"
production
of neutal
atoms addition
of hydrogen
and broming from
hydrogen
-Hey and Waters
-Hey and Waters
(BzO)2, heat
BzO
H
Br
Me
BzO
H
Br
CCl4
Br
Br
Me
Me
> 60% yield
Me
Cl3C
Br
Br
Cl
H
Br
H
Br
Me
Me
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
Kharasch,
S.
J.
Chem.
1937,
2,1969.
288.
Kharasch,
M.M.
S.W.
etChem.
al.Org.
Science,
1945
122,
108.
Hey,
D.; Waters,
Rev.
1937,
21,
Hey, D.; Waters, W. Chem. Rev. 1937, 21, 1969.
Radical Addition Mechanism as First Defined
! The 'Peroxide Effect' independantly defined by Kharash et al. as well as Hey and Waters (1937)
HBr, ROOR
H3C
Me
Me
Br
room temp
Me
Br
minor
major
Kharasch, M. S. J. Org. Chem. 1937, 2, 288.
! Kharasch later reported the radical addition of halomethanes to olefins (1945)
(BzO)2, heat
Me
CCl4
> 60% yield
Cl3C
Me
Cl
Kharasch, M. S. et al. Science, 1945 122, 108.
The Kharasch Addition Reaction of Halomethanes to Olefins
! Kharasch reported the radical addition of carbon-based radicals to olefins (1945)
AcO
Me
OAc
Cl
!
AcO
2 H3C
OAc
Me
Cl3C
CCl4
2 CO2
Initiation
H3C
CH3Cl
CCl4
R
Cl3C
Cl3C
R
Cl3C
Propagation
Cl3C
Cl3C
R
R
Cl3C
CCl4
Cl3C
Cl
R
R
R
Cl3C
Polymerization
R
R = Ar
Kharasch, M. S. Science 1945, 122, 108.
The Kharasch Addition Reaction of Halomethanes to Olefins
! Kharasch reported the use of several radical electrophiles in his new radical reaction
Cl Cl
Cl
Br
OMe
hex
hex
O
Br
Br
CBr3
hex
CCl3
OEt
hex
O
(AcO)2, 40% yield
h!, 88% yield
(AcO)2, 78% yield
(AcO)2, 54% yield
JACS, 1945, 1626
JACS, 1946, 154
JACS, 1947, 1105
JACS, 1948, 1055
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
Br
Ph
CBr4, light
CBr3
Ph
96%
Ph
CCl4, (AcO)2
quant
Cl
CCl3
n
The Failed Polymerizations of Minisci
! Surprisingly, substantial monoadduct formation was observed with carbon tetrachloride
NC
CCl4, ROOR
NC
CN
CCl3
Cl
autoclave, 160 °C
CCl3
Cl
n
'significant amount'
NC
CHCl3, ROOR
NC
CN
CCl3
H
autoclave, 160 °C
CHCl2
Cl
n
new regioisomer
! Standard peroxide initiated radical mechanisms occur via hydrogen abstraction
NC
RO
H
CCl3
Cl3C
NC
NC
CCl3
CCl3
H
H
CCl3
Cl3C
Complete selectivity for opposite regioisomer suggested a new mechanism
Minisci, F. Chem. Ind. (Milan), 1956, 122, 371.
Radical Chain Termination by Metal Halide Salts (Jay Kochi)
! Also in 1956, Kochi was studying the oxidation of alkyl radicals by metal salts
N2Cl
Ph
0% polymer
R
Meerwein Arylation
CuCl
good yields
Cl
acetone
R
Ph
CuCl or FeCl2
!CuCl
Ph
Ph
CuCl2
Cl
CuCl
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)
Minisci's reaction could have contained metal halides
Kochi, J. J. Am. Chem. Soc. 1956, 78, 4815.
Accidental Discovery of Catalytic Atom Transfer Radical Chemstry
! Minisci's steel autoclave was corroded and had likely leached iron into the reaction
and could have been oxidized to FeCl3 by chlorine radicals
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
Cl
Cl
R
Cl
Cl
1 mol% CuCl (or FeCl2)
R
Cl3C
Cl
2 equiv solvent, 80!120 °C
1 equiv
2 equiv
Ph
46-89% yield
CN
CO2Et
C6H13
Minisci, F. et al. Gazzeta 1961, 91, 1030.
Asscher, M. et al. J. Chem. Soc. 1963, 1887.
