Polar Interactions Encoded in Lipophilicity

The parameter A, being a global measure of a solute's polarity, should by definition contain the same information as, e.g., Eqs. (1) or (2), except for the volume term. This has been confirmed for octanol/water (Eq. (5)) and alkane/water (Eq. (6)) partition coefficients [5]:

Aonanoi = - 0.636(±0.124)jr* - 3.90(±0.20) ft - 0.186(± 0.103) n = 168, r2 = 0.918, 5 = 0.25 (5)

Aalkane = 1.37(± 0.30) ti* - 6.19(± 0.48) ¡3 - 3.42(±0.35) a - 0.626(± 0.234) n = 104, r2 = 0.944, 5 = 0.46 (6)

These equations make explicit the individual polar terms which are negatively related to lipophilicty and account for most polar interactions between a solute and the two solvent phases. In the case of the octanol/water system (Eq. (5)), the main contributor to a solute's polarity is thus its H-bond acceptor basicity (|3), and to a lesser extent its H-bond donor acidity (a) and dipolarity/polarizability (jt*). By contrast, the polar interactions expressed in alkane/water partition coefficients (Eq. (6)) are the H-bond donor acidity (a) and the H-bond acceptor basicity (/3), and to a lesser extent the dipolarity/polarizability (Jt*).

One very important point must be made here, namely that the above analyses (i.e., Eqs. (1), (2), (5), and (6)) are valid only for large and well-distributed series of solutes. For smaller and biased series, it is not unfrequent to observe that the A parameter will contain a different balance of polar forces, e.g., Aoctanol may depend more on a than on p. This has the major consequence that the factorization of A into individual components may be misleading and should be verified for each series. If this is not possible, interpretation should remain cautious and avoid any conclusion about the nature of the major polar force(s) involved. This caution is all the more reasonable considering the often neglected overlaps that exist between jt*, a and (3.

At this stage, we can offer the preliminary conclusion that lipophilicity encodes such polar interactions as H-bonds, orientation forces and induction forces, the relative contributions of which may be difficult or impossible to assess in any given series of solutes. In addition, ionic solutes generate intermolecular forces not included in the jt*, a and (i parameters, namely ion-dipole interactions and reinforced H-bonds.

4.2.4 Nonpolar Interactions Encoded in Lipophilicity

The steric term used in factorizing lipophilicity, and which Eqs. (1) and (2) tell us correlates positively with it, is best approached by what it is not. Thus, the volume parameter can be defined as a descriptor of the solute's capacity to enter nonpolar interactions with the aqueous and organic phases, i.e., hydrophobic interactions and dispersion forces. Whether cavity formation also plays a role is debatable and will not be discussed here.

To simplify the vocabulary, it is convenient to equate with hydrophobicity the nonpolar interactions encoded by the steric term. In this nomenclature, hydrophobicity is not synonymous with lipophilicity, but a mere component of it.

4.2.5 Recognition Forces Encoded in Lipophilicity

At this point, a general and qualitative expression of Eq. (4) can be written, namely [3]:

Lipophilicity = Hydrophobicity — Polarity (7)

Such an expression allows us to compare section 4.2.1 with sections 4.2.2-4.2.4. This is done in Fig. 1, where the polar component of lipophilicity is seen to correspond to ion-dipole bonds, hydrogen bonds, orientation forces and induction forces, while the hydrophobic component corresponds to dispersion forces and hydrophobic interactions.

Only a limited number of recognition forces cannot find expression in lipophilicity as conventionally measured, namely ionic bonds, charge transfer interactions and aryl/ aryl stacking interactions. The latter two would require an aromatic solvent, e.g., benzene or nitrobenzene, to be used in partitioning experiments. As for ionic interactions, they might perhaps be approachable in HPLC using an ionic stationary phase, but the problem of counterions and their influence is far from solved.

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