Crystal structure of 8-(4-methylphenyl)-2′-deoxyadenosine hemihydrate

8-(4-Methylphenyl)-2′-deoxyadenosine was synthesized using a Suzuki–Miyaura cross-coupling reaction of 8-bromo-d-2′-deoxyadenosine and 4-methylphenylboronic acid in the presence of Pd(OAc)2 and a salton-derived ligand as a highly catalytically active system. There are two independent molecules plus one solvent water in the asymmetric unit and the packing in the crystal lattice is heavily influenced by hydrogen bonding

In the asymmetric unit, equalling the unit cell (triclinic, P1, Z = 1), two molecules of the title compound, 8-(4-methylphenyl)-d-2 0 -deoxyadenosine, C 17 H 19 N 5 O 3 , are present, with distinct conformations of the two sugar moieties, together with one solvent water molecule. All three ribose O atoms are involved in hydrogen bonding and the crystal packing is largely determined by hydrogen-bonding or hydrogen-heteroatom interactions (O-HÁ Á ÁO, O-HÁ Á ÁN, N-HÁ Á ÁO, C-HÁ Á ÁO and C-HÁ Á ÁN) with one independent molecule directly linked to four neighbouring molecules and the other molecule directly linked to six neighbouring molecules. The two independent molecules of the asymmetric unit display three weak intramolecular C-H-to-heteroatom contacts, two of which are very similar despite the different conformations of the deoxyribosyl moieties. The aromatic ring systems of both molecules are in proximity to each other and somehow aligned, though not coplanar. The absolute structures of the two molecules were assumed with reference to the reactant 8-bromo-d-2 0deoxyadenosine as they could not be determined crystallographically.

Chemical context
Alkyl, alkenyl or alkynyl modified purines are known for having interesting biological activities. Many of these modified nucleosides show, for instance, potential for/activity as drug candidates, biological probes etc (Manfredini et al., 1995). Attempts to implement green, i.e. eco-friendly, procedures for the synthesis of modified nucleosides involve the use of palladium complexes as active catalysts because of their proven ability to perform such catalytic transformations even in aqueous media (Agrofoglio et al., 2003;Gayakhe et al., 2016). Modifying the nucleoside bases by substitution of the C-H functions of purine and pyrimidine can be utilized for instance to install or increase fluorescence properties. Fluorescent nucleosides might then be employed as probes for studying the impact of changes in the biological environment: DNA damage, drug-DNA or protein-DNA interactions for instance. Such DNA probes are relevant for both chemical biologists as well as bio-organic chemists (Tanpure et al., 2013). Structural elucidation of substituted nucleosides in general will aid our understanding of mechanistic aspects in this respect and provide a basis for in silico studies. The synthesis and crystal structure of the title compound, 8-(4-methylphenyl)-d-2 0 -deoxyadenosine are presented here as part of our studies in this regard.

Structural commentary
In the title compound, two molecules of C 17 H 19 N 5 O 3 crystallize together with one molecule of water in the triclinic space group P1 with Z = 1. The two molecules (mole 1 and mole 2, Figs. 1 and 2) differ in the puckering of the deoxyribose sugar, which is the most interesting feature of this novel molecular structure. In mole 1 with 3 0 -exo puckering, the -CH 2 -OH substituent on C2 (in the C 4 0 position according to typical nucleoside labelling, see Scheme) and the hydroxyl substituent on C3 (C 3 0 position) are both axial or rather axial, whereas in mole 2 with 3 0 -endo puckering they are both equatorial. For the parent molecule, d-deoxyadenosine, two crystal structures are available in the literature: one in pure form (Sato, 1984) and one as the monohydrate (Storr et al., 2009). In the absence of water, the sugar adopts the 3 0 -endo confirmation with C 3 0 above the ' C 4 0 -O-C 1 0 plane by 0.5 Å (Sato, 1984). In the presence of water, both the oxygen and hydrogen atoms of the hydroxyl substituent on C3 0 are involved in hydrogen bonds with water and the sugar adopts the 3 0 -exo ring pucker with C 3 0 below the C 4 0 -O-C 1 0 plane by 0.52 Å (Storr et al., 2009). Hydrogen bonding in the crystal lattice apparently influences the ring pucker of deoxyribose moieties. In the present structure, bearing two molecules with distinct ring pucker, the hydroxyl group bound to C3 0 of the 3 0 -exo form (mole 1) is involved in one hydrogen bond as donor with water (O2-H2OÁ Á ÁO7 ii ; see Table 1 for distances and angles) and that of the 3 0 -endo form (mole 2) is involved in bifurcated hydrogen bonding with two purine moieties (O5-H5OÁ Á ÁN3 vi and N9-H9NÁ Á ÁO5 ii ). Here C 3 0 is located 0.45 Å below (mole 1) and 0.82 Å above (mole 2) the respective C 4 0 -O-C 1 0 planes. The methylene-hydroxyl oxygen atom O4 on C19 (exo-C 4 '; mole 2) is involved as acceptor in a hydrogen bond with the water molecule (O7-H70OÁ Á ÁO4 vii ). The two independent compound molecules of the asymmetric unit displayed in a comparable orientation to show the distinct conformation of the deoxyribosyl moiety (top: mole 1; bottom: mole 2). Displacement ellipsoids are shown at the 50% probability level.

