Stereoselective Synthesis of Unsaturated and Functionalized l-NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-Transfer Conditions

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the γ-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K(3)PO(4) as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.     

A mild esterification process in phosphonium salt ionic liquid

A general, high yielding procedure is described for the esterification of carboxylic acids through carboxylate alkylation in phosphonium salt ionic liquid.     

Carboxylate phosphabetaines based on tertiary phosphines and unsaturated dicarboxylic acids

By reaction of triorganylphosphines with unsaturated dicarboxylic acids adducts of betaine structure were synthesized whose stability depended on the character of substituents at phosphorus and on the structure of acid. The betaine obtained from phosphines and maleic and fumaric acids redily underwent decarboxylation into the corresponding monoacyl phosphonium derivatives. The structure of the latter was established by means of X-ray crystallography. The adduct prepared from phosphines and itaconic acid was stabilized by intramolecular hydrogen bond between the acylate anionic center and the “second” carboxy group.     

PHOTOCHEMICAL REACTIONS OF THYMINE WITH CARBOXYLIC ACIDS. A MODEL FOR NUCLEIC ACID-PROTEIN PHOTOCROSSLINKING

When nucleic acid bases are UV-irradiated in the presence of carboxylic acids or carboxylate anions new photoproducts are formed as compared to the bases irradiated in the absence of carboxylic acids. The behavior of thymine and thymidine has been examined in detail. At least four photoproducts are formed in the presence of propionic acid and three in the presence of butyric acid. None of them appears to be a cyclobutyl dimer. From the concentration dependence of the rate of photoproduct formation it is concluded that the reactive excited species is the first excited singlet state of thymine. When ¹⁴C-labelled thymine is irradiated in the presence of polyglutamic acid an important part of the radioactive material is covalently linked to the polymer. Photochemical reaction of thymine with glutamic (or aspartic) acid could thus induce crosslinks between proteins and nucleic acids. It is also shown that these photoproducts are stable under usual conditions of acidic hydrolysis of UV-irradiated DNA.     

Carboxylic acids as substrates in homogeneous catalysis

In organic molecules carboxylic acid groups are among the most common functionalities. Activated derivatives of carboxylic acids have long served as versatile connection points in derivatizations and in the construction of carbon frameworks. In more recent years numerous catalytic transformations have been discovered which have made it possible for carboxylic acids to be used as building blocks without the need for additional activation steps. A large number of different product classes have become accessible from this single functionality along multifaceted reaction pathways. The frontispiece illustrates an important reason for this: In the catalytic cycles carbon monoxide gas can be released from acyl metal complexes, and gaseous carbon dioxide from carboxylate complexes, with different organometallic species being formed in each case. Thus, carboxylic acids can be used as synthetic equivalents of acyl, aryl, or alkyl halides, as well as organometallic reagents. This review provides an overview of interesting catalytic transformations of carboxylic acids and a number of derivatives accessible from them in situ. It serves to provide an invitation to complement, refine, and use these new methods in organic synthesis.     

Carboxylate-substituted radicals from phenylselenide derivatives. Designs on models for coenzyme B12-dependent enzyme-catalyzed rearrangements

Laser flash photolysis (266 nm) of alpha- and beta-phenylselenyl esters, carboxylic acids, and carboxylates in aqueous acetonitrile media gave the corresponding radicals by homolytic cleavage of the phenylselenyl groups. In the beta-substituted systems, acid and carboxylate radicals reacted in intramolecular reporter reactions with approximately equal rate constants. For the alpha-substituted systems, an ester- and carboxylic acid-substituted radical reacted in an intramolecular reporter reaction with the same rate constants, but the analogous alpha-carboxylate radical, a radical anion, reacted an order of magnitude less rapidly and with an activation energy that is 3 kcal/mol greater than that found for analogues. A kinetic titration of the equilibrating alpha-acid and alpha-carboxylate radicals gave pKa = 4.6. The results indicate that alpha-ester and alpha-carboxylic acid radicals are unlikely to be appropriate models for alpha-carboxylate radicals, the intermediates formed in a large subset of coenzyme B12-dependent enzyme-catalyzed reactions.     

Photoinduced switching of intramolecular hydrogen bond between amide NH and carboxyl oxygen

In this study, we synthesized two novel carboxylic acid and carboxylate compounds, both of which had an amide group linked with an azomethine moiety to introduce photoinduced switching of the intramolecular NH...O hydrogen bond. We suggest that the cis-carboxylate compound forms a stronger intramolecular NH...O hydrogen bond than the cis-carboxylic acid compound.     

