X-ray crystal structures of halogen containing nucleobase derivatives in unsolvated and DMSO solvated forms

Article abstract of DOI:10.1007/s11224-009-9570-5

A series of halogenated nucleobase derivatives 1-4 is reported to yield solvent-free (2) and DMSO solvated crystals (1, 3, 4) on the crystallization from DMSO with one of them (4) containing an additional molecule of water. The molecular and crystal structures are described and comparatively discussed with reference to previous results on related compounds. The molecule of 1 is planar, molecules of 2 and 3 show syn alignment with reference to the heterocyclic ring and common C2′-endo conformation of the ribose residue, while 4 is also syn aligned but C4′-exo in the sugar conformation. The packing structures reveal typical aggregations created via networks of hydrogen bonds. These involve conventional N-H···N, N-H···O and O-H···O interactions between nucleobase and ribose units as well as solvent molecules, additionally supported by weak C-H···O contacts but excluding the participation of halogen···halogen interactions as well as halogen···heteroatom contacts in the supramolecular structure formation. Springer Science+Business Media, LLC 2009.

Full text of DOI:10.1007/s11224-009-9570-5

Struct Chem (2010) 21:245–254
DOI 10.1007/s11224-009-9570-5
ORIGINAL RESEARCH
X-ray crystal structures of halogen containing nucleobase
derivatives in unsolvated and DMSO solvated forms
Frank Eißmann
Edwin Weber
•
Diana Schindler
•
Received: 13 July 2009 / Accepted: 27 November 2009 / Published online: 11 December 2009
Ó Springer Science+Business Media, LLC 2009
Abstract A series of halogenated nucleobase derivatives
–4 is reported to yield solvent-free (2) and DMSO sol-
genetic coding, biological information storage and protein
1
biosynthesis [1, 2]. In addition, the ability of nucleobases
to form duplexes and other secondary structures [3] is
becoming more and more widespread in the construction of
new materials for potential nanotechnological applications
[4–9]. With reference to this behavior, the hybridization
of nucleobases with fluorophores [10, 11] or metal com-
plexes [12] has led to the creation of programmable supra-
molecular devices and architectures [13–16], all showing
the particular interaction property of nucleobases as an
important principle [17, 18].
vated crystals (1, 3, 4) on the crystallization from DMSO
with one of them (4) containing an additional molecule of
water. The molecular and crystal structures are described
and comparatively discussed with reference to previous
results on related compounds. The molecule of 1 is planar,
molecules of 2 and 3 show syn alignment with reference to
0
the heterocyclic ring and common C2 -endo conformation
of the ribose residue, while 4 is also syn aligned but
0
C4 -exo in the sugar conformation. The packing structures
reveal typical aggregations created via networks of
hydrogen bonds. These involve conventional N–HꢀꢀꢀN,
N–HꢀꢀꢀO and O–HꢀꢀꢀO interactions between nucleobase and
ribose units as well as solvent molecules, additionally
supported by weak C–HꢀꢀꢀO contacts but excluding the
participation of halogenꢀꢀꢀhalogen interactions as well as
halogenꢀꢀꢀheteroatom contacts in the supramolecular
structure formation.
In order to make chemical systems of this type acces-
sible, halogenated nucleobase derivatives are suitable basic
compounds or intermediates in a respective synthesis.
A particular advantage of these halogenated compounds is
that they can be used for a variety of modern C–C cou-
plings, including the reactions originally developed by
Sonogashira-Hagihara [19], Suzuki-Miyaura [20] or Stille
[21] as being the methods most frequently practiced
[
22–27]. These halogen derivatives are easily prepared via
Keywords Nucleobase derivatives ꢀ Halogen
compounds ꢀ DMSO solvates ꢀ X-ray analysis ꢀ
Hydrogen bonding
simple halogenation of the respective parent compound.
Hence, halogenated derivatives of nucleobases and
nucleosides have been known for a long time [28–30],
involving the description of crystal structures in several
cases of compounds of this kind [31–34]. However, all the
crystals for the structural analysis have been obtained from
aqueous solution, frequently giving rise to hydrate forma-
tion [31, 32], while structures of crystals that were grown
from non-aqueous solution are, as far as we know, not
mentioned in the literature, although one may expect the
crystal structure to be influenced by the solvent. From
among the rather rare cases of organic solvents that dis-
solve nucleobases and nucleosides to a sufficient extent,
DMSO was selected which is a highly polar solvent and
strong acceptor in hydrogen bonding but only a weak
Introduction
The pairing of nucleobases via hydrogen bonding is a
fundamental process in many biological events, such as
F. Eißmann ꢀ D. Schindler ꢀ E. Weber (&)
Institut f u¨ r Organische Chemie, Technische Universit a¨ t
Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg,
Sachsen, Germany
e-mail: edwin.weber@chemie.tu-freiberg.de
123

2
46
Struct Chem (2010) 21:245–254
hydrogen bonding donor [35]. Nevertheless, solvated
aggregate structures could be formed that might exhibit
interesting modes of interaction between particular nucle-
obase derivatives and DMSO. It was also a challenge to
study potential halogen contacts [36–38] emanating from
the halogen substituent.
calculations were performed using PLATON [44] and
molecular graphics were generated using SHELXTL [45].
