Acceleration and deceleration factors on the hydrolysis reaction of 4,6-O-benzylidene acetal group

Article abstract of DOI:10.1021/acs.joc.0c00395

The benzylidene acetal group is one of the most important protecting groups not only in carbohydrate chemistry but also in general organic chemistry. In the case of 4,6-O-benzylidene glycosides, we previously found that the stereochemistry at 4-position altered the reaction rate constant for hydrolysis of benzylidene acetal group. However, a detail of the acceleration or deceleration factor was still unclear. In this work, the hydrolysis reaction of benzylidene acetal group was analyzed using the Arrhenius and Eyring plot to obtain individual parameters for glucosides (Glc), mannosides (Man), and galactosides (Gal). The Arrhenius and Eyring plot indicated that the pre-exponential factor (A) and ΔS? were critical for the smallest reaction rate constant of Gal among nonacetylated substrates. On the other hand, both E_a/ΔH? and A/ΔS? were influential for the smallest reaction rate constant of Gal among diacetylated substrates. All parameters obtained suggested that the rate constant for hydrolysis reaction was regulated by protonation and hydration steps along with solvation. The obtained parameters support wide use of benzylidene acetal group as orthogonal protection of cis- and trans-fused bicyclic systems through the fast hydrolysis of the trans-fused benzylidene acetal group.

Full text of DOI:10.1021/acs.joc.0c00395

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Article
Acceleration and Deceleration Factors on the
Hydrolysis Reaction of 4,6-O-Benzylidene Acetal Group
Yuta Maki, Kota Nomura, Ryo Okamoto, Masayuki Izumi, Yasuhisa Mizutani, and Yasuhiro Kajihara
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00395 • Publication Date (Web): 28 Apr 2020
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Acceleration and Deceleration Factors on the Hydrolysis Reaction of 4,6-O-Benzylidene
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Acetal Group
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Yuta Maki,1,2* Kota Nomura,1,2 Ryo Okamoto,1,2 Masayuki Izumi,1,3 Yasuhisa Mizutani,1 and
Yasuhiro Kajihara1,2*
1. Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama,
Toyonaka, Osaka 560-0043, Japan
2. Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka
University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
* Yuta Maki: makiyt11@chem.sci.osaka-u.ac.jp; Yasuhiro Kajihara: kajihara@chem.sci.osaka-
u.ac.jp
<Abstract>
Benzylidene acetal group is one of the most important protecting groups not only in
carbohydrate chemistry but also in general organic chemistry. In the case of 4,6-O-benzylidene-
glycosides, we previously found that the stereochemistry at 4-position altered the reaction rate
constant for hydrolysis of benzylidene acetal group. However, a detail of the acceleration or
deceleration factor is still unclear. In this work, the hydrolysis reaction of benzylidene acetal
group was analyzed using the Arrhenius and Eyring plot to obtain individual parameters for
glucosides (Glc), mannosides (Man), and galactosides (Gal). The Arrhenius and Eyring plot
indicated that the pre-exponential factor (A) and ΔS‡ were critical for the smallest reaction rate
constant of Gal among non-acetylated substrates. On the other hand, both of Ea/ΔH‡ and A/ΔS‡
were influential for the smallest reaction rate constant of Gal among di-acetylated substrates. All
parameters obtained suggested that the rate constant for hydrolysis reaction was regulated by
protonation and hydration steps along with solvation. The obtained parameters support wide use
of benzylidene acetal group as orthogonal protection of cis-, and trans-fused bicyclic systems
through the fast hydrolysis of trans-fused benzylidene acetal group.
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<Introduction>
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Benzylidene acetal group is one of the most frequently used protecting groups not only in
carbohydrate chemistry but also in general organic chemistry.1-3 With the benzylidene acetal
group, 1,3-diol can be selectively protected in the presence of other multiple hydroxy groups due
to a thermodynamically favored six membered ring. For instance, benzylidene acetal formation
of a hexopyranoside affords a 4,6-O-benzylidene-protected product. The benzylidene acetal
formation step is a critical manipulation of protecting group in the initial stage to obtain various
building blocks toward oligosaccharide synthesis.4 The resulting benzylidene acetal group is
usually removed by hydrogenation or acidic hydrolysis, and a reductive opening reaction converts
the 4,6-O-benzylidene acetal group into a 4-O or 6-O benzyl group.2,5,6
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We previously reported that benzylidene acetal groups of glucose (Glc) and mannose (Man)
hydrolyzed faster than that of galactose (Gal) in mild acidic conditions and this interesting finding
enabled us to achieve the semisynthesis of human type triantennary sialyloligosaccharide.7 To
understand the selectivity, we prepared 4,6-O-benzylidene-protected glucoside, mannoside, and
galactoside, and then compared the reaction rate constants for hydrolysis of benzylidene acetal
group under 60% aqueous acetic acid at room temperature (Figure 1a). As a result, we found that
the stereochemistry at 4-position was critical for the rate constant for hydrolysis of benzylidene
acetal group: hydrolysis of a benzylidene acetal group with axial 4-position was slower in
comparison to that with equatorial 4-position. The Capon group also previously reported the
kinetics of hydrolysis of 4,6-O-benzylidene hexopyranosides by 96% aqueous ethanol and
ethanolic hydrochloric acid (Figure 1a).8 The data showed that a trans-fused benzylidene acetal
group hydrolyzed faster rather than cis-fused one. In addition, the Lehmann et al. demonstrated
selective cleavage of a trans-fused benzylidene acetal group in the presence of cis-fused one
(Figure 1b).9 As mentioned, there are some examples showing selective deprotection of the
benzylidene acetal group, and therefore these results need to be rationally interpreted because
acceleration and deceleration factors of hydrolysis of benzylidene acetal groups are not
understood well.
