Crystal structure of the thalidomide analog (3aR*,7aS*)-2-(2,6-dioxopiperidin-3-yl)hexa­hydro-1H-iso­indole-1,3(2H)-dione

Hijji, Y.; Benjamin, E.; Jasinski, J.P.; Butcher, R.J.

doi:10.1107/S2056989018014317

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ISSN: 2056-9890

Volume 74| Part 11| November 2018| Pages 1595-1598

https://doi.org/10.1107/S2056989018014317

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Crystal structure of the thalidomide analog (3aR,7aS)-2-(2,6-dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione

Yousef Hijji,^a Ellis Benjamin,^b Jerry P. Jasinski ^c and Ray J. Butcher ^d ^*

^aDepartment of Chemistry and Earth Sciences, Qatar University, Doha, Qatar, ^bDepartment of Chemistry, Richard Stockton College of New Jersey, Galloway, NJ 08205, USA, ^cDepartment of Chemistry, Keene State College, 229 Main Street, Keene NH 03435, USA, and ^dDepartment of Chemistry, Howard University, 525 College Street NW, Washington, DC 20059, USA
^*Correspondence e-mail: rbutcher99@yahoo.com

Edited by A. J. Lough, University of Toronto, Canada (Received 23 August 2018; accepted 10 October 2018; online 16 October 2018)

The title compound, C₁₃H₁₆N₂O₄, crystallizes in the monoclinic centrosymmetric space group, P2₁/c, with four molecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine-2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, except for the six-membered unsaturated ring substituted for the aromatic ring. In the crystal, the molecules are linked into inversion dimers by R²₂(8) hydrogen bonding involving the N—H group. In addition, there are bifurcated C—H⋯O interactions involving one of the O atoms on the pyrrolidine-2,5-dione with graph-set notation R¹₂(5). These interactions along with C—H⋯O interactions involving one of the O atoms on the piperidine-2,6-dione ring link the molecules into a complex three-dimensional array. There is pseudomerohedral twinning present which results from a 180° rotation about the [100] reciprocal lattice direction and with a twin law of 1 0 0 0 $[\overline{1}]$ 0 0 0 $[\overline{1}]$ [BASF 0.044 (1)].

Keywords: crystal structure; thalidomide analogs; pseudomerohedral twinning.

CCDC reference: 1872551

1. Chemical context

Thalidomide (1) is one of the most notorious drugs in pharmaceutical history because of the humanitarian disaster in the 1950s (Burley & Lenz, 1962 ; Stephans, 1988 ; Bartlett et al., 2004 ; Wu et al., 2005 ; Melchert & List, 2007 ). Thalidomide possesses a single stereogenic carbon in the glutarimide ring, and it is conceivable that the unexpected teratogenic side effects are ascribed to the (S)-enantiomer of 1 (Blaschke et al., 1979 ). However, this has been a matter of debate because considerable chiral inversion should take place during the incubation of enantiomerically pure 1 (Nishimura et al., 1994 ; Knoche & Blaschke, 1994 ; Wnendt et al., 1996 ). Despite the tragic disaster, the unique biological properties of 1 prompted its return to the market in the 21st century for the treatment of multiple myeloma and leprosy (Matthews & McCoy, 2003 ; Hashimoto et al., 2004 ; Franks et al., 2004 ; Brennen et al., 2004 ; Luzzio et al., 2004 ; Sleijfer et al., 2004 ; Kumar et al., 2004 ; Hashimoto, 2008 ; Knobloch & Rüther, 2008 ). Furthermore, a large number of papers on novel medical uses of 1 continue to appear in the biological and medicinal literature (Matthews & McCoy, 2003; Hashimoto et al., 2004; Franks et al., 2004; Brennen et al., 2004; Luzzio et al., 2004; Sleijfer et al., 2004; Kumar et al., 2004; Hashimoto, 2008; Knobloch & Rüther, 2008).

