Direct participation of counter anion in acid hydrolysis of glycoside

Article abstract of DOI:10.1039/c2ob25451d

The mechanism of acid hydrolysis of glycoside has been investigated since the end of the 19th century accompanied by lots of literatures published on the mechanism, although little attention has surprisingly been paid to the action of counter anion of acid. In this paper, it was investigated whether or not counter anion of acid directly participates in acid hydrolysis of glycosides, methyl α- and β-d-glucopyranosides (MGP) in water, aqueous 74%, and 82% 1,4-dioxane systems. Because proton activity of a reaction system is the important rate-determining parameter in the universally acknowledged mechanism, it was carefully estimated in this study. The results suggested that bromide anion directly participates in the acid hydrolysis reaction of MGP in a water solvent system and the participation of bromide anion is further pronounced in aqueous 74% and 82% 1,4-dioxane solvent systems. It was also suggested that chloride anion directly participates in these dioxane solvent systems.

Full text of DOI:10.1039/c2ob25451d

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PAPER
Direct participation of counter anion in acid hydrolysis of glycoside†
Hung Duy Phan, Tomoya Yokoyama* and Yuji Matsumoto
Received 1st March 2012, Accepted 10th July 2012
DOI: 10.1039/c2ob25451d
The mechanism of acid hydrolysis of glycoside has been investigated since the end of the 19th century
accompanied by lots of literatures published on the mechanism, although little attention has surprisingly
been paid to the action of counter anion of acid. In this paper, it was investigated whether or not counter
anion of acid directly participates in acid hydrolysis of glycosides, methyl α- and β-D-glucopyranosides
(MGP) in water, aqueous 74%, and 82% 1,4-dioxane systems. Because proton activity of a reaction
system is the important rate-determining parameter in the universally acknowledged mechanism, it was
carefully estimated in this study. The results suggested that bromide anion directly participates in the acid
hydrolysis reaction of MGP in a water solvent system and the participation of bromide anion is further
pronounced in aqueous 74% and 82% 1,4-dioxane solvent systems. It was also suggested that chloride
anion directly participates in these dioxane solvent systems.
Introduction
Acid hydrolysis of glycoside has been investigated since the end
of the 19th century, especially focusing on the mechanism and
effect of the structure on the rate.1–28 The mechanism has been
established and universally acknowledged at least for most gly-
copyranosides, as shown in Scheme 1. The first step is protona-
tion of the exocyclic oxygen of the glycosidic bond affording
the conjugate acid, and rapidly attains equilibrium. The conju-
gate acid liberates the aglycon to afford the cyclic cation. This
second step is the slowest and rate-determining. Only the conju-
gate acid can advance to the rate-determining step. Owing to
these mechanisms, acid hydrolysis of glycoside shows character-
istics of specific acid catalysis.3,5,7 The water addition and con-
secutive release of a proton afford the hydrolysis product.
It is believed that water does not steadily assist the release of
the aglycon,7,9 and hence, the discrete cyclic cation forms.
Consequently, the reaction is apparently unimolecular and
shows characteristics of SN1-type substitution reaction
(A1 mechanism).9 On the basis of these characteristics, concen-
tration of glycoside and proton activity, viz. only concentration
of the conjugate acid of glycoside, are the only practical rate-
determining parameters in acid hydrolysis of glycoside.
Solvent dissociating power and temperature are the other
Scheme 1 The universally acknowledged mechanism of acid hydroly-
sis reaction of glycoside. A glycoside compound, methyl α-D-glucopyra-
noside (MGPα), is representatively described.
rate-determining parameters, although the power is referred to
only when reactions are compared between different solvent
systems.
When a chemical reaction using various acids is concerned,
the counter anions are always potential species to influence the
reaction. However as described above, it is generally accepted
that proton activity is the only practical rate-determining para-
meter in acid hydrolysis of glycoside. On the basis of this
general acceptance, counter anion can influence acid hydrolysis
of glycoside only indirectly via its interaction with proton
Laboratory of Wood Chemistry, Department of Biomaterial Sciences,
Graduate School of Agricultural and Life Sciences, The University of
Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
E-mail: yokoyama@woodchem.fp.a.u-tokyo.ac.jp;
Fax: +81-3-5841-2678; Tel: +81-3-5841-5264
†Electronic supplementary information (ESI) available: Figures of
the same kind as Fig. 1 and 2 for the other systems. See DOI:
10.1039/c2ob25451d
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Table 1 List of all the reaction systems employed in this studya
Solvent: H2O (0% 1,4-dioxane)
HCl
HBr
H2SO4
CH3SO3H
MGPb
Pinacol
BnAni
Donec
Done
Done
Not done
Done
Done
Not done
Not done
Not done
Done
Done
Not doned
Solvent: aqueous 74% 1,4-dioxane
HCl
HBr
H2SO4
CH3SO3H
MGP
Pinacol
BnAni
Done
Done
Not done
Done
Done
Not done
Done
Done
Not done
Not done
Done
Done
Fig. 1 Structure of model compounds used as starting materials.
affecting the strength of proton activity, although some counter
anions have relatively strong nucleophilicity and others do not.
These backgrounds have motivated us to confirm whether or not
counter anions are certainly inert in acid hydrolysis of glycoside.
