Mechanism of methyl esterification of carboxylic acids by trimethylsilyldiazomethane

Article abstract of DOI:10.1002/anie.200702131

Minimal hazard: A deuterium-labeling study reveals that, contrary to prior assumption, the safe, reliable, and widely adopted method for methyl esterification of carboxylic acids using trimethylsilyldiazomethane (TMS-CHN₂) proceeds through the concurrent acid-catalyzed methanolytic liberation of diazomethane (see scheme).

Full text of DOI:10.1002/anie.200702131

Angewandte
Chemie
DOI: 10.1002/anie.200702131
Reaction Mechanisms
Mechanism of Methyl Esterification of Carboxylic Acids by
Trimethylsilyldiazomethane**
Erik Kühnel, David D. P. Laffan, Guy C. Lloyd-Jones,* Teresa Martínez del Campo,
Ian R. Shepperson, and Jennifer L. Slaughter
Despite being toxic, flammable, photosensitive, thermally
unstable, and shock sensitive, diazomethane (CH2N2, 1) has
had extensive application in synthesis, especially for the O-
methylation (esterification) of carboxylic acids (2!3),
Scheme 1.
modification of the conditions reported by Seyferth et al.
involving the addition of methanol as a cosolvent (20% v/v,
4.94m), increased the yields of methyl esters 3 to near
quantitative (90–99%).[5a,b] Unlike 1, which is
a gas
(b.p. ꢀ238C) and requires prior generation from toxic and
ꢀ
irritant N-methyl N-nitroso species, TMS CHN2 (4) is a
stable liquid (b.p. 968C)[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 CH3OH in toluene
or benzene)[5a] have been widely adopted as a safe and
convenient alternative to the use of 1 for methyl esterifica-
tion,[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/CH3OH proceeds
through the in situ methanolytic liberation of diazomethane
(1).
Scheme 1. Methyl esterification of carboxylic acids (2) by diazome-
thane (1) and by trimethylsilyl diazomethane (4), with Aoyama–Shioiri
mechanism for 4!3+5. Bn=benzyl.
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 TMS-
methyl esters 5, through the presence of a large excess (>
50 equiv) of methanol in benzene,[5] or toluene.[3,6] 1H NMR
analysis demonstrates that, in the absence of added acid, 4
does not observably react with CD3OD (5m) in [D8]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 (2b) with 4, and correlated the partitioning between
methyl ester 3b and TMS-methyl ester 5b as a function of
methanol concentration and isotope effect (CL3OL; L = H/
D). To ensure that the partitioning (3b/5b) was not compro-
mised by competing or subsequent processes, we conducted
the methyl esterification of benzoic acid (2c) in the presence
of labeled esters of phenyl acetic acid (Scheme 2; a) 2H3-3b,
b) 2H2-5b). Experiments performed with phenyl acetic acid
In 1968 Seyferth et al. reported[1] that the trimethylsilyl
[2,3]
ꢀ
(TMS) derivative of diazomethane (TMS CHN2, 4),
described by Lappert et al.[2a] reacts with acetic acid (2a) in
dry benzene to generate TMS-methyl acetate (5a), Scheme 1.
This reaction was proposed to arise from the protonation of 4
by 2a and then nucleophilic substitution of N2 by acetate in
the resulting TMS-substituted methyl diazonium intermedi-
ate (6a!5a).[1,4] However, AcOTMS and methyl acetate (3a)
were also generated in 40–60% yield. Seyferth et al. sug-
gested that the intermolecular protodesilylation of intermedi-
ate 6a by the acetic acid generates a methyl diazonium
intermediate [AcO][CH3N2] (7a), thus yielding 3a.[1] In 1981
Aoyama, Shioiri, and co-workers reported that a simple
[*] E. Kühnel, Prof. Dr. G. C. Lloyd-Jones, T. Martínez del Campo,
Dr. I. R. Shepperson, J. L. Slaughter
School of Chemistry
2
(2b) and labeled esters of benzoic acid (2H3-3c and H2-5c)
University of Bristol
Cantock’s Close, Bristol, BS81TS (UK)
Fax: (+44)117-929-8611
proceeded analogously. The complete lack of participation of
the co-reacted esters in all of these experiments confirms that:
1) the labeled products 3 and 5 are stable under the reaction
conditions, 2) the product ratios 3/5 are kinetic and not
thermodynamic, and 3) the methyl esters 3 are not generated
in situ from 5 by TMS cleavage.
E-mail: guy.lloyd-jones@bris.ac.uk
Dr. D. D. P. Laffan
AstraZeneca
Macclesfield Works
Analysis of the reaction of phenyl acetic acid (2b) under
the conditions reported by Aoyama, Shioiri, and co-workers
(5m CH3OH)[5a] in terms of attack of 6b by methanol (k2,
Figure 1) against nucleophilic attack of phenylacetate to
Hurdsfield Industrial Estate
Macclesfield, Cheshire SK102NA (UK)
[**] We thank AstraZeneca for generous funding. T.M.C. thanks the MEC
(Spain) for a predoctoral grant.
