A computational QM/MD 17O NMR study of tautomeric equilibrium of mycotoxin citrinin in dichloromethane solution

Abstract

The tautomeric equilibrium of citrinin in dichloromethane was investigated using classical molecular dynamics and linear-response QM/MM calculations of ¹⁷O NMR shielding constants. MD simulations showed that solvent distribution around the para- and ortho-quinone methide tautomers is essentially uniform, as expected for an isotropic non-hydrogen-bonding solvent of medium polarity. The tautomeric ratio between the p- and o-citrinin forms was optimized to best match experimental and computed relative ¹⁷O NMR spectra. The resulting tautomeric ratio of p-to-o-citrinin of 7:4 closely reproduces the experimental value of 4:3, confirming the near-thermodynamic equivalence of the two tautomers, with a slight preference for the para form. A thermodynamic-cycle-based quantum-chemical estimate yielded virtually the same qualitative conclusion. Attempts to include the endiol tautomer of citrinin showed it to be unstable in a dielectric-continuum solvent model; thus, the endiol tautomer is not expected to form in dichloromethane and does not contribute to the observed NMR spectra.