It is surprising, furthermore, that only a few researches have
focused on the role of counter anion. Painter ruled out the possi-
bility of the direct participation of counter anions in acid
hydrolysis reaction of glycosides, methyl α- and β-D-glucopyra-
nosides (MGPα, MGPβ), although the possibility seemed to be
suspectedly remained for bromide anion in the hydrolysis of
MGPβ.14 Zaranyika et al. and Charmot et al. discussed on the
role of counter anion in acid hydrolysis of polysaccharide with
crystalline structure18,19 and on catalytic action of dihydrogen-
phosphate,28 respectively. Only these papers currently seem to
focus on the role of counter anion in acid hydrolysis of glyco-
side. Therefore, we decided to examine the effect of counter
anion on acid hydrolysis of glycoside using MGPα and MGPβ,
although it was suggested that the mechanism of MGPβ might
possibly differ from that of MGPα.14,26
Solvent: aqueous 82% 1,4-dioxane
HCl
HBr
H2SO4
CH3SO3H
MGP
Pinacol
BnAni
Done
Done
Not done
Done
Done
Not done
Done
Done
Not done
Not done
Done
Done
a Concentration of the acids and temperature were 0.20 mol l−1 and
85 °C in all systems employed. b Pair of MGPα and MGPβ. c Reaction
was done. d Reaction was not done.
In this study, a pair of MGPα and MGPβ was hydrolyzed in
hydrochloric, hydrobromic, or sulfuric acid solution, and their
disappearances were examined in detail to understand the role of
counter anion in acid hydrolysis of glycoside. Other solvent
systems using aqueous 74% and 82% 1,4-dioxane solutions were
also applied to examine the effect of solvent constitution on the
action of counter anion. Proton activity of an acid hydrolysis
reaction system relative to that of another system was carefully
estimated in this study.
Chemical structures of the compounds used as starting
materials are shown in Fig. 1. MGPα, MGPβ, 2,3-dimethyl-
butane-2,3-diol (pinacol), and N-benzyl aniline (BnAni) were
applied to starting compounds. All kinds of reactions employed
in this study are summarized in Table 1.
Fig. 2 Actual experimental data points observed when a pair of MGPα
and MGPβ was acid-hydrolyzed in the H2O solvent systems, and the
best fit curves obtained from these data points of each reaction. The
hydrolysis with HCl, HBr, or H2SO4 was repeated 5, 3, or 5 times,
respectively.
required to draw disappearance curves of the compounds that
exactly fitted to experimental data points of each of the reaction
systems. Fig. 2 representatively displays experimental data points
and the disappearance curves that fit best to these points, when a
pair of MGPα and MGPβ was treated in the H2O solvent
systems. (See ESI† on the other systems.) Each of the curves
was hand-drawn. The hand-drawn curves always seemed to fit to
the experimental data points better than those prepared by com-
putational approximations. This was because several experimen-
tal data points could fuzzily be judged as those with significant
deviations caused by experimental error in the hand-drawing.
Results and discussion
Method for obtaining appropriate pseudo-first-order reaction
rate constant
In this study, each of a pair of MGPα and MGPβ, pinacol, or
BnAni was acid hydrolyzed, and their disappearance behaviours
were kinetically examined to discuss the effect of counter anion
on the hydrolysis rates. Because the difference in the hydrolysis
rates between some reaction systems was often small, it was
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Table 2 List of coefficients of determination (R2) for the hand-drawn
curvesa
Solvent: H2O (0% 1,4-dioxane)
HCl
HBr
H2SO4
CH3SO3H
MGPα
MGPβ
Pinacol
BnAni
0.987
0.996
0.985
0.995
0.994
Not done
0.980
0.992
0.991
Not done
Not done
Not done
Not done
0.994
0.995
Not doneb
Solvent: aqueous 74% 1,4-dioxane
HCl
HBr
H2SO4
CH3SO3H
MGPα
MGPβ
Pinacol
BnAni
0.997
0.998
0.981
Not done
0.996
0.997
0.990
Not done
0.996
0.999
0.993
Not done
Not done
Not done
0.993
0.997
Fig. 3 Representative logarithmic plots for the disappearances of
MGPα and MGPβ in the H2O solvent systems. [MGP]: concentration of
MGPα or MGPβ, [MGP]0: initial concentration of MGPα or MGPβ.
Solvent: aqueous 82% 1,4-dioxane
HCl
HBr
H2SO4
CH3SO3H
Table 3 List of pseudo-first-order reaction rate constants (kobs
)
MGPα
MGPβ
Pinacol
BnAni
0.997
0.993
0.995
Not done
0.998
0.999
0.997
Not done
0.993
0.998
0.998
Not done
Not done
Not done
0.992
obtained from acid hydrolysis reactions of MGPa
Solvent: H2O (0% 1,4-dioxane)
0.999
a Concentration of the acids and temperature were 0.20 mol l−1 and
85 °C in all systems employed. b Reaction was not done.
HCl
HBr
H2SO4
α, β
MGPα
3.37
0.997
MGPβ
6.22
0.999
MGPα
4.04
1.00
MGPβ
7.41
1.00
MGPα
3.26
MGPβ
6.29
0.999
b
kobs
R2 c
1.00
On the other hand, computational approximations treated all the
experimental data points equally to draw a curve even when
some of the data points were largely deviant. Indeed, the curves
obtained by computation were almost the same with the hand-
drawn curves when these curves were prepared after deleting the
data points that were judged as those with significant deviations
in the hand-drawing. As a reference, the coefficients of determi-
nation for the hand-drawn curves are listed in Table 2. Most of
the coefficients were more than 0.990. Even the worst one was
0.980. These results ensured the appropriateness of the hand-
drawn best fit curves.
Several data points on each of the best-fit curves were utilized
for preparation of the logarithmic plot for the disappearance of
the starting compound, which gave a pseudo-first-order reaction
rate constant. Fig. 3 shows the representative logarithmic plots
for the hydrolyses of a pair of MGPα and MGPβ in the H2O
solvent systems. (See ESI† on the other systems.)
