Ion-Pair Mediation Enables Ambient Urea Formation from CO 2 and NH 3 in Microdroplets

Urea can form spontaneously from CO 2 and NH 3 at aqueous microdroplet interfaces under ambient conditions, without catalysts or external energy input. However, the molecular mechanism behind this highly efficient transformation remains unclear, largely due to the transient nature of key intermediates. Using large-scale quantum mechanics/molecular mechanics (QM/MM) metadynamics simulations with an explicit air–water interface, we identify an ion-pair-mediated pathway featuring low activation barriers that rationalizes the observed reactivity. CO 2 reacts with two NH 3 molecules to form a stable H 2 NCOO ‐ ⋯ NH 4 + ion pair─a species recently detected in microdroplet experiments─with an activation barrier of only ∼ 9.4 kcal/mol. The intrinsic interfacial electric field (∼0.1 V/Å) further lowers this barrier to ∼ 4.4 kcal/mol. Subsequent nucleophilic attack by a third NH 3 on the ion pair yields urea through a concerted proton-transfer process with a remarkably low barrier of ∼ 8.1 kcal/mol. In contrast, pathways proceeding via neutral carbamic acid (H 2 NCOOH) exhibit barriers exceeding 18.0 kcal/mol, and the initial formation of protonated carbamic acid itself requires a barrier of 22.9 kcal/mol, rendering both routes kinetically noncompetitive. This work provides key atomistic insights into spontaneous urea formation in microdroplets and underscores the importance of the distinct physicochemical features of the interfacial microenvironment in enabling prebiotically relevant chemistry.