Direct Solvent‐Free Amide Bond Formation Catalyzed by Anatase‐TiO2 Surface: Insight from Modeling

Amide bond formation processes are of paramount relevance for a broad spectrum of applications. Conventional amidation protocols typically rely on drastic reaction conditions and the use/disposal of large amounts of chemicals. These limitations may be bypassed by heterogeneously catalyzed amidation at dry conditions. However, progress is hindered because the mechanisms of these processes are largely unexplored. By using ab initio metadynamics, a concerted one‐step mechanism is proposed for the solvent‐free condensation of methylamine and formic acid on TiO 2 (101)‐anatase, leading to methylformamide with concomitant release of molecular water. The activation barrier—14.3 kcal mol −1 —is in line with the mild conditions experimentally adopted in amide bond syntheses on TiO 2 nanoparticles. The mechanism disclosed herein reveals the key role of Ti 4+ sites located on stoichiometric (101) anatase surfaces in promoting amide‐bond formation at the TiO 2 /vapor interface. The acid strength of the adsorbed HCOOH molecules may be tuned by the HCOOH surface coverage, thus influencing the outcome of the amidation reaction. These molecular‐level insights may foster further endeavors to improve/upscale TiO 2 ‐catalyzed amide syntheses at dry conditions, while raising the interest toward amidation processes at the surface/vapor interface promoted by economically and environmentally sustainable metal oxide nanomaterials.