Calculation of relative free energy differences for the covalent hydration of organic compounds: A combined quantum mechanical and free energy perturbation study

The relative free energy difference (ΔΔG_hyd) for the reversible addition of water to two unsaturated molecules is accurately computed using a combination of ab initio quantum mechanical calculations and free energy perturbation methods. Initial attempts to calculate the absolute hydration free energy difference (ΔG_hyd) for formaldehyde and trichloroacetaldehyde gave values that differed substantially from experimental results even after inclusion of electron correlation energy contributions using third-order (MP3) and fourth-order (MP4) Møller-Plesset perturbation theory and QCISD(T) correlation methods at the 6-31G** basis set level. Inaccuracies in ΔG_hyd were attributed to errors in the calculation of both ΔG_gas and ΔΔG_sol. Gas phase quantum mechanical free energies (ΔG_gas) varied significantly (2–3 kcal/mol) depending on the level of theory. Errors in ΔΔG_sol were attributed to slow convergence of the calculations using the thermodynamic cycle perturbation (TCP) method with explicit solvent. These errors were minimized or canceled, however, when relative hydration free energy differences (ΔΔG_hyd) were calculated using a combination of ab initio quantum mechanical calculations and free energy perturbation methods. Calculated values for a variety of aldehydes and ketones were consistent with experimental data. © 1995 John Wiley & Sons, Inc.     

Atomic-scale investigation of the interaction between coniferyl alcohol and laccase for lignin degradation using molecular dynamics simulations and spectroscopy

The interaction between coniferyl alcohol (CA) and laccase (LAC) was investigated using molecular dynamics (MD) simulations and spectral experiments. The mode of interaction between CA and LAC was established by MD simulations. The micro-environmental changes, stability and rigidity of the LAC-CA system were assessed by relevant parameters. These parameters include root mean square deviation (RMSD), root mean square fluctuation (RMSF) and radius of gyration (Rg). The calculated binding free energy (ΔG_binding=??19.99?kcal·mol.^?1), the van der waals (VDW) contribution (ΔG_vdw=?23.99?kcal·mol^?1) and the electrostatic energy (ΔG_ele=?23.09?kcal·mol^?1) of LAC-CA system demonstrated that the interaction of LAC-CA was a spontaneous process and the main interaction forces were van der Waal's and electrostatic forces. The values of ΔG_vdw and ΔG_ele were negative, which demonstrated that VDW interactions and electrostatic interactions were favorable for the binding of CA and LAC. The binding constants, thermodynamic parameters, molecular force types and binding distances confirmed the interaction between CA and LAC and further verified the rationality of the theoretical model by spectral experiments. The MD simulations and experimental approaches provide clues for the discovery of new mediators and useful references for the mechanism of microbial degradation of lignin and industrialization of lignocellulose.     

Effect of solvent on the free energy of activation of S_N2 reaction between phenacyl bromide and amines

The kinetics of SN2 reaction between phenacyl bromide and various amines in 12 different solvents were studied. Solvent effects on the rate of this reaction and free energy of activation, ΔG# , were interpreted by applying the Abraham-Kam-let-Taft (AKT) equation. UK solvent polarity (π1*), solvent hydrogen-bond basicity (β1) and Hildebrand cohesive density energy (δH2) are those parameters which increase the rate constant and decrease ΔG# , while solvent hydrogen-bond acidity (α1) will have the compensatory effect. A comparison among obtained values of second rate constants, k2, for different amines in a given solvent indicates that the amine reactivities are highly dependent on their structures. The consequent decrease of the rate constant for different amines in any given solvent was found to be: primary > secondary> tertiary. This order results from steric effects of amines.     

