C₅ and C₇ intra­molecular hydrogen bonds stabilize the structure of N-pyrazinoyl-gabapentin (Pyr-Gpn-OH)

2-{1-[(Pyrazin-2-ylformamido)­meth­yl]cyclo­hex­yl}acetic acid (Pyr-Gpn-OH), C₁₄H₁₉N₃O₃, is an N-protected derivative of gabapentin (Gpn). The compound crystallizes in the triclinic space group P and the mol­ecular conformation is stabilized by intra­molecular five- (C₅) and seven-membered (C₇) hydrogen-bonded rings. The packing of the mol­ecules reveals inter­molecular O-H...O and C-H...N hydrogen bonds, together with [pi]-[pi] inter­actions.

S1. Introduction

The use of gabapentin [(1-amino­methyl)­cyclo­hexane­acetic acid, Gpn] as a γ-amino acid is of great inter­est in the area of peptide design (Ananda et al., 2003; Vasudev et al., 2007; Balaram, 2010). Gabapentin has been used widely as an anti­epileptic drug and has been employed for the treatment of neuropathic pain (Wheeler, 2002; Stefan & Feuerstein, 2007; Rosenberg et al., 1997; Maneuf et al., 2003). It has been extensively investigated for the occurrence of polymorphic crystal forms (Ibers, 2001; Reece & Levendis, 2008). The insertion of additional residues into the α-peptide backbone by the introduction of β-, γ- and higher ω-amino acids leads to greater conformational diversity due to the enhanced conformational space. There are four conformational variables, i.e. φ, θ₁, θ₂ and ψ for a γ-amino acid (Fig. 1). The presence of substituents at the central C^β atom of gabapentin limits the range of conformations about the C^γ—C^β (θ₁) and C^β—C^α (θ₂) bonds to the gauche conformation (Ananda et al., 2003; Aravinda, Ananda et al., 2003). In the present study, we have synthesized the N-protected pyrazinoyl derivative of gabapentin, namely 2-{1-[(pyrazin-2-ylformamido)­methyl]­cyclo­hexyl}­acetic acid, Pyr-Gpn-OH, in order to investigate the effect of the pyrazinoyl group on the conformation of gabapentin. The pyrazinoyl group has been introduced as an N-terminal protecting group of borteozomib, a reversible inhibitor of the proteolytic activity of 26S proteasome (Voorhees & Orlowski, 2006; Baker et al., 2009). Previous studies have shown that the amide of pyrazinoic acid, i.e. pyrazinamide, is used as a first-line drug to treat tuberculosis (Snider & Castro, 1998). Under acidic conditions it is thought to be a prodrug of pyrazinoic acid, which is a compound with anti­mycobacterial activity (Cyanamon et al., 1992).

S2. Experimental

S2.1. Synthesis and crystallization

For the synthesis of Pyr-Gpn-OH, pyrazine-2-carb­oxy­lic acid (3 mmol, 372 mg) was dissolved in dry CH₂Cl₂ [Qu­antity?] and N-methyl­morpholine (200 µl) was added, followed by Gpn-OMe.HCl (3 mmol, 666.5 mg) and EDCI.HCl (Define?; 3 mmol, 576 mg) under ice-cold conditions. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, water was added [Qu­antity?] and then the reaction mixture was extracted with CH₂Cl₂ (3 × 5 ml). The combined organic layer was washed with 2 N HCl (2 × 5 ml), Na₂CO₃ (2 × 5 ml) and brine (2 × 5 ml). The organic layer was passed over anhydrous Na₂SO₄ and evaporated to give Pyr-Gpn-OMe (yield 610 mg, 69.8%).

Pyr-Gpn-OMe (2 mmol, 580 mg) was dissolved in methanol (2 ml) and 2 N NaOH (1 ml), and the reaction mixture stirred at room temperature for 4 h. The methanol was evaporated off and the residue extracted with di­ethyl ether (2 × 5 ml). The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (3 × 5 ml). The combined organic layer was washed with brine solution (1 × 5 ml). The ethyl acetate layer was passed over anhydrous Na₂SO₄ and evaporated to give Pyr-Gpn-OH (yield 380 mg, 69.0%). [Comment states Pyr-Gpn-OH was crystallized by slow evaporation from a mixture of ethyl acetate–hexane. Therefore, please complete procedure here. Solvent ratio?]

