Radical Cations•+: Generation, Reactivity, Stability
R
A
R
MacMillan Group Meeting
4-27-11
by
Anthony Casarez
A
Three Main Modes to Generate Radical Cations
  Chemical oxidation
D
A
D
A
  Photoinduced electron transfer (PET)
1) D
A
2) D
A
h!
h!
D
A*
D
A
D*
A
D
A
  Electrochemical oxidation (anodic oxidation)
D
Anode
D
Chemical Oxidation
  Stoichiometric oxidant: SET
O
O
Me
Me
N
Bn
N
N
t-Bu
Ce(NH4)2(NO3)6
Bn
DME
H
t-Bu
H
hexyl
Me3SiO
O
N
hexyl
FeCl3, DMF
Me3SiO
MacMillan et al. Science 2007, 316, 582.
Booker-Milburn, K. I. Synlett 1992, 809.
Photoinduced Electron Transfer
  PET: Organic arene
CN
NC
CN
OMe
OMe
h!, MeCN, MeOH
CN
  PET: Metal mediated
h!, MgSO4,
MeNO2, Ru(bpy)32+
MeO
R
MeN
NMe
MeO
R
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.
Electrochemical Oxidation
  Anodic oxidation
Me O
Me O
anode, MeOH
DCM, NaClO4
2,6-lutidine
MeO
MeO
N
N
H
CO2Me
N
anode, 2,6-lutidine
Et
MeCN, Et4NClO4
N
H
CO2Me
Et
Ponsold, K.; Kasch, H. Tetrahedron Lett. 1979, 4463.
M. J. Gašić et al. J. Chem. Soc. Chem. Comm. 1993, 1496.
Primary Fate of Radical Cations
Key Points
  A radical cation will be generated from the electrophore on the molecule with the lowest
oxidation potential (usually π 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.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or π-A+ + B•
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or π-A+ + B•
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Thermochemical Cycle: Calculating pKaʼs
R-H
!G[pKa(RH•+)]
R• + H+
Eox(R–)
Eox(RH)
R-H
!G[pKa(RH)]
R– + H+
  ΔG = –nF[Eox(RH) – Eox(R–)]
  pKa(RH•+) = ΔG/2.303RT
Nicholas, A. M. de P.; Arnold, D. R. Can. J. Chem. 1982, 60, 2165.
Deprotonation
  Acidity of a radical cation is severely increased compared to the neutral counterpart. H
H
H
H
H
H–B+
B
R-H
pKa (π-RH•+)
pKa (π-RH)
reference
PhCH2CN
–32
21.9
a
PHCH2SO2Ph
–25
23.4
b
Ph2CH2
–25
32.2
c
PhCH3
–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
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.
Deprotonation
Ph
Me
O
H
N
N
B
Me
R-H
Me
Ph
O
N
N
Me
H–B+
pKa (RH•+)
pKa (RH)
–13
27.9
–11
27.0
–11
24.4
Me
O
H
Ph
N
N
Me
Et
O
H
Ph
N
N
Et
O
O
N
Ph
2
H
Bordwell, F. G.; Zhang, X. J. Org. Chem. 1992, 57, 4163.
Secondary Reactions
  Secondary Reactions play a major role in “radical cation” chemistry.
Code
Secondary Rxn
Product
Oxidation System
R•ox
R•
R+
cation
anode, chemical
R•red
R•
R–
anion
PET
various
all
R•rad
typical radical behavior
R•add.ox
R• + C=C
R–C–C•
R–C–C+
cation
anode, chemical
R•add.red
R• + C=C
R–C–C•
R–C–C–
anion
PET
anion
PET
R•RA
R• + R•–
R–R•–
Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
π-RH•+ Deprotonation
  π-RH•+ deprotonation followed by a secondary reactivity pathway (benzylic radical) Me O
anode, MeOH
DCM, NaClO4
2,6-lutidine
95%
MeO
Me O
Me O
anode
B
H
MeO
MeO
B
Me O
H
MeO
MeO
Me O
MeOH
Me O
MeO
MeO
MeO
Ponsold, K.; Kasch, H. Tetrahedron Lett. 1979, 4463.
