Cocrystals of the anti­biotic trimethoprim with glutarimide and 3,3-di­methyl­glutarimide held together by three hydrogen bonds

The anti­biotic trimethoprim [5-(3,4,5-tri­meth­oxy­benz­yl)pyrimidine-2,4-di­amine] was cocrystallized with glutarimide (piperidine-2,6-dione) and its 3,3-dimethyl derivative (4,4-di­methyl­piperidine-2,6-dione). The cocrystals, viz. trimethoprim–glutarimide (1/1), C₁₄H₁₈N₄O₃·C₅H₇NO₂, (I), and trimethoprim–3,3-di­methyl­glutarimide (1/1), C₁₄H₁₈N₄O₃·C₇H₁₁NO₂, (II), are held together by three neighbouring hydrogen bonds (one central N—H...N and two N—H...O) between the pyrimidine ring of trimethoprim and the imide group of glutarimide, with an ADA/DAD pattern (A = acceptor and D = donor). These heterodimers resemble two known cocrystals of trimethoprim with barbituric acid and its 5,5-diethyl derivative. Trimethoprim shows a conformation in which the planes of the pyrimidine and benzene rings are approximately perpendicular to one another. In its glutarimide coformer, five of the six ring atoms lie in a common plane; the C atom opposite the N atom deviates by about 0.6 Å. The crystal packing of each of the two cocrystals is characterized by an extended network of hydrogen bonds and contains centrosymmetrically related trimethoprim homodimers formed by a pair of N—H...N hydrogen bonds. This structural motif occurs in five of the nine published crystal structures in which neutral trimethoprim is present.

S1. Introduction

The pyrimidine derivative trimethoprim inhibits the enzyme di­hydro­folate redu­ctase (DHFR), which catalyzes the vital reduction of di­hydro­folate to tetra­hydro­folate and whose inhibition leads eventually to cell death. Since trimethoprim shows a remarkable specificity for bacterial (as compared to mammalian) DHFR, it has been used as an anti­biotic against bacterial infections for decades (Feeney, 2000). The combination of trimethoprim with sulfamethoxazole, known as cotrimoxazole, has frequently been used against Pneumocystis carinii pneumonia (Hughes et al., 1974; Hughes, 1987). The crystal structures of trimethoprim bound to E. coli and chicken DHFR suggested that the loss of one hydrogen bond between an amino group of trimethoprim and a carbonyl group of DHFR may cause the observed specificity (Matthews et al., 1985), but the crystal structure of trimethoprim complexed with mouse DHFR and the cofactor NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) urged some caution concerning the exact binding mode (Groom et al., 1991). There is also a large co-operative effect between trimethoprim and NADPH, which has been investigated by multidimensional NMR spectroscopy (Kovalevskaya et al., 2007).

As a simple model of molecular recognition, we have studied a number of cocrystals of the anti­fungal drug 5-fluoro­cytosine, which exhibit an unsymmetric AAD/DDA pattern (A = acceptor and D = donor) of three neighbouring hydrogen bonds (Tutughamiarso et al., 2012; Tutughamiarso & Egert, 2012). In the course of a systematic study of cocrystals between pairs of compounds held together by a symmetric ADA/DAD pattern (Ton & Egert, 2015), we became inter­ested in trimethoprim because of its DAD arrangement, with a pyrimidine N atom as a hydrogen-bond acceptor located between two amino substituents as donor groups. Therefore, we crystallized trimethoprim with glutarimide and two of its derivatives, which all possess the appropriate ADA arrangement of functional groups, and were successful with glutarimide itself and 3,3-di­methyl­glutarimide, whereas the cocrystallization experiments with the spiro compound 3,3-tetra­methyl­eneglutarimide yielded only crystals of lower quality (Ton, 2010).

We also hoped that we would gain better insight into the hydrogen-bond inter­actions between the different components in the solid state. Since hydrogen bonds play a key role for the formation of supra­molecular complexes between a drug and its receptor, the structures of suitable cocrystals can be very helpful for the design of new active pharmaceutical ingredients (APIs) in the form of cocrystals with improved physical properties and better bioavailability (Vishweshwar et al., 2006; Yadav et al., 2009). Also the development of new APIs often makes use of the information about inter­actions between API candidates and their protein-binding pocket (Böhm & Klebe, 1996).

S2. Experimental

S2.1. Crystallization

S2.1.1. Trimethoprim–glutarimide (1/1), (I)

Trimethoprim (0.03 mmol, 8.7 mg) and glutarimide (0.03 mmol, 3.3 mg) were dissolved separately in a small amount (20 drops from a Pasteur pipette) of di­methyl sulfoxide (DMSO). The solutions were joined in a flask with a screw shutter and the mixture was kept at 323 K. After several days, crystals of (I) were obtained as colourless blocks.

S2.1.2. Trimethoprim–3,3-di­methyl­glutarimide (1/1), (II)

Trimethoprim (0.03 mmol, 8.7 mg) and 3,3-di­methyl­glutarimide (0.03 mmol, 4.2 mg) were dissolved separately in 40 drops of methanol and the resulting solution diluted with a further 15 drops. The solutions were joined in a flask with a screw shutter and the mixture was kept at room temperature. After several days, crystals of (II) were obtained as colourless blocks.

S2.2. Refinement

All H atoms were located unequivocally by difference Fourier synthesis. Subsequently, H atoms bonded to C atoms were refined using a riding model, with C—H = 0.98 (methyl), 0.99 (methyl­ene) or 0.95 Å (aromatic). Methyl groups were allowed to rotate about their local threefold axis. H atoms bonded to N atoms were refined isotropically. For all riding H atoms, fixed individual displacement parameters were employed, with U_iso(H) = 1.5U_eq(C) for methyl or 1.2U_eq(C) for all other H atoms.

In (I), glutarimide atom C4' is disordered, with a site-occupation factor of 0.879 (7) for the major-occupied site. The two minor-disorder bonds involving atom C4'B were restrained to a distance of 1.49 Å. In (II), the refinement of an extinction coefficient improved the agreement between structure model and experimental data significantly.

S3. Comment

Cocrystal (I) crystallized in the space group P2₁/n with one molecule of trimethoprim and one molecule of glutarimide in the asymmetric unit, which form the expected heterodimer [the angle between component rings atoms N1/N3/C2/C4–C6 and N1'/C2'/C5'/C6' is 23.99 (9)°] held together by three hydrogen bonds, one central N—H···N and two neighbouring N—H···O hydrogen bonds (Fig. 1). The planar pyrimidine and benzene rings of trimethoprim (r.m.s. deviations = 0.014 and 0.003 Å, respectively, for all non-H atoms) form an angle of 86.35 (5)° caused by the dihedral angles about the two single bonds connecting these groups [ϕ₁ (C4—C5—C7—C8) = -74.68 (17)° and ϕ₂ (C5—C7—C8—C9) = -34.70 (18)°]. The neighbouring meth­oxy substituents of the benzene ring show the usual conformational behaviour: while the methyl groups of the outer substituents take the electronically favoured position in the plane of the benzene ring, steric reasons prevent such a conformation for the central meth­oxy substituent, whose O—CH₃ bond is approximately perpendicular to the plane of the ring [C10—C11—O11—C15 = -96.84 (16)°]. In the glutarimide molecule, five of the six ring atoms form a planar arrangement (r.m.s. deviation = 0.013 Å), from which the two disordered positions of atom C4', which is opposite to the ring N atom, deviate to either side. The crystal packing is stabilized by further hydrogen bonds through inversion centres, with participation of the trimethoprim N—H bonds which are not involved in inter­actions with glutarimide, viz. N2—H···N1 hydrogen bonds leading to the formation of trimethoprim homodimers with an R₂²(8) pattern in graph-set notation (Bernstein et al., 1995), and somewhat longer N—H···O inter­actions from atom N4 to the central meth­oxy group, which generate trimethoprim homodimers with an R₂²(20) pattern. This gives rise to an extended network of hydrogen bonds (Fig. 2 and Table 2).

Cocrystal (II) crystallized in the space group P1, also with one planar heterodimer [angle between the pyrimidine ring and glutarimide = 3.97 (8)°] in the asymmetric unit (Fig. 3). The hydrogen-bond pattern of the heterodimer and the conformations of its constituents compare well with (I). The angle of 72.21 (5)° between the planar pyrimidine and benzene rings [r.m.s. deviations = 0.007 and 0.010 Å, respectively; dihedral angles ϕ₁ = -86.60 (15)° and ϕ₂ = 35.83 (16)°], the orientation of the meth­oxy substituents with the central meth­oxy group approximately perpendicular to the plane of the benzene ring [C10—C11—O11—C15 = -97.87 (13)°] and also the conformation of the glutarimide ring with five atoms in a plane (r.m.s. deviation = 0.022 Å) and atom C4' deviating by 0.624 (2) Å are very similar. Again an extended network of hydrogen bonds is observed in the crystal with hydrogen-bonded ribbons running in the [110] direction, approximately parallel to (114). As in (I), R₂²(8) trimethoprim homodimers formed by a pair of N2—H···N1 hydrogen bonds across an inversion centre and inter­molecular N—H···O hydrogen bonds from the trimethoprim amino group at atom C4 are observed, but this time the latter are accepted by carbonyl atom O6' of 3,3-di­methyl­glutarimide (which is also involved in the formation of the heterodimer); this gives rise to an R₄²(8) motif with four N—H···O hydrogen bonds, also across an inversion centre (Fig. 4 and Table 3).

Although the quality of the crystals obtained from the cocrystallization experiments of trimethoprim with 3,3-tetra­methyl­eneglutarimide was not satisfactory, the crystal structure could be solved (Ton, 2010) and showed features similar to those of cocrystals (I) and (II), viz. a heterodimer held together by three hydrogen bonds, the additional formation of R₂²(8) trimethoprim homodimers and an extended hydrogen-bond network. A search of the Cambridge Structural Database (CSD, Version 5.35 of November 2013, plus two updates; Groom & Allen, 2014) yielded nine structures containing neutral trimethoprim (not protonated at the pyrimidine ring), excluding metal complexes. Most of these structures show R₂²(8) heterodimers [CSD refcodes QAXHEX (Bettinetti et al., 2000) and SMZTMP (Giuseppetti et al., 1980)] or R₂²(8) trimethoprim homodimers [BEXVOP (Shimizu & Nishigaki, 1982), LIBCOQ (Delori & Jones, 2011) and RIWLOY (Sardone et al., 1997)]; the crystal structure of the 1:1 molecular complex between trimethoprim and sulfadimidine (RASSUZ; Bettinetti & Sardone, 1997) contains both. Also the crystal structure of trimethoprim itself (AMXBPM10; Koetzle & Williams, 1976) shows R₂²(8) homodimers across inversion centres. Only two cocrystals [BIGCUP (Shimizu et al., 1982) and GIGQIX (Thomas Mu­thiah et al., 2007)] contain heterodimers with an ADA/DAD hydrogen-bond pattern, the coformers being barbituric acid (GIGQIX) and its 5,5-di­ethyl derivative (BIGCUP), respectively, the constitution of which is very similar to that of the glutarimides employed by us.

In order to obtain cocrystals with a specific inter­action pattern, for example, ADA/DAD, as in the present investigation, the molecules constituting the supra­molecular complex must not only possess a certain kind and geometrical arrangement of the inter­acting functional groups, but have to meet other conditions as well (e.g. they should show similar solubility properties). Thus, the molecular components to be employed must be carefully selected. Nevertheless, the crystallization experiments and the investigation of potential cocrystals can be very tedious and time-consuming. Therefore, we have developed and successfully applied a strategy for obtaining cocrystals in a systematic way, in which the most promising combinations of components are detected as early as possible (Ton & Egert, 2015).

Computing details

For both compounds, data collection: X-AREA (Stoe & Cie, 2001); cell refinement: X-AREA (Stoe & Cie, 2001); data reduction: X-AREA (Stoe & Cie, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2008) and XP (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures

	Fig. 1. A perspective view of cocrystal (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probality level. Dashed lines indicate hydrogen bonds. Only the major occupied site of the glutarimide ring is shown.
	Fig. 2. A partial packing diagram of cocrystal (I). Only the major occupied site of the glutarimide ring is shown. Hydrogen bonds are shown as dotted lines. [Symmetry codes: (i) -x+1, -y+1, -z+1; (ii) -x, -y+1, -z+2.]
	Fig. 3. A perspective view of cocrystal (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probality level. Dashed lines indicate hydrogen bonds.
	Fig. 4. A partial packing diagram of cocrystal (II). Hydrogen bonds are shown as dotted lines. [Symmetry codes: (i) -x, -y+1, -z+1; (ii) -x+1, -y, -z+1.]

(I) 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine–piperidine-2,6-dione (1/1)

Crystal data

C14H18N4O3·C5H7NO2	Z = 4
Mr = 403.44	F(000) = 856
Monoclinic, P21/n	Dx = 1.293 Mg m^−3
Hall symbol: -P 2yn	Mo Kα radiation, λ = 0.71073 Å
a = 8.774 (2) Å	µ = 0.10 mm^−1
b = 17.046 (3) Å	T = 173 K
c = 14.168 (3) Å	Block, colourless
β = 102.04 (3)°	0.38 × 0.31 × 0.25 mm
V = 2072.4 (7) Å^3

Data collection

Stoe IPDS II two-circle diffractometer	3128 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.063
Graphite monochromator	θmax = 25.8°, θmin = 3.6°
phi scans	h = −10→10
27135 measured reflections	k = −20→20
3885 independent reflections	l = −17→17

