Synthesis, spectroscopic characterisation, and combined DFT/GFN2-xTB study of ethyl 4-[2-(3-hydroxy-4-methoxyphenyl)-4-oxo-1,3-thiazinan-3-yl]benzoate
DOI:
https://doi.org/10.64354/6t2fr763Keywords:
1,3-Thiazinan-4-one; Schiff base; Isovanillin; Benzocaine; Density functional theory; Frontier molecular orbitals; Molecular electrostatic potentialAbstract
Ethyl 4-[2-(3-hydroxy-4-methoxyphenyl)-4-oxo-1,3-thiazinan-3-yl]benzoate (7), a new six-membered sulfur/nitrogen heterocycle, was obtained in two steps from isovanillin and benzocaine: acid-catalysed condensation gave the azomethine 1, which was cyclised with 3-mercaptopropanoic acid under azeotropic removal of water (68% yield). Both compounds were characterised by FT-IR, ¹H and ¹³C NMR, HRMS and elemental analysis. Ring closure is established by four infrared markers — loss of the azomethine band at 1641 cm⁻¹, a new aliphatic C–H stretch at 2989 cm⁻¹, a +34 cm⁻¹ shift of the ester carbonyl to 1713 cm⁻¹ and a new lactam band at 1673 cm⁻¹ — and by the replacement of the imine singlet at 8.43 ppm by the sp³ N,S-acetal C2–H singlet at 5.95 ppm, together with a new ¹³C lactam carbonyl at 171.6 ppm. The electronic structure was examined at B3LYP/6-31G(d) after an ETKDG/MMFF94/GFN2-xTB conformer search. Harmonic wavenumbers from a numerical GFN2-xTB Hessian reproduce the nine measured fingerprint bands with a mean absolute deviation of 24 cm⁻¹; paired t and Wilcoxon tests detect no systematic bias (p = 0.75 and 0.85) and the optimum scaling factor is 1.001. The frontier orbitals are separated in space, the HOMO on the hydroxy/methoxy-substituted ring and the LUMO on the benzoate ring, giving a wide gap of 4.63 eV and a chemical hardness of 2.32 eV. On the Domingo scale the molecule is at once a strong electrophile (ω = 2.71 ± 0.03 eV) and a strong nucleophile (N = 3.50 ± 0.06 eV), the uncertainties being ±1 SD over an ensemble of 11 conformers. The electrostatic potential runs from −37.1 to +41.1 kcal mol⁻¹, its deepest minima over the two carbonyl oxygens.
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