Stereodynamics of Hemiacetal Formation in Pyridine-3-Carbaldehyde and Pyrimidine-5-Carbaldehyde Derivatives: Implications for the Soai Reaction.

The Soai reaction is a unique example of self-amplifying asymmetric autocatalysis, in which a chiral zinc alkoxide not only promotes its own formation from pyridine-3-carbaldehydes and pyrimidine-5-carbaldehydes by alkylation with diisopropylzinc but also amplifies the enantiomeric excess of the added nonracemic alcohol. Both the asymmetric autocatalysis and the positive nonlinear effect have been attributed to equilibria involving the zinc alkoxide product, including dimerization and hemiacetalate formation with the substrate aldehyde. Hemiacetal formation is therefore of central importance for the efficiency of the autocatalytic cycle. Here, we report kinetic investigations of the dynamic hemiacetal formation of Soai aldehydes, showing a correlation of hemiacetal formation rates with autocatalytic reactivity. Hemiacetal formation with a series of alcohols was studied by 1H NMR spectroscopy and temperature-dependent dynamic HPLC (DHPLC), providing mechanistic insight into the stereodynamics governing this key equilibrium. The Gibbs free activation energy ΔGǂ for the formation of hemiacetals with isopropanol for pyridine-3-carbaldehydes is in the range between 94.6 and 95.5 kJ/mol and for pyrimidine-5-carbaldehydes it is between 85.9 and 88.4 kJ/mol.