Carbenes and Carbene Complexes I

Introduction
A very interesting (honest) class of radical-like molecules
Steadily becoming more important as they find far more synthetic applications
We will primarily concentrate on their synthetic uses and not a theoretical treatment of their
structure and reactivity.
Having said that we do need to look at some of the basics...
Free Carbenes
p-orbital
R

R
R

carbene

triplet
carbene

sp 2

representation

singlet
carbene

A carbene is a divalent carbon species linked to two adjacent groups by a covalent bond
It possess two non-bonding electrons and six valence electrons
If the non-bonding electrons have anti-parallel spins then singlet carbene
If the non-bonding electrons have parallel spins in different orbitals then triplet carbene
Generally carbenes are expected to be triplet carbenes (Hund's rule) but substituents can
change this and in organic chemistry we normally use singlet carbenes
They are electron deficient like carbocations
But they possess a non-bonding pair like carbanion hence can be represented as shown
above
The nature of substituents R have profound effects on the electronics of the carbenes and
their reactions
Carbene Complexes
Carbenes can be stabilised by complexation with transition metals
Two extremes are known (as well as the whole spectrum inbetween)
R1 +
[M]

R1
+
[M]

R2

R2

Fischer carbenes

Schrock carbenes

Carbene complexes of low valent / low oxidation state 18 e metals are electrophilic at
carbon and are called Fischer carbenes (often behave like a glorified carbonyl group)
Carbene complexes of high valent / high oxidation state <18 e metals are nucleophilic
at carbon and are called Schrock carbenes

Carbenoids
A slightly confusing class of compounds
Includes intermediates that exhibit reactions similar to carbenes without necessarily having
any structures defined previously
For the purposes of this course we will limit ourselves to the following:
Decomposition of diazo-compounds in the presence of Rh, Cu, Pd (Next lecture)

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Free Carbenes
One very common reaction for free carbenes: cyclopropanation
OBn
CHCl3, NaOH

BnO
BnO

carbene approaches
from least hindered
face
Cl

OBn
BnO
BnO

Cl

Mechanism
hydrolysis of
chloroform

Cl3C H

Cl

OH

Cl

Cl

Cl

Cl

BnO

Cl

Cl

OBn

BnO
concerted reaction
with ALL bonds made
and broken at same
time
OBn

OBn

BnO
BnO

BnO

Cl

BnO

Cl

Cl

Cl

Can be used in the ring expansion of aromatic compounds

OMe

Cl
Cl

Cl
O

Mechanism
Cl
Cl
O Me

Cl

Cl
O

O
Me

Cl

Although free carbenes can be used in a number of other transformations they find little
use these days have been replaced by the more selective carbene complexes and
carbenoids
Big problem is the harsh conditions required to form them

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Fischer Carbene Complexes

Emphasize that this is a simplified view as we are interested in their use in organic synthesis

LnM

XR1
+

XR1

delocalisation
stabilises complex

LnM

R2

R2

X = heteroatom (O, S, N)

electrophilic at
carbon

Preparation

The most common means to synthesise Fischer carbene complexes is from metal carbonyl
compounds
O
(OC) 5Cr

CO

Li
(OC) 5Cr

eg. Me3O+BF4
or R2OTf

(OC) 5Cr

hard alkylating
agent

CH3 COBr

OR2
(OC) 5Cr

OCOCH3

R2OH
(OC) 5Cr

addition / elimination
mechanism

They are also readily prepared from acyl halides

O

K 2[Cr(CO)5]
Cl

Cl

O
(OC) 5Cr

Cl

(OC) 5Cr

Use in Synthesis
As the complexes are electrophilic on carbon they behave in an analogous manner to
carbonyls
Nucleophilic Substitution
Cr(CO)5
Ph