Results and discussion
Following this approach, here we present the results of
an X-ray structural analysis performed on the crystals
of 5-iodocytosine (1) and of three different derivatives of
bromo substituted nucleosides (2–4), as specified in Fig. 1,
which were obtained from DMSO solution. These struc-
tures are discussed in comparison with reported data of the
structures produced from aqueous solution [31, 32, 34].
Crystallization of the halogenated nucleobase or nucleoside
derivatives 1–4 (Fig. 1) from DMSO solution yielded sol-
vated species of compounds 1, 3 and 4. In the cases of 1
and 3, they were shown to be 1:1 stoichiometric solvates
with DMSO, while 4 crystallized as a mixed hydrate sol-
vate containing 4, water and DMSO in a stoichiometric
1:1:1 ratio, which corresponds with NMR integrations and
elemental analyses of the particular species. Remarkably,
the halogenated nucleoside 2 was obtained in solvent-free
crystals. Crystal data and details of the refinement of the
Experimental
structures, 1ꢀDMSO, 2, 3ꢀDMSO and 4ꢀH OꢀDMSO, are
2
5
-Iodocytosine (1) was obtained by iodination of cytosine
summarized in Table 1. Selected torsion angles for the
nucleoside derivatives that define the principal molecular
conformations are listed in Table 2. Parameters of the
hydrogen bonding interactions are specified in Table 3,
whereas Fig. 2 shows the molecular structures, including
atom labeling schemes. Packing illustrations and diagrams
involving specific modes of hydrogen bonding are given in
Figs. 3–7.
with iodine in aqueous KOH [30]. 8-Bromoadenosine (2)
was synthesized from adenosine and bromine in a buffered
aqueous solution (NaOAc/HOAc) [39]; 8-bromoguanosine
(3) was analogously prepared from guanosine but with the
bromination carried out in water [40]. Reaction of 8-bro-
moguanosine with i-butyryl chloride in pyridine was used
0
0
0
to yield 2-i-butyramido-8-bromo-9-(2 ,3 ,5 -tri-O-i-butyryl-
b-D-ribofuranosyl)purin-6-one (4) [26].
Crystals of the compounds suitable for X-ray analysis
were formed by slow evaporation of corresponding solutions
of 1–4 in DMSO. The X-ray diffraction intensities were
recorded on a Bruker Kappa diffractometer equipped with
an APEX II CCD area detector and graphite-monochroma-
Structure of 5-iodocytosineꢀDMSO (1ꢀDMSO)
The compound crystallizes in the monoclinic space group
P2 /c with one molecule of 1 and one DMSO molecule in
1
the asymmetric unit. The molecular structure of the
nucleobase largely agrees with an already known solvent-
free structure of compound 1 [34]. The pyrimidine ring is
nearly planar with the exocyclic amino group not deviating
significantly from the least-squares plane of the ring atoms.
The crystal is predominantly stabilized by hydrogen
bonding, including both nucleobase and DMSO molecules
(Table 3). They form a tape structure with the tapes located
parallel to the Miller plane 101 and the individual tapes
elongating in direction of the b-axis to yield an ABAB layer
structure parallel to the bc-plane (Fig. 3a). Within a single
tape, eight-membered hydrogen bonded rings that link
the nucleobase molecules are found (Fig. 3b) involving
˚
tized MoK radiation (k = 0.71073 A) employing u and x
a
scan modes. The data were corrected for Lorentz and
polarization effects. Semiempirical absorption corrections
were applied using the SADABS program [41] and the
SAINT program was utilized for integration of the diffrac-
tion profiles [42]. The crystal structures were solved by
direct methods using SHELXS-97 and refined by full-matrix
2
least-squares refinement against F using SHELXL-97 [43].
