Intramolecular Hydrogen Bonding as a Factor in Determining the K1/K2 Ratios of Dicarboxylic Acids.

Eberson, Lennart; Wadsö, Ingemar; Lindberg, Bengt; Meier, Hans; Munch‐Petersen, Jon

doi:10.3891/acta.chem.scand.17-1552

Cited by 47 publications

(22 citation statements)

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“…For example, in neutral molecules, such as macrocyclic polyethers [30,31], pKa values of the -COOH groups can be elevated by as much as 1.5 units [30]. Similarly, in many dicarboxylic acids, the observed high pKa 2 values have been ascribed, in part, to breaking, upon dissociation, of the H-bond donated by the -COOH group in the monoanion [32-34]. McCoy [33] applied the method suggested by Westheimer and Benfey [35] to estimate intramolecular H-bonding effects on the elevation of pKa 2 values in water of maleic acid and several other 1,2 dicarboxylic acids with fairly rigid skeletons.…”

Section: Discussionmentioning

confidence: 99%

Revalidation and rationale for high pKa values of unconjugated bilirubin

Ostrow

Mukerjee

2007

BMC Biochem

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Section: Discussionmentioning

confidence: 99%

Revalidation and rationale for high pKa values of unconjugated bilirubin

Ostrow

Mukerjee

2007

BMC Biochem

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“…Mukerjee (1,2) There is considerable evidence that dimerization of moderately long-chain fatty acids in water occurs (2,8), but it appears probable (9) that the principal dimer is not A2= but HA2-, and that a hydrogen bond between a protonated and an unprotonated carboxyl group plays an important role in the association. Evidence for the formation of remarkably strong hydrogen bonds of this type also comes from pKa measurements of dicarboxylic acids containing hydrocarbon groups (10)(11)(12)(13) (16) for the same acid at pH 8.5. For this acid the conditions for applicability of Eq.…”

Section: Thermodynamic Formulationmentioning

confidence: 99%

Hydrophobicity of Long Chain n -Alkyl Carboxylic Acids, as Measured by Their Distribution Between Heptane and Aqueous Solutions

Smith

Tanford

1973

Proc. Natl. Acad. Sci. U.S.A.

167

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Previous data for the distribution of the n-alkyl carboxylic acids between aqueous buffers and heptane have suggested that the free energy of transfer between the two solvents does not increase with the length of the alkyl chain beyond palmitic acid, indicating a limit to the hydrophobicity of the alkyl chain at a length of about 15 carbon atoms. It is shown in this paper that previous measurements were influenced by unexpectedly strong pH-dependent association of the long-chain acids in the aqueous phase. Under conditions where such association becomes negligible, the free energy of transfer becomes a strictly linear function of alkyl chain length for all acids up to behenic acid (C21H43COOH).This work was undertaken to examine the suggestion of Mukerjee (1, 2) that the hydrophobicity of n-alkyl carboxylic acids does not increase indefinitely with the length of the alkyl chain,. but reaches a limit at a chain length of about 15 carbon atoms. Mukerjee's suggestion was based on the studies of Goodman (3) of the distribution of fatty acids between aqueous solutions and liquid heptane, and in particular on anomalous results obtained for C,5COOH and C17COOH. In this paper the measurements of Goodman have been repeated and extended, and their interpretation has been reinvestigated. An additional acid, behenic acid (C21COOH), has been included in the study. THERMODYNAMIC FORMULATIONThe unitary free energy of transfer of an acid HA between water and a hydrocarbon such as heptane may be taken as a measure of its hydrophobicity; this quantity, in turn, is pro- There is considerable evidence that dimerization of moderately long-chain fatty acids in water occurs (2,8), but it appears probable (9) that the principal dimer is not A2= but HA2-, and that a hydrogen bond between a protonated and an unprotonated carboxyl group plays an important role in the association. Evidence for the formation of remarkably strong hydrogen bonds of this type also comes from pKa measurements of dicarboxylic acids containing hydrocarbon groups (10-13). Moreover, the work of Eagland and Franks (9) has shown that formation of HA2-alone cannot account for anomalous titration behavior of CXCOOH, C,3COOH, and C15COOH, and that higher aggregates such as H2A3-, H2A4=, etc., must be invoked to explain the results. Since the formation of all such associated species depends on pH as well as total concentration, these findings suggest that pH may have 289

