Theoretical and experimental study on the reactions between 3,5-di-O-p-toluoyl-d-2-deoxyribosyl chloride and alcohols

Article abstract of DOI:10.1016/j.molstruc.2010.03.064

The solvent effect on the reactions of 3,5-di-O-p-toluoyl-d-2-deoxyribosyl chloride with alcohols has been studied with the help of density functional theory (DFT) method using the polarized continuum model (PCM). Moreover, the calculation allows a discussion of the solvent effect on the ratio of α- to β-anomer to compare with the experimental result. The results obtained by the present calculations are in excellent agreement with the experimental findings.

Full text of DOI:10.1016/j.molstruc.2010.03.064

Journal of Molecular Structure 977 (2010) 1–5
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Theoretical and experimental study on the reactions between
3,5-di-O-p-toluoyl-D-2-deoxyribosyl chloride and alcohols
*
QiaoCui Shi , Rong Sun, XiangWei Cheng
Experimental Center Zhejiang Police College, Hangzhou 310053, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The solvent effect on the reactions of 3,5-di-O-p-toluoyl-D-2-deoxyribosyl chloride with alcohols has
Received 27 January 2010
Received in revised form 16 March 2010
Accepted 29 March 2010
Available online 2 April 2010
been studied with the help of density functional theory (DFT) method using the polarized continuum
model (PCM). Moreover, the calculation allows a discussion of the solvent effect on the ratio of - to
b-anomer to compare with the experimental result. The results obtained by the present calculations
a
are in excellent agreement with the experimental findings.
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Solvent effect
3,5-Di-O-p-toluoyl-D-2-deoxyribosyl
chloride
DFT
PCM
1. Introduction
3,5-Di-O-p-toluoyl-
the O-nucleoside by the reaction between 3,5-di-O-p-toluoyl-D-2-
deoxyribosyl chloride and alcohols neither to say under our opti-
mized conditions. As a consequence, in this work, we synthesized
a series of new O-nucleoside through the reaction of 3,5-di-O-p-tol-
D
-2-deoxyribosyl chloride (Scheme 1) is a
common and important starting material for most syntheses of
the nucleoside analogues [1,2]. Nucleoside analogues are of wide
biological interest. For example, they can be used for site-directed
modification of DNA/RNA fragments with respect to the studies of
structures and functions of nucleic acids [3–5]. Additionally, many
nucleoside analogs exhibit antiviral, antibiotic and anticancer
activity [6]. Therefore, it should be of significance to study the
nucleoside analogues.
uoyl-
of b- to
D
-2-deoxyribosyl chloride with alcohols, meanwhile, the ratio
-anomer in different solvents were analyzed using High
a
Performance Liquid Chromatography (HPLC). On the other hand,
theoretical study of the solvent effect on the selectivity of this reac-
tion and the reaction mechanism were also carried out.
2. Experiment
From Scheme 1 we can see: 3,5-di-O-p-toluoyl-D-2-deoxyribo-
syl chloride is a chiral compound and it has a stereogenic center
on the position of C1, hence when it reacts with the alcohol, the
product afforded is commonly constituted by two diastereomers
Methanol (0.0960 g, 3.0 mmol) was added to a solution of 3,5-
di-O-p-toluoyl-D-2-deoxyribosyl chloride (1.0734 g, 2.5 mmol) in
tetrahydrofuran (20 ml), and the mixture was stirred at room tem-
perature for several hours (Scheme 2). The reaction was monitored
by thin layer chromatography (TLC). After the reaction, the mixture
was evaporated in vacuo, the residue was then diluted with petro-
leum ether (20 ml) and the precipitation was filtrated. The filtrate
was concentrated again in vacuo to give the product in 94.5% yield.
The isomers were separated by silica gel column chromatography
and a series of diastereomers as new compounds were obtained
(a- and b-anomers), and the ratio of a- to b-anomer is related to
the reaction conditions. However, only the b-anomer shows phys-
iological activity [7,8]. Thus, in order to get more of the desired
anomer, exploring the effect of the reaction conditions on the ratio
of
a
- to b-anomer should be essential.
In our previous work, we explored the selectivity of the anomers
in the reaction between 3,5-di-O-p-toluoyl- -2-deoxyribofuranosyl
D
and identified by 1H NMR and GC–MS. The ratio of b- to
a-anomer
in different solvents were analyzed using HPLC (Tables 1–7).
chloride and bis-O-(trimethylsilyl)-5-S-benzyl-mercaptouracil [9].
Meanwhile, the nucleoside analogues can also be synthesized by
the formation of O-nucleoside besides N-nucleoside [10–17] and
C-nucleoside [18], to the best of our knowledge, few has synthesized
2.1. General
The 1H NMR spectra was measured on a Bruker Avance-500
spectromer operating at 500 MHz, and the chemical shifts are
* Corresponding author. Tel./fax: +86 057187787134.
E-mail address: qcshi@126.com (Q. Shi).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.03.064

2
Q. Shi et al. / Journal of Molecular Structure 977 (2010) 1–5
Table 1
O
Cl
5
O
1
4
1-O-methyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
O
Solventb
Productivity (%)
b-anomer (%)
a
-anomer (%)
b/a
3
O
2
CH3CN
CH2Cl2
THF
96.4
95.2
94.5
92.0
53.1
49.8
48.4
48.3
43.3
45.4
46.1
43.7
1.23
1.10
1.05
1.11
O
Cl
CHCl3
a
The ratio of 3,5-di-O-p-toluoyl-D-2-deoxyribosyl chloride to methanol was
1:1.2.
b
Cl
For different solvents, the reaction was reacted for the same period of time.
Scheme 1. 3,5-Di-O-p-toluoyl-D-2-deoxyribosyl chloride.
reported in parts per million on d scale downfield from tetrame-
thysilane (TMS) used as an internal standard and signal patterns
are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. All the solvents are analytical reagent.
Table 2
1-O-ethyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
Solventb
Productivity (%)
b-anomer (%)
a
-anomer (%)
b/a
CH3CN
CH2Cl2
THF
96.5
90.9
88.4
86.3
57.5
50.6
47.6
45.4
39.0
40.3
40.8
40.9
1.47
1.25
1.17
1.11
2.2. Representative data
CHCl3
1-O-ethyl-3,5-di-O-p-toluoyl-a-D
-2-deoxyribosyl: 1H-NMR(CDCl3,
a
The ratio of 3,5-di-O-p-toluoyl-
For different solvents, the reaction was reacted for the same period of time.
D
-2-deoxyribosyl chloride to ethanol was 1:1.2.
500 MHz): 7.94–7.99 (m, 4H, Ar–H); 7.39–7.42 (m, 4H, Ar–H);
b
3
5.39–5.42 (m, 1H, H-3); 5.30–5.31 (d, 1H, J1,2 = 4.8, H-1); 4.59–
4.61 (m, 1H, H-4); 4.52–4.54 (m, 2H, H-5); 3.80–3.83 (m, 1H,
OCH2CH3); 3.43–3.53 (m, 1H, OCH2CH3); 2.48–2.54 (m, 1H, H-2);
2.18–2.21 (m, 1H, H-2); 1.22–1.25 (t, 3H, CH2CH3). Mp: 66–68 °C.
Table 3
1-O-ethyl-3,5-di-O-p-toluoyl-b-
-2-deoxyribosyl: 1H-NMR(CDCl3,
D
1-O-isopropyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
500 MHz): 7.94–8.03 (m, 4H, Ar–H); 7.39–7.42 (m, 4H, Ar–H);
Solventb
Productivity (%)
b-anomer (%)
a
-anomer (%)
b/
14.4
1.13
1.23
1.33
a
3
0
5.59–5.62 (m, 1H, H-3); 5.35,5.36 (dd, 1H, J1,2 = 2.0, 3J1,2 = 5.6,
CH3CN
CH2Cl2
THF
92.4
91.4
89.5
89.1
86.4
48.6
49.3
52.0
6.0
42.8
40.2
39.1
H-1); 4.54–4.59 (m, 1H, H-4); 4.47–4.52 (m, 2H, H-5); 3.74–3.81
(m, 1H, OCH2CH3); 3.43–3.51 (m, 1H, OCH2CH3); 2.52–2.58 (m,
1H, H-2); 2.33–2.39 (m, 1H, H-20); 1.15–1.18 (t, 3H, CH2CH3).
Mp: 70–71 °C.
CHCl3
a
The ratio of 3,5-di-O-p-toluoyl-
1:1.2.
D-2-deoxyribosyl chloride to isopropanol was
1-O-isopropyl-3,5-di-O-p-toluoyl-a-D
-2-deoxyribosyl:1H-NMR-
b
(CDCl3, 500 MHz): 7.95–8.03 (m, 4H, Ar–H); 7.39–7.42 (m, 4H, Ar–
H); 5.42–5.43 (m, 1H, H-3); 5.40 (d, 1H, 3J1,2 = 5.4, H-1); 4.58–4.60
(m, 1H, H-4); 4.51–4.54 (m, 2H, H-5); 3.96–3.98 (m, 1H,
OCH(Me)2); 2.46–2.51 (m, 1H, H-2); 2.15–2.31 (m, 1H, H-20);
1.14–1.26 (m, 6H, 2CH3). Mp: 89–90 °C.
For different solvents, the reaction was reacted for the same period of time.
stationary points were fully optimized at the B3LYP/6-31Gꢀ [20]
level of theory. Before optimization, the BioMedCAche 5.02
program package [21] was used by means of CONFLEX [22]
conformational search procedure to locate low-energy conforma-
tions of all the products. The B3LYP functional is composed of
Becke’s three-parameter hybrid exchange functional (B3)
[23,24], as implemented in GAUSSIAN 98 [25], and the correlation
functional of Lee, Yang, and Parr (LYP) [26]. The energy differ-
ences between products and solvation energies for products were
computed using solvation model PCM with the permittivities of
36.64, 8.93, 7.58 and 4.9 for CH3CN, CH2Cl2, THF and CHCl3,
respectively.
1-O-isopropyl-3,5-di-O-p-toluoyl-b-
-2-deoxyribosyl: 1H-NMR-
D
(CDCl3, 500 MHz): 7.94–8.03 (m, 4H, Ar–H); 7.38–7.42 (m, 4H,
3
Ar–H); 5.57–5.61 (m, 1H, H-3); 5.48, 5.50 (dd, 1H, J1,2 = 2.6,
0
3J1,2 = 5.4, H-1); 4.54–4.55 (m, 1H, H-4); 4.49–4.52 (m, 2H, H-5);
3.91–3.97 (m, 1H, OCH(Me)2); 2.47–2.53 (m, 1H, H-2); 2.34–2.40
(m, 1H, H-20); 1.14–1.19 (m, 6H, 2CH3). Mp: 82–83 °C.
3. Calculation
The calculations were performed with the GAUSSIAN 98 pro-
gram package [19], using DFT method. The geometries of all the
O
O
Cl
RO
O
O
O
O
ROH
+
O
O
O
O
Cl
Cl
Cl
Cl
R=CH3, CH3CH2, i-C3H7, C3H7, C4H9, C6H11, C10H19
1: R=CH3;
2: R=CH3CH2;
5: R=C4H9; 6:R=C6H11
3: R=i-C3H7;
4: R=C3H7
;
7:R=C10H19
Scheme 2. The reaction route.

Q. Shi et al. / Journal of Molecular Structure 977 (2010) 1–5
3
On the other hand, when the reaction was carried out for the
same period of time in the four different solvents we selected, with
the increasing of the solvent polarity, the yields of the products
increase, which means that the products can more easily be
obtained in polar solvent than in apolar one. On the whole, the
4. Results and discussion
3,5-di-O-p-toluoyl- -2-deoxyribosyl chloride reacted with alco-
hols in acetonitrile, dichloromethane, tetrahydrofuran and chloro-
form, respectively, at room temperature for several hours, the
products were analyzed by HPLC and the results were collected
in Tables 1–7. The experimental outcomes show on one hand, of
D
ratio of b-anomer to
a-anomer increases with the increasing of
solvent polarity except for a few one, this maybe for the reason
that in the selected reaction time, this few reactions have not
reached their equilibrium. Why polar solvent is preferred in the
reaction? We suppose, this maybe related to the mechanism of
the reaction.
Concerning the mechanism of the Hilbert–Johnson reaction,
two possible pathways were proposed in the literature works so
far (Scheme 3). Path (1) is SN2 mechanism [12], Path (2) is carbo-
nium ion mechanism with a neighboring-group participation effect
(the group of C(2) links to the carbonium ion, and the group of C(5)
links to the carbonium ion if there are no groups on the C(2))
all the products studied, the ratio of b- to
one, that is to say, b-anomer could be more easily obtained than
-anomer and is the predominant product in the reaction, which
a-anomer is greater than
a
is in accordance with what we concluded when exploring the
selectivity of the anomers in the Hilbert–Johnson reaction [9]. In
addition, the conformations of all the products were optimized
and the energy differences between the two isomers are collected
in Table 8. It was found that the energies of b-anomers are lower
than that of
a-anomers, so the b-anomer is more stable than the
a-anomer and is the major product of the reaction, which con-
[12,27,28], which determines that the
a-anomer is the predomi-
forms to the experimental results (Tables 1–7) very well.
nant product in the reaction. However, in our previous study we
proposed a different mechanism (Scheme 4) [9], in which a carbo-
nium ion 3b with a neighboring-group participation effect (the
group of C(3) links to the carbonium ion instead of the group of
C(5)) is formed.
Table 4
1-O-n-propyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
Solventb
Productivity (%)
b-anomer (%)
a-anomer(%)
b/a
The optimized conformation of the carbonium ion 3b with min-
imal energy was obtained (Fig. 1). In this conformation, the dis-
tance between oxygen atom in carbonyl group of 5-(p-
chlorobenzoyl) on C(3) and C(1) is 1.513 Å (within the range of a
normal bond distance), but the distance between oxygen atom in
carbonyl group of 5-(p-chlorobenzoyl) which links C(5) and C(1)
is 5.215 Å, somewhat out of the normal bond distance. Meanwhile,
we also calculated the minimal energy of 3b and 2d, the result
shows that the energy of 3b is about 5.02 kcal/mol lower than that
of 2d, it indicates that the conformation of 3b is priority to 2d, and
the neighboring-group participation effect determines that the
b-anomer is the predominant product in the reaction, which is in
CH3CN
CH2Cl2
THF
88.8
85.3
84.6
83.3
58.6
46.1
43.4
43.3
30.2
39.2
41.2
40.0
1.94
1.18
1.05
1.08
CHCl3
a
The ratio of 3,5-di-O-p-toluoyl-
1.2:1.
D-2-deoxyribosyl chloride to n-propanol was
b
For different solvents, the reaction was reacted for the same period of time.
Table 5
1-O-n-butyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
Solventb
Productivity (%)
b-anomer (%)
a-anomer (%)
b/a
CH3CN
CH2Cl2
THF
93.6
87.2
84.7
81.8
50.9
45.5
45.0
42.5
42.7
41.7
39.7
39.2
1.19
1.09
1.13
1.08
Table 8
Energy differences between
a- and b-anomer (b-anomer – a-anomer) (kcal/mol).
CHCl3
a
Entry
CH3CN
CH2Cl2
THF
CHCl3
The ratio of 3,5-di-O-p-toluoyl-D-2-deoxyribosyl chloride to n-butanol was
1a
2
3
4
5
6
7
ꢁ0.76
ꢁ0.77
ꢁ0.65
ꢁ0.15
ꢁ0.37
ꢁ0.26
ꢁ0.080
ꢁ0.65
ꢁ0.75
ꢁ0.58
ꢁ0.13
ꢁ0.38
ꢁ0.31
ꢁ0.089
ꢁ0.64
ꢁ0.72
ꢁ0.61
ꢁ0.18
ꢁ0.31
ꢁ0.20
ꢁ0.18
ꢁ0.69
ꢁ0.70
ꢁ0.63
ꢁ0.17
ꢁ0.44
ꢁ0.27
ꢁ0.26
1.2:1.
b
For different solvents, the reaction was reacted for the same period of time.
Table 6
1-O-cyclohexyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
Solventb
Productivity (%)
b-anomer (%)
a-anomer (%)
b/a
a
See Scheme 2 for the definition of 1–4.
CH3CN
CH2Cl2
THF
95.0
92.9
91.8
91.5
52.3
52.8
49.3
64.2
42.7
40.1
42.5
27.3
1.22
1.32
1.16
2.35
CHCl3
RCOOH2C
RCOO
SN2
(1)
O
a
OR
The ratio of 3,5-di-O-p-toluoyl-
D-2-deoxyribosyl chloride to cyclohexanol was
1.2:1.
b
For different solvents, the reaction was reacted for the same period of time.
5
RCOOH2C
O
2
2b
4
Cl
1
R
RCOO
3
Table 7
1-O-menthyl-3,5-di-O-p-toluoyl-D-2-deoxyribosyl.a
O
C
RCOOH2C
RCOO
2a
Solventb
Productivity (%)
b-anomer (%)
a
-anomer (%)
b/a
CH2
O
O
O
CH3CN
CH2Cl2
THF
90.8
87.5
80.7
69.4
61.4
47.8
45.6
41.0
29.4
39.7
35.1
28.4
2.09
1.21
1.30
1.44
(2)
RCOO
CHCl3
(R=p-chlorobenzoyl)
2d
2c
a
The ratio of 3,5-di-O-p-toluoyl-
D
-2-deoxyribosyl chloride to menthol was 1.2:1.
b
For different solvents, the reaction was reacted for the same period of time.
Scheme 3. Two typical mechanism of the Hilbert–Johnson reaction.

4
Q. Shi et al. / Journal of Molecular Structure 977 (2010) 1–5
RCOOH2C
5
O
RCOOH2C
O
RCOOH2C
O
2
4
O
Cl
O
1
RCOO
RCOO
C
3
R
2a
3a
3b
(R=p-chlorobenzoyl)
Scheme 4. The proposed mechanism of the reaction.
show that the b-anomer is the predominant product of the reac-
tion, meanwhile, the increase of the solvent polarity facilitates
the formation of the products.
A new possible reaction pathway is proposed by theoretical cal-
culation, which is a carbonium ion mechanism with a neighboring-
group participation effect. The mechanism determines that the b-
anomer is the predominant product in the reaction. All the exper-
imental results are in accord with the calculation outcomes very
well.
Acknowledgment
Fig. 1. Carbonium ion.
This work wast supported by the National Natural Science
Foundation of Zhejiang Province (Grant No. Y4080223).
Table 9
Solvation energies of products (kcal/mol).
Appendix A. Supplementary material
Products
CH3CN
CH2Cl2
THF
CHCl3
1 b-anomera
ꢁ13.56
ꢁ13.26
ꢁ13.48
ꢁ13.23
ꢁ13.33
ꢁ13.08
ꢁ13.18
ꢁ13.53
ꢁ13.39
ꢁ13.63
ꢁ13.38
ꢁ13.57
ꢁ13.50
ꢁ12.81
ꢁ11.32
ꢁ11.11
ꢁ11.32
ꢁ11.07
ꢁ11.17
ꢁ10.96
ꢁ10.99
ꢁ11.32
ꢁ11.15
ꢁ11.34
ꢁ11.16
ꢁ11.36
ꢁ11.23
ꢁ10.69
ꢁ10.70
ꢁ10.50
ꢁ10.67
ꢁ10.44
ꢁ10.56
ꢁ10.32
ꢁ10.33
ꢁ10.60
ꢁ10.39
ꢁ10.66
ꢁ10.55
ꢁ10.63
ꢁ10.50
ꢁ10.04
ꢁ9.32
ꢁ9.04
ꢁ9.28
ꢁ9.06
ꢁ9.21
ꢁ8.93
ꢁ8.94
ꢁ9.20
ꢁ9.05
ꢁ9.15
ꢁ9.11
ꢁ9.25
ꢁ9.07
ꢁ8.67
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2010.03.064.
1
a
-anomer
2 b-anomer
-anomer
3 b-anomer
-anomer
4 b-anomer
-anomer
5 b-anomer
-anomer
6 b-anomer
-anomer
7 b-anomer
-anomer
2
a
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good accordance with the experimental results (Tables 1–7) and
our calculated outcomes (Table 8). Solvent with strong polarity
can distribute the charges on the carbonium ion and will be favor-
able for the production of b-anomer.
The interaction between all the nucleosides and solvents were
calculated and the results were collected in Table 9. As can be seen
from the results: the interaction energies (absolute value) of sol-
vents and products increase with the increasing of solvent polarity,
that is to say, increasing polarity of the solvent could facilitate the
formation of the products, which is in accordance with the exper-
imental results in Tables 1–7.
5. Conclusion
The effect of solvent on the ratio of a-anomer to b-anomer was
studied by both experimental and theoretical methods. The calcu-
lation was carried out with the GAUSSIAN 98 program package at
the B3LYP/6-31Gꢀ level, and the solvent effect was investigated
using PCM model. The experiment and calculation results both
[21] BioMedCAche 5.02, Fujitsu Limited, Tokyo, Japan.

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