1-Ethyl 2-methyl 3,4-bis­(acet­yloxy)pyrrolidine-1,2-di­carboxyl­ate: crystal structure, Hirshfeld surface analysis and computational chemistry

Dallasta Pedroso, S.; Caracelli, I.; Zukerman-Schpector, J.; Soto-Monsalve, M.; De Almeida Santos, R.H.; Correia, C.R.D.; Llanes Garcia, A.L.; Kwong, H.C.; Tiekink, E.R.T.

doi:10.1107/S205698902000701X

research communications

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ISSN: 2056-9890

Volume 76| Part 6| June 2020| Pages 967-972

https://doi.org/10.1107/S205698902000701X

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1-Ethyl 2-methyl 3,4-bis(acetyloxy)pyrrolidine-1,2-dicarboxylate: crystal structure, Hirshfeld surface analysis and computational chemistry

^aLaboratório de Cristalografia, Esterodinâmica e Modelagem Molecular, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil, ^bDepartmento de Física, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil, ^cInstituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil, ^dInstituto de Química, Universidade Estadual de Campinas, UNICAMP, CP 6154, CEP 13084-917 Campinas, Brazil, and ^eResearch Centre for Crystalline Materials, School of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia
^*Correspondence e-mail: ignez@df.ufscar.br

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 18 May 2020; accepted 24 May 2020; online 29 May 2020)

The title compound, C₁₃H₁₉NO₈, is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C—C bond; the C_m—C_a—C_a—C_me torsion angle is 38.26 (15)° [m = methylcarboxylate, a = acetyloxy and me = methylene]. While the N-bound ethylcarboxylate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supramolecular double-layers are formed by weak methyl- and methylene-C—H⋯O(carbonyl) interactions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional interactions between them. The Hirshfeld surface is dominated by H⋯H (55.7%) and H⋯C/C⋯H (37.0%) contacts; H⋯H contacts are noted in the inter-double-layer region. The interaction energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal.

Keywords: crystal structure; pyrrolidine; Hirshfeld surface analysis; NCI plots; computational chemistry.

CCDC reference: 2005478

1. Chemical context

A number of diseases, especially diabetes but also including viral diseases, cystic fibrosis and cancer, can be treated with α-glucosidase inhibitors (Dhameja & Gupta, 2019 ; Kiappes et al., 2018 ); for a review of the relevant patent literature, see Brás et al. (2014 ). Imino- and aza-sugars are strong inhibitors of the enzyme and are attracting current interest for chaperone therapy of Gaucher disease (Matassini et al., 2020 ). The tri-hydroxyl-substituted compound, aminociclitol, (I), is a known α-glucosidase inhibitor and is a natural product, being found in several plants (Assefa et al., 2020 ). The synthesis of (I) can proceed from several key intermediates (Garcia, 2008 ; Liu & Ma, 2017 ) and it is this consideration that prompted the structural investigation of the title compound, C₁₃H₁₉NO₈, (II). Specifically, the HCl salt of (I) can be prepared from (II) after being subjected to a sequence of reactions comprising a reduction step, reflux acid hydrolysis, chromatographic purification on ion-exchange resin Dowex-H⁺ and, finally, hydrochloride formation. In this way, (I)·HCl was obtained in 67% yield (Garcia, 2008). In connection with supporting structural studies (Zukerman-Schpector et al., 2017 ) of crucial intermediates related to the synthesis of pharmacologically active (I), herein, the crystal and molecular structures of (II) are described. This is complemented by a detailed analysis of the supramolecular architecture by Hirshfeld surface analysis, non-covalent interactions plots and computational chemistry.

2. Structural commentary

The molecular structure of (II), Fig. 1, features a tetra-substituted pyrrolidine ring. The conformation of the five-membered ring is best described as being twisted about the C2—C3 bond; the C1—C2—C3—C4 torsion angle is 38.26 (15)° indicating a (+)syn-clinal configuration. With respect to the five-membered ring, the N-bound methylcarboxylate substituent occupies an equatorial position; the sum of angles about the N1 atom amounts to 360°, indicating this is an sp² centre. At the C1–C3 centres, the methylcarboxylate and 2 × acetyloxy substituents, respectively, occupy axial positions. For the molecule illustrated in Fig. 1, the chirality of each of the C1–C3 atoms is R, S and S, respectively; the centrosymmetric unit cell contains equal numbers of each enantiomer. When viewed towards the approximate plane through the pyrrolidine ring, the N-bound substituent is approximately co-planar, the C2-acetyloxy lies to one side of the plane, and the C1- and C3-substituents lie to the other side.

Figure 1
The molecular structure of (II), showing the atom-labelling scheme and displacement ellipsoids at the 35% probability level.

