Radical Cations - +: Generation, Reactivity, Stability

Radical Cations+: Generation, Reactivity, Stability
MacMillan Group Meeting 4-27-11 by Anthony Casarez
Three Main Modes to Generate Radical Cations
Chemical oxidation
D A D A
Photoinduced electron transfer (PET)

h!
1) D
A*
2) D
h!
D*
Electrochemical oxidation (anodic oxidation)
Anode
Chemical Oxidation
Stoichiometric oxidant: SET
O N Bn H N
Me
O N
Me
t-Bu
Ce(NH4)2(NO3)6 DME
Bn H
t-Bu
hexyl
hexyl
Me3SiO O
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 OMe CN OMe
h!, MeCN, MeOH

CN
PET: Metal mediated

h!, MgSO4, MeNO2, Ru(bpy)32+
R MeN NMe
MeO
MeO
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
anode, 2,6-lutidine
Et
N N H
MeCN, Et4NClO4
CO2Me
CO2Me
Et
Ponsold, K.; Kasch, H. Tetrahedron Lett. 1979, 4463. M. J. Gai 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 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.
Symbol CH AH AB CC CX Nu CA R ET Rad RA H Dim
Classication CH deprotonation AH deprotonation AB bond cleavage CC bond cleavage CX bond cleavage Nu attack cycloaddition rearrangement electron transfer radical attack radical anion attack hydrogen transfer dimerization
Primary Product -C + H+ or n-C + H+ -A + H+ -A + B+ or -A+ + B -C + C+ -C + X+ Nu--A-B+ cycloaddition rearrangement -A-B or -A-B2+ R--A-B+ RA--A-B H--A-B+ (-A-B)22+
A C O, N, S, X A C C A A A A A A A A
B H H B C Si, Sn B B B B B B B B
Primary Product -C + H+ or n-C + H+ -A + H+ -A + B+ or -A+ + B -C + C+ -C + X+ Nu--A-B+ cycloaddition rearrangement -A-B or -A-B2+ R--A-B+ RA--A-B H--A-B+ (-A-B)22+
Thermochemical Cycle: Calculating pKas
R-H
!G[pKa(RH+)]
R + H+
Eox(RH) !G[pKa(RH)]
Eox(R)
R-H
R + H+
G = nF[Eox(RH) Eox(R)]
pKa(RH+) = G/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
HB+
R-H PhCH2CN PHCH2SO2Ph Ph2CH2 PhCH3 indene (3-H) CpH uorene (9-H) C5Me5H
pKa (-RH+) 32 25 25 20 18 17 17 6.5
pKa (-RH) 21.9 23.4 32.2 43 20.1 18.0 22.6 26.1
reference a b c c d c,e f 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 Me Ph O Me
Me
HB+
R-H
Me O Ph Me Et O Ph Et
O Ph H N O
2
pKa (RH+)
pKa (RH)
13
N
27.9
11
N
27.0
11
24.4
Bordwell, F. G.; Zhang, X. J. Org. Chem. 1992, 57, 4163.
Secondary Reactions
Secondary Reactions play a major role in radical cation chemistry.
Code Rox Rred Rrad Radd.ox Radd.red RRA
Secondary Rxn R R R+ R
Product cation anion various cation anion anion
Oxidation System anode, chemical PET all anode, chemical PET PET
typical radical behavior R + C=C R + C=C RCC RCC RCC+ RCC
R + R
RR
-RH+ Deprotonation
-RH+ deprotonation followed by a secondary reactivity pathway (benzylic radical)
Me O
Me O
Me O
anode, MeOH DCM, NaClO4 2,6-lutidine 95%
anode
H
MeO
MeO
MeO
B
Me O MeO H MeO Me O
MeOH
Me O
MeO
MeO
MeO
Ponsold, K.; Kasch, H. Tetrahedron Lett. 1979, 4463.
Determining n vs Electrophores
Consider the ionization potential of the separate n- and - moieties

H N H
NH3 9.24 eV 10.17 eV
7.69 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 (-amino radical)
Me N Me
Me
OH
H H H
anode, MeOH KOH, 73%
n donor
Me N OMe
Me N
Me 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
NH2
H N H
anode
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.
-CH+ Deprotonation
Deprotonation of the radical ion pair happens by the solvent
NC
CN
h!, 81% MeCN MeCN

