Chloroacetic Anhydride Research Articles

Obtaining substituted phenol derivatives with potential antimicrobial activity

Objectives. With the growing resistance of pathogenic microorganisms to antibiotics, the development of new antimicrobial drugs offering specific mechanisms of action becomes an urgent task. Only few antimicrobials offer a broad spectrum of activity against gram-positive and gram-negative bacteria, molds, and yeasts. In this regard, the purpose of the work was to develop methods for synthesizing biologically active derivatives of alkyl-substituted phenols (reactions at the hydroxy group) to study their biological effect.Methods. The synthesis of imidazole acetates of substituted phenols was carried out in two stages. At the first stage, the chloroacetyl derivative of the selected compounds was obtained, to which imidazole was then added. O-acylation reactions at the first stage of the synthesis were carried out under varying conditions. The first version of the synthesis was carried out using chloroacetyl chloride as an acylating agent together with a high-boiling solvent. In the second variant, chloroacetic anhydride was used, along with an attempt to replace the solvent with a low-boiling one. A thymol methoxy derivative was additionally synthesized by a known method using methyl iodide and varying the reaction parameters.Results. The parameters of chloroacetylation and methoxylation of aromatic alcohols were optimized with rational selection of solvents and the ratio of reagents in the reactions. Synthesized thymol (2-isopropyl-5-methylphenol) and propofol (2,6-isopropylphenol) derivatives contained imidazole as an additional pharmacophore with affinity for microorganism cell membrane proteins. A thymol methoxy derivative comprising an aromatic ether exhibiting increased hydrophobicity was also obtained. The synthesized compounds were characterized by NMR spectroscopy.Conclusions. Chloroacetyl derivatives of aromatic alcohols can be effectively synthesized by cooling the reaction mixture using an excess quantity of an acylating agent and increasing the reaction time (compared to literature data). The yield of thymol chloroacetate was 75%, while that of propofol chloroacetate was 30%. This can be explained by the sterically hindered reaction of the propofol alcohol group, which has isopropyl substituents at the second and sixth positions of the benzene ring.

ChemInform Abstract: Efficient Synthesis of Polyfunctionalized Thiophene‐2,3‐diones and Thiophen‐3(2H)‐ones Using β‐Oxodithioesters.

Efficient methods for the preparation of polyfunctionalized thiophene-2,3-diones and thiophen-3(2H)-ones using β-oxodithioesters were described. In this study, β-oxodithioesters were found to react directly with oxalyl chloride producing 4-aroyl-5-(methylthio)thiophene-2,3-diones in 96–98% yields. However, β-oxodithioesters were found to react efficiently with chloroacetic anhydride in the presence of a base catalyst such as DMAP, which gave 4-aroyl-5-(methylthio)thiophen-3(2H)-ones in 61–77% yields.

Regioselective nitration of 2- and 4-nitrotoluenes over systems comprising nitric acid, an acid anhydride and a zeolite

Nitration of 2-nitrotoluene using nitric acid, acet ic anhydride and Hβ zeolite produces a 97% yield of 2,4-dinitotoluene along with 3% of 2,6-din itrotoluene. Nitration of 4-nitrotoluene under similar reaction conditions produces 2,4-dinitrotol uene in 89% yield. When chloroacetic anhydride was used instead of acetic anhydride, nit ration of 4-nitotoluene produced a quantitative yield (>99%) of 2,4-nitrotoluene.

Detection of chlorine-labelled chitosan in Scots pine by energy-dispersive X-ray spectroscopy

The aim of this study was to use energy-dispersive X-ray spectroscopy (EDX) to localize chitosan in the cell wall of chitosan-impregnated Scots pine. It was of interest to investigate the concentration of chitosan in wood to gain further knowledge and understanding of the distribution of chitosan in the wooden matrix. After deacetylation, chitosan was re-acetylated with chloroacetic anhydride to achieve a covalent bonding of chloride to the chitosan polymer. Chloride-labelled chitosan was measured by EDX using a scanning electron microscope and described as chloride intensity. Analysis of free chloride anions was performed by dialysis and inductively coupled plasma atomic emission spectroscopy. There was a significant correlation between the molecular weight of chitosan and the intensity of covalent-bonded chloride to the chitosan polymer. High molecular weight chitosan showed a better interaction with the cell wall structure than low molecular chitosan.

