Crystal engineering of a 1:1 5-fluoro­cytosine–4-hy­droxy­benzaldehyde cocrystal: insights from X-ray crystallography and Hirshfeld analysis

Sangavi, M.; Mohana, M.; Butcher, R.J.; McMillen, C.D.

doi:10.1107/S2056989025004463

research communications

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 81| Part 6| June 2025| Pages 549-553

https://doi.org/10.1107/S2056989025004463

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Crystal engineering of a 1:1 5-fluorocytosine–4-hydroxybenzaldehyde cocrystal: insights from X-ray crystallography and Hirshfeld analysis

Marimuthu Sangavi,^a Marimuthu Mohana,^b ^* Ray J. Butcher ^c and Colin D. McMillen ^d

^aDepartment of Chemistry, Thanthai Periyar Government Arts and Science College, Tiruchirappalli-620 023, (Affiliated to Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India), Tamil Nadu, India, ^bDepartment of Chemistry, Periyar Maniammai Institute of Science and Technology (Deemed to be University), Thanjavur 613 403, Tamil Nadu, India, ^cDepartment of Chemistry, Howard University, Washington, DC 20059, USA, and ^dDepartment of Chemistry, Clemson University, H.L. Hunter Laboratories, Clemson, SC 29634, USA
^*Correspondence e-mail: [email protected]

Edited by S.-L. Zheng, Harvard University, USA (Received 25 April 2025; accepted 17 May 2025; online 23 May 2025)

The 1:1 cocrystal of 5-fluorocytosine (5FC) and 4-hydroxybenzaldehyde (4HB), C₄H₄FN₃O·C₇H₆O₂ has been synthesized and its structure characterized by single-crystal X-ray diffraction and Hirshfeld surface analysis. The compound crystallizes in the monoclinic P2₁/c space group. A robust supramolecular architecture is stabilized by N—H⋯O, N—H⋯N, C—H⋯O and C—H⋯F hydrogen bonds, forming R₂²(8), R₄⁴(22), R₆⁶(32), and R₈⁸(34) ring motifs. The N—H⋯O and N—H⋯N hydrogen bonds form strong directional interactions, contributing to the R₂²(8) and R₈⁸(34) motifs through dimeric and extended ring structures. O—H⋯O interactions link 5FC and 4HB molecules, generating an R₆⁶(32) ring that enhances the packing. Weaker C—H⋯F bonds help form the R₄⁴(22) tetrameric motif, supporting the overall three-dimensional supramolecular framework. Additionally, C—F⋯π interactions between the fluorine atom and the aromatic ring add further to the crystal cohesion. Hirshfeld surface analysis and two-dimensional fingerprint plots confirm that O⋯H/H⋯O contacts are the most significant, highlighting the central role of hydrogen bonding in the stability and organization of the crystal structure.

Keywords: cocrystal; supramolecular network; dimeric motif; tetrameric motif; Hirshfeld surface analysis,fingerprint plots.

CCDC reference: 2452037

1. Chemical context

Cocrystals have gained considerable attention in supramolecular chemistry for their ability to improve the physical and chemical properties of active pharmaceutical ingredients (APIs) and functional materials without altering the molecular structure of the drug. They are defined as crystalline, single-phase solids composed of two or more distinct molecular and/or ionic compounds, typically in a stoichiometric ratio, which are neither simple salts nor solvates (Aitipamula et al., 2012 ; Almarsson & Zaworotko, 2004 ). Cocrystals are stabilized through non-covalent interactions such as hydrogen bonding, π–π stacking, halogen bonding, and van der Waals forces. Their design is guided by the principles of crystal engineering, involving the careful selection of suitable coformers and the application of supramolecular synthons, such as the R₂²(8) hydrogen-bonded motif (Etter, 1990 ; Etter et al., 1990 ; Desiraju, 1995 ). In the pharmaceutical industry, cocrystallization offers a promising strategy for enhancing the solubility, stability, and bioavailability of poorly soluble drugs. (Alvani & Shayanfar, 2022 ; Shi et al., 2024 ). Compared to conventional techniques such as salt formation, micronization, solid dispersion, amorphous forms, and encapsulation, cocrystals offer the advantage of maintaining a stable crystalline structure, which facilitates detailed characterization by X-ray diffraction (Bolla & Nangia, 2016 ; Bolla et al., 2022 ).

2. Structural commentary

Single-crystal X-ray diffraction analysis reveals that the title compound crystallizes in the monoclinic P2₁/c space group with one molecule each of 5-fluorocytosine (5FC) and 4-hydroxybenzaldehyde (4HB) present in the asymmetric unit. An ellipsoid plot of the compound is shown in Fig. 1. Proton transfer does not occur between the hydroxyl group of benzaldehyde and the pyrimidine ring nitrogen atom of 5FC. The C—O bond length in the hydroxyl group of the 4HB molecule is 1.3520 (13) Å, with the corresponding internal bond angle [C2A—N1A—C3A = 120.00 (8)°] in agreement with reported literature values (Louis et al., 1982 ; Mohana et al., 2016 , 2023 ; Sangavi et al., 2024 ).

Figure 1
The molecular structure of the title cocrystal with displacement ellipsoids drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines.

3. Supramolecular features and Hirshfeld surface analysis

The primary interaction motif is formed via N—H⋯O and C—H⋯F hydrogen bonds (Table 1). The N4A amino group and F1A atom of the 5FC molecule interact with the O2B and C7B atoms of the 4HB molecule, resulting in an R₂²(8) heterodimeric synthon. Heterodimers are further linked through a weak C—H⋯Oⁱⁱⁱ [symmetry code: (iii) −x + 2, −y + 1, −z + 1] hydrogen bond involving the C4A atom of 5FC and the O1B atom of 4HB. The interaction leads to the formation of an R₄⁴(22) tetrameric synthon. The tetrameric motif is further extended through a homodimeric R₂²(8) synthon, formed by N—H⋯Nⁱ [symmetry code: (i) −x, y + $[{1\over 2}]$ , −z + $[{3\over 2}]$ ] and N—H⋯Oⁱⁱ [symmetry code: (ii) −x, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ ] hydrogen bonds. These interactions involve atoms N1A, N2A, N3A and O1A of the 5-fluorocytosine (5FC) molecule. The formation of this homodimeric synthon bridges adjacent tetrameric units, resulting in a large R₈⁸(34) ring motif. The alternating arrangement of R₄⁴(22) and R₈⁸(34) rings leads to the development of a three-dimensional supramolecular cage-like architecture. This network is further consolidated by O—H⋯O hydrogen-bonding interactions between the O1A atom of the 5FC molecule and the hydroxyl (–OH) group of the 4-hydroxybenzaldehyde (4HB) molecule. The hydrogen bonding occurs via an O—H⋯O^iv [symmetry code: (iv) x + 1, −y + $[{1\over 2}]$ , z − $[{1\over 2}]$ ] interaction, forming an R₆⁶(32) ring motif (Fig. 2). This interaction strengthens the packing and adds complexity to the supramolecular network. In addition to hydrogen bonding, the crystal structure is further consolidated by weak C—H⋯F and C—F⋯π interactions. The C—F⋯π interaction (Fig. 3) is observed between 5FC molecules [C1A⋯Cg^v = 3.2676 (9) Å, C1A—F1A⋯Cg = 89.41 (6)°, where Cg is the centroid of the 5FC ring; symmetry code: (v) 1 + x, y, z]. The observed angle is consistent with values reported in the literature (Sikorski et al., 2005 ; Vangala et al., 2002 ).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2A—H1⋯N1Aⁱ	0.88 (1)	2.06 (1)	2.9354 (12)	175 (1)
N3A—H1CC⋯O2B	0.89 (1)	2.10 (1)	2.9848 (13)	170 (1)
N3A—H1A⋯O1Aⁱⁱ	0.90 (1)	2.04 (1)	2.9328 (12)	176 (1)
C4A—H4A⋯O1Bⁱⁱⁱ	0.93	2.48	3.2905 (14)	145
O1B—H1B⋯O1A^iv	0.86 (2)	1.85 (2)	2.6934 (13)	166 (2)
C6B—H6B⋯F1Aⁱⁱⁱ	0.93	2.56	3.3446 (14)	143
C7B—H7B⋯F1A	0.93	2.51	2.9886 (14)	112
Symmetry codes: (i) $[-x, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) ; (iv) $[x+1, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Figure 2
Three-dimensional supramolecular cage-like architecture formed via N—H⋯O, N—H⋯N, O—H⋯O, C—H⋯F and C—H⋯O hydrogen bonds. [Symmetry codes: (i) −x, y + $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (ii) −x, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (iii) −x + 2, −y + 1, −z + 1; (iv) x + 1, −y + $[{1\over 2}]$ , z − $[{1\over 2}]$ .]

Figure 3
A view of the C—F⋯π interaction (symmetry operation 1 + x, y, z).

