Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer

Abstract

Guanylhydrazones have been known for a long time and have wide applications in organic synthesis, medicinal chemistry, and material science; however, little attention has been paid toward their electronic and structural properties. Quantum chemical analysis on several therapeutically important guanylhydrazones indicated that all of them prefer the azine tautomeric state (by about 3-12 kcal/mol). A set of simple and conjugated azines were designed using quantum chemical methods, whose tautomeric preference toward the azine tautomer is in the range of 3-8 kcal/mol. Twenty new azines were synthesized and isolated in their neutral state. Variable temperature NMR study suggests existence of the azine tautomer even at higher temperatures with no traces of the hydrazone tautomer. The crystal structures of two representative compounds confirmed that the title compounds prefer to exist in their azine tautomeric form.

Geometrical Isomerism in Guanabenz Free Base: Synthesis, Characterization, Crystal Structure, and Theoretical Studies

“…35 The characterization of the product by 1 H NMR spectroscopy in DMSO-d 6 confirms the formation of guanabenz in its preferred azine tautomeric state as it is evidenced from the presence of two broad singlets of two protons each at 5.81 and 5.84 ppm, which are the characteristic probe for the presence of the azine tautomer. 19 Further, the confirmation for the presence of azine tautomer was provided by 13 C NMR spectroscopy where a signal at δ 161.98 ppm was observed which is attributed to the C(NH 2 ) 2 carbon, a characteristic probe of the azine tautomer. From the 1 H NMR study, we observed the presence of only one isomer, and it is assumed to belong to the E-isomer of guanabenz.…”

“…The reaction mass was stirred to get clear solution, and The reaction mass was stirred at room temperature which resulted in the formation of precipitate of product in 1 h (Scheme 1). 19 The resultant precipitates were filtered and washed with water (2 × 2 mL) to remove the excess of NaOH. The precipitates were dried under reduced pressure to afford guanabenz free base in 96% yield.…”

Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis

“…Phenyl and thiophene rings are bio-isosters 26 , and the former offers more synthetic versatility, i.e., can be substituted for structure activity relationship (SAR) acquisition. We substituted isothioureas with guanylhydrazones, as the latter groups show good stability and a pKa range closer to neutrality due to the delocalization of their charge on three N atoms (favored azine form vs. disfavored hydrazone form, 4.5 ≤ ΔGT ≤ 6.5 Kcal/mol 27 , Supplementary Fig. 3 ).…”

Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies

“…All reagents and solvents were purchased from the Sigma and Merck companies and were all used without further purification. All the 2‐benzylidenehydrazinecarboximidamide derivatives ( 3a ‐ n ) were prepared according to the known literature procedure 26 . Melting points were measured on a standard (Thermo) apparatus.…”

“…X‐ray crystallographic and theoretical studies of substituted guanyl hydrazones studies indicate that guanyl hydrazones should be represented as azines. The azine tautomers are found to be about 3 to 12 kcal/mol more stable than the hydrazone tautomers 26,27 …”