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 their coordinates restrained to geometric positions; their displacement parameters were restrained to a value 20% greater than the parent atom.

S3. Results and discussion

The compound Pyr-Gpn-OH was crystallized by slow evaporation from a mixture of ethyl acetate–hexane [Solvent ratio?] in the triclinic space group P1. In most cases, N-protected derivatives of gabapentin crystallize in monoclininic space groups (Ananda et al., 2003). Fig. 2 shows the molecular conformation determined for the crystal structure of Pyr-Gpn-OH. The backbone dihedral angles are φ = 93.3 (2)°, θ₁ = 43.5 (2)°, θ₂ = 55.9 (2)° and ψ = 116.4 (2)°. Hydrogen-bond parameters are listed in Table 2.

In the crystal structure, five- (C₅) and seven-membered (C₇) intra­molecular hydrogen bonds are present. The C₅ (N—H···N) intra­molecular hydrogen bond is observed between atom N2 of the pyrazine ring and the NH group of gabapentin, while the C₇ (N—H···O) hydrogen bond is observed between GpnNH and the carbonyl group of the terminal carb­oxy­lic acid group. The C₇ hydrogen bond in gabapentin may be considered as an expansion of C₅ hydrogen-bonded structures described in fully extended conformations of α-peptides (Benedetti et al., 1984, 1988; Valle et al., 1986). In addition to the C₅ and C₇ hydrogen bonds, a weak C—H···O inter­action is also observed between Gpn C^γH and Pyr CO groups. These kinds of inter­actions are important determinants of molecular conformation and crystal packing (Desiraju, 1996; Steiner, 1997; Lo Prestil et al., 2006).

The dihedral angles about the C^γ—C^β (θ₁) and C^β—C^α (θ₂) bonds are restricted to the gauche conformation due to the presence of substituents at the C^β atom, which limits the range of rotation. The cyclo­hexane ring adopts a chair conformation, with axial amino methyl and equatorial carb­oxy­methyl groups, as observed in derivatives of gabapentin, Piv-Gpn-OH and Tos-Gpn-OH (Ananda et al., 2003). In Pyr-Gpn-OH, the N-terminal protecting group favours a trans geometry with ω₀ = -175.1 (2)°.

Fig. 3 shows the packing of the molecules of Pyr-Gpn-OH in the crystal structure, down the a axis. The molecules are arranged via O—H···.O and C—H···N (pyrazine N atom) inter­molecular hydrogen bonds, together with π–π inter­actions between the pyrazine rings, which are stacked in a face-to-face (3.76 Å) and edge-to-face (6.04 Å) manner (Fig. 3). π–π inter­actions have been reported to induce self-assembly in peptides (Ma et al., 2010; Wang & Chau, 2011). The distances between the centroids of the pyrazine rings are within the range for stabilizing π–π inter­actions (Burley & Petsko, 1985; Waters, 2002; Aravinda, Shamala et al., 2003; Sengupta et al., 2005). Fig. 4 shows a space-filling model for the structure of Pyr-Gpn-OH, and depicts the layers formed by alternating π–π and hydro­phobic inter­actions.

S4. Conclusions

The present X-ray analysis of Pyr-Gpn-OH demonstrates the stabilization of the crystal structure by C₅, C₇ and C—H···O intra­molecular hydrogen bonds. The molecules in the crystal are packed by inter­molecular O—H···O and C—H···N hydrogen bonds, together with π–π inter­actions between pyrazine rings.