All non-hydrogen atoms were refined anisotropically;
hydrogen atoms were generated at ideal geometrical posi-
tions and refined with the appropriate riding model or
positioned by Difference Fourier synthesis. Geometrical
Fig. 1 Chemical structures of
the nucleobase derivatives
studied in this paper
1
23

Struct Chem (2010) 21:245–254
247
Table 1 Crystallographic data for the compounds studied
Compound
1ꢀDMSO
INO
2
3ꢀDMSO
12BrN
4ꢀH
2
OꢀDMSO
Empirical formula
Formula weight (g mol
Temperature (K)
C
H
4 4
3
ꢀC
H
2 6
OS
C
10
H
12BrN
O
5 4
C
10
H
5 5 2
O ꢀC H
6
OS
C
26
H
36BrN
O
5 9
ꢀH
2
OꢀC
2 6
H OS
-
1
)
315.13
173(2)
0.71073
346.16
296(2)
0.71073
440.28
296(2)
0.71073
738.65
90(2)
˚
Wavelength (A)
0.71073
Crystal system, space group Monoclinic, P2
1
/c
Monoclinic, P2
1
Orthorhombic, P2
1
2
2
1 1
1 1 1
Orthorhombic, P2 2 2
Unit cell dimensions
˚
a (A)
˚
b (A)
11.3335(3)
9.4638(2)
9.8621(3)
90
5.11690(10)
17.8949(4)
6.9879(2)
90
6.6841(6)
10.9379(11)
22.977(2)
90
9.7254(3)
11.4087(4)
31.2293(10)
90
˚
c (A)
a (°)
b (°)
c (°)
105.1790(10)
90
98.984(2)
90
90
90
90
90
3
˚
V (A )
1020.89(5)
4
632.01(3)
2
1679.9(3)
4
3465.0(2)
4
Z
-
3
Calculated density (g cm
)
2.050
1.819
1.741
2.613
1.416
Absorption coefficient
3.315
3.275
1.309
-
1
)
(
mm
F(000)
Crystal size (mm )
h range for data collection (°) 2.85–25.99
Limiting indices -13 B h B 13
608
348
896
1544
3
0.22 9 0.37 9 0.43
0.04 9 0.14 9 0.23
2.95–27.99
0.12 9 0.14 9 0.32
2.06–25.49
0.13 9 0.20 9 0.55
2.19–30.50
-6 B h B 6
-8 B h B 5
-13 B h B 13
-16 B k B 16
-44 B l B 44
-
-
11 B k B 11
12 B l B 12
-23 B k B 23
-9 B l B 9
-13 B k B 12
-27 B l B 27
Reflections collected/unique 27458/1996
[
16271/3050
[R(int) = 0.0401]
12165/3106
[R(int) = 0.0541]
50172/10563
[R(int) = 0.0411]
R(int) = 0.0204]
Completeness to h (%)
99.8
99.9
99.4
99.9
Refinement method
Full-matrix least-squares Full-matrix least-squares Full-matrix least-squares
2
Full-matrix least-squares on
2
F
2
2
on F
on F
on F
Data/restraints/parameters
2
Goodness-of-fit on F
1996/0/120
1.147
3050/1/184
1.019
3106/0/234
0.974
10563/2/472
1.047
Final R indices [I [ 2r(I)]
R
1
= 0.0147,
wR = 0.0354
= 0.0151,
wR = 0.0356
Largest diff. peak and hole 0.345 and -0.318
R
1
= 0.0242,
wR = 0.0555
= 0.0291,
wR = 0.0571
0.392 and -0.193
R
1
= 0.0316,
wR = 0.0374
= 0.0402,
wR = 0.0694
0.767 and -0.399
R
1
= 0.0352, wR
2
2
= 0.0752
= 0.0825
2
2
2
R indices (all data)
R
1
R
1
R
1
R
1
= 0.0616, wR
2
2
2
0.584 and -0.559
-
3
˚
e A )
(
conventional N–HꢀꢀꢀN and N–HꢀꢀꢀO contacts as the char-
acteristic feature. The tape structure is not completely pla-
nar, because the nucleobase molecules are slightly rotated
to each other (interplanar angle between the least-squares
planes of two pyrimidine rings of 9.27(12)°). This specific
hydrogen bonding pattern seems to be a rather robust
supramolecular synthon [46] since it is also present both in
the structures of the solvent-free compound 1 [34] and
create another type of eight-membered hydrogen bonded
cyclic pattern formed by means of N–HꢀꢀꢀO and weaker
C–HꢀꢀꢀO contacts [47], with the carbonyl oxygen of the
nucleobase being the acceptor of a three-centered hydrogen
bond. Between the single tapes, there are weak C–HꢀꢀꢀN
interactions [47, 48] including nucleobase and DMSO
molecules as well as offset face-to-face p–p stacking
interactions [49] between pyrimidine rings. However, the
iodine atom of 1 is not engaged in any contact relevant to
the packing structure. Nevertheless, it acts as an acceptor
for an intramolecular hydrogen bond with the neighboring
N–H group of the pyrimidine ring (N4-H4BꢀꢀꢀI5).
5
-bromocytosine [33]. The DMSO molecules are also
components of the tapes. They are located in longitudinal
direction at both sides of the tape, operating as hydrogen
bonding acceptors as well as hydrogen bonding donors to
123

2
48
Struct Chem (2010) 21:245–254
Table 2 Selected torsion angles for the nucleoside derivatives
rise to the formation of molecular layers (Fig. 4). They
exhibit a specific zig-zag pattern which is defined by the
dihedral angle of 21.18(6)° between the planes of two
neighboring purines. Within an individual layer, the
sequence is ABAB, with the layers differing in the orien-
tation of the ribose units. This enables molecules within the
layer to form N–HꢀꢀꢀO (N6, O15) and O–HꢀꢀꢀN (O13, N7)
hydrogen bonds between the purine and ribose moieties of
neighboring molecules. These layers are linked through
strong O–HꢀꢀꢀO hydrogen bonding interactions that include
O12 and O15 atoms of two ribose units, completing the
network structure of hydrogen bonds. Although the bro-
mine substituent affects the molecular conformation of 2,
the halogen atom is not involved in a definite intermolec-
ular contact, as before.
