Diprotic Molecules with Two Different Ion Pair Partitionings

Niflumic acid partitions into octanol as a neutral species, an anion, and a cation [8]. Solution of Eq. (19) for three-log P case of a diprotic molecule produces the complicated equation log D = log (A0 +A,+ A2) (29)

where

Eq. (29) is illustrated with the examples niflumic acid in Fig. 13a, nitrazepam in Fig. 13b, buprenorphine in Fig. 13c, and quinine in Fig. 13 d. Niflumic acid and quinine also illustrate the effect of salt on the partitioning of ions.

logD

logD

logD

Buprenorphine.HCl (23°C. 0.1SM KCl)

Buprenorphine.HCl (23°C. 0.1SM KCl)

pH

logD

Figure 13. Lipophilicity profiles for diprotic substances illustrating the partitioning of two ion pairs along with the neutral species, (a) Niflumic acid lipophilicity plots at 0.15 m NaCl (upper curve) and 0.03M NaCl (lower curve). The curve levels off below pH 2 because the cation partitions into octanol; the curve levels off for pH > 8 because the anion partitions into octanol. For 0.15 M : log P(XH,+) 3.20, log P(XH) 3.88, log P(X) 1.23; for 0.03M : 2.48, 3.71, 0.44. (b) Nitrazepam cation (log P 1.21), neutral (2.38), and anion (0.64) species octanol/water partitioning, (c) Buprenorphine cation (0.09), neutral (4.82), and anion (2.69) partitioning (d) Quinine lipophilicity profiles. At 0.155 m KC1, log P(X) 3.47, log P(XH+) 0.87; at 0.005 m KC1, log P(X) 3.43, log P(XH+) 0.00, log P(XH22+) -0.21.

7.3.10 Macro-pA"a, Micro-pA',,, and Zwitterions

In certain types of molecule it is possible that chemically (or stereochemically) different species of the same stoichiometric composition are formed. The pH-metric titration technique cannot distinguish between such tautomeric species. In such cases the determined pKa is a composite constant, a "macroconstant". The thermodynamic experiment is a "proton counting" technique. It cannot identify the site in the molecule the proton comes from. It can only be said that a proton emerges from somewhere in the molecule. On the other hand, "microconstants" are characteristic of individual species, of which there may be more than one with the same composition.

We will use lowercase k for microconstants and uppercase K for macroconstants. (Unfortunately the lower case k is standard notation for rate constants. In the present context there should be no confusion.) Fig: 14 shows microconstant and macroconstant schemes for a diprotic molecule undergoing tautomerization; niflumic acid would be an example of such a molecule [8]. Fig. 14 is labeled with proton formation constants K and k, rather than proton dissociation constants K,,. The two types of constants are inversely related: log Ki = pKa2 and log K2 = pKal. The use of formation constants simplifies the form of the derived relationships between micro- and macroconstants.

The tautomeric constant is defined as

= Icf / k° = k2° / kr where the microconstants are defined in terms of the quotients kz = [XH] / [XH°]

microconstants zwitterion

zwitterion

union/zed

union/zed ma c ro constant s

0 0

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