Related literature

For related literature, see: Ananda et al. (2003); Aravinda, Ananda, Shamala & Balaram (2003); Aravinda, Shamala, Das, Sriranjini, Karle & Balaram (2003); Baker et al. (2009); Balaram (2010); Benedetti et al. (1984, 1988); Burley & Petsko (1985); Cyanamon et al. (1992); Desiraju (1996); Ibers (2001); Lo Prestil, Soave & Destro (2006); Ma et al. (2010); Maneuf et al. (2003); Reece & Levendis (2008); Rosenberg et al. (1997); Sengupta et al. (2005); Snider & Castro (1998); Stefan & Feuerstein (2007); Steiner (1997); Valle et al. (1986); Vasudev et al. (2007); Voorhees & Orlowski (2006); Wang & Chau (2011); Waters (2002); 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. The conformation parameters used to define the backbone torsion angles of Pyr-Gpn.
	Fig. 2. The molecular conformation of Pyr-Gpn-OH in the crystal, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the ??% probability level [Please complete]. Intramolecular hydrogen bonds are represented as dotted lines.
	Fig. 3. The molecular packing of Pyr-Gpn-OH, down the a axis, showing π–π (green in the electronic version of the journal), and O—H···O and C—H···N interactions (blue?) as dashed lines. The centroid–centroid distances are shown.
	Fig. 4. Space-filling model for the structure of Pyr-Gpn-OH, showing the layers formed by π–π and hydrophobic interactions. [Plot looks distorted - H atoms are oval. Please check, and revise if necessary]

2-{1-[(Pyrazin-2-ylformamido)methyl]cyclohexyl}acetic acid

Crystal data

C14H19N3O3	Z = 2
Mr = 277.32	F(000) = 296
Triclinic, P1	Dx = 1.288 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.7253 (4) Å	Cell parameters from 3944 reflections
b = 8.6778 (5) Å	θ = 3.6–28.0°
c = 11.5759 (7) Å	µ = 0.09 mm^−1
α = 72.136 (5)°	T = 293 K
β = 87.590 (4)°	Rod, colourless
γ = 75.671 (4)°	0.41 × 0.15 × 0.10 mm
V = 715.16 (7) Å^3

Data collection

Oxford Xcalibur Sapphire3 diffractometer	3326 independent reflections
Radiation source: fine-focus sealed tube	2048 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.033
Detector resolution: 16.1049 pixels mm^-1	θmax = 28.0°, θmin = 3.6°
ω scans	h = −10→10
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2010)	k = −11→11
Tmin = 0.986, Tmax = 1.000	l = −15→15
12592 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.050	All H-atom parameters refined
wR(F^2) = 0.161	w = 1/[σ^2(Fo^2) + (0.0805P)^2 + 0.0541P] where P = (Fo^2 + 2Fc^2)/3
S = 1.01	(Δ/σ)max < 0.001
3326 reflections	Δρmax = 0.18 e Å^−3
258 parameters	Δρmin = −0.15 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.025 (5)