Hirshfeld surface (HS) analysis was performed for the title compound to visualize and quantify its intermolecular interactions. Fig. 4 presents the van der Waals interactions using a Hirshfeld surface mapped over d_norm (Spackman & Jayatilaka, 2009 ), generated with Crystal Explorer 21 (Spackman et al., 2021 ). This analysis reveals significant intermolecular hydrogen bonds of the types N—H⋯O, N—H⋯N and O—H⋯O interactions. In the surface representation, red areas indicate strong hydrogen bonding, blue regions correspond to contacts close to the sum of the van der Waals radii, and white regions represent weaker interactions.

Figure 4
The Hirshfeld surface mapped over d_norm showing the N—H⋯O, N—H⋯N and O—H⋯O interactions as dashed gray lines.

To analyze the relative contributions of different intermolecular interactions, two-dimensional fingerprint plots were generated (McKinnon et al., 2007 ) and these are shown in Fig. 5. These plots indicate that the most prominent contacts are O⋯H/H⋯O (26.6%), followed by H⋯H (25.5%), C⋯H/H⋯C (16.7%), N⋯H/H⋯N (10.0%) and F⋯H/H⋯F (6.2%). The crystallographic analysis reveals a robust supramolecular network in the title compound, stabilized by hydrogen bonds (N—H⋯O, N—H⋯N, O—H⋯O and C—H⋯F) and C—F⋯π interactions, forming a three-dimensional cage-like supramolecular architecture. Hirshfeld surface analysis highlights prominent O⋯H/H⋯O interactions, alongside other significant contacts, contributing to crystal stability. The study demonstrates how non-covalent interactions, including hydrogen-bonding and π interactions, govern the molecular packing and cohesion, supporting the principles of supramolecular chemistry in crystal engineering.

Figure 5
Fingerprint plots showing the total contribution of individual interactions and those delineated into O⋯H/H⋯O, H⋯H, C⋯H/H⋯C, N⋯H/H⋯N and F⋯H/H⋯F interactions.

4. Database survey

5-Fluorocytosine (5FC) is a synthetic antimycotic compound, first synthesized in 1957 and widely used as an antitumor agent. It is also active against fungal infection (Portalone & Colapietro, 2007 ; Vermes et al., 2000 ). It becomes active by deamination of 5FC into 5-fluorouracil by the enzyme cytosine deaminase (CD) and inhibits RNA and DNA synthesis (Morschhauser, 2003 ). The Cambridge Structural Database (CSD, v5.45, June 2024; Groom et al., 2016 ) reference codes for the monohydrate are BIRMEU, BIRMEU01, BIRMEU02, BIRMEU03, MEBQUG, MEBQIU, MEBQOA and GATMUL (Louis et al., 1982; Portalone & Colapietro, 2006 ; Hulme & Tocher, 2006 ; Portalone, 2011 ), and for the polymorphs: DUKWIQ, DUKWAI and DUKWEM (Tutughamiarso et al., 2009 ). A wide range of cocrystals has also been documented, such as XOQQUS, MECTUL, MECVEX, MECVIB, MECVOH, MECVUN, MECWAU, MECWEY, MECWOI, MECWUO, MECXEZ, MECXID, MECXOJ, GIFWIF, UJUJAM, and POCWUD (Souza et al., 2019 ;Tutughamiarso et al., 2012 ; Tutughamiarso & Egert, 2012 ; Mohana et al., 2016, 2023; Sangavi et al., 2024). Salts include WEWZAA01, SIJXAM, SIJXIU, SIJXUG, EDATOS, GIFWEB, POCXAK, ZAPFEE and ROLTUJ WEWZAA01, SIJXAM, SIJXIU, SIJXUG, EDATOS, GIFWEB, POCXAK, ZAPFEE and ROLTUJ (Perumalla et al., 2013a ,b ; Prabakaran et al., 2001 ; Mohana et al., 2017 ; Karthikeyan et al., 2014 ) have been reported in the literature. 4-Hydroxybenzaldehydes are potential therapeutic agents for the treatment of human angiostrongyliasis. The crystal structure of 4-hydroxybenzaldehyde (Jasinski et al., 2008 ), as well as its cocrystal (Nowak & Sikorski, 2023 ) and polymorphic forms (Simões et al., 2013 ) have also been reported. 5FC contains multiple hydrogen-bond donors and acceptors, including amino and carbonyl groups, and 4-HBA offers hydroxyl and aldehyde functionalities capable of forming hydrogen bonds, along with an aromatic ring that can engage in π–π interactions. The present work focuses on the supramolecular hydrogen bonding interactions in the crystal structure of 1:1 cocrystals of 5-fluorocytosine-4-hydroxybenzaldehyde.

