The methanol disolvate and the dihydrate of fexofenadine, an anti­histamine drug

Fexofenadine [systematic name: (±)-(4-{1-hydroxy-4-[4-(hydroxydiphenyl­methyl)­piperidinium-1-yl]-butyl}phenyl)-2-methyl­propionate], crystallizes in two forms, viz. as the methanol disolvate, C₃₂H₃₉NO₄·2CH₄O, and as the dihydrate, C₃₂H₃₉NO₄·2H₂O. It exists in the two structures as a zwitterion, which self-assembles as dimers sustained by a pair of charged-assisted N—H...OOC hydrogen bonds. In the methanol disolvate, the supramolecular organization consists of discrete fexofenadine dimers solvated by four mol­ecules of methanol. The dihydrate structure is sustained by a more extended hydrogen-bonding scheme, wherein the hydrated dimeric entities are inter­linked by additional hydrogen bonds. The fexofenadine mol­ecule adopts different and differently disordered conformations of the 1-hydroxy­butyl residue in the two structures.

S1. Comment

We have been investigating the structural chemistry and pseudo-polymorphism of a series of pharmaceutical compounds (Tessler & Goldberg, 2004a,b, 2005a,b). Fexofenadine is an antihistamine used to relieve hay fever and allergy symptoms. The drug is administered orally in its hydrochloride form as the active ingredient. Fexofenadine was approved by the US Food and Drug Administration in July 1995. It works by preventing the activation of H1-receptor-containing cells by histamine, a chemical which is released in the body by other cells. Fexofenadine (L) contains several functional groups with hydrogen-bonding capacity, and normally exists as a zwitterion. Therefore, not surprisingly, it forms sizeable single crystals more readily in a solvated (with polar and protic solvents) rather than a pure form, as co-crystallization with protic solvents allows for better (strain free) optimization of the hydrogen-bonding potential (Etter, 1991).

The conformational flexibility of L aids in the formation of pseudo-polymorphic crystals of this compound. In this context, we were able to crystallize and analyze (at ca 110 K) the structures of the methanol disolvate, (I), and the dihydrate, (II), of L. The corresponding molecular structures are illustrated in Fig. 1, showing the different conformations of the molecular framework.

The main conformational degrees of freedom of the fexofenadine framework are about the C7—C14 and C26—C29 single bonds, and atoms C19–C22 in the central aliphatic chain (Tables 1 and 3). Inspection of the torsion angles indicates a minor difference between the two structures in the conformation about the C7—C14 bond. More significant variation is associated with the rotation of the α,α-dimethyl acetic acid residue with respect to the adjacent phenyl ring in (I) and (II), in order to optimize the corresponding intermolecular interaction scheme (see below). However, the most distinct flexibility is apparent in the N1—C19—C20—C21 and C19—C20—C21—C22 torsion angles (Tables 1 and 3). They impart a bent molecular framework structure in (I), as opposed to a more extended conformation in (II). The disorder of the O2—H functions, with C20—C21—C22—O2A torsion angles of 59.4 (3)° in (I) and 60.6 (4)° in (II) at the major site, but with C20—C21—C22—O2B torsion angles of −5.6 (7)° in (I) and −28.8 (4)° in (II) at the minor site, further attests to the conformational flexibility of L.

The above conformational details (Tables 1 and 3) are closely related to the intermolecular interaction patterns revealed by the two crystals. The most dominant intermolecular interaction in both structures is the charge-assisted hydrogen-bonding attraction between the NH⁺ and the COO⁻ sites of adjacent molecules (Jeffrey, 1997). This leads to the the formation of dimeric entities paired by two NH⁺···COO⁻ hydrogen bonds between molecules related to each other by crystallographic inversion (Tables 2 and 4).

In (I), the two methanol molecules incorporated into the lattice provide the solvation environment as H-atom acceptors for the two hydroxylic acid functions O1—H and O2—H (disordered as O2A and O2B), which point to the concave side of the paired molecules, by hydrogen bonding (Table 2). Each methanol species also solvates the carboxylate function by donating its H atom to the second carboxylate O atom (O4). The hydrogen-bonded clusters in this structure consist of two molecules of fexofenadine and four molecules of methanol, and have an oval shape (Fig. 2, Table 2). The crystal packing of these discrete hydrogen-bonded clusters in (I) is stabilized by common dispersion between their lipophilic C—H lined surfaces.

While similar NH⁺···COO⁻ bound dimers form in structure (II) around inversion centres, the different conformation of the fexofenadine framework causes the O2—H site to point outward and be exposed on the periphery of the dimeric entities to hydrogen-bonding interaction with neighbouring dimers (Fig. 3). This results in the formation of an extended hydrogen-bonding pattern that propagates continuously throughout the crystal within molecular layers perpendicular to the a axis and centered at x = 0 (Fig. 4). The water molecules incorporated into (II) take part in the solvation of one of the hydroxylic acid functions (O1—H) and of the carboxylate anion. In this structure, the fexofenadine dimers are interlinked with neighbouring dimeric entities by four additional hydrogen bonds, utilizing to this end the disordered O2—H H-atom donors and the COO⁻ H-atom acceptors (Table 4). The crystal packing of the hydrogen-bonded layers in (II) is illustrated in Fig. 4.

All bond lengths and angles are in normal ranges (Reference for standard values?), including indication of partial delocalization of the electron density within the C32—O3 and C32—O4 bonds of the carboxylate group, which is consistent with the zwitterionic nature of L. To the authors' knowledge, this is the first crystallographic report of the fexofenadine structure (Cambridge Structural Database, Version?; Allen, 2002).

S2. Experimental

Crude fexofenadine powder was obtained from Teva Pharmaceutical Industries Ltd. Compound (I) was crystallized by slow evaporation from methanol. Compound (II) was crystallized by slow evaporation from wet acetonitrile. Thermal analyses of both compounds confirmed their chemical purity. In both cases, the crystals obtained were characterized by relatively high mosaicity, which is most probably affected by the conformational disorder of the fexofenadine compound, and yielded generally weak diffraction. Correspondingly, the crystallographic refinements were based on data sets containing a high percentage of weak reflections and they concluded in relatively high R values. Attempts to crystallize unsolvated fexofenadine were not successful.

S3. Refinement

Both compounds reveal structural disorder, which results in two posssible positions for the central O2—H group in each structure. In the refined structural models, the relative occupancies of these positions refined to 0.867 (5) (O2A) and 0.133 (5) (O2B) in (I), and 0.573 (5) (O2A) and O.427 (5) (O2B) in (II), while the bond lengths for C22—O2A and C22—O2B were restrained to be similar. In both structures, the methyl H atoms were constrained to an ideal geometry, with C—H = 0.98 Å and U_iso(H) = 1.5U_eq(C), but were allowed to rotate freely about the parent C—C bonds. All other H atoms bound to C atoms were placed in idealized positions and were constrained to ride on their parent atoms, with C—H distances in the range 0.95–0.99 Å and with U_iso(H) = 1.2U_eq(C). In (I), H atoms attached to N and O atoms (except for the minor O2B site) were located in difference Fourier maps and their parameters were refined freely (except for the H atom attached to O2A, which did not refine well and was fixed in its initial position). The H atom attached to atom O2B was fixed in an initially calculated position, with U_iso(H) = 1.2U_eq(O2B). In (II), only H atoms bound to atoms O1 and N1 were located in a difference Fourier map and their parameters were refined freely. The H atoms attached to the disordered O2A and O2B sites, as well as water H atoms, were placed in calculated positions by taking into account the most probable hydrogen-bonding interactions, as indicated by O···O intermolecular distances <3.0 Å. These H atoms did not refine well and were subsequently held fixed in their initial positions. The U_iso(H) parameters were refined for the water H atoms, while the H atoms on O2A and O2B were assigned U_iso(H) = 1.2U_eq(O).