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)] = 0.041	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.104	H atoms treated by a mixture of independent and constrained refinement
S = 1.18	w = 1/[σ^2(Fo^2) + (0.058P)^2] where P = (Fo^2 + 2Fc^2)/3
3885 reflections	(Δ/σ)max = 0.001
290 parameters	Δρmax = 0.31 e Å^−3
2 restraints	Δρmin = −0.22 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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
N1	0.35985 (13)	0.50636 (7)	0.57770 (8)	0.0251 (3)
C2	0.46253 (16)	0.55371 (8)	0.63566 (10)	0.0230 (3)
N2	0.60173 (15)	0.56461 (8)	0.61140 (10)	0.0309 (3)
H2A	0.666 (2)	0.6001 (12)	0.6448 (14)	0.042 (5)*
H2B	0.613 (2)	0.5460 (11)	0.5549 (15)	0.040 (5)*
N3	0.43890 (14)	0.58999 (7)	0.71665 (8)	0.0248 (3)
C4	0.29946 (16)	0.57890 (8)	0.74043 (10)	0.0240 (3)
N4	0.27641 (17)	0.61399 (8)	0.82188 (10)	0.0338 (3)
H4A	0.350 (2)	0.6451 (12)	0.8541 (14)	0.043 (5)*
H4B	0.196 (2)	0.6035 (11)	0.8472 (13)	0.039 (5)*
C5	0.17950 (16)	0.53359 (8)	0.68165 (9)	0.0227 (3)
C6	0.22041 (16)	0.49896 (8)	0.60289 (10)	0.0242 (3)
H6	0.1443	0.4672	0.5629	0.029*
C7	0.01762 (16)	0.52871 (8)	0.70136 (10)	0.0258 (3)
H7A	−0.0531	0.5082	0.6428	0.031*
H7B	−0.0174	0.5825	0.7125	0.031*
C8	−0.00020 (16)	0.47757 (8)	0.78714 (9)	0.0238 (3)
C9	0.08865 (17)	0.40970 (8)	0.80935 (10)	0.0260 (3)
H9	0.1641	0.3961	0.7728	0.031*
C10	0.06690 (17)	0.36149 (8)	0.88542 (10)	0.0275 (3)
O10	0.15032 (13)	0.29384 (6)	0.91296 (8)	0.0371 (3)
C11	−0.04298 (17)	0.38206 (8)	0.94015 (10)	0.0274 (3)
O11	−0.05919 (13)	0.33722 (6)	1.01941 (7)	0.0328 (3)
C12	−0.13137 (16)	0.45052 (8)	0.91736 (10)	0.0263 (3)
O12	−0.23431 (12)	0.46624 (6)	0.97554 (8)	0.0338 (3)
C13	−0.11032 (16)	0.49815 (8)	0.84050 (10)	0.0256 (3)
H13	−0.1710	0.5443	0.8249	0.031*
C14	0.2669 (2)	0.27369 (10)	0.85991 (13)	0.0439 (4)
H14A	0.2181	0.2672	0.7916	0.066*
H14B	0.3174	0.2245	0.8850	0.066*
H14C	0.3449	0.3156	0.8668	0.066*
C15	−0.1843 (2)	0.28144 (10)	0.99616 (12)	0.0374 (4)
H15A	−0.2810	0.3089	0.9676	0.056*
H15B	−0.1970	0.2544	1.0551	0.056*
H15C	−0.1600	0.2430	0.9500	0.056*
C16	−0.32823 (19)	0.53548 (10)	0.95372 (12)	0.0372 (4)
H16A	−0.2608	0.5808	0.9507	0.056*
H16B	−0.3877	0.5440	1.0042	0.056*
H16C	−0.4003	0.5289	0.8913	0.056*
N1'	0.65530 (16)	0.72199 (8)	0.80898 (10)	0.0325 (3)
H1'	0.598 (2)	0.6804 (13)	0.7864 (15)	0.049 (5)*
C2'	0.78363 (18)	0.73759 (9)	0.77020 (11)	0.0307 (3)
O2'	0.81893 (13)	0.69207 (7)	0.71155 (8)	0.0388 (3)
C3'	0.8712 (2)	0.81218 (11)	0.80146 (12)	0.0438 (4)
H3'1	0.8325	0.8539	0.7539	0.053*	0.879 (7)
H3'2	0.9830	0.8039	0.8019	0.053*	0.879 (7)
H3'3	0.9745	0.7972	0.8401	0.053*	0.121 (7)
H3'4	0.8897	0.8384	0.7425	0.053*	0.121 (7)
C4'A	0.8543 (2)	0.83987 (11)	0.90221 (15)	0.0351 (6)	0.879 (7)
H4'1	0.9132	0.8042	0.9519	0.042*	0.879 (7)
H4'2	0.8989	0.8932	0.9145	0.042*	0.879 (7)
C4'B	0.8079 (18)	0.8691 (7)	0.8552 (12)	0.044 (5)*	0.121 (7)
H4'3	0.7600	0.9110	0.8104	0.053*	0.121 (7)
H4'4	0.8949	0.8931	0.9021	0.053*	0.121 (7)
C5'	0.6882 (2)	0.84107 (10)	0.90966 (12)	0.0424 (4)
H5'1	0.6349	0.8845	0.8695	0.051*	0.879 (7)
H5'2	0.6823	0.8519	0.9774	0.051*	0.879 (7)
H5'3	0.7407	0.8352	0.9783	0.051*	0.121 (7)
H5'4	0.6094	0.8830	0.9066	0.051*	0.121 (7)
C6'	0.60338 (19)	0.76596 (10)	0.87836 (12)	0.0365 (4)
O6'	0.49030 (16)	0.74405 (9)	0.90849 (11)	0.0598 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0279 (6)	0.0263 (6)	0.0218 (6)	−0.0019 (5)	0.0070 (5)	−0.0033 (5)
C2	0.0269 (7)	0.0226 (6)	0.0198 (6)	0.0024 (5)	0.0056 (5)	0.0008 (5)
N2	0.0272 (7)	0.0411 (7)	0.0264 (7)	−0.0062 (6)	0.0102 (5)	−0.0113 (6)
N3	0.0273 (6)	0.0270 (6)	0.0212 (6)	−0.0021 (5)	0.0073 (5)	−0.0035 (5)
C4	0.0299 (7)	0.0214 (6)	0.0219 (7)	0.0005 (5)	0.0084 (5)	0.0012 (5)
N4	0.0367 (8)	0.0394 (7)	0.0298 (7)	−0.0119 (6)	0.0170 (6)	−0.0139 (6)
C5	0.0269 (7)	0.0209 (6)	0.0206 (6)	0.0000 (5)	0.0058 (5)	0.0048 (5)
C6	0.0279 (7)	0.0233 (7)	0.0211 (7)	−0.0030 (5)	0.0043 (5)	0.0002 (5)
C7	0.0269 (7)	0.0266 (7)	0.0246 (7)	−0.0005 (6)	0.0068 (6)	0.0032 (6)
C8	0.0257 (7)	0.0250 (7)	0.0203 (7)	−0.0058 (5)	0.0037 (5)	−0.0010 (5)
C9	0.0278 (7)	0.0283 (7)	0.0231 (7)	−0.0016 (6)	0.0082 (6)	−0.0005 (5)
C10	0.0330 (8)	0.0246 (7)	0.0232 (7)	−0.0021 (6)	0.0022 (6)	0.0004 (5)
O10	0.0484 (7)	0.0311 (6)	0.0338 (6)	0.0083 (5)	0.0133 (5)	0.0087 (5)
C11	0.0319 (8)	0.0309 (7)	0.0185 (7)	−0.0081 (6)	0.0034 (6)	0.0021 (5)
O11	0.0411 (6)	0.0347 (6)	0.0222 (5)	−0.0089 (5)	0.0061 (4)	0.0049 (4)
C12	0.0256 (7)	0.0333 (8)	0.0206 (7)	−0.0059 (6)	0.0060 (6)	−0.0033 (6)
O12	0.0354 (6)	0.0417 (6)	0.0276 (5)	−0.0002 (5)	0.0141 (4)	0.0009 (5)
C13	0.0259 (7)	0.0274 (7)	0.0229 (7)	−0.0017 (5)	0.0039 (5)	0.0002 (6)
C14	0.0566 (11)	0.0382 (9)	0.0393 (9)	0.0184 (8)	0.0158 (8)	0.0064 (7)
C15	0.0410 (9)	0.0356 (9)	0.0369 (9)	−0.0080 (7)	0.0112 (7)	0.0026 (7)
C16	0.0321 (8)	0.0495 (10)	0.0316 (8)	0.0046 (7)	0.0101 (6)	−0.0038 (7)
N1'	0.0339 (7)	0.0293 (7)	0.0339 (7)	−0.0057 (6)	0.0064 (6)	−0.0075 (6)
C2'	0.0343 (8)	0.0282 (7)	0.0276 (7)	0.0016 (6)	0.0020 (6)	0.0035 (6)
O2'	0.0393 (6)	0.0367 (6)	0.0422 (7)	0.0001 (5)	0.0127 (5)	−0.0038 (5)
C3'	0.0550 (11)	0.0402 (9)	0.0351 (9)	−0.0168 (8)	0.0068 (8)	0.0023 (7)
C4'A	0.0432 (11)	0.0251 (9)	0.0333 (11)	−0.0087 (8)	−0.0005 (8)	−0.0011 (8)
C5'	0.0591 (11)	0.0314 (8)	0.0337 (9)	−0.0029 (8)	0.0029 (8)	−0.0070 (7)
C6'	0.0359 (9)	0.0381 (9)	0.0337 (8)	−0.0017 (7)	0.0031 (7)	−0.0104 (7)
O6'	0.0502 (8)	0.0739 (10)	0.0619 (9)	−0.0234 (7)	0.0269 (7)	−0.0377 (8)