3. Supramolecular features

There are two classes of identifiable non-covalent C—H⋯O interactions occurring in the crystal of (II). As identified in PLATON (Spek, 2020 ), methyl-C9—H⋯O5(carbonyl) contacts (Table 1) occur between centrosymmetrically related molecules to form a dimeric aggregate and an 18-membered {⋯OCOC₃OCH}₂ synthon, Fig. 2(a). The second level, i.e. weaker, of C—H⋯O interactions assemble molecules into a supramolecular layer in the ab plane, Fig. 2(b), at separations beyond normally accepted values in PLATON (Spek, 2020). Here, a methylene-C3—H atom is bifurcated, forming contacts with the carbonyl-O1 and O3 atoms of a translationally related molecule along the a-axis direction. This is complemented by a methyl-C11—H⋯O7(carbonyl) interaction occurring along the b-axis direction, Fig. 2(c). The layer thus formed by these contacts is connected into a double-layer via the methyl-C9—H⋯O5(carbonyl) interactions mentioned above. The double-layers stack along the c axis without directional interactions between them.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C9—H9B⋯O5ⁱ	0.96	2.53	3.403 (3)	151
C3—H3⋯O1ⁱⁱ	0.98	2.62	3.419 (2)	139
C3—H3⋯O3ⁱⁱ	0.98	2.61	3.453 (2)	144
C11—H11A⋯O7ⁱⁱⁱ	0.96	2.66	3.329 (3)	127
Symmetry codes: (i) -x, -y, -z+2; (ii) x-1, y, z; (iii) x, y-1, z.

Figure 2
Molecular packing in (II): (a) supramolecular dimer sustained by methyl-C9—H⋯O5(carbonyl) contacts, (b) layer sustained by methyl-C11—H⋯O7(carbonyl) and bifurcated methylene-C3—H⋯O1,O3(carbonyl) contacts (non-participating H atoms are omitted) and (c) a view of the unit-cell contents shown in projection down the a axis. The C—H⋯O interactions are shown as blue dashed lines.

4. Non-covalent interaction plots

Before embarking on a more detailed analysis of the overall molecular packing of (II), in particular of the inter-layer region along the c axis, non-covalent interaction plots (Johnson et al., 2010 ; Contreras-García et al., 2011 ) were calculated to analyse in more detail the nature of the specified C—H⋯O contacts described in Supramolecular features. This method analyses the electron density (and derivatives) around the specified intermolecular contacts and generates colour-based isosurfaces as detailed in the cited literature. The results, through a three-colour scheme, enable the visualization of contacts as being attractive (blue isosurface), repulsive (red) or otherwise. For the weak interactions in focus, a green isosurface indicates a weakly attractive interaction.

The isosurfaces for three identified C—H⋯O contacts are given in the upper view of Fig. 3, and each displays a green isosurface indicating weakly attractive interactions. The lower views of Fig. 3 show the plots of RDG versus sign(λ²)ρ(r) for the three sets of C—H⋯O interactions. The green peaks apparent at density values less than 0.0 a.u. indicate these are weakly attractive interactions.

Figure 3
Non-covalent interaction plots for the following interactions in (II): (a) methyl-C9—H⋯O5(carbonyl), (b) methyl-C11—H⋯O7(carbonyl) and (c) bifurcated methylene-C3—H⋯O1,O3(carbonyl).

5. Hirshfeld surface analysis

In order to understand further the interactions operating in the crystal of (II), the calculated Hirshfeld surfaces were mapped over the normalized contact distance, d_norm (McKinnon et al., 2004 ) and electrostatic potential (Spackman et al., 2008 ) with associated two-dimensional (2-D) (full and delineated) fingerprint (FP) plots (Spackman & McKinnon, 2002 ). These were generated using Crystal Explorer 17 (Turner et al., 2017 ) following literature procedures (Tan et al., 2019 ). The potentials were calculated using the STO-3G basis set at the Hartree–Fock level of theory. The bright-red spots on the Hirshfeld surface mapped over d_norm, Fig. 4(a), near the carbonyl-O (O1, O3, O5 and O7) and methyl-C—H (H3 and H9B) atoms correspond to the C—H⋯O interactions listed in Table 1. These observations were confirmed through the Hirshfeld surface mapped over the calculated electrostatic potential in Fig. 4(b), where the surface around carbonyl-O and methyl-C—H atoms are shown in red (negative electrostatic potential) and blue (positive electrostatic potential), respectively. Besides the C—H⋯O interactions listed in Table 1, a long C13—H13A⋯O5 interaction is reflected in the d_norm surface as a faint red spot in Fig. 5(a). In addition, short, intra-layer C⋯O contacts with separations 0.01–0.04 Å shorter than the sum of their van der Waals radii, Table 2, are observed as faint red spots on the d_norm surface in Fig. 5(b), reflecting the specific influence of the C8, C10 and O1 atoms participating in these contacts.

Table 2
Summary of short interatomic contacts (Å) in (I)^a

Contact	Distance	Symmetry operation
H4B⋯H11C	2.32	x + 1, y + 1, z
H9B⋯O5^b	2.42	−x, −y, −z + 2
H3⋯O1^b	2.55	x − 1, y, z
H3⋯O3 ^b	2.53	x − 1, y, z
H11A⋯O7^b	2.59	−x, −y + 1, −z
H13A⋯O5	2.58	x + 1, y + 1, z
C8⋯O5	3.191 (2)	x + 1, y, z
C10⋯O1	3.204 (2)	x − 1, y, z
C10⋯O7	3.185 (3)	x, y − 1, z
Notes: (a) The interatomic distances are calculated in Crystal Explorer 17 (Turner et al., 2017) whereby the X—H bond lengths are adjusted to their neutron values. (b) These interactions correspond to the interaction listed in Table 1.

Figure 4
Two views of the Hirshfeld surface mapped for (II) over (a) d_norm in the range of −0.083 to +1.828 arbitrary units and (b) the calculated electrostatic potential in the range of −0.077 to 0.054 a.u.

Figure 5
Views of the Hirshfeld surface mapped over d_norm for (II) in the range −0.083 to +1.828 arbitrary units, highlighting within red circles (a) a weak C—H⋯O interaction and (b) C⋯O contacts.

The corresponding two-dimensional fingerprint plot for the Hirshfeld surface of (II) is shown with characteristic pseudo-symmetric wings in the upper left and lower right sides of the d_e and d_i diagonal axes, respectively, in Fig. 6(a). The individual H⋯H, H⋯O/O⋯H, H⋯C/C⋯H, O⋯O, O⋯C/C⋯O and H⋯N/N⋯H contacts are illustrated in the delineated two-dimensional fingerprint plots (FP) in Fig. 6(b)–(g), respectively; the percentage contributions from different interatomic contacts are summarized in Table 3. The H⋯H contacts contribute 55.7% to the overall Hirshfeld surface with a beak-shape distribution in the FP with shortest d_e = d_i ∼2.4 Å. This short interatomic H⋯H contact involving the methyl-H11C and methylene-H4B atoms, Table 2, is around the sum of their van der Waals separation and occurs in the intra-layer region along the b axis. Consistent with the C—H⋯O interactions making the major contribution to the directional interactions in the crystal, H⋯O/O⋯H contacts contribute 37.0% to the overall Hirshfeld surface. A distinctive feature in the FP of Fig. 6(c), is the two symmetric spikes at d_e + d_i ∼2.4 Å. Although H⋯C/C⋯H, O⋯O, O⋯C/C⋯O and H⋯N/N⋯H appear as splash-like distributions of points at d_e + d_i ∼3.0 Å, Fig. 6(d)–(g), their contributions to the overall Hirshfeld surface are each below than 3.0%. These contacts and the remaining interatomic contacts have only a small effect on the packing, as the sum of their contributions to the overall Hirshfeld surface is less than 8%.

Table 3
Percentage contributions of interatomic contacts to the Hirshfeld surface for (II)

Contact	Percentage contribution
H⋯H	55.7
H⋯O/O⋯H	37.0
H⋯C/C⋯H	2.7
O⋯O	2.3
O⋯C/C⋯O	1.9
H⋯C/C⋯H	0.4

Figure 6
(a) The full two-dimensional fingerprint plot for (II) and (b)–(g) those delineated into H⋯H, O⋯H/H⋯O, C⋯H/H⋯C, O⋯O, C⋯O/O⋯C and H⋯N/N⋯H contacts, respectively.

6. Energy frameworks

The pairwise interaction energies between the molecules in the crystal of (II) were calculated using the wave function at the B3LYP/6-31G(d,p) level of theory. The total energy comprise four terms: electrostatic (E_ele), polarization (E_pol), dispersion (E_dis) and exchange-repulsion (E_rep) and were scaled as 1.057, 0.740, 0.871 and 0.618, respectively (Edwards et al., 2017 ). The characteristics of the intermolecular interactions in term of their energies are collated in Table 4. In the absence of conventional hydrogen bonding in the crystal, the dispersive component makes the major contribution to the interaction energies (Table 4). According to the total interaction energy, molecules within the supramolecular double layer are stabilized by C—H⋯O interaction, C⋯O short contacts and long-range H⋯H contacts. Whereas molecules between the supramolecular double layers are stabilized by long-range H⋯H contacts. Views of the energy framework diagrams down the b axis are shown in Fig. 7 and serve to emphasize the contribution of dispersion forces in the stabilization of the crystal.

Table 4
Summary of interaction energies (kJ mol⁻¹) calculated for (II)

Contact	R (Å)	E_ele	E_pol	E_dis	E_rep	E_tot
Intra-double-layer
C3—H3⋯O1ⁱⁱ +
C3—H3⋯O3ⁱⁱ +
O1⋯C10^iv +
O5⋯C8ⁱⁱ	6.8	−19.4	−8.3	−33.6	19.3	−44.0
H9B⋯H13C^v +
H13B⋯H13B^v	8.2	−5.1	−1.6	−28.4	11.0	−24.5
C13—H13A⋯O5^vi +
H4B⋯H11C^vi +
H7C⋯H11B^vi	9.0	−8.8	−2.1	−20.8	10.7	−22.4
C11—H11A⋯O7ⁱⁱⁱ +
C13—H13C⋯O4ⁱⁱⁱ +
C10⋯O7^vii	7.9	−8.1	−2.9	−20.2	12.5	−20.6
H9A⋯H13A^viii +
H9C⋯H9C^viii	9.3	−6.5	−2.1	−19.8	14.4	−16.7
C9—H9B⋯O5ⁱ	9.1	−10.2	−2.3	−12.9	13.9	−15.1
C7—H7B⋯O7^ix	9.9	−3.6	−0.9	−15.1	4.8	−14.7
Inter-double-layer region
H4A⋯H6A^x +
H7B⋯H11B^x	8.1	−5.0	−1.8	−41.4	17.3	−31.9
H7A⋯H11C^xi	8.9	−0.9	−0.4	−10.8	6.2	−6.8
Symmetry codes: (i) −x, −y, −z + 2; (ii) x − 1, y, z; (iii) x, y − 1, z; (iv) x + 1, y, z; (v) −x, −y + 1, −z + 2; (vi) x + 1, y + 1, z; (vii) x, y + 1, z; (viii) −x + 1, −y + 1, −z + 2; (ix) −x, −y + 1, −z; (x) −x, −y, −z + 1; (xi) −x − 1, −y, −z + 1.

Figure 7
Perspective views of the energy frameworks calculated for (II) 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 55 with a cut-off value of 5 kJ mol⁻¹ within 2 × 2 × 2 unit cells.

7. Database survey

There are no close precedents for the substitution pattern observed in the tetra-substituted pyrrolidine ring of (II) with, arguably, the most closely related structure being that of (III) (KULQEP; Szcześniak et al., 2015 ), at least in terms of the substitution pattern around the ring; the chemical diagram for (III) is shown in Fig. 8.

Figure 8
Chemical diagram for (III).

8. Synthesis and crystallization

A solution of (2R,3S,4S)-3,4-bis(acetyloxy)-1-(ethoxycarbonyl)pyrrolidine-2-carboxylic acid (40 mg, 0.132 mmol) in methanol (1 ml) was cooled to 273–278 K after which an excess of a cold, freshly prepared solution of CH₂N₂ in ether was added. The mixture was stirred at room temperature for 10 min. Excess CH₂N₂ was eliminated by purging the balloon with a dry air flow. The purge was collected on a solution of HOAc in MeOH. The reaction solution was concentrated to dryness and the residue was purified by flash column chromatography on silica gel, using a mixture of EtOAc/n-hexane (1:3). Yield: 41.7 mg (quantitative) of (II). Colourless irregular crystals for the X-ray analysis were obtained by the slow evaporation of its n-hexane solution. M.p. 347.6–348.7 K.

The ¹H and ¹³C NMR reflect the presence of two conformational rotamers in solution. ¹H NMR (500 MHz, CDCl₃): δ = 5.38 (s, 1H, H₃); 5.11 (s, 1H, H₄); 4.51 and 4.42 (2s, 1H, H₂); 4.23–4.05 (2m, 2H, CH₂CH₃); 3.91 and 3.87 (2dd, J = 12.8 Hz and 5.5 Hz, 1H, H_4a); 3.772 and 3.766 (2s, 3H, CO₂CH₃); 3.63 and 3.59 (2d, J = 12.8 Hz, 1H, H_4b); 2.10 and 2.09 (2s, 3H, Ac); 2.01 and 2.00 (2s, 3H, Ac); 1.28 and 1.21 (2t, J = 7.0 Hz, 3H, CH₂CH₃). ¹H NMR (500 MHz, C₆D₆, r.t.): δ = 5.62 (s, 1H, H₃); 5.07 and 5.02 (2ap t, J = 2.7 Hz, 1H, H₃); 4.78 (s, 0.6H, H₁); 4.55 (s, 0.4H, H₁); 4.12 and 4.10 (2q, J = 7.0 Hz, 0.4H, CH₂CH₃); 4.01–3.88 (q + m, J = 7.0 Hz, 2H, CH₂CH₃ and H_4a); 3.84–3.76 (m, 1H, H_4b); 3.65 (dd, J = 12.2 Hz and 2.4 Hz, 0.6H, H_4a); 3.31 and 3.30 (2s, 3H, CO₂CH₃); 1.48 and 1.45 (2s, 3H, Ac); 1.43 and 1.42 (2s, 3H, Ac); 0.94 and 0.92 (2t, J = 7.0 Hz, 3H, CH₂CH₃). ¹³C NMR (125 MHz, CDCl₃, r.t.): δ = 169.4; 169.3; 169.2; 168.8; 168.7; 154.8; 154.4; 77.9; 76.9; 74.5; 73.5; 63.6; 63.5; 61.9; 61.7; 52.7; 52.6; 50.6; 50.4; 20.74; 20.70; 20.65; 14.5. Microanalysis calculated for C₁₃H₁₉NO₈: C 49.21, H 6.04, N 4.41%. Found: C 48.89, H 6.52, N 4.50%.

9. 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 = 0.96–0.98 Å) and were included in the refinement in the riding-model approximation, with U_iso(H) set to 1.2–1.5U_eq(C).

Table 5
Experimental details

Crystal data
Chemical formula	C₁₃H₁₉NO₈
M_r	317.29
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	290
a, b, c (Å)	6.8291 (5), 7.8670 (11), 15.814 (3)
α, β, γ (°)	100.607 (11), 99.011 (10), 105.054 (7)
V (Å³)	787.5 (2)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.11
Crystal size (mm)	0.40 × 0.35 × 0.10

Data collection
Diffractometer	Enraf Nonius TurboCAD-4
No. of measured, independent and observed [I > 2σ(I)] reflections	4880, 4573, 2571
R_int	0.020
(sin θ/λ)_max (Å⁻¹)	0.703

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.042, 0.128, 0.99
No. of reflections	4573
No. of parameters	203
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.18, −0.17
Computer programs: CAD-4 EXPRESS (Enraf Nonius, 1989 ), XCAD4 (Harms & Wocadlo, 1995 ), SIR2014 (Burla et al., 2015 ), SHELXL2018/3 (Sheldrick, 2015 ), ORTEP-3 for Windows (Farrugia, 2012 ), MarvinSketch (ChemAxon, 2010 ), DIAMOND (Brandenburg, 2006 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2005478

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S205698902000701X/hb7916sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S205698902000701X/hb7916Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S205698902000701X/hb7916Isup3.cml

checkCIF report

Computing details top

Data collection: CAD-4 EXPRESS (Enraf Nonius, 1989); cell refinement: CAD-4 EXPRESS (Enraf Nonius, 1989); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SIR2014 (Burla et al., 2015); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012), MarvinSketch (ChemAxon, 2010) and DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2010).

1-Ethyl 2-methyl 3,4-bis(acetyloxy)pyrrolidine-1,2-dicarboxylate top

Crystal data top

C₁₃H₁₉NO₈	Z = 2
M_r = 317.29	F(000) = 336
Triclinic, P1	D_x = 1.338 Mg m⁻³
a = 6.8291 (5) Å	Mo Kα radiation, λ = 0.71073 Å
b = 7.8670 (11) Å	Cell parameters from 25 reflections
c = 15.814 (3) Å	θ = 10.8–18.2°
α = 100.607 (11)°	µ = 0.11 mm⁻¹
β = 99.011 (10)°	T = 290 K
γ = 105.054 (7)°	Irregular, colourless
V = 787.5 (2) Å³	0.40 × 0.35 × 0.10 mm

Data collection top

Enraf Nonius TurboCAD-4 diffractometer	θ_max = 30.0°, θ_min = 2.7°
Radiation source: Enraf Nonius FR590	h = −9→9
non–profiled ω/2θ scans	k = 0→11
4880 measured reflections	l = −22→21
4573 independent reflections	3 standard reflections every 120 min
2571 reflections with I > 2σ(I)	intensity decay: 2%
R_int = 0.020

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.128	H-atom parameters constrained
S = 0.99	w = 1/[σ²(F_o²) + (0.0579P)² + 0.0763P] where P = (F_o² + 2F_c²)/3
4573 reflections	(Δ/σ)_max = 0.001
203 parameters	Δρ_max = 0.18 e Å⁻³
0 restraints	Δρ_min = −0.17 e Å⁻³

