Solvent effects on tautomeric equilibria
Molecules often exist in nature as equilibrium mixture of its tautomers. This is a critical issue in drug design since one of a drug tautomers can cause serious side effects. Solvent effects can play an important role in shifting the tautomeric ...
Molecules often exist in nature as equilibrium mixture of its tautomers. This is a critical issue in drug design since one of a drug tautomers can cause serious side effects. Solvent effects can play an important role in shifting the tautomeric equilibria. A well known example is the tautomeric equilibrium between 2-hydroxypyridine and 2-pyridone.
It is known that 2-hydroxypyridine (left structure) is slightly more stable compared to its 2-pyridone (right structure) tautomer in the gas phase. However, in polar solvent such as water, 2-pyridone is favor. This exercise is designed to provide an understanding on the roles of solvent effects on tautomeric equilibria.
Procedure: Using tools in Avisto for this exercise. You can download Avisto and its tools at Astonis.
1. Build 3D structures of both molecules: There are two ways to do this. One is to use MolLib to send out pyridine then use MolDesign to edit the structure to make the two tautomers. The other way is to use MarvinSketch to draw these tautomers then convert them to 3D one at a time.
2. Use Mopac CUI Cloud or Pro to find the stable structures of these tautomers in the gas phase and in water using the AM1 Hamiltonian.
| Properties | 2-hyroxypyridine (gas phase) | 2-hydroxypyridine (in water) | 2-pyridone (gas phase) | 2-pyridone (in water) |
| Heat of formation (kcal/mol) | ||||
| dipole moment (D) |
- Calculate the relative stability by the difference between the heats of formation of the two tautomers in the gas phase and in solution.
- Calculate the free energy of solvation of a tautomer which is the difference between the heats of formation of the tautomer in the gas phase and in water. Correlate the free energies of solvation with the dipole moments of each tautomer in the gas phase.
3. Use PsiViewer to plot the iso-value electrostatic potential surface (use iso value = 0.1) then compare the size of the surface.
4. Compare the structures of these tautomers in the gas phase and in water. What can you conclude about the effects of solvent on these neutral molecules.
What is the rationale for the shift in the tautomeric equilibria in favor of 2-hydroxypyridine in the gas phase to 2-pyridone in water?
