Weak C—H...X (X = O, N) hydrogen bonds in the crystal structure of di­hydro­berberine

Di­hydro­berberine (systematic name: 9,10-dimeth­oxy-6,8-dihydro-5H-1,3-dioxolo[4,5-g]iso­quinolino­[3,2-a]iso­quinoline), C₂₀H₁₉NO₄, a reduced form of pharmacologically important berberine, crystallizes from ethanol without inter­stitial solvent. The mol­ecule shows a dihedral angle of 27.94 (5)° between the two arene rings at the ends of the mol­ecule, owing to the partial saturation of the inner quinolizine ring system. Although lacking classical O—H or N—H donors, the packing in the crystalline state is clearly governed by C—H...N and C—H...O hydrogen bonds involving the two acetal-type C—H bonds of the 1,3-dioxole ring. Each di­hydro­berberine mol­ecule is engaged in four hydrogen bonds with neighbouring mol­ecules, twice as donor and twice as acceptor, thus forming a two-dimensional sheet network that lies parallel to the (100) plane.

S1. Introduction

Di­hydro­berberine (see Scheme 1, parts a and b) is a reduced form of berberine (see Scheme 1, part c), an iso­quinoline alkaloid isolated from shrubs of the genus berberis. It is a very important pharmacological compound with a diverse range of biological activities (Amin et al., 1969; Akhter et al., 1979; Swabb et al. 1981; Sack & Froehlich, 1982; Sun et al., 1988; Yuan et al. 1994; Birdsall & Kelly, 1997; Gibbs & Seddon, 2000). With a change of only one degree of unsaturation in its chemical structure, di­hydro­berberine does not show diminished biological activity but rather has improved results in some cases. Due to its enhanced bioavailability, di­hydro­berberine improves in vivo efficacy in terms of counteracting increased adiposity and insulin resistance in high-fat rodents (Turner et al., 2008). It has also been found to be effective in site-specific sustained release of drugs to the brain by undergoing in vivo transformation into berberine (Bodor et al., 1981; Brewster & Bodor, 1983; Bodor & Brewster, 1983). Further derivatization of di­hydro­berberine by the introduction of hy­droxy and cyano groups onto the reduced ring leads to active anti­malarials (Vennerstrom & Klayman, 1988), avian myeblastosis virus inhibitors (AMV–RT) (Kusumoto et al., 1991), anti­tumour agents (Kim et al., 1997), anti­fungals (Dostál et al., 1999), mitogen-activated protein kinase inhibitors (MAPKK) (Jang et al., 2002), promoters of glucose metabolism and insulin secretion (Xu et al., 2011) and CD36 antagonists (Li et al., 2010). Di­hydro­berberine has found use as an inter­mediate in the synthesis of substituted berberine analogues which were found to act as anti­cancer agents (Zhang et al., 2012), pancreatic lipase inhibitory agents (Mohammad et al., 2013), anti­fungal agents (Li et al., 2013), Toxoplasma gondii inhibitors (Krivogorsky et al., 2012) and mitochondria-targeted anti­oxidants (Lyamzaev et al., 2011), and which have shown activity as anti­babesial (Subeki et al., 2005) and anti­leishmania agents (Marquis et al., 2003) and as HIV-1 RT inhibitors (Vennerstrom et al., 1990).

With such varied and important biological activity obtained through a minor change in the unsaturation of the compound, we were motivated to characterize di­hydro­berberine structurally by X-ray crystallography. Surprisingly, while the structure of berberine crystallized with a variety of counter-anions has been reported (Moniot & Shamma, 1979; Abadi et al., 1984; Kariuki & Jones, 1995; Marek, Sečkářová et al., 2003; Tong et al., 2010; Chahine et al., 2011), as have the structures of an assortment of 8-substituted derivatives of di­hydro­berberine (Man et al., 2001; Marek, Hulová et al., 2003; Dostál et al., 2004; Maier et al., 2010; Man et al., 2011), a determination of the crystal structure of di­hydro­berberine itself has not been undertaken. Herein, we report its crystal structure from X-ray diffraction data at 150 K.

