Nitronate and related anions

A nitronate (IUPAC name: azinate) is the conjugate base of a nitroalkane: the resonance form of an α-deprotonated nitro compound. Nitronates strongly resemble the enolates of carbonyl compounds.

Resonance forms of the nitronate anion: a carbanion next to a nitro group, and a C=N double bond with both oxygens negatively charged

Deprotonation at the α carbon of a nitroalkane is almost as easy as at the OH of an alcohol: its pK_a is around 17 in DMSO (about 9–10 in water). The nitro group stabilizes the charge even better than a carbonyl.

A base removes a hydrogen from the carbon next to the nitro group of nitroethane, whose pKa is 17, and the nitronate forms with the charge delocalized

The Henry reaction

The so-called Henry reaction, discovered as far back as 1895, is based on nitronates: it is the addition of a nitroalkane to an aldehyde or ketone under basic conditions, a reaction analogous to the aldol reaction (hence its other name, the nitroaldol reaction). The β-nitro alcohols obtained are very versatile intermediates:

The nitroalkane and the carbonyl compound give a beta-nitro alcohol with base, which gives a nitroalkene on dehydration, an alpha-nitro ketone on oxidation and a beta-amino alcohol on reduction

Its mechanism holds no surprises: the nucleophilic nitronate attacks the electrophilic carbonyl carbon and the resulting alkoxide is protonated.

The nitronate carbon attacks the aldehyde carbonyl; the alkoxide formed takes up a proton to give the nitro alcohol

Stereochemistry

In the absence of any additives, the nitronate and the aldehyde approach one another so as to minimize electrostatic repulsions, that is, with the electron-rich oxygen atoms in an anti arrangement. As for the R groups, the stereochemistry of the adduct depends on their bulkiness; the anti diastereomer usually predominates.

Newman projections of the two approaches with the oxygens anti: the one on the left leads to the anti product and the one on the right to the syn product — *Anti* product (left) and *syn* product (right).

The diastereoselectivity of the reaction can be controlled by adding metal catalysts that chelate the oxygen atoms, thus forcing the nitronate and the aldehyde into a gauche arrangement. The bulky R groups prefer the anti arrangement as usual. If the metal catalyst is enantiomerically pure, the two approaches that were in principle mirror images become diastereomeric, and the reaction is not only diastereoselective but also enantioselective:

Two approaches with the metal chelated to the oxygens of the nitronate and the aldehyde, giving the S,R and R,S products; the asterisk indicates that the catalyst is chiral — (*) = R or S: the catalyst is chiral.

A synthesis example

Synthesis of propranolol