1-(9H-Carbazol-4-yl­oxy)-3-{[2-(2-meth­oxy­phen­oxy)eth­yl]amino}­propan-2-ol hemihydrate: a carvedilol solvatomorph

In the title racemic hemihydrated solvatomorph of carvedilol (carv), C₂₄H₂₆N₂O₄·0.5H₂O, the asymmetric unit contains two independent organic moieties and one water mol­ecule. Within this 2(carv)·H₂O unit, the mol­ecular components are strongly linked by hydrogen bonds and the unit acts as the basic building block for the crystal structure. Inter­actions parallel to (10) generate hydrogen-bonded layers which are further linked by much weaker C—H...N/O inter­actions. The con­for­mations of the organic molecules, as well as the hydrogen-bonding inter­actions connecting them, are compared with other related structures in the literature.

S1. Comment

Carvedilol is a drug indicated for use in the treatment of mild-to-moderate congestive heart failure, acting both as a β1/β2-blocker and as an α1-blocker. It counteracts the (sometimes undesirable) effect of natural norepinephrine, a drug/hormone produced in the human body which by binding to the β1- and β2-adrenergic receptors (Stafylas & Sarafidis, 2008) stimulates the nerves controlling the muscles of the heart, and by binding to the α1-adrenergic receptors on blood vessels causes them to constrict and thus raise blood pressure (Othman et al., 2007). Through a blocking action towards these receptors, carvedilol lowers blood pressure and reduces heart failure.

There are at present five reported structures containing some form of carvedilol (carv): two of them are different polymorphs of the carvedilol free base [(II) (Chen et al., 1998) and (III) (Yathirajan et al., 2007)], two others are phosphate salts of the protonated carvH⁺ cation [carvH⁺·H₂PO₄^-·0.5H₂O, (IV) (Chernyshev et al., 2009), and carvH⁺·H₂PO₄^-·C₃H₈O, (V) (Chernyshev et al., 20105)], and the fifth structure is a copper complex with carvedilol acting as a mono-deprotonated ligand {[Cu(carv)Cl(MeOH)]₂·4MeOH, (VI); Zoroddu et al., 2003}. We report here a hemihydrated form of the drug, namely 1-(9H-carbazol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol hemihydrate, (I), where two independent carvedilol molecules (labelled as A and B) share a single water molecule, itself a key component in the crystal structure organization, as discussed below.

The compound crystallizes as a racemate in the centrosymmetric space group P2₁/n (Fig. 1). The two independent carvedilol molecules have internal distances and angles quite similar to each other and to those of the previously reported examples. Similarities include the presence in both molecules of an O atom (O1) disordered over two sites on the host C atom (C21), with one configuration clearly dominant (see Refinement section for details).

In spite of their metric similarities, the conformations of molecules A and B in (I) are quite different, even though both central chains are essentially planar and the lateral aromatic side groups are structurally similar. The differences arise at the ends of the central chain, where the carbazole system and the MeOC₆H₄– groups are attached; it is here that the torsion angles defining the three-dimensional molecular structure show significant differences (Table 2, entries 1–2). Fig. 2(a) presents a combined view of both molecules after a least-squares fit of their `skeletal spine' (atoms C11–C23); the way in which the side wings depart from each other is apparent.

But this behaviour is not exclusive to molecules A and B in (I); a very similar behaviour can be observed in the remaining noncoordinated carvedilol molecules/ions [(II)–(V)] mentioned above: all of them present a rather planar aliphatic central chain, as shown by the torsion angles involving the constituent atoms (Table 1, entries 3–5), differing by just a few degrees from a perfect antiperiplanar local conformation [with the sole exception of C11—C21—C31—N1 for compound (V)]. This can be seen in Fig 2b, where a similar fit as in Fig. 2a is shown, but performed on all six molecular units. Fig. 2a clearly shows the variety of conformations attainable through the combination of the rather low energy barrier to rotation in the aliphatic chain and the highly interactive character of both aromatic ends (the carbazole group, via its donor N92—H92 group, and the MeOC₆H₄– unit through its O1 acceptor). In the case of (I), this latter tendency is enhanced by the presence of a highly active water molecule, which is determinant for the final packing of the structure.

Table 2 presents numerical values for the most significant hydrogen bonds in the structure and Fig. 1 displays all those in which O1W takes part. The molecule acts as a double donor–double acceptor (Table 2, entries 1–2 and 3–4, respectively). The water molecule is attached to carvedilol molecule A through hydrogen bonds 1 and 2, giving rise to an R₂²(10) ring (Bernstein et al., 1995). The third hydrogen bond links independent carvedilol molecules A and B into a strongly bound 2(carv)·H₂O unit. Finally, the remaining hydrogen bond accepted by O1W (Table 2, entry 4, and Fig. 1) links these three-component units into broad ribbons parallel to [101] (Fig. 3).

There are two further conventional hydrogen bonds in the structure of (I) (Table 2, entries 5–6), which link ribbons together along [010] and define broad planes paralell to (101). Strikingly, neither of the N1A—H1AN nor N92B—H92BN groups are involved in hydrogen-bonding interactions: interplanar linkage is achieved through much weaker C—H···N/O contacts and no significant π–π interactions could be detected in the structure. The resulting packing scheme is schematicaly depicted in Fig. 3, where some of these planes (in different shading) are seen down b, with their projected image running along [101].

As a final remark about which are the leading sites for hydrogen bonding in carvedilol, in unsolvated polymorphs (II) and (III) there are two direct contacts joining adjacent molecules with each other and giving rise to characteristic two-dimensional structures. These interactions, of the hydroxy–amine O—H···N and carbazole–methoxy N—H···O types, are quite similar in both unsolvated structures, in spite of circumstancial differences in the unit cell, the atomic conformation and the packing disposition, as shown in Yathirajan et al. (2007).

