Hydration free energy difference of acetone, acetamide, and urea.

The hydration free energy and hydration entropy difference of urea and acetone, and of acetamide and acetone have been calculated both by free energy perturbation and by the method of thermodynamic integration. The obtained results show a striking asymmetry between the thermodynamic changes accompanying the replacement of the first and second CH(3) group of acetone by NH(2). Thus, the first CH(3)NH(2) exchange is found to lead to an about 10 kJmol decrease in the energy, 8 kJmol decrease in the Helmholtz free energy, and 5-10 Jmol K decrease in the entropy of hydration, while similar values accompanying the second CH(3)NH(2) exchange are found to be about -65 kJmol, -35 kJmol and -100 Jmol K, respectively. These results indicate that the two NH(2) groups of the urea molecule have a strong synergetic effect on the thermodynamics of the hydration of urea. The fact that the replacement of the two CH(3) groups of acetone by NH(2) leads to a strong decrease in the hydration entropy indicates that urea clearly has an ordering effect on nearby water.