Study on reactions of 2-(dinitromethylene)-4,5-imidazolidinedione

Some new reactions of 2-(dinitromethylene)-4,5-imidazolidinedione (1) with water, alcohols, carboxylic acids, and alkalis were discovered. By reaction of 1 with carboxylic acids, large particle size 1,1-diamino-2,2-dinitroethylene (2) was prepared. By reaction of 1 with methanol, the methanol adduct (4) was synthesized and characterized. By reaction of 1 with water, the synthetic pathway of 2-methylimidazole to 2 could be achieved in a continuous process. By reaction of 1 with KOH, 2 and potassium dinitromethane (6) could be formed at different temperature, respectively. Compounds 1 and 4 decomposed into parabanic acid (5), losing nitrogen oxides and carbon oxides. Some explosive properties of 1 were studied. The mechanisms of synthesis of 1, 2, and 5 are discussed.     

Reaction of an Introverted Carboxylic Acid with Carbodiimide

The reaction of carboxylic acids with carbodiimides is reviewed, and an ‘introverted’ carboxylic acid is proposed as a means of trapping reactive intermediates along the reaction pathway. The introverted acid is a cavitand with the carboxylic function directed toward the floor of the cavity. Its reaction with diisopropyl carbodiimide gives a covalent adduct that is either the elusive O-acylisourea or the commonly encountered N-acylurea.     

Mechanism of silver- and copper-catalyzed decarboxylation reactions of aryl carboxylic acids

Silver- and copper-catalyzed decarboxylation reactions of aryl carboxylic acids were investigated with the aid of density functional theory calculations. The reaction mechanism starts with a carboxylate complex of silver or copper. Decarboxylation occurs via ejecting CO(2) from the carboxylate complex followed by protodemetallation with an aryl carboxylic acid molecule to regenerate the starting complex. Our results indicated that the primary factor to affect the overall reaction barriers is the ortho steric destabilization effect on the starting carboxylate complexes for most cases. Certain ortho substituents that are capable of coordinating with the catalyst metal center without causing significant ring strain stabilize the decarboxylation transition states and reduce the overall reaction barriers. However, the coordination effect is found to be the secondary factor when compared with the ortho effect.     

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.     

Synthesis of Novel 2‐Vinylcyclopropane Phosphonic Acids

2‐Vinylcyclopropane‐1‐phosphonic acid diesters 1a–d were synthesized by the reaction of trans‐1,4‐dibromo‐2‐butene with α‐substituted phosphonic acid diesters. Esterification of 1‐ethoxycarbonyl‐2‐vinylcyclopropane‐1‐carboxylic acid with dimethyl 2‐hydroxyethyl‐phosphonate gave the 2‐vinylcyclopropane phosphonic acid dimethylester 1e. The silylation of phosphonic acid diesters 1a–e by halotrimethylsilanes followed by solvolysis with methanol or water resulted in the formation of phosphonic acids 2a–e. In the case of steric hinderance of the phosphoryl group, monoesters 3c,d were also formed. Furthermore, ethyl carboxylate 1b could be chemoselectively cleaved by aqueous potassium hydroxide to carboxylic acid 4.     

Ion-pair interaction in pyridinium carboxylate solutions

Ion-pair interactions between pyridinium cations and various carboxylate anions are explored using noisy light based coherent anti-Stokes Raman scattering (I(2)CARS). Binary mixtures of pyridine and various carboxylic acids (including halo-acetic acids, straight-chain carboxylic acids, and pivalic acid) are prepared. A Br?nsted type acid-base reaction occurs in these mixtures to create pyridinium and carboxylate ions. Both pyridine, itself, and pyridinium have strong I(2)CARS signals originating from their ring breathing modes. The vibrational frequency of the ring breathing mode for pyridine is blue-shifted by hydrogen bonding, and that same mode for pyridinium is red-shifted by ion-pair interaction. Frequency shift data for the ring breathing mode of pyridine and pyridinium are presented. These data are discussed in terms of a simplistic model for the electronic behavior of these compounds.     

Kinetics of amide formation through carbodiimide/N-hydroxybenzotriazole (HOBt) couplings

The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropyl ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concentration of HOBt, showing that the rate-determining step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observed rate constants for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH2(2+), 6) and the carboxylate group. The observed rate constants fall sharply at high pH, as the fraction of EDCI as EDCIH2(2+) continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate constant, kP, for reaction between the carboxylate group of acid, 3, and EDCIH2(2+) has a value of kP = 4.1 x 10(4) M(-1) s(-1) at 20 degrees C, some 10(5) times higher than similar rate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal aromatic amine of 3 to give the diamide 5.     

Boron-Catalyzed α-Functionalizations of Carboxylic Acids

Catalytic, chemoselective, and asymmetric α-functionalizations of carboxylic acids promise up-grading simple feedstock materials to value-added functional molecules, as well as late-stage structural diversifications of multifunctional molecules, such as drugs and their leads. In this personal account, we describe boron-catalyzed α-functionalizations of carboxylic acids developed in our group (five reaction types). The reversible boron carboxylate formation is key to the acidification of the α-protons and enolization using mild organic bases, allowing for chemoselective and asymmetric bond formations of carboxylic acids. The ligand effects on reactivity and stereoselectivity, substrate scopes, and mechanistic insights are summarized.     