Solvent: aqueous 74% 1,4-dioxane
HCl
HBr
H2SO4
α, β
kobs
R2
MGPα
12.3
0.998
MGPβ
24.7
0.999
MGPα
14.2
0.999
MGPβ
25.1
0.991
MGPα
7.69
MGPβ
14.7
1.00
0.999
Solvent: aqueous 82% 1,4-dioxane
HCl
HBr
H2SO4
α, β
kobs
R2
MGPα
35.5
0.998
MGPβ
63.8
1.00
MGPα
48.6
0.996
MGPβ
85.1
0.988
MGPα
16.6
MGPβ
34.6
0.997
0.999
a Concentration of the acids and temperature were 0.20 mol l−1 and
85 °C in all systems employed. b Unit: ×10−2 h−1 c Square of correlation
.
coefficient.
therefore, that D-glucose was the sole reaction product in all reac-
tion systems employed, although it was not quantified.
General description of acid hydrolysis
The disappearance curves of pinacol and BnAni in all the
reaction systems employed could be approximated to pseudo-
first-order reactions with the correlation coefficients very close to
unity, with the exceptions of several systems (Tables 5 and 7,
respectively). Almost no compounds other than 3,3-dimethyl-
butan-2-one (pinacolone in Scheme 2) and benzyl alcohol +
aniline (Scheme 3) were detected as reaction products in the
pinacol and BnAni reactions, respectively. Several minor reaction
products other than pinacolone were detected in the pinacol reac-
tions in the aqueous 1,4-dioxane solvent systems. It is rational to
The disappearance curves of MGPα and MGPβ in all the reac-
tion systems could be approximated to pseudo-first-order reac-
tions with the correlation coefficients very close to unity, with
the exceptions of several systems (Table 3). MGPα was always
hydrolyzed slower than MGPβ in all cases (Table 3), which is in
accordance with previous findings.11 In the following text, the
term MGP indicates both MGPα and MGPβ. No compounds
other than D-glucose were detected as degradation products in
any reaction system employed. It is rational to presume,
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conjugate acid of 4-nitroaniline in the acid 0%, aqueous 74%,
and aqueous 82% 1,4-dioxane solutions containing 72% H2SO4.
It is assumed that the existence of the conjugate acid of 4-nitro-
aniline and 4-nitroaniline itself can be ignored in the neutral
solutions and the acid solutions containing 72% H2SO4, respecti-
vely. On the basis of An, Aa, and observed Asystem, the proportion
of 4-nitroaniline applied to the UV measurement that is present
as its conjugate acid can be calculated using the following
equation: Conjugate acid (%) = (An − Asystem)/(An − Aa) × 100.
As can be recognized from the values of An and Aa, the value of
Asystem observed in a system becomes smaller with the increase
in proton activity of the system. Proton activity of a reaction
system employed can be compared with that in another
employed reaction system on the basis of the values of Asystem in
these systems. However, proton activity observed by this method
should not be compared between systems with different content
of 1,4-dioxane but between those with the same content of
1,4-dioxane.
Scheme 2 The universally acknowledged mechanism of the pinacol
rearrangement.
Proton activity should also be estimated at 85 °C, which was
employed in the acid hydrolysis reactions of MGP, because
proton activity of a system at room temperature must be different
from that at an elevated temperature. To estimate proton activity
at 85 °C, it should be appropriate to compare the rates of a stan-
dard chemical reaction between the employed reaction systems
because it is difficult to measure stably the UV absorbance at
85 °C. It is prerequisite for this standard chemical reaction,
however, that its mechanism shows characteristics of specific
acid catalysis and SN1-type substitution reaction without partici-
pation or assistance of any nucleophile (A1 mechanism). If these
prerequisites are not satisfied, not only proton activity but also
concentration of possible nucleophiles can be a rate-determining
parameter, and consequently, proton activity cannot be estimated.
The pinacol rearrangement (conversion of pinacol to pinacolone
under acidic conditions) seemed to satisfy these prerequisites
and was applied to the standard chemical reaction. The mechan-
ism of the pinacol rearrangement is shown in Scheme 2. Protona-
tion of the oxygen of a hydroxyl group and subsequent release
of the H2O molecule afford the tertiary carbocation. A methyl
anion on the other tertiary carbon migrates to the cation center,
and consecutive release of the proton affords pinacolone. The
discrete tertiary carbocation is believed to form without any
assistance of the methyl anion migration to release the H2O mo-
lecule.29 Because only the conjugate acid of pinacol can advance
to the rate-determining step, the release of the H2O molecule, the
pinacol rearrangement shows characteristics of specific acid cata-
lysis, and hence, concentration of pinacol and proton activity,
viz. concentration of the conjugate acid of pinacol, are the only
practical rate-determining parameters. Furthermore, counter
anion and solvent cannot participate in the reaction owing to
the large steric hindrance of the reaction center of pinacol. On
the basis of these reaction characteristics, proton activity of the
employed reaction systems was estimated from the disappearance
rates of pinacol in the pinacol rearrangement under conditions
identical to those of the acid hydrolysis reaction of MGP.
Scheme 3 Estimated mechanism of acid hydrolysis reaction of BnAni.
presume, however, that pinacolone was almost the sole reaction
product in the pinacol reaction, and benzyl alcohol and aniline
were the only products in the BnAni reaction in all reaction
systems employed, although these compounds were not
quantified.
There are four rate-determining parameters in the acid
hydrolysis reactions employed in this study: proton activity, con-
centration of compound, solvent dissociating power, and temp-
erature. Because all of the hydrolysis reactions could be
approximated to pseudo-first-order reactions, concentration of
compound is not focused on in the following text. Temperature
is not referred to in the following text, since all the hydrolysis
reactions were conducted at 85 °C. Solvent dissociating power is
discussed only when the acid hydrolysis reactions in different
solvent systems are compared. Because of these factors, proton
activity is mainly discussed in the following text.