Determining n vs π Electrophores
  Consider the ionization potential of the separate n- and π- moieties H
N
H
7.69 eV
NH3
9.24 eV
10.17 eV
Me
N
Me
HNMe2
7.17 eV
9.24 eV
8.24 eV
  Oxidation with typically take place at the center with the lower ionization potential
Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
H. M. Rosenstock et al. J. Phys. Chem. Ref. Data 1977, 6, Suppl. 1.
n-RH•+ Deprotonation
  n-RH•+ deprotonation followed by a secondary reactivity pathway (α-amino radical) Me
N
Me
N
anode, MeOH
Me
OH
KOH, 73%
H
H
H
n donor
Me
N
OMe
Me
Me
N
N
H
H
OMe
T. Shono et al. J. Am. Chem. Soc. 1982, 104, 5753.
n-RH•+ Deprotonation
  Typical arene oxidation products are observed
H2N
H
N
NH2
H
H
anode
N
H
H
N
NH2
! donor
N
N
  Observation of these products indicates that the arene is the site of oxiation, not N-lone pairs
T. Shono et al. J. Am. Chem. Soc. 1982, 104, 5753.
σ-CH•+ Deprotonation
  Deprotonation of the radical ion pair happens by the solvent NC
CN
NC
CN
h!, 81%
MeCN
H
NC
CN
NC
CN
MeCN
Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.
σ-CH•+ Deprotonation
  Deprotonation of the radical ion pair happens by the solvent NC
CN
NC
CN
NC
CN
NC
CN
CN
NC
CN
CN
NC
CN
h!, 81%
MeCN
H
MeCN
Adm
CN
NC
Adm
NC
CN
NC
Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.
π-AH•+ Deprotonation
  π-OH•+ deprotonation is very prevalent while π-NH•+ deprotonations are rare.
anode, MeOH
HO
O
OMe
MeCN, 69%
Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.
π-AH•+ Deprotonation
  π-OH•+ deprotonation is very prevalent while π-NH•+ deprotonations are rare.
anode, MeOH
MeCN, 69%
HO
HO
O
MeCN
HOMe
O
OMe
–H+
O
O
Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.
π-AH•+ Deprotonation
  Reaction at the ortho-position can also occur
OH
TEMPO-modified
anode
OH
(–)-sparteine, 91%
OH
98% ee
  Implementing a biased substrate forces reaction at the ortho-position
T. Osa et al. J. Chem. Soc. Chem. Commum. 1994, 2535.
n-AH•+ Deprotonation: Very Limited
  The details surrounding the cycloaddition below are speculative at best.
Ph
N
H
NHPh
Th•+ ClO4–
MeCN
Ph
N
NHPh
–2H+
H
N
–e–
Me
N
Ph
NPh
N
Me
  The limited examples show how rare these deprotonations are
Shine, H. J.; Hoque, A. K. M. M. J. Org. Chem. 1988, 53, 4349.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
π-A-B•+ Bond Dissociation
  Dienolether has a lower oxidation potential than the enolether
Me3Si
O
Ce(NH4)2(NO3)6
OTMS
O
MeCN, 77%
Me
O
–e–
–SiMe3+ –e–
SiMe3+
Me3Si
O
Me
H
OTMS
O
O
CH2
Me
H
H
Me
OTMS
  Eventhough [O] may happen at n (lone pairs), the resonance structure affords the π-oxidized
product.
Ruzziconi et al. Tetrahedron Lett. 1993, 34, 721.
π-A-B•+ Bond Dissociation
  Certain Mukaiyama–Michael reactions are postulated to operate via a radical cation initiated