In the present hemihydrated form (I), there are instead four hydrogen bonds connecting adjacent A and B molecules, but this is a deceiving difference: a closer look shows that, in fact, the single hydration water molecule can be considered as only an intermediate step in a more complex set-up of the same type of interactions. The scheme below shows the way in which this is achieved, and how the same bonding scheme can be envisioned by just thinking of the interactions involving O1W—H1WA/B as `transparent'. Thus, the water molecule would not play any genuine interacting role but `propagating' instead the leading interactions, generated by the same participants as in (II) and (III). This is only one of the many roles that hydration water molecules can play in crystal structures; a very detailed analysis (for the particular case of inorganic/geological compounds, but readily extendable to any general case) can be found in Hawthorne (1992).

Related literature

For related literature, see: Bernstein et al. (1995); Chen et al. (1998); Chernyshev et al. (2009, 2010); Hawthorne (1992); Othman et al. (2007); Stafylas & Sarafidis (2008); Yathirajan et al. (2007); Zoroddu et al. (2003).

S2. Experimental

The original material, kindly provided by Laboratorios Quesada Farmacéutica, was dissolved in chloroform and the solution was left to slowly concentrate at ambient temperature in air. After one week, well developed single crystals in the form of rhomboidal plates, suitable for X-ray diffraction, were obtained. Since no particular effort was made to have a water-free solvent nor to inhibit air/moisture from getting into the solution, the reasons for the presence of a solvation water molecule may be multiple. A thermogravimetric experiment in the temperature range 300–600 K showed a diffuse mass loss in the range 340–370 K (mass loss found = 2.26%; expected mass loss for 0.5H₂O = 2.17%).

S3. Refinement

In both independent molecules, atom O1 attached to C21 appears split over two sites, but with different occupancies, viz. 0.873 (3):0.127 (3) in molecule A and 0.821 (3):0.179 (3) in molecule B. This disorder is thus configurational, with both moieties in the selected asymmetric unit having the S configuration for the major fraction. The split O atoms were restrained to have the same C—O distance and the same anisotropic displacement parameters (SADI and EADP instructions in SHELXL). All the H atoms (except those attached to O1A' and O1B', which consequently were not included in the model) were found in a difference Fourier map. Those attached to C atoms were placed at calculated positions (C—H = 0.93 Å and methyl C—H = 0.96 Å) and were allowed to ride. Those attached to O and N atoms were refined for a further few cycles with restrained O—H = N—H = 0.90 (1) Å distances, and left to ride afterwards. In all cases, displacement parameters were taken as U_iso(H) = kU_eq(carrier), where k = 1.5 for the methyl groups and 1.2 for all other H atoms.

Computing details

Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell refinement: CrysAlis PRO (Oxford Diffraction, 2009); data reduction: CrysAlis PRO (Oxford Diffraction, 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: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures

	Fig. 1. The molecular structure of (I), showing the atom-labelling scheme and with ellipsoids drawn at the 30% probability level. Only the major component of disordered atom O1A/B is shown. Hydrogen bonds are shown as dashed lines. [Symmetry code: (i) -x + 1/2, y - 1/2, -z + 1/2.]
	Fig. 2. (a) The overlap of the two independent molecules (A and B) in (I), after a least-squares fit of their `scheletal spine' C11—C21(O1)—C31—N2—C13—C23. (b) The same as for (a) but performed with the remaining carvedilol structures in the literature. [See Comment for definitions of structures (II), (III), (IV) and (V)].
	Fig. 3. A packing diagram for (I), viewed down [010], showing in projection the broad (101) planes (seen as [101] ribbons, drawn in alternating dark and light shading).

1-(9H-Carbazol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol hemihydrate

Crystal data

C24H26N2O4·0.5H2O	F(000) = 1760
Mr = 415.48	Dx = 1.268 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 7816 reflections
a = 13.550 (3) Å	θ = 4.2–25.5°
b = 16.780 (3) Å	µ = 0.09 mm^−1
c = 19.150 (4) Å	T = 291 K
β = 94.36 (3)°	Plate, colourless
V = 4341.5 (15) Å^3	0.28 × 0.18 × 0.08 mm
Z = 8

Data collection

Oxford Diffraction Gemini CCD S Ultra diffractometer	8928 independent reflections
Radiation source: fine-focus sealed tube	5209 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.035
Thick–slice ω scans	θmax = 26.5°, θmin = 3.6°
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009)	h = −16→16
Tmin = 0.98, Tmax = 0.99	k = −21→20
34926 measured reflections	l = −24→21

