1:1 Cocrystal of (S)-3-(ammonio­meth­yl)-5-methyl­hexa­noate and (S)-mandelic acid

The title compound, C₈H₁₇NO₂·C₈H₈O₃, exists as a complex with the base (pregabalin) in the predicted zwitterion form, based on the pK_a differences between the acid and base. The asymmetric unit consists of two molecules of each component. The -NH₃ group adopts the standard propeller conformation. The structure forms pairs of hydro­phobic and hydro­philic inter­actions along both the a and c axes.

Key indicators

• Single-crystal X-ray study
• T = 296 K
• Mean [sigma](C-C) = 0.007 Å
• R factor = 0.058
• wR factor = 0.148
• Data-to-parameter ratio = 10.2

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT029_ALERT_3_C _diffrn_measured_fraction_theta_full Low .......       0.96
PLAT094_ALERT_2_C Ratio of Maximum / Minimum Residual Density ....       2.75
PLAT220_ALERT_2_C Large Non-Solvent    C     Ueq(max)/Ueq(min) ...       3.26 Ratio
PLAT220_ALERT_2_C Large Non-Solvent    C     Ueq(max)/Ueq(min) ...       2.59 Ratio
PLAT222_ALERT_3_C Large Non-Solvent    H     Ueq(max)/Ueq(min) ...       3.69 Ratio
PLAT340_ALERT_3_C Low Bond Precision on C-C Bonds (x 1000) Ang ...          7
PLAT432_ALERT_2_C Short Inter X...Y Contact  O2     ..  C4      ..       3.00 Ang.
PLAT432_ALERT_2_C Short Inter X...Y Contact  O8     ..  C9      ..       3.01 Ang.

Alert level G
HYDTR01_ALERT_1_G  Extra text has been found in the _refine_ls_hydrogen_treatment fi
            Explanatory text should be in the _publ_section_refinement field.
            Hydrogen treatment given as constr'
            Hydrogen treatment identified as  constr
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           28.23
           From the CIF: _reflns_number_total               4159
           Count of symmetry unique reflns         4368
           Completeness (_total/calc)             95.22%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C1     = .          S
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C11    = .          S
PLAT860_ALERT_3_G Note: Number of Least-Squares Restraints .......          1

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   8 ALERT level C = Check and explain
   5 ALERT level G = General alerts; check

   3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   5 ALERT type 2 Indicator that the structure model may be wrong or deficient
   4 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

The title complex, (I), is an important intermediate in the overall synthesis of pregabalin. Pregabalin, marketed as Lyrica by Pfizer (see https://www.lyrica.com), is an approved drug for the treatment of diabetic nerve and shingle pain amongst others.

Taking advantage of the complex's unusual physio-chemical properties, mandelic acid is used to resolve racemic pregabalin on industrial scale. A crystallization of 1:1 mandelic acid to pregabalin results in the free form. Complex (I) forms only with an excess of mandelic acid.

The complex is resolved by either 1) adding two molar equivalents of the acid or 2) adding a slight excess of mandelic acid combined with an inorganic acid, the method of Pope and Peachy (Pope & Peachey, 1899). The resolved pregabalin–mandelic acid complex is isolated and recrystallized to remove the complexed mandelic acid and recover the free form (Hoekstra et al., 1997; Mulhern, 1996). At ratios of 1:1 pregabalin with mandelic acid, the free form was isolated from both slurries and crystallizations. However, with 1:2 pregabalin:mandelic acid, (I) was isolated under both conditions.

All strong hydrogen bond acceptors and donors are utilized. The ratio of donors to acceptors is 5 to 3. Two extra donating protons donate to the same acceptor; resulting in one hydrogen bond acceptor (delocalized carbonyl) accepting three protons. This is an unusual finding. While there are many examples of carbonyl with three hydrogen bonds, it is unusual for a carboxylate to accept three hydrogen bonds.

Some close contacts between the carboxylate group and protons (D—H···A) on the NH₃ group were not hydrogen bonds (e.g. N2—H2B—O8). In these cases, the hydrogen bond angles were very bent and the geometry of the accepting OH group did not appear to favor accepting a hydrogen bond. The closeness of these accepting and donating groups could be a function of the forced propeller NH₃ conformation or the opposite charges of carboxylate and NH₃ groups.

Related literature

For related literature, see: Hoekstra et al. (1997); Mulhern (1996); Pope & Peachey (1899).

S2. Experimental

Attempts to crystallize a suitable diffraction quality crystal took some time. Many of the crystals grown were non-merohedrally twinned at a ratio of 10:1. With careful technique, sheets of crystal could be removed from the twinned crystals. The sheets were high quality single crystals, yet were not of acceptable volume to diffract well. The twinned structures did not refine as well as this untwinned structure. We choose a untwinned crystal and collected for long exposures. The chirality of pregabalin was determined by relative configuration from the fixed chiral center of the mandelic acid.

S3. Refinement

Friedel pairs were merged in the absence of signifcant anomalous scattering effects. H atoms bound to carbon were positioned geometrically, with C—H distances of 0.95 Å, and refined using a riding model.

Computing details

Data collection: XSCANS (Siemens, 1991); cell refinement: XSCANS (Siemens, 1991); data reduction: SAINT-Plus (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP (Sheldrick, 1996); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

	Fig. 1. ORTEP diagram. Atomic displacement ellipsoids are at 30% probability, hydrogen atoms are given as arbritary radii.
	Fig. 2. Hydrophilic/hydrophobic interactions visible by looking down the a axis. Protons involoved in hydrogen bonding are shown in green.

(S)-3-(ammoniomethyl)-5-methylhexanoate–(S)-mandelic acid (1/1)

Crystal data

C8H17NO2·C8H8O3	F(000) = 672
Mr = 311.37	Dx = 1.198 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 815 reflections
a = 6.2922 (13) Å	θ = 3.0–18.4°
b = 27.423 (6) Å	µ = 0.09 mm^−1
c = 10.009 (2) Å	T = 296 K
β = 90.84 (3)°	Plate, colourless
V = 1726.9 (6) Å^3	0.22 × 0.11 × 0.05 mm
Z = 4

Data collection

Bruker SMART APEX2 CCD diffractometer	4159 independent reflections
Radiation source: fine-focus sealed tube	2488 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.096
φ and ω scans	θmax = 28.2°, θmin = 1.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −8→8
Tmin = 0.956, Tmax = 0.996	k = −36→36
38738 measured reflections	l = −13→13

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)] = 0.059	H-atom parameters constrained
wR(F^2) = 0.148	w = 1/[σ^2(Fo^2) + (0.0842P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.92	(Δ/σ)max < 0.001
4159 reflections	Δρmax = 0.58 e Å^−3
407 parameters	Δρmin = −0.21 e Å^−3
1 restraint	Absolute structure: Flack (1983), with 3849 Friedel pairs
Primary atom site location: structure-invariant direct methods

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

	x	y	z	Uiso*/Ueq
C1	0.1574 (8)	0.34998 (17)	0.3221 (4)	0.0322 (10)
H1	0.0160	0.3398	0.3511	0.039*
O7	0.8185 (5)	0.41070 (11)	1.0833 (3)	0.0319 (7)
O4	0.2132 (5)	0.38722 (12)	0.5318 (3)	0.0329 (7)
H4	0.2384	0.4126	0.5723	0.049*
O10	0.3202 (5)	0.46157 (11)	0.6609 (3)	0.0312 (7)
O1	0.7161 (5)	0.48461 (11)	0.2123 (3)	0.0314 (7)
H1A	0.7378	0.4591	0.1721	0.047*
O9	0.0740 (5)	0.44728 (11)	0.8170 (3)	0.0309 (7)
C2	0.7324 (7)	0.47677 (17)	0.3419 (4)	0.0260 (10)
O8	0.5720 (5)	0.42446 (11)	0.9265 (3)	0.0306 (7)
O2	0.7914 (5)	0.43870 (12)	0.3910 (3)	0.0316 (7)
N1	0.2478 (6)	0.46247 (13)	1.0859 (3)	0.0280 (8)
H1B	0.3520	0.4532	1.0323	0.042*
H1C	0.1254	0.4498	1.0568	0.042*
H1D	0.2754	0.4520	1.1685	0.042*
O5	0.2925 (5)	0.43222 (12)	0.3533 (3)	0.0337 (7)
N2	0.7488 (6)	0.40986 (13)	0.6580 (3)	0.0300 (9)
H2A	0.8432	0.4193	0.7198	0.045*
H2B	0.6220	0.4223	0.6767	0.045*
H2C	0.7891	0.4203	0.5781	0.045*
C3	0.7354 (7)	0.35569 (17)	0.6570 (4)	0.0305 (10)
H3A	0.8756	0.3423	0.6417	0.037*
H3B	0.6429	0.3454	0.5840	0.037*
O3	0.6535 (6)	0.51155 (13)	0.5613 (3)	0.0378 (8)
H3	0.5372	0.4993	0.5760	0.057*
C4	0.2282 (7)	0.39496 (17)	0.4026 (4)	0.0276 (10)
O6	0.1506 (6)	0.35999 (13)	0.1826 (3)	0.0449 (9)
H6	0.0403	0.3745	0.1636	0.067*
C5	0.2322 (7)	0.51655 (17)	1.0857 (4)	0.0309 (10)
H5A	0.3717	0.5303	1.1038	0.037*
H5B	0.1390	0.5267	1.1568	0.037*
C6	0.7182 (7)	0.39958 (15)	0.9754 (4)	0.0245 (9)
C7	0.6390 (7)	0.27979 (16)	0.7801 (4)	0.0289 (10)
H7A	0.7830	0.2671	0.7808	0.035*
H7B	0.5741	0.2711	0.6949	0.035*
C8	0.1473 (7)	0.53650 (16)	0.9530 (4)	0.0278 (10)
H8	0.0023	0.5243	0.9390	0.033*
C9	0.2197 (7)	0.47262 (16)	0.7684 (4)	0.0248 (9)
C10	0.6498 (7)	0.33543 (16)	0.7893 (4)	0.0263 (9)
H10	0.5047	0.3477	0.7999	0.032*
C11	0.6697 (7)	0.52180 (16)	0.4222 (4)	0.0280 (9)
H11	0.5329	0.5341	0.3884	0.034*
C12	0.2836 (7)	0.52008 (16)	0.8331 (4)	0.0274 (9)
H12A	0.2779	0.5455	0.7656	0.033*
H12B	0.4302	0.5173	0.8634	0.033*
C13	0.7829 (7)	0.35234 (16)	0.9105 (4)	0.0271 (9)
H13A	0.7787	0.3269	0.9777	0.032*
H13B	0.9293	0.3555	0.8829	0.032*
C14	0.8380 (7)	0.56137 (16)	0.4073 (4)	0.0273 (9)
C15	0.3129 (7)	0.30842 (18)	0.3442 (4)	0.0317 (10)
C16	0.1376 (8)	0.59252 (15)	0.9640 (4)	0.0299 (10)
H16A	0.2819	0.6050	0.9670	0.036*
H16B	0.0721	0.6009	1.0481	0.036*
C17	1.0324 (7)	0.55679 (19)	0.4744 (4)	0.0365 (11)