fragmentation
O
OTES
Me
Me
Ph
OTES
OEt
Me
OEt
Me
O Me
LA
DCM , –78 °C
Me O
Ph
OEt
Me
Lewis Acid
4°–4° product
4°–2° product
Product ratio
Bu2Sn(OTf)2
85
0
100:0
SnCl4
95
0
100:0
Et3SiClO4
93
0
100:0
TiCl4
97
2.4
97:3
Me
J. Otera et al. J. Am. Chem. Soc. 1991, 113, 4028.
Mukaiyama–Michael Proposed Catalytic Cycle
Et3SiO Me
catalyst regeneration
Me O
Ph
SnCl4
OEt
Me
Me
O
Ph
Me
Me
Et3SiCl
Cl3Sn
R•–R• coupling
Ph
O
O
Me
Me
Me
SnCl4
O
OEt
Me
complexation
Me
Ph
Me
SnCl3
O
Et3SiCl
Ph
Cl–
Me
Me
OTES
Me
OEt
OTES
Me
OEt
Me
Me
e– transfer
J. Otera et al. J. Am. Chem. Soc. 1991, 113, 4028.
n-A-B•+ Bond Dissociation
  Limited mostly to azoalkanes and triazines
Me
Me
OH
Me
OH
h!, DCA
N
N2
N
Ph2
N
OH
N
Me
Me
Me
Me
Me
BET
OH
O
Me
Me
Adam, W.; Sendelbach, J. J. Org. Chem. 1993, 58, 5316.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
π-C-C•+ Bond Dissociation
  Fragmentation of a β-ether generates an oxocarbenium ion
MeO
MeO
MeO
NC
HOMe
CN
h!, MeCN, MeOH
MeO
OMe
–H+
H+
DCB
Arnold, D. R.; Maroulis, A. J. J. Am. Chem. Soc. 1976, 98, 5931.
Stereoelectronic Effects in Deprotonation and Fragmentation   Deprotonation
  Fragmentation
Ph
OMe
H
h!, DCB
R
N.R.
collidine, MeCN
Me
H
R
O
Me
H
H
h!, DCB
H
Ph
collidine, MeCN
Me
Ph
Me
Ph
Me
H
O
"*
R
Poniatowski, A.; Floreancig, P. A. In Carbon-Centered Free Radicals and Radical
Cations; 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.
π-C-C•+ Bond Dissociation
  Nucleophile assisted C–C bond fragmentation with complete inversion of stereochemistry
HOMe
Ph
Me
Ph
D
h!, 1-CN
Ph
Me
MeCN, MeOH
Ph
D
–H+
Ph
OMe
Ph Me
D
1-CN
H+
Ph
OMe
Ph Me
D
  Nucleophile assisted π-C-C•+ fragmentation is limited to strained systems
Dinnocenzo et al. J. Am. Chem. Soc. 1990, 112, 2462.
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
anode,
2,6-lutidine
N
N
H
CO2Me
N
MeCN,
Et4NClO4
Et
N
H
N
CO2Me
N
H
Et
Et
CO2Me
–e–
N
Et
N
NaBH4
H
N
H
V
CHO2Me
N
N
N
H
V
CO2Me Et
N
CO2Me
Et
Et
N
H
MeO2C OH Me
AcO
OMe
M. J. Gašić et al. J. Chem. Soc. Chem. Comm. 1993, 1496.
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
anode,
2,6-lutidine
N
N
H
CO2Me
N
MeCN,
Et4NClO4
Et
N
H
N
CO2Me
N
H
Et
Et
CO2Me
–e–
N
Et
N
NaBH4
H
N
H
V
CHO2Me
N
N
N
H
V
CO2Me Et
N
CO2Me
Et
Et
N
H
MeO2C OH Me
AcO
OMe
M. J. Gašić et al. J. Chem. Soc. Chem. Comm. 1993, 1496.
n-C-C•+ Bond Dissociation
TCB
Me
OH
O
Me
O
TCB, h!
O
RSH, H2O, 90%
AcO
O
AcO
  Easily oxidized acetal
Me
TCB
O
Me
O
O
AcO
AcO
H2O O
A. Albini et al. Tetrahedron Lett. 1994, 50, 575.
σ-C-C•+ Bond Dissociation
Cl
Cl3Fe
Me3SiO
FeCl3, DMF
Me3SiO
–SiMe3
O
H
H
64%
H
  ESR studies on strained systems show that
the inner C-C bond is selectively weakened
  Trapping of the pendant olefin and Cl•
abstraction form the bicycle
Booker-Milburn, K. I. Synlett 1992, 809.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
π-C-X•+ Bond Dissociation: Calculated BDEʼs
  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
ΔHR(p-C-X•+) BDE kcal/mol
ΔHR(p-C-X) BDE kcal/mol
Ref
PhCH2• + Me3Si+
+30
+77
a
PhCH2–Cl•+
PhCH22+ + Cl•
+40
+72
b
PhCH2–Br•+
PhCH22+ + Br•
+26
+58
b
PhCH2–OMe•+
PhCH22+ + •OMe
+43
+71
b
PhCH2–SMe•+
PhCH22+ + •SMe
+38
+61
b
PhS• + Xan+
–11
+26.4
c
–18.6
+40.3
c
Reaction
PhCH2–SiMe3•+
PhS–Xan•+
PhS–TPCP•+
PhS• + TPCP+
Xan = 9-xanthyl; TPCP = 1,2,3-triphenylcyclopropenyl
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. π-C-X•+ Bond Dissociation
  R3Si– and R3Sn– moieties can be used as “super protons”
