REACTIVE INTERMEDIATES: CARBENES

CARBENES: Reactive 6-electron divalent carbon fragments R2C:

sp

ca. 32-42 kJ mol-1

R
R

Triplet

Singlet

RCR 130-150

RCR 100-110

H2C: = carbene = methylene = methylidene

R
H

N
= adamant-1-yl

R =
H

N
R
Isolable singlet carbene - Crystallographically
characterised.
(Wanzlick et al. 1970)
2p

C
sp2

Stable triplet carbene - half-life ca. 1 week in inert atmosphere.

(Iwamoto et al., 2004)

R2C .... M

Kinetically reactive transition metal 'carbenoid' of

uncertain structure. Involved in catalytic carbene
transfer. Structures generally unknown.

Br(CO)4Cr C

CH3
OCH3

Kinetically unreactive structurally characterised metal

carbene complex. Used as a stoichiometric (i.e. noncatalytic) carbene transfer reagent.

Relationship of carbenes to other reactive fragments:

X
C

- X

C:

C:

R+

Carbanion

+
C R
Carbocation

Loss of a leaving group from carbanionic carbon is one synthetic

pathway to carbenes.

The formal carbene-carbocation relationship

suggests that carbenes can also act as nucleophiles.

GENERATION OF CARBENES:
(1) -ELIMINATION OF HX OR X2 FROM AN ORGANIC HALIDE
X

- X, -Y

C:

Y
How do we know that a carbene is formed?

Base H2
C

CH3
Base,
- HCl

CH3

H2
C

Base
- HCl

CH3

C
H2

CH3

CH2Cl

C
H2

_
CHCl
- Cl-

Base, - HCl
-Elimination

CH3

H2
C

C
H2

CH:

-Elimination
H2
C

CH3

H+

H2
C

H2
C

C
H

C
H2

CH2

CD2Cl

Rearrangement

Base, - DCl
-Elimination

-Elimination

C
H

CD2

CH3

H2
C

C
H2

CD:

Rearrangement

CH3

H2
C

C
H

CHD

H 3C

H2
C

C
H2

CH2Cl

C6H5Na

H3C

H3C

C
H

C
H

CH2

94% a-Elimination
6% b-Elimination

NaOCH3
H2
C

H2
C

CH2

10% a-Elimination
90% b-Elimination

H 3C

H2
C

C
H2

CH2Cl

Base, - HCl
-Elimination

H H
C CH:
H3C C
H2

CH3
Insertion of carbene into
-CH bond.

Geuther (1862), Hine (1950):

HCCl3 + 4 NaOH

NaHCO2 + 3 NaCl + 2 H2O

NaOH + HCCl3

H2O + NaCCl3
NaCl + :CCl2

NaCCl3

RCH CHR

HCCl3
NaOH

RCH CHR
CCl2

Carbene generation via lithium-halogen exchange:

RLi+R1Br

RX + R1Li

The reaction of an organolithium compound with an organic halide is a

general one and proceeds - as you might expect - in the direction of
combining lithium with the most carbanion-stabilising organic group.
Starting with carbon tetrabromide it is a convenient route to
dibromocarbene:
LiBr

BuBr+LiCBr3

CBr4 + BuLi

:CBr2

elimination
Carbene generation via -elimination under mild non-basic conditions:
Thermolysis of sodium trichloroacetate:
O
Cl3C C

O Na+

CO2+NaCCl3

NaCl

:CCl2

The Simmons-Smith reaction:

OH

OH
CH2I2
Zn/Cu

CH2I2+Zn

CH2

:CH2+ZnI2

Although the active carbene transfer reagent is thought to be the zinc

carbenoid [I2Zn...CH2] it seems that the organozinc reagents ICH 2ZnI
and/or IZnCH2ZnI are formed first. Note the stereospecificity of the
reaction.

(2) -ELIMINATION OF N2 FROM DIAZO-COMPOUNDS

R1

+ _
C N N

R1

or h
or[M]

C:

+ N2

(i) p-TolSO2NHNH2, H+
(ii) Na, HOCH2CH2OH

RHC:

R2

R2

The Bamford-Stevens Reaction:

R-CHO

(p-Tol = 4-CH3C6H5; HOCH2CH2OH = ethylene glycol)

R-CHO + H2N-NH-SO2Tol-p

H+
RCH=N-NH-SO2Tol-p + H2O
p-Toluenesulphonylhydrazone

RCH=N-NH-SO2Tol-p

NaOR
- H+

RCH=NNSO2Tol-p

Acidic H, activated
by -sulphonyl group.
_
+
RCH=N=N + [SO2Tol-p]
p-Toluene
Diazoalkane
sulphinate
anion
_ +
RCHN N

RCH=NNSO2Tol-p

_
+
RCH=N=N
_ +
RCHN N

RHC: + N2

-Carbonyl diazo-compounds - Important precursors of -carbonyl

carbenes:
+ _
xs.CH2=N=N

RCOCl

RCOCl+

(Diazomethane)

+ _
RCOCH=N=N

+ _
CH2=N=N

_
+
CH2NN

_
+
CH2NN

+
RCOCH2NN+Cl
+ _
RCOCH=N=N+H+

+
RCOCHNN
H
_ +
CH2NN

+HCl

CH3Cl+N2

H
R

C + _
C
N
N
O

C +
C
N
N
_
O

Carbonyl
diazocompound
H
R

C +
C
N
N
_
O
Diazonium
enolate

Diazonium
enolate
,[Rh]
N2

H
R

O
Carbonylcarbene

REACTIONS OF CARBENES:
Carbenes are highly electron-deficient since the carbene carbon has only
6 electrons in the valence shell. Hence carbenes are highly electrophilic
species. This is reflected in the three major classes of carbene reactions.
(1) Carbene insertions
(2) Carbene additions
(3) Carbene rearrangements
Insertion into single bonds:
R1

C: +

R2

R1

A
B

R2

Addition to multiple bonds - formation of 3-membered rings:

R1
R2

C: +

R1

A
B

R2

Rearrangement (intramolecular insertion into a single bond):

R

R
C C

R
C C

R1

R1

C C

R1

A
B C

R1

B C

R1

CARBENE INSERTIONS INTO E-H BONDS:

R1

C: +

R2

R1

H
E

R2

E = C, Si, O, S, Se, F, Cl, Br

Simple carbenes are highly reactive and show little or no selectivity in

C-H insertion:
_
+
CH2=N=N + CH3CH2CH(CH3)2

Statistical distribution of
insertion products

Carbonyl carbenes are more selective:

EtOCOCH=N2

3 CH > 2 CH > 1 CH insertion

[Rh]

Intramolecular insertions also show enhanced selectivity:

NNHTs
Base,

2
3

- H2O

1,5-insertion
66%

TsNHNH2

1
5
4

1,3-insertion 1,2-insertion
10%
(Rearrangement)
22%

N.B. Ts = p-TolSO2-

Carbene C-H insertion in a natural product synthesis:

H 3C H
O

Ar
N2

[Rh]

CO2CH3

Ar

CH3

H
CO2CH3

Ar

CH3

CH3
CH3

-Cuparenone

Carbene insertion into an O-H bond:

O
CH3

[Rh]
CHN2

+ ROH

CH3

CH2OR

+ N2

Carbene insertion into an N-H bond - Merck industrial synthesis of a

-lactam antibiotic:
O
NH
O

N2 CO2R

[Rh]
C6H6

N
O

CO2R
Carbapenam

CARBENE ADDITION REACTIONS:

Cyclopropane synthesis:
C 6H 5
CHCl3
KOBut

C 6H 5

Cl
Cl

1 Eq. R3SnH
[In]

C 6H 5

Cl
H

1 Eq. R3SnH
[In]

C 6H 5

H
H

Metal-halogen
exchange

C6H5CHBr2 + n-BuLi

Li
C6H5CH

Br

-Elimination
- LiBr
C 6H 5
H

Cyclohexene

C6H5

C:

The stereochemistry of carbene addition to alkenes can be used as a test

of whether the carbene is reacting via the singlet or the triplet spin state:

Alkenes react with singlet carbene in a concerted fashion - alkene

stereochemistry is preserved in the cyclopropane product:

LUMO

HOMO

HOMO

LUMO
X
R

:CXY
R

Note that the parallel orientation of the planes of the interacting singlet
carbene and alkene are not what you would expect from the geometry of
the two fragments in the cyclopropane product.

LUMO

HOMO

HOMO

LUMO

If the fragments approach with what would intuitively be the 'correct'

orientation no net bonding will result.

Alkenes react with triplet (i.e. diradical) carbene in a stepwise fashion the alkene stereochemistry is lost in the cyclopropane product:

RAPID

R
H

H
H

Spin-flip: SLOW
Y

R
H

X
H
R

H
H

Y
R
H

H
R

Y
H
R

Carbene additions to arenes: 6

trienes:

7 ring-expansion to yield cyclohepta-

[Rh]

+ N2 CHCO2Et

CHCO2Et
Norcaradiene
Electrocyclic
rearrangement

CHCO2Et

Carbene additions to pyrrole - 5

6 ring-expansion to yield pyridines:

Cl
CHCl3/OHN
_

N
H
OH

N
_

Cl

:CCl2
CHCl3/OH-

- Cl

Cl

CARBENE REARRANGEMENTS:
Mechanism: 1,2 migration of hydride or a carbanion:
R
R1

R1

R3

R3
C

R2

R2

Migratory aptitude: R = H >> aryl > alkyl

Arndt-Eistert Reaction - homologisation of carboxylic acid derivatives:
RCO2H

SOCl2

xs. CH2N2

RCOCl

RCOCHN2

h, or [M]

RCH2COZ

HZ

Z = OH, OR, NR2 etc.

C C O

C:
C

O
Wolff Rearrangement
of an acylcarbene to a
ketene.

H2O
R

R
C C O

C C
H

+
OH2

OH

OH

OH
C C

C C
H H
O