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concentrations, intermediate 6b will be a non-dissociated ion
pair, and 2) the background reaction of 6b with acid 2b
(Seyferth-type mechanism,[1] Scheme 1) noticeably contrib-
utes. At higher methanol concentrations, the line of best-fit
yields k2/k3 = 7.9 dm3 molꢀ1 as the partitioning of 6b towards
methanol (!3b) and the ion-pair reaction (!5b). Consistent
with the analysis of the scheme in Figure 1, the [3b/5b] ratio
was independent of [2b]0 (0.05–0.2m).
When the reaction of phenyl acetic acid (2b) was carried
out in the presence of tBuOH (1.6m), the same ratio of 3b/5b
resulted as at [CH3OH] = 0, and thus tBuOH does not interact
productively with 6b. In the presence of tBuOD (1.6m), the
TMS-methyl ester [2Hn]-5b is obtained with a high proportion
Scheme 2. Control experiments conducted with benzoic acid (2c) and
2H-labeled phenyl acetic esters 3b and 5b. Experiments, in which the
Bn and Ph were reversed, proceeded analogously.
2
of the H2 isotopologue (75%), thus demonstrating that the
protonation of 4 by [2H1]-2b, to generate [2H1]-6b, is
reversible (K1), with the tBuOD acting as a nonparticipative
2H reservoir. Analysis of the dependency of methyl [2Hn]-3b
against TMS-methyl [2Hn]-5b esterification on the concen-
tration of CD3OD also yielded a simple correlation, Figure 1,
line B. Curvature is again observed at low [CD3OD] such that
line B meets the y axis at the same point as line A (CH3OH).
A key point that emerges is that in the linear regime (> 0.2m
CD3OD), the gradient of line B (k2/k3 = 6.2 dm3 molꢀ1) is less
than that of line A, which indicates that there is a small and
normal kinetic isotope effect (KIE; kH/kD) for the reaction of
6b with CL3OL. The differential gradients of A and B suggest
the KIE (k2(H)/k2(D)) that arises from the capture of 6b by
methanol to be 1.8 ꢁ 0.5, in the concentration range 0.2–
0.75m. The small magnitude of the KIE suggests an early
transition state that arises from an exothermic reaction of 6b
with the methanol. A second set of reactions were conducted
with CH3OH/CD3OD mixtures (Figure 1, Graph II). The
approximately linear correlation of [[2Hn]-3b/[2Hn]-5b] (y
axis) against cD, the mole fraction of exchangeable 2H (x axis),
suggests that partitioning of 6b involves the transfer of a
single proton from the methanol (k3).[8]
Figure 1. Kinetics of the reaction of phenyl acetic acid (2b) with TMS-
diazomethane (4. Graph I: line A: 2b (0.05m), 4 (0.06m) in toluene at
RT; line B: as A except CD3OD employed. Graph II: proton-inventory of
[3b/5b] at [CL3OL]=0.2m against cD, the mole fraction of exchange-
able deuteriumacross the system{ 2b + 4 + CL3OL}.
The isotope ratios in esters [2Hn]-3b and [2Hn]-5b act as
proxies for the ratios in the corresponding methyl diazonium
[2Hn]-7b and TMS-methyl diazonium [2Hn]-6b intermediates.
When reactions are conducted in CD3OD (0.2–0.8m; cD =
0.65–0.88), comparison of the isotope distributions in [2Hn]-5b
with statistical distributions based on cD (Figure 2, Graph III)
shows that 6b undergoes around 90% equilibration with the
CL3OL medium (6b![2Hn]-6b) before partitioning to [2Hn]-
3b and [2Hn]-5b.
generate 5b (k3, Figure 1), suggests that the fate of 6b will be
determined by the absolute methanol concentration
[CH3OH], the steric bulk/nucleophilicity of the carboxylate
ion (k3), and the pKa of 2b (k2 and K1, see below). With the
additional information provided by Scheme 2 regarding the
inertness of the products under the reaction conditions, the
analysis predicts that [3b]/[5b] = {(k2/k3) ” [CH3OH]}, inde-
pendent of the concentration of either 2 or 4, and that
[3b]/[5b] will be constant when CH3OH is in large excess.