Proposed Mechanism of Atom Transfer Radical Addition (ATRA)
! Metal catalyst participates in both initiation and termination steps, relative rates dictate selectivity
Catalytic Redox Mechanism:
! Red. halogen abstraction
R
X
R'
R
CuIX
monoadduct
X
generates radical
R'
R
! Oxid. halogen abstraction
ka1
kd1
ka2
kd2
R'
R
R'
terminates radical
R
kt
CuIIX2
R
Selective ATRA Requires:
1. Low radical concentration
R'
R
R'
kadd
kt
R
R'
R
kt
kp
kd1 and kd2 >> ka1 and ka2
2. Slow product activation (vs sm)
ka1 >> ka2
telomer
R
R
R
R'
R
R
n
R
'
R'
polymer
3. Oxidation must be fast vs prop.
kd2 >> kp
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
So Many Different Catalysts...
MLnXn
Y Y
Y
Y
X
R
Y
X
(cat.)
Y
R
! 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)
CCl4
hex
Cl3C
galvinoxyl
0% yield
Cl
RuCl2(PPh3)3
hex
(76%, no spintrap)
80 °C, 4 h
Matsumoto, H. et al. Tetrahedron Lett. 1973, 14, 5147.
! Metal catalyst impacts diastereoselectivity of CCl4 addition to cyclohexene
RuCl2(PPh3)3
Cl
CCl4
80 °C, 4 h
(BzO)2
CCl3
Cl
CCl4
80 °C, 4 h
CCl3
77% yield
96:4 (trans:cis)
low yield
53:47 (trans:cis)
Matsumoto, H. et al. Tetrahedron Lett. 1975, 15, 899.
Effect not seen with Cu: Asscher, M. et al. J. Chem. Soc. Perkin Trans. 2 1973, 1000.
Intermediate radical species likely exist as coordinated radical pairs (Ru system)
Attempts at Enantioselective Kharasch Addition
! Chiral ligands could potentially induce enantioselectivity
Ru2Cl4(diop)3
CCl4
73% yield
Cl
Ph
Ph
100 °C, 6 h
CCl3
13% ee
! Coordinated metal-radical pair should participate in enantiodetermining chlorination
Cl
Cl3C
RuL*nCl2
Ph
CCl4
L* = (!)-diop
H
Me
ATRA
Cl3CCH2CHPh
RuIIICl3
Me
Cycle
Cl3C
RuIIICl3
O
CH2PPh2
CH2PPh2
O
H
Ph
Kamigata, N. et al. Bull. Chem. Soc. Jpn. 1987, 60, 3687.
Similar result with RhCl-diop system: Murai, S. et al. Angew. Chem. Int. Ed. Eng. 1981, 20, 475.
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Reactions (ATRC)
X
FG
ML2Xn
FG
X
(cat.)
! Area 2. Intermolecular Kharasch Type Haloalkylation Reactions
FG
X
R
ML2Xn
(cat.)
FG
R
X
Selected Intramolecular ATRA: 5-Exo Trig Cyclizations
! A variety of cyclization substrates and catalytic systems have been developed over 35+ years
RuCl2(PR3)3 catalysts: 1973 (Nagai)
CuX catalysts: 1963 (Asscher & Vofsi)
~30% typical loading, > 100°C temperatures
1-10% typical loadings, > 80°C temperatures
Cl
Cl
Cl
RuCl2(PPh3)3
Cl
Cl
Cl
PhH, 155 °C
MeO2C
Cl
Cl
MeO2C
Cl
MeO2C
Cl
MeO2C
PhH, 165 °C
Me
71%, 2:1 dr
Weinreb, S. et al. J. Org. Chem. 1990, 55, 1281.
95% yield
Cl
CuCl
MeCN, 140 °C
O
Cl
RuCl2(PPh3)3
Cl
Cl
O
H
77%, 1:1 dr
Me
CuCl
MeCN, 110 °C
O
RuCl2(PPh3)3
PhH, 165 °C
Cl
Cl
79% yield
Cl
Cl
F
F
N
H
57% yield
Br
CuBr
Cl
Cl
O
O
Cl
Cl
Cl
O
N
H
Br
H
O
Cl
N
H
MeCN, 80 °C
84% yield
F
F
O
Clark, A. Chem. Soc. Rev. 2002, 31, 1.
N
H
Intramolecular Atom Transfer Radical Cyclization Ligand Effects
! 5-Exo trig cyclization of unsaturated !-haloamide substrates yields lactam scaffolds
X
Cl
O
Cl
30 mol% catalyst
N
solvent, temp
Cl
Cl
O
Cl
N
Ts
Ts
Catalyst
X
Solvent
Temp.
