Steric inhibition of resonance: a revision and quantitative estimation on the basis of aromatic carboxylic acids

The classical concepts of steric inhibition of resonance (SIR) and primary steric effect (van der Waals interactions) were revised with the aid of methyl-substituted benzoic acids. The quantum chemical model was based on the energies of various conformations, calculated at the RHF/6-31 +G(d,p) and B3LYP/6-311 + G(3df,2pd)//RHF/6-31 +G(d,p) levels. The molecule of 2-methylbenzoic acid is planar: no SIR is possible, and van der Waals interaction is practically equal in the acid molecule and in its anion. Therefore, the increased strength of this acid is not due to any steric effect but can be described in terms of electrostatic interaction pole/induced dipole, which lowers the energy of the anion. The molecule of 2,6-dimethylbenzoic acid is nonplanar. SIR is significant in the acid molecule but equal or even greater in the anion. The higher acidity cannot be connected with SIR and can be explained also by electrostatic interaction. In 2,3,5,6-tetramethylbenzoic acid, SIR is greater and may be responsible for one third of the acid-strengthening effect. The concept of SIR is to be applied with caution; even when the nonplanar conformation is proven, SIR need not be responsible for any observable quantity, and particularly not for the acidic and basic properties.     

Acidity of hydroxamic acids and amides

The relatively strong acidity of hydroxamic acids was analyzed by means of isodesmic reactions in which this acid or its anion is formed from simpler precursors. Acidity of amides was analyzed in the same way. Energies of all compounds involved in the reactions were calculated at the B3LYP/AUG-cc-pVTZ//B3LYP/6-311 + G(d,p) level; at this level a good agreement was reached with the sparse experimental data. Interpretation of the results was the same as in the recent discussion of the acidity of carboxylic acids, and the conclusions were similar: both amides and hydroxamic acids are stabilized with respect to simpler reference molecules of amines or N-alkylhydroxylamines, respectively. However, their anions are stabilized still more and are responsible for the acidity. This effect is stronger in hydroxamic acids or amides than in carboxylic acids. The problem of whether it is due to resonance depends on the definition of this term. Semiquantitative comparison suggests that resonance in hydroxamic acids is more important than in amides and still more than in carboxylic acids. The stronger acidity of hydroxamic acids compared to amides is due to the destabilizing inductive effect of the hydroxyl group in the acid molecule, not to any effect in the anion.     

Background of the Hammett equation as observed for isolated molecules: meta- and para-substituted benzoic acids

Fundamental model compounds for the Hammett equation, meta- and para-substituted benzoic acids, were investigated by the density functional theory at the B3LYP/6-311+G(d,p) level. Energies of 25 acids and of their anions were calculated in all possible conformations and from them the energies of the assumed mixture of conformers. Relative acidities correlated with the experimental gas-phase acidities almost within the experimental uncertainty, much more precisely than in the case of previous calculations at lower levels. Dissection of the substituent effects into those operating in the acid molecule and in the anion was carried out by means of isodesmic reactions starting from monosubstituted benzenes. Both effects are cooperating in the resulting effect on the acidity; those in the acid molecule are smaller but not negligible. They are also responsible for some deviations from the Hammett equation (through-resonance of para donor substituents) and for the weaker resonance in the acid molecule in meta derivatives; in the anions the inductive and resonance effects are almost equal. On the other hand, the cooperation of effects in the acid and in the anion makes the relative acidity more sensitive to electron withdrawing and is probably one of the reasons why the Hammett equation is so generally valid.     

Observation of amide anions in solution by electrospray ionization mass spectrometry

Negative quasimolecular ions of aromatic carboxylic acid amides have been observed unexpectedly under electrospray ionization conditions. Hypothetically, deprotonation of either carboxamide or carboximidic acid tautomers can produce anions with equivalent resonance structures, the stability of which is affected by conjugated aromatic substituents. In this study, a series of meta and para substituted benzamides were analyzed using electrospray ionization mass spectrometry in aqueous methanolic solutions. The degree of ionization was found to be pH dependent and was enhanced by electron-withdrawing substituents and suppressed by electron-donating groups. The observed effect on apparent acidity can be accounted for by resonance stabilization.     

