Structural Chemistry

, Volume 21, Issue 1, pp 245–254

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

Authors

  • Frank Eißmann
    • Institut für Organische ChemieTechnische Universität Bergakademie Freiberg
  • Diana Schindler
    • Institut für Organische ChemieTechnische Universität Bergakademie Freiberg
    • Institut für Organische ChemieTechnische Universität Bergakademie Freiberg
Original Research

DOI: 10.1007/s11224-009-9570-5

Cite this article as:
Eißmann, F., Schindler, D. & Weber, E. Struct Chem (2010) 21: 245. doi:10.1007/s11224-009-9570-5

Abstract

A series of halogenated nucleobase derivatives 14 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.

Keywords

Nucleobase derivativesHalogen compoundsDMSO solvatesX-ray analysisHydrogen bonding

Introduction

The pairing of nucleobases via hydrogen bonding is a fundamental process in many biological events, such as genetic coding, biological information storage and protein 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 [49]. With reference to this behavior, the hybridization of nucleobases with fluorophores [10, 11] or metal complexes [12] has led to the creation of programmable supramolecular devices and architectures [1316], all showing the particular interaction property of nucleobases as an important principle [17, 18].

In order to make chemical systems of this type accessible, 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 couplings, including the reactions originally developed by Sonogashira-Hagihara [19], Suzuki-Miyaura [20] or Stille [21] as being the methods most frequently practiced [2227]. These halogen derivatives are easily prepared via simple halogenation of the respective parent compound. Hence, halogenated derivatives of nucleobases and nucleosides have been known for a long time [2830], involving the description of crystal structures in several cases of compounds of this kind [3134]. However, all the crystals for the structural analysis have been obtained from aqueous solution, frequently giving rise to hydrate formation [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 dissolve 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 hydrogen bonding donor [35]. Nevertheless, solvated aggregate structures could be formed that might exhibit interesting modes of interaction between particular nucleobase derivatives and DMSO. It was also a challenge to study potential halogen contacts [3638] emanating from the halogen substituent.

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 (24), as specified in Fig. 1, which were obtained from DMSO solution. These structures are discussed in comparison with reported data of the structures produced from aqueous solution [31, 32, 34].
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Fig. 1

Chemical structures of the nucleobase derivatives studied in this paper

Experimental

5-Iodocytosine (1) was obtained by iodination of cytosine 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-bromoguanosine with i-butyryl chloride in pyridine was used to yield 2-i-butyramido-8-bromo-9-(2′,3′,5′-tri-O-i-butyryl-β-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 14 in DMSO. The X-ray diffraction intensities were recorded on a Bruker Kappa diffractometer equipped with an APEX II CCD area detector and graphite-monochromatized MoKα radiation (λ = 0.71073 Å) employing φ and ω 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 diffraction profiles [42]. The crystal structures were solved by direct methods using SHELXS-97 and refined by full-matrix least-squares refinement against F2 using SHELXL-97 [43]. All non-hydrogen atoms were refined anisotropically; hydrogen atoms were generated at ideal geometrical positions and refined with the appropriate riding model or positioned by Difference Fourier synthesis. Geometrical calculations were performed using PLATON [44] and molecular graphics were generated using SHELXTL [45].

Results and discussion

Crystallization of the halogenated nucleobase or nucleoside derivatives 14 (Fig. 1) from DMSO solution yielded solvated 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 solvate 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 structures, 1·DMSO, 2, 3·DMSO and 4·H2O·DMSO, are 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. 37.
Table 1

Crystallographic data for the compounds studied

Compound

1·DMSO

2

3·DMSO

4·H2O·DMSO

Empirical formula

C4H4INO3·C2H6OS

C10H12BrN5O4

C10H12BrN5O5·C2H6OS

C26H36BrN5O9·H2O·C2H6OS

Formula weight (g mol−1)

315.13

346.16

440.28

738.65

Temperature (K)

173(2)

296(2)

296(2)

90(2)