  The dependence of k on MeOH, H2O,
Bu4NF indicates Nu-assisted Si-bond
cleavage SiMe3
anode, Et4NOTs
OMe
MeOH, 91%
J. Yoshida et al. Tetrahedron Lett. 1986, 27, 3373.
P. S. Mariano et al. J. Am. Chem. Soc. 1984, 106, 6439.
π-C-X•+ Bond Dissociation
  R3Si– and R3Sn– moieties can be used as “super protons”
  The dependence of k on MeOH, H2O,
Bu4NF indicates Nu-assisted Si-bond
cleavage ClO4–
N
Me
SiMe3
h!, MeCN
anode, Et4NOTs
SiMe3
OMe
MeOH, 91%
N
Me
SiMe3
–Me3
Si+
N
Me
70%
Me
  Iminium salts can act as photooxidants under PET conditions
N
J. Yoshida et al. Tetrahedron Lett. 1986, 27, 3373.
P. S. Mariano et al. J. Am. Chem. Soc. 1984, 106, 6439.
n-C-X•+ Bond Dissociation
  Iminium ion used in the “cation pool” method is generated via n-C-X•+ cleavage
N
Bn4NBF4, DCM
SiMe3
BF4–
anode, –78 °C
CO2Me
N
CO2Me
–e–
–F
N
SiMe3
CO2Me
N
CO2Me
  F– assisted C–Si bond cleavage
J. Yoshida et al. J. Am. Chem. Soc. 2005, 127, 7324.
π-C-X•+ Bond Dissociation
  “Cation pool” oxidizes benzylsilane directly
OMe
BF4–
N
DCM, –50 °C
Me3Si
OMe
CO2Me
88%
N
CO2Me
1.35 V vs SCE
  Oxidation potential of benzylsilane must be <1.5 V, otherwise a catalytic benzylstannane can be
added to initiate the reaction
Me
BF4–
N
DCM, –50 °C
Me3Si
Me
CO2Me
12%
N
CO2Me
1.55 V vs SCE
J. Yoshida et al. J. Am. Chem. Soc. 2007, 129, 1902.
π-C-X•+ Bond Dissociation
  “Cation pool” oxidizes benzylsilane directly
OMe
BF4–
N
DCM, –50 °C
Me3Si
N
88%
OMe
CO2Me
CO2Me
1.35 V vs SCE
  Oxidation potential of benzylsilane must be <1.5 V, otherwise a catalytic benzylstannane can be
added to initiate the reaction
Me
BF4–
N
DCM, –50 °C
Me3Si
N
97%
Me
CO2Me
CO2Me
1.55 V vs SCE
Bu3Sn
10 mol%
Me
J. Yoshida et al. J. Am. Chem. Soc. 2007, 129, 1902.
Proposed Mechanism
Initiation
Me3Si
OMe
BF4–
N
N
CO2Me
CO2Me
OMe
Me3Si
N
Me3Si+
CO2Me
OMe
Me3Si
OMe
Propagation
Propagation
OMe
  Stronger oxidant
than iminium ion
N
CO2Me
BF4–
N
CO2Me
OMe
J. Yoshida et al. J. Am. Chem. Soc. 2007, 129, 1902.
n-C-X•+ Bond Dissociation
SiMe3
N
DCN, h!
H
i-PrOH, 90%
N
Me
97:3 dr
O
hexyl
N
O
OMe
DCA, h!, 67%
hexyl
N
OMe
MeCn/MeOH
SiMe3
O
N
O
O
Me
SiMe3
O
N
N
O
Me
H
O
Bn
DCA, h!
O
MeCN, 59%
O
N
N
Bn
O
N
O
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.
σ-C-X•+ Bond Dissociation
ClO4–
N
h!, 42%
Ph
SiMe3
N
MeCN
Me
Ph
CO2Me
–Me3Si+
N
Ph
SiMe3
Me
  Coupling of the radical cation to the oxidant is the prominent primary fate after σ-C-X•+ cleavage CN
SiMe3
NC
h!, 66%
MeCN
NC
Mariano P. S.; Ohga, K. J. Am. Chem. Soc. 1982, 104, 617.
