Crystal engineering of a 1:1 5-fluorocytosine–4-hydroxybenzaldehyde cocrystal: insights from X-ray crystallography and Hirshfeld analysis International Union of Crystallography 06/01/2025 10656167 10.1107/S2056989025004463 Acta Crystallographica Section E Crystallographic Communications 2056-9890 81 6 Marimuthu SangaviMarimuthu MohanaRay J ButcherColin D McMillen The 1:1 cocrystal of 5-fluorocytosine (5FC) and 4-hydroxybenzaldehyde (4HB), C4H4FN3O·C7H6O2has been synthesized and its structure characterized by single-crystal X-ray diffraction and Hirshfeld surface analysis. The compound crystallizes in the monoclinicP21/cspace group. A robust supramolecular architecture is stabilized by N—H...O, N—H...N, C—H...O and C—H...F hydrogen bonds, formingR22(8),R44(22),R66(32), andR88(34) ring motifs. The N—H...O and N—H...N hydrogen bonds form strong directional interactions, contributing to theR22(8) andR88(34) motifs through dimeric and extended ring structures. O—H...O interactions link 5FC and 4HB molecules, generating anR66(32) ring that enhances the packing. Weaker C—H...F bonds help form theR44(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.

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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, �-� 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 R 2 2 (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 crys-talline structure, which facilitates detailed characterization by X-ray diffraction (Bolla & Nangia, 2016;Bolla et al., 2022).

Structural commentary

Single-crystal X-ray diffraction analysis reveals that the title compound crystallizes in the monoclinic P2 1 /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) A ˚, 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., 2016Mohana et al., , 2023;;Sangavi et al., 2024).

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 R 2 2 (8) heterodimeric synthon. Heterodimers are further linked through a weak C-H� � �O iii [symmetry code: (iii) Àx + 2, Ày + 1, Àz + 1] hydrogen bond involving the C4A atom of 5FC and the O1B atom of 4HB. The interaction leads to the formation of an R 4 4 (22) tetrameric synthon. The tetrameric motif is further extended through a homodimeric R 2 2 (8) synthon, formed by N-H� � �N i [symmetry code: (i) Àx, y + 1 2 , Àz + 3 2 ] and N-H� � �O ii [symmetry code: (ii) Àx, y À 1 2 , Àz + 3 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 R 8 8 (34) ring motif. The alternating arrangement of R 4 4 ( 22) and R 8 8 (34) rings leads to the development of a three-dimensional supramolecular cagelike 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, Ày + 1 2 , z À 1 2 ] interaction, forming an R 6 6 (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� � �� interactions. The C-F� � �� interaction (Fig. 3) is observed between 5FC molecules [C1A� � �Cg v = 3.2676 ( 9 The molecular structure of the title cocrystal with displacement ellipsoids drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines.

Figure 2

Three-dimensional supramolecular cage-like architecture formed via

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

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). 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.

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� � �� interactions, forming a threedimensional 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 � interactions, govern the molecular packing and cohesion, supporting the principles of supramolecular chemistry in crystal engineering.

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., 2016Mohana et al., , 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 (Simo ˜es 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 �-� interactions. The present work focuses on the supramolecular hydrogen bonding interactions in the crystal structure of 1:1 cocrystals of 5-fluorocytosine-4-hydroxybenzaldehyde.

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.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The H atoms of the N-H, -NH 2 and OH groups were located in difference-Fourier maps and refined freely. Other H atoms were placed geometrically (C-H = 0.93 A ˚) and refined using a riding model with U iso (H) = 1.2U eq (C).

Funding information

1.04 2243 reflections 180 parameters 4 restraints Primary atom site location: dual Secondary atom site location: difference Fourier map Hydrogen site location: mixed H atoms treated by a mixture of independent and constrained refinement w = 1/[σ 2 (F o 2 ) + (0.0563P) 2 + 0.2241P] where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.20 e Å -3 Δρ min = -0.19 e Å -3 Extinction correction: SHELXL2019/2 (Sheldrick, 2015b), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0088 (13) sup-2 Acta Cryst. (2025). E81, 549-553

Special details

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 (Å 2 ) 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 (Å 2 ) U 11 U 22 U 33 U 12 U 13 U 23 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) supporting information sup-3 Acta Cryst. (2025). E81, 549-553 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) 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

Computer programs: CrysAlis PRO(Rigaku OD, 2023), SHELXT(Sheldrick, 2015a), SHELXL2019/2(Sheldrick, 2015b), PLATON(Spek, 2020), Mercury(Macrae et al., 2020), POVRay(Cason, 2004) and publCIF(Westrip, 2010).