Role of the anomeric effect in methanediamines in the gas phase and aqueous solutions

An ab initio study of methylenediamine and several methylated derivatives in the gas phase and aqueous solution was performed. The conformational preferences can be considered adequately described at the HF/6‐31G**//HF/6‐31G** level, because these results agree with those obtained using larger basis sets and including ZPE and electron correlation. The energy ordering is clearly dependent on the number and position of the methyl groups present in a molecule. For a first set of the compounds, the energies obtained were interpreted in terms of the anomeric effect because the favored conformers show two or one anti orientation between the nitrogen lone pair and the C N polar bond. Reverse anomeric effects were found for a second set of compounds. The NBO analysis was used to interpret these energetic tendencies and the rotational barrier around the N C bonds. Thus, the preference for the anti‐Lp N C N orientations is mainly due to charge delocalization, always stronger than the electrostatic and steric contributions included in the Lewis term. However, the origin for the reverse anomeric effect may be related to the steric hindrance associated with the methylation. The influence of water on the conformational preferences was evaluated by means of the PCM method. Contrary to expectation, the anomeric effect is not reduced in water, and the most stable conformers in the gas phase are maintained in solution. The electrostatic term of the free solvation energy is the main responsible of the energetic changes, and depends strongly on local solute–solvent interactions. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 135–150, 2001     

Kinetic study of specific base catalyzed hydrolysis of ethyl acrylate in water-ethanol binary system

Kinetic study of hydroxide anion catalyzed hydrolysis of ethyl acrylate has been carried in ethanol-water (10–50% v/v) binary systems at the temperature range 30 ± 0.1, 35 ± 0.1, 40 ± 0.1, and 45 ± 0.1°C. Calculated specific rate constant values decreases with increasing proportion of ethanol at all temperatures. The observed retardation of a base catalyzed hydrolysis reaction is explained on the basis of fact that the formation of polarized transition state is disfavored with increase in % of ethanol. The relation between the change in dielectric constant due to variation in binary mixtures and change in specific rate constant are explained on the basis of electrostatic and non electrostatic contributions of solvent mixtures. The variation of ΔG*, ΔH*, ΔS* with solvent composition and the specific effect of water on the reaction rate kinetics are also discussed.     

Effect of the composition of a solution on the enthalpies of solvation of piperidine in methanol-acetonitrile and dimethylsulfoxide-acetonitrile mixed solvents

Heat effects of dissolution of piperidine (ppd) are measured by calorimetry at 298.15 K over the range of composition of acetonitrile-methanol (AN-MeOH) mixed solvents. Based on the Δ_sol H ^○(ppd)_AN-MeOH values obtained using the literature data on Δ_sol H ^○ (ppd) in acetonitrile-dimethylsulfoxide (AN-DMSO) mixed solvents and the vaporization enthalpy of ppd, the enthalpies of solvation of amine in AN-MeOH and AN-DMSO binary mixtures are calculated. A rise in the exothermicity of solvation of piperidine is observed upon the transition from AN to DMSO and MeOH, due mainly to the enhanced solvation of the amino group of ppd as a result of changes in the acid-base properties of the mixed solvent.     

Effect of Preferential Solvation on the Thermodynamic Properties of Antidepressant Drug Trazodone in Aqueous Ethanol: Linear Free‐Energy Relationships

Dissociation constants (pK_a) of trazodone hydrochloride (TZD⋅HCl) in EtOH/H₂O media containing 0, 10, 20, 30, 40, 50, 60, 70, and 80% (v/v) EtOH at 288.15, 298.15, 308.15, and 318.15 K were determined by potentiometric techniques. At any temperature, pK_a decreased as the solvent was enriched with EtOH. The dissociation and transfer thermodynamic parameters were calculated, and the results showed that a non‐spontaneous free‐energy change (Δ_dissG^o>0) and unfavorable enthalpy (Δ_dissH^o>0) and entropy (Δ_dissS^o<0) changes occurred on dissociation of trazodone hydrochloride. The free‐energy change or pK_a varied nonlinearly with the reciprocal dielectric constant, indicating the inadequacy of the electrostatic approach. The dissociation equilibria are discussed on the basis of the standard thermodynamics of transfer, solvent basicity, and solute‐solvent interactions. The values of Δ_transG^o and Δ_transH^o increased negatively with increasing EtOH content, revealing a favorable transfer of trazodone hydrochloride from H₂O to EtOH/H₂O mixtures and preferential solvation of H⁺ and trazodone (TZD). Also, Δ_transS^o values were negative and reached a minimum, in the H₂O‐rich zone that has frequently been related to the initial promotion and subsequent collapse of the lattice structure of water. The pK_a or Δ_dissG^o values correlated well with the Dimroth‐Reichardt polarity parameter E_T(30), indicating that the physicochemical properties of the solute in binary H₂O/organic solvent mixtures are better correlated with a microscopic parameter than the macroscopic one. Also, it is suggested that preferential solvation plays a significant role in influencing the solvent dependence of dissociation of trazodone hydrochloride. The solute‐solvent interactions were clarified on the basis of the linear free‐energy relationships of Kamlet and Taft. The best multiparametric fit to the Kamlet‐Taft equation was evaluated for each thermodynamic parameter. Therefore, these parameters in any EtOH/H₂O mixture up to 80% were accurately derived by means of the obtained equations.     

