REACTIVE INTERMEDIATES: CARBENES

CARBENES: Reactive 6-electron divalent carbon fragments R2C:

2 R ca. 32-42 kJ mol-1 R

sp C C
R R
Triplet Singlet
RCR 130-150 RCR 100-110
H2C: = carbene = methylene = methylidene

R
H N
R = = adamant-1-yl
H N
R

Isolable singlet carbene - Crystallographically

characterised.
(Wanzlick et al. 1970)

2p

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.

CH3
Br(CO)4Cr C
OCH3

Kinetically unreactive structurally characterised metal

carbene complex. Used as a stoichiometric (i.e. non-
catalytic) carbene transfer reagent.

Relationship of carbenes to other reactive fragments:

X _ - X R+ +
C C: C: C R

Carbanion 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 C:
Y

How do we know that a carbene is formed?

H2 _
C CHCl
CH3 C
Base - H+ H2 - Cl-

H2 H2
C CH2Cl Base, - HCl C CH:
CH3 C -Elimination CH3 C
H2 H2
Base, -Elimination
- HCl

H2
C CH2
CH3 C Rearrangement
H

H2 H2
C CD2Cl Base, - DCl C CD:
CH3 C CH3 C
H2 -Elimination H2
Base
- HCl -Elimination Rearrangement

H2 H2
C CD2 C CHD
CH3 C CH3 C
H H
 H2 H2
C CH2Cl C6H5Na C CH2
H 3C C H3C C
H2 H
94% a-Elimination
NaOCH3
6% b-Elimination

H2
C CH2
H3C C
H
10% a-Elimination
90% b-Elimination

H2 H H
C CH2Cl Base, - HCl C CH:
H 3C C -Elimination H3C C
H2 H2

CH3
Insertion of carbene into
-CH bond.

Geuther (1862), Hine (1950):

HCCl3 + 4 NaOH NaHCO2 + 3 NaCl + 2 H2O

NaOH + HCCl3 H2O + NaCCl3

NaCCl3 NaCl + :CCl2

HCCl3
RCH CHR RCH CHR
NaOH
CCl2
Carbene generation via lithium-halogen exchange:

RX + R1Li RLi+R1Br

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
CBr4 + BuLi BuBr+LiCBr3 :CBr2
elimination

Carbene generation via -elimination under mild non-basic conditions:

Thermolysis of sodium trichloroacetate:

O
NaCl
Cl3C C CO2+NaCCl3 :CCl2
O Na+
The Simmons-Smith reaction:
OH OH

CH2I2
CH2
Zn/Cu

CH2I2+Zn :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 + _ R1
or h
C N N C: + N2
or[M]
R2 R2

The Bamford-Stevens Reaction:

(i) p-TolSO2NHNH2, H+
R-CHO RHC:
(ii) Na, HOCH2CH2OH

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

H+
R-CHO + H2N-NH-SO2Tol-p
RCH=N-NH-SO2Tol-p + H2O
p-Toluenesulphonylhydrazone

NaOR
RCH=N-NH-SO2Tol-p RCH=NNSO2Tol-p
- H+

Acidic H, activated
by -sulphonyl group.
_
+
:

RCH=NNSO2Tol-p RCH=N=N + [SO2Tol-p]

p-Toluene
Diazoalkane
sulphinate
_ _ + anion
+
RCH=N=N RCHN N
_ +
RCHN N RHC: + N2
-Carbonyl diazo-compounds - Important precursors of -carbonyl
carbenes:

+ _
xs.CH2=N=N + _
RCOCl RCOCH=N=N
(Diazomethane)
_
+ _ +
CH2=N=N CH2NN

_ + +
RCOCl+ CH2NN RCOCH2NN+Cl

+ + _
RCOCHNN RCOCH=N=N+H+
H

_ +
CH2NN +HCl CH3Cl+N2

H H
R C + _ R C +
C N C N
N _ N
O O

Carbonyl Diazonium
diazocompound enolate

H H
R C + ,[Rh] R C
C N C
_ N N2
O O
Diazonium Carbonylcarbene
enolate
 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 A R1 A
C: + C
B B
R2 R2

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

R1 A R1 A
C: + C
B B
R2 R2

Rearrangement (intramolecular insertion into a single bond):

R R A A
C C C C B C B C
R1 R1 R1 R1

R R1
C C
CARBENE INSERTIONS INTO E-H BONDS:
R1 H R1 H
C: + C
E E
R2 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:
O NNHTs

:
TsNHNH2 Base, 1
2
3 5
- H2O 4

1,5-insertion 1,3-insertion 1,2-insertion

66% 10% (Rearrangement)
22%

N.B. Ts = p-TolSO2-
Carbene C-H insertion in a natural product synthesis:

H 3C H
O O O
Ar [Rh]
H
N2 CO2CH3 CO2CH3 CH3
Ar Ar CH3
CH3 CH3
-Cuparenone

Carbene insertion into an O-H bond:

O O
[Rh]
C + ROH C + N2
CH3 CHN2 CH3 CH2OR

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

-lactam antibiotic:

O
[Rh]
O
NH N
C6H6
O O
N2 CO2R CO2R
Carbapenam
CARBENE ADDITION REACTIONS:

Cyclopropane synthesis:

C 6H 5 C 6H 5 C 6H 5
CHCl3 Cl 1 Eq. R3SnH Cl
KOBut Cl [In] H

1 Eq. R3SnH
[In]
C 6H 5
H
H

Li
Metal-halogen
C6H5CHBr2 + n-BuLi C6H5CH
exchange
Br
-Elimination
- LiBr
C 6H 5

H Cyclohexene C6H5
C:
H

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 Y
R :CXY
R R 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:

X RAPID X
Y Y
X H R R H
Y R H H H H R
R R

Spin-flip: SLOW

X X
Y Y
R H
H H H R
R R

X Y X Y

H R H H
R H R R
Carbene additions to arenes: 6 7 ring-expansion to yield cyclohepta-
trienes:

[Rh]
+ N2 CHCO2Et CHCO2Et

Norcaradiene

Electrocyclic
rearrangement
CHCO2Et

Carbene additions to pyrrole - 5 6 ring-expansion to yield pyridines:

Cl
Cl
CHCl3/OH- - Cl -
Cl
N N
_ N
H

OH
:CCl2

CHCl3/OH-
N
_
CARBENE REARRANGEMENTS:
Mechanism: 1,2 migration of hydride or a carbanion:
R R1 R3
R3
C C C C
R1 R2 R
R2

Migratory aptitude: R = H >> aryl > alkyl

Arndt-Eistert Reaction - homologisation of carboxylic acid derivatives:
SOCl2 xs. CH2N2
RCO2H RCOCl RCOCHN2

h, or [M]

H
R R C:
RCH2COZ HZ
C C O C
H
Z = OH, OR, NR2 etc. O

Wolff Rearrangement
of an acylcarbene to a
ketene.

H2O
+
R R OH2 R OH
C C O C C C C
H H O H OH

R OH
C C
H H O