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Urease is a metalloenzyme that catalyzes the hydrolysis of urea, and its modulation has an important role in both the agricultural and medical industry. Even though numerous molecules have been tested against ureases of different species, their clinical translation has been limited due to chemical and metabolic stability as well as side effects. Therefore, screening new compounds against urease would be of interest in part due to rising concerns regarding antibiotic resistance. In this work, we collected and curated a diverse set of 2640 publicly available small-molecule inhibitors of jack bean urease and developed a classifier using a random forest machine learning method with high predictive performance. In addition, the physicochemical features of compounds were paired with molecular docking and protein–ligand fingerprint analysis to gather insight into the current activity landscape. We observed that the docking score could not differentiate active from inactive compounds within each chemical family, but scores were correlated with compound activity when all compounds were considered. Additionally, a decision tree model was built based on 2D and 3D Morgan fingerprints to mine patterns of the known active-class compounds. The final machine learning model showed good prediction performance against the test set (81% and 77% precision for active and inactive compounds, respectively). Finally, this model was employed, as a proof-of-concept, on an in-house library to predict new hits that were then tested against urease and found to be active. This is, to date, the largest, most diverse dataset of compounds used to develop predictive in silico models. Overall, the results highlight the usefulness of using machine learning classifiers and molecular docking to predict novel urease inhibitors.

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.

A pharmacophore model for inhibitors of Escherichia coli’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1H-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between N-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1H-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.

HIV-2 infection is frequently neglected in HIV/AIDS campaigns. However, a special emphasis must be given to HIV-2 as an untreated infection that also leads to AIDS and death, and for which the efficacy of most available drugs is limited against HIV-2. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry. Here, we developed and optimized a computer-assisted drug design approach of an important HIV-2 glycoprotein that allows us to explore and gain further insights at the molecular level into protein structures and interactions crucial for the inhibition of HIV-2 cell entry. The 3D structure of a key HIV-2ROD gp125 region was generated by a homology modeling campaign. To disclose the importance of the main structural features and compare them with experimental results, 3D-models of six mutants were also generated. These mutations revealed the selective impact on the behavior of the protein. Furthermore, molecular dynamics simulations were performed to optimize the models, and the dynamic behavior was tackled to account for structure flexibility and interactions network formation. Structurally, the mutations studied lead to a loss of aromatic features, which is very important for the establishment of π-π interactions and could induce a structural preference by a specific coreceptor. These new insights into the structure-function relationship of HIV-2 gp125 V3 and surrounding regions will help in the design of better models and the design of new small molecules capable to inhibit the attachment and binding of HIV with host cells.

Lipoaminoacids (LAA) are an important group of biosurfactants, formed by a polar hydrophilic part (amino acid) and a hydrophobic tail (lipid). The gemini LAA structures allow the formation of a supramolecular complex with bioactive molecules, like DNA, which provides them with good transfection efficiency. Since lipases are naturally involved in lipid and protein metabolism, they are an alternative to the chemical production of LAA, offering an eco-friendly biosynthetic process option. This work aimed to design the production of novel cystine derived gemini through a bioconversion system using immobilized lipases. Three lipases were used: porcine pancreatic lipase (PPL), lipase from Thermomyces lanuginosus (TLL), and lipase from Rizhomucor miehei (RML). PPL was immobilized in sol-gel lenses. L-cystine dihydrochloride and dodecylamine were used as substrates for the bioreaction. The production of LAA was evaluated by thin layer chromatography (TLC), and colorimetric reaction with eosin. The identification and quantification was carried out by High Performance Liquid Chromatographer-Mass Spectrometry (HPLC-MS/MS). The optimization of media design included co-solvent (methanol, dimethylsulfoxide), biphasic (n-hexane and 2-propanol) or solvent-free media, in order to improve the biocatalytic reaction rates and yields. Moreover, a new medium was tested where dodecylamine was melted and added to the cystine and to the biocatalyst, building a system of mainly undissolved substrates, leading to 5 mg/mL of LAA. Most of the volume turned into foam, which indicated the production of the biosurfactant. For the first time, the gemini derived cystine lipoaminoacid was produced, identified, and quantified in both co-solvent and solvent-free media, with the lipases PPL, RML, and TLL.