Wavelength (Å)

0.71073

0.71073

0.71073

0.71073

Crystal system, space group

Monoclinic, P21/c

Monoclinic, P21

Orthorhombic, P212121

Orthorhombic, P212121

Unit cell dimensions

    

 a (Å)

11.3335(3)

5.11690(10)

6.6841(6)

9.7254(3)

 b (Å)

9.4638(2)

17.8949(4)

10.9379(11)

11.4087(4)

 c (Å)

9.8621(3)

6.9879(2)

22.977(2)

31.2293(10)

 α (°)

90

90

90

90

 β (°)

105.1790(10)

98.984(2)

90

90

 γ (°)

90

90

90

90

 V3)

1020.89(5)

632.01(3)

1679.9(3)

3465.0(2)

Z

4

2

4

4

Calculated density (g cm−3)

2.050

1.819

1.741

1.416

Absorption coefficient (mm−1)

3.315

3.275

2.613

1.309

F(000)

608

348

896

1544

Crystal size (mm3)

0.22 × 0.37 × 0.43

0.04 × 0.14 × 0.23

0.12 × 0.14 × 0.32

0.13 × 0.20 × 0.55

θ range for data collection (°)

2.85–25.99

2.95–27.99

2.06–25.49

2.19–30.50

Limiting indices

−13 ≤ h ≤ 13

−6 ≤ h ≤ 6

−8 ≤ h ≤ 5

−13 ≤ h ≤ 13

−11 ≤ k ≤ 11

−23 ≤ k ≤ 23

−13 ≤ k ≤ 12

−16 ≤ k ≤ 16

−12 ≤ l ≤ 12

−9 ≤ l ≤ 9

−27 ≤ l ≤ 27

−44 ≤ l ≤ 44

Reflections collected/unique

27458/1996 [R(int) = 0.0204]

16271/3050 [R(int) = 0.0401]

12165/3106 [R(int) = 0.0541]

50172/10563 [R(int) = 0.0411]

Completeness to θ (%)

99.8

99.9

99.4

99.9

Refinement method

Full-matrix least-squares on F2

Full-matrix least-squares on F2

Full-matrix least-squares on F2

Full-matrix least-squares on F2

Data/restraints/parameters

1996/0/120

3050/1/184

3106/0/234

10563/2/472

Goodness-of-fit on F2

1.147

1.019

0.974

1.047

Final R indices [I > 2σ(I)]

R1 = 0.0147, wR2 = 0.0354

R1 = 0.0242, wR2 = 0.0555

R1 = 0.0316, wR2 = 0.0374

R1 = 0.0352, wR2 = 0.0752

R indices (all data)

R1 = 0.0151, wR2 = 0.0356

R1 = 0.0291, wR2 = 0.0571

R1 = 0.0402, wR2 = 0.0694

R1 = 0.0616, wR2 = 0.0825

Largest diff. peak and hole (e Å−3)

0.345 and −0.318

0.392 and −0.193

0.767 and −0.399

0.584 and −0.559

Table 2

Selected torsion angles for the nucleoside derivatives

Denotationa

Torsion angles (°)

2

3·DMSO

4·H2O·DMSO

χ

59.77(30)

66.06(38)

64.79(26)

v0

−22.01(23)

−28.17(31)

−23.34(18)

v1

35.40(20)

39.95(29)

−4.13(18)

v2

−34.75(20)

−35.92(30)

27.92(19)

v3

23.35(23)

21.00(32)

−42.37(18)

v4

−1.03(25)

4.24(32)

41.46(18)

aDefinition: χ (C4–N9–C11–O10), v0 (C14–O10–C11–C12), v1 (O10–C11–C12–C13), v2 (C11–C12–C13–C14), v3 (C12–C13–C14–O10), v4 (C11–O10–C14–C13)

Table 3

Hydrogen bonding interactions

Atoms involved

Symmetry

Distance (Å)

Angle (°)

D(D···A)

d(H···A)