H17	1.0617	0.5289	0.5245	0.044*
C18	0.7999 (8)	0.60233 (18)	0.3304 (5)	0.0367 (11)
H18	0.6715	0.6060	0.2842	0.044*
C19	0.5152 (8)	0.31030 (19)	0.2856 (5)	0.0384 (11)
H19	0.5557	0.3379	0.2385	0.046*
C20	0.0145 (8)	0.61907 (18)	0.8497 (5)	0.0399 (12)
H20	0.0888	0.6128	0.7660	0.048*
C21	0.5157 (9)	0.25445 (18)	0.8912 (5)	0.0428 (12)
H21	0.5905	0.2610	0.9759	0.051*
C22	1.1817 (8)	0.59351 (18)	0.4668 (4)	0.0376 (12)
H22	1.3100	0.5902	0.5132	0.045*
C23	0.2604 (9)	0.26761 (19)	0.4164 (5)	0.0402 (12)
H23	0.1288	0.2663	0.4574	0.048*
C24	0.5162 (10)	0.19979 (18)	0.8693 (6)	0.0511 (15)
H24A	0.6601	0.1882	0.8684	0.077*
H24B	0.4476	0.1924	0.7854	0.077*
H24C	0.4411	0.1841	0.9403	0.077*
C25	0.9565 (9)	0.6381 (2)	0.3230 (5)	0.0482 (14)
H25	0.9322	0.6652	0.2692	0.058*
C26	0.5924 (11)	0.2306 (2)	0.3709 (5)	0.0581 (16)
H26	0.6859	0.2045	0.3796	0.070*
C27	0.0182 (11)	0.6735 (2)	0.8746 (6)	0.0572 (15)
H27A	−0.0547	0.6807	0.9559	0.086*
H27B	−0.0511	0.6900	0.8014	0.086*
H27C	0.1628	0.6845	0.8822	0.086*
C28	1.1461 (9)	0.63459 (19)	0.3927 (5)	0.0438 (13)
H28	1.2466	0.6594	0.3895	0.053*
C29	0.6519 (9)	0.2718 (2)	0.2975 (5)	0.0416 (12)
H29	0.7840	0.2729	0.2571	0.050*
C30	−0.2121 (10)	0.6011 (2)	0.8329 (7)	0.0638 (18)
H30A	−0.2891	0.6226	0.7741	0.096*
H30B	−0.2793	0.6004	0.9184	0.096*
H30C	−0.2115	0.5688	0.7957	0.096*
C31	0.3978 (11)	0.2285 (2)	0.4298 (5)	0.0567 (16)
H31	0.3583	0.2011	0.4783	0.068*
C32	0.2890 (11)	0.2730 (2)	0.9043 (9)	0.079 (3)
H32A	0.2092	0.2651	0.8248	0.118*
H32B	0.2907	0.3077	0.9165	0.118*
H32C	0.2241	0.2578	0.9800	0.118*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.033 (3)	0.036 (3)	0.027 (2)	0.006 (2)	−0.0049 (18)	−0.0074 (18)
O7	0.0370 (18)	0.0379 (19)	0.0205 (15)	0.0059 (14)	−0.0067 (12)	−0.0043 (12)
O4	0.0414 (19)	0.0353 (18)	0.0218 (15)	−0.0024 (15)	−0.0011 (13)	−0.0026 (12)
O10	0.0360 (18)	0.0360 (19)	0.0217 (15)	−0.0011 (14)	0.0076 (12)	−0.0036 (12)
O1	0.041 (2)	0.0336 (18)	0.0199 (15)	0.0036 (15)	−0.0018 (13)	−0.0023 (12)
O9	0.0288 (17)	0.0393 (19)	0.0248 (15)	−0.0096 (14)	0.0014 (12)	−0.0033 (13)
C2	0.021 (2)	0.034 (3)	0.023 (2)	−0.0046 (19)	−0.0009 (16)	−0.0015 (17)
O8	0.0279 (16)	0.0377 (19)	0.0260 (15)	0.0076 (14)	−0.0030 (12)	−0.0009 (13)
O2	0.0337 (18)	0.0352 (19)	0.0258 (15)	0.0051 (14)	−0.0005 (12)	0.0009 (13)
N1	0.0240 (19)	0.037 (2)	0.0232 (18)	0.0005 (17)	0.0012 (14)	−0.0012 (15)