Geometric parameters (Å, º)

N1—C6	1.3498 (19)	C14—H14B	0.9800
N1—C2	1.3522 (18)	C14—H14C	0.9800
C2—N2	1.3489 (19)	C15—H15A	0.9800
C2—N3	1.3571 (18)	C15—H15B	0.9800
N2—H2A	0.89 (2)	C15—H15C	0.9800
N2—H2B	0.89 (2)	C16—H16A	0.9800
N3—C4	1.3483 (19)	C16—H16B	0.9800
C4—N4	1.3520 (19)	C16—H16C	0.9800
C4—C5	1.425 (2)	N1'—C2'	1.378 (2)
N4—H4A	0.89 (2)	N1'—C6'	1.387 (2)
N4—H4B	0.87 (2)	N1'—H1'	0.89 (2)
C5—C6	1.375 (2)	C2'—O2'	1.2230 (19)
C5—C7	1.506 (2)	C2'—C3'	1.504 (2)
C6—H6	0.9500	C3'—C4'B	1.416 (9)
C7—C8	1.5299 (19)	C3'—C4'A	1.540 (3)
C7—H7A	0.9900	C3'—H3'1	0.9900
C7—H7B	0.9900	C3'—H3'2	0.9900
C8—C13	1.390 (2)	C3'—H3'3	0.9900
C8—C9	1.394 (2)	C3'—H3'4	0.9900
C9—C10	1.400 (2)	C4'A—C5'	1.482 (3)
C9—H9	0.9500	C4'A—H4'1	0.9900
C10—O10	1.3779 (18)	C4'A—H4'2	0.9900
C10—C11	1.402 (2)	C4'B—C5'	1.504 (9)
O10—C14	1.432 (2)	C4'B—H4'3	0.9900
C11—O11	1.3900 (17)	C4'B—H4'4	0.9900
C11—C12	1.401 (2)	C5'—C6'	1.501 (2)
O11—C15	1.4374 (19)	C5'—H5'1	0.9900
C12—O12	1.3702 (18)	C5'—H5'2	0.9900
C12—C13	1.401 (2)	C5'—H5'3	0.9900
O12—C16	1.436 (2)	C5'—H5'4	0.9900
C13—H13	0.9500	C6'—O6'	1.218 (2)
C14—H14A	0.9800
C6—N1—C2	114.90 (12)	H16A—C16—H16B	109.5
N2—C2—N1	116.84 (13)	O12—C16—H16C	109.5
N2—C2—N3	117.32 (13)	H16A—C16—H16C	109.5
N1—C2—N3	125.84 (13)	H16B—C16—H16C	109.5
C2—N2—H2A	117.6 (13)	C2'—N1'—C6'	126.52 (14)
C2—N2—H2B	117.3 (12)	C2'—N1'—H1'	117.3 (13)
H2A—N2—H2B	123.0 (18)	C6'—N1'—H1'	116.2 (13)
C4—N3—C2	117.00 (12)	O2'—C2'—N1'	119.49 (14)
N3—C4—N4	117.15 (13)	O2'—C2'—C3'	123.39 (15)
N3—C4—C5	121.86 (12)	N1'—C2'—C3'	117.10 (14)
N4—C4—C5	120.98 (13)	C4'B—C3'—C2'	120.3 (5)
C4—N4—H4A	118.6 (13)	C2'—C3'—C4'A	112.96 (14)
C4—N4—H4B	122.5 (12)	C4'B—C3'—H3'1	75.9
H4A—N4—H4B	118.5 (18)	C2'—C3'—H3'1	109.0
C6—C5—C4	114.89 (13)	C4'A—C3'—H3'1	109.0
C6—C5—C7	122.88 (13)	C4'B—C3'—H3'2	126.4
C4—C5—C7	122.11 (12)	C2'—C3'—H3'2	109.0
N1—C6—C5	125.38 (13)	C4'A—C3'—H3'2	109.0
N1—C6—H6	117.3	H3'1—C3'—H3'2	107.8
C5—C6—H6	117.3	C4'B—C3'—H3'3	107.3
C5—C7—C8	115.81 (12)	C2'—C3'—H3'3	107.3
C5—C7—H7A	108.3	C4'A—C3'—H3'3	79.7
C8—C7—H7A	108.3	H3'1—C3'—H3'3	134.9
C5—C7—H7B	108.3	C4'B—C3'—H3'4	107.3
C8—C7—H7B	108.3	C2'—C3'—H3'4	107.3
H7A—C7—H7B	107.4	C4'A—C3'—H3'4	135.1
C13—C8—C9	120.40 (13)	H3'2—C3'—H3'4	74.5
C13—C8—C7	119.08 (12)	H3'3—C3'—H3'4	106.9
C9—C8—C7	120.48 (12)	C5'—C4'A—C3'	110.88 (15)
C8—C9—C10	120.10 (13)	C5'—C4'A—H4'1	109.5
C8—C9—H9	119.9	C3'—C4'A—H4'1	109.5
C10—C9—H9	119.9	C5'—C4'A—H4'2	109.5
O10—C10—C9	124.04 (14)	C3'—C4'A—H4'2	109.5
O10—C10—C11	116.01 (13)	H4'1—C4'A—H4'2	108.1
C9—C10—C11	119.93 (13)	C3'—C4'B—C5'	116.9 (7)
C10—O10—C14	116.58 (12)	C3'—C4'B—H4'3	108.1
O11—C11—C12	119.95 (13)	C5'—C4'B—H4'3	108.1
O11—C11—C10	120.49 (13)	C3'—C4'B—H4'4	108.1
C12—C11—C10	119.49 (13)	C5'—C4'B—H4'4	108.1
