The ability of the vanadyl pyrophosphate (1 0 0) surface to selectively activate n-butane in the slow step of paraffin oxyfunctionalisation was investigated. Quantum chemical calculations were performed on small cluster models for orthophosphate and pyrophosphate surface terminations. Electrostatic potential surfaces for n-butane and the catalyst clusters show favourable electrostatic interaction, with the reactant oriented to maximise Coulombic attraction between terminal hydrogens and surface oxygens. Site-selectivity for covalent interaction at the reactant–surface interface, as measured by frontier molecular orbital (FMO) surfaces and Fukui functions, indicates that surface vanadium species can selectively cleave methylene CH bonds for butane activation. Both surface terminations, orthophosphate and pyrophosphate, feature the same activation mechanism. The pyrophosphate model, however, has a higher concentration of surface PO oxygen species which feature prominently in the high-lying occupied orbitals. Hence, the pyrophosphate-terminated surface may promote subsequent controlled oxidation of activated n-butane to maleic anhydride. The susceptibility of maleic anhydride to further reaction at the surface was also examined using the active site reactivity analyses.