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Radical Cations+: Generation, Reactivity, Stability
MacMillan Group Meeting4-27-11
by
Anthony Casarez
R A R A
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Three Main Modes to Generate Radical Cations
Electrochemical oxidation (anodic oxidation)
Chemical oxidation
Photoinduced electron transfer (PET)
D A D A
DAnode
D
D A D A* D Ah!
D A D* A D Ah!
1)
2)
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Chemical Oxidation
Stoichiometric oxidant: SET
MacMillan et al. Science2007, 316, 582.
Booker-Milburn, K. I. Synlett1992, 809.
H
hexyl
DME
N
NBn
O Me
t-Bu
H
hexyl
N
NBn
O Me
t-BuCe(NH4)2(NO3)6
OMe3SiO FeCl3, DMFMe3SiO
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Photoinduced Electron Transfer
PET: Organic arene
OMe
NC CN
h!, MeCN, MeOH
OMe
CN
CN
PET: Metal mediated
Arnold, D. R.; Maroulis, A. J. J. Am. Chem. Soc.1976, 98, 5931.
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc.2010, 132, 8572.
R
MeOh!, MgSO4,
MeNO2, Ru(bpy)32+
MeN NMeR
MeO
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Electrochemical Oxidation
Anodic oxidation
Ponsold, K.; Kasch, H. Tetrahedron Lett.1979, 4463.
M. J. Gai et al. J. Chem. Soc.Chem. Comm. 1993, 1496.
MeO
MeO
anode, MeOH
DCM, NaClO4
2,6-lutidine
MeO
MeO
NH
N
EtCO2Me
anode, 2,6-lutidine
MeCN, Et4NClO4 NH
N
EtCO2Me
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Primary Fate of Radical Cations
A radical cation will be generated from the electrophore on the molecule with the lowest
oxidation potential (usually or n, where n = nonbonding electrons).
The chemistry of the resultant radical cation is determined from the functionality around its
periphery.
Deprotonation of the radical cation is a major pathway, resulting in a radical which adheres
to typical radical reactivity patterns.
Secondary reactions play a major role in our generation and use of radical cations.
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Key Points
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or -A+ + B A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or -A+ + B A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Nicholas, A. M. de P.; Arnold, D. R. Can. J. Chem.1982, 60, 2165.
Thermochemical Cycle: Calculating pKas
G = nF[Eox
(RH) Eox
(R)]
pKa(RH+) = G/2.303RT
R-H
Eox(RH)
R-H!G[pKa(RH
+)]R + H+
!G[pKa(RH)]
Eox(R)
R + H+
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Deprotonation
a) Bordwell et al. J. Phys. Org. Chem. 1988, 1, 209. b) Bordwell et al. J. Phys. Org. Chem.1988, 1,225. c) Bordwell, F. G.; Cheng, J.-P. J. Am. Chem. Soc. 1989, 111, 1792. d) Bordwell, F. G.; Satish,A. V. J. Am. Chem. Soc. 1992, 114, 10173. e) Bordwell, F. G.; Cheng, J.-P. J. Am. Chem. Soc. 1988,
110, 2872. f) Bordwell, F. G.; Cheng, J.-P.; Bausch, M. J. J. Am. Chem. Soc. 1988, 110, 2867.
Acidity of a radical cation is severely increased compared to the neutral counterpart.
R-H
pKa ( -RH+
)
pKa ( -RH)
reference
PhCH2CN 32 21.9 a
PHCH2SO2Ph 25 23.4 b
Ph2CH2 25 32.2 cPhCH3 20 43 c
indene (3-H) 18 20.1 d
CpH
17
18.0
c,e
fluorene (9-H) 17 22.6 f
C5Me5H 6.5 26.1 e
H
H
H
H
HHB
+
B
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Deprotonation
Bordwell, F. G.; Zhang, X. J. Org. Chem. 1992, 57, 4163.
R-H pKa (RH+) pKa (RH)
13 27.9
11 27.0
11 24.4
N
NO
Ph
H
Me
Me
N
NO
Ph
H
Et
Et
Ph
O
N
O
2
H
N N
OPh
H B
HB+MeMe
N N
OPh
MeMe
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Secondary Reactions
Secondary Reactions play a major role in radical cation chemistry.
