Molecular recognition probes of solvation thermodynamics in solvent mixtures

High-throughput UV-Vis experiments using four molecular recognition-based probes, made by the combination of two hydrogen bond acceptors, tri-n-butylphosphine oxide and N,N'-bis(2-ethylhexyl)acetamide, and two hydrogen bond donors, 4-phenylazophenol and 4-nitrophenol, were performed. The association constants for the 1 : 1 H-bond interaction involved in each probe system were measured in mixtures of a polar and non-polar solvent, di-n-hexyl ether and n-octane, respectively. Similar behaviour was observed for all four systems. When the concentration of the polar solvent was low, the association constant was identical to that observed in pure n-octane. However, once the concentration of the polar solvent exceeded a threshold, the association constant decreased linearly with the concentration of di-n-hexyl ether. Selective solvation in mixtures can be understood based on the competition between the multiple competing equilibria in the system. In this case, solvation thermodynamics are dominated by competition of the ether for solvation of H-bond donors. For the more polar solute, 4-nitrophenol, the selective solvation starts at lower concentrations of the polar solvent compared with the less polar solute, 4-phenylazophenol. Thus the speciation and hence the properties of systems containing multiple solutes and multiple solvents can be estimated from the H-bond properties and the concentrations of the individual functional groups.     

Spectral Investigations of Preferential Solvation and Solute–Solvent Interactions of Free Base and Protonated 5,10,15,20-Tetrakis(4-trimethyl-ammonio-phenyl)-porphine Tetratosylate in Aqueous Organic Mixed Solvents

The solvatochromic properties of the free base and the protonated 5,10,15,20-tetrakis(4-trimethyl-ammonio-phenyl)-porphine tetratosylate (TTMAPP) were studied in pure water, methanol, ethanol, 2-propanol, and their corresponding aqueous mixtures. The correlation of the empirical solvent polarity scale (E _T) values of TTMAPP with composition of the solvents were analyzed by the solvent exchange model of Bosch and Roses to clarify the preferential solvation of the probe dyes in the binary mixed solvents. The solvation shell composition effects in preferential solvation of the solute dyes were investigated in terms of both solvent–solvent and solute–solvent interactions and also the local mole fraction of each solvent composition was calculated in the cybotactic region of the probe. The effective mole fraction variation may provide significant physicochemical insights in the microscopic and molecular level of interactions between TTMAPP species and the solvent components and, therefore, can be used to interpret the solvent effect on kinetics and thermodynamics of TTMAPP.     

Preferential solvation and solvation shell composition of free base and protonated 5, 10, 15, 20-tetrakis(4-sulfonatophenyl)porphyrin in aqueous organic mixed solvents

The solvatochromic properties of the free base and the protonated 5, 10, 15, 20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) were studied in pure water, methanol, ethanol (protic solvents), dimethylsulfoxide, DMSO, (non-protic solvent), and their corresponding aqueous-organic binary mixed solvents. The correlation of the empirical solvent polarity scale (E(T)) values of TPPS with composition of the solvents was analyzed by the solvent exchange model of Bosch and Roses to clarify the preferential solvation of the probe dyes in the binary mixed solvents. The solvation shell composition and the synergistic effects in preferential solvation of the solute dyes were investigated in terms of both solvent-solvent and solute-solvent interactions and also, the local mole fraction of each solvent composition was calculated in cybotactic region of the probe. The effective mole fraction variation may provide significant physico-chemical insights in the microscopic and molecular level of interactions between TPPS species and the solvent components and therefore, can be used to interpret the solvent effect on kinetics and thermodynamics of TPPS. The obtained results from the preferential solvation and solvent-solvent interactions have been successfully applied to explain the variation of equilibrium behavior of protonation of TPPS occurring in aqueous organic mixed solvents of methanol, ethanol and DMSO.     

Drastic changes in the fluorescence properties of NBD probes with the polarity of the medium: involvement of a TICT state?

The spectroscopic and photophysical properties of two 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) derivatives with different substituents on the nitrogen group are reported in 18 solvents. The solvatochromic shifts were analysed by correlating with polarity scales. The results, together with the help of modified neglect of diatomic overlap (MNDO) calculations, enable the polarity of the ground and first singlet excited states to be determined. Experiments based on variations in temperature and viscosity establish that the two probes undergo different de-excitation pathways. The possibilities of internal rotation leading to a twisted intramolecular charge transfer (TICT) state in the case of diethylamino-NBD are discussed. A study in binary solvent mixtures outlines specific solvent—solute interactions. Appropriate restrictions are emphasized on the utilization of NBD probes in biological fields.     