O5	0.0374 (19)	0.039 (2)	0.0242 (16)	−0.0067 (15)	−0.0007 (12)	0.0009 (13)
N2	0.029 (2)	0.035 (2)	0.0262 (19)	−0.0013 (17)	−0.0017 (15)	0.0020 (15)
C3	0.029 (3)	0.038 (3)	0.024 (2)	−0.001 (2)	0.0017 (17)	−0.0009 (18)
O3	0.044 (2)	0.046 (2)	0.0234 (15)	−0.0087 (17)	0.0108 (13)	−0.0042 (13)
C4	0.021 (2)	0.039 (3)	0.023 (2)	0.005 (2)	−0.0016 (16)	−0.0005 (18)
O6	0.055 (2)	0.052 (2)	0.0273 (17)	0.0177 (18)	−0.0158 (15)	−0.0076 (15)
C5	0.028 (2)	0.036 (3)	0.028 (2)	0.001 (2)	−0.0014 (17)	−0.0052 (18)
C6	0.026 (2)	0.029 (2)	0.0177 (19)	−0.0035 (18)	0.0016 (15)	0.0002 (15)
C7	0.024 (2)	0.032 (3)	0.030 (2)	−0.0041 (19)	0.0001 (18)	−0.0045 (17)
C8	0.025 (2)	0.032 (3)	0.026 (2)	−0.0004 (19)	0.0006 (17)	−0.0038 (17)
C9	0.025 (2)	0.029 (2)	0.020 (2)	−0.0009 (19)	−0.0022 (15)	0.0003 (16)
C10	0.026 (2)	0.030 (2)	0.023 (2)	0.0022 (18)	−0.0001 (16)	−0.0024 (16)
C11	0.026 (2)	0.033 (3)	0.025 (2)	0.0010 (19)	0.0031 (16)	−0.0037 (17)
C12	0.027 (2)	0.030 (3)	0.025 (2)	−0.0011 (19)	0.0061 (16)	−0.0040 (17)
C13	0.026 (2)	0.031 (3)	0.024 (2)	0.0010 (19)	−0.0047 (16)	−0.0030 (17)
C14	0.032 (2)	0.029 (2)	0.021 (2)	0.000 (2)	0.0030 (17)	−0.0027 (17)
C15	0.037 (3)	0.033 (3)	0.024 (2)	0.002 (2)	−0.0084 (18)	−0.0072 (18)
C16	0.034 (3)	0.027 (3)	0.029 (2)	0.004 (2)	0.0043 (18)	−0.0050 (17)
C17	0.035 (3)	0.047 (3)	0.027 (2)	0.000 (2)	−0.0001 (19)	0.000 (2)
C18	0.039 (3)	0.033 (3)	0.037 (3)	−0.001 (2)	−0.006 (2)	0.008 (2)
C19	0.039 (3)	0.034 (3)	0.042 (3)	0.005 (2)	−0.003 (2)	−0.001 (2)
C20	0.043 (3)	0.036 (3)	0.040 (3)	0.006 (2)	0.004 (2)	0.000 (2)
C21	0.050 (3)	0.032 (3)	0.046 (3)	−0.012 (2)	0.012 (2)	0.001 (2)
C22	0.037 (3)	0.048 (3)	0.028 (2)	−0.008 (2)	0.0046 (19)	−0.010 (2)
C23	0.041 (3)	0.041 (3)	0.039 (3)	−0.001 (2)	0.000 (2)	0.002 (2)
C24	0.051 (4)	0.031 (3)	0.072 (4)	−0.005 (3)	0.008 (3)	0.006 (3)
C25	0.059 (4)	0.037 (3)	0.049 (3)	−0.011 (3)	0.012 (3)	0.004 (2)
C26	0.072 (5)	0.057 (4)	0.044 (3)	0.021 (3)	−0.015 (3)	−0.001 (3)
C27	0.070 (4)	0.038 (3)	0.064 (4)	0.007 (3)	0.004 (3)	0.001 (3)
C28	0.052 (3)	0.038 (3)	0.041 (3)	−0.013 (3)	0.011 (2)	−0.007 (2)
C29	0.040 (3)	0.049 (3)	0.035 (3)	0.009 (2)	−0.003 (2)	−0.010 (2)
C30	0.054 (4)	0.039 (4)	0.097 (5)	0.003 (3)	−0.031 (3)	0.006 (3)
C31	0.080 (5)	0.045 (4)	0.044 (3)	0.006 (3)	−0.008 (3)	0.010 (3)
C32	0.051 (4)	0.043 (4)	0.145 (7)	0.005 (3)	0.050 (4)	0.010 (4)