Computing details

For both compounds, data collection: COLLECT (Nonius, 1999); cell refinement: DENZO (Otwinowski & Minor, 1997); data reduction: DENZO; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996) and Mercury (Bruno et al., 2002); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The molecular structure of (a) (I) and (b) (II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level at ca 110 K. Both of the disordered positions for atom O2 are shown (O2A and O2B). H atoms bound to N and O atoms are involved in the hydrogen bonding and are shown; all other H atoms have been omitted for clarity.
	Fig. 2. The hydrogen-bonding assembly mode in (I), showing the fexofenadine dimer solvated by four molecules of methanol. The dimer consists of molecules related by inversion at (1/2, 1/2, 1). Only the major disordered site (O2A) is shown. H atoms have been omitted for clarity, except for those attached to N and O atoms that are involved in the hydrogen bonding. Hydrogen bonds are denoted by dashed lines. [Symmetry code: (i) 1 − x, 1 − y, 2 − z.]
	Fig. 3. The hydrogen-bonding assembly mode in (II), showing the fexofenadine dimer solvated by molecules of water (shown as small spheres), and further hydrogen bonding of this dimer to neighbouring molecules through atoms O2 and O3 [only the major disordered site (O2A) is shown; see also Table 4]. The dimer consists of molecules related by inversion at (1, 0, 1/2). H atoms have been omitted for clarity, except for those attached to N and O atoms that are involved in the hydrogen bonding. Hydrogen bonds are denoted by dashed lines. The spheres marked with an asterisk (without H atoms attached to them) mark the O2A sites of two additional molecules of fexofenadine hydrogen-bonded to the carboxylate groups of the central dimer.
	Fig. 4. The crystal packing of (II), showing four fexofenadine dimers and the solvate water molecules (small spheres). Hydrogen bonds are denoted by dashed lines. H atoms have been omitted for clarity. The dimeric entities are distributed between two different continuously hydrogen-bonded layers formed in the crystal which are centered at x = 0.0 and x = 1.0. A t the interface between the layers (at x = 1/2), the diphenylmethyl embraces provide the stabilizing van der Waals interaction.

(I) (±)-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidinium-1-yl]- butyl}phenyl)-2-methylpropionate methanol disolvate

Crystal data

C32H39NO4·2CH4O	F(000) = 1224
Mr = 565.73	Dx = 1.225 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 6836 reflections
a = 20.8661 (3) Å	θ = 2.1–27.9°
b = 9.6138 (2) Å	µ = 0.08 mm^−1
c = 16.0702 (5) Å	T = 110 K
β = 107.8870 (8)°	Prism, colourless
V = 3067.90 (12) Å^3	0.30 × 0.25 × 0.25 mm
Z = 4

Data collection

Nonius KappaCCD area-detector diffractometer	4405 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.072
Graphite monochromator	θmax = 27.9°, θmin = 2.1°
Detector resolution: 56 microns pixels mm^-1	h = −27→25
0.8° ϕ and ω scans	k = −11→11
22588 measured reflections	l = −21→21
7172 independent 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)] = 0.064	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.168	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	w = 1/[σ^2(Fo^2) + (0.0734P)^2 + 1.5166P] where P = (Fo^2 + 2Fc^2)/3
7172 reflections	(Δ/σ)max = 0.007
396 parameters	Δρmax = 0.42 e Å^−3
3 restraints	Δρmin = −0.41 e Å^−3

Special details

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.

The O2 site reveals a slight disorder, with relative occupancies of 86.7 (5)% (O2A) and 13.3 (5)% (O2B).