Regioselective Nitration of Deactivated Mono-Substituted Benzenes Using Acyl Nitrates Over Reusable Acidic Zeolite Catalysts

Nitration of benzonitrile was investigated using a nitric acid/acid anhydride/zeolite catalyst system under different reaction conditions. Trifluoroacetic and chloroacetic anhydrides were found to be the most active among the anhydrides tried. Also, zeolites Hβ and Fe3+β (Si/Al = 12.5) were found to be the most active catalysts. For example, nitration of benzonitrile with trifluoroacetyl nitrate under reflux conditions in dichloromethane gave 3- and 4-nitrobenzonitriles in quantitative yield, of which the para-isomer represented 24–28%. The yield of para-isomer was improved to 33% when passivated Hβ was used under similar reaction conditions. This is easily the most para-selective nitration of benzonitrile ever recorded. Also, no ortho-isomer was formed under the conditions tried. The zeolite can be easily recovered, regenerated by heating and reused up to six times to give results similar to those obtained with a fresh sample of the catalyst. The nitration system was applied successfully to a range of deactivated mono-substituted benzenes to give para-isomers in significantly higher proportions than in the corresponding traditional nitration reactions.

Cu(II)-catalyzed THM formation during water chlorination and monochloramination: A comparison study

The catalytic effect of Cu(II) on trihalomethane (THM) formation during chlorination and monochloramination of humic acid (HA) containing water was comparatively investigated under various pH conditions. Results indicate that in the presence of Cu(II), the formation of THMs was significantly promoted as pH decreased in both chlorination and monochloramination. More THMs were formed during Cu(II)-catalyzed monochloramination which was partially due to enhanced hydroxyl radical ( OH) generation as demonstrated by electron spin resonance (ESR) analysis. To discriminate the reactive moieties of HA, nine model compounds, which approximately represented the chemical structure of HA, were individually oxidized by chlorine or monochloramine. Results show that Cu(II) could promote THM formation through reacting with citric acid and similar structures in HA. During chlorination and monochloramination of citric acid in the absence of Cu(II), major intermediates including chlorocarboxylic acid, chloroacetone and chloroacetic anhydride were identified. However, the catalysis of Cu(II) did not produce any new intermediate. The complexation of Cu(II) with model compounds was characterized via FTIR analysis. The reaction mechanism for Cu(II)-catalyzed THM formation was proposed to comprise two pathways: (1) indirect catalysis in which OH oxidizes the large molecules of HA into small ones to enhance THM formation; and (2) direct catalysis in which Cu(II) complexes with HA to accelerate the decarboxylation steps for THM formation.

Acylation of a 6‐(Methylamino)‐5‐nitrosopyrimidine and 1,3‐Dipolar Cycloaddition of an 8‐Methylisoxanthopterin N(5)‐Oxide. Synthesis of C(6),N(8)‐Disubstituted Isoxanthopterins