Theory for estimation of relative proton activity
Measurement of the Hammett acidity function is a common way
to estimate proton activity of a reaction system. Hence, proton
activity of the reaction systems employed was estimated from the
UV absorbances of 4-nitroaniline at 380, 372, or 370 nm
(Asystem) when it was dissolved in the reaction systems with the
0% (H2O), aqueous 74%, or aqueous 82% 1,4-dioxane solution,
respectively, at room temperature. The values of An are defined
as the UV absorbances of 4-nitroaniline in the neutral 0%,
aqueous 74%, and aqueous 82% 1,4-dioxane solutions. The
values of Aa are similarly defined as the UV absorbances of the
Effect of counter anion in water
Pseudo-first-order reaction rate constants obtained from the acid
hydrolysis of MGP are listed in Table 3. In the H2O solvent
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Table 4 List of UV absorbances of 4-nitroaniline (98 mg l−1
measured at room temperature and proportion of its conjugate acid (CA)
present
)
Table 5 List of pseudo-first-order reaction rate constants (kobs)
obtained from the pinacol rearrangementa
Solvent: H2O (0% 1,4-dioxane)
Solvent: H2O (0% 1,4-dioxane)
HCl
10.3
HBr
10.4
H2SO4
Condition
An or Aa
Neutral
0.937
Acid (72% H2SO4)
0.000
b
kobs
R2 c
10.5
0.985
0.993
0.999
Acida
Asystem
HCl
0.258
72.5
0.57 (ca. 0.65)
HBr
0.261
72.1
H2SO4
0.266
71.6
0.59 (ca. 0.55)
b
Solvent: aqueous 74% 1,4-dioxane
CA (%)
c
H0
0.58 (ca. 0.65)
HCl
HBr
H2SO4
CH3SO3H
Solvent: aqueous 74% 1,4-dioxane
kobs
R2
2.35
0.991
3.21
0.996
3.47
0.997
2.72
0.998
Condition
An or Aa
Neutral
1.088
Acid (72% H2SO4)
0.000
Solvent: aqueous 82% 1,4-dioxane
Acid
Asystem
CA (%)
HCl
0.969
10.9
HBr
0.954
12.3
H2SO4
0.972
10.7
HCl
HBr
H2SO4
CH3SO3H
kobs
R2
3.67
0.966
7.26
0.996
6.31
0.999
2.89
1.00
Solvent: aqueous 82% 1,4-dioxane
a Concentration of the acids and temperature were 0.20 mol l−1 and
85 °C in all systems employed. b Unit: ×10−2 h−1 c Square of correlation
.
Condition
Neutral
1.101
Acid (72% H2SO4)
−0.016
coefficient.
An or Aa
Acid
Asystem
CA (%)
HCl
0.947
13.8
HBr
0.947
13.8
H2SO4
0.975
11.3
slightly larger than AHCl-0, although there were no noticeable
differences between AHCl-0, AHBr-0, and AH SO -0. These values
suggest that proton activities of three acid reaction systems are
not different at least at room temperature in the H2O solvent
systems.
a Concentration of the acids were 0.20 mol l−1
.
b Asystem: AHCl-0, AHBr-0
,
c H0:
2
4
A
H SO -0, AHCl-74, AHBr-74, AH SO -74, AHCl-82, AHBr-82, or AH SO -82
.
2
4
2
4
2
4
The Hammett acidity functions were calculated on the basis of CA and
the pKa value of 4-nitroaniline (0.99). The values in the parentheses are
those estimated from the data in the ref. 30.
Table 5 lists pseudo-first-order reaction rate constants obtained
from the pinacol rearrangement in the reaction systems
employed. Proton activity at 85 °C can be estimated from this
rate constant as described in the previous section. The rate con-
stants in three acid systems are not different from one another
(Table 5). It is suggested, therefore, that proton activities of three
acid reaction systems are not different even under conditions of
the actual hydrolysis reaction of MGP in the H2O solvent
systems.
Because proton activity of the H2O solvent systems with three
acids is not found to be different, it is proposed that Br− directly
participates in the hydrolysis reaction of MGP. A possible par-
ticipation mechanism is that Br− assists the CH3OH liberation in
Scheme 1 from the opposite side, which is similar to SN2-type
substitution reaction. Another possible mechanism is that Br−
assists the α-D-glucopyranose liberation attacking the CH3
carbon of the aglycon of the cyclic cation from the opposite
side. Since Br− is not lost and the concentration of Br− is not
changed in either mechanism, the acid hydrolysis reaction of
MGP follows the pseudo-first-order reaction rate law even when
Br− participates in the hydrolysis reaction. It is a further research
topic to examine possibilities of these mechanisms utilizing a
glycoside compound with an aglycon sterically bulkier than CH3
group.
systems, the rate constant of MGP in the HCl system is almost
the same as that in the H2SO4 system. This result suggests that
proton activity of these systems is the same and a molecule of
H2SO4 releases only one proton. The hydrolysis of MGP was
slightly but clearly more rapid in the HBr system than those in
the other two acid systems, although the concentrations of these
three acids were the same. The rate constants of both MGPα and
MGPβ in the HBr system are about 1.2 times as large as those in
the HCl and H2SO4 systems. Proton activity is the only practical
rate-determining parameter on the basis of Scheme 1. Hence,
proton activity of the HBr system is possibly higher than those
of the other two acid systems. Alternatively, it may be suggested
that Br− directly participates in the hydrolysis of MGP, if the
proton activities of the HCl and HBr systems are not different. It
is required to estimate proton activity of three acid systems.