Time
Yield
CuCl
Cl
MeCN
80 °C
24 h
97%
CuCl-bipy (5%)
Cl
CH2Cl2
23 °C
0.2 h
91%
CuCl-bipy
H
CH2Cl2
23 °C
24 h
0%
CuCl-NPMI
H
CH2Cl2
23 °C
72 h
15%
CuCl-tren-Me6
H
CH2Cl2
23 °C
2h
90%
Me
N
N
N
Me2N
NMe2
bipy
tren-Me6
N
N
NMe2
NPMI
Clark, A. Tetrahdron Lett. 1999, 40, 4885.
Radical-Polar Crossover Mechanism: Addition to Enamides
! Electrophilic radicals add to acyl enamines, terminate via radical-polar crossover mechanism
Me
Me
Br
O
30 mol% CuBr•L
CH2Cl2, rt, 20 min
Bn
82%, 1:1 ratio
!CuLBr2
O
Me
Me
O
N
Bn
Me
Me2N
=L
N
Me
CuLBr
Me
N
O
N
NMe2
NMe2
Bn
Me
CuLBr2
!CuLBr
N
Me
O
Me
!H+
N
Bn
Bn
! While this triethylenetetramine ligand is highly active, the perfect Cu system remains unknown
Cl
O
Cl
Cl
30 mol% CuBr•L
N
CH2Cl2, rt
Bn
Cl
O
Cl
0% yield
N
complex mixture
Bn
Clark, A. Tetrahdron Lett. 1999, 40, 4885.
Cascade Cyclization Using Copper Redox Catalyst
! Radical mono- and bicyclization utilizing copper-bipy as catalyst (Dan Yang)
O
Cl
O
Cl
O
CO2Et
CuCl•bipy
OEt
Cl
Me
DCE, 80 °C
21 h
Me
Me
Me
79% yield
3:1 dr
Cl
! Bicyclization under the conditions outlined above give modest yields and diastereocontrol
O
O
O
O
O
O
CO2Et
Cl
Me
Cl
OEt
61%
2:1 dr
Cl
Me
Cl
Cl
Me
Cl
OEt
33%
3:2 dr
CO2Et
Me
Cl
Cl
Yang, D. et al. Org. Lett. 2006, 8, 5757.
Intramolecular Atom Transfer Radical Cyclization
! Medium ring heterocycle formation via redox reaction affords 8 and 9 membered lactones
Cl
O
Cl3
n
O
30 mol% CuCl-bipy
Cl
Cl
n
0.1 M DCE
O
O
n = 1: 60% yield
n = 2: 59% yield
80 °C, 18 h
Pirrung, F. et al. Synlett. 1993, 50, 739.
! Macrocyclization reactions were also accomplished using a tridentate ligand
O
O
O
O
O
O
CCl3
O
10 mol% CuCl-ligand
O
0.2 M DCE, 80 °C
O
70% yield
O
N
N
Cl
O
Cl
Cl
N
N
O
Clark, A. et al. J. Chem. Soc. Perkin Trans. 1, 2000, 671.
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
FG
ML2Xn
FG
X
(cat.)
n= 0-13
n
n
! Successful radical precursors in ATRC reactions so far are highly activated
O
O
Cl
RO
Cl
Cl
O
Cl
R2N
Cl
O
Cl
H
Cl
Cl
I
R2N
F
O
R2N
O
F
O
R
R2N
Cl
Cl
O
NR2
RO
Cl
R
Me
R2N
Cl
Me
OR
RO
Cl
Cl
Cl
Cl
O
Cl
RO
R
Cl
Selected Examples of Atom Transfer Radical Addition Chemistry
! Area 1. Intramolecular Atom Transfer Radical Addition Reactions (ATRC)
X
FG
ML2Xn
FG
X
(cat.)
n= 0-13
n
n
! Successful
radical precursors
in ATRC
reactions
so far
highly activated
Area 2. Intermolecular
Kharasch
Addition
Reactions
of are
Polyhaloalkanes
O
O
Cl
RO
Cl
O
Cl
R2N
X
Cl
Y
Cl
Y
O
Cl
R'
R2NML2Xn
F
R
H
Cl
Cl
I
F
O
R
R2N
Cl
Cl
O
Y NR2
ROR'
R
(cat.)