Abstractmagnified imageAcylation of 2‐amino‐4‐(benzyloxy)‐6‐(methylamino)‐5‐nitrosopyrimidine (5) with acetic anhydride or chloroacetic anhydride in the presence of 4‐(dimethylamino)pyridine (DMAP) led to the C(2)‐acylamino derivatives 6 and 7, respectively. In the absence of a base, acetylation did not lead to a product, while chloroacetylation led to the 6‐chloropteridine 11. Chloroacetylation in the presence of Hünig's base provided the pteridinone N(5)‐oxide 10, suggesting that acylation of 5 is readily reversible, and that the unfavourable equilibrium must be displaced by a follow‐up reaction to trap the acylation product. Acylation of 5 with hexadienoyl chloride, followed by intramolecular Diels–Alder reaction, provided the pteridinone 12. A high yielding 1,3‐dipolar cycloaddition of the acylnitrone 10 to electron‐poor and electron‐rich dipolarophiles, followed by spontaneous N,O‐bond cleavage, gave the C(6)‐substituted pteridinones 19a–19e that were deprotected to the pteridine‐4,7(3H,8H)‐diones 20a–20e. Substitution of the 6‐chloropterin 11 provided the 6‐morpholinopteridine 25. Sonogashira coupling yielded the fluorescent [(pteridin‐6‐yl)ethynyl]‐glucopyranoside 26, 6‐ethynylpteridine 28, and 6,6′‐(ethynediyl)bispteridine 29. The alkyne 28 reacted with Me3SiCl and LiBr in MeCN to produce the bromoalkene 31.

Synthesis and Characterization of Amino Acid Modified Chitooligosaccharides

AbstractAmino acid modified chitooligosaccharides were synthesized by the new synthetic route. The chloroacetyl‐chitooliogosaccharide intermediates were prepared under a mild condition via a reaction between chitooligosaccharide (COS) and chloroacetic anhydride. The intermediates were subsequently reacted with a variety of amino acids, e.g., glycine, aspartic acid, alanine, arginine, and serine, under a basic condition, yielding amino acid modified COS products. The degree of chloroacetylation was calculated based on new 1H NMR absorption peaks at 3.80 and 3.94 ppm, corresponding to NHCOCH2Cl and OCOCH2Cl, respectively. The degrees of chloroacetylation determined were 0.40, 0.44, 0.62, and 0.93 when the mole ratios of chloroacetic anhydride to COS were 0.5, 1, 2, and 4, respectively. The chemical structures of the COS derivatives were also determined using 1H NMR spectroscopy. The biological properties of the derivatives were evaluated. Cytotoxicity of the derivatives was assessed by a direct contact, using L929 cells. An MTT assay was a method of choice to evaluate the efficacy of the derivatives to enhance the proliferation of L929 cells.

Zinc perchlorate hexahydrate [Zn(ClO 4) 2·6H 2O] as acylation catalyst for poor nucleophilic phenols, alcohols and amines: Scope and limitations

Commercially available zinc perchlorate hexahydrate [Zn(ClO 4) 2·6H 2O] was found to be a highly efficient catalyst for acylation of electron deficient phenols, sterically hindered alcohols and electron deficient and sterically hindered amines. The acetylated derivatives were obtained in excellent yields under solvent-free conditions and at room temperature. However, the reaction of highly electron deficient and sterically hindered phenol, e.g., 2,4-dinitrophenol required heating at 80 °C. In case of reactions with alkoxy or dialkoxy benzylic alcohols, a complex product mixtures were formed containing the corresponding dibenzylic ethers. The catalyst was found to be of general use with respect to other acylating agents such as propionic, iso-butyric, pivalic, benzoic and chloroacetic anhydrides. However, the rate of acylation was influenced by the steric and electronic factors of the anhydrides and followed the order Ac 2O > (PhCO) 2O > (EtCO) 2O > ( i PrCO) 2O > ( t BuCO) 2O ≫ (ClCH 2CO) 2O. Benzoylation and pivalation of phenols (including electron deficient phenols), dihydric phenol and sterically hindered alcohol afforded excellent yields. The catalytic activity of various zinc compounds was found to be of the order Zn(ClO 4) 2·6H 2O > ZnI 2 ∼ ZnBr 2 > ZnCl 2 ≫ Zn(OAc) 2 > ZnCO 3 and was parallel to the acidic strength of the corresponding protic acids.