The role of metalloproteinases (MMPs) on the migration and invasion of cancer cells has been correlated with tumor aggressiveness, namely with the up-regulation of MMP-2 and 9. Herein, two pyridine-containing macrocyclic compounds, [15]pyN5 and [16]pyN5, were synthesized, chemically characterized and evaluated as potential MMP inhibitors for breast cancer therapy using 3D and 2D cellular models. [15]pyN5 and [16]pyN5 (5&ndash, 20 &micro, M) showed a marked inhibition of MMPs activity (100% at concentrations &ge, 7.5 &mu, M) when compared to ARP-100, a known MMP inhibitor. The inhibitory activity of [15]pyN5 and [16]pyN5 was further supported through in silico docking studies using Goldscore and ChemPLP scoring functions. Moreover, although no significant differences were observed in the invasion studies in the presence of all MMPs inhibitors, cell migration was significantly inhibited by both pyridine-containing macrocycles at concentrations above 5 &mu, M in 2D cells (p &lt, 0.05). In spheroids, the same effect was observed, but only with [16]pyN5 at 20 &mu, M and ARP-100 at 40 &mu, M. Overall, [15]pyN5 and [16]pyN5 led to impaired breast cancer cell migration and revealed to be potential inhibitors of MMPs 2 and 9.

Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation.

Proteasome emerged as an important target in recent pharmacological research due to its pivotal role in degrading proteins in the cytoplasm and nucleus of eukaryotic cells, regulating a wide variety of cellular pathways, including cell growth and proliferation, apoptosis, DNA repair, transcription, immune response, and signaling processes. The last two decades witnessed intensive efforts to discover 20S proteasome inhibitors with significant chemical diversity and efficacy. To date, the US FDA approved to market three proteasome inhibitors: bortezomib, carfilzomib, and ixazomib. However new, safer and more efficient drugs are still required. Computer-aided drug discovery has long being used in drug discovery campaigns targeting the human proteasome. The aim of this review is to illustrate selected in silico methods like homology modeling, molecular docking, pharmacophore modeling, virtual screening, and combined methods that have been used in proteasome inhibitors discovery. Applications of these methods to proteasome inhibitors discovery will also be presented and discussed to raise improvements in this particular field.

Phototoxic and radical-generating debromination reactions of monobrominated hypericin with bromine at one of four possible positions were investigated using density functional theory. The study was performed on two closely lying conformational isomers, differing in the relative orientations of the two anthracene units of the hypericin core. Calculated adiabatic electron affinities show that the molecules have the ability to, in aqueous solution, extract an electron from the surrounding. The electron might then be passed on to molecular oxygen, forming reactive superoxide radical anions. If electron extraction from the molecule does not occur in this step, the molecule might dissociate, generating a negatively charged bromine as a leaving group and a hypericin radical capable of forming direct binding to biological molecules. This reaction was found possible for those species substituted by Br at two of the four positions, with barriers of similar to 13 kcal/mol in aqueous solution. Debromination was not found energetically possible for neither the neutral ground state compounds nor the bay-deprotonated species. (c) 2008 Wiley Periodicals, Inc.

Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used to elucidate the photochemistry and photophysics of eight different perylenequinones (PQ). The objective of this work has been to quantitatively investigate the photodynamic therapeutic potential of this family of compounds and give an overview of their photoreactivity. The effects of solvation were evaluated through single-point calculations using the integral equation formalism of the polarised continuum model. It is concluded that the eight studied perylenequinones can generate singlet oxygen (in aqueous solution) and superoxide radical anions, and that the autoionisation of two nearby PQ molecules is possible.

Time-resolved photoacoustic calorimetry (TR-PAC) was used to investigate the energetics of O–H bonds of phenol, catechol, pyrogallol, and phloroglucinol. Values of −27.1 ± 3.9, −44.1 ± 4.4 and −1.6 ± 3.8 kJ mol−1, respectively, were obtained for the solution-phase (acetonitrile) O–H bond dissociation enthalpies of the last three compounds relative to the O–H bond dissociation enthalpy in phenol, ΔDHosln(ArO–H) = DHosln(ArO–H) − DHosln(PhO–H). A value of 388.7 ± 3.7 kJ mol−1 was determined for the PhO–H bond dissociation enthalpy in acetonitrile. Density functional theory (MPW1PW91/aug-cc-pVDZ) calculations and complete basis set (CBS-4M) calculations were carried out to analyse intramolecular hydrogen bonding and to predict gas-phase O–H bond dissociation enthalpies, DHo(ArO–H). A microsolvation model, based on the DFT calculations, was used to study the differential solvation of the phenols and their radicals in acetonitrile and to bridge solution- and gas-phase data. The results strongly suggest that ΔDHosln(ArO–H) ≈ ΔDHo(ArO–H). Hence, to calculate absolute gas-phase O–H bond dissociation enthalpies in substituted phenols from the corresponding solution-phase values, the solvation enthalpies of the substituted phenols and their radicals are not required.

