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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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Representative titration curves overlaid with plots of equilibration times. The pKa′′ ± SE is shown for each titration. Equilibration times are indicative of the quality of a titration. Plots a and b represent near ideal parameter selections. Plot c has more points than needed. Equilibration times may be influenced by the production of insoluble KCl (c) or the concentration or nature of the ion pair produced (d).
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fig3: Representative titration curves overlaid with plots of equilibration times. The pKa′′ ± SE is shown for each titration. Equilibration times are indicative of the quality of a titration. Plots a and b represent near ideal parameter selections. Plot c has more points than needed. Equilibration times may be influenced by the production of insoluble KCl (c) or the concentration or nature of the ion pair produced (d).

Mentions: One can see from the comparisons in parts a−c of Figure 2 that titrations in octanol cover a greater pH range than in water. It is the two ionization constants of water in octanol that determine this range. Most of our initial concerns about such titrations dealt with the electrode, whether it would function properly, be stable, and give meaningful values. Representative titration curves are shown in parts a−d of Figure 3. The electrode equilibration time overlaid on these curves gives a sense of the quality of the titrations and relieves much of the concern about the electrode response. The slower response time in octanol requires loosening the equilibration requirement to 0.010 ΔpH units/min instead of 0.002 for aqueous systems. Electrode stress is evident with the initial few points and during periods of more rapid pH change. Parts a and b of Figure 3 show typical curves for a carboxylic acid and aliphatic amine. Titrations can be applied to more complex molecules, such as an internally compensated zwitterion, Figure 3c, which requires determining the pKa′′ of water, as well as a carboxylic acid and an amine. Interestingly, the pKa′′ results agree with observations made from the lipophilicity profile of charge-compensated zwitterions, that the amines are more basic and the acids more acidic, in octanol than in water.8,12 Insoluble KCl is produced in Figure 3c, which may affect equilibration time. Figure 3d, for CO2 (and/or H2CO3), illustrates a small sample size requiring only 0.03 mL of titrant in 15 mL of octanol. The second pKa′′ of carbonate could not be determined due to insolubility of the double salt.


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

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

Representative titration curves overlaid with plots of equilibration times. The pKa′′ ± SE is shown for each titration. Equilibration times are indicative of the quality of a titration. Plots a and b represent near ideal parameter selections. Plot c has more points than needed. Equilibration times may be influenced by the production of insoluble KCl (c) or the concentration or nature of the ion pair produced (d).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Representative titration curves overlaid with plots of equilibration times. The pKa′′ ± SE is shown for each titration. Equilibration times are indicative of the quality of a titration. Plots a and b represent near ideal parameter selections. Plot c has more points than needed. Equilibration times may be influenced by the production of insoluble KCl (c) or the concentration or nature of the ion pair produced (d).
Mentions: One can see from the comparisons in parts a−c of Figure 2 that titrations in octanol cover a greater pH range than in water. It is the two ionization constants of water in octanol that determine this range. Most of our initial concerns about such titrations dealt with the electrode, whether it would function properly, be stable, and give meaningful values. Representative titration curves are shown in parts a−d of Figure 3. The electrode equilibration time overlaid on these curves gives a sense of the quality of the titrations and relieves much of the concern about the electrode response. The slower response time in octanol requires loosening the equilibration requirement to 0.010 ΔpH units/min instead of 0.002 for aqueous systems. Electrode stress is evident with the initial few points and during periods of more rapid pH change. Parts a and b of Figure 3 show typical curves for a carboxylic acid and aliphatic amine. Titrations can be applied to more complex molecules, such as an internally compensated zwitterion, Figure 3c, which requires determining the pKa′′ of water, as well as a carboxylic acid and an amine. Interestingly, the pKa′′ results agree with observations made from the lipophilicity profile of charge-compensated zwitterions, that the amines are more basic and the acids more acidic, in octanol than in water.8,12 Insoluble KCl is produced in Figure 3c, which may affect equilibration time. Figure 3d, for CO2 (and/or H2CO3), illustrates a small sample size requiring only 0.03 mL of titrant in 15 mL of octanol. The second pKa′′ of carbonate could not be determined due to insolubility of the double salt.

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