Volume 17 Number 3 March 2015 Pages 1321–1928
Green
Chemistry
Cutting-edge research for a greener sustainable future
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ISSN 1463-9262
COMMUNICATION
Hai Dong et al.
Zemplén transesterification: a name reaction that has misled us for
90 years
Green Chemistry
COMMUNICATION
Cite this: Green Chem., 2015, 17,
1390
Published on 24 November 2014. Downloaded on 12/03/2015 15:23:21.
Received 15th October 2014,
Accepted 21st November 2014
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Zemplén transesterification: a name reaction that
has misled us for 90 years†
Bo Ren,a Meiyan Wang,b Jingyao Liu,b Jiantao Ge,a Xiaoling Zhanga and Hai Dong*a
DOI: 10.1039/c4gc02006e
www.rsc.org/greenchem
We demonstrated that using NaOH and NaOMe in methanol for
deacylation are identical, indicating that the Zemplén condition
has been misleading us for almost 90 years. The traditional basecatalyzed mechanism cannot be used to explain our results. We
propose that H-bond complexes play key roles in the base-catalyzed process, explaining why deacylation in methanol can be
catalyzed by hydroxide.
Acyl groups are widely used as protecting groups in organic
synthesis strategies, particularly in carbohydrate chemistry.1
With the addition of acylation reagents under mild conditions,
the hydroxyl groups of substrates readily form esters as intermediate products, and the esters are easily removed under
Zemplén conditions when required.1,2 For almost 90 years, it
has been believed that the regular hydrolysis of an ester using
a base such as potassium hydroxide (KOH) or sodium hydroxide (NaOH) requires a stoichiometric amount of base for each
ester functional group, and it generates a large amount of potassium or sodium acetate, whereas Zemplén deacylation uses
only a catalytic amount of sodium methoxide (NaOMe).2 At
present, Zemplén deacylation, performed with a catalytic
amount of sodium methoxide in methanol, is a standard tool
in laboratories and industrial settings.1 Its inherent disadvantage is the retention of sodium ions in solution. Because the
sodium ions can be removed using H+-exchanged resin, industrial deacylation techniques generally involve ion-exchanged
columns. The H+-exchanged resin can be regenerated with acid
after ion exchange. This procedure would be omitted from deacylation in laboratories, and especially in industry settings,
a
School of Chemistry & Chemical Engineering, Huazhong University of Science &
Technology, Luoyu Road 1037, 430074 Wuhan, P.R. China.
E-mail: [email protected]; Fax: (+86) 27-87793242
b
Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and
Computational Chemistry, Jilin University, Liutiao Road 2, Changchun, 130023,
P. R. China
† Electronic supplementary information (ESI) available: General methods,
general method for measuring KIE values, Fig. S1–S6, computational methods,
and Cartesian coordinates, energies and results of frequency calculations. See
DOI: 10.1039/c4gc02006e
1390 | Green Chem., 2015, 17, 1390–1394
supposing that the reaction were catalyzed by a methoxyl
anion resin; at a first glance, it appears impossible due to the
difficulty of acquiring methoxyl anion resin. In 1981, Goodman’s group found that hydroxyl anion exchanged resin could
be used for the catalytic deacylation of sugars in methanol.3
They believed that the deacylation could be catalyzed by methoxyl anion, and the methoxyl anion could be generated by a
series of ion exchanges with the hydroxyl anion at the resin
surface. Despite its reported efficiency,4 this method has
unfortunately not been extensively adopted, possibly because
of the unconvincing explanation. In this study, we have proved
that the Zemplén condition had been misleading us for almost
90 years. We found that deacylation using a hydroxyl anion
base in methanol does not in fact require a stoichiometric
amount of base for each ester functional group. The results of
our experiments indicate that the use of NaOH in methanol is
identical to that of NaOMe in methanol for deacylation. The
development of the Zemplén condition was based on the traditional base-catalyzed mechanism, which cannot be used to
explain our results (Fig. 1a). Therefore, deacylation can be performed with a catalytic amount of hydroxyl anion resin, and
the resin can be repeatedly reused in the same process after
being simply filtered. These results cannot be explained by the
traditional base-catalyzed mechanism. We propose that the
H-bond complex play key roles in this base-catalyzed process
Fig. 1 (a) Traditional mechanism of deacylation catalyzed by a hydroxyl
anion. (b) Our proposed mechanism of deacylation catalyzed by an
H-bond complex.
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(Fig. 1b), supported by theoretical studies. An inverse kinetic
isotope effect (KIE) may give direct evidence to support the
H-bond-involved principle. Therefore, the traditional basecatalyzed principle in the textbook might be discarded.