C11—O11—C15	112.37 (11)	H4'3—C4'B—H4'4	107.3
O12—C12—C11	115.27 (12)	C4'A—C5'—C6'	113.67 (15)
O12—C12—C13	124.37 (13)	C6'—C5'—C4'B	118.4 (4)
C11—C12—C13	120.36 (13)	C4'A—C5'—H5'1	108.8
C12—O12—C16	116.87 (12)	C6'—C5'—H5'1	108.8
C8—C13—C12	119.71 (13)	C4'B—C5'—H5'1	76.4
C8—C13—H13	120.1	C4'A—C5'—H5'2	108.8
C12—C13—H13	120.1	C6'—C5'—H5'2	108.8
O10—C14—H14A	109.5	C4'B—C5'—H5'2	128.4
O10—C14—H14B	109.5	H5'1—C5'—H5'2	107.7
H14A—C14—H14B	109.5	C4'A—C5'—H5'3	78.8
O10—C14—H14C	109.5	C6'—C5'—H5'3	107.7
H14A—C14—H14C	109.5	C4'B—C5'—H5'3	107.7
H14B—C14—H14C	109.5	H5'1—C5'—H5'3	135.0
O11—C15—H15A	109.5	C4'A—C5'—H5'4	134.0
O11—C15—H15B	109.5	C6'—C5'—H5'4	107.7
H15A—C15—H15B	109.5	C4'B—C5'—H5'4	107.7
O11—C15—H15C	109.5	H5'2—C5'—H5'4	74.4
H15A—C15—H15C	109.5	H5'3—C5'—H5'4	107.1
H15B—C15—H15C	109.5	O6'—C6'—N1'	119.66 (15)
O12—C16—H16A	109.5	O6'—C6'—C5'	123.26 (15)
O12—C16—H16B	109.5	N1'—C6'—C5'	117.03 (15)
C6—N1—C2—N2	−178.07 (12)	C10—C11—C12—O12	−179.25 (12)
C6—N1—C2—N3	3.1 (2)	O11—C11—C12—C13	176.85 (12)
N2—C2—N3—C4	179.94 (12)	C10—C11—C12—C13	0.0 (2)
N1—C2—N3—C4	−1.2 (2)	C11—C12—O12—C16	−179.32 (12)
C2—N3—C4—N4	179.01 (13)	C13—C12—O12—C16	1.5 (2)
C2—N3—C4—C5	−2.27 (19)	C9—C8—C13—C12	0.3 (2)
N3—C4—C5—C6	3.52 (19)	C7—C8—C13—C12	177.99 (12)
N4—C4—C5—C6	−177.81 (13)	O12—C12—C13—C8	178.68 (12)
N3—C4—C5—C7	−172.70 (12)	C11—C12—C13—C8	−0.5 (2)
N4—C4—C5—C7	6.0 (2)	C6'—N1'—C2'—O2'	177.55 (15)
C2—N1—C6—C5	−1.6 (2)	C6'—N1'—C2'—C3'	−4.0 (2)
C4—C5—C6—N1	−1.5 (2)	O2'—C2'—C3'—C4'B	168.2 (9)
C7—C5—C6—N1	174.67 (13)	N1'—C2'—C3'—C4'B	−10.3 (10)
C6—C5—C7—C8	109.40 (15)	O2'—C2'—C3'—C4'A	−154.99 (16)
C4—C5—C7—C8	−74.68 (17)	N1'—C2'—C3'—C4'A	26.6 (2)
C5—C7—C8—C13	147.65 (13)	C4'B—C3'—C4'A—C5'	60.8 (8)
C5—C7—C8—C9	−34.70 (18)	C2'—C3'—C4'A—C5'	−49.8 (2)
C13—C8—C9—C10	0.3 (2)	C2'—C3'—C4'B—C5'	22.1 (18)
C7—C8—C9—C10	−177.29 (12)	C4'A—C3'—C4'B—C5'	−64.3 (10)
C8—C9—C10—O10	−179.38 (13)	C3'—C4'A—C5'—C6'	50.8 (2)
C8—C9—C10—C11	−0.8 (2)	C3'—C4'A—C5'—C4'B	−55.4 (8)
C9—C10—O10—C14	0.8 (2)	C3'—C4'B—C5'—C4'A	69.6 (11)
C11—C10—O10—C14	−177.80 (14)	C3'—C4'B—C5'—C6'	−21.0 (17)
O10—C10—C11—O11	2.48 (19)	C2'—N1'—C6'—O6'	−177.79 (17)
C9—C10—C11—O11	−176.17 (12)	C2'—N1'—C6'—C5'	4.6 (2)
O10—C10—C11—C12	179.33 (12)	C4'A—C5'—C6'—O6'	153.46 (19)
C9—C10—C11—C12	0.7 (2)	C4'B—C5'—C6'—O6'	−169.4 (9)
C12—C11—O11—C15	86.33 (16)	C4'A—C5'—C6'—N1'	−29.0 (2)
C10—C11—O11—C15	−96.84 (16)	C4'B—C5'—C6'—N1'	8.1 (9)
O11—C11—C12—O12	−2.39 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1′—H1′···N3	0.89 (2)	2.17 (2)	3.0565 (19)	172.0 (18)
N2—H2A···O2′	0.89 (2)	2.15 (2)	3.0393 (19)	174.1 (18)
N4—H4A···O6′	0.89 (2)	2.13 (2)	2.997 (2)	164.3 (17)
N2—H2B···N1^i	0.89 (2)	2.14 (2)	3.0220 (18)	176.3 (17)
N4—H4B···O11^ii	0.87 (2)	2.64 (2)	3.3419 (19)	137.9 (15)