Otsuji et al. Tetrahedron Lett. 1985, 26, 461.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Nu-π-A-B•+
  Moeller en route to (–)-alliacol A
O
OTBS Me
Me
anode, LiClO4
Me
TBSO
Me
Me
2,6-lutidine
MeOH/DCM, 88%
O
H
Me
TBSO
O
  Trauner en route to (–)-guanacastepene E
Me
Me
Me
Me
TBDPSO
O
OBn
TBSO
Me
Me
Me
anode, LiClO4
2,6-lutidine
MeOH/DCM, 81%
H
Me
TBDPSO
O
MeO
OBn
H
O
Mihelcic, J.; Moeller, K D. J. Am. Chem. Soc. 2004, 126, 9106.
Trauner et al. J. Am. Chem. Soc. 2006, 128, 17057.
Nu-n-A-B•+
anode THF, H2O
NaBF4, 70%
Me
Me
NHOAc
H2O
OH
NOAc
–H+
NOAc
–H+
–e–
Me
NHOAc
Me
H
NOAc
Me
  The authors do not rule out the possibility of olefin oxidation as an alternative mechanism
Karady et al. Tetrahedron Lett. 1989, 30, 2191.
Nu-n-A-B•+
N
AcOH
N
PTOC
Me
t-BuSH, 60%
O
PTOC =
S
O
N
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc. 1987, 109, 3163.
Nu-n-A-B•+
N
AcOH
N
PTOC
Me
t-BuSH, 60%
H
NH
N
–H+
HSR
  Initially formed nitrene is immediately protonated
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc. 1987, 109, 3163.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Cycloaddition
  Experimental kinetic data for radical cation cycloadditions (rt)
Reaction
p-An
p-An
k [M–1s–1]
comments
reference
3 x 108
Mostly [4 + 2] endo adduct; ratio of/to [2 + 2]
varied by concentration
a, b
<6.7 x 107
1) [2 + 2] terminated by C-H•– deprotonation
2) concerted reaction
b
Me
Me
p-An
1) 1.4 x 109
2) 1.4 x 109
3) 1 x 1010
p-An
p-An
p-An
Me
1) concerted cycloaddition assumed
2) distonic 1,4-radical cation intermediate
c,d
7 x 108
21% Diels–Alder adduct
e
1.5 x 106
80% Diels–Alder adduct
e
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. J
J. Am. Chem. Soc. 1994, 116, 6895. e) Schepp, N. P; Johnston, L. J J. Am. Chem. Soc. 1994, 116, 10330. Diels–Alder [4 + 2] Cycloaddition
  Shown to operate via a cation radical chain mechanism H
DCM, 70%
Ar3N
–SbCl
H
5
5:1 endo/exo
Suprafacial selectivity observed
k = 3 x 108 [M–1s–1]
DP + Ar3N•+
Ar3N + DP•+
DP•+ + D
A•+
A•+ + DP
2DP•+
DP•+
A + DP•+
dication
Propagation
Termination
H+ + DP•
Bauld et al. J. Am. Chem. Soc. 1981, 109, 3163.
Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc. 1987, 109, 1157
Diels–Alder [4 + 2] Cycloaddition
  Shown to operate via a cation radical chain mechanism H
DCM, 70%
Ar3N
–SbCl
H
5
5:1 endo/exo
H
H
Initiator
Ar3N
H
H
Propagator
Bauld et al. J. Am. Chem. Soc. 1981, 109, 3163.
Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc. 1987, 109, 1157
[2 + 2] Cycloaddition
  Photoredox catalyzed radical cation formation
MeO
h!, MgSO4, 88%
MeNO2, Ru(bpy)32+
MeO
MeN
O
NMe
H
H
O
Concerted cycloaddition
MeO
–e–
+e–
O
  Electron donating substituent on the arene is necessary to promote the initial oxidation Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572.
[2 + 2] Cycloaddition
  Stereoconvergent transformation
OMe
MeO
h!, MgSO4, 71%
MeNO2, Ru(bpy)32+
H
O
MeN
H
NMe
O
6:1 dr
isomerization > cycloaddition
MeO
MeO
h!, MgSO4, 82%
MeNO2, Ru(bpy)32+
O
H
MeN
H
NMe
O
5:1 dr
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Claisen Rearrangement: A Representative Example
  Though potentially powerful, the radical cation Claisen rearrangement has found very limited
use in synthsis
OMe
OMe
O
MeO
•
MeCN, 65%
Ar3N
–SbCl
5
OH
MeO
  The radical cation Cope rearrangement seems to be limited to aryl substituted systems.