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Figure 1. Hydrolysis of Benzylidene Acetal Groups of Monosaccharides. (a) Faster hydrolysis
of benzylidene acetal groups of Glc and Man rather than that of Gal as previously reported.7,8 (b)
Selective hydrolysis of trans-fused benzylidene acetal group in the presence of cis-fused
benzylidene acetal group as previously reported.9 (c) Representative reaction scheme performed
in this study.
In this work, to get insights into the selective hydrolysis reaction of benzylidene acetal group,
we measured parameters derived from the Arrhenius equation and the Eyring equation.10,11 The
Arrhenius rate law is derived from empirical observations of the macroscopic rate constant for a
particular conversion reaction. This rate law determines energy for the reaction barrier. On the
other hand, the Eyring equation is derived from transition state theory, where the reactants and
activated complex are assumed to be in equilibrium. This equation affords information about
activation parameters: the enthalpy of activation (ΔH‡), the entropy of activation (ΔS‡), and the
Gibbs free energy of activation (ΔG‡). In general, these two analyses enabled us to get an insight
into a reaction mechanism.12 Here, we report mechanistic studies for the hydrolysis reactions of
4,6-O-benzylidene monosaccharides based on the parameters derived from the Arrhenius and
Eyring equations.
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<Results>
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We first prepared three monosaccharide substrates 1-3 having benzylidene acetal groups and
their acetylated derivatives 4-6 (Figure 1a)7 . Briefly, commercially available methyl--D-gluco-,
manno-, and galactopyranosides were used for the formation of benzylidene acetal groups. The
resulting 4,6-O-benzylidene-protected monosaccharides were subjected to acetylation using
pyridine and acetic anhydride. 1H and 13C NMR data are shown in Supporting Information.
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We then investigated the hydrolysis of benzylidene acetal groups at 10, 23, 28, and 33 oC,
respectively. The obtained monosaccharides were dissolved in 60% d-AcOH/D2O
(monosaccharide: 10 mM), and the reactions were monitored by 1H NMR (Figure 1c). A ratio of
a 4,6-O-benzylidene-protected monosaccharide versus a hydrolyzed product was estimated using
an integral of either a methyl proton or an anomeric proton. In the practical synthesis of
oligosaccharides, because a condition at lower temperature is suitable to have selective removal
of benzylidene acetal group rather than that at higher temperature, the range of temperature we
set here were considered to be suitable conditions to compare the hydrolysis reactions.
In this study, we obtained pseudo-first order rate constants as previously described by the
Capon group, using the conventional equation (Eq. 1).8 Considering the reaction mechanism of
the hydrolysis of benzylidene acetal groups, proton and water molecules are also involved along
with 4,6-O-benzylidene-protected monosaccharide. Although reaction rate constants for second-
or higher order reactions are important to understand the detail,13-15 we considered that pseudo-
first order reaction shown as Eq. 1 was easy to compare and discuss based on the data reported
by the Capon group. However, the Capon group did not evaluate several parameters derived by
the Arrhenius and Eyring equations. We obtained reaction rate constants (k) at the four
temperatures (Supporting Information), and the obtained values were used for the Arrhenius
and Eyring plots in order to discuss enthalpic and entropic behavior of benzylidene acetal group.
[퐴]
ln
= ― 푘푡
Eq. 1
(
)
[퐴]0
[A]0 is the initial concentration of a 4,6-O-benzylidene-protected monosaccharide, [A] is the
concentration of a 4,6-O-benzylidene-protected monosaccharide, k is the reaction rate constant
(sec-1), and t is the reaction time (sec).
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First, we obtained individual activation energies (Ea) and pre-exponential factors (A) for the
hydrolysis of benzylidene acetal groups of six monosaccharides based on the Arrhenius equation
(Eq. 3). Plotting ln (k) as a function of reciprocal of temperature [ln (k) versus 1/T] gave a linear
line (Figure 2 a and b). Based on the slope (= -Ea/R) and the intercept (= ln A), we obtained Ea
and A values as shown in Figure 2 e.
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푘 = 퐴 × exp ( ―퐸
)
푎
Eq. 2
Eq. 3
푅푇
ln (푘) = ln (퐴) ― 푅퐸푇푎
k is the reaction rate constant, A is the pre-exponential factor, and Ea is the activation energy.
