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Automated potentiometric titrations in KCl/water-saturated octanol: method for quantifying factors influencing ion-pair partitioning.

Scherrer RA, Donovan SF - Anal. Chem. (2009)

Bottom Line: Hydrogen bonding and steric factors have a greater influence on ion pairs than they do on neutral species, yet these factors are missing from current programs used to calculate log P(I) and log D.On the other hand, hydrogen bonding groups near the charge center have the opposite effect by lowering the free energy of the ion pair.This work also brings attention to the fascinating world of nature's highly stabilized ion pairs.

View Article: PubMed Central - PubMed

Affiliation: BIOpKa, White Bear Lake, Minnesota 55110, USA. rascherrer@biopka.com

ABSTRACT
The knowledge base of factors influencing ion pair partitioning is very sparse, primarily because of the difficulty in determining accurate log P(I) values of desirable low molecular weight (MW) reference compounds. We have developed a potentiometric titration procedure in KCl/water-saturated octanol that provides a link to log P(I) through the thermodynamic cycle of ionization and partitioning. These titrations have the advantage of being independent of the magnitude of log P, while maintaining a reproducibility of a few hundredths of a log P in the calculated difference between log P neutral and log P ion pair (diff (log P(N - I))). Simple model compounds can be used. The titration procedure is described in detail, along with a program for calculating pK(a)'' values incorporating the ionization of water in octanol. Hydrogen bonding and steric factors have a greater influence on ion pairs than they do on neutral species, yet these factors are missing from current programs used to calculate log P(I) and log D. In contrast to the common assumption that diff (log P(N - I)) is the same for all amines, they can actually vary more than 3 log units, as in our examples. A major factor affecting log P(I) is the ability of water and the counterion to approach the charge center. Bulky substituents near the charge center have a negative influence on log P(I). On the other hand, hydrogen bonding groups near the charge center have the opposite effect by lowering the free energy of the ion pair. The use of this titration method to determine substituent ion pair stabilization values (IPS) should bring about more accurate log D calculations and encourage species-specific QSAR involving log D(N) and log D(I). This work also brings attention to the fascinating world of nature's highly stabilized ion pairs.

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The thermodynamic cycle of the ionization and partitioning of an acid between octanol and water.
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fig1: The thermodynamic cycle of the ionization and partitioning of an acid between octanol and water.

Mentions: In order to consider single phase titrations in octanol, one needs a definition of pH, or its equivalent, and pKa in that system. We proposed such definitions for two-phase octanol/water systems, Figure 1, some years ago.(6) The protons are in equilibrium between the two phases so that the net free energy per unit volume in the octanol is equal to the free energy per unit volume in the aqueous phase. In other words, fewer protons in octanol, with higher free energy, balance a greater number of protons in water having a lower free energy. We define the pH of the octanol phase as being equivalent to the pH of the aqueous phase and call the values equal, even though the pH terminology in octanol has no meaning in solution theory. This definition puts all titrations in octanol on the same scale. It affects pKa calculations, and by definition, all log PI and log D calculations the same way, so there should be no relative error between compounds. The pKa in octanol (pKa oct), is equal to the pH at which the concentrations of the neutral and ionized species in the octanol phase are equal.(6) Both pKa oct and log PI are dependent on the counterion concentration, so that concentration must be stated, or it is otherwise assumed to be at physiological concentration, 0.15 M. The concept of a pKa in octanol is not a familiar one, but its presence has been evident for many years in the lipophilic profiles of ionizable compounds (log D vs pH plots) covering a sufficient pH range.6,10 The pKa oct is at the lower inflection, complementing the aqueous pKa at the upper inflection. The pKa oct can be calculated from two-phase titrations, as described below. Two-phase titrations provide reference pKa oct values for our single-phase titrations.


Automated potentiometric titrations in KCl/water-saturated octanol: method for quantifying factors influencing ion-pair partitioning.

Scherrer RA, Donovan SF - Anal. Chem. (2009)

The thermodynamic cycle of the ionization and partitioning of an acid between octanol and water.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664611&req=5

fig1: The thermodynamic cycle of the ionization and partitioning of an acid between octanol and water.
Mentions: In order to consider single phase titrations in octanol, one needs a definition of pH, or its equivalent, and pKa in that system. We proposed such definitions for two-phase octanol/water systems, Figure 1, some years ago.(6) The protons are in equilibrium between the two phases so that the net free energy per unit volume in the octanol is equal to the free energy per unit volume in the aqueous phase. In other words, fewer protons in octanol, with higher free energy, balance a greater number of protons in water having a lower free energy. We define the pH of the octanol phase as being equivalent to the pH of the aqueous phase and call the values equal, even though the pH terminology in octanol has no meaning in solution theory. This definition puts all titrations in octanol on the same scale. It affects pKa calculations, and by definition, all log PI and log D calculations the same way, so there should be no relative error between compounds. The pKa in octanol (pKa oct), is equal to the pH at which the concentrations of the neutral and ionized species in the octanol phase are equal.(6) Both pKa oct and log PI are dependent on the counterion concentration, so that concentration must be stated, or it is otherwise assumed to be at physiological concentration, 0.15 M. The concept of a pKa in octanol is not a familiar one, but its presence has been evident for many years in the lipophilic profiles of ionizable compounds (log D vs pH plots) covering a sufficient pH range.6,10 The pKa oct is at the lower inflection, complementing the aqueous pKa at the upper inflection. The pKa oct can be calculated from two-phase titrations, as described below. Two-phase titrations provide reference pKa oct values for our single-phase titrations.

Bottom Line: Hydrogen bonding and steric factors have a greater influence on ion pairs than they do on neutral species, yet these factors are missing from current programs used to calculate log P(I) and log D.On the other hand, hydrogen bonding groups near the charge center have the opposite effect by lowering the free energy of the ion pair.This work also brings attention to the fascinating world of nature's highly stabilized ion pairs.

View Article: PubMed Central - PubMed

Affiliation: BIOpKa, White Bear Lake, Minnesota 55110, USA. rascherrer@biopka.com

ABSTRACT
The knowledge base of factors influencing ion pair partitioning is very sparse, primarily because of the difficulty in determining accurate log P(I) values of desirable low molecular weight (MW) reference compounds. We have developed a potentiometric titration procedure in KCl/water-saturated octanol that provides a link to log P(I) through the thermodynamic cycle of ionization and partitioning. These titrations have the advantage of being independent of the magnitude of log P, while maintaining a reproducibility of a few hundredths of a log P in the calculated difference between log P neutral and log P ion pair (diff (log P(N - I))). Simple model compounds can be used. The titration procedure is described in detail, along with a program for calculating pK(a)'' values incorporating the ionization of water in octanol. Hydrogen bonding and steric factors have a greater influence on ion pairs than they do on neutral species, yet these factors are missing from current programs used to calculate log P(I) and log D. In contrast to the common assumption that diff (log P(N - I)) is the same for all amines, they can actually vary more than 3 log units, as in our examples. A major factor affecting log P(I) is the ability of water and the counterion to approach the charge center. Bulky substituents near the charge center have a negative influence on log P(I). On the other hand, hydrogen bonding groups near the charge center have the opposite effect by lowering the free energy of the ion pair. The use of this titration method to determine substituent ion pair stabilization values (IPS) should bring about more accurate log D calculations and encourage species-specific QSAR involving log D(N) and log D(I). This work also brings attention to the fascinating world of nature's highly stabilized ion pairs.

Show MeSH