θ(D–H···A)

1·DMSO

 N1–H1···N3

x + 1, y − 1/2, −z + 3/2

2.821(2)

1.97

163.1

 N4–H4A···O2

x + 1, y + 1/2, −z + 3/2

2.913(2)

2.03

178.0

 N4–H4B···O21

x, y + 1, z

3.019(2)

2.37

131.0

 C21–H21A···N4

x, −y + 3/2, z + 1/2

3.293(3)

2.75

115.7

 N4–H4B···I5

x, y, z

3.2958(17)

2.82

115.2

 C22–H22A···O2

x + 1, y − 1/2, −z + 3/2

3.381(3)

2.41

173.9

2

 O12–H17···O13

x, y, z

2.701(3)

2.31

109.9

 O15–H19···N3

x, y, z

2.761(3)

1.95

169.7

 O13–H18···N7

x + 1, y + 1/2, −z + 1

2.788(3)

1.99

162.8

 O12–H17···O15

x, y, z + 1

2.881(2)

2.16

146.8

 N6–H6A···O15

x + 2, y − 1/2, −z

3.032(3)

2.28

145.8

 C12–H12···N3

x, y, z

3.273(3)

2.60

126.3

 C2–H2···O12

x, y, z − 1

3.332(3)

2.58

138.3

 C11–H11···Br8

x, y, z

3.347

2.84

112.9

3·DMSO

 O12–H17···O15

x − 1, y, z

2.645(3)

1.90

151.2

 O13–H18···O21

x, y, z

2.662(3)

1.84

174.3

 O12–H17···O13

x, y, z

2.714(3)

2.31

111.1

 N1–H1···O6

x + 1/2, −y − 1/2, −z

2.755(3)

1.91

165.3

 O15–H19···O10

x, y, z

2.850(3)

2.56(4)

100(3)

 O15–H19···N3

x, y, z

2.899(4)

2.03(4)

167(3)

 N2–H3···O12

x + 1, y, z

2.937(3)

2.12

159.2

 N2–H2···O6

x + 1/2, −y − 1/2, −z

3.108(3)

2.39

141.3

 C12–H12···O15

x, y, z

3.114(4)

2.57

114.7

 C21–H21C···O6

x + 3/2, −y, z + 1/2

3.154(4)

2.53

122.6

 N2–H2···O21

x + 2, y − 1/2, −z + 1/2

3.163(4)

2.48

137.2

 C21–H21B···O10

x + 1, y − 1/2, −z + 1/2

3.232(4)

2.54

129.4

 C12–H12···N3

x, y, z

3.241(4)

2.57

125.9

 C11–H11···Br8

x, y, z

3.293(3)

2.76

114.9

 C14–H14···O12

x + 1, y + 1/2, −z + 1/2

3.448(4)

2.56

150.7

 C22–H22C···O15

x − 1, y, z

3.470(5)

2.60

151.0

4·H2O·DMSO

 O61–H61A···O51

x − 1/2, −y + 1/2, −z + 2

2.565(8)

1.745(16)

165(4)

 N1–H1···O16

x, y, z

2.664(2)

1.98

133.3

 N2–H2···O61

x, y, z

2.739(2)

1.88

165.7

 O61–H61A···O41

x − 1/2, −y + 1/2, −z + 2

2.812(4)

1.979(12)

171(4)

 C51–H51B···O41

x − 1/2, −y + 1/2, −z + 2

2.819(9)

2.01

137.8

 O61–H61B···N7

x − 1, y, z

2.8866(19)

2.076(13)

165(3)

 C52–H52B···O41

x − 1/2, −y + 1/2, −z + 2

3.024(9)

2.17

144.4

 C41–H41A···O28

x + 1/2, −y + 1/2, −z + 2

3.179(5)

2.26

156.6

 C52–H52A···N3

x, y, z

3.194(9)

2.62

117.3

 C41–H41B···O41

x − 1/2, −y + 1/2, −z + 2

3.219(5)