Geometric parameters (Å, º)

C1—O6	1.424 (5)	C12—H12B	0.9700
C1—C15	1.516 (7)	C13—H13A	0.9700
C1—C4	1.535 (6)	C13—H13B	0.9700
C1—H1	0.9800	C14—C18	1.381 (6)
O7—C6	1.279 (5)	C14—C17	1.392 (6)
O4—C4	1.315 (5)	C15—C23	1.375 (7)
O4—H4	0.8200	C15—C19	1.410 (7)
O10—C9	1.292 (5)	C16—C20	1.554 (7)
O1—C2	1.317 (5)	C16—H16A	0.9700
O1—H1A	0.8200	C16—H16B	0.9700
O9—C9	1.255 (5)	C17—C22	1.380 (7)
C2—O2	1.210 (5)	C17—H17	0.9300
C2—C11	1.528 (6)	C18—C25	1.393 (7)
O8—C6	1.240 (5)	C18—H18	0.9300
N1—C5	1.486 (6)	C19—C29	1.366 (7)
N1—H1B	0.8900	C19—H19	0.9300
N1—H1C	0.8900	C20—C27	1.515 (8)
N1—H1D	0.8900	C20—C30	1.516 (8)
O5—C4	1.207 (5)	C20—H20	0.9800
N2—C3	1.488 (6)	C21—C24	1.515 (7)
N2—H2A	0.8900	C21—C32	1.522 (8)
N2—H2B	0.8900	C21—H21	0.9800
N2—H2C	0.8900	C22—C28	1.365 (7)
C3—C10	1.540 (6)	C22—H22	0.9300
C3—H3A	0.9700	C23—C31	1.384 (8)
C3—H3B	0.9700	C23—H23	0.9300
O3—C11	1.426 (5)	C24—H24A	0.9600
O3—H3	0.8200	C24—H24B	0.9600
O6—H6	0.8200	C24—H24C	0.9600
C5—C8	1.526 (6)	C25—C28	1.377 (8)
C5—H5A	0.9700	C25—H25	0.9300
C5—H5B	0.9700	C26—C31	1.368 (9)
C6—C13	1.508 (6)	C26—C29	1.402 (8)
C7—C10	1.530 (6)	C26—H26	0.9300
C7—C21	1.532 (6)	C27—H27A	0.9600
C7—H7A	0.9700	C27—H27B	0.9600
C7—H7B	0.9700	C27—H27C	0.9600
C8—C16	1.541 (6)	C28—H28	0.9300
C8—C12	1.552 (6)	C29—H29	0.9300
C8—H8	0.9800	C30—H30A	0.9600
C9—C12	1.506 (6)	C30—H30B	0.9600
C10—C13	1.536 (6)	C30—H30C	0.9600
C10—H10	0.9800	C31—H31	0.9300
C11—C14	1.525 (6)	C32—H32A	0.9600
C11—H11	0.9800	C32—H32B	0.9600
C12—H12A	0.9700	C32—H32C	0.9600
O6—C1—C15	107.3 (3)	C10—C13—H13B	108.1
O6—C1—C4	111.3 (4)	H13A—C13—H13B	107.3
C15—C1—C4	110.2 (4)	C18—C14—C17	119.1 (4)
O6—C1—H1	109.3	C18—C14—C11	121.2 (4)
C15—C1—H1	109.3	C17—C14—C11	119.7 (4)
C4—C1—H1	109.3	C23—C15—C19	118.3 (5)
C4—O4—H4	109.5	C23—C15—C1	121.9 (4)
C2—O1—H1A	109.5	C19—C15—C1	119.8 (4)
O2—C2—O1	124.0 (4)	C8—C16—C20	115.7 (4)
O2—C2—C11	124.4 (4)	C8—C16—H16A	108.3
O1—C2—C11	111.6 (4)	C20—C16—H16A	108.3
C5—N1—H1B	109.5	C8—C16—H16B	108.3
C5—N1—H1C	109.5	C20—C16—H16B	108.3
H1B—N1—H1C	109.5	H16A—C16—H16B	107.4
C5—N1—H1D	109.5	C22—C17—C14	120.1 (5)