A density functional theory study of the 5-exo cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals

Density functional theory computations were done to study the 5-exo radical cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals. The methoxy electron donor group substitution reduced the barrier to reaction by about 0.5 kcal/mol. On the other hand, the electron acceptor group substitutions (ethoxycarbonyl, carboxylic acid, carboxylate, and cyano) raised the barrier to reaction by varying amounts (0.5-2.1 kcal /mol). The entropic terms of these cyclization reactions are briefly discussed. Solvent effects on these reactions were explored by calculations that included a polarizable continuum model for the solvent. The density functional theory calculated results were found to be in good agreement with the experimental data available in the literature and help to explain some of the observed variation in these types of cyclization reactions with various substitutions. Our results also provide an explanation for why the rate constant for the carboxylate group substituted radical was found to be an order of magnitude smaller than the rate constant for those radicals with carboxylic acid and ethoxycarbonyl substitutions.     

Charge development in the transition state for decarboxylations in water: spontaneous and acetone-catalyzed decarboxylation of aminomalonate

A covalent imminium adduct, formed by condensation of aminomalonate with acetone, undergoes decarboxylation (k = 0.03 s-1 at 25 degrees C) in water 30 000 times more rapidly than does aminomalonate in the absence of acetone. A Br?nsted plot of the observed rates of decarboxylation of these and other ionized carboxylic acids, as a function of the pKC-H values of the carbon acids generated by their decarboxylation, exhibits a betalg value of 0.7, indicating that the structures of the transition states for decarboxylation of the carboxylate forms of these acids approaches the structures of the carbanions generated by their decarboxylation. On the basis of an estimated pKC-H value for benzene in water ( approximately 43), extrapolation of that Br?nsted plot leads to the prediction that benzoate decarboxylation should proceed at detectable rates in water at temperatures below the critical point. That prediction was confirmed experimentally. Using this same relationship, and extrapolating to the observed rate constant for enzymatic decarboxylation of orotidine 5'-monophosphate, we estimate that the "effective" pKa value of the 6-CH group of uridine 5'-monophosphate, the product of decarboxylation, is 9.5 at the active site of yeast OMP decarboxylase.     

In situ infrared spectroscopic analysis of the adsorption of aromatic carboxylic acids to TiO2, ZrO2, Al2O3, and Ta2O5 from aqueous solutions

In situ infrared spectroscopy has been used to investigate the adsorption of a range of simple aromatic carboxylic acids from aqueous solution to metal oxides. Thin films of TiO2, ZrO2, Al2O3 and Ta2O5 were prepared by evaporation of aqueous sols on single reflection ZnSe prisms. Benzoic acid adsorbed very strongly to ZrO2, in a bridging bidentate fashion, but showed only weak adsorption to TiO2 and Ta2O5. Substituted aromatic carboxylic acids; salicylic, phthalic and thiosalicylic, were found to adsorb to each metal oxide. Salicylic and phthalic acids adsorbed to the metal oxides via bidentate interactions, involving coordination through both carboxylate and substituent groups. Thiosalicylic acid adsorbed to the metal oxides as a bridging bidentate carboxylate with no coordination through the thiol substituent group.     

Synthetic utility of an isolable nucleoside phosphonium salt

The reaction of O6-benzyl-3',5'-bis- O-( tert-butyldimethylsilyl)-2'-deoxyxanthosine with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) yielded the nucleoside C-2 tris(dimethylamino)phosphonium hexafluorophosphate salt as a stable, isolable species. This is in contrast to reactions of inosine nucleosides with BOP, where the in situ formed phosphonium salts undergo subsequent reaction to yield O6-(benzotriazol-1-yl)inosine derivatives. The phosphonium salt obtained from the 2'-deoxyxanthosine derivative can be effectively used to synthesize N2-modified 2'-deoxyguanosine analogues. Using this salt, a new synthesis of an acrolein-2'-deoxyguanosine adduct has also been accomplished.     

Manipulation of an intramolecular NH...O hydrogen bond by photoswitching between stable E/Z isomers of the cinnamate framework

Novel carboxylic acid derivatives were synthesized, which allowed switching of the intramolecular distance between amide group and carboxylic oxygen atoms using E to Z photoisomerization of the cinnamate framework. An intramolecular NH...O hydrogen bond was formed in the Z carboxylate compound not only in solution but also in the solid state. The pK(a) value of the carboxylic acid was lowered as a consequence of the E/Z photoisomerization.