Jul 2026· Journal of Physical Chemistry A· Vol 130, pp. 5802-5821· 0 citations· 38 references
Medicine
Abstract
We report the pKa values for 15 mono- and disubstituted hydroxycoumarins determined using UV-vis absorbance spectroscopy and computational methods. Six of these values, including the pKa of 5-hydroxycoumarin, are reported for the first time. While the primary focus is on the effects of hydroxyl substitution on the benzene ring, we also examine how a 4-methyl substituent may influence acidity in a subset of four coumarin pairs. The experimental results are supported by two kinds of density functional theory calculations. Time-dependent DFT (TD-DFT) models of the UV-vis spectra show strong agreement with experimental observations of 30 species and facilitate spectral interpretation. In addition, pKa values are predicted through a thermodynamic-cycle calculation that combines gas-phase Gibbs free energies with solvation free energies. This computational method accurately reproduces pKa values for a training set (mean absolute error, MAE = 0.37) and yields predictions for the full experimental data set (MAE = 0.65). Together, the experimental and computational results provide a comprehensive view of the structure-acidity relationships in a diverse series of simple hydroxycoumarins.
In this paper we validate Group Contribution (GC) parameters for substituted phenols and dihydroxybenzenes including catechol, resorcinol and hydroquinone with respect to a recently developed Group Contribution method for estimating the heat of formation of organic compounds with chemical accuracy (1 kcal/mol). For the compounds studied, we found differences greater than this threshold between experimental data from different publications. Using quantum mechanical methods in conjunction with common knowledge from physical organic chemistry, we were able to validate the GC model values and thereby extend the applicability range of the previously developed model. It could be concluded that most GC-predicted values can be considered trustworthy, assuming the B3LYP correction for steric interaction between ortho t-butyl and hydroxyl groups is included. As with earlier studies, we found that G4 quantum-calculated values can serve as a reliable source of gas-phase heats of formation of organic compounds.
Robert J. Meier, P. Rablen· Applied Sciences· 0 citations
Gibbs free energy values obtained from quantum-chemical calculations were used to determine the formation constants of homo- and heteroligand copper(II) complexes with various ligands (amino acids, diimines, and phosphorylated dithiocarbamates) in an aqueous medium. A computationally robust, yet moderately expensive, level of theory—B3LYP/def2-TZVPPD—was employed. Solvent effects were accounted for using two models: C-PCM and SMD. A key prerequisite for obtaining reliable results is the use of a reference complex with a known formation constant that is structurally and solvation-wise similar to the compound under study. In this context, “similarity” implies identical stoichiometry, the same coordination number, the same number of water molecules in the inner coordination sphere; matching charges, however, is considerably less critical. The importance of considering conformers and isomers to obtain the most accurate values is demonstrated. The more rigid the structure and the greater the degree of similarity between the studied and reference compounds, the better the agreement between calculated and experimental data; the discrepancy can be as low as 0.1–0.2 logarithmic units. When an appropriate reference is selected, the average deviation of the calculated stability constants is less than 1 logarithmic unit.
N. S. Aksenin, Mikhail S. Bukharov, V. Shtyrlin et al.· Inorganics· 0 citations
The thermodynamics of protonation equilibria and equilibria between enol and keto tautomers occurring in naturally found hydroxy derivatives of trans-resveratrol analogues were investigated. Reaction Gibbs free energies at room temperature were obtained using the B3LYP functional together with a continuum solvation model for water. From these data, acidity constants (pK a) and tautomerization constants (pK T) were calculated for the electronic ground state (S0) and the lowest excited singlet state (S1). The results reveal a pronounced dependence of both equilibria on the position of the hydroxy substituents. Upon photoexcitation, the compounds become considerably stronger acids and indicate, in many cases, a shift toward the keto tautomers rather than the parent enol forms. Moreover, our results support the feasibility of proton transfer from a hydroxy group on one aromatic ring to the adjacent ring via the central −CHCH– bridge. Such processes may be relevant for nonradiative de-excitation pathways and for the protective biochemical functions of these compounds in plants.
