Aminolysis Of Esters Research Articles

Role of Solvent on Nonenzymatic Peptide Bond Formation Mechanisms and Kinetic Isotope Effects

Based on the hypothesis that similar mechanisms are involved in the peptide bond formation in aqueous solution and in the ribosome, the aminolysis of esters in aqueous solution has been the subject of numerous studies as the reference reaction for the catalyzed process. The mechanisms proposed in the literature have been explored in the present paper by hybrid QM/MM molecular dynamics simulations. The free energy profiles have been computed with the QM region of the system described at semiempirical AM1 level and by DFT within the M06-2X functional. According to the results, the formation of adduct zwitterion species is a preliminary step required for all possible mechanisms. Then, from different conformers of this species, four different paths were found: three of them taking place through concerted mechanisms of four-, six- and eight-membered ring transition states, and a stepwise mechanism through a neutral intermediate. Comparison of the free energy profiles indicates that the concerted mechanisms would be kinetically favored, with free energy barriers in very good agreement with experimental data. Calculations of kinetic isotope effects, when including the solute interactions with the first solvation shell, show that the 8-membered ring TS renders values in better agreement with available experimental data. Quantitative discrepancies can be attributed to different employed models in experiments and calculations.

Aminolysis of Benzyl 2-Pyridyl Thionocarbonate and t-Butyl 2-Pyridyl Thionocarbonate: Effects of Nonleaving Groups on Reactivity and Reaction Mechanism

A kinetic study is reported for nucleophilic substitution reactions of benzyl 2-pyridyl thionocarbonate (5b) and t-butyl 2-pyridyl thionocarbonate (6b) with a series of alicyclic secondary amines in at . General-base catalysis, which has often been reported to occur for aminolysis of esters possessing a C=S electrophilic center, is absent for the reactions of 5b and 6b. The Brnsted-type plots for the reactions of 5b and 6b are linear with = 0.29 and 0.43, respectively, indicating that the reactions of 5b proceed through a stepwise mechanism with formation of a zwitterionic tetrahedral intermediate () being the rate-determining step while those of 6b proceed through a concerted mechanism. The reactivity of 5b and 6b is similar to that of their oxygen analogues (i.e., benzyl 2-pyridyl carbonate 5a and t-butyl 2-pyridyl carbonate 6a, respectively), indicating that the effect of modification of the electrophilic center from C=O to C=S (i.e., from 5a to 5b and from 6a to 6b) on reactivity is insignificant. In contrast, 6b is much less reactive than 5b, indicating that the replacement of the in 5b by the t-Bu in 6b results in a significant decrease in reactivity as well as a change in the reaction mechanism (i.e., from a stepwise mechanism to a concerted pathway). It has been concluded that the contrasting reactivity and reaction mechanism for the reactions of 5b and 6b are not due to the electronic effects of and t-Bu but are caused by the large steric hindrance exerted by the bulky t-Bu in 6b.

ChemInform Abstract: Enzymatic Synthesis of N‐Acylethanolamines: Direct Method for the Aminolysis of Esters.

Abstract Immobilized Candida antarctica (Novozyme 435) catalyzed synthesis of N -acylethanolamines is described. Treatment of methyl esters with lipase and amines yielded the desired amides within 2–24 h with yields ranging from 41% to 98%.

A novel sulfonated prosthetic group for [18F]-radiolabelling and imparting water solubility of biomolecules and cyanine fluorophores

Synthesis and some applications of a novel [(18)F]-fluorinated prosthetic group based on the promising sultone radiochemistry and suitable for the labelling of amine-containing (bio)chemical compounds are described. The combined sequential use of two easy and efficient conjugation reactions namely the fluoride ring-opening of a 1,3-propanesultone moiety and the aminolysis of an N-hydroxysuccinimidyl ester is the key component of this original radiolabelling strategy. The mild reaction conditions and the release of a free sulfonic acid moiety as a result of the [(18)F]-induced sultone ring-opening reaction, both make this [(18)F]-conjugation method suitable for the radiofluorination of fragile and hydrophobic biomolecules and fluorophores, particularly by making the separation of the targeted [(18)F]-tagged sulfonated compound from its starting precursor easier and thus faster. The ability of this unusual prosthetic group to readily introduce the radioisotope within complex (bio)molecular architectures has been demonstrated by (1) the preparation of the first [(18)F]-labelled cyanine 5.5 (Cy 5.5) dye, a suitable precursor for the construction of hybrid positron emission tomography/near-infrared fluorescence (PET/NIRF) imaging probes and (2) the radiolabelling of a biologically relevant peptide bearing a single lysine residue.

Advanced chemical recycling of poly(ethylene terephthalate) through organocatalytic aminolysis

We report the effective organocatalysis of the aminolytic depolymerization of waste poly(ethylene terephthalate) (PET) using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) producing a broad range of crystalline terephthalamides. This diverse set of monomers possesses great potential as building blocks for high performance materials with desirable thermal and mechanical properties deriving from the terephthalic moiety and amide hydrogen bonding. Further, a computational study established mechanistic insight into self-catalyzed and organocatalyzed aminolysis of terephthalic esters, suggesting that the bifunctionality of TBD particularly concerning activation of the carbonyl group differentiates TBD from other organic bases.

Enzymatic synthesis of N-acylethanolamines: direct method for the aminolysis of esters

Immobilized Candida antarctica (Novozyme 435) catalyzed synthesis of N-acylethanolamines is described. Treatment of methyl esters with lipase and amines yielded the desired amides within 2–24h with yields ranging from 41% to 98%.

Pentacoordinate Silicon Complexes with N‐(2‐pyridylmethyl)­salicylamide as a Dianionic (ONN′) Tridentate Chelator

AbstractThe title compound, N‐(2‐pyridylmethyl)salicylamide (1), was synthesized by ester aminolysis of methyl salicylate and 2‐picolylamine. In the presence of triethylamine as a supporting base, the salicylamide moiety reacts with the organodichlorosilanes RR′SiCl2 to form the desired six‐membered heterocycles of the type RR′Si–O–(o‐C6H4)–C(=O)N(pic), with pic being the 2‐pyridylmethyl (i.e., 2‐picolyl) moiety and RR′ = Me, Me (2a); Me, Ph (2b); Ph, Ph (2c); Bn, Bn (2d); All, Ph (2e) and Ph, H (2f). Despite the absence of notable ring strain release Lewis acidity (i.e., only a six‐membered chelate is formed by the dianion, and smaller rings are not present in the compound), the poor electron withdrawal from silicon by its C– or H– substituents and the flexible methylene bridge between the salicylamide and the pyridine moiety, the pyridine N donor atom furnishes pentacoordinate silicon coordination spheres in all of these compounds 2a–2f. The coordination number of the silicon atom was confirmed by single‐crystal X‐ray diffraction analysis for the solid state and by 29Si NMR spectroscopy for the solution state.

DBU as a catalyst for the synthesis of amides via aminolysis of methyl esters

Benzoato de metila e p-clorofenil acetato de metila reagem com benzilamina e pirrolidina levando as correspondentes amidas. Estas reacoes sao mais rapidas na presenca de 20 mol% de DBU, fornecendo os produtos com rendimentos levemente superiores. Quando um diester derivado do acido L-aspartico foi usado como substrato, a reacao com benzilamina e pirrolidina foi quimiosseletiva para o ester metilico, levando as correspondentes amidas em bons rendimentos. Reacao do monoester metilico do acido aspartico com estas aminas conduziu a amidas com um grupo acido livre em C1. Anilina, menos basica e menos nucleofilica, nao formou os produtos esperados tanto na ausencia quanto na presenca de DBU. Atraves do monitoramento da reacao por ESI-MS, foi possivel interceptar os intermediarios-chave cationicos formados nas reacoes entre o benzoato de metila e o p-clorofenil acetato de metila com a benzilamina, os quais foram caracterizados por ESI-MS/MS. Methyl benzoate and methyl p-chlorophenyl acetate react with neat benzylamine and pyrrolidine to form the corresponding amides. These reactions are faster in the presence of 20 mol% of DBU providing slight better yields. When a diester derived from L-aspartic acid was used as substrate, the reaction with benzylamine and pyrrolidine in the presence of DBU was chemoselective and led to the corresponding amides in good yields. Reaction of aspartic acid monomethyl ester with these amines led to amides having a free carboxy group (at C1). Less nucleophilic and less basic aniline failed to form the expected products in both absence and presence of DBU. By monitoring the course of reaction by ESI-MS, key charged intermediates formed by the reactions of methyl benzoate and methyl p-chlorophenyl acetate with benzylamine were intercepted and further characterized by ESI-MS/MS.

Synthesis, Characterization and Biological Evaluations of Ciprofloxacin Carboxamide Analogues

Present work comprises of synthesis various analogues of ciprofloxacin by introducing new functionality at carboxylic group position via ester aminolysis reaction. For this purpose the carboxylic group at C-3 was esterified and later subjected to nucleophilic attack at the carbonyl carbon by various aromatic amines. Structure of the analogues was confirmed by different techniques i.e. IR, <TEX>$^1H$</TEX> NMR and mass spectrometry. The antibacterial activity of the derivatives was also assessed with the parent against a series of Gram-positive and Gram-negative bacteria. The synthesized compounds showed diverse antimicrobial profile among which most compounds possessed a comparable or better activity in comparison to the ciprofloxacin. Additionally unlike ciprofloxacin, some of the derivatives were also found to show antifungal activity.

Pseudomonas stutzeri lipase: a useful biocatalyst for aminolysis reactions

The use of Pseudomonas stutzerilipase (PSL) as a biocatalyst for aminolysis reactions with bulky substrates has been investigated. PSL compared favorably to Novozym® 435 (immobilized Candida antarcticalipase B, NOV435) in the aminolysis of various bulky methyl esters and amines. While NOV435 demonstrated a higher rate of aminolysis with methyl 2-phenylpropionic acid as the acyl donor, PSL outperformed NOV435 with secondary amines as the nucleophile. Methanol inhibition and a low affinity for bulky acyl donors were found to be the two main reasons for relatively low rates in the PSL-catalyzed aminolysis reactions. It was demonstrated that the use of molsieve 4A had a significant effect on the aminolysis rate and amide yield, since it enabled the effective removal of the inhibiting methanol from the reaction mixture.

Synthesis, characterization and biological activity of a series of carboxamide derivatives of ofloxacin

The present study was designed to help develop new agents with better antimicrobial profiles. Specifically, we focused on modification of the basic structure of ofloxacin by introducing new functionality at its C3 position. For this purpose, the carboxylic group at the C3 position of ofloxacin was replaced by an amide group through an ester aminolysis reaction. The structure of these derivatives was established by various analytical techniques i.e., IR, (1)H-NMR, (13)C-NMR CHNS elemental analysis and mass spectrometry. The antibacterial activity of ofloxacin and its derivatives against ten different Gram-positive and Gram-negative microorganisms was studied using a disk susceptibility method. These compounds were further tested for their activity against various fungi and compared to ofloxacin. The synthesized compounds showed diverse antimicrobial profiles. Among them, a few compounds possessed a comparable or better activity in comparison to the reference drug.

ChemInform Abstract: Environmentally Friendly Transesterification and Transacylation Reactions under LiBr Catalysis.

A room-temperature, convenient transesterification of various esters, induced by catalytic amounts of lithium bromide and diethylamine in a solvent-free environment, is described. Products are obtained in good purity by simple filtration to remove the catalyst and evaporation of the volatile portion. The procedure has also been successfully applied to transacetylation and aminolysis of esters.

ChemInform Abstract: Amidation of Esters Assisted by Mg(OCH3)2 or CaCl2.

AbstractThe title reagents facilitate the direct aminolysis of various esters by NH3 (or NH4Cl) and amine hydrochlorides.

Catalytic Role of Vicinal OH in Ester Aminolysis: Proton Shuttle versus Hydrogen Bond Stabilization

This computational study provoked by the process of peptide bond formation in the ribosome investigates the influence of the vicinal OH group in monoacylated diols on the elementary acts of ester aminolysis. Two alternative approaches for this influence on ester ammonolysis were considered: stabilization of the transition states by hydrogen bonds and participation of the vicinal hydroxyl in proton transfer (proton shuttle). The activation due to hydrogen bonds of the vicinal hydroxyl via tetragonal transition states was rather modest; the free energy of activation was reduced by only 5.2 kcal/mol compared to the noncatalyzed reaction. The catalytic activation via the proton shuttle mechanism with participation of the vicinal OH in the proton transfer via hexagonal transition states resulted in considerable reduction of the free energy of activation to 33.5 kcal/mol, i.e., 16.0 kcal/mol lower than in the referent process. Accounting for the influence of the environment on the reaction center by a continuum model (for ε from 5 to 80) resulted in further stabilization of the rate-determining transition state by 4-5 kcal/mol. The overall reduction of the reaction barrier by about 16 kcal/mol as compared to the noncatalyzed process corresponds to about 10(9)-fold acceleration of the reaction, in agreement with the experimental estimate for acceleration of this process in the ribosome.

ChemInform Abstract: Boron Triiodide - N,N-Diethylaniline Complex: A New Reagent for Cleaving Esters.

Abstract Boron triiodide N,N-diethylaniline complex was used for the hydrolysis, transesterification, and aminolysis of esters.

ChemInform Abstract: The Myth of Coupling Reagents

Coupling reagents have been proposed for peptide synthesis ever since the introduction of the method because of the convenience of the procedure, which consists of peptide bond formation by addition of a specific condensing agent to the mixture of carboxyl and amine components. However, truly efficient and yet innocuous coupling reagents are hard to find. Most coupling reagents give rise to unwanted reactions, which can be traced to certain characteristic structural features in their molecules. Such features are illustrated with the intermediates generated by dicyclohexylcarbodiimide and N-ethyl-5-phenyl-isoxazolium-3'-sulfonate (Woodward's reagent K). Some side reactions can be avoided if peptide bond formation is carried out in two separate steps: activation of the carboxyl group of the carboxyl component in the form of an active ester, followed by the catalyzed aminolysis of the active ester.

