Novel methods for the prediction of logP,pK(a), and logD

Novel methods for predicting logP, pK(a), and logD values have been developed using data sets (592 molecules for logP and 1029 for pK(a)) containing a wide range of molecular structures. An equation with three molecular properties (polarizability and partial atomic charges on nitrogen and oxygen) correlates highly with logP (r2 = 0.89). The pK(a)s are estimated for both acids and bases using a novel tree structured fingerprint describing the ionizing centers. The new models have been compared with existing models and also experimental measurements on test sets of common organic compounds and pharmaceutical molecules.     

A reliable and efficient first principles-based method for predicting pKa values. III. Adding explicit water molecules: Can the theoretical slope be reproduced and pKa values predicted more accurately?

A popular method for predicting pK(a) values for organic molecules in aqueous solution is to establish empirical linear least-squares fits between calculated deprotonation energies and known experimental pK(a) values. In virtually all such calculations, the empirically observed slope of the pK(a) vs. ΔE fit is significantly less than the theoretical value, 1/(2.303RT) (which is 0.73 mol/kcal at room temperature). In our own continuum solvation calculations (Zhang et al., J Phys Chem A 2010, 114, 432), the empirical slope for carboxylic acids was only 0.23 mol/kcal, despite the excellent fit to the experimental pK(a) values. There has been much speculation about the reason for this phenomenon. Although the ΔE - pK(a) relation neglects entropic effects, these are expected to largely cancel. The most likely cause for the strange behavior of the fitted slope is explicit solute-solvent (water) interactions, especially involving the ions, which cannot be described accurately by continuum solvation models. We used our previously developed pK(a) protocol (OLYP/6-311+G(d,p)//3-21G(d) with the COSMO solvation model) to investigate the effect of adding one or two explicit water molecules to the system. The slopes for organic acids (especially carboxylic acids) are much closer to the theoretical value when explicit water molecules are added to both the neutral molecule and the anion. However, explicit water molecules have almost no effect on the slopes for organic bases. Adding explicit water molecules to the ions only produces intermediate results. Unfortunately, linear fits involving explicit water molecules have much larger errors than with continuum solvation models alone and are also much more expensive. Consequently, they are not suitable for large-scale pK(a) calculations. The results compared with literature values showed that our predicted pK(a) s are more accurate.     

Prediction of acidity in acetonitrile solution with COSMO-RS

The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of pK(a) values in acetonitrile. For a variety of 93 organic acids, the directly calculated values of the free energies of dissociation in acetonitrile showed a very good correlation with the pK(a) values (r(2) = 0.97) in acetonitrile, corresponding to a standard deviation of 1.38 pK(a) units. Thus, we have a prediction method for acetonitrile pK(a) with the intercept and the slope as the only adjusted parameters. Furthermore, the pK(a) values of CH acids yielding large anions with delocalized charge can be predicted with a rmse of 1.12 pK(a) units using the theoretical values of slope and intercept resulting in truly ab initio pK(a) prediction. In contrast to our previous findings on aqueous acidity predictions the slope of the experimental pK(a) versus theoretical DeltaG(diss) was found to match the theoretical value 1/RT ln (10) very well. The predictivity of the presented method is general and is not restricted to certain compound classes. However, a systematic correction of -7.5 kcal mol(-1) is required for compounds that do not allow electron-delocalization in the dissociated anion. The prediction model was tested on a diverse test set of 129 complex multifunctional compounds from various sources, reaching a root mean square deviation of 2.10 pK(a) units.     

The active site of a zinc-dependent metalloproteinase influences the computed pK(a) of ligands coordinated to the catalytic zinc ion

TNF-alpha converting enzyme (TACE) is a multidomain, membrane-anchored protein that includes a Zn-dependent protease domain. It releases the soluble form of cytokine tumor necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor. TACE is a metalloprotease containing a catalytic glutamic acid, Glu-406, and a Zn(2+) ion ligated to three imidazoles. The protonation states of the active site glutamic acid and inhibitors are important factors in understanding the potency of inhibitors with acidic zinc-ligating groups such as hydroxamic and carboxylic acids. Density functional methods were utilized to compute pK(a) values using a model of the catalytic site of TACE and to predict a concomitant mechanism of binding, consistent with lowering the pK(a) of the bound ligand and raising the pK(a) of the active site Glu-406. Weak acids, such as hydroxamic acids, bind in their neutral form and then transfer an acidic proton to Glu-406. Stronger acids, such as carboxylic acids, bind in their anionic form and require preprotonation of Glu-406. Similar binding events would be expected for other zinc-dependent proteases.     