H
NC
CN
NC
CN
NC
CN
Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.
-CH+ Deprotonation
Deprotonation of the radical ion pair happens by the solvent
NC
CN
h!, 81% MeCN MeCN

H
NC
CN
NC
CN
NC
CN
Adm
CN
NC Adm
CN
NC
CN
NC
CN
NC
CN
NC
CN
Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.
-AH+ Deprotonation
-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.
anode, MeOH
HO
OMe
MeCN, 69%
Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.
-AH+ Deprotonation
-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.
anode, MeOH
HO
MeCN, 69%
MeCN
HO
HOMe
O OMe
H+
Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.
-AH+ Deprotonation
Reaction at the ortho-position can also occur
TEMPO-modified anode
OH
OH OH
()-sparteine, 91%
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 H
NHPh
Th+ ClO4 MeCN
Ph H N
NHPh Me
e 2H+
Ph N
N NPh 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 Product -C + H+ or n-C + H+ -A + H+ -A + B+ or n-A + B+ -C + C+ -C + X+ Nu--A-B+ cycloaddition rearrangement -A-B or -A-B2+ R--A-B+ RA--A-B H--A-B+ (-A-B)22+
-A-B+ Bond Dissociation
Dienolether has a lower oxidation potential than the enolether

O H O Me
OTMS Me3Si O Me
Ce(NH4)2(NO3)6 MeCN, 77%
e SiMe3+
Me3Si O O H CH2 Me H
SiMe3+ e
OTMS O Me OTMS
Eventhough [O] may happen at n (lone pairs), the resonance structure affords the -oxidized product.
Ruzziconi et al. Tetrahedron Lett. 1993, 34, 721.
-A-B+ Bond Dissociation
Certain MukaiyamaMichael reactions are postulated to operate via a radical cation initiated fragmentation
O Ph
Me Me Me Me
OTES OEt
OTES OEt
LA DCM , 78 C
Ph
O Me
Me O OEt Me Me
Lewis Acid Bu2Sn(OTf)2 SnCl4 Et3SiClO4 TiCl4
44 product 85 95 93 97
42 product 0 0 0 2.4
Product ratio 100:0 100:0 100:0 97:3
J. Otera et al. J. Am. Chem. Soc. 1991, 113, 4028.
MukaiyamaMichael Proposed Catalytic Cycle
Et3SiO Me Ph
Me O OEt Me Me
catalyst regeneration
O Me Me
SnCl4
Ph
Et3SiCl
Cl3Sn
O O Me Me Me Me OEt Ph O
SnCl4 Me
RR coupling
Ph
complexation
Me
SnCl3 O Ph Cl Me Me Me Me OTES OEt Me Me OTES OEt
Et3SiCl
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 N N Me Me OH N N Me Me OH
h!, DCA Ph2
N2
Me OH Me
Me
BET
Me
Adam, W.; Sendelbach, J. J. Org. Chem. 1993, 58, 5316.
-C-C+ Bond Dissociation
Fragmentation of a -ether generates an oxocarbenium ion
MeO NC CN
MeO
MeO
HOMe
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!, DCB collidine, MeCN
N.R.
R O Me H Ph
Me H
h!, DCB collidine, MeCN
Ph
Me
Me H O
Me
Ph
"*
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.
Nucleophile assisted CC bond fragmentation with complete inversion of stereochemistry
HOMe
Ph Ph Me D
h!, 1-CN MeCN, MeOH
Ph Ph
Me D
H+
Ph Ph Me
OMe D
1-CN
H+
Ph Ph Me
OMe D
Nucleophile assisted -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
N N H
anode, 2,6-lutidine
Et
N N H N H
CO2Me
MeCN, Et4NClO4
CO2Me
Et
CO2Me
Et
Et
NaBH4
H N H V CHO2Me N H V
N N CO2Me Et
CO2Me Et
Et AcO N H MeO2C OH Me OMe
M. J. Gai et al. J. Chem. Soc. Chem. Comm. 1993, 1496.
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
N N H
anode, 2,6-lutidine
Et
N N H N H
CO2Me
MeCN, Et4NClO4
CO2Me
Et
CO2Me
Et
Et
NaBH4
H N H V CHO2Me N H V
N N CO2Me Et
CO2Me Et
Et AcO N H MeO2C OH Me OMe
M. J. Gai et al. J. Chem. Soc. Chem. Comm. 1993, 1496.
TCB
Me
O O Me
OH
TCB, h! RSH, H2O, 90%

