Hydrogen-bonding linkage of thymidine derivatives with carboxylic acid and pyridyl groups in a crystalline state

Article abstract of DOI:10.1166/jnn.2013.6173

Thymidine derivatives with carboxylic acid and pyridyl groups were synthesized for constructing one-dimensional network structure based on hydrogen bonding in crystalline state. The solid sate structures and hydrogen bonding networks of the thymidine derivatives were characterized by single X-ray diffraction analysis. The thymidine derivatives formed a zwitterion structure with a pyridinium proton and a carboxylate moiety in a crystalline state due to transfer of a proton from the carboxylic acid to the pyridyl moiety. Strong hydrogen bonds between the pyridinium proton and the carboxylate moiety connected the thymidine units, resulting in a one-dimensional polymeric structure with a uniform direction reminiscent of the structure of single-strand polythymidine. The chemical structure of the pyridyl group affects the hydrogen-bonding networks. The well-designed hydrogen-bonding interaction served as connecting parts for polythymidine mimics even in the presence of other hydrogen-bonding motifs such as nucleobases. Copyright

Full text of DOI:10.1166/jnn.2013.6173

Copyright © 2013 American Scientific Publishers
All rights reserved
Printed in the United States of America
Journal of
Nanoscience and Nanotechnology
Vol. 13, 4593–4600, 2013
Hydrogen-Bonding Linkage of Thymidine Derivatives with
Carboxylic Acid and Pyridyl Groups in a Crystalline State
Junichi Hoshino, Junpei Kuwabara∗, and Takaki Kanbara∗
Tsukuba Research Center for Interdisciplinary Materials Science (TIMS), Graduate School of Pure and Applied Sciences,
University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8573, Japan
Thymidine derivatives with carboxylic acid and pyridyl groups were synthesized for constructing
one-dimensional network structure based on hydrogen bonding in crystalline state. The solid sate
structures and hydrogen bonding networks of the thymidine derivatives were characterized by single
X-ray diffraction analysis. The thymidine derivatives formed a zwitterion structure with a pyridinium
proton and a carboxylate moiety in a crystalline state due to transfer of a proton from the carboxylic
acid to the pyridyl moiety. Strong hydrogen bonds between the pyridinium proton and the carboxylate
moiety connected the thymidine units, resulting in a one-dimensional polymeric structure with a
uniform direction reminiscent of the structure of single-strand polythymidine. The chemical structure
of the pyridyl group affects the hydrogen-bonding networks. The well-designed hydrogen-bonding
interaction served as connecting parts for polythymidine mimics even in the presence of other
hydrogen-bonding motifs such as nucleobases.
Keywords: Hydrogen-Bonding, Thymidine, Crystal Structure.
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Copyright: American Scientific Publishers
1. INTRODUCTION
best hydrogen-bond donor and the best hydrogen-bonding
acceptor will preferentially form hydrogen bonds to one
another.”6 Based on the rule, we focused on a demonstra-
tion of a precise control of hydrogen-bonding networks
forming a supramolecular architecture in the presence
of several kinds of hydrogen-bonding motifs in a crys-
talline state. The target of the present work is hydrogen-
bonding linkages of deoxynucleoside derivatives forming
one-dimensional network structures because nucleobases
are representative hydrogen-bonding motifs in nature and
supramolecular chemistry.7 Therefore, discrimination of a
hydrogen bonding of a linkage moiety from that of nucle-
obase is required to construct one-dimensional network
structures. In our molecular design, the best hydrogen-
bonding donor is a carboxylic acid and the best hydrogen-
bonding acceptor is a pyridyl group; there have been
several reports on strong hydrogen bonding between a car-
boxylic acid and a pyridyl group.8 A transfer of a proton
of the carboxylic acid moiety to the pyridyl group forms
carboxylate and pyridinium groups. The strong hydro-
gen bonding between carboxylate and pyridinium is also
expected, based on literature reports.9 Herein, we report a
hydrogen-bonding linkage of thymidine derivatives bear-
ing carboxylic acid and pyridyl groups. To investigate the
structural effects of a pyridyl group on supramolecular
structures, 3 kinds of thymidine derivatives were system-
atically designed and characterized in a crystal state.
Hydrogen bonding is one of the great tools in supramolec-
ular chemistry because it possesses directionality and
adequate strength to construct designed supramolecu-
lar architectures.1 For example, supramolecular fibers,
micelles, vesicles, and helical columnar structures have
been constructed of hydrogen-bonding networks.2 In addi-
tion, recent developments of nanomaterials have cre-
ated various structures and functions such as regular
pores3 and dynamic properties.4 Further development of
such systems requires molecular-level structural controls
that can be accomplished by supramolecular structures
regulated by well-defined hydrogen bonding networks.
Although various kinds of hydrogen-bonding motifs have
been evaluated in terms of their structures and associate
constants,5 further precise control of hydrogen bonding is
still required to enable selective formations of designed
supramolecular architectures, which leads to creation of
novel nanomaterials. For instance, in the presence of sev-
eral kinds of hydrogen-bonding motifs in a molecule,
discrimination of hydrogen-bonding pairs is necessary
to avoid undesired hydrogen-bonding connections. One
of the methods to differentiate hydrogen-bonding motifs
was reported by Aakeröy and coworkers as follows: “the
∗Authors to whom correspondence should be addressed.
J. Nanosci. Nanotechnol. 2013, Vol. 13, No. 7
1533-4880/2013/13/4593/008
doi:10.1166/jnn.2013.6173
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Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Hoshino et al.
O
O
NH
NH
O
N
O
N
N
O
O
O
c
HO
b
HO
O
O
.
N
HCl
1· HCl
2
O
N
O
N
O
O
NH
NH
NH
NH
O
O
O
N
O
N
O
a
d
e
O
O
O
O
HO
Ph3CO
HO
HO
OH
OH
O
O
N
N
3
O
O
NH
NH
O
N
O
N
O
g
f
O
O
HO
HO
O
O
N
N
4
Scheme 1. Reagents and conditions: (a) trityl chloride, pyridine, 100 ꢀC, 30 min (91%); (b) (i) 4-chloropyridine hydrochloride, KOH, DMSO, r.t,
50 h; (ii) HCl aq., EtOH, 80 ꢀC, 1 h (93%); (c) (i) TEMPO, BAIB, CH2Cl2, r.t, 2 h; (ii) CH3CN/H2O, r.t, 17 h (69%); (d) (i) NaH, THF, ultra sonic,
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20 min; (ii) 4-(bromomethyl)-pyridine hydroxybromide, ultra sonic, 40 min; (iii) H2O, r.t, 5 min; (iv) HCl aq., EtOH, 80 ꢀC, 1 h (88%); (e) TEMPO,
IP: 208.98.249.39 On: Tue, 08 Dec 2015 11:25:51
ꢀC, 1 h (75%);
BAIB, CH Cl , r.t, 2 h; (ii) CH CN/H O, r.t, C27ohpy(6r2ig%h);t:(fA) m(i)e2r-icchalonroSpycriideinnet,ifKicOPH,uDbMlisShOe, rrs.t, 70 h; (ii) HCl aq., EtOH, 80
2
2
3
2
(g) (i) TEMPO, BAIB, CH2Cl2, r.t, 2 h; (ii) CH3CN/H2O, r.t, 24 h (80%).
2. RESULTS AND DISCUSSION
2.2. Crystal Structures
2.1. Synthesis
Figure 1 shows an ORTEP drawing of 1·H2O and Figure 2
shows the crystal lattice. The unit cell contained a water
molecule hydrogen-bonded with the hydroxy group in
compound 1. The hydrogen bond between the imido
5ꢁ-O-tritylthymidine was prepared according to a pub-
lished procedure (Scheme 1).10 The reaction of 5ꢁ-O-
tritylthymidine with 4-chloropyridine was carried out in
the presence of KOH in DMSO.11 After introduction
of a pyridyl group at the 3ꢁ position, the trityl group
was removed by treatment with HCl. After purification
by column chromatography, 3ꢁ-O-(4-pyridyl)thymidine
hydrochloride (1 · HCl) was isolated at 93% yield. Oxida-
tion of the methylene moiety in 3ꢁ-O-(4-pyridyl)thymidine
hydrochloride using 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) and bisacetoxyiodobenzene (BAIB)12 gave 3ꢁ-O-
(4-pyridyl)thymidine-5ꢁ-carboxylic acid (2) at 69% yield.
The reaction of 5ꢁ-O-tritylthymidine and picolylchloride
in the presence of NaH yielded 3ꢁ-O-picolylthymidine
at 88% yield.13 3ꢁ-O-picolylthymidine-5ꢁ-carboxylic acid
(3) was synthesized under oxidation conditions similar
to those for 2. 3ꢁ-O-(2-pyridyl)thymidine-5ꢁ-carboxylic
acid (4) was obtained by the same procedure as 2
using 2-pyridylchloride as starting material instead of
4-pyridylchloride.
Fig. 1. ORTEP drawing of 1 · H2O with thermal ellipsoids shown at
the 30% probability level.
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Hoshino et al.
Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Fig. 2. Crystal lattice of 1·H2O exhibiting hydrogen bonding between
the imido proton in thymine and the pyridyl moiety. Oxygen atoms are
shown in red, nitrogen-blue, carbon-gray, and hydrogen-light gray.
proton (H16) in the thymine moiety and the pyridyl moiety
(N3) was observed in the crystalline lattice (Table I).
Compound 2 crystallized with DMSO molecules in the
orthorhombic space group P212121. The ORTEP drawing
of 2 · DMSO shows transfer of a proton from the car-
boxylic acid to the pyridyl moiety, which resulted in for-
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mation of a zwitterion structure (Fig. 3(a)). The position
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of the hydrogen atom on N3 was deCteorpmyirnigedht:bAymaedriicf-an Scientific Publishers
ference Fourier map. The crystal structure of 2·H2O was
Fig. 3. (a) ORTEP drawing of 2·DMSO with thermal ellipsoids shown
quite similar to that of 2·DMSO (Fig. 3(b)). On the other
hand, the crystal lattice of 2·H2O and 2·DMSO differed
in their hydrogen-bonding networks (Figs. 4 and 5). In
the crystal lattice of 2 · DMSO, the hydrogen bonds of
at the 30% probability level. One of the DMSO molecules was omitted
for clarity. (b) ORTEP drawing of 2·H2O with thermal ellipsoids shown
at the 30% probability level. One of the water molecules was omitted for
clarity.
Table I. Pertient hydrogen-bonding interactions for 1·H2O, 2·DMSO,
2·H2O, 3·H2O and 4·H2O [Å and ꢀ].
D–H···A
1·H2O
d(D–H) d(H···A) d(D···A) ∠(DHA)
N(3)–H(16)···N(2)
0.86
0.87
1.97
1.94
2.92
2.78
168
163
O(5)–H(17)···O(6)
2·DMSO
N(2)–H(26)···O(7)
N(3)–H(27)···O(3)
2·H2O
0.90
0.90
1.96
1.77
2.82
2.66
171
171
N(2)–H(14)···O(4)
N(3)–H(15)···O(4)
O(7)–H(18)···O(5)
3·H2O
0.86
0.86
0.89
1.94
1.77
2.00
2.79
2.61
2.85
170
164
161
N(2)–H(1)···O(8)
N(3)–H(17)···O(5)
4·H2O
1.01
1.10
1.81
1.57
2.89
2.62
176
159
N(2)–H(21)···O(13)
N(5)–H(22)···O(6)
O(3)–H(24)···O(14)
O(14)–H(26)···O(5)
O(15)–H(25)···O(6)
0.86
0.86
0.91
0.90
0.90
1.95
1.97
1.77
2.06
1.90
2.80
2.83
2.68
2.94
2.79
171
175
172
163
170
Fig. 4. Crystal lattice of 2 · DMSO exhibiting hydrogen bonding
between the pyridinium proton and the carboxylate moiety. Oxygen
atoms are shown in red, nitrogen-blue, sulfur-yellow, carbon-gray, and
hydrogen-light gray.
J. Nanosci. Nanotechnol. 13, 4593–4600, 2013
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Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Hoshino et al.
Fig. 5. Crystal lattice of 2·H2O. Red colour represents the chain struc-
ture connected by hydrogen bonding between the pyridinium proton and
Fig. 7. Crystal lattice of 3·H2O exhibiting hydrogen bonding between
the pyridinium proton and the carboxylate moiety. Oxygen atoms are
shown in red, nitrogen-blue, carbon-gray, and hydrogen-light gray.
the carboxylate moiety. Blue colour represents the molecules with the
imido proton hydrogen-bonded to the carboxylate moiety on the chain
structure. The solvating molecules and protons except for pyridinium
proton and imido proton were omitted for clarity.
3·H2O is different from that in 2·H2O. The imido proton
(H1) in the thymine moiety formed a hydrogen bond with
a water molecule, and did not interact with the carboxylate
moiety (Fig. 7).
the carboxylate moiety (O3) and pyridinium proton (H27)
formed a one-dimensional polymeric structure (Fig. 4). In
addition, the polymeric structure possesses 3ꢁ to 5ꢁ direc-
tionality, which is caused by the asymmetrically attached
hydrogen-bonding donor and acceptor at the 3ꢁ and 5ꢁ
positions. The one-dimensional structure with directional-
ity is reminiscent of the structure of single-stranded DNA.
The imido proton (H26) in the thymine moiety hydro-
gen bonded with the oxygen atom (O7) of DMSO. On
the other hand, the crystal lattice of 2 · H2O shows that
Compound 4 crystallized with water molecules in the
triclinic space group P1. Figure 8 shows the molecular
structure of one of the two independent molecules of com-
pound 4, which has a 2-pyridyl group at the 3ꢁ posi-
tion. The crystal structure of 4·H2O revealed a hydrogen
atom on O5 in the carboxylic acid moiety, determined
by a difference Fourier map. The neutral structure is a
stark contrast to the zwitterion structure of compounds 2
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the carboxylate moiety (O4) interacts with the pyridinium
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proton (H15) and the imido proton (H14) in the thymine
Copyright: American Scientific Publishers
and 3. The difference is presumably due to low basic-
ity of the 2-pyridyl moiety in compound 4 because the
basicity of 2-methoxypyridine is much lower than that
of 4-methoxypyridine.14 Figure 9 shows the crystal lat-
tice of 4 · H2O. Since the 2-pyridyl group did not serve
as a hydrogen-bonding acceptor due to its low basicity,
a polymeric chain structure did not form. Instead of the
chain-like network, the hydrogen bonds formed a thymine–
thymine dimer structure.
moiety (Fig. 5). The combination of two hydrogen bonds
formed a branched polymeric structure. Since the distance
of O4···H15 (1.773 Å) is much shorter than O4···H14
(1.938 Å), hydrogen bonding between the carboxylate
moiety and pyridinium proton (O4···H15) predominates.
The crystal structure of 3 · H2O exhibited a zwitterion
structure and a polymeric chain structure with hydrogen
bonds between the carboxylate moiety (O5) and pyri-
dinium proton (H17), analogous to compound 2 (Figs. 6
and 7). However, the hydrogen bond of the imido proton in
Fig. 6. ORTEP drawing of 3·H2O with thermal ellipsoids shown at the
30% probability level. The water molecules without hydrogen-bonding
interaction with compound 3 were omitted for clarity.
Fig. 8. ORTEP drawing of 4·H2O with thermal ellipsoids shown at the
30% probability level. Molecular structure of one of the two independent
molecules was shown. One of the water molecules was omitted for clarity.
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Hoshino et al.
Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Compound 3 possesses an additional methylene moiety
at the 3ꢁ position in comparison to compound 2. The small
structural change affected the hydrogen-bonding network
(Fig. 7). 3·H2O exhibited a single-strand polymeric struc-
ture in contrast to the branched structure of 2 · H2O. The
electron density of the pyridyl nitrogen atom in compound
3 is considered to be lower than that of compound 2 on
the basis of the fact that the basicity of 4-methylpyridine
was lower than that of 4-methoxypyridine.14 The lower
electron density of the pyridyl nitrogen atom makes hydro-
gen bonding of N-H···O stronger.15 Therefore, hydrogen
bonding between the pyridinium proton and the carboxy-
late moiety in compound 3 should be stronger than that
in compound 2. The strong hydrogen-bonding network in
compound 3 is likely to prevent the participation of the
imido proton in the hydrogen-bonding network. In contrast
to compounds 2 and 3, compound 4 had a neutral structure
due to low basicity of the 2-pyridyl moiety. These results
Fig. 9. Crystal lattice of 4 · H2O exhibiting a thymine–thymine dimer
structure. Oxygen atoms are shown in red, nitrogen-blue, carbon-gray,
and hydrogen-light gray.
suggest that the structure of the pyridyl group plays an
important role in determining network structure.
3. DISCUSSION
4. CONCLUSION
The crystal lattice of 3ꢁ-O-(4-pyridyl)thymidine (1) pos-
sessed hydrogen bonds between the imido proton and the
pyridyl group (Fig. 2). Transformation of the hydroxy
group to the carboxylic acid group by oxidation led to
The introduction of carboxylic acid and pyridyl groups
into thymidine enables the formation of one-dimensional
chain structure based on hydrogen bonding between the
pyridinium proton and the carboxylate group. This work
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a large change in the hydrogen-bonding network because
of the strong acidic nature of carboxylic acid. Protona-
tion of the pyridyl moiety by carboxylic acid resulted in
hydrogen bonding between the pyridinium proton and the
carboxylate moiety,9 which was observed in 2 · DMSO
(Fig. 4). The carboxylate moiety is the strongest hydrogen-
bonding acceptor in the molecule due to its anionic
nature. The pyridinium proton is considered the strongest
hydrogen-bonding donor because it forms hydrogen bonds
with the strongest hydrogen-bonding acceptor. The second
strongest hydrogen-bonding donor, the imido proton, inter-
acts with DMSO, which is the second strongest hydrogen-
bonding acceptor. These observations are fully consistent
with the law that the best hydrogen-bond donor and the
best hydrogen-bonding acceptor will preferentially form
hydrogen bonds with one another.6 Therefore, transforma-
tion of the hydroxy group into the carboxylic acid group
is necessary to control the designed hydrogen-bonding
network forming the single-strand polymeric structure
without a mixture of the several kinds of hydrogen-
bonding motifs. On the other hand, 2 · H2O exhibited a
relatively complex network of hydrogen bonds (Fig. 5).
The imido proton (H14) in the thymine moiety partici-
pated in hydrogen bonding with the carboxylate group as
well as the pyridinium proton (H15). The absence of a
proper hydrogen-bonding acceptor for the second strongest
hydrogen-bonding donor, the imido proton, is attributed
to the branched network structure in the crystal lattice of
2·H2O.
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revealed two kinds of methods to control hydrogen bond-
Copyright: American Scientific Publishers
ing of the thymidine derivatives for forming the selec-
tive one-dimensional chain structure. One of them is a
choice of a proper hydrogen-bonding acceptor for the
second strongest hydrogen-bonding donor, the imido pro-
ton. The other is a molecular design for strong hydro-
gen bonding of N–H···O to avoid the interaction of the
imido proton. These results will lead to a precise control
of target hydrogen-bonding networks forming designed
supramolecular architectures without influence of other
hydrogen-bonding motifs.
5. EXPERIMENTAL DETAILS
All reagents were purchased from Kanto Chemical Co.,
Aldrich, TCI, and Wako Pure Chemical, and used with-
out further purification. 5ꢁ-O-tritylthymidine was prepared
by the published procedure.10 Reactions were checked for
completion by TLC (Merck, silica gel 60 F254ꢀ. Flash
chromatography was performed using silica gel 60 (Kanto
Kagaku, 0.063–0.210 mm). NMR experiments were per-
formed on a Bruker Avance 400, 600 and JEOL EX-270
instrument and 4,4-dimethyl-4-silapentane-1-sulfonic acid
(DSS) was employed as external standard in D2O. Cou-
pling constants (Jꢀ are in Hz. Multiplicities are reported
as follows: s, singlet, d, doublet, dd, doublets of dou-
blets, t, triplet, q, quartet, m, multiplet, and br, broad.
MALDI-MS spectra were recorded on a Kratos-Shimadzu
J. Nanosci. Nanotechnol. 13, 4593–4600, 2013
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Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Hoshino et al.
AXIMA-CFR plus MALDI-TOF MS and a AB SCIEX
TOF/TOF™ 5800. Elemental analyses were performed on
a Perkin Elmer 2400 CHN elemental analyzer.
6.3. 3ꢁ-O-(4-picolyl)Thymidine
Sodium hydride (333.2 mg, 10 mmol) was added to a
solution of 5ꢁ-O-tritylthymidine (484.5 mg, 1.00 mmol) in
dry THF (75 mL) and the mixture was stirred ultrasoni-
cally for 20 min under nitrogen. 4-(bromomethyl)pyridine
hydrobromide (303.5 mg, 1.20 mmol) was then added to
the mixture and stirred ultrasonically for 40 min. H2O
(0.50 mL) was slowly added to the reaction mixture and
stirred for 5 min. After solvent removal, the residue was
dissolved in EtOH (10 mL). HCl aq. (35–37%, 1.6 mL)
was added to the solution and stirred for 1 h at 80 ꢀC. After
solvent evaporation, the residue was washed with CHCl3
and filtered off. The product was isolated by column chro-
matography on silica gel using CHCl3:MeOH (3:2) as elu-
ent (88%).
6. SYNTHESIS
6.1. 3ꢁ-O-(4-pyridyl)Thymidine Hydrochloride (1)
KOH (2.61 g, 46.5 mmol) and 4-chloropyridine hydrochlo-
ride (837 mg, 5.58 mmol) were added to a solution
of 5ꢁ-O-tritylthymidine (2.25 g, 4.65 mmol) in DMSO
(46.5 mL). After stirring at room temperature for 50 h, the
reaction mixture was diluted with ethyl acetate (150 mL).
The resulting precipitate was filtered off and the filtrate
ꢀ
was concentrated under reduced pressure at 80 C. The
residue was dissolved in ethyl acetate and washed with
brine. The organic phase was separated and dried over
Na2SO4. After evaporation of solvent, EtOH (16 mL) and
HCl aq. (35–37%, 660 ꢁL) were added. Before evapora-
1H NMR (400 MHz, DMSO-d6ꢀꢂH: 11.33 (1H, s), 8.81
(2H, d, J = 6ꢃ0 Hz), 7.85 (2H, s), 7.72 (1H, d, J = 1ꢃ0 Hz),
6.20 (1H, dd, J = 8ꢃ5, 5.8 Hz), 4.83 (2H, s), 4.28 (1H, d,
J = 5ꢃ8 Hz), 4.08 (1H, d, J = 2ꢃ0 Hz), 3.62 (2H, d, J =
4ꢃ0 Hz), 2.36 (1H, ddd, i = 17.9, 6.0, 4.1 Hz), 2.25–2.18
(1H, m), 1.79 (3H, s); 13C{1H} NMR (100 MHz, CD3OD)
ꢂC: 164.9, 160.8, 151.0, 141.1, 136.6, 124.4, 110.4, 85.1,
85.0, 80.7, 68.3, 61.8, 36.7, 11.0. MALDI-MS (m/z) calcd
for C16H19N3O5 334.1 (M + H)+, found 334.1 (M + H)+;
Anal. calcd for C16H19N3O5 ·2H2O: C, 52.03; H, 6.28; N,
101.38; found: C, 52.04; H, 5.86; N, 11.39.
ꢀ
tion of volatiles, the mixture was stirred for 1 h 80 C.
After solvent evaporation, the product was isolated by col-
umn chromatography on silica gel using CHCl3:MeOH
(9:1 → 4:1) as eluent (93%).
1H NMR (270 MHz, D2O) ꢂH: 8.58 (2H, d, J = 6ꢃ3 Hz),
7.69 (1H, s), 7.49 (2H, d, J = 6ꢃ1 Hz), 6.38 (1H, t, J =
7ꢃ2 Hz), 5.43 (1H, s), 4.47 (1H, s), 3.89 (2H, d, J =
4ꢃ1 Hz), 3.64 (2H, q, J = 7ꢃ0 Hz), 2.66 (2H, t, J = 5ꢃ3 Hz),
1.91 (3H, s), 1.17 (3H, t, J = 7ꢃ0 Hz); 13C{1H} NMR
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ꢁ
ꢁ
IP: 208.98.249.39 On: Tue, 08 Dec 2015 11:25:51
(150 MHz, CD3OD) ꢂC: 169.8, 164.9, 144.0, 136.3, 113.6,
6.4. 3 -O-(4-picolyl)Thymidine-5 -Carboxylic Acid (3)
Copyright: American Scientific Publishers
110.6, 85.0, 84.2, 80.9, 79.0, 61.3, 36.4, 11.0; MALDI-MS
A
mixture of 3ꢁ-O-(4-picolyl)thymidine (95.4 mg,
(m/z) calcd for C15H18N3O5 320.1 (M+H)+, found 320.9
(M + H)+; Anal. calcd for C15H17N3O5 · MeOH · HCl: C,
47.62; H, 5.33; N, 11.11; found: C, 47.65; H, 5.27; N,
11.14.
0.286 mmol), TEMPO (9.0 mg, 0.060 mmol), and bisace-
toxyiodobenzene (BAIB) (184 mg, 0.570 mmol) in CH2Cl2
(4.0 mL) was stirred for 2 h at room temperature. A mix-
ture of CH3CN/H2O (volume ratio 1/1, 14 ꢁL) was added
to the reaction mixture. After stirring for 27 h, the result-
ing precipitate was separated by filtration and washed with
CH2Cl2. The precipitate was purified by column chro-
matography on silica gel using CHCl3:CH3OH (4:1 → 1:1)
as eluent (62%).
6.2. 3ꢁ-O-(4-pyridyl)Thymidine-5ꢁ-Carboxylic Acid (2)
A mixture of 3ꢁ-O-(4-pyridyl)thymidine hydrochloride
(82.4 mg, 0.258 mmol), TEMPO (9.0 mg, 0.060 mmol),
and bisacetoxyiodobenzene (BAIB) (184 mg, 0.570 mmol)
in CH2Cl2 (4.0 mL) was stirred for 2 h at room tempera-
ture. A mixture of MeCN/H2O (volume ratio 1/1, 14 ꢁL)
was added to the reaction mixture. After stirring for 17 h,
the resulting precipitate was filtered off and washed with
CH2Cl2. The product was isolated from the precipitate by
column chromatography on silica gel using CHCl3:MeOH
(4:1 → 1:1) as eluent (69%).
1H NMR (400 MHz, DMSO-d6ꢀꢂH: 11.34 (1H, s), 8.56
(2H, dd, J = 4ꢃ3, 1.5 Hz), 8.00 (1H, d, J = 1ꢃ0 Hz), 7.38
(2H, d, J = 5ꢃ8 Hz), 6.31 (1H, dd, J = 9ꢃ0, 5.5 Hz),
4.69 (2H, dd, J = 26ꢃ1, 13.6 Hz), 4.67 (1H, s), 4.46
(1H, d, J = 5ꢃ0 Hz), 2.43 (1H, dd, J = 14ꢃ1, 5.5 Hz),
2.13 (1H, ddd, J = 18ꢃ9, 9.4, 4.9 Hz), 1.79 (3H, d, J =
1ꢃ0 Hz); 13C{1H} NMR (100 MHz, DMSO-d6ꢀꢂC: 171.8,
163.6, 150.4, 148.7, 136.3, 122.0, 109.4, 85.4, 81.9, 81.3,
68.4, 35.6, 12.3; MALDI-MS (m/z) calcd for C16H17N3O6
348.1 (M + H)+, found 348.1 (M + H)+; Anal. calcd for
C16H17N3O6 ·2.5H2O: C, 48.98; H, 5.65; N, 10.71; found:
C, 48.87; H, 5.67; N, 10.62.
1H NMR (270 MHz, D2O) ꢂH: 8.40 (2H, d, J =
6ꢃ3 Hz), 8.35 (1H, s), 7.16 (2H, d, J = 6ꢃ4 Hz), 6.52
(1H, dd, J = 9ꢃ2, 5.5 Hz), 5.37 (1H, d, J = 4ꢃ8 Hz),
4.65 (1H, s), 2.63 (1H, dd, J = 14ꢃ5, 5.3 Hz), 2.39–2.29
(1H, m), 1.93 (3H, s); 13C{1H} NMR (68 MHz, D2O)
ꢂC: 178.6, 169.1, 166.1, 154.4, 152.6, 140.9, 114.2, 113.9,
88.7, 86.5, 83.5, 38.2, 14.4; MALDI-MS (m/z) calcd for
C15H16N3O6 334.1 (M+H)+, found 333.9 (M+H)+; Anal.
calcd for C15H15N3O62·5H2O: C, 47.62; H, 5.33; N, 11.11;
found: C, 47.65; H, 5.27; N, 11.14.
6.5. 3ꢁ-O-(2-pyridyl)Thymidine
KOH (112.2 mg, 2.0 mmol) and 2-chloropyridine
(27.2 mg, 0.24 mmol) were added to a solution of 5ꢁ-O-
4598
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Hoshino et al.
Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Table II. Crystal Data and Details of Structure Refinement of Complexes 1·H2O, 2·DMSO, 2·H2O, 3·H2O and 4·H2O.
1·H2O
2·DMSO
2·H2O
3·H2O
4·H2O
Chemical formula
Formula weight
Crystal system
Space group
a, Å
b, Å
c, Å
ꢄ, deg
ꢅ, deg
C15H17O5N3 ·H2O
C15H15O6N3 ·2DMSO
C15H15N3O6 ·2H2O
C16H17N3O6 ·4H2O
C15H15N3O6 ·H2O
337.33
489.56
369.33
419.39
351.32
Orthorhombic
P212121 (no. 19)
7.2506 (4)
9.2336 (6)
23.9075 (14)
Orthorhombic
P212121 (no. 19)
10.1427 (5)
12.9727 (5)
16.8589 (7)
Orthorhombic
P212121 (no. 19)
4.5434 (5)
Orthorhombic
P212121 (no. 19)
6.423 (2)
Triclinic
P1 (no. 1)
6.3260 (5)
8.4455 (7)
16.0128 (13)
97.0800 (10)
100.1340 (10)
108.9050 (10)
781.66 (11)
2
18.980 (2)
19.420 (2)
14.345 (5)
20.900 (7)
ꢆ, deg
V , Å3
2302.95 (15)
4
2218.26 (16)
4
1674.6 (3)
4
10.330
776
1925.8 (11)
4
10.447
888
Z
ꢁ, cm−1
9.281
712
2.916
1032
10.280
368.00
F (000)
Dcalcd, g cm−3
Crystal size, mm
No. of date
No. of unique date
No. of variables
R (I > 2ꢇꢈIꢀꢀ
R (all reflections)
RW (all reflections)
Flack parameter
GOF
1.400
1.466
1.465
1.446
1.493
0.18×0.16×0.06
0.40×0.40×0.35
0.12×0.05×0.02
0.30×0.060×0.05
0.29×0.19×0.13
8976
21619
9331
10407
8713
3493
222
5054
295
3667
244
4183
272
6594
469
0.0443
0.0454
0.1243
0.37 (15)
1.046
0.0408
0.0426
0.1162
0.4 (2)
1.063
0.0430
0.0457
0.1222
0.01 (7)
1.040
0.0540
0.0631
0.1363
0.3 (3)
1.177
0.0572
0.0733
0.1571
0.4 (2)
1.043
tritylthymidine (96.9 mg, 0.2 mmol) in DMSO (2 mL).
(4.0 mL) was stirred for 2 h at room temperature. A mix-
ture of CH CN/H O (volume ratio 1/1, 14 ꢁL) was added
to the reaction mixture. After stirring for 24 h, the result-
ing precipitate was separated by filtration and washed with
Et2O (80%).
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tion mixture was diluted with ethyl acetate. The resulting
precipitate was filtered off and the filtrate was concen-
ꢀ
trated under reduced pressure at 80 C. The residue was
1H NMR (400 MHz, DMSO-d6ꢀꢂH: 11.35 (1H, s),
8.20–8.18 (1H, m), 8.00 (1H, d, J = 1ꢃ0 Hz), 7.78 (1H,
ddd, J = 8ꢃ7, 6.7, 1.6 Hz), 7.06 (1H, ddd, J = 7ꢃ2, 5.0,
0.9 Hz), 6.93 (1H, d, J = 8ꢃ3 Hz), 6.36 (1H, t, J =
7ꢃ3 Hz), 5.82 (1H, t, J = 2ꢃ0 Hz), 4.62 (1H, d, J =
1ꢃ3 Hz), 2.43 (2H, dt, J = 7ꢃ7, 2.8 Hz), 1.80 (3H, d, J =
1ꢃ0 Hz); 13C{1H} NMR (100 MHz, DMSO-d6ꢀꢂC: 171.5,
163.6, 161.6, 150.5, 146.7, 139.8, 117.9, 111.2, 109.5,
85.5, 81.8, 77.2, 35.9, 12.4; MALDI-MS (m/z) calcd for
C15H15N3O6Na 356.1 (M+Na)+, found 356.1 (M+Na)+;
Anal. calcd for C15H15N3O6 · H2O: C, 51.28; H, 4.88; N,
11.96; found: C, 51.61; H, 4.74; N, 12.04.
dissolved in ethyl acetate and washed with brine. The
organic phase was separated and dried over Na2SO4. After
solvent removal, EtOH (2 mL) and HCl aq. (35–37%,
77.3 ꢁL) were added. Before evaporation of volatiles, the
mixture was stirred for 3 h at 80 C. The product was
isolated by column chromatography on silica gel using
CHCl3:CH3OH (10:1) as eluent (75%).
ꢀ
1H NMR (600 MHz, CD3OD) ꢂH: 8.15 (1H, td, J = 2ꢃ4,
1.5 Hz), 7.93 (1H, d, J = 1ꢃ1 Hz), 7.72 (1H, ddd, J =
8ꢃ7, 6.8, 1.5 Hz), 6.99 (1H, ddd, J = 7ꢃ2, 5.1, 0.9 Hz),
6.87 (1H, d, J = 8ꢃ7 Hz), 6.39 (1H, dd, J = 8ꢃ5, 5.8 Hz),
5.62–5.60 (1H, m), 4.21 (1H, q, J = 2ꢃ8 Hz), 3.94 (2H,
ddd, J = 38ꢃ2, 12.0, 3.2 Hz), 2.51–2.42 (2H, m), 1.93
(3H, d, J = 1ꢃ5 Hz).; 13C{1H} NMR (125 MHz, CD3OD)
ꢂC: 166.4, 164.1, 152.5, 147.9, 140.5, 138.1, 118.6, 112.6,
111.9, 87.0, 86.4, 77.1, 63.1, 38.9, 12.5; MALDI-MS (m/z)
calcd for C15H17N3O5Na 342.1 (M + Na)+, found 342.1
(M+Na)+; Anal. calcd for C15H17N3O5: C, 56.42; H, 5.37;
N, 13.16; found: C, 56.18; H, 5.46; N, 12.92.
6.7. Preparative Methods
(I) 1·H2O
Crystals were obtained by slow evaporation of its solu-
tion in water after neutralization of 1·HCl.
(II) 2·DMSO
Crystals were obtained by the slow diffusion of acetoni-
trile to the solution of 2 in DMSO.
(III) 2·H2O
6.6. 3ꢁ-O-(2-pyridyl)Thymidine-5ꢁ-Carboxylic Acid (4)
A
mixture of 3ꢁ-O-(2-pyridyl)thymidine (82.4 mg,
Crystals were obtained by the slow cooling of hot water
solution of 2.
0.258 mmol), TEMPO (9.0 mg, 0.060 mmol), and bisace-
toxyiodobenzene (BAIB) (184 mg, 0.570 mmol) in CH2Cl2
J. Nanosci. Nanotechnol. 13, 4593–4600, 2013
4599

Hydrogen-Bonding Linkage of Thymidine Derivatives with Carboxylic Acid and Pyridyl Groups
Hoshino et al.
(IV) 3·H2O
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ment of the complexes are summarized in Table II.
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non-hydrogen atoms with anisotropic thermal parame-
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were placed at the calculated positions and were included
in the structure calculation without further refinement
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033; or e-mail: deposit@ccdc.cam.ac.uk.
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Acknowledgments: This work was partly supported by
Grant-in-Aid for Young Scientists. The authors are grateful
to the Chemical Analysis Center of University of Tsukuba
for X-ray diffractional studies, elemental analyses, and
NMR spectroscopy. The authors wish to thank to Profes-
sor Masaaki Ichinohe for the supports on the measurement
and refinement of the crystal structure.
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Received: 7 February 2012. Accepted: 10 February 2012.
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J. Nanosci. Nanotechnol. 13, 4593–4600, 2013