S2. Experimental

S2.1. Synthesis and crystallization

To a stirred solution of berberine chloride (3.71 g, 10 mmol) and K₂CO₃ (3.6 g, 30 mmol) in MeOH (125 ml), a 5% NaOH solution (5 ml) containing NaBH₄ (0.3 g, 7.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, and the precipitated product was filtered and washed with 30% EtOH (20 ml) followed by 80% EtOH (20 ml). It was then recrystallized from absolute EtOH (400 ml) to afford 2.8 g (83%) of (I) as green–brown needles [Pale-yellow prisms given in CIF tables - please clarify]. MS m/z: 340. ¹H NMR (CDCl₃, δ, p.p.m.): 7.19 (s, 1H), 6.76 (s, 2H), 6.59 (s, 1H), 5.97 (s, 1H), 5.96 (s, 2H), 4.34 (s, 2H), 3.86 (s, 6H), 3.15 (t, 2H), 2.89 (t, 2H).

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms were identified in the final difference map, and their positions were refined with isotropic displacement parameters that were approximately 1.2–1.5 times the equivalent displacement parameters of the C atoms to which they were attached.

S3. Results and discussion

The structure of di­hydro­berberine is derived from berberine (Fig. 1) by reduction of the N7—C8 bond. The partial saturation of the quinolizine ring system at the C5—C6 and N7—C8 positions induces a bending of the fused-ring system (see Scheme 1, part b and Fig. 2), with the fully unsaturated arene rings at the ends of the molecule disposed at a dihedral angle of 27.9°. The corresponding angle in berberine is approximately 12.5° (Kariuki & Jones, 1995), owing to the unsaturation at the N7—C8 bond. Atoms C6 and C8 are both folded up towards the top side of the di­hydro­quinolizine ring system, as presented in the figure, such that the angle between the C5/C4a/C13b/C13a/N7 and C5/C6/N7 mean planes is 37.0°, and that between the N7/C13a/C13/C12a/C8a and N7/C8/C8a mean planes is 41.3°. The tertiary N atom is slightly pyramidal, displaced by 0.315 Å from the plane of the three surrounding C atoms. As such, it constitutes a chiral centre. The molecule depicted in Fig. 2 shows the S configuration; the opposite enanti­omer necessarily occurs in the unit cell as well, related by an inversion centre to the molecule shown, as the space group is centric.

Importantly, the unit-cell packing arrangement for di­hydro­berberine occurs as two-dimensional sheets, the formation of which is governed by a network of hydrogen bonds, despite the absence of a typical O—H or N—H donor in the molecule. Here, the acetal-type –CH₂– group of the 1,3-dioxole ring is sufficiently activated by the geminal O atoms that both of its H atoms function as hydrogen-bond donors. One pair of hydrogen-bond inter­actions occurs between this –CH₂– group and the tertiary amine N atom of a neighbouring molecule, the two molecules being disposed about a centre of symmetry as a pair of enanti­omers. Such pairs of molecules are easily seen (Fig. 3 [Should this be Fig. 2?]) situated along the a edges of the unit cell, the mid-point of which is coincident with the inversion centre. A second set of hydrogen bonds is formed between the other H atom of the acetal-type –CH₂– group and the meth­oxy O atom of another molecule further along the c axis and related to the first molecule by a 2₁ screw axis. Each enanti­omeric pair of di­hydro­berberine molecules, typified by the one at the very centre of the unit-cell diagram in Fig. 3 [Fig. 2?], enjoys four hydrogen bonds of this second type, one at each corner of the diad, such that the network is extended above and below in the direction of the b axis.

The donor–acceptor distance in the first type of hydrogen bond noted above (C2···N7) is 3.5326 (17) Å, and the D—H···A angle is 152.5 (11)°. For the second set of hydrogen bonds involving a meth­oxy O atom as acceptor, the corresponding values are 3.3031 (15) Å and 156.2 (11)°. These distances and angles are typical of a `weak hydrogen bond', as defined by Desiraju & Steiner (1999). The occurrence of acetal-type C—H···O hydrogen bonds has been shown to be important in governing the properties of polymethyl­ene glycol and related oligomeric and small molecules. In di­methyl­ene glycol, HOCH₂OCH₂OH, two inter­nal hydrogen bonds of this type occur in the energy-minimized structure and have been computationally assessed as conferring approximately 2.65 kcal mol^-1 (1 kcal mol^-1 = 4.184 kJ mol^-1) of stabilization per hydrogen bond (Martin & Miller, 2009). Although individually weak as hydrogen bonds, the collective effect of multiple C—H···X bonds of this type becomes important. It has been assumed that the therapeutic efficacy of berberine arises from a capacity to function as an inter­calator into DNA. The foregoing observation of C—H···X (X = O or N) hydrogen bonds in the crystal packing of di­hydro­berberine suggests the possibility that analogous hydrogen bonds may exert themselves in the inter­action of berberine (and variants thereof) with DNA, in addition to the π–π stacking that occurs upon inter­calation.