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1	0.85065 (8)	0.25534 (16)	0.95396 (10)	0.0268 (4)
H1O	0.8327 (15)	0.202 (3)	0.989 (2)	0.049 (9)*
O2A	0.46297 (10)	0.06053 (17)	0.82889 (13)	0.0308 (6)	0.867 (5)
H2OA	0.5006	0.0873	0.8727	0.093 (16)*	0.867 (5)
O2B	0.4092 (6)	0.0485 (9)	0.7607 (8)	0.027 (4)*	0.133 (5)
H2OB	0.4287	0.0084	0.7189	0.032*	0.133 (5)
O3	0.36132 (8)	0.58642 (15)	1.11448 (10)	0.0287 (4)
O4	0.32270 (8)	0.70335 (15)	0.98886 (11)	0.0297 (4)
N1	0.63474 (9)	0.24557 (18)	0.74387 (13)	0.0215 (4)
H1N	0.6284 (13)	0.292 (3)	0.7906 (17)	0.032 (7)*
C1	0.93531 (12)	0.3742 (2)	0.88167 (17)	0.0315 (6)
H1	0.9292	0.4061	0.9347	0.038*
C2	0.97854 (14)	0.4452 (3)	0.84589 (19)	0.0399 (6)
H2	1.0021	0.5246	0.8750	0.048*
C3	0.98773 (14)	0.4015 (3)	0.76802 (19)	0.0407 (7)
H3	1.0172	0.4507	0.7436	0.049*
C4	0.95328 (13)	0.2852 (3)	0.72634 (18)	0.0370 (6)
H4	0.9589	0.2545	0.6728	0.044*
C5	0.91075 (12)	0.2135 (2)	0.76240 (16)	0.0312 (5)
H5	0.8878	0.1334	0.7334	0.037*
C6	0.90082 (11)	0.2564 (2)	0.84048 (15)	0.0255 (5)
C7	0.85197 (11)	0.1790 (2)	0.87858 (15)	0.0247 (5)
C8	0.87673 (12)	0.0295 (2)	0.90400 (15)	0.0258 (5)
C9	0.91272 (12)	−0.0023 (2)	0.99032 (16)	0.0303 (5)
H9	0.9234	0.0697	1.0329	0.036*
C10	0.93327 (13)	−0.1383 (3)	1.01516 (17)	0.0346 (6)
H10	0.9574	−0.1583	1.0744	0.042*
C11	0.91873 (13)	−0.2435 (3)	0.95417 (18)	0.0369 (6)
H11	0.9322	−0.3362	0.9714	0.044*
C12	0.88444 (14)	−0.2137 (3)	0.86785 (19)	0.0396 (6)
H12	0.8753	−0.2859	0.8254	0.048*
C13	0.86332 (13)	−0.0792 (2)	0.84290 (17)	0.0336 (6)
H13	0.8394	−0.0603	0.7834	0.040*
C14	0.78052 (11)	0.1794 (2)	0.81106 (15)	0.0229 (5)
H14	0.7832	0.1305	0.7573	0.027*
C15	0.72809 (11)	0.1041 (2)	0.84322 (15)	0.0252 (5)
H15A	0.7432	0.0075	0.8595	0.030*
H15B	0.7241	0.1514	0.8961	0.030*
C16	0.65971 (12)	0.1017 (2)	0.77358 (15)	0.0252 (5)
H16A	0.6630	0.0473	0.7227	0.030*
H16B	0.6268	0.0546	0.7972	0.030*
C17	0.68667 (11)	0.3260 (2)	0.71555 (15)	0.0244 (5)
H17A	0.6709	0.4230	0.7021	0.029*
H17B	0.6912	0.2840	0.6614	0.029*
C18	0.75475 (11)	0.3272 (2)	0.78479 (15)	0.0246 (5)
H18A	0.7513	0.3775	0.8370	0.029*
H18B	0.7874	0.3774	0.7622	0.029*
C19	0.57039 (11)	0.2413 (2)	0.66770 (15)	0.0242 (5)
H19A	0.5790	0.1892	0.6191	0.029*
H19B	0.5580	0.3376	0.6472	0.029*
C20	0.51128 (11)	0.1749 (2)	0.68867 (15)	0.0256 (5)
H20A	0.5260	0.0840	0.7171	0.031*
H20B	0.4753	0.1566	0.6331	0.031*
C21	0.48148 (12)	0.2607 (2)	0.74773 (16)	0.0257 (5)
H21A	0.5184	0.2952	0.7983	0.031*
H21B	0.4578	0.3424	0.7148	0.031*
C22	0.43287 (13)	0.1779 (2)	0.78063 (17)	0.0305 (6)
H22A	0.3979	0.1416	0.7275	0.037*	0.867 (5)
H22B	0.4685	0.1476	0.8349	0.037*	0.133 (5)
C23	0.39524 (12)	0.2615 (2)	0.83062 (15)	0.0266 (5)
C24	0.32577 (12)	0.2531 (2)	0.80871 (15)	0.0263 (5)
H24	0.3015	0.2000	0.7592	0.032*
C25	0.29084 (12)	0.3214 (2)	0.85814 (15)	0.0252 (5)
H25	0.2432	0.3133	0.8420	0.030*
C26	0.32455 (12)	0.4012 (2)	0.93066 (14)	0.0226 (5)
C27	0.39454 (12)	0.4119 (2)	0.95153 (15)	0.0251 (5)
H27	0.4187	0.4673	0.9999	0.030*
C28	0.42936 (12)	0.3430 (2)	0.90279 (15)	0.0271 (5)
H28	0.4770	0.3514	0.9186	0.033*
C29	0.28703 (12)	0.4647 (2)	0.98987 (14)	0.0247 (5)
C30	0.21488 (12)	0.5093 (2)	0.93878 (16)	0.0301 (5)
H30A	0.2162	0.5749	0.8926	0.045*
H30B	0.1939	0.5542	0.9787	0.045*
H30C	0.1885	0.4272	0.9125	0.045*
C31	0.28375 (14)	0.3543 (2)	1.05783 (16)	0.0327 (6)
H31A	0.2579	0.2739	1.0279	0.049*
H31B	0.2618	0.3939	1.0983	0.049*
H31C	0.3295	0.3247	1.0906	0.049*
C32	0.32692 (12)	0.5950 (2)	1.03564 (15)	0.0247 (5)
O5	0.79472 (10)	0.14643 (17)	1.07495 (12)	0.0337 (4)
H5O	0.7542 (17)	0.182 (3)	1.057 (2)	0.053 (10)*
C33	0.78843 (16)	0.0039 (3)	1.0927 (2)	0.0435 (7)
H33A	0.8305	−0.0292	1.1344	0.065*
H33B	0.7789	−0.0494	1.0383	0.065*
H33C	0.7515	−0.0084	1.1177	0.065*
O6	0.58651 (13)	0.1004 (2)	0.94094 (18)	0.0795 (9)
H6O	0.617 (2)	0.172 (4)	0.963 (2)	0.081 (12)*
C34	0.60201 (17)	−0.0223 (3)	0.98536 (19)	0.0505 (8)
H34A	0.6385	−0.0684	0.9695	0.076*
H34B	0.5622	−0.0825	0.9701	0.076*
H34C	0.6165	−0.0039	1.0484	0.076*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0324 (9)	0.0246 (8)	0.0239 (9)	0.0001 (7)	0.0093 (7)	−0.0022 (7)
O2A	0.0352 (13)	0.0173 (10)	0.0402 (13)	0.0025 (8)	0.0121 (10)	0.0027 (8)
O3	0.0353 (10)	0.0245 (8)	0.0248 (9)	0.0016 (7)	0.0071 (8)	−0.0030 (7)
O4	0.0383 (10)	0.0202 (8)	0.0292 (9)	−0.0012 (7)	0.0086 (8)	0.0027 (7)
N1	0.0231 (10)	0.0193 (9)	0.0235 (10)	0.0015 (7)	0.0092 (8)	−0.0013 (8)
C1	0.0328 (14)	0.0257 (12)	0.0354 (14)	0.0016 (10)	0.0097 (11)	0.0016 (10)
C2	0.0392 (16)	0.0292 (13)	0.0528 (18)	−0.0046 (11)	0.0166 (14)	−0.0002 (12)
C3	0.0398 (16)	0.0337 (14)	0.0551 (18)	0.0024 (11)	0.0243 (14)	0.0086 (13)
C4	0.0365 (15)	0.0413 (15)	0.0380 (15)	0.0060 (11)	0.0184 (13)	0.0035 (12)
C5	0.0284 (13)	0.0318 (13)	0.0332 (14)	0.0026 (10)	0.0093 (11)	−0.0011 (10)
C6	0.0237 (12)	0.0226 (11)	0.0298 (13)	0.0062 (9)	0.0075 (10)	0.0022 (9)
C7	0.0259 (12)	0.0236 (11)	0.0250 (12)	0.0024 (9)	0.0084 (10)	−0.0020 (9)
C8	0.0242 (12)	0.0236 (11)	0.0306 (13)	0.0020 (9)	0.0097 (10)	0.0002 (9)
C9	0.0288 (13)	0.0296 (12)	0.0320 (13)	0.0024 (10)	0.0087 (11)	−0.0014 (10)
C10	0.0348 (15)	0.0328 (13)	0.0350 (14)	0.0064 (10)	0.0088 (12)	0.0053 (11)
C11	0.0367 (15)	0.0257 (12)	0.0467 (16)	0.0083 (10)	0.0106 (13)	0.0039 (11)
C12	0.0424 (16)	0.0275 (13)	0.0445 (16)	0.0056 (11)	0.0069 (13)	−0.0078 (11)
C13	0.0350 (14)	0.0303 (13)	0.0324 (14)	0.0057 (10)	0.0059 (12)	−0.0030 (10)
C14	0.0254 (12)	0.0204 (11)	0.0240 (12)	0.0014 (8)	0.0093 (10)	0.0004 (9)
C15	0.0283 (13)	0.0209 (11)	0.0261 (12)	0.0031 (9)	0.0077 (10)	0.0021 (9)
C16	0.0298 (13)	0.0165 (10)	0.0290 (13)	−0.0001 (8)	0.0087 (10)	0.0004 (9)
C17	0.0275 (13)	0.0203 (11)	0.0276 (12)	0.0020 (9)	0.0117 (10)	0.0036 (9)
C18	0.0260 (12)	0.0203 (11)	0.0291 (12)	0.0011 (9)	0.0110 (10)	0.0021 (9)
C19	0.0251 (12)	0.0230 (11)	0.0242 (12)	0.0028 (9)	0.0072 (10)	−0.0018 (9)
C20	0.0243 (12)	0.0234 (11)	0.0287 (13)	−0.0001 (9)	0.0075 (10)	−0.0041 (9)
C21	0.0285 (13)	0.0210 (11)	0.0286 (12)	0.0022 (9)	0.0104 (10)	−0.0017 (9)
C22	0.0356 (14)	0.0209 (11)	0.0391 (15)	−0.0004 (9)	0.0174 (12)	−0.0019 (10)
C23	0.0366 (14)	0.0175 (11)	0.0292 (13)	−0.0014 (9)	0.0152 (11)	0.0001 (9)
C24	0.0343 (14)	0.0195 (11)	0.0274 (12)	−0.0030 (9)	0.0129 (11)	−0.0028 (9)
C25	0.0273 (12)	0.0238 (11)	0.0255 (12)	−0.0002 (9)	0.0095 (10)	0.0003 (9)
C26	0.0317 (13)	0.0166 (10)	0.0202 (11)	0.0031 (8)	0.0091 (10)	0.0028 (8)
C27	0.0318 (13)	0.0212 (11)	0.0214 (12)	−0.0001 (9)	0.0070 (10)	−0.0003 (9)
C28	0.0269 (13)	0.0221 (11)	0.0320 (13)	−0.0005 (9)	0.0084 (11)	0.0009 (10)
C29	0.0330 (13)	0.0203 (11)	0.0223 (12)	−0.0002 (9)	0.0105 (10)	−0.0012 (9)
C30	0.0318 (14)	0.0286 (12)	0.0312 (13)	0.0002 (10)	0.0114 (11)	−0.0048 (10)
C31	0.0487 (16)	0.0233 (12)	0.0295 (13)	−0.0064 (10)	0.0171 (12)	−0.0015 (10)
C32	0.0277 (13)	0.0231 (11)	0.0258 (13)	0.0015 (9)	0.0118 (10)	−0.0028 (9)
O5	0.0389 (11)	0.0283 (9)	0.0359 (10)	0.0028 (8)	0.0144 (9)	0.0037 (7)
C33	0.0615 (19)	0.0275 (13)	0.0516 (17)	0.0007 (12)	0.0323 (15)	0.0006 (12)
O6	0.0642 (16)	0.0480 (13)	0.0881 (19)	−0.0280 (11)	−0.0328 (14)	0.0360 (13)
C34	0.071 (2)	0.0282 (14)	0.0420 (17)	−0.0044 (13)	0.0019 (15)	0.0015 (12)

