Solvent Effects on the Structure-Activity Relationship of Pharmacological Active 3-Substituted-5,5-Diphenylhydantoins

Absorption spectra of eight 3-substituted-5,5-diphenylhydantoins have been recorded in fourteen solvents in the range 200–400 nm. The effect of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions are analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The lipophilic activity of the investigated hydantoins was estimated by the calculation of log ₁₀ P values with the Advanced Chemistry Development Software. The calculated values of log ₁₀ P were correlated with the ratio of the contributions of specific solvent interactions, and, by employing the linear dependence thus obtained, the pharmacological activity of the studied hydantoin derivatives is discussed.     

Solvent Effects on the Structure-Activity Relationship of Phenytoin-like Anticonvulsant Drugs

The absorption spectra of nine compounds structurally related to phenytoin (5,5-diphenylhydantoin) were recorded in twelve solvents over the range of 200 to 400 nm. The effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The lipophilic activity of the investigated hydantoins was estimated by calculation of their log ₁₀ P values. The calculated values of log ₁₀ P were correlated with the ratio of the contributions of specific and non-specific solute/solvent interactions. The correlation equations were combined with the corresponding ED₅₀ values to generate new equations that demonstrate exact relationship between solute/solvent interactions and the structure-activity parameters.     

Solvatochromic studies on the hydrogen-bond donating and dipolarity/polarizability properties of the polyethylene oxide/silica interface

The polarity of the polyethylene oxide(PEO)/silica interface in 1,2-dichloroethane as solvent is classified by means of linear solvation energy (LSE) relationships . The properties of the bare silica particle surface and the silica/PEO interface is expressed by two terms: the dipolarity/polarizability (π*) of the interface and the hydrogen-bond donating ability (α) of the surface silanols. These terms can be defined by using the Kamlet–Taft solvent parameters α and π* as a reference system. The interfacial polarity parameters α and π* were calculated by means of correlation analyses of the energy of the UV/vis absorption maxima of the surface polarity indicators: di-cyano-bis(1,10-phenanthroline) iron II, bis-4,4′-(N,N-dimethylamino) benzophenone, and 2,6-diphenyl-4-(2,4,6-triphenyl-N-pyridino)phenolate when adsorbed onto the PEO/silica particle surface. The experimental values of the E _T(30) parameter of the PEO/silica interface are compared with independently calculated values employing specific LSE relations derived for well-behaved regular solvents and functionalized silicas. PEO adsorption on silica causes a decrease in the value of the α parameter of the silica surface and an evident increase in the dipolarity/polarizability of the interface. Received: 16 December 1998 Accepted in revised form: 8 January 1999     

溶剂效应的TLSER描述及其在几类异构化反应中的应用

建立了适合于描述党溶剂效应的理论线性溶剂化能相关(TLSER)模型。并用该模型对四类异构化反应在不同溶剂下的反应自由能或活化自由能与溶剂的分子结构之间的关系进行了研究,确证了模型的合理性。     

Kinetics and Mechanism of Monomolecular Heterolysis of Commercial Organohalogen Compounds: XXX.1 Correlation Analysis of Solvation Effects in Heterolysis of tert-Butyl Chloride

Quantitative analysis of the effect of solvent parameters on the rate of heterolysis of tert-butyl chloride was performed; the reaction rate is fairly described by the polarity, polarizability, and electrophilicity parameters or by the ionizing ability parameter, while the nucleophilicity of the solvent has no rate effect. A negative effect of nucleophilic solvation was revealed in protic solvents.     

Solvent effect on the racemization kinetics of d-2,2′-dimethoxybiphenyl-6,6′-dicarboxylic acid

The rate constants of racemization of d-2,2′-dimethoxybiphenyl-6,6′-dicarboxylic acid in different solvents can be satisfactorily described by multiparameter equations based on the linear free energy relationship. The main factors responsible for solvent effects are their polarizability and electrophilic solvation power.     

Anisotropic solvent model of the lipid bilayer. 1. Parameterization of long-range electrostatics and first solvation shell effects

A new implicit solvation model was developed for calculating free energies of transfer of molecules from water to any solvent with defined bulk properties. The transfer energy was calculated as a sum of the first solvation shell energy and the long-range electrostatic contribution. The first term was proportional to solvent accessible surface area and solvation parameters (σ(i)) for different atom types. The electrostatic term was computed as a product of group dipole moments and dipolar solvation parameter (η) for neutral molecules or using a modified Born equation for ions. The regression coefficients in linear dependencies of solvation parameters σ(i) and η on dielectric constant, solvatochromic polarizability parameter π*, and hydrogen-bonding donor and acceptor capacities of solvents were optimized using 1269 experimental transfer energies from 19 organic solvents to water. The root-mean-square errors for neutral compounds and ions were 0.82 and 1.61 kcal/mol, respectively. Quantification of energy components demonstrates the dominant roles of hydrophobic effect for nonpolar atoms and of hydrogen-bonding for polar atoms. The estimated first solvation shell energy outweighs the long-range electrostatics for most compounds including ions. The simplicity and computational efficiency of the model allows its application for modeling of macromolecules in anisotropic environments, such as biological membranes.     