ChemInform Abstract: Kinetics of Aminolysis of Some Benzoyl Fluorides and Benzoic Anhydrides in Non-hydroxylic Solvents

The kinetic form of the spontaneous aminolysis of benzoyl fluorides in non-hydroxylic solvents is unlike that reported for the other benzoyl halides but is similar to that found for the aminolysis of esters. Variations on the mechanisms currently advocated for ester aminolysis are suggested for the benzoyl fluoride reactions. Tetrahedral intermediates are likely, but their rate-determining breakdown to products may involve a simultaneous proton transfer to the leaving fluoride ion. The kinetic behaviour differs from that found for aqueous solutions. The kinetics of the spontaneous aminolysis of benzoic anhydrides by primary amines, and by morpholine, in dioxane solution are first-order in each reagent over a wide amine concentration range, but the aminolysis by imidazoles involves also an important kinetic term second-order in amine. The mechanistic implications are discussed. Again the observations differ from some of those reported for aqueous solutions. For aminolyses of a variety of acylating agents, kinetic observations using non-hydroxylic solvents show that the easier it is for the leaving group to depart, owing to the structure of the acylating agent and/or that of the attacking amine, the less important become paths involving two or more amine molecules, but that such paths are generally more important than they are in hydroxylic solvents.

Kinetic studies and predictions on the hydrolysis and aminolysis of esters of 2-S-phosphorylacetates

Background: Heterobifunctional cross-linking agents are useful in both protein science and organic synthesis. Aminolysis of reactive esters in aqueous systems is often used in bioconjugation chemistry, but it must compete against hydrolysis processes. Here we study the kinetics of aminolysis and hydrolysis of 2-S-phosphorylacetate ester intermediates that result from displacement of bromide by a thiophosphate nucleophile from commonly used bromoacetate ester cross-linking agents.Results: We found cross-linking between uridine-5′-monophosphorothioate and D-glucosamine using N-hydroxybenzotriazole and N-hydroxysuccinimde bromoacetates to be ineffective. In order to gain insight into these shortfalls, 2-S-(5′-thiophosphoryluridine)acetic acid esters were prepared using p-nitrophenyl bromoacetate or m-nitrophenyl bromoacetate in combination with uridine-5′-monophosphorothioate. Kinetics of hydrolysis and aminolysis of the resulting p- and m-nitrophenyl 2-S-(5′-thiophosphoryluridine)acetates were determined by monitoring the formation of phenolate ions spectrophotometrically as a function of pH. The p- and m-nitrophenyl 2-S-(5′-thiophosphoryluridine)acetates showed similar reactivity profiles despite the significant difference in the pKaH values of their nitrophenolate leaving groups. Both were more reactive with respect to hydrolysis and aminolysis in comparison to their simple acetate progenitors, but their calculated selectivity towards aminolysis vs hydrolysis, while reasonable, would not lead to clean reactions that do not require purification. Extrapolations of the kinetic data were used to predict leaving group pKa values that could lead to improved selectivity towards aminolysis while retaining reasonable reaction times.Conclusions: Both p- and m-nitrophenyl 2-S-(5′-thiophosphoryluridine)acetates show some selectivity towards aminolysis over hydrolysis, with the m-nitrophenolate system displaying slightly better selectivity. Extrapolation of the data for hydrolysis and aminolysis of these esters suggests that the use of readily accessible trifluoroethyl 2-S-(5′-thiophosphoryluridine)acetate with a leaving group pKaH of 12.4 should afford better selectivity while maintaining reasonable reaction times. Kinetically, p- and m-nitrophenyl 2-S-(5′-thiophosphoryluridine)acetates show similar properties to o-nitrophenyl 2-S-ethylacetate, and show no evidence for intramolecular catalysis of hydrolysis or aminolysis by the phosphoryl groups.

Amidation of esters assisted by Mg(OCH3)2 or CaCl2

Abstract Magnesium methoxide (Mg(OCH3)2) and calcium chloride have been shown to facilitate the direct aminolysis of esters by ammonia to primary amides. Methyl, ethyl, isopropyl, and tert-butyl esters were converted to the corresponding carboxamides in good yields. Reactions have been run on a larger scale and without the safety liability inherent in the use of magnesium nitride (Mg3N2). Ammonium chloride and amine hydrochlorides have been used successfully in the place of ammonia with magnesium methoxide.

Environmentally friendly transesterification and transacylation reactions under LiBr catalysis

A room-temperature, convenient transesterification of various esters, induced by catalytic amounts of lithium bromide and diethylamine in a solvent-free environment, is described. Products are obtained in good purity by simple filtration to remove the catalyst and evaporation of the volatile portion. The procedure has also been successfully applied to transacetylation and aminolysis of esters.