O
R2N
O
X
Cl Y
R
Me
R2N
Cl
Me
OR
RO
Cl
Cl
Cl
Cl
O
Cl
RO
R
Cl
Perfluoroalkylation of Olefins Using ATRA
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
O
F3C
O
S
1 mol% RuCl2(PPh3)2
R
Cl
Cl
1 equiv
CF3
R
benzene, 120 °C
2 equiv
! The reaction works well with highly activated olefins but is sensitive to sterics (1,2-substitution)
Cl
F3C
RuL*nCl2
Ph
Cl
F3CSO2Cl
Cl
CF3
CF3
CF3
SO2
Me
O2N
79% yield
O
ATRA
87% yield
Cycle
CF3
46% yield
RuIIICl3
Cl
CF3
OEt
41% yield
Cl
CF3
Cl
R
RuIIICl3
Cl
CF3
CF3
Me
66% yield
R
23% yield
Kamigata. J. Chem. Soc. Perkin Trans. 1. 1991, 627.
Perfluoroalkylation of Olefins Using ATRA
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
O
F3C
O
S
1 mol% RuCl2(PPh3)2
R
Cl
Cl
1 equiv
CF3
R
benzene, 120 °C
2 equiv
! The reaction works well with highly activated olefins but is sensitive to sterics (1,2-substitution)
Cl
Cl
Cl
CF3
CF3
CF3
O2N
Me
79% yield
87% yield
Cl
Cl
O
46% yield
Cl
CF3
OEt
41% yield
CF3
CF3
Me
66% yield
23% yield
Kamigata. J. Chem. Soc. Perkin Trans. 1. 1991, 627.
Arene Perfluoroalkylation Using Sulfonyl Chloride Reagents
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
O
F3C
O
S
R
1 mol% RuCl2(PPh3)2
R
Cl
1 equiv
CF3
benzene, 120 °C
2-5 equiv
! Benzene substrates react but are completely regio-permiscuous
CF3
OMe
CF3
Br
53% yield
2:1:1 (o:m:p)
39% yield
1:1:1 (o:m:p)
CF3
Me
CF3
36% yield
1:1:1 (o:m:p)
CF3
41% yield
Me
CF3
trace
CN
63% yield
Me
Kamigata. N. J. Chem. Soc. Perkin Trans. 1. 1994, 1339.
Arene Perfluoroalkylation Using Sulfonyl Chloride Reagents
! Kamigata's group describe a ruthenium catalyzed radical trifluromethylation protocol
1 1mol%
2(PPh
3)2)
mol%RuCl
RuCl
(PPh
OO OO
SS
F3FC3C ClCl
1 1equiv
equiv
2
RR
CF3
CF3
3 2
R
benzene,
benzene,120
120°C°C
R
2-5
2-5equiv
equiv
! Benzene
substrates
react butcompounds
are completely
Five-membered
heterocyclic
workregio-permiscuous
with increased regiocontrol
CF3
O
OMe
53% yield
CF3
2:1:1 (o:m:p)
CF3
S
Me
77%
30%
CF3
N CF3
N
H
Bn
Br
0%
CF3
39% yield
1:1:1 (o:m:p)
53%
CF3
36% yield
Me
CF3
S
1:1:1 (o:m:p)
OHC
73%
CF3
CF3
N
S
26%
CF3
Me
CF3N
trace Ac
CN
61%
41%
CFyield
3
CF3
63%
COPh
yield
Me
92%
Kamigata. N. J. Chem. Soc. Perkin Trans. 1. 1994, 1339.
Trifluoromethylation of Electron-Poor Enolsilane Substrates
! Ruthenium catalyzed sulfonyl chloride decomposition also works on silyl enol ethers
O
S
F3C
Cl
R'
R
1 equiv
benzene, 120 °C
R'
2 equiv
O
CF3
O
O
CF3
CF3
CF3
Cl
55% yield
CF3
R
O
O2N
O
1 mol% RuCl2(PPh3)2
OTMS
O
MeO
51% yield
58% yield
0% yield
O
O
O
CF3
Ph
Me
CF3
O
CF3
H
CF3
Ph
Bn
tBu
28% yield
35% yield
43% yield
0% yield
Kamigata. N. Phosporus, Sulphur, and Silicon 1997, 155.
