Synthesis and structure of a 1:1 co-crystal of hexa­methyl­ene­tetra­mine carb­oxy­borane and acetamino­phen

Ayudhya, T.; Raymond, C.; Dingra, N.

doi:10.1107/S2056989020015327

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 76| Part 12| December 2020| Pages 1854-1858

https://doi.org/10.1107/S2056989020015327

Open

access

Synthesis and structure of a 1:1 co-crystal of hexamethylenetetramine carboxyborane and acetaminophen

Theppawut Ayudhya,^a Casey Raymond ^b and Nin Dingra ^a ^*

^aDepartment of Chemistry, University of Texas Permian Basin, Odessa, Texas, USA, and ^bDepartment of Chemistry, State University of New York at Oswego, Oswego, New York, USA
^*Correspondence e-mail: dingra_n@utpb.edu

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 4 October 2020; accepted 17 November 2020; online 24 November 2020)

Hexamethylenetetramine carboacetaminophenborane, a molecule with two pharmacophores attached to a central carboxyborate moiety, was synthesized and crystals were grown with an acetaminophen co-crystal former to result in the title 1:1 co-crystal [hexamethylenetetramine 4-acetamidophenyl 2-boranylacetate–4-acetamidophenol (1/1)], C₁₅H₂₂BN₅O₃·C₈H₉NO₂. In the first of these molecules, both the borate-ester and acetylamino groups are considerably twisted away from the plane of the intervening benzene ring [dihedral angles = 76.89 (9) and 65.42 (9)°, respectively]. The extended structure of this co-crystal features N—H⋯O and O—H⋯O hydrogen bonds, which link the components into (100) sheets and weak C—H⋯O hydrogen bonds help to consolidate the structure.

Keywords: co-crystal structure; amine carboxyborane; acetaminophen; CORCB.

CCDC reference: 1828957

1. Chemical context

Crystal structures of pure drugs are of great interest in the pharmaceutical industry since these structures provide an understanding of the intermolecular interactions that explain the physical and chemical properties of the solid (Desiraju, 2007 ). Modifications made to the active pharmaceutical ingredients to enhance the biological availability often include crystal engineering. For instance, the recrystallization of acetaminophen, C₈H₉NO₂ (also known as paracetamol), gives crystal form II, which displays better solubility and compressibility than form I (Naumov et al., 1998 ; Agnew et al., 2016 ). Another approach that has been brought into attention is using crystal formers or co-formers to improve the physicochemical characteristics of the solids. Recent developments in co-crystallization show potential advantages of drug–coformer co-crystals as well as drug–drug co-crystals (Kaur et al., 2017 ; Cheney et al., 2011 ; Nugrahani et al., 2007 ; Dalpiaz et al., 2018 ).

A group of organo–boron compounds, namely amine carboxyboranes, have been studied extensively for their diverse biological effects such as anti-inflammatory, anti-neoplastic and anti-osteoporotic activities (Hall et al., 1995 , 1990 ; Murphy et al., 1996 ). Their fundamental structure contains tetravalent amines connected to a boron atom of the carboxyborane moiety with an N—B coordinate covalent bond (Spielvogel et al., 1976 ). As a result of the ease of structural transformability, this group is very amenable to modification such as exchanging various amine groups and esterification on the carboxyborate. Our interest in amine carboxyboranes stemmed from their innate structure that undergoes decarbonylation to produce CO, H₂, and the amine group when placed in aqueous solution. We have shown amine carboxyboranes to be a group of molecules that can be used as carbon monoxide releasers (Ayudhya et al., 2017 ). Moreover, we have recently reported that this process is accelerated by reactive oxygen species (ROS) increasing the rate at which CO and the amine group is released (Ayudhya et al., 2018 ). Considering the amine compounds are drug molecules, carboxyboranes can be used as a system to deliver drugs that contain amino groups. Since we started our endeavor with drug-conjugated carboxyboranes (Ayudhya et al., 2018), we speculated that carboxyboranes may be able to carry more than one drug. In addition to the amine group on the boron atom, ester and amide derivatives at the carboxyborate end have been shown previously (Das et al., 1990 ).

As part of this work, we now describe the crystal structure of the title co-crystal, C₁₅H₂₂BN₅O₃·C₈H₉NO₂, (I), which resulted from the synthetic concept that conjugating two different pharmacophores to the carboxyborate moiety may make a molecule that has multiple biological effects.

2. Structural commentary

The asymmetric unit of the resulting monoclinic crystal (space group P2₁/c) contains one C₁₅H₂₂BN₅O₃ ester (CORCB-1-APAP) and one C₈H₉NO₂ acetaminophen molecule (Fig. 1). The hexamethylenetetraamine (hmta) moiety of the ester is syn to the C9=O3 carboxy carbonyl group and the aromatic C3–C8 ring is approximately perpendicular to the plane of the B1/C9/O2/O3 ester carboxylate group [dihedral angle = 76.89 (9)°] while the C1/C2/N1/O1 acetylamino group is twisted out of plane of the ring by 65.42 (9)°; the dihedral angle between the pendant groups is 11.70 (10)°.