Solubilities of cefodizime disodium in aqueous alcohol mixtures at atmospheric pressure and different temperatures

Using dynamic method and the laser monitoring observation technique, the solubility of cefodizime disodium in water + (ethanol, 1-propanol, and 2-propanol) was measured as a function of temperature from 278.15 K to 318.15 K under atmospheric pressure. The experimental data were correlated with a simple model of molecular thermodynamics for solubility of solid in liquid. The model parameters were fitted, and the solution enthalpies Δ_solH and solution entropies Δ_solS were estimated. Δ_solH and Δ_solS are all positive. The endothermic effect of solution process may be due to the fact that the newly bond energy between cefodizime disodium and solvent molecules is not powerful enough to compensate the energy needed to break the original association bond in various solvents, and the system needs to absorb heat from surroundings and manifests as Δ_solH > 0. The reason for the entropy increase during the dissolution process is that the solutes disrupt the alignment of solvent molecules and therefore reduced the degree of order of the system while they were dissolved in various solvents. The positive Δ_solH and Δ_solS revealed that the dissolution process of cefodizime disodium was an entropy-driven process.     

Saturation molalities and standard molar enthalpies of solution of cytidine(cr), hypoxanthine(cr), thymidine(cr), thymine(cr), uridine(cr), and xanthine(cr) in H2O(l)

Saturation molalities m(sat) in H₂O(l) have been measured for the substances cytidine(cr), hypoxanthine(cr), thymidine(cr), thymine(cr), uridine(cr), and xanthine(cr) by using h.p.l.c. The states of hydration were established by performing Karl-Fischer analyses on samples of these substances, which had been allowed to equilibrate with their respective aqueous saturated solutions for several days at T≈298 K and then dried with air at T≈296 K for ≈24 h. The crystalline forms of the substances were identified by comparison of the results of X-ray diffraction measurements with results from the literature. Also, molar enthalpies of solution Δ_solH_m(cal) for these substances were measured by using an isoperibol solution calorimeter. A self-association (stacking) model was used to estimate values of the activity coefficients γ and relative apparent molar enthalpies L_φ for these substances. These γ and L_φ values were used to adjust the measured values of m(sat) and Δ_solH_m(cal) to the standard state and thus obtain values of the standard molar Gibbs free energy Δ_solG^∘_m and enthalpy changes Δ_solH_m^∘ for the dissolution reactions of these substances. The values of the pKs and of the standard molar enthalpies of the ionization reactions were also used to account for speciation of the substances in the calculations of Δ_solG_m^∘ and Δ_solH_m^∘. Values of standard molar enthalpies of formation Δ_fH_m^∘, standard molar Gibbs free energies of formation Δ_fG_m^∘, and standard partial molar entropies S_2,m^∘ for the aqueous species of hypoxanthine and xanthine were calculated. A detailed summary and comparison of thermodynamic results from the literature for these substances is presented.     

