4-Nitrobenzyl 3,4-bis(acetyloxy)-2-(4-methoxyphenyl)pyrrolidine-1-carboxylate: crystal structure, Hirshfeld surface analysis and computational chemistry

The title compound, containing a tetra-substituted pyrrolidine ring, has an N-bound (equatorial) 4-nitrophenyl)ethylcarboxylate group with an adjacent C-bound 4-methoxyphenyl (bisectional) and then two acetyloxy subtituents in equatorial and axial positions, respectively. The five-membered ring is twisted about the bond bearing the acetyloxy subtituents.

The title compound, C 23 H 24 N 2 O 9 , is a tetra-substituted pyrrolidine derivative with a twisted conformation, with the twist evident in the C-C bond bearing the adjacent acetyloxy substituents. These are flanked on one side by a C-bound 4-methoxyphenyl group and on the other by a methylene group. The almost sp 2 -N atom [sum of angles = 357 ] bears a 4-nitrobenzyloxycarbonyl substituent. In the crystal, ring-methylene-C-HÁ Á ÁO(acetyloxy-carbonyl) and methylene-C-HÁ Á ÁO(carbonyl) interactions lead to supramolecular layers lying parallel to (101); the layers stack without directional interactions between them. The analysis of the calculated Hirshfeld surfaces indicates the combined importance of HÁ Á ÁH (42.3%), HÁ Á ÁO/OÁ Á ÁH (37.3%) and HÁ Á ÁC/CÁ Á ÁH (14.9%) surface contacts. Further, the interaction energies, largely dominated by the dispersive term, point to the stabilizing influence of HÁ Á ÁH and OÁ Á ÁO contacts in the interlayer region.

Chemical context
The structure of the title tetra-substituted pyrrolidine derivative, (I), was determined in connection with our on-going structural studies characterizing key synthetic intermediates in the synthesis of various -glucosidase inhibitors (Zukerman-Schpector et al., 2017;Dallasta Pedroso et al., 2020). -Glucosidase inhibitors are an important class of drugs employed in the treatment of a variety of diseases such as cancer, cystic fibrosis, diabetes and influenza (Kiappes et al., 2018;Dhameja & Gupta, 2019).
More specifically, (I) was generated during a study designed to synthesize the hydroxylated proline derivative, (2R,3S,4R)-3,4-dihydroxypyrrolidine-2-carboxylic acid, (II) (Garcia, 2008). In addition to being an -glucosidase inhibitor, (II) is also found as a sub-structure of natural bioactive compounds such as, for example, a component of the repeated decapeptide sequence of the adhesive protein Mytilus edulis foot protein 1 (Mefp1), which is produced by the marine mussel Mytilus edulis and is responsible for the fixation capacity of the mussel to rock (Taylor & Weir, 2000). The synthetic study determined that in the final stages of the reaction sequence towards (II), it was not possible to smoothly remove the Nbound 4-nitrobenzyloxycarbonyl (PNZ) protecting group via catalytic hydrogenation as the ensuing mixture was difficult to purify. Therefore, it proved necessary to remove the PNZ protecting group through acid hydrolysis at reflux temperature, resulting in a low overall yield (34%) suggesting that there was no advantage in using PNZ.
The crystal and molecular structures of (I) are described herein with this experimental study complemented by a detailed analysis of the molecular packing by a combination of Hirshfeld surface analysis, non-covalent interaction plots and computational chemistry.

