H-bond acidity

Insertion Reactions. Isocyanates also may undergo iasertion reactions with C—H bonds. Acidic compounds, such as 1,3-dicarbonyl compounds (6), react readily at room temperature to form carboxyamides. At higher temperatures carboxyamides frequentiy undergo secondary reactions leading to cyclized products (33,34). 

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] ... 

As the solute descriptors (E, S, A, B and V) represent the solute influence on various solute-solvent phase interachons, the regression coefficients e, s, a, h and V correspond to the complementary effect of the solvent phases on these interactions. As an example, consider the product aA in Eq. (4). Since A is the H-bond acidity of the solute, a is the H-bond basicity of the system. In other words, the intermolecular forces discussed in Sections 12.1.1.2 and 12.1.1.3 are present in all Abraham s log P factorization equations, with the exception of those interactions involving ions. This is the reason why Abraham s equahons are valid for neutral species only. 

In this equation E (R2) is the excess molar refraction, S (tt ) is the solute dipolarity-polarizabiUty, A (2a ) and B(2 3 ) are the solute H-bond acidity and basicity, respectively, and Vis the McGowan characteristic volume (in cm mol /100). The solute size, V, (molecule favors octanol) together with solute H-bond basicity, B, (favors water) are the dominating parameters of this equation. The use of Bo(2P ) resulted in equation... 

Overall H-bond acidity (Absolv) also as Saj1 [8]... 

Product of overall H-bond acidity and basicity (Absolv) Molecular polarizability in A3 (HYBOT) [23] also Alpha Overall H-bond basicity (Absolv) also as Sp 1 [8]... 

Soluble in water H-bonding, acid strength given by pKa... 

FIGURE 9.7 Variation of Kamlet-Taft solvatochromic parameters for methanol/C02 mixtures as a function of added CO2 at 298 K and 17.2 MPa (A)n (dipolarity/polarizability, ( ) (H-bond acidity), and (T)/8 (H-bond basicity). (Adapted from Y. Cui, S. V. Olesik, Anal. Chem., 63 1812(1991).)... 

H-bond acidity and basicity respectively v, p, a, b and c are the multilinear regression parameters. This equation was later modified [59] leading to a new Equation (5.7) ... 

The second approach using gradient mode to assess log P values first proposed by Valko et al. is the use of the chromatographic hydro phobicity index (CHI) obtained from a single fast gradient run (<15 min) [103]. Since CHI is considered as a relevant parameter for QSAR studies, it was demonstrated using LSER that differences occur between CHI parameters and true log P because C HI (and log k) are sensitive to H-bond acidity ability whereas log P is not [104]. Thus, CHIs have to be used with precaution. 

MEASUREMENTS OF H-BOND ACIDITY, BASICITY AND POLARISABILITY-DIPOLARITY BY HPLC... 

The importance of H-bond acidity, basicity and polarisability-dipolarity in describing various partition processes and solubility... 

The power of the solvation equation approach is that it can characterise various partition systems and lipophilicity scales by five molecular descriptors (dispersivity, size, polarisability-dipolarity, H-bond acidity and basicity). All of the five descriptors should be included into the linear regression equations by definition. When one or two coefficients are not significantly different from zero, it means that that particular property does not play a significant role in the partition. 

It has been shown above that basic molecular descriptors like size, H-bond acidity-basicity and polarisability-dipolarity can be used to describe various water-solvent partitions, biological partition processes, and can be used even for estimating the aqueous solubility of compounds. However, the measurement of these molecular descriptors is very time-consuming, and it is not easy to access existing data. Promising results revealed that the fast reversed-phase chromatographic retention data (CHI) could be correlated with such descriptors with a good overall statistical fit (low standard error. 

Using a solver technique (we have used the solver add-in in Microsoft Excel 6.0 ), one can calculate the 3 molecular descriptors (H-bond acidity, H-bond basicity and polarisability-dipolarity). Plass et al. 1122] published the molecular descriptors of tripeptide derivatives based on the above-described method. Although reasonably sensible data were obtained, the method has not yet been validated on a large number of... 

Using the measured CHI data of the model compounds we can set up a correlation equation to express the H-bond acidity (a), H-bond basicity (f) and the polarisability-dipolarity (n) parameters by the CHI values obtained on a particular stationary phase with a particular mobile phase. The plot of the database descriptors as a function of the estimated ones based on the measured CHI values can be seen in Figs. 12.20-12.22. The best equations for the estimation of the descriptors are also shown in the figures. It can be seen that the CHI values obtained on Luna C-18 columns with acetonitrile and trifluoroethanol gradients are used for the fi and the ir calculations. The CHI values... 

The coordination of aromatic rings to transition metals, such as in h -C H A(CO)3, increases C—H bond acidity enough to allow C—H bond exchange with EtOD ... 

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