5. Synthesis and crystallization

The title compound was synthesized by mixing a hot ethanolic solution of 5-fluorocytosine with 4-hydroxybenzaldehyde in a 1:1 molar ratio. The solution was heated in a water bath at 333 K for 30 minutes and then allowed to cool slowly to room temperature. After a few days, colorless crystals had separated out of the mother liquor.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The H atoms of the N—H, –NH₂ and OH groups were located in difference-Fourier maps and refined freely. Other H atoms were placed geometrically (C—H = 0.93 Å) and refined using a riding model with U_iso(H) = 1.2U_eq(C).

Table 2
Experimental details

Crystal data
Chemical formula	C₄H₄FN₃O·C₇H₆O₂
M_r	251.22
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	297
a, b, c (Å)	4.2126 (1), 9.6687 (1), 26.8628 (5)
β (°)	94.186 (1)
V (Å³)	1091.21 (3)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	1.07
Crystal size (mm)	0.27 × 0.21 × 0.17

Data collection
Diffractometer	XtaLAB Synergy, Dualflex, HyPix
Absorption correction	Analytical (CrysAlis PRO; Rigaku OD, 2023 $[Rigaku OD. (2023). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, England.]$ )
T_min, T_max	0.782, 0.840
No. of measured, independent and observed [I > 2σ(I)] reflections	19824, 2243, 2127
R_int	0.019
(sin θ/λ)_max (Å⁻¹)	0.630

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.034, 0.101, 1.04
No. of reflections	2243
No. of parameters	180
No. of restraints	4
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.20, −0.19
Computer programs: CrysAlis PRO (Rigaku OD, 2023 $[Rigaku OD. (2023). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, England.]$ ), SHELXT (Sheldrick, 2015a ), SHELXL2019/2 (Sheldrick, 2015b ), PLATON (Spek, 2020 ), Mercury (Macrae et al., 2020 ), POVRay (Cason, 2004 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2452037

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989025004463/oi2017sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989025004463/oi2017Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989025004463/oi2017Isup3.cml

checkCIF report

Computing details top

4-Amino-5-fluoro-1H-pyrimidin-2-one–4-hydroxybenzaldehyde (1/1) top

Crystal data top

C₄H₄FN₃O·C₇H₆O₂	F(000) = 520
M_r = 251.22	D_x = 1.529 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 4.2126 (1) Å	Cell parameters from 18043 reflections
b = 9.6687 (1) Å	θ = 3.3–76.2°
c = 26.8628 (5) Å	µ = 1.07 mm⁻¹
β = 94.186 (1)°	T = 297 K
V = 1091.21 (3) Å³	Block, colorless
Z = 4	0.27 × 0.21 × 0.17 mm

Data collection top

XtaLAB Synergy, Dualflex, HyPix diffractometer	2243 independent reflections
Radiation source: micro-focus sealed X-ray tube	2127 reflections with I > 2σ(I)
Detector resolution: 10.0000 pixels mm^-1	R_int = 0.019
ω scans	θ_max = 76.2°, θ_min = 3.3°
Absorption correction: analytical (CrysAlisPro; Rigaku OD, 2023)	h = −3→5
T_min = 0.782, T_max = 0.840	k = −12→12
19824 measured reflections	l = −33→33

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.034	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.101	w = 1/[σ²(F_o²) + (0.0563P)² + 0.2241P] where P = (F_o² + 2F_c²)/3
S = 1.04	(Δ/σ)_max = 0.001
2243 reflections	Δρ_max = 0.20 e Å⁻³
180 parameters	Δρ_min = −0.19 e Å⁻³
4 restraints	Extinction correction: SHELXL2019/2 (Sheldrick, 2015b), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: dual	Extinction coefficient: 0.0088 (13)

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. The data collection, cell refinement, and data reduction were performed using CrysAlisPro (Rigaku OD, 2023). Structure solution was carried out with SHELXT 2014/5 (Sheldrick, 2015a) and refinement was done using SHELXL-2016/6 (Sheldrick, 2015b). Molecular graphics were prepared using PLATON (Spek, 2020), Mercury (Macrae et al., 2020) and POVRay (Cason 2004).

