Crystal structure of 4-nitrophenyl 6-O-ethyl-β-d-galactopyranoside monohydrate

The pyranoid ring of the title compound C14H19NO8·H2O has a 4 C 1 conformation and the 4-nitrophenyl moiety is essentially planar. The galactoside molecules are connected by several O—H⋯O hydrogen bonds, forming a sheet lying parallel to (100), and by intermolecular C—H⋯O interactions.

The synthesis and crystal structure of the title compound, C 14 H 19 NO 8 ÁH 2 O, prepared in three steps from 6-O-ethyl-1,2;3,4-di-O-isopropylidene--d-galactopyranose using protecting-group strategies employed in carbohydrate chemistry, is reported. The asymmetric unit consists of a single galactoside molecule, in which the pyranoid ring has a 4 C 1 conformation and the 4-nitrophenyl moiety is essentially planar. In the crystal, each carbohydrate is surrounded by other dgalactose residues and water molecules, linked by O-HÁ Á ÁO hydrogen bonds involving all hydroxy groups, giving a two-dimensional substructure lying parallel to (100) and extended into three dimensions by C-HÁ Á ÁO interactions.

Chemical context
Small molecules containing d-galactose moieties substituted at non-anomeric positions have been assayed against galactosidases (Viana et al., 2011;McCarter et al., 1992;Huber & Gaunt, 1983) and lectins (Butera et al., 2009;Salameh et al., 2005). Trypanosoma cruzi trans-sialidase (TcTS) (Mendonça-Previato et al., 2010), an enzyme involved in Chagas's disease infection, is inhibited by -d-galactopyranosides substituted at the C6 ring site, which are in general more potent than the corresponding analogues modified at other ring positions of the carbohydrate (Harrison et al., 2011). In this context, the title compound C 14 H 19 NO 8 was designed and synthesized to be evaluated against TcTS and T. cruzi invasion of host cells. The synthesis and crystal structure of this compound as the monohydrate (I) is reported herein.

Supramolecular features
In the crystal, a carbohydrate moiety is connected to eight neighboring d-galactose residues by several direct and watermediated classical hydrogen bonds (Table 1), establishing a network of interactions (Fig. 2). Regarding only the O-HÁ Á ÁO interaction type, there are O2-H2BÁ Á ÁO6 i , O3-H3BÁ Á ÁO1W ii and O4-H4BÁ Á ÁO3 iii hydrogen bonds. In addition, there is a single-water bridge connecting O3 to O2 of a nearby galactoside molecule (O1W-H1WAÁ Á ÁO2 iv and O1W-H1WBÁ Á ÁO3 v ; for symmetry codes, see Table 1). A two-dimensional substructure in the form of a sheet lying parallel to (100) is formed. The overall three-dimensional supramolecular aggregation is completed by intermolecular C-HÁ Á ÁO interactions: C3-H3AÁ Á ÁO4 vi connects carbohydrate rings stacked along the a axis and C13-H13AÁ Á ÁO12 vii connects ethyl and nitro groups along the c axis. The 4-nitrophenyl substituent groups are arranged in parallel planes (Fig. 3), with an interplanar distance of 3.4355 (14) Å , but the slip angle (48.3 ) prevents overlapping and therefore nointeractions are present [ring-centroid separation = 5.163 (2) Å ].

Database survey
To the best of our knowledge, this is the first report of the crystal structure of an aryl 6-O-substituted--d-galactopyranoside in the literature. In the Cambridge Structural Database (Version 5.38; Groom et al., 2016), the structural data for the closely related analogue 4-nitrophenyl -dgalactopyranoside have been deposited (CSD Refcode VUCYO1; Gubica et al., 2009). Both galactosides are monohydrates and their molecular geometry and intermolecular interaction profiles in the crystal lattice are quite similar. The aromatic ring of the 6-unsubstituted galactoside is less planar

Figure 2
Selected interactions in the crystal lattice with O-HÁ Á ÁO hydrogen bonds shown as turquoise dashed lines and C-HÁ Á ÁO interactions shown as blue dashed lines.

Figure 3
Crystal packing of the title compound, showing the stacked galactoside molecules along the a axis. For clarity, H atoms are not shown.

Figure 1
The molecular structure of the title compound with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.
due to the increased rotation of the N1-C10 bond, since the angle between the mean planes of the phenyl and nitro groups is ca 5.1 , compared to 2.6 (5) in the title compound. According to the authors (Gubica et al., 2009), the deviation from coplanarity of these fragments in the 4-nitrophenyl -d-galactopyranoside structure is due to intermolecular interactions involving the nitro group. In our crystallographic study on compound (I) we did not observe classical hydrogen bonds to 4-nitrophenyl O-atom acceptors, but only the weak C13-H13AÁ Á ÁO12 interaction noted above.

Synthesis and crystallization
The chemical synthesis of 4-nitrophenyl 6-O-ethyl--dgalactopyranoside monohydrate (I) was achieved in three steps, as shown in Fig. 4. Initially the O-alkylation of 1,2;3,4-di-O-isopropylidene-d-galactopyranose was carried out as reported in the literature furnishing the 6-O-alkylated derivative (2) (Cironi & Varela, 2001;McKeown & Hayward, 1960). Next, the peracetylated -d-galactopyranosyl chloride (3) was prepared in a three-step one-pot reaction as follows. To a solution of (2) (0.59 g, 2.06 mmol) in acetyl chloride (2.92 mL, 41.13 mmol) was added methanol (0.42 mL) under ice-bath conditions. The mixture was stirred at room temperature for 2h in a closed system and concentrated hydrochloric acid (0.34 mL) was then added and the resulting mixture was stirred at room temperature for 24 h, also in a closed system. The reaction was quenched with crushed ice (about 30 mL) and the mixture was extracted with dichloromethane (3 Â 25 mL). The organic layers were washed with a saturated aqueous sodium bicarbonate solution (2 Â 60 mL) and water (60 mL), then dried over anhydrous sodium sulfate and concentrated. The brown oil obtained (0.68 g, 94% yield) was used in the next step without further purification.
Classical procedures in carbohydrate chemistry were employed in the next two steps (Conchie et al., 1957). The glycosylation of 4-nitrophenol with (3) in alkaline medium gave (4) in 46% yield. Treatment with sodium methoxide to remove the acetyl groups furnished (I) (as the monohydrate), in 84% yield. Colorless crystals of (I) (m.p. 424.1-424.9 K) suitable for X-ray diffraction analysis were obtained by slow evaporation of an acetone solution (about 0.7 mg/mL) at room temperature.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Oxygen-bound H atoms were located in a difference-Fourier map and refined with distance restraints of 0.82 Å (hydroxy group H) and 0.89 Å (water H) with U iso (H) = 1.5 U eq (O). Carbon-bound H atoms were constrained to an ideal geometry with C-H distances in the range 0.93-0.98 Å , U iso (H) = 1.5 U eq (C) for methyl H atoms and U iso (H) = 1.2 U eq (C) for other H atoms. In the absence of significant anomalous scattering effects, the Flack structure parameter (Flack, 1983)     analysis and the absolute configuration is inferred from the known d-galacto configuration of the starting material, and remained unchanged during the synthesis. The beta configuration of C1 is confirmed by the coupling constant J 1,2 = 7.6 Hz, obtained from NMR spectroscopy.

Funding information
Funding for this research was provided by: Fundaçã o de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG); Conselho Nacional de Desenvolvimento Científico e Tecnoló gico (CNPq). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.20 e Å −3 Δρ min = −0.23 e Å −3 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. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.