Factorization of Molecular Lipophilicity

As a ratio of two concentrations at saturation, the partition coefficient (log P)is the net result of all intermolecular forces between a solute and the two phases between which it partitions. When a given type of interaction elicited bythe solute, say H-bond donation, is of equal energy in the two solvents, the two interactions will compensate each other and log P will contain no information about them.

One highly informative interpretation of lipophilicity is based on its factorization of log P into the so-called solvatochromic parameters [4], The major such parameters are:

• jt*, a measure of the solute's dipolarity/polarizability and thus of its capacity to elicit orientation and induction forces;

• a and ft, the solute's H-bond donor acidity and H-bond acceptor basicity, respective-

• In addition to jc*, a and ¡3, analyses of this type require a parameter to assess the solute's capacity to elicit nonpolar interactions (see section 4.2.4). A steric parameter such as the molar or molecular volume (V) is able to account satisfactorily for such interactions.

Thus, the octanol/water and the heptane/water partition coefficient can be expressed as [4]:

logPocanoi = 5.83(± 0.53) V/100 - 0.74(± 0.31)jt* - 3.51(± 0.38)£ - 0.15(± 0.23)a - 0.02(± 0.34)

log Pheptane = 6.78(± 0.69) V7100 - 1.02(± 0.39) ji* - 5.35(± 0.50) ft - 3.54(± 0.30)a - 0.06(± 0.43)

As a result of equations of this type, it is now common to factorize lipophilicity into two sets of terms, namely polar terms negatively related to lipophilicity (section 4.2.3) and nonpolar terms positively related to lipophilicity (section 4.2.4).

A complementary approach towards factorizing lipophilicity has been proposed by us a few years ago [5]. This approach is based a) on the fact that n-alkanes are completely apolar and non-polarizable, and b) on the well-documented linear relationship that exists within «-alkanes between partition coefficients and molecular or molar volumes. The latest version of this relation between log P and molecular volume (V) is [6]:

log Poctanoi = 0.0309(± 0.0014) V + 0.346(± 0.199)

In a plot of Vversus log P, the observations fall either on the straight line (i.e., n-alkanes) or below it (all other solutes). To the best of our knowledge, no solute has yet been found which would lie above the line defined by n-alkanes. In other words, solutes either are completely apolar (i.e., n-alkanes), or are polar to a slight or large degree (all other solutes). The information of relevance in the present context is the vertical distance between a solute and the line for n-alkanes, a distance that has been taken as a measure of the global polarity of a given solute. This parameter of polarity has been designated as A (capital lambda = inverted V); for a given solute in a given solvent system (e.g., octanol/water or alkane/water), it is defined as the difference between its measured lipophilicity and that intrapolated for a hypothetical n-alkane of identical volume.

Using Eq. (3) and the A parameter, lipophilicity can thus be factorized into a polar and a nonpolar term, as exemplified by Eq. (4) for the octanol/water system:

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