DFT investigations of the unusual reactivity of 2‐pyridinecarboxaldehyde in base‐catalyzed aldol reactions with acetophenone

The aldol reaction is recognized as an archetypal method to form carbon‐carbon bonds. Base‐catalyzed aldol reactions of aryl aldehydes with aryl methyl ketones typically produce condensation products (chalcones). However, 2‐pyridinecarboxaldehye, 2‐quinolinecarboxaldehyde, and 2‐ and 3‐fluorobenzaldehyde undergo tandem aldol‐Michael reactions with aryl enolates to yield conjugate addition products. To elucidate the different reactivities of aldol products formed in the reactions of benzaldehyde and 2‐pyridinecarboxaldehyde with the sodium enolate of acetophenone, density functional theory (DFT) calculations were performed to compare the energies of conformational isomers of the intermediates formed in the reaction, the energies of the corresponding condensation products, and the kinetic barriers to dehydration and conjugate addition. Computational results support the formation of the trans isomer of the condensation product in base‐catalyzed aldol reactions of either benzaldehyde or 2‐pyridinecarboxaldehyde with acetophenone. The susceptibility of the condensation product to conjugate addition is determined to result from the lower LUMO energy of trans‐1‐phenyl‐3‐(2‐pyridinyl)‐2‐propen‐1‐one. Consequently, the kinetic barrier for conjugate addition of a second equivalent of enolate with the condensation product of 2‐pyridinecarboxaldehyde is found to be significantly lower. Similar results were obtained for the reactions of fluorobenzaldehydes with aryl enolates. The susceptibility of 2‐pyridinecarboxaldehyde to undergo tandem condensation‐conjugate addition in base‐catalyzed aldol reactions with aryl methyl ketones is calculated to result from the lower LUMO energies of their condensation products. The kinetic barriers for the conjugate addition reactions of the condensation products obtained from aldol reactions of acetophenone and benzaldehyde or 2‐pyridinecarboxaldehyde are compared. The study is extended to 2‐ and 3‐fluorobenzaldehyde to account for the reactivity of electron deficient aromatic aldehydes in aldol reactions.