Crystal structure of the acyclic form of 1-deoxy-1-[(4-methoxyphenyl)(methyl)amino]-d-fructose

The monoclinic unit contains a rare acyclic keto tautomer of the amino sugar involved in the extensive hydrogen-bonding patterns. The acyclic conformation is a minor species in the compound’s solution.

The title compound, C 14 H 21 NO 6 , (I), crystallizes exclusively in the acyclic keto form. In solution of (I), the acyclic tautomer represents only 10% of the population in equilibrium, with the other 90% consisting of -pyranose, -furanose, -pyranose, and -furanose cyclic forms. The carbohydrate chain in (I) has a zigzag conformation and the aromatic amine group has a transitional sp 2 /sp 3 geometry. Bond lengths and valence angles in the carbohydrate portion compare well with the average values for related acyclic polyol structures. All of the hydroxyl groups are involved in intermolecular hydrogen bonding and form a two-dimensional network of infinite chains, which are interlinked by intramolecular hydrogen bonds and organized into R 8 8 (16) homodromic ring patterns. A comparative Hirshfeld surfaces analysis of (I) and four other 1-amino-1-deoxy-d-fructose derivatives suggests the balance of hydrophilic/ hydrophobic interactions plays a role in the crystal packing, favoring the acyclic isomer.

Chemical context
Reducing carbohydrates, for instance aldoses (glucose, mannose, xylose) or ketoses (fructose, ribulose), mutarotate in solutions such that the predominant species in equilibrium consist of cyclic pyranose and furanose hemiacetals or hemiketals, respectively (Angyal, 1992). Free aldehyde or ketone forms are thermodynamically unfavorable and normally comprise less than 1% of the population in the equilibria. Crystallization of reducing monosaccharides naturally affords the most populous, predominantly pyranose, anomers (Jeffrey, 1990). Previously, we have demonstrated that exceptions to this rule may be found among 1-amino-1-deoxy-ketoses. Only four acyclic ketosamine structures have been accurately characterized by X-ray diffraction so far (Mossine et al., 1995(Mossine et al., , 2002(Mossine et al., , 2009); however, it was suggested that the hydrophobic nature of the amino substituents may play a supporting role in stabilization of the unique structures (Mossine et al., 2009). Given that the concept of acyclic intermediates is essential for understanding the mechanisms of many enzymatic and nonenzymatic transformations of carbohydrates in general (see, for example, Buchholz & Seibel, 2008;Wang et al., 2014) and natural fructosamines in particular (Nursten, 2005), the availability of precise structural knowledge on the open-chain 1-amino-1-deoxy-ketoses is of interest to the field. We report here on the structure of title compound, alternatively named as d-fructose-N-methyl-p-anisidine, C 14 H 21 NO 6 , (I), aiming to expand this knowledge.

Structural commentary
The molecular structure and atomic numbering for (I) are shown in Fig. 1. The molecule may be considered as a conjugate of a carbohydrate, 1-amino-1-deoxy-d-fructose, and an aromatic amine, N-methyl-p-anisidine, which are joined through the common amino group. The carbohydrate portion in (I) exists in the acyclic keto form. Remarkably, in the aqueous solution of (I), the acyclic keto form is a minor constituent of the established equilibrium, at 10.3% of the total population as follows from the 13 C NMR data ( Table 1). The predominant -pyranose anomer (52.0%) and smaller proportions of the -furanose, -pyranose, and -furanose cyclic forms constitute the rest of the equilibrium composition (Fig. 2).
The carbohydrate fragment of the molecule is in the zigzag conformation, having four out of six of its carbon atoms, C3, C4, C5, and C6, located in one plane. The conformation around the carbonyl group is also nearly flat and involves atoms N1, C1, C2, O2, C3, and O3, with the carbonyl O2 in the syn-periplanar position with respect to both N1 and O3 [respective torsion angles are 11.7 (3) and À7.0 (3) ]. This type of conformation is preferred for the -aminocarbonyl group, due to influence of the C-H ! C O * and C-H ! C O * hyperconjugation in conditions when interaction between the nitrogen lone pair (LP) and the carbonyl *system is not significant (Ducati et al., 2006). Indeed, the LP-N1-C1-C2 torsion angle estimate is close to 180 in (I). In the sugar portion of (I), the average C-O bond distances (1.43 AE 0.01Å ) and the valence angles in hydroxyl groups are close to the average values for a number of crystalline alditol structures (Jeffrey & Kim, 1970) and acyclic ketosamines (Mossine et al., 1995(Mossine et al., , 2002(Mossine et al., , 2009. Two heteroatom contacts, O3-HÁ Á ÁO4 and O6-HÁ Á ÁO5, although weakly directional (Table 2), are cooperatively integrated into the hydrogenbonding scheme (see Section 3) and thus are good candidates to qualify for intramolecular hydrogen bonds. The tertiary amino group geometry is a flattened pyramid, with the distance from the N1 apex to the C1-C7-C13 base being 0.219 Å and the average base-face dihedral angle 17.2 . The N1-C7 distance, at 1.403 Å , is significantly shorter than the distances from N1 to the aliphatic carbons C1 and C13 [1.444 (3) and 1.455 (3) Å ]. Such geometry is characteristic for amino groups with a mixed sp 3 /sp 2 hybridization, likely due to a partial resonance of the nitrogen p-electrons with a neighboring -system, such as the benzene ring in (I). In the solidstate 13 C NMR spectrum (Fig. 3), the peaks corresponding to the carbons C1, C7, and C13 are split, indicating a conformational dimorphism of the tertiary amino group, possibly due to an inversion of configuration at the N1 atom.  Table 1 Distribution (%) of cyclic and acyclic forms of some 1-amino-1-deoxy-d-fructose derivatives in D 2 O/pyridine (1:1) at 293 K, as estimated from the 13 C NMR spectra, and in the crystalline state.   Atomic numbering and displacement ellipsoids at the 50% probability level for (I). Intramolecular O-HÁ Á ÁO interactions are shown as dotted lines.

Figure 2
Isomerization equilibrium of (I) in solution.

Supramolecular features
Compound (I) crystallizes in the monoclinic space group P2 1 , with two equivalent molecules per unit cell. The molecular packing of (I) features 'hydrophilic' and 'hydrophobic' layers propagating in the ab plane (Fig. 4). The carbohydrate residues form a two-dimensional network of hydrogen bonds organized as a system of two homodromic infinite chains, with Á Á ÁO3-HÁ Á ÁO5-HÁ Á Á and Á Á ÁO4-HÁ Á ÁO6-HÁ Á Á recurrent sequences of intermolecular hydrogen bonds. These chains are topologically connected by the intramolecular short heteroatom contacts O3-HÁ Á ÁO4 and O6-HÁ Á ÁO5. Basic hydrogen-bonding patterns of the resulting network are depicted in Fig. 5 and include fused homodromic R 8 8 (16) and antidromic R 2 2 (4) rings (the pattern notation according to Bernstein et al., 1995). The intermolecular heteroatom contacts that define the hydrogen bonding in (I) are not confined exclusively to the carbohydrate portion of the molecule ( Fig. 6), however. In addition, there are two close C-HÁ Á ÁO2 contacts involving the carbonyl group, and two short C-HÁ Á Á contacts between the methyl groups and the benzene ring centroids (Cg1), which may qualify as weak hydrogen bonds (Table 3, Fig. 6). The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) revealed that a major proportion of the intermolecular contacts in crystal structure of (I) is provided by non-or low-polar interactions of the HÁ Á ÁH and CÁ Á ÁH type ( Fig. 7 and Table 4).  Table 3 Suspected C-HÁ Á ÁA contacts (Å , ).

Figure 3
Solid-state 13 C NMR spectrum of powdered crystalline (I).

Figure 4
The molecular packing in (I). Color code for crystallographic axes: reda, green -b, blue -c. Hydrogen bonds are shown as cyan dotted lines.

Figure 5
Hydrogen-bonding pattern in the crystal structure of (I).
d-fructose-p-toluidine (Frupti, CCDC 126260), d-fructose-Nethyl-p-chloroaniline (FruNEpca, CCDC 717803), and d-fructose-N-allylaniline (FruNAlla, CCDC 717417). Each of these 1-amino-1-deoxy-d-fructose derivatives features an aromatic substituent at the amino group. They also display a similar to (I) distribution of the cyclic and acyclic tautomeric forms in solutions (Table 1). However, only FruNMpti and FruNEpca were reported to adopt the acyclic keto conformations in crystalline state. Frupti (Gomez de Anderez et al., 1996), FruNAlla (Mossine et al., 2009a), as well as the rest of the 1-amino-1-deoxy-d-fructose derivatives whose structures were solved by X-ray diffraction methods (about 15 structures so far), crystallize in the -d-fructopyranose anomeric form (Table 1). The unusual propensity of some 1-amino-1-deoxyd-fructose derivatives, including (I), to crystallize in a thermodynamically unfavored acyclic form is difficult to explain, given that the number of the available solved structures is thus far too small. Modelling the energies of intermolecular interactions experienced by these molecules in solutions versus crystal environments was beyond the goals of the current study. However, some initial clues can be derived from analysis of data compiled in Table 1, this work, as well as in Table 1 from our previous study (Mossine et al., 2009). First, only fructosamine derivatives decorated with an aromatic amino substituent can, but not always, crystallize as the acyclic keto tautomer. As pointed out in Section 2, a neighboringsystem may resonate with the amine p-electrons thus making them unavailable for -bonding. Next, among N-aryl derivatives of 1-amino-1-deoxy-d-fructose, only those lacking a proton bound to the tertiary amino group can crystallize in the acyclic form. Indeed, no hydrogen bonds involving N1 were detected in acyclic (I), FruNMpti or FruNEpca (Mossine et al., 2009). In contrast, the structures of Frupti, FruAlla and all the rest of the 1-amino-1-deoxy-d-fructose derivatives reveal at least one hydrogen-mediated intramolecular heteroatom contact between the amino nitrogen atom and an oxygen atom originating from the carbohydrate portion of the molecule, most often the anomeric O2. Thus, the inability of the amino group to form stable intramolecular hydrogen bonds with the carbohydrate portion plays a role in stabilization of the acyclic tautomer. Finally, a comparative Hirshfeld surfaces analysis (Table 4) of these structures suggests that the extended linear conformation of the acyclic tautomer may require more of the 'hydrophilic space' available in the crystal structure, as compared to the pyranose anomers. This argument also seems  Table 4 Contributions (%) of specific contact types to the Hirshfeld surfaces of 1-amino-1-deoxy-d-fructose derivatives.

Synthesis and crystallization
The preparation of (I) was performed following a protocol described previously (Mossine et al., 2009). Briefly, a mixture of 5.4 g (0.03 moles) of d-glucose, 2.7 g (0.022 moles) of p-anisidine and 0.55 mL of 3-mercaptopropionic acid catalyst/ antioxidant was stirred for 6 h in 12 mL of isopropanol in a screw-capped glass vial at 360 K. The reaction progress was followed by TLC. The purification step included an ionexchange on Amberlite IRN-77 (H + ), with 0.2 M NH 4 OH in 50% ethanol as an eluant, and was followed by flash filtration on a short silica column using 5% MeOH in CH 2 Cl 2 as an eluant. Crystallization of the compound was aided by the addition of a small amount of acetone to the syrupy evaporation residue.  Fig. 3 and the minor peak assignments are listed in Supplementary Table S1.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5. Hydroxy and nitrogen-bound H atoms were located in difference-Fourier analyses and were allowed to refine fully. Other H atoms were placed at calculated positions and treated as riding, with C-H = 0.98 Å (methyl), 0.99 Å (methylene) or 1.00 Å (methine) and with U iso (H) = 1.2U eq (methine or methylene) or 1.5U eq (methyl). The Flack absolute structure parameter determined [0.3 (5) for 1149 quotients (Parsons et al., 2013)] is consistent with the (3S,4R,5R) configuration which was assigned for this chain system on the basis of the known configuration for the starting material d-glucose (McNaught, 1996).

1-Deoxy-1-[(4-methoxyphenyl)(methyl)amino]-D-fructose
Crystal data 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.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )