An unusual conformation of gabapentin (Gpn) in Pyr-Gpn-NH-NH-Pyr stabilized by weak inter­actions

The crystal structure of N-[(1-{2-oxo-2-[2-(pyrazin-2-ylcarbon­yl)hydrazin-1-yl]eth­yl}cyclo­hex­yl)meth­yl]pyrazine-2-carbox­amide monohydrate (Pyr-Gpn-NN-NH-Pyr·H₂O), C₁₉H₂₃N₇O₃·H₂O, reveals an unusual trans-gauche (tg^-) conformation for the gabapentin (Gpn) residue around the C^[gamma]-C^[beta] ([theta]₁) and C^[beta]-C^[alpha] ([theta]₂) bonds. The mol­ecular conformation is stabilized by intra­molecular N-H...N hydrogen bonds and weak C-H...O inter­actions. The packing of the mol­ecules in the crystal lattice shows a network of strong N-H...O and O-H...O hydrogen bonds together with weak C-H...O and [pi]-[pi] inteactions.

S1. Introduction

Gabapentin {2-[1-(amino­methyl)­cyclo­hexyl]­acetic acid, Gpn} is a β,β-disubstituted γ-amino acid, which has has been used as an anti­epileptic drug, as well as employed for the treatment of neuropathic pain (Wheeler, 2002; Stefan & Feuerstein, 2007; Rosenberg et al., 1997; Maneuf et al., 2003). Gabapentin has been extensively studied for the occurrence of polymorphic crystal forms (Ibers, 2001; Reece & Levendis, 2008). It has been widely used in the construction of hybrid peptides, as well as in oligomers (Vasudev et al., 2009; Balaram, 2010). In order to study the influence of pyrolidine rings on the conformation of gabapentin, we synthesized N-[(1-{2-oxo-2-[2-(pyrazin-2-yl­carbonyl)­hydrazin-1-yl]ethyl}­cyclo­hexyl)­methyl]­pyrazine-2-carboxamide monohydrate (Pyr-Gpn-NN—NH-Pyr.H₂O; Pyr is pyrazol-2-yl­carbonyl), (I), in which Pyr groups are positioned at the N- and C-termini of the Gpn residue. In our previous study, a gauche conformation was reported for the Gpn residue in Pyr-Gpn-OH, in which only the N-terminus is protected by a Pyr group (Wani et al., 2013).

S2. Experimental

S2.1. Synthesis and crystallization

S2.1.1. Preparation of Pyr-Gpn-OMe

Pyrazine carb­oxy­lic acid (3.0 mmol, 372.0 mg) was dissolved in dry dichlo­methane (CH₂Cl₂) and then added to N-methyl­morpholine (200 µl) followed by Gpn–OMe·HCl (3.0 mmol, 666.5 mg) and EDCI·HCl (3.0 mmol, 576.0 mg) under ice-cold conditions. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, water was added to the reaction mixture and extracted with CH₂Cl₂ (3 × 5.0 ml). The combined organic layer was washed with 2 N HCl (2 × 5.0 ml), Na₂CO₃ (2 × 5.0 ml) and brine solution (5.0 ml). The organic layer was passed over anhydrous Na₂SO₄ and evaporated under vacuum to give Pyr-Gpn-OMe (yield 610.0 mg, 69.8%).

S2.1.2. Preparation of Pyr-Gpn-NH—NH~2~

Pyr-Gpn-OMe (1.0 mmol, 291.0 mg) was dissolved in dry methanol (1.0 ml) and added to hydrazine hydrate (100 µl). The reaction mixture was stirred for 5 h at room temperature. After completion of the reaction, the solvent was evaporated under vacuum to dryness and water (5.0 ml) was added. The product was extracted with ethyl acetate (3 × 5.0 ml), washed with brine solution (5.0 ml), passed over anhydrous Na₂SO₄ and evaporated under vacuum to give Pyr-Gpn-NH—NH₂ (yield 200 mg, 68.72%).