UV/Vis Spectroscopic Properties of N -(2′-Hydroxy-4′- N , N -dimethyl-aminobenzylidene)-4-nitroaniline in Various Solvents and Solid Environments

 N-(2′-Hydroxy-4′-N,N-dimethylaminobenzylidene)-4-nitroaniline [HDBN] has been used as a model for investigating intra- and intermolecular D–A (donor–acceptor) interactions in various environments by means of UV/Vis spectroscopy. UV/Vis spectra of HDBN have been measured in various solvents, ethanolic solutions of different pH, adsorbed on silica, and in the solid state. A bathochromic shift of ν_max is observed with increasing the dipolarity/polarizability and HBD (hydrogen bond donor) capacity of the solvent, which is described by means of a multiple LSE (linear solvation energy) relationship in terms of the empirical Kamlet-Taft solvent polarity parameters. The adsorption of HDBN on Aerosil^? 300-silica particles in non-HBA (hydrogen bond acceptor) solvents is explained in the same sense. Mobile protons and sol–gel entrapping cause a hypsochromic shift due to protonation of the lone electron pair of the 4′-N,N-dimethylamino group. Hydroxide ions attack the 2′-hydroxy group which causes a bathochromic shift. A strong intramolecular hydrogen bond between the 2′-hydroxyl hydrogen and the imine nitrogen atom is present in the solid-state structure causing an unprecedented bathochromic shift.     

Synthesis, structure, and solvatochromic properties of pharmacologically active 5-substituted 5-phenylhydantoins

Abstract  

A series of 5-substituted 5-phenylhydantoins was synthesized and their UV absorption spectra were recorded in the region 200–400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent–solute hydrogen-bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The lipophilicities of the investigated hydantoins were estimated by calculation of their log P values. The quantitative relationship between the ratio of the contributions of specific solvent interactions and the corresponding lipophilicity parameter is discussed. The correlation equations were combined with the corresponding ED₅₀ values and different physicochemical parameters to generate new equations that demonstrate the reasonable relationships between solute–solvent interactions and the structure–activity parameters. In order to determine a spectroscopic assignment of the absorption bands in different solvents, quantum chemical calculations were done.     

Reactions of 2-thiophenesulphonyl chloride with anion and neutral nucleophiles: Solvent effects on nucleophilic reactivity correlations

The reaction kinetics of 2-thiophenesulphonyl chloride with anion and neutral nucleophiles was studied in H₂O, D₂O and in protic solvents-H₂O (10% $\text{v}\text{v}$) and aprotic solvents-H₂O (10% $\text{v}\text{v}$) mixtures at 25°. Analysing the rate constants measured in water by Bronsted, Ritchie and Edwards equations the conclusion drawn that, for the nucleophilic order against the sulphonyl sulphur, basicity is of prime importance, although there may well be some dependence on polarizability and solvation. Solvent isotope effects show that the reactions occur by nucleophilic catalysis rather than by a general base mechanism. Water is the solvent in which there is the greater reactivity than in either protic solvents or aprotic-protic mixtures. By solubility measurements and applying Parker's equation the contributions of solvation energies of both reactants and transition states to the free energy of activation are calculated. Solvent effects on nucleophilic reactivities are discussed in terms of S parameters (similar to Ritchie N₊ parameters), and by the approach of multiparameter empirical correlations. The data point out that solvation plays a large role on nucleophilic order. A complete comprehension of the problem would require an equation that takes into some account solvent effects. The homogeneous comparison of 2-thiophenesulphonyl chloride data with those of α-disulphone, p-anisyl p-methoxybenzenesulphinyl sulphone and benzenesulphonyl chloride shows that the same factors are involved in driving the nucleophilic reactivity for these compounds.     

A Continuum Reaction Field Theory of Polarizable, Nondipolar, Quadrupolar Solvents: Ab Initio Study of Equilibrium Solvation in Benzene

A continuum theory to describe solvation in nondipolar quadrupolar solvents is developed by accounting for electronic polarizability. A general Hamiltonian for a solute–solvent system in an arbitrary nonequilibrium configuration is obtained in terms of two field variables—densities of the solvent quadrupole and induced dipole moments. Equilibrium solvation is studied by optimizing this Hamiltonian with account of cavity boundaries. As an application, electronic structures and free energies of small molecules in benzene are examined with ab initio methods. Solvation stabilization due to solvent quadrupole moments is found to be substantial; for the solutes considered here, it is comparable to and often in excess of that arising from solvent-induced dipole moments.     

Preferential solvation of etoricoxib in some aqueous binary cosolvent mixtures at 298.15 K

Preferential solvation parameters of etoricoxib in several aqueous cosolvent mixtures were calculated from solubilities and other thermodynamic properties by using the IKBI method. Cosolvents studied were as follows: 1,4-dioxane, N,N-dimethylacetamide, 1,4-butanediol, N,N-dimethylformamide, ethanol and dimethyl sulfoxide. Etoricoxib exhibits solvation effects, being the preferential solvation parameter δx_1,3, negative in water-rich and cosolvent-rich mixtures but positive in mixtures with similar proportions of both solvents. It is conjecturable that the hydrophobic hydration in water-rich mixtures plays a relevant role in drug solvation. In mixtures of similar solvent proportions where etoricoxib is preferentially solvated by the cosolvents, the drug could be acting as Lewis acid with the more basic cosolvents. Finally, in cosolvent-rich mixtures the preferential solvation by water could be due to the more acidic behaviour of water. Nevertheless, the specific solute–solvent interactions in the different binary systems remain unclear because no relation between preferential solvation magnitude and cosolvent polarities has been observed.     

UV/Vis Spectroscopic Properties of <Emphasis Type="Italic">N</Emphasis>-(2′-Hydroxy-4′-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethyl-aminobenzylidene)-4-nitroaniline in Various Solvents and Solid Environments

Summary.  N-(2′-Hydroxy-4′-N,N-dimethylaminobenzylidene)-4-nitroaniline [HDBN] has been used as a model for investigating intra- and intermolecular D–A (donor–acceptor) interactions in various environments by means of UV/Vis spectroscopy. UV/Vis spectra of HDBN have been measured in various solvents, ethanolic solutions of different pH, adsorbed on silica, and in the solid state. A bathochromic shift of ν_max is observed with increasing the dipolarity/polarizability and HBD (hydrogen bond donor) capacity of the solvent, which is described by means of a multiple LSE (linear solvation energy) relationship in terms of the empirical Kamlet-Taft solvent polarity parameters. The adsorption of HDBN on Aerosil^? 300-silica particles in non-HBA (hydrogen bond acceptor) solvents is explained in the same sense. Mobile protons and sol–gel entrapping cause a hypsochromic shift due to protonation of the lone electron pair of the 4′-N,N-dimethylamino group. Hydroxide ions attack the 2′-hydroxy group which causes a bathochromic shift. A strong intramolecular hydrogen bond between the 2′-hydroxyl hydrogen and the imine nitrogen atom is present in the solid-state structure causing an unprecedented bathochromic shift. Corresponding author. E-mail: stefan.spange@chemie.tu-chemnitz.de Received July 8, 2002; accepted (revised) September 30, 2002     

On the origin of ionic liquid‐induced variations in hydroxypropyl methacrylate propagation rate coefficients

Pulsed laser polymerizations were used to study the propagation kinetics of hydroxypropyl methacrylate (HPMA) in ionic liquids (ILs) and common organic solvents. The functional monomer was chosen to investigate the complex interplay of all interactions between monomer molecules and between monomer and solvent molecules and to obtain a deeper understanding of the impact of these interactions. The solvent effect on the HPMA propagation rate coefficient (k_p) was examined using a linear solvation energy relationship (LSER) based on Kamlet‐Taft solvatochromic parameters π*, α, and β. The results suggest that dipolarity/polarizability, associated with π*, and hydrogen bond–donating ability of the solvents, accounted for by α, majorly contribute to variations in k_p. Hydrogen bond–accepting (electron pair donating) ability of the solvents (β parameter) is of much lesser importance. In addition, LSER enables the prediction of HPMA k_p based on solvatochromic parameters of the solvents. The results suggest that interactions between the hydroxyl group of the monomer and the anion are dominant compared with classical hydrogen bonding between carbonyl and hydroxyl groups of the monomer units. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3188–3199, 2010     

Solvatochromism in Binary Solvent Mixtures by Means of a Penta‐tert‐butyl Pyridinium N‐Phenolate Betaine Dye