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)] = 0.054	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.147	H-atom parameters constrained
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0606P)^2 + 1.0836P] where P = (Fo^2 + 2Fc^2)/3
8928 reflections	(Δ/σ)max < 0.001
558 parameters	Δρmax = 0.44 e Å^−3
6 restraints	Δρmin = −0.39 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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1W	0.28801 (17)	0.28032 (13)	0.48425 (10)	0.0985 (7)
H1WA	0.2644	0.3217	0.5078	0.118*
H1WB	0.3114	0.2482	0.5193	0.118*
O1A	0.24312 (14)	0.54882 (11)	0.47036 (10)	0.0637 (6)	0.870 (3)
H1AO	0.3025	0.5549	0.4530	0.076*	0.870 (3)
O1A'	0.2355 (8)	0.4141 (5)	0.4078 (6)	0.0637 (6)	0.130 (3)
O2A	0.15989 (13)	0.52262 (11)	0.31989 (8)	0.0676 (5)
O3A	0.29530 (11)	0.28260 (9)	0.64066 (8)	0.0519 (4)
O4A	0.39372 (12)	0.17141 (10)	0.58257 (9)	0.0639 (5)
N1A	0.21370 (13)	0.41020 (11)	0.55305 (10)	0.0495 (5)
H1AN	0.2526	0.4515	0.5671	0.059*
N92A	0.23618 (15)	0.67682 (13)	0.13462 (12)	0.0625 (6)
H92A	0.2426	0.7159	0.1031	0.075*
C11A	0.11541 (19)	0.50437 (19)	0.38320 (13)	0.0675 (7)
H11A	0.0685	0.4611	0.3747	0.081*
H11B	0.0793	0.5506	0.3980	0.081*
C21A	0.19187 (17)	0.48069 (13)	0.44078 (12)	0.0528 (6)
H21A	0.2210	0.4353	0.4187	0.063*	0.870 (3)
H21C	0.2262	0.5270	0.4609	0.063*	0.130 (3)
C31A	0.14132 (17)	0.44198 (15)	0.50011 (12)	0.0536 (6)
H31A	0.1002	0.4810	0.5214	0.064*
H31B	0.0988	0.3992	0.4816	0.064*
C12A	0.1941 (2)	0.75231 (17)	0.24043 (19)	0.0772 (9)
H12A	0.2025	0.8028	0.2218	0.093*
C22A	0.1652 (2)	0.7420 (2)	0.3070 (2)	0.0856 (10)
H22A	0.1528	0.7869	0.3333	0.103*
C32A	0.1538 (2)	0.6672 (2)	0.33682 (15)	0.0736 (8)
H32A	0.1359	0.6628	0.3826	0.088*
C42A	0.16935 (17)	0.59970 (15)	0.29797 (13)	0.0530 (6)
C4XA	0.19817 (15)	0.60798 (13)	0.22990 (11)	0.0435 (5)
C5XA	0.21653 (14)	0.55195 (13)	0.17577 (11)	0.0428 (5)
C52A	0.21471 (15)	0.46943 (14)	0.17002 (13)	0.0517 (6)
H52A	0.2015	0.4380	0.2082	0.062*
C62A	0.23286 (19)	0.43474 (17)	0.10684 (16)	0.0663 (7)
H62A	0.2302	0.3796	0.1022	0.080*
C72A	0.2549 (2)	0.4810 (2)	0.05055 (15)	0.0749 (8)
H72A	0.2673	0.4561	0.0087	0.090*
C82A	0.25906 (18)	0.5619 (2)	0.05430 (13)	0.0676 (8)
H82A	0.2746	0.5924	0.0161	0.081*
C8XA	0.23923 (16)	0.59760 (15)	0.11726 (12)	0.0519 (6)
C1XA	0.21006 (17)	0.68425 (15)	0.20235 (14)	0.0554 (6)
C13A	0.16927 (17)	0.37854 (14)	0.61433 (12)	0.0522 (6)
H13A	0.1249	0.3352	0.5999	0.063*
H13B	0.1303	0.4200	0.6344	0.063*
C23A	0.24480 (17)	0.34895 (14)	0.66882 (12)	0.0518 (6)
H23A	0.2917	0.3910	0.6821	0.062*
H23B	0.2130	0.3326	0.7102	0.062*
C14A	0.37027 (16)	0.24906 (13)	0.68254 (12)	0.0459 (5)
C24A	0.42360 (17)	0.18875 (14)	0.65094 (13)	0.0510 (6)
C34A	0.50127 (19)	0.15301 (16)	0.68881 (15)	0.0650 (7)
H34A	0.5366	0.1129	0.6683	0.078*
C44A	0.5276 (2)	0.17556 (19)	0.75651 (16)	0.0751 (8)
H44A	0.5807	0.1509	0.7815	0.090*
C54A	0.4760 (2)	0.23415 (18)	0.78744 (14)	0.0690 (7)
H54A	0.4941	0.2493	0.8334	0.083*
C64A	0.39714 (18)	0.27089 (15)	0.75053 (13)	0.0559 (6)
H64A	0.3620	0.3106	0.7718	0.067*
C74A	0.4551 (2)	0.11854 (18)	0.54626 (16)	0.0802 (9)
H74A	0.4270	0.1110	0.4992	0.120*
H74B	0.4595	0.0681	0.5700	0.120*
H74C	0.5202	0.1411	0.5453	0.120*
O1B	0.43774 (14)	0.41066 (13)	0.44197 (12)	0.0729 (7)	0.818 (3)
H1BO	0.3957	0.3709	0.4504	0.087*	0.818 (3)
O1B'	0.5984 (5)	0.4352 (4)	0.4410 (6)	0.0729 (7)	0.182 (3)
O2B	0.62003 (11)	0.26366 (10)	0.40459 (9)	0.0598 (5)
O3B	0.47403 (11)	0.47989 (10)	0.69084 (9)	0.0578 (4)
O4B	0.30484 (12)	0.55210 (10)	0.67066 (9)	0.0595 (4)
N1B	0.56603 (18)	0.40881 (12)	0.57276 (11)	0.0701 (6)
