The Cannizzaro reaction is interesting because its mechanism is analogous to the hydride reductions of carbonyls which occur in the biological pathway of many living organisms. One of the most important biological reducing agents is NADH (the reduced form of nicotinamide adenine dinucleotide) which can act as a source of the hydride ion. NADH donates a hydride to carbonyls in an analogous fashion to the alkoxide ion intermediate of the Cannizzaro reaction. A set of lone pair electrons on a NADH nitrogen atom pushes the hydride off as a leaving group forming NAD+ (the oxidized form of nicotinamide adenine dinucleotide). The ejected hydride adds as a nucleophile to a wide variety of carbonyl containing biological molecules. Some examples of this addition are described below.
Nicotinamide Adenine Dinucleotide - a Hydride Transfer Coenzyme
Although we are talking about hydrides acting as nucleophiles and leaving groups in this section, you already know that discreet hydride ions are far too unstable to exist as actual intermediates in the organic reactions of living cells. Biochemical redox reactions involving hydride transfer require the participation of a hydride transfer coenzyme. In reactions involving carbonyl compounds, a molecule called nicotinamide adenine dinucleotide generally plays this role. The full structure of the oxidized form of this coenzyme, abbreviated NAD+, is shown below, with the active nicotinamide group colored blue.
Because the redox chemistry occurs specifically at the nicotinamide part of the molecule, typically the rest of the molecule is simply designated as an 'R' group. NAD+ and NADP+ both function in biochemical redox reactions as hydride acceptors: that is, as oxidizing agents. The other forms of the coenzyme, NADH and NADPH, serve as hydride donors: that is, as reducing agents.
The phosphate on the nucleotide pentose group of NADP+ and NADPH is located far from the nicotinamide ring, and does not participate directly in the hydride transfer function of the cofactor.
This reaction can be simplified in the following way:
Stereochemistry of Hydride Transfer Reactions
Ketone/aldehyde hydrogenase reactions are stereospecific in two distinct ways. In the hydrogenase direction, attack by the hydride can occur from either the re or the si face of an asymmetrical carbonyl, leading to the S or R alcohol depending on the priorities of R1 and R2 (in the example R1 has higher priority than R2).
The specificity is determined by which side of the ketone or aldehyde substrate the NAD(P)H cofactor is bound to in the active site. In addition, hydrogenases specifically catalyze the transfer of either the pro-R or the pro-S hydrogen at C4 of the nicotinamide ring. In the example below, the pro-R hydrogen of NADH is transferred to reduce the ketone.