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(a)
-8
(b)
-8
8
-9
-9
9
-10
-11
-12
-13
-14
-10
Man 2
Glc 1
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-11
diAc Glc 4
diAc Man 5
-12
Gal 3
-13
diAc Gal 6
-14
3.3
3.4
103/ T
3.5
3.3
3.4
103/ T
3.5
(c)
-13
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(d)
-13
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Man 2
Glc 1
diAc Glc 4
diAc Man 5
Gal 3
diAc Gal 6
3.3
3.4
103/ T
3.5
3.3
3.4
103/ T
3.5
(e)
Glc 1
Man 2
Gal 3
diAc Glc 4 diAc Man 5 diAc Gal 6
Ea
(kJ/mol)
A (s-1)
76.6 ± 4.5 79.3 ± 5.6 72.4 ± 6.3 76.2 ± 1.1 74.7 ± 1.5 77.9 ± 5.3
20.6 × 108 93.9 × 108 0.70 × 108 9.22 × 108 4.05 × 108 3.67 × 108
ΔH‡ (kJ/mol)
TΔS‡ (kJ/mol)
ΔG‡ (kJ/mol)
74.1 ± 4.4
-22.3 ± 4.5 -18.5 ± 5.6 -30.6 ± 6.5 -24.3 ± 1.1 -26.3 ± 1.6 -26.6 ± 5.2
96.1 ± 0.2 95.2 ± 0.2 100 ± 0.2 97.9 ± 0.2 98.5 ± 0.2 102 ± 0.3
76.9 ± 5.6 70.1 ± 6.4 73.8 ± 1.0 72.3 ± 1.5 75.4 ± 5.3
Figure 2. The Arrhenius and the Eyring Plot. (a) and (b) are data of the Arrhenius plot for
hydrolysis reactions of non-acetylated (1-3) and di-acetylated substrates (4-6). Activation energy
(Ea) and pre-exponential factor (A) were obtained using an intercept (= ln A) and a slope (= -Ea/R).
(c) and (d) are data of the Eyring plot for hydrolysis reactions of non-acetylated (1-3) and di-
acetylated substrates (4-6). ΔS‡ and ΔH‡ values were obtained based on the slope (= -ΔH‡/R) and
the intercept [= ln(κkB/h)+ ΔS‡ /R]], and the ΔG‡ values were obtained based on Eq. 6. (e) is
summary of the obtained parameters, and the standard error is shown for Ea, ΔS‡, ΔH‡, and ΔG‡.
In the case of non-acetylated substrates 1-3, we found that the pre-exponential factor (A)
value of Gal 3 was lower than those of Glc 1 and Man 2, resulting in slower hydrolysis of Gal
benzylidene acetal group. The A value is called as frequency factor and generally includes factors
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such as collision frequency and collision cross-section. The A value is proportional to a reaction
rate constant, while Ea value exponentially changes the reaction rate constant (Eq. 2). Although
the analysis showed that the Ea values of Glc 1 (76.6±4.5 kJ/mol) and Man 2 (79.3±5.6 kJ/mol)
were relatively higher than that of Gal 3 (72.4±6.3 kJ/mol), the hydrolysis experiments showed
opposite results. The benzylidene acetal group of Gal 3 hydrolyzed slower than those of Glc 1
and Man 2. On the other hand, the A value obtained supported the experimental result. The A
value of Gal 3 was concomitantly smaller (0.70×108 sec-1) compared to those of Glc 1 (20.6×108
sec-1) and Man 2 (93.9×108 sec-1).
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Regarding di-acetylated substrates, both A and Ea values were not involved in slower
hydrolysis of Gal 6. The A value of Gal 6 (3.67×108 sec-1) was not significantly lower than those
of Glc 4 and Man 5 (9.22×108 sec-1 and 4.05×108 sec-1). The Ea values of Glc 4, Man 5, and Gal
6 did not significantly differ (Glc 4: 76.2±1.1 kJ/mol, Man 5: 74.7±1.5 kJ/mol, Gal 6: 77.9±5.3
kJ/mol). Even though the benzylidene acetal group of Gal 6 hydrolyzed clearly slower, we did
not observe the significant difference in terms of the Ea and A values.
Next, we then employed the Eyring equation (Eq. 4 and 5) to obtain the enthalpy and entropy
of activation (ΔH‡ and ΔS‡). Plotting ln(k/T) as a function of reciprocal of T [ln(k/T) versus 1/T]
gave a linear line as shown in Figure 2 c and d.16 Then, we estimated ΔH‡ and ΔS‡ values of the
hydrolysis of benzylidene acetal groups according to the slope (= -ΔH‡/R) and the intercept [=
ln(κkB/h)+ ΔS‡ /R]], along with ΔG‡ values calculated based on Eq. 6. In this work, we uniformly
considered transmission coefficient (κ) as 1.0, because we assumed that the used substrates were
structurally similar and then the probability to get to the product via transition state would not
significantly differ due to the structural similarity,17 resulting in the same level of the κ values.
‡
Δ푆 ‡
푅
푘퐵푇
ℎ
푘 = κ
exp
)
exp ( ―∆퐻
)
Eq. 4
Eq. 5
(
(
)
푅푇
∆푆 ‡
‡
ln (푇푘) = ― ∆퐻 + ln (κ푘 ) +
퐵
푅푇
ℎ
푅
κℎ
∆퐺 ‡ = ― 푅푇 ln (휒푘 푇
)
Eq. 6
퐵
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∆퐺 ‡ = ∆퐻 ‡ ― 푇∆푆 ‡
Eq. 7
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Among non-acetylated substrates 1-3, the ΔG‡ value of Gal 3 was the highest, mainly due to
the negatively highest ΔS‡ value. When we compared the results of ΔH‡, the values of Glc 1
(74.1±4.4 kJ/mol) and Man 2 (76.9±5.6 kJ/mol) were relatively higher than that of Gal 3 (70.1±6.4
kJ/mol). In general, higher ΔH‡ increases ΔG‡, resulting in a smaller reaction rate constant. On
the other hand, the TΔS‡ value of Gal 3 (-30.6±6.5 kJ/mol) was more negative than those of Glc
1 (-22.3±4.5 kJ/mol) and Man 2 (-18.5±5.6 kJ/mol). These values indicated that the hydrolysis of
benzylidene acetal group of Gal 3 was less preferable due to the most negative ΔS‡ value. Hence,
this feature resulted in the higher ΔG‡ value of Gal 3 (100±0.2 kJ/mol) in comparison to those of
Glc 1 (96.1±0.2 kJ/mol) and Man 2 (95.2±0.2 kJ/mol).
In the case of di-acetylated substrates 4-6, we also found that the ΔG‡ value of Gal 6 (102±0.3
kJ/mol) was higher than those of Glc 4 (97.9±0.2 kJ/mol) and Man 5 (98.5±0.2 kJ/mol). In terms
of the ΔH‡ values of the substrates, we observed that the value of Gal 6 (75.4±5.3 kJ/mol) was
slightly higher than those of Glc 4 (73.8±1.0 kJ/mol) and Man 5 (72.3±1.5 kJ/mol). The TΔS‡
value of Gal 6 (-26.6±5.2 kJ/mol) was almost same as that of Man 5 (-26.3±1.6 kJ/mol) and
slightly more negative than that of Glc 4 (-24.3±1.1 kJ/mol). Thus, we concluded that both of
enthalpic and entropic factors contributed to the higher ΔG‡ value of di-acetylated Gal 6 (102±0.3
kJ/mol) compared with those of di-acetylated Glc 4 (97.9±0.2 kJ/mol) and Man 5 (98.5±0.2
kJ/mol),17 resulting in slower hydrolysis of benzylidene acetal group of Gal 6.
Based on these experimental results, we found that pre-exponential factor (A) value of Gal
3 was smaller than those of Glc 1 and Man 3, and the ΔG‡ values of Gal 3 and acetylated Gal 4
were larger than other free and acetylated Glc 1, 4 and Man 2, 5.
<Discussion>
Data we obtained suggested that the axial 4-OH of Gal clearly increased ΔG‡ to slow down
the hydrolysis of 4,6-O-benzylidene acetal group. The ΔG‡ values of Gal with and without Ac
groups were 3~5 kJ/mol higher than those of Glc and Man. When we considered Eq. 8 at 296 K
(χ was assumed to be 1.0), the 3~5 kJ/mol difference of ΔG‡ resulted in 4~8 times smaller reaction
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rate constant for the hydrolysis of benzylidene acetal group of Gal in comparison to those of Glc
and Man as shown in Figure 3 [k(calc)]. These data are in good agreement with the observed
difference of the rate constants that 4,6-O-benzylidene acetal group of Glc and Man hydrolyzed
faster than that of Gal [Figure 3. k(obsd)]. The previous study by the Capon group also reported
that a 4,6-O-benzylidene acetal group of Gal hydrolyzed 2-4 times slower rather than those of Glc
and Man.8
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‡
푘 = χ푘퐵푇 exp ( ― ∆퐺
)
푅푇
Eq. 8
ℎ
Figure 3. Reaction Rate Constants for the Hydrolysis of Benzylidene Acetal Groups of
Glycosides at 296K. The k(calc) value was obtained based on an obtained ΔG‡ value using Eq.
8, where transmission coefficient was uniformly assumed to be 1.0. The k(obsd) value at 296 K
was obtained as described in Supporting Information.
In this study, we obtained parameters by plotting based on the Arrhenius equation and the
Eyring equation, and the both results were well consistent. The Arrhenius plot employs ln(k) as a
function of 1/T, while the Eyring plot employs ln(k/T) as a function of 1/T. Ideally, an Ea value
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correlates with ΔH‡.11,18 Moreover, A and ΔS‡ values show similar tendency.19 In the case of Ea
and ΔH‡ values, we did not find significant difference among non-acetylated substrates. Similarly,
di-acetylated substrates showed similar tendency in terms of Ea and ΔH‡ values. On the other
hand, in the case of A and ΔS‡ values, we observed the lower values of Gal 3 among non-
acetylated substrates, while the values of Gal 6 were similar to those of di-acetylated Glc 4 and
Man 5. Thus, we got insight into these parameters for understanding of smaller hydrolysis reaction
rate of Gal.
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Obtained data suggested that A and ΔS‡ values were critical for the hydrolysis rate constants
of non-acetylated substrates 1, 2, and 3, while both of Ea /ΔH‡ and A /ΔS‡ values were critical in
the case of di-acetylated substrates. In general, lower ΔS‡ suggests that the transition state
complex is more ordered and rigid.16,17 To further understand what factors affected the hydrolysis
of benzylidene acetal groups and caused the slower hydrolysis of benzylidene acetal groups of
Gal, we considered potential reasons based on the obtained data as below.