Figure 1
The molecular structure of (I)

with displacement ellipsoids drawn at the 50% probability level.

Based on the observed geometry, we may assume that the bonding in this difunctionalized carboxyborate is very similar to that in the previously reported crystal structure of C₇H₁₅BN₄O₂ or CORCB-1 [Ayudhya et al., 2017; Cambridge Structural Database (Groom et al., 2016 ) refcode UDAQOI]. The only significant difference is in the slightly longer C9—O2 single bond, 1.399 (2) Å in the difunctionalized title compound compared to 1.353 (3) Å in CORCB-1. This lengthening is expected to be due to the weak ester bond, which is confirmed by rapid hydrolysis. There are only small differences in B—N and B—C bond lengths between the two materials with some lengthening seen in the difunctionalized compound. In the co-crystallized acetaminophen molecule in (I), the dihedral angle between the C18–C23 benzene ring and the acetylamino C16/C17/N6/O5 grouping is 54.61 (10)°.

3. Supramolecular features

During crystallization, the new difunctionalized molecule, CORCB-1-APAP, forms a co-crystal with acetaminophen at a 1:1 ratio with hydrogen-bonding interactions (Table 1) between them (Figs. 2 and 3). In comparison to the CORCB-1 crystal reported previously, which features hydrogen bonds between the amino and carboxylic acid groups (Ayudhya et al., 2017), this new structure cannot form hydrogen bonds in the CORCB-1 region due to the replacement of carboxylic acid with an ester functional group. As a result, a co-crystal former such as acetaminophen is needed for crystal formation to provide stable hydrogen bonds: with acetaminophen molecules flanking CORCB-1-APAP; no interactions are observed between these difunctionalized compounds. The co-crystal shows three classical hydrogen bonds. The first is an N6—H6N⋯O1 hydrogen bond (H⋯O = 2.00 Å) found between the N—H group of acetaminophen and the C=O acceptor from CORCB-1-APAP. This type of bond has been previously reported in the acetaminophen co-crystal with citric acid (Elbagerma et al., 2011 ). Pure acetaminophen crystals typically only form hydrogen bonds between N—H⋯O—H and O—H⋯O=C. The second interaction N1—H1N⋯O4—H4O is between CORCB-1-APAP and another acetaminophen molecule. The bond length (2.18 Å) of this hydrogen bond is similar to the N—H⋯O—H bond (2.09 Å) from the known acetaminophen crystal form II (Agnew et al., 2016; Thomas et al., 2011 ). The third hydrogen bond does not involve CORCB-1-APAP: it is exclusively formed between two acetaminophen molecules and this O4—H4O⋯O5=C17 bond (1.85 Å) is identical in length to that of acetaminophen crystal form II (1.85 Å). Several weak C—H⋯O hydrogen bonds may help to consolidate the structure.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C10—H10A⋯O3	0.97	2.52	3.184 (2)	125
C12—H12B⋯O3	0.97	2.46	3.135 (2)	126
N1—H1N⋯O4ⁱ	0.86	2.18	3.0217 (19)	168
O4—H4O⋯O5ⁱⁱ	0.82	1.85	2.6619 (18)	174
N6—H6N⋯O1	0.86	2.00	2.8415 (19)	166
C10—H10B⋯O3ⁱⁱⁱ	0.97	2.49	3.413 (2)	159
C15—H15A⋯O4^iv	0.97	2.50	3.160 (2)	125
C20—H20⋯O5ⁱⁱ	0.93	2.51	3.195 (2)	130
Symmetry codes: (i) $[x, -y+{\script{3\over 2}}, z+{\script{1\over 2}}]$ ; (ii) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (iii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iv) .

Figure 2
Unit cell packing of (I)

viewed down the c-axis direction, with additional molecules added along the b-axis direction. Acetaminophen molecules are green; hydrogen bonds are shown as dashed yellow lines.

Figure 3
Detail of the packing of (I)

showing hydrogen bonds (yellow lines) between the components of the co-crystal. Three acetaminophen molecules are shown but only the two on the left are hydrogen bonded with CORCB-1-APAP. The third acetaminophen molecule, which accepts a hydrogen bond from the second, is oriented in the same way as the first and repeats the pattern.

A molecular packing projection of (I) is shown in Fig. 4 for clear representation of each pair of CORCB-1-APAP and its co-former, acetaminophen. As noted, the observed hydrogen-bond lengths in this co-crystal are similar to those from acetaminophen form II packing while the overall packing looks similar to form I (Naumov et al., 1998).

Figure 4
Molecular packing diagram for (I)

viewed down [010].

4. Database survey

The crystal structures of amine carboxyborane have been reported as dimers (Spielvogel et al., 1980 ; Rana et al., 2002 ; Vyakaranam et al., 2002 ). The CORCB-1 crystal structure does not show typical hydrogen bonding from carboxylic acid groups and does not show dimer formation (Ayudhya et al., 2017). Acetaminophen co-crystallized structures to name a few are with ibuprofen (Stone et al., 2009 ), citric acid (Elbagerma et al., 2011), theophylline (Childs et al., 2007 ) and morpholine (Oswald et al., 2002 ).

