A new look at acid catalyzed deacetylation of carbohydrates: A regioselective synthesis and reactivity of 2-O-acetyl aryl glycopyranosides

Article abstract of DOI:10.1016/j.carres.2018.02.003

In the present work we report that acetyl groups of per – acetylated aryl glycosides have different reactivity during the acidic deacetylation using HCl/EtOH in CHCl_3, which leads to preferential deacetylation at O-3, O-4 and O-6. Thereby, the one-step preparation of 2-O-acetyl aryl glycosides with simple aglycon was accomplished for the first time. It was proved that the found reagent is to be general and unique for the preparation of series of 2-О-acetyl aryl glycosides. We have determined the influence of both carbohydrate moiety and the aglycon on the selectivity of deacetylation reaction by kinetic experiments. Using DFT/B3LYP/6-31G(d,p) and semi-empirical АМ1 methods we have found that the highest activation barrier is for 2-О-acetyl group. This completely explains the least reactivity of 2-О-acetyl group.

Full text of DOI:10.1016/j.carres.2018.02.003

Accepted Manuscript
A new look at acid catalyzed deacetylation of carbohydrates: A regioselective
synthesis and reactivity of 2-O-acetyl aryl glycopyranosides
Elena V. Stepanova, Marina O. Nagornaya, Victor D. Filimonov, Rashid R. Valiev,
Maxim L. Belyanin, Anna K. Drozdova, Victor N. Cherepanov
PII:
S0008-6215(17)30915-1
10.1016/j.carres.2018.02.003
CAR 7519
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 16 December 2017
Revised Date: 28 January 2018
Accepted Date: 4 February 2018
Please cite this article as: E.V. Stepanova, M.O. Nagornaya, V.D. Filimonov, R.R. Valiev, M.L. Belyanin,
A.K. Drozdova, V.N. Cherepanov, A new look at acid catalyzed deacetylation of carbohydrates: A
regioselective synthesis and reactivity of 2-O-acetyl aryl glycopyranosides, Carbohydrate Research
(2018), doi: 10.1016/j.carres.2018.02.003.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A new look at acid catalyzed deacetylation of carbohydrates: a
regioselective synthesis and reactivity of 2-O-acetyl aryl glycopyranosides
Elena V. Stepanova,a1 Marina O. Nagornaya,a Victor D. Filimonov,a Rashid R. Valiev,b,c
Maxim L. Belyanin,a Anna K. Drozdova,b Victor N. Cherepanovb
aDepartment of Biotechnology and Organic Chemistry, National Research Tomsk
Polytechnic University, 30 Lenin Avenue, Tomsk 634050, Russia
bTomsk State University, Lenin Avenue 36, Tomsk 634050, Russia
cUniversity of Helsinki, Department of Chemistry, P.O. Box 55 (A.I. Virtanens plats 1), FIN-
00014 University of Helsinki, Finland
Abstract
In the present work we report that acetyl groups of per – acetylated aryl glycosides have
different reactivity during the acidic deacetylation using HCl/EtOH in CHCl3, which leads to
preferential deacetylation at O-3, O-4 and O-6. Thereby, the one-step preparation of 2-O-acetyl
aryl glycosides with simple aglycon was accomplished for the first time. It was proved that the
found reagent is to be general and unique for the preparation of series of 2-О-acetyl aryl
glycosides. We have determined the influence of both carbohydrate moiety and the aglycon on
the selectivity of deacetylation reaction by kinetic experiments. Using DFT/B3LYP/6-31G(d,p)
and semi-empirical АМ1 methods we have found that the highest activation barrier is for 2-О-
acetyl group. This completely explains the least reactivity of 2-О-acetyl group.
1 Corresponding author at present address: Department of Biotechnology and Organic
Chemistry, National Research Tomsk Polytechnic University, 30 Lenin Avenue, Tomsk, 634050,
Russia. Tel.: 7 (3822) 56 38 61; fax: +7 (3822) 56 36 37.