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

(II) 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine–4,4-dimethylpiperidine-2,6-dione (1/1)

Crystal data

C14H18N4O3·C7H11NO2	V = 1157.9 (4) Å^3
Mr = 431.49	Z = 2
Triclinic, P1	F(000) = 460
Hall symbol: -P 1	Dx = 1.238 Mg m^−3
a = 7.361 (2) Å	Mo Kα radiation, λ = 0.71073 Å
b = 12.032 (2) Å	µ = 0.09 mm^−1
c = 14.132 (3) Å	T = 173 K
α = 109.59 (3)°	Block, colourless
β = 92.48 (3)°	0.47 × 0.37 × 0.34 mm
γ = 99.14 (3)°

Data collection

Stoe IPDS II two-circle diffractometer	3479 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.048
Graphite monochromator	θmax = 25.6°, θmin = 3.6°
phi scans	h = −8→8
15922 measured reflections	k = −14→14
4314 independent reflections	l = −17→17

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)] = 0.038	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.106	w = 1/[σ^2(Fo^2) + (0.0621P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.15	(Δ/σ)max < 0.001
4314 reflections	Δρmax = 0.28 e Å^−3
306 parameters	Δρmin = −0.14 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.028 (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.

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

	x	y	z	Uiso*/Ueq
N1	−0.00496 (17)	0.33643 (10)	0.45211 (8)	0.0355 (3)
C2	0.1689 (2)	0.36416 (12)	0.49913 (9)	0.0317 (3)
N2	0.2411 (2)	0.48082 (11)	0.54479 (10)	0.0420 (3)
H2A	0.353 (3)	0.5024 (17)	0.5830 (15)	0.061 (6)*
H2B	0.172 (2)	0.5332 (16)	0.5411 (13)	0.048 (5)*
N3	0.27401 (16)	0.28306 (10)	0.50554 (8)	0.0303 (3)
C4	0.20120 (18)	0.16549 (11)	0.45853 (9)	0.0279 (3)
N4	0.31079 (18)	0.08684 (11)	0.46390 (9)	0.0338 (3)
H4A	0.428 (3)	0.1189 (16)	0.5029 (14)	0.053 (5)*
H4B	0.268 (2)	0.0086 (15)	0.4378 (11)	0.031 (4)*
C5	0.02039 (19)	0.12678 (12)	0.40617 (9)	0.0295 (3)
C6	−0.07234 (19)	0.21877 (13)	0.40805 (10)	0.0331 (3)
H6	−0.1947	0.1966	0.3752	0.040*
C7	−0.06721 (19)	−0.00315 (12)	0.35179 (10)	0.0318 (3)
H7A	−0.2031	−0.0109	0.3521	0.038*
H7B	−0.0259	−0.0516	0.3901	0.038*
C8	−0.02350 (17)	−0.05609 (11)	0.24254 (9)	0.0260 (3)
C9	0.15111 (17)	−0.02102 (11)	0.21564 (9)	0.0266 (3)
H9	0.2420	0.0368	0.2649	0.032*
C10	0.19194 (16)	−0.07109 (11)	0.11629 (9)	0.0255 (3)
O10	0.35487 (12)	−0.03742 (9)	0.08127 (7)	0.0371 (3)
C11	0.06178 (17)	−0.15892 (11)	0.04408 (9)	0.0244 (3)
O11	0.10689 (12)	−0.21160 (8)	−0.05321 (6)	0.0287 (2)
C12	−0.11425 (17)	−0.19251 (10)	0.07096 (10)	0.0267 (3)
O12	−0.23328 (13)	−0.27587 (8)	−0.00618 (8)	0.0386 (3)
C13	−0.15581 (17)	−0.14061 (11)	0.17032 (10)	0.0284 (3)
H13	−0.2752	−0.1634	0.1883	0.034*
C14	0.4816 (2)	0.06485 (16)	0.14772 (12)	0.0487 (4)
H14A	0.4169	0.1325	0.1732	0.073*
H14B	0.5832	0.0865	0.1109	0.073*
H14C	0.5314	0.0455	0.2046	0.073*
C15	0.04138 (19)	−0.15778 (12)	−0.12177 (10)	0.0317 (3)
H15A	−0.0941	−0.1708	−0.1274	0.048*
H15B	0.0824	−0.1944	−0.1884	0.048*
H15C	0.0912	−0.0714	−0.0962	0.048*
C16	−0.4233 (2)	−0.30057 (16)	0.00986 (15)	0.0537 (4)
H16A	−0.4345	−0.3361	0.0629	0.081*
H16B	−0.4939	−0.3568	−0.0529	0.081*
H16C	−0.4721	−0.2257	0.0306	0.081*
N1'	0.63437 (17)	0.36411 (10)	0.63542 (9)	0.0335 (3)