Fast high-throughput method for the determination of acidity constants by capillary electrophoresis. II. Acidic internal standards

A fast method for the determination of acidity constants by CZE has been recently developed. This method is based on the use of an internal standard of pK(a) similar to that of the analyte. In this paper we establish the reference pK(a) values of a set of 24 monoprotic neutral acids of varied structure that we propose as internal standards. These compounds cover the most usual working pH range in CZE and facilitate the selection of adequate internal standards for a given determination. The reference pK(a) values of the acids have been established by the own internal standard method, i.e. from the mobility differences between different acids of similar pK(a) in the same pH buffers. The determined pK(a) values have been contrasted to the literature pK(a) values and confirmed by determination of the pK(a) values of some acids of the set by the classical CE method. Some systematic deviations of mobilities have been observed in NaOH buffer in reference to the other used buffers, overcoming the use of NaOH in the classical CE method. However, the deviations affect in a similar degree to the test compounds and internal standards allowing thus, the use of NaOH buffer in the internal standard method. This fact demonstrates the better performance of the internal standard method over the classical method to correct mobility deviations, which together with its fastness makes it an interesting method for the routine determination of accurate pK(a) values of new pharmaceutical drugs and drug precursors.     

Prediction of 3-hydroxypyridin-4-one (HPO) hydroxyl pKa values

As an aid in optimising the design of 3-hydroxypyridin-4-ones (HPOs) intended for use as therapeutic Fe(3+) chelating agents, various quantum mechanical (QM) and semi-empirical (QSAR) methods have been explored for predicting the pK(a) values of the hydroxyl groups in these compounds. Using a training set of 15 HPOs with known hydroxyl pK(a) values, reliable predictions are shown to be obtained with QM calculations using the B3LYP/6-31+G(d)/CPCM model chemistry (with Pauling radii, and water as solvent). With this methodology, the observed hydroxyl pK(a) values for the training set compound are closely matched by the predicted pK(a) values, with the correlation between the observed and predicted values giving r(2) = 0.98. Predictions subsequently made by this method for a test set of 48 HPOs of known hydroxyl pK(a) values (11 of which were determined experimentally in this study), gave predicted pK(a) values accurate to within ±0.2 log units. In order to further investigate the predictive power of the method, two novel HPOs were synthesised and their hydroxyl pK(a) values were determined experimentally. Comparison of these predicted pK(a) values against the measured values gave absolute deviations of 0.13 (10.18 vs. 10.31) and 0.43 (5.58 vs. 5.15).     

First-principles prediction of the pK(a)s of anti-inflammatory oxicams

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.     

Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines

From the pK(a) values of the conjugate acids of a large series of hydroxylated piperidines and hexahydropyridazines, a consistent difference in basicity was found between stereoisomers having an axial or equatorial hydroxyl (OH) group either beta or gamma to the amine. Compounds with an equatorial OH group in the 3-position were 0.8 pH units more acidic than otherwise identical compounds with an axial OH group, whilst compounds with an equatorial OH group in the 4-position relative to the amine were 0.4 pH units more acidic than the corresponding compound with an axial OH. A similar effect was observed for the COOMe substituent. The difference in electron-withdrawing power of axial and equatorial substituents was explained by a difference in charge-dipole interactions in the two systems. Since this stereoelectronic substituent effect causes differences in basicity in different conformers, certain piperidines and hexahydropyridazines were found to change conformation upon protonation. A method for predicting the pK(a) of piperidines which takes stereochemistry into account is described.     