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Figure 4. Potential Factors of the Hydrolysis Reactions of Benzylidene Acetal Group. (a)
trans-fused benzylidene acetal groups of Glc and Man are shown along with cis-fused
benzylidene acetal group of Gal. (b) The Newman projections indicate the anti- and gauche
conformation of the C-O bonds. (c) Structures of the protonated benzylidene acetal groups. In the
case of Gal benzylidene acetal group, the attached proton to the 6-O might be accessed by ring
oxygen, potentially resulting in the equilibrium of proton transfer. (d) Solvation effect during the
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hydrolysis reaction on cis- and trans-fused benzylidene acetal groups. (e) The reaction
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mechanism of hydrolysis of benzylidene acetal group.
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First, we considered stabilization of the benzylidene acetal group of Gal based on the Gauche
effect.20,21 As the gauche-rotamer has a 2.4 – 3.4 kJ/mol lower energy than the anti-rotamer in the
case of 1,2-difluoroethane,22,23 a gauche-conformation of electronegative substituents are stable
rather than an anti-conformation. In the case of 4,6-O-benzylidene-protected glycosides, the 6C-
6O bond is gauche to the 5C-5O bond in the cis-fused system (Figure 4 b ii) while trans-fused
Glc and Man have the anti-conformation (Figure 4 b i). The * orbital of 5C-5O bond (acceptor)
was potentially stabilized by the Gauche effect interacting with 6C-H bond (donor) in the case of
Gal (Figure 4 b). Similarly, the * orbital of 6C-6O bond of Gal could be stabilized, however,
such stabilization is not possible in the case of Glc and Man. Therefore, the Gauche effect
potentially changed the energy level of the 4,6-O-benzylidene-protected Gal. Assuming that the
Gauche effect of cis-fused benzylidene acetal group disappears in the transition state such as
protonation of the oxygen and opening of the acetal ring, ΔH‡ (or Ea) of Gal would become greater.
However, we did not observe such greater ΔH‡ (or Ea) value of Gal. Thus, the Gauche effect is
less likely influential in the hydrolysis of benzylidene acetal group.
Second, the attached proton on 6-O during the protonation step could be sterically accessible
by a 5-O lone pair, while the attached proton in the trans-fused system is hard to be accessed by
a lone pair of 5-O (Figure 4 c). Equilibrium between 6-O protonation and 5-O protonation might
disturb the intermediate to proceed to the following C-O bond cleavage step (Figure 4 e, step i-
ii). There are some reports showing the participation of the neighboring functional group in the
case of the hydrolysis of acetal,17,24-26 however, the existence of such equilibrium was not
supported by the parameters obtained in this work.
We also considered the effect of ring puckering to understand the factors regulating TΔS‡.27
A sugar ring puckers according to the flexibility of the sugar ring, resulting in some conformers.
Some conformers would be reactive toward protonation or hydration. Capon et al. previously
implied that cis-fused system is structurally more flexible than trans-fused system and also
mentioned that cis-fused benzylidene acetal group of Gal could take two conformers (4C1 and
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1C4).8 This sugar behavior potentially results in higher TΔS‡ of Gal than the rigid trans-fused Glc
and Man derivatives. However, we observed smaller TΔS‡ of non-acetylated Gal 3 and the TΔS‡
of di-acetylated Gal 6 was similar to those of Glc 4 and Man 5. Thus, we considered that the effect
of ring puckering on TΔS‡ is not so significant.
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The cis-fused bicyclic system of Gal has a convex and concave face (Figure 4 a) and this
factor potentially changes TΔS‡ lower. In general, TΔS‡ becomes lower in the case that a substrate
has structurally limited angles and space for access of reagents in order to get to the transition
state. The concave face of the cis-fused system is generally less accessible.28-30 The trans-fused
systems of Glc and Man do not have convex and concave faces and then are easily accessed from
both of up and down sides. Our data showed the slow hydrolysis of benzylidene acetal group of
non-acetylated Gal 3 along with lower TΔS‡, suggesting that the steric factor is likely to be
involved in the entropy and disturbs protonation and hydration steps (Figure 4 e, step i, iii, and
v).12,31-33
Similarly, conformational limitation was also indicated by the smallest A value of Gal 3
among non-acetylated substrates. The A value varies according to collision frequency and
structural limitation. In order for a 4,6-O-benzylidene-protected substrate to give a hydrolyzed
product, proton and water molecules need to access the substrate in appropriate angles with
sufficient energy (> Ea). Thus, the clearly smaller A value of Gal 3 indicates that Gal is structurally
less preferable for the approach of proton and water molecules to get to the transition state.
Moreover, a positive charge might be stabilized by solvation during protonation of 4-O or
6-O and following C-O bond cleavage step (Figure 4 d and e). Usually, solvation is involved in
both of entropic and enthalpic factors, and thus the stabilization by solvation could change not
only ΔS‡ but also ΔH‡. Because a trans-fused system can be easily accessed from both of top and
down sides of the bicyclic ring as mentioned above, we considered that trans-fused structure was
better solvated and then subject to the rapid hydrolysis. To the contrary, the cis-fused bicyclic
system has a less accessible concave face and then might be less stabilized by the solvation of
water, potentially resulting in the slow hydrolysis. Previously, Galema and Hoiland reported that
the stereochemistry of monosaccharide changed hydration compatibility of the monosaccharide.34
Thus, it is likely that solvation by water molecule may contribute to the observed hydrolysis rate
constant.
