pKa values in organic chemistry – Making maximum use of the available data

Acids and bases are ubiquitous. Sometimes, it is essential to know the accurate strength (pK_a values) of the acids/bases to work with, but sometimes just acidity/basicity order is enough. We often receive requests to measure pK_a values of different substances in different solvents for answering questions like “what acids can be used to protonate this substance” or “what base is able to deprotonate that compound?” Such questions can, in fact, often be answered using published pK_a data in different solvents. This digest/tutorial will give an overview of how to make efficient use of the existing pK_a data.     

Ab initio prediction of the gas- and solution-phase acidities of strong Brønsted acids: the calculation of pKa values less than -10

The intrinsic gas-phase acidities of a series of 21 Br?nsted acids have been predicted with G3(MP2) theory. The G3(MP2) results agree with high level CCSD(T)/CBS acidities for H(2)SO(4), FSO(3)H, CH(3)SO(3)H, and CF(3)SO(3)H to within 1 kcal/mol. The G3(MP2) results are in excellent agreement with experimental gas-phase acidities in the range 342-302 kcal/mol to within <1 kcal/mol for 14 out of 15 acids. Five of the six acids in the range of 302-289 kcal/mol had an average deviation of 5.5 kcal/mol and the strongest acid, (CF(3)SO(2))(3)CH, deviated by 15.0 kcal/mol. These high-level calculations strongly suggest that the experimental acidities in this very acidic part of the scale need to be remeasured. The CCSD(T)/CBS (mixed exponential Gaussian) additive approach for CH(3)CO(2)H, HNO(3), H(2)SO(4), CH(3)SO(3)H, FSO(3)H, and CF(3)SO(3)H gives excellent agreement (+/-1 kcal/mol) with experiment for the DeltaH(f)(0)'s of non-sulfur containing species, and supports the low end of the experimental values for H(2)SO(4) and FSO(3)H. Use of a larger basis set (aug-cc-pV5Z) in the CBS extrapolation improves the agreement with experiment for both H(2)SO(4) and FSO(3)H. The G3(MP2) heats of formation for RSO(3)H molecules tend to be underestimated as compared to the CCSD(T)/CBS approach by 2.5-7.0 kcal/mol. COSMO solvation calculations were used to predict solution free energies and pK(a) values with pK(a)'s up to -17.4. Including the solvation of the proton gives good agreement with experimental pK(a) values in the very acidic regime, whereas it is less reliable for weaker acids. The use of CH(3)CO(2)H and HNO(3) as reference acids in the less acidic and more acidic regions of the scale, respectively, provided improved results to within +/-2 pK(a) units in nearly all cases (+/-3 kcal/mol accuracy).     

Brønsted acidic ionic liquids and their zwitterions: synthesis, characterization and pKa determination

Imidazolium chlorides with one or two carboxylic acid substituent groups, 1-methyl-3-alkylcarboxylic acid imidazolium chloride, [Me[(CH2)nCOOH]im]Cl (n=1, 3), and 1,3-dialkylcarboxylic acid imidazolium chloride, [[(CH2)nCOOH]2im]Cl (n=1, 3), have been synthesized via their corresponding acid esters. Deprotonation of the carboxylic acid functionalized imidazolium chlorides with triethylamine affords the corresponding zwitterions [Me[(CH2)nCOO]im] (n=1, 3) and [[(CH2)nCOOH][(CH2)nCOO]im] (n=1, 3). Subsequent reaction of the zwitterions with strong acids gives the new imidazolium salts [Me[(CH2)nCOOH]im]X (n=1, 3; X=BF4, CF3SO3) and [[(CH2)nCOOH]2im]X (n=1, 3; X=BF4, CF3SO3), which exhibit melting points as low as -61 degrees C. The solid-state structures of two of the carboxylic acid functionalized imidazolium salts have been determined by single-crystal X-ray diffraction analysis. Extensive hydrogen bonding is present between the chloride and the imidazolium, with eight Cl.H interactions below 3 A. The pK(a) values of all the salts, determined by potentiometric titration, lie between 1.33 and 4.59 at 25 degrees C.     