Table 4 lists UV absorbances of 4-nitroaniline at 380, 372, or
370 nm (Asystem) in the 0% (H2O), aqueous 74%, or aqueous
82% 1,4-dioxane solvent systems, respectively, and the pro-
portions of 4-nitroaniline applied to the UV measurement that
was present as its conjugate acid when 4-nitroaniline was dis-
solved in each of the reaction systems employed. The Hammett
acidity functions (H0) in the H2O systems of this study are indi-
cated in Table 4 with those estimated from the data in the litera-
ture.30 Proton activity of the reaction systems at room
temperature can be estimated from Asystem, as described in the
previous section. In the H2O solvent systems, An and Aa were
0.937 and 0.000, respectively. As can be seen, AHBr-0 was
The results obtained cannot completely rule out the possibility
that the faster hydrolysis of MGP in the HBr system might result
from its possibly higher solvent dissociating power than those in
the other two acid systems. If this is the case, Br− indirectly par-
ticipates in the reaction. This possibility seems to be doubtful,
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however, because the powers of the HCl and H2SO4 systems
should not be different from each other based on the hydrolysis
rates in these systems. Although there might be other possible
mechanisms for explaining the faster hydrolysis of MGP in the
HBr system, the direct participation of Br− should be the most
plausible.
this is the case, the assumption of complete absence of the
nucleophile participation in the pinacol rearrangement is valid
only in the H2O solvent systems.
In spite of the suggested highest proton activity in the H2SO4
system, the hydrolysis of MGP in this system was slower than
those in the other two acid systems. This result strongly suggests
that not only Br− but also Cl− directly participates in the
hydrolysis reaction of MGP in the aqueous 74% 1,4-dioxane
solvent systems. Possible mechanisms must be similar to those
proposed in the previous section. Because it was suggested that
the acid hydrolysis mechanism of glycopyranosides is not exo-
cyclic cleavage (Scheme 1) but mainly endocyclic anomeric
C–O bond cleavage under anhydrous conditions with the pres-
ence of a Lewis acid,13,16,20,22,24 however, other possible mech-
anisms, such as attack on the anomeric carbon from the direction
opposite from the endocyclic anomeric C–O bond, may be pro-
posed. The rate constant of MGP in the HBr system is about
1.7–1.8 times as large as that in the H2SO4 system, although
proton activity of the H2SO4 system must be higher than that of
the HBr system. This ratio is about 1.2 in the H2O solvent
system. The participation of Br− and Cl− should be more signifi-
cant in the aqueous 74% 1,4-dioxane solvent systems than that
of Br− in the H2O solvent system. The slightly faster hydrolysis
of MGP in the HBr system than in the HCl system may result
from either or both of higher proton activity in the former than
in the latter system, as suggested above, and more active partici-
pation of Br− in the hydrolysis reaction of MGP than Cl−.
It should be shown that the molar ratio of 1,4-dioxane to H2O
in aqueous 74% 1,4-dioxane solution (v/v) is about 0.6.
Effect of counter anion in aqueous 74% 1,4-dioxane
In the aqueous 74% 1,4-dioxane solvent systems, the rate con-
stants of the hydrolysis reactions of MGP in the HCl and HBr
systems are larger than that in the H2SO4 system (Table 3). The
rate constant in the HCl system is slightly smaller than that in the
HBr system. These results may suggest the direct participation of
not only Br− but also Cl− in the hydrolysis reaction of MGP. To
confirm this possibility, proton activity of three acid systems
should be estimated.
The maximal absorption wavelength of 4-nitroaniline was
372 nm in the aqueous 74% 1,4-dioxane solutions, and the
values of An and Aa were 1.088 and 0.000, respectively.
The value of AHCl-74 was not different from AH SO -74, although
2
4
AHBr-74 was slightly smaller than the other two (Table 4). These
results suggest that proton activity of the HCl system is not
different from that of the H2SO4 system at least at room tempera-
ture, although proton activity of the HBr system may be slightly
higher than those of the other two acid systems.
The rate constants of the pinacol rearrangement obtained from
the aqueous 74% 1,4-dioxane solvent systems with three acids
are not significantly different from one another, but decrease in
the order of: H2SO4 > HBr > HCl (Table 5). It should be
focused on that the rate in the H2SO4 system is greater than
those in the other two acid systems. It seems clear that nucleo-
Effect of counter anion in aqueous 82% 1,4-dioxane
−
−
philicity of HSO4 (and SO42−) is very low and HSO4 (and
SO42−) does not directly participate in the sterically largely hin-
dered pinacol rearrangement. Solvent dissociating power of three
acid systems should not either be considered to be different. A
possible explanation for the faster pinacol rearrangement in the
In the aqueous 82% 1,4-dioxane solvent systems, the rate con-
stants for the hydrolysis reactions of MGP decrease in the order
of: HBr > HCl > H2SO4 (Table 3). A fairly large difference was
observed not only between the H2SO4 and the other two acid
systems but also between the HCl and HBr systems, which is not
the same as for those observed in the aqueous 74% 1,4-dioxane
solvent systems. Similar to the aqueous 74% 1,4-dioxane solvent
systems, it is suggested that not only Br− but also Cl− directly
participates in the hydrolysis reaction of MGP and the former is
more active than the latter. To confirm this, proton activity of
three acid systems must be estimated.
