Quantum Mechanics

Molecular quantum mechanics (qm) is used to study the electronic structure of molecules. Usually I use qm calculations when I don't trust results obtained by using molecular mechanics (I use qm to verify force field parameters). Other problems of special interest to medicinal chemists where QM is the preferred method of choice are protonation state (ph values), tautomers and electrostatic potential.

indazole tautomers

The above equation describes the tautomerisation between the two indazole tautomers (isomers). There are two nitrogen atoms in indazole, but only one of them are protonated at physiological ph (7.4, the ph of human blood ). The below table displays the energy difference between the two tautomers. Different qm methods and basis sets were used both in gas phase and aqueous solution. 1H-indazole is found to be the most stable tautomer in all cases. This is confirmed experimentally by spectroscopic observations in gas phase. (In this case the wavelengths used in the measurements was probably verified by a QM calculation)

qm method	qm basis	qm energy kJ/mol
DFT(b3lyp)/SOLV	6-311g**++	-8.3
DFT(b3lyp)	6-311g**++	-20.4
HF/SOLV	6-311g**++	-17.3
HF	6-311g**++	-31.2
DFT(b3lyp)/SOLV	3-21g	-15.1
DFT(b3lyp)	3-21g	-25.6
HF/SOLV	3-21g	-27.8
HF	3-21g	-41.7

Below are displayed pictures of various surfaces calculated for the two indazole isomers. These surfaces map different properties such as electronic potential or total electron density, or they display molecular orbitals. Comparing property surfaces for different ligands can give clues to which properties are important for the binding of the ligands to a protein of interest where as molecular orbitals can reveal details on a molecules reactivity.

indazole density surfaces 1