5. Synthesis and crystallization

The synthesis of amine carboxyborane derivatives such as methyl ester of various amine carboxyborates have been described previously. Several esterification methods of amine carboxyboranes with alcohols include using DCC to make 98% yield (Spielvogel et al., 1986 ) and using a catalytic amount of hydrogen bromide, which provides nearly quantitative yields (Győri et al., 1995 ). In our process, esterification is completed before the amine exchange reaction and not vice versa. The synthesis of hexamethylenetetramine carboacetaminophenborane (CORCB-1-APAP) involves several steps using trimethylamine carboxyborane (CORCB-3) as the starting material. Trimethylamine carboxyborane, synthesized by the previously reported method (Spielvogel et al., 1976) is first esterified at the carboxyborate moiety with acetaminophen (APAP). The esterification was carried out in a mixed solvent system of chloroform and THF (1:1) at 313 to 318 K for five days and the crude product was purified by a series of recrystallizations. CORCB-1-APAP and acetaminophen co-crystals for X-ray data collection were grown in mixed solvents of hexane/chloroform using the solution crystallization method.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were treated as riding atoms in geometrically idealized positions [N—H = 0.86, O—H = 0.82 and C—H = 0.93–0.97 Å with U_iso(H) = 1.2U_eq(N,O,C) or 1.2U_eq(Cmethyl)].

Table 2
Experimental details

Crystal data
Chemical formula	C₁₅H₂₂BN₅O₃·C₈H₉NO₂
M_r	482.35
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	20.760 (4), 9.5527 (19), 12.045 (2)
β (°)	91.929 (4)
V (Å³)	2387.2 (8)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.23 × 0.06 × 0.05

Data collection
Diffractometer	Bruker APEXII CCD
No. of measured, independent and observed [I > 2σ(I)] reflections	29824, 4870, 3044
R_int	0.091
(sin θ/λ)_max (Å⁻¹)	0.625

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.041, 0.072, 1.08
No. of reflections	4870
No. of parameters	319
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.24, −0.22
Computer programs: APEX2 and SAINT (Bruker, 2007 ), SHELXS97 (Sheldrick, 2008 ), SHELXL2014/7 (Sheldrick, 2015 ), SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 1828957

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989020015327/hb7947sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020015327/hb7947Isup2.hkl

CheckCIF. DOI: https://doi.org/10.1107/S2056989020015327/hb7947sup4.pdf

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2007); cell refinement: SAINT (Bruker, 2007); data reduction: SAINT (Bruker, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010).

Hexamethylenetetramine 4-acetamidophenyl 2-boranylacetate–4-acetamidophenol (1/1) top

Crystal data top

C₁₅H₂₂BN₅O₃·C₈H₉NO₂	F(000) = 1024
M_r = 482.35	D_x = 1.342 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 20.760 (4) Å	Cell parameters from 7373 reflections
b = 9.5527 (19) Å	θ = 5.8–54.1°
c = 12.045 (2) Å	µ = 0.10 mm⁻¹
β = 91.929 (4)°	T = 293 K
V = 2387.2 (8) Å³	Needle, colorless
Z = 4	0.23 × 0.06 × 0.05 mm

Data collection top

Bruker APEXII CCD diffractometer	R_int = 0.091
Radiation source: sealed tube	θ_max = 26.4°, θ_min = 2.0°
phi and ω scans	h = −25→25
29824 measured reflections	k = −11→11
4870 independent reflections	l = −15→15
3044 reflections with I > 2σ(I)

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.041	H-atom parameters constrained
wR(F²) = 0.072	w = 1/[σ²(F_o²) + (0.018P)²] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max < 0.001
4870 reflections	Δρ_max = 0.24 e Å⁻³
319 parameters	Δρ_min = −0.22 e Å⁻³
0 restraints

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.