Polar group enhanced gas-phase acidities of carboxylic acids: an investigation of intramolecular electrostatic interaction

We studied the effects of polar groups on the gas-phase acidities of carboxylic acids experimentally and computationally. In this connection, the gas-phase acidities (DeltaH(acid), the enthalpy of deprotonation, and DeltaG(acid), the deprotonation free energy) of borane-complexed methylaminoacetic acid ((CH(3))2N(BH(3))CH(2)CO(2)H) and methylthioacetic acid (CH(3)S(BH(3))CH(2)CO(2)H) were measured using the kinetic method in a flowing afterglow-triple quadrupole mass spectrometer. The values of DeltaH(acid) and DeltaG(acid) of (CH(3))2N(BH(3))CH(2)CO(2)H were determined to be 328.8 +/- 1.9 and 322.1 +/- 1.9 kcal/mol, and those of CH(3)S(BH(3))CH(2)CO(2)H were determined to be 325.8 +/- 1.9 and 319.2 +/- 1.9 kcal/mol, respectively. The theoretical enthalpies of deprotonation of (CH(3))2N(BH(3))CH(2)CO(2)H (329.2 kcal/mol) and CH(3)S(BH(3))CH(2)CO(2)H (325.5 kcal/mol) were calculated at the B3LYP/6-31+G(d) level of theory. The calculated enthalpies of deprotonation of N-oxide-acetic acid (CH(3)NOCH(2)CO(2)H, 329.4 kcal/mol) and S-oxide-acetic acid (CH(3)SOCH(2)CO(2)H, 328.6 kcal/mol) are comparable to the experimental results for borane-complexed methylamino- and methylthioacetic acids. The enthalpy of deprotonation of sulfone-acetic acid (CH(3)SO2CH(2)CO(2)H, 326.1 kcal/mol) is about 2 kcal/mol lower than the S-oxide-acetic acid. The calculated enthalpy of deprotonation of sulfoniumacetic acid, (CH(3))2S+CH(2)CO(2)H, is 243.0 kcal/mol. Compared to the corresponding reference molecules, CH(3)NHCH(2)CO(2)H and CH(3)SCH(2)CO(2)H, the dipolar group and the monopolar group substituted carboxylic acids are stronger acids by 11-14 and 97 kcal/mol, respectively. We correlated the changes of the acidity upon a polar group substitution to the electrostatic free energy within the carboxylate anion. The acidity enhancements in polar group substituted carboxylic acids are the results of the favorable electrostatic interactions between the polar group and the developing charge at the carboxyl group.     

Acidity of ortho-substituted benzoic acids: an infrared and theoretical study of the intramolecular hydrogen bonds

The structures of ortho-substituted benzoic acids with substituents bearing hydrogen atoms (OH, NH2, COOH and SO2NH2) were investigated by means of IR spectroscopy and of density functional theory at the B3LYP/6-311 + G(d,p) level. All possible conformations, hydrogen bonds, tautomeric forms and zwitterions were taken into consideration and particular attention was given to intramolecular H-bonds and their effect on acidity. Strong H-bonds in the anions of all four acids, were revealed by calculations. In three cases they were confirmed by the IR spectra of the tetrabutylammonium salts in tetrachloromethane solution, while the salt of 1,2-benzenedicarboxylic acid was not sufficiently soluble. The H-bonds are of different strengths but in all cases they are the main cause of the strengthened acidity of these acids in the gas phase and also in solution, although their effect is opposed by weaker H-bonds present in the undissociated acid molecules. The substituent effect on the acidity was evaluated in terms of isodesmic reactions, separately in the acid molecules and in the anions. While the acidity of the 2-OH and 2-NH2 acids is determined essentially by the H-bonds, that of the 2-COOH and 2-SO2NH2 acids is strengthened by the polar effect operating in the undissociated molecule in addition to the H-bond in the anion. The steric inhibition of resonance (SIR), estimated from model conformations with fixed torsional angles, is of little importance. This analysis goes significantly beyond the classical explanation obtained from the acidities in solution but essentially conforms with it.     