H1B—N1—H1D	109.5	C22—C17—H17	119.9
H1C—N1—H1D	109.5	C14—C17—H17	119.9
C3—N2—H2A	109.5	C14—C18—C25	119.0 (5)
C3—N2—H2B	109.5	C14—C18—H18	120.5
H2A—N2—H2B	109.5	C25—C18—H18	120.5
C3—N2—H2C	109.5	C29—C19—C15	120.4 (5)
H2A—N2—H2C	109.5	C29—C19—H19	119.8
H2B—N2—H2C	109.5	C15—C19—H19	119.8
N2—C3—C10	112.0 (3)	C27—C20—C30	110.6 (5)
N2—C3—H3A	109.2	C27—C20—C16	109.6 (4)
C10—C3—H3A	109.2	C30—C20—C16	112.8 (4)
N2—C3—H3B	109.2	C27—C20—H20	107.9
C10—C3—H3B	109.2	C30—C20—H20	107.9
H3A—C3—H3B	107.9	C16—C20—H20	107.9
C11—O3—H3	109.5	C24—C21—C32	110.3 (5)
O5—C4—O4	124.6 (4)	C24—C21—C7	110.0 (4)
O5—C4—C1	124.2 (4)	C32—C21—C7	113.4 (5)
O4—C4—C1	111.2 (4)	C24—C21—H21	107.7
C1—O6—H6	109.5	C32—C21—H21	107.7
N1—C5—C8	112.4 (3)	C7—C21—H21	107.7
N1—C5—H5A	109.1	C28—C22—C17	121.7 (5)
C8—C5—H5A	109.1	C28—C22—H22	119.1
N1—C5—H5B	109.1	C17—C22—H22	119.1
C8—C5—H5B	109.1	C15—C23—C31	121.8 (5)
H5A—C5—H5B	107.9	C15—C23—H23	119.1
O8—C6—O7	123.8 (4)	C31—C23—H23	119.1
O8—C6—C13	120.4 (4)	C21—C24—H24A	109.5
O7—C6—C13	115.8 (4)	C21—C24—H24B	109.5
C10—C7—C21	115.5 (4)	H24A—C24—H24B	109.5
C10—C7—H7A	108.4	C21—C24—H24C	109.5
C21—C7—H7A	108.4	H24A—C24—H24C	109.5
C10—C7—H7B	108.4	H24B—C24—H24C	109.5
C21—C7—H7B	108.4	C28—C25—C18	122.1 (5)
H7A—C7—H7B	107.5	C28—C25—H25	118.9
C5—C8—C16	108.0 (3)	C18—C25—H25	118.9
C5—C8—C12	112.2 (4)	C31—C26—C29	120.5 (6)
C16—C8—C12	111.5 (4)	C31—C26—H26	119.7
C5—C8—H8	108.3	C29—C26—H26	119.7
C16—C8—H8	108.3	C20—C27—H27A	109.5
C12—C8—H8	108.3	C20—C27—H27B	109.5
O9—C9—O10	124.2 (4)	H27A—C27—H27B	109.5
O9—C9—C12	120.3 (4)	C20—C27—H27C	109.5
O10—C9—C12	115.5 (4)	H27A—C27—H27C	109.5
C7—C10—C13	111.8 (4)	H27B—C27—H27C	109.5
C7—C10—C3	108.9 (3)	C22—C28—C25	117.9 (5)
C13—C10—C3	112.1 (4)	C22—C28—H28	121.1
C7—C10—H10	108.0	C25—C28—H28	121.1
C13—C10—H10	108.0	C19—C29—C26	119.7 (5)
C3—C10—H10	108.0	C19—C29—H29	120.1
O3—C11—C14	107.2 (3)	C26—C29—H29	120.1
O3—C11—C2	112.1 (4)	C20—C30—H30A	109.5
C14—C11—C2	109.8 (3)	C20—C30—H30B	109.5
O3—C11—H11	109.2	H30A—C30—H30B	109.5
C14—C11—H11	109.2	C20—C30—H30C	109.5
C2—C11—H11	109.2	H30A—C30—H30C	109.5
C9—C12—C8	115.9 (4)	H30B—C30—H30C	109.5