Related literature

For related literature, see: Abadi et al. (1984); Akhter et al. (1979); Amin et al. (1969); Birdsall & Kelly (1997); Bodor & Brewster (1983); Bodor et al. (1981); Brewster & Bodor (1983); Chahine et al. (2011); Desiraju & Steiner (1999); Dostál et al. (1999, 2004); Gibbs & Seddon (2000); Jang et al. (2002); Kariuki & Jones (1995); Kim et al. (1997); Krivogorsky et al. (2012); Kusumoto et al. (1991); Li et al. (2010, 2013); Lyamzaev (2011); Maier et al. (2010); Man et al. (2001, 2011); Marek, Hulová, Dostál & Marek (2003); Marquis et al. (2003); Martin & Miller (2009); Mohammad et al. (2013); Moniot & Shamma (1979); Sack & Froehlich (1982); Subeki, Matsuura, Takahashi, Yamasaki, Yamato, Maede, Katakura, Suzuki, Trimurningsih, Chairul & Yoshihara (2005); Sun et al. (1988); Swabb et al. (1981); Tong et al. (2010); Turner et al. (2008); Vennerstrom & Klayman (1988); Vennerstrom et al. (1990); Xu et al. (2011); Yuan et al. (1994); Zhang et al. (2012).

Computing details

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures

	Fig. 1. The molecular structure of dihydroberberine, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. A cell-packing diagram for dihydroberberine, with weak hydrogen bonds indicated by dashed lines.

9,10-Dimethoxy-6,8-dihydro-5H-1,3-dioxolo[4,5-g]isoquinolino[3,2-a]isoquinoline

Crystal data

C20H19NO4	F(000) = 712
Mr = 337.36	Dx = 1.377 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 6.9562 (15) Å	Cell parameters from 9822 reflections
b = 8.3067 (17) Å	θ = 2.5–29.5°
c = 28.343 (6) Å	µ = 0.10 mm^−1
β = 96.458 (3)°	T = 150 K
V = 1627.3 (6) Å^3	Needle, green–brown
Z = 4	0.30 × 0.26 × 0.10 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer	3120 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.037
ϕ and ω scans	θmax = 26.4°, θmin = 2.6°
Absorption correction: multi-scan (SADABS; Sheldrick, 2009)	h = −8→8
Tmin = 0.850, Tmax = 0.990	k = −10→10
24555 measured reflections	l = −33→35
3339 independent reflections

Refinement

Refinement on F^2	Hydrogen site location: difference Fourier map
Least-squares matrix: full	All H-atom parameters refined
R[F^2 > 2σ(F^2)] = 0.041	w = 1/[σ^2(Fo^2) + (0.0593P)^2 + 0.474P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.104	(Δ/σ)max < 0.001
S = 1.06	Δρmax = 0.26 e Å^−3
3339 reflections	Δρmin = −0.36 e Å^−3
303 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
72 restraints	Extinction coefficient: 0.046 (3)

Special details

Experimental. The diffraction data were obtained from 3 sets of 400 frames, each of width 0.5° in ω, collected at ϕ = 0.00, 90.00 and 180.00°, and 2 sets of 800 frames, each of width 0.45° in ϕ, collected at ω = -30.00 and 210.00°. The scan time was 60 sec/frame.