H1'	0.522 (3)	0.3398 (15)	0.5955 (14)	0.050 (5)*
C2'	0.6890 (2)	0.48679 (12)	0.68843 (10)	0.0337 (3)
O2'	0.58454 (16)	0.55520 (9)	0.68556 (9)	0.0485 (3)
C3'	0.8773 (2)	0.52742 (12)	0.74509 (11)	0.0361 (3)
H3'A	0.8784	0.6029	0.8021	0.043*
H3'B	0.9673	0.5454	0.6998	0.043*
C4'	0.94108 (18)	0.43534 (12)	0.78683 (10)	0.0317 (3)
C5'	0.91750 (19)	0.31542 (12)	0.69934 (10)	0.0330 (3)
H5'A	1.0150	0.3214	0.6543	0.040*
H5'B	0.9372	0.2524	0.7272	0.040*
C6'	0.73329 (19)	0.27654 (12)	0.63749 (10)	0.0310 (3)
O6'	0.66948 (15)	0.17077 (9)	0.58926 (8)	0.0417 (3)
C7'	0.8208 (2)	0.42118 (14)	0.86976 (11)	0.0425 (4)
H7'1	0.8610	0.3624	0.8961	0.064*
H7'2	0.6910	0.3934	0.8414	0.064*
H7'3	0.8337	0.4987	0.9246	0.064*
C8'	1.1439 (2)	0.47784 (14)	0.83005 (13)	0.0470 (4)
H8'1	1.1829	0.4202	0.8582	0.070*
H8'2	1.1587	0.5566	0.8834	0.070*
H8'3	1.2202	0.4840	0.7763	0.070*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0448 (7)	0.0368 (7)	0.0287 (6)	0.0253 (5)	0.0026 (5)	0.0085 (5)
C2	0.0444 (8)	0.0340 (7)	0.0232 (6)	0.0237 (6)	0.0070 (6)	0.0106 (5)
N2	0.0495 (8)	0.0317 (7)	0.0465 (8)	0.0253 (6)	−0.0037 (6)	0.0085 (6)
N3	0.0406 (6)	0.0305 (6)	0.0253 (5)	0.0211 (5)	0.0052 (5)	0.0098 (5)
C4	0.0388 (7)	0.0318 (7)	0.0202 (6)	0.0198 (6)	0.0094 (5)	0.0114 (5)
N4	0.0421 (7)	0.0262 (6)	0.0349 (6)	0.0171 (5)	−0.0006 (5)	0.0083 (5)
C5	0.0379 (7)	0.0354 (7)	0.0211 (6)	0.0188 (6)	0.0107 (5)	0.0111 (5)
C6	0.0372 (7)	0.0420 (8)	0.0242 (6)	0.0208 (6)	0.0049 (5)	0.0103 (6)
C7	0.0349 (7)	0.0380 (7)	0.0291 (7)	0.0146 (6)	0.0112 (6)	0.0156 (6)
C8	0.0303 (6)	0.0265 (6)	0.0281 (6)	0.0137 (5)	0.0080 (5)	0.0140 (5)
C9	0.0252 (6)	0.0301 (7)	0.0243 (6)	0.0084 (5)	0.0010 (5)	0.0079 (5)
C10	0.0227 (6)	0.0303 (7)	0.0272 (6)	0.0111 (5)	0.0054 (5)	0.0115 (5)
O10	0.0232 (5)	0.0494 (6)	0.0302 (5)	0.0017 (4)	0.0079 (4)	0.0044 (4)
C11	0.0295 (6)	0.0218 (6)	0.0247 (6)	0.0125 (5)	0.0051 (5)	0.0078 (5)
O11	0.0363 (5)	0.0268 (5)	0.0238 (4)	0.0136 (4)	0.0057 (4)	0.0060 (4)
C12	0.0291 (6)	0.0186 (6)	0.0324 (7)	0.0060 (5)	0.0023 (5)	0.0083 (5)
O12	0.0315 (5)	0.0299 (5)	0.0427 (6)	−0.0030 (4)	0.0028 (4)	0.0014 (4)
C13	0.0272 (6)	0.0250 (6)	0.0375 (7)	0.0080 (5)	0.0104 (5)	0.0142 (5)
C14	0.0251 (7)	0.0645 (11)	0.0408 (9)	−0.0064 (7)	0.0058 (6)	0.0042 (7)
C15	0.0354 (7)	0.0298 (7)	0.0295 (7)	0.0030 (6)	0.0000 (5)	0.0116 (5)
C16	0.0297 (8)	0.0482 (10)	0.0669 (11)	−0.0023 (7)	0.0030 (7)	0.0034 (8)
N1'	0.0386 (7)	0.0279 (6)	0.0355 (6)	0.0143 (5)	−0.0011 (5)	0.0097 (5)
C2'	0.0450 (8)	0.0274 (7)	0.0337 (7)	0.0149 (6)	0.0056 (6)	0.0132 (6)
O2'	0.0560 (7)	0.0316 (6)	0.0581 (7)	0.0236 (5)	−0.0058 (5)	0.0103 (5)
C3'	0.0407 (8)	0.0268 (7)	0.0433 (8)	0.0080 (6)	0.0040 (6)	0.0146 (6)
C4'	0.0353 (7)	0.0271 (7)	0.0335 (7)	0.0086 (6)	0.0011 (6)	0.0107 (5)
C5'	0.0366 (7)	0.0317 (7)	0.0349 (7)	0.0163 (6)	0.0039 (6)	0.0124 (6)
C6'	0.0393 (7)	0.0274 (7)	0.0302 (7)	0.0158 (6)	0.0062 (6)	0.0105 (5)
O6'	0.0476 (6)	0.0266 (5)	0.0480 (6)	0.0163 (5)	−0.0067 (5)	0.0062 (4)
C7'	0.0581 (9)	0.0406 (8)	0.0325 (8)	0.0157 (7)	0.0082 (7)	0.0142 (6)
C8'	0.0433 (9)	0.0378 (8)	0.0572 (10)	0.0089 (7)	−0.0080 (7)	0.0140 (7)

