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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)
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
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
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
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
Cr(CO)5 Et OMe
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]
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
Mechanism
Bu3Sn H O W(CO)5 OTf H SnBu3 O W(CO)5 reductive elimination
SnBu3
H base
O H
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
+
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
O CO insertion
R big R small
OMe
cyclisation
OH
OMe
OMe
Work-up
OMe (OC) 5Cr Et
+
O Et 45 C, THF OH Et
O OMe
Et Cr(CO)3
MeOH
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
OMOM
50 C, 35 %
MOMO MeO OMe OTBS MeO O OH
MOMO
OH
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
R1 M
2+ 2
R2
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
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
Methylenation
NR3
R Ti O
X Ti O
R X
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
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]
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
R MLn R
n
MLn
MLn
LnM
MLn
Synthetic Applications
iPr
O O
Ph
OH
20 C, 2 hrs, 91 % MeO 2C
CO2Me
10
[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
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