AcO AcO O
Easily oxidized acetal

Me O O O AcO
TCB
Me
AcO
H2O O
A. Albini et al. Tetrahedron Lett. 1994, 50, 575.
Cl3Fe
Me3SiO
Cl
FeCl3, DMF 64%
Me3SiO
SiMe3
ESR studies on strained systems show that the inner C-C bond is selectively weakened
Trapping of the pendant olen and Cl abstraction form the bicycle
Booker-Milburn, K. I. Synlett 1992, 809.
-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 PhCH2SiMe3+ PhCH2Cl+ PhCH2Br+ PhCH2OMe+ PhCH2SMe+ PhSXan+ PhSTPCP+ PhCH2 + Me3Si+ PhCH22+ + Cl PhCH22+ + Br PhCH22+ + OMe PhCH22+ + SMe PhS + Xan+ PhS + TPCP+
HR(p-C-X+) BDE kcal/mol

+30 +40 +26 +43 +38 11 18.6
HR(p-C-X) BDE kcal/mol

+77 +72 +58 +71 +61 +26.4 +40.3
Ref a b b b b c c
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.
-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 MeOH, 91%
OMe
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 k on MeOH, H2O, Bu4NF indicates Nu-assisted Si-bond cleavage
SiMe3
anode, Et4NOTs MeOH, 91%
OMe
ClO4
Me SiMe3
h!, MeCN 70%
Me SiMe3
Me3
Si+
Me
Me
Iminium salts can act as photooxidants under PET conditions
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
SiMe3
Bn4NBF4, DCM anode, 78 C

BF4
N CO2Me
CO2Me
e
F
SiMe3
N CO2Me
CO2Me
F assisted CSi bond cleavage
J. Yoshida et al. J. Am. Chem. Soc. 2005, 127, 7324.
Cation pool oxidizes benzylsilane directly

OMe N CO2Me Me3Si OMe
DCM, 50 C 88%
N CO2Me
BF4
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 N CO2Me Me3Si Me
DCM, 50 C 12%
N CO2Me
BF4
1.55 V vs SCE
Cation pool oxidizes benzylsilane directly

OMe N CO2Me Me3Si OMe
DCM, 50 C 88%
N CO2Me
BF4
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 N CO2Me Me3Si Me
DCM, 50 C 97%
N CO2Me
BF4
1.55 V vs SCE
Bu3Sn
10 mol%
Me
Proposed Mechanism
Initiation
Me3Si OMe OMe Me3Si OMe BF4 N CO2Me N CO2Me
N CO2Me
Me3Si+
Me3Si OMe
Propagation Propagation
OMe
Stronger oxidant than iminium ion
N CO2Me
BF4
N CO2Me OMe
n-C-X+ Bond Dissociation

Me
SiMe3 N
DCN, h! i-PrOH, 90%
97:3 dr
O hexyl N OMe SiMe3 O N Me O O N Me O O
DCA, h!, 67% MeCn/MeOH
hexyl
OMe
SiMe3 O N Bn
H N
Bn
DCA, h! MeCN, 59%

N O
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.
ClO4
N Me
Ph
h!, 42%
SiMe3
MeCN
Ph
CO2Me
Me3Si+
N Me Ph SiMe3
Coupling of the radical cation to the oxidant is the prominent primary fate after -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.
Nu--A-B+
Moeller en route to ()-alliacol A
OTBS Me Me Me TBSO O O Me
anode, LiClO4 2,6-lutidine MeOH/DCM, 88%
Me Me TBSO O
Trauner en route to ()-guanacastepene E

Me Me Me Me Me OBn TBSO Me Me H TBDPSO O MeO H O OBn
anode, LiClO4 2,6-lutidine MeOH/DCM, 81%
Me
TBDPSO 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 NHOAc Me NHOAc
OH NOAc
H2O
H+
NOAc
H+ e
NOAc
Me
Me
Me
The authors do not rule out the possibility of olen oxidation as an alternative mechanism
Karady et al. Tetrahedron Lett. 1989, 30, 2191.
Nu-n-A-B+
AcOH
PTOC
Me
t-BuSH, 60%
O S N
PTOC =
Newcomb, M.; Deeb, T. M. J. Am. Chem. Soc. 1987, 109, 3163.
Nu-n-A-B+
AcOH
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.
Cycloaddition
Experimental kinetic data for radical cation cycloadditions (rt)