Thus, over the years, there has been increasing interest in thalidomide and its derivatives for the treatment of various hematologic malignancies (Singhal et al., 1999 ; Raje & Anderson, 1999 ), solid tumors (Kumar et al., 2002 ), and a variety of inflammatory and autoimmune diseases (Tseng et al., 1996 ). Recent studies have uncovered a variety of mechanisms of thalidomide action. It was reported in 1991 that thalidomide is a selective inhibitor of tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS) stimulated human monocytes (Moreira et al., 1993 ; Sampaio et al., 1991 ). TNF-a is a key pro-inflammatory cytokine, and elevated levels have been linked with the pathology of a number of inflammatory and autoimmune diseases including rheumatoid arthritis, Crohn's disease, aphthous ulcers, cachexia, graft versus host disease, asthma, ARDS and AIDS (Eigler et al., 1997 ). Taken together, the immunomodulatory properties of thalidomide, which are dependent on the type of immune cell activated as well as the type of stimulus that the cell receives, provide a rationale for the mechanism of thalidomide action in the context of autoimmune and inflammatory disease states. Other pharmacologic activities of thalidomide include its inhibition of angiogenesis (D'Amato et al., 1994 ) and its anti-cancer properties (Bartlett et al., 2004). In the late 1990′s it was reported that thalidomide is efficacious for the treatment of multiple myeloma (MM), a hematological cancer caused by growth of tumor cells derived from the plasma cells in the bone marrow (Singhal et al., 1999; Raje & Anderson, 1999).

A medicinal chemistry program to optimize the immunomodulatory properties of thalidomide and reduce its side-effects led to the discovery of lenalidomide (2), which is a potent immunomodulator that is ∼800 times more potent as an inhibitor of TNF-α in LPS-stimulated hPBMC (Muller et al., 1999 ; Zeldis et al., 2011 ). In the US, lenalidomide was approved by the FDA in 2005 for low- or intermediate-1-risk myelodysplastic

Structural optimization of thalidomide, 1 also led to the discovery of pomalidomide (3), which is tenfold more potent than lenalidomide as a TNF-a inhibitor and IL-2 stimulator (Muller et al., 1999; Zeldis et al., 2011). Pomalidomide is currently undergoing late-stage clinical development for the treatment of multiple myeloma and myeloproliferative neoplasm-associated myelofibrosis (Galustian & Dalgleish, 2011 ; Begna et al., 2012 ). In clinical trials for multiple myeloma, pomalidomide has been shown to be effective in overcoming resistance to lenalidomide and thalidomide, as well as the proteosome inhibitor bortezomib (Schey & Ramasamy, 2011 ).

These studies have shown the efficacy of a continued search for more pharmacologically active analogs of thalidomide and its derivatives. Focus has previously been on modifying the basic thalidomide skeleton by changing its substituents. However, there have been very few studies on related derivatives where the six-membered ring is changed from an aromatic to an unsaturated ring. In view of the wide interest in these types of compounds for their pharmacological activities, the structure of (3aR,7aS)-2-(2,6-dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione, 4, is reported where the only change to thalidomide is the substitution of an unsaturated six-membered for the aromatic ring.

As a result of this interest in thalidomide, the crystal structure of this molecule in both the racemic and enantiomerically pure forms have been determined multiple times (Lovell, 1970 , 1971 ; Reepmeyer et al., 1994 ; Allen & Trotter, 1971 ; Caira et al., 1994 ; Suzuki et al., 2010 ; Maeno et al., 2015 ). Two polymorphs of the racemic derivative have been determined crystallizing in the space groups P2₁/n (Allen & Trotter, 1971; Suzuki et al., 2010; Maeno et al., 2015) and P2₁/c (Lovell, 1970) or C2/c (Reepmeyer et al., 1994; Caira et al., 1994). The crystal packing in the C2/c structure is determined by intermolecular N–H⋯O hydrogen bonding that is more extensive than that reported for the racemate of thalidomide crystallizing in space group P2₁/n.