E-mail addresses: eline_m@mail.ru, glycoside.m@gmail.com (E.V. Stepanova).
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Key words: aryl glycosides, regioselective deacetylation, reactivity, partially acylated
carbohydrates, transition states modeling
2

ACCEPTED MANUSCRIPT
Highlights:
•
•
•
•
Different reactivity of acetyl groups of glycosides in acid-catalyzed deacetylation
Regioselective preparation of 2-O-acetyl aryl glycosides was accomplished
The influence of carbohydrate structure on regioselectivity of deacetylation
Different reactivity of Ac groups is explained by activation barriers
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1 Introduction
Aryl glycosides are one of the most common plant secondary metabolites and are of
interest as naturally occurring bioactive substances. Aryl glycosides play an important role in
plant development and interaction with other organisms, namely protection of plants from
microbes, insects and herbivores [1]. A large number of studies have been carried out to establish
antiparasitic, antitumor, antiviral activity of arylglycosides [2,3].
Partially acetylated aryl glycosides are widely found in nature. Particularly, many
examples of 2-O-acetyl arylglycosides can be found [4, 5]. Several 2-O-acetyl arylglycosies are
known as chemotaxonomic markers for the plants of Salicaceae family such as 2-acetylsalicin
[6] and 2-acetylsalicortin [7]. Partially acetylated aryl glycosides are also interesting for
pharmacology as they have different bioactivity comparing to non-acetylated compounds with
the same skeleton [8,9]. Synthesis of these compounds was not accomplished to date due to the
complex procedure of the selective introduction of a single acetyl group into the molecule of
glycoside and the feasibility of acetyl group to migrate [10, 11, 12, 13]. Only few examples of
synthesis of 2-O-acetyl aryl glycosides with simple aglycon are published requiring many steps
[14].
Generally, acetyl groups are widely used as protective in carbohydrate chemistry [15]. In
some syntheses 2-O-acyl protecting group in carbohydrate moiety might be strongly required for
the selective trans – glycosylation as a participating group [16]. Thus, 2-O-acetyl gluco- and
galactopyranosyl building blocks can find application in oligosaccharide synthesis. To remove
acetyl groups from carbohydrate moiety base- catalyzed methods such as Zemplen [17] or
similar [18, 19, 20] procedures are commonly used. Acidic catalysis is applied only in the case of
selective removal of acetyl group in the presence of benzoyl [21] or other ester groups [22, 23,
24, 25]. However, acidic catalysis is unfavorable in carbohydrate chemistry due to the low
stability of glycosidic linkage in acidic medium [26] and thus has less attention in syntheses.
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Nevertheless, in the present work we show that acidic – catalyzed deasetylation can find wider
applications in carbohydrate synthesis due to the different reactivity of acetyl groups.
In our previous work, we demonstrated that the treatment of per – acetylated glycosides
bearing bulky ortho – substituted aglycon with HCl in EtOH and CHCl3 reagent does not break
the glycosidic bond and selectively removes three acetyl groups. As a result, the 2-O-acetyl
glycosides were prepared with moderate to high yields [27]. In the present research we report
that bulky ortho – substituted phenols are not obligatory to achieve selectivity and any aryl
aglycon can be present for the preparation of 2-O-acetyl glycosides. We study the influence of
both carbohydrate moiety and the aglycon on regioselectivity of deacetylation in the described
conditions (HCl in EtOH and CHCl3). We also elucidate the nature of this phenomenon using
experimental and theoretical methods.
2 Materials and methods
2.1 General
Silicagel MN Kieselgel 60 0.04 - 0.063 mm was used for column chromatography.
Commercially available solvents were used after drying, distillation and were kept under
molecular sieves 4 . HPLC analysis was carried out on an Agilent Compact LC with a 150 × 4.6
mm Eclipse Plus C-18 (5 µm) column, eluted with a gradient of H2O – CH3CN containing 0.1%
trifluoroacetic acid from 0% to 100 % CH3CN in 20 min and a flowrate of 1 mL/min. Probe
volume was 20 µL. UV detection was performed at 220 nm. The preparation of glycosides 1-9
was carried out according to the known procedure from 1,2,3,4,6-tetra-O-acetyl-β-D-
glucopyranose or 1,2,3,4,6-tetra-O-acetyl-β-D-galactopyranose using BF3·Et2O and Et3N [28].
