Communications- The Reaction of Aminomethyltrimethylsilane with Nitrous Acid.

Fessenden, Ralph J.; Freenor, Francis J.

doi:10.1021/jo01064a639

“…The TMS group in intermediate 6 bears diazomethane ( 1 ) as a potential nucleofuge and the carboxylate counterion can assist the nucleophilic attack of methanol at the silicon center13 by deprotonation of the developing methoxonium group ( 8 , Scheme ). The carboxylic acid 2 thus acts as a catalyst, first as a general acid ( K 1 ), then as a general base, ( k 2 ), for the methanolysis of 4 to generate free diazomethane ( 1 ) 14. The methyl ester is generated in a subsequent, but standard, reaction of the carboxylic acid ( 2 ) with the diazomethane 1 ( K 4 , k 5 ).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Methyl Esterification of Carboxylic Acids by Trimethylsilyldiazomethane

Kühnel

¹

,

Laffan

²

,

Lloyd‐Jones

³

et al. 2007

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Despite being toxic, flammable, photosensitive, thermally unstable, and shock sensitive, diazomethane (CH 2 N 2 , 1) has had extensive application in synthesis, especially for the Omethylation (esterification) of carboxylic acids (2!3), Scheme 1.In 1968 Seyferth et al. reported [1] that the trimethylsilyl (TMS) derivative of diazomethane (TMS À CHN 2 , 4), [2,3] described by Lappert et al.[2a] reacts with acetic acid (2 a) in dry benzene to generate TMS-methyl acetate (5 a), Scheme 1. This reaction was proposed to arise from the protonation of 4 by 2 a and then nucleophilic substitution of N 2 by acetate in the resulting TMS-substituted methyl diazonium intermediate (6 a!5 a). [1,4] However, AcOTMS and methyl acetate (3 a) were also generated in 40-60 % yield. Seyferth et al. suggested that the intermolecular protodesilylation of intermediate 6 a by the acetic acid generates a methyl diazonium intermediate [AcO][CH 3 N 2 ] (7 a), thus yielding 3 a.[1] In 1981 Aoyama, Shioiri, and co-workers reported that a simple modification of the conditions reported by Seyferth et al. involving the addition of methanol as a cosolvent (20 % v/v, 4.94 m), increased the yields of methyl esters 3 to near quantitative (90-99 %).[5a,b] Unlike 1, which is a gas (b.p. À23 8C) and requires prior generation from toxic and irritant N-methyl N-nitroso species, TMS À CHN 2 (4) is a stable liquid (b.p. 96 8C) [1] that is easily handled and is commercially available.Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co-workers (4, 5m CH 3 OH in toluene or benzene) [5a] have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification, [3] especially by analytical chemists for acid derivatization prior to chromatographic analysis.[6] Although it is known that methanol is not the methylating agent, [7] the mechanism of the reaction has not been investigated in any detail.[3b, 5a] Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4/CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane (1).The key feature of the conditions reported by Aoyama, Shioiri, and co-workers [5a] is the high-yielding and rapid (< 5 min) generation of methyl esters 3, rather than TMSmethyl esters 5, through the presence of a large excess (> 50 equiv) of methanol in benzene, [5] or toluene. [3,6] 1 H NMR analysis demonstrates that, in the absence of added acid, 4 does not observably react with CD 3 OD (5 m) in [D 8 ]toluene over a period of hours, although very slow H/D exchange is detected over longer periods. To explore the key role of methanol, we have focused on the reaction of phenyl acetic acid (2 b) with 4, and correlated the partitioning between methyl ester 3 b and TMS-methyl ester 5 b as a function of methanol concentration and isotope effect (CL 3 OL; L = H/ D). To ensure that the partitioning (3 b/5 b) was not compromised by competing or subsequent processes, we conducted the methyl esterification of benzoic acid (2 c) in ...

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“…The carboxylic acid 2 thus acts as a catalyst, first as a general acid (K 1 ), then as a general base, (k 2 ), for the methanolysis of 4 to generate free diazomethane (1). [14] The methyl ester is generated in a subsequent, but standard, reaction of the carboxylic acid (2) with the diazomethane 1 (K 4 , k 5 ).…”

mentioning

confidence: 99%

Mechanism of Methyl Esterification of Carboxylic Acids by Trimethylsilyldiazomethane

Kühnel

¹

,

Laffan

²

,

Lloyd‐Jones

³

et al. 2007

View full text Add to dashboard Cite

Despite being toxic, flammable, photosensitive, thermally unstable, and shock sensitive, diazomethane (CH 2 N 2 , 1) has had extensive application in synthesis, especially for the Omethylation (esterification) of carboxylic acids (2!3), Scheme 1.In 1968 Seyferth et al. reported [1] that the trimethylsilyl (TMS) derivative of diazomethane (TMS À CHN 2 , 4), [2,3] described by Lappert et al.[2a] reacts with acetic acid (2 a) in dry benzene to generate TMS-methyl acetate (5 a), Scheme 1. This reaction was proposed to arise from the protonation of 4 by 2 a and then nucleophilic substitution of N 2 by acetate in the resulting TMS-substituted methyl diazonium intermediate (6 a!5 a). [1,4] However, AcOTMS and methyl acetate (3 a) were also generated in 40-60 % yield. Seyferth et al. suggested that the intermolecular protodesilylation of intermediate 6 a by the acetic acid generates a methyl diazonium intermediate [AcO][CH 3 N 2 ] (7 a), thus yielding 3 a.[1] In 1981 Aoyama, Shioiri, and co-workers reported that a simple modification of the conditions reported by Seyferth et al. involving the addition of methanol as a cosolvent (20 % v/v, 4.94 m), increased the yields of methyl esters 3 to near quantitative (90-99 %).[5a,b] Unlike 1, which is a gas (b.p. À23 8C) and requires prior generation from toxic and irritant N-methyl N-nitroso species, TMS À CHN 2 (4) is a stable liquid (b.p. 96 8C) [1] that is easily handled and is commercially available.Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co-workers (4, 5m CH 3 OH in toluene or benzene) [5a] have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification, [3] especially by analytical chemists for acid derivatization prior to chromatographic analysis.[6] Although it is known that methanol is not the methylating agent, [7] the mechanism of the reaction has not been investigated in any detail.[3b, 5a] Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4/CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane (1).The key feature of the conditions reported by Aoyama, Shioiri, and co-workers [5a] is the high-yielding and rapid (< 5 min) generation of methyl esters 3, rather than TMSmethyl esters 5, through the presence of a large excess (> 50 equiv) of methanol in benzene, [5] or toluene. [3,6] 1 H NMR analysis demonstrates that, in the absence of added acid, 4 does not observably react with CD 3 OD (5 m) in [D 8 ]toluene over a period of hours, although very slow H/D exchange is detected over longer periods. To explore the key role of methanol, we have focused on the reaction of phenyl acetic acid (2 b) with 4, and correlated the partitioning between methyl ester 3 b and TMS-methyl ester 5 b as a function of methanol concentration and isotope effect (CL 3 OL; L = H/ D). To ensure that the partitioning (3 b/5 b) was not compromised by competing or subsequent processes, we conducted the methyl esterification of benzoic acid (2 c) in ...

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