2.38

142.9

 C42–H42A···O41

x − 1/2, −y + 1/2, −z + 2

3.273(5)

2.39

149.4

 C11–H11···Br8

x, y, z

3.2871(5)

2.74

115.0

 C51–H51B···O51

x − 1/2, −y + 1/2, −z + 2

3.388(11)

2.55

143.6

 C51–H51A···O6

x − 1/2, −y + 1/2, −z + 2

3.411(9)

2.56

145.1

 C30–H30C···O6

x − 1/2, −y + 1/2, −z + 2

3.412(3)

2.45

165.6

 C15–H15B···O41

x − 1/2, −y + 1/2, −z + 2

3.441(5)

2.50

159.4

 C52–H52B···O51

x − 1/2, −y + 1/2, −z + 2

3.469(10)

2.56

154.5

 C13–H13···O61

x, y, z

3.501(2)

2.54

161.2

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Fig. 2

Molecular structures and atomic labeling schemes for a1·DMSO, b2, c3·DMSO and d4·H2O·DMSO

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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

Structure of 5-iodocytosine·DMSO (1·DMSO)

The compound crystallizes in the monoclinic space group P21/c with one molecule of 1 and one DMSO molecule in 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 conventional N–H···N and N–H···O contacts as the characteristic feature. The tape structure is not completely planar, 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 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 create another type of eight-membered hydrogen bonded cyclic pattern formed by means of N–H···O and weaker C–H···O 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–H···N interactions [47, 48] including nucleobase and DMSO molecules as well as offset face-to-face π–π 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-H4B···I5).

Structure of 8-bromoadenosine (2)

The crystal structure of this solvent-free compound, crystallizing in the non-centrosymmetric space group P21, has 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 conformational property of the molecule rather than on current aspects of supramolecular behavior.

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) Å 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 χ = 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–H···O contact (O12–H17···O13) and a weak C–H···Br interaction (C11–H11···Br8). The ribose sugar residue 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 description, due to their planar structure, the purine moieties give 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 orientation of the ribose units. This enables molecules within the layer to form N–H···O (N6, O15) and O–H···N (O13, N7) hydrogen bonds between the purine and ribose moieties of neighboring molecules. These layers are linked through strong O–H···O hydrogen bonding interactions that include O12 and O15 atoms of two ribose units, completing the network structure of hydrogen bonds. Although the bromine substituent affects the molecular conformation of 2, the halogen atom is not involved in a definite intermolecular contact, as before.
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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

Structure of 8-bromoguanosine·DMSO (3·DMSO)

Unlike 8-bromoadenosine (2), described above, the present 8-bromoguanosine (3) yields a DMSO solvate on crystallization from this solvent. The crystals belong to the non-centrosymmetric space group P212121 which was also 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 compound 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–H17···O13, C12–H12···N3 and C11–H11···Br8) and additional intramolecular O–H···O and C–H···O contacts (O15–H19···O10 and C12–H12···O15) (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 corresponding torsion angle χ of the glycosidic bond is 66.06(38)° (Table 2). The purine ring is planar to within experimental error. The ribose sugar residue is C2′-endo (relating to C12 in Fig. 2). This atom deviates 0.610(3) Å from the least-squares plane of the other four ribose ring atoms. Concerning that, the structural parameters of the 8-bromoguanosine molecule in 3·DMSO 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.

