Synthesis and Use of Acid Chlorides

The best reagents for converting carboxylic acids to acid chlorides are thionyl chloride (SOCI2) and oxalyl chloride (COCl)2 because they form gaseous byproducts that do not contaminate the product. Oxalyl chloride is particularly easy to use because it boils at 62°C and any excess is easily evaporated from the reaction mixture. 

The mechanisms of these reactions begin like the reaction of an alcohol with thionyl chloride. Either oxygen atom of the acid can attack sulfur, replacing chloride by a mechanism that looks like sulfur s version of nucleophilic acyl substitution. The product is an interesting, reactive chlorosulfite anhydride. 

This reactive anhydride undergoes nucleophilic acyl substitution by chloride ion to give the acid chloride. 

Propose a mechanism for the reaction of benzoic acid with oxalyl chloride. This mechanism begins like the thionyl chloride reaction, to give a reactive mixed anhydride. Nucleophilic  

Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution by the addition-elimination mechanism discussed on the previous page. Attack by the alcohol at the electrophilic carbonyl group gives a tetrahedral intermediate. Loss of chloride and deprotonation give the ester. 

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Mechanism 20-3 Esterification Using Diazomethane 966 20-12 Condensation ofAcids with Amines Direct Synthesis of Amides 966 20-13 Reduction of Carboxylic Acids 967 20-14 Alkylation of Carboxylic Acids to Form Ketones 968 20-15 Synthesis and Use of Acid Chlorides 969... 

Scheme 3.16 High-dilution synthesis of diaza[18]crown-6 and thence [2.2.2] and [2.2.1] cryptands. Note the use of acid chloride groups to enhance reaction rate.9...

Besides the mild conditions and excellent chemo- and regioselectivity the scope of this one-pot coupling-cycloaddition isoxazole synthesis is fairly broad. Due to acid chlorides as halide coupling partners, amines and hydroxy groups inevitably need to be protected prior to the reaction. Therefore, the use of acid chlorides 7 is principally limited to (hetero)aromatic compounds and derivatives without ot-hydrogen atoms. As an exception, the cyclopropyl group is tolerated as a... 

Work on improving the thermal resistance and particularly the resistance to carbonization (short circuiting of layers of enameled wires under the influence of temperature) via special glycols led to diphenols [29,30]. Diphenols are not reactive under the conditions of a normal poly(ester-imide) synthesis. In synthesis the lower aliphatic diesters of diphenols were used [29-32]. The use of acid chlorides in the polyester reaction with aromatic OH-groups was also protected by patents [33-35] but it seems unlikely that this reaction was performed on the production scale. 

Chlorine s most important use is as bleach in the manufacture of paper and cloth. It is also used widely as a chemical reagent in the synthesis and manufacture of metallic chlorides, chlorinated solvents, pesticides, polymers, synthetic rubbers, and refrigerants. Sodium hypochlorite which is a component of commercial bleaches, cleaning solutions, and disinfectants for drinking water, wastewater purification systems, and swimming pools—releases chlorine gas when it comes in contact with acids. 

Alternatively, the free carboxylic acid can react with methylamine to form the corresponding N-methylamide (a secondary amide moiety), followed by amidocarbonylation with paraformaldehyde and syngas (CO/H2) in the presence of dicobalt octacarbonyl (C02(C0)8) at 120 °C to give N-acyl sarcosinate in excellent yields. The product selectivity is typically 95% at 92% N-methylamide conversion. This synthesis approach avoids use of acid chloride, and allows the introduction of both the carboxylic acid and secondary amide functionalities in a single step. 

Reduction of Acid Chlorides to Aldehydes. Palladium catalysis of acid chlorides to produce aldehydes is known as the Rosenmund reduction and is an indirect method used in the synthesis of aldehydes from organic acids. 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

Most condensations of this type start with 2-aminobenzoic acid (anthranilic acid) derivatives. In an early, extensive work on the synthesis and chemistry of dianthranilides", acid chlorides 1 were used as starting materials.2... 

Similarly, Pd/tppts was used by Hoechst (Kohlpainter and Beller, 1997) as the catalyst in the synthesis of phenylacetic acid by biphasic carbonylation of benzyl chloride (Fig. 2.29). The new process replaces a classical synthesis by reaction of benzyl chloride with sodium cyanide, followed by hydrolysis of the resulting benzyl cyanide. Although the new process produces one equivalent of sodium chloride, this is substantially less salt production than in the original process. Moreover, sodium cyanide is about seven times as expensive per kg as carbon monoxide. 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

A much more systematic approach involves the use of p-chlorides carrying non-participating groups at C-2 as is exemplified by the Wolfrom synthesis of p-isomaltose octa-acetate from 1,2,3,4-tetra-O-acetyl-p-D-glucopyranose and 3,4,6-tri-0-acetyl-2-0-nitro-p-D-glucopyranosyl chloride In this work silver carbonate was used as acid acceptor and soluble silver perchlorate was fmmd to exert valuable catalytic influence, but later the perchlorate itself was used in an application to a tiisacchar-ide s mthesis which incorporated the trityl ether modification 2 ). 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel rafts reaction, thiadiazole acetic acid derivatives, and halo ketones via the Arndt Eistert synthesis and carbinols by hydride reduction <68AHC(9)107>. The dialkylcadmium conversion of acid chlorides into ketones fails in the 1,2,5-thiadiazole series. The major product is either a tertiary carbinol or the corresponding dehydration product, by virtue of the high reactivity of the intermediate ketone. 

The Bayer synthesis of ciprofloxacin (1) patented in 1981 utilized 2,4-dichloro-5-fluorobenzoyl chloride (15) as the starting material. With the aide of magnesium ethoxide, condensation of acid chloride 15 and diethyl malonate assembled ketone 16, which was subsequently decarboxylated using tosylic acid to form ethyl 2,4-dichloro-5-fluorobenzoylacetate (17) in 82% yield in two steps from 15. A Dieckman-like condensation of 17 with ethyl orthoformate was carried out in refluxing acetic anhydride... 

A 48-membered library of 2-arylbenzoxazoles has been prepared by the condensation of substituted 2-aminophenols with a series of acid chlorides. The reactions proceeded in the absence of a base in sealed tubes in an automated microwave instrument, which used sequential rather than parallel reaction processing. Comparisons to the conventional thermal conditions demonstrated the importance of the high temperatures and pressures achieved under microwave heating, which ensured that the reactions proceeded efficiently (Scheme 3.16)26. An analogous synthesis ofbenzoxazolesby the cyclocondensation reaction of 2-aminophenols with S-methylisothioamide hydroiodides on silica gel, under microwave irradiation, has also been reported (Scheme 3.16)27. 

Halides are often prepared in a single step from alcohols through use of the Appel reaction. The reagents in this synthesis are tri-phenylphasphine and a halogen species such as tetrachloromethane, hexachloroacetone, or iodine. In place of the Appel reaction it is often possible to use inorganic acid chlorides, including phosphorus tribromide or thionyl chloride (see Chapter 16). 

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