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
O1	0.74498 (12)	0.89863 (11)	−0.09389 (3)	0.0290 (2)
O3	0.43038 (12)	0.85112 (11)	−0.12696 (3)	0.0282 (2)
O9	0.58292 (12)	0.59221 (9)	0.24003 (3)	0.0236 (2)
O10	0.84226 (12)	0.77577 (10)	0.29163 (3)	0.0266 (2)
N7	0.46787 (13)	0.67091 (11)	0.09423 (3)	0.0210 (2)
C2	0.60588 (18)	0.93356 (15)	−0.13430 (4)	0.0270 (3)
H2A	0.653 (2)	0.8937 (17)	−0.1624 (5)	0.026 (3)*
H2B	0.579 (2)	1.0513 (19)	−0.1352 (5)	0.030 (4)*
C3a	0.44450 (17)	0.82606 (13)	−0.07873 (4)	0.0230 (3)
C4	0.30567 (17)	0.77169 (14)	−0.05198 (4)	0.0248 (3)
H4	0.169 (2)	0.7508 (19)	−0.0663 (5)	0.036 (4)*
C4a	0.36090 (16)	0.74528 (13)	−0.00335 (4)	0.0222 (2)
C5	0.21335 (17)	0.69133 (16)	0.02836 (4)	0.0275 (3)
H5B	0.152 (2)	0.7900 (19)	0.0431 (5)	0.034 (4)*
H5A	0.104 (2)	0.6334 (19)	0.0102 (5)	0.034 (4)*
C6	0.30798 (18)	0.58474 (15)	0.06752 (4)	0.0269 (3)
H6A	0.356 (2)	0.483 (2)	0.0539 (5)	0.034 (4)*
H6B	0.215 (2)	0.5542 (18)	0.0906 (5)	0.029 (3)*
C8	0.54753 (18)	0.58566 (14)	0.13716 (4)	0.0242 (3)
H8A	0.615 (2)	0.4872 (19)	0.1281 (5)	0.030 (4)*
H8B	0.438 (2)	0.5517 (17)	0.1536 (5)	0.027 (3)*
C8a	0.68522 (15)	0.69326 (13)	0.16752 (4)	0.0199 (2)
C9	0.70076 (15)	0.69167 (12)	0.21664 (4)	0.0199 (2)
C10	0.84150 (16)	0.78621 (13)	0.24334 (4)	0.0207 (2)
C11	0.96563 (16)	0.88100 (14)	0.21999 (4)	0.0233 (2)
H11	1.062 (2)	0.9454 (18)	0.2374 (5)	0.026 (3)*
C12a	0.80743 (15)	0.79218 (13)	0.14370 (4)	0.0212 (2)
C12	0.94666 (16)	0.88470 (14)	0.17061 (4)	0.0239 (3)
H12	1.028 (2)	0.9530 (18)	0.1544 (5)	0.027 (3)*
C13b	0.55134 (16)	0.77202 (13)	0.01702 (4)	0.0203 (2)
C13	0.77269 (16)	0.80068 (14)	0.09234 (4)	0.0222 (2)
H13	0.862 (2)	0.8640 (17)	0.0765 (5)	0.026 (3)*
C13a	0.60501 (16)	0.74508 (13)	0.06851 (4)	0.0202 (2)
C14	0.69151 (16)	0.82815 (13)	−0.01168 (4)	0.0221 (2)
H14	0.830 (2)	0.8455 (17)	0.0012 (5)	0.029 (4)*
C14a	0.63324 (16)	0.85395 (13)	−0.05881 (4)	0.0224 (2)
C15	0.41212 (19)	0.67361 (17)	0.25133 (5)	0.0316 (3)
H15A	0.335 (2)	0.703 (2)	0.2222 (6)	0.041 (4)*
H15B	0.448 (2)	0.772 (2)	0.2702 (6)	0.037 (4)*