S2.1.3. Preparation of Pyr-Gpn-NH—NH-Pyr.H~2Õ, (I)

Pyr-COOH (0.5 mmol, 62.0 mg) was dissolved in dry di­chloro­methane followed by the addition of N-methyl­morpholine (50 µl), EDCI (0.5 mmol, 96.0 mg) and Pyr-Gpn-NH—NH₂ (0.5 mmol, 145.0 mg). The reaction mixture was stirred for 16 h. The solvent was evaporated completely and water was added. The product was extracted with ethyl acetate (3 × 5.0 ml), followed by washing with 2 N HCl (1 × 5.0 ml), Na₂CO₃ (5.0 ml) and brine solution (5.0 ml). The organic layer was passed over anhydrous Na₂SO₄ and evaporated under vacuum to dryness to yield the product, which was purified by column chromatography (yield 68.91%, 100 mg). Pyr-Gpn-NN—NH-Pyr was crystallized by slow evaporation from an methanol–water (9:1 v/v) mixture as the monohydrate.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms were located in a difference Fourier map and both their coordinates and U_iso(H) values were refined.

S3. Results and discussion

The conformation of the molecule of (I) (Fig. 1a) is stabilized by intra­molecular (C₅) N—H···N hydrogen bonds (N1—H1N···N11 and N3—H3N···N22) and a weak C—H···O inter­action between the Gpn C^γH and Pyr groups (C3—H3···O1^iv; see Table 3 for details and symmetry code). A similar kind of C₅ N—H···H and C—H···O inter­action was observed in the crystal structure of Pyr-Gpn-OH (Wani et al., 2013). Weak C—H···O inter­actions play a crucial role in the control of the molecular conformation (Venugopalan & Kishore, 2013) and the packing of molecules in the crystal lattice (Desiraju, 1996; Steiner, 1997; Lo Prestil et al., 2006). The Gpn residue adopts a trans–gauche (tg^-) conformation around the C^γ—C^β (θ₁) and C^β—C^α (θ₂) bonds. The backbone dihedral angles are listed in Table 2. Generally, the values of torsion angles θ₁ and θ₂ of Gpn residue in protected derivatives, as well as in peptide sequences (Vasudev et al., 2009; Balaram, 2010; Vasudev et al., 2011), are restricted to the gauche–gauche (gg) conformation due to the substitution of the cyclo­hexyl ring at the β-position. In the case of the o­cta­peptide, viz. Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (Chatterjee et al., 2009), the Gpn residue favours a gauche–trans (gt) conformation. To the best of our knowledge, this is the only example of a gt conformation for a Gpn residue in a peptide reported in the literature. Fig. 1(b) shows the L-shaped structure of the molecule. The cyclo­hexyl ring adopts a classical chair conformation, with an equatorial orientation of the amino­methyl group [the corresponding puckering parameters are Q = 0.555 (3) Å, θ = 1.0 (3)° and ϕ = 35 (17)° (Cremer & Pople, 1975)].

Fig. 2 shows the hydrogen-bond inter­actions formed by the molecule. The dimer around the centre of inversion is stabilized by a pair of N—H···O hydrogen bonds, i.e. N1—H1N···O1(-x, -y-1, -z). The hydrogen-bond parameters are listed in Table 3. The water molecule forms a hydrogen bond with amide atom N2 and also bridges the symmetry-related molecules O1A at (-x-1/2, y-1/2, -z-1/2) and O1B at (-x-1/2, y+1/2, -z-1/2) through O—H···O(carbonyl) hydrogen bonds. In addtion to these hydrgen bonds, a strong N—H···N hydrogen bond between atom N3 and pyrazine atom N12 [N3—H3N···N12(-x, -y, -z)] is present, together with weak C—H···O hydrogen bonds between atoms C3 and C9 of the pyrazine ring and carbonyl atom O1 and water atom O1w, respectively [C9—H9···O1w(-x-1, -y-1, -z) and C3—H3···O1(x, y+1, z)]. Fig. 3 illustrates the spatial arrangement of the pyrazine rings in the crystal lattice. The pyrazine rings of symmetry-related molecules come close in space and the distance between the centroids are listed in Table 3. It can been seen that only the distance between centroids c1 and c10 and between c7 and c8 fall below the 4Å cut-off for stacking π–π inter­actions (Burley & Petsko, 1985, 1988; Ma et al., 2010). Fig. 4 shows the packing of the molecules of (I) in the crystal along the b axis, held together by strong N—N···N, O—H···O and N—H···O hydrogen bonds, and by weaker C—H···O inter­actions and a network of π–π inter­actions.