Cr(CO)5

HCl
Li

(OC) 5Cr

OMe

Ph

OMe

Ph

Ph

Aldol-like Reaction
Cr(CO)5
pK a 8

Cr(CO)5

Base

OMe

OMe

remarkably stable

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Cr(CO)5

Cr(CO)5
Et

BuLi

(CO) 5Cr

PhCHO
OMe

OMe

OH

MeO

Ph

Me

Michael Reaction
Li

OMe

R1

(OC) 5Cr

O
OMe
(OC) 5Cr
R1

R2

reacts 10 4 x faster
than acrylate

DielsAlder Reaction
OMe

(OC) 5Cr

(OC) 5Cr

OMe

Demetallation
Of course to be of any use the metal needs to be readily removed
Heteroatom substituted Fischer carbene complexes are rather stable
Still a number of ways of achieving it
Oxidation
H

W(CO)5

[O]

O
O

O
O

[O] = CAN, DMSO, air

CSn Bond Formation

The conversion of the carbene complexes to an alternative organometallic reagent allows

a variety of further elaborations to be achieved
H

H
O

W(CO)5

Bu3SnOTf, Et3 N
O

SnBu3

H
can be used in the
Stille reaction,
transmetallation etc

Mechanism
Bu3Sn

OTf
H

W(CO)5

O
base

SnBu3
O

W(CO)5

reductive
elimination
O

SnBu3

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Dtz Reaction
There are very few reliable methods for the construction of substituted benzenes
A very valuable example is the Dtz benzannulation
Proceeds in one step with predictable regiochemistry
OMe

OH

Rbig

Rbig

50 C

(OC) 5Cr

+
Rsmall

1 CO

Rsmall

(OC) 3Cr

OMe

Mechanism
The mechanism is still contraversial
Two possible mechanisms
Give the most commonly quoted
regiochemistry has the
largest substituent facing
away from carbene

rate
determining step

Rbig
CO

Cr(CO)5
OMe

Cr(CO)4
OMe

ligand
dissociation

Rbig

Rsmall

alkyne
co-ordination

smallR

Cr(CO)4
OMe

4 -complex
[2+2]-like

R big

CO
insertion

(OC) 3Cr

R big

3
Cr(CO)4 -vinylcarbene
complex

R small

R small

R big
Cr(CO)4
R small

OMe

OMe

OMe

reduced steric
hinderance
cyclisation

O
R big
R small
(OC) 3Cr

OH
aromatisation

OMe

R big
R small
(OC) 3Cr

OMe

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Work-up
OMe

Et

(OC) 5Cr

+
O
Et
45 C,
THF
OH
Et

O
OMe

air or FeCl3
decomplexation

Et
Cr(CO)3

CAN
(Ce(NH4) 2(NO3) 6
oxidation

MeOH

OH

O
Et

Et

Et
MeO

OMe

Et

OMe

Use in Synthesis

OTBS

MOMO

Et

Et

OMe

MeO

Cr(CO)5

TBSO
BnO

EtO

OMOM

50 C,
35 %
MOMO

OMe

OTBS

MeO

OH

OH

O
HO

MeO

MOMO

OH

5 steps
33 %

OTBS
BnO
EtO

N
H

fredericamycin A
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Schrock Carbene Complexes

Unlike the Fischer complexes, Schrock complexes do not have a heteroatom to
stabilise "carbocationic" character and are nucleophilic at carbon
R1

R1

M
R2

2+

R2

The most common examples are:

Ti

Me
Me

via elimination

Ti

Ti

Petasis' Reagent
H2
Me
C
Ti
Al
Cl
Me

NR3

Ti

Tebbe's Reagent
iPr
Cl
Cl

PCy3
Ru
PCy3

N
R

iPr Mo
(F3C) 2MeCO
(F3C) 2MeCO

Grubb's Catalyst

Ph

Schrock's Catalyst

Synthetic Applications of Schrock Carbene Complexes

Schrock carbene complexes play a key role as both reagents and catalysts in organic synthesis
They have found widespread application as intermediates in the preparation of organometallics
We will concentrate on just two applications: olefination and alkene metathesis

Carbonyl Olefination

R1

R3

reagent

O
R2

R1

R2

Last year you met the Wittig and related reactions as well as the Peterson olefination
Some Schrock carbene complexes can also achieve this transformation
Titanium complexes (like Tebbe's or Petasis' reagent) can olefinate a wider range of
substrates than the Wittig reaction
They are also far less basic so can be used on more sensitive compounds