Geometric parameters (Å, º)

O1—C7	1.424 (3)	C17—H17A	0.9900
O1—H1O	0.93 (3)	C17—H17B	0.9900
O2A—C22	1.404 (3)	C18—H18A	0.9900
O2A—H2OA	0.9161	C18—H18B	0.9900
O2B—C22	1.340 (8)	C19—C20	1.516 (3)
O2B—H2OB	0.9660	C19—H19A	0.9900
O3—C32	1.253 (3)	C19—H19B	0.9900
O4—C32	1.272 (3)	C20—C21	1.526 (3)
N1—C16	1.504 (3)	C20—H20A	0.9900
N1—C17	1.511 (3)	C20—H20B	0.9900
N1—C19	1.514 (3)	C21—C22	1.507 (3)
N1—H1N	0.92 (3)	C21—H21A	0.9900
C1—C2	1.389 (4)	C21—H21B	0.9900
C1—C6	1.395 (3)	C22—C23	1.515 (3)
C1—H1	0.9500	C22—H22A	1.0000
C2—C3	1.388 (4)	C22—H22B	1.0000
C2—H2	0.9500	C23—C24	1.385 (3)
C3—C4	1.386 (4)	C23—C28	1.400 (3)
C3—H3	0.9500	C24—C25	1.396 (3)
C4—C5	1.383 (4)	C24—H24	0.9500
C4—H4	0.9500	C25—C26	1.392 (3)
C5—C6	1.395 (3)	C25—H25	0.9500
C5—H5	0.9500	C26—C27	1.398 (3)
C6—C7	1.533 (3)	C26—C29	1.533 (3)
C7—C8	1.539 (3)	C27—C28	1.389 (3)
C7—C14	1.551 (3)	C27—H27	0.9500
C8—C9	1.393 (3)	C28—H28	0.9500
C8—C13	1.402 (3)	C29—C30	1.538 (3)
C9—C10	1.395 (3)	C29—C31	1.540 (3)
C9—H9	0.9500	C29—C32	1.558 (3)
C10—C11	1.376 (4)	C30—H30A	0.9800
C10—H10	0.9500	C30—H30B	0.9800
C11—C12	1.381 (4)	C30—H30C	0.9800
C11—H11	0.9500	C31—H31A	0.9800
C12—C13	1.385 (3)	C31—H31B	0.9800
C12—H12	0.9500	C31—H31C	0.9800
C13—H13	0.9500	O5—C33	1.414 (3)
C14—C15	1.528 (3)	O5—H5O	0.88 (3)
C14—C18	1.532 (3)	C33—H33A	0.9800
C14—H14	1.0000	C33—H33B	0.9800
C15—C16	1.519 (3)	C33—H33C	0.9800
C15—H15A	0.9900	O6—C34	1.365 (3)
C15—H15B	0.9900	O6—H6O	0.93 (4)
C16—H16A	0.9900	C34—H34A	0.9800
C16—H16B	0.9900	C34—H34B	0.9800
C17—C18	1.512 (3)	C34—H34C	0.9800
C7—O1—H1O	110.7 (18)	N1—C19—H19A	108.7
C22—O2A—H2OA	109.3	C20—C19—H19A	108.7
C22—O2B—H2OB	109.5	N1—C19—H19B	108.7
C16—N1—C17	110.85 (17)	C20—C19—H19B	108.7
C16—N1—C19	111.50 (16)	H19A—C19—H19B	107.6
C17—N1—C19	108.08 (17)	C19—C20—C21	115.18 (18)
C16—N1—H1N	108.1 (16)	C19—C20—H20A	108.5
C17—N1—H1N	107.1 (16)	C21—C20—H20A	108.5
C19—N1—H1N	111.1 (16)	C19—C20—H20B	108.5
C2—C1—C6	120.6 (2)	C21—C20—H20B	108.5
C2—C1—H1	119.7	H20A—C20—H20B	107.5
C6—C1—H1	119.7	C22—C21—C20	112.31 (18)
C1—C2—C3	120.8 (2)	C22—C21—H21A	109.1
C1—C2—H2	119.6	C20—C21—H21A	109.1
C3—C2—H2	119.6	C22—C21—H21B	109.1
C4—C3—C2	119.0 (2)	C20—C21—H21B	109.1
C4—C3—H3	120.5	H21A—C21—H21B	107.9
C2—C3—H3	120.5	O2B—C22—C21	130.1 (5)
C5—C4—C3	120.2 (2)	O2A—C22—C21	112.5 (2)
C5—C4—H4	119.9	O2B—C22—C23	114.0 (5)
C3—C4—H4	119.9	O2A—C22—C23	110.5 (2)
C4—C5—C6	121.4 (2)	C21—C22—C23	114.86 (18)
C4—C5—H5	119.3	O2A—C22—H22A	106.1
C6—C5—H5	119.3	C21—C22—H22A	106.1
C1—C6—C5	118.0 (2)	C23—C22—H22A	106.1
C1—C6—C7	120.9 (2)	O2B—C22—H22B	93.4
C5—C6—C7	121.1 (2)	C21—C22—H22B	93.4
O1—C7—C6	106.17 (18)	C23—C22—H22B	93.4
O1—C7—C8	110.37 (18)	C24—C23—C28	118.0 (2)
C6—C7—C8	110.42 (18)	C24—C23—C22	120.5 (2)
O1—C7—C14	109.16 (17)	C28—C23—C22	121.5 (2)
C6—C7—C14	109.48 (18)	C23—C24—C25	121.1 (2)
C8—C7—C14	111.11 (18)	C23—C24—H24	119.5
C9—C8—C13	117.6 (2)	C25—C24—H24	119.5
C9—C8—C7	120.2 (2)	C26—C25—C24	121.2 (2)
C13—C8—C7	122.1 (2)	C26—C25—H25	119.4
C8—C9—C10	121.0 (2)	C24—C25—H25	119.4
C8—C9—H9	119.5	C25—C26—C27	117.6 (2)
C10—C9—H9	119.5	C25—C26—C29	121.1 (2)
C11—C10—C9	120.3 (2)	C27—C26—C29	121.12 (19)
C11—C10—H10	119.9	C28—C27—C26	121.2 (2)
C9—C10—H10	119.9	C28—C27—H27	119.4
C10—C11—C12	119.7 (2)	C26—C27—H27	119.4
C10—C11—H11	120.1	C27—C28—C23	120.9 (2)
C12—C11—H11	120.1	C27—C28—H28	119.6
C11—C12—C13	120.3 (2)	C23—C28—H28	119.6
C11—C12—H12	119.9	C26—C29—C30	112.49 (18)
C13—C12—H12	119.9	C26—C29—C31	107.94 (18)
C12—C13—C8	121.1 (2)	C30—C29—C31	108.8 (2)