Venkatachalam et al J. Chem. Soc Chem. Commun. 1994, 511.
Primary Fate of Radical Cations
  Both radical (Rad) and radical anion (RA) have been previously discussed
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Primary Fate of Radical Cations
Symbol
Classification
CH
C–H deprotonation
AH
A–H deprotonation
AB
Primary Product
A
B
C
H
π-A• + H+
O, N, S, X
H
A–B bond cleavage
π-A• + B+ or n-A• + B+
A
B
CC
C–C bond cleavage
π-C• + C+
C
C
CX
C–X bond cleavage
π-C• + X+
C
Si, Sn
Nu
Nu attack
Nu-π-A-B•+ A
B
CA
cycloaddition
cycloaddition
A
B
R
rearrangement
rearrangement
A
B
ET
electron transfer
π-A-B or π-A-B2+ A
B
Rad
radical attack
R-π-A-B+
A
B
RA
radical anion attack
RA-π-A-B
A
B
H
hydrogen transfer
H-π-A-B+
A
B
Dim
dimerization
(π-A-B)22+
A
B
π-C• + H+ or n-C• + H+ Schmittle, M.; Burghart, A. Angew. Chem. Int. Ed. Engl. 1997, 36, 2550.
Hydrogen Transfer
  The Hofmann–Löffler–Freytag reaction
N–C homolysis
NCS, ether
NH
N
N
NEt3, h!, quant
H
N
N
H
N
H
Cl
H• abstraction
N
N
–H+
SN2 ring closure
N
H
N
–H+
H
N
H
N
Cl
Cl•
  Typically a 1,5-H-atom abstraction
Kimura, M.; Ban, Y. Synthesis 1976, 201.
Hydrogen Transfer
HO
N
  The Hofmann–Löffler–Freytag reaction
Me
NCS, DCM
NH
OH
N
Cl
0 °C, 85%
Me
Me
Me
N
Me
Me
Cl
Me
hν, TFA
KOH, EtOH
39%
N
Me
  Intermediate en route to the synthesis of kobusine
Kimura, M.; Ban, Y. Synthesis 1976, 201.
Radical Cations in Synthesis: Floreancig Lab
  Epoxonium cyclization
Bn
O
OMe
Me
O
Me
O
Ot-bu
O
Me
O
h!, NMQPF6, O2
NaOAc, Na2S2O3
DCE, PhMe, 79%
O
MeO
H
O
O
O
Me
H
  Cyclic acetal formation en route to theopederin D
MeO
OMe
O
O
Me
O
CbzHN
Bn
H
h!, NMQPF6,
NaOAc, Na2SO3
Me
Me
OMe
O
DCE, PhMe, 76%
O
Me
CbzHN
O
O
O
H
2:1 dr
OMe
O
Houk and Floreancig et al. J. Am. Chem. Soc. 2007, 129, 7915.
Floreancig et al. Angew. Chem. Int. Ed. Engl. 2008, 47, 7317.
Radical Cations in Synthesis
  Used in Moellerʼs synthesis of nemorensic acid Me
Me
S
Me
OH Me
S
anode, 71%
Et4NOTs
MeOH/THF
Me
S
Me
O
MeO
S
  Bogerʼs synthesis of vinblastine
N
OH
N
N
H
CO2Me
Et
i. FeCl3, 2h
N
Et
MeO
N
Et
OAc
H
Me HO CO2Me
ii. Fe2(ox)3–NaBH4
air, 0 °C, lutidine
43%
H
N
N
H
MeO2C
MeO
Et
N
OAc
H
Me HO CO2Me
Moeller et al J. Am. Chem. Soc. 2002, 124, 10101.
Boger et al J. Am. Chem. Soc. 2008, 130, 420.
Radical Cations in Synthesis: MacMillan Lab
O
O
R
H
R'
H
R
R'
!-arylation
O
!-enolation
SOMO-activated
O
O
Me
O
N
R'
R'
H
H
Bn
intramolecular
!-arylation
O
t-Bu
N
H
R
R
!-vinylation
O
NO2
H
R'
R
!-nitroalkylation
H
R
R'
!-allylation