The solvatochromic behavior of a penta‐tert‐butyl prydinium N‐phenolate betaine dye was studied using UV‐visible spectrophotometry in several binary mixture solvents. The solvent polarity parameter, E_T (1) (kcal. mol^?1) was calculated from the position of the longest‐wavelength intramolecular charge transfer absorption band of this penta‐tert‐butyl betaine dye. For binary solvent mixtures, all plots of E_T (1) versus the mole fraction of a more polar component are nonlinear owing to preferential solvation of the probe by one component of the binary solvent mixture. In the computation of E_T (1) it was assumed that the two solvents mixed interact to form a common structure with an E_T (1) value not always intermediate between those of the two solvents mixed. The results obtained are explained by the strong synergism observed for some of the binary mixtures with strong hydrogen bond donors (HBD) solvents such as alcohols.     

A solvolysis model for 2-chloro-2-methyladamantane based on the linear solvation energy approach

Solvolysis/dehydrohalogenation rates of 2-chloro-2-methyladamantane (CMA) in 15 hydrogen-bond acidic and/or basic solvents are studied. The rates of reaction in these solvents have been correlated with the solvation equation developed by Kamlet, Abraham, and Taft. The linear solvation energy relationship (LSER) derived from this study is given by the following equation: log k = -5.409 + 2.219 + 2.505alpha(1) - 1.823beta(1) where , alpha(1), and beta(1) are the solvation parameters that measure the solvent dipolarity/polarizability, hydrogen-bond acidity (electrophilicity), and hydrogen-bond basicity (nucleophilicity). A high correlation coefficient (r = 0.996, SD = 0.191) was achieved. The cavity term, which includes the Hildebrand parameter for solvent cohesive energy density, delta(H), was not found to be statistically significant for this reaction substrate. The resulting equation allows calculated rates of reaction in other solvents and provides insight into the reaction pathway. In a previously reported correlation for another tertiary chloride, tert-butyl chloride (TBC), the coefficients for alpha(1) and are significantly larger and the coefficient for is statistically significant. In addition, the coefficient for beta(1) in the TBC correlation is positive, rather than negative, indicating that the transition states for TBC and CMA are significantly different. These results demonstrate why the uses of simple solvolytic correlation methods may be invalid even for comparisons of similar type substrates, e.g., tertiary chlorides. Also, these results provide confidence in the use of multiple linear regression analysis for predicting solvolytic rates in additional solvents.     

Influence de la solvatation preferentielle sur les dimensions des polymeres en solution dans des melanges de solvants

We have studied the dependence of the intrinsic viscosity number of polymers on the composition of binary solvents. The systems studied are: polystyrene in CCl₄/CH₃OH, C₆H₆/CH₃OH and C₆H₆/heptane and poly-2-vinylpyridine in CHCl₃/CH₃CH₂OH. We have also studied, for the same systems, preferential solvation of the polymers, using light scattering.We have observed that, near the θ point, short polystyrene chains exhibit a higher expansion than long chains. This was explained in terms of the dependence of preferential solvation on molecular weight.For the system poly-2-vinylpyridine/CH₃CH₂OH/CHCl₃, we have established the viscosity increment dependence on solvent composition. The curve describing this increment differs markedly from the theoretical curve based on G^E values (excess free energy) of the solvent mixture. However, taking into consideration the process of preferential solvation, the experimental curve can be corrected and becomes very similar in shape to the theoretical curve but there still remains a quantitative difference between the two curves.     

Solvatochromism of the π* ← n transition of acetone by combined quantum mechanical—classical mechanical calculations

The solvent shift of the π* ← n transition of acetone in water, acetonitrile, and tetrachloromethane was calculated in a combined quantum mechanical—classical mechanical approach, using both dielectric continuum and explicit, polarizable molecular solvent models. The explicit modeling of solvent polarizability allows for a separate analysis of electrostatic, induction, and dispersion contributions to the shifts. The calculations confirm the qualitative theories about the mechanisms behind the blue shift in polar solvents and the red shift in nonpolar solvents, the solvation of the ground state due to electrostatic interactions being preferential in the former, and favorable dispersion interaction with the excited state, in the latter case. Good quantitative agreement for the solvent shift between experiment (+1,700, +400, and −350 cm⁻¹ in water, acetonitrile, and tetrachloromethane, respectively) and the explicit solvent model (+1,821, +922, and −381 cm⁻¹) was reached through a modest Monte Carlo sampling of the solvent degrees of freedom. A consistent treatment of the solvent could only be realized in the molecular solvent model. The dielectric-only model needs reparameterization for each solvent. © 1996 John Wiley & Sons, Inc.