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
O
O
R
R'
N
BrCCl3 (3 equiv)
R
45 °C, 12 h
Cl4
Ti
O
R
O
7 mol% RuCl2(PPh3)3
Ph
O
O
TiCl4, i-Pr2NEt, CH2Cl2
O
R
O
R'
N
CCl3
R
Ph
Cl4
Ti
O
O
R'
N
O
R
R
Ph
O
CCl3
R'
N
R
RuIII + Br
Ph
Cl4
Ti
O
O
R
O
R'
CCl3
R
Ph
RuII
Cl4
Ti
Cl4
Ti
O
N
BrCCl3
O
R
O
O
N
R'
CCl3
R
Ph
O
R
O
N
R'
CCl3
R
Ph
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
O
O
R
R'
N
BrCCl3 (3 equiv)
R
45 °C, 12 h
O
O
R
O
N
O
Cl4
Ti
O
O
R'
N
O
Bn
R
Ph
89%,
>98:2 dr
O
O
O
Me
Me
N
O
BnR R
Ph
99%, >98:2 dr
Ph
CCl3
R'
CCl3
O
O BrCCl
N3
6
CCl3
Me
Me
Bn
CCl3
Bn
Me
R
RuIII + Br
63%, >98:2 dr
RuII
91%, >98:2 dr
Cl4
Ti
Cl4
Ti
OO OO
O
C4H9
O
N
CCl3
R
O
O R' N
N
Ph
Cl4
Ti
CCl3
O
O
Me
R
R
R'
N
O
Me
CCl3
O
O
7 mol% RuCl2(PPh3)3
Ph
Cl4
Ti
O
O
TiCl4, i-Pr2NEt, CH2Cl2
O
OO
Me R
Me
R
NN
O
O
O
OBn
R'
O
4
CCl
3 3
CCl
Bn
Ph
87%, >98:2 dr
O
N
Me
R
Me
N
Ts
O N
R'
CCl3 CCl3
R
Bn
Ph
61%, >98:2 dr
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
Atom Transfer Radical Addition Reactions With Titanium Enolates
! Zakarian group published the first highly diastereoselective intermolecular Kharasch addition
O
O
R
R'
N
BrCCl3 (3 equiv)
R
45 °C, 12 h
O
O
O
N
Me
R
Me
R
Ph
O
O
Cl4
Ti
Cl
R'
N
O
Cl
O
Me
R
O
N Cl
O
Me
Me
Me
Me
R
Bn
R
Ph
71%, 1.6:1 dr
CCl3
R
O Cl
O
Cl
OEt
Cl
O BrCCl
N3
Me
O
Me
Me
Bn
83%, >98:2 dr
Cl4
Ti
OO OO Cl
R'
CCl3
Bn
Me
R
Cl4
Ti
CF
O
3O
O
N
Me
Ph
64%, >98:2 dr
O
N
R
R'
N
Ph
CCl3
O R' N
Me
Bn
O Cl
O
O
O
O
7 mol% RuCl2(PPh3)3
Ph
Cl4
Ti
O
O
TiCl4, i-Pr2NEt, CH2Cl2
O
OO
Me R
NN
RuIII + Br
71%, >98:2 dr
Cl4
Ti
R'
Bn
Ph
76%, >98:2 dr
O
O
O
Cl
O
N
O
Me
CCl3 OCO2Bn
Me
R
RuII
Me
R
Me
O
Cl
N
Me
R'
OMe
CCl
O 3
R
Bn
Ph
75%, 1.3:1 dr
Zakarian, A. et al. J. Am. Chem. Soc. 2010, ASAP.
AtomTransfer
TransferRadical
RadicalPolymerization
Polymerization(ATRP)
(ATRP)
Atom
Atom Transfer Radical Polymerization (ATRP)
1995,Krzysztof
KrzysztofMatyjaszewski
Matyjaszewskiand
andMitsuo
MitsuoSawamoto
Sawamotopicked
pickedup
upwhere
whereMinisci
Miniscileft
leftoff
off(1956)
(1956)
!! InIn1995,
In
1995,
Krzysztof Matyjaszewski
and
Mitsuo
Sawamoto
picked
uppolymerization)
where
Minisci left off (1956)
! They
They
independantly
reportedaanew
new
method
(ATRP
living
radical
polymerization)
!!
independantly
reported
method
(ATRP
ororliving
radical
! They independantly reported a new method (ATRP or living radical polymerization)
Sawamoto
Sawamoto
Matyjaszewski
Matyjaszewski
KyotoUniversity
University
Kyoto
Sawamoto
Carnegie
Mellon
Carnegie
Mellon
Matyjaszewski
Kyoto University
Carnegie Mellon
'LivingRadical
RadicalPolymerization'
Polymerization'
'Living
'AtomTransfer
TransferRadical
RadicalPolymerization'
Polymerization'
'Atom
submittedSeptember
September6,6,1994
1994
submitted
'Living Radical Polymerization'
Macromolecules,1995,
1995,28,
28,1721.