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

	x	y	z	U_iso*/U_eq
C1	0.05099 (9)	1.08726 (18)	0.86077 (16)	0.0285 (5)
H1A	0.0175	1.1125	0.8076	0.043*
H1B	0.0732	1.1701	0.8859	0.043*
H1C	0.0324	1.0413	0.9229	0.043*
C2	0.09783 (9)	0.98985 (19)	0.80733 (15)	0.0227 (4)
O1	0.07872 (6)	0.88651 (12)	0.75419 (10)	0.0260 (3)
N1	0.16095 (7)	1.02002 (14)	0.82219 (12)	0.0228 (4)
H1N	0.1715	1.0898	0.8640	0.027*
C3	0.21163 (8)	0.94201 (17)	0.77195 (15)	0.0194 (4)
C4	0.25773 (9)	0.87339 (17)	0.83793 (16)	0.0221 (4)
H4	0.2543	0.8727	0.9147	0.026*
C5	0.30902 (9)	0.80567 (17)	0.78963 (15)	0.0217 (5)
H5	0.3401	0.7601	0.8337	0.026*
C6	0.31331 (8)	0.80687 (17)	0.67507 (16)	0.0186 (4)
C7	0.26699 (8)	0.87268 (17)	0.60850 (15)	0.0209 (4)
H7	0.2700	0.8718	0.5316	0.025*
C8	0.21585 (9)	0.94021 (17)	0.65765 (15)	0.0214 (4)
H8	0.1844	0.9843	0.6134	0.026*
O2	0.36389 (6)	0.73601 (11)	0.62473 (10)	0.0221 (3)
C9	0.42431 (8)	0.80105 (18)	0.63013 (15)	0.0189 (4)
O3	0.42901 (6)	0.91608 (12)	0.67315 (10)	0.0242 (3)
B1	0.47824 (10)	0.7044 (2)	0.57512 (19)	0.0210 (5)
H1B1	0.4721	0.6078	0.5971	0.025*
H1B2	0.4735	0.7095	0.4948	0.025*
N2	0.54897 (7)	0.75441 (14)	0.61337 (11)	0.0164 (3)
C10	0.55901 (8)	0.75507 (18)	0.73918 (14)	0.0191 (4)
H10A	0.5288	0.8198	0.7712	0.023*
H10B	0.5502	0.6624	0.7679	0.023*
N3	0.62411 (7)	0.79543 (14)	0.77251 (12)	0.0206 (4)
C11	0.63675 (9)	0.93610 (17)	0.72684 (15)	0.0236 (5)
H11A	0.6065	1.0022	0.7571	0.028*
H11B	0.6799	0.9653	0.7502	0.028*
N4	0.63096 (7)	0.93989 (14)	0.60505 (12)	0.0197 (4)
C12	0.56578 (8)	0.89959 (17)	0.57118 (15)	0.0191 (4)
H12A	0.5615	0.9008	0.4907	0.023*
H12B	0.5356	0.9672	0.5997	0.023*
C13	0.59876 (8)	0.65314 (17)	0.56842 (15)	0.0209 (4)
H13A	0.5903	0.5597	0.5958	0.025*
H13B	0.5947	0.6509	0.4880	0.025*
N5	0.66398 (7)	0.69366 (14)	0.60153 (12)	0.0202 (4)
C14	0.66971 (9)	0.69583 (18)	0.72354 (15)	0.0234 (5)
H14A	0.7134	0.7217	0.7462	0.028*
H14B	0.6615	0.6026	0.7518	0.028*
C15	0.67633 (9)	0.83683 (18)	0.56036 (16)	0.0244 (5)
H15A	0.7201	0.8639	0.5816	0.029*
H15B	0.6725	0.8372	0.4799	0.029*
C16	0.06429 (10)	0.69737 (19)	0.99581 (16)	0.0331 (5)
H16A	0.0271	0.6676	1.0348	0.050*
H16B	0.0528	0.7742	0.9477	0.050*
H16C	0.0974	0.7267	1.0484	0.050*
C17	0.08889 (9)	0.57733 (19)	0.92747 (16)	0.0244 (5)
O5	0.09247 (6)	0.45723 (12)	0.96712 (10)	0.0300 (3)
N6	0.10633 (7)	0.60827 (14)	0.82433 (12)	0.0243 (4)
H6N	0.1048	0.6947	0.8043	0.029*
C18	0.12735 (9)	0.50769 (17)	0.74469 (15)	0.0211 (4)
C19	0.08895 (9)	0.39203 (18)	0.71821 (15)	0.0227 (4)
H19	0.0513	0.3762	0.7559	0.027*
C20	0.10712 (9)	0.30031 (18)	0.63528 (15)	0.0232 (5)
H20	0.0820	0.2221	0.6183	0.028*
C21	0.16282 (9)	0.32553 (18)	0.57793 (15)	0.0213 (4)
O4	0.17995 (6)	0.24556 (12)	0.48852 (11)	0.0272 (3)
H4O	0.1529	0.1843	0.4771	0.033*