−
2−
H2SO4 system is that HSO4 further dissociates to SO4 in the
aqueous 74% 1,4-dioxane solvent system at 85 °C, which makes
proton activity of the H2SO4 system higher than those of the
other two acid systems, although this phenomenon does not
seem to appear at room temperature on the basis of the compari-
son of the UV absorbances of 4-nitroaniline between three acid
systems. To confirm this phenomenon, the rate of the pinacol
rearrangement in another acid system, 0.2 mol l−1 CH3SO3H in
the aqueous 74% dioxane solution, was examined. The rate con-
stant is smaller than that in the H2SO4 system and between those
in the HCl and HBr systems (Table 5). This result should
confirm that some H2SO4 molecules release two protons in the
aqueous 74% 1,4-dioxane solvent system at 85 °C. The higher
proton activity of the H2SO4 system must result in the fast
pinacol rearrangement. The rate difference between the HCl and
HBr systems probably results from the difference in proton
activity between these two systems as suggested by the above
UV absorbances. It may be possible that Br− directly participates
in the pinacol rearrangement in the aqueous 74% 1,4-dioxane
solvent system to a very small extent even though no nucleophile
has been assumed to participate in the pinacol rearrangement. If
The maximal absorption wavelength of 4-nitroaniline was
370 nm in the aqueous 82% 1,4-dioxane solutions, and the
values of An and Aa were 1.101 and −0.016, respectively. As
shown in Table 4, AHCl-82 was the same as AHBr-82, and AH SO -82
2
4
was larger than the other two. These results suggest that proton
activity of the H2SO4 system is lower than those of the other two
acid systems at least at room temperature. Because the low
proton activity of the H2SO4 system possibly resulted in the
slowest hydrolysis reaction of MGP, proton activity should also
be estimated at 85 °C from the rate of the pinacol rearrangement.
The rate constant of the pinacol rearrangement in the HCl
system is smaller than those in the other two acid systems
(Table 5). The rate constant in the HBr system is slightly larger
than that in the H2SO4 system (Table 5). The reason for the fast
pinacol rearrangement in the H2SO4 system can be attributed to
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Table 6 List of ratio of the rate constant for the hydrolysis reaction of
MGPβ to MGPαa
the high proton activity of this system, which could be
confirmed, similarly to the aqueous 74% 1,4-dioxane solvent
system, by the slow pinacol rearrangement in the 82% 1,4-
dioxane solvent system with 0.2 mol l−1 CH3SO3H. Similarly to
the 74% 1,4-dioxane solvent systems, there are two possible
explanations for the observation that the pinacol rearrangement
is faster in the HBr than in the HCl system. Proton activity of the
HBr system is higher than that of the HCl system and/or Br−
directly participates in the pinacol rearrangement in the aqueous
82% 1,4-dioxane solvent systems. The latter may be more plaus-
ible owing to the fact that the difference in the rates of the
pinacol rearrangement between the HBr and HCl systems is
larger in the 82% aqueous 1,4-dioxane solvent systems than that
in the 74% systems.
Because the hydrolysis of MGP was much slower in the
H2SO4 system than those in the other two acid systems despite
the higher proton activity in the former system at 85 °C, it is
strongly suggested that not only Br− but also Cl− directly partici-
pates in the hydrolysis reaction of MGP. Br− may participate
more actively than Cl−. Possible participation mechanisms are
the same as those described in the previous section. The rate
constants in the HBr system are about 2.5–2.9 times as large as
those in the H2SO4 system, although proton activity of the
H2SO4 system should be higher than that of the HBr system.
These ratios are about 1.2 and 1.7–1.8 in the H2O and the
aqueous 74% 1,4-dioxane solvent systems, respectively. The par-
ticipation of not only Br− but also Cl− should be more signifi-
cant in the aqueous 82% 1,4-dioxane solvent systems than that
in the H2O and the aqueous 74% 1,4-dioxane solvent systems.
It should be shown that the molar ratio of 1,4-dioxane to H2O
in aqueous 82% 1,4-dioxane solution (v/v) is about 1.0.
Solvent: H2O (0% 1,4-dioxane)
HCl
1.85
HBr
1.83
H2SO4
1.99
Ratio
Solvent: aqueous 74% 1,4-dioxane
HCl
HBr
1.77
H2SO4
1.91
Ratio
2.08
Solvent: aqueous 82% 1,4-dioxane
HCl
HBr
1.75
H2SO4
2.08
Ratio
1.80
a Concentration of the acids and temperature were 0.20 mol l−1 and
85 °C in all systems employed.
of the hydrolysis of MGP between three solvent systems. The
other factor for the determination of the rate of the hydrolysis of
MGP, concentration of the conjugate acid of MGP, can be recog-
nized from the CA column of Table 4. Concentration of the con-
jugate acid of MGP may be estimated to be highest in the H2O
solvent system and similar in the other two solvent systems,
although the actual difference in the concentration between three
solvent systems is unclear at 85 °C. The hydrolysis reaction of
MGP should be fastest in the H2O solvent system among three
solvent systems only on the basis of the concentration of the con-
jugate acid of MGP.
To estimate relative solvent dissociating power between the
0% (H2O), aqueous 74%, and aqueous 82% 1,4-dioxane solvent
systems, it should be appropriate to compare the rates of a
chemical reaction in these systems using a particular acid. The
prerequisites for this chemical reaction are as follows: (1) the
rate is not dependent on proton activity but only solvent disso-
ciating power, (2) the rate-determining step is not ionization but
dissociation, and (3) no nucleophile participates in the reaction.
