Electrostatic And Hydrogen Bonding In A Lowdielectric Medium

Section 3.3.4 pointed out that cosolvents alter aqueous ionization constants; as the dielectric constant of the mixture decreases, acids appear to have higher pKa values and bases appear (to a lesser extent than acids) to have lower values. A lower dielectric constant implies that the force between charged species increases, according to Coulomb's law. The equilibrium reaction in Eq. (3.1) is shifted to the left in a decreased dielectric medium, which is the same as saying that pKa increases. Numerous studies indicate that the dielectric constant in the region of the polar head groups of phospholipids is ^32, the same as the value of methanol. [381,446-453] Table 5.2 summarizes many of the results.

These and other values [381,406] allow us to depict the dielectric spectrum of a bilayer, shown in Fig. 5.2. Given this view, one can think of the phospholipid bilayer as a dielectric microlamellar structure; as a solute molecule positions itself closer to the center of the hydrocarbon region, it experiences lower dielectric field (Fig. 5.2). At the very core, the value is near that of vacuum. A diatomic molecule of Na+Cl— in vacuum would require more energy to separate into two distinct ions than that required to break a single carbon-carbon bond!

This means that ions will not easily enter the interior of bilayers without first forming contact ion pairs. It is reasonable to imagine that simple drug-counterion pairs, such as (BH+ . . . Cl—) will undergo exchange of charge pairs (BH+ for Na+ originally in the vicinity of =PO—) on entering the head-group region, to form, for example, (=PO—. . . +HB), with the release of Na+ and Cl—, as depicted in Fig. 5.1. We called such an imagined pairing SIP in Section 5.1 [149].

An interesting hypothesis may be put forward. The interfacial pKamem (Fig. 5.1) that a solute exhibits depends on the dielectric environment of its location in the bilayer. Simple isotropic water-miscible solvents may be used to approximate pKmem. Pure methanol (e 32), may do well for the bilayer zone containing the phosphate groups; pure 1,4-dioxane (e 2) may mimic some of the dielectric properties of the hydrocarbon region. It appears that psKa values of several weak bases, when extrapolated to 100% cosolvent, do approximate pK^™ values [119,162,172]. Fernandez and Fromherz made favorable comparisons using dioxane [448]. This idea is of considerable practical use, and has been largely neglected in the literature.

TABLE 5.2 Dielectric Constants of Water-Lipid Interfaces (Expanded from Ref. 453)a






Unilamellar vesicles

Polar head/acyl core

Chemical reaction,

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