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.28490 (19)	0.08131 (19)	0.64555 (9)	0.0568 (3)
O2	0.12213 (18)	0.24723 (18)	0.57354 (8)	0.0513 (3)
O3	0.35221 (19)	0.33818 (18)	0.83767 (9)	0.0586 (3)
O4	0.20434 (18)	0.14935 (17)	0.91551 (8)	0.0504 (3)
O5	−0.5275 (2)	−0.0729 (2)	0.83254 (9)	0.0662 (4)
O6	−0.32790 (16)	−0.06328 (15)	0.73314 (7)	0.0424 (3)
O7	−0.2014 (3)	0.6135 (2)	0.78612 (11)	0.0753 (4)
O8	−0.08692 (17)	0.40628 (15)	0.84074 (7)	0.0426 (3)
N1	0.0250 (2)	0.1764 (2)	0.69258 (9)	0.0433 (3)
C1	0.0322 (2)	0.0990 (2)	0.76913 (10)	0.0372 (3)
H1	0.041065	−0.024702	0.752792	0.045*
C2	−0.1782 (2)	0.0948 (2)	0.79177 (10)	0.0357 (3)
H2	−0.177363	0.096071	0.853908	0.043*
C3	−0.2178 (2)	0.2626 (2)	0.76694 (10)	0.0388 (3)
H3	−0.364464	0.257939	0.758613	0.047*
C4	−0.1353 (2)	0.2683 (2)	0.68313 (11)	0.0430 (4)
H4A	−0.244190	0.204920	0.631224	0.052*
H4B	−0.076679	0.392201	0.679209	0.052*
C5	0.1565 (2)	0.1615 (2)	0.63798 (10)	0.0424 (4)
C6	0.2518 (3)	0.2410 (3)	0.50973 (13)	0.0631 (5)
H6A	0.234590	0.116529	0.480776	0.076*
H6B	0.396809	0.298206	0.538377	0.076*
C7	0.1853 (4)	0.3399 (4)	0.44469 (15)	0.0818 (7)
H7A	0.041201	0.282919	0.417435	0.123*
H7B	0.266749	0.337723	0.400460	0.123*
H7C	0.204764	0.463198	0.474089	0.123*
C8	0.2155 (2)	0.2132 (2)	0.84352 (11)	0.0404 (3)
C9	0.3834 (3)	0.2283 (4)	0.98760 (14)	0.0766 (7)
H9A	0.506912	0.224946	0.966399	0.115*
H9B	0.370682	0.160845	1.032257	0.115*
H9C	0.391528	0.351722	1.012025	0.115*
C10	−0.4972 (2)	−0.1374 (2)	0.76304 (12)	0.0461 (4)
C11	−0.6347 (3)	−0.3050 (3)	0.69971 (16)	0.0697 (6)
H11A	−0.581462	−0.404559	0.706145	0.104*
H11B	−0.639848	−0.289168	0.640732	0.104*
H11C	−0.771979	−0.329842	0.711270	0.104*
C12	−0.0926 (3)	0.5768 (2)	0.84243 (13)	0.0500 (4)
C13	0.0585 (4)	0.7066 (3)	0.92107 (15)	0.0696 (6)
H13A	0.194942	0.735689	0.908739	0.104*
H13B	0.058933	0.652183	0.970653	0.104*
H13C	0.018502	0.815216	0.934292	0.104*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0482 (7)	0.0740 (9)	0.0610 (8)	0.0303 (7)	0.0206 (6)	0.0223 (7)
O2	0.0509 (7)	0.0668 (8)	0.0457 (6)	0.0205 (6)	0.0212 (5)	0.0231 (6)
O3	0.0431 (6)	0.0550 (8)	0.0714 (8)	0.0012 (6)	0.0106 (6)	0.0205 (7)
O4	0.0476 (6)	0.0545 (7)	0.0462 (6)	0.0117 (6)	0.0003 (5)	0.0186 (6)
O5	0.0573 (8)	0.0702 (10)	0.0703 (9)	0.0073 (7)	0.0301 (7)	0.0171 (8)
O6	0.0357 (5)	0.0405 (6)	0.0475 (6)	0.0065 (5)	0.0088 (5)	0.0092 (5)
O7	0.0854 (11)	0.0571 (9)	0.0929 (11)	0.0370 (8)	0.0070 (9)	0.0284 (8)
O8	0.0440 (6)	0.0367 (6)	0.0497 (6)	0.0151 (5)	0.0096 (5)	0.0122 (5)
N1	0.0395 (7)	0.0576 (9)	0.0448 (7)	0.0230 (6)	0.0144 (6)	0.0243 (6)
C1	0.0345 (7)	0.0403 (8)	0.0423 (8)	0.0148 (6)	0.0098 (6)	0.0168 (7)
C2	0.0327 (7)	0.0348 (8)	0.0397 (8)	0.0087 (6)	0.0082 (6)	0.0105 (6)
C3	0.0322 (7)	0.0404 (8)	0.0458 (8)	0.0125 (6)	0.0082 (6)	0.0127 (7)
C4	0.0411 (8)	0.0497 (10)	0.0446 (8)	0.0186 (7)	0.0094 (7)	0.0196 (7)
C5	0.0359 (7)	0.0520 (10)	0.0389 (8)	0.0111 (7)	0.0086 (6)	0.0118 (7)
C6	0.0635 (12)	0.0808 (15)	0.0527 (11)	0.0219 (11)	0.0292 (9)	0.0195 (10)
C7	0.0946 (17)	0.112 (2)	0.0566 (12)	0.0356 (15)	0.0357 (12)	0.0387 (13)
C8	0.0357 (7)	0.0424 (9)	0.0477 (9)	0.0155 (7)	0.0101 (6)	0.0154 (7)
C9	0.0645 (13)	0.0948 (18)	0.0570 (12)	0.0172 (12)	−0.0142 (10)	0.0169 (12)
C10	0.0358 (8)	0.0443 (9)	0.0596 (10)	0.0088 (7)	0.0106 (7)	0.0200 (8)
C11	0.0448 (10)	0.0558 (12)	0.0917 (16)	−0.0003 (9)	0.0043 (10)	0.0075 (11)
C12	0.0516 (9)	0.0402 (9)	0.0677 (12)	0.0181 (8)	0.0229 (9)	0.0213 (9)
C13	0.0803 (14)	0.0425 (11)	0.0764 (14)	0.0050 (10)	0.0192 (12)	0.0075 (10)

