Regioselective cyclocondensations with thiobarbituric acid: spirocyclic and azocine products, X-ray characterization, and antioxidant evaluation

Abstract

Multicomponent cyclocondensations of 5-amino-3-methyl-1-phenyl-1H-pyrazole (AMPZ), thiobarbituric acid, and p-formaldehyde under conventional thermal heating or ultrasonic irradiation were studied. Treatment of the reaction mixture in ethanol in an ultrasonic bath for 3 h produced azocine compound 4b, while the same mixture in ethanol under reflux conditions for 15 h produced spiro compound 4a. This work encompasses intricate experimental details, X-ray diffraction measurements, and multifaceted computational analyses employing methods such as the density functional theory and Hirshfeld surface analysis. Crystallographic investigations revealed the molecular structure of the compound and clarified its interactions involving hydrogen bonds and weak intermolecular forces. This article describes the synthesis and characterization of a novel spirocyclic compound. The study also evaluated the antioxidant potential in vitro using the DPPH and ABTS methods. The results showed that these compounds showed the best free radical scavenging ability, even in very small amounts, and that even at very low concentrations, these compounds showed excellent radical scavenging potential. Surprisingly, these compounds exhibited strong (ABTS⁺) radical scavenging activities, mainly attributed to the HAT mechanism, indicating their potential as therapeutic agents. Facile multipurpose, three-component selective procedures for new spiroheterocycles have been proposed, presenting intriguing perspectives in the field of medicine, particularly in the field of antioxidants. The geometric values of the computationally optimized structure were calculated using the density functional theory in LC-BLYP/6-31(d), aligned with the X-ray diffraction data, reinforcing the precision of our findings.

Fig. 1. The derivatives of azocine and azocane have interesting biological properties.

Scheme 1. Synthesis of bridged-azocine.

Scheme 2. Conditions and synthesis of spiro-pyrazolopyridine (4a) and 1,3-diazocine (4b).

Scheme 3. Proposed mechanism for the synthesis of 4a and 4b.

Fig. 2. IR spectra calculated using DFT (B3LYP/6-31G*) (A and B) and experimental (C and D) IR spectra for 4a and 4b.

Fig. 3. The frontier molecular orbitals and related energies of 4a and 4b are expressed in kJ mol⁻¹.

Fig. 4. Donor–acceptor map of the molecules studied in the gas phase.

Fig. 5. ORTEP plot of the 4b. Thermal ellipsoids were drawn at a 30% of probability. The H atoms were omitted for simplicity.

Fig. 6. Crystal packing of 4b.

Fig. 7. Overall, the Hirshfeld surface (left) of 4b and the fingerprint plot (right) are shown.

Fig. 8. Donor–acceptor map (DAM) diagram. These four regions were distinguished and described in detail by Martinez et al. The dashed lines separating the regions indicate only image clarification.