1721.
Macromolecules,
submitted September 6, 1994
cited1,571
1,571times
times
cited
Macromolecules, 1995, 28, 1721.
submittedFebruary
February16,
16,1995
1995
submitted
'Atom Transfer Radical Polymerization'
Am.Chem.
Chem.Soc.,
Soc.,1995,
1995,117,
117,5614.
5614.
J.J.Am.
submitted February 16, 1995
cited2,374
2,374times
times
cited
J. Am. Chem. Soc., 1995, 117, 5614.
cited 1,571 times
cited 2,374 times
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Selective ATRA Requires:
R
X
R'
R
CuIX
monoadduct
X
1. Low radical concentration
R'
R
kd1 and kd2 >> ka1 and ka2
ka1
kd1
ka2
kd2
R'
R
2. Slow product activation (vs sm)
R'
R
kt
ka1 >> ka2
CuIIX2
R
3. Oxidation must be fast vs prop.
teleomer
R'
R
R'
kadd
kd2 >> kp
kt
R
R'
R
kt
kp
R'
R
Polymerization Can Occur If:
R
R
R'
R
1. Above requirements are met
R
n
R'
polymer
2. Starting Halogen is consumed
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Selective ATRA Requires:
R
X
R'
R
CuIX
monoadduct
X
1. Low radical concentration
R'
R
kd1 and kd2 >> ka1 and ka2
ka1
kd1
ka2
kd2
R'
R
2. Slow product activation (vs sm)
R'
R
kt
ka1 >> ka2
CuIIX2
R
3. Oxidation must be fast vs prop.
teleomer
R'
R
R'
kadd
kd2 >> kp
kt
R
R'
R
kt
kp
R'
R
Polymerization Can Occur If:
R
R
R'
R
1. Above requirements are met
R
n
R'
polymer
2. Starting Halogen is consumed
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
Atom Transfer Radical Polymerization (ATRP)
! In 1995, Krzysztof Matyjaszewski and Mitsuo Sawamoto picked up where Minisci left off (1956)
Selective ATRA Requires:
R
X
R'
R
CuIX
monoadduct
X
1. Low radical concentration
kd1 and kd2 >> ka1 and ka2
ka1
kd1
ka2
kd2
2. Slow product activation (vs sm)
ka1 >> ka2
3. Oxidation must be fast vs prop.
CuIIX2
R
R'
R
R'
kadd
kd2 >> kp
kp
R'
R'
R
Polymerization Can Occur If:
1. Above requirements are met
n
R'
P
X
MnXn
P
MnXn
polymer
+m
2. Starting Halogen is consumed
Figure adapted from: Matyjaszewski, K. et al. Chem. Soc. Rev. 2008, 1087.
Transfer
Radical
! MatyjaszewskiAtom
polymerized
styrene
usingPolymerization
a copper chloride (ATRP)
bipy system
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized
styrene
using a copper chloride
bipy system
Cl
1 mol% CuCl
Me
Ph
95% consumption
Ph
! Matyjaszewski
styrene using a copper chloride bipy system
Me polymerized
Ph
PDI = 1.3!1.45
3 mol% bipy
1 equiv
Ph
n
Cl
0.01 Cl
equiv
°C,CuCl
3h
1130
mol%
Me
Ph
95% consumption
Ph
1
mol%
CuCl
Ph
Me
95% consumption
Ph
Me
PDI
= 1.3!1.45
Cl
Ph
3 mol% bipy
n
Ph
Cl Transfer
PDI
= 1.3!1.45
Atom
Radical
Polymerization
(ATRP)
Cl
Ph
3 mol% bipy
n
1 equiv
0.01 equiv
130 °C, 3 h
1 equiv
0.01 equiv
°C, 3 h of how consistent chain growth is
! PDI = polydispersity
index,130
a measure
Me
Ph
! Matyjaszewski
polymerized
styrene
usingina acopper
bipyofsystem
! PDI equal
to one: all of
the chains
given chloride
sample are
the same length
! Sawamoto
system utilized
somea well-developed
conditions
! PDI = polydispersity
index,
measure of howruthenium
consistentphosphine
chain growth
is
! Good PDI values are typically > 1.5
!MePDI equal toClone: all of the
chains
are of the same
length
1 mol%
CuClin a given sample
Me
Ph
95% consumption
Me
Ph
Mn = number average molecular weight
0.5
PDI
1.3!1.45
Men CO
90%= consumption
Cl2Me
Ph
3 mol%
mol%>RuCl
bipy
! Good
are typically
1.5 2(PPh3)3 total
CO2MePDI
weight / number
of
molecules
CCl3
1 equiv
0.01 equiv PDI = M
PDI = 1.3!1.4
M°C,
130
h
Cl
2.0
n /mol%
w 3MeAl(OAr)
n
2
Mn = number average molecular weight
1 equiv
0.01 equiv
toluene, 60 °C, 4
Mh
w = weight average molecular weight
total weight / number of molecules
PDI = Mn / Mw
average weight of average molecule
Me
Ph
values
CCl4