Total dissociative electron attachment cross sections of selected amino acids

Total dissociative electron attachment cross sections are presented for the amino acids, glycine, alanine, proline, phenylalanine, and tryptophan, at energies below the first ionization energy. Cross section magnitudes were determined by observation of positive ion production and normalization to ionization cross sections calculated using the binary-encounter-Bethe method. The prominent 1.2 eV feature in the cross sections of the amino acids and the closely related HCOOH molecule is widely attributed to the attachment into the -COOH pi* orbital. The authors discuss evidence that direct attachment to the lowest sigma* orbital may instead be responsible. A close correlation between the energies of the core-excited anion states of glycine, alanine, and proline and the ionization energies of the neutral molecules is found. A prominent feature in the total dissociative electron attachment cross section of these compounds is absent in previous studies using mass analysis, suggesting that the missing fragment is energetic H-.     

Potentiometric determination of the total acidity and concentration of citric acid in wines

The method of potentiometric titration with a copper electrode is used for the determination of the total acidity and concentration of citric acid (CA) in identifying the adulteration of wines. The procedure is suitable for the determination of citric acid in wines in the range from 0.1 to 3.5 g/L in the presence of 30-fold amounts of tartaric, acetic, malic, succinic acids and a 10-fold amount of oxalic acid after the separation of organic carboxylic acids on an AV-17-8 anion exchanger. The procedure was developed and certified for the potentiometric determination of the mass fraction of citric acid in table wines and wine materials with an error not exceeding 20%. The criteria (mass fraction of citric acid, the percentage of citric acid in the total acidity, and the shape of the curves of potentiometric titration) were proposed for revealing the adulteration of the acid composition of wines.     

Enantiomeric separation of hydroxy acids and carboxylic acids by diamino-beta-cyclodextrins (AB,AC,AD) in capillary electrophoresis

Selectively modified 6,6'-dideoxy-6,6'-L-diamino-beta-cyclodextrins (AB, AC, AD) were successfully used as chiral selectors for the enantiomeric separation of hydroxy acids and carboxylic acids (in particular, phenoxyalkanoic acid herbicides) in capillary electrophoresis (CE). Chiral separations were obtained at a low selector concentration (1 mM) with good enantioselectivity and resolution factors. Separations were optimized as a function of pH. The different position of the charged groups on the upper rim greatly influenced the separation, accounting for electrostatic interactions between the protonated amino groups of the cyclodextrins (CDs) and the carboxylate of the selectands. The best enantiomeric separation of hydroxy acids was obtained with the AC regioisomer, whereas carboxylic acids were well resolved only by the AB regioisomer. A recognition model is proposed, based on two-dimensional nuclear magnetic resonance (2-D NMR) experiments, in which the orientation of the guest in the inclusion complex is determined by the electrostatic interactions between the selectand and the CD upper rim.     

Calorimetric study of the ionization process for 2,4-dinitrophenol in water—dimethylsulphoxide mixtures at 25°C

The ionization and solution enthalpies of 2,4-dinitrophenol were measured calorimetrically at 25°C in water—DMSO mixtures ranging from 0.1 to 0.8 mole fraction of DMSO.

The greater acidity of 2,4-dinitrophenol with respect to 2,5-dinitrophenol is explained on the basis of the observation that in the anion the π-withdrawing resonance effect of the para nitro group stabilizes the benzene ring while in the undissociated molecule the contrary is true.     