Next, we interpreted the results of di-acetylated substrates 4-6. In this case, on the other
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hand, the effect of entropy was not critical for the highest ΔG‡ value of Gal 6. We did not observe
the significant difference of TΔS‡ between the acetylated substrates (Glc 4: -24.3±1.1 kJ/mol,
Man 5: -26.3±1.6 kJ/mol, Gal 6: -26.6±5.2 kJ/mol), although non-acetylated derivatives showed
clear difference (Glc 1: -22.3±4.5 kJ/mol, Man 2: -18.5±5.6 kJ/mol, Gal 3: -30.6±6.5 kJ/mol).
Similarly, the A values of di-acetylated substrates 4-6 were almost identical, but non-acetylated
ones showed the large difference. These data indicated that acetyl groups changed the molecular
behavior of 4,6-O-benzylidene-protected glycosides, and this factor diminished the clear
difference of A and TΔS‡ values among the three acetylated substrates.
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Then, we considered the effect of the acetyl groups. We considered that acetyl groups
disturbed the access of proton and water molecules due to their steric hindrance and hydrophobic
nature. Especially, Man has an axial 2-OH and the acetylated substituent might disturb the access
of molecules from the upper face. In addition, considering solvation, a solute molecule is
surrounded by hydrogen network of water molecules, and a hydroxy group of carbohydrate can
form hydrogen bonds to water molecules.34,35 As shown in Figure 3, the reaction rate constants
for the hydrolysis of benzylidene acetal groups of Glc and Gal decreased about 2 times, while the
rate constant of Man became 3 times smaller after acetylation. We considered that the non-
protected 2-OH of Man might enhance the access of water molecule from the upper face via
hydrogen bond network, while acetylated 2-OH of Man disturbed the access due to its steric and
hydrophobic nature. In terms of obtained parameters, after acetylation, the A and TΔS‡ values of
Man became smaller, and other parameters slightly changed, resulting in 2-3 kJ/mol higher ΔG‡
of di-acetylated substrates compared with non-acetylated ones as shown in Figure 2 e. As a result,
the ΔG‡ of Gal 6 was higher than those of Glc 4 and Man 5, and the reaction rate constant of Gal
6 was the lowest among the di-acetylated substrates as shown in Figure 3.
Finally, we considered the rate-determining step (RDS) of the hydrolysis reactions. The
cleavage step of a C-O bond (Figure 4 e, step ii) is usually RDS in the hydrolysis of acetal as
reported previously.36,37 In this work, the observed ΔS‡ values were clearly negative. In general,
a negative ΔS‡ value potentially indicates that RDS is involved in molecular combining step,11
because the degree of order is lost when two molecules get combined into single molecule in the
transition state.31 Thus, it is likely that protonation or hydration step, which is a molecular
combining step, was RDS. Fife previously proposed that a hydration step concerted with C-O
bond cleavage was the RDS in the case of the hydrolysis of 2-(p-substituted phenyl)-4,4,5,5-
tetramethyl-1,3-dioxolanes.32 Moreover, Fife et al. also mentioned that proton transfer to the
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substrate could be the RDS most likely concerted with C-O bond cleavage step.12 In our study,
the obtained TΔS‡ values were all negative, suggesting that a molecular combining step, such as
protonation or hydration, was potentially involved in the RDS.
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In summary, we obtained the parameters using the Arrhenius and Eyring equations to get an
insight into acidic hydrolysis of 4,6-O-benzylidene acetal groups of monosaccharides. In the case
of non-acetylated substrates, the ΔS‡ value was found to be critical to increase the ΔG‡ value of
Gal 3, and the A value was also critical for the smaller reaction rate constant of Gal 3 in
comparison to Glc 1 and Man 2. On the other hand, in the case of acetylated substrates, both of
Ea/ΔH‡ and A/ΔS‡ were influential for the smallest reaction rate constant of Gal 6. These data
obtained potentially support the selective hydrolysis of benzylidene acetal group of trans-fused
mode rather than stable cis-fused group such as mannosides and glucosides.
EXPERIMENTAL SECTION
General Experimental Methods.
1H and 13C NMR spectra were recorded on a 400 MHz spectrometer (Bruker Avance III). A
non-acetylated substrate (1.9 mg, 6.7 μmol) was dissolved in pre-heated or pre-cooled 60 % d-
AcOH in D2O (668 μL), and a di-acetylated substrate (2.0 mg, 5.5 μmol) was dissolved in pre-
heated or pre-cooled 60 % d-AcOH in D2O (546 μL). An aliquot of the mixture (50-100 μL) was
separated and the reaction was conducted in a NMR tube at 10, 23, 28, and 33 oC, respectively.
The hydrolysis reaction was monitored by 1H NMR (dummy scan : 4, number of scan: 16 or 32)
o
at the time point of 1, 3, 6, and 9 hours for a reaction at 10 C, 0.5, 1, 3, 6, and 9 hours for a
o
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reaction at 23 C, 0.5, 1, 2, and 3 hours for a reaction at 28 C, or 0.5, 1, 2, and 3 hours for a
o
reaction at 33 C. The Arrhenius plot and the Eyring plot were prepared based on a software
(Origin Pro 2019, OriginLab Corporation, USA) according to the manufacture protocol.