! Upon
complete
conversion,
more
monomerofwas
and completely
incorporated
! PDI
= polydispersity
index,
a measure
howadded
consistent
chain growth
is
Mw = weight average molecular weight
! Radical
inhibited
reactions
! PDI scavengers
equal to one:completely
all of the chains
in a/ stopped
given
sample
are of
the same
length
average
weight
of average
molecule
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
! GoodofPDI
valuesmonomers
are typically
> 1.5 for 'Block polymers' (""""####)
! Addition
different
allowed
PDI = Mn / Mw
Matyjaszewski,
K. average
et al. J. Am.
Chem.weight
Soc. 1995, 117, 5614.
Mn = number
molecular
Sawamoto, M. et al. Macromolecules 1995, 28, 1721.
total weight / number of molecules
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
Mw = weight average molecular weight
Atom Transfer Radical Polymerization (ATRP)
! Matyjaszewski polymerized styrene using a copper chloride bipy system
Me
1 mol% CuCl
Ph
Cl
1 equiv
Ph
0.01 equiv
Ph
3 mol% bipy
Cl
Me
n
95% consumption
Ph
PDI = 1.3!1.45
130 °C, 3 h
! Sawamoto system utilized some well-developed ruthenium phosphine conditions
Me
CO2Me
CCl4
0.5 mol% RuCl2(PPh3)3
2.0 mol% MeAl(OAr)2
1 equiv
0.01 equiv
Me
CO2Me
Cl
CCl3
n
90% consumption
PDI = 1.3!1.4
toluene, 60 °C, 4 h
! 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.
Matyjaszewski, K. et al. J. Am. Chem. Soc. 1995, 117, 5614.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
P
kdeact
+m
kp
Mn+1X2 / Ligand
kt
termination
! Different ATRP systems possess discrete rate properties based on the following
Initiator (Alkyl Halide)
redox potential
MnX / Ligand
Catalyst
solubilities, redox potentials
m
monomer
unique ATRP keq
I
X
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
P
kdeact
+m
Mn+1X2 / Ligand
kt
kp
termination
! 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
Me
O
R
OR
O
OR
N
N
! Only copper catalysts have been successful in polymerizing all of the above classes
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
P
kdeact
+m
Mn+1X2 / Ligand
kt
kp
termination
! 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
P
Me
O
R
OR
O
OR
N
N
! Only copper catalysts have been successful in polymerizing all of the above classes
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
P
kdeact
+m
Mn+1X2 / Ligand
kt
kp
termination
! 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
P
M
X
Me
O
R
OR
O
OR
N
N
! Only copper catalysts have been successful in polymerizing all of the above classes
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
P
kdeact
+m
Mn+1X2 / Ligand
kt
kp
termination
! 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
P
X
Me
O
R
OR
O
OR
N
N
! Only copper catalysts have been successful in polymerizing all of the above classes
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
P
X
X
O
R
Me
OR
O
X
X
OR
X
N
N
! Initiators tend to look like the desired monomer units (similar redox, kinetic properties)
Matyjaszewski, K. et al. Chem. Rev. 2001, 101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
P
X
X
O
X
X
OR
O
R
X
N
N
R
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)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
more stable cations
N
RuBrCp*PPh3
P
X
X
RuClCp*PPh3
N
Me
X
N
O
FeIII(phen)3
R
OR
RuCl2(PPh3)3
X
N
X
OR
R
CuCl(bipy)2
faster
ATRP catalysts
X
Me2N
CuCl(TPA)
N
O
N
N
NMe2
NMe2
N
CuCl(Me6-tren)
N
CuX, RuX2, NiX2
NiX2, RuX2
FeX2, CuX
CuX
CuX
-0.5
-1 V
0.5 like the desired monomer
0
+1
! VInitiators tend to look
units (similar redox,
kinetic properties)
(vs SCE)
! Metals typically used to initiate each indicated Matyjaszewski,
monomer class
(ligands
play
huge
role)
K. et
al. Chem.
Rev.
2001,
101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
more stable cations
N
RuBrCp*PPh3
P
X
X
RuClCp*PPh3
N
Me
X
N
O
FeIII(phen)3
R
OR
RuCl2(PPh3)3
X
N
X
OR
R
CuCl(bipy)2
faster
ATRP catalysts
X
Me2N
CuCl(TPA)
N
O
N
N
NMe2
NMe2
N
CuCl(Me6-tren)
N
CuX, RuX2, NiX2
NiX2, RuX2
FeX2, CuX
CuX
CuX
-0.5
-1 V
0.5 like the desired monomer
0
+1
! VInitiators tend to look
units (similar redox,
kinetic properties)
(vs SCE)
! Metals typically used to initiate each indicated Matyjaszewski,
monomer class
(ligands
play
huge
role)
K. et
al. Chem.
Rev.
2001,
101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
more stable cations
N
RuBrCp*PPh3
P
X
X
RuClCp*PPh3
N
Me
X
N
O
FeIII(phen)3
R
OR
RuCl2(PPh3)3
X
N
X
OR
R
CuCl(bipy)2
faster
ATRP catalysts
X
Me2N
CuCl(TPA)
N
O
N
N
NMe2
NMe2
N
CuCl(Me6-tren)
N
CuX, RuX2, NiX2
NiX2, RuX2
FeX2, CuX
CuX
CuX
-0.5
-1 V
0.5 like the desired monomer
0
+1
! VInitiators tend to look
units (similar redox,
kinetic properties)
(vs SCE)
! Metals typically used to initiate each indicated Matyjaszewski,
monomer class
(ligands
play
huge
role)
K. et
al. Chem.
Rev.
2001,
101, 2921.
Atom Transfer Radical Polymerization (ATRP)
I
X
MnX / Ligand
Mn+1X2 / Ligand
I
m
kact
P X
MnX / Ligand
Mn+1X2 / Ligand
P
kdeact
+m
kt
kp
termination
! 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
more stable cations
N
RuBrCp*PPh3
P
X
X
RuClCp*PPh3
N
Me
X
N
O
FeIII(phen)3
R
OR
RuCl2(PPh3)3
X
N
X
OR
R
CuCl(bipy)2
faster
ATRP catalysts
X
Me2N
CuCl(TPA)
N
O
N
N
NMe2
NMe2
N
CuCl(Me6-tren)
N
CuX, RuX2, NiX2
NiX2, RuX2
FeX2, CuX
CuX
CuX
-0.5
-1 V
0.5 like the desired monomer
0
+1
! VInitiators tend to look
units (similar redox,
kinetic properties)
(vs SCE)
! Metals typically used to initiate each indicated Matyjaszewski,
monomer class
(ligands
play
huge
role)
K. et
al. Chem.
Rev.
2001,
101, 2921.
New Catalyst Systems Allow for ATRA Reactions Under Mild Conditions
! Newer highly active ruthenium catalysts initiate rapidly at room temperature
Ru
Ph3P
O
Cl
EtO
Ph
Cl
2 equiv
Cl
Cl
0.1 mol% catalyst
Mg powder
1 equiv
toluene, rt
O
Ph
EtO
Cl
H
Cl
24 h, 97% yield
5% RuCl2(PPh3)3: 155 °C, 16 h: 71% yield
Severin, K. Chem. Eur. J. 2007, 6899.
ML2Xn
FG
X
(cat.)
n= 0-13
n
n
Potential Future Atom Transfer Radical Chemistry
Potential Future Atom Transfer Radical Chemistry
! Successful radical precursors in ATRC reactions so far are highly activated
O
O
Cl
RO
Cl
Cl
O
Cl
R2N
Cl
O
Cl
H
Cl
Cl
I
R2N
F
O
R2N
O
F
O
R
R2N
Cl
Cl
O
NR2
RO
Cl
R
Me
R2N
Cl
OR
RO
Cl
Cl
Me
Cl
Cl
O
Cl
RO
R
Br
Me
Br
R'
Br
R'
Br
R'
Br
R'
Br
Me
O
Br
OR
R'
O
Br
R
R'
Br
N R'
Br
R'
N
R
O
R
OR
O
R
N
N
Cl