Code Secondary Rxn Product Oxidation SystemRox R
R+ cation anode, chemical
Rred R R anion PET
Rrad typical radical behavior various allRadd.ox R + C=C RCC RCC+ cation anode, chemicalRadd.red R
+ C=C RCC RCC anion PET
RRA R + R RR anion PET
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
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Ponsold, K.; Kasch, H. Tetrahedron Lett.1979, 4463.
-RH+Deprotonation
-RH+ deprotonation followed by a secondary reactivity pathway (benzylic radical)
MeO
MeO
anode, MeOH
DCM, NaClO42,6-lutidine
95%
MeO
MeO
HB
MeO
MeO
anode
MeO
MeO
MeOH
B
MeO
MeO
MeO
HMe
O
MeO
MeO
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Determining n vsElectrophores
Oxidation with typically take place at the center with the lower ionization potential
Consider the ionization potential of the separate n- and - moieties
NH
H
NMe
Me
NH3
9.24 eV 10.17 eV
HNMe2
9.24 eV 8.24 eV
7.69 eV
7.17 eV
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
H. M. Rosenstock et al. J. Phys. Chem. Ref. Data1977, 6, Suppl. 1.
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T. Shono et al. J. Am. Chem. Soc.1982, 104, 5753.
n-RH+Deprotonation
n-RH+ deprotonation followed by a secondary reactivity pathway (-amino radical)
NMe
Me
anode, MeOH
KOH, 73%
N
Me
H
H
H
OH
N
Me
H H
N
Me
OMe
N
Me
OMe
n donor
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T. Shono et al. J. Am. Chem. Soc.1982, 104, 5753.
n-RH+Deprotonation
NH
H
! donor
anodeN
H
H
H2N NH2
HN
NH2
N
N
Typical arene oxidation products are observed
Observation of these products indicates that the arene is the site of oxiation, not N-lone pairs
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Albini et al. J. Chem. Soc. Chem. Commun.1995, 41.
-CH+Deprotonation
Deprotonation of the radical ion pair happens by the solvent
NC CN
CNNC
h!, 81%
MeCN
NC CN
CNNCH
MeCN
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Albini et al. J. Chem. Soc. Chem. Commun.1995, 41.
-CH+Deprotonation
Deprotonation of the radical ion pair happens by the solvent
NC CN
CNNC
h!, 81%
MeCN
NC CN
CNNCH
MeCN
NC CN
CNNC
NC
CN
CNNC
AdmAdm CN
CNNC
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Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron1991, 47, 655.
-AH+Deprotonation
-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.
O OMe
HO
anode, MeOHMeCN, 69%
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Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron1991, 47, 655.
-AH+Deprotonation
-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.
O
HO
MeCN
O
OO OMe
HOMe
H+
HO
anode, MeOHMeCN, 69%
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T. Osa et al. J. Chem. Soc. Chem. Commum. 1994, 2535.
-AH+Deprotonation
Reaction at the ortho-position can also occur
OH
TEMPO-modifiedanode
()-sparteine, 91%
OH
OH
98% ee
Implementing a biased substrate forces reaction at the ortho-position
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Shine, H. J.; Hoque, A. K. M. M. J. Org. Chem. 1988, 53, 4349.
n-AH+Deprotonation: Very Limited
The details surrounding the cycloaddition below are speculative at best.
NNHPh
Ph
H
Th+ ClO4
MeCN
NNHPh
Ph
H
N Me
e
2H+ N
NPh
N
Me
Ph
The limited examples show how rare these deprotonations are
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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-A-B+Bond Dissociation
O
Me
OTMS
MeCN, 77%
Ce(NH4)2(NO3)6
H
O
Me
O
Me3Si
Dienolether has a lower oxidation potential than the enolether
OMe3Si
e
O
SiMe3+
H
CH2
Me
OTMS
H
O
Me
OTMS
eSiMe3+
Eventhough [O] may happen at n (lone pairs), the resonance structure affords the -oxidized
product.
Ruzziconi et al. Tetrahedron Lett.1993, 34, 721.