We were surprised to find that the penta-acetyl glucosides
were completely deacetylated by 0.1 equiv. of NaOH in methanol. Indeed, only 0.02 equiv. of NaOH was used for each ester
functional group of the glucoside. At first, this result appeared
to be impossible due to the preconception that deacylation
with NaOH in methanol requires a stoichiometric amount of
base for each ester functional group, and it generates a large
amount of sodium acetate. To clarify this result, additional
experiments were conducted to compare the use of NaOH with
that of NaOMe; 0.1, 0.02 and 0.01 equiv. of each of the two
bases was used to deacetylate glucoside 1 (entries 1 and 2 in
Table 1). The free glucoses 2 were obtained in quantitative
yields in 0.5 h and 4 h with the use of 0.1 and 0.02 equiv.,
respectively, of either NaOH or NaOMe. When the amount of
either base was decreased by 0.01 equiv., the deacetylation of
glycoside 1 remained incomplete for a period of 24 h. These
results indicate that the use of NaOH in methanol is identical
to the use of NaOMe in methanol for the deacylation of glucoside 1. In the following experiments, various bases, including
KOH, sodium sulfide (Na2S), potassium sulfide (K2S), sodium
carbonate (Na2CO3), potassium carbonate (K2CO3), calcium
oxide (CaO) and magnesium oxide (MgO), were used as catalysts (entries 3–9 in Table 1). The deacetylation of 1 was completed in 0.5 h with 0.1 equiv. of KOH; in 1 h with 0.1 equiv. of
Na2S and K2S; in 4 h with 0.1 equiv. of Na2CO3 and K2CO3;
Table 1
basesa
Deacylation of penta-acetyl glucoside 1 catalyzed by various
Entry
Base
Amount (eq.)
Time/h
Yieldb
1
NaOMe
2
NaOH
3
4
5
6
7
8
9
10d
KOH
Na2S
K2S
Na2CO3
K2CO3
CaO
MgO
NaOMe
11d
NaOH
0.1
0.02
0.01
0.1
0.02
0.01
0.1
0.1
0.1
0.1
0.1
0.2
0.2
1/100
10/90
50/50
1/100
10/90
50/50
0.5
4
24
0.5
4
24
0.5
1
1
4
4
8
24
0.5
1
24
0.5
1
24
Quant.
Quant.
—c
Quant.
Quant.
—c
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
—c
Quant.
Quant.
—c
Quant.
Quant.
—c
a
Reagents and conditions: substrates (100 mg), MeOH (1 mL), rt.
NMR yield. c Uncompleted deacylation. d Bases (0.1 eq.), addition of
water (1–50%).
b
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and in 8 h with 0.2 equiv. of CaO. With 0.2 equiv. of MgO, the
deacetylation remained incomplete for a period of 24 h. These
results indicate that it is incorrect to assume that deacetylation
can only be catalyzed by the methoxyl anion in methanol. Dry
methanol has traditionally been used as the solvent on the
grounds that any water in the methanol will consume the
NaOMe, thereby preventing deacetylation. However, our experiments showed that water has little effect on the deacetylation
(entries 10 and 11 in Table 1). With 0.1 equiv. of NaOH or
NaOMe, the deacetylation of 1 was completed in 0.5 h and 1 h
when the methanol contained 1% and 10% of water, respectively.
The deacetylation achieved around 60% completion (observed
from TLC plate) even when the methanol contained 50% water.
