Henry Reaction Revisited. Crucial Role of Water in an Asymmetric Henry Reaction Catalyzed by Chiral NNO-Type Copper(II) Complexes

Chiral copper­(II) and cobalt­(III) complexes (1–5 and 6, respectively) derived from Schiff bases of (S)-2-(aminomethyl)­pyrrolidine and salicylaldehyde derivatives were employed in a mechanistic study of the Henry reaction-type condensation of nitromethane and o-nitrobenzaldehyde in CH₂Cl₂ (CD₂Cl₂), containing different amounts of water. The reaction kinetics was monitored by ¹H and ¹³C NMR. The addition of water had a different influence on the activity of the two types of complexes, ranging from a crucial positive effect in the case of the copper­(II) complex 2 to insignificant in the case of the stereochemically inert cobalt­(III) complex 6. No experimental support was found by ¹H NMR studies for the classical Lewis acid complexation of the carbonyl group of the aldehyde by the central copper­(II) ion, and, moreover, density functional theory (DFT) calculations support the absence of such coordination. On the other hand, a very significant complexation was found for water, and it was supported by DFT calculations. In fact, we suggest that it is the Brønsted acidity of the water molecule coordinated to the metal ion that triggers the aldehyde activation. The rate-limiting step of the reaction was the removal of an α-proton from the nitromethane molecule, as supported by the observed kinetic isotope effect equaling 6.3 in the case of the copper complex 2. It was found by high-resolution mass spectrometry with electrospray ionization that the copper­(II) complex 2 existed in CH₂Cl₂ in a dimeric form. The reaction had a second-order dependence on the catalyst concentration, which implicated two dimeric forms of the copper­(II) complex 2 in the rate-limiting step. Furthermore, DFT calculations help to generate a plausible structure of the stereodetermining transition step of the condensation.