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
H1G	0.686 (2)	0.488 (2)	0.1769 (16)	0.058 (5)*
H1N	0.355 (3)	0.457 (3)	0.1255 (19)	0.073 (6)*
H2B	0.627 (3)	0.306 (3)	0.492 (2)	0.083 (7)*
H5	0.131 (3)	0.911 (3)	0.1984 (19)	0.068 (6)*
H2G	0.658 (2)	0.341 (2)	0.1307 (17)	0.058 (5)*
H2	−0.139 (3)	0.650 (3)	−0.0047 (19)	0.077 (6)*
H1A	0.371 (3)	0.281 (3)	0.342 (2)	0.078 (7)*
H4B	0.829 (3)	0.102 (3)	0.2722 (19)	0.068 (6)*
H2A	0.511 (3)	0.122 (3)	0.427 (2)	0.080 (7)*
H1B	0.515 (3)	0.476 (3)	0.3923 (17)	0.062 (5)*
H3	−0.304 (3)	0.896 (3)	0.050 (2)	0.085 (7)*
H6G	1.080 (4)	0.148 (3)	0.346 (2)	0.101 (8)*
H5G	0.980 (4)	0.305 (4)	0.247 (3)	0.124 (13)*
H4G	0.777 (3)	0.507 (3)	0.471 (2)	0.087 (7)*
H3B	0.823 (3)	0.066 (3)	0.421 (3)	0.104 (9)*
H1D	1.060 (4)	0.380 (4)	0.412 (3)	0.129 (11)*
H1M	0.483 (4)	−0.116 (4)	0.260 (3)	0.120 (10)*
H3G	0.785 (4)	0.556 (4)	0.318 (3)	0.118 (10)*
H2D	0.965 (4)	0.242 (4)	0.501 (3)	0.113 (13)*
N2	0.0902 (2)	0.64318 (19)	0.07084 (14)	0.0555 (4)
C2	−0.0822 (3)	0.7087 (3)	0.04216 (19)	0.0610 (5)
C3	−0.1777 (3)	0.8475 (3)	0.0709 (2)	0.0676 (6)
N3	−0.1018 (3)	0.9239 (2)	0.13047 (18)	0.0770 (6)
C5	0.0719 (3)	0.8599 (3)	0.1575 (2)	0.0676 (6)
C6	0.1689 (2)	0.7219 (2)	0.12800 (16)	0.0507 (5)
C0'	0.3641 (3)	0.6548 (2)	0.15965 (16)	0.0526 (5)
O0	0.45127 (19)	0.73629 (17)	0.19233 (15)	0.0750 (5)
N1	0.4342 (2)	0.50270 (18)	0.15107 (13)	0.0512 (4)
C1G	0.6165 (3)	0.4068 (3)	0.18565 (17)	0.0522 (5)
C1B	0.6390 (2)	0.2881 (2)	0.31614 (15)	0.0463 (4)
C1A	0.4881 (3)	0.1961 (3)	0.34526 (18)	0.0556 (5)
C1'	0.4672 (2)	0.0999 (2)	0.26079 (18)	0.0535 (5)
O1	0.4980 (2)	−0.06169 (17)	0.31539 (14)	0.0766 (5)
O2	0.4235 (2)	0.16177 (18)	0.15526 (14)	0.0800 (5)
C1B1	0.6297 (3)	0.3843 (3)	0.4090 (2)	0.0579 (5)
C1G1	0.7878 (3)	0.4591 (4)	0.4060 (3)	0.0856 (9)
C1D	0.9640 (4)	0.3269 (6)	0.4232 (5)	0.1135 (13)
C1G2	0.9768 (3)	0.2346 (5)	0.3296 (4)	0.1009 (12)
C1B2	0.8196 (3)	0.1594 (3)	0.3335 (3)	0.0713 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N2	0.0678 (11)	0.0495 (9)	0.0588 (9)	−0.0233 (8)	0.0016 (8)	−0.0230 (8)
C2	0.0650 (13)	0.0623 (12)	0.0664 (13)	−0.0266 (11)	0.0017 (10)	−0.0261 (11)
C3	0.0637 (14)	0.0751 (15)	0.0705 (14)	−0.0211 (12)	0.0061 (11)	−0.0288 (12)
N3	0.0736 (13)	0.0793 (13)	0.0879 (13)	−0.0074 (10)	−0.0007 (10)	−0.0483 (11)
C5	0.0757 (15)	0.0648 (13)	0.0757 (14)	−0.0161 (11)	−0.0057 (11)	−0.0406 (12)
C6	0.0682 (12)	0.0413 (9)	0.0484 (10)	−0.0199 (9)	0.0012 (8)	−0.0169 (8)
C0'	0.0694 (12)	0.0426 (10)	0.0535 (10)	−0.0224 (9)	0.0011 (9)	−0.0187 (8)
O0	0.0791 (10)	0.0548 (8)	0.1081 (12)	−0.0284 (7)	−0.0078 (8)	−0.0386 (8)
N1	0.0608 (10)	0.0456 (9)	0.0545 (9)	−0.0180 (8)	−0.0039 (7)	−0.0213 (7)
C1G	0.0557 (11)	0.0587 (11)	0.0546 (11)	−0.0218 (10)	0.0137 (9)	−0.0305 (10)
C1B	0.0481 (9)	0.0506 (10)	0.0504 (10)	−0.0115 (8)	0.0018 (7)	−0.0309 (8)
C1A	0.0754 (14)	0.0515 (11)	0.0498 (12)	−0.0268 (11)	0.0066 (10)	−0.0213 (10)
C1'	0.0599 (11)	0.0471 (10)	0.0624 (12)	−0.0201 (9)	−0.0019 (9)	−0.0231 (9)
O1	0.1225 (13)	0.0489 (8)	0.0686 (10)	−0.0361 (9)	−0.0017 (8)	−0.0203 (7)
O2	0.1212 (13)	0.0572 (9)	0.0672 (10)	−0.0219 (9)	−0.0310 (9)	−0.0226 (8)
C1B1	0.0643 (13)	0.0654 (13)	0.0600 (13)	−0.0169 (11)	0.0028 (10)	−0.0413 (11)
C1G1	0.0698 (15)	0.113 (2)	0.116 (2)	−0.0320 (14)	0.0060 (14)	−0.087 (2)
C1D	0.0646 (17)	0.158 (3)	0.161 (4)	−0.024 (2)	−0.0146 (19)	−0.111 (3)
C1G2	0.0474 (14)	0.138 (3)	0.148 (3)	−0.0034 (16)	−0.0053 (16)	−0.101 (3)
C1B2	0.0628 (13)	0.0753 (15)	0.0874 (17)	0.0008 (11)	−0.0115 (11)	−0.0538 (15)