a
Denotation
Torsion angles (°)
2
3ꢀDMSO
4ꢀH OꢀDMSO
2
v
59.77(30)
-22.01(23)
35.40(20)
66.06(38)
-28.17(31)
39.95(29)
-35.92(30)
21.00(32)
4.24(32)
64.79(26)
-23.34(18)
-4.13(18)
27.92(19)
v
v
v
v
v
a
0
1
2
3
4
-34.75(20)
23.35(23)
-42.37(18)
41.46(18)
-1.03(25)
Definition: v (C4–N9–C11–O10), v
O10–C11–C12–C13), v
O10), v (C11–O10–C14–C13)
0
(C14–O10–C11–C12), v
1
(
2 3
(C11–C12–C13–C14), v (C12–C13–C14–
4
Structure of 8-bromoadenosine (2)
Structure of 8-bromoguanosineꢀDMSO (3ꢀDMSO)
The crystal structure of this solvent-free compound, crys-
tallizing in the non-centrosymmetric space group P2 , has
1
Unlike 8-bromoadenosine (2), described above, the present
8-bromoguanosine (3) yields a DMSO solvate on crystal-
lization from this solvent. The crystals belong to the non-
centrosymmetric space group P2 2 2 which was also
already been published in 1970 [32]. In order to lead to
more precise structural parameters, the structure solution
was reconsidered using modern technical equipment.
Moreover, in the previous paper, the structure of 2 is
reported only rather briefly with an emphasis on the con-
formational property of the molecule rather than on current
aspects of supramolecular behavior.
1
1 1
found for the reported structure of the 1:2 stoichiometric
hydrate of 3 [32], obtained from aqueous solution. This
allows an interesting comparison of the crystal structures
not only between the brominated nucleosides 2 and 3 but
also between 3 in DMSO solvated and hydrated forms.
A specific feature of the molecular structure of com-
pound 3 is the intramolecular hydrogen bond connecting
the O15 hydroxyl proton with the N3 atom of the guanine
ring (Fig. 2c). The molecular conformation is furthermore
stabilized both by weaker hydrogen bonding interactions as
shown in the structure of 8-bromoadenosine (2) (O12–
H17ꢀꢀꢀO13, C12–H12ꢀꢀꢀN3 and C11–H11ꢀꢀꢀBr8) and addi-
tional intramolecular O–HꢀꢀꢀO and C–HꢀꢀꢀO contacts (O15–
H19ꢀꢀꢀO10 and C12–H12ꢀꢀꢀO15) (Fig. 2c). Considering
these particular interactions and the bulk of the bromo
substituent, the syn orientation of the ribose moiety with
reference to the purine unit is an obvious fact. The corre-
sponding torsion angle v of the glycosidic bond is
66.06(38)° (Table 2). The purine ring is planar to within
The bond parameters of the previous [32] and the
present data are in reasonable agreement (Fig. 2b). The
purine ring is planar to within experimental error, while
the plane of the ribose unit, defined by C11, C13, C14 and
O10, is rotated about 76.02(6)° towards the plane of the
˚
nucleobase. The distance of 1.3340(33) A between the
atoms C6 and N6 suggests a double bond, giving rise to a
planar structure of the amino group. The torsion angle of
the atom sequence C4–N9–C11–O10 with v = 59.77(30)°
(
Table 2) indicates a syn alignment of the sugar moiety.
This means that the sterical hindrance caused by the purine
ring is less significant than the hindrance caused by the
bromo substituent of C8. Furthermore, this conformation is
stabilized by a strong intramolecular hydrogen bond
between O15 and N3 and a weaker one between C12 and
N3. Additional stabilization results from an intramolecular
O–HꢀꢀꢀO contact (O12–H17ꢀꢀꢀO13) and a weak C–HꢀꢀꢀBr
interaction (C11–H11ꢀꢀꢀBr8). The ribose sugar residue
0
experimental error. The ribose sugar residue is C2 -endo
˚
(relating to C12 in Fig. 2). This atom deviates 0.610(3) A
from the least-squares plane of the other four ribose ring
atoms. Concerning that, the structural parameters of the
8-bromoguanosine molecule in 3ꢀDMSO are very similar to
the corresponding ones in the adenosine derivative 2 and
also to those in the known dihydrate of 3 [32]. In particular,
the latter finding shows that the different solvents in the
crystals do not significantly affect the molecular structure
of 3.
0
shows a so-called C2 -endo conformation, explained in
more depth in the earlier paper [32].
Irrespective of the solvent used for recrystallization—
water in the previous and DMSO in the present study—
compound 2 was obtained in crystals free from solvent.