The present study provides the first example of gabapentin (Gpn) with a trans–gauche (tg) conformation, which may be useful in the constuction of folded structures in designed peptide sequences.

Related literature

For related literature, see: Balaram (2010); Burley & Petsko (1985, 1988); Chatterjee et al. (2009); Cremer & Pople (1975); Desiraju (1996); Ibers (2001); Lo Prestil, Soave & Destro (2006); Ma et al. (2010); Maneuf et al. (2003); Reece & Levendis (2008); Rosenberg et al. (1997); Stefan & Feuerstein (2007); Steiner (1997); Vasudev et al. (2009, 2011); Venugopalan & Kishore (2013); Wani et al. (2013); Wheeler (2002).

Computing details

Data collection: CrysAlis PRO (Oxford Diffraction, 2010); cell refinement: CrysAlis PRO (Oxford Diffraction, 2010); data reduction: CrysAlis PRO (Oxford Diffraction, 2010); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: PLATON (Spek, 2009).

Figures

	Fig. 1. (a) The molecular structure of (I), showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 40% probability level. H atoms are shown as small spheres of arbitrary radii. (b) Ball-and-stick model showing the bend conformation (L-shaped) of the molecule in the crystal.
	Fig. 2. (a) Hydrogen-bond interactions around the asymmetric unit. Only H atoms involved in hydrogen-bond interactions are shown. [Symmetry codes: (i) -x, -y-1, -z; (ii) -x-1/2, y-1/2, -z-1/2; (iii) -x-1/2, y+1/2, -z-1/2; (iv) -x, -y, -z; (v) -x-1, -y-1, -z; (vi) x, y+1, z.]
	Fig. 3. (a) The crystal packing in (I), showing the spatial arrangement of pyrazine rings in the crystal lattice. The centroids are marked as cx (x = 1–10). (b) A side view of the interactions (rotation by 90°) showing only the π–π interaction between molecules at (x, y, z) and (-x+1, -y+1, -z) in the packing.
	Fig. 4. Packing arrangement of molecules viewed down the b axis.

N-[(1-{2-Oxo-2-[2-(pyrazin-2-ylcarbonyl)hydrazin-1-yl]ethyl}cyclohexyl)methyl]pyrazine-2-carboxamide monohydrate

Crystal data

C19H23N7O3·H2O	F(000) = 880
Mr = 415.46	Dx = 1.385 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 2317 reflections
a = 13.6666 (6) Å	θ = 3.7–27.0°
b = 9.6505 (5) Å	µ = 0.10 mm^−1
c = 15.1672 (7) Å	T = 293 K
β = 95.079 (5)°	Rod, color less
V = 1992.54 (16) Å^3	0.36 × 0.21 × 0.18 mm
Z = 4

Data collection

Oxford Diffraction Xcalibur Sapphire3 diffractometer	4294 independent reflections
Radiation source: fine-focus sealed tube	2355 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.037
Detector resolution: 16.1049 pixels mm^-1	θmax = 27.0°, θmin = 3.6°
ω scan	h = −16→17
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2010)	k = −10→12
Tmin = 0.736, Tmax = 1.000	l = −17→19
8191 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.049	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.098	All H-atom parameters refined
S = 1.01	w = 1/[σ^2(Fo^2) + (0.021P)^2] where P = (Fo^2 + 2Fc^2)/3
4294 reflections	(Δ/σ)max < 0.001
371 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

Special details

Experimental. CrysAlis PRO, Oxford Diffraction Ltd., Version 1.171.34.40 (release 27–08–2010 CrysAlis171. NET) (compiled Aug 27 2010,11:50:40) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
N11	0.19775 (15)	−0.0425 (2)	0.01077 (11)	0.0427 (5)
C1	0.2630 (2)	0.0354 (3)	0.05892 (16)	0.0480 (7)
C2	0.26399 (19)	0.1779 (3)	0.05208 (16)	0.0441 (7)
N12	0.20100 (15)	0.2465 (2)	−0.00223 (12)	0.0428 (5)
C3	0.13474 (19)	0.1694 (3)	−0.05044 (15)	0.0383 (6)
C4	0.13362 (16)	0.0265 (2)	−0.04413 (12)	0.0305 (5)
C5	0.05833 (17)	−0.0572 (2)	−0.09960 (13)	0.0335 (5)
O1A	0.00271 (13)	−0.00090 (17)	−0.15713 (9)	0.0533 (5)
N1	0.05941 (15)	−0.1925 (2)	−0.08103 (12)	0.0367 (5)
C1G	−0.01094 (17)	−0.2917 (3)	−0.12154 (15)	0.0350 (6)
C1B	0.03100 (16)	−0.3948 (2)	−0.18618 (12)	0.0296 (5)
C1A	−0.05447 (17)	−0.4929 (3)	−0.21817 (13)	0.0337 (6)
C1'	−0.10941 (17)	−0.5496 (2)	−0.14363 (13)	0.0326 (5)
O1	−0.07365 (12)	−0.62770 (17)	−0.08624 (9)	0.0462 (4)
C1B1	0.0647 (2)	−0.3143 (3)	−0.26593 (15)	0.0388 (6)
C1G1	0.1149 (2)	−0.4068 (3)	−0.33001 (16)	0.0506 (8)
C1D	0.2007 (2)	−0.4852 (4)	−0.28350 (19)	0.0567 (8)
C1G2	0.1699 (2)	−0.5664 (3)	−0.20428 (16)	0.0454 (7)
C1B2	0.11899 (17)	−0.4734 (3)	−0.14114 (14)	0.0341 (6)
N2	−0.20278 (14)	−0.5018 (2)	−0.14512 (11)	0.0370 (5)
N3	−0.25854 (14)	−0.5292 (2)	−0.07469 (12)	0.0389 (5)
C6	−0.31863 (16)	−0.6379 (2)	−0.07557 (13)	0.0327 (5)
O1B	−0.32636 (11)	−0.72574 (17)	−0.13399 (9)	0.0464 (5)
C7	−0.37834 (16)	−0.6443 (2)	0.00259 (13)	0.0337 (5)
C8	−0.4356 (2)	−0.7578 (3)	0.01617 (17)	0.0510 (7)
N21	−0.49065 (16)	−0.7673 (3)	0.08426 (14)	0.0627 (7)
C9	−0.4863 (2)	−0.6581 (4)	0.13822 (17)	0.0582 (8)
C10	−0.4294 (2)	−0.5454 (4)	0.12545 (17)	0.0573 (8)
N22	−0.37462 (14)	−0.5351 (2)	0.05707 (12)	0.0475 (6)
O1W	−0.32394 (17)	−0.3516 (3)	−0.27109 (12)	0.0600 (6)
H3	0.0836 (16)	0.214 (2)	−0.0900 (12)	0.048 (7)*
H2G	−0.0641 (15)	−0.237 (2)	−0.1528 (11)	0.035 (6)*
H4B	0.1653 (16)	−0.405 (2)	−0.1158 (12)	0.046 (7)*
H3B	0.0964 (14)	−0.527 (2)	−0.0892 (11)	0.033 (6)*
H5G	0.1252 (15)	−0.642 (2)	−0.2246 (11)	0.031 (6)*
H1B	0.0091 (17)	−0.267 (2)	−0.2964 (13)	0.054 (7)*
H2	0.3140 (17)	0.232 (2)	0.0890 (13)	0.056 (7)*
H2A	−0.1004 (15)	−0.444 (2)	−0.2593 (12)	0.040 (6)*
H1G	−0.0373 (15)	−0.342 (2)	−0.0714 (12)	0.044 (6)*
H1	0.3104 (17)	−0.009 (2)	0.0977 (13)	0.056 (8)*
H1A	−0.0323 (15)	−0.577 (2)	−0.2499 (12)	0.045 (7)*
H1N	0.1002 (18)	−0.216 (3)	−0.0337 (14)	0.068 (9)*
H2B	0.1110 (16)	−0.246 (2)	−0.2423 (12)	0.046 (7)*
H8	−0.4355 (15)	−0.840 (2)	−0.0264 (12)	0.046 (7)*
H3N	−0.2530 (19)	−0.466 (3)	−0.0298 (14)	0.074 (9)*
H6G	0.2285 (16)	−0.610 (2)	−0.1709 (12)	0.050 (7)*
H3G	0.0662 (17)	−0.469 (3)	−0.3586 (13)	0.056 (8)*
H1W	−0.370 (3)	−0.393 (3)	−0.304 (2)	0.115 (16)*