Geometric parameters (Å, º) top

O1—C5	1.2098 (19)	C3—H3	0.9800
O2—C5	1.345 (2)	C4—H4A	0.9700
O2—C6	1.446 (2)	C4—H4B	0.9700
O3—C8	1.1961 (19)	C6—C7	1.484 (3)
O4—C8	1.3312 (19)	C6—H6A	0.9700
O4—C9	1.445 (2)	C6—H6B	0.9700
O5—C10	1.195 (2)	C7—H7A	0.9600
O6—C10	1.3499 (19)	C7—H7B	0.9600
O6—C2	1.4385 (18)	C7—H7C	0.9600
O7—C12	1.195 (2)	C9—H9A	0.9600
O8—C12	1.348 (2)	C9—H9B	0.9600
O8—C3	1.4496 (19)	C9—H9C	0.9600
N1—C5	1.351 (2)	C10—C11	1.483 (3)
N1—C1	1.4518 (19)	C11—H11A	0.9600
N1—C4	1.464 (2)	C11—H11B	0.9600
C1—C8	1.524 (2)	C11—H11C	0.9600
C1—C2	1.528 (2)	C12—C13	1.496 (3)
C1—H1	0.9800	C13—H13A	0.9600
C2—C3	1.521 (2)	C13—H13B	0.9600
C2—H2	0.9800	C13—H13C	0.9600
C3—C4	1.523 (2)

C5—O2—C6	115.92 (14)	O2—C6—H6B	110.4
C8—O4—C9	115.73 (15)	C7—C6—H6B	110.4
C10—O6—C2	116.20 (12)	H6A—C6—H6B	108.6
C12—O8—C3	118.19 (13)	C6—C7—H7A	109.5
C5—N1—C1	121.34 (13)	C6—C7—H7B	109.5
C5—N1—C4	125.77 (13)	H7A—C7—H7B	109.5
C1—N1—C4	112.89 (12)	C6—C7—H7C	109.5
N1—C1—C8	111.47 (13)	H7A—C7—H7C	109.5
N1—C1—C2	102.32 (12)	H7B—C7—H7C	109.5
C8—C1—C2	113.23 (13)	O3—C8—O4	124.90 (16)
N1—C1—H1	109.9	O3—C8—C1	125.34 (15)
C8—C1—H1	109.9	O4—C8—C1	109.73 (13)
C2—C1—H1	109.9	O4—C9—H9A	109.5
O6—C2—C3	108.78 (12)	O4—C9—H9B	109.5
O6—C2—C1	106.68 (12)	H9A—C9—H9B	109.5
C3—C2—C1	103.23 (12)	O4—C9—H9C	109.5
O6—C2—H2	112.5	H9A—C9—H9C	109.5
C3—C2—H2	112.5	H9B—C9—H9C	109.5
C1—C2—H2	112.5	O5—C10—O6	122.72 (16)
O8—C3—C2	102.26 (11)	O5—C10—C11	125.62 (16)
O8—C3—C4	111.80 (12)	O6—C10—C11	111.66 (16)
C2—C3—C4	103.54 (13)	C10—C11—H11A	109.5
O8—C3—H3	112.8	C10—C11—H11B	109.5
C2—C3—H3	112.8	H11A—C11—H11B	109.5
C4—C3—H3	112.8	C10—C11—H11C	109.5
N1—C4—C3	103.35 (12)	H11A—C11—H11C	109.5
N1—C4—H4A	111.1	H11B—C11—H11C	109.5
C3—C4—H4A	111.1	O7—C12—O8	122.72 (18)
N1—C4—H4B	111.1	O7—C12—C13	126.78 (18)
C3—C4—H4B	111.1	O8—C12—C13	110.46 (16)
H4A—C4—H4B	109.1	C12—C13—H13A	109.5
O1—C5—O2	125.04 (15)	C12—C13—H13B	109.5
O1—C5—N1	124.93 (15)	H13A—C13—H13B	109.5
O2—C5—N1	110.02 (14)	C12—C13—H13C	109.5
O2—C6—C7	106.76 (17)	H13A—C13—H13C	109.5
O2—C6—H6A	110.4	H13B—C13—H13C	109.5
C7—C6—H6A	110.4