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-A-B+Bond Dissociation
Certain MukaiyamaMichael reactions are postulated to operate via a radical cation initiated
fragmentation
OEt
OTES
DCM , 78 C
LA
Ph
O
Ph
O
Me
Me
OEt
OTES
Me
Me
Me Me
Me Me
OEt
O
Lewis Acid 44 product 42 product Product ratioBu2Sn(OTf)2 85 0 100:0
SnCl4 95 0
100:0
Et3SiClO4 93 0 100:0
TiCl4 97 2.4 97:3
J. Otera et al. J. Am. Chem. Soc.1991, 113, 4028.
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MukaiyamaMichael Proposed Catalytic Cycle
J. Otera et al. J. Am. Chem. Soc.1991, 113, 4028.
SnCl4Ph
O
Me
Me
OEt
OTES
Me
MeOEt
OTES
Me
Me
Ph
O
Me
Me
SnCl4
Ph
O
Me
Me
SnCl3
ClEt3SiCl
Ph
O
Me
Me
OEt
O
Me
Me
Cl3Sn
Et3SiCl
Ph
Et3SiO Me Me
Me Me
OEt
O
etransfer
RR coupling complexation
catalyst regeneration
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n-A-B+Bond Dissociation
Adam, W.; Sendelbach, J. J. Org. Chem.1993, 58, 5316.
N
N
Me
Me
OHh!, DCA
Ph2
O MeMe
N
N
Me
Me
OHN2
OH
Me
Me
Me
OH
Me
BET
Limited mostly to azoalkanes and triazines
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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-C-C+Bond Dissociation
Fragmentation of a -ether generates an oxocarbenium ion
Arnold, D. R.; Maroulis, A. J. J. Am. Chem. Soc.1976, 98, 5931.
MeO
NC CN
h!, MeCN, MeOH
MeOMeO
HOMe
OMeMeO
DCB
H+
H+
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Stereoelectronic Effects in Deprotonation and Fragmentation
Poniatowski, A.; Floreancig, P. A. In Carbon-Centered Free Radicals and RadicalCations; Forbes, M. E., Ed.; Wiley & Sons: New Jersey, 2010; Vol 3., pp 43-60.
D. R. Arnold et al. Can. J. Chem.1997, 75, 384.
Deprotonation Fragmentation
Me
h!, DCB
collidine, MeCN
N.R.
Me
h!, DCB
collidine, MeCN
Me
H
HH
O
Ph
RH
H
Me
OMe
R
Ph
H
R
Me
"*Ph
Ph
O
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-C-C+Bond Dissociation
Nucleophile assisted CC bond fragmentation with complete inversion of stereochemistry
Dinnocenzo et al. J. Am. Chem. Soc.1990, 112, 2462.
Ph
Ph
Me
D
h!, 1-CN
MeCN, MeOH
Ph
Ph
Me
D
HOMe
Ph
Ph
OMe
Me D
H+
1-CN
H+ Ph
Ph
OMe
Me D
Nucleophile assisted -C-C+ fragmentation is limited to strained systems
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n-C-C+Bond Dissociation
To drive the reaction, the electrophore must be highly prone to oxidation or the resulting radical
must be stabilized by a moiety on the molecule
M. J. Gai
et al. J. Chem. Soc.Chem. Comm. 1993, 1496.
N
H
N
EtCO2Me
anode,2,6-lutidine
MeCN,
Et4NClO4N
H
N
EtCO2Me
N
H
N
EtCO2Me
e
N
N
EtCO2Me
N
N
H
Et
OMe
OHMeO2C
AcO
NH
N
EtCO2MeV
NaBH4
NH
N
H
CHO2MeV
Et
Me
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n-C-C+Bond Dissociation
To drive the reaction, the electrophore must be highly prone to oxidation or the resulting radical
must be stabilized by a moiety on the molecule
M. J. Gai
et al. J. Chem. Soc.Chem. Comm. 1993, 1496.
N
H
N
EtCO2Me
anode,2,6-lutidine
MeCN,
Et4NClO4N
H
N
EtCO2Me
N
H
N
EtCO2Me
e
N
N
EtCO2Me
N
N
H
Et
OMe
OHMeO2C
AcO
NH
N
EtCO2MeV
NaBH4
NH
N
H
CHO2MeV
Et
Me
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Me
AcO
O
O
TCB, h!
RSH, H2O, 90%
AcO
Me
O
O
OHTCB
Me
AcO
O
O
AcO
Me
O
O
TCB
H2O
n-C-C+Bond Dissociation
A. Albini et al. Tetrahedron Lett. 1994, 50, 575.
Easily oxidized acetal
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-C-C+Bond Dissociation
Booker-Milburn, K. I. Synlett1992, 809.
