Free Radical Formation of p-Nitrophenacyl Esters of Carboxylic Acids and Their Detection by High-Performance Liquid Chromatography with Electron Spin Resonance

Abstract

p-Nitrophenacyl esters derived from p-nitrophenacyl bromide and carboxylic acids were determined by high-performance liquid chromatography with electron spin resonance. p-Nitrophenacyl bromide was used as the pre-column reagent to determine the carboxylic acids. The p-nitrophenacyl esters gave free radicals by hydrolysis with alkaline solution, and then the free radicals were detected with electron spin resonance. The separation of these esters was achieved within 20 min.     

Formation of a carboxyl group satellite line in the n.m.r. spectra of solid carboxylic acids

The structural factors resulting in the formation of the carboxyl group satellite line on the low field side of the ¹H n.m.r. spectra of carboxylic acids in the solid state have been determined from the temperature dependences of the carboxyl proton chemical shifts of acetic, dimethylacetic, ethylacetic, phenylacetic, benzoic, o-methylbenzoic, p-methylbenzoic and adamantyl carboxylic acids. The carboxyl group low field satellite forms at temperatures near the melting point only in the case of carboxylic acids with bulky hydrocarbon radicals (o-methylbenzoic and adamantyl carboxylic acids).     

FLASH PHOTOLYSIS STUDY OF ALIPHATIC AMINO ACIDS AND PEPTIDES IN AQUEOUS SOLUTION*

Abstract— The intermediates produced in the photolysis of oxygen-free aqueous solutions of a number of aliphatic amino acids and peptides were observed spectrophotometrically using the fast-reaction technique of flash photolysis. Included among the compounds examined are the N-acetyl derivatives of glycine, alanine, sarcosine, glutamic acid and glycylglycine; the esters and amides of these N-acetyl compounds; diketopiperazines; the amino acids glycine, alanine and β-alanine; and finally the oligopeptides di-, tri- and tetraglycine. The direct optical excitation of these compounds was found to lead primarily to a photo-induced decarboxylation reaction:
The transient spectra of the radicals produced have been identified. The quantum yields of these processes were found to be directly proportional to the p K _a of the carboxyl groups of the corresponding ground-state molecules, and hence to the concentration of the non-ionized carboxylic acids. The φ's of these processes for the ionized acids were close to zero. The dependence of φ upon pH is correlated to the absorption spectra of these compounds. The quantum yields of the corresponding esters were lower but independent of pH. No intermediates were observed from excitation of the amine derivatives. Other photolytic reactions are suggested. The photo-decarboxylation of alanine and diglycine were found to be monophotonic, while that of N-acetyl alanine, N-acetyl diglycine, and tetraglycine were found to be biphotonic. A triplet excited state precursor is indicated for the latter group of compounds. These and other results are discussed.     

High yielding methyl esterification catalyzed by indium(III) chloride

The carboxylic acids are efficiently converted into the methyl esters in methanol using indium(III) chloride as the catalyst. This method is applicable for aromatic and aliphatic carboxyl moieties as well as amino acids in high yields.     

Diazo compounds for the bioreversible esterification of proteins

A diazo compound is shown to convert carboxylic acids to esters efficiently in an aqueous environment. The basicity of the diazo compound is critical: low basicity does not lead to a reaction but high basicity leads to hydrolysis. This reactivity extends to carboxylic acid groups in a protein. The ensuing esters are hydrolyzed by human cellular esterases to regenerate protein carboxyl groups. This new mode of chemical modification could enable the key advantages of prodrugs to be translated from small-molecules to proteins.     

Light induced interactions of benzo[a]pyrene with carboxylic acids

Abstract The in vitro photochemical behaviour of benzo[a]pyrene (BP) in presence of short and long chain carboxylic acids is studied. The direct irradiation (295–400 or 320–400 nm) of BP in solution in the presence of saturated carboxylic acids destroys more than 70% of this carcinogen in 72 h with a 150 W Xe arc lamp. Consumption of BP alone under similar conditions is less than 10%. The principal product resulting from direct interaction of BP with carboxylic acids is characterized as 6-acyloxybenzo[a]pyrene by means of UV, IR, NMR and mass spectroscopy. The other pathways of destruction may involve polymerization. Saturated fatty acids are shown to favour photoacyloxyation, while unsaturated fatty acids appear to facilitate polymerization of BP. The effect of different factors, such as the carboxylic acid involved, solvent, and wavelength on photoacyloxylation reaction as well as on the consumption of BP is discussed. Photoinduced interaction of BP with carboxylic acids seems to involve radical cation as well as free radicals of the hydrocarbon. Biological properties of BP esters in terms of primary irritancy and carcinogenic activity have also been tested by mouse skin assay. Both long and short chain esters do not show any carcinogenic activity; conversely, long chain esters are shown to be more severe irritants as compared to short chain esters or BP.     