2. Structural commentary

The title compound, C₁₃H₁₆N₂O₄, 4 (Fig. 1), crystallizes in the monoclinic centrosymmetric space group, P2₁/c, with four molecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine-2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, 1, except for the six-membered unsaturated ring substituted for the aromatic ring. In the five-membered pyrrolidine-2,5-dione ring, the atoms O1, C1, N1, C8 and O2 form a plane (r.m.s. deviation of fitted atoms = 0.0348 Å) with C2 and C7 deviating from this plane by −0.186 (7) and 0.219 (7) Å, respectively. The ring itself adopts a conformation in which it is twisted about the C2–C7 axis [P = 257.4 (5) and τ = 22.5 (2); Rao et al., 1981 ]. In the six-membered piperidine-2,6-dione ring, the group, O3, C10, N2, C11and O4 is also planar (r.m.s. deviation of fitted atoms = 0.0042 Å). The cyclohexane ring adopts a chair conformation [puckering parameters Q = 0.536 (3), θ = 157.7 (3)° and φ = 324.2 (8)°; Boeyens, 1978 ). Otherwise, the metrical parameters for all bonds are in the standard range for such structures.

Figure 1
The molecular structure of the title compound 4, with the atom-numbering scheme. Atomic displacement parameters are drawn at the 30% probability level.

3. Supramolecular features

Similarly to the hydrogen-bonding patterns found in both the enantiomerically pure form of thalidomide (Lovell, 1971; Maeno et al., 2015) and the racemic P2₁/n polymorph (Allen & Trotter, 1971; Suzuki et al., 2010; Maeno et al., 2015), the molecules of the title compound are linked into inversion dimers by R₂²(8) (Etter et al., 1990 ) hydrogen bonding (Table 1) involving the N—H group as shown in Fig. 2. In addition, there are bifurcated C—H⋯O interactions involving O2 with graph-set notation R₂¹(5). These interactions, along with C—H⋯O interactions involving O4, link the molecules into a complex three-dimensional array.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2N⋯O3ⁱ	0.88 (5)	2.07 (5)	2.928 (3)	165 (4)
C7—H7A⋯O4ⁱⁱ	1.00	2.42	3.150 (3)	129
C9—H9A⋯O1ⁱⁱⁱ	1.00	2.65	3.385 (3)	130
C12—H12A⋯O2ⁱⁱ	0.99	2.53	3.143 (3)	120
C13—H13A⋯O2	0.99	2.56	3.142 (3)	118
C13—H13B⋯O2ⁱⁱ	0.99	2.52	3.163 (3)	122
Symmetry codes: (i) -x+1, -y+2, -z+1; (ii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) -x+1, -y+1, -z+1.

Figure 2
Packing diagram viewed along the a axis showing the extensive N—H⋯O and C—H⋯O interactions (drawn as dashed lines) linking the molecules into a complex three-dimensional array.

4. Database survey

A search of the Cambridge Structural Database (CSD version 5.39; Groom et al., 2016 ) using a skeleton containing the three rings as in thalidomide but without the ketone substituents gave 39 hits but not a single example where the six-membered aromatic ring in the isoindoline moiety is changed to an unsaturated six-membered ring.

5. Synthesis and crystallization

Some details of the synthesis have been previously reported (Benjamin & Hijji, 2017 ). cis-1,2-Cyclohexane dicarboxylic acid anhydride (0.10 g, 0.65 mmol), glutamic acid (0.095 g, 0.65 mmol), DMAP (0.02 g, 0.16 mmol), and ammonium chloride (NH₄Cl) (0.040 g, 0.75 mmol) were mixed thoroughly in a CEM-sealed vial with a magnetic stirrer. The sample was heated for 6 min at 423 K in a CEM Discover microwave powered at 150 W. It was then cooled rapidly to 313 K and dissolved in 15 ml of (1:1) ethyl acetate:acetone. The organic layer was washed with 2× 10 ml of distilled water and dried over sodium sulfate (anhydrous). The organic layer was concentrated under vacuum and precipitated with hexanes (30 ml) affording a white solid. Crystals suitable for X-ray experiments were grown by slow evaporation of an ethyl acetate/acetone (1:1) solution. M.p. 463–465 K, (0.12 g, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.0 (s, 1 H, NH), 4.9 (dd, 1 H, 12.5, 5.5 Hz, CHCO), 3.0 (m, 1 H), 2.8 (m, 1 H), 2.8 (m, 1 H), 2.5 (m, 1 H), 1.9 (m, 1 H), 1.7 (m, 3 H),, 1.6 (m, 1 H), 1.4 (m, 4 H); ¹³C NMR (100 MHz, DMSO-d₆) 178.8 (C=O), 178.7 (C=O), 172.7 (C=O), 169.4 (C=O), 48.7 (CH), 39.1 (CH), 38.8 (CH), 30.7 (CH₂), 23.1 (CH₂), 22.9 (CH₂), 21.1 (CH₂), 21.05 (CH₂), 21.00 (CH₂); MS 264 (M⁺); 236, 210, 179, 154, 112, 82, 67, 54, 41.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were positioned geometrically and treated as riding on their parent atoms and refined with C—H distances of 0.99–1.00 Å and U_iso(H) = 1.2U_eq(C). The H attached to N2 was refined isotropically. There is pseudomerohedral twinning present, which results from a 180° rotation about the [100] reciprocal lattice direction and with a twin law of 1 0 0 0 $[\overline{1}]$ 0 0 0 $[\overline{1}]$ [BASF 0.044 (1)].