Methyl 4,6-O-benzylidene--D-glucopyranoside (1)
Methyl -D-glucopyranoside (500 mg, 2.57 mmol) and camphor-10-sulfonic acid (179 mg,
0.77 mmol) were dried in vacuo for 1 hour, and then CH3CN (26 ml) was added. To the mixture,
benzaldehyde dimethyl acetal (575 μl, 3.83 mmol) was added. The resulting mixture was stirred
at room temperature. After 11 hours, triethylamine (107 μl, 0.77 mmol) was added, and the
mixture was concentrated. The resulting residue was dissolved in EtOAc (50 ml) and washed by
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sat. aq. NaHCO3 (50 ml). The organic layer was dried over Na2SO4, filtered, and concentrated.
The resulting residue was recrystallized from ethanol and petroleum ether to give methyl 4,6-O-
benzylidene--D-glucopyranoside (303 mg, 1.07 mmol, 42%) as a white solid. HRMS m/z: [M
+ H]+ calcd for C14H18O6 283.1176, found 283.1175.
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1H NMR (CDCl3, 400 MHz, TMS):  7.54-7.44 (m, 2H), 7.44-7.31 (m, 3H), 5.51 (s, 1H), 4.75
(d, J = 3.92 Hz, 1H), 4.27 (dd, J = 9.63, 4.23 Hz, 1H), 3.90 (ddd, J = 9.25 Hz, 1H), 3.84-3.67 (m,
2H), 3.59 (ddd, 1H), 3.46 (dd, J = 9.32 Hz, 1H), 3.43 (s, 3H), 3.15 (s, 1H), 2.60 (s,1H). 13C NMR
(CDCl3, 100 MHz, TMS):  137.06, 129.25, 128.32, 126.34, 101.93, 99.81, 80.94, 72.82, 71.60,
68.93, 62.36, 55.53.
Methyl 2,3-di-O-acetyl-4,6-O-benzylidene--D-glucopyranoside (4)
Methyl 4,6-O-benzylidene--D-glucopyranoside (280 mg, 0.99 mmol) was dissolved in
pyridine (5 ml) and acetic anhydride (5 ml), and the mixture was stirred at room temperature for
9 hours. After the completion of the reaction, MeOH (6 ml) was added on the ice bath. The
resulting mixture was concentrated and co-evaporated with toluene. The residue was then purified
by silica gel column chromatography (EtOAc/ hexane = 2:5, φ18 mm). The fractions containing
the desired product were collected and evaporated to give methyl 2,3-di-O-acetyl-4,6-O-
benzylidene--D-glucopyranoside (90.8 mg, 0.25 mmol, 25%) as a white solid. HRMS m/z: [M
+ H]+ calcd for C18H22O8 367.1387, found 367.1384.
1H NMR (CDCl3, 400 MHz, TMS):  7.51-7.41 (m, 2H), 7.41-7.31(m, 3H), 5.59 (dd, 1H, J =
9.70 Hz), 5.51 (s, 1 H), 5.0-4.86 (m, 2H), 4.30 (dd, J = 10.18, 4.77 Hz, 1H), 3.93 (ddd, J = 10.00,
4.79 Hz, 1H), 3.77 (dd, J = 10.31 Hz, 1H), 3.65 (dd, J = 9.61 Hz, 1H), 3.41 (s, 3H), 2.09 (s, 3H),
2.05 (s, 3H). 13C NMR (CDCl3, 100 MHz, TMS):  170.42, 169.79, 136.94, 129.08, 128.23,
126.16, 101.58, 97.63, 79.24, 71.61, 68.98, 68.87, 62.34, 55.37, 20.83, 20.77.
Methyl 4,6-O-benzylidene--D-mannopyranoside (2)38
To a solution of methyl -D-mannopyranoside (3.02 g, 15.6 mmol) in DMF (42 ml), p-
toluenesulfonic acid monohydrate (890 mg, 4.68 mmol) and benzaldehyde dimethyl acetal (2.33
ml, 15.5 mmol) was added. The resulting mixture was stirred at 60 oC under the reduced pressure
(200 mbar). After 6 hours, the mixture was concentrated. The resulting residue was dissolved in
EtOAc (300 ml) and washed by sat. aq. NaHCO3 (150 ml). The resulting water layer was washed
by EtOAc (150 ml). The organic layer was combined, washed by brine (200 ml), dried over
Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column
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chromatography (φ50 mm, EtOAc/hexane = 3:1) to give methyl 4,6-O-benzylidene--D-
mannopyranoside (1.35 g, 4.80 mmol, 31%) as a white solid. HRMS m/z: [M + H]+ calcd for
C14H18O6 283.1176, found 283.1173.
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1H NMR (CDCl3, 400 MHz, TMS):  7.54-7.44 (m, 2H), 7.44-7.33 (m, 3H), 5.56 (s 1H), 4.74 (d,
J = 1.29 Hz, 1H), 4.28 (dd, J = 9.08, 3.55 Hz, 1H), 4.05 (ddd, J = 9.38, 3.53 Hz, 1H), 4.00, (ddd,
J = 3.47, 1.32 Hz, 1H), 3.90 (dd, J = 9.14 Hz, 1H), 3.86-3.78 (m, 2H), 3.39 (s, 3H), 2.76 (s, 2H).
