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).
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)<N(2)<N(6)<N(1)<N(4)<N(5) reflects the 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.
Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland. Electronic address: Jolanta.Latosinska@amu.edu.pl.
Jolanta Natalia
JN
Latosińska
Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznań, Poland.
Magdalena
M
Latosińska
"Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia; Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia.
Janez
J
Seliger
"Jozef Stefan" Institute, Jamova 39, 1000 Ljubljana, Slovenia.
Veselko
V
Žagar
Department of Paediatric Dentistry, Karol Marcinkowski University of Medical Sciences, Bukowska 70, 60-812 Poznań, Poland.
Dorota V
DV
Burchardt
Department of Paediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Szpitalna 27/33, 60-572 Poznan, Poland.
Katarzyna
K
Derwich
D000970:Antineoplastic Agents / Q000737:chemistry*; D003606:Dacarbazine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D011789:Quantum Theory; D013696:Temperature
D000970:Antineoplastic Agents; D003606:Dacarbazine
Crystalline pattern in solid; Desmotropism; Imidazole derivative; Proton transfer and dynamical averaging; Topology of interactions