Table 2
Experimental details

Crystal data
Chemical formula	C₁₃H₁₆N₂O₄
M_r	264.28
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	123
a, b, c (Å)	11.4519 (3), 9.2370 (3), 11.8727 (4)
β (°)	90.475 (3)
V (Å³)	1255.87 (7)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.87
Crystal size (mm)	0.42 × 0.34 × 0.18

Data collection
Diffractometer	Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2012 $[Rigaku OD (2012). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.822, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	9733, 2626, 2572
R_int	0.024
(sin θ/λ)_max (Å⁻¹)	0.633

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.066, 0.208, 1.19
No. of reflections	2626
No. of parameters	177
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.33, −0.35
Computer programs: CrysAlis PRO (Rigaku OD, 2012 $[Rigaku OD (2012). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SHELXS97 and SHELXTL (Sheldrick, 2008 ) and SHELXL2018/3 (Sheldrick, 2015 ).

Supporting information

CCDC reference: 1872551

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989018014317/lh5881sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989018014317/lh5881Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989018014317/lh5881Isup3.cml

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2012); cell refinement: CrysAlis PRO (Rigaku OD, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

(3aR*,7aS*)-2-(2,6-Dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione top

Crystal data top

C₁₃H₁₆N₂O₄	F(000) = 560
M_r = 264.28	D_x = 1.398 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54178 Å
a = 11.4519 (3) Å	Cell parameters from 7629 reflections
b = 9.2370 (3) Å	θ = 3.7–77.3°
c = 11.8727 (4) Å	µ = 0.87 mm⁻¹
β = 90.475 (3)°	T = 123 K
V = 1255.87 (7) Å³	Prism, colorless
Z = 4	0.42 × 0.34 × 0.18 mm

Data collection top

Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini diffractometer	2572 reflections with I > 2σ(I)
Detector resolution: 10.5081 pixels mm^-1	R_int = 0.024
ω scans	θ_max = 77.5°, θ_min = 3.7°
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2012)	h = −9→14
T_min = 0.822, T_max = 1.000	k = −10→11
9733 measured reflections	l = −14→14
2626 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.066	Hydrogen site location: mixed
wR(F²) = 0.208	H atoms treated by a mixture of independent and constrained refinement
S = 1.19	w = 1/[σ²(F_o²) + (0.1179P)² + 1.1244P] where P = (F_o² + 2F_c²)/3
2626 reflections	(Δ/σ)_max < 0.001
177 parameters	Δρ_max = 0.33 e Å⁻³
0 restraints	Δρ_min = −0.35 e Å⁻³

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refined as a two-component twin