H1BN	0.5243	0.4506	0.5689	0.084*
N92B	0.83405 (15)	0.05758 (13)	0.37494 (11)	0.0592 (5)
H92B	0.8630	0.0126	0.3612	0.071*
C11B	0.52607 (17)	0.30175 (15)	0.39877 (14)	0.0569 (6)
H11C	0.4748	0.2646	0.4101	0.068*
H11D	0.5109	0.3208	0.3513	0.068*
C21B	0.53121 (15)	0.37069 (14)	0.44955 (13)	0.0561 (6)
H21B	0.5768	0.4143	0.4434	0.067*	0.818 (3)
H21D	0.4678	0.3978	0.4444	0.067*	0.182 (3)
C31B	0.55511 (19)	0.34371 (15)	0.52308 (13)	0.0602 (7)
H31C	0.5029	0.3086	0.5365	0.072*
H31D	0.6161	0.3133	0.5253	0.072*
C12B	0.66218 (19)	0.03827 (16)	0.31987 (13)	0.0620 (7)
H12B	0.6724	−0.0126	0.3025	0.074*
C22B	0.5727 (2)	0.07544 (16)	0.30890 (14)	0.0654 (7)
H22B	0.5217	0.0493	0.2829	0.078*
C32B	0.55514 (18)	0.15063 (16)	0.33505 (14)	0.0622 (7)
H32B	0.4935	0.1744	0.3259	0.075*
C42B	0.62921 (16)	0.19049 (14)	0.37482 (12)	0.0490 (6)
C4XB	0.72200 (15)	0.15456 (14)	0.38649 (11)	0.0449 (5)
C5XB	0.81393 (16)	0.17907 (14)	0.42352 (11)	0.0457 (5)
C52B	0.84559 (17)	0.24554 (15)	0.46309 (12)	0.0514 (6)
H52B	0.8015	0.2863	0.4717	0.062*
C62B	0.94260 (18)	0.24983 (17)	0.48910 (13)	0.0614 (7)
H62B	0.9642	0.2940	0.5153	0.074*
C72B	1.00929 (19)	0.1892 (2)	0.47701 (14)	0.0694 (8)
H72B	1.0750	0.1942	0.4942	0.083*
C82B	0.97977 (19)	0.12194 (18)	0.44005 (14)	0.0657 (7)
H82B	1.0241	0.0809	0.4331	0.079*
C8XB	0.88259 (17)	0.11727 (15)	0.41375 (12)	0.0512 (6)
C1XB	0.73731 (17)	0.07931 (14)	0.35798 (12)	0.0503 (6)
C13B	0.57266 (17)	0.37980 (14)	0.64444 (13)	0.0545 (6)
H13C	0.6335	0.3497	0.6528	0.065*
H13D	0.5180	0.3436	0.6500	0.065*
C23B	0.57064 (16)	0.44389 (15)	0.69836 (13)	0.0554 (6)
H23C	0.5830	0.4215	0.7449	0.066*
H23D	0.6212	0.4834	0.6913	0.066*
C14B	0.45288 (16)	0.53384 (13)	0.74099 (13)	0.0490 (6)
C24B	0.36116 (17)	0.57241 (13)	0.72988 (13)	0.0500 (6)
C34B	0.33437 (19)	0.62667 (15)	0.77908 (15)	0.0628 (7)
H34B	0.2741	0.6530	0.7722	0.075*
C44B	0.3955 (2)	0.64255 (16)	0.83839 (16)	0.0737 (8)
H44B	0.3757	0.6789	0.8712	0.088*
C54B	0.4851 (2)	0.60496 (17)	0.84908 (15)	0.0686 (7)
H54B	0.5262	0.6159	0.8890	0.082*
C64B	0.51438 (17)	0.55074 (15)	0.80040 (14)	0.0567 (6)
H64B	0.5754	0.5255	0.8075	0.068*
C74B	0.21597 (18)	0.59679 (16)	0.65450 (15)	0.0687 (8)
H74D	0.1829	0.5771	0.6119	0.103*
H74E	0.2322	0.6520	0.6489	0.103*
H74F	0.1732	0.5913	0.6920	0.103*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1W	0.1287 (18)	0.1000 (17)	0.0654 (13)	0.0502 (14)	−0.0013 (12)	−0.0267 (11)
O1A	0.0613 (12)	0.0712 (14)	0.0597 (12)	−0.0187 (10)	0.0120 (9)	−0.0040 (10)
O1A'	0.0613 (12)	0.0712 (14)	0.0597 (12)	−0.0187 (10)	0.0120 (9)	−0.0040 (10)
O2A	0.0837 (13)	0.0746 (13)	0.0470 (10)	0.0113 (10)	0.0202 (9)	0.0092 (9)
O3A	0.0552 (10)	0.0488 (9)	0.0519 (9)	0.0090 (7)	0.0044 (8)	−0.0041 (7)
O4A	0.0588 (10)	0.0612 (11)	0.0708 (12)	0.0129 (8)	−0.0016 (9)	−0.0198 (9)
N1A	0.0497 (11)	0.0492 (12)	0.0501 (11)	0.0006 (9)	0.0068 (9)	0.0015 (9)
N92A	0.0622 (13)	0.0602 (15)	0.0651 (15)	−0.0086 (10)	0.0048 (11)	0.0189 (11)
C11A	0.0578 (16)	0.096 (2)	0.0494 (15)	0.0009 (14)	0.0106 (12)	0.0102 (14)
C21A	0.0506 (14)	0.0591 (15)	0.0491 (14)	−0.0043 (11)	0.0064 (11)	−0.0006 (11)
C31A	0.0480 (14)	0.0640 (16)	0.0493 (14)	−0.0016 (11)	0.0063 (11)	0.0039 (12)
C12A	0.0649 (18)	0.0526 (18)	0.112 (3)	−0.0026 (13)	−0.0065 (17)	−0.0087 (17)
C22A	0.074 (2)	0.070 (2)	0.112 (3)	0.0104 (16)	0.0001 (19)	−0.039 (2)
C32A	0.0644 (17)	0.091 (2)	0.0663 (18)	0.0081 (15)	0.0091 (14)	−0.0236 (17)
C42A	0.0446 (14)	0.0637 (17)	0.0501 (15)	0.0086 (11)	−0.0005 (11)	−0.0044 (12)
C4XA	0.0334 (11)	0.0504 (14)	0.0457 (13)	0.0031 (9)	−0.0029 (10)	−0.0010 (10)
C5XA	0.0304 (11)	0.0531 (14)	0.0444 (13)	0.0022 (9)	0.0000 (9)	0.0020 (10)
