Experimental and Hirshfeld Surface Investigations for Unexpected Aminophenazone Cocrystal Formation under Thiourea Reaction Conditions via Possible Enamine Assisted Rearrangement

Abstract

Considering the astounding biomedicine properties of pharmaceutically active drug, 4-aminophenazone, also known as 4-aminoantipyrine, the work reported in this manuscript details the formation of novel cocrystals of rearranged 4-aminophenazone and 4-nitro-N-(4-nitrobenzoyl) benzamide in 1:1 stoichiometry under employed conditions for thiourea synthesis by exploiting the use of its active amino component. However, detailed analysis via various characterization techniques such as FT-IR, nuclear magnetic resonance spectroscopy and single crystal XRD, for this unforeseen, but useful cocrystalline synthetic adduct (4 and 5) prompted us to delve into its mechanistic pathway under provided reaction conditions. The coformer 4-nitro-N-(4-nitrobenzoyl) benzamide originates via nucleophilic addition reaction following tetrahedral mechanism between para-nitro substituted benzoyl amide and its acid halide (1). While the enamine nucleophilic addition reaction by 4-aminophenazone on 4-nitrosubstituted aroyl isothiocyanates under reflux temperature suggests the emergence of rearranged counterpart of cocrystal named N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbonothioyl)-4-nitrobenzamide. Crystallographic studies reveal triclinic system P-1 space group for cocrystal (4 and 5) and depicts two different crystallographically independent molecules with prominent C–H···O and N–H···O hydrogen bonding effective for structure stabilization. Hirshfeld surface analysis also displays hydrogen bonding and van der Waals interactions as dominant interactions in crystal packing. Further insight into the cocrystal synthetic methodologies supported the occurrence of solution-based evaporation/cocrystallization methodology in our case during purification step, promoting the synthesis of this first-ever reported novel cocrystal of 4-aminophenazone with promising future application in medicinal industry.

Síntesis de tioureas con isoniacida y niacida estructural: test frente a bacterias Gram + y Gram –

“…El espectro 13 C-RMN muestra las señales 181,5; 168,19 y 163,61 ppm correspondientes a los grupos tiocarbonilo (C=S), carbonilo (C=O) unido al anillo bencénico y carbonilo (C=O) unido al anillo de piridina, respectivamente. El desplazamiento del grupo tiocarbonilo (C=S) encontrado en este compuesto es característico de varios compuestos tipo benzoiltioureas [29], [30].…”

Probing the Reactions of Thiourea (CH4N2S) with Metals (X = Au, Hf, Hg, Ir, Os, W, Pt, and Re) Anchored on Fullerene Surfaces (C59X)

“…Thiourea is applied in little amounts in various fields such as photography, used as a fixing or repairing agent, 7 in the industry for the production of thermosetting resin, as an insecticide, in the treatment of textiles, 8 and as a starting ingredient for some colors and pharmaceuticals. 9 Thiourea is also used as a reagent in organic synthesis due to its bitter taste and color (it is a white crystalline chemical substance). 10 Above all, thiourea is soluble in water.…”