Site-specific solvation determined by intermolecular nuclear Overhauser effect--measurements and molecular dynamics

Site-specific solvation has been determined by intermolecular NOE measurements between solvent and solute. The experimental effect is shown on the four compounds 2-butanol, L-alanyl-L-tryptophan (Ala-Trp), adenosine and the disodium salt of adenosine 5'-monophosphate (5'-AMP) in the two solvents water and dimethyl sulfoxide (DMSO). The strength of NOE transfer correlates with the average distribution of solvent molecules around the corresponding solvation sites represented by the number of solvent molecules in a first solvation sphere, which can be obtained from molecular dynamics simulations in water. Saturation transfer between exchanging protons explains some deviations from this correlation. The NOE transfer measurements provide information on specific solute-solvent interactions and contribute to a better understanding of solvation phenomena. On the basis of a distinct relationship between steric solvation hindrance and the strength of NOE transfer, the application of such measurements for conformational analysis has been demonstrated for the first time.     

Characterizing ionic liquids on the basis of multiple solvation interactions

Room-temperature ionic liquids (RTILs) are useful in many chemical applications. Recent publications have attempted to determine the polarity of RTILs using empirical solvent polarity scales. The results have indicated that most RTILs have similar polarities. Nevertheless, RTILs are capable of behaving quite differently when used as solvents in organic synthesis, matrixes in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, liquid-liquid extraction, and as stationary phases in gas chromatography. The work presented in this study uses a linear free energy approach to characterize 17 RTILs on the basis of their distinct multiple solvation interactions with probe solute molecules. This model provides data that can be used to help identify the interactions and properties that are important for specific chemical applications.     

What can you learn from a molecular probe? New insights on the behavior of C343 in homogeneous solutions and AOT reverse micelles

The behavior of C343, a common molecular probe utilized in solvation dynamics experiments, was studied in homogeneous media and in aqueous and nonaqueous reverse micelles (RMs). In homogeneous media, the Kamlet and Taft solvatochromic comparison method quantified solute-solvent interactions from the absorption and emission bands showing that the solvatochromic behavior of the dye depends not only on the polarity of the medium but also on the hydrogen-bonding properties of the solvent. Specifically, in the ground state the molecule displays a bathochromic shift with the polarity polarizability (pi) and the H-bond acceptor (beta) ability of the solvents and a hypsochromic shift with the hydrogen donor ability (alpha) of the media. The carboxylic acid group causes C343 to display greater sensitivity to the beta than to the pi polarity parameter; this sensitivity increases in the excited state, while the dependence on alpha vanishes. This demonstrates that C343 forms a stable H-bond complex with solvents with high H-bond acceptor ability (high beta) and low H-bond donor character (low alpha). Spectroscopy in nonpolar solvents reveals J-aggregate formation. With information from the Kamlet-Taft analysis, C343 was used to explore RMs composed of water or polar solvents/sodium 1,4-bis-2-ethylhexylsulfosuccinate (AOT)/isooctane using absorption, emission, and time-resolved spectroscopies. Sequestered polar solvents included ethylene glycol (EG), formamide (FA), N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA). Dissolved in the AOT RM systems at low concentration, C343 exists as a monomer, and when introduced to the RM samples in its protonated form, C343 remains protonated driving it to reside in the interface rather than the water pool. The solvathochromic behavior of the dye depends the specific polar solvent encapsulated in the RMs, revealing different types of interactions between the solvents and the surfactant. EG and water H-bond with the AOT sulfonate group destroying their bulk H-bonded structures. While water remains well segregated from the nonpolar regions, EG appears to penetrate into the oil side of the interface. In aqueous AOT RMs, C343 interacts with neither the sulfonate group nor the water, perhaps because of intramolecular H-bonding in the dye. DMF and DMA interact primarily through dipole-dipole forces, and the strong interactions with AOT sodium counterions destroy their bulk structure. FA also interacts with the Na+ counterions but retains its H-bond network present in bulk solvent. Surprisingly, FA appears to be the only polar solvent other than water forming a "polar-solvent pool" with macroscopic properties similar to the bulk.     