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

	x	y	z	U_iso*/U_eq
F1A	0.6004 (2)	0.39753 (7)	0.63425 (3)	0.0557 (2)
O1A	−0.1067 (2)	0.40145 (8)	0.79019 (3)	0.0439 (2)
N1A	0.1299 (2)	0.27556 (9)	0.73165 (3)	0.0331 (2)
N2A	0.1501 (2)	0.51932 (9)	0.73260 (3)	0.0344 (2)
H1	0.076 (3)	0.5966 (14)	0.7444 (6)	0.050 (4)*
N3A	0.3795 (3)	0.15570 (10)	0.67141 (4)	0.0401 (3)
H1CC	0.492 (3)	0.1523 (16)	0.6446 (5)	0.049 (4)*
H1A	0.294 (3)	0.0798 (14)	0.6845 (5)	0.045 (4)*
C1A	0.4154 (3)	0.40215 (11)	0.67318 (4)	0.0351 (3)
C2A	0.3072 (2)	0.27452 (11)	0.69223 (4)	0.0313 (2)
C3A	0.0531 (2)	0.39737 (10)	0.75270 (4)	0.0323 (2)
C4A	0.3331 (3)	0.52236 (11)	0.69305 (4)	0.0356 (3)
H4A	0.399417	0.605918	0.680151	0.043*
O1B	1.1638 (2)	0.27251 (10)	0.35919 (3)	0.0520 (3)
H1B	1.074 (4)	0.2080 (18)	0.3414 (7)	0.076 (5)*
O2B	0.6793 (3)	0.13585 (11)	0.57435 (3)	0.0605 (3)
C1B	1.0816 (3)	0.25581 (12)	0.40653 (4)	0.0383 (3)
C2B	0.8831 (3)	0.14938 (12)	0.42006 (4)	0.0421 (3)
H2B	0.798860	0.087622	0.396053	0.050*
C3B	0.8117 (3)	0.13552 (13)	0.46892 (4)	0.0450 (3)
H3B	0.677170	0.064757	0.477749	0.054*
C4B	0.9386 (3)	0.22637 (12)	0.50533 (4)	0.0401 (3)
C5B	1.1361 (3)	0.33238 (13)	0.49140 (4)	0.0440 (3)
H5B	1.222274	0.393527	0.515464	0.053*
C6B	1.2064 (3)	0.34827 (13)	0.44238 (5)	0.0471 (3)
H6B	1.336473	0.420430	0.433386	0.056*
C7B	0.8656 (3)	0.21566 (14)	0.55746 (4)	0.0474 (3)
H7B	0.972343	0.275878	0.579901	0.057*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1A	0.0776 (5)	0.0414 (4)	0.0534 (5)	−0.0025 (3)	0.0416 (4)	0.0020 (3)
O1A	0.0648 (5)	0.0344 (4)	0.0352 (4)	0.0058 (4)	0.0229 (4)	0.0028 (3)
N1A	0.0453 (5)	0.0265 (4)	0.0287 (4)	−0.0013 (3)	0.0106 (4)	0.0013 (3)
N2A	0.0456 (5)	0.0250 (4)	0.0338 (5)	0.0007 (3)	0.0103 (4)	−0.0009 (3)
N3A	0.0588 (6)	0.0295 (5)	0.0341 (5)	−0.0013 (4)	0.0177 (4)	−0.0018 (4)
C1A	0.0421 (6)	0.0337 (6)	0.0310 (5)	−0.0024 (4)	0.0131 (4)	0.0025 (4)
C2A	0.0383 (5)	0.0296 (5)	0.0265 (5)	−0.0006 (4)	0.0053 (4)	0.0009 (4)
C3A	0.0416 (5)	0.0285 (5)	0.0274 (5)	0.0006 (4)	0.0065 (4)	0.0018 (4)
C4A	0.0423 (6)	0.0290 (5)	0.0364 (5)	−0.0035 (4)	0.0096 (4)	0.0047 (4)
O1B	0.0734 (6)	0.0513 (5)	0.0327 (4)	−0.0134 (4)	0.0137 (4)	0.0001 (4)
O2B	0.0838 (7)	0.0605 (6)	0.0404 (5)	0.0017 (5)	0.0255 (5)	0.0006 (4)
C1B	0.0477 (6)	0.0370 (5)	0.0311 (5)	0.0040 (4)	0.0082 (4)	0.0018 (4)
C2B	0.0536 (7)	0.0389 (6)	0.0343 (6)	−0.0031 (5)	0.0075 (5)	−0.0055 (4)
C3B	0.0549 (7)	0.0419 (6)	0.0397 (6)	−0.0053 (5)	0.0140 (5)	−0.0004 (5)
C4B	0.0464 (6)	0.0422 (6)	0.0324 (5)	0.0101 (5)	0.0080 (4)	−0.0005 (4)
C5B	0.0528 (7)	0.0425 (6)	0.0367 (6)	0.0017 (5)	0.0026 (5)	−0.0072 (5)
C6B	0.0595 (7)	0.0406 (6)	0.0418 (6)	−0.0090 (5)	0.0083 (5)	−0.0015 (5)
C7B	0.0569 (7)	0.0521 (7)	0.0342 (6)	0.0110 (6)	0.0102 (5)	−0.0031 (5)