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

 remember Schrock
carbene complexes are
nucleophilic at carbon

Methylenation

H2
Me
C
Ti
Al
Cl
Me

titanium highly
oxo-philic

X
O

like Wittig driving

force is forming M=O

Ti

+
Ti

NR3

[2+2]
cycloaddition

Ti
O

X = H, R, OR, NR2
So much more versatile than Wittig
RO

RO

Tebbe
RO

RO

OR

OR

OR

O
Ph

OR

Petasis
O

Ph

TBS

TBS

Disadvantage
Probably the biggest disadvantage of such reagents is that it is very hard to transfer
anything other than methylene
A number of examples of higher order alkylidene reagents have been reported but they are
difficult and expensive to prepare
There are one or two exceptions and we will use one to introduce the next topic....
BnO

BnO
O

TiCp2

4 equiv
Tebbe
reagent

a higher
alkylidene
complex

O
O

BnO
O

TiCp2

Cp2Ti
olefination

olefin metathesis
BnO
H

BnO
H

O
H

O
O

H
O

TiCp2
H

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

O
O

Alkene Metathesis
The process in which two alkenes exchange their alkylidene fragments
+

metathesis
catalyst

+
volatile so drives
reaction to completion

The process has found extensive use in both academia and industry
Again we will concentrate on two variations:
Ring-Opening Metathesis Polymerisation (ROMP)
Ring-Closing Metathesis (RCM)
General Mechanism
LnM

CH2

R
R

co-ordination between
metal and alkene
LnM

LnM

R
+
LnM CH2

cycloreversion

LnM

[2+2]

CH2
R

cycloreversion

LnM
R

[2+2]
R

LnM
R

Scope and Limitations of Catalysts

The two most commonly employed catalysts by organic chemists are Schrock catalyst [Mo]
and Grubb's catalysts [Ru]

iPr
Cl
Cl

PCy3
Ru
PCy3

N
R

iPr Mo
(F3C) 2MeCO
(F3C) 2MeCO

Grubb's Catalyst

Ph

Schrock's Catalyst

Schrock's catalyst functions efficiently with terminal and internal alkenes

Grubb's catalyst is less reactive, it works with terminal alkenes and only slowly, if at all, with
internal
[Mo] is stable in inert conditions (away from oxygen or protic solvents)
[Ru] is stable on the open bench

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

Ring-Opening Metathesis Polymerisation (ROMP)

Industrially important in the production of polymers
R
LnM

MLn

LnM

MLn

MLn
R
n

By 1990 12,000 tonnes a year of this polymer was made by ROMP

Ring-Closing Metathesis (RCM)

Over the last decade there has been a dramatic increase in the use of RCM for synthesis
Reason for this is that the catalysts show good functional group tolerance
Operate under mild conditions
Readily prepare medium to large ring sizes which is notoriously hard to achieve
driving force often the
generation of a volatile alkene
Ln
M

LnM

LnM

MLn

MLn

Synthetic Applications
good functional
group tolerance

iPr

O
O

iPr Mo
(F3 C)2 MeCO
(F3 C)2 MeCO

20 C, 2 hrs,
91 %
MeO 2C

Ph

OH

CO2Me

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

10

 RCM capable of forming large rings from highly functionalised precursors

no need to protect
alcohol with [Ru] catalyst

internal alkene
not harmed
O
S

HO

[Ru]
85 %

S
HO

N
O

O
O

OR

OR

epothilone A
Of course, no lecture would be complete without an example of an asymmetric variant
A desymmetrisation strategy

iPr

iPr

cat. 2 % (5 min.)

Mo
O
O

Ph
Ph

99 % e.e.

What have we learnt?

The basic characteristics of carbenes
That carbenes can be divided in to a number of classes
Basic reactions of free carbenes
Use of Fischer carbenes
The use of Schrock carbenes and olefination and metathesis

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

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