CH3OH dehydrogenation on a metal function occurs in tandem with C-C coupling of HCHO with enolates derived from alkanals or alkanones on acid-base pairs at anatase TiO2 surfaces with very high specificity for nucleophilic attack by enolates on HCHO over larger carbonyl molecules. The measured rate constants for enolate coupling with HCHO are >10(3)-fold larger than for its coupling with acetone. Free energies derived from theoretical treatments of reactions between C-2-C-4 bound enolates and carbonyls show that such specificity for nucleophilic attack on HCHO reflects smaller entropy losses upon formation of the transition state (TS), instead of enthalpic effects caused by weaker steric effects or the stronger electrophilic character of HCHO compared with larger carbonyls. The easier steric access and higher electrophilicity of the carbonyl C atom of HCHO in C-C coupling with enolates are compensated by a later TS by and stronger van der Waals contacts for the corresponding reactions of the larger carbonyls. The preeminence of entropic effects over enthalpic stabilization reflects the greater structural organization imposed by surfaces on TS structures compared with similar reactions and structures in gaseous or liquid media. Such organization imposes significant entropic penalties that become least consequential for smaller electrophiles, thus enabling highly selective routes for sequential addition of C-1 groups at nucleophilic C atoms in co-reactants using HCHO, whether added or formed in situ from CH3OH, as the monomer source. Such entropy-driven specificity is therefore a unique and unrecognized characteristic of reactions catalyzed by surfaces.