Acidity of carboxylic acids: a rebuttal and redefinition

A recent theory of ionization of carboxylic acids divided the process of ionization into two steps and attributed the main importance to the electrostatic potential of the acid molecule. The origin of the acidity was thus seen in the high energy of the acid molecule and not in the stabilization of the anion by resonance. In this paper, the theory was revised on the basis of further calculations at an MP2/6-31++G(2d,p) level which followed in two steps the reverse process, protonation of the formate anion. The results were compared to those of the methanolate anion as reference. A contradictory conclusion was obtained: the reason for the acidity is in the electrostatic potential of the anion. As a model compound without resonance, 2,2,2-trifluoroethanol was investigated in the same way. The results were qualitatively similar, although any resonance in the anion is not possible. One can conclude that the acidity of carboxylic acids is due to the low energy of their anions; this follows unambiguously from the isodesmic reactions on the basis of either the experimental enthalpies of formation or the calculated energies. It is more difficult to decide whether this low energy is caused by resonance, because any model of the carboxylate anion without resonance is necessarily imperfect and the whole concept is not exactly defined. Several such models were reexamined and improved by separating the effect operative in the anion from those in the neutral acid molecule. While the electrostatic model did not allow any significant conclusion, two models based on VB calculation and on correlation analysis, respectively, furnished qualitatively concordant results: resonance in the anion is diminished by the resonance in the acid molecule, and both together are responsible for less than one-half of the acidity enhancement as compared to the acidity of alcohols. The ratio is reversed in water solution: resonance is then the more important factor responsible for some two-thirds of the enhanced acidity.     

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.     

Photosensitization by phenylalanine of carboxylic acids, amides, and peptides in frozen aqueous solution

Abstract— In order to elucidate the mechanism of the photosensitization of proteins and peptides by aromatic amino acids, the behaviour of aliphatic carboxylic acids and amides upon irradiation in frozen aqueous solution in the presence of phenylalanine (l-Phe) has been studied by EPR spectroscopy. EPR signals are much stronger when acids or amides are irradiated in the presence of l-Phe, showing that they are photosensitized by the aromatic amino acid. The species observed are either alkyl radicals, or radicals formed by abstraction of a hydrogen atom from a molecule of acid or arnide. A mechanism is proposed which involves the capture by carboxyl or amide carbonyl groups of hydrated electrons released by the photo-excited l-Phe, followed by the splitting of the resulting anion free radical with the formation of alkyl radicals, and transfer reactions leading to more stable free radicals. In peptides, which are also photosensitized by l-Phe, electrons are captured preferably by the carboxylic carbonyl groups.     

Colorimetric determination of organic compounds by formation of hydroxamic acids

Carboxylic acids, their chlorides, anhydrides, esters, lactones, amides, lactams and imides react with hydroxylamine to give hydroxamic acids which are then treated with iron(III). Other compounds or groups of compounds can also be determined after a prior conversion into hydroxylamine-reactive derivatives. The calorimetric applications of these reactions are reviewed. The effect of various factors is discussed. A selective procedure for determination of acid chlorides and anhydrides and an improved procedure for determination of carboxylic esters and lactones are presented.     

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.     

Acidity trends in alpha,beta-unsaturated alkanes, silanes, germanes, and stannanes.

The gas-phase acidity of ethyl-, vinyl-, ethynyl-, and phenyl-substituted silanes, germanes, and stannanes has been measured by means of FT-ICR techniques. The effect of unsaturation on the intrinsic acidity of these compounds and the corresponding hydrocarbons was analyzed through the use of G2 ab initio and DFT calculations. In this way, it was possible to get a general picture of the acidity trends within group 14. As expected, the acid strength increases down the group, although the acidity differences between germanium and tin derivatives are already rather small. As has been found before for amines, phosphines, and arsines, the carbon, silicon, germanium, and tin alpha,beta-unsaturated compounds are stronger acids( )than their saturated analogues. The acidifying effect of unsaturation is much larger for carbon than for Si-, Ge-, and Sn-containing compounds. The allyl anion is better stabilized by resonance than its Si, Ge, and Sn analogues, [CH(2)(-)(delta)--CH(+)(delta)(') --CH(2)(-)(delta)](-) vs [CH(2)(-)(delta)()II = CH(-)(delta)()III - XH(2)(-)(delta)()IV](-) (X = Si, Ge, Sn). The enhanced acid strength of unsaturated compounds is essentially due to a greater stabilization of the anion with respect to the neutral, because the electronegativity of the alpha,beta-unsaturated carbon group increases with its degree of unsaturation. The phenyl derivatives are systematically weaker acids than the corresponding ethynyl derivatives by 15-20 kJ mol(-)(1). Experimentally, toluene acidity is very close to that of propyne, because the deprotonation of propyne takes place preferentially at the =CH group rather than at the -CH(3) group.     

The role of chalcogen-chalcogen interactions in the intrinsic basicity acidity of beta-chalcogenovinyl(thio)aldehydes HC([double bond]X)[bond]CH[double bond]CH[bond]CYH

The intrinsic acidity and basicity of a series of beta-chalcogenovinyl(thio)aldehydes HC([double bond]X)[bond]CH[double bond]CH[bond]CYH (X=O, S; Y=Se, Te) were investigated by B3LYP/6-311+G(3df,2p) density functional and G2(MP2) calculations on geometries optimized at the B3LYP/6-31G(d) level for neutral molecules and at the B3LYP/6-31+G(d) level for anions. The results showed that selenovinylaldehyde and selenovinylthioaldehyde should behave as Se bases in the gas phase, because the most stable neutral conformer is stabilized by an X[bond]H...Se (X=O, S) intramolecular hydrogen bond (IHB). In contrast the Te-containing analogues behave as oxygen or sulfur bases, because the most stable conformer is stabilized by typical X...Y[bond]H chalcogen-chalcogen interactions. These compounds have a lower basicity than expected because either chalcogen-chalcogen interactions or IHBs become weaker upon protonation. Similarly, they are also weaker acids than expected because deprotonation results in a significantly destabilized anion. Loss of the proton from the X[bond]H or Y[bond]H groups is a much more favorable than from the C[bond]H groups. Therefore, for Se compounds the deprotonation process results in loss of the X[bond]H...Se (X=O, S) IHBs present in the most stable neutral conformer, while for Te-containing compounds the stabilizing X...Y[bond]H chalcogen-chalcogen interaction present in the most stable neutral conformer becomes repulsive in the corresponding anion.     

In search of ultrastrong Brønsted neutral organic superacids: a DFT study on some cyclopentadiene derivatives

An efficient but reasonably accurate B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) computational procedure showed that pentasubstituted cyclopentadienes such as (CN)5C5H, (NO2)5C5H, and (NC)5C5H containing strongly electron-withdrawing groups are neutral organic superacids of unprecedented strength. The boldface denotes the atom attached to the cyclopentadiene framework. All of them exhibit prototropic tautomerism by forming somewhat more stable structures with C=NH, NO2H, and N=CH exocyclic fragments, respectively. The acidity (DeltaH(acid)) of these is lower, but only to a rather small extent. The DeltaH(acid) enthalpies of these last three tautomers are estimated to be 271, 276, and 282 kcal mol(-1), respectively. Hence, the most stable tautomers of (CN)5C5H and (NC)5C5H represent a legitimate target for synthetic chemists. On the other hand, (NO2)5C5H is less suitable for practical applications, because of its high energy density. The origin of the highly pronounced acidity of these compounds was analyzed by using the recently developed triadic formula. It is found that very high Koopmans' ionization energy (IE)n(Koop) of conjugate bases exerts a decisive influence on acidity. It follows as a corollary that the overwhelming effect leading to very high acidity is due to the properties of the final state. An alternative picture is offered by homodesmotic reactions, wherein the cyclic systems are compared with their linear counterparts. It is found that the acidity of cyclopentadiene (CP) is a consequence of aromatic stabilization in the CP- anion. The extreme acidity of pentacyanocyclopentadiene (CN)5C5H is due to aromatization of the five-membered ring and a strong anionic resonance effect in the resultant conjugate base. The neutral organic superacids predicted by the present calculations may help to bridge the gap between existing very strong acids and bases.     

On the Origin of the Enhanced Acidity of Chalcocyclopentadienes (Cyclopentadiene Chalcogenols) in the Gas Phase

The intrinsic acidity of chalcocyclopentadienes (CpXH; X=O, S, Se, Te) is investigated by high‐level G3B3 and G2 ab initio as well as B3LYP DFT calculations, which show that, independent of the nature of the heteroatom, all chalcocyclopentadienes are stronger acids in the gas phase than cyclopentadiene. However the acidity does not increase regularly down the group, and the acidity enhancement for Te derivatives is five times larger than for O derivatives, but only twice that of S‐containing compounds. The most favorable deprotonation process corresponds to loss of the proton attached to the heteroatom, with the sole exception of the 5‐substituted 1,3‐cyclopentadienes, for which the O and S derivatives are predicted to behave as carbon acids. No matter the nature of the heteroatom, the 1‐substituted 1,3‐cyclopentadienes are the strongest acids. The intrinsic acidity of all isomers, namely, 1‐substituted, 2‐substituted, and 5‐substituted 1,3‐cyclopentadienes, increases with increasing aromaticity of the anion formed on deprotonation, and therefore the Te compound is the strongest acid for the three series. However, the intrinsic acidity of chalcocyclopentadienes is not dictated by aromaticity, so that, in general, the most stable deprotonated species do not coincide with the most aromatic ones.     

