The Formose Reaction with SO₂: A Computational Study

This study examines the influence of SO₂ and its hydrate H₂SO₃ on the free energies of the core autocatalytic cycle of the formose reaction. We find that SO₂ and H₂SO₃ readily condense with aldehyde and alcohol functional groups to form bisulfite analogs of formose proto-metabolites under modeled conditions. The bisulfite functional group can provide intramolecular catalytic enhancement in specific isomers towards aldol additions and the retroaldol step that regenerates two equivalents of glycolaldehyde from tetrose. The bisulfite moiety reduces the favorability of the parasitic Cannizzaro side-reaction both thermodynamically and kinetically, thus potentially furnishing more throughput towards forming sugars. As a prebiotic analog to phosphate, we find that bisulfite slightly stabilizes ribose over its C₅ aldose diastereomers thermodynamically, although the effect is modest and may be influenced by solution dynamics.