This may indicate that the molecule is rather well suited to
yield a balanced packing structure without the help of
additional solvent molecules. In a more detailed descrip-
tion, due to their planar structure, the purine moieties give
In the crystal packing structure, the nucleobase and
DMSO molecules are held together by a complex network
1
23

Struct Chem (2010) 21:245–254
249
Table 3 Hydrogen bonding
interactions
˚
Distance (A)
Atoms involved
Symmetry
Angle (°)
D(DꢀꢀꢀA)
d(HꢀꢀꢀA)
h(D–HꢀꢀꢀA)
1
ꢀDMSO
N1–H1ꢀꢀꢀN3
-x ? 1, y - 1/2, -z ? 3/2
-x ? 1, y ? 1/2, -z ? 3/2
x, y ? 1, z
2.821(2)
2.913(2)
3.019(2)
3.293(3)
3.2958(17)
3.381(3)
1.97
2.03
2.37
2.75
2.82
2.41
163.1
178.0
131.0
115.7
115.2
173.9
N4–H4AꢀꢀꢀO2
N4–H4BꢀꢀꢀO21
C21–H21AꢀꢀꢀN4
N4–H4BꢀꢀꢀI5
C22–H22AꢀꢀꢀO2
x, -y ? 3/2, z ? 1/2
x, y, z
-x ? 1, y - 1/2, -z ? 3/2
2
O12–H17ꢀꢀꢀO13
O15–H19ꢀꢀꢀN3
O13–H18ꢀꢀꢀN7
O12–H17ꢀꢀꢀO15
N6–H6AꢀꢀꢀO15
C12–H12ꢀꢀꢀN3
C2–H2ꢀꢀꢀO12
x, y, z
2.701(3)
2.761(3)
2.788(3)
2.881(2)
3.032(3)
3.273(3)
3.332(3)
3.347
2.31
1.95
1.99
2.16
2.28
2.60
2.58
2.84
109.9
169.7
162.8
146.8
145.8
126.3
138.3
112.9
x, y, z
-x ? 1, y ? 1/2, -z ? 1
x, y, z ? 1
-x ? 2, y - 1/2, -z
x, y, z
x, y, z - 1
x, y, z
C11–H11ꢀꢀꢀBr8
ꢀDMSO
3
O12–H17ꢀꢀꢀO15
O13–H18ꢀꢀꢀO21
O12–H17ꢀꢀꢀO13
N1–H1ꢀꢀꢀO6
x - 1, y, z
2.645(3)
2.662(3)
2.714(3)
2.755(3)
2.850(3)
2.899(4)
2.937(3)
3.108(3)
3.114(4)
3.154(4)
3.163(4)
3.232(4)
3.241(4)
3.293(3)
3.448(4)
3.470(5)
1.90
1.84
2.31
1.91
2.56(4)
2.03(4)
2.12
2.39
2.57
2.53
2.48
2.54
2.57
2.76
2.56
2.60
151.2
174.3
111.1
165.3
100(3)
167(3)
159.2
141.3
114.7
122.6
137.2
129.4
125.9
114.9
150.7
151.0
x, y, z
x, y, z
x ? 1/2, -y - 1/2, -z
x, y, z
O15–H19ꢀꢀꢀO10
O15–H19ꢀꢀꢀN3
N2–H3ꢀꢀꢀO12
x, y, z
x ? 1, y, z
N2–H2ꢀꢀꢀO6
x ? 1/2, -y - 1/2, -z
x, y, z
C12–H12ꢀꢀꢀO15
C21–H21CꢀꢀꢀO6
N2–H2ꢀꢀꢀO21
-x ? 3/2, -y, z ? 1/2
-x ? 2, y - 1/2, -z ? 1/2
-x ? 1, y - 1/2, -z ? 1/2
x, y, z
C21–H21BꢀꢀꢀO10
C12–H12ꢀꢀꢀN3
C11–H11ꢀꢀꢀBr8
C14–H14ꢀꢀꢀO12
C22–H22CꢀꢀꢀO15
x, y, z
-x ? 1, y ? 1/2, -z ? 1/2
x - 1, y, z
4
ꢀH OꢀDMSO
2
O61–H61AꢀꢀꢀO51
N1–H1ꢀꢀꢀO16
x - 1/2, -y ? 1/2, -z ? 2
x, y, z
2.565(8)
2.664(2)
2.739(2)
2.812(4)
2.819(9)
2.8866(19)
3.024(9)
3.179(5)
3.194(9)
3.219(5)
3.273(5)
3.2871(5)
3.388(11)
3.411(9)
1.745(16)
1.98
165(4)
133.3
165.7
171(4)
137.8
165(3)
144.4
156.6
117.3
142.9
149.4
115.0
143.6
145.1
N2–H2ꢀꢀꢀO61
x, y, z
1.88
O61–H61AꢀꢀꢀO41
C51–H51BꢀꢀꢀO41
O61–H61BꢀꢀꢀN7
C52–H52BꢀꢀꢀO41
C41–H41AꢀꢀꢀO28
C52–H52AꢀꢀꢀN3
C41–H41BꢀꢀꢀO41
C42–H42AꢀꢀꢀO41
C11–H11ꢀꢀꢀBr8
C51–H51BꢀꢀꢀO51
C51–H51AꢀꢀꢀO6
x - 1/2, -y ? 1/2, -z ? 2
x - 1/2, -y ? 1/2, -z ? 2
x - 1, y, z
1.979(12)
2.01
2.076(13)
2.17
x - 1/2, -y ? 1/2, -z ? 2
x ? 1/2, -y ? 1/2, -z ? 2
x, y, z
2.26
2.62
x - 1/2, -y ? 1/2, -z ? 2
x - 1/2, -y ? 1/2, -z ? 2
x, y, z
2.38
2.39
2.74
x - 1/2, -y ? 1/2, -z ? 2
x - 1/2, -y ? 1/2, -z ? 2
2.55
2.56
123

2
50
Struct Chem (2010) 21:245–254
Table 3 continued
˚
Distance (A)
Atoms involved
Symmetry
Angle (°)
D(DꢀꢀꢀA)
d(HꢀꢀꢀA)
h(D–HꢀꢀꢀA)
C30–H30CꢀꢀꢀO6
C15–H15BꢀꢀꢀO41
C52–H52BꢀꢀꢀO51
C13–H13ꢀꢀꢀO61
x - 1/2, -y ? 1/2, -z ? 2
x - 1/2, -y ? 1/2, -z ? 2
x - 1/2, -y ? 1/2, -z ? 2
x, y, z
3.412(3)
3.441(5)
3.469(10)
3.501(2)
2.45
2.50
2.56
2.54
165.6
159.4
154.5
161.2
Fig. 2 Molecular structures and
atomic labeling schemes for
a 1ꢀDMSO, b 2, c 3ꢀDMSO and
d 4ꢀH OꢀDMSO
2
of strong and weaker hydrogen bonds (Fig. 5) involving
guanine–guanine, guanine–solvent, ribofuranosyl–ribofur-
anosyl and ribofuranosyl–solvent interactions (Table 3).
