The catalysis of the amide-bond formation for the concerted reaction of acetic acid and methylamine on clay mineral surfaces has been studied by means of density functional theory calculations. Two typical cluster models for surface defects representing hydrogen-bonded interactions (physical defect) and a Lewis acid (chemical) defect have been selected. Additionally, a series of catalysts of varying strength (Al3+, AlCl3, Al(OH) 3, [Al(H2O)5]3+, H+, H3O+, H3O+-H2O, H 2O, and (H2O)2), which can act as Lewis or Brønsted acids was investigated as well. Reaction energies, activation barriers and corresponding thermodynamic quantities have been calculated. The results show a strongly asynchronous mechanism with the prior formation of a N-C dative bond followed by a proton transfer from nitrogen to oxygen as the rate-determining step. The barrier height was reduced substantially by the interaction with the catalyst. Solvation effects were taken into account by explicit inclusion of water molecules and by the polarizable continuum solvation model (PCM).