C22	0.20183 (9)	0.43896 (18)	0.60524 (15)	0.0242 (5)
H22	0.2398	0.4542	0.5681	0.029*
C23	0.18357 (9)	0.53024 (18)	0.68920 (15)	0.0238 (5)
H23	0.2095	0.6067	0.7078	0.029*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0260 (12)	0.0238 (10)	0.0363 (13)	0.0017 (9)	0.0109 (10)	−0.0002 (9)
C2	0.0258 (12)	0.0189 (10)	0.0237 (12)	0.0016 (9)	0.0041 (9)	0.0036 (9)
O1	0.0257 (8)	0.0202 (7)	0.0320 (8)	−0.0011 (6)	0.0027 (6)	−0.0018 (6)
N1	0.0211 (9)	0.0188 (8)	0.0286 (10)	0.0010 (7)	0.0035 (8)	−0.0056 (7)
C3	0.0181 (11)	0.0149 (10)	0.0254 (12)	−0.0012 (8)	0.0047 (9)	−0.0010 (8)
C4	0.0274 (12)	0.0188 (10)	0.0203 (11)	−0.0021 (9)	0.0053 (9)	0.0014 (8)
C5	0.0230 (11)	0.0159 (10)	0.0262 (12)	0.0018 (8)	0.0005 (9)	0.0032 (8)
C6	0.0155 (10)	0.0115 (9)	0.0292 (12)	−0.0014 (8)	0.0069 (9)	−0.0016 (8)
C7	0.0259 (11)	0.0175 (10)	0.0195 (11)	−0.0039 (8)	0.0032 (9)	−0.0016 (8)
C8	0.0201 (11)	0.0178 (10)	0.0260 (12)	0.0014 (8)	−0.0029 (9)	0.0015 (8)
O2	0.0177 (7)	0.0171 (7)	0.0316 (8)	−0.0019 (5)	0.0048 (6)	−0.0060 (6)
C9	0.0174 (10)	0.0182 (10)	0.0213 (11)	−0.0004 (8)	0.0017 (9)	0.0033 (8)
O3	0.0208 (7)	0.0172 (7)	0.0349 (8)	−0.0014 (6)	0.0043 (6)	−0.0062 (6)
B1	0.0214 (13)	0.0172 (11)	0.0246 (13)	−0.0034 (9)	0.0028 (10)	−0.0016 (9)
N2	0.0197 (9)	0.0131 (7)	0.0168 (9)	0.0019 (6)	0.0044 (7)	−0.0007 (6)
C10	0.0231 (11)	0.0170 (9)	0.0174 (11)	0.0035 (8)	0.0043 (9)	0.0020 (8)
N3	0.0205 (9)	0.0206 (8)	0.0209 (9)	0.0048 (7)	0.0004 (7)	0.0010 (7)
C11	0.0201 (11)	0.0193 (10)	0.0312 (12)	0.0006 (8)	−0.0001 (9)	−0.0042 (9)
N4	0.0167 (9)	0.0174 (8)	0.0252 (10)	0.0010 (7)	0.0034 (7)	0.0032 (7)
C12	0.0212 (11)	0.0157 (9)	0.0206 (11)	0.0002 (8)	0.0025 (9)	0.0053 (8)
C13	0.0221 (11)	0.0180 (10)	0.0231 (11)	0.0035 (8)	0.0071 (9)	−0.0027 (8)
N5	0.0171 (9)	0.0197 (8)	0.0239 (10)	0.0017 (7)	0.0047 (7)	0.0013 (7)
C14	0.0212 (11)	0.0215 (10)	0.0274 (12)	0.0041 (8)	0.0001 (9)	0.0030 (9)
C15	0.0192 (11)	0.0244 (11)	0.0298 (12)	0.0004 (8)	0.0061 (9)	0.0042 (9)
C16	0.0420 (14)	0.0275 (11)	0.0299 (13)	0.0095 (10)	0.0036 (11)	0.0009 (9)
C17	0.0259 (12)	0.0228 (11)	0.0245 (12)	0.0017 (9)	−0.0014 (10)	0.0003 (9)
O5	0.0389 (9)	0.0225 (7)	0.0287 (8)	0.0038 (6)	0.0033 (7)	0.0040 (6)
N6	0.0338 (10)	0.0145 (8)	0.0247 (10)	0.0014 (7)	0.0018 (8)	0.0004 (7)
C18	0.0241 (11)	0.0176 (10)	0.0216 (11)	0.0022 (9)	−0.0009 (9)	0.0010 (8)
C19	0.0205 (11)	0.0209 (10)	0.0270 (12)	0.0009 (8)	0.0037 (9)	0.0024 (9)
C20	0.0230 (11)	0.0171 (10)	0.0296 (12)	−0.0026 (8)	0.0035 (10)	0.0000 (9)
C21	0.0239 (11)	0.0166 (10)	0.0236 (12)	0.0047 (8)	0.0013 (9)	0.0018 (8)
O4	0.0275 (8)	0.0218 (7)	0.0326 (8)	−0.0007 (6)	0.0080 (7)	−0.0037 (6)
C22	0.0203 (11)	0.0249 (11)	0.0275 (12)	−0.0018 (9)	0.0013 (9)	0.0047 (9)
C23	0.0241 (12)	0.0199 (10)	0.0271 (12)	−0.0044 (8)	−0.0028 (10)	0.0020 (9)