The most prominent interaction between adjacent guanine
moieties is an N–HꢀꢀꢀO type hydrogen bond including the
N1 ring proton in one and the O6 carbonyl oxygen atom in
a symmetry related residue, creating an eight-membered
hydrogen bonded ring as a specific supramolecular pattern.
This particular mode of interaction is also shown in the
structure of the hydrated compound 3 [32]. The guanine
oxygen atom O6 is also involved in an N–HꢀꢀꢀO hydrogen
inverse trifurcated system of hydrogen bonds around O6.
Furthermore, there is an N–HꢀꢀꢀO contact between the
guanine N2 atom and the oxygen atom of the DMSO. As
expected for the ribofuranosyl moiety, possessing several
hydrogen bonding donor and acceptor sites, this group
contributes substantially to the stabilization of the crystal
structure. Different conventional O–HꢀꢀꢀO and N–HꢀꢀꢀO
hydrogen bonds as well as a weaker C–HꢀꢀꢀO contact are
formed that link the ribofuranosyl unit to solvent mole-
cules, to the guanine moiety and to the ribofuranosyl res-
idue of a neighboring molecule (Table 3). However, a
significant contact involving the bromine atom, such as an
interaction of BrꢀꢀꢀBr type [50] or between Br and another
heteroatom [36, 37], is not detectable in the structure.
bond to the NH group of an adjacent guanine moiety, and
2
in addition to this forms a weak C–HꢀꢀꢀO contact [47] to
H21C of the solvent molecule, thus giving rise to an
1
23

Struct Chem (2010) 21:245–254
251
Fig. 3 Packing structure of
1
ꢀDMSO: a view down the
b-axis; b excerpt showing the
tape formation. Hydrogen bond
interactions are represented as
broken lines
0
0
0
Structure of 2-i-butyramido-8-bromo-9-(2 ,3 ,5 -tri-
O-i-butyryl-b-D-ribofuranosyl)purin-6-oneꢀH OꢀDMSO
SOF = 0.319(2) for S51, O51, C51, C52, H51A-H51C,
H52A-H52C).
2
(
4ꢀH OꢀDMSO)
Owing to the i-butyryl protecting group at O15, the
formation of an intramolecular O15–H19ꢀꢀꢀN3 hydrogen
bond, as present in both 2 and 3ꢀDMSO, is excluded here.
2
Due to the i-butyryl substituents, this particular derivative 4
of 8-bromoguanosine (3) is considered to be rather
hydrophobic compared to the compounds 1–3 discussed so
far. Unexpectedly the crystals of 4 obtained from DMSO
solution were isolated as a mixed solvate containing 1:1
stoichiometric amounts of water and DMSO. The crystals
were found to belong to the orthorhombic space group
P2 2 2 . The asymmetric unit consists of one nucleoside
Instead of this, the molecular structure of 4 in 4ꢀH OꢀDMSO
2
is stabilized by another intramolecular hydrogen bond
between N1 of the guanine moiety and the carbonyl oxygen
atom of the N-bound butyryl residue, additionally supported
by a C11–H11ꢀꢀꢀBr8 interaction similar to the molecular
structures of 2 and 3 (Fig. 2d). On the other hand, in the
molecular structure of 4, the ribose unit is conformationally
in a syn position with reference to the purine system
(v = 64.79(26)°), being in agreement with the structures of
the nucleosides 2 and 3. However, in contrast to compounds
1
1 1
molecule, one molecule of water and one molecule of
DMSO which is twofold disordered (SOF = 0.681(2) for
S41, O41, C41, C42, H41A–H41C, H42A–H42C and
123

2
52
Struct Chem (2010) 21:245–254
Fig. 6 Packing structure of 4ꢀH
2
OꢀDMSO viewed down the a-axis.
The second disordered position of the DMSO molecule as well as the
nonrelevant H atoms are omitted. Relevant hydrogen bond interac-
tions are represented as broken lines
Fig. 4 Packing illustration of compound 2, viewed down the a-axis,
showing the supramolecular layer structure with relevant hydrogen
bond interactions given as broken lines
derivatives of 8-bromoadenosine (2) and 8-bromoguanosine
(3) [51, 52]. The tri-O-acetylated derivatives are reported to
0
occur in a C1 -exo conformation in the case of 8-bromo-
0
0
0
adenosine and in a C2 -exo or rather a C3 -endo/C2 -exo
conformation in the case of 8-bromoguanosine [52].
