Diazomethane, reactions with carboxylic acid

The single most valuable application of diazomethane is its reaction with carboxylic acids to provide the equivalent methyl ester, under very mild conditions. This and other reactions of the reagent have been well reviewed. ... 

Diazomethane, CH Nj, is used in the organic chemistry laboratory despite its danger because it produces very high yields and is selective for reaction with carboxylic acids. Write the products of the following reactions. 

One frequently used method for preparing methyl esters is by reaction of carboxylic acids with diazomethane, CH2N2. 

The reaction occurs in two steps (1) protonation of diazomethane by the carboxylic acid to yield methyldiazonium ion, CH3N2+, plus a carboxylate ion and (2) reaction of the carboxylate ion with CH3N2+. 

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Methylation. The reaction with diazomethane has often been used for differentiating the acidic groups (28, 35, 38, 45, 46, 69). Diazomethane reacts, in general, with carboxylic acids, forming methyl esters which are easily hydrolyzed by dilute hydrochloric acid. With phenols, ethers are formed which are stable to hydrolysis. Alcohols are methylated only if catalysts are present, e.g., BF, ZnClj (70), or HjO (71). As Garten et al. 

Sections F and G of Scheme 3.2 give some specific examples of ester synthesis by the reaction of carboxylic acids with diazomethane and by carboxylate alkylation. 

Diazomethane is a toxic, explosive yellow gas that dissolves in ether and is fairly safe to use in ether solutions. The reaction of diazomethane with carboxylic acids probably involves transfer of the acid proton, giving a methyldiazonium salt. This diazonium salt is an excellent methylating agent, with nitrogen gas as a leaving group. 

A mild method for the specific preparation of methyl esters is the reaction of carboxylic acids with diazomethane. Since diazomethane is very toxic and explosive, it must be handled with care, and is best suited for small-scale preparations. 

Esterification of acids. The widely used reaction of diazomethane with carboxylic acids was discovered by von Pechmann, who noted also the effectiveness of the reagent for the melhylation of phenols, mineral acids, hydrogen cyanide, and phthalimide. The reagent also methylates tropolones, alkylsulfonic acids, " and arylsulfonic acids. " The fact that neutral alcohols do not react with diuzomethane suggests that an acidic substance supplies a proton required for catalysis of the esteriflcatlon. 

Quinoxaline-2-carboxaldehyde has been converted into the 2-carboxylic acid by oxidation with potassium permanganate in acetone and reduced to the 2-hydroxymethyl compound by treatment with formalin and potassium hydroxide. It also undergoes other typical reactions of aromatic aldehydes such as benzoin formation on reaction with potassium cyanide - and condensation reactions with malonic acid and its diethyl ester and Schiff base formation. Acid-catalyzed reaction of quinoxaline-2-carboxaldehyde with ethylene glycol gives the cyclic acetal the diethylacetal has been prepared by reaction of 2-dibromomethylquinoxaline with sodium ethoxide. " An indirect preparation of the oxime 11 is achieved by treatment of 2-nitromethyl-quinoxaline (10) with diazomethane followed by thermolysis of the resulting nitronic ester. 

An interesting case of an alcohol reacting with diazomethane at a rate competitive with a carboxylic acid has been reported (eq 15). In this case, the tertiary structure of the molecule is thought to place the alcohol and the carboxylic acid in proximity to each other. Protonation of the diazomethane by the carboxylic acid leads to a diazonium ion in proximity to the alcohol as well as the carboxylate. These species then attack the diazonium ion at competitive rates to provide the methyl ether and ester. No reaction is observed upon treatment of the corresponding hydroxy ester with diazomethane, indicating that the acid is required to activate the diazomethane. 

Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion. Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.Cesium fluoride in DMF is another useful combination. Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively difficult to prepare by the acid-catalyzed esterification method (Fischer esterification) which will be discussed in Section 3.4.2. Sections F and G of Scheme 3.2 give some specific examples of ester synthesis by the reaction of carboxylic acids with diazomethane and by carboxylate alkylation. 

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