Density functional study of the conformations and intramolecular proton transfer in thiohydroxamic acids

The conformational preferences of thiohydroxamic acids (N-hydroxythioamides) are investigated by the density functional B3LYP/6-311++G(3df,3pd)//B3LYP/6-31G(d) method in this work. Unlike hydroxamic acids, the thione and thiol forms are found to be equally stable in the gas phase, and the reaction pathways for the interconversion between the thione and thiol forms have been deduced to involve rotation about the C[double bond, length as m-dash]N bond of the thiol tautomer in the rate-determining step. The effect of aqueous solvation on the reactions has also been investigated. It is found that inclusion of a few explicit water molecules in an implicit solvent calculation is necessary in order to accurately account for hydrogen bonding effects. Thiohydroxamic acids, like their hydroxamic acid analogues, are found to be N-acids, both in the gas phase and in aqueous solution.     

Mechanism of cis-enamide formation from N-(alpha-silyl)allyl amides: synthetic potential of stepwise dyotropic rearrangements

A novel transformation of silyl amides to N-cis-propenyl amides was recently reported, the reaction of which is a formal 10-electron double sigmatropic, or dyotropic, rearrangement. Density functional calculations (B3LYP/6-311++G(3d,3p)//B3LYP/6-31G(d)) have been carried out to investigate the mechanism of this reaction. A two-step process involving sequential 1,4-silyl and 1,4-hydrogen shifts is predicted. The 1,3-dipolar azomethine ylide intermediate profits from charge stabilization by allylic resonance and phenyl conjugation. The consecutive thermal migration of two sigma-bonds (stepwise dyotropic rearrangement) is an example of a host of reactions with synthetic potential.     

Solid phase extraction purification of carboxylic acid products from 96-well format solution phase synthesis with DOWEX 1x8-400 formate anion exchange resin

The anion exchange resin DOWEX 1x8-400 formate has been developed for the isolation or resin capture of carboxylic acids from solution phase reactions in a 96-well format using a batchwise solid phase extraction technique. Eleven different anion exchange resins (formate forms) were evaluated for their efficiency at scavenging aryl and aliphatic carboxylic acids from solution. The model carboxylic acids had pK(a)s ranging from 3.40 to 4.89. Exchange efficiency onto the resin was pK(a) dependent with the carboxylic acids but not with their diisopropylethylammonium salts. Exchange off of the resin also showed pK(a) dependence with the stronger acids requiring more concentrated solvent acid for exchange. DOWEX 1x8-400 formate was determined to have superior capacity and the fastest exchange rate. Solvents suitable for exchanging the acids onto the resin were CH2Cl2, methanol, and various solvent/water mixtures. Solvents suitable for exchanging the carboxylic acids off of the resin were TFA/solvent or HCO2H/solvent mixtures. The resin was found to swell best in CH2Cl2 and in polar protic solvents such as water, alcohols, and acids. Application of this technique to the crude product mixtures from an arrayed reductive amination and an arrayed Stille reaction provided product carboxylic acids in yields averaging 57% and purities averaging 89%.     

Acidity trends in alpha,beta-unsaturated sulfur, selenium, and tellurium derivatives: comparison with C-, Si-, Ge-, Sn-, N-, P-, As-, and Sb-containing analogues

The gas-phase acidity of CH3-CH2XH (X=S, Se, Te), CH2=CHXH (X=S, Se, Te) and PhXH (X=S, Se) compounds was measured by means of Fourier transform ion cyclotron resonance mass spectrometry. To analyze the role that unsaturation plays on the intrinsic acidity of these systems, a parallel theoretical study, in the framework of the G2 and the G2(MP2) theories, was carried out for all ethyl, ethenyl (vinyl), ethynyl, and phenyl O-, S-, Se-, and Te-containing derivatives. Unsaturated compounds are stronger acids than their saturated analogues, because of the strong pi-electron donor ability of the heteroatoms that contributes to a large stabilization of the unsaturated anions. Ethynyl derivatives are stronger acids than vinyl compounds, while phenyl derivatives have an intrinsic acidity intermediate between that of the corresponding vinyl and ethynyl analogues. The CH2=CHXH vinyl compounds (enol-like) behave systematically as slightly stronger acids than their CH3-C(H)X (keto-like) tautomers. Vinyl derivatives are stronger acids than ethyl compounds, because the anion stabilization attributable to unsaturation is greater than that undergone in the neutral compounds. Conversely, the enhanced acidity of the ethynyl derivatives with respect to the vinyl compounds is due to two concomitant effects, the stabilization of the anion and the destabilization of the neutral compound. The acidities of ethyl, vinyl, and ethynyl derivatives containing heteroatoms of Groups 14, 15, and 16 of the periodic table are closely related, and reflect the differences in electronegativity of the CH3CH2-, CH2=CH-, and CH[triple chemical bond]C- groups.     

