Solvation H-bonded

VhD54 VlY49 1.7 1 solvated H bond and 3 van der Waals contacts... 

VlY49 VhN54 1.6 1 solvated H bond and 1 van der Waals contact... 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

Figure 17.4 The phase diagrams of the systems (a) HF/H2O and (b) HCI/H2O. Note that for hydrofluoric acid all the solvates contain >1HF per H2O, whereas for hydrochloric acid they contain <1HC1 per H2O. This is because the H bonds F-H F and F-H O are stronger than O-H O, whereas C1-H---C1 and C1-H---0 are weaker than 0-H---0. Accordingly the solvates in the former system have the crystal structures [HsOJ+F , [H30]+[HF2] and [H30] [H3F4], whereas the latter are [H30]+C1 , [H502]" C1 and [H502]" CP. H2O. The structures of HCI.6H2O and the metastable HCI.4H2O are not known.

Aromatic denitrocyclizations have been used for many years in some well-known synthetic reactions. Probably the best known example is the Turpin synthesis of phenoxazines and similar synthesis of phenothiazines. The classical setup used usually base-catalyzed reactions in polar protic solvents, very often alcohols. In many cases using polar aprotic solvents was found advantageous. Besides the mentioned influence of the H-bonding, better ionization and lower solvation of the nucleophile are also important. Sf Ar reactions proceed through strongly polarized complexes, which are well soluble and highly polarized in polar aprotic solvents. 

The substituent effects on the H-bonding in an adenine-uracil (A-U) base pair were studied for a series of common functional groups [99JPC(A)8516]. Substitutions in the 5 position of uracil are of particular importance because they are located toward the major groove and can easily be introduced by several chemical methods. Based on DFT calculation with a basis set including diffuse functions, variations of about 1 kcal/mol were found for the two H-bonds. The solvent effects on three different Watson-Crick A-U base pairs (Scheme 100) have been modeled by seven water molecules creating the first solvation shell [98JPC(A)6167]. 

Dynamic light-scattering experiments or the analysis of some physicochemical properties have shown that finite amounts of formamide, A-methylformamide, AA-dimethyl-formamide, ethylene glycol, glycerol, acetonitrile, methanol, and 1,2 propanediol can be entrapped within the micellar core of AOT-reversed micelles [33-36], The encapsulation of formamide and A-methylformamide nanoclusters in AOT-reversed micelles involves a significant breakage of the H-bond network characterizing their structure in the pure state. Moreover, from solvation dynamics measurements it was deduced that the intramicellar formamide is nearly completely immobilized [34,35],... 

H-bonding is an important, but not the sole, interatomic interaction. Thus, total energy is usually calculated as the sum of steric, electrostatic, H-bonding and other components of interatomic interactions. A similar situation holds with QSAR studies of any property (activity) where H-bond parameters are used in combination with other descriptors. For example, five molecular descriptors are applied in the solvation equation of Kamlet-Taft-Abraham excess of molecular refraction (Rj), which models dispersion force interactions arising from the polarizability of n- and n-electrons the solute polarity/polarizability (ir ) due to solute-solvent interactions between bond dipoles and induced dipoles overall or summation H-bond acidity (2a ) overall or summation H-bond basicity (2(3 ) and McGowan volume (VJ [53] ... 

R. H., Kamlet, M. J. Linear solvation relationships. 39. A multiple parameter equation for P values of (H-bond acceptor basicities) of the XYZP=0 compounds. /. Org. Chem. 1988, 53, 1737-1741. 

The nonlinear character of log has not often been discussed previously. Nevertheless, Jorgensen and Duffy [26] argued the need for a nonlinear contribution to their log S regression, which is a product of H-bond donor capacity and the square root of H-bond acceptor capacity divided by the surface area. Indeed, for the example above their QikProp method partially reflects for this nonlinearity by predichng a much smaller solubility increase for the indole to benzimidazole mutation (0.45 versus 1.82 [39, 40]). Abraham and Le [41] introduced a similar nonlinearity in the form of a product of H -bond donor and H -bond acceptor capacity while all logarithmic partition coefficients are linear regressions with respect to their solvation parameters. Nevertheless, Abraham s model fails to reflect the test case described above. It yields changes of 1.8(1.5) and 1.7(1.7) [42] for the mutations described above. 

From the results described above it is clear that a different QSPR model can be obtained depending on what data is used to train the model and on the method used to derive the model. This state of affairs is not so much a problem if, when using the model to predict the solubility of a compound, it is clear which model is appropriate to use. The large disparity between models also highlights the difficulty in extrapolating any physical significance from the models. Common to all models described above is the influence of H-bonding, a feature that does at least have a physical interpretation in the process of aqueous solvation. 

QuantlogP, developed by Quantum Pharmaceuticals, uses another quantum-chemical model to calculate the solvation energy. As in COSMO-RS, the authors do not explicitly consider water molecules but use a continuum solvation model. However, while the COSMO-RS model simpUfies solvation to interaction of molecular surfaces, the new vector-field model of polar Uquids accounts for short-range (H-bond formation) and long-range dipole-dipole interactions of target and solute molecules [40]. The application of QuantlogP to calculate log P for over 900 molecules resulted in an RMSE of 0.7 and a correlation coefficient r of 0.94 [41]. 

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 ... 

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