Acid-base characterization of molecular weight fractionated humic acid

Acid-base properties of molecular weight fractionated humic acids (HAs) were investigated by the acid-base potentiometric titration. The acidic group contents (C(A(t))) and the average values of apparent pK (pK(app)) were evaluated by applying a modified Henderson-Hasselbalch equation to the experimental titration curves. The average values of pK(app) of the fractionated and unfractionated HAs were about 4.1-4.4, and the distribution of pK(app) values could be represented by the relationships between alpha and pK(app) plots in the range 2-8. The C(A(t)) values increased with a decrease in molecular size, as did the aromaticity. This suggests that the acidic group contents are related to the aromaticity of the HA.     

Effect of degree,type, and position of unsaturation on the pKa of long-chain fatty acids

Titration of a series of C(18) fatty acids yields pK(a) values that decrease with an increasing degree of unsaturation in the fatty acid chain. The pK(a) values of stearic, elaidic, oleic, linoleic, and linolenic acids were studied and compared to values of area per molecule in a spread monolayer of these acids. The decrease in pK(a) was found to relate to melting point temperature and area per molecule in the spread fatty acid monolayer. The pK(a) value was determined by first dissolving the fatty acid in a high pH solution (pH>10) and subsequently titrating the solution with HCl to obtain the characteristic S-shaped curves used to calculate the pK(a) values. The pK(a) values of stearic, elaidic, oleic, linoleic, and linolenic acids were found to be 10.15, 9.95, 9.85, 9.24, and 8.28, respectively. These pK(a) values were in the same order as area per molecule values of fatty acids in spread monolayers. This suggests that as area per molecule increases the intermolecular distance increases and pK(a) decreases due to reduced cooperation between adjacent carboxyl groups.     

Acid-base equilibria in nonpolar media. 2.(1) Self-consistent basicity scale in THF solution ranging from 2-methoxypyridine to EtP(1)(pyrr) phosphazene

Relative ion-pair basicities Delta(pK)(ip) of 25 substituted aryl and alkyl iminophosphoranes (phosphazenes) and 20 other N-bases (various pyridines, amines, amidines) have been measured in THF medium using the UV-Vis and/or (13)C NMR methods. The Delta(pK)(ip) values were corrected for ion pairing using the Fuoss equation to obtain relative ionic basicities Delta(pK)(alpha). Based on the measurements, a basicity scale ranging from 2-methoxypyridine to EtP(1)(pyrr) and having a total span over 18 pK units has been created. The scale has been anchored to the pK(alpha) value of triethylamine (pK(alpha) = 12.5). The results are compared to pK(a) values in various other solvents and in the gas phase. The pK(alpha) values give better correlations than the pK(ip) values, thus indirectly validating the procedure of correction for ion pairing. The predictability of the basicity together with suitable spectral properties in the UV range make the phenylphosphazenes convenient neutral indicators in the high basicity range where the choice of neutral indicators is very limited.     

Acid-base equilibria in gamma-butyrolactone studied by use of pH-ISFETs

pH-ISFETs were used in the study of acid-base equilibria in gamma-butyrolactone (GBL). After the spectrophotometric determination of the pK(a) value of 3,5-dichloropicric acid, the pK(a) values and homo-conjugation constants of various acids (including the conjugate acids of bases) were determined potentiometrically using a Ta(2)O(5)-type pH-ISFET. The values of pK(a) in GBL were in a linear relation with those in propylene carbonate (PC) and 1.0 units smaller on average. The difference in pK(a) between GBL and PC was mainly attributable to the difference in proton solvation. The autoprotolysis constant of GBL, roughly estimated by a rapid titration with a Si(3)N(4)-ISFET, was about 30 on the pK(SH) scale. A comparative study was made of the response speeds of the Ta(2)O(5)- and Si(3)N(4)-type pH-ISFETs and a conventional pH-glass electrode. The result was Si(3)N(4)-ISFET > Ta(2)O(5)-ISFET > glass electrode. Because GBL is not stable against acids and bases, the use of pH-ISFETs was much more convenient than the use of the conventional glass electrode.     

Formation and stability of peptide enolates in aqueous solution

Second-order rate constants k(DO) (M(-1) s(-1)) were determined in D(2)O for deprotonation of the N-terminal alpha-amino carbon of glycylglycine and glycylglycylglycine zwitterions, the internal alpha-amino carbon of the glycylglycylglycine anion, and the acetyl methyl group and the alpha-amino carbon of the N-acetylglycine anion and N-acetylglycinamide by deuterioxide ion. The data were used to estimate values of k(HO) (M(-1) s(-1)) for proton transfer from these carbon acids to hydroxide ion in H(2)O. Values of the pK(a) for these carbon acids ranging from 23.9 to 30.8 were obtained by interpolation or extrapolation of good linear correlations between log k(HO) and carbon acid pK(a) established in earlier work for deprotonation of related neutral and cationic alpha-carbonyl carbon acids. The alpha-amino carbon at a N-protonated N-terminus of a peptide or protein is estimated to undergo deprotonation about 130-fold faster than the alpha-amino carbon at the corresponding internal amino acid residue. The value of k(HO) for deprotonation of the N-terminal alpha-amino carbon of the glycylglycylglycine zwitterion (pK(a) = 25.1) is similar to that for deprotonation of the more acidic ketone acetone (pK(a) = 19.3), as a result of a lower Marcus intrinsic barrier to deprotonation of cationic alpha-carbonyl carbon acids. The cationic NH(3)(+) group is generally more strongly electron-withdrawing than the neutral NHAc group, but the alpha-NH(3)(+) and the alpha-NHAc substituents result in very similar decreases in the pK(a) of several alpha-carbonyl carbon acids.     

pKa prediction from an ab initio bond length: part 3--benzoic acids and anilines

The prediction of pK(a) from a single ab initio bond length has been extended to provide equations for benzoic acids and anilines. The HF/6-31G(d) level of theory is used for all geometry optimisations. Similarly to phenols (Part 2 of this series of publications), the meta-/para-substituted benzoic acids can be predicted from a single model constructed from one bond length. This model had an impressive RMSEP of 0.13 pK(a) units. The prediction of ortho-substituted benzoic acids required the identification of high-correlation subsets, where the compounds in the same subset have at least one of the same (e.g. halogens, hydroxy) ortho substituent. Two pK(a) equations are provided for o-halogen benzoic acids and o-hydroxybenzoic acids, where the RMSEP values are 0.19 and 0.15 pK(a) units, respectively. Interestingly, the bond length that provided the best model differed between these two high-correlation subsets. This demonstrates the importance of investigating the most predictive bond length, which is not necessarily the bond involving the acid hydrogen. Three high-correlation subsets were identified for the ortho-substituted anilines. These were o-halogen, o-nitro and o-alkyl-substituted aniline high-correlation subsets, where the RMSEP ranged from 0.23 to 0.44 pK(a) units. The RMSEP for the meta-/para-substituted aniline model was 0.54 pK(a) units. This value exceeded our threshold of 0.50 pK(a) units and was higher than both the m-/p-benzoic acids in this work and the m-/p-phenols (RMSEP = 0.43) of Part 2. Constructing two separate models for the meta- and para- substituted anilines, where RMSEP values of 0.63 and 0.33 pK(a) units were obtained respectively, revealed it was the meta-substituted anilines that caused the large RMSEP value. For unknown reasons the RMSEP value increased with the addition of a further twenty meta-substituted anilines to this model. The C-N bond always produced the best correlations with pK(a) for all the high-correlation subsets. A higher level of theory and an ammonia probe improved the statistics only marginally for the hydroxybenzoic acid high-correlation subsets.     

Thermodynamic dissociation constants of isocaine, physostigmine and pilocarpine by regression analysis of potentiometric data

Concentration and mixed dissociation constant(s) of three drug acids, H(J)L, isocaine, physostigmine and pilocarpine, at various ionic strengths, I, in the range 0.03-0.81 and 25 degrees C have been determined with the use of regression analysis of potentiometric titration data when common parameter, pK(a), and group parameters E'(0), L(0), and H(T) are simultaneously refined. Internal calibration of the glass electrode cell in the concentration scale [H(+)] performed during titration was used. The estimate of ill-conditioned group parameters has a great influence on a systematic error in estimated pK(a) and therefore it makes the computational strategy important. As more group parameters are refined and a better fit achieved, a more reliable estimate of dissociation constants results. The thermodynamic dissociation constant, pK(a)(T), an ill-conditioned ion-size parameter, ?, and the salting-out coefficient, C, were estimated by non-linear regression of {pK(a), I} data and an extended Debye-Hückel equation. The goodness-of-fit test based on regression diagnostics is a measure of the reliability of parameters, and proves that reliable estimates for isocaine pK(a)(T)(=)8.96(1), ?=8(3) A and C=0.50(3) at 25 degrees C, for physostigmine pK(a)(T)(=)8.07(3), ?=19(26) A and C=0.64(3) at 25 degrees C, and for pilocarpine pK(a)(T)(=)7.00(1), ?=7(1) A and C=0.53(2) at 25 degrees C were found.     

Perturbation of the NH2 pKa value of adenine in platinum(II) complexes: distinct stereochemical internucleobase effects

The degree of acidification of the exocyclic N6 amino group of the model nucleobase 9-methyladenine (9MeA) in relation to the number and site(s) of Pt(II) binding has been studied in detail. It is found that twofold Pt(II) binding to N1 and N7 lowers the pK(a) value from 16.7 in the free base to 12-8. The lowest pK(a) values are observed when the resulting N6H(-) amide group is intramolecularly stabilized by an H-bond donor such as the N6H(2) group of a suitably positioned second 9MeA ligand. Deprotonation of the N6 amino group facilitates Pt migration from N1 to N6, and subsequent reprotonation of the N1 position yields a twofold N7,N6-metalated form of the rare imino tautomer of 9MeA, which has a pK(a) value of 5.03. These findings demonstrate a principle that is of potential relevance to the topic of "shifted pK(a)" values of adenine nucleobases, which is believed to be important with regard to acid-base catalysis of RNAs at physiological pH values. The principle states that a nucleobase pK(a) value can be sufficiently lowered to reach near-neutral values and that the pK(a) value of the protonated base does not necessarily have to be increased to accomplish this effect.     

Effect of temperature on the chromatographic retention of ionizable compounds. III. Modeling retention of pharmaceuticals as a function of eluent pH and column temperature in RPLC

We propose a general simple equation for accurately predicting the retention factors of ionizable compounds upon simultaneous changes in mobile phase pH and column temperature at a given hydroorganic solvent composition. Only four independent experiments provide the input data: retention factors measured in two pH buffered mobile phases at extreme acidic and basic pH values (e. g., at least +/- 2 pH units far from the analyte pK(a)) and at two column temperatures. The equations, derived from the basic thermodynamics of the acid-base equilibria, additionally require the knowledge of the solute pK(a )and enthalpies of acid-base dissociation of both the solute and the buffer components in the hydroorganic solvent mixture. The performance of the predictive model is corroborated with the comparison between theoretical and experimental retention factors of several weak acids and bases of important pharmacological activity, in mobile phases containing different buffer solutions prepared in 25% w/w ACN in water and at several temperatures.     

pKa of residue 66 in Staphylococal nuclease. I. Insights from QM/MM simulations with conventional sampling

A combined quantum mechanical/molecular mechanical (QM/MM) potential function is used in a thermodynamic integration approach to calculate the pK(a) of residue 66 in two mutants (V66E, V66D) of Staphylococal nuclease relative to solution. Despite the similarity in chemical nature and experimentally measured pK(a) of the two buried titritable residues, the behaviors of the two mutants and the computed pK(a) values vary greatly in the simulations. For Glu66, the side chain is consistently observed to spontaneously flip out from the protein interior during titration, and the overall protein structure remains stable throughout the simulations. The computed pK(a) shifts using conventional sampling techniques with multiple nanoseconds per lambda window (Set A and B) are generally close to the experimental value, therefore indicating that large-scale conformational rearrangements are not as important for V66E as suggested by the recent study of Warshel and co-worker. For Asp66, by contrast, flipping of the shorter side chain is not sufficient for getting adequate solvent stabilization of the ionized state. As a result, more complex behaviors such as partial unfolding of a nearby beta-sheet region is observed, and the computed pK(a) shift is substantially higher than the experimental value unless Asp66 is biased to adopt the similar configurations as Glu66 in the V66E simulations. Collectively, these studies suggest that the lack of electronic polarization is not expected to be the dominant source of error in microscopic pK(a) shift calculations, while the need of enhanced sampling is more compelling for predicting the pK(a) of buried residues. Furthermore, the comparison between V66E and V66D also highlights that the microscopic interpretation of similar apparent pK(a) values and effective "dielectric constants" of proteins can vary greatly in terms of the residues that make key contributions and the scale of structural/hydration response to titration, the latter of which is difficult to predict a priori. Perturbative analyses of interactions that contribute to the titration free energy point to mutants that can be used to verify the microscopic mechanisms of titration in V66E/D SNase proteins.     

Mechanisms of acid decomposition of dithiocarbamates. 3. Aryldithiocarbamates and the torsional effect

The acid decomposition of some p-substituted aryldithiocarbamates (arylDTCs) was observed in 20% aqueous ethanol at 25 degrees C, mu = 1.0 (KCl, for pH > 0). The pH-rate profiles showed a dumbell shape with a plateau where the observed first-order rate constant k(obs) was equal to k(o), the rate constant of the decomposition of the dithiocarbamic acid species. The acid dissociation constants of the dithiocarbamic acids (pK(a)) and their conjugate acids (pK(+)) were calculated from the pH-rate profiles. Comparatively, k(o) was more than 10(4)-fold faster than alkyldithiocarbamates (alkDTCs) with similar pK(N) (the acid dissociation constant of the parent amine). It was observed that the values of pK(a) and pK(+)were 5 and 8 units of pK, respectively, higher than the expected values from the pK(N) of alkylDTCs. The higher values were attributed to the inhibition of the delocalization of the nitrogen electron pair into the benzene ring because of the strong electron withdrawal effect of the thiocarbonyl group. Comparison of the activation parameters showed that the rate acceleration was due to a decrease in the enthalpy of activation. Proton inventory indicated the existence of a multiproton transition state, and it was consistent with an S to N proton transfer through a water molecule. There are two hydrogens contributing to a secondary SIE, and there are also two protons that are being transferred at the transition state to form a zwitterion followed by fast C-N bond cleavage. The mechanism could also be a concerted asynchronic process where the N-protonation is more advanced than the C-N bond breakdown. The kinetic barrier is similar to the torsional barrier of thioamides, suggesting that the driving force to reach the transition state is the needed torsion of the C-N bond that inhibits the resonance with the thiocarbonyl group and the aromatic moiety, increasing the basicity of the nitrogen and making the proton transfer thermodynamically favorable.     

First-principle calculation of equilibrium cesium ion-pair acidities in tetrahydrofuran

The ion-pair acidities of organic acids in THF are fundamental to synthetic organic chemistry. Although the ion-pair acidities of a number of carbon acids have been experimentally measured by Streitwieser and co-workers, it is important to develop a theoretical method that can accurately predict these quantities because not all the organic acids (e.g., very weak acids or complex synthetic intermediates with multiple acidic positions) are amenable to experimental characterization. In the present study is reported the first theoretical protocol for predicting the cesium ion-pair acidities in THF whose reliability has been tested against almost all the available experimental data. It is found that the root-mean-square error of the current theoretical model equals 1.2 pK units. With the newly developed theoretical method in hand, the structures of cesium ion pairs of different types of carbon acids are then studied. The cesium ion-pair acidities in THF and absolute ionic acidities in DMSO are also systematically compared, which confirms Streitwieser's previous finding that the two scales of acidities have only minor difference. Significantly, from detailed energy analysis the mechanism for the "fortunate" match of the two scales of acidities is found. That is, the combined process of the Cs binding ("micro"-solvation) and the solvation of the ion pair resembles the one-step solvation of a carbanion in DMSO. Finally, it is found that the cesium ion-pair acidities of nitrogen acids in THF have only minor difference from the absolute ionic acidities in DMSO. Consequently, one can easily estimate the cesium ion-pair acidities of almost all types of organic nitrogen acids in THF on the basis of Bordwell's data.