Abiotic ribonucleoside formation in aqueous microdroplets: mechanistic exploration, acidity, and electric field effects

Aqueous microdroplets have been reported to dramatically increase the rate of chemical reactions. Proposed mechanisms for this acceleration include confinement effects upon droplet evaporation, and Brønsted acid or electric field catalysis at the air-water interface. However, computational investigations indicate that the operation of these mechanisms is reaction-dependent, with conclusive evidence for a role for electric field catalysis still lacking. Here, we present a computational investigation of the reported abiotic phosphorylation of ribose and the subsequent formation of ribonucleosides, focusing on acidity and oriented external electric field (OEEF) effects. The most plausible reaction mechanism identified involves the protonation of ribose, followed by carbocation formation and an S$_N$2 substitution step. Without an OEEF, all considered pathways are thermally inaccessible. However, in the presence of a significant OEEF, the S$_N$2-based pathway, leading to the $\beta$-ribonucleoside isomer, becomes highly stabilized, reducing the energetic span to a thermally accessible 12-13 kcal/mol. Surprisingly, the OEEF-mediated reaction closely mirrors the enzymatic mechanism of phosphorolysis via S$_N$2 substitution, including a pronounced anomeric selectivity. Our results support the hypothesis that some reactions in aqueous microdroplets are accelerated by electric fields and provide further evidence for the importance of electrostatic catalysis in biological systems, particularly for phosphorylase enzymes.