The hydration of the hydroxyl OH radical has been investigated by microsolvation modeling and statistical mechanics Monte Carlo simulations. The microsolvation approach was based on density functional theory (DFT) calculations for OH–(H2O)1–6 and (H2O)1–7 clusters. The results from microsolvation indicate that the binding enthalpies of the OH radical and water molecule to small water clusters are similar. Monte Carlo simulations predict that the hydration enthalpy of the OH radical, ΔhydH(OH,g), is −39.1 kJ mol−1. From this value we have estimated that the band gap of liquid water is 6.88 eV, which is in excellent agreement with the result of Coe et al. [J. Chem. Phys. 107, 6023 (1997)]. We have compared the structure of the hydrated OH solution with the structure of pure liquid water. The structural differences between the two systems reflect the strong role played by the OH radical as a proton donor in water. From sequential Monte Carlo/DFT calculations the dipole moment of the OH radical in liquid wate...

Monte Carlo statistical mechanics simulations, density-functional theory calculations, time-resolved photoacoustic calorimetry, and isoperibol reaction-solution calorimetry experiments were carried out to investigate the solvation enthalpies and solvent effects on the energetics of the phenol O−H bond in benzene and acetonitrile. A good agreement between theoretical and experimental results is obtained for the solvation enthalpies of phenol in benzene and acetonitrile. The theoretical calculations also indicate that the differences between the solvation enthalpies of phenol (PhOH) and phenoxy radical (PhO•) in both benzene and acetonitrile are significantly smaller than previous estimations based on the ECW model. The results for the solvation enthalpies are used to obtain the O−H bond dissociation enthalpies in benzene and acetonitrile. For benzene and acetonitrile, the theoretical results of 89.4 ± 1.2 and 90.5 ± 1.7 kcal mol-1, respectively, are in good agreement with the experimental values (90.9 ± 1....

Sequential Monte Carlo/Quantum Mechanical (S-MC/QM) calculations of the dipole moment of liquid water using extensive and different quantum chemical methods and statistically converged results give an induced dipole moment of 0:74 � 0:14 D. This corresponds to a dipole moment of liquid water of 2:60 � 0:14 D, in excellent agreement with the value derived from the dielectric constant and other previous theoretical estimates. Change in multipole moments are also reported using statistically converged MP2/aug-cc-pVQZ calculations. 2003 Elsevier Science B.V. All rights reserved.

We are reporting density functional theory results for the binding energies, structures, and vibrational spectra of (H-Cl)2–6 and (H-F)2–10 clusters. The performance of different functionals has been investigated. The properties of HF clusters predicted by hybrid functionals are in good agreement with experimental information. The HCl dimer binding energy ΔEe is underestimated by hybrid functionals. The Perdew and Wang exchange and correlation functional (PW91) result for ΔEe is −9.6 kJ mol−1, in very good agreement with experiment (−9.5 kJ mol−1). However, PW91 overestimates binding energies of larger clusters. Hydrogen bonding cooperativity depends on the cluster size n but reaches a limit for moderately sized clusters (n=8 for HF). The average shift to low frequencies (Δν) of the X-H (X=Cl,F) stretching vibration relative to the monomer is in good agreement with experimental data for HF clusters in solid neon. However, some discrepancies with experimental results for HCl clusters were observed. The behavior of Δν as a function of the cluster size provides an interesting illustration of hydrogen-bond cooperative effects on the vibrational spectrum. The representation of the electronic density difference shows the rearrangement of the electronic density induced by hydrogen bonding in the clusters and supports the view that hydrogen-bond cooperativity is related to electronic sharing and delocalization.

