Carbenes and Carbene Complexes

Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis

1

Carbenes and Carbene Complexes IIntroduction

• 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...

R

R

Free Carbenes

R

C

R

carbene singlet carbene

triplet carbene

representation

• 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

R2

[M]δ+ δ– R1

R2[M]δ+δ–

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)

R CR

R CR

p-orbital

sp2


2

Free Carbenes

• One very common reaction for free carbenes: cyclopropanation

Cl3C H OH

CHCl3, NaOH

Cl ClCl

O

OBn

BnO

BnO

O

OBn

BnO

BnO

Cl

Cl

Mechanism

Cl Cl

Cl Cl

O

OBn

BnO

BnO

ClCl

O

OBn

BnO

BnO

Cl

Cl

O

OBn

BnO

BnO

• carbene approaches from least hindered

face

• concerted reaction with ALL bonds made and broken at same

time

• hydrolysis of chloroform

• Can be used in the ring expansion of aromatic compounds

OMeCl

O

Cl Cl

Mechanism

O

ClCl

Me

Cl

O

Me Cl

Cl

O

• 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


3

Fischer Carbene Complexes

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

R2

XR1

LnM

R2

XR1

LnMδ+δ–

X = heteroatom (O, S, N)

Preparation

• The most common means to synthesise Fischer carbene complexes is from metal carbonyl compounds

(OC)5Cr CO + R Li(OC)5Cr R

O

(OC)5Cr R

O

(OC)5Cr R

OR2

(OC)5Cr R

OCOCH3R2OH

CH3COBrhard alkylating agent

• eg. Me3O+BF4

– or R2OTf

• addition / elimination mechanism

• They are also readily prepared from acyl halides

ClCl

O K2[Cr(CO)5]

(OC)5CrCl

O

(OC)5CrO

Use in Synthesis

• As the complexes are electrophilic on carbon they behave in an analogous manner to carbonyls

Nucleophilic Substitution

Ph OMe

Cr(CO)5

Li (OC)5Cr

Ph OMePh Ph

Cr(CO)5HCl

H

Aldol-like Reaction

HOMe

Cr(CO)5

R

OMe

Cr(CO)5

R

Base

• remarkably stable

• pKa ≈ 8

• electrophilic at carbon

• delocalisation stabilises complex


4

Et OMe

Cr(CO)5

OMe

Cr(CO)5

Me

MeO

(CO)5Cr

Ph

OHBuLi PhCHO

(OC)5Cr

R2

OMe

R1O

(OC)5Cr

OMe

O

R1

R2

Michael Reaction

Li

Diels–Alder Reaction

(OC)5Cr

OMe+

(OC)5Cr OMe

• reacts 104 x faster than acrylate

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

O

O

W(CO)5H

H

O

O

OH

H

[O]

[O] = CAN, DMSO, air

C–Sn Bond Formation

• The conversion of the carbene complexes to an alternative organometallic reagent allows a variety of further elaborations to be achieved

O

O

H

HW(CO)5 Bu3SnOTf, Et3N

O

O

H

HSnBu3

O

O

H

HW(CO)5

H O

O

H

HW(CO)5

SnBu3

O

O

H

HSnBu3

Mechanism

Bu3Sn OTf

base

reductive elimination

• can be used in the Stille reaction,

transmetallation etc


5

Dötz Reaction

(OC)5Cr

OMe Rbig

Rsmall

50 ˚C

– 1 CO

OH

Rbig

Rsmall

OMe(OC)3Cr

+

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

Mechanism

• The mechanism is still contraversial• Two possible mechanisms• Give the most commonly quoted

