The mechanism of cross-ketonization of acetic acid/propionic acid mixture over SiO2 was investigated by semiempirical quantum chemical AM1 method. We have modeled the catalyst by a molecular electroneutral cluster Si8O19H6. The hydrogen atoms that are not involved in the surface hydroxyl groups are added to satisfy the valency of the Si-O bonds that were disrupted by cutting out the cluster from the bulk of the catalyst. It has been found that adjacent acid-base pair of the catalytic sites provokes dissociative adsorption of the acetic acid molecules resulting in the formation of surface carboxylate species. The reaction is a barrierless process with enthalpy ΔHf = -102.1 kcal/mol. When the Lewis acid sites of the catalyst surface occur to be blocked by carboxylate species, the propionic acid molecules begin to interact with the active species located in the gas phase. It can be supposed that at the temperature range of the ketonization reaction being about 250-400 оС, water molecules on the oxide surface could serve as the source of protons and hydroxyl ions, and act as acid-basic catalyst. The proton attack is directed to the hydroxyl group oxygen atom having the highest π-electron density (4.459) in the molecule, and results in the formation of a water molecule and propionyl cation. As the adsorbed carboxylate species is directed towards the catalyst surface by its carboxyl group, the attack on it by propionyl cation is possible only from the methyl group side. The reaction proceeds spontaneously with enthalpy ΔHf= −176.6 kcal/mol. The yield of this bimolecular electrophilic substitution reaction is a carbon dioxide molecule and the target product − a 2-butanone molecule