13C NMR (CDCl3, 400 MHz, TMS):  137.21, 129.31, 128.38, 126.28, 102.31, 101.25, 78.90,
70.86, 68.85, 68.66, 62.90, 55.11.
Methyl 2,3-di-O-acetyl-4,6-O-benzylidene--D-mannopyranoside (5)
Methyl 4,6-O-benzylidene--D-mannopyranoside (528 mg, 1.87 mmol) was dissolved in
pyridine (9.4 ml) and acetic anhydride (9.4 ml), and the mixture was stirred at room temperature
under an atmosphere of Ar. After 22 hours, MeOH (12 ml) was added on an ice bath. The resulting
mixture was concentrated and co-evaporated with toluene. The residue was then purified by silica
gel column chromatography (EtOAc/ hexane = 1:2, φ 33 mm). The fractions containing the
desired product were collected and evaporated to give methyl 2,3-di-O-acetyl-4,6-O-
benzylidene--D-mannopyranoside39 (647 mg, 1.77 mmol, 94%) as a white solid. HRMS m/z:
[M + H]+ calcd for C18H22O8 367.1387, found 367.1386.
1H NMR (CDCl3, 400 MHz, TMS):  7.52-7.42 (m, 2H), 7.42-7.32 (m, 3H), 5.58 (s, 1H), 5.40
(dd, J = 10.07, 3.51 Hz, 1H), 5.35 (dd, J = 3.55, 1.60 Hz, 1H), 4.67 (d, J = 1.48 Hz, 1H), 4.30
(dd, J = 10.01, 4.43 Hz, 1H), 4.04 (dd, J = 9.41 Hz, 1H), 3.95 (ddd, J = 9.93, 4.52 Hz, 1H), 3.86
(dd, J = 10.09 Hz, 1H), 3.41 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H). 13C NMR (CDCl3, 100 MHz,
TMS):  169.89, 169.84, 137.13, 129.15, 128.28, 126.22, 101.96, 99.62, 76.13, 70.06, 68.77,
68.35, 63.77, 55.23, 20.88, 20.84.
Methyl 4,6-O-benzylidene--D-galactopyranoside (3)
To a solution of methyl -D-galactopyranoside (1.02 g, 4.79 mmol) in CH3CN (48 ml),
camphor-10-sulfonic acid (334 mg, 1.44 mmol) and benzaldehyde dimethyl acetal (1.07 ml, 7.13
mmol) were added. The resulting mixture was stirred at room temperature under an atmosphere
of Ar. After 1.5 h, triethylamine (430 μl, 3.08 mmol) was added, and the mixture was concentrated.
The resulting residue was dissolved in EtOAc and washed by sat. aq. NaHCO3. The organic layer
was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica
gel column chromatography (φ28 mm, EtOAc/ hexane = 2:5) to give methyl 4,6-O-benzylidene-
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-D-glucopyranoside (1.00 g, 3.56 mmol, 74%) as a white solid. HRMS m/z: [M + H]+ calcd for
C14H18O6 283.1176, found 283.1173.
1H NMR (CDCl3, 400 MHz, TMS):  7.58-7.44 (m, 2H), 7.44-7.31 (m, 3H), 5.55 (s, 1H), 4.93
(d, J = 2.93 Hz, 1H), 4.29 (dd, J = 12.52, 1.54 Hz, 1H), 4.26 (dd, J = 3.00, 0.95 Hz, 1H), 4.08
(dd, J = 12.53, 1.77 Hz, 1H), 4.01-3.81 (m, 2H), 3.69 (ddd, J = 1.26 Hz, 1H), 3.46 (s, 3H), 2.50
(s, 1H), 2.26 (s, 1H). 13C NMR (CDCl3, 100 MHz, TMS):  137.51, 129.24, 128.28, 126.28,
101.31, 100.22, 75.87, 69.90, 69.82, 69.34, 62.74, 55.74.
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Methyl 2,3-di-O-acetyl-4,6-O-benzylidene--D-galactopyranoside (6) was synthesized as
previously reported.7
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at ---.
Data on integrals of each compounds, calculation of reaction rate constant (k), Arrhenius plot,
and Eyring plot (PDF)
AUTHOR INFORMATION
Corresponding Author
*makiyt11@chem.sci.osaka-u.ac.jp
*kajihara@chem.sci.osaka-u.ac.jp
Present Address
3 M.I.: Faculty of Science and Technology, Kochi University, 2-5-1 Akebono-cho, Kochi, Kochi
780-8520, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Japan Society for the Promotion of Science (A JSPS Research
Fellowship for Young Scientists to Y. Maki. and Grants-in-Aid for Creative Scientific Research:
17H01214 to Y.K) is acknowledged and appreciated. The authors also thank Prof. Michio Murata
for his advice on the Eyring plot.
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REFERENCES
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(1) Glycochemical Synthesis; Shang-Cheng, H., Medel Manuel L., Z., Eds; John Wiley & Sons,
Inc., 2016.
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