Structural commentary
The molecular structure of (I), Fig. 1, is constructed about a tetra-substituted pyrrolidine ring with a N1-bound (4-nitrophenyl)ethylcarboxylate group and, respectively, C1-C3bound 4-methoxyphenyl, acetyloxy and acetyloxy substituents. For the illustrated molecule, Fig. 1, the chirality of the C1-C3 atoms follows the sequence R, R and S, but it is noted that due crystal symmetry, the centrosymmetric unit cell contains equal numbers of the enantiomers. The conformation of the fivemembered ring is twisted about the C2-C3 bond with the C1-C2-C3-C4 torsion angle being 39.70 (16) , consistent with a (+)syn-clinal configuration. The sum of the angles about the N1 atom is 356.7 , indicating an approximate sp 2 centre.
The N1-bound group occupies an equatorial position with those at the C1-C3 centres being bisectional, equatorial and axial, respectively (Spek, 2020). When viewed towards the approximate plane through the pyrrolidine ring, the N-bound carboxylate group is approximately co-planar, i.e. excluding the nitrobenzene residue. The C1-substituent lies to the opposite side of the plane than the C2 and C3-acetyloxy groups; the dihedral angle between the acetyloxy CO 2 planes is 57.7 (2) .
With respect to the least-squares plane through the pyrrolidine ring, the nitrobenzene and methoxybenzene rings are splayed, as seen in the dihedral angles of 58.58 (8) and 77.65 (6) , respectively; the dihedral angle between the benzene rings is 50.56 (5) . There is a twist in the nitrobenzene ring as seen in the value of the C11-C10-N2-O4 torsion angle of 17.7 (3) . By contrast, the methoxy group is co-planar with the ring to which it is connected, as shown by the C15-C16-O5-C19 torsion angle of 176.2 (2) .

Supramolecular features
The only directional non-covalent interactions of note in the crystal of (I) are two weak C-HÁ Á ÁO contacts as listed in Table 1. The presence of ring-methylene-C4-HÁ Á ÁO7(acetyloxy-carbonyl) interactions lead to helical chains along the baxis direction, being propagated by 2 1 symmetry. The other interactions falling within the distance criteria of PLATON (Spek, 2020) are methylene-C6-HÁ Á ÁO1(carbonyl) interactions, formed between centrosymmetrically related (4nitrophenyl)ethylcarboxylate groups, which lead to the formation of ten-membered {Á Á ÁOCOCH} 2 synthons. These serve to connect the helical chains into a layer lying parallel to (101), Fig. 2(a). A view of the unit-cell contents is shown in Fig. 2(b), highlighting the stacking of layers, without directional interactions between them.
versus sign( 2 )(r) plot in the lower view, i.e. indicating the density value is less than 0.0 a.u., suggest these interactions are weakly attractive. The same is true for the ring-methylene-C4-HÁ Á ÁO7(acetyloxy-carbonyl) interactions that lead to the helical chain, Fig. 3(b).

Hirshfeld surface analysis
The Hirshfeld surface analysis of (I) involved the calculation of the d norm -surface plots, electrostatic potential (calculated using the STO-3G basis set at the Hartree-Fock level of theory) and two-dimensional fingerprint plots following literature procedures (Tan et al., 2019) using Crystal Explorer 17 (Turner et al., 2017). The weak methylene-C6-HÁ Á Á O1(carbonyl) interactions are reflected as bright-red spots near the methylene-H6A and carbonyl-O1 atoms on the d normsurface plot of (I) shown in Fig. 4. Additional diffuse red spots are also noted near the methoxy-O5 and carbonyl-O7 atoms in Fig. 4, which reflect their participation in short C5Á Á ÁO5 and C4Á Á ÁO7 contacts with separations $0.1 Å shorter than the sum of their van der Waals radii, Table 2. Further, faint spots near atom H4B as well as the O5 and O7 atoms (each difficult to discern in Fig

Figure 4
A view of the Hirshfeld surface mapped for (I) over d norm in the range À0.090 to +1.583 arbitrary units showing the C-HÁ Á ÁO interactions as black dashed lines. Table 2 Summary of short interatomic contacts (Å ) in (I) a .
As illustrated in Fig. 7(a), the two-dimensional fingerprint plot for the Hirshfeld surface of (I) is shown in the upper left and lower right sides of the d e and d i diagonal axes, and those delineated into HÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, OÁ Á ÁO and OÁ Á ÁC/CÁ Á ÁO contacts are illustrated in Fig. 7 respectively. The percentage contributions from different interatomic contacts are summarized in Table 3. The HÁ Á ÁH contacts contribute 42.3% to the overall Hirshfeld surface with the shortest contact, manifested in the round-shape peak tipped at d e = d i $2.4 Å , Fig. 7(b), corresponding to the H17Á Á ÁH23B inter-layer contact listed in Table 2. The HÁ Á ÁO/ OÁ Á ÁH contacts contribute 37.3% to the overall Hirshfeld surface, reflecting the significant C-HÁ Á ÁO contacts evident in the packing, Tables 1 and 2. The shortest contacts are reflected as two sharp spikes at d e + d i $2.5 Å in Fig. 7(c). The HÁ Á ÁC/ CÁ Á ÁH contacts that match the long-range C-HÁ Á ÁC inter- Two views of the Hirshfeld surface mapped over d norm for (I) in the range À0.090 to +1.583 arbitrary units, highlighting evidence for long-range C-HÁ Á ÁC interactions and OÁ Á ÁO short contacts within red circles (see text).

Figure 6
A view of the Hirshfeld surface mapped over the calculated electrostatic potential for (I). The potentials were calculated using the STO-3 G basis set at the Hartree-Fock level of theory over a range of À0.067 to 0.040 a.u. The red and blue regions represent negative and positive electrostatic potentials, respectively.

Energy frameworks
The pairwise interaction energies between the molecules in the crystal of (I) were calculated by summing up four energy components, comprising the electrostatic (E ele ), polarization (E pol ), dispersion (E dis ) and exchange-repulsion (E rep ) energies as per the literature (Turner et al., 2017). In the present study, the energy framework of (I) was generated by employing the 6-31G(d,p) basis set with the B3LYP function. The individual energy components as well as the total inter-action energies are collated in Table 4. As anticipated, the dispersive component makes the major contribution to the interaction energies owing to the absence of conventional hydrogen bonding in the crystal. The most significant stabilization energies are found in the intra-layer region and arise from the directional contacts outlined in Hirshfeld surface analysis as well as two additional C-HÁ Á ÁO interactions, i.e. methylene-C4-H4AÁ Á ÁO4(nitro) and methyl-C21-H21CÁ Á Á O4(nitro) with HÁ Á ÁO separations of 2.63 and 2.77 Å , respectively. The stabilization energies in the inter-layer region are also dominated by the E dis terms associated with the HÁ Á ÁH contacts as well as the long-range C-HÁ Á ÁO interactions (À14.4 kJ mol À1 ). For the former, the maximum energy is not found for the shortest H17Á Á ÁH23B contact (À7.1 kJ mol À1 ), Table 2 and Fig. 8(b), but rather for a pair of benzene-HÁ Á ÁH(methyl) interactions occurring in close proximity in a hydrogen-rich region but at longer separations (À34.2 kJ mol À1 ). For the inter-layer O4Á Á ÁO4 contact mentioned above, there are almost equal contributions from E ele and E dis , Table 4, giving rise to a total interaction energy of À27.7 kJ mol À1 . The magnitudes of intermolecular energies are represented graphically in Fig. 8, and clearly demonstrate the dominance of the E dis in the molecular packing.

Database survey
There are relatively few related structures having a similar substitution pattern to the tetra-substituted pyrrolidine ring of (I). The chemical diagrams for the two most closely related structures, (III), which has two hydroxyl substituents rather than acetyloxy (ALAVOA; Qian et al., 2016), and (IV), which has more complex substituents (RAJDUC; Coleman et al., 2004), are shown in Fig. 9.

Figure 8
Perspective views of the energy frameworks calculated for (I) and viewed down the b axis showing (a) electrostatic potential force, (b) dispersion force and (c) total energy. The radii of the cylinders are proportional to the relative magnitudes of the corresponding energies and were adjusted to the same scale factor of 50 with a cut-off value of 5 kJ mol À1 within 1 Â 1 Â 1 unit cells.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 5. The carbon-bound H atoms were placed in calculated positions (C-H = 0.93-0.98 Å ) and were included in the refinement in the riding model approximation, with U iso (H) set to 1.2-1.5U eq (C).

4-Nitrobenzyl 3,4-bis(acetyloxy)-2-(4-methoxyphenyl)pyrrolidine-1-carboxylate
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.