A. Kováčová, M. Michalík, Vladimír Lukeš· ACS Omega· 0 citations
Cocrystallization has emerged as an important strategy in supramolecular chemistry for tuning the physicochemical properties of active pharmaceutical ingredients (APIs). In this study, a cocrystal composed of nitrofurantoin (NF) and 4-hydroxybenzamide (4HBAM) is systematically investigated using combined experimental and computational approaches. Fourier-transform infrared (FT-IR) and Raman spectroscopy were employed to probe vibrational characteristics, while density functional theory (DFT) calculations were performed to optimize the molecular structure and evaluate interaction energies, thermodynamic parameters, and electronic properties. The calculated thermodynamic parameters yielded negative values of enthalpy (ΔH) and Gibbs free energy (ΔG), indicating that the formation of the NF-4HBAM (1,2) cocrystal is exothermic and thermodynamically favourable within the adopted DFT model, while the negative entropy change (ΔS) reflects the increased ordering accompanying cocrystal formation. The calculated interaction energy supports the stability of the hydrogen-bonded assembly. Spectroscopic results show pronounced red shifts in the vibrational frequencies of amide, phenolic OH, and carbonyl (CO) groups, suggesting the presence of strong intermolecular hydrogen bonds of the type NH···O and OH···OC. These interactions are further validated through atom-in-molecules (AIM) and natural bond orbital (NBO) analyses. Frontier molecular orbital analysis reveals a donor-acceptor electronic arrangement, with electron density localized primarily on 4HBAM (HOMO) and NF (LUMO), while global reactivity descriptors indicate increased polarizability and comparatively lower kinetic stability of the cocrystal relative to isolated components. Overall, the study provides a detailed molecular-level insight into the structural and spectroscopic behaviour of the NF-4HBAM system, highlighting its potential relevance in pharmaceutical applications.
A. Shukla, Eram Khan, Sarita Yadav et al.· Spectrochimica Acta Part A -...· 0 citations
This study investigates structure-property and structure-limitation relationships in a series of newly synthesised low-molecular-weight acylhydrazone derivatives obtained via ultrasonic-assisted condensation of heterocyclic aldehydes (pyrimidine, morpholine, and imidazole derivatives) with 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide and 4-hydroxybenzhydrazide. The primary objective was to determine how structural variation within the heterocyclic and acyl fragments influences optical, electrochemical, thermal, and aggregation behaviour. Electrochemical studies revealed a single irreversible reduction process, mainly associated with the electron-withdrawing fragment, with LUMO orbital localization on the thiadiazole or hydrazone linkage, as supported by theoretical calculations. UV-Vis absorption maxima were largely solvent-independent across seven solvents of varying polarity. All compounds exhibited blue emission, except for the molecule containing the morpholine-thiadiazole derivative. However, the fluorescence quantum yields were low (Φ ≤ 4.1%), constituting a major photophysical limitation. Metal-complexation experiments showed weak optical responses to the tested metal cations, indicating limited binding affinity. Aggregation studies showed divergent behaviour depending on molecular structure, including aggregation-enhanced emission in the pyrimidine-thiadiazole derivative. Overall, the results demonstrate that although structural modification modulates electronic distribution and aggregation behaviour, the low emission efficiency and weak metal coordination significantly limit the potential of these materials for sensing or imaging applications.
S. Kotowicz, M. Korzec, Jan Grzegorz Małecki et al.· Chemistry· 0 citations
The dissolution behavior of 2,2′-dihydroxybiphenyl in thirteen mono-solvents–including methyl acetate, ethyl acetate, 2-propanol, methyl propionate, ethanol, 1-propanol, isopropyl acetate, acetonitrile, methanol, n-propyl acetate, 1-butanol, 2-butanol, and isobutanol—was investigated using the static equilibrium method at temperatures ranging from 278.15 K to 313.15 K under 100 kPa. The results showed that solubility increased with rising temperature across all solvents, with methyl acetate exhibiting the highest solubility and isobutanol the lowest. Experimental data were successfully correlated using the van’t Hoff, λh, Wilson, and NRTL models, with the NRTL model providing the most accurate predictions. Mixing thermodynamic analysis revealed that although the dissolution process is exothermic (ΔmixH<0), it is predominantly entropy-driven. This behavior is attributed to the significant increase in system disorder upon solvation, which outweighs the energetic favorability at elevated temperatures. Furthermore, a discrepancy between intermolecular interaction energies and experimental trends was observed: despite stronger hydrogen-bonding capabilities in alcohols, solubility was lower than in esters. This is quantitatively rationalized by considering the energy penalty of disrupting extensive solvent self-association networks in alcohols, which offsets the gains from solute-solvent interactions. These findings provide essential data and theoretical insights for the industrial purification and solvent selection for 2,2′-dihydroxybiphenyl.
Huiyan Pan, Yao-fei Huang, Junlei Shi et al.· Physica Scripta· 0 citations