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.     

Photochemical generation of aliphatic radicals from benzophenone oxime esters: simple synthesis of alkylbenzenes and alkylpyridines

Photolysis of benzophenone oxime esters, prepared with aliphatic carboxylic acids and benzophenone oxime, in benzene and pyridine generates various primary, secondary and tertiary aliphatic radicals selectively, and corresponding alkylbenzenes and alkylpyridines are produced in good yields, respectively.     

Visible‐Light‐Photosensitized Aryl and Alkyl Decarboxylative Functionalization Reactions

Despite significant progress in aliphatic decarboxylation, an efficient and general protocol for radical aromatic decarboxylation has lagged far behind. Herein, we describe a general strategy for rapid access to both aryl and alkyl radicals by photosensitized decarboxylation of the corresponding carboxylic acids esters followed by their successive use in divergent carbon–heteroatom and carbon–carbon bond‐forming reactions. Identification of a suitable activator for carboxylic acids is the key to bypass a competing single‐electron‐transfer mechanism and “switch on” an energy‐transfer‐mediated homolysis of unsymmetrical σ‐bonds for a concerted fragmentation/decarboxylation process.     

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.     

High-Energy Phosphonium Compounds and Their Application to Polymer Synthesis

High-energy phosphonium compounds, the N-phosphonium salts of pyridines, were prepared by the oxidation of phosphorous acid and its esters with mercuric salts or halogens in pyridines, or by a hydrolysis-dehydration reaction of diphenyl and triaryl phosphites or phosphonites. These salts are very reactive to nucleophiles, activating carboxyl, amino, or hydroxyl compounds via the corresponding N-phosphonium salts to yield carboxylic amides and esters in high yields on further aminolysis, alcoholysis, and acidolysis. These reactions, especially the hydrolysis-dehydration reactions with phosphites, were successfully extended to the direct polycondensation reaction of dicarboxylic acids with diamines, of free α-amino acids or dipeptides, and of carbon dioxide and disulfide with diamines under mild conditions, yielding linear polymers of high molecular weight (polyamides, polypeptides, polyureas, and polythioureas).     

Photosensitized Intermolecular Carboimination of Alkenes through the Persistent Radical Effect

An intermolecular, two‐component vicinal carboimination of alkenes has been accomplished by energy transfer catalysis. Oxime esters of alkyl carboxylic acids were used as bifunctional reagents to generate both alkyl and iminyl radicals. Subsequently, addition of the alkyl radical to an alkene generates a transient radical for selective radical–radical cross‐coupling with the persistent iminyl radical. Furthermore, this process provides direct access to aliphatic primary amines and α‐amino acids by simple hydrolysis.     

Synthesis of C-acyl furanosides via the cross-coupling of glycosyl esters with carboxylic acids

C-Acyl furanosides are versatile synthetic precursors to a variety of natural products, nucleoside analogues, and pharmaceutical molecules. This report addresses the unmet challenge in preparing C-acyl furanosides by developing a cross-coupling reaction between glycosyl esters and carboxylic acids. A key step is the photoredox activation of the glycosyl ester, which promotes the homolysis of the strong anomeric C–O bond through CO₂ evolution to afford glycosyl radicals. This method embraces a large scope of furanoses, pyranoses, and carboxylic acids, and is readily applicable to the synthesis of a thymidine analogue and diplobifuranylone B, as well as the late-stage modification of (+)-sclareolide. The convenient preparation of the redox active glycosyl ester from native sugars and the compatibility with common furanoses exemplifies the potential of this method in medicinal chemistry.

A cross-coupling of glycosyl esters with carboxylic acids to prepare C-acyl furanosides and pyranosides. The reaction proceeds through photoredox activation of the glycosyl ester to afford glycosyl radicals.     