Geometric parameters (Å, º) top

C1—C2	1.506 (2)	C11—H11B	0.9700
C1—H1A	0.9600	N4—C12	1.452 (2)
C1—H1B	0.9600	N4—C15	1.477 (2)
C1—H1C	0.9600	C12—H12A	0.9700
C2—O1	1.235 (2)	C12—H12B	0.9700
C2—N1	1.348 (2)	C13—N5	1.451 (2)
N1—C3	1.439 (2)	C13—H13A	0.9700
N1—H1N	0.8600	C13—H13B	0.9700
C3—C8	1.383 (2)	N5—C14	1.471 (2)
C3—C4	1.388 (2)	N5—C15	1.480 (2)
C4—C5	1.390 (2)	C14—H14A	0.9700
C4—H4	0.9300	C14—H14B	0.9700
C5—C6	1.386 (2)	C15—H15A	0.9700
C5—H5	0.9300	C15—H15B	0.9700
C6—C7	1.382 (2)	C16—C17	1.511 (2)
C6—O2	1.404 (2)	C16—H16A	0.9600
C7—C8	1.391 (2)	C16—H16B	0.9600
C7—H7	0.9300	C16—H16C	0.9600
C8—H8	0.9300	C17—O5	1.244 (2)
O2—C9	1.399 (2)	C17—N6	1.339 (2)
C9—O3	1.2174 (19)	N6—C18	1.436 (2)
C9—B1	1.611 (3)	N6—H6N	0.8600
B1—N2	1.597 (2)	C18—C23	1.381 (2)
B1—H1B1	0.9700	C18—C19	1.393 (2)
B1—H1B2	0.9700	C19—C20	1.390 (2)
N2—C10	1.523 (2)	C19—H19	0.9300
N2—C12	1.522 (2)	C20—C21	1.388 (2)
N2—C13	1.528 (2)	C20—H20	0.9300
C10—N3	1.449 (2)	C21—O4	1.377 (2)
C10—H10A	0.9700	C21—C22	1.386 (2)
C10—H10B	0.9700	O4—H4O	0.8200
N3—C11	1.479 (2)	C22—C23	1.397 (2)
N3—C14	1.479 (2)	C22—H22	0.9300
C11—N4	1.468 (2)	C23—H23	0.9300
C11—H11A	0.9700

C2—C1—H1A	109.5	C12—N4—C11	108.57 (14)
C2—C1—H1B	109.5	C12—N4—C15	108.70 (14)
H1A—C1—H1B	109.5	C11—N4—C15	108.42 (14)
C2—C1—H1C	109.5	N4—C12—N2	111.71 (13)
H1A—C1—H1C	109.5	N4—C12—H12A	109.3
H1B—C1—H1C	109.5	N2—C12—H12A	109.3
O1—C2—N1	122.26 (17)	N4—C12—H12B	109.3
O1—C2—C1	120.98 (17)	N2—C12—H12B	109.3
N1—C2—C1	116.74 (16)	H12A—C12—H12B	107.9
C2—N1—C3	123.69 (15)	N5—C13—N2	111.70 (13)
C2—N1—H1N	118.2	N5—C13—H13A	109.3
C3—N1—H1N	118.2	N2—C13—H13A	109.3
C8—C3—C4	119.91 (17)	N5—C13—H13B	109.3
C8—C3—N1	119.80 (16)	N2—C13—H13B	109.3
C4—C3—N1	120.24 (16)	H13A—C13—H13B	107.9
C5—C4—C3	120.23 (17)	C13—N5—C14	108.77 (14)
C5—C4—H4	119.9	C13—N5—C15	108.97 (13)
C3—C4—H4	119.9	C14—N5—C15	108.22 (14)
C6—C5—C4	119.25 (17)	N5—C14—N3	112.10 (14)
C6—C5—H5	120.4	N5—C14—H14A	109.2
C4—C5—H5	120.4	N3—C14—H14A	109.2
C7—C6—C5	120.97 (17)	N5—C14—H14B	109.2
C7—C6—O2	118.98 (16)	N3—C14—H14B	109.2
C5—C6—O2	120.00 (16)	H14A—C14—H14B	107.9
C6—C7—C8	119.33 (17)	N4—C15—N5	111.96 (14)
C6—C7—H7	120.3	N4—C15—H15A	109.2
C8—C7—H7	120.3	N5—C15—H15A	109.2
C3—C8—C7	120.29 (17)	N4—C15—H15B	109.2
C3—C8—H8	119.9	N5—C15—H15B	109.2
C7—C8—H8	119.9	H15A—C15—H15B	107.9
C9—O2—C6	116.62 (13)	C17—C16—H16A	109.5
O3—C9—O2	118.65 (16)	C17—C16—H16B	109.5
O3—C9—B1	130.19 (16)	H16A—C16—H16B	109.5
O2—C9—B1	111.15 (14)	C17—C16—H16C	109.5
N2—B1—C9	110.79 (14)	H16A—C16—H16C	109.5
N2—B1—H1B1	109.5	H16B—C16—H16C	109.5
C9—B1—H1B1	109.5	O5—C17—N6	123.05 (17)
N2—B1—H1B2	109.5	O5—C17—C16	120.52 (17)
C9—B1—H1B2	109.5	N6—C17—C16	116.43 (16)
H1B1—B1—H1B2	108.1	C17—N6—C18	124.75 (15)
C10—N2—C12	107.66 (13)	C17—N6—H6N	117.6
C10—N2—C13	106.47 (13)	C18—N6—H6N	117.6
C12—N2—C13	107.04 (13)	C23—C18—C19	119.95 (17)
C10—N2—B1	112.47 (14)	C23—C18—N6	119.97 (16)
C12—N2—B1	113.27 (13)	C19—C18—N6	119.95 (16)
C13—N2—B1	109.56 (13)	C20—C19—C18	119.82 (18)
N3—C10—N2	111.84 (14)	C20—C19—H19	120.1
N3—C10—H10A	109.2	C18—C19—H19	120.1
N2—C10—H10A	109.2	C21—C20—C19	119.93 (17)
N3—C10—H10B	109.2	C21—C20—H20	120.0
N2—C10—H10B	109.2	C19—C20—H20	120.0
H10A—C10—H10B	107.9	O4—C21—C20	122.30 (16)
C10—N3—C11	108.32 (13)	O4—C21—C22	117.09 (16)
C10—N3—C14	108.77 (14)	C20—C21—C22	120.50 (17)
C11—N3—C14	108.20 (14)	C21—O4—H4O	109.5
N4—C11—N3	112.61 (14)	C21—C22—C23	119.29 (17)
N4—C11—H11A	109.1	C21—C22—H22	120.4
N3—C11—H11A	109.1	C23—C22—H22	120.4
N4—C11—H11B	109.1	C18—C23—C22	120.47 (17)
N3—C11—H11B	109.1	C18—C23—H23	119.8
H11A—C11—H11B	107.8	C22—C23—H23	119.8

O1—C2—N1—C3	4.5 (3)	C11—N4—C12—N2	−58.36 (17)
C1—C2—N1—C3	−176.59 (16)	C15—N4—C12—N2	59.38 (18)
C2—N1—C3—C8	64.0 (2)	C10—N2—C12—N4	56.54 (17)
C2—N1—C3—C4	−118.63 (19)	C13—N2—C12—N4	−57.59 (18)
C8—C3—C4—C5	1.6 (3)	B1—N2—C12—N4	−178.46 (14)
N1—C3—C4—C5	−175.82 (15)	C10—N2—C13—N5	−57.80 (17)
C3—C4—C5—C6	−0.4 (3)	C12—N2—C13—N5	57.13 (18)
C4—C5—C6—C7	−0.9 (3)	B1—N2—C13—N5	−179.67 (14)
C4—C5—C6—O2	−178.39 (15)	N2—C13—N5—C14	59.31 (18)
C5—C6—C7—C8	0.9 (2)	N2—C13—N5—C15	−58.47 (18)
O2—C6—C7—C8	178.43 (15)	C13—N5—C14—N3	−59.61 (18)
C4—C3—C8—C7	−1.5 (3)	C15—N5—C14—N3	58.64 (18)
N1—C3—C8—C7	175.85 (15)	C10—N3—C14—N5	59.51 (19)
C6—C7—C8—C3	0.3 (3)	C11—N3—C14—N5	−57.96 (18)
C7—C6—O2—C9	105.80 (17)	C12—N4—C15—N5	−59.85 (19)
C5—C6—O2—C9	−76.6 (2)	C11—N4—C15—N5	57.99 (18)
C6—O2—C9—O3	−3.1 (2)	C13—N5—C15—N4	59.57 (19)
C6—O2—C9—B1	176.90 (15)	C14—N5—C15—N4	−58.56 (18)
O3—C9—B1—N2	17.3 (3)	O5—C17—N6—C18	4.0 (3)
O2—C9—B1—N2	−162.61 (14)	C16—C17—N6—C18	−176.28 (16)
C9—B1—N2—C10	56.76 (19)	C17—N6—C18—C23	−130.07 (19)
C9—B1—N2—C12	−65.61 (19)	C17—N6—C18—C19	54.1 (2)
C9—B1—N2—C13	174.96 (14)	C23—C18—C19—C20	−0.5 (3)
C12—N2—C10—N3	−56.73 (17)	N6—C18—C19—C20	175.33 (16)
C13—N2—C10—N3	57.78 (17)	C18—C19—C20—C21	−1.1 (3)
B1—N2—C10—N3	177.79 (13)	C19—C20—C21—O4	−173.96 (16)
N2—C10—N3—C11	58.28 (17)	C19—C20—C21—C22	2.3 (3)
N2—C10—N3—C14	−59.11 (17)	O4—C21—C22—C23	174.61 (15)
C10—N3—C11—N4	−60.21 (18)	C20—C21—C22—C23	−1.8 (3)
C14—N3—C11—N4	57.55 (18)	C19—C18—C23—C22	1.0 (3)
N3—C11—N4—C12	60.24 (18)	N6—C18—C23—C22	−174.86 (16)
N3—C11—N4—C15	−57.68 (18)	C21—C22—C23—C18	0.2 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C10—H10A···O3	0.97	2.52	3.184 (2)	125
C12—H12B···O3	0.97	2.46	3.135 (2)	126
N1—H1N···O4ⁱ	0.86	2.18	3.0217 (19)	168
O4—H4O···O5ⁱⁱ	0.82	1.85	2.6619 (18)	174
N6—H6N···O1	0.86	2.00	2.8415 (19)	166
C10—H10B···O3ⁱⁱⁱ	0.97	2.49	3.413 (2)	159
C15—H15A···O4^iv	0.97	2.50	3.160 (2)	125
C20—H20···O5ⁱⁱ	0.93	2.51	3.195 (2)	130

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

Acknowledgements

The authors thank M. Zeller for the X-ray data collection and the NSF for funding the diffractometer (DMR-1337296) at Youngstown State University.

References

Agnew, L. R., Cruickshank, D. L., McGlone, T. & Wilson, C. C. (2016). Chem. Commun. 52, 7368–7371. CrossRef CAS Google Scholar
Ayudhya, T. I., Pellechia, P. J. & Dingra, N. N. (2018). Dalton Trans. 47, 538–543. Web of Science CrossRef CAS PubMed Google Scholar
Ayudhya, T. I., Raymond, C. C. & Dingra, N. N. (2017). Dalton Trans. 46, 882–889. Web of Science CSD CrossRef CAS PubMed Google Scholar
Bruker (2007). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Cheney, M. L., Weyna, D. R., Shan, N., Hanna, M., Wojtas, L. & Zaworotko, M. J. (2011). J. Pharm. Sci. 100, 2172–2181. CSD CrossRef CAS PubMed Google Scholar
Childs, S. L., Stahly, G. P. & Park, A. (2007). Mol. Pharm. 4, 323–338. Web of Science CSD CrossRef PubMed CAS Google Scholar
Dalpiaz, A., Ferretti, V., Bertolasi, V., Pavan, B., Monari, A. & Pastore, M. (2018). Mol. Pharm. 15, 268–278. CSD CrossRef CAS PubMed Google Scholar
Das, M. K., Mukherjee, P. & Roy, S. (1990). Bull. Chem. Soc. Jpn, 63, 3658–3660. CrossRef CAS Google Scholar
Desiraju, G. R. (2007). Angew. Chem. Int. Ed. 46, 8342–8356. Web of Science CrossRef CAS Google Scholar
Elbagerma, M. A., Edwards, H. G. M., Munshi, T. & Scowen, I. J. (2011). CrystEngComm, 13, 1877–1884. Web of Science CSD CrossRef CAS Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Győri, B., Berente, Z., Emri, J. & Lázár, I. (1995). Synthesis, 1995, 191–194. Google Scholar
Hall, I. H., Rajendran, K. G., Chen, S. Y., Wong, O. T., Sood, A. & Spielvogel, B. F. (1995). Arch. Pharm. Pharm. Med. Chem. 328, 39–44. CrossRef CAS Google Scholar
Hall, I. H., Spielvogel, B. F. & Sood, A. (1990). Anticancer Drugs, 1, 133–142. CrossRef CAS PubMed Google Scholar
Kaur, R., Cavanagh, K. L., Rodríguez-Hornedo, N. & Matzger, A. J. (2017). Cryst. Growth Des. 17, 5012–5016. Web of Science CSD CrossRef CAS PubMed Google Scholar
Murphy, M. E., Elkins, A. L., Shrewsbury, R. P., Sood, A., Spielvogel, B. F. & Hall, I. H. (1996). Met.-Based Drugs, 3, 31–47. CrossRef CAS Google Scholar
Naumov, D. Yu., Vasilchenko, M. A. & Howard, J. A. K. (1998). Acta Cryst. C54, 653–655. CSD CrossRef CAS IUCr Journals Google Scholar
Nugrahani, I., Asyarie, S., Soewandhi, S. N. & Ibrahim, S. (2007). Int. J. Pharm. 3, 475–481. CAS Google Scholar
Oswald, I. D. H., Allan, D. R., McGregor, P. A., Motherwell, W. D. S., Parsons, S. & Pulham, C. R. (2002). Acta Cryst. B58, 1057–1066. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Rana, G., Vyakaranam, K., Zheng, C., Li, S., Spielvogel, B. F. & Hosmane, N. S. (2002). Main Group Met. Chem. 25, 179–180. CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spielvogel, B. F., Ahmed, F. U. & Mcphail, A. T. (1986). Synthesis, 1986, 833–835. CrossRef Google Scholar
Spielvogel, B. F., Das, M. K., McPhail, A. T., Onan, K. D. & Hall, I. H. (1980). J. Am. Chem. Soc. 102, 6343–6344. CSD CrossRef CAS Web of Science Google Scholar
Spielvogel, B. F., Wojnowich, L., Das, M. K., McPhail, A. T. & Hargrave, K. D. (1976). J. Am. Chem. Soc. 98, 5702–5703. CSD CrossRef CAS PubMed Web of Science Google Scholar
Stone, K. H., Lapidus, S. H. & Stephens, P. W. (2009). J. Appl. Cryst. 42, 385–391. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Thomas, L. H., Wales, C., Zhao, L. & Wilson, C. C. (2011). Cryst. Growth Des. 11, 1450–1452. Web of Science CSD CrossRef CAS Google Scholar
Vyakaranam, K., Rana, G., Chong, G., Zheng, S. L., Spielvogel, B. F. & Hosmane, N. S. (2002). Main Group Met. Chem. 25, 181–182. CAS Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.