In the crystal packing structure, the nucleobase and DMSO molecules are held together by a complex network of strong and weaker hydrogen bonds (Fig. 5) involving guanine–guanine, guanine–solvent, ribofuranosyl–ribofuranosyl and ribofuranosyl–solvent interactions (Table 3). The most prominent interaction between adjacent guanine moieties is an N–H···O 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–H···O hydrogen bond to the NH2 group of an adjacent guanine moiety, and in addition to this forms a weak C–H···O contact [47] to H21C of the solvent molecule, thus giving rise to an inverse trifurcated system of hydrogen bonds around O6. Furthermore, there is an N–H···O 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–H···O and N–H···O hydrogen bonds as well as a weaker C–H···O contact are formed that link the ribofuranosyl unit to solvent molecules, to the guanine moiety and to the ribofuranosyl residue of a neighboring molecule (Table 3). However, a significant contact involving the bromine atom, such as an interaction of Br···Br type [50] or between Br and another heteroatom [36, 37], is not detectable in the structure.
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Fig. 5

Packing structure of 3·DMSO viewed down the a-axis. Relevant hydrogen bond interactions are represented as broken lines; nonrelevant H atoms are omitted for clarity

Structure of 2-i-butyramido-8-bromo-9-(2′,3′,5′-tri-O-i-butyryl-β-d-ribofuranosyl)purin-6-one·H2O·DMSO (4·H2O·DMSO)

Due to the i-butyryl substituents, this particular derivative 4 of 8-bromoguanosine (3) is considered to be rather hydrophobic compared to the compounds 13 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 P212121. The asymmetric unit consists of one nucleoside 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 SOF = 0.319(2) for S51, O51, C51, C52, H51A-H51C, H52A-H52C).

Owing to the i-butyryl protecting group at O15, the formation of an intramolecular O15–H19···N3 hydrogen bond, as present in both 2 and 3·DMSO, is excluded here. Instead of this, the molecular structure of 4 in 4·H2O·DMSO 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–H11···Br8 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 (χ = 64.79(26)°), being in agreement with the structures of the nucleosides 2 and 3. However, in contrast to compounds 2 and 3, the ribofuranosyl moiety in 4 adopts a C4′-exo conformation (Table 2). The occurrence of this rather unusual C4′-exo conformation is obviously caused by the hydroxyl protecting groups. Similar unusual conformations have also been found for other hydroxyl protected derivatives of 8-bromoadenosine (2) and 8-bromoguanosine (3) [51, 52]. The tri-O-acetylated derivatives are reported to occur in a C1′-exo conformation in the case of 8-bromoadenosine 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 interactions 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–H···O and C–H···O 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 molecules are in the form of C–H···O [35] interactions yielding an inverse bifurcated hydrogen bonding pattern (Fig. 7b). Furthermore, the DMSO molecules are involved in a C–H···O contact to the atom O28 of the proximate i-butyryl group as well as in a contact to H61A of the water molecule.
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Fig. 6

Packing structure of 4·H2O·DMSO 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 interactions are represented as broken lines

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Fig. 7

Hydrogen bonded strand formation in the structure of 4·H2O·DMSO: a strand consisting of 4 and H2O (nonrelevant H atoms are omitted); b strand formed of DMSO molecules (disordered position 1). Hydrogen bond interactions are represented as broken lines

Structural comparisons and conclusions

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 14 are nearly planar in structure. Both in the compounds 2 and 3, the purine and sugar moieties are in a syn alignment mainly stabilized by a strong intramolecular O–H···N hydrogen bond, and the ribose sugar residues show a typical C2′-endo conformation. By contrast, the molecular structure of 4 differs significantly from 2 and 3. Due to the i-butyryl protecting groups, the conformation of 4 is stabilized by an intramolecular N–H···O hydrogen bond involving a carbonyl oxygen atom of the N-bound butyryl residue and the ribofuranosyl moiety, and adopts an unusual 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–H···N (1), N–H···O (14) and O–H···O (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–H···O contacts [47] involving the DMSO molecules in the cases of 1, 3 and 4 while face-to-face π–π 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 [3638, 53]. However, the bromine atoms in 2, 3 and 4 cooperate in the formation of the particular conformations.

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 halogenated nucleobase and nucleoside derivatives without appreciable change of the molecular conformation.

Supplementary data

CCDC 739698 (1·DMSO), 739699 (2), 739700 (3·DMSO) and 739697 (4·H2O·DMSO) contain the supplementary 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].

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© Springer Science+Business Media, LLC 2009