Formation of Carboxylic Acid Chlorides

Carboxyl groups in diorgano telluriums can be converted to chlorocarbonyl groups by treating the acids with oxalyl chloride at 20° or with butyl dichloromethyl ether/zinc chloride at 0°. 

Oxalyl chloride was used for the preparation of aryl 2-chlorocarbonylethen-l-yl telluriums  

3-H3CO-C6H4, 3,5-(H3C0)C6H3, 4-H3C-CO-C6H4, 3-F-Ce,H4, 1-naphthyl 

2-Chlorocarbonyl-l-methylethen-l-yl Phenyl Tellurium In a nitrogen-purged, 100-m/ flask containing a magnetic stirrer are placed 25 ml (37 g, 0.3 mol) of oxalyl chloride and 5g (17 mmol) of 2-carboxy-l-methylcthcn-1 -yl phenyl tellurium. The mixture is stirred at 20° for 60 min and then checked for the presence of acid by H-NMR spectroscopy. If the reaction is not complete the mixture is stirred at 40° until all acid has been consumed. Excess oxalyl chloride is removed by evaporation under reduced pressure and the acid chloride remains as a waxy, red solid. 

The acid chlorides prepared in this manner (for individual compounds, see reaction scheme) were not purified but converted to heterocyclic compounds through treatment with aluminum chloride  

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For the formation of carboxylic acid chlorides from carboxylic acids different procedures are known. Often thionyl chloride or oxalyl chloride, both with catalytic amounts of DMF, are used. The reaction with thionyl chloride requires elevated temperatures and often provides various byproducts. Oxalyl chloride is useable at room temperature or... 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

Thionyl chloride is another activating agent employed for reactions between aromatic carboxylic acids and phenols in pyridine solution. The mechanism suggested does not involve the formation of an acid chloride but assumes the existence of an intermediary mixed sulfinic anhydride which undergoes reaction with phenolic endgroups (Scheme 2.32).311... 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

Problem 18.9 (a) In the formation of an acid chloride, which bond of a carboxylic acid is broken, C—OH or CO -H (b) When labeled methanol, CH3 OH, was allowed to react with ordinary benzoic acid, the methyl benzoate produced was found to be enriched in O, whereas the water formed contained only ordinary oxygen. In this esterification, which bond of the carboxylic acid is broken, C—OH or CO—H Which bond of the alcohol ... 

Intramolecular trapping studies have verified the intermediacy of acyl radicals in the conversion of carboxylic acid chlorides to samarium acyl anions by Smli. Treatment of 2-allyloxybenzoyl chlorides with Sml2 resulted in a very rapid reaction, frtrni which cyclopropanol products could be isolated in yields of up to 60% (equation 8iy Apparently, initial formation of the acyl radical was followed by rapid radical cyclization. The 3-keto radical generated by this process undergoes cyclization by a radical or anionic process, affording the observed cyclopropanols (Section 1.9.2.3.1). 

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

The Cl in the cation of the salt (A) may be replaced by OSOC1 or the residue from one of the chlorinating agents mentioned above. Formation of the acid chloride by SOCl2 is activated by even catalytic amounts of dimethylformamide (1/20 mole per mole of carboxylic acid) since, according to (g), dimethylformamide is continuously re-formed. Carboxylic acids can be converted into their chlorides by SOCl2-dimethylformamide even when they react poorly with SOCl2 alone. 

The most frequently used approaches for derivatizing carboxylic acids are esterification with a variety of single-enantiomer alcohols, or formation of amides with single-enantiomer amines [234,252]. The formation of amide derivatives requires activation of the carboxylic acid by formation of the acid chloride with thionyl chloride, mixed anhydrides with chloroformates, N-acylimidazoles with 1,1 -carbonyldiimidazole or N-acylureas with dicyclohexylcarbodiimide. Esterification reactions generally re-... 

Preparation of Carboxylic Acid Chlorides. As described in the original article, oxalyl chloride is widely need for the synthesis of carboxylic acid chlorides. This general approach has found use in new chemistry fields such as combinatorial chemistry and dendrimer synthesis. An interesting downstream application was formation of macrocyclic diamides without resorting to high dilution. ... 

Similarly, reaction of carboxylic acid halides with sodium azide led to the formation of the respective acyl azides, which are stable. " By contrast, reaction of carboxylic acid chlorides with sodium azide in toluene at 70-100 °C transpires via a Curtins rearrangement to generate isocyanates. The details of these transformations are outlined in eqs 41-43. 

Potassium fluoride Cyclopropanes from halides with formation of carboxylic acid fluorides from carboxylic acid chlorides... 

The reaction of carboxylic acid chlorides with low-valent metal complexes leads to the formation of acyl complexes, which can undergo decarbonylation to give a-bonded metal alkyls, alkenyls, or aryl complexes. This decarbonylation has been used to synthesize aiylsilanes from aryl acid chlorides in the presence of nickel(0) or palladium(0) complexes as catalysts. Similarly, acyl cyanides undergo decarbonylation with palladium(O) complexes to afford nitriles or alkenes, depending on the substrate. ... 

The Schmidt rearrangement is essentially the same as the Curtins rearrangement (as indeed are the Hofinann and Lessen rearrangements) in that the acid azide is generated directly from the carboxylic acid on treatment with sulfuric acid (H2SO4) and hydrazoic acid (HN3). So, formation of the acid chloride is not necessary, but it... 

Sn 1-active alkyl halides require longer reaction times (typically 3-6 h), and the yields are lower. f-Butyl chloride and adamantyl bromide have been used successfully, but the generality of the procedure needs to be demonstrated (eq 4). In contrast, acylation reactions using a wide variety of carboxylic acid chlorides have been carried out (eq 5). The initial products are protected forms of Q ,/3-diketo esters which can be isolated in yields of 72-93%. Deprotection is accomplished using MeOH/HCl. The products are vicinal tricarbonyl compounds having the usual characteristic chemical properties such as rapid formation of hydrated derivatives. The protected forms can be used directly in the synthesis of heterocycles. ... 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is the formation of an acid chloride. Molecules devoid of acid-sensitive functional groups can be converted to the acid chloride with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride, usually in a hydrocarbon solvent, provides the acid chloride under essentially neutral conditions. 

In cases where sensitivity of the compound precludes the formation of an acid chloride, a-diazo ketones can be synthesized by the DCC-mediated coupling of diazomethane to carboxylic acids (eq 9). ... 

Stabilization Mechanism. Zinc and cadmium salts react with defect sites on PVC to displace the labHe chloride atoms (32). This reaction ultimately leads to the formation of the respective chloride salts which can be very damaging to the polymer. The role of the calcium and/or barium carboxylate is to react with the newly formed zinc—chlorine or cadmium—chlorine bonds by exchanging ligands (33). In effect, this regenerates the active zinc or cadmium stabilizer and delays the formation of significant concentrations of strong Lewis acids. 

Acid chloride—con l d esters from, 802-803 from carboxylic acids, 794-795 Grignard reaction of, 804-805 hydrolysis of, 802 IR spectroscopy of, 822-823 ketones from, 805 mechanism of formation from carboxylic acids, 795 naming, 786... 

The main synthetic application of the Wolff rearrangement is for the one-carbon homologation of carboxylic acids.242 In this procedure, a diazomethyl ketone is synthesized from an acyl chloride. The rearrangement is then carried out in a nucleophilic solvent that traps the ketene to form a carboxylic acid (in water) or an ester (in alcohols). Silver oxide is often used as a catalyst, since it seems to promote the rearrangement over carbene formation.243... 

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