C52A	0.0411 (13)	0.0560 (16)	0.0573 (15)	0.0014 (10)	0.0001 (11)	−0.0005 (12)
C62A	0.0559 (16)	0.0676 (18)	0.074 (2)	0.0062 (13)	−0.0025 (14)	−0.0177 (16)
C72A	0.0644 (18)	0.103 (3)	0.0573 (18)	0.0095 (16)	0.0055 (14)	−0.0205 (17)
C82A	0.0549 (16)	0.102 (2)	0.0463 (16)	−0.0027 (15)	0.0099 (12)	0.0036 (15)
C8XA	0.0425 (13)	0.0612 (16)	0.0516 (15)	−0.0036 (11)	0.0013 (11)	0.0060 (12)
C1XA	0.0421 (13)	0.0508 (15)	0.0716 (18)	−0.0001 (11)	−0.0061 (12)	−0.0021 (13)
C13A	0.0545 (14)	0.0514 (14)	0.0525 (14)	0.0069 (11)	0.0155 (12)	0.0040 (11)
C23A	0.0596 (15)	0.0488 (14)	0.0483 (14)	0.0073 (11)	0.0122 (11)	−0.0012 (11)
C14A	0.0440 (13)	0.0408 (13)	0.0538 (14)	−0.0036 (10)	0.0106 (11)	0.0066 (10)
C24A	0.0475 (13)	0.0444 (13)	0.0619 (16)	−0.0043 (11)	0.0093 (12)	−0.0012 (11)
C34A	0.0553 (16)	0.0598 (17)	0.080 (2)	0.0123 (12)	0.0055 (14)	0.0025 (14)
C44A	0.0655 (18)	0.088 (2)	0.071 (2)	0.0162 (15)	−0.0021 (15)	0.0137 (16)
C54A	0.0685 (18)	0.087 (2)	0.0515 (16)	0.0080 (15)	0.0030 (14)	0.0082 (14)
C64A	0.0618 (16)	0.0587 (16)	0.0485 (15)	0.0016 (12)	0.0124 (12)	0.0022 (12)
C74A	0.0761 (19)	0.076 (2)	0.088 (2)	0.0175 (15)	0.0012 (16)	−0.0276 (17)
O1B	0.0560 (13)	0.0698 (15)	0.0941 (17)	0.0124 (10)	0.0143 (12)	0.0021 (12)
O1B'	0.0560 (13)	0.0698 (15)	0.0941 (17)	0.0124 (10)	0.0143 (12)	0.0021 (12)
O2B	0.0397 (9)	0.0614 (11)	0.0775 (12)	−0.0010 (7)	−0.0015 (8)	−0.0153 (9)
O3B	0.0431 (9)	0.0642 (11)	0.0662 (11)	0.0120 (7)	0.0055 (8)	−0.0127 (9)
O4B	0.0516 (10)	0.0573 (11)	0.0691 (11)	0.0133 (8)	0.0018 (8)	−0.0007 (8)
N1B	0.1002 (18)	0.0449 (13)	0.0648 (14)	−0.0054 (11)	0.0041 (12)	−0.0052 (11)
N92B	0.0547 (13)	0.0598 (13)	0.0637 (13)	0.0068 (10)	0.0073 (10)	−0.0087 (11)
C11B	0.0422 (13)	0.0625 (16)	0.0658 (16)	−0.0008 (11)	0.0022 (12)	−0.0025 (13)
C21B	0.0446 (14)	0.0534 (15)	0.0707 (17)	−0.0040 (11)	0.0076 (12)	0.0011 (13)
C31B	0.0672 (16)	0.0475 (15)	0.0663 (17)	−0.0080 (12)	0.0080 (13)	−0.0049 (12)
C12B	0.0641 (17)	0.0581 (16)	0.0648 (17)	−0.0097 (13)	0.0106 (13)	−0.0150 (13)
C22B	0.0558 (16)	0.0673 (18)	0.0725 (18)	−0.0151 (13)	0.0006 (13)	−0.0179 (14)
C32B	0.0423 (14)	0.0703 (18)	0.0733 (18)	−0.0052 (12)	−0.0005 (12)	−0.0104 (14)
C42B	0.0443 (13)	0.0519 (14)	0.0513 (14)	−0.0058 (11)	0.0065 (11)	−0.0064 (11)
C4XB	0.0413 (13)	0.0530 (14)	0.0409 (12)	−0.0068 (10)	0.0061 (10)	0.0027 (10)
C5XB	0.0432 (13)	0.0585 (15)	0.0359 (12)	−0.0049 (11)	0.0061 (10)	0.0052 (10)
C52B	0.0496 (14)	0.0629 (16)	0.0420 (13)	−0.0062 (11)	0.0051 (11)	−0.0040 (11)
C62B	0.0551 (16)	0.0810 (19)	0.0478 (14)	−0.0122 (14)	0.0006 (12)	−0.0061 (13)
C72B	0.0457 (15)	0.104 (2)	0.0575 (17)	−0.0020 (15)	−0.0038 (12)	−0.0004 (16)
C82B	0.0501 (16)	0.084 (2)	0.0623 (17)	0.0081 (13)	0.0024 (13)	−0.0005 (15)
C8XB	0.0494 (14)	0.0625 (16)	0.0423 (13)	0.0015 (12)	0.0077 (11)	0.0033 (11)
C1XB	0.0489 (14)	0.0552 (15)	0.0477 (14)	−0.0035 (11)	0.0100 (11)	−0.0025 (11)
C13B	0.0468 (13)	0.0544 (15)	0.0642 (16)	0.0026 (11)	0.0158 (12)	−0.0003 (12)
C23B	0.0409 (13)	0.0619 (16)	0.0637 (16)	0.0085 (11)	0.0074 (11)	−0.0026 (12)
C14B	0.0441 (13)	0.0436 (13)	0.0605 (15)	−0.0021 (10)	0.0127 (11)	0.0006 (11)
C24B	0.0470 (13)	0.0396 (13)	0.0645 (16)	0.0025 (10)	0.0111 (12)	0.0027 (11)
C34B	0.0547 (15)	0.0490 (15)	0.085 (2)	0.0086 (12)	0.0092 (14)	−0.0062 (14)
C44B	0.076 (2)	0.0537 (17)	0.092 (2)	0.0030 (14)	0.0118 (17)	−0.0221 (15)
C54B	0.0625 (17)	0.0661 (18)	0.0768 (19)	−0.0103 (14)	0.0021 (14)	−0.0163 (15)
C64B	0.0408 (13)	0.0542 (15)	0.0755 (18)	−0.0037 (11)	0.0078 (12)	−0.0059 (13)
C74B	0.0537 (16)	0.0650 (18)	0.087 (2)	0.0154 (12)	0.0017 (14)	0.0127 (14)