Acetylation of poly(2-hydroxyethyl acrylate) gel beads obtained from sedimentation polymerization

Sedimentation polymerization of an aqueous 2-hydroxyethyl acrylate solution with some crosslinkers was carried out using a simple sedimentation polymerization apparatus to give millimeter-size and very narrow size distributed poly(2-hydroxyethyl acrylate) (PHEA) gel beads. Also, heterogeneous acetylation of the resulting PHEA gel beads with acylating agents such as acetic anhydride, a mixture of acetic anhydride and pyridine, and chloroacetic anhydride was performed under various conditions. The selective esterification of PHEA gel beads proceeded smoothly in toluene from surface to give a novel core-shell type gel consisting of an unreacted core and acetylated shell, and finally afforded almost quantitatively acetylated PHEA gel. The unreacted core became small while maintaining a spherical shape during reaction. The reaction resembled to that of the corresponding cylindrical PHEA gel, and was strongly affected by the network structure of the obtained PHEA gel beads and the reactivity of acylating agents.

Acetylation of poly(2-hydroxyethyl acrylate) gel and synthesis of core-shell type gel

Heterogeneous esterification of poly(2-hydroxyethyl acrylate) (PHEA) gel with acylating agents such as acetic anhydride, a mixture of acetic anhydride and pyridine, and chloroacetic anhydride was carried out under various conditions. The selective esterification of PHEA gel proceeded smoothly in toluene from surface to give a novel core-shell type gel (gel capsule) consisting of a hydrophilic unreacted core and hydrophobic acetylated shell, and finally afford almost quantitative acetylated PHEA gel. The reaction was strongly affected by kinds and concentration of acylating agents. The swelling of the obtained gel capsule was studied. Although the gel capsule obtained from the esterification of PHEA gel with acetic anhydride showed much the same swelling behavior as the original PHEA gel, the shell layer resulting from the esterification of PHEA gel with a mixture of acetic anhydride and pyridine showed a high degree of esterification and worked as a permeability barrier of water.

Chemo‐enzymatic Synthesis of Conformationally Constrained Oligosaccharides.

N-Acetyllactosamine derivative 4, which has a methylene amide tether between C-6 and C-2′, was enzymatically glycosylated using rat liver α-2,6-sialyltransferase (ST6GalI) or recombinant human fucosyltansferase V (FucT-V) to give conformationally constrained trisaccharides 5 and 6, respectively. The methylene amide linker of 4 was installed by a two-step procedure, which involved acylation of a C-6 amino function of a LacNAc derivative with chloroacetic anhydride followed by macrocyclization by nucleophilic displacement of the chloride by a C-2′ hydroxyl. The conformational properties of 4 were determined by a combination of NOE and trans-glycosidic heteronuclear coupling constant measurements and molecular mechanics simulations and these studies established that the glycosidic linkage of 4 is conformationally constrained and resides in only one of the several energy minima accessible to LacNAc. The apparent kinetic parameters of transfer to LacNAc and conformationally constrained saccharides 3 and 4 indicates that fucosyltransferase V recognize LacNAc in its A-conformer whereas α-2,6-sialyltransferase recongizes the B-conformer of LacNAc.

Preparation of labeled bis‐amino acid Hydroxyethylamino sulfonamide hiv protease inhibitors

AbstractPreparation of radiolabeled sulfonamide HIV protease inhibitors, DMP852 and DMP853 is described. The C‐14 labeling of DMP852 was accomplished by acylation of the intermediate amine with [1‐14C]‐chloroacetic anhydride followed by the treatment of the chloroacetyl derivative with methylamine. Due to the rapid loss of the methylglycine moiety during metabolism studies, a route that involved an oxidation‐reduction sequence was employed to prepare tritium labeled DMP852. Similar methodology was utilized to prepare tritium labeled DMP853. Copyright © 2003 John Wiley & Sons, Ltd.