Saturation molalities and standard molar enthalpies of solution of adenosine(cr), guanosine · 2H2O(cr), inosine(cr), and xanthosine · 2H2O(cr) in H2O(l)

Saturation molalities m(sat) in H₂O(l) have been measured for the substances adenosine(cr), guanosine · 2H₂O(cr), inosine(cr), and xanthosine · 2H₂O(cr) over the temperature range T=287.91 K to T=308.18 K by using h.p.l.c. The indicated states of hydration of these substances were established by performing Karl–Fischer analyses of samples of these substances which had been equilibrated over H₂O(l) and of samples obtained by passing air over the wet crystals (air dried samples). The crystalline phases of these substances were identified by comparison of the results of X-ray diffraction measurements with results from the literature. Molar enthalpies of solution Δ_solH_m for adenosine(cr) and inosine(cr) were measured by using an isoperibol solution calorimeter. A “stacking” or “self-association” model was used to estimate values of the activity coefficients γ and relative apparent molar enthalpies L_φ for these substances. These γ and L_φ values were used to adjust the measured values of m(sat) and Δ_solH_m to the standard state and obtain values of the standard molar Gibbs free energy and enthalpy changes Δ_solG^∘_m and Δ_solH^∘_m, respectively, for the dissolution reactions of these substances. Values of Δ_solH^∘_m calculated from the temperature dependence of values of Δ_solG^∘_m were in good agreement with the values of Δ_solH^∘_m obtained by using calorimetry.     

MP2, DFT‐D,and PCM study of the HMB–TCNE complex: Thermodynamics,electric properties,and solvent effects

Geometry, thermodynamic, and electric properties of the π‐EDA complex between hexamethylbenzene (HMB) and tetracyanoethylene (TCNE) are investigated at the MP2/6‐31G* and, partly, DFT‐D/6‐31G* levels. Solvent effects on the properties are evaluated using the PCM model. Fully optimized HMB–TCNE geometry in gas phase is a stacking complex with an interplanar distance 2.87 × 10^?10 m and the corresponding BSSE corrected interaction energy is ?51.3 kJ mol^?1. As expected, the interplanar distance is much shorter in comparison with HF and DFT results. However the crystal structures of both (HMB)₂–TCNE and HMB–TCNE complexes have interplanar distances somewhat larger (3.18 and 3.28 × 10^?10 m, respectively) than our MP2 gas phase value. Our estimate of the distance in CCl₄ on the basis of PCM solvent effect study is also larger (3.06–3.16 × 10^?10 m). The calculated enthalpy, entropy, Gibbs energy, and equilibrium constant of HMB–TCNE complex formation in gas phase are: ΔH⁰ = ?61.59 kJ mol^?1, ΔS = ?143 J mol^?1 K^?1, ΔG⁰ = ?18.97 kJ mol^?1, and K = 2,100 dm³ mol^?1. Experimental data, however, measured in CCl₄ are significantly lower: ΔH⁰ = ?34 kJ mol^?1, ΔS = ?70.4 J mol^?1 K^?1, ΔG⁰ = ?13.01 kJ mol^?1, and K = 190 dm³ mol^?1. The differences are caused by solvation effects which stabilize more the isolated components than the complex. The total solvent destabilization of Gibbs energy of the complex relatively to that of components is equal to 5.9 kJ mol^?1 which is very close to our PCM value 6.5 kJ mol^?1. MP2/6‐31G* dipole moment and polarizabilities are in reasonable agreement with experiment (3.56 D versus 2.8 D for dipole moment). The difference here is due to solvent effect which enlarges interplanar distance and thus decreases dipole moment value. The MP2/6‐31G* study supplemented by DFT‐D parameterization for enthalpy calculation, and by the PCM approach to include solvent effect seems to be proper tools to elucidate the properties of π‐EDA complexes. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Measuring the enthalpies of interaction between glycine,L-cysteine,glycylglycine, and sodium dodecyl sulfate in aqueous solutions

Calorimetric measurements of enthalpies of solution Δ_sol H ^m for glycine, L-cysteine, and glycylglycine in aqueous solutions of sodium dodecyl sulfate (SDS) with concentrations of up to 0.05 mol kg^–1 are made. Standard enthalpy of solution Δ_sol H ⁰ and enthalpy of transfer Δ_tr H ⁰ of the dipeptide from water into mixed solvent are calculated. The calculated enthalpy coefficients of paired interactions of amino acids and dipeptide with SDS prove to be positive. Hydrophobic interactions between the biomolecules and SDS are found to have a major impact on the enthalpies of interaction in the three-component systems under study, within the indicated range of concentrations.     