C12—C13—H13	119.5	C26—C29—C32	108.22 (18)
C8—C13—H13	119.5	C30—C29—C32	108.76 (18)
C15—C14—C18	107.78 (18)	C31—C29—C32	110.70 (18)
C15—C14—C7	113.36 (18)	C29—C30—H30A	109.5
C18—C14—C7	112.06 (18)	C29—C30—H30B	109.5
C15—C14—H14	107.8	H30A—C30—H30B	109.5
C18—C14—H14	107.8	C29—C30—H30C	109.5
C7—C14—H14	107.8	H30A—C30—H30C	109.5
C16—C15—C14	111.48 (18)	H30B—C30—H30C	109.5
C16—C15—H15A	109.3	C29—C31—H31A	109.5
C14—C15—H15A	109.3	C29—C31—H31B	109.5
C16—C15—H15B	109.3	H31A—C31—H31B	109.5
C14—C15—H15B	109.3	C29—C31—H31C	109.5
H15A—C15—H15B	108.0	H31A—C31—H31C	109.5
N1—C16—C15	112.04 (17)	H31B—C31—H31C	109.5
N1—C16—H16A	109.2	O3—C32—O4	124.5 (2)
C15—C16—H16A	109.2	O3—C32—C29	118.79 (19)
N1—C16—H16B	109.2	O4—C32—C29	116.7 (2)
C15—C16—H16B	109.2	C33—O5—H5O	108 (2)
H16A—C16—H16B	107.9	O5—C33—H33A	109.5
N1—C17—C18	112.39 (18)	O5—C33—H33B	109.5
N1—C17—H17A	109.1	H33A—C33—H33B	109.5
C18—C17—H17A	109.1	O5—C33—H33C	109.5
N1—C17—H17B	109.1	H33A—C33—H33C	109.5
C18—C17—H17B	109.1	H33B—C33—H33C	109.5
H17A—C17—H17B	107.9	C34—O6—H6O	114 (2)
C17—C18—C14	111.53 (18)	O6—C34—H34A	109.5
C17—C18—H18A	109.3	O6—C34—H34B	109.5
C14—C18—H18A	109.3	H34A—C34—H34B	109.5
C17—C18—H18B	109.3	O6—C34—H34C	109.5
C14—C18—H18B	109.3	H34A—C34—H34C	109.5
H18A—C18—H18B	108.0	H34B—C34—H34C	109.5
N1—C19—C20	114.31 (18)
C6—C1—C2—C3	0.7 (4)	C19—N1—C17—C18	−175.62 (17)
C1—C2—C3—C4	−0.3 (4)	N1—C17—C18—C14	56.6 (2)
C2—C3—C4—C5	−0.4 (4)	C15—C14—C18—C17	−57.6 (2)
C3—C4—C5—C6	0.6 (4)	C7—C14—C18—C17	177.05 (18)
C2—C1—C6—C5	−0.5 (3)	C16—N1—C19—C20	63.2 (2)
C2—C1—C6—C7	−178.8 (2)	C17—N1—C19—C20	−174.76 (17)
C4—C5—C6—C1	−0.1 (3)	N1—C19—C20—C21	71.4 (2)
C4—C5—C6—C7	178.1 (2)	C19—C20—C21—C22	−168.4 (2)
C1—C6—C7—O1	2.2 (3)	C20—C21—C22—O2B	−5.6 (7)
C5—C6—C7—O1	−176.0 (2)	C20—C21—C22—O2A	59.4 (3)
C1—C6—C7—C8	−117.4 (2)	C20—C21—C22—C23	−173.0 (2)
C5—C6—C7—C8	64.3 (3)	O2B—C22—C23—C24	−40.4 (6)
C1—C6—C7—C14	119.9 (2)	O2A—C22—C23—C24	−102.3 (3)
C5—C6—C7—C14	−58.3 (3)	C21—C22—C23—C24	129.1 (2)
O1—C7—C8—C9	−19.5 (3)	O2B—C22—C23—C28	136.2 (6)
C6—C7—C8—C9	97.6 (3)	O2A—C22—C23—C28	74.2 (3)
C14—C7—C8—C9	−140.7 (2)	C21—C22—C23—C28	−54.4 (3)
O1—C7—C8—C13	159.4 (2)	C28—C23—C24—C25	−1.4 (3)
C6—C7—C8—C13	−83.6 (3)	C22—C23—C24—C25	175.3 (2)
C14—C7—C8—C13	38.1 (3)	C23—C24—C25—C26	0.6 (3)
C13—C8—C9—C10	−1.4 (4)	C24—C25—C26—C27	0.8 (3)
C7—C8—C9—C10	177.5 (2)	C24—C25—C26—C29	−174.15 (19)
C8—C9—C10—C11	0.6 (4)	C25—C26—C27—C28	−1.3 (3)
C9—C10—C11—C12	0.9 (4)	C29—C26—C27—C28	173.6 (2)
C10—C11—C12—C13	−1.5 (4)	C26—C27—C28—C23	0.5 (3)
C11—C12—C13—C8	0.7 (4)	C24—C23—C28—C27	0.9 (3)
C9—C8—C13—C12	0.8 (4)	C22—C23—C28—C27	−175.7 (2)
C7—C8—C13—C12	−178.1 (2)	C25—C26—C29—C30	−34.6 (3)
O1—C7—C14—C15	−64.3 (2)	C27—C26—C29—C30	150.6 (2)
C6—C7—C14—C15	179.91 (17)	C25—C26—C29—C31	85.3 (2)
C8—C7—C14—C15	57.7 (2)	C27—C26—C29—C31	−89.4 (2)
O1—C7—C14—C18	58.0 (2)	C25—C26—C29—C32	−154.8 (2)
C6—C7—C14—C18	−57.8 (2)	C27—C26—C29—C32	30.4 (3)
C8—C7—C14—C18	179.96 (19)	C26—C29—C32—O3	−104.5 (2)
C18—C14—C15—C16	57.9 (2)	C30—C29—C32—O3	133.1 (2)
C7—C14—C15—C16	−177.52 (17)	C31—C29—C32—O3	13.6 (3)
C17—N1—C16—C15	53.3 (2)	C26—C29—C32—O4	74.6 (2)
C19—N1—C16—C15	173.75 (18)	C30—C29—C32—O4	−47.9 (3)
C14—C15—C16—N1	−57.3 (2)	C31—C29—C32—O4	−167.3 (2)
C16—N1—C17—C18	−53.2 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O5	0.93 (3)	1.86 (3)	2.763 (2)	163 (3)
O2A—H2OA···O6	0.92	1.80	2.680 (3)	162
N1—H1N···O3^i	0.92 (3)	1.88 (3)	2.772 (2)	163 (2)
O5—H5O···O4^i	0.88 (3)	1.90 (3)	2.756 (3)	166 (3)
O6—H6O···O4^i	0.93 (4)	1.74 (4)	2.666 (3)	175 (4)