Time-resolved photoacoustic calorimetry (TR-PAC) and quantum chemistry calculations were used to investigate the energetics of sulfur-hydrogen bonds in thiophenol and four para-substituted thiophenols, 4-XC 6 H 4 SH (X = CH 3 , OCH 3 , Cl, and CF 3 ). The result obtained for the PhS-H gas-phase bond dissociation enthalpy, derived from the PAC experimental results in solution, is 349.4 ′ 4.5 kJ mol - 1 . This value is significantly higher than recent literature values but agrees with a value suggested some 20 years ago in a widely used review. The PAC result also concurs with the value computed at a high theory level, G3(MP2), 346.8 kJ mol - 1 . The data obtained for the substituted thiophenols support the idea that substituent effects are less pronounced on the S-H bond dissociation enthalpy than on the O-H bond dissociation enthalpy of the corresponding phenols.

The energetics of the C-Cl bond in 2-chloropropionic acid was investigated by using a combination of experimental and theoretical methods. The standard molar enthalpy of formation of liquid (S)-(-)-2-chloropropionic acid,at 298.15 K, was determined as Δ f H o m (C 3 H 5 O 2 Cl, 1) = -(534.6 ′ 1.1) kJ.mol - 1 , by rotating-bomb combustion calorimetry. The corresponding enthalpy of vaporization, Δ v a p H o m (C 3 H 5 O 2 Cl) = (64.9 ′ 0.5) kJ.mol - 1 , was also obtained from vapor pressure versus temperature measurements by the transpiration method, leading to Δ f H o m (C 3 H 5 O 2 Cl, g) = -(469.7 ′ 1.2) kJ.mol - 1 . This value, together with the enthalpy of the isodesmic and isogyric gas-phase reaction CH 3 CH(X)COOH(g) + C 2 H 5 (g) CH3CHCOOH(g) + C 2 H 5 X(g) (X = H, Cl) predicted by density functional theory calculations and other auxiliary data, was used to derive the enthalpy of formation of the gaseous 1-carboxyethyl radical as Δ f H o m [CH(CH 3 )COOH, g] = -(293 ′ 3) kJ.mol - 1 , from which DH°[H-CH(CH 3 )COOH] = 380.7 ′ 3.9 kJ.mol - 1 and DH°[Cl-CH(CH 3 )COOH] = 298.0 ′ 3.2 kJ.mol - 1 were obtained. These values are compared with the corresponding C-H and C-Cl bond dissociation enthalpies in XCH 2 COOH, XCH 3 , XC 2 H 5 , XCH 2 -Cl, XCH(CH 3 )Cl, XCH=CH 2 , and XC 6 H 5 (X = H, Cl). The order DH°(C-H) > DH°(C-Cl) is observed for the carboxylic acids and all other RX compounds. Comparison of DH°[X-CH(CH 3 )COOH] and DH°[X-CH 2 COOH] (X = H, Cl) indicates that the replacement of a hydrogen of the CH 2 group of XCH 2 COOH by a methyl group leads to a decrease of both the C-H and C-Cl bond dissociation enthalpy. It is finally concluded that the major qualitative trends exhibited by the C-Cl bond dissociation enthalpies for the series of compounds addressed in this work can be predicted based on Pauling's electrostatic-covalent model.

We are reporting ab initio and density functional theory (DFT) calculations for the phenol O–H bond dissociation energy in the gas phase and in phenol–water clusters. We have tested a series of recently proposed functionals and verified that DFT systematically underestimates the O–H bond dissociation energy of phenol. However, O–H bond dissociation energies in water clusters are in reasonable agreement with experimental data for phenol in solution. We have evaluated electronic difference densities in phenol–water, phenoxy–water, and water, and we are suggesting that the representation of this quantity gives an interesting picture of the electronic density rearrangement induced by hydrogen bond interactions in phenol–water clusters. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001

Recent measurements of the dielectric permittivity of hydrofluorocarbons in the liquid phase have allowed calculation of the dipole moments in a liquid environment. These values were based on Kirkwood theory, and were significantly greater than the corresponding gas phase dipole moments. In order to understand some features suggesting possible hindered rotation of the molecules in the liquid, density functional and self-consistent-reaction-field calculations for a series of HFC molecules including CHF2CF3 (HFC-125), CH2FCF3 (HFC-134a), CH3CF3 (HFC-143a), CH2F2 (HFC-32) and CHF2CH3 (HFC-152a) are reported. Particular emphasis has been given to the calculation of dimerisation energies, rotational potentials, polarisabilities and dipole moments. We discuss hydrogen bonding in hydrofluorocarbon dimers and the relationship between the structure and charge distribution of the dimers and the dipole moment in the liquid predicted by relative permittivity measurements. For HFC-32 we have calculated the average dipole moment in small clusters (n = 2–10). The structure of the clusters has been determined by density functional theory optimisations (n = 2–6) and Monte Carlo simulations (n = 2–10). The average dipole moment of the HFC-32 decamer is 2.35 D, which represents a 17% increase relative to the free monomer (2.0 D). We find that the enhancement of the monomer dipole induced by hydrogen bonding in HFC-32 clusters is much less pronounced in comparison with the considerable increase (50%) observed in water clusters.

