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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 C sp 2 R R C R R R C

carbene

triplet carbene

singlet 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 + [M] R2 R1 + [M] 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 BnO BnO CHCl3, NaOH BnO BnO OBn carbene approaches from least hindered face Cl Cl

Mechanism
hydrolysis of chloroform OBn Cl3C H OH Cl Cl Cl BnO BnO concerted reaction with ALL bonds made and broken at same time OBn BnO BnO Cl O Cl BnO BnO OBn Cl Cl Cl Cl

Cl

Cl

Can be used in the ring expansion of aromatic compounds


OMe Cl Cl Cl O

Mechanism
Cl Cl O 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

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
XR1 + R2 XR1 LnM R2 delocalisation stabilises complex

LnM electrophilic at carbon

X = heteroatom (O, S, N) Preparation

The most common means to synthesise Fischer carbene complexes is from metal carbonyl compounds
O (OC) 5Cr CO O R (OC) 5Cr CH3 COBr R2OH (OC) 5Cr addition / elimination mechanism OCOCH3 R R

Li (OC) 5Cr

eg. Me3O+BF4 or R2OTf

hard alkylating agent OR2 (OC) 5Cr R

They are also readily prepared from acyl halides


O Cl Cl K 2[Cr(CO)5] (OC) 5Cr O Cl (OC) 5Cr O

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

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

Base

Cr(CO)5 OMe

remarkably stable

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

Cr(CO)5 Et OMe

Cr(CO)5 BuLi OMe Me PhCHO

(CO) 5Cr MeO

OH Ph

Michael Reaction
OMe (OC) 5Cr R1 R2 reacts 10 4 x faster than acrylate OMe (OC) 5Cr Li O (OC) 5Cr R1 R
2

O OMe

DielsAlder Reaction

+
(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 H 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 H O SnBu3

H can be used in the Stille reaction, transmetallation etc H

Mechanism
Bu3Sn H O W(CO)5 OTf H SnBu3 O W(CO)5 reductive elimination

SnBu3

H base

O H

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 (OC) 5Cr Rbig OH

50 C

Rbig Rsmall (OC) 3Cr OMe

+
Rsmall

1 CO

Mechanism The mechanism is still contraversial Two possible mechanisms Give the most commonly quoted
rate determining step CO regiochemistry has the largest substituent facing away from carbene Rbig Cr(CO)5 OMe Cr(CO)4 OMe
Rbig Rsmall

ligand dissociation

alkyne co-ordination

smallR

Cr(CO)4 OMe

4 -complex [2+2]-like

R big (OC) 3Cr R small

O CO insertion

R big R small

3 Cr(CO)4 -vinylcarbene complex

R big Cr(CO)4 R small OMe

OMe

OMe reduced steric hinderance

cyclisation

O R big R small (OC) 3Cr aromatisation R big R small (OC) 3Cr

OH

OMe

OMe

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

Work-up
OMe (OC) 5Cr Et

+
O Et 45 C, THF OH Et

O OMe

Et Cr(CO)3

air or FeCl3 decomplexation

MeOH

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

OH Et

O Et

O Et

O OMe

Et

O MeO
OTBS

Et OMe

O O

Et

Use in Synthesis

MOMO MeO

OMe Cr(CO)5

TBSO BnO EtO N

OMOM

50 C, 35 %
MOMO MeO OMe OTBS MeO O OH

MOMO

OH

OTBS BnO EtO N

5 steps 33 %
O OH

O HO O 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 M R2

R1 M
2+ 2

R2

The most common examples are:

Ti

Me Me

H2 Me C Ti Al Cl Me

Ti

via elimination

Ti

Petasis' Reagent
NR3

Ti

Tebbe's Reagent
iPr Cl Cl PCy3 Ru PCy3 N R iPr Mo (F3C) 2MeCO (F3C) 2MeCO Ph

Grubb's Catalyst

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
O R1 R2

reagent
R1

R3 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

Methylenation

remember Schrock carbene complexes are nucleophilic at carbon + Ti R O [2+2] cycloaddition X

H2 Me C Ti Al Cl Me like Wittig driving force is forming M=O

NR3

titanium highly oxo-philic

R Ti O

X Ti O

R X

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


RO O O RO O

Tebbe
RO OR OR RO OR OR

O Ph O TBS

Petasis
Ph O 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 O O H 4 equiv Tebbe reagent O Cp2Ti olefination BnO H O H O H BnO H O O H O O O TiCp2 H BnO O O H a higher alkylidene complex O O BnO O O H

TiCp2

TiCp2

olefin metathesis

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

Alkene Metathesis
The process in which two alkenes exchange their alkylidene fragments
R metathesis catalyst R

+
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 R R + LnM CH2 co-ordination between metal and alkene LnM R R R CH2 R cycloreversion LnM R R CH2

[2+2]

LnM R

cycloreversion

LnM R R

[2+2]

LnM R 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 Ph

Grubb's Catalyst

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 R LnM MLn R

R MLn R
n

MLn

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 LnM Ln M

MLn

LnM

MLn

Synthetic Applications
iPr

good functional group tolerance

O O

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

Ph

OH

20 C, 2 hrs, 91 % MeO 2C

CO2Me

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

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RCM capable of forming large rings from highly functionalised precursors


no need to protect alcohol with [Ru] catalyst O S HO O O OR O O OR O N internal alkene not harmed

[Ru] 85 %

S HO O N

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

iPr

iPr N

cat. 2 % (5 min.)
H O

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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