OMe

Cr(CO)5

OMe

Cr(CO)4

OMe

Cr(CO)4

Rbig

smallR

Cr(CO)4

OMe

Rbig

Rsmall

Rbig Cr(CO)4

Rsmall

OMe

Rbig

Rsmall

OMe

O

(OC)3Cr

OMe

Rsmall

Rbig

O

(OC)3Cr OMe

Rsmall

Rbig

OH

(OC)3Cr

– CO

Rbig Rsmall

ligand dissociation

alkyne co-ordination

[2+2]-like

η3-vinylcarbene complexCO

insertion

cyclisation

aromatisation

• rate determining step

• regiochemistry has the largest substituent facing

away from carbene

• reduced steric hinderance

• η4-complex


6

Cr(CO)3

Work-up

O

OMe

(OC)5Cr

Et

Et

+

45 ˚C, THF

O

OH

Et

Et

OMe

O

OH

Et

Et

OMe

O

O

Et

Et

MeO OMe

air or FeCl3decomplexation MeOH

CAN (Ce(NH4)2(NO3)6

oxidation

O

O

Et

Et

O

Use in Synthesis

OMOM

MOMO

MeOCr(CO)5

OMe

NEtO

BnOTBSO

OTBS

NEtO

BnOOTBS

MeO

MOMO

MOMO

OMe OTBS

OH

NH

O

O

MeO

OH

OH O

O

HO

O

+

50 ˚C, 35 %

5 steps33 %

fredericamycin A


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Schrock Carbene Complexes

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

R2

R1

M ≡ M 2+ 2–

R2

R1

• The most common examples are:

TiH

TiMe

Me≡ Ti via α–elimination

Petasis' Reagent

Ti

H2C

ClAl

Me

Me

NR3Ti

Tebbe's Reagent

N

Mo

iPr

iPrPh

(F3C)2MeCO(F3C)2MeCO

PCy3

Ru

PCy3

Cl

Cl R

Schrock's CatalystGrubb'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 R2

O reagent

R1 R2

R3

• 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


8

Methylenation

Ti

H2C

ClAl

Me

Me

NR3Ti

δ–δ+ XR

O

TiO

R

XTi O

XR

• remember Schrock carbene complexes are nucleophilic at carbon

• titanium highly oxo-philic

• like Wittig driving force is forming M=O

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

[2+2] cycloaddition

O O

OR

OR

RO

RO O

OR

OR

RO

RO

PhO

TBS

O

PhO

TBS

Tebbe

Petasis

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....

O

O

O

O

BnO

HTiCp2

O

O

O

O

BnO

H

Cp2Ti

O

TiCp2

O

O

O

BnO

H

O

O

TiCp2

OOH

BnO

H

HO

OH

H

OH

BnO

4 equiv Tebbe

reagent

• olefin metathesis

• a higher alkylidene complex

• olefination


9

Alkene Metathesis

• The process in which two alkenes exchange their alkylidene fragments

R + Rmetathesis

catalyst RR +

• 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

δ–δ+

RR

LnM CH2 LnM

R R

LnM

R

LnM

R

R

LnM

R RR

LnM CH2R

RR

[2+2]

[2+2]cyclo-

reversion

cyclo-reversion

• co-ordination between metal and alkene

Scope and Limitations of Catalysts

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

N

Mo

iPr

iPrPh


PCy3

Ru

PCy3

Cl

Cl R

Schrock's CatalystGrubb'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


10

Ring-Opening Metathesis Polymerisation (ROMP)

• Industrially important in the production of polymers

LnMR

MLnR

MLnR

MLn

R

R

n

LnM R

• 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

LnM

MLn

MLnLnM

LnM

+

• driving force often the generation of a volatile alkene

Synthetic Applications

OO

MeO2C CO2Me

OO

H

H

N

Mo

iPr

iPrPh


20 ˚C, 2 hrs, 91 %

• good functional group tolerance


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O

N

S

OO

HO

OR

O

N

S

OO

HO

OR

O

[Ru]85 %

epothilone A

• RCM capable of forming large rings from highly functionalised precursors

• no need to protect alcohol with [Ru] catalyst • internal alkene

not harmed

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

Ocat. 2 % (5 min.)

OH

99 % e.e.

N

MoO

O

iPriPr

PhPh

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

Carbenes and Carbene Complexes

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