Arsenorgano-Verbindungen. XX. Synthese und Reaktionsverhalten der Diphenylarsinocarbonsäuren

Organo-arsenic Compounds. XX. Synthesis and Reactivity of Diphenylarsino Carboxylic Acids Natrium diphenylarside reacts with chlorocarboxylic acids and their amides or esters in liquid ammonia to give the corresponding diphenylarsino carboxylic acids, amides, and esters. Their properties and some reactions are described. The synthesis of secondary ω-phenylarsino carboxylic acids from 2 and 3 has been studied.     

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.     

Strong dissimilarities between the gas-phase acidities of saturated and alpha,beta-unsaturated boranes and the corresponding alanes and gallanes

The effect that unsaturation has on the intrinsic acidity of boranes, alanes, and gallanes, was analyzed by B3 LYP and CCSD(T)/6-311+G(3df,2p) calculations on methyl-, ethyl-, vinyl-, and ethynylboranes, -alanes and -gallanes, and on the corresponding hydrides XH3. Quite unexpectedly, methylborane, which behaves as a carbon acid, is predicted to have an intrinsic acidity almost 200 kJ mol(-1) stronger than BH3, reflecting the large reinforcement of the C--B bond, which upon deprotonation becomes a double bond through the donation of the lone pair created on the carbon atom into the empty p orbital of the boron. Also unexpectedly, and for the same reason, the saturated and alpha,beta-unsaturated boranes are much stronger acids than the corresponding hydrocarbons, in spite of being carbon acids as well. The Al derivatives also behave as carbon acids, but in this case the most favorable deprotonation process occurs at C beta, leading to the formation of rather stable three-membered rings, again through the donation of the C beta lone pair into the empty p orbital of Al. For Ga-containing compounds the deprotonation of the GaH2 group is the most favorable process. Therefore only Ga derivatives behave similarly to the analogues of Groups 14, 15, and 16 of the periodic table, and the saturated derivatives exhibit a weaker acidity than the unsaturated ones. Within Group 13, boranes are stronger acids than alanes and gallanes. For ethyl and vinyl derivatives, alanes are stronger acids than gallanes. We have shown, for the first time, that acidity enhancement for primary heterocompounds is not only dictated by the position of the heteroatom in the periodic table and the nature of the substituent, but also by the bonding rearrangements triggered by the deprotonation of the neutral acid.     

Deuteration of α,β-acetylenic esters, amides, or carboxylic acids without using deuterium gas: synthesis of 2,2,3,3-tetradeuterioesters, amides, or acids

An easy, simple, rapid, and nonhazardous deuteration of the C-C triple bond of α,β-acetylenic esters, amides, or acids by means of samarium diiodide in the presence of D₂O, provides an efficient method for synthesizing 2,2,3,3-tetradeuterioesters, amides, or carboxylic acids, respectively. When H₂O is used instead of D₂O, saturated carboxylic esters, amides, or acids were isolated. A mechanism to explain these reduction reactions has been proposed.     

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.     

Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1S,2R)-tranylcypromine

Primary amidations of carboxylic acids 1 or 3 with NH₄Cl in the presence of ClCO₂Et and Et₃N were developed to afford the corresponding primary amides in 22% to quantitative yields. Additionally, we have applied the amidation to the preparation of various amides containing hydroxamic acids and achieved the synthesis of (1S,2R)-tranylcypromine as an antidepressant medicine via Lossen rearrangement.     

Organo-arsenverbindungen : XXXI. Synthese und eigenschaften sekundärer arsinofunktioneller carbonsäuren und ihrer derivate

Sodium phenylarside and sodium-n-butylarside react with chloro (bromo) carboxylic acids and their sodium salts, amides or esters in liquid ammonia to give the corresponding secondary arsino carboxylic acid derivatives. Their properties and reactions are described. In some cases the derivatives of arsindiyl-di-carboxylic acids are obtained as by-products due to transmetalation reactions.