Raman, ATRIR and NMR spectra, conformational stability, vibrational assignments, normal coordinates analysis and DFT calculations of hydrochlorothiazide drug

The Raman (4000-50 cm⁻¹), attenuated total reflectance (ATR) infrared (4000-400 cm⁻¹) spectra of Hydrochlorothiazide (C₇H₈ClN₃O₄S₂; HCTZ) have been recorded in the solid state in addition to LCMS in the dimer and trimer ranges. The ¹H, ¹³C and ¹⁵N NMR spectra were also recorded in addition to DEPT (45, 90 and 135) of HCTZ sample dissolved DMSO‑d6. Initially, three conformers resulting from the rotation of -SO₂NH₂ moiety around C₉-S₁₁ were proposed, namely gauche, trans and cis conformers. And then Density Functional Theory (DFT) calculations for an isolated molecule were carried out employing both B3LYP and P3PW91 methods at 6-31G(d), 6-311+G(d), 6–311++G(d,p) basis set. The cis isomer is a transition state owing to the prediction of an imaginary wavenumber, while the gauche being more stable than trans by ∼438–538 cm⁻¹ (∼1.25–1.54 kcal) employing the afore-mentioned computations. Moreover, we carried out a potential surface scan for the gauche to determine SO₂NH₂ barriers to internal rotations and to ensure the optimal gauche is the most stable conformer. Aided by normal coordinate analysis (NCA) in addition to the atomic displacements in Cartesian coordinates (ADCC), confident vibrational assignment of the observed infrared and Raman bands are proposed for all fundamentals of the gauche rotamer. Nevertheless, force constants (FCs) in internal coordinates were also estimated using the above-mentioned methods and basis sets as well. The ¹H, ¹³C and ¹⁵N chemical shifts were also correlated to their corresponding atoms. The results are reported herein and compared with HCTZ and its cocrystals whenever appropriate.