H9	−0.5276 (16)	−0.666 (2)	0.1860 (13)	0.050 (7)*
H1D	0.2475 (18)	−0.417 (3)	−0.2651 (14)	0.061 (9)*
H2N	−0.2321 (17)	−0.449 (3)	−0.1945 (13)	0.062 (8)*
H4G	0.1394 (17)	−0.347 (2)	−0.3749 (13)	0.060 (7)*
H10	−0.4308 (19)	−0.471 (3)	0.1644 (15)	0.082 (10)*
H2D	0.2281 (19)	−0.556 (3)	−0.3246 (15)	0.086 (9)*
H2W	−0.290 (2)	−0.299 (3)	−0.3002 (17)	0.089 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N11	0.0455 (13)	0.0364 (12)	0.0449 (10)	−0.0020 (11)	−0.0043 (10)	0.0012 (10)
C1	0.0448 (17)	0.0474 (19)	0.0494 (14)	−0.0016 (15)	−0.0086 (13)	0.0008 (14)
C2	0.0401 (15)	0.0429 (17)	0.0490 (14)	−0.0102 (15)	0.0030 (13)	−0.0080 (13)
N12	0.0441 (13)	0.0348 (13)	0.0499 (11)	−0.0056 (11)	0.0060 (10)	−0.0062 (10)
C3	0.0419 (15)	0.0330 (15)	0.0402 (12)	0.0011 (13)	0.0047 (12)	−0.0009 (12)
C4	0.0341 (13)	0.0297 (14)	0.0281 (10)	−0.0029 (12)	0.0058 (10)	0.0002 (10)
C5	0.0357 (14)	0.0321 (14)	0.0331 (11)	−0.0022 (13)	0.0047 (10)	−0.0014 (11)
O1A	0.0606 (12)	0.0425 (11)	0.0529 (9)	0.0007 (10)	−0.0171 (9)	0.0059 (9)
N1	0.0408 (12)	0.0303 (12)	0.0380 (10)	−0.0034 (11)	−0.0021 (10)	−0.0001 (10)
C1G	0.0315 (13)	0.0325 (14)	0.0406 (13)	−0.0046 (13)	0.0003 (11)	−0.0045 (12)
C1B	0.0298 (12)	0.0304 (13)	0.0287 (10)	−0.0023 (11)	0.0031 (9)	0.0021 (10)
C1A	0.0324 (13)	0.0380 (15)	0.0305 (11)	−0.0034 (12)	0.0020 (10)	−0.0008 (11)
C1'	0.0355 (14)	0.0266 (13)	0.0353 (11)	−0.0078 (12)	0.0005 (11)	−0.0015 (10)
O1	0.0468 (10)	0.0438 (11)	0.0478 (8)	−0.0006 (9)	0.0025 (8)	0.0159 (8)
C1B1	0.0370 (15)	0.0424 (17)	0.0368 (12)	−0.0031 (14)	0.0020 (12)	0.0104 (12)
C1G1	0.0549 (19)	0.061 (2)	0.0387 (14)	−0.0053 (17)	0.0163 (14)	0.0101 (14)
C1D	0.0493 (19)	0.066 (2)	0.0582 (17)	0.0093 (19)	0.0222 (15)	0.0058 (17)
C1G2	0.0413 (16)	0.0464 (18)	0.0491 (14)	0.0022 (15)	0.0080 (13)	0.0004 (14)
C1B2	0.0323 (13)	0.0352 (15)	0.0342 (12)	−0.0016 (12)	0.0002 (11)	0.0040 (11)
N2	0.0332 (11)	0.0443 (13)	0.0341 (10)	−0.0075 (11)	0.0070 (9)	0.0074 (10)
N3	0.0397 (12)	0.0418 (13)	0.0367 (10)	−0.0131 (11)	0.0116 (9)	−0.0041 (10)
C6	0.0270 (12)	0.0313 (14)	0.0392 (12)	−0.0023 (12)	0.0003 (10)	0.0004 (11)
O1B	0.0463 (10)	0.0465 (11)	0.0475 (8)	−0.0116 (9)	0.0094 (8)	−0.0125 (8)
C7	0.0263 (12)	0.0382 (15)	0.0369 (11)	−0.0022 (12)	0.0041 (10)	0.0006 (11)
C8	0.0519 (17)	0.0461 (17)	0.0578 (15)	−0.0054 (16)	0.0209 (14)	−0.0010 (14)
N21	0.0575 (15)	0.0644 (18)	0.0704 (14)	−0.0086 (14)	0.0303 (13)	0.0089 (13)
C9	0.0492 (17)	0.074 (2)	0.0545 (16)	−0.0012 (18)	0.0233 (15)	0.0046 (16)
C10	0.0540 (18)	0.069 (2)	0.0512 (15)	0.0009 (18)	0.0169 (14)	−0.0145 (16)
N22	0.0455 (13)	0.0519 (15)	0.0471 (11)	−0.0071 (12)	0.0150 (10)	−0.0095 (11)
O1W	0.0508 (13)	0.0806 (18)	0.0489 (11)	0.0038 (13)	0.0070 (11)	0.0177 (12)