Because it is difficult to prepare H2O, aqueous 74%, and 82%
1,4-dioxane solvent systems with the proton activities identical
to one another, the prerequisite (1) is required. The prerequisite
(2) is based on the conjugate acid of MGP dissociating to the
cyclic cation and the neutral CH3OH molecule in the rate-
determining step (Scheme 1). Acid hydrolysis of a quaternary
ammonium cation releasing the neutral amine compound seems
to satisfy prerequisites (1) and (2). Application of CH3SO3H can
satisfy prerequisite (3). An acid hydrolysis reaction of D-gluco-
pyranosyl aniline using CH3SO3H seems to be the best reaction.
Because this compound could not easily be obtained, however,
BnAni was chosen due to its easy availability. The mechanism
of acid hydrolysis reaction of BnAni is shown in Scheme 3. The
conjugate acid of BnAni is the only species present in any
solvent system that results in the independence of the reaction
rate on proton activity of the system. The conjugate acid dis-
sociates to the benzyl cation and the neutral aniline molecule,
although the latter compound is consecutively protonated.
On the basis of these theories, BnAni was acid-hydrolyzed in the
Comparison of effect of counter anion between different solvent
systems
Table 6 lists ratios of the rate constants for the hydrolysis reac-
tion of MGPβ to MGPα in the reaction systems employed. These
ratios seem to have a tendency to be small and large in the HBr
and H2SO4 systems, respectively, in three different solvent
systems. This may suggest that the pronounced direct partici-
pation of the counter anion in the hydrolysis reaction of MGP
decreases this ratio. If this is the case, the direct participation of
counter anion may be more significant in the hydrolysis reaction
of MGPα than in that of MGPβ owing to the decrease of the
ratio with the increase of the 1,4-dioxane content.
The hydrolysis rate of MGP increases with increasing 1,4-
dioxane content in the solution, when the rates are compared
between three different solvent systems with a particular acid
(Table 3). Concentration of the conjugate acid of MGP and
solvent dissociating power are the factors that determine the rela-
tive rate of the hydrolysis reaction of MGP in three different
solvent systems, when the rates are compared between these
systems and absence of participation of counter anion is
assumed. MGP is hydrolyzed more rapidly in a solvent with
higher solvent dissociating power than in another solvent even
when the proton activity of these systems is the same. Therefore,
relative solvent dissociating power of three different solvent
systems should be examined to discuss the difference in the rate
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phenomenon that the solvation of Br− and Cl− decreases with
the increase of the 1,4-dioxane content in the solvent. When
these anions are naked rather than solvated by the solvent
molecules, their nucleophilicity is high. Acceptor number (AN
or acceptivity), which can be an index of the strength as electron
pair acceptor and of the ability to solvate anions and nucleo-
philes, of H2O and 1,4-dioxane is 54.8 and 10.8, respectively.
AN of aqueous 74% and 82% 1,4-dioxane is estimated at 41.1
and 38.5, respectively, based on the data shown in the litera-
ture.32 It was shown that there is a clearly linear relationship
between AN of a solvent and the logarithm of the second order
rate constant of an SN2 type substitution reaction, CH3 − I + I−*
(radioactive), in the solvent.33,34 These data reinforce the above
described attribution of the enhanced participation of Br− and
Cl− with the increase of the 1,4-dioxane content in the solvent.
It was also reported that the rate of another SN2 type substitution
reaction, CH3 − OTs + X− (halide anion), in an aqueous N,N-
dimethylformamide solution decreases in the order of: I− > Br−
> Cl−, while the order is exactly the reverse in pure N,N-
dimethylformamide (AN: 16.0),35 suggesting the dependence of
nucleophilicity of halide anions on solvent. This dependency
probably explains the phenomena observed in this study that
only Br− directly participates in the hydrolysis reaction of MGP
in the H2O solvent system, and on the other hand, both anions
directly participate in the aqueous 1,4-dioxane solvent systems.
Table 7 List of pseudo-first-order reaction rate constants (kobs
)
obtained from the hydrolysis reaction of BnAnia
Systemb
0% (H2O)
74%
82%
5.70
c
kobs
1.16
0.995
3.90
0.997
R2 d
0.981
a The applied acid and temperature were 0.2 mol l−1 CH3SO3H and
85 °C in all systems. b The percentages in the line show the 1,4-dioxane
contents (v/v) in the systems. c Unit: ×10−2 h−1 d Square of correlation
.
coefficient.
H2O, aqueous 74%, and aqueous 82% 1,4-dioxane solvent
systems using CH3SO3H as an acid to examine the relative
solvent dissociation power of three different solvent systems.
Table 7 lists pseudo-first-order reaction rate constants obtained
from the acid hydrolysis reaction of BnAni in three solvent
systems using CH3SO3H as an acid. The approximation of the
disappearances of BnAni to pseudo-first-order reactions was
good (Table 7 and see ESI†). The rate of the BnAni hydrolysis
decreased in the order of: 82% > 74% > 0% (H2O) 1,4-dioxane
solvent systems. This order is the reverse of that observed for
common SN1-type substitution reactions,31 in which the rate-
determining step is not dissociation of a cation to another cation
and a neutral molecule but ionization of a neutral molecule to a
positively and negatively charged ions. Therefore, it can be
possible to consider that solvent system with higher content of
1,4-dioxane also have higher solvent dissociation power in the
rate-determining step of the hydrolysis reaction of MGP
(Scheme 1), although the structure of the conjugate acid of
BnAni is different from that of MGP. BnAni consists of two rela-
tively hydrophobic substructures, benzyl group and aniline,
while MGP consists of two relatively hydrophilic structures, glu-
cosyl group and methanol. Although this fact may influence the
rate of the hydrolysis reactions, the hydrolysis reaction of MGP
may be fastest in the 82% 1,4-dioxane solvent system among
three solvent systems only on the basis of the solvent dis-
sociation powers.
Because the effects of concentration of the conjugate acid of
MGP and solvent dissociating power on the rate of the hydrolysis
reaction of MGP are not consistent with each other in three
solvent systems, it cannot be suggested which solvent system
has the highest potential ability to move the hydrolysis reaction
of MGP forward. However, this result does not reduce the
importance of the suggestion that the counter anions, Br− and
Cl−, directly participate in the hydrolysis reaction of MGP when
the observed difference in the rate between the different acid
systems in each of the solvent systems is taken into
consideration.
Conclusions
The following features are suggested from the results obtained in
this study. Bromide anion directly participates in the acid
hydrolysis reaction of MGP and the participation is further pro-
nounced with the increase of the 1,4-dioxane content in solvent
system probably owing to the lower solvation of bromide anion
in solvent system with higher content of 1,4-dioxane. Chloride
anion also directly participates in the hydrolysis reaction of
MGP in the dioxane solvent systems. Bromide anion may
directly participate even in the pinacol rearrangement in the
dioxane solvent systems, although the reaction center of the
pinacol rearrangement is sterically highly hindered.
Experimental
Materials
All the chemicals used in this study were commercially avail-
able. Deionized H2O was used in all the experiments. 1,4-
Dioxane was refluxed with NaBH4 and subsequently distilled.
It is rationally assumed in this paper, as described in the pre-
vious sections, that solvent dissociating power is not different
between different acid systems when the solvent contains a par-
ticular level of 1,4-dioxane.
Acid hydrolysis reaction
All the reactions were run in a three-necked round-bottomed
glass flask (50 ml) equipped with a condenser, thermometer, and
magnetic stirrer. The air in the flask was primarily replaced with
N2. To the flask was added 27 ml of a 0.222 mol l−1 HCl, HBr,
or H2SO4 solution, and the temperature was raised to 85 °C.
Then, 3 ml of a solution containing each of a pair of MGPα and
MGPβ (50 mmol l−1 each), pinacol (200 mmol l−1), or BnAni
(200 mmol l−1) was added, and the reaction was started.
As described in the previous sections, Br− and Cl− are
suggested to directly participate in the hydrolysis reaction of
MGP in all the solvent systems and the aqueous 1,4-dioxane
solvent systems, respectively. Furthermore, their participations
are enhanced with the increase of the 1,4-dioxane content in the
solvent. This enhancement should be attributed to the presumed
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Concentration of the acids in the prepared solutions (30 ml) was
0.20 mol l−1 in all cases. Initial concentration of the starting
compounds was 5.0 mmol l−1 for each of MGPα and MGPβ,
20.0 mmol l−1 for piancol or BnAni. Aqueous 74% or 82% 1,4-
dioxane solution (v/v) was substituted for the above H2O sol-
utions in the other two reaction series. CH3SO3H was also
applied to some runs. Concentration of the acids and the starting
compounds in the prepared aqueous 1,4-dioxane solutions was
the same as that in the H2O solutions. All kinds of reactions
employed in this study are summarized in Table 1. Each kind of
acid hydrolysis reaction was repeated at least 3 times to confirm
the reproducibilities except that each of the reactions using
CH3SO3H was repeated twice.
4.6 mm, Phenomenex, Inc.). oven temperature: 40 °C, flow rate:
1.0 ml min−1, solvent system: CH3OH/2.0 mmol l−1 NaOH solu-
tion = 20/80 (v/v) for 10 min; gradient to 75/25 for 20 min;
20/80 for 10 min, total time: 40 min.
Notes and references
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Quantification of MGP
At prescribed times, 1 ml of the reaction solution was withdrawn
and transferred to a glass flask containing potassium carbonate
and an internal standard compound, myo-inositol, with cooling
in a cold water bath. Then, the mixture was dried under reduced
pressure. The dried sample was acetylated with acetic anhydride
and sodium acetate at 120 °C for 3 h. The acetylated solution
was injected into GC (GC-14B, Shimadzu Co., Kyoto, Japan)
equipped with a flame ionization detector using He as carrier
gas. Analysis conditions were as follows: The injector and detec-
tor were at 220 °C and 230 °C, respectively. Separation was
achieved on a TC-17 capillary column (30 m × 0.25 mm ×
0.25 μm, GL Sciences Inc., Tokyo, Japan). The temperature was
increased from 200 °C to 220 °C at 4 °C min−1 and maintained
for 10 min.
Quantification of pinacol
At prescribed times, 1 ml of the reaction solution was withdrawn
and transferred to a glass tube containing potassium carbonate
with cooling in a cold water bath. An internal standard com-
pound, 2,4,6-trimethylphenol, dissolved in chloroform, was
added to the flask and extracted. The chloroform layer was with-
drawn and the aqueous layer was further extracted with fresh
chloroform twice. The combined chloroform layer was dried
with anhydrous sodium sulfate and then injected into the GC
using helium as carrier gas. Analysis conditions were as follows:
The injector and detector were at 220 °C and 230 °C, respect-
ively. Separation was achieved on the TC-17 capillary column.
The temperature was increased from 50 °C to 180 °C at 10 °C
min−1 with an initial interval of 5 min and final maintenance for
2 min.
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Quantification of BnAni
At prescribed times, 1 ml of the reaction solution was withdrawn
and transferred to a glass tube containing potassium carbonate
and an internal standard compound, 4-acetyl-1,2-dimethoxy-
benzene, with cooling in a cold water bath. After filtration, the
mixture was injected into HPLC (LC-10A, Shimadzu Co.)
equipped with an SPD-M10A detector (226 nm, LC-10A,
Shimadzu Co.). Conditions for HPLC analysis were as follows:
Column: Luna
5
u
C18(2) 100
A
(150 mm
×
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