All physicochemical data for glycosides 1-9 was in good agreement with those published in
literature.
2.2 General deacetylation procedure
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To a solution or suspension of per-acetyl glucoside 1-9 (1 mmol) in CHCl3 (1 ml) and 96%
EtOH (3 ml) a 36% solution of hydrochloric acid (1 ml, 10 mmol) was added and the complete
dissolution of glycoside was observed. The reaction mixture was thermostated at 30 °C until
HPLC showed the maximal peak of 2-O-acetyl glycoside (retention times are given in Table 1).
The reaction mixture was treated with anion-exchange resin AB-17 until a pH of 7 was reached,
filtered, and concentrated under vacuum. The residue was subjected to column chromatography
using CHCl3 – EtOH 15:1 → 4:1 as eluents to give 2-O-acetyl glycosides 1a-8a and non-
acetylated glycosides 1b-9b. Spectral characteristics of all resulted 2-O-acetyl glucopyranosides
1a-8a are given in the Support information file 1.
2.3 Optimization of reaction conditions
The optimization was carried out using glycoside 1 and the following parameters (HPLC
monitoring):
1. Reaction temperature. Temperature less than 30 °C inhibits the reaction however does
not influence the selectivity. Temperature higher than 30 °C both increase the reaction rate and
significantly decreases selectivity.
2. Solvent composition. Varying the ethanol-chloroform ratio leads to the loss of
homogeneity to form either two non-mixable phases or the crystallization of glycoside 1. Both
cases lead to not comparable and unpredictable results.
3. The amount (concentration) of HCl. We use 36% HCl with the total concentration in the
reaction mass of 2 mol/L. The lowering of HCl concentration leads to the reduction of reaction
rate but no yield increase of 2-O-acetates was observed. The higher concentrations of HCl lead
to the higher reaction rates and less selectivity.
Thus, the less reaction temperatures and lower HCl concentrations can be used to achieve
similar reaction products but requires more time. However, higher temperatures and HCl
concentrations are not recommended due to the loss of selectivity
2.4 Kinetic calculations
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Rate constant was measured for the reaction of a single 2-O-acetyl group ethanolysis of
glycoside 1a (Scheme 1). Calibration curve (the dependence of peak area from concentration)
was prepared for glycoside 1a at concentrations 0.25 mg/ml, 0.5 mg/ml and 1 mg/ml using
HPLC (Figure 1 A). The 0.5 ml ampule with screwed cap was filled with 2-O-acetyl glucoside
1a (5 mg, 16.7 µmol) and the mixture of EtOH (28.5 µl), CHCl3 (12.5 µl) and HCl 36% (4.5 µl,
45 µmol) with the total concentration of HCl 1 M. The ampoule was closed tightly and
thermostated at 30 °C. At pre-selected times the 2 µl aliquot was taken, quenched with the
mixture of acetonitrile – water 1:1 (200 µl) and analyzed by HPLC three times and the average
peak area was calculated. The concentrations of compound 1a in the reaction mixture were found
according to the calibration curve. The graphics for the dependences of concentration of 1a (C)
on time (t) (Figure 1 B) and ln (C) on t (Figure 1 C) were plotted. The reaction rate constant k
was estimated from the slope (Figure 1 C) assuming the reaction to be first-order in [glycoside
1a].
Scheme 1: The reaction of glycoside 1a ethanolysis
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Figure 1: Kinetic measurements for the reaction of acetyl group of compound 1
ethanolysis. A): the calibration curve for glycoside 1a which shows the dependence of peak area
(HPLC) from the concentration of glycoside 1a; B): the concentration profile (mol/L) of
glycoside 1a during the reaction; C): linear plot for the dependence of ln(C) of glycoside 1a on
time.
The described procedures were applied also for all samples 2a-8a to estimate rate constants
of 2-O-acetyl group ethanolysis. The fitting of the experimental data was satisfactory for all the
samples. The values of rate constants, obtained from different runs carried out under the same
experimental conditions, were reproducible to within 9%.
Activation energy was estimated experimentally for glycoside 1a in the same manner,
when thermostating the reaction at 30, 40 and 50 °C and rate constants were determined for the
reactions at each temperature. Activation energy was estimated from the slope using Arrhenius
graph (Figure 2, see also Table 4 in the section 3.2).
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Figure 2: Arrhenius plot for the reaction of 2-O-acetyl group ethanolysis of 2-O-acetyl
phenyl glucopyranoside 1a.
2.5 Quantum chemical modeling
The acid catalyzed transesterification reaction at low concentrations of acids is generally
accepted to occur via a stepwise mechanism [29]. It includes the formation of a protonated
adduct I and then the rate-determining step which is the nucleophilic attack with the formation of
transition state (TS) [30] (Scheme 2). For the modeling and investigation of these reaction steps
the quantum chemical model was built using the AM1 [31] semi-empirical method and density
functional theory (DFT) [32] using the B3LYP [33] functional and 6-31G(d,p) basis set.
O
O
O
O
O
O
O
O
H+
EtOH
lim
OPh
OPh
OPh
OH+
H2
C
OPh
OPh
OH
C
H
O
C
OH
H3C
H3C
C OH
CH3
H3C
O
OH
O
C
C
OH+
H3C
H3C
O
H3C
H2
H2
CH3
1
I
RC
TS
PC
protonation step
nucleophilic attack
Scheme 2: Mechanism of acid-catalyzed ethanoholysis of 2-O-acetyl group for phenyl 2,3,4,6-
tetra-O-acetyl glucopyranoside (1).
The first step (protonation) is not rate-determining whereas the second step (nucleophilic
attack) determines and characterizes the whole process and the reactivity of substrates [34].
Therefore, for the first step we calculated only Gibbs energies to characterize the reaction within
the thermodynamic criteria, and for the second step we modeled the transition states, and
calculated both Gibbs energies and activation barriers.
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To calculate Gibbs energies for the first (protonation) step the equilibrium geometries of
ground electronic states of reagents and products were modeled at AM1 level of theory in the gas
phase. The following structures of reagents were modeled: the per – acetylated glycoside 1 and
the complex of proton and ethanol. The most stable complex consists of one proton and three
ethanol molecules [30]. As a result of the first step of reaction the products are protonated
intermediate I and a trimer of ethanol.
The second step (nucleophilic attack) involves the formation of reactant complex RC from
the protonated glycoside 1 and one ethanol molecule. In TS, the tetrahedral intermediate
decomposes to form a new ester (ethyl acetate) and 2-OH of glucoside (as demonstrated on
Scheme 2). As a result, the product complex PC appears. The equilibrium geometries of ground
electronic states for both RC and PC were obtained at AM1 level of theory. In order to calculate
the activation barrier the geometries of TS were received using AM1 method.
Note that the nucleophilic attack can be the interaction between water molecule and the
protonated glycoside 1 due to the water is present in the solvent composition. However, the
amount of water in reaction mass is almost four times less than ethanol. We obtained the TS and
activation energy for this reaction, too at AM1 level of theory.
Also, the activation energy of 2-O-acetyl phenylglucoside (1a) deacetylation was
calculated at AM1 and B3LYP/6-31G(d,p) levels of theory. For the verification of using levels
of theory the comparison of theoretical and experimental values of activation energy was carried
out.