Geometric parameters (Å, º)

N2—C2	1.325 (3)	C1A—C1'	1.503 (2)
N2—C6	1.338 (2)	C1A—H1A	1.01 (2)
C2—C3	1.375 (3)	C1A—H2A	0.96 (2)
C2—H2	1.02 (2)	C1'—O2	1.199 (2)
C3—N3	1.329 (3)	C1'—O1	1.314 (2)
C3—H3	0.97 (2)	O1—H1M	0.93 (3)
N3—C5	1.330 (3)	C1B1—C1G1	1.513 (3)
C5—C6	1.378 (3)	C1B1—H2B	0.99 (2)
C5—H5	0.94 (2)	C1B1—H1B	1.01 (2)
C6—C0'	1.492 (3)	C1G1—C1D	1.523 (4)
C0'—O0	1.232 (2)	C1G1—H4G	0.96 (2)
C0'—N1	1.329 (2)	C1G1—H3G	1.10 (3)
N1—C1G	1.449 (2)	C1D—C1G2	1.519 (4)
N1—H1N	0.91 (2)	C1D—H1D	0.95 (3)
C1G—C1B	1.533 (3)	C1D—H2D	0.97 (3)
C1G—H1G	0.968 (19)	C1G2—C1B2	1.508 (4)
C1G—H2G	0.975 (19)	C1G2—H6G	0.93 (3)
C1B—C1B2	1.532 (3)	C1G2—H5G	0.97 (3)
C1B—C1B1	1.540 (2)	C1B2—H4B	0.97 (2)
C1B—C1A	1.540 (2)	C1B2—H3B	1.08 (3)
C2—N2—C6	116.12 (16)	C1B—C1A—H2A	107.3 (13)
N2—C2—C3	122.69 (19)	H1A—C1A—H2A	108.4 (17)
N2—C2—H2	115.1 (12)	O2—C1'—O1	122.56 (17)
C3—C2—H2	122.2 (12)	O2—C1'—C1A	124.60 (18)
N3—C3—C2	121.6 (2)	O1—C1'—C1A	112.82 (18)
N3—C3—H3	115.9 (13)	C1'—O1—H1M	109.9 (18)
C2—C3—H3	122.5 (13)	C1G1—C1B1—C1B	113.19 (17)
C3—N3—C5	115.73 (19)	C1G1—C1B1—H2B	108.2 (13)
N3—C5—C6	122.96 (19)	C1B—C1B1—H2B	108.4 (13)
N3—C5—H5	118.6 (12)	C1G1—C1B1—H1B	109.5 (11)
C6—C5—H5	118.4 (12)	C1B—C1B1—H1B	108.6 (11)
N2—C6—C5	120.85 (19)	H2B—C1B1—H1B	108.8 (17)
N2—C6—C0'	118.04 (15)	C1B1—C1G1—C1D	111.5 (3)
C5—C6—C0'	121.11 (16)	C1B1—C1G1—H4G	107.8 (14)
O0—C0'—N1	123.34 (18)	C1D—C1G1—H4G	109.1 (14)
O0—C0'—C6	121.32 (16)	C1B1—C1G1—H3G	109.0 (15)
N1—C0'—C6	115.34 (15)	C1D—C1G1—H3G	109.3 (15)
C0'—N1—C1G	125.42 (16)	H4G—C1G1—H3G	110 (2)
C0'—N1—H1N	114.4 (13)	C1G2—C1D—C1G1	110.5 (2)
C1G—N1—H1N	120.0 (13)	C1G2—C1D—H1D	108 (2)
N1—C1G—C1B	113.67 (14)	C1G1—C1D—H1D	109 (2)
N1—C1G—H1G	105.9 (11)	C1G2—C1D—H2D	105 (2)
C1B—C1G—H1G	109.7 (11)	C1G1—C1D—H2D	108.5 (19)
N1—C1G—H2G	109.3 (11)	H1D—C1D—H2D	116 (3)
