Role of the amide group in the design of the superbases constructed upon bicyclo[2.2.2]octane framework. Intra- vs. intermolecular hydrogen bonding

Abstract

A series of bicyclo[2.2.2]octanes (BCO) and 1–methylenebicyclo[2.2.2]octanes (MBCO) containing superbasic subunits supplemented with amide functionality were modeled using the DFT approach. The gas phase basicities (GB) for all modeled bases span the range of 1025–1128 kJ mol−1, and their pKa are mostly above 26, going up to 33–35 for N–heterocyclic carbenes. The energies of the intramolecular hydrogen bonds (IHB) are compared with those in the flexible analogs. Increasing rigidity by switching from the MBCO to the BCO system only slightly affects IHB and substrate binding. The additional amide group strongly increases the energy of substrate binding (ΔGsb), reaching values of −45 kJ mol−1. Solvation removes the effect of the IHB even in the protonated forms, indicating minimal competition between the intramolecular and intermolecular hydrogen bonding. Calculated data suggest that most of the modeled bicyclic bases are promising candidates as the new base organocatalysts for aldol and similar reactions.