H15C	0.345 (2)	0.5992 (19)	0.2696 (5)	0.034 (4)*
C16	0.9879 (2)	0.86329 (18)	0.32026 (5)	0.0329 (3)
H16A	1.116 (3)	0.8288 (19)	0.3155 (6)	0.038 (4)*
H16B	0.975 (2)	0.979 (2)	0.3140 (6)	0.040 (4)*
H16C	0.964 (2)	0.8394 (19)	0.3533 (6)	0.036 (4)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0291 (5)	0.0389 (5)	0.0192 (4)	0.0000 (4)	0.0033 (3)	0.0036 (3)
O3	0.0323 (5)	0.0336 (5)	0.0179 (4)	−0.0008 (4)	−0.0010 (3)	−0.0003 (3)
O9	0.0258 (4)	0.0217 (4)	0.0232 (4)	−0.0035 (3)	0.0017 (3)	0.0039 (3)
O10	0.0285 (4)	0.0328 (5)	0.0176 (4)	−0.0071 (3)	−0.0013 (3)	0.0003 (3)
N7	0.0213 (5)	0.0226 (5)	0.0183 (5)	−0.0030 (4)	−0.0010 (4)	0.0002 (3)
C2	0.0319 (6)	0.0309 (6)	0.0183 (6)	0.0032 (5)	0.0025 (5)	−0.0002 (5)
C3a	0.0294 (6)	0.0218 (5)	0.0168 (5)	0.0033 (4)	−0.0016 (4)	−0.0027 (4)
C4	0.0227 (6)	0.0273 (6)	0.0232 (6)	0.0005 (4)	−0.0026 (4)	−0.0031 (4)
C4a	0.0223 (5)	0.0226 (5)	0.0213 (5)	0.0017 (4)	0.0008 (4)	−0.0027 (4)
C5	0.0204 (6)	0.0376 (7)	0.0236 (6)	−0.0033 (5)	−0.0011 (4)	−0.0004 (5)
C6	0.0264 (6)	0.0295 (6)	0.0237 (6)	−0.0084 (5)	−0.0017 (5)	−0.0009 (5)
C8	0.0298 (6)	0.0208 (5)	0.0209 (6)	−0.0037 (5)	−0.0016 (5)	0.0010 (4)
C8a	0.0194 (5)	0.0183 (5)	0.0214 (5)	0.0022 (4)	−0.0004 (4)	0.0000 (4)
C9	0.0199 (5)	0.0174 (5)	0.0222 (5)	0.0015 (4)	0.0014 (4)	0.0024 (4)
C10	0.0215 (5)	0.0220 (5)	0.0180 (5)	0.0026 (4)	−0.0002 (4)	0.0004 (4)
C11	0.0187 (5)	0.0261 (5)	0.0241 (6)	−0.0022 (4)	−0.0022 (4)	−0.0007 (4)
C12a	0.0179 (5)	0.0236 (5)	0.0217 (6)	0.0030 (4)	0.0011 (4)	0.0008 (4)
C12	0.0185 (5)	0.0292 (6)	0.0238 (6)	−0.0024 (4)	0.0018 (4)	0.0036 (4)
C13b	0.0220 (5)	0.0189 (5)	0.0196 (5)	0.0024 (4)	0.0004 (4)	−0.0021 (4)
C13	0.0194 (5)	0.0271 (6)	0.0201 (5)	0.0000 (4)	0.0028 (4)	0.0007 (4)
C13a	0.0206 (5)	0.0203 (5)	0.0196 (5)	0.0032 (4)	0.0022 (4)	−0.0012 (4)
C14	0.0212 (5)	0.0239 (5)	0.0205 (5)	0.0018 (4)	0.0002 (4)	−0.0016 (4)
C14a	0.0251 (6)	0.0207 (5)	0.0217 (6)	0.0026 (4)	0.0045 (4)	−0.0012 (4)
C15	0.0261 (6)	0.0363 (7)	0.0332 (7)	−0.0043 (5)	0.0073 (5)	0.0021 (6)
C16	0.0314 (7)	0.0443 (8)	0.0217 (6)	−0.0082 (6)	−0.0026 (5)	−0.0043 (5)

