Unusual case of desmotropy. Combined spectroscopy (¹H-¹4N NQDR) and quantum chemistry (periodic hybrid DFT/QTAIM and Hirshfeld surface-based) study of solid dacarbazine (anti-neoplastic).

ABSTRACT

Antineoplastic chemo-therapeutic drug 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide (Dacarbazine, DTIC), has been studied experimentally in solid state by ¹H-¹4N NQDR double resonance at 295 K and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM) and Hirshfeld surfaces analysis. Only one set of eighteen resonance frequencies was found in the experiment. This indicates the presence of six inequivalent nitrogen sites -N(CH3), -NH2, -NH- and three -N= (of which one is a ring, two are from triazene) in the DTIC molecule. This contradicts the X-ray data which revealed the multiplication of nitrogen sites due to unusual desmotropism. The averaging of NQR frequencies caused by the fast in NQR time-scale exchange of protons in a double-well potential combined with the oscillations of twisted supramolecular synthons was proposed as a potential mechanism responsible for this apparent contradiction. An effective improvement in the quality of the spectrum reproduction was achieved when the calculations were performed assuming the periodic boundary conditions, BLYP functional, the DNP basis set and taking the 3×3×3 k-point separation. The ordering of the nitrogen sites according to the increasing quadrupole coupling constant (QCC) N(3)metabolic pathway of DTIC. Two sites N(5) and N(4) with the highest QCC are responsible for the first step - conversion to MTIC (5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide) required for effective processes of binding dacarbazine to DNA (demethylation of N(5)), and the second step - fast conversion of MTIC to 5-amino-1H-imidazole-4-carboxamide (AIC; remove -N(4)-N(5)HCH3). N(5) does not participate in any, while N(4) participates in weak C(2)H⋯N(4) interaction which can be readily broken. The four remaining nitrogen atoms N(1), N(2), N(3) and N(6) participate in strong intermolecular N(1)H⋯N(2) and intramolecular N(3)-H⋯N(6) bonds, which stiffen the crystalline structure.