Mechanistic insights into formose side reactions: Cannizzaro disproportionation and competing pathways

As a leading candidate for prebiotic synthesis of carbohydrates, the formose reaction has been the subject of extensive investigation. However, formaldehyde’s reactivity enables competing pathways that divert the formose condensation, generating dead-end products. Here, we employ our recently developed roto-translationally invariant potential-driven molecular dynamics to investigate the side pathways in the formose reaction network, identifying several new reaction mechanisms. Complementary density functional theory calculations with transition state optimization demonstrate the Cannizzaro disproportionation (yielding methanol and formate) as the dominant competing pathway, exhibiting a lower Gibbs free energy barrier (16.5 kcal mol−1) than both formaldehyde dimerization (26.9 kcal mol−1) and the formose autocatalytic cycle (18.0 kcal mol−1). In addition, carbon monoxide, carbon dioxide, and hydrogen gas may also form as by-products, with respective formation barriers of 24.2, 28.4, and 32.3 kcal mol−1. These results advance our understanding of reaction competition in prebiotic carbohydrate synthesis.