Geometric parameters (Å, º)

O1—C14a	1.3800 (14)	C8—C8a	1.5071 (15)
O1—C2	1.4433 (14)	C8—H8A	0.990 (15)
O3—C3a	1.3752 (14)	C8—H8B	0.976 (15)
O3—C2	1.4352 (15)	C8a—C9	1.3842 (16)
O9—C9	1.3843 (13)	C8a—C12a	1.4082 (16)
O9—C15	1.4342 (15)	C9—C10	1.4075 (15)
O10—C10	1.3710 (13)	C10—C11	1.3900 (16)
O10—C16	1.4240 (15)	C11—C12	1.3911 (17)
N7—C13a	1.4062 (14)	C11—H11	0.952 (15)
N7—C6	1.4605 (14)	C12a—C12	1.3944 (16)
N7—C8	1.4621 (14)	C12a—C13	1.4501 (15)
C2—H2A	0.955 (15)	C12—H12	0.953 (15)
C2—H2B	0.995 (15)	C13b—C14	1.4171 (16)
C3a—C4	1.3698 (17)	C13b—C13a	1.4821 (15)
C3a—C14a	1.3891 (16)	C13—C13a	1.3613 (16)
C4—C4a	1.4058 (16)	C13—H13	0.966 (15)
C4—H4	1.008 (16)	C14—C14a	1.3683 (16)
C4a—C13b	1.4020 (16)	C14—H14	1.004 (15)
C4a—C5	1.5065 (16)	C15—H15A	0.966 (17)
C5—C6	1.5116 (17)	C15—H15B	0.991 (17)
C5—H5B	1.034 (16)	C15—H15C	0.959 (16)
C5—H5A	0.994 (16)	C16—H16A	0.959 (18)
C6—H6A	1.004 (16)	C16—H16B	0.976 (18)
C6—H6B	1.000 (15)	C16—H16C	0.990 (16)
C14a—O1—C2	104.13 (9)	O9—C9—C8a	120.26 (10)
C3a—O3—C2	104.44 (9)	O9—C9—C10	119.27 (10)
C9—O9—C15	112.06 (9)	C8a—C9—C10	120.42 (10)
C10—O10—C16	117.34 (9)	O10—C10—C11	125.34 (10)
C13a—N7—C6	117.87 (9)	O10—C10—C9	115.20 (10)
C13a—N7—C8	115.34 (9)	C11—C10—C9	119.46 (10)
C6—N7—C8	112.91 (9)	C10—C11—C12	119.85 (10)
O3—C2—O1	107.12 (9)	C10—C11—H11	120.7 (8)
O3—C2—H2A	109.5 (8)	C12—C11—H11	119.5 (8)
O1—C2—H2A	109.3 (8)	C12—C12a—C8a	118.61 (10)
O3—C2—H2B	108.2 (8)	C12—C12a—C13	123.32 (10)
O1—C2—H2B	108.9 (8)	C8a—C12a—C13	117.92 (10)
H2A—C2—H2B	113.7 (12)	C11—C12—C12a	121.30 (11)
C4—C3a—O3	128.62 (10)	C11—C12—H12	120.3 (8)
C4—C3a—C14a	121.52 (10)	C12a—C12—H12	118.4 (8)
O3—C3a—C14a	109.72 (10)	C4a—C13b—C14	119.68 (10)
C3a—C4—C4a	117.53 (10)	C4a—C13b—C13a	120.21 (10)
C3a—C4—H4	121.8 (9)	C14—C13b—C13a	120.10 (10)
C4a—C4—H4	120.7 (9)	C13a—C13—C12a	121.22 (10)
C13b—C4a—C4	121.35 (11)	C13a—C13—H13	121.1 (8)
C13b—C4a—C5	118.50 (10)	C12a—C13—H13	116.8 (8)
C4—C4a—C5	120.13 (10)	C13—C13a—N7	119.00 (10)
C4a—C5—C6	110.04 (10)	C13—C13a—C13b	122.97 (10)
C4a—C5—H5B	110.2 (9)	N7—C13a—C13b	117.79 (10)
C6—C5—H5B	109.5 (8)	C14a—C14—C13b	117.67 (10)
C4a—C5—H5A	111.6 (9)	C14a—C14—H14	119.9 (8)
C6—C5—H5A	110.0 (9)	C13b—C14—H14	122.4 (8)
H5B—C5—H5A	105.5 (12)	C14—C14a—O1	128.05 (11)
N7—C6—C5	109.69 (10)	C14—C14a—C3a	122.24 (11)
N7—C6—H6A	110.2 (9)	O1—C14a—C3a	109.58 (10)
C5—C6—H6A	110.4 (9)	O9—C15—H15A	109.0 (10)
N7—C6—H6B	107.1 (8)	O9—C15—H15B	110.1 (9)
C5—C6—H6B	111.7 (9)	H15A—C15—H15B	109.5 (13)
H6A—C6—H6B	107.7 (12)	O9—C15—H15C	106.3 (9)
N7—C8—C8a	110.18 (9)	H15A—C15—H15C	111.7 (13)
N7—C8—H8A	109.2 (8)	H15B—C15—H15C	110.3 (13)
C8a—C8—H8A	110.5 (8)	O10—C16—H16A	112.3 (10)
N7—C8—H8B	107.1 (8)	O10—C16—H16B	110.7 (10)
C8a—C8—H8B	112.3 (8)	H16A—C16—H16B	109.6 (14)
H8A—C8—H8B	107.5 (12)	O10—C16—H16C	104.6 (9)
C9—C8a—C12a	120.31 (10)	H16A—C16—H16C	109.3 (13)
C9—C8a—C8	122.77 (10)	H16B—C16—H16C	110.3 (13)
C12a—C8a—C8	116.84 (10)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2A···O10^i	0.955 (15)	2.407 (15)	3.3031 (15)	156.2 (11)
C2—H2B···N7^ii	0.995 (15)	2.620 (15)	3.5326 (17)	152.5 (11)

Symmetry codes: (i) x, −y+3/2, z−1/2; (ii) −x+1, −y+2, −z.