Geometric parameters (Å, º)

O1W—H1WA	0.9000	C74A—H74C	0.9600
O1W—H1WB	0.8999	O1B—C21B	1.431 (2)
O1A—C21A	1.432 (2)	O1B—H1BO	0.9001
O1A—H1AO	0.9000	O1B—H21D	0.4606
O1A—H21C	0.4619	O1B'—C21B	1.432 (2)
O1A'—C21A	1.432 (2)	O1B'—H21B	0.4617
O1A'—H21A	0.4625	O2B—C42B	1.363 (3)
O2A—C42A	1.369 (3)	O2B—C11B	1.421 (3)
O2A—C11A	1.428 (3)	O3B—C14B	1.366 (3)
O3A—C14A	1.367 (3)	O3B—C23B	1.439 (3)
O3A—C23A	1.433 (3)	O4B—C24B	1.361 (3)
O4A—C24A	1.372 (3)	O4B—C74B	1.432 (3)
O4A—C74A	1.432 (3)	N1B—C31B	1.449 (3)
N1A—C31A	1.457 (3)	N1B—C13B	1.453 (3)
N1A—C13A	1.459 (3)	N1B—H1BN	0.9000
N1A—H1AN	0.8999	N92B—C1XB	1.375 (3)
N92A—C8XA	1.372 (3)	N92B—C8XB	1.383 (3)
N92A—C1XA	1.376 (3)	N92B—H92B	0.9001
N92A—H92A	0.9000	C11B—C21B	1.510 (3)
C11A—C21A	1.508 (3)	C11B—H11C	0.9700
C11A—H11A	0.9700	C11B—H11D	0.9700
C11A—H11B	0.9700	C21B—C31B	1.491 (3)
C21A—C31A	1.517 (3)	C21B—H21B	0.9700
C21A—H21A	0.9700	C21B—H21D	0.9700
C21A—H21C	0.9701	C31B—H31C	0.9700
C31A—H31A	0.9700	C31B—H31D	0.9700
C31A—H31B	0.9700	C12B—C22B	1.365 (4)
C12A—C22A	1.372 (5)	C12B—C1XB	1.389 (3)
C12A—C1XA	1.381 (4)	C12B—H12B	0.9300
C12A—H12A	0.9300	C22B—C32B	1.385 (4)
C22A—C32A	1.392 (4)	C22B—H22B	0.9300
C22A—H22A	0.9300	C32B—C42B	1.385 (3)
C32A—C42A	1.380 (4)	C32B—H32B	0.9300
C32A—H32A	0.9300	C42B—C4XB	1.397 (3)
C42A—C4XA	1.396 (3)	C4XB—C1XB	1.397 (3)
C4XA—C1XA	1.398 (3)	C4XB—C5XB	1.445 (3)
C4XA—C5XA	1.435 (3)	C5XB—C52B	1.397 (3)
C5XA—C52A	1.389 (3)	C5XB—C8XB	1.415 (3)
C5XA—C8XA	1.411 (3)	C52B—C62B	1.372 (3)
C52A—C62A	1.381 (4)	C52B—H52B	0.9300
C52A—H52A	0.9300	C62B—C72B	1.392 (4)
C62A—C72A	1.379 (4)	C62B—H62B	0.9300
C62A—H62A	0.9300	C72B—C82B	1.375 (4)
C72A—C82A	1.361 (4)	C72B—H72B	0.9300
C72A—H72A	0.9300	C82B—C8XB	1.376 (3)
C82A—C8XA	1.390 (4)	C82B—H82B	0.9300
C82A—H82A	0.9300	C13B—C23B	1.493 (3)
C13A—C23A	1.490 (3)	C13B—H13C	0.9700
C13A—H13A	0.9700	C13B—H13D	0.9700
C13A—H13B	0.9700	C23B—H23C	0.9700
C23A—H23A	0.9700	C23B—H23D	0.9700
C23A—H23B	0.9700	C14B—C64B	1.387 (3)
C14A—C64A	1.375 (3)	C14B—C24B	1.403 (3)
C14A—C24A	1.407 (3)	C24B—C34B	1.378 (3)
C24A—C34A	1.370 (3)	C34B—C44B	1.380 (4)
C34A—C44A	1.372 (4)	C34B—H34B	0.9300
C34A—H34A	0.9300	C44B—C54B	1.370 (4)
C44A—C54A	1.367 (4)	C44B—H44B	0.9300
C44A—H44A	0.9300	C54B—C64B	1.382 (4)
C54A—C64A	1.381 (4)	C54B—H54B	0.9300
C54A—H54A	0.9300	C64B—H64B	0.9300
C64A—H64A	0.9300	C74B—H74D	0.9600
C74A—H74A	0.9600	C74B—H74E	0.9600
C74A—H74B	0.9600	C74B—H74F	0.9600
H1WA—O1W—H1WB	102.0	C21B—O1B—H1BO	101.6
C21A—O1A—H1AO	111.4	C21B—O1B—H21D	0.2
C21A—O1A—H21C	0.8	H1BO—O1B—H21D	101.7
H1AO—O1A—H21C	112.2	C21B—O1B'—H21B	1.0
C21A—O1A'—H21A	1.1	C42B—O2B—C11B	118.80 (17)