Me3SiO FeCl3, DMFO
H
H
Cl
H
Cl3Fe
SiMe3
64%
Me3SiO
Trapping of the pendant olefin and Cl
abstraction form the bicycle ESR studies on strained systems show that
the inner C-C bond is selectively weakened
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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-C-X+Bond Dissociation: Calculated BDEs
Aromatic ionization severely weakens the adjacent bond by ~30 kcal/mol on average
Si and Sn are the most common X-groups used as fragmentation substrates
Reaction HR(p-C-X+)
BDE kcal/molHR(p-C-X)
BDE kcal/mol RefPhCH2SiMe3
+ PhCH2 + Me3Si
+ +30 +77 a
PhCH2Cl+ PhCH2
2+ + Cl +40 +72 b
PhCH2Br+ PhCH2
2+ + Br +26 +58 b
PhCH2OMe+ PhCH2
2+ + OMe +43 +71 b
PhCH2SMe+ PhCH2
2+ + SMe +38 +61 b
PhSXan+ PhS + Xan+ 11 +26.4 c
PhSTPCP+ PhS + TPCP+ 18.6 +40.3 c
a) J. P. Dinnocenzo et al. J. Am. Chem. Soc. 1989, 111, 8973.b) Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.c) E. M. Arnett el al. J. Am. Chem. Soc. 1992, 114, 221.
Xan = 9-xanthyl; TPCP = 1,2,3-triphenylcyclopropenyl
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-C-X+Bond Dissociation
J. Yoshida et al. Tetrahedron Lett.1986, 27, 3373.
P. S. Mariano et al. J. Am. Chem. Soc.1984, 106, 6439.
R3Si and R3Sn moieties can be used as super protons
The dependence of kon MeOH, H2O,
Bu4NF indicates Nu-assisted Si-bond
cleavage
SiMe3 OMeanode, Et4NOTs
MeOH, 91%
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-C-X+Bond Dissociation
J. Yoshida et al. Tetrahedron Lett.1986, 27, 3373.
P. S. Mariano et al. J. Am. Chem. Soc.1984, 106, 6439.
R3Si and R3Sn moieties can be used as super protons
The dependence of kon MeOH, H2O,
Bu4NF indicates Nu-assisted Si-bond
cleavage
SiMe3 OMeanode, Et4NOTs
MeOH, 91%
Iminium salts can act as photo-
oxidants under PET conditions
N
SiMe3
MeClO4
h!, MeCN
70%
N
SiMe3
Me N Me
Me3Si+
N
Me
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n-C-X+Bond Dissociation
J. Yoshida et al. J. Am. Chem. Soc.2005, 127, 7324.
N
CO2Me
BF4
N
CO2Me
SiMe3
Bn4NBF4, DCM
anode, 78 C
N
CO2Me
SiMe3
F
N
CO2Me
e
Iminium ion used in the cation pool method is generated via n-C-X+ cleavage
F assisted CSi bond cleavage
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-C-X+Bond Dissociation
Cation pool oxidizes benzylsilane directly
Oxidation potential of benzylsilane must be
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-C-X+Bond Dissociation
Cation pool oxidizes benzylsilane directly
Oxidation potential of benzylsilane must be
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OMe
N
CO2MeBF4
N
CO2MeBF4
OMe
Me3Si
OMe
Me3Si
Me3Si+
N
CO2Me
N
CO2Me
OMe
OMe
Me3Si
N
CO2Me
OMe
Propagation
Proposed Mechanism
J. Yoshida et al. J. Am. Chem. Soc.2007, 129, 1902.
Propagation
Initiation
Stronger oxidant
than iminium ion
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n-C-X+Bond Dissociation
Pandy, G.; Reddy, G. D. Tetrahedron Lett. 1992, 33, 6533. Steckhan et al.Angew. Chem. Int.Ed. Engl. 1995, 34, 2137. Mariano et al. J. Org. Chem.
1992, 57, 6037.
N
SiMe3 DCN, h!
i-PrOH, 90% N
H
Me
97:3 dr
O
O
N
Bn
SiMe3
DCA, h!