Saturated vapor pressures and enthalpies of evaporation of esters of glycerol and lower carboxylic acids

Saturated vapor pressures and enthalpies of evaporation of trisubstituted esters of glycerol and carboxylic acids C₁–C₅ with normal and branched structure were determined by the transpiration method in the temperature range of 300–371 K. Dependences of enthalpies of evaporation on the number of carbon atoms in a molecule and on the retention indices are established. Prognostic possibilities of existing calculation schemes are analyzed for compounds with three carboxyl groups in a molecule.     

Facile synthesis of diphenylmethyl esters from 2-diphenylmethoxypyridine using catalytic boron trifluoride·diethyl etherate

A practical method for the direct preparation of diphenylmethyl (DPM) esters from 2-diphenylmethoxypyridine is described. The reaction was readily performed in the presence of a catalytic amount of boron trifluoride-diethyl etherate at room temperature. Using this reaction protocol, various carboxylic acids were converted to DPM esters with high yields. This method is highly effective for the protection of carboxylic acids and the synthesis of DPM esters, and offers a promising approach for facile esterification of a variety of carboxylic acids.     

Carbon-13 spin–lattice relaxation in strongly associated molecules: Carboxylic acids

¹³C spin–lattice relaxation times determined for the protonated carbons of carboxylic acids and methyl esters give indications of solution dimerization with the free acids. Since isopthalic and fumaric acids have two carboxyl functions they are able to polymerize in solution. Unlike the case for molecular aggregation due to weak hydrogen bonding in solution (e.g. alcohols, phenols), the ¹³C T₁ values of mono carboxylic acids are not significantly affected by dilution to c. 10^?2 M. Variable temperature T₁ measurements of both the mono and dibasic acids gave activation energies for molecular reorientation of the order of 2 kcal mol^?1, considerably lower than E_a for hydrogen bonded alcohols and comparable with E_a for the unassociated methyl esters of propionic and benzoic acids.     

Carbon-13 n.m.r. spectra of branched carboxylic acids and their derivatives

¹³C n.m.r. spectra have been measured for 39 compounds with branched structures including carboxylic acids, their methyl and ethyl esters, nitriles and chlorinated esters. The results obtained indicate that the ¹³ C n.m.r. technique is applicable to structure assignment of acids and their derivatives containing various numbers of substituents on the chain. The dependence of the carboxylic carbon chemical shift on the number and structure of α-positioned substituents has been determined. Calculation of the chemical shifts for branched carboxylic acids, esters and nitriles from the corresponding increments using the additivity scheme is shown to be possible in principle.     

Oxidation of carboxylic acids by horseradish peroxidase results in prosthetic heme modification and inactivation

Hemoproteins are powerful oxidative catalysts. However, despite the diversity of functions known to be susceptible to oxidation by these catalysts, it is not known whether they can oxidize carboxylic acids to carboxylic radicals. We report here that incubation of horseradish peroxidase (HRP) at acidic pH with H(2)O(2) in acetate buffer results in rapid modification of the heme group and loss of catalytic activity. Mass spectrometry and NMR indicate that an acetoxy group is covalently bound to the delta-meso-carbon in the modified heme. A heme with a hydroxyl group on the 8-methyl is also formed as a minor product. These reactions do not occur if protein-free heme and H(2)O(2) are co-incubated in acetate buffer, if the HRP reaction is carried out at pH 7, in the absence of H(2)O(2), or if citrate rather than acetate buffer is used. A similar heme modification is observed in incubations with n-caproic and phenylacetic acids. A mechanism involving oxidation of the carboxyl group to a carboxylic radical followed by addition to the delta-meso-position is proposed. This demonstration of the oxidation of a carboxylic acid solidifies the proposal that a carboxylic radical mediates the normal covalent attachment of the heme to the protein in the mammalian peroxidases and CYP4 family of P450 enzymes. The hemoprotein-mediated oxidation of carboxylic acids, ubiquitous natural constituents, may play other roles in biology.     

2-Halogenoethyl and 2-halogenoethylthiol esters of furan series carboxylic acids

The corresponding 2-chloroethyl (2-chloroethylthiol) esters are synthesized by the action of ethylene chlorohydrin (chloroethylmercaptan) on the acid chlorides of 5-nitrofuran carboxylic acid and 3-(5-nitrofuryl-2)acrylic acid. The acid chlorides of benzoic, furan carboxylic, and 3-(furyl-2)-acryllc acids react with ethylene sulfide, to give 2-chloroethyl esters of those acids. Ethylene oxide does not react with the acid chlorides of benzoic acid and furan series carboxylic acids either at room temperature or on heating at 50° for 1 hour.     

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.