In further experiments, various substrates, including pentaacetyl/benzoyl-galactosides 3, glucosides 5 and mannosides 6,
and methyl tetra-acetyl α-galactosides 8, α-glucosides 9,
β-galactosides 12, β-glucosides 13 and α-mannosides 16, were
deacylated in methanol using 0.1 equiv. of NaOH and NaOMe
separately. This showed that (Table 2), irrespective of whether
NaOH or NaOMe was used, the deacetylated free glycosides
were obtained from the acetylated substrates in quantitative
yields in 2–12 h. Additional experiments were conducted to
compare the use of NaOH and NaOMe in the deprotection of
benzyloxycarbonyl and pivaloyl groups. All of the deprotections
were completed in 2 h. In the case of the deacylation of acetylated thio-containing glycosides, slightly more than a stoichiometric amount of the base is necessary for each thioacetate
group because the sulfhydryl group formed will neutralize the
base. Therefore, 1.1 equiv. and 2.1 equiv. of NaOMe were used
in the deacetylation of penta-acetyl 1-thio-glucoside 20 and
methyl tetra-acetyl 2,4-dithio-glucoside 22, producing free thioglucosides in quantitative yields in 2 h, respectively. Testing
NaOH with these substrates gave the same results. The results
of all of these experiments indicate that the use of NaOH is
identical to that of NaOMe. As the effects on deacylation using
NaOH in methanol and NaOMe in methanol are identical, it is
reasonable that hydroxyl anion resin can be used in deacylation instead of NaOH. When hydroxyl anion resin was used in
the deacylation of each of the compounds 3, 5, 6, 8, 9, 12, 13,
16, 18 and 19, all of the deacylations were completed in
2–12 h. As hydroxyl anion resin is a catalyst, we hypothesized
that it should be reused repeatedly in this process without
time restrictions. To test this assumption, we used hydroxyl
anion resin (425 mg, 1 equiv. for the substrate but 0.2 eq. for
each of the acetyl groups) to deacetylate penta-acetyl glucoside
1 (100 mg) in 1 mL of methanol with stirring. The first
deacetylation was completed in 0.5 h. After filtration, the resin
was reused. The second deacetylation was completed in 1 h.
With repetition, the deacetylation extended the reaction time
to 2, 2.5, 3, 4 and 5 h, until the seventh deacetylation (a in
Fig. 2). We suspected that tiny chips of hydroxyl anion chipped
from the resin surface due to stirring had reduced the catalytic
activity of the resin. Therefore, stirring was avoided in the subsequent experiments, during which deacetylation extended the
reaction time from 0.5 to 2 h, with repetition until the 10th
deacetylation (b in Fig. 2), confirming our conjecture.
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Table 2
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Entry
Green Chemistry
Deacylation catalyzed by NaOMe, NaOH or −OH-resina
Substrate
Product
Yielde
1a,b
Quant
2a,b
Quant
3a,b
Quant
4a,b
Quant
Fig. 2 Deacetylation with the repeated reuse of a catalytic amount of
−
OH-exchange resin.
5a,b
Quant
6a,b
Quant
7a
Quant
8a
Quant
9c
Quant
10d
a
Quant
[a]
Reagents and conditions:
substrates (100 mg), NaOMe or NaOH
(0.1 eq.), MeOH (1 mL), rt.; [b] substrates (100 mg), hydroxyl anion
resin (85 mg/0.1 eq.), MeOH (1 mL), rt.; [c] substrates (100 mg), NaOMe
or NaOH (1.1 eq.), MeOH (1 mL), rt.; [d] substrates (100 mg), NaOMe or
NaOH (2.1 eq.), MeOH (1 mL), rt.; [e] NMR yield. Isolation yield >90%.
The process by which the hydroxyl anion catalyzes deacylation is of interest. According to the traditional base-catalysis
principle (Fig. 1a),2 there are only two possible reaction paths
(Fig. 3). One possibility is the reaction path proposed by
Goodman,3 which is shown in Fig. 3a: The hydroxyl anion first
deprotonates methanol to form a methoxyl anion, which is followed by deacylation catalyzed by the methoxide formed. If
this was the case, the addition of water should restrain the formation of the methoxyl anion so as to stop the reaction. Thus,
the experimental results of adding water (entries 10 and 11 in
1392 | Green Chem., 2015, 17, 1390–1394
Fig. 3 Proposed two possible transesterification paths catalyzed by
hydroxide, in light of the traditional base-catalysis principle.
Table 1) proved this path inefficient. The other possibility is
shown in Fig. 3b: deacylation could be catalyzed by the
hydroxyl anion to form an acetate anion, which is followed by
the esterification of methanol with the acetate anion. However,
because the esterification of methanol does not occur when
sodium acetate is dissolved in methanol, path b is also
excluded. The aforementioned analyses indicate that transesterification catalyzed by hydroxyl cannot be explained by the
traditional base-catalysis principle.
Recently, a principle that hydrogen bonds between hydroxyl
groups and acetate anions involve the constitution of the ratedetermining transition-state structure in pyridine-catalyzed
acetylation of hydroxyl groups has been widely accepted with
theoretical chemistry studies on the mechanism.5 In our previous studies, we had developed new and improved reaction
routes in which intermolecular non-covalent forces play key
roles.6–8 The mechanism studies also showed that the hydrogen bonds between hydroxyl groups and anions play key roles
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Fig. 4 Proposed transesterification paths catalyzed by −OH and MeO−
via the H-bond complex.
in the intramolecular acetyl group migration6 and in the regioselective acetylation catalyzed by acetate anions.8 These results
inspired us to propound that the H-bonds between hydroxyl
groups and anions must also play key roles in deacylation.