MeCN, 59%
Nhexyl
O
OMe
SiMe3
DCA, h!, 67%
MeCn/MeOH
NO O
Me
Nhexyl
O
OMe
NO O
Me
N O
N
H
N O
O
O
Bn
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-C-X+Bond Dissociation
Mariano P. S.; Ohga, K. J. Am. Chem. Soc.1982, 104, 617.Otsuji et al. Tetrahedron Lett. 1985, 26, 461.
CN
NC
h!, 66%
MeCNSiMe3
NC
NClO4
Me
SiMe3
h!, 42%
N
CO2Me
PhPh
N
Me
Ph SiMe3
Me3Si+
MeCN
Coupling of the radical cation to the oxidant is the prominent primary fate after -C-X+ cleavage
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Nu--A-B+
Mihelcic, J.; Moeller, K D. J. Am. Chem. Soc.2004, 126, 9106.Trauner et al. J. Am. Chem. Soc.2006, 128, 17057.
OTBS
TBSOO
Me
Me
Meanode, LiClO4
2,6-lutidineMeOH/DCM, 88%
O
TBSOO
Me
Me
Me
H
Moeller en route to ()-alliacol A
Trauner en route to ()-guanacastepene E
O
TBDPSO
Me
MeMe
Me
OBn
TBSO
anode, LiClO4
2,6-lutidineMeOH/DCM, 81%
O
TBDPSO
Me
MeMe
Me
OBn
OMeO
H
H
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Nu-n-A-B+
Karady et al. Tetrahedron Lett. 1989, 30, 2191.
Me NHOAc
anode THF, H2O
NaBF4, 70%
Me
NOAc
Me NHOAc
Me
NOAcH
H+
e
Me
NOAc
OHH2O
H+
The authors do not rule out the possibility of olefin oxidation as an alternative mechanism
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Nu-n-A-B+
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc.1987, 109, 3163.
NPTOC
t-BuSH, 60%
AcOH NMe
N
S
O
O
PTOC =
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Nu-n-A-B+
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc.1987, 109, 3163.
NPTOC
t-BuSH, 60%
AcOH NMe
NH N
H
HSR
H+
Initially formed nitrene is immediately protonated
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Cycloaddition
a) Calhoun, G. C.; Schuster, G. B. J. Am. Chem. Soc. 1984, 106, 6870. b) Lorenz, K. T.; Bauld, N. L. J. Am.Chem. Soc. 1987, 109, 1157. c) Takamuku et al. J. Org. Chem. 1991, 56, 6240. d) Schepp, N. P; Johnston, L. JJ. Am. Chem. Soc. 1994, 116, 6895. e) Schepp, N. P; Johnston, L. J J. Am. Chem. Soc. 1994, 116, 10330.
Reaction k[M1s1] comments reference
3 x 108Mostly [4 + 2] endo adduct; ratio of/to [2 + 2]
varied by concentrationa, b
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DielsAlder [4 + 2] Cycloaddition
Bauld et al. J. Am. Chem. Soc.1981, 109, 3163.Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc. 1987, 109, 1157
Suprafacial selectivity observed
Shown to operate via a cation radical chain mechanism
DP + Ar3N+ Ar3N + DP
+
DP+ + D A+
A+ + DP A + DP+
DCM, 70%
H
H
5:1 endo/exo
Ar3NSbCl5
2DP+ dication
DP+ H+ + DP
Propagation
Termination
k= 3 x 108 [M1s1]
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DielsAlder [4 + 2] Cycloaddition
Shown to operate via a cation radical chain mechanism
DCM, 70%
H
H
5:1 endo/exo
Ar3NSbCl5
Bauld et al. J. Am. Chem. Soc.1981, 109, 3163.Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc. 1987, 109, 1157
PropagatorHH
H
H
Ar3N
Initiator
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[2 + 2] Cycloaddition
Photoredox catalyzed radical cation formation
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc.2010, 132, 8572.