Geometric parameters (Å, º)

N11—C1	1.333 (3)	C1G1—C1D	1.516 (4)
N11—C4	1.332 (3)	C1G1—H3G	0.97 (2)
C1—C2	1.379 (3)	C1G1—H4G	0.97 (2)
C1—H1	0.94 (2)	C1D—C1G2	1.524 (3)
C2—N12	1.316 (3)	C1D—H1D	0.95 (2)
C2—H2	0.99 (2)	C1D—H2D	1.02 (3)
N12—C3	1.338 (3)	C1G2—C1B2	1.524 (3)
C3—C4	1.383 (3)	C1G2—H5G	0.98 (2)
C3—H3	0.98 (2)	C1G2—H6G	1.00 (2)
C4—C5	1.505 (3)	C1B2—H4B	0.97 (2)
C5—O1A	1.232 (2)	C1B2—H3B	1.014 (18)
C5—N1	1.335 (3)	N2—N3	1.391 (2)
N1—C1G	1.454 (3)	N2—H2N	0.96 (2)
N1—H1N	0.90 (2)	N3—C6	1.332 (3)
C1G—C1B	1.542 (3)	N3—H3N	0.91 (2)
C1G—H2G	0.99 (2)	C6—O1B	1.224 (2)
C1G—H1G	0.997 (19)	C6—C7	1.499 (3)
C1B—C1B2	1.531 (3)	C7—N22	1.338 (3)
C1B—C1B1	1.542 (3)	C7—C8	1.372 (3)
C1B—C1A	1.548 (3)	C8—N21	1.334 (3)
C1A—C1'	1.514 (3)	C8—H8	1.02 (2)
C1A—H2A	0.97 (2)	N21—C9	1.332 (3)
C1A—H1A	1.00 (2)	C9—C10	1.361 (4)
C1'—O1	1.220 (2)	C9—H9	0.96 (2)
C1'—N2	1.355 (3)	C10—N22	1.336 (3)
C1B1—C1G1	1.526 (3)	C10—H10	0.93 (3)
C1B1—H1B	0.97 (2)	O1W—H1W	0.86 (3)
C1B1—H2B	0.96 (2)	O1W—H2W	0.84 (3)
C1—N11—C4	115.6 (2)	C1D—C1G1—H3G	111.7 (14)
N11—C1—C2	122.1 (3)	C1B1—C1G1—H3G	108.6 (13)
N11—C1—H1	118.4 (15)	C1D—C1G1—H4G	108.8 (14)
C2—C1—H1	119.5 (15)	C1B1—C1G1—H4G	107.5 (14)
N12—C2—C1	122.6 (3)	H3G—C1G1—H4G	108.7 (17)
N12—C2—H2	118.0 (13)	C1G1—C1D—C1G2	111.5 (2)
C1—C2—H2	119.4 (14)	C1G1—C1D—H1D	105.3 (16)
C2—N12—C3	115.8 (2)	C1G2—C1D—H1D	110.7 (14)
N12—C3—C4	121.9 (2)	C1G1—C1D—H2D	111.2 (15)
N12—C3—H3	119.9 (13)	C1G2—C1D—H2D	106.3 (15)
C4—C3—H3	118.2 (13)	H1D—C1D—H2D	112 (2)
N11—C4—C3	122.0 (2)	C1D—C1G2—C1B2	111.5 (2)
N11—C4—C5	117.4 (2)	C1D—C1G2—H5G	109.9 (10)
C3—C4—C5	120.5 (2)	C1B2—C1G2—H5G	109.3 (11)
O1A—C5—N1	125.1 (2)	C1D—C1G2—H6G	110.5 (12)