C1B—C1G—H2G	108.3 (11)	C1B2—C1G2—C1D	111.5 (3)
H1G—C1G—H2G	110.0 (15)	C1B2—C1G2—H6G	107.6 (16)
C1B2—C1B—C1G	109.94 (16)	C1D—C1G2—H6G	109.6 (16)
C1B2—C1B—C1B1	108.88 (15)	C1B2—C1G2—H5G	106.4 (19)
C1G—C1B—C1B1	111.26 (15)	C1D—C1G2—H5G	113 (2)
C1B2—C1B—C1A	109.17 (17)	H6G—C1G2—H5G	108 (2)
C1G—C1B—C1A	110.92 (14)	C1G2—C1B2—C1B	113.2 (2)
C1B1—C1B—C1A	106.58 (14)	C1G2—C1B2—H4B	110.6 (12)
C1'—C1A—C1B	115.47 (15)	C1B—C1B2—H4B	109.2 (12)
C1'—C1A—H1A	107.4 (12)	C1G2—C1B2—H3B	108.5 (14)
C1B—C1A—H1A	108.4 (12)	C1B—C1B2—H3B	108.4 (14)
C1'—C1A—H2A	109.6 (13)	H4B—C1B2—H3B	106.8 (18)
C6—N2—C2—C3	−1.2 (3)	N1—C1G—C1B—C1A	43.51 (19)
N2—C2—C3—N3	−0.5 (3)	C1B2—C1B—C1A—C1'	−65.4 (2)
C2—C3—N3—C5	1.5 (3)	C1G—C1B—C1A—C1'	55.9 (2)
C3—N3—C5—C6	−0.9 (3)	C1B1—C1B—C1A—C1'	177.17 (18)
C2—N2—C6—C5	1.9 (3)	C1B—C1A—C1'—O2	−65.2 (3)
C2—N2—C6—C0'	−178.66 (16)	C1B—C1A—C1'—O1	116.4 (2)
N3—C5—C6—N2	−0.9 (3)	C1B2—C1B—C1B1—C1G1	53.0 (3)
N3—C5—C6—C0'	179.67 (19)	C1G—C1B—C1B1—C1G1	−68.3 (2)
N2—C6—C0'—O0	167.00 (17)	C1A—C1B—C1B1—C1G1	170.6 (2)
C5—C6—C0'—O0	−13.5 (3)	C1B—C1B1—C1G1—C1D	−55.2 (3)
N2—C6—C0'—N1	−13.6 (2)	C1B1—C1G1—C1D—C1G2	55.1 (5)
C5—C6—C0'—N1	165.85 (18)	C1G1—C1D—C1G2—C1B2	−55.6 (5)
O0—C0'—N1—C1G	4.3 (3)	C1D—C1G2—C1B2—C1B	56.3 (4)
C6—C0'—N1—C1G	−175.07 (15)	C1G—C1B—C1B2—C1G2	68.7 (3)
C0'—N1—C1G—C1B	93.3 (2)	C1B1—C1B—C1B2—C1G2	−53.4 (3)
N1—C1G—C1B—C1B2	164.35 (15)	C1A—C1B—C1B2—C1G2	−169.4 (2)
N1—C1G—C1B—C1B1	−74.95 (18)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O2	0.91 (2)	2.40 (3)	2.965 (2)	120.2 (19)
N1—H1N···N2	0.91 (2)	2.25 (2)	2.707 (2)	111 (2)
C1G—H1G···O0	0.96 (2)	2.49 (2)	2.852 (3)	102.0 (15)
O1—H1M···O0^i	0.94 (3)	1.75 (3)	2.670 (2)	165 (3)
C1B2—H4B···N3^ii	0.97 (2)	2.54 (2)	3.503 (4)	171.0 (19)

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