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.66960 (17)	0.4309 (2)	0.56402 (17)	0.0291 (4)
O2	0.67111 (18)	0.8499 (2)	0.76606 (18)	0.0305 (5)
O3	0.58392 (17)	0.8448 (2)	0.51862 (17)	0.0299 (5)
O4	0.21720 (17)	0.9000 (2)	0.64578 (19)	0.0339 (5)
N1	0.64254 (19)	0.6373 (2)	0.66901 (18)	0.0228 (5)
N2	0.4008 (2)	0.8685 (2)	0.58537 (19)	0.0263 (5)
H2N	0.393 (4)	0.952 (5)	0.550 (3)	0.043 (10)*
C1	0.7100 (2)	0.5317 (3)	0.6160 (2)	0.0233 (5)
C2	0.8368 (2)	0.5762 (3)	0.6283 (2)	0.0240 (5)
H2A	0.886927	0.491448	0.648892	0.029*
C3	0.8713 (2)	0.6388 (3)	0.5124 (2)	0.0288 (6)
H3A	0.893112	0.558146	0.461791	0.035*
H3B	0.802837	0.688401	0.478581	0.035*
C4	0.9729 (2)	0.7454 (3)	0.5201 (2)	0.0311 (6)
H4A	1.043151	0.695475	0.549779	0.037*
H4B	0.990952	0.783222	0.444218	0.037*
C5	0.9407 (2)	0.8704 (3)	0.5979 (2)	0.0295 (6)
H5A	1.003226	0.944367	0.597275	0.035*
H5B	0.867389	0.916344	0.571200	0.035*
C6	0.9248 (2)	0.8128 (3)	0.7171 (2)	0.0278 (6)
H6A	0.899178	0.893048	0.766341	0.033*
H6B	1.001037	0.777727	0.746054	0.033*
C7	0.8356 (2)	0.6895 (3)	0.7240 (2)	0.0236 (5)
H7A	0.850009	0.636936	0.796398	0.028*
C8	0.7103 (2)	0.7412 (3)	0.7241 (2)	0.0235 (5)
C9	0.5186 (2)	0.6584 (3)	0.6460 (2)	0.0236 (5)
H9A	0.491323	0.576348	0.597625	0.028*
C10	0.5061 (2)	0.7980 (3)	0.5776 (2)	0.0239 (5)
C11	0.3047 (2)	0.8261 (3)	0.6481 (2)	0.0264 (5)
C12	0.3171 (2)	0.6889 (3)	0.7153 (2)	0.0285 (6)
H12A	0.288711	0.606388	0.669460	0.034*
H12B	0.267804	0.695498	0.783153	0.034*
C13	0.4435 (2)	0.6608 (3)	0.7512 (2)	0.0260 (5)
H13A	0.470638	0.737979	0.802975	0.031*
H13B	0.449314	0.566826	0.790999	0.031*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0298 (9)	0.0199 (9)	0.0374 (10)	−0.0011 (7)	−0.0051 (8)	−0.0043 (7)
O2	0.0306 (10)	0.0200 (9)	0.0407 (11)	0.0001 (7)	−0.0028 (8)	−0.0059 (7)
O3	0.0280 (10)	0.0269 (10)	0.0347 (10)	0.0042 (7)	0.0006 (8)	0.0055 (7)
O4	0.0266 (9)	0.0273 (10)	0.0478 (12)	0.0052 (8)	−0.0031 (8)	−0.0019 (9)
N1	0.0226 (10)	0.0164 (9)	0.0294 (10)	0.0004 (8)	−0.0062 (8)	0.0003 (8)
N2	0.0260 (11)	0.0189 (10)	0.0337 (11)	0.0043 (8)	−0.0044 (9)	0.0023 (9)
C1	0.0265 (12)	0.0173 (11)	0.0259 (11)	0.0017 (9)	−0.0049 (9)	0.0024 (9)
C2	0.0245 (11)	0.0177 (11)	0.0297 (12)	0.0005 (9)	−0.0039 (9)	0.0002 (9)
C3	0.0297 (13)	0.0276 (13)	0.0291 (13)	−0.0027 (10)	−0.0008 (10)	−0.0019 (10)
C4	0.0306 (13)	0.0319 (14)	0.0309 (13)	−0.0046 (11)	−0.0008 (10)	0.0011 (10)
C5	0.0286 (13)	0.0252 (13)	0.0345 (14)	−0.0050 (10)	−0.0035 (10)	0.0027 (10)
C6	0.0250 (12)	0.0275 (12)	0.0309 (13)	−0.0053 (10)	−0.0045 (10)	−0.0006 (10)
C7	0.0240 (11)	0.0216 (11)	0.0253 (11)	−0.0020 (9)	−0.0039 (9)	0.0014 (9)
C8	0.0250 (11)	0.0195 (11)	0.0258 (11)	−0.0010 (9)	−0.0043 (9)	0.0017 (9)
C9	0.0219 (11)	0.0170 (11)	0.0319 (12)	0.0015 (8)	−0.0070 (9)	−0.0005 (9)
C10	0.0253 (11)	0.0180 (11)	0.0283 (11)	0.0021 (9)	−0.0054 (9)	−0.0006 (9)
C11	0.0242 (12)	0.0213 (12)	0.0336 (13)	0.0007 (9)	−0.0054 (10)	−0.0053 (10)
C12	0.0245 (12)	0.0217 (12)	0.0393 (14)	−0.0016 (9)	−0.0017 (10)	0.0001 (10)
C13	0.0239 (12)	0.0218 (12)	0.0322 (13)	−0.0007 (9)	−0.0034 (10)	0.0030 (9)

