Substituent group contributions

The Importance of the Tg of the polymer in determining permeability is evident from the relationship in Figure 2. In most cases, the Tg is available from literature compilations (.11). Methods of estimating Tg from substituent group contributions have been described (12,13). Some qualitative guidelines for predicting the change in Tg with polymer structure are ... 

Additivity—The Basic Premise. The concept of additivity of substituent group contributions is merely an expression of the medicinal chemist s intuition which has so successfully led to the development of useful therapeutic agents in the past 70 years. However, it is such a basic... 

Free and Wilson gave a more general description of this mathematical (empirical) model in 1964 (30). According to their method, the defined biological response (BR) of a congener in a homologous series is equal to the sum of the substituent group contributions to the activity plus that of the parent structure (/x), Equation 5. For example, Purcell has used... 

The underlying concept of all QSAR analyses is the additivity of substituent group contributions to biological activity values in the logarithmic scale. This additivity comes from the fact that QSAR models are linear free-energy related. All... 

In fact, considering the basic structure of these materials (vide supra), it can be immediately realized that the basic features of poly(organophosphazenes) are the result of two main contributions. The first one is fixed and is basically related to the intrinsic properties of the -P=N- inorganic backbone, while the second is variable and mostly connected to the chemical and physical characteristics of the phosphorus substituent groups. Skeletal properties in phos-phazene macromolecules intrinsically due to the polymer chain are briefly summarized below. 

Results for these CEBEs are presented in Table 1. As can be seen, for the carvone variants I-V the various substitutions have absolutely no effect at the carbonyl C=0 core, and are barely significant at the chiral center that lies between the carbonyl and substituent groups in these molecules. Only upon fluorine substitution at the tail (molecule VI) does the C=0 CEBE shift by one-half of an electronvolt the second F atom substitution adjacent to the C=0 in the difluoro derivative, VII contributes a further 0.6-eV shift. This effect can be rationalized due to the electron-withdrawing power of an F atom. Paradoxically, it is these fluorine-substituted derivatives, VI, VII, that arguably produce b curves most similar to the original carvone conformer, I, yet they are the only ones to produce a perturbation of the ground-state electron density at the C li core. This contributes further evidence to suggest that, at least for the C li... 

A fundamental assumption of the approach is that contributions to a from several substituent groups on the same parent compound are additive. The additivity assumption also holds for the more general Hansch model that will be discussed below. 

The second extrathermodynamic method that we discuss here differs from Hansch analysis by the fact that it does not involve experimentally derived substitution constants (such as o, log P, MR, etc.). The method was originally developed by Free and Wilson [29] and has been simplified by Fujita and Ban [30]. The subject has been extensively reviewed by Martin [7] and by Kubinyi [8]. The method is also called the de novo approach, as it is derived from first principles rather than from empirical observations. The underlying idea of Free-Wilson analysis is that a particular substituent group at a specific substitution site on the molecule contributes a fixed amount to the biological activity (log 1/C). This can be formulated in the form of the linear relationship ... 

In a broad sense, one may include the Free-Wilson equation within the class of linear free energy relationships (LFER). It is also subjected to the assumption of additivity of the contributions to the biological activity by substituent groups at different substitution sites. The assumption requires, for example, that there is no hydrogen bonding interaction between the various substitution groups. 

Eqn. 8.3 indicates that the binding of nicotinates to the catalytic site of carboxylesterase depends first and mainly on substituent bulk (optimal MR = 35, which corresponds to a quite large substituent such as heptyl or 2-phenoxyethyl). In addition, affinity increases with increasing lipophilicity. The influence of A S appears complex and difficult to interpret, perhaps suggesting that the interaction of the carbonyl C-atom with the catalytic OH group contributes to affinity. 

Values of molar volumes can be calculated from densities measured for the liquid salt, or can be calculated as for hypothetical subcooled liquid at 298.15 K using the group contribution method [47]. As expected, the molar volumes of 1,3-dialkylimidazolium salts and quaternary ammonium salts increase progressively as the length of alkyl chain of the substituent increases. Some molar volumes values at 298.15 K are listed in Table 1.3. 

The results in Table I agree with the postulated reaction mechanism. In most of cases two, isomeric pyridones 4 and 5 are formed. The structure of the N-substituent also contributes to the ratio of products, such as in the case of a series of 3-tcrt-butylpyridinium salts where the percentage of 2-pyridone decreases from 14% (N-methyl) to 0% if the N-methyl group is replaced by sterically larger and more lipophilic substituents R . Substituents like CO2H, COMe, COPh, and NOj result in the pyridone function being specifically introduced into the 6-position, so that only 5 can be obtained after Decker oxidation. Only one case (R = Me, R = CN) has been reported (7IJCS(B)131) in which traces of a 4-pyridone 6 were formed. 

---