Intrinsic pKa values of 3'-N-α-l-aminoacyl-3'-aminodeoxyadenosines determined by pH dependent 1H NMR in H2O

3'-(α-L-Aminoacylamido)deoxyadenosines are ribosomal A-site binders and mimic the nascent peptide accepting 3'-terminus of aminoacyl transfer RNA. Their α-amino groups exhibit intrinsic basicities in bulk water that differ by up to 1.8 pK(a) units. Only the neutral form of these nucleophiles can be active during ribosomal peptidyl transfer catalysis.     

Complexation between α-cyclodextrin and PEGylated-PAMAM dendrimers at low and high pH values

Poly(ethylene glycol)-grafted-poly(amido amine) (PEGylated-PAMAM) dendrimers have attracted increasing amounts of attention because of their improved stability, toxicity, and better particle drug leakage property. The complexation of α-cyclodextrin (α-CD) with grafted PEG segments on the surface of PAMAM dendrimers was elucidated by light scattering and titration calorimetry. At pH 10, complexation between α-CD and PEGylated-PAMAM occurred once α-CD was titrated into the PAMAM solution. We observed for the first time a unique phenomenon at pH 2, where no binding took place until a critical α-CD concentration (C*) of ～8.0 mM was reached. The size of the nanostructures increased from 6.7 to 57.6 nm when the α-CD concentration was increased from 0.5 to 15 mM at pH 2. The zeta potential of PEGylated-PAMAM at pH 2 was +6.7 mV. Thus, the dendrimers possessed positive charges attributed to the protonation of primary amine groups on PAMAM chains that impart electrostatic repulsive forces to the system. The morphology of the complex is expected to be different at two different pH values (2 and 10) because the former produces a clear solution and the latter forms a turbid solution with white precipitates.     

Determination of Surface pKa of Pure Mercaptoacetic Acid and 2-Mercaptobenzothiazole Mixed Monolayers by Impedance Titration

Interfacial proton transfer reactions of pure mercaptoacetic acid (MA) and 2-mercaptobenzothiazole (Mbz) mixed self-assembled monolayers (SAMs) have been studied using a.c. impedance titration method. The charge-transfer resistance (Rct) is measured with the monolayer composition and the ionic strength ofpH solution. The surface pKa can be obtained by the plots of Rct and pH, the reasons of shifts of surface pKa are also explained.     

无机氢化物的pKa与mQ的关系

元素的周期数连接性指数(mQ)的0Q、1Q定义为:0Q=∑(ni)-0.5,1Q=∑(ni·nj)-0.5.0Q与1Q均对13种p区氢化物呈现唯一性表征,并与其酸性强度pKa的相关系数为:0.9587、0.9919,引入nd的三元相关系数为0.9951.对pKa的预测结果优于文献方法.     

取代羧酸pKa的分子树拓扑研究

基于非氢原子i的酸性点价(δai)建构分子树拓扑指数(mT)及其分支指数(mTC)和叶指数(mTx),并提出表征诱导效应的叶指数(mT′x).通过最佳变量子集算法获得38种羧酸的pKa与0TC、1TC、0T′x的回归方程:pKa=3.0352-1.25700T′x-0.15540TC+0.07811TC,R=0.9766.通过Jackknife法检验,该模型具有总体稳健性.优于文献的七元最佳回归模型(R=0.957),与其分子力学方法(CoMFA)结果(R=0.988)较为接近.结果表明,所建拓扑指数是合理的,具有科学性基础.     

溶液相有机化合物pKa的量子化学计算*

寻找一种理论计算方法来验证和补充实验数据,得到较为精确的溶剂化自由能和pK_a值,是众多理论化学家长期以来研究的重要方向。本综述较为详细地总结了近年发展起来的PCM理论模型在溶液相化合物溶剂化自由能、特别是近十年来有机化合物pK_a值的量子化学计算中的最新成果,比较了各种不同计算方法的精确性和各自特点。     

Quantitative structure–permeability relationships at various pH values for neutral and amphoteric drugs and drug-like compounds$

Abstract

Human intestinal absorption is a key property for orally administered drugs and is dependent on pH. This study focuses on neutral and amphoteric compounds and their membrane permeabilities across the range of pH values found in the human intestine. The membrane permeability values for 15 neutral and 60 amphoteric compounds at pH 3, 5, 7.4 and 9 were measured using the parallel artificial membrane permeability assay (PAMPA). For each data series the quantitative structure–permeability relationships were developed and analysed. The results show that the membrane permeability of neutral compounds is attributed to a single structural characteristic, the hydrogen bond donor ability. Amphoteric compounds are more complex because of their chemical constitution, and therefore require three-parameter models to describe and predict membrane permeability. Analysis of the models for amphoteric compounds reveals that membrane permeability depends on multiple structural characteristics: the partition coefficient, hydrogen bond properties and the shape of the molecules. In addition to conventional validation strategies, two external compounds (isradipine and omeprazole) were tested and revealed very good agreement of pH profiles between experimental and predicted membrane permeability for all of the developed models. Selected QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.184).     