Only the principle involving H-bonds could perfectly explain
all of our experimental results obtained in this study. Thus,
during deacylation catalyzed by NaOMe, an H-bond complex
[MeOH⋯OMe]− may be instantly formed when a catalytic
amount of NaOMe is dissolved in methanol without considering the solvation (a in Fig. 4). The acetyl group is then transformed into methoxide through transition state a. During
deacylation catalyzed by NaOH, an H-bond complex
[MeOH⋯OH]− may be instantly formed (b in Fig. 4). Thus, it
has to be hypothesized that the energy barrier of transition
state b is lower than that of transition state c such that the
acetyl group can be transformed into methoxide through transition state b; otherwise, the acetyl group would be transformed into hydroxide through transition state c to restrain
the catalytic process. To support this hypothesis, theoretical
calculations were performed (Fig. S7†). To simplify the calculation, the deacetylations of ethyl acetate catalyzed by methoxide and hydroxide in methanol were used as models for DFT
calculations without considering the solvation. The energy
barrier of ethyl acetate with [MeO⋯H⋯OMe]− for transesterification is 19.9 kcal mol−1 (Fig. 4a). The process with
[MeO⋯H⋯OH]− involves two pathways with energy barriers of
18.4 and 21.1 kcal mol−1, giving the former process preference
(Fig. 4b).
It is known that an inverse secondary isotope effect would
occur when the bending vibration of OH bonds in a transition
state become more restricted.9 Clearly, the bending vibration
of OH bonds in transition states a and b, which are the ratedetermining transition-state structures (Fig. 4), become more
This journal is © The Royal Society of Chemistry 2015
Communication
restricted due to the involvement of H-bond; thus, leading to
inverse secondary isotope effects. Therefore, an inverse kinetic
isotope effect (KIE) may give direct evidences to support the Hbond-involved principle. We chose two simple molecules, ethyl
benzoate and phenylmethyl acetate, as models, and measured
their KIE values through the measurement of their rate constants for deacylation catalyzed separately by NaOH and
NaOMe in normal methanol and d-methanol (Fig. S1–S4†). For
both of the model molecules, the measured KIE values (kH/kD)
were less than 0.5 (Fig. S3 and S4†), irrespective of whether
NaOH or NaOMe was used, showing inverse secondary isotope
effects. The 1H NMR spectrum of deacylation catalyzed by
NaOH showed only the esters that functioned as starting
materials (ethyl benzoate and phenylmethyl acetate), the esters
formed by transesterification (methyl benzoate and methyl
acetate) and the alcohols produced (ethanol and phenylmethanol) (Fig. S5 and S6†). It could be observed that no acids
were formed by the hydrolysis, indicating that the outcomes of
the transesterifications were identical to those of NaOMe-catalyzed deacylation.
In this study, all of the yields reported were based on the
NMR analysis. To demonstrate the potential for industry,
penta-acetyl-glucoside 1 (10 g) were deacylated in methanol
(100 mL) using 0.1 equiv. of NaOH (105 mg), KOH (144 mg)
and hydroxyl anion resin (8.5 g) separately. After stirring at
room temperature for 2 h (experiments shown in detail in
ESI†), the free glucoses 2 were obtained in 92% (4.24 g), 97%
(4.48 g) and 89% (4.1 g) isolation yields, respectively.
Conclusions
We have shown that using NaOH and NaOMe in methanol for
deacylation are identical. This indicates that the Zemplén condition has been misleading us for almost 90 years, and methoxide can be completely replaced by hydroxide in the
deacylation. The traditional base-catalyzed mechanism cannot
be used to explain our results. We proposed that H-bonds play
key roles in this base-catalyzed process. Both kinetic isotope
effect (KIE) studies and theoretical calculations may support
this principle. Therefore, hydroxyl anion-exchanged resin as a
catalyst is used in deacylation instead of NaOMe or NaOH,
which is fully supported by theory. The resin can be repeatedly
reused in the same process without additional treatment. We
believe that the application of the hydroxyl anion in deacylation has great theoretical and practical significance in both
laboratory and industrial settings. With the use of the hydroxyl
anion resin in industry, the H+-exchange columns in deacylation may be reduced, and substantial savings may be made in
terms of equipment, materials and operations.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (nos. 21272083). The authors are also
Green Chem., 2015, 17, 1390–1394 | 1393
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grateful to Dr Shitao Fu in the Analytical and Test Center of
School of Chemistry and Chemical Engineering for his
support with the NMR instrument.
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