Inductive effects in isolated molecules: 4-substituted bicyclo[2.2.2]octane-1-carboxylic acids

Energies of sixteen 4-substituted bicyclo[2.2.2]octane-1-carboxylic acids, their anions, and pertinent 1-substituted bicyclo[2.2.2]octanes were calculated within the framework of density functional theory at the B3LYP/6-311 + G(d,p) level. Substituent effects were evaluated separately in the acid molecule and in the anion in terms of isodesmic homodesmotic reactions. In both cases, the substituent effects are proportional and of opposite sense, that in the anion being eight times greater; in the effect on acidity they are summed. The calculated acidities are in agreement with experimental values with a standard deviation of 1.1 kJ mol-1, and are recommended as a model for evaluating the inductive effect of various substituents, whether they are experimentally accessible or not. The resulting values are closely related to other scales but can be determined more reliably, particularly when compared with the previous quantum chemical method. We also checked electrostatic calculations and confirmed their very approximate character, particularly in the case of unsymmetrical substituents or of substituents with zero dipole moment.     

High-performance CE: an effective method to study lactonization of alpha2,8-linked oligosialic acid

A sensitive and efficient method using high-performance CE (HPCE) and neuraminidase hydrolysis was developed to study the lactonization and hydrolysis of alpha2,8-pentasialic acid. Eleven lactone species of pentasialic acid formed in glacial acetic acid were detected and classified into three groups based on the number of carboxylic acids: monolactones with four carboxylic acids, dilactones with three carboxylic acids, and trilactones with two carboxylic acids. These lactones eluted between the original pentamer (with five carboxylic acids) and the fully lactonized species (with one carboxylic acid) in HPCE. Eight of the isomers were identified by hydrolysis with neuraminodase. Results obtained from previous reports and from this study together reveal a general rule for predicting the subtle difference in the acidity of each carboxylic acid in oligosialic acids: the closer the carboxylic acid is to the nonreducing end, the more acidic it is. Therefore, the elution order of lactone isomers having the same number of carboxylic groups can be predicted from the position of the free carboxylic groups in pentasialic acid. We used this principle and the results of hydrolysis with neuraminidase to identify hexamer lactone isomers separated by HPCE.     

Novel photopolymerizations initiated by alkyl radicals generated from photocatalyzed decarboxylation of carboxylic acids over oxide semiconductor nanoparticles: Extended photo-Kolbe reactions

Polymerizations of vinyl acetate are photocatalyzed by TiO₂ nanoparticles in presence of carboxylic acids including propionic acid, n-butyric acid and pivalic acid. Nuclear magnetic resonance (NMR) analysis using ¹³C-labeled n-butyric acid as the probing molecule demonstrates that the polymerization of vinyl acetate is initiated by alkyl radicals generated from photocatalytic decarboxylation of the carboxylic acid. A universal mechanism is established with extending the photo-Kolbe reaction from acetic acid to the carboxylic acids with longer chains. Kinetics studies find that n-butyric acid has higher initiation rate than acetic acid, indicating more efficient decarboxylation for butyric acid than acetic acid in their aqueous solutions. It is proved that carboxylates participate in the decarboxylation. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectra are obtained with aqueous solutions of the carboxylic acids in contact with a layer of the TiO₂ nanoparticles, and the observations are discussed with respect to the interaction between the TiO₂ and carboxylic acids.     

Thermal transformation of acid compounds in high TAN crude oil

The Liaohe crude oil with high total acid number (TAN) was subjected to thermal reaction at 300℃to 500℃. Reaction products were collected and analyzed by negative-ion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS) to determine acid compounds in the crude oil. The double-bond equivalence (DBE) versus carbon number was used to characterize the oxygenated components in the feed and reaction products. The O2 class which mainly corresponds to naphthenic acids decarboxylated at 350-400℃, resulting in a sharply decrease in TAN. Phenols (O1 class) are more thermally stable than carboxylic acids. Carboxylic acids were also thermally cracked into smaller molecular size acids, evidenced by the presence of acetic acid, propanoic acid, and butyric acid in the liquid product. These small acid species are strong acids likely responsible for corrosion problems in refineries.     

Electrostatic stabilization of liquid crystalline ordering in binary melts of sodium and potassium alkanoates

The mesophase electrostatic stabilization energy (E) has been examined by using the ionic continuous solid solution model for binary systems of sodium and potassium alkanoates with a common anion. It is found that E increases with a decrease in chain length of the alkanoate anion and that there is an inverse proportionality between E and the square of the mesophase bilayer spacing. The electrostatic stabilization factor is shown to be responsible for the formation of an ionic mesophase in binary acetate and propionate systems derived from two non-mesomorphic components.     