Corrected values of osmotic and activity coefficients of aqueous NaTcO4 and HTcO4 at 25°C

Published isopiestic molalities for aqueous NaTcO₄ and HTcO₄ solutions at 25°C have been reexamined. Our calculations indicate that published smoothed values of the osmotic coefficients and mean molal activity coefficients _± of NaTcO₄ are substantially in error, by up to 100% for and 300% for _±. Published smoothed values of and _± for HTcO₄ solutions are in somewhat better agreement with the input data, but the reported are sometimes higher and sometimes lower than experimental values, by up to 6%. Consequently, we have reanalyzed isopiestic data for these two systems, and find that errors arose in representing the data mathematically. We report parameters for an extended form of the specific ion interaction equations and for Pitzer's equations, and corrected values of and _± are tabulated for aqueous NaTcO₄ and HTcO₄.     

Biodegradable and biocompatible inorganic–organic hybrid materials. I. Synthesis and characterization

The hydroxyl or vinyl end-groups of linear or three-arm star-shaped poly(ε-caprolactone) (PCL) chains have been derivatized into triethoxysilane groups reactive in the sol-gel process. New transparent hybrid materials that combine tetraethylorthosilicate (TEOS) and PCL known for biodegradability and biocompatibility have accordingly been prepared. The sol-gel process is, however, limited by the early vitrification of the reactive system. However, thermal posttreatment can overcome these diffusional and/or kinetic limitations as assessed by a set of analytical methods. The thermal stability of PCL is improved by incorporation into the silica network. Conversely, the thermal stability of the ceramer depends on the effective PCL content. The extent of PCL incorporation into the silica network depends on PCL molecular weight, number, and reactivity of the PCL functional groups. IR spectroscopy has shown that hydrogen bonding occurs between the ester groups of PCL and residual OH groups of the silicate component. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35 : 2295–2309, 1997     

Pyrilocyanines. 36.α-thienyl substituted pyrilo- and thiopyrilocyanines

Symmetrical and nonsymmetrical 2,6- (and 4,6-)-di--thienyl substituted - and -pyrilo- and thiopyrilocyanines have been synthesized. The effect of changing the phenyl groups for -thienyl on the electronic absorption spectral parameters of the dyes obtained is discussed. It was found that such a change leads to a decrease in the effective length and increase in the electron donor ability of the hetero fragments containing these groups. The more intense coloring of the thienyl substituted dyes is due to interaction of the polymethine and quasilocal electronic transitions.For Communication 35 see [1].Institute of Organic Chemistry, National Academy of Sciences of Ukraine Kiev 253660. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 494–500, April, 1998.     

A prelude of the 2004 Antwerp Quality Conference: Targets and target values—integrating quality management and costing

Questions about the value of services in the health care sector and the quality of them have been addressed frequently during the last decade, but as separate issues. In this article a method is proposed to combine these two issues. The starting point is the observation that competition will become fiercer among providers in the health care sector . Moreover, the patients opinion about quality in terms of convenience, emotional attention, etc., will be important in a competitive environment and will determine which health care service providers will be successful. These developments will have an impact on the engineering of the health care chain. Methods are discussed to integrate the determination of the value of innovations and new products, and the design of quality systems. The system of target costing is focused upon. It takes the outcome of care processes as desired by customers or the users as the starting point both for pricing the services as well as for designing the delivery system. This will not only improve cost control, but also quality improvements in two ways. First, the delivery system will be better adapted (and integrated if more health care providers are involved) to the needs of the patients, and second quality will improve as health care providers analyze, redesign, and monitor their processes more extensively.Presented at the 9th Conference on Quality in the Spotlight, 18–19 March 2004, Antwerp, Belgium