Amide interactions in aqueous and organic medium

Enthalpies of solution of amides in organic solvents and water have been used in the pure base method to calculate the enthalpy of hydrogen bond formation of the N-H proton of N-methylformamide (NMF) and N-methylacetamide (NMA) to water. NMA forms a 1.2 kcal mol^-1 stronger hydrogen bond with water than does NMF. The hydrogen bond enthalpy of formamide and acetamide to DMA, DMF, and water has also been estimated. Both formamide and acetamide form two N-H hydrogen bonds with DMA and DMF but only one with water. The enthalpies for the formation of the water to amide carbonyl hydrogen bonds with NMF and NMA have also been calculated. Each carbonyl can bond to two water molecules with the NMA carbonyl being the better proton acceptor. Water molecules are found to structure about methyl groups contributing 1.7 kcal mol^-1 per methyl group to the interaction enthalpy of the amide and water. The methyl group when attached to the amide carbon also alters the electron density in the CON linkage leading to a greater basicity for the acetamide carbonyl and a greater acidity for the acetamide N-H proton. Analysis of the transfers of the amides from organic to aqueous medium allows calculation of the interaction enthalpies of the amides in these solvents. The relative importance of amide hydrogen bonding to water in determining the enthalpy contribution to stability in water may be seen from these interaction enthalpies.