Cartesian coordinates of atoms for all optimized geometries are given in the Support
information file 2. At present work, the thermal correction was used for all calculations at T=303
K because all experimental reactions occurred at this temperature. Due to inadequate results of
COSMO [35] and PCM [36] solvation models in the case of ionic compounds, we carried out all
calculations for a gas phase. It should be noted, that semi-empirical AM1 method demonstrates
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good qualitative results [37] and is comparable with the density functional results [38], too. So,
we chose this method for the calculation.
All calculations were carried out using GAUSSIAN software [39].
3 Results and discussion
3.1 Kinetic study
In the present work, we found that acetyl groups of per – acetylated aryl glycosides 1-9
have different reactivity in the reaction of acidic deacetylation using the following conditions: 10
M hydrochloric acid (1 mL) – 96% EtOH (3 mL) – CHCl3 (1 mL) per 1 mmol of tetraacetyl aryl
glycoside 1-9 (Table 1). Such solvent ratio allows obtaining completely homogenous reaction
mixture. We found that the main products of this reaction are 2-O-acetyl aryl glycosides 1a-9a,
the results are summarized in Table 1.
We found out that the monosaccharide moiety has a great influence on the regioselectivity
of this reaction. Thus, for the compounds with the same aglycon regioselectivity (Table 1,
column 4) decreases in the order: β-D-galactoside (3) > β-D-glucoside (2) >> α-D-glucoside (9).
In the case of glycoside 9 we detected several monoacetyl isomers and were not able to isolate
individual products from this mixture. This fact indicates that 1,2-trans configuration of
anomeric center is required for regioselective preparation of 2-O-acetyl glycosides.
In order to reveal the influence of aglycon on acetyl group reactivity we evaluated rate
constants of acetyl group at O-2 of glycosides 1a-8a ethanolysis (Table 1, column 7). For this, 2-
O-acetyl glycosides 1a-8a were subjected to the reaction (as for 1a, Scheme 1, section 2.2) using
the described conditions. We found out that the structure of the aglycon has a certain effect on
the regioselectivity of the β-D aryl glycosides deacetylation. Thus, in the series of aryl glycoside
1 and para – substituted glycosides 4, 6, 8, the regioselectivity decreases with the increasing of
the electron-donating properties of the substituents. In addition, ortho – group in pairs of equal
electronic substituents impedes the reaction and increases the yield of 2-O-acetyl product (entries
2, 5, 7 in comparison to 4, 6, 8).
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It worth to note that in the case of methoxyphenyl glycosides 7 and 8 a substantial amount
of isomeric monoacetates 7c and 8c were isolated (Table 1, entries 7 and 8, respectively). We
established the structure of these isomers to be 3-O-acetyl glucopyranosides using NMR method.
During the ethanolysis of glycosides 1-6 only small amount of isomeric monoacetates
(presumably, 3-O-acetates) 1c-6c was detected by HPLC or not detected at all (were not
isolated).
Table 1: Results of HCl – catalyzed deacetylation of per – acetylated glycosides 1-9
OAc
OH
OH
HCl
EtOH
CHCl3
30 °C
-EtOAc
R1
R1
R1
O
O
O
HO
HO
AcO
AcO
HO
AcO
O
O
O
OAc
OAc
OH
R2
R2
R2
1-8
1c-9c
1a-9a
E
nt
ry
Retention
time of 2-O-
acetyl
product at
HPLC, min
3
Initial
Preparative
yield of 2-
O-acetyl
compound/
2-O-acetyl
product
2Ac: 3Ac
ratioa
Reaction
time, h
Substituent
Rate constant,b h-1
product, %
1
1/1a
2/2a
2
4
98:2
96:4
5
6
12
6
45
55
7
1
2
3
R1=R2=H
12.1
10.2
0.122±0.028
0.106±0.011
R1=CH3, R2=H
R1=CH3, R2=H
(β-D-Galp)c
10.2
100:0
11
35
0.084±0.008
3/3a
4
5
6
7
8
9
R1= H,R2=CH3
R1=NO2, R2=H
R1=H, R2= NO2
R1=OMe, R2=H
R1=H, R2= OMe
R1=CH3, R2=H
(α-D-Glcp)d
10.2
9.3
9.5
8.8
9.1
94:6
100:0
92:8
85:15
80:20
10
12
10
12
8
25
22
19
45
21
0.111±0.005
0.183±0.019
0.235±0.035
0.282±0.034
0.315±0.037
4/4a
5/5a
6/6a
7/7a
8/8a
9.9
60:30
8e
-
-
9/9a
a)
b)
1a-8a to 1b-8b (see Scheme 1)
The ratio of glycoside 1a-9a to 1c-9c, correspondingly
Rate constants were determined for a single 2-O-acetyl group ethanolysis of glycosides
c)
d)
e)
o-cresyl 2,3,4,6 tetra-O-acetyl-β-D-galactopyranoside was used as initial compound
o-cresyl 2,3,4,6 tetra-O-acetyl-α-D-glucopyranoside was used as initial compound
Time of maximal concentration of monoacetyl glycoside detected by HPLC
3.2 Mechanism modeling and the activation energy calculation
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The protonation step as the first step was modeled for each acetyl group of per – acetylated
glycoside 1. The geometries of each structure required for this step illustrating 2-O-acetyl group
protonation are given in Figure 3. The calculated ΔGs of this step for each isomeric monoacetate
(acetyl group at O-2, O-3, O-4 or O-6) are given in Table 2, the energy of reagents is taken for a
zero. According to the results, the reaction is possible according to thermodynamic criteria at the
temperature (30 °C). The protonation of O-6 acetyl group carbonyl is the most energetically
preferred because ΔGs for the protonation step of other acetyl groups (O-2, O-3 and O-4) are less
for 7-10 kcal/mol.
Figure 3: The modeling of protonation step of acid-catalysed deacetylation of compound 1
for protonation of 2-O-acetyl group
Table 2: Energies of products in the respect to reagents for the protonation step of acid-catalysed
deacetylation of compound 1 calculated by AM1 method, in kcal/mol
Acetyl
∆G of the
protonation step
Relative energies of
products
group
protonated
O-2
-132.4
-132.4
-135.0
-142.6
10.2
10.2
7.6
0
O-3
O-4
O-6
In general, the obtained results give thermodynamic characteristic of the first (protonation)
step whereas do not explain the unusual reactivity of 2-O-acetyl group due to the second step (an
interaction with the nucleophile) is rate-determining.
The optimized structures of RC, TS, PC for the second step (nucleophilic attack) of the
reaction at O-2 of glycoside 1 are shown in Figure 4. The quantitative characteristics of this step
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for all isomers (ΔGs between RC and PC and activation energies) are summarized in Table 3. As
seen from Figure 4 (B), the imaginary frequency of TS involves the vibration of the proton
which transfers from ethanol oxygen to glucose oxygen O-2.
Figure 4: Optimized geometries for (A) RC, (B) TS (the imaginary frequency is illustrated
by an arrow) and (C) PC of the ethanolysis reaction of O-2 acetyl group of per-acetylated phenyl
glycoside 1.
Table 3: Relative energies of RC, TS and in respect to the energy of PC; activation
energies and Gibbs energies of the rate-determine stage of etanolysis of each acetyl group in
tetrracetyl phenylglycoside 1 calculated by AM1 method, in kcal/mol
Acetyl group
RC
TS
Activation energy
PC
∆G
position
O-2
O-3
O-4
O-6
4.1
46.0
53.1
54.1
43.7
41.9
39.2
39.2
12.3
0
0
0
0
-4.1
13.9
14.9
31.4
-13.9
-14.9
-31.4
According to the results all reactions are thermodynamically permitted. However, the
activation barrier is maximal for the reaction at 2-O-acetyl group. Thus, it fully indicates the
least reactivity of 2-O-acetyl group in acid-catalyzed reaction.
Assuming acetyl groups at 2, 3 and 4 positions react at similar concentrations the ratio
t=exp(-E3,4/kT)/exp(-E2/kT) gives a value of 88, where Ei is the activation energy of i-acetyl
group. This rough estimation leads to conclusion that 3- and 4-O acetyl groups react almost two
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orders of magnitude faster than 2-O-acetyl group. 6-O-Acetyl group reacts much faster than all
other acetyl groups because of activation barrier exceeds 3 times. However, the yields of 2-O-
acetyl aryl glycosides in reaction of deacetylation are not high and not exceed 55%. As noted
above, the hydrolysis reaction may occur instead of ehanolysis. Therefore, the interaction
between water molecule and the protonated glycoside 1 can be involved in the step of transition
stay formation (Table 4 shows this interaction for 2-O-acetyl group). The results of activation
energy calculation of transition states (TS) of hydrolysis are summarized in Table 4. Although
concentration of water is very negligible in comparison with ethanol as solvent, this reaction can
reduce the yield of 2-O acetyl glycosides due to the activation barrier is almost same and very
small for all acetyl groups.
Table 4 - Activation energies of the rate-determine stage of hydrolysis of each acetyl
group of tetraacetyl phenylglycoside 1 calculated by AM1 method, in kcal/mol
Acetyl group
Activation energy
position
O-2
O-3
O-4
O-6
2.0
3.5
1.6
2.2
Also, we calculated the activation barrier for 2-O-acetyl group of 1a deacetylation. The
results of quantum-chemical calculations using both AM1 and DFT/B3LYP methods as well as
experimental data are summarized in Table 5. According to the results, AM1 method leads to an
insignificant overestimation of activation energy by 9 kcal/mol and generally gives an adequate
values, therefore, we can assume that the above calculated activation energies using the AM1
method are acceptable for the reactivity evaluation. The results obtained using DFT/B3LYP
method are in a good agreement with the experiment. Thus, activation energies given in Tables 2
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and 3 can be overestimated by 9 kcal/mol in general; nevertheless, the calculated results
correctly reproduce the regularity of acetyl groups of per – acetylated glycoside reactivity in
acid-catalyzed deacetylation. Also, the together experimental and theoretical results show that
the ethanolysis mechanism prevails over hydrolysis in spite of small activation barrier for the
latter.
Table 5: Activation energy for the reaction of 2-O-acetyl group ethanolysis of 2-O-acetyl
phenyl glucopyranoside 1a
Activation energy,
Calculation method
in kcal/mol
DFT/B3LYP/6-
31G(d,p)
25.3
AM1
ExP
30
21.4
4 Conclusions
Thus, we established that the reactivity of 2-O-acetyl group of per – acetylated β-D-aryl
glycosides (glucopyranosides and galactopyranosides) is less than other acetyl groups during the
ethanolysis reaction using HCl/EtOH in CHCl3. This result gives the base for the synthetic
method for the preparation of 2-O-acetyl aryl glycosides. The least reactivity of 2-O-acetyl group
is explained by the highest activation barrier of rate-determining step of nucleophilic attack for
the formation of tetrahedral transition state according to the quantum-chemical calculations.
According to our estimation, the reactivity of 2-O-acetyl group is 88 times less than for 3-, 4- or
6-acetyl groups.
5 Supplementary material
Spectral data, physicochemical properties of monoacetyl glycosides 1a-8a, 7c and 8c as
well as 1H, 13C, and 2D NMR spectra are given in the Support information file 1. The
geometries of calculated molecules (RC, PC) and transition states (TS) are given in the Support
information 2.
6 Acknowledgements
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This work was supported by the Tomsk Polytechnic University Competitiveness
Enhancement Program grant [Project Number VIU-TOVPM-316/2017 and by The Tomsk State
University Competitiveness Improvement Programme grant (N8.1.03.2017).
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Highlights:
1. We revealed different reactivity of acetyl groups of glycosides in acid-catalyzed
deacetylation
2. Regioselective preparation of 2-O-acetyl aryl glycosides was accomplished
3. The influence of carbohydrate structure on regioselectivity was revealed
4. Different reactivity of Ac groups is explained by activation barriers