Figure 2
The two crystallographically independent molecules of the asymmetric unit overlaid. The root-mean-square deviation (rmsd) and the maximum distance between atom positions are 0.8296 and 2.6760 Å , respectively.
The aromatic six-membered rings of the two distinct molecules are to some extent aligned with each other, forming pairs of phenyl and pyrimidine rings. They are neither coplanar nor perfectly overlaid, however. The respective planes for the mole 1 phenyl ring and mole 2 pyrimidine ring pair are at an angle of 15.1 (2) and those of the mole 1 pyrimidine ring and mole 2 phenyl ring pair exhibit an angle of 14.6 (2) . The centroid-centroid distance for the former pair is 3.652 (3) Å and it is 3.621 (3) Å for the latter. The intramolecular angles between the planes of the aromatic sixmembered ring systems are 36.8 (2) and 36.5 (2) for mole 1 and mole 2, respectively, i.e. very similar.
In both molecules, the conformation of the base with respect to the ribose moiety is syn, i.e. the pyrimidine ring and the deoxyribose moiety face the same direction. This is in contrast to the two known structures of d-deoxyadenosine (Sato, 1984;Storr et al., 2009) and one structure of a derivative with an inverted configuration at C 3 0 (Robins et al., 2007) but in accordance with the six other derivatives bearing a substituent at the C 8 position (here C10 and C27) and no further substituents on deoxyadenosine that are reported in the literature (Vrá bel et al., 2007;Storr et al., 2009Storr et al., , 2010. In all six cases, the substituents are aromatic in nature and more sterically demanding than the pyrimide ring of the purine base. The glycosidic torsion angles O-C 1 0 -N 9 -C 4 for the unsubstituted structures range from À94.76 (Robins et al., 2007) to the more usual À178.74 (Storr et al., 2009) for unsubstituted deoxyadenosine structures with an anti conformation. For substituted structures, which are in a syn conformation, these angles range from 48.73 for a p-fluoro-p-biphenyl substituent to 91.90 for a p-methoxyphenyl substituent (Storr et al., 2009). Here the respective torsion angles are 87.40 for mole 1 and 86.32 for mole 2, suggesting that this torsion angle and the pucker mode are independent of each other.
Bond lengths and angles of the purine bases in the two molecules are very similar to previously reported values in related compounds. As is typical, the bond between C 5 and C 6 is the longest [mole 1, C8-C9, 1.409 (6) Å ; mole 2, C25-C26, 1.393 (5) Å ] and the bond between N 7 and C 8 is the shortest [mole 1, N5-C10, 1.315 (5) Å ; mole 2, N10-C27, 1.323 (5) Å ] of the planar heterocyclic ring system. For mole 2, these values are close to the low and high ends, respectively, of the reported values whereas those of mole 1 are rather average. For the deoxyribose ring, the shortest distance is usually found for the O-C 1 0 bond as is the case here. The locations of the longest bonds do vary. Most often it is the , neither of which being unprecedented (Storr et al., 2009(Storr et al., , 2010. Most values found here fall inside the observed ranges for sugar moieties, the link between the sugar and base or the purine bases of the three known unsubstituted and the six substituted structures of d-2 0 -deoxyadenosine. The exceptions are C 3 0 -C 4 0 for mole 1 [C2-C3, 1.504 (7) Å ; range of literature known structures is 1.509-1.549 Å ], C 4 -N 3 for mole 2 [C23-N7, 1.332 (5) Å ; range in the literature is 1.336-1.357 Å ] and C 5 -N 7 for both moles [C9-N5, 1.378 (5) Å , C26-N10, 1.377 (5) Å ; range 1.380-1.394 Å ], all of which being the shortest observed to date. No systematic influence of the substituent on the deoxyadenosine backbone with respect to distances and angles of the parent molecule was observed as closely related compounds (phenyl-, p-methoxyphenyl (both Storr et al., 2009) and p-methylphenyl (this work) do not exhibit apparent similarities in this regard.
The water O atom (O7) utilizes both hydrogen atoms and both lone pairs to act as a hydrogen-bonding donor and acceptor with two nitrogen atoms (N4-O7 iv , O7-H7OÁ Á ÁN5 vii ) of the purine base of mole 1, as donor to the hydroxymethyl oxygen atom (O7-H70OÁ Á ÁO4 vii ) of mole 2 and as acceptor from the hydroxyl oxygen atom (O2-- N9Á Á ÁH4O-O4 viii ) plus further two mediated by water.

Synthesis and crystallization
The title compound, 8-(4-methylphenyl)-d-2 0 -deoxyadenosine was synthesized based on a recently reported method (Bhilare et al., 2016). The compound was obtained by the crosscoupling reaction of 8-bromo-2 0 -deoxyadenosine and research communications Table 1 Hydrogen-bond geometry (Å , ).  (5)  175 4-methylphenyl boronic acid in the presence of Pd(OAc) 2 and PTABS (phospha-tris-aza-adamantyl-butane-saltone) ligand in neat water. The reaction was carried out in a Schlenk tube using a Schlenk system under a nitrogen atmosphere. All other reagents and solvents were purchased commercially and used without any further purification. Synthesis of 8-(4-methylphenyl)-D-2 0 0 0 -deoxyadenosine: To a solution of palladium acetate (1.12 mg, 1.0 mol %) and PTABS ligand (2.93 mg, 2.0 mol %) in degassed water (1.0 ml) at ambient temperature under N 2 was added 8-bromo-d-2 0deoxyadenosine (0.5 mmol) and the solution was stirred for 5 min at 353 K. The reaction mixture was allowed to cool to room temperature and then 4-(methyl)phenyl boronic acid (0.75 mmol) was added along with triethylamine (0.14 ml, 1 mmol) and degassed water (2.0 ml). The resulting solution was then stirred at 353 K for 12 h. The reaction progress was observed by TLC analysis. After the completion of the reaction, the solvent was removed in vacuo and the resultant residue obtained was purified using column chromatography in a CH 2 Cl 2 :MeOH solvent system (96:4) to afford the desired product as a white solid (143 mg, 84% yield). UV-visible absorption and fluorescence emission in methanol (10 mM

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2.
The hydrogen atoms of water and the two -NH 2 groups were located but refined with constraints (SHELXL instruc-tion: SADI 0.05 O7 H7O O7 H70O and SADI 0.05 N4 H4N N4 H40N N9 H9N N9 H90N). The hydrogen atoms of the hydroxyl groups were attached with a riding model [SHELXL instruction: HFIX 147; U iso (H) = 1.5U eq (O)] with the orientation taken from the actually present electron density. When refined freely, the O-H distances became very long while using distance constraints did not improve the refinement compared with HFIX. The C-bound hydrogen atoms were included in calculated positions and treated as riding: C-H = 0.93-0.98 Å with U iso (H) = 1.5U eq (C) for methyl groups and U iso (H) = 1.2U eq (C) for all other C-H bonds.     (Altomare et al., 1994); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015) and WinGX (Farrugia, 2012); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2006); software used to prepare material for publication: CIFTAB (Sheldrick, 2015).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.