Geometric parameters (Å, º) top

F1A—C1A	1.3498 (12)	O1B—H1B	0.857 (15)
O1A—C3A	1.2521 (13)	O2B—C7B	1.2122 (17)
N1A—C2A	1.3397 (13)	C1B—C6B	1.3889 (17)
N1A—C3A	1.3558 (13)	C1B—C2B	1.3907 (16)
N2A—C4A	1.3578 (14)	C2B—C3B	1.3746 (16)
N2A—C3A	1.3715 (13)	C2B—H2B	0.9300
N2A—H1	0.877 (13)	C3B—C4B	1.3920 (17)
N3A—C2A	1.3231 (14)	C3B—H3B	0.9300
N3A—H1CC	0.891 (13)	C4B—C5B	1.3887 (18)
N3A—H1A	0.900 (12)	C4B—C7B	1.4594 (15)
C1A—C4A	1.3353 (15)	C5B—C6B	1.3791 (17)
C1A—C2A	1.4235 (14)	C5B—H5B	0.9300
C4A—H4A	0.9300	C6B—H6B	0.9300
O1B—C1B	1.3520 (13)	C7B—H7B	0.9300

C2A—N1A—C3A	120.00 (8)	O1B—C1B—C2B	122.30 (10)
C4A—N2A—C3A	121.95 (9)	C6B—C1B—C2B	119.97 (10)
C4A—N2A—H1	120.1 (10)	C3B—C2B—C1B	119.96 (11)
C3A—N2A—H1	117.8 (10)	C3B—C2B—H2B	120.0
C2A—N3A—H1CC	121.8 (10)	C1B—C2B—H2B	120.0
C2A—N3A—H1A	115.6 (9)	C2B—C3B—C4B	120.64 (11)
H1CC—N3A—H1A	122.4 (14)	C2B—C3B—H3B	119.7
C4A—C1A—F1A	121.33 (9)	C4B—C3B—H3B	119.7
C4A—C1A—C2A	120.77 (10)	C5B—C4B—C3B	118.92 (10)
F1A—C1A—C2A	117.90 (9)	C5B—C4B—C7B	118.91 (11)
N3A—C2A—N1A	119.97 (9)	C3B—C4B—C7B	122.16 (11)
N3A—C2A—C1A	120.74 (9)	C6B—C5B—C4B	120.93 (11)
N1A—C2A—C1A	119.29 (9)	C6B—C5B—H5B	119.5
O1A—C3A—N1A	121.43 (9)	C4B—C5B—H5B	119.5
O1A—C3A—N2A	118.86 (9)	C5B—C6B—C1B	119.58 (11)
N1A—C3A—N2A	119.71 (9)	C5B—C6B—H6B	120.2
C1A—C4A—N2A	118.21 (9)	C1B—C6B—H6B	120.2
C1A—C4A—H4A	120.9	O2B—C7B—C4B	126.30 (12)
N2A—C4A—H4A	120.9	O2B—C7B—H7B	116.9
C1B—O1B—H1B	107.7 (13)	C4B—C7B—H7B	116.9
O1B—C1B—C6B	117.73 (11)