Concerted cycloaddition
e +e
MeO
O
Electron donating substituent on the arene is necessary to promote the initial oxidation
MeO
O
O
HH
MeO
h!, MgSO4, 88%
MeNO2, Ru(bpy)32+
MeN NMe
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MeO
O
O
HH
MeO
h!, MgSO4, 82%
MeNO2, Ru(bpy)
3
2+
MeN NMe
O
HH
MeO
h!, MgSO4, 71%
MeNO2, Ru(bpy)32+
MeN NMe
O
OMe
6:1 dr
5:1 dr
[2 + 2] Cycloaddition
Stereoconvergent transformation
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc.2010, 132, 8572.
isomerization > cycloaddition
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Claisen Rearrangement: A Representative Example
Though potentially powerful, the radical cation Claisen rearrangement has found very limited
use in synthsis
Venkatachalam et al J. Chem. Soc Chem. Commun.1994, 511.
OMe
MeO
O
MeCN, 65%
Ar3NSbCl5
OMe
MeO
OH
The radical cation Cope rearrangement seems to be limited to aryl substituted systems.
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
Both radical (Rad) and radical anion (RA) have been previously discussed
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Primary Fate of Radical Cations
Schmittle, M.; Burghart, A. Angew. Chem. Int.Ed. Engl. 1997, 36, 2550.
Symbol Classification Primary Product A BCH CH deprotonation -C + H+ or n-C + H+ C H
AH AH deprotonation -A + H+ O, N, S, X H
AB AB bond cleavage -A + B+ or n-A + B+ A B
CC CC bond cleavage -C + C+ C C
CX CX bond cleavage -C + X+ C Si, Sn
Nu Nu attack Nu--A-B+ A B
CA cycloaddition cycloaddition A B
R rearrangement rearrangement A B
ET electron transfer -A-Bor -A-B2+ A B
Rad radical attack R--A-B+ A B
RA radical anion attack RA--A-B A B
H hydrogen transfer H--A-B+ A B
Dim dimerization (-A-B)22+ A B
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Hydrogen Transfer
The HofmannLfflerFreytag reaction
Kimura, M.; Ban, Y. Synthesis1976, 201.
NH N
NCS, ether
NEt3, h!, quant
N N
Cl
HN N
H
H
N NH
Cl
HN N
H H+
Cl
N NH+
Typically a 1,5-H-atom abstraction
NC homolysis
H abstraction
SN2 ring closure
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Hydrogen Transfer
The HofmannLfflerFreytag reaction
Kimura, M.; Ban, Y. Synthesis1976, 201.
Intermediate en route to the synthesis of kobusine
Me
OH
HO
N
NH
MeMe
NCS, DCM
0 C, 85%
N
MeMe
Cl
h, TFA
KOH, EtOH39%
NN
MeMe
Cl
Me
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Radical Cations in Synthesis: Floreancig Lab
Epoxonium cyclization
Houk and Floreancig et al. J. Am. Chem. Soc.2007, 129, 7915.
Floreancig et al. Angew. Chem. Int.Ed. Engl. 2008, 47, 7317.
Cyclic acetal formation en route to theopederin D
Bn O
OMe MeO
MeO
Ot-bu
O
h!, NMQPF6, O2NaOAc, Na2S2O3
DCE, PhMe, 79% O
O
O
OMe
Me
H
H
O
MeO
O
O
OMeH
OMeO
CbzHN
Bn
OO
Me
Me h!, NMQPF6,NaOAc, Na2SO3
DCE, PhMe, 76% O
O
OMeH
O
OMe
CbzHN
O
MeMe
2:1 dr
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Radical Cations in Synthesis
Used in Moellers synthesis of nemorensic acid
Moeller et al J. Am. Chem. Soc.2002, 124, 10101.Boger et al J. Am. Chem. Soc.2008, 130, 420.
Bogers synthesis of vinblastine
S
OHMe S
Me
O
Me
MeMe
Me
S
S
MeO
anode, 71%
Et4NOTsMeOH/THF
NH
N
EtCO2Me
ii. Fe2(ox)3NaBH4air, 0 C, lutidine
43%
N
N
H
Et
MeO
HO CO2Me
OAc
i. FeCl3, 2h
NH
N
H
MeO2C
Et
N
N
H
Et
MeO
HO CO2Me
OAc
OH
Me
Me
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Radical Cations in Synthesis: MacMillan Lab
N
NBn
O Me
t-Bu
R
SOMO-activated
H
R
O
H
R
O
!-enolation
!-allylation
!-vinylation
H
O
R
!-nitroalkylation
HR
O
!-arylation
intramolecular!-arylation
R'
O
H
H
OR'
R'
R'
R'
H
R
O NO2
R'
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