Symmetry code: (i) −x+1, −y+1, −z+2.

(II) (±)-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidinium-1-yl]- butyl}phenyl)-2-methylpropionate dihydrate

Crystal data

C32H39NO4·2H2O	F(000) = 1160
Mr = 537.67	Dx = 1.231 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 5703 reflections
a = 23.8180 (9) Å	θ = 2.2–27.9°
b = 9.8444 (3) Å	µ = 0.08 mm^−1
c = 12.3959 (4) Å	T = 110 K
β = 93.1770 (12)°	Chunk, colourless
V = 2902.05 (17) Å^3	0.25 × 0.15 × 0.15 mm
Z = 4

Data collection

Nonius KappaCCD area-detector diffractometer	3243 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.082
Graphite monochromator	θmax = 27.9°, θmin = 2.2°
Detector resolution: 56 microns pixels mm^-1	h = −31→31
0.4° ϕ scans	k = −12→12
19430 measured reflections	l = −15→16
6860 independent 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)] = 0.073	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.214	H atoms treated by a mixture of independent and constrained refinement
S = 0.99	w = 1/[σ^2(Fo^2) + (0.0992P)^2 + 0.8167P] where P = (Fo^2 + 2Fc^2)/3
6860 reflections	(Δ/σ)max = 0.004
373 parameters	Δρmax = 0.37 e Å^−3
0 restraints	Δρmin = −0.26 e Å^−3

Special details

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.