Solvent Effect on the Gibbs Energy of Proton Transfer in the 2,6-Dichlorophenol-Triethylamine Complex

Using dipole moment measurements, the Gibbs energy ΔG_PT of proton transfer in the complex of 2,6-dichlorophenol with triethylamine was determined in different solvents. The effect of solvent on ΔG_PT was quantitatively discussed in terms of reaction field models for homogeneous and heterogeneous dielectric media. The specific complex–solvent interactions which, in addition to electrostatic interaction, stabilize the PT polar form of the complex is discussed as a function of the empirical parameters describing the polar and hydrogen-donating (electron-accepting) properties of the solvent.     

Lanthanide thermodynamic predictions—V. Stabilities of lanthanide anions in liquid ammonia

The stabilities (as ΔG⁰_f) of monatomic lanthanide anions in liquid ammonia are estimated from a simple electrostatic model. It is shown that the existence of lanthanide anions in this solvent is highly improbable.     

DFT Study of Solvent Effects for Some Organic Molecules Using a Polarizable Continuum Model

Forty ionic molecules are studied by DFT (B3LYP, B3P86), MP4 with different basis sets using the PCM/UAHF model within the self-consistent reaction-field method to assess solvent effects. For these molecules, the solvation free energies (ΔG _sol) in water and the dipole moments in vacuoas well as in water are obtained. By comparing the calculated values of ΔG _sol with experimental values and molecular simulation results, it is found that the ΔG _sol values generated by the DFT method are in better agreement with experimental values. Moreover, especially for the B3LYP/6-31+G_∗ level, the results of both ΔG _sol and dipole moments are more accurate considering the lower computational cost. It can be noted that the dipole moments of solutes in water show some increase relative to those in vacuo.     

Thermodynamic activation parameters for viscous flow of aqueous solutions of butylamines

The thermodynamic activation parameters, enthalpies, ΔH?^≠, free energies, ΔG ^≠, and entropies, ΔS?^≠, for viscous flow of the systems, water (W)?+?n-butylamine (NBA), W?+?sec-butylamine (SBA) and W?+?tert-butylamine (TBA), have been determined by using the density and the viscosity data. These properties and their excess values have been represented graphically against their composition. With respect to the composition, ΔG ^≠ show a typical behaviour for all the systems – a fast rise in the water-rich region with a maximum followed by the values that decline up to the pure state of amines. The ΔH?^≠ and ΔS?^≠ versus composition curves follow the similar trend. For all systems the excess properties, ΔG ^≠E, ΔH ^?≠E and ΔS?^≠E are characterized by sharp maxima in the water-rich region, which are thought to be mainly due to the hydrophobic hydration and the hydrophilic effect.     

The free energy–reaction coordinate profile for α-chymotryptic hydrolysis of a series of N-acetyl-α-L-amino acid methyl esters