C42A—O2A—C11A	121.2 (2)	C14B—O3B—C23B	116.47 (18)
C14A—O3A—C23A	116.99 (17)	C24B—O4B—C74B	117.24 (19)
C24A—O4A—C74A	117.03 (19)	C31B—N1B—C13B	111.3 (2)
C31A—N1A—C13A	113.31 (17)	C31B—N1B—H1BN	120.1
C31A—N1A—H1AN	105.9	C13B—N1B—H1BN	109.4
C13A—N1A—H1AN	107.9	C1XB—N92B—C8XB	109.9 (2)
C8XA—N92A—C1XA	109.3 (2)	C1XB—N92B—H92B	125.6
C8XA—N92A—H92A	122.5	C8XB—N92B—H92B	124.4
C1XA—N92A—H92A	127.7	O2B—C11B—C21B	107.27 (18)
O2A—C11A—C21A	111.5 (2)	O2B—C11B—H11C	110.3
O2A—C11A—H11A	109.3	C21B—C11B—H11C	110.3
C21A—C11A—H11A	109.3	O2B—C11B—H11D	110.3
O2A—C11A—H11B	109.3	C21B—C11B—H11D	110.3
C21A—C11A—H11B	109.3	H11C—C11B—H11D	108.5
H11A—C11A—H11B	108.0	O1B—C21B—O1B'	101.5 (4)
O1A—C21A—O1A'	126.3 (5)	O1B—C21B—C31B	111.4 (2)
O1A—C21A—C11A	111.4 (2)	O1B'—C21B—C31B	104.1 (5)
O1A'—C21A—C11A	99.6 (6)	O1B—C21B—C11B	107.26 (19)
O1A—C21A—C31A	106.18 (18)	O1B'—C21B—C11B	120.3 (5)
O1A'—C21A—C31A	102.8 (5)	C31B—C21B—C11B	111.8 (2)
C11A—C21A—C31A	109.66 (19)	O1B—C21B—H21B	101.6
O1A—C21A—H21A	126.7	O1B'—C21B—H21B	0.5
O1A'—C21A—H21A	0.5	C31B—C21B—H21B	104.5
C11A—C21A—H21A	99.7	C11B—C21B—H21B	119.8
C31A—C21A—H21A	102.3	O1B—C21B—H21D	0.1
O1A—C21A—H21C	0.4	O1B'—C21B—H21D	101.5
O1A'—C21A—H21C	126.7	C31B—C21B—H21D	111.5
C11A—C21A—H21C	111.2	C11B—C21B—H21D	107.2
C31A—C21A—H21C	106.0	H21B—C21B—H21D	101.6
H21A—C21A—H21C	127.1	N1B—C31B—C21B	113.3 (2)
N1A—C31A—C21A	111.07 (18)	N1B—C31B—H31C	108.9
N1A—C31A—H31A	109.4	C21B—C31B—H31C	108.9
C21A—C31A—H31A	109.4	N1B—C31B—H31D	108.9
N1A—C31A—H31B	109.4	C21B—C31B—H31D	108.9
C21A—C31A—H31B	109.4	H31C—C31B—H31D	107.7
H31A—C31A—H31B	108.0	C22B—C12B—C1XB	117.4 (2)
C22A—C12A—C1XA	116.9 (3)	C22B—C12B—H12B	121.3
C22A—C12A—H12A	121.5	C1XB—C12B—H12B	121.3
C1XA—C12A—H12A	121.5	C12B—C22B—C32B	122.4 (2)
C12A—C22A—C32A	122.9 (3)	C12B—C22B—H22B	118.8
C12A—C22A—H22A	118.5	C32B—C22B—H22B	118.8
C32A—C22A—H22A	118.5	C42B—C32B—C22B	120.1 (2)
C42A—C32A—C22A	119.5 (3)	C42B—C32B—H32B	119.9
C42A—C32A—H32A	120.3	C22B—C32B—H32B	119.9
C22A—C32A—H32A	120.3	O2B—C42B—C32B	125.4 (2)
O2A—C42A—C32A	126.1 (2)	O2B—C42B—C4XB	115.56 (19)
O2A—C42A—C4XA	114.8 (2)	C32B—C42B—C4XB	119.0 (2)
C32A—C42A—C4XA	119.1 (3)	C42B—C4XB—C1XB	119.1 (2)
C42A—C4XA—C1XA	119.5 (2)	C42B—C4XB—C5XB	133.4 (2)
C42A—C4XA—C5XA	133.3 (2)	C1XB—C4XB—C5XB	107.51 (19)
C1XA—C4XA—C5XA	107.2 (2)	C52B—C5XB—C8XB	118.6 (2)
C52A—C5XA—C8XA	118.8 (2)	C52B—C5XB—C4XB	135.3 (2)
C52A—C5XA—C4XA	135.0 (2)	C8XB—C5XB—C4XB	106.1 (2)
C8XA—C5XA—C4XA	106.2 (2)	C62B—C52B—C5XB	119.0 (2)
C62A—C52A—C5XA	119.1 (2)	C62B—C52B—H52B	120.5
C62A—C52A—H52A	120.5	C5XB—C52B—H52B	120.5
C5XA—C52A—H52A	120.5	C52B—C62B—C72B	121.2 (2)
