Oxygen and Nitrogen in Competitive Situations: Which is the Hydrogen‐Bond Acceptor?

Abstract In the design of novel protein ligands one of the major challenges is the replacement of functional groups to modify and improve the binding characteristics. Often nitrogen‐ and oxygen‐containing groups are exchanged, or both atoms occur in a competitive situation. We have investigated the hydrogen‐bonding abilities of oxygen atoms covalently bound to two non‐hydrogen atoms of which at least one is formally assigned to an sp 2 ‐type hybridization. In particular, examples in which such oxygen atoms compete with nitrogen atoms in the same molecular segment have been studied. Based on interaction energies obtained from ab initio calculations for complexes of these molecules with water, the oxygen atoms can be classified as rather weak hydrogen‐bond acceptors; nitrogen atoms present in the same fragment exhibit much stronger interaction energies. The ab initio results are confirmed by the relative frequencies with which oxygen and nitrogen atoms are found to be involved in hydrogen bonding in the crystal structures of organic molecules containing the fragments of interest.