C9—C12—H12A	108.3	C26—C31—C23	119.1 (5)
C8—C12—H12A	108.3	C26—C31—H31	120.4
C9—C12—H12B	108.3	C23—C31—H31	120.4
C8—C12—H12B	108.3	C21—C32—H32A	109.5
H12A—C12—H12B	107.4	C21—C32—H32B	109.5
C6—C13—C10	116.9 (4)	H32A—C32—H32B	109.5
C6—C13—H13A	108.1	C21—C32—H32C	109.5
C10—C13—H13A	108.1	H32A—C32—H32C	109.5
C6—C13—H13B	108.1	H32B—C32—H32C	109.5
O6—C1—C4—O5	−7.7 (6)	O6—C1—C15—C23	−129.1 (5)
C15—C1—C4—O5	111.3 (5)	C4—C1—C15—C23	109.5 (5)
O6—C1—C4—O4	173.5 (4)	O6—C1—C15—C19	48.5 (5)
C15—C1—C4—O4	−67.5 (5)	C4—C1—C15—C19	−72.9 (5)
N1—C5—C8—C16	180.0 (4)	C5—C8—C16—C20	−168.5 (4)
N1—C5—C8—C12	−56.7 (5)	C12—C8—C16—C20	67.7 (5)
C21—C7—C10—C13	67.5 (5)	C18—C14—C17—C22	1.9 (6)
C21—C7—C10—C3	−168.1 (4)	C11—C14—C17—C22	−176.9 (4)
N2—C3—C10—C7	179.5 (4)	C17—C14—C18—C25	−0.5 (7)
N2—C3—C10—C13	−56.2 (5)	C11—C14—C18—C25	178.2 (4)
O2—C2—C11—O3	−10.0 (6)	C23—C15—C19—C29	1.9 (7)
O1—C2—C11—O3	170.5 (4)	C1—C15—C19—C29	−175.9 (4)
O2—C2—C11—C14	109.0 (5)	C8—C16—C20—C27	179.8 (4)
O1—C2—C11—C14	−70.4 (4)	C8—C16—C20—C30	56.2 (6)
O9—C9—C12—C8	−4.7 (6)	C10—C7—C21—C24	179.5 (5)
O10—C9—C12—C8	173.5 (4)	C10—C7—C21—C32	55.6 (6)
C5—C8—C12—C9	89.1 (5)	C14—C17—C22—C28	−1.0 (7)
C16—C8—C12—C9	−149.6 (4)	C19—C15—C23—C31	−1.6 (7)
O8—C6—C13—C10	−4.2 (6)	C1—C15—C23—C31	176.1 (5)
O7—C6—C13—C10	173.8 (4)	C14—C18—C25—C28	−1.8 (8)
C7—C10—C13—C6	−148.1 (4)	C17—C22—C28—C25	−1.2 (7)
C3—C10—C13—C6	89.3 (5)	C18—C25—C28—C22	2.6 (8)
O3—C11—C14—C18	−131.2 (4)	C15—C19—C29—C26	−1.3 (7)
C2—C11—C14—C18	106.8 (5)	C31—C26—C29—C19	0.5 (8)
O3—C11—C14—C17	47.6 (5)	C29—C26—C31—C23	−0.2 (9)
C2—C11—C14—C17	−74.5 (5)	C15—C23—C31—C26	0.8 (8)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O10	0.82	1.69	2.501 (4)	173
O1—H1A···O7^i	0.82	1.68	2.493 (4)	171
N1—H1B···O8	0.89	1.92	2.808 (5)	172
N1—H1C···O7^ii	0.89	2.23	3.052 (5)	154
N1—H1D···O5^iii	0.89	1.93	2.812 (5)	172
N2—H2A···O9^iv	0.89	1.90	2.771 (5)	167
N2—H2B···O10	0.89	2.19	3.048 (5)	163
N2—H2C···O2	0.89	1.94	2.804 (4)	163
O3—H3···O10	0.82	1.92	2.708 (4)	160
O6—H6···O7^v	0.82	1.88	2.689 (4)	167

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