Reaction k [M1s1] comments Mostly [4 + 2] endo adduct; ratio of/to [2 + 2] varied by concentration 1) [2 + 2] terminated by C-H deprotonation 2) concerted reaction 1) concerted cycloaddition assumed 2) distonic 1,4-radical cation intermediate reference
3 x 108
Me Me
a, b
p-An p-An
<6.7 x 107 1) 1.4 x 109 2) 1.4 x 109 3) 1 x 1010
p-An p-An
c,d
p-An
7 x 108
21% DielsAlder adduct
p-An
Me
1.5 x 106
80% DielsAlder adduct
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.
DielsAlder [4 + 2] Cycloaddition
Shown to operate via a cation radical chain mechanism

DCM, 70% Ar3N
SbCl 5
H H
5:1 endo/exo
Suprafacial selectivity observed
DP + Ar3N+ DP+ + D
k = 3 x 108 [M1s1]
Ar3N + DP+ A+ A + DP+ dication H+ + DP

Propagation
A+ + DP 2DP+ DP+
Termination
Bauld et al. J. Am. Chem. Soc. 1981, 109, 3163. Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc. 1987, 109, 1157
DielsAlder [4 + 2] Cycloaddition
Shown to operate via a cation radical chain mechanism

DCM, 70% Ar3N
SbCl 5
H H
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 MeO
h!, MgSO4, 88% MeNO2, Ru(bpy)32+

O MeN NMe H O H
Concerted cycloaddition
MeO
e
O
+e
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

O H MeN NMe O H
6:1 dr
isomerization > cycloaddition

MeO MeO

O H MeN NMe O H
5:1 dr
Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572.
Claisen Rearrangement: A Representative Example
Though potentially powerful, the radical cation Claisen rearrangement has found very limited use in synthsis
OMe O
OMe
MeCN, 65% Ar3N

SbCl 5
OH
MeO
MeO
The radical cation Cope rearrangement seems to be limited to aryl substituted systems.
Venkatachalam et al J. Chem. Soc Chem. Commun. 1994, 511.

Both radical (Rad) and radical anion (RA) have been previously discussed
Symbol CH AH AB CC CX Nu CA R ET Rad RA H Dim Classication CH deprotonation AH deprotonation AB bond cleavage CC bond cleavage CX bond cleavage Nu attack cycloaddition rearrangement electron transfer radical attack radical anion attack hydrogen transfer dimerization Primary Product -C + H+ or n-C + H+ -A + H+ -A + B+ or n-A + B+ -C + C+ -C + X+ Nu--A-B+ cycloaddition rearrangement -A-B or -A-B2+ R--A-B+ RA--A-B H--A-B+ (-A-B)22+ A C O, N, S, X A C C A A A A A A A A B H H B C Si, Sn B B B B B B B B
Hydrogen Transfer
The HofmannLferFreytag reaction
NC homolysis
NCS, ether
NH N N H N N H H N
NEt3, h!, quant
Cl
H abstraction
H+
N Cl
H+
SN2 ring closure
Cl
Typically a 1,5-H-atom abstraction
Kimura, M.; Ban, Y. Synthesis 1976, 201.
Hydrogen Transfer
HO
OH
The HofmannLferFreytag reaction
Me
NH
NCS, DCM 0 C, 85%
Cl
Me
Me
Me
Me
Cl
h, TFA KOH, EtOH 39%
Me
Me
Me
Intermediate en route to the synthesis of kobusine
Kimura, M.; Ban, Y. Synthesis 1976, 201.
Radical Cations in Synthesis: Floreancig Lab
Epoxonium cyclization
Me O H O O O Me H
Bn OMe Me O Me O
O O
Ot-bu
h!, NMQPF6, O2 NaOAc, Na2S2O3 DCE, PhMe, 79%