Ab-initio molecular dynamics and hybrid explicit-implicit solvation model for aqueous and nonaqueous solvents: GFP chromophore in water and methanol solution as case study

Solute–solvent interactions are proxies for understanding how the electronic density of a chromophore interacts with the environment in a more exhaustive way. The subtle balance between polarization, electrostatic, and non-bonded interactions need to be accurately described to obtain good agreement between simulations and experiments. First principles approaches providing accurate configurational sampling through molecular dynamics may be a suitable choice to describe solvent effects on solute chemical–physical properties and spectroscopic features, such as optical absorption of dyes. In this context, accurate energy potentials, obtained by hybrid implicit/explicit solvation methods along with employing nonperiodic boundary conditions, are required to represent bulk solvent around a large solute–solvent cluster. In this work, a novel strategy to simulate methanol solutions is proposed combining ab initio molecular dynamics, a hybrid implicit/explicit flexible solvent model, nonperiodic boundary conditions, and time dependent density functional theory. As case study, the robustness of the proposed protocol has been gauged by investigating the microsolvation and electronic absorption of the anionic green fluorescent protein chromophore in methanol and aqueous solution. Satisfactory results are obtained, reproducing the microsolvation layout of the chromophore and, as a consequence, the experimental trends shown by the optical absorption in different solvents.     

Controlled self-assembly of triphenylene-based molecular nanostructures

Molecular nanostructures of the disc-shaped molecule hexapentyloxytriphenylene have been fabricated on length scales ranging from 30 nm to 1.5 mum following self-assembly arising from pi-pi interactions in organic solvents. The size and density of the molecular nanostructures deposited onto glass and indium tin oxide-coated glass substrates were characterized by atomic force microscopy. Dynamic light scattering and spectroscopic evidence of predeposition aggregation in solution are presented, suggesting that the nanostructures are organized in solution and then deposited onto the substrate. Correlations between the relative solvent polarity and the size of molecular nanostructures as well as between the solute concentration in dilute solutions and their density on the substrate are discussed.     

Chromatographic and spectroscopic methods for the determination of solvent properties of room temperature ionic liquids

Room temperature ionic liquids are novel solvents with favorable environmental and technical features. Synthetic routes to over 200 room temperature ionic liquids are known but for most ionic liquids physicochemical data are generally lacking or incomplete. Chromatographic and spectroscopic methods afford suitable tools for the study of solvation properties under conditions that approximate infinite dilution. Gas-liquid chromatography is suitable for the determination of gas-liquid partition coefficients and activity coefficients as well as thermodynamic constants derived from either of these parameters and their variation with temperature. The solvation parameter model can be used to define the contribution from individual intermolecular interactions to the gas-liquid partition coefficient. Application of chemometric procedures to a large database of system constants for ionic liquids indicates their unique solvent properties: low cohesion for ionic liquids with weakly associated ions compared with non-ionic liquids of similar polarity; greater hydrogen-bond basicity than typical polar non-ionic solvents; and a range of dipolarity/polarizability that encompasses the same range as occupied by the most polar non-ionic liquids. These properties can be crudely related to ion structures but further work is required to develop a comprehensive approach for the design of ionic liquids for specific applications. Data for liquid-liquid partition coefficients is scarce by comparison with gas-liquid partition coefficients. Preliminary studies indicate the possibility of using the solvation parameter model for interpretation of liquid-liquid partition coefficients determined by shake-flask procedures as well as the feasibility of using liquid-liquid chromatography for the convenient and rapid determination of liquid-liquid partition coefficients. Spectroscopic measurements of solvatochromic and fluorescent probe molecules in room temperature ionic liquids provide insights into solvent intermolecular interactions although interpretation of the different and generally uncorrelated "polarity" scales is sometimes ambiguous. All evidence points to the ionic liquids as a unique class of polar solvents suitable for technical development. In terms of designer solvents, however, further work is needed to fill the gaps in our knowledge of the relationship between ion structures and physicochemical properties.     

