Acidity and hydrogen bonding of carboxyl groups

Eberson, Lennart

doi:10.1002/9780470771099.ch6

Cited by 21 publications

(9 citation statements)

References 186 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Simple carboxylic acid-containing drugs have nearly the same pK a at 25 and 37°C [4, 17–19], whereas simple bases usually have a decreased pK a at the biorelevant temperature (ΔpK a /ΔT ≈ −0.03 °C −1 ) [2–5, 8] (e.g., propranolol has the pK a values 9.53 and 9.17 at 25 and 37°C, respectively). Neglecting the temperature effect can lead to inaccurate interpretations of pharmacokinetic mechanisms of ionizable drugs, and potentially contributing to poorer in vitro – in vivo correlations (IVIVC).…”

Section: Introductionmentioning

confidence: 99%

Biorelevant pKa (37°C) predicted from the 2D structure of the molecule and its pKa at 25°C

Sun

Avdeef

2011

Journal of Pharmaceutical and Biomedical Analysis

View full text Add to dashboard Cite

Values of the ionization constants at 37°C, which are scarcely reported, are more meaningful for interpreting mechanisms of cellular transport by ionizable molecules and in mechanistic dissolution studies, which are often performed at the biorelevant temperature. An equation was developed where the pKa values of drug-like molecules determined at 25°C can be simply converted to values at 37°C, without additional measurement. The differences between the values, ΔpKa = pKa37 − pKa25, were linearly fitted to a function of pKa25 and the standard entropy of ionization, ΔSo, where the latter term was approximated by the five Abraham linear free energy solvation descriptors using multiple linear regression. The Abraham descriptors (H-bond donor and acceptor strengths, dipolar solute-solvent interactions potential, the pi- and n-electrons dispersion force, and molar volume) were determined from the 2-dimensional structure of the molecules. A total of 143 mostly drug-like molecules (207 pKa values at 25°C and at 37°C) were chosen for the study. The pKa values of many were determined here for the first time. Included were 34 weak acids, 85 weak bases, and 24 amphoteric compounds (6 ordinary ampholytes, 18 zwitterions).

show abstract

Section: Introductionmentioning

confidence: 99%

Biorelevant pKa (37°C) predicted from the 2D structure of the molecule and its pKa at 25°C

Sun

Avdeef

2011

Journal of Pharmaceutical and Biomedical Analysis

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 97%

“…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).…”

mentioning

confidence: 99%

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Lightner

Holmes

McDonagh

1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

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

show abstract

“…In these extracted complexes, the individual diphosphonic acid molecules are either monodeprotonated or fully protonated. Data for pK a values of analogous series of unsubstituted diphosphonic acids (38) and dicarboxylic acids (39) show that the pK a of the most acidic proton increases as the number of methylene groups bridging the two acidic groups (POOH or COOH) increases. However, the pK a of the second acidic proton is often observed to remain the same or even decrease as the acidic groups are separated by longer alkylene chains.…”

Section: P Nmr and Infrared Spectroscopymentioning

confidence: 99%

Metal extraction by silyl-substituted diphosphonic acids. II. Effect of alkylene bridge length on aggregation and metal ion extraction behavior

McAlister

Dietz

Chiarizia

et al. 2002

Separation Science and Technology

View full text Add to dashboard Cite

In an ongoing effort to determine the relationship between structure and function in diphosphonic acids, the aggregation and solvent extraction chemistry of four novel silicon-substituted diphosphonic acids, P,P 0 -di[3-(trimethylsilyl)-1-propyl] propylene-(H 2 DTMSP[PrDP]), butylene-(H 2 DTMSP[BuDP]), pentylene-(H 2 DTMSP[PDP]), and hexylene diphosphonic acid (H 2 DTMSP[HDP]), were investigated. Vapor pressure osmometry indicates that H 2 DTMSP[PrDP] and H 2 DTMSP[PDP] are dimeric in toluene at 258C, while H 2 DTMSP[BuDP] and H 2 DTMSP[HDP] are primarily trimeric and hexameric, respectively. The solvent extraction of selected alkaline earth cations (Ca, Sr, and Ba) and representative tri-, tetra-, and hexavalent actinides 2289[Am(III), Th(IV), and U(VI)], from nitric acid solutions into oxylene solutions of the ligands has been studied and compared to results reported previously for some analogous di(2-ethylhexyl)-substituted diphosphonic acids. Differences observed in the magnitude of distribution ratios, based on the number of bridging methylene groups, have been explained considering factors such as ligand aggregation, chelate ring size, PyO basicity (qualitatively determined by 31 P nuclear magnetic resonance and infrared spectroscopy), and the relative acidities of the ligands.

show abstract

Acidity and hydrogen bonding of carboxyl groups

Cited by 21 publications

References 186 publications

Biorelevant pKa (37°C) predicted from the 2D structure of the molecule and its pKa at 25°C

Biorelevant pKa (37°C) predicted from the 2D structure of the molecule and its pKa at 25°C

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Metal extraction by silyl-substituted diphosphonic acids. II. Effect of alkylene bridge length on aggregation and metal ion extraction behavior

Contact Info

Product

Resources

About