The effect of added nucleophiles (methanol and 1,4-butanediol) on the steady-state kinetics of α-chymotryptic hydrolysis of a series of N-acetyl-L-amino acid methyl esters, R-CH(NHCOCH₃)C(O)OCH₃, has been studied. As a result, the rate and equilibrium constants of the ‘elementary’ steps of the enzyme process have been determined. It has also been demonstrated how the free energy–reaction coordinate profile changes if the structure (the size of the hydrocarbon chain) of the ‘chemically inert’ substrate fragment R is varied. The effects observed can be described by the following equation: where ΔG_s and ΔG_a are the free energies of formation of metastable intermediates, i.e., the enzyme–substrate complex and the acylenzyme, respectively, ΔG₂≠ and ΔG₃≠ are the free energies of activation for the chemical steps, i.e., enzyme acylation and acylenzyme hydrolysis, respectively; and ΔG_trans^(R) is the free energy of transfer of substrate group R from water into a nonaqueous solvent. To explain the results obtained, a mechanism for enzyme–substrate interaction is suggested according to which the potential free energy of sorption of substrate group R on the enzyme is 2 ΔG_trans^(R). Such a high gain in the free energy of hydrophobic interaction may only be realized if (a) in the free enzyme the sorption region has a thermodynamically unfavorable contact with the aqueous medium, and (b) water is forced out of the active center as a result of the hydrophobic interaction of substrate group R with the enzyme. Such a model is in agreement with the published x-ray data on the structure of the crystalline enzyme. The kinetic experiment has proved that not all the potential free energy of sorption is realized as binding force. Thus the true free energy of the binding of substrate group R with the protein does not exceed half the maximum value, both in the enzyme–substrate complex and acylenzyme.     

Actinide thermodynamic predictions—II. Stabilities of actinide anions in liquid ammonia

The stabilities (as ΔG_f^o) of monatomic actinide anions in liquid ammonia are estimated from a simple electrostatic model. It is shown that, with the possible exception of Md^?, the existence of actinide anions in this solvent is highly improbable.     

Evaluating the Solvent Stark Effect from Temperature-Dependent Solvatochromic Shifts of Anthracene

The solvent Stark effect on the spectral shifts of anthracene is studied with temperature-dependent solvatochromic measurements. The Stark contribution Δv_Stark to the absorption shift Δv_p in polar solvents is measured to be Δv_Stark=(53±35) cm⁻¹, in reasonable agreement with dielectric continuum theory estimate of 28 cm⁻¹, whereas the major shift Δv_p∼300 cm⁻¹ presumably originates from the solute quadrupole. We pay attention to the accurate correction of Δv_p for the nonpolar contribution that is crucial when the shifts are modest in magnitude.     

New insight into the substituent effects on the hydrolytic deamination of saturated and unsaturated cytosine

Ab initio calculations were carried out to understand the effect of electron donating groups (EDG) and electron withdrawing groups (EWG) at the C5 position of cytosine (Cyt) and saturated cytosine (H₂Cyt) of the deamination reaction. Geometries of the reactants, transition states, intermediates, and products were fully optimized at the B3LYP/6-31G(d,p) level in the gas phase as this level of theory has been found to agree very well with G3 theories. Activation energies, enthalpies, and Gibbs energies of activation along with the thermodynamic properties (ΔE, ΔH, and ΔG) of each reaction were calculated. A plot of the Gibbs energies of activation (ΔG^‡) for C5 substituted Cyt and H₂Cyt against the Hammett σ-constants reveal a good linear relationship. In general, both EDG and EWG substituents at the C5 position in Cyt results in higher ΔG^‡ and lower σ values compared to those of H₂Cyt deamination reactions. C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) increase ΔG^‡ values for Cyt, while the same substituents decrease ΔG^‡ values for H₂Cyt which is likely due to steric effects. However, the Hammett σ-constants were found to decrease at the C5 position of cytosine (Cyt) and saturated cytosine (H2Cyt) on the deamination reaction. Both ΔG^‡ and σ values decrease for the substituents Cl and Br in the Cyt reaction, while ΔG^‡ values increase and σ decrease in the H₂Cyt reaction. This may be due to high polarizability of bromine which results in a greater stabilization of the transition state in the case of bromine compared to chlorine. Regardless of the substituent at C5, the positive charge on C4 is greater in the TS compared to the reactant complex for both the Cyt and H₂Cyt. Moreover, as the charges on C4 in the TS increase compared to reactant, ΔG^‡ also increase for the C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) in Cyt, while ΔG^‡ decrease in H₂Cyt. In addition, analysis of the frontier MO energies for the transition state structures shows that there is a correlation between the energy of the HOMO–LUMO gap and activation energies.