Free energy dipole solvation

MD simulations in expHcit solvents are stiU beyond the scope of the current computational power for screening of a large number of molecules. However, mining powerful quantum chemical parameters to predict log P via this approach remains a challenging task. QikProp [42] is based on a study [3] which used Monte Carlo simulations to calculate 11 parameters, including solute-solvent energies, solute dipole moment, number of solute-solvent interactions at different cutoff values, number of H-bond donors and acceptors (HBDN and HBAQ and some of their variations. These parameters made it possible to estimate a number of free energies of solvation of chemicals in hexadecane, octanol, water as well as octanol-water distribution coefficients. The equation calculated for the octanol-water coefficient is ... 

Simple electrostatic models can be used to interpret the activity coefficients of polar molecules in terms of just three parameters a radius, the dipole moment of the solute, and the dielectric constant of the solvent. The continuum model of the solvent can be used to deduce a value for the free energy of solvation of a spherical molecule of radius r containing a point dipole at its center. The value obtained by Kirkwood from electrostatic theory is... 

Proton NMR studies of N-methyl formamide (NMF) and NMA at high dilution in deuterated solvents have shown that the level of cis isomer of NMF is 8% in water, 10.3% in chloroform, 8.8% in benzene, and 9.2% in cyclohexane, while the level of cis-NMA (a model for the secondary peptide bond) is 1.5% in water and does not change very much in nonpolar solvents [18]. Ab initio molecular calculations suggest that the small difference in dipole moments in cis and trans forms explain the relative insensitivity of amides to solvent change, unlike esters [22,41], This may be explained by nearly identical free energies of solvation for the two isomers [18]. The energy difference between cis and trans isomers in aqueous solution (AG° = 2.5 kcal mol-1) accounts for the preferential trans conformation adopted by most peptide bonds. Similar results were obtained with nonproline tertiary amides [22]. 

Salomon evaluated absolute enthalpies of solvation in water and in PC. The results of these calculations are found in Appendices 2.11.3 and 2.11.5. They differ significantly from those discussed above and this is attributed to the large difference in the ion-dipole interaction energy between the solvent and anions and cations of equal radii. Salomon also suggested that individual free energies of solvation may be obtained from a plot of differences in conventional free energies versus l/rj. For ions of equal charge and radius, AG iv(H+) is obtained from... 

If the two charges of the dipole featuring in the layer model are replaced with a single point charge, then the one-layer continuous model relating to electrolyte solutions is obtained. According to this model, the part of the free energy of solvation due to electrostatic interactions is [Ab 78 ]... 

Experimentalists often hold the view that the desolvation of the nucleophile is in the initial stage so high that the activation barrier is practically determined by it. According to the MC calculations [55,56], this claim appears to be erroneous, at least as regards the reaction under consideration. Equally erroneous seems to be the conclusion, drawn by Dewar and co-workers from MNDO [17] and AMI [57] calculations and an analysis of experimental data, to the effect that the free energies of solvation of the ion-dipole complex and the transition state are roughly equal. 

The earlier attempt to approach the electrostatic contribution to the free energy of solvation is due to Kirkwood (1934). This model is based on a multipole expansion of the charge distribution of the solute at the center of a spherical cavity surroimded by a continuum represented by the dielectric permittivity of the solvent. When this expansion is limited to rank 1 which corresponds to a pure dipole fi, one finds the Onsager model (Onsager 1936) in which the electrostatic contribution to the free energy of solvation by a solvent of dielectric constant e of a molecule having a dipole moment in a cavity of radius a takes the expression ... 

Solvent effects on conformational equilibria can be pronounced, with higher populations of more polar isomers in polar solvents. This is reflected in Bell s expression for the free energy of solvation of a dipole fx with radius / in a continuum with dielectric constant e. ... 

Taking account of the free energy of solvation of a sphere of radius r having a dipole moment fii... 

---