Although the hydrogen donor capacity of 4 is restricted
by the substitution with the i-butyryl groups, the water and
DMSO molecules, as the other components of the crystal
structure, compensate for this. Hence, hydrogen bonds that
involve the solvent molecules are the dominating interac-
tions stabilizing the crystal packing (Fig. 6). In addition,
there are van der Waals type contacts between the i-propyl
residues. A particular structural feature of the packing is
the strand formation of compound 4 along the a-axis.
Within these strands, the purine bases are oriented parallel
to the ab-plane and linked together via water molecules
through N–HꢀꢀꢀO and C–HꢀꢀꢀO hydrogen bonding (Fig. 7a).
The DMSO molecules are also arranged in strands along
the a-axis. These strands are surrounded by purine bases in
direction of the c-axis and of O15 i-butyryl groups in
direction of the b-axis. Contacts between the DMSO mol-
ecules are in the form of C–HꢀꢀꢀO [35] interactions yielding
an inverse bifurcated hydrogen bonding pattern (Fig. 7b).
Furthermore, the DMSO molecules are involved in a
C–HꢀꢀꢀO contact to the atom O28 of the proximate i-butyryl
group as well as in a contact to H61A of the water
molecule.
Fig. 5 Packing structure of 3ꢀDMSO viewed down the a-axis.
Relevant hydrogen bond interactions are represented as broken lines;
nonrelevant H atoms are omitted for clarity
0
2 and 3, the ribofuranosyl moiety in 4 adopts a C4 -exo
conformation (Table 2). The occurrence of this rather
0
unusual C4 -exo conformation is obviously caused by the
hydroxyl protecting groups. Similar unusual conformations
have also been found for other hydroxyl protected
1
23

Struct Chem (2010) 21:245–254
253
Fig. 7 Hydrogen bonded strand
formation in the structure of
4
ꢀH
consisting of 4 and H
nonrelevant H atoms are
2
OꢀDMSO: a strand
2
O
(
omitted); b strand formed of
DMSO molecules (disordered
position 1). Hydrogen bond
interactions are represented as
broken lines
Structural comparisons and conclusions
In summary, it is suggested by this study that, aside from
water, DMSO as a cocrystallizing solvent molecule is also
capable of stabilizing the solid state structure of haloge-
nated nucleobase and nucleoside derivatives without
appreciable change of the molecular conformation.
Considering the compounds 1 and 3, their molecular
structures are largely the same in solvent-free and DMSO
solvated (1) or DMSO solvated and dihydrated forms (3), as
follows from a comparison of previously reported [32, 34]
and present findings. The pyrimidine and purine rings of
1
–4 are nearly planar in structure. Both in the compounds 2
Supplementary data
and 3, the purine and sugar moieties are in a syn alignment
mainly stabilized by a strong intramolecular O–HꢀꢀꢀN
hydrogen bond, and the ribose sugar residues show a typical
CCDC 739698 (1ꢀDMSO), 739699 (2), 739700 (3ꢀDMSO)
and 739697 (4ꢀH OꢀDMSO) contain the supplementary
2
0
C2 -endo conformation. By contrast, the molecular struc-
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/data_
request/cif [or from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ,
UK; fax: ?44(0)1223-336033; e-mail: deposit@ccdc.cam.
ac.uk].
ture of 4 differs significantly from 2 and 3. Due to the
i-butyryl protecting groups, the conformation of 4 is stabi-
lized by an intramolecular N–HꢀꢀꢀO hydrogen bond
involving a carbonyl oxygen atom of the N-bound butyryl
residue and the ribofuranosyl moiety, and adopts an unusual
0
0
C4 -exo conformation instead of C2 -endo as before, while
the purine and sugar moieties remain in syn position.
Hydrogen bonded strands (4), tapes (1) and layers (2, 3)
are the predominant supramolecular motifs in the packing
structures, mainly created by conventional N–HꢀꢀꢀN (1),
N–HꢀꢀꢀO (1–4) and O–HꢀꢀꢀO (2, 3) hydrogen bonds. They
include both the nucleobase and ribose units as well as the
solvent molecules. A further support stems from weak
C–HꢀꢀꢀO contacts [47] involving the DMSO molecules in
the cases of 1, 3 and 4 while face-to-face p–p stacking
interactions [49] are of no significant consequence, with the
exception of 1, at best. Another remarkable finding is that
in none of the present crystal structures is the halogen atom
engaged in any significant contact relevant to the packing,
although halogen interactions are considered to form
supramolecular synthons [36–38, 53]. However, the bro-
mine atoms in 2, 3 and 4 cooperate in the formation of the
particular conformations.