Geometric parameters (Å, º) top

O1—C1	1.207 (3)	C4—H4B	0.9900
O2—C8	1.208 (3)	C5—C6	1.525 (4)
O3—C10	1.217 (3)	C5—H5A	0.9900
O4—C11	1.213 (3)	C5—H5B	0.9900
N1—C8	1.394 (3)	C6—C7	1.532 (3)
N1—C1	1.397 (3)	C6—H6A	0.9900
N1—C9	1.456 (3)	C6—H6B	0.9900
N2—C10	1.374 (3)	C7—C8	1.513 (3)
N2—C11	1.390 (4)	C7—H7A	1.0000
N2—H2N	0.88 (5)	C9—C13	1.522 (4)
C1—C2	1.515 (3)	C9—C10	1.531 (3)
C2—C7	1.544 (3)	C9—H9A	1.0000
C2—C3	1.548 (4)	C11—C12	1.503 (4)
C2—H2A	1.0000	C12—C13	1.528 (4)
C3—C4	1.527 (4)	C12—H12A	0.9900
C3—H3A	0.9900	C12—H12B	0.9900
C3—H3B	0.9900	C13—H13A	0.9900
C4—C5	1.525 (4)	C13—H13B	0.9900
C4—H4A	0.9900

C8—N1—C1	112.6 (2)	C5—C6—H6B	108.9
C8—N1—C9	122.3 (2)	C7—C6—H6B	108.9
C1—N1—C9	123.4 (2)	H6A—C6—H6B	107.8
C10—N2—C11	127.0 (2)	C8—C7—C6	113.4 (2)
C10—N2—H2N	118 (3)	C8—C7—C2	103.24 (19)
C11—N2—H2N	115 (3)	C6—C7—C2	117.1 (2)
O1—C1—N1	123.9 (2)	C8—C7—H7A	107.5
O1—C1—C2	128.4 (2)	C6—C7—H7A	107.5
N1—C1—C2	107.5 (2)	C2—C7—H7A	107.5
C1—C2—C7	103.9 (2)	O2—C8—N1	123.9 (2)
C1—C2—C3	105.49 (19)	O2—C8—C7	128.2 (2)
C7—C2—C3	113.9 (2)	N1—C8—C7	107.8 (2)
C1—C2—H2A	111.1	N1—C9—C13	113.9 (2)
C7—C2—H2A	111.1	N1—C9—C10	107.4 (2)
C3—C2—H2A	111.1	C13—C9—C10	111.9 (2)
C4—C3—C2	112.8 (2)	N1—C9—H9A	107.8
C4—C3—H3A	109.0	C13—C9—H9A	107.8
C2—C3—H3A	109.0	C10—C9—H9A	107.8
C4—C3—H3B	109.0	O3—C10—N2	121.2 (2)
C2—C3—H3B	109.0	O3—C10—C9	122.6 (2)
H3A—C3—H3B	107.8	N2—C10—C9	116.2 (2)
C5—C4—C3	109.7 (2)	O4—C11—N2	119.1 (2)
C5—C4—H4A	109.7	O4—C11—C12	124.1 (3)
C3—C4—H4A	109.7	N2—C11—C12	116.8 (2)
C5—C4—H4B	109.7	C11—C12—C13	112.1 (2)
C3—C4—H4B	109.7	C11—C12—H12A	109.2
H4A—C4—H4B	108.2	C13—C12—H12A	109.2
C6—C5—C4	109.2 (2)	C11—C12—H12B	109.2
C6—C5—H5A	109.8	C13—C12—H12B	109.2
C4—C5—H5A	109.8	H12A—C12—H12B	107.9
C6—C5—H5B	109.8	C9—C13—C12	108.3 (2)
C4—C5—H5B	109.8	C9—C13—H13A	110.0
H5A—C5—H5B	108.3	C12—C13—H13A	110.0
C5—C6—C7	113.2 (2)	C9—C13—H13B	110.0
C5—C6—H6A	108.9	C12—C13—H13B	110.0
C7—C6—H6A	108.9	H13A—C13—H13B	108.4

C8—N1—C1—O1	179.5 (2)	C9—N1—C8—C7	−174.9 (2)
C9—N1—C1—O1	−15.2 (4)	C6—C7—C8—O2	−34.8 (4)
C8—N1—C1—C2	−5.3 (3)	C2—C7—C8—O2	−162.5 (3)
C9—N1—C1—C2	160.0 (2)	C6—C7—C8—N1	147.1 (2)
O1—C1—C2—C7	−167.9 (2)	C2—C7—C8—N1	19.4 (3)
N1—C1—C2—C7	17.2 (2)	C8—N1—C9—C13	−67.6 (3)
O1—C1—C2—C3	72.0 (3)	C1—N1—C9—C13	128.4 (2)
N1—C1—C2—C3	−102.9 (2)	C8—N1—C9—C10	56.9 (3)
C1—C2—C3—C4	155.2 (2)	C1—N1—C9—C10	−107.1 (3)
C7—C2—C3—C4	41.9 (3)	C11—N2—C10—O3	179.1 (2)
C2—C3—C4—C5	−58.7 (3)	C11—N2—C10—C9	−0.4 (4)
C3—C4—C5—C6	64.9 (3)	N1—C9—C10—O3	25.9 (3)
C4—C5—C6—C7	−55.2 (3)	C13—C9—C10—O3	151.6 (2)
C5—C6—C7—C8	−80.1 (3)	N1—C9—C10—N2	−154.6 (2)
C5—C6—C7—C2	40.0 (3)	C13—C9—C10—N2	−28.9 (3)
C1—C2—C7—C8	−21.7 (2)	C10—N2—C11—O4	−179.6 (2)
C3—C2—C7—C8	92.6 (2)	C10—N2—C11—C12	0.4 (4)
C1—C2—C7—C6	−147.1 (2)	O4—C11—C12—C13	−151.1 (3)
C3—C2—C7—C6	−32.8 (3)	N2—C11—C12—C13	28.9 (3)
C1—N1—C8—O2	172.5 (2)	N1—C9—C13—C12	178.0 (2)
C9—N1—C8—O2	6.9 (4)	C10—C9—C13—C12	55.9 (3)
C1—N1—C8—C7	−9.4 (3)	C11—C12—C13—C9	−56.1 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2N···O3ⁱ	0.88 (5)	2.07 (5)	2.928 (3)	165 (4)
C7—H7A···O4ⁱⁱ	1.00	2.42	3.150 (3)	129
C9—H9A···O1ⁱⁱⁱ	1.00	2.65	3.385 (3)	130
C12—H12A···O2ⁱⁱ	0.99	2.53	3.143 (3)	120
C13—H13A···O2	0.99	2.56	3.142 (3)	118
C13—H13B···O2ⁱⁱ	0.99	2.52	3.163 (3)	122

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

Funding information

This report was made possible by a NPRP award [NPRP-7-495-1-094] from Qatar National Research Fund (a member of The Qatar Foundation). The statements made herein are solely the responsibility of the authors. RJB is grateful for the NSF award 1205608, Partnership for Reduced Dimensional Materials, for partial funding of this research as well as the Howard University Nanoscience Facility access to liquid nitrogen. RJB also acknowledges the NSF MRI program (grant No. CHE-0619278) for funds to purchase an X-ray diffractometer.

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