Structural, vibrational, and thermochemical properties of phenol−(H2O)1-6 and phenoxy radical−(H2O)1-4 complexes were calculated by using density functional theory. The insertion of a phenol molecu...

Herein we demonstrate for the first time that a boron promoted one-pot assembly reaction may be used to discover novel enzyme inhibitors. Inhibitors for HNE were simply assembled in excellent yields, high diastereoselectivities and IC50 up to 1.10 μM, based on components like salicylaldehyde, aryl boronic acids and amino acids. The combination of synthetic, biochemical, analytical and theoretical studies allowed the identification of the 4-methoxy or the 4-diethyl amino substituent of the salicylaldehyde as the most important recognition moiety and the imine alkylation, lactone ring opening as key events in the mechanism of inhibition.

Allopsoralens are angular psoralen derivatives presenting advantages over the parent compound because of monofunctional DNA-photobinding and consequent lower toxicity. Allopsoralen molecules with three different substituents and different protonation states were studied using the molecular dynamics technique. The location of these molecules when inside the lipid bilayer is of major importance because their photochemical properties can change with the environment. Also, the ability of psoralens to form photoadducts with unsaturated phospholipids depends on the preference of the molecules to locate themselves closer to the bilayer middle were the double bond functionality can be found. Herein we show that the allopsoralens tend to accumulate inside the lipid bilayer closer to the water interface when protonated or closer to the interface middle otherwise. Allopsoralens containing one amine terminated carbon chain tend to have different rotational and orientational behaviour and an orientation preference close to the ones shown by the lipids. The size and chemical nature of the substituent also affect the molecular mobility and capacity to interact with water molecules and the nitrogen or phosphorus atoms of the lipids.

The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy, Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine.. - Modelling and Simulation Research Center (ESEE) ; Swedish Research Council ; Faculty of Science and Technology at Orebro University ; National University of Ireland, Galway ; The Portuguese Fundacao para a Ciencia e a Tecnologia. - Financial Support from the Modelling and Simulation Research Center (ESEE), the Swedish Research Council, the Faculty of Science and Technology at Orebro University, and the National University of Ireland, Galway (LAE), is gratefully acknowledged. We also acknowledge generous grants of computing time at the National Supercomputing Center (NSC) in Linkoping. The Portuguese Fundacao para a Ciencia e a Tecnologia is also acknowledged for financial support.

Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.

Molecular docking studies of two duplex DNA sequences as target fragments and allopsoralen as ligand were performed. The calculated interaction energies showed that the ligand can be docked into the minor groove as well as become intercalated. However, unlike psoralen, allopsoralen preferred binding mode for non-poly-TA sequences is minor groove binding. Calculated energies for intercalation between different base pairs suggest that the predicted sequence selectivity for allopsoralen is analogous to that observed for psoralen. Intercalation is favored in 5'-TpA sites in poly-TA sequences. (C) 2007 Elsevier B.V. All rights reserved.

The energetics of the phenolic O-H bond in the three hydroxybenzoic acid isomers and of the intramolecular hydrogen O-H- - -O-C bond in 2-hydroxybenzoic acid, 2-OHBA, were investigated by using a combination of experimental and theoretical methods. The standard molar enthalpies of formation of monoclinic 3- and 4-hydroxybenzoic acids, at 298.15 K, were determined as Delta(f)(3-OHBA, cr) = -593.9 +/- 2.0 kJ x mol(-1) and Delta(f)(4-OHBA, cr) = -597.2 +/- 1.4 kJ x mol(-1), by combustion calorimetry. Calvet drop-sublimation calorimetric measurements on monoclinic samples of 2-, 3-, and 4-OHBA, led to the following enthalpy of sublimation values at 298.15 K: Delta(sub)(2-OHBA) = 94.4 +/- 0.4 kJ x mol(-1), Delta(sub)(3-OHBA) = 118.3 +/- 1.1 kJ x mol(-1), and Delta(sub)(4-OHBA) = 117.0 +/- 0.5 kJ x mol(-1). From the obtained Delta(f)(cr) and Delta(sub) values and the previously reported enthalpy of formation of monoclinic 2-OHBA (-591.7 +/- 1.3 kJ x mol(-1)), it was possible to derive Delta(f)(2-OHBA, g) = -497.3 +/- 1.4 kJ x mol(-1), Delta(f)(3-OHBA, g) = -475.6 +/- 2.3 kJ x mol(-1), and Delta(f)(4-OHBA, cr) = -480.2 +/- 1.5 kJ x mol(-1). These values, together with the enthalpies of isodesmic and isogyric gas-phase reactions predicted by density functional theory (B3PW91/aug-cc-pVDZ, MPW1PW91/aug-cc-pVDZ, and MPW1PW91/aug-cc-pVTZ) and the CBS-QMPW1 methods, were used to derive the enthalpies of formation of the gaseous 2-, 3-, and 4-carboxyphenoxyl radicals as (2-HOOCC(6)H(4)O(*), g) = -322.5 +/- 3.0 kJ.mol(-1) Delta(f)(3-HOOCC(6)H(4)O(*), g) = -310.0 +/- 3.0 kJ x mol(-1), and Delta(f)(4-HOOCC(6)H(4)O(*), g) = -318.2 +/- 3.0 kJ x mol(-1). The O-H bond dissociation enthalpies in 2-OHBA, 3-OHBA, and 4-OHBA were 392.8 +/- 3.3, 383.6 +/- 3.8, and 380.0 +/- 3.4 kJ x mol(-1), respectively. Finally, by using the ortho-para method, it was found that the H- - -O intramolecular hydrogen bond in the 2-carboxyphenoxyl radical is 25.7 kJ x mol(-1), which is ca. 6-9 kJ x mol(-1) above the one estimated in its parent (2-OHBA), viz. 20.2 kJ x mol(-1) (theoretical) or 17.1 +/- 2.1 kJ x mol(-1) (experimental).

The energetics of the phenol O–H bond in methanol and the water O–H bond in liquid water were investigated by microsolvation modelling and statistical mechanics Monte Carlo simulations. The microsolvation approach was based on density functional theory calculations. Optimised structures for clusters of phenol and the phenoxy radical with one and two methanol molecules are reported. By analysing the differential solvation of phenol and the phenoxy radical in methanol, we predict that the phenol O–H homolytic bond dissociation enthalpy in solution is 24.3±11 kJ/mol above the gas-phase value. The analysis of the water O–H bond dissociation by microsolvation was based on optimised structures of OH•–(H2O)1−6 and –(H2O)1−7 clusters. Microsolvation modelling and statistical mechanics simulations predict that the HO–H bond dissociation enthalpies in the gas phase and in liquid water are very similar. Our results stress the importance of estimating the differences between the solvation enthalpies of the radical species and the parent molecule and the limitations of local models based on microsolvation.

The O–H and S–H homolytic bond dissociation enthalpies of a set of disubstituted phenols and thiophenols (NH2, OH, CH3, Cl, CF3, and NO2) have been computed by a density functional theory procedure with the 6-311++G(d,p) basis set. A very good agreement between our results and available experimental ones is observed. The effect of substituents on structure, charges and BDEs are investigated and their correlation with Hammett parameters is studied. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008

Monte Carlo simulations and thermodynamic perturbation theory calculations have been carried out to analyze the differential hydration of phenol (PhOH) and phenoxy radical (PhO•). The hydration enthalpy of phenol predicted by different phenol−water interaction models is in good agreement with experimental data. On the basis of the difference in the hydration enthalpy of phenol and phenoxy radical, we find that the O−H bond dissociation enthalpy in water is above the recommended experimental value for the gas phase by ca. 7 kcal/mol. This result is in agreement with photoacoustic calorimetry measurements for phenol in other polar solvents. Thermodynamic perturbation theory results for the relative hydration Gibbs energy of phenol and phenoxy radical are also reported. The structure of the solutions suggests that the differential solvation of phenol and phenoxy radical can be related to the strong character of phenol as a hydrogen bond donor in comparison with the role played by phenoxy radical as a hydroge...