References
1. Voet D, Voet JG (2004) Biochemistry, 3rd edn. Wiley, New York
2
3
. Blackburne GM, Gait MJ, Loakes D (2006) Nucleic acids in
chemistry and biology, 3rd edn. Royal Society of Chemistry,
Cambridge
. Bloomfield VA, Crothers DM, Tinoco J (2000) Nucleic acids—
structures, properties and functions. University Science Books,
Sausalito
4
5
6
. Wagenknecht HA (2009) Angew Chem 121:2878
. Wagenknecht HA (2009) Angew Chem Int Ed 48:2838
. Park SH, Pistol C, Alm SJ, Reif JH, Lebeck AR, Dwyer C,
LaBean TH (2006) Angew Chem 118:749
7
. Park SH, Pistol C, Alm SJ, Reif JH, Lebeck AR, Dwyer C,
LaBean TH (2006) Angew Chem Int Ed 45:735
. Wengel J (2004) Org Biomol Chem 2:277
8
9
. Seeman NC (2003) Nature 421:427
10. Printz M, Richert C (2009) Chem Eur J 15:3390
123

2
54
Struct Chem (2010) 21:245–254
1
1
1. Lindegaard D, Madsen AS, Astakhova IV, Malakhov AD, Babu
BR, Korshun VA, Wengel J (2008) Bioorg Med Chem 16:94
2. Kalek M, Madsen AS, Wengel J (2007) J Am Chem Soc
37. Metrangolo P, Meyer F, Pilati T, Resnati G, Terraneo G (2008)
Angew Chem 120:6206
38. Metrangolo P, Meyer F, Pilati T, Resnati G, Terraneo G (2008)
Angew Chem Int Ed 47:6114
1
29:9392
1
1
1
1
1
3. Ogasawara S, Maeda M (2008) Angew Chem 120:8971
4. Ogasawara S, Maeda M (2008) Angew Chem Int Ed 47:8839
5. Feldkamp U, Niemeyer CM (2006) Angew Chem 118:1888
6. Feldkamp U, Niemeyer CM (2006) Angew Chem Int Ed 45:1856
7. Sessler JL, Lawrence CM, Jayawickramarajah J (2007) Chem
Soc Rev 36:314
8. Sivakova S, Rowan SJ (2005) Chem Soc Rev 34:9
9. Takahashi S, Kuroyama Y, Sonogashira K, Hagihara N (1980)
Synthesis 627
0. Miyaura N, Suzuki A (1995) Chem Rev 95:2457
1. Milstein D, Stille JK (1978) J Am Chem Soc 100:3636
2. Hudson RHE, Dambenieks AK (2006) Heterocycles 68:1325
3. Firth AG, Fairlamb IJS, Darley K, Baumann CG (2006) Tetra-
hedron Lett 47:3529
39. Ikehara M, Kaneko M (1970) Tetrahedron 26:4251
40. Niles JC, Wishnok JS, Tannenbaum SR (2000) Chem Res Tox-
icol 13:390
41. Sheldrick GM (2004) SADABS: program for empirical absorp-
tion corrections. University of G o¨ ttingen, Germany
42. Bruker (2004) SAINT version 6.45a. Bruker AXS Inc., Madison,
WI
43. Sheldrick GM (2008) Acta Crystallogr A64:112
44. Spek AL (2009) Acta Crystallogr D65:148
45. Sheldrick GM (1999) SHELXTL version 5.1: program for the
solution and refinement of crystal structures. Bruker AXS Inc.,
Madison, WI
46. Nangia A, Desiraju GR (1998) In: Weber E (ed) Design of
organic solids. Topics in current chemistry, vol 198. Springer,
Berlin-Heidelberg, pp 57–95
47. Desiraju GR, Steiner T (1999) The weak hydrogen bond in
structural chemistry and biology. Oxford University Press,
Oxford
48. Mazik M, Bl a¨ ser D, Boese R (2001) Tetrahedron 57:5791
49. Dance I (2004) In: Atwood JL, Steed JW (eds) Encyclopedia of
supramolecular chemistry. Marcel Dekker, New York, pp 1076–
1092
1
1
2
2
2
2
2
4. Western EC, Daft JR, Johnson EM, Gannett PM, Shaughnessy
KH (2003) J Org Chem 68:6767
2
2
2
2
2
3
3
5. Collier A, Wagner GK (2008) Chem Commun 178
6. Sessler JL, Wang B, Harriman A (1995) J Am Chem Soc 117:704
7. Greco NJ, Tor Y (2007) Tetrahedron 63:3515
8. Fischer E, Reese L (1883) Liebigs Ann Chem 221:336
9. Bruhns G (1890) Ber Dtsch Chem Ges 23:225
0. Johnson TB, Johns CO (1906) J Biol Chem 1:305
1. Bugg CE, Thewalt AA (1969) Biochem Biophys Res Commun
50. Reddy CM, Kirchner MT, Gundakaram RC, Padmanabhan KA,
Desiraju GR (2006) Chem Eur J 12:2222
3
7:623
3
3
3
3
2. Tavale SS, Sobell HM (1970) J Mol Biol 48:109
3. Kato M, Takenaka A, Sasada Y (1979) Bull Chem Soc Jpn 52:49
4. Okabe N, Tamaki K, Suga T (1995) Acta Crystallogr C51:2696
5. Cs o¨ regh I, Czugler M, Weber E, Sj o¨ gren A, Cserz o¨ M (1986)
J Chem Soc Perkin Trans 2:507
51. Tollin P, Low JN, Howie RA (1988) Acta Crystallogr C44:185
52. Mande SS, Lalitha HN, Ramakumar S, Viswamitra MA (1992)
Nucleosides Nucleotides 11:1089
53. Awwadi FF, Willett RD, Peterson KA, Twamley B (2006) Chem
Eur J 12:8952
3
6. Metrangolo P, Resnati G (2004) In: Atwood JL, Steed JW (eds)
Encyclopedia of supramolecular chemistry. Marcel Dekker, New
York, pp 628–635
1
23