MeO O
Cyclic acetal formation en route to theopederin D

OMe O Me O CbzHN Bn H O O Me OMe O
MeO
h!, NMQPF6, NaOAc, Na2SO3 DCE, PhMe, 76%

CbzHN O O H O O
Me Me OMe
2:1 dr
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 Moellers synthesis of nemorensic acid

Me Me S Me OH Me S
anode, 71% Et4NOTs MeOH/THF
Me O MeO S
Me S
Bogers synthesis of vinblastine

N N H N CO2Me N Et OH
Et
i. FeCl3, 2h ii. Fe2(ox)3NaBH4 air, 0 C, lutidine 43%

N H MeO2C MeO
Et OAc H Me HO CO2Me N
Et MeO OAc H Me HO CO2Me N
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 H R H R' R O O R'
!-arylation
!-enolation
SOMO-activated
O H O R' Bn N H R N H t-Bu R Me O R'
intramolecular !-arylation
!-vinylation
O H R
NO2 R' H
R'
!-nitroalkylation
!-allylation

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Radical Cations - +: Generation, Reactivity, Stability

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Radical Cations+: Generation, Reactivity, Stability

MacMillan Group Meeting 4-27-11 by Anthony Casarez

Three Main Modes to Generate Radical Cations

Photoinduced electron transfer (PET)

Electrochemical oxidation (anodic oxidation)

Stoichiometric oxidant: SET

Photoinduced Electron Transfer

PET: Organic arene

h!, MeCN, MeOH

PET: Metal mediated

anode, MeOH DCM, NaClO4 2,6-lutidine

Primary Fate of Radical Cations

Primary Fate of Radical Cations

Symbol CH AH AB CC CX Nu CA R ET Rad RA H Dim

Primary Fate of Radical Cations

Symbol CH AH AB CC CX Nu CA R ET Rad RA H Dim

Thermochemical Cycle: Calculating pKas

Nicholas, A. M. de P.; Arnold, D. R. Can. J. Chem. 1982, 60, 2165.

pKa (-RH+) 32 25 25 20 18 17 17 6.5

pKa (-RH) 21.9 23.4 32.2 43 20.1 18.0 22.6 26.1

Bordwell, F. G.; Zhang, X. J. Org. Chem. 1992, 57, 4163.

Secondary Reactions play a major role in radical cation chemistry.

Code Rox Rred Rrad Radd.ox Radd.red RRA

Product cation anion various cation anion anion

typical radical behavior R + C=C R + C=C RCC RCC RCC+ RCC

-RH+ deprotonation followed by a secondary reactivity pathway (benzylic radical)

anode, MeOH DCM, NaClO4 2,6-lutidine 95%

Ponsold, K.; Kasch, H. Tetrahedron Lett. 1979, 4463.

Consider the ionization potential of the separate n- and - moieties

NH3 9.24 eV 10.17 eV

HNMe2 7.17 eV 9.24 eV 8.24 eV

n-RH+ deprotonation followed by a secondary reactivity pathway (-amino radical)

anode, MeOH KOH, 73%

T. Shono et al. J. Am. Chem. Soc. 1982, 104, 5753.

Typical arene oxidation products are observed

Deprotonation of the radical ion pair happens by the solvent

h!, 81% MeCN MeCN

Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.

Deprotonation of the radical ion pair happens by the solvent

h!, 81% MeCN MeCN

Albini et al. J. Chem. Soc. Chem. Commun. 1995, 41.

-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.

Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.

-OH+ deprotonation is very prevalent while -NH+ deprotonations are rare.

Morrow, G. W.; Chen, Y. Swenton, J. S. Tetrahedron 1991, 47, 655.

Reaction at the ortho-position can also occur

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.

Th+ ClO4 MeCN

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 CH AH AB CC CX Nu CA R ET Rad RA H Dim

-A-B+ Bond Dissociation

Dienolether has a lower oxidation potential than the enolether

Ce(NH4)2(NO3)6 MeCN, 77%

Ruzziconi et al. Tetrahedron Lett. 1993, 34, 721.

-A-B+ Bond Dissociation

Lewis Acid Bu2Sn(OTf)2 SnCl4 Et3SiClO4 TiCl4

Product ratio 100:0 100:0 100:0 97:3

J. Otera et al. J. Am. Chem. Soc. 1991, 113, 4028.