Correlations and predictions of carboxylic acid pKa values using intermolecular structure and properties of hydrogen-bonded complexes

Density functional theory calculations have been preformed on a series of hydrogen-bonded complexes of substituted aliphatic and aromatic carboxylic acids with ammonia. Molecular properties, particularly those related to hydrogen bonding, have been carefully examined for their interdependence as well as dependence on the acidity of the acid. The bond length and stretching frequency of the hydroxyl group and the hydrogen-bond length and energy of the complex are shown to be highly correlated with each other and are linearly correlated with available literature pKa values of the carboxylic acids. The linear correlations resulting from the fit to the available pKa values can be used to predict the pKa values of similar carboxylic acids. The pKa values so predicted using the different molecular properties are highly consistent and in good agreement with the literature values. This study suggests that calculated molecular properties of hydrogen-bonded complexes allow effective and systematic prediction of pKa values for a large range of organic acids using the established linear correlations. This approach is unique in its capability to determine the acidity of a particular functional group or the local acidity within a large molecular system such as a protein.     

Proton transfer reactions of matrix-assisted laser desorption/ionization matrix monomers and dimers

The gas-phase basicities of monomeric and dimeric deprotonated ferulic and sinapic acids, common matrix-assisted laser desorption/ionization (MALDI) matrices, were determined. A new bracketing method based on structure-reactivity correlations was developed for deriving gas-phase basicities from reaction efficiencies. The matrix dimer anions were found to be significantly less basic than the monomer anions, by about 115 kJ/mol. The low basicity of the dimer anion can qualitatively be explained by resonance stabilization. The energies for proton transfer from dimers to monomers are therefore about 1.2 eV lower than for proton transfer between monomers. For the MALDI process, proton transfer reactions involving matrix dimers provide a low energy pathway for matrix and analyte ion formation.     

Efficient allylation of aldehydes promoted by carboxylic acids

A variety of carboxylic acids have been screened for mediating the allylation of aldehydes with allytributyltin in different solvents. A novel, general, and practical method of allylation of aldehydes promoted by carboxylic acids under mild reaction conditions has been developed. Among them, p-nitrobenzoic acid afforded high to quantitative yields of the homoallylic alcohol products, and can be easily recovered after workup by aqueous HCl. Glyoxylic acid self-catalyzed the allylation without adding any other promoter or catalyst to give the corresponding allylation product in good yield. The regioselectivity of the crotylation of aldehydes is tunable by controlling the acidity of the carboxylic acids. The crotylation of aldehydes produced the alpha-adduct as major products in moderate to good yields with CF(3)CO(2)H as a promoter. A possible mechanism for the allylation is also discussed.     

Accurate pKa determination for a heterogeneous group of organic molecules.

Single-molecule studies that allow to compute pKa values, proton affinities (gas-phase acidity/basicity) and the electrostatic energy of solvation have been performed for a heterogeneous set of 26 organic compounds. Quantum mechanical density functional theory (DFT) using the Becke-half&half and B3LYP functionals on optimized molecular geometries have been carried out to investigate the energetics of gas-phase protonation. The electrostatic contribution to the solvation energies of protonated and deprotonated compounds were calculated by solving the Poisson equation using atomic charges generated by fitting the electrostatic potential derived from the molecular wave functions in vacuum. The combination of gas-phase and electrostatic solvation energies by means of the thermodynamic cycle enabled us to compute pKa values for the 26 compounds, which cover six distinct chemical groups (carboxylic acids, benzoic acids, phenols, imides, pyridines and imidazoles). The computational procedure for determining pKa values is accurate and transferable with a root-mean-square deviation of 0.53 and 0.57 pKa units and a maximum error of 1.0 pKa and 1.3 pKa units for Becke-half&half and B3LYP DFT functionals, respectively.