O1A—C5—C4	120.5 (2)	C1B2—C1G2—H6G	108.7 (12)
N1—C5—C4	114.4 (2)	H5G—C1G2—H6G	106.9 (17)
C5—N1—C1G	124.1 (2)	C1G2—C1B2—C1B	113.28 (18)
C5—N1—H1N	114.1 (17)	C1G2—C1B2—H4B	109.3 (12)
C1G—N1—H1N	120.9 (17)	C1B—C1B2—H4B	107.5 (13)
N1—C1G—C1B	115.11 (18)	C1G2—C1B2—H3B	112.1 (11)
N1—C1G—H2G	106.2 (12)	C1B—C1B2—H3B	108.6 (11)
C1B—C1G—H2G	109.9 (10)	H4B—C1B2—H3B	105.7 (14)
N1—C1G—H1G	105.6 (11)	C1'—N2—N3	120.11 (19)
C1B—C1G—H1G	110.4 (12)	C1'—N2—H2N	121.3 (13)
H2G—C1G—H1G	109.3 (16)	N3—N2—H2N	118.6 (13)
C1B2—C1B—C1B1	108.79 (18)	C6—N3—N2	121.41 (19)
C1B2—C1B—C1G	110.95 (17)	C6—N3—H3N	122.9 (16)
C1B1—C1B—C1G	109.12 (19)	N2—N3—H3N	115.7 (16)
C1B2—C1B—C1A	112.21 (19)	O1B—C6—N3	124.5 (2)
C1B1—C1B—C1A	109.39 (17)	O1B—C6—C7	121.7 (2)
C1G—C1B—C1A	106.33 (17)	N3—C6—C7	113.76 (19)
C1'—C1A—C1B	113.41 (16)	N22—C7—C8	121.8 (2)
C1'—C1A—H2A	108.7 (11)	N22—C7—C6	117.6 (2)
C1B—C1A—H2A	109.4 (13)	C8—C7—C6	120.6 (2)
C1'—C1A—H1A	105.0 (11)	N21—C8—C7	122.7 (3)
C1B—C1A—H1A	113.1 (12)	N21—C8—H8	117.9 (11)
H2A—C1A—H1A	106.8 (15)	C7—C8—H8	119.4 (11)
O1—C1'—N2	122.6 (2)	C9—N21—C8	115.1 (2)
O1—C1'—C1A	124.2 (2)	N21—C9—C10	122.6 (3)
N2—C1'—C1A	113.2 (2)	N21—C9—H9	114.0 (13)
C1G1—C1B1—C1B	112.8 (2)	C10—C9—H9	123.3 (14)
C1G1—C1B1—H1B	110.4 (12)	N22—C10—C9	122.5 (3)
C1B—C1B1—H1B	109.6 (12)	N22—C10—H10	118.9 (16)
C1G1—C1B1—H2B	108.8 (12)	C9—C10—H10	118.6 (16)
C1B—C1B1—H2B	106.6 (11)	C10—N22—C7	115.3 (2)
H1B—C1B1—H2B	108.5 (18)	H1W—O1W—H2W	113 (3)
C1D—C1G1—C1B1	111.6 (2)
C4—N11—C1—C2	−0.2 (3)	C1A—C1B—C1B1—C1G1	−68.6 (3)
N11—C1—C2—N12	0.0 (4)	C1B—C1B1—C1G1—C1D	−55.4 (3)
C1—C2—N12—C3	0.5 (3)	C1B1—C1G1—C1D—C1G2	54.1 (4)
C2—N12—C3—C4	−0.8 (3)	C1G1—C1D—C1G2—C1B2	−53.7 (4)
C1—N11—C4—C3	−0.1 (3)	C1D—C1G2—C1B2—C1B	55.0 (3)
C1—N11—C4—C5	−179.77 (18)	C1B1—C1B—C1B2—C1G2	−54.2 (3)
N12—C3—C4—N11	0.6 (3)	C1G—C1B—C1B2—C1G2	−174.3 (2)
N12—C3—C4—C5	−179.75 (17)	C1A—C1B—C1B2—C1G2	67.0 (2)
N11—C4—C5—O1A	−173.53 (18)	O1—C1'—N2—N3	7.0 (3)
C3—C4—C5—O1A	6.8 (3)	C1A—C1'—N2—N3	−171.38 (18)
N11—C4—C5—N1	5.7 (3)	C1'—N2—N3—C6	−93.9 (3)
C3—C4—C5—N1	−173.9 (2)	N2—N3—C6—O1B	4.2 (4)
O1A—C5—N1—C1G	−5.3 (3)	N2—N3—C6—C7	−175.46 (18)
C4—C5—N1—C1G	175.44 (17)	O1B—C6—C7—N22	−171.5 (2)
C5—N1—C1G—C1B	110.0 (2)	N3—C6—C7—N22	8.2 (3)
N1—C1G—C1B—C1B2	55.6 (3)	O1B—C6—C7—C8	7.5 (3)
N1—C1G—C1B—C1B1	−64.3 (3)	N3—C6—C7—C8	−172.9 (2)
N1—C1G—C1B—C1A	177.87 (19)	N22—C7—C8—N21	−0.4 (4)
C1B2—C1B—C1A—C1'	73.6 (2)	C6—C7—C8—N21	−179.3 (2)
C1B1—C1B—C1A—C1'	−165.6 (2)	C7—C8—N21—C9	0.2 (4)
C1G—C1B—C1A—C1'	−47.9 (3)	C8—N21—C9—C10	−0.5 (4)
C1B—C1A—C1'—O1	−65.7 (3)	N21—C9—C10—N22	1.0 (5)
C1B—C1A—C1'—N2	112.6 (2)	C9—C10—N22—C7	−1.0 (4)
C1B2—C1B—C1B1—C1G1	54.3 (3)	C8—C7—N22—C10	0.7 (3)
C1G—C1B—C1B1—C1G1	175.4 (2)	C6—C7—N22—C10	179.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···N11	0.90 (2)	2.21 (3)	2.673 (3)	112 (2)
N1—H1N···O1^i	0.90 (2)	2.42 (2)	3.066 (2)	130 (2)
O1W—H1W···O1A^ii	0.87 (3)	2.13 (4)	2.960 (3)	161 (3)
N2—H2N···O1W	0.96 (2)	1.88 (2)	2.817 (3)	162 (2)
O1W—H2W···O1B^iii	0.84 (3)	2.08 (3)	2.879 (3)	160 (3)
N3—H3N···N22	0.91 (3)	2.31 (2)	2.660 (3)	103 (2)
N3—H3N···N12^iv	0.91 (3)	2.27 (3)	3.043 (3)	142 (2)
C1G—H2G···O1A	0.985 (19)	2.46 (2)	2.867 (3)	104.5 (14)
C9—H9···O1W^v	0.96 (2)	2.51 (2)	3.424 (3)	160.1 (17)
C3—H3···O1^vi	0.98 (2)	2.64 (2)	3.459 (3)	141 (2)

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