C3A—N1A—C2A—N3A	−179.36 (10)	O1B—C1B—C2B—C3B	178.79 (11)
C3A—N1A—C2A—C1A	0.55 (16)	C6B—C1B—C2B—C3B	−0.23 (19)
C4A—C1A—C2A—N3A	177.61 (11)	C1B—C2B—C3B—C4B	−0.64 (19)
F1A—C1A—C2A—N3A	−1.78 (16)	C2B—C3B—C4B—C5B	0.72 (18)
C4A—C1A—C2A—N1A	−2.30 (17)	C2B—C3B—C4B—C7B	179.39 (11)
F1A—C1A—C2A—N1A	178.31 (9)	C3B—C4B—C5B—C6B	0.07 (18)
C2A—N1A—C3A—O1A	−178.50 (10)	C7B—C4B—C5B—C6B	−178.65 (11)
C2A—N1A—C3A—N2A	1.84 (16)	C4B—C5B—C6B—C1B	−0.9 (2)
C4A—N2A—C3A—O1A	177.67 (10)	O1B—C1B—C6B—C5B	−178.06 (11)
C4A—N2A—C3A—N1A	−2.66 (16)	C2B—C1B—C6B—C5B	1.01 (19)
F1A—C1A—C4A—N2A	−179.10 (9)	C5B—C4B—C7B—O2B	173.98 (12)
C2A—C1A—C4A—N2A	1.53 (17)	C3B—C4B—C7B—O2B	−4.7 (2)
C3A—N2A—C4A—C1A	0.92 (17)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2A—H1···N1Aⁱ	0.88 (1)	2.06 (1)	2.9354 (12)	175 (1)
N3A—H1CC···O2B	0.89 (1)	2.10 (1)	2.9848 (13)	170 (1)
N3A—H1A···O1Aⁱⁱ	0.90 (1)	2.04 (1)	2.9328 (12)	176 (1)
C4A—H4A···O1Bⁱⁱⁱ	0.93	2.48	3.2905 (14)	145
O1B—H1B···O1A^iv	0.86 (2)	1.85 (2)	2.6934 (13)	166 (2)
C6B—H6B···F1Aⁱⁱⁱ	0.93	2.56	3.3446 (14)	143
C7B—H7B···F1A	0.93	2.51	2.9886 (14)	112

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

Funding information

We thank Howard University and the National Science Foundation Major Research Instrumentation program (NSF DMR-2117502) for financially supporting the acquisition of the Rigaku Synergy single-crystal X-ray diffractometer used in this study.