C5—N1—C1—C8	76.02 (19)	C2—C3—C4—N1	−27.36 (15)
C4—N1—C1—C8	−103.88 (15)	C6—O2—C5—O1	−0.3 (3)
C5—N1—C1—C2	−162.67 (14)	C6—O2—C5—N1	−179.62 (15)
C4—N1—C1—C2	17.43 (18)	C1—N1—C5—O1	2.0 (3)
C10—O6—C2—C3	−96.72 (15)	C4—N1—C5—O1	−178.13 (17)
C10—O6—C2—C1	152.54 (13)	C1—N1—C5—O2	−178.67 (14)
N1—C1—C2—O6	80.73 (14)	C4—N1—C5—O2	1.2 (2)
C8—C1—C2—O6	−159.17 (12)	C5—O2—C6—C7	178.98 (17)
N1—C1—C2—C3	−33.83 (15)	C9—O4—C8—O3	−6.4 (3)
C8—C1—C2—C3	86.27 (14)	C9—O4—C8—C1	171.57 (15)
C12—O8—C3—C2	−176.59 (13)	N1—C1—C8—O3	−8.7 (2)
C12—O8—C3—C4	73.23 (17)	C2—C1—C8—O3	−123.40 (18)
O6—C2—C3—O8	168.91 (11)	N1—C1—C8—O4	173.33 (13)
C1—C2—C3—O8	−78.04 (13)	C2—C1—C8—O4	58.60 (17)
O6—C2—C3—C4	−74.78 (14)	C2—O6—C10—O5	3.0 (2)
C1—C2—C3—C4	38.26 (15)	C2—O6—C10—C11	−176.72 (15)
C5—N1—C4—C3	−173.74 (15)	C3—O8—C12—O7	0.4 (2)
C1—N1—C4—C3	6.15 (18)	C3—O8—C12—C13	−177.58 (14)
O8—C3—C4—N1	82.01 (15)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C9—H9B···O5ⁱ	0.96	2.53	3.403 (3)	151
C3—H3···O1ⁱⁱ	0.98	2.62	3.419 (2)	139
C3—H3···O3ⁱⁱ	0.98	2.61	3.453 (2)	144
C11—H11A···O7ⁱⁱⁱ	0.96	2.66	3.329 (3)	127

Symmetry codes: (i) −x, −y, −z+2; (ii) x−1, y, z; (iii) x, y−1, z.

Summary of short interatomic contacts (Å) in (I)^a top

Contact	Distance	Symmetry operation
H4B···H11C	2.32	x + 1, y + 1, z
H9B···O5^b	2.42	-x, -y, -z + 2
H3···O1^b	2.55	x - 1, y, z
H3···O3 ^b	2.53	x - 1, y, z
H11A···O7^b	2.59	-x, -y + 1, -z
H13A···O5	2.58	x + 1, y + 1, z
C8···O5	3.191 (2)	x + 1, y, z
C10···O1	3.204 (2)	x - 1, y, z
C10···O7	3.185 (3)	x, y - 1, z

Notes: (a) The interatomic distances are calculated in Crystal Explorer 17 (Turner et al., 2017) whereby the X—H bond lengths are adjusted to their neutron values. (b) These interactions correspond to the interaction listed in Table 1.

Percentage contributions of interatomic contacts to the Hirshfeld surface for (II) top

Contact	Percentage contribution
H···H	55.7
H···O/O···H	37.0
H···C/C···H	2.7
O···O	2.3
O···C/C···O	1.9
H···C/C···H	0.4

Summary of interaction energies (kJ mol^-1) calculated for (II) top

Contact	R (Å)	E_ele	E_pol	E_dis	E_rep	E_tot
Intra-double-layer
C3—H3···O1ⁱⁱ +
C3—H3···O3ⁱⁱ +
O1···C10^iv +
O5···C8ⁱⁱ	6.8	-19.4	-8.3	-33.6	19.3	-44.0
H9B···H13C^v +
H13B···H13B^v	8.2	-5.1	-1.6	-28.4	11.0	-24.5
C13—H13A···O5^vi +
H4B···H11C^vi +
H7C···H11B^vi	9.0	-8.8	-2.1	-20.8	10.7	-22.4
C11—H11A···O7ⁱⁱⁱ +
C13—H13C···O4ⁱⁱⁱ +
C10···O7^vii	7.9	-8.1	-2.9	-20.2	12.5	-20.6
H9A···H13A^viii +
H9C···H9C^viii	9.3	-6.5	-2.1	-19.8	14.4	-16.7
C9—H9B···O5ⁱ	9.1	-10.2	-2.3	-12.9	13.9	-15.1
C7—H7B···O7^ix	9.9	-3.6	-0.9	-15.1	4.8	-14.7
Inter-double-layer region
H4A···H6A^x +
H7B···H11B^x	8.1	-5.0	-1.8	-41.4	17.3	-31.9
H7A···H11C^xi	8.9	-0.9	-0.4	-10.8	6.2	-6.8

Symmetry codes: (i) -x, -y, -z + 2; (ii) x - 1, y, z; (iii) x, y - 1, z; (iv) x + 1, y, z; (v) -x, -y + 1, -z + 2; (vi) x + 1, y + 1, z; (vii) x, y + 1, z; (viii) -x + 1, -y + 1, -z + 2; (ix) -x, -y + 1, -z; (x) -x, -y, -z + 1; (xi) -x - 1, -y, -z + 1.

Footnotes

‡Additional correspondence author, e-mail: edwardt@sunway.edu.my.

Funding information

The Brazilian agencies Coordination for the Improvement of Higher Education Personnel, CAPES, Finance Code 001 and the National Council for Scientific and Technological Development (CNPq) are acknowledged for grants (312210/2019–1, 433957/2018–2 and 406273/2015–4) to IC, for a fellowship (303207/2017–5) to JZS and a scholarship to SDP. Sunway University Sdn Bhd is also thanked for funding (grant. No. STR-RCTR-RCCM-001–2019).

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