Chemo-enzymatic synthesis of conformationally constrained oligosaccharides

N-Acetyllactosamine derivative 4, which has a methylene amide tether between C-6 and C-2', was enzymatically glycosylated using rat liver alpha-2,6-sialyltransferase (ST6GalI) or recombinant human fucosyltransferase V (FucT-V) to give conformationally constrained trisaccharides 5 and 6, respectively. The methylene amide linker of 4 was installed by a two-step procedure, which involved acylation of a C-6 amino function of a LacNAc derivative with chloroacetic anhydride followed by macrocyclization by nucleophilic displacement of the chloride by a C-2' hydroxyl. The conformational properties of 4 were determined by a combination of NOE and trans-glycosidic heteronuclear coupling constant measurements and molecular mechanics simulations and these studies established that the glycosidic linkage of 4 is conformationally constrained and resides in only one of the several energy minima accessible to LacNAc. The apparent kinetic parameters of transfer to LacNAc and conformationally constrained saccharides 3 and 4 indicates that fucosyltransferase V recognize LacNAc in its A-conformer whereas alpha-2,6-sialyltransferase recognizes the B-conformer of LacNAc.

Heterogeneous chloroacetylation of chitosan powder in the presence of sodium bicarbonate

AbstractBecause of the importance of the chloroacetyl group to carbohydrate synthesis, the objective of this work is to disclose a method that has been found useful for the heterogeneous chloroacetylation of chitosan powder in which sodium bicarbonate is used as the base for the neutralization of the acid byproduct. A series of reactions were conducted to determine the more optimal conditions under which to perform acylation. The three varied aspects of the reaction were the acylating reagent (chloroacetyl chloride and chloroacetic anhydride), the solvent (methylene chloride and N,N‐dimethylformamide), and the temperature (0 or 44 °C). According to Fourier transform infrared (FTIR), the chitosan powder being refluxed in methylene chloride in the presence of chloroacetic anhydride constituted the best conditions. By incorporating these conditions and increasing the amount of the base, we obtained a chloroacetylated chitosan powder that, characterized by FTIR, solid‐state cross‐polarity/magic‐angle spinning 13C NMR, and elemental analysis, had degrees of N‐ and O‐chloroacetylation of 0.32 and 0.15, respectively. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 4174–4181, 2001

Conversion of Complex Sialooligosaccharides into Polymeric Conjugates and their Anti-Influenza Virus Inhibitory Potency

ABSTRACT To investigate the specificity of various influenza virus strains we have prepared polyacrylic type conjugates of undecasaccharide (Neu5Acα2-6Galβ1-4GlcNAcβ1-2Manα1)2-3,6Manβ1-4GlcNAcβ1-4GlcNAc (YDS), and trisaccharides 6‵-sialyl-N-acetyllactosamine (6‵SLN), 6‵-sialyllactose (6‵SL), and 3‵-sialyllactose (3‵SL). Free oligosaccharides were transformed to glycosylamine-1-N-glycyl derivatives by sequential action of NH4HCO3, chloroacetic anhydride, and aqueous NH3. The known derivatization protocol has been optimized for these sialooligosaccharides. Coupling of obtained amino-spacered derivatives with poly(4-nitrophenyl acrylate) gave rise to two types of conjugates, namely with polyacrylic acid and polyacrylamide backbones; the conversion proceeded quantitatively and without destruction of the oligosaccharides. The content of oligosaccharides in the conjugates was 10, 20, and 30% mol for 3‵SL, 6‵SL, 6‵SLN, and 2, 5 and 10% mol for YDS. Free oligosaccharides and the glycoconjugates were tested as inhibitors of influenza virus adhesion, and also as blockers of virus infectivity in MDCK cell culture. Biantennary YDS demonstrated similar activity to trisaccharide 6‵SLN both as the free form and neoglycoconjugate.

Multiple oligodeoxyribonucleotide syntheseson a reusable solid-phase CPG support via the hydroquinone-O,O'-diacetic acid (Q-Linker) linker arm.

A strategy for oligodeoxyribonucleotide synthesis on a reusable CPG solid-phase support, derivatized with hydroxyl groups instead of amino groups, has been developed. Ester linkages, through a base labile hydroquinone- O, O '-diacetic acid ( Q-Linker ) linker arm, were used to couple the first nucleoside to the hydroxyl groups on the support. This coupling was rapidly accomplished (10 min) using O -benzotriazol-1-yl- N, N, N ', N '-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole as the activating reagents. Oligodeoxyribonucleotide synthesis was performed using existing procedures and reagents, except a more labile capping reagent, such as chloro-acetic anhydride, methoxyacetic anhydride or t-butylphenoxyacetic anhydride, was used instead of acetic anhydride. After each oligodeoxyribonucleotide synthesis, the product was cleaved from the support with ammonium hydroxide (3 min) and deprotected as usual. Residual linker arms or capping groups were removed by treatment with ammonium hydroxide/methylamine reagent and the regenerated support was capable of reuse. Up to six different oligodeoxyribonucleotide syntheses or up to 25 cycles of nucleoside derivatization and cleavage were consecutively performed on the reusable support. This method may provide a significant cost advantage over conventional single-use solid supports currently used for the manufacture of antisense oligodeoxyribonucleotides.

Synthesis of chiral azamacrocycles using the bis(α‐chloroacetamide)s derived from chiral 1,2‐diphenylethylenediamine

AbstractOptically active diphenyl‐substituted tetraaza‐12‐crown‐4 diamide (10), tetraaza‐15‐crown‐5 diamide (12), tetraaza‐18‐crown‐6 diamide (11), and hexaaza‐18‐crown‐6 diamide (9) ligands were prepared by treating the appropriate secondary diamines with the (R,R)‐ and (S,S)‐ forms of 1,2‐bis(N‐methyl‐α‐chloracetamido)‐1,2‐diphenylethane (20). Macrocyclic diamides 9 and 10 were reduced to form the optically active diphenyl‐substituted hexaaza‐18‐crown‐6 (13) and tetraaza‐12‐crown‐4 (14), respectively. Reduction of macrocyclic diamide ligands 11 and 12 gave a complex mixture of products from which the desired tetraaza‐15‐crown‐5 and 18‐crown‐6 compounds could not be isolated. Dichloride 20 was prepared by treating the chiral forms of 1,2‐ diphenylethylenediamine with chloroacetic anhydride or chloroacetyl chloride. The crystal structures for the (R,R)‐form of dichloride 20 and the (S,S)‐forms of macrocycles 10 and 11 are reported.

Chemical modification of hydroxyl functions: Introduction of hydrolyzable ester function and bactericidal quaternary ammonium groups

Polymers carrying a hydrolyzable ester function and bactericidal quaternary ammonium salts were successfully synthesized in 2 steps. The first one was the modification of hydroxyl functions of poly(vinyl alcohol) by chloroacetic anhydride. The structure of synthesized polymers was confirmed by infrared (IR), 1H-, and 13C- nuclear magnetic resonance (NMR). The kinetic results were consistent with a 1-order reaction, and the activation energy in the case of total modification was found to be 16.8 kJ mol−1. The second step was the quaternization of the pendant chlorine atom with a long alkyl chain or aromatic tertiary amines. The percentage of grafting was almost total, except with 3-diethylaminophenol, probably due to steric hindrance. The thermal degradation of polymers was studied. Side chains carrying quaternary ammonium salts begin to degrade at 168°C with the emission of chloride and amine compounds. At about 250°C, acetic and chloroacetic acid are evolved due to acetate and chloroacetate side chains. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 70: 2657–2666, 1998

Coordinated Acylimido Complexes Formed by Reaction of Nitridorhenium and Nitridomolybdenum Porphyrins with Substituted Acetic Anhydrides

Acylimidorhenium and molybdenum porphyrin complexes were prepared by reaction of the corresponding nitridometalloporphyrins with substituted acetic anhydrides and their spectral and electrochemical properties were determined. Analysis of the electronic spectral changes with time and initial reactant concentration confirmed that the acylimido formation reaction was first-order in each reactant and second-order overall. Second-order rate constants for formation of the chloroacetic anhydride complex increased in the order Mn < Cr < Re < Mo . In contrast with the previously reported reactivity of acylimidomanganese and chromium porphyrin complexes, the rhenium and molybdenum derivatives were unreactive towards triphenylphosphine, strained olefins and silyl ethylene ethers.