References

Aitipamula, S., Banerjee, R., Bansal, A. K., Biradha, K., Cheney, M. L., Choudhury, A. R., Desiraju, G. R., Dikundwar, A. G., Dubey, R., Duggirala, N., Ghogale, P. P., Ghosh, S., Goswami, P. K., Goud, N. R., Jetti, R. R. K. R., Karpinski, P., Kaushik, P., Kumar, D., Kumar, V., Moulton, B., Mukherjee, A., Mukherjee, G., Myerson, A. S., Puri, V., Ramanan, A., Rajamannar, T., Reddy, C. M., Rodriguez-Hornedo, N., Rogers, R. D., Row, T. N. G., Sanphui, P., Shan, N., Shete, G., Singh, A., Sun, C. C., Swift, J. A., Thaimattam, R., Thakur, T. S., Kumar Thaper, R., Thomas, S. P., Tothadi, S., Vangala, V. R., Variankaval, N., Vishweshwar, P., Weyna, D. R. & Zaworotko, M. J. (2012). Cryst. Growth Des. 12, 2147–2152. Web of Science CrossRef CAS Google Scholar
Almarsson, O. & Zaworotko, M. J. (2004). Chem. Commun. pp. 1889–1896. Web of Science CrossRef Google Scholar
Alvani, A. & Shayanfar, A. (2022). Cryst. Growth Des. 22, 6323–6337. CrossRef CAS Google Scholar
Bolla, G. & Nangia, A. (2016). Chem. Commun. 52, 8342–8360. Web of Science CrossRef CAS Google Scholar
Bolla, G., Sarma, B. & Nangia, A. K. (2022). Chem. Rev. 122, 11514–11603. Web of Science CrossRef CAS PubMed Google Scholar
Cason, C. J. (2004). POV-RAY for Windows. Persistence of Vision Raytracer Pvt Ltd, Victoria, Australia. http://www.povray.org Google Scholar
Desiraju, G. R. (1995). Angew. Chem. Int. Ed. Engl. 34, 2311–2327. CrossRef CAS Web of Science Google Scholar
Etter, M. C. (1990). Acc. Chem. Res. 23, 120–126. CrossRef CAS Web of Science Google Scholar
Etter, M. C., Urbanczyk-Lipkowska, Z., Zia-Ebrahimi, M. & Panunto, T. W. (1990). J. Am. Chem. Soc. 112, 8415–8426. CSD CrossRef CAS Web of Science 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
Hulme, A. T. & Tocher, D. A. (2006). Cryst. Growth Des. 6, 481–487. Web of Science CSD CrossRef CAS Google Scholar
Jasinski, J. P., Butcher, R. J., Narayana, B., Swamy, M. T. & Yathirajan, H. S. (2008). Acta Cryst. E64, o187. Web of Science CSD CrossRef IUCr Journals Google Scholar
Karthikeyan, A., Thomas Muthiah, P. & Perdih, F. (2014). Acta Cryst. E70, 328–330. CSD CrossRef IUCr Journals Google Scholar
Louis, T., Low, J. N. & Tollin, P. (1982). Cryst. Struct. Commun. 11, 1059–1064. CAS Google Scholar
Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235. Web of Science CrossRef CAS IUCr Journals Google Scholar
McKinnon, J. J., Jayatilaka, D. & Spackman, M. A. (2007). Chem. Commun. pp. 3814–3816. Web of Science CrossRef Google Scholar
Mohana, M., Muthiah, P. T., Sanjeewa, L. D. & McMillen, C. D. (2016). Acta Cryst. E72, 552–555. Web of Science CSD CrossRef IUCr Journals Google Scholar
Mohana, M., Thomas Muthiah, P. & McMillen, C. D. (2017). Acta Cryst. E73, 361–364. CSD CrossRef IUCr Journals Google Scholar
Mohana, M., Thomas Muthiah, P., McMillen, C. D. & Butcher, R. J. (2023). Acta Cryst. C79, 61–67. Web of Science CSD CrossRef IUCr Journals Google Scholar
Morschhäuser, J. (2003). Pharm. Unserer Zeit 32, 124–129. PubMed Google Scholar
Nowak, P. & Sikorski, A. (2023). RSC Adv. 13, 20105–20112. CSD CrossRef CAS PubMed Google Scholar
Perumalla, S. R., Pedireddi, V. R. & Sun, C. C. (2013a). Cryst. Growth Des. 13, 429–432. Web of Science CSD CrossRef CAS Google Scholar
Perumalla, S. R., Pedireddi, V. R. & Sun, C. C. (2013b). Mol. Pharm. 10, 2462–2466. Web of Science CSD CrossRef CAS PubMed Google Scholar
Portalone, G. (2011). Chem. Cent. J. 5, 51. Web of Science CSD CrossRef PubMed Google Scholar
Portalone, G. & Colapietro, M. (2006). Acta Cryst. E62, o1049–o1051. Web of Science CSD CrossRef IUCr Journals Google Scholar
Portalone, G. & Colapietro, M. (2007). J. Chem. Crystallogr. 37, 141–145. Web of Science CSD CrossRef CAS Google Scholar
Prabakaran, P., Murugesan, S., Muthiah, P. T., Bocelli, G. & Righi, L. (2001). Acta Cryst. E57, o933–o936. Web of Science CSD CrossRef IUCr Journals Google Scholar
Rigaku OD. (2023). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, England. Google Scholar
Sangavi, M., Kumaraguru, N., Butcher, R. J. & McMillen, C. D. (2024). Acta Cryst. C80, 30–36. Web of Science CSD CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Shi, J., Zhang, Y., An, Q., Li, Y. & Liu, L. (2024). J. Solid State Chem. 331, 124545. CSD CrossRef Google Scholar
Sikorski, A., Krzymiński, K., Niziołek, A. & Błażejowski, J. (2005). Acta Cryst. C61, o690–o694. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Simões, R. G., Bernardes, C. E. S. & da Piedade, M. E. M. (2013). Cryst. Growth Des. 13, 2803–2814. Google Scholar
Souza, M. S., Diniz, L. F., Alvarez, N., da Silva, C. C. P. & Ellena, J. (2019). New J. Chem. 43, 15924–15934. Web of Science CSD CrossRef CAS Google Scholar
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm 11, 19–32. Web of Science CrossRef CAS Google Scholar
Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D. & Spackman, M. A. (2021). J. Appl. Cryst. 54, 1006–1011. Web of Science CrossRef CAS IUCr Journals Google Scholar
Spek, A. L. (2020). Acta Cryst. E76, 1–11. Web of Science CrossRef IUCr Journals Google Scholar
Tutughamiarso, M. & Egert, E. (2012). Acta Cryst. B68, 444–452. Web of Science CSD CrossRef IUCr Journals Google Scholar
Tutughamiarso, M., Bolte, M. & Egert, E. (2009). Acta Cryst. C65, o574–o578. Web of Science CSD CrossRef IUCr Journals Google Scholar
Tutughamiarso, M., Wagner, G. & Egert, E. (2012). Acta Cryst. B68, 431–443. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Vangala, V. R., Nangia, A. & Lynch, D. E. (2002). Chem. Commun. pp. 1304–1305. CSD CrossRef Google Scholar
Vermes, A., Guchelaar, H. J. & Dankert, J. (2000). J. Antimicrob. Chemother. 46, 171–179. Web of Science CrossRef PubMed CAS Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

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