C72A—C62A—C52A	120.7 (3)	C52B—C62B—H62B	119.4
C72A—C62A—H62A	119.6	C72B—C62B—H62B	119.4
C52A—C62A—H62A	119.6	C82B—C72B—C62B	121.2 (2)
C82A—C72A—C62A	122.1 (3)	C82B—C72B—H72B	119.4
C82A—C72A—H72A	119.0	C62B—C72B—H72B	119.4
C62A—C72A—H72A	119.0	C72B—C82B—C8XB	117.9 (3)
C72A—C82A—C8XA	117.7 (3)	C72B—C82B—H82B	121.0
C72A—C82A—H82A	121.1	C8XB—C82B—H82B	121.0
C8XA—C82A—H82A	121.1	C82B—C8XB—N92B	129.8 (2)
N92A—C8XA—C82A	129.7 (2)	C82B—C8XB—C5XB	122.0 (2)
N92A—C8XA—C5XA	108.7 (2)	N92B—C8XB—C5XB	108.1 (2)
C82A—C8XA—C5XA	121.6 (2)	N92B—C1XB—C12B	129.8 (2)
N92A—C1XA—C12A	129.4 (3)	N92B—C1XB—C4XB	108.3 (2)
N92A—C1XA—C4XA	108.5 (2)	C12B—C1XB—C4XB	121.9 (2)
C12A—C1XA—C4XA	122.0 (3)	N1B—C13B—C23B	114.1 (2)
N1A—C13A—C23A	112.40 (19)	N1B—C13B—H13C	108.7
N1A—C13A—H13A	109.1	C23B—C13B—H13C	108.7
C23A—C13A—H13A	109.1	N1B—C13B—H13D	108.7
N1A—C13A—H13B	109.1	C23B—C13B—H13D	108.7
C23A—C13A—H13B	109.1	H13C—C13B—H13D	107.6
H13A—C13A—H13B	107.9	O3B—C23B—C13B	107.32 (19)
O3A—C23A—C13A	108.51 (18)	O3B—C23B—H23C	110.3
O3A—C23A—H23A	110.0	C13B—C23B—H23C	110.3
C13A—C23A—H23A	110.0	O3B—C23B—H23D	110.3
O3A—C23A—H23B	110.0	C13B—C23B—H23D	110.3
C13A—C23A—H23B	110.0	H23C—C23B—H23D	108.5
H23A—C23A—H23B	108.4	O3B—C14B—C64B	124.5 (2)
O3A—C14A—C64A	125.3 (2)	O3B—C14B—C24B	115.5 (2)
O3A—C14A—C24A	115.3 (2)	C64B—C14B—C24B	120.0 (2)
C64A—C14A—C24A	119.4 (2)	O4B—C24B—C34B	125.1 (2)
C34A—C24A—O4A	124.9 (2)	O4B—C24B—C14B	116.4 (2)
C34A—C24A—C14A	119.1 (2)	C34B—C24B—C14B	118.5 (2)
O4A—C24A—C14A	116.0 (2)	C24B—C34B—C44B	121.2 (2)
C24A—C34A—C44A	120.9 (3)	C24B—C34B—H34B	119.4
C24A—C34A—H34A	119.5	C44B—C34B—H34B	119.4
C44A—C34A—H34A	119.5	C54B—C44B—C34B	120.2 (3)
C54A—C44A—C34A	120.2 (3)	C54B—C44B—H44B	119.9
C54A—C44A—H44A	119.9	C34B—C44B—H44B	119.9
C34A—C44A—H44A	119.9	C44B—C54B—C64B	119.9 (3)
C44A—C54A—C64A	120.0 (3)	C44B—C54B—H54B	120.0
C44A—C54A—H54A	120.0	C64B—C54B—H54B	120.0
C64A—C54A—H54A	120.0	C54B—C64B—C14B	120.1 (2)
C14A—C64A—C54A	120.3 (2)	C54B—C64B—H64B	119.9
C14A—C64A—H64A	119.8	C14B—C64B—H64B	119.9
C54A—C64A—H64A	119.8	O4B—C74B—H74D	109.5
O4A—C74A—H74A	109.5	O4B—C74B—H74E	109.5
O4A—C74A—H74B	109.5	H74D—C74B—H74E	109.5
H74A—C74A—H74B	109.5	O4B—C74B—H74F	109.5
O4A—C74A—H74C	109.5	H74D—C74B—H74F	109.5
H74A—C74A—H74C	109.5	H74E—C74B—H74F	109.5
H74B—C74A—H74C	109.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1WA···N1A	0.90	1.88	2.775 (3)	178
O1W—H1WB···O4A	0.90	2.04	2.920 (3)	165
O1B—H1BO···O1W	0.90	2.24	3.131 (4)	173
N92A—H92A···O1W^i	0.90	2.01	2.862 (3)	158
N1B—H1BN···O1B^ii	0.90	2.40	3.043 (3)	129
O1A—H1AO···N1B^ii	0.90	1.98	2.863 (3)	167

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