The OH₂ group is disordered between two sites with relative occupancies of 57.3 (5)% and 42.7 (5)%.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1	0.65682 (9)	0.2288 (2)	0.02468 (16)	0.0358 (5)
H1O	0.6791 (19)	0.160 (5)	0.032 (4)	0.091 (16)*
O2A	0.88893 (11)	0.2721 (3)	0.6076 (2)	0.0343 (11)	0.573 (5)
H2OA	0.8707	0.3534	0.6147	0.041*	0.573 (5)
O2B	0.91596 (11)	0.3884 (3)	0.5251 (2)	0.0362 (16)	0.427 (5)
H2OB	0.8915	0.4224	0.5638	0.043*	0.427 (5)
O3	1.16757 (8)	0.0061 (2)	0.84173 (15)	0.0344 (5)
O4	1.20251 (9)	0.1383 (2)	0.71789 (18)	0.0450 (6)
N1	0.79394 (10)	0.1641 (3)	0.3159 (2)	0.0318 (6)
H1N	0.8050 (13)	0.105 (3)	0.259 (2)	0.042 (9)*
C1	0.65377 (12)	0.5546 (3)	0.1509 (3)	0.0378 (8)
H1	0.6760	0.5394	0.2158	0.045*
C2	0.64212 (14)	0.6877 (4)	0.1168 (3)	0.0492 (9)
H2	0.6570	0.7621	0.1579	0.059*
C3	0.60912 (15)	0.7114 (4)	0.0239 (3)	0.0528 (10)
H3	0.6012	0.8019	0.0009	0.063*
C4	0.58752 (16)	0.6026 (4)	−0.0358 (3)	0.0554 (10)
H4	0.5644	0.6186	−0.0995	0.066*
C5	0.59940 (14)	0.4710 (3)	−0.0034 (2)	0.0428 (8)
H5	0.5845	0.3974	−0.0454	0.051*
C6	0.63311 (12)	0.4444 (3)	0.0907 (2)	0.0330 (7)
C7	0.64265 (12)	0.2945 (3)	0.1219 (2)	0.0314 (7)
C8	0.58692 (12)	0.2385 (3)	0.1602 (2)	0.0317 (7)
C9	0.56465 (12)	0.2871 (3)	0.2546 (2)	0.0374 (7)
H9	0.5839	0.3569	0.2946	0.045*
C10	0.51540 (13)	0.2356 (3)	0.2910 (3)	0.0412 (8)
H10	0.5013	0.2694	0.3560	0.049*
C11	0.48643 (14)	0.1352 (4)	0.2336 (3)	0.0466 (9)
H11	0.4525	0.0993	0.2587	0.056*
C12	0.50754 (14)	0.0877 (3)	0.1392 (3)	0.0468 (9)
H12	0.4876	0.0196	0.0984	0.056*
C13	0.55758 (13)	0.1383 (3)	0.1031 (2)	0.0391 (8)
H13	0.5718	0.1037	0.0384	0.047*
C14	0.68940 (12)	0.2750 (3)	0.2127 (2)	0.0308 (7)
H14	0.6809	0.3378	0.2731	0.037*
C15	0.69294 (12)	0.1314 (3)	0.2592 (2)	0.0314 (7)
H15A	0.6559	0.1050	0.2849	0.038*
H15B	0.7026	0.0669	0.2018	0.038*
C16	0.73690 (11)	0.1232 (3)	0.3519 (2)	0.0324 (7)
H16A	0.7261	0.1838	0.4110	0.039*
H16B	0.7387	0.0291	0.3802	0.039*
C17	0.79194 (12)	0.3052 (3)	0.2688 (2)	0.0323 (7)
H17A	0.7828	0.3713	0.3254	0.039*
H17B	0.8292	0.3291	0.2428	0.039*
C18	0.74792 (11)	0.3125 (3)	0.1759 (2)	0.0306 (7)
H18A	0.7583	0.2496	0.1179	0.037*
H18B	0.7469	0.4057	0.1458	0.037*
C19	0.83689 (12)	0.1528 (3)	0.4088 (2)	0.0354 (7)
H19A	0.8343	0.0614	0.4414	0.042*
H19B	0.8281	0.2204	0.4646	0.042*
C20	0.89674 (12)	0.1756 (3)	0.3759 (2)	0.0390 (8)
H20A	0.8995	0.2676	0.3444	0.047*
H20B	0.9052	0.1091	0.3192	0.047*
C21	0.94075 (12)	0.1620 (3)	0.4697 (2)	0.0369 (7)
H21A	0.9369	0.0711	0.5027	0.044*
H21B	0.9786	0.1668	0.4407	0.044*
C22	0.93695 (13)	0.2682 (3)	0.5570 (3)	0.0396 (8)
H22A	0.9384	0.3570	0.5181	0.048*	0.573 (5)
H22B	0.9071	0.2312	0.6024	0.048*	0.427 (5)
C23	0.98852 (12)	0.2681 (3)	0.6337 (2)	0.0337 (7)
C24	0.99955 (12)	0.1579 (3)	0.7028 (2)	0.0361 (7)
H24	0.9734	0.0850	0.7036	0.043*
C25	1.04759 (12)	0.1533 (3)	0.7696 (2)	0.0359 (7)
H25	1.0535	0.0781	0.8170	0.043*
C26	1.08800 (12)	0.2566 (3)	0.7695 (2)	0.0296 (7)
C27	1.07671 (12)	0.3661 (3)	0.7012 (2)	0.0340 (7)
H27	1.1029	0.4388	0.6999	0.041*
C28	1.02776 (12)	0.3714 (3)	0.6346 (2)	0.0352 (7)
H28	1.0212	0.4477	0.5888	0.042*
C29	1.14214 (12)	0.2461 (3)	0.8419 (2)	0.0311 (7)
C30	1.17967 (13)	0.3709 (3)	0.8371 (3)	0.0385 (8)
H30A	1.1904	0.3847	0.7627	0.058*
H30B	1.2135	0.3575	0.8845	0.058*
H30C	1.1592	0.4508	0.8610	0.058*
C31	1.12794 (13)	0.2225 (3)	0.9597 (2)	0.0380 (8)
H31A	1.1054	0.2987	0.9843	0.057*
H31B	1.1628	0.2159	1.0052	0.057*
H31C	1.1065	0.1380	0.9649	0.057*
C32	1.17373 (12)	0.1222 (3)	0.7971 (2)	0.0319 (7)
O5	0.74115 (10)	0.4684 (2)	0.50036 (18)	0.0526 (7)
H5AO	0.7737	0.4981	0.5495	0.111 (17)*
H5BO	0.7313	0.5502	0.4605	0.079 (13)*
O6	0.72081 (11)	0.7041 (3)	0.3815 (2)	0.0588 (7)
H6AO	0.6915	0.7708	0.4018	0.050 (10)*
H6BO	0.7489	0.7508	0.3447	0.082 (14)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0350 (12)	0.0400 (13)	0.0329 (11)	0.0044 (10)	0.0049 (9)	−0.0045 (10)
O2A	0.029 (2)	0.037 (2)	0.037 (2)	0.0024 (15)	0.0073 (16)	−0.0017 (17)
O2B	0.036 (3)	0.027 (3)	0.045 (3)	0.008 (2)	0.005 (2)	0.006 (2)
O3	0.0379 (12)	0.0283 (12)	0.0369 (11)	0.0006 (9)	0.0014 (9)	0.0034 (10)
O4	0.0487 (14)	0.0385 (13)	0.0496 (13)	0.0044 (10)	0.0203 (11)	0.0018 (11)
N1	0.0295 (14)	0.0326 (15)	0.0334 (14)	0.0025 (11)	0.0034 (11)	0.0019 (12)
C1	0.0303 (17)	0.0354 (19)	0.0477 (19)	0.0018 (13)	0.0030 (14)	0.0037 (16)
C2	0.045 (2)	0.038 (2)	0.065 (2)	−0.0011 (16)	0.0044 (18)	−0.0001 (18)
C3	0.054 (2)	0.035 (2)	0.070 (3)	0.0099 (17)	0.009 (2)	0.0139 (19)
C4	0.059 (2)	0.055 (2)	0.052 (2)	0.0065 (19)	−0.0026 (18)	0.0117 (19)
C5	0.047 (2)	0.042 (2)	0.0395 (18)	0.0032 (15)	−0.0010 (16)	0.0060 (16)
C6	0.0296 (16)	0.0326 (18)	0.0376 (17)	−0.0018 (13)	0.0085 (13)	0.0020 (14)
C7	0.0301 (16)	0.0324 (17)	0.0323 (16)	0.0011 (12)	0.0050 (13)	0.0002 (14)
C8	0.0294 (16)	0.0293 (17)	0.0363 (16)	0.0025 (12)	0.0019 (13)	0.0032 (14)
C9	0.0308 (17)	0.0346 (18)	0.0469 (19)	−0.0048 (13)	0.0045 (14)	−0.0040 (15)
C10	0.0377 (18)	0.044 (2)	0.0425 (18)	−0.0020 (15)	0.0088 (15)	0.0032 (16)
C11	0.0351 (19)	0.048 (2)	0.057 (2)	−0.0090 (16)	0.0107 (16)	0.0048 (18)
C12	0.047 (2)	0.048 (2)	0.045 (2)	−0.0181 (16)	0.0026 (16)	0.0000 (17)
C13	0.0355 (18)	0.045 (2)	0.0374 (17)	−0.0043 (15)	0.0036 (14)	−0.0014 (15)
C14	0.0269 (15)	0.0330 (17)	0.0328 (15)	0.0005 (12)	0.0048 (12)	0.0015 (14)
C15	0.0300 (16)	0.0341 (17)	0.0306 (15)	−0.0007 (13)	0.0051 (12)	0.0012 (14)
C16	0.0285 (16)	0.0356 (17)	0.0333 (16)	0.0006 (13)	0.0042 (13)	0.0032 (14)
C17	0.0289 (16)	0.0279 (17)	0.0401 (17)	0.0011 (12)	0.0038 (13)	0.0000 (14)
C18	0.0303 (16)	0.0284 (16)	0.0335 (16)	−0.0007 (12)	0.0045 (13)	0.0023 (13)
C19	0.0346 (17)	0.0407 (19)	0.0307 (16)	0.0004 (14)	0.0007 (13)	0.0000 (14)
C20	0.0333 (17)	0.049 (2)	0.0342 (17)	0.0056 (14)	0.0009 (14)	−0.0103 (15)
C21	0.0289 (16)	0.0418 (19)	0.0398 (17)	0.0057 (13)	0.0012 (13)	−0.0040 (15)
C22	0.0405 (19)	0.0389 (19)	0.0387 (17)	0.0122 (15)	−0.0040 (15)	−0.0045 (15)
C23	0.0334 (17)	0.0364 (18)	0.0311 (16)	0.0097 (14)	−0.0013 (13)	−0.0054 (14)
C24	0.0316 (17)	0.0364 (19)	0.0401 (17)	−0.0023 (13)	−0.0001 (14)	0.0001 (15)
C25	0.0343 (17)	0.0352 (18)	0.0381 (17)	0.0011 (14)	0.0014 (14)	0.0040 (14)
C26	0.0285 (16)	0.0300 (17)	0.0307 (15)	0.0029 (12)	0.0045 (12)	−0.0013 (13)
C27	0.0373 (17)	0.0300 (17)	0.0349 (17)	−0.0004 (13)	0.0044 (14)	−0.0020 (14)
C28	0.0399 (18)	0.0298 (17)	0.0360 (17)	0.0073 (14)	0.0029 (14)	0.0005 (14)
C29	0.0318 (16)	0.0294 (17)	0.0320 (16)	−0.0018 (12)	0.0019 (13)	−0.0007 (13)
C30	0.0391 (18)	0.0292 (17)	0.0471 (19)	−0.0027 (14)	0.0005 (15)	−0.0015 (15)
C31	0.0391 (18)	0.0398 (19)	0.0350 (17)	0.0028 (14)	0.0015 (14)	−0.0015 (15)
C32	0.0294 (16)	0.0300 (17)	0.0362 (17)	−0.0028 (13)	0.0005 (13)	0.0019 (15)
O5	0.0608 (16)	0.0490 (16)	0.0475 (14)	−0.0143 (12)	−0.0026 (12)	0.0065 (12)
O6	0.0543 (16)	0.0555 (16)	0.0679 (16)	−0.0027 (13)	0.0143 (13)	0.0132 (14)