The predicted first-order dependency of [3b]/[5b] (y axis,
Figure 1) on [CH3OH] (x axis) was explored at methanol
concentrations below that of the standard synthetic procedure
(5m), so that the [3b]/[5b] ratios could be accurately
measured (Figure 1, Graph I, line A). Curvature in the
correlation is evident at very low methanol concentration,
such that when [CH3OH] = 0, thus, under “Seyferth condi-
tions”,[1] a non-zero value (0.31) of [3b]/[5b] is observed. This
effect probably arises from two factors: 1) at low methanol
However, analysis of the methyl ester [2Hn]-3b reveals
very different 2H distributions to those predicted by the
Aoyama–Shioiri–Seyferth mechanism, Scheme 1. For exam-
ple, at 0.75m concentration of CD3OD (Figure 2, Graph IV)
the apparent isotope effect for the conversion of [2Hn]-6b into
[2Hn]-3b is 7.5 ꢁ 0.5 (open circles). Since the isotope effect for
methanolysis of 6b (k2(H)/k2(D)) is only 1.8 ꢁ 0.5 under these
conditions (Figure 2, Graph IV, closed circles), this conclu-
sively proves that the reaction of methanol with TMS-methyl
diazonium 6b does not lead directly to methyl ester 3b.
Instead, a process of 2H/1H selection (with a net KIE of 7.5 ꢁ
ꢀ
0.5) must occur after C Si bond cleavage, but prior to
generation of [2Hn]-3b. A likely candidate for such equilibra-
tion is diazomethane (1). Indeed, reaction of ethanol-free 1
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Reaction of phenyl acetic acid (2b) with 4 in
toluene/MeOH (0.5m) in the presence of the
stronger para-nitrobenzoic acid (2d, 0–
20 mol%) resulted in a moderate linear
increase in the ratio of 3b/5b (from 4/1 to
9/1; Scheme 4), albeit accompanied by the
para-nitrobenzoate esters 3d and 5d.
The much stronger acid HBF4, known to
induce the methylation of alcohols by both
1[15] and 4,[5d] proved much more efficient.
Using just 2 mol% led to essentially instan-
taneous esterification of 2b and to a pro-
found increase in the selectivity for 3b over
5b (> 40/1). Since the HBF4 also catalyses
the etherification of the methanol,[5d,15] an
excess of 4 (2.5 equiv) is required to attain
complete conversion of 2b.
Figure 2. Graph III: d0-, d1-, and d2-isotope distributions for [2Hn]-5b as a function of cD;
observed data: squares d2, circles d1, crossed circles d0; solid lines: statistical distribu-
tions. Graph IV: d0-, d1-, d2-, and d3-isotope distributions for [2Hn]-3b at [CD3OD]0 =0.75m
(cD =0.88) as a function of KIE; solid lines: based on isotope distribution in [2Hn]-6b (as
determined from [2Hn]-5b); observed data: closed circles, using k2(H)/k2(D) =1.8ꢁ0.5,
open circles using kH/kD (net)=7.5 ꢁ0.5.
In conclusion, we have demonstrated that
methyl esterification of carboxylic acids with
TMS-diazomethane (4) under the Aoyama–
with 2b in toluene/CD3OD (5m; cD = 0.98) gave [2Hn]-3b in
which 48% was the [2H3]-isotopologue. Equilibration of 1
with the CL3OL medium, via methyl diazonium 7b, is thus
slightly greater than the rate of generation of 3b, thus
facilitating partial generation of [2H2]-1.[9] Under identical
2
ꢀ
conditions (cD = 0.98), TMS CHN2 (4) also gave [ H3]-3b as
48% of the [2H3]-isotopologue. On using O-[D1]-phenyl acetic
acid ([2H1]-2b; 5m MeOD; cD = 0.99), we isolated [2H3]-3b in
92% yield with 96% methyl per-deuteration.
In general, C-protodesilylation reactions proceed through
either a pre-or postp-rotonation mechanism. Synchronous
protonation (as in Scheme 1) is rare. In the pre-protonation
mechanism, an sp2-hybridized carbon atom, a or g to the
silicon atom, is protonated to generate a b-carbocation from
which R3Si is eliminated. Thus allyl, vinyl, and cyclopropyl-
methylene silanes readily undergo cleavage,[10] whereas alkyl
silanes are inert. The cationic moiety of intermediate 6 bears
Scheme 3. A modified mechanism for the methyl esterification of
carboxylic acids (2) by 4 in toluene/MeOH.
only sp3-hybridized carbon atoms, and thus lacks an appro-
priate orbital for C-protonation. The post-protonation mech-
anism involves the nucleophilic displacement of the silyl
group[11] to generate a carbanion.[12] The TMS group in
intermediate 6 bears diazomethane (1) as a potential nucleo-
fuge and the carboxylate counterion can assist the nucleo-
philic attack of methanol at the silicon center[13] by deproto-
nation of the developing methoxonium group (8, Scheme 3).
The carboxylic acid 2 thus acts as a catalyst, first as a general
acid (K1), then as a general base, (k2), 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 (K4, k5).
Scheme 4. Acid-catalyzed methanolysis of 4, which facilitates higher
selectivity in the esterification of 2b (0.05m).