Geometric parameters (Å, º)

N1—C6	1.3405 (19)	C14—H14A	0.9800
N1—C2	1.3538 (19)	C14—H14B	0.9800
C2—N2	1.340 (2)	C14—H14C	0.9800
C2—N3	1.3608 (16)	C15—H15A	0.9800
N2—H2A	0.91 (2)	C15—H15B	0.9800
N2—H2B	0.884 (18)	C15—H15C	0.9800
N3—C4	1.3519 (18)	C16—H16A	0.9800
C4—N4	1.3556 (16)	C16—H16B	0.9800
C4—C5	1.422 (2)	C16—H16C	0.9800
N4—H4A	0.95 (2)	N1'—C6'	1.3798 (16)
N4—H4B	0.886 (16)	N1'—C2'	1.3947 (19)
C5—C6	1.3833 (18)	N1'—H1'	0.928 (19)
C5—C7	1.510 (2)	C2'—O2'	1.2211 (16)
C6—H6	0.9500	C2'—C3'	1.493 (2)
C7—C8	1.5302 (17)	C3'—C4'	1.5411 (18)
C7—H7A	0.9900	C3'—H3'A	0.9900
C7—H7B	0.9900	C3'—H3'B	0.9900
C8—C13	1.388 (2)	C4'—C8'	1.527 (2)
C8—C9	1.3972 (18)	C4'—C5'	1.532 (2)
C9—C10	1.3969 (17)	C4'—C7'	1.537 (2)
C9—H9	0.9500	C5'—C6'	1.498 (2)
C10—O10	1.3708 (15)	C5'—H5'A	0.9900
C10—C11	1.3952 (19)	C5'—H5'B	0.9900
O10—C14	1.4319 (19)	C6'—O6'	1.2270 (18)
C11—O11	1.3872 (15)	C7'—H7'1	0.9800
C11—C12	1.4021 (18)	C7'—H7'2	0.9800
O11—C15	1.4388 (15)	C7'—H7'3	0.9800
C12—O12	1.3663 (17)	C8'—H8'1	0.9800
C12—C13	1.4018 (18)	C8'—H8'2	0.9800
O12—C16	1.4275 (18)	C8'—H8'3	0.9800
C13—H13	0.9500
C6—N1—C2	115.20 (11)	H14B—C14—H14C	109.5
N2—C2—N1	117.15 (12)	O11—C15—H15A	109.5
N2—C2—N3	117.62 (13)	O11—C15—H15B	109.5
N1—C2—N3	125.21 (13)	H15A—C15—H15B	109.5
C2—N2—H2A	119.3 (12)	O11—C15—H15C	109.5
C2—N2—H2B	117.4 (11)	H15A—C15—H15C	109.5
H2A—N2—H2B	123.1 (17)	H15B—C15—H15C	109.5
C4—N3—C2	117.39 (12)	O12—C16—H16A	109.5
N3—C4—N4	116.12 (12)	O12—C16—H16B	109.5
N3—C4—C5	121.85 (11)	H16A—C16—H16B	109.5
N4—C4—C5	122.03 (13)	O12—C16—H16C	109.5
C4—N4—H4A	117.5 (11)	H16A—C16—H16C	109.5
C4—N4—H4B	120.3 (10)	H16B—C16—H16C	109.5
H4A—N4—H4B	121.9 (15)	C6'—N1'—C2'	125.52 (12)
C6—C5—C4	114.49 (13)	C6'—N1'—H1'	117.6 (11)
C6—C5—C7	121.44 (12)	C2'—N1'—H1'	116.8 (11)
C4—C5—C7	124.08 (11)	O2'—C2'—N1'	119.64 (13)
N1—C6—C5	125.83 (13)	O2'—C2'—C3'	123.38 (13)
N1—C6—H6	117.1	N1'—C2'—C3'	116.97 (12)
C5—C6—H6	117.1	C2'—C3'—C4'	114.06 (12)
C5—C7—C8	115.19 (11)	C2'—C3'—H3'A	108.7
C5—C7—H7A	108.5	C4'—C3'—H3'A	108.7
C8—C7—H7A	108.5	C2'—C3'—H3'B	108.7
C5—C7—H7B	108.5	C4'—C3'—H3'B	108.7
C8—C7—H7B	108.5	H3'A—C3'—H3'B	107.6
H7A—C7—H7B	107.5	C8'—C4'—C5'	110.09 (12)
C13—C8—C9	119.81 (11)	C8'—C4'—C7'	109.91 (13)
C13—C8—C7	120.18 (11)	C5'—C4'—C7'	109.85 (12)
C9—C8—C7	119.99 (12)	C8'—C4'—C3'	109.73 (12)
C10—C9—C8	119.93 (12)	C5'—C4'—C3'	107.77 (11)
C10—C9—H9	120.0	C7'—C4'—C3'	109.46 (11)
C8—C9—H9	120.0	C6'—C5'—C4'	115.05 (11)
O10—C10—C11	115.17 (11)	C6'—C5'—H5'A	108.5
O10—C10—C9	124.22 (12)	C4'—C5'—H5'A	108.5
C11—C10—C9	120.58 (11)	C6'—C5'—H5'B	108.5
C10—O10—C14	117.48 (10)	C4'—C5'—H5'B	108.5
O11—C11—C10	119.99 (11)	H5'A—C5'—H5'B	107.5
O11—C11—C12	120.73 (12)	O6'—C6'—N1'	119.80 (13)
C10—C11—C12	119.27 (11)	O6'—C6'—C5'	122.27 (12)
C11—O11—C15	112.28 (9)	N1'—C6'—C5'	117.93 (12)
O12—C12—C13	125.47 (12)	C4'—C7'—H7'1	109.5
O12—C12—C11	114.58 (11)	C4'—C7'—H7'2	109.5
C13—C12—C11	119.94 (12)	H7'1—C7'—H7'2	109.5
C12—O12—C16	118.23 (12)	C4'—C7'—H7'3	109.5
C8—C13—C12	120.39 (11)	H7'1—C7'—H7'3	109.5
C8—C13—H13	119.8	H7'2—C7'—H7'3	109.5
C12—C13—H13	119.8	C4'—C8'—H8'1	109.5
O10—C14—H14A	109.5	C4'—C8'—H8'2	109.5
O10—C14—H14B	109.5	H8'1—C8'—H8'2	109.5
H14A—C14—H14B	109.5	C4'—C8'—H8'3	109.5
O10—C14—H14C	109.5	H8'1—C8'—H8'3	109.5
H14A—C14—H14C	109.5	H8'2—C8'—H8'3	109.5
C6—N1—C2—N2	−179.55 (12)	C10—C11—O11—C15	−97.87 (13)
C6—N1—C2—N3	−1.10 (19)	C12—C11—O11—C15	81.83 (13)
N2—C2—N3—C4	−179.38 (11)	O11—C11—C12—O12	−2.02 (16)
N1—C2—N3—C4	2.17 (19)	C10—C11—C12—O12	177.69 (10)
C2—N3—C4—N4	178.32 (11)	O11—C11—C12—C13	178.32 (10)
C2—N3—C4—C5	−1.43 (17)	C10—C11—C12—C13	−1.97 (17)
N3—C4—C5—C6	−0.18 (17)	C13—C12—O12—C16	9.77 (19)
N4—C4—C5—C6	−179.92 (11)	C11—C12—O12—C16	−169.87 (13)
N3—C4—C5—C7	179.55 (11)	C9—C8—C13—C12	1.09 (17)
N4—C4—C5—C7	−0.19 (18)	C7—C8—C13—C12	−177.73 (11)
C2—N1—C6—C5	−0.78 (19)	O12—C12—C13—C8	−179.71 (11)
C4—C5—C6—N1	1.36 (19)	C11—C12—C13—C8	−0.10 (17)
C7—C5—C6—N1	−178.38 (11)	C6'—N1'—C2'—O2'	−175.54 (13)
C6—C5—C7—C8	93.12 (14)	C6'—N1'—C2'—C3'	5.5 (2)
C4—C5—C7—C8	−86.60 (15)	O2'—C2'—C3'—C4'	148.90 (14)
C5—C7—C8—C13	−145.35 (12)	N1'—C2'—C3'—C4'	−32.16 (17)
C5—C7—C8—C9	35.83 (16)	C2'—C3'—C4'—C8'	172.07 (12)
C13—C8—C9—C10	−0.02 (17)	C2'—C3'—C4'—C5'	52.18 (16)
C7—C8—C9—C10	178.81 (11)	C2'—C3'—C4'—C7'	−67.25 (16)
C8—C9—C10—O10	175.97 (11)	C8'—C4'—C5'—C6'	−168.30 (12)
C8—C9—C10—C11	−2.08 (17)	C7'—C4'—C5'—C6'	70.54 (15)
C11—C10—O10—C14	170.55 (12)	C3'—C4'—C5'—C6'	−48.65 (15)
C9—C10—O10—C14	−7.60 (18)	C2'—N1'—C6'—O6'	178.44 (13)
O10—C10—C11—O11	4.55 (16)	C2'—N1'—C6'—C5'	−1.8 (2)
C9—C10—C11—O11	−177.23 (10)	C4'—C5'—C6'—O6'	−155.05 (13)
O10—C10—C11—C12	−175.16 (10)	C4'—C5'—C6'—N1'	25.15 (17)
C9—C10—C11—C12	3.06 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1′—H1′···N3	0.928 (19)	2.06 (2)	2.985 (2)	178.9 (17)
N2—H2A···O2′	0.91 (2)	2.06 (2)	2.966 (2)	172.3 (17)
N4—H4A···O6′	0.95 (2)	2.00 (2)	2.946 (2)	173.8 (16)
N2—H2B···N1^i	0.884 (18)	2.121 (19)	3.0027 (18)	174.3 (15)
N4—H4B···O6′^ii	0.886 (16)	2.188 (16)	2.9637 (16)	145.9 (13)

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