Effects of polar protic solvents on dual emissions of 3-hydroxychromones

3-Hydroxychromones (3HC), exhibit dual emissions highly sensitive to solvent properties due to excited state intramolecular proton transfer (ESIPT). Therefore, 3HCs find wide applications as fluorescence probes in biological systems. Here, it is particularly important to understand the fluorescence behaviour of 3HCs in polar environments. Herein, we studied 3-hydroxyflavone, 2-(2-furyl)-3-hydroxychromone and 2-(2-benzofuryl)-3-hydroxychromone in high polarity solvents characterized by different H-bond donor abilities, donor concentrations and acceptor abilities. Our results show that the dual emissions of the dyes are insensitive to solvent basicity but strongly depend on the two other parameters. Moreover, furyl-and benzofuryl-substituted dyes were significantly more sensitive than the 3-hydroxyflavone to H-bond donor ability, while all three dyes showed roughly equivalent high sensitivity to H-bond donor concentration. These results can be explained by different mechanisms. Thus, the sensitivity of all three dyes to increasing concentrations of H-bond donors probably results from increase in the population of solvated dye with disrupted intramolecular H-bonds. Meantime, the sensitivity to H-bond donor ability of the solvent, observed mainly with furyl and benzofuryl dyes, is probably related to the strength of the H-bonds between the solvent and the 4-carbonyl group of the dye with intact intramolecular H-bonds. The present results provide new insights for further applications of 3HC derivatives as environment-sensitive probes and labels of biological molecules.     

Preferential solvation of indomethacin and naproxen in ethyl acetate + ethanol mixtures according to the IKBI method

The preferential solvation parameters of indomethacin and naproxen in ethyl acetate + ethanol mixtures are derived from their thermodynamic properties by using the inverse Kirkwood–Buff integrals method. It is found that both drugs are sensitive to solvation effects, so the preferential solvation parameter, δx_EA,D, is negative in ethanol-rich and ethyl acetate-rich mixtures but positive in compositions from 0.36 to 0.71 in mole fraction of ethyl acetate. It is conjecturable that in ethanol-rich mixtures, the acidic interaction of ethanol on basic sites of the analgesics plays a relevant role in the solvation. The more solvation by ethyl acetate in mixtures of similar co-solvent compositions could be due to polarity effects. Finally, the slight preference of these compounds for ethanol in ethyl acetate-rich mixtures could be explained as the common participation of basic sites in both solvents and the acidic site of ethanol. Nevertheless, the specific solute–solvent interactions remain unclear.     

Density functional theory of solvation and its relation to implicit solvent models

We describe a density functional theory approach to solvation in molecular solvents. The solvation free energy of a complex solute can be obtained by direct minimization of a density functional, instead of the thermodynamic integration scheme necessary when using atomistic simulations. In the homogeneous reference fluid approximation, the expression of the free-energy functional relies on the knowledge of the direct correlation function of the pure solvent. After discussing general molecular solvents, we present a generic density functional describing a dipolar solvent and we show how it can be reduced to the conventional implicit solvent models when the solvent microscopic structure is neglected. With respect to those models, the functional includes additional effects such as the microscopic structure of the solvent, the dipolar saturation effect, and the nonlocal character of the dielectric constant. We also show how this functional can be minimized numerically on a three-dimensional grid around a solute of complex shape to provide, in a single shot, both the average solvent structure and the absolute solvation free energy.     

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.     

New highly fluorescent ketocyanine polarity probes

The syntheses and spectral properties of three new and highly fluorescent solvent polarity probes are described. They are found to be extremely sensitive to solvent polarity in that spectral red shifts in both absorption and fluorescence spectra occur upon increasing solvent polarity. Excitation and emission data of the dyes in a set of different polar solvents are given. The emission data are compared with the standard ET^N values of solvent polarity and a linear correlation is obtained over a wide range. The origin of the unusual solvatochromic properties is discussed in terms of the resonance structures of this new group of molecular probes. Their outstanding features include high spectral sensitivity to polarity, high molar absorptivities, high fluorescence quantum yields, longwave excitation and emission, insignificant quenching by oxygen, and a sufficient stability in aqueous solution. Therefore, the new probes are considered to be advantageous over other polarity probes used so far in probing biochemical and biological systems.     

Dynamic stokes shift and excitation wavelength dependent fluorescence of dipolar molecules in room temperature ionic liquids

Room temperature ionic liquids (RTILs) are viscous media consisting entirely of ions. Because of the complex nature of various interactions in these media, the solvent properties of the RTILs are very little understood. Since the fluorescence response of molecules comprising conjugated electron donor and acceptor groups, referred to as dipolar molecules, is one of the most frequently exploited sources of information on complex media, whose properties are largely unknown, it is possible to obtain insight into the structure and dynamics of the RTILs by studying the fluorescence behavior of dipolar solutes in these complex media. The most commonly exploited utility of a fluorescent dipolar system is in the estimation of the polarity of the media from its steady state fluorescence response. While several dipolar systems do provide estimates of the polarity of various RTILs, there can be circumstances when the steady state emission frequency of a dipolar system may not truly reflect the equilibrium solvation energy and, hence, the polarity of the medium. The fluorescence response of a dipolar system can be dependent on the excitation wavelength, an observation not commonly encountered in conventional solvents of similar polarities. On the other hand, the time-resolved fluorescence behavior of a dipolar solute in polar medium is one of the primary sources of information on the time-scale of reorganization of the solvent molecules around the photoexcited species. As the RTILs are sufficiently polar media, the time-dependent fluorescence data of the dipolar systems provide insight into the dynamics and mechanism of solvation in these media, which differ considerably from the conventional solvents. These aspects have been discussed taking into consideration the inherent absorption and fluorescence behavior of the imidazolium ionic liquids.     

COSMO-RS: A novel view to physiological solvation and partition questions

Both, dielectric continuum solvation models as well as surface or group based methods using polarity and lipophilicity parameters have been proven to be useful tools for the analysis of solvation and partition questions. For the first time, COSMO-RS provides an integrated theory, which combines the aspects of continuum solvation and surface interactions, and which ends up with chemical potentials of molecules in almost arbitrary solvents and mixtures. Due to its sound theoretical basis, COSMO-RS does not only provide a new quantitative access to solvation and partition properties in well defined solvents, but it also opens a novel view and gives a better understanding of the general problem of solvation. Finally, this allows for a generalisation of COSMO-RS to sophisticatedphysiological partition problems involving as complex phases as blood, brain, or cell membranes. The use of COSMO-RS for drug discovery and design is demonstrated by applications to blood-brain partition coefficients, and water solubility.     

Linear models for prediction of ibuprofen crystal morphology based on hydrogen bonding propensities

Solvents have a significant impact on the final crystal form of organic solids during solution crystallization. The use of polarity scales such as Hildebrand solubility parameter and dielectric constant for solvent selection often proves too generalized and do not provide enough insights into the solvent–solute intermolecular interactions directly affecting crystal growth and morphology. This paper addresses the challenging task of selecting an appropriate single component solvent property index that most accurately and sufficiently characterizes crystal morphology. Cooling crystallization experiments were carried out in a wide range of solvents using ibuprofen as a model pharmaceutical compound. Subsequently, optical microscope images were used for quantitative characterization of morphology. Linear models that correlate ibuprofen crystal morphology with pure solvent properties were developed. Our results show that, in general, there is a negative linear correlation between crystal aspect ratio (morphology) and a given solvent index. Some correlations revealed significant deviations which were explained with the help of infrared spectroscopic measurements. The “acceptance number” was identified as an index that significantly captures the ibuprofen–solvent hydrogen bonding intermolecular interactions. Predictions, using model based on acceptance number, were found to compare very well with experimentally determined aspect ratio data from the open literature. Finally, based on insights gained from this work, a flowchart which serves as a useful solvent selection guideline for crystallization of ibuprofen is proposed.     

Molecular density functional theory of solvation: from polar solvents to water

A classical density functional theory approach to solvation in molecular solvent is presented. The solvation properties of an arbitrary solute in a given solvent, both described by a molecular force field, can be obtained by minimization of a position and orientation-dependent free-energy density functional. In the homogeneous reference fluid approximation, limited to two-body correlations, the unknown excess term of the functional approximated by the angular-dependent direct correlation function of the pure solvent. We show that this function can be extracted from a preliminary MD simulation of the pure solvent by computing the angular-dependent pair distribution function and solving subsequently the molecular Ornstein-Zernike equation using a discrete angular representation. The corresponding functional can then be minimized in the presence of an arbitrary solute on a three-dimensional cubic grid for positions and Gauss-Legendre angular grid for orientations to provide the solvation structure and free-energy. This two-step procedure is proved to be much more efficient than direct molecular dynamics simulations combined to thermodynamic integration schemes. The approach is shown to be relevant and accurate for prototype polar solvents such as the Stockmayer solvent or acetonitrile. For water, although correct for neutral or moderately charged solute, it tends to underestimate the tetrahedral solvation structure around H-bonded solutes, such as spherical ions. This can be corrected by introducing suitable three-body correlation terms that restore both an accurate hydration structure and a satisfactory energetics.