Geometric parameters (Å, º)

O1—C7	1.425 (3)	C16—H16A	0.9900
O1—H1O	0.86 (5)	C16—H16B	0.9900
O2A—C22	1.335 (4)	C17—C18	1.516 (4)
O2A—H2OA	0.9167	C17—H17A	0.9900
O2B—C22	1.335 (4)	C17—H17B	0.9900
O2B—H2OB	0.8445	C18—H18A	0.9900
O3—C32	1.282 (3)	C18—H18B	0.9900
O4—C32	1.239 (3)	C19—C20	1.521 (4)
N1—C16	1.508 (4)	C19—H19A	0.9900
N1—C19	1.501 (4)	C19—H19B	0.9900
N1—C17	1.506 (4)	C20—C21	1.528 (4)
N1—H1N	0.96 (3)	C20—H20A	0.9900
C1—C6	1.391 (4)	C20—H20B	0.9900
C1—C2	1.400 (4)	C21—C22	1.511 (4)
C1—H1	0.9500	C21—H21A	0.9900
C2—C3	1.378 (5)	C21—H21B	0.9900
C2—H2	0.9500	C22—C23	1.511 (4)
C3—C4	1.385 (5)	C22—H22A	1.0000
C3—H3	0.9500	C22—H22B	1.0000
C4—C5	1.381 (5)	C23—C28	1.381 (4)
C4—H4	0.9500	C23—C24	1.398 (4)
C5—C6	1.404 (4)	C24—C25	1.376 (4)
C5—H5	0.9500	C24—H24	0.9500
C6—C7	1.539 (4)	C25—C26	1.401 (4)
C7—C8	1.536 (4)	C25—H25	0.9500
C7—C14	1.550 (4)	C26—C27	1.387 (4)
C8—C13	1.382 (4)	C26—C29	1.533 (4)
C8—C9	1.396 (4)	C27—C28	1.392 (4)
C9—C10	1.376 (4)	C27—H27	0.9500
C9—H9	0.9500	C28—H28	0.9500
C10—C11	1.381 (5)	C29—C30	1.523 (4)
C10—H10	0.9500	C29—C31	1.535 (4)
C11—C12	1.381 (5)	C29—C32	1.552 (4)
C11—H11	0.9500	C30—H30A	0.9800
C12—C13	1.389 (4)	C30—H30B	0.9800
C12—H12	0.9500	C30—H30C	0.9800
C13—H13	0.9500	C31—H31A	0.9800
C14—C15	1.527 (4)	C31—H31B	0.9800
C14—C18	1.536 (4)	C31—H31C	0.9800
C14—H14	1.0000	O5—H5AO	1.0021
C15—C16	1.514 (4)	O5—H5BO	0.9672
C15—H15A	0.9900	O6—H6AO	1.0011
C15—H15B	0.9900	O6—H6BO	0.9502
C7—O1—H1O	117 (3)	C17—C18—H18A	109.4
C22—O2A—H2OA	119.5	C14—C18—H18A	109.4
C22—O2B—H2OB	116.2	C17—C18—H18B	109.4
C16—N1—C19	109.9 (2)	C14—C18—H18B	109.4
C16—N1—C17	110.6 (2)	H18A—C18—H18B	108.0
C19—N1—C17	111.8 (2)	N1—C19—C20	113.1 (2)
C16—N1—H1N	110.1 (18)	N1—C19—H19A	109.0
C19—N1—H1N	108.4 (18)	C20—C19—H19A	109.0
C17—N1—H1N	106.1 (18)	N1—C19—H19B	109.0
C6—C1—C2	120.7 (3)	C20—C19—H19B	109.0
C6—C1—H1	119.7	H19A—C19—H19B	107.8
C2—C1—H1	119.7	C19—C20—C21	113.4 (2)
C3—C2—C1	120.4 (3)	C19—C20—H20A	108.9
C3—C2—H2	119.8	C21—C20—H20A	108.9
C1—C2—H2	119.8	C19—C20—H20B	108.9
C2—C3—C4	119.6 (3)	C21—C20—H20B	108.9
C2—C3—H3	120.2	H20A—C20—H20B	107.7
C4—C3—H3	120.2	C22—C21—C20	114.7 (3)
C5—C4—C3	120.4 (3)	C22—C21—H21A	108.6
C5—C4—H4	119.8	C20—C21—H21A	108.6
C3—C4—H4	119.8	C22—C21—H21B	108.6
C4—C5—C6	121.0 (3)	C20—C21—H21B	108.6
C4—C5—H5	119.5	H21A—C21—H21B	107.6
C6—C5—H5	119.5	O2A—C22—C21	116.3 (3)
C1—C6—C5	118.0 (3)	O2B—C22—C21	115.9 (3)
C1—C6—C7	124.7 (3)	O2A—C22—C23	113.1 (3)
C5—C6—C7	117.2 (3)	O2B—C22—C23	117.7 (3)
O1—C7—C6	105.1 (2)	C21—C22—C23	111.8 (2)
O1—C7—C8	110.4 (2)	O2A—C22—H22A	104.8
C6—C7—C8	107.7 (2)	C21—C22—H22A	104.8
O1—C7—C14	111.3 (2)	C23—C22—H22A	104.8
C6—C7—C14	113.0 (2)	O2B—C22—H22B	102.9
C8—C7—C14	109.2 (2)	C21—C22—H22B	102.9
C13—C8—C9	118.0 (3)	C23—C22—H22B	102.9
C13—C8—C7	121.3 (3)	C28—C23—C24	117.5 (3)
C9—C8—C7	120.7 (3)	C28—C23—C22	122.0 (3)
C10—C9—C8	121.3 (3)	C24—C23—C22	120.3 (3)
C10—C9—H9	119.4	C25—C24—C23	121.1 (3)
C8—C9—H9	119.4	C25—C24—H24	119.5
C9—C10—C11	120.4 (3)	C23—C24—H24	119.5
C9—C10—H10	119.8	C24—C25—C26	121.6 (3)
C11—C10—H10	119.8	C24—C25—H25	119.2
C10—C11—C12	119.0 (3)	C26—C25—H25	119.2
C10—C11—H11	120.5	C27—C26—C25	117.1 (3)
C12—C11—H11	120.5	C27—C26—C29	122.6 (3)
C11—C12—C13	120.7 (3)	C25—C26—C29	120.4 (3)
C11—C12—H12	119.6	C26—C27—C28	121.2 (3)
C13—C12—H12	119.6	C26—C27—H27	119.4
C12—C13—C8	120.6 (3)	C28—C27—H27	119.4
C12—C13—H13	119.7	C23—C28—C27	121.4 (3)
C8—C13—H13	119.7	C23—C28—H28	119.3
C15—C14—C18	107.6 (2)	C27—C28—H28	119.3
C15—C14—C7	114.2 (2)	C30—C29—C26	113.5 (2)
C18—C14—C7	112.4 (2)	C30—C29—C31	108.7 (2)
C15—C14—H14	107.4	C26—C29—C31	110.2 (2)
C18—C14—H14	107.4	C30—C29—C32	108.8 (2)
C7—C14—H14	107.4	C26—C29—C32	104.6 (2)
C16—C15—C14	110.9 (2)	C31—C29—C32	111.0 (2)
C16—C15—H15A	109.5	C29—C30—H30A	109.5
C14—C15—H15A	109.5	C29—C30—H30B	109.5
C16—C15—H15B	109.5	H30A—C30—H30B	109.5
C14—C15—H15B	109.5	C29—C30—H30C	109.5
H15A—C15—H15B	108.0	H30A—C30—H30C	109.5
N1—C16—C15	111.0 (2)	H30B—C30—H30C	109.5
N1—C16—H16A	109.4	C29—C31—H31A	109.5
C15—C16—H16A	109.4	C29—C31—H31B	109.5
N1—C16—H16B	109.4	H31A—C31—H31B	109.5
C15—C16—H16B	109.4	C29—C31—H31C	109.5
H16A—C16—H16B	108.0	H31A—C31—H31C	109.5
C18—C17—N1	110.1 (2)	H31B—C31—H31C	109.5
C18—C17—H17A	109.6	O4—C32—O3	122.6 (3)
N1—C17—H17A	109.6	O4—C32—C29	118.9 (3)
C18—C17—H17B	109.6	O3—C32—C29	118.5 (2)
N1—C17—H17B	109.6	H5AO—O5—H5BO	103.0
H17A—C17—H17B	108.1	H6AO—O6—H6BO	108.8
C17—C18—C14	111.3 (2)
C6—C1—C2—C3	1.1 (5)	C19—N1—C17—C18	−179.7 (2)
C1—C2—C3—C4	0.0 (5)	N1—C17—C18—C14	58.8 (3)
C2—C3—C4—C5	−0.7 (5)	C15—C14—C18—C17	−58.6 (3)
C3—C4—C5—C6	0.5 (5)	C7—C14—C18—C17	174.7 (2)
C2—C1—C6—C5	−1.4 (4)	C16—N1—C19—C20	173.0 (2)
C2—C1—C6—C7	−179.0 (3)	C17—N1—C19—C20	−63.9 (3)
C4—C5—C6—C1	0.6 (5)	N1—C19—C20—C21	−179.0 (3)
C4—C5—C6—C7	178.4 (3)	C19—C20—C21—C22	−65.2 (4)
C1—C6—C7—O1	−135.5 (3)	C20—C21—C22—O2A	60.6 (4)
C5—C6—C7—O1	46.9 (3)	C20—C21—C22—O2B	−28.8 (4)
C1—C6—C7—C8	106.9 (3)	C20—C21—C22—C23	−167.5 (3)
C5—C6—C7—C8	−70.7 (3)	O2A—C22—C23—C28	−117.8 (3)
C1—C6—C7—C14	−13.9 (4)	O2B—C22—C23—C28	−29.3 (4)
C5—C6—C7—C14	168.5 (3)	C21—C22—C23—C28	108.6 (3)
O1—C7—C8—C13	0.0 (4)	O2A—C22—C23—C24	65.7 (4)
C6—C7—C8—C13	114.3 (3)	O2B—C22—C23—C24	154.3 (3)
C14—C7—C8—C13	−122.7 (3)	C21—C22—C23—C24	−67.8 (4)
O1—C7—C8—C9	179.6 (3)	C28—C23—C24—C25	0.4 (4)
C6—C7—C8—C9	−66.2 (3)	C22—C23—C24—C25	177.0 (3)
C14—C7—C8—C9	56.9 (4)	C23—C24—C25—C26	−1.5 (5)
C13—C8—C9—C10	1.0 (5)	C24—C25—C26—C27	1.8 (4)
C7—C8—C9—C10	−178.6 (3)	C24—C25—C26—C29	−177.7 (3)
C8—C9—C10—C11	−0.8 (5)	C25—C26—C27—C28	−1.0 (4)
C9—C10—C11—C12	−0.2 (5)	C29—C26—C27—C28	178.5 (3)
C10—C11—C12—C13	1.0 (5)	C24—C23—C28—C27	0.4 (4)
C11—C12—C13—C8	−0.8 (5)	C22—C23—C28—C27	−176.1 (3)
C9—C8—C13—C12	−0.2 (5)	C26—C27—C28—C23	0.0 (4)
C7—C8—C13—C12	179.4 (3)	C27—C26—C29—C30	4.1 (4)
O1—C7—C14—C15	−72.1 (3)	C25—C26—C29—C30	−176.4 (3)
C6—C7—C14—C15	169.9 (2)	C27—C26—C29—C31	126.2 (3)
C8—C7—C14—C15	50.0 (3)	C25—C26—C29—C31	−54.3 (3)
O1—C7—C14—C18	50.9 (3)	C27—C26—C29—C32	−114.4 (3)
C6—C7—C14—C18	−67.1 (3)	C25—C26—C29—C32	65.1 (3)
C8—C7—C14—C18	173.1 (2)	C30—C29—C32—O4	−39.1 (4)
C18—C14—C15—C16	58.1 (3)	C26—C29—C32—O4	82.5 (3)
C7—C14—C15—C16	−176.3 (2)	C31—C29—C32—O4	−158.7 (3)
C19—N1—C16—C15	−179.1 (2)	C30—C29—C32—O3	143.0 (3)
C17—N1—C16—C15	57.1 (3)	C26—C29—C32—O3	−95.4 (3)
C14—C15—C16—N1	−58.6 (3)	C31—C29—C32—O3	23.4 (4)
C16—N1—C17—C18	−56.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1O···O5^i	0.86 (5)	2.00 (5)	2.822 (3)	160 (4)
O2A—H2OA···O3^ii	0.92	1.85	2.758 (3)	168
O2B—H2OB···O3^ii	0.84	2.05	2.897 (3)	180
N1—H1N···O3^iii	0.96 (3)	1.81 (3)	2.768 (3)	174 (3)
O5—H5AO···O3^ii	1.00	1.89	2.868 (3)	164
O5—H5BO···O6	0.97	1.81	2.776 (3)	174
O6—H6BO···O4^iv	0.95	1.80	2.741 (3)	172

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