The competing generation of TMS-methyl esters 5 can be
a problem when making derivatives for chromatographic
analysis,[6a,d] and is exacerbated by weak carboxylic acids,
which generate a more nucleophilic carboxylate anion (k3).
The mechanism outlined in Scheme 3 shows that the carbox-
ylic acid plays two separate roles in the reaction: 1) it
catalyses the generation of 1 from 4 and 2) acts as a reactant
to generate the methyl ester 3. The 3/5 ratio obtained with one
acid can therefore be influenced by the presence of another.
Shioiri conditions,[5] a procedure widely adopted for its
safety,[3,6] proceeds by a methanolytic protodesilylation of 4
to generate the free diazomethane (1). Two key features of
the mechanism, outlined in Scheme 3, are that the protona-
tion of both 4 and 1 are reversible (K1 and K4), and that the
apparent partitioning of intermediate 6 can be perturbed by
co-reaction with strong acids. This information has facilitated
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Communications
Use Synthons Org. Chem. 1993, 1, 51 – 101; c) A. Presser, A.
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[4] J. A. Soderquist, E. I. Miranda, Tetrahedron Lett. 1993, 34, 4905 –
4908.
the development of an HBF4-catalysed method to substan-
tially improve the selectivity for 3 over 5. It also reveals how
CD3 esters can be generated in useful isotopic purity (> 96%
methyl per-deuteration) using [2H2]-1, generated in situ from
4 and MeOD, as a much safer alternative to the use of
preformed 1.[6c,16]
[5] a) N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull.
1981, 29, 1475 – 1478; b) T. Shioiri, T. Aoyama, N. Hashimoto,
patent (Japan), JP57130925, 1982; c) see also: T. Aoyama, S.
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[7] Footnote 26 in reference [3b].
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[11] For an example, see: G. M. Poliskie, M. M. Mader, R. van Well,
Tetrahedron Lett. 1999, 40, 589 – 592; notably under the con-
Experimental Section
[2H3]-3b: All manipulations prior to work-up were conducted using
MeOD-washed glassware.
A solution of 4 in Et2O (0.50 mL,
1.0 mmol) was stirred in a mixture of toluene (20.86 mL) and
MeOD (4.17 mL) under nitrogen for 5 h. The acid O-[2H1]-2b
(136 mg, 1.0 mmol) dissolved in MeOD (1.0 mL) was then added to
give a yellow solution. After stirring for 30 min at ambient temper-
ature, during which period there was nitrogen evolution and a gradual
dissipation of color, the reaction mixture was diluted with ether
(20 mL) and AcOH (10% aq, 10 mL) added. The aqueous phase was
extracted three times with diethyl ether and the combined organic
extractions washed with saturated aq Na2CO3 solution, dried
(MgSO4) and evaporated to give [2H3]-3b as a colorless solid
(138 mg, 92%). 1H NMR analysis indicated the ratio of [2Hn]-
3b/[2Hn]-5b of greater than 50/1 and that [2Hn]-3b comprised
90.6% [2H3]-3b, 7.9% [2H2]-3b, 1.3% [2H1]-3b, and < 0.2% 3b.
Received: May 15, 2007
Published online: August 9, 2007
ꢀ
ditions described therein, Ph2MeSi octane is completely inert.
[12] C. Eaborn, D. R. M. Walton, G. Seconi, J. Chem. Soc. Chem.
Commun. 1975, 937 – 939.
Keywords: diazo compounds · diazomethane · esterification ·
[13] For examples, see: a) D. G. Anderson, D. E. Webster, J. Chem.
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[14] R. Fessenden, F. J. Freenor, J. Org. Chem. 1961, 26, 1681 – 1682.
[15] M. Neeman, M. C. Caserio, J. D. Roberts, W. S. Johnson,
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[16] a) K. J. van der Merwe, P. S. Steyn, S. H. Eggers, Tetrahedron
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L. C. Haddad, J. S. Marhevka, Spectrochim. Acta Part B 1987, 42,
253 – 267.
.
isotopic labeling · reaction mechanisms
[1] a) D. Seyferth, H. Menzel, A. W. Dow, T. C. Flood, J. Am. Chem.
Soc. 1968, 90, 1080 – 1082; b) D. Seyferth, H. Menzel, A. W. Dow,
T. C. Flood, J. Organomet. Chem. 1972, 44, 279 – 290.
[2] a) M. F. Lappert, J. Lorberth, Chem. Commun. 1967, 836 – 837;
b) T. Shioiri, T. Aoyama, S. Mori, Org. Synth. 1993, 8, 612 – 615.
[3] For reviews of the use of 4, see: a) J. Podlech, J. Prakt. Chem./
Chem.-Ztg. 1998, 340, 679 – 682; b) T. Shioiri, T. Aoyama, Adv.
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