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“…In bilirubin, proton dissociation might be facilitated somewhat by stabilization of the resulting carboxylate anion by intramolecular hydrogen bonding to a dipyrrinone, but this stabilization would be offset by electrostatic repulsion between carboxylate and lactam oxygens. When large effects of intramolecular hydrogen bonding occur in dicarboxylic acids, they are manifested by abnormally large values of K a1 /K a2 (17,51,52), which is clearly not the case for bilirubin.…”

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confidence: 99%

“…In addition, the focus on deprotonation or dissociation has neglected the potential stabilization of the carboxylate anion by intramolecular hydrogen bonding. In general, the effect of intramolecular hydrogen bonding on the pK a values of dicarboxylic acids is small except for instances in which intramolecular hydrogen bonding between carboxyl and carboxylate groups occurs in the monoanion (17,51,52), which is sterically unlikely for bilirubin, though possible for biliverdin. In such acids, for example maleic or phthalic acid, hydrogen bonding invariably lowers pK a1 rather than increases it, as claimed for bilirubin (30).…”

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confidence: 99%

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Lightner

Holmes

McDonagh

1996

Journal of Biological Chemistry

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Biliverdin and bilirubin are naturally-occurring tetrapyrrolic bile pigments containing two propionic acid side chains. These side chains, and their propensity for ionization, are critical in the biological disposition of the pigments. Surprisingly, accurate dissociation constants for the propionic acid groups of biliverdin are unknown, and a wide range of values, extending over some 4 orders of magnitude, has been suggested for the K a values of the propionic acid groups of bilirubin in aqueous solutions. Recently, pK a values of 6.7-9.3 have been reported for bilirubin-values much greater than the value of ϳ5 typical of propionic acid groups. These curiously high values, currently being used to explain the biological transport and metabolism of bilirubin and related compounds, have been attributed to intramolecular hydrogen bonding. We have determined the pK a values of 99% Bilirubin and biliverdin are blue-green and yellow-orange pigments formed from heme during normal metabolism in humans and other animals (1, 2). Like heme, biliverdin and bilirubin have two propionic acid groups and low solubility in water (1-3). The acidity constants of bilirubin have been determined many times during the past 40 years (4 -13), but those of heme and biliverdin have not been measured (3). A mean pK a of ϳ5.3 has been predicted for porphyrin dicarboxylic acids (14), and pK a values of ϳ5.0 and ϳ7.2 have been estimated for biliverdin (3). A wide range of pK a values has been reported for bilirubin, with most investigators favoring a pK a of 6.2 to 6.5 (15), but recent determinations suggest that the true pK a values are even higher (6.8 to Ն 9.3) because of intramolecular hydrogen bonding (11,12). Since most carboxylic acid pK a values are ϳ5 and values Ͼ6 are seldom encountered (16 -18), these recent determinations imply a remarkable and unprecedented effect of intramolecular hydrogen bonding on proton dissociation. To investigate this effect, we have used 13 C NMR to study the dissociation of hydrogen-bonded and non-hydrogen-bonded pyrrolic acids and to determine the pK a values of mesobilirubin-XIII␣ (1) and mesobiliverdin-XIII␣ (2), two synthetic surrogates that differ from bilirubin and biliverdin, respectively, only by trivial differences in the nature, i.e. vinyl groups reduced to ethyl, and sequence of alkyl side chains on the lactam rings. Being remote from the propionic acid side chains, the alkyl substituents on the lactam rings are expected

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Intramolecular Hydrogen Bonding as a Factor in Determining the K1/K2 Ratios of Dicarboxylic Acids.

Cited by 47 publications

References 0 publications

Revalidation and rationale for high pKa values of unconjugated bilirubin

Revalidation and rationale for high pKa values of unconjugated bilirubin

Hydrophobicity of Long Chain n -Alkyl Carboxylic Acids, as Measured by Their Distribution Between Heptane and Aqueous Solutions

On the Acid Dissociation Constants of Bilirubin and Biliverdin

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