REACTIVE INTERMEDIATES: CARBENES

CARBENES: Reactive 6-electron divalent carbon fragments R2C:

H2C: = carbene = methylene = methylidene

(Wanzlick et al. 1970)

Stable triplet carbene - half-life ca. 1 week in inert atmosphere.

(Iwamoto et al., 2004)

Kinetically reactive transition metal 'carbenoid' of uncertain structure. Involved in catalytic carbene transfer. Structures generally unknown.

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:

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

How do we know that a carbene is formed?

Geuther (1862), Hine (1950):

Carbene generation via lithium-halogen exchange:

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:

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

Thermolysis of sodium trichloroacetate:

The Simmons-Smith reaction:

Although the active carbene transfer reagent is thought to be the zinc carbenoid [I2Zn...CH2] it seems that the organozinc reagents ICH2ZnI and/or IZnCH2ZnI are formed first. Note the stereospecificity of the reaction.

(2) -ELIMINATION OF N2 FROM DIAZO-COMPOUNDS

The Bamford-Stevens Reaction:

-Carbonyl diazo-compounds - Important precursors of -carbonyl carbenes:


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:

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

Rearrangement (intramolecular insertion into a single bond):

CARBENE INSERTIONS INTO E-H BONDS:

Simple carbenes are highly reactive and show little or no selectivity in C-H insertion:

Carbonyl carbenes are more selective:

Intramolecular insertions also show enhanced selectivity:

Carbene C-H insertion in a natural product synthesis:

Carbene insertion into an O-H bond:

Carbene insertion into an N-H bond - Merck industrial synthesis of a -lactam antibiotic:

CARBENE ADDITION REACTIONS:

Cyclopropane synthesis:

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:

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.

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:

Carbene additions to arenes: 67 ring-expansion to yield cyclohepta-trienes:

Carbene additions to pyrrole - 56 ring-expansion to yield pyridines:

CARBENE REARRANGEMENTS:

Mechanism: 1,2 migration of hydride or a carbanion:

Migratory aptitude: R = H > aryl > alkyl

Arndt-Eistert Reaction - homologisation of carboxylic acid derivatives: