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Article

5-Fluorocytosine/Isocytosine Monohydrate. The First Example of Isomorphic and Isostructural Co-Crystal of Pyrimidine Nucleobases

by
Gustavo Portalone
Department of Chemistry, ‘Sapienza’ University of Rome, 00185 Rome, Italy
Crystals 2020, 10(11), 999; https://0-doi-org.brum.beds.ac.uk/10.3390/cryst10110999
Submission received: 1 October 2020 / Revised: 31 October 2020 / Accepted: 2 November 2020 / Published: 3 November 2020
(This article belongs to the Special Issue Design, Synthesis, and Structures of Modified RNA/DNA Bases)
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Abstract

:
To date, despite the crucial role played by cytosine, uracil, and thymine in the DNA/RNA replication process, no examples showing isomorphic and isostructural behavior among binary co-crystals of natural or modified pyrimidine nucleobases have been so far reported in the literature. In view of the relevance of biochemical and pharmaceutical compounds such as pyrimidine nucleobases and their 5-fluoroderivatives, co-crystals of the molecular complex formed by 5-fluorocytosine and isocytosine monohydrate, C4H4FN3O·C4H5N3O·H2O, have been synthesized by a reaction between 5-fluorocytosine and isocytosine. They represent the first example of isomorphic and isostructural binary co-crystals of pyrimidine nucleobases, as X-ray diffraction analysis shows structural similarities in the solid-state organization of molecules with that of the (1:1) 5-fluorocytosine/5-fluoroisocytosine monohydrate molecular complex, which differs solely in the H/F substitution at the C5 position of isocytosine. Molecules of 5-fluorocytosine and isocytosine are present in the crystal as 1H and 3H-ketoamino tautomers, respectively. They form almost coplanar WC base pairs through nucleobase-to-nucleobase DAA/ADD hydrogen bonding interactions, demonstrating that complementary binding enables the crystallization of specific tautomers. Additional peripheral hydrogen bonds involving all available H atom donor and acceptor sites of the water molecule give a three-dimensional polymeric structure. In the absence of H⋯F hydrogen-bonding interactions, the robustness of the supramolecular architectures based on three-point recognition synthons is responsible for the existence of isostructurality between the two molecular complexes.

1. Introduction

In the formation of binary co-crystals, a second substance may be incorporated into the crystal lattice by replacing the molecules of the first component, leaving unit-cell dimensions and space groups unaltered (isomorphism). This can happen particularly if molecules of the two substances are structural homologues. However, isomorphism does not necessarily imply isostructurality, i.e., the situation where two crystal structures of different chemical composition exhibit the same spatial arrangement of molecules, in the formation of crystals or co-crystals [1,2]. Although small changes in the molecular structure can significantly affect molecular disposition in the crystal, specific functional groups or atoms can be interchanged without modifying crystal packing, provided that such groups (or atoms) are not involved in hydrogen bonds [3]. Concerning the exchange of the hydrogen/fluorine atoms, a systematic investigation in the Cambridge Structural Database (CSD) of almost 125,000 pairs of crystal structures yielded 645 pairs containing molecules which differed only in the substitution of H with F atoms, and 21% of them showed structural similarities in the solid-state organization [4].
Considering this, and the fact that the properties of molecular substances in the solid state depend essentially on their chemical nature, their stoichiometry and their reciprocal disposition in space, from the structural chemistry point of view pyrimidine nucleobases and their fluorosubstituted derivatives deserve special attention. On one side, the fundamental importance of cytosine, uracil, and thymine for structural molecular biology and supramolecular chemistry has been well-known for decades. On the other hand, it has been shown that the formation of haloderivatives of cytosine in DNA can be responsible for several modifications in the structure of DNA observed in human tumors [5], and mass spectrometry has been applied to detect halocytosines as free nucleobases to evaluate cytosine halogenation as an endogenous mutagenic pathway in human tissue [6]. Therefore, it is surprising that hardly any example showing isomorphic and isostructural behaviors between co-crystals of natural pyrimidine nucleobases and co-crystals of their fluorosubstituted derivatives can be found in the literature. In addition, although isostructurality is relatively common in crystals of multi-component systems, the author’s literature search found only four cases of crystal packing similarity of centro/noncentrosymmetric co-crystals formed by pyrimidine nucleobases/5-fluorosubstituted derivatives with polymorphic centro/noncentro symmetric crystals of the 5-fluorosubstituted coformers. These four examples (Scheme 1), in which there was no indication of C–H⋯F intermolecular interactions, refer to the crystal structures of:
i)
the monoclinic P21/c forms of monohydrate (1:1) 5-fluorocytosine/cytosine, SAVKIM [7], and monohydrate 5-fluorocytosine, BIRMEU02 [8];
ii)
the monoclinic P21/n forms of (1:1) 5-fluorocytosine/cytosine, ADAJAT [9], and 5-fluorocytosine, MEBQEQ [8];
iii)
the tetragonal P41212 forms of (1:1) 5-fluorocytosine/cytosine, ADAJAT01 [9], and 5-fluorocytosine, MEBQEQ01 [8];
iv)
the orthorhombic Pnma forms of (1:1) N,N-dimethyluracil/N,N-dimethyl-5-fluorouracil, N,N-dimethyl-5-fluorouracil, OKATEB and KAMSAS01, respectively [10], and N,N-dimethyluracil, DMURAC01 [11].
Notably, in all the crystal structures of the isostructural pairs SAVKIM/BIRMEU02, ADAJAT/MEBQEQ and ADAJAT01/MEBQEQ01 5-fluorocytosine and cytosine are present as 1H-ketoamino tautomers. Consequently, the DAA/ADD triple hydrogen bond interaction between nucleobases is precluded, and dimerization is obtained through two independent DA/AD interactions based on the same constituent hydrogen bonds: (ring)N–H⋯N(imino) and (amino)N–H⋯O (carbonyl) (Figure 1).
In light of previous observations, this paper reports the single-crystal X-ray structure of co-crystals of (1:1) 5-fluorocytosine/isocytosine monohydrate, (I). The solid-state arrangement of molecules of (I) has then been compared with the structurally related fluorocytosine/5-fluoroisocytosine monohydrate molecular complex, PANLAS [12]. The latter molecular complex differs from (I) in changing F/H atoms at the 5 position of isocytosine (Scheme 2).
The choice of the components of this binary co-crystal was made from consideration of the following points.
5-Fluorocytosine (Flucytosine) is a synthetic monofluorinated analog of cytosine. This compound can exist in different tautomeric forms, due to the presence of solvent-exchangeable protons. In the crystal, it exhibits polymorphism and is known only in the 1H-ketoamino form, the most stable tautomer in aqueous solution [13]. It is structurally very similar to its parent nucleobase and satisfies steric requirements at enzyme receptor sites, therefore it is commonly used as antimetabolite. Flucytosine can act as an antifungal agent, as it is deaminated by cytosine deaminase of the fungal cells to give 5-fluorouracil, resulting in RNA miscoding. 5-Fluorocytosine also plays an important role in the treatment of different types of cancer, although its use is limited by severe side effects [14].
Isocytosine (2-aminouracil), an isomer of cytosine, deserved special attention in experiments with an artificial pyrimidine base pair to expand the genetic alphabet of DNA, and to understand how the complementarity originally appeared in the form of the G–C [15]. Isocytosine is subject to prototropic tautomerism between the 1H and 3H-ketoamino forms, and it can form in solid-state intermolecular complexes with one or the other tautomer. In the 3H-ketoamino form, the most stable tautomer in polar solvents [16,17], isocytosine undergoes base pairing in a WC manner with unnatural isoguanine, and in a reversed WC manner with natural guanine, and has been used for structural studies of nucleic acids [18] as well as for hydrogen-bonding in nucleobases [19]. It has been shown that isocytosine could provide a base for a putative new prodrug 5-fluoroisocytosine, when used together with a putative isocytosine deaminase [20].
A search on the ConQuest module [21], version 2020.1.1 of the Cambridge Crystallographic Database (CSD version 5.41, August 2020 update) [22] for neutral 5-fluorocytosine and neutral isocytosine gave 14 hits. From this survey, 12 hits contained pure or solvate 5-fluorocytosine as 1H-ketoamino tautomer (refcodes: BIRMEU, BIRMEU01, BIRMEU02, BIRMEU03, DUKWAI, DUKWEW, DUKWIQ, MEBQEQ, MEBQEQ01, MEBQIU, MEBQOA, and MEBQUG [8,23,24,25]), and only two contained pure isocytosine as 1H or 3H-ketoamino tautomer (refcodes: ICYTIN and ICYTIN01 [26,27]).
In this work, analysis of the degree of similarity of (I) with PANLAS demonstrated that (1:1) 5-fluorocytosine/5-fluoroisocytosine monohydrate was the first example of isomorphic and isostructural co-crystals of pyrimidine nucleobases. The experimental results were complemented with Hirshfeld surface analysis to evaluate the contribution of different intermolecular interactions in the crystal packing.
Interestingly, in PANLAS, 5-fluoroisocytosine is present as a 3H-ketoamino tautomer, a tautomeric form never found in crystals of the isomer 5-fluorocytosine but observed for pure isocytosine. This tautomer favors pairing in the WC manner with 5-fluorocytosine through an intermolecular triple hydrogen bond. Any attempts to grow crystals to determine the solid-state structure of pure 5-fluoroisocytosine, which has not been reported so far, failed.
This article is a continuation of the work carried out in this laboratory on the design, solid-state synthesis and crystal structure determination of binary/ternary co-crystals of unnatural/5-halosubstituted nucleobases in which coformers are held together by hydrogen (or halogen) bonds [28,29,30,31,32,33,34,35,36].

2. Materials and Methods

2.1. Crystal Preparation

The 5-fluorocytosine and isocytosine were purchased from Aldrich (99% purity) and subjected to further purification by successive sublimation under reduced pressure. For the mechanochemical synthesis of co-crystals, equimolecular amounts (0.1 mmol in 1:1 stoichiometric ratio) of pure products were taken in an agate mortar and pestle, and then mixed and ground manually without the addition of any solvent. Crystallization of the ground powder was adjusted in methanol. The resulting solution (1 mL) was heated at 60 °C with continuous stirring for 6 h under reflux, and then slowly cooled to room temperature and filtered. Single crystals were obtained via slow evaporation of methanol solution at room temperature after ca three days.

2.2. Single Crystal Structure Analysis

The details of crystal data, data collection and structure refinement are summarized in Table 1. The data set was collected on an Xcalibur S CCD diffractometer (graphite-monochromated Mo Kα radiation, λ = 0.710689 Å) at room temperature using the CrysAlisPro software package (Rigaku Oxford Diffraction, Yarnton, United Kingdom, 2018) [37]. The crystal structure was solved by direct methods using SIR2004 [38]. All the non-hydrogen atoms were refined anisotropically by the full-matrix least-squares method based on F2 using SHELXL-2014/7 [39], within the WinGX system [40]. All H atoms were found through difference Fourier, but for refinement all C-bound H atoms were placed in calculated positions, with C–H = 0.93 Å and Uiso (H) = 1.2Ueq of the parent C atom, and refined as riding on the adjacent atoms. Positional and isotropic thermal parameters of H atoms of the heteroatoms were freely refined, giving N–H and O–H (water molecule) distances in the range 0.89 (3)–0.94 (3) and 0.87 (4)–0.88 (4) Å, respectively. The molecular and packing diagrams were prepared using the Mercury 3.9 program package [41]. The Hirshfeld surface analysis was carried out using Crystal Explorer17 (University of Western Australia, Crawley, AU, Australia [42]). The Cambridge Crystallographic Data Centre (CCDC) 2032880 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge, CB2 1EZ, United Kingdom; Fax: +44 1223 336033; Email: [email protected]).

3. Results and Discussion

3.1. Structural Analysis

The title compound, (I), crystallized in the triclinic centrosymmetric space group P-1, and the asymmetric unit comprised of two molecules of 5-fluorocytosine and isocytosine and one water molecule of crystallization (Figure 2). In (I), as found for pure coformers, only the aminooxo tautomers were observed, with the N1a and N3 positions carrying the acidic proton. As already mentioned, in the solid state 5-fluoroisocytosine was present only in the 1H-ketoamino form, whereas isocytosine had two stable 1H and 3H-ketoamino tautomers. In the title compound, the presence of isocytosine as 3H-ketoamino tautomer favored the formation of almost-coplanar WC base pairs with 5-fluorocytosine (the two molecules being inclined by 5.4 (1)° to one another) through a DAA/ADD hydrogen-bonding pattern (three-point interaction, TPI) of R22(12) graph-set motif [43,44,45]. The values of bond lengths and angles agreed with those of the corresponding geometrical parameters found in the crystal structures showing 5-fluorocytosine monohydrate [8,23,24] and isocytosine [26,27] as 1H and 3H-ketoamino tautomers, respectively.
Analysis of crystal structure similarity (CSS) was undertaken for the pair PANLAS/(I), using the graphical user interface of the Mercury program (CSD version 2020.2.0, Materials module). With this methodology, based on the COMPACK algorithm [46], from each CIF file a cluster of molecules (default size equal to 15) was obtained by picking a molecule plus a number of its closest neighboring molecules, and analyzing the overlapping molecules in the two clusters was then attempted. Two crystal structures are isostructural to within a specified tolerance (the default distance and angle tolerances being 20% and 20°, respectively) if, by comparing a cluster of 15 molecules, the algorithm returns 15 out of 15 molecules in common within the tolerance parameters set. The root mean square deviations in atomic positions (RMSD) were then calculated for the overlapping molecules in the two clusters. Analysis of the PXRD pattern was also performed using the already-cited CSD Materials module. With this method, the comparison of simulated PXRD patterns from each CIF file returned a similarity index (PXS) which ranged from 0 (completely dissimilar patterns) to 1 (identical patterns). These similarity methods were applied to the pair PANLAS/(I) for the comparison of a cluster extended to 20 molecules, as more than one molecule was present in the asymmetric unit [47]. The calculations of CSS, PXS and RMSD showed that the central molecule plus 19 symmetry-related molecules were in a common packing shell (Table 2).
Comparison of the simulated PXRD patterns shows some differences (Figure 3), as PXRD is sensitive to chemical composition and even to small variations in cell metrics and atomic displacement parameters originated by data collection performed under different temperatures (PANLAS, 150 K; (I), 298 K) [47], but results returned by similarity methods suggests that these co-crystals have the same crystal packing.
The isomorphism of the crystal structures was determined by using the unit-cell parameters of the two crystal structures to calculate the unit-cell similarity index (Π) [48]. If Π = 0, then the matched crystal structures are isomorphous. In the present case, the Π index was close to zero (zero up to the first decimal place), suggesting the isomorphism of the pair PANLAS/(I) (Table 2).
Taken together, all these results indicated (1:1) 5-fluorocytosine/isocytosine monohydrate to be isomorphic and isostructural with (1:1) 5-fluorocytosine/5-fluoroisocytosine monohydrate molecular (Figure 4), which differed solely in the H/F substitution at the C5 position of isocytosine. Neither of the two atoms was involved in the hydrogen bonding as donor or acceptor functional groups, although the F⋯F close contact [2.9003 (15) Å] observed in PANLAS between adjacent TPI dimers within a ribbon was replaced in (I) by the F⋯H contact (3.175 Å).
Crystal packing is mainly controlled by interactions between nucleobases, and the hydrogen-bonding scheme (Table 3) shows that TPI pairs and water molecules have the dual role of hydrogen bond donors and acceptors. Specifically, ribbons running approximately along the c axis were formed by two different R24(8) hydrogen bond rings which involved strong N–H⋯O (carbonyl) hydrogen bonds of adjacent antiparallel TPI heterodimers (Figure 4a). Nonetheless, water molecules play a fundamental role in the hydrogen bonding interactions, which include four intermolecular contacts. Acting as both hydrogen bond donors and acceptors, water molecules join together two TPI heterodimers by forming R33(10) hydrogen bond rings within a ribbon. Moreover, water molecules interact as hydrogen bond acceptors with a third TPI heterodimer from an adjacent ribbon through weak C–H⋯O intermolecular interactions, favoring the formation of a two-dimensional network. Neighboring networks are held together by water-mediated Ow–O hydrogen bonds (Figure 4b).

3.2. Hirshfeld Surface Analysis

The 3D Hirshfeld surface, mapped over normalized contact distance dnorm [49], and the 2D fingerprint plots, which give the contribution of the interatomic contacts to the Hirshfeld surface, are shown in Figure 5. The most prominent interactions, due to N–H⋯O intermolecular hydrogen bonds, are shown by large and deep red spots on the surface. The H⋯H contacts, representing van der Waals interactions, were the most populated contacts and contributed 28.9% of the total intermolecular contacts. The abundance of the O⋯H/H⋯O (18.9%) and N⋯H/H⋯N (14.3%) contacts confirmed that intermolecular hydrogen bond interactions play important roles in the crystal packing. Lower percentages were found for C⋯H/H⋯C (11.5%) and F⋯H/H⋯F (10.7%). The contributions of the N⋯C/C⋯N (3.9%), O⋯C/C⋯O (3.4%), C⋯C (2.0%), O⋯N/N⋯O (1.8%), N⋯F/F⋯N (1.7%) and C⋯F/F⋯C (1.7%) also supplement the overall crystal packing. Other intermolecular contacts contributed less than 2% to the Hirshfeld surface mapping.
The replacement in PANLAS of the H atom by the F atom at the 5 position of isocytosine affected, as expected, the contribution of the contacts involving the above-mentioned atoms. In passing from PANLAS to (I), the decrease in the contribution for the H⋯H, C⋯H/H⋯C and N⋯H/H⋯N contacts (−6.5, −2.7 and −1.7%, respectively) was essentially balanced with the increase for the C⋯F/F⋯C, N⋯F/F⋯N, F⋯F, O⋯F/F⋯O and H⋯F/F⋯H (+3.3, 1.6, 1.5, 1.2 and 0.5%, respectively).

4. Conclusions

In summary, in this work the crystal structure of (1:1) 5-fluorocytosine/isocytosine monohydrate molecular complex has been analyzed in terms of spatial disposition and compared with that of the structurally-related fluorocytosine/5-fluoroisocytosine monohydrate molecular complex. From the evaluation of results obtained with the similarity methods, it has been shown that this molecular complex exhibits isomorphism and isostructurality with (1:1) 5-fluorocytosine/5-fluoroisocytosine monohydrate molecular complex. The crystal structure was sustained by the base-pairing interaction between the 1H-ketoamino form of 5-fluorocytosine and the 3H-ketoamino form of isocytosine, demonstrating that complementary binding enables the crystallization of specific tautomers. The robustness of the supramolecular architectures based on three-point recognition synthon, which benefits from the presence of isocytosine in the 3H-ketoamino form, was responsible of the existence of isostructurality between (I) and PANLAS. Indeed, particularly in the presence of strong interactions such as TPI, no change in the supramolecular arrangement due to the substitution of the H atom with the fluorine atom is expected, if neither of the two atoms are involved in hydrogen bonding as donor or acceptor functional groups [50]. The solidity of triple hydrogen-bonding interaction has been invoked to tolerate the H/F exchange in isostructural co-crystals of (1:1) barbiturate melamine complexes [51].
The understanding of changes in noncovalent interactions induced by chemical modifications of nucleobases is essential for investigating molecular recognition processes involved in DNA/RNA base pairing. Therefore, crystal structure determination of molecular complexes of nucleobases with their fluorinated derivatives, where covalently bound fluorine atoms cannot compete with stronger heteroatoms as acceptors in the formation of hydrogen bonds [52,53], can provide important experimental insights into the nature of DNA/RNA pairing interactions between natural bases and their close unnatural analogs [54].

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Kálmán, A.; Párkányi, L.; Argay, G. Classification of the isostructurality of organic molecules in the crystalline state. Acta Crystallogr. Sect. B Struct. Sci. 1993, 49, 1039–1049. [Google Scholar] [CrossRef]
  2. Ranjan, S.; Devarapalli, R.; Kundu, S.; Saha, S.; Deolka, S.; Vangala, V.R.; Reddy, C.M. Isomorphism: ‘Molecular similarity to crystal structure similarity’ in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid. IUCrJ 2020, 7, 173–183. [Google Scholar] [CrossRef] [Green Version]
  3. Corpinot, M.K.; Guo, R.; Tocher, D.A.; Buanz, A.B.M.; Gaisford, S.; Price, S.L.; Bučar, D.-K. Are Oxygen and Sulfur Atoms Structurally Equivalent in Organic Crystals? Cryst. Growth Des. 2017, 17, 827–833. [Google Scholar] [CrossRef]
  4. Giangreco, I.; Cole, J.C.; Thomas, E. Mining the Cambridge Structural Database for Matched Molecular Crystal Structures: A Systematic Exploration of Isostructurality. Cryst. Growth Des. 2017, 17, 3192–3203. [Google Scholar] [CrossRef]
  5. Valinluck, V.; Liu, P.; Kang, J.I.; Burdzy, A.; Sowers, L.C. 5-Halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2). Nucleic Acids Res. 2005, 33, 3057–3064. [Google Scholar] [CrossRef] [Green Version]
  6. Byun, J.; Henderson, J.P.; Heinecke, J.W. Identification and quantification of mutagenic halogenated cytosines by gas chromatography, fast atom bombardment, and electrospray ionization tandem mass spectrometry. Anal. Biochem. 2003, 317, 201–209. [Google Scholar] [CrossRef]
  7. Braun, D.E.; Kahlenberg, V.; Griesser, U.J. Experimental and Computational Hydrate Screening: Cytosine, 5-Flucytosine, and Their Solid Solution. Cryst. Growth Des. 2017, 17, 4347–4364. [Google Scholar] [CrossRef] [PubMed]
  8. Hulme, A.T.; Tocher, D.A. The Discovery of New Crystal Forms of 5-Fluorocytosine Consistent with the Results of Computational Crystal Structure Prediction. Cryst. Growth Des. 2006, 6, 481–487. [Google Scholar] [CrossRef]
  9. Braun, D.E.; Griesser, U.J. Prediction and experimental validation of solid solutions and isopolymorphs of cytosine/5-flucytosine. CrystEngComm 2017, 19, 3566–3572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Portalone, G.; Moilanen, J.O.; Tuononen, H.M.; Rissanen, K. Role of Weak Hydrogen Bonds and Halogen Bonds in 5-Halo-1,3-dimethyluracils and Their Cocrystals—A Combined Experimental and Computational Study. Cryst. Growth Des. 2016, 16, 2631–2639. [Google Scholar] [CrossRef]
  11. Khomenko, V.G.; Mitkevich, V.V.; Sukhodub, L.F. The crystal structures of two methyl derivatives of uracil with C–H⋯O hydrogen bonding. Bull. Nat. Acad. Sci. Ukraine: Geol. Chem. Biol. Sci. 1986, 10, 34–37. [Google Scholar]
  12. Hulme, A.T.; Tocher, D.A. 4-Amino-5-fluoropyrimidin-2(1H)-one-2-Amino-5-fluoropyrimidin-4(3H)-one-water (1/1/1). Acta Cryst. 2005, 61, o2112–o2113. [Google Scholar] [CrossRef]
  13. Mohammad-Hasani, E.; Beyramabadi, S.A.; Pordel, M. Tautomerism and non-covalent interactions of flucytosine with armchair (5,5) SWCNT and γ-Fe2O3 nanoparticles: A DFT study. Indian J. Chem. 2017, 56, 626–632. [Google Scholar]
  14. Vermes, A.; Guchelaar, H.J.; Dankert, J. Flucytosine: A review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother. 2000, 46, 171–179. [Google Scholar] [CrossRef]
  15. Hirao, I.; Kimoto, M.; Yamashige, R. Natural versus Artificial Creation of Base Pairs in DNA: Origin of Nucleobases from the Perspectives of Unnatural Base Pair Studies. Acc. Chem. Res. 2012, 45, 2055–2065. [Google Scholar] [CrossRef] [PubMed]
  16. Gorb, L.; Podolyan, Y.; Leszczynski, J. A theoretical investigation of tautomeric equilibria and proton transfer in isolated and monohydrated cytosine and isocytosine molecules. J. Mol. Struct. THEOCHEM 1999, 487, 47–55. [Google Scholar] [CrossRef]
  17. Pohl, R.; Socha, O.; Sala, M.; Rejman, D.; Dračínský, M. The Control of the Tautomeric Equilibrium of Isocytosine by Intermolecular Interactions. Eur. J. Org. Chem. 2018, 2018, 5128–5135. [Google Scholar] [CrossRef]
  18. Yang, X.-L.; Sugiyama, H.; Ikeda, S.; Saito, I.; Wang, A.H.-J. Structural Studies of a Stable Parallel-Stranded DNA Duplex Incorporating Isoguanine:Cytosine and Isocytosine:Guanine Basepairs by Nuclear Magnetic Resonance Spectroscopy. Biophys. J. 1998, 75, 1163–1171. [Google Scholar] [CrossRef] [Green Version]
  19. Camacho-García, J.; Montoro-García, C.; López-Pérez, A.M.; Bilbao, N.; Romero-Pérez, S.; González-Rodríguez, D. Synthesis and complementary self-association of novel lipophilic π-conjugated nucleoside oligomers. Org. Biomol. Chem. 2015, 13, 4506–4513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Aučynaitė, A.; Rutkienė, R.; Tauraitė, D.; Meškys, R.; Urbonavičius, J. Discovery of Bacterial Deaminases That Convert 5-Fluoroisocytosine Into 5-Fluorouracil. Front. Microbiol. 2018, 9, 2375. [Google Scholar] [CrossRef]
  21. Bruno, I.J.; Cole, J.C.; Edgington, P.R.; Kessler, M.; Macrae, C.F.; McCabe, P.; Pearson, J.; Taylor, R. New software for searching the Cambridge Structural Database and visualizing crystal structures. Acta Crystallogr. Sect. B Struct. Sci. 2002, 58, 389–397. [Google Scholar] [CrossRef]
  22. Groom, C.R.; Bruno, I.J.; Lightfoot, M.P.; Ward, S.C. The Cambridge Structural Database. Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater. 2016, 72, 171–179. [Google Scholar] [CrossRef]
  23. Louis, T.; Low, J.N.; Tollin, P. 5-Fluorocytosine. Cryst. Struct. Commun. 1982, 11, 1059–1064. [Google Scholar]
  24. Portalone, G.; Colapietro, M. Redetermination of 5-fluorocytosine monohydrate. Acta Crystallogr. Sect. E Struct. Rep. Online 2006, 62, 1049–1050. [Google Scholar] [CrossRef]
  25. Tutughamiarso, M.; Bolte, M.; Egert, E. New pseudopolymorphs of 5-fluorocytosine. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 2009, 65, o574–o578. [Google Scholar] [CrossRef]
  26. Sharma, B.D.; McConnell, J.F. The crystal and molecular structure of isocytosine. Acta Crystallogr. 1965, 19, 797–806. [Google Scholar] [CrossRef]
  27. Portalone, G.; Colapietro, M. Redetermination of isocytosine. Acta Crystallogr. Sect. E Struct. Rep. Online 2007, 63, o1869–o1871. [Google Scholar] [CrossRef]
  28. Brunetti, B.; Portalone, G.; Piacente, V. Sublimation Thermodynamic Parameters for 5-Fluorouracil and Its 1-Methyl and 1,3-Dimethyl Derivatives from Vapor Pressure Measurements. J. Chem. Eng. Data 2002, 47, 17–19. [Google Scholar] [CrossRef]
  29. Portalone, G.; Colapietro, M. First example of cocrystals of polymorphic maleic hydrazide. J. Chem. Crystallogr. 2004, 34, 609–612. [Google Scholar] [CrossRef]
  30. Portalone, G.; Colapietro, M. Asymmetric base pairing in the complex 5-fluorocytosinium chloride/5-fluorocytosine monohydrate. J. Chem. Crystallogr. 2006, 37, 141–145. [Google Scholar] [CrossRef]
  31. Portalone, G.; Colapietro, M. Solid-Phase Molecular Recognition of Cytosine Based on Proton-Transfer Reaction. J. Chem. Crystallogr. 2008, 39, 193–200. [Google Scholar] [CrossRef]
  32. Portalone, G. Supramolecular association in proton-transfer adducts containing benzamidinium cations. I. Four molecular salts with uracil derivatives. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 2010, 66, o295–o301. [Google Scholar] [CrossRef]
  33. Portalone, G. Solid-phase molecular recognition of cytosine based on proton-transfer reaction. Part II. supramolecular architecture in the cocrystals of cytosine and its 5-Fluoroderivative with 5-Nitrouracil. Chem. Central J. 2011, 5, 51. [Google Scholar] [CrossRef] [Green Version]
  34. Portalone, G.; Irrera, S. Supramolecular structure of unnatural nucleobases: Revised structure of (2:1) 6-methylisocytosinium dihydrogen monophosphate adduct. J. Mol. Struct. 2011, 991, 92–96. [Google Scholar] [CrossRef]
  35. Portalone, G.; Rissanen, K. Multifacial Recognition in Binary and Ternary Cocrystals from 5-Halouracil and Aminoazine Derivatives. Cryst. Growth Des. 2018, 18, 5904–5918. [Google Scholar] [CrossRef] [Green Version]
  36. Portalone, G. Site Selectivity of Halogen Oxygen Bonding in 5- and 6-Haloderivatives of Uracil. Crystals 2019, 9, 467. [Google Scholar] [CrossRef] [Green Version]
  37. CrysAlis, P.R.O. Rigaku Oxford Diffraction; Agilent Technologies UK Ltd.: Yarnton, UK, 2018. [Google Scholar]
  38. Burla, M.C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G.L.; De Caro, L.; Giacovazzo, C.; Polidori, G.; Spagna, R. SIR2004: An improved tool for crystal structure determination and refinement. J. Appl. Crystallogr. 2005, 38, 381–388. [Google Scholar] [CrossRef] [Green Version]
  39. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, C71, 3–8. [Google Scholar] [CrossRef]
  40. Farrugia, L.J. WingX and ORTEP for Windows: An update. J. Appl. Cryst. 2012, 45, 849–854. [Google Scholar] [CrossRef]
  41. Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; Van De Streek, J.; Wood, P.A. Mercury CSD 2.0—New features for the visualization and investigation of crystal structures. J. Appl. Crystallogr. 2008, 41, 466–470. [Google Scholar] [CrossRef]
  42. Turner, M.J.; Mckinnon, J.J.; Wolff, S.K.; Grimwood, D.J.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. CrystalExplorer17. The University of Western Australia. 2017. Available online: http://hirshfeldsurface.net (accessed on 2 November 2020).
  43. Etter, M.C.; Macdonald, J.C.; Bernstein, J. Graph-set analysis of hydrogen-bond patterns in organic crystals. Acta Crystallogr. Sect. B Struct. Sci. 1990, 46, 256–262. [Google Scholar] [CrossRef]
  44. Bernstein, J.; Davis, R.E.; Shimoni, L.; Chang, N.-L. Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals. Angew. Chem. Int. Ed. 1995, 34, 1555–1573. [Google Scholar] [CrossRef]
  45. Motherwell, W.D.S.; Shields, G.P.; Allen, F.H. Visualization and characterization of non-covalent networks in molecular crystals: Automated assignment of graph-set descriptors for asymmetric molecules. Acta Crystallogr. Sect. B Struct. Sci. 1999, 55, 1044–1056. [Google Scholar] [CrossRef]
  46. Chisholm, J.A.; Motherwell, S. COMPACK: A program for identifying crystal structure similarity using distances. J. Appl. Crystallogr. 2005, 38, 228–231. [Google Scholar] [CrossRef] [Green Version]
  47. Sacchi, P.; Nauha, E.; Cruz-Cabeza, A.J.; Lusi, M.; Bernstein, J. Invitation to Submit: The Cambridge Structural Database Same or different—That is the question: Identification of crystal forms from crystal structure data. CrystEngComm 2020. [Google Scholar] [CrossRef]
  48. Oliveira, M.A.; Peterson, M.L.; Klein, D. Continuously Substituted Solid Solutions of Organic Co-Crystals. Cryst. Growth Des. 2008, 8, 4487–4493. [Google Scholar] [CrossRef]
  49. Spackman, M.A.; Jayatilaka, D. Hirshfeld surface analysis. CrystEngComm 2009, 11, 19–32. [Google Scholar] [CrossRef]
  50. Chopra, D.; Row, T.N.G. Role of organic fluorine in crystal engineering. CrystEngComm 2011, 13, 2175–2186. [Google Scholar] [CrossRef]
  51. Nangia, A. Packing similarities in organic crystals with C–H/C–F exchange: A database analysis of CH3/CF3 pairs. New J. Chem. 2000, 24, 1049–1055. [Google Scholar] [CrossRef]
  52. Dunitz, J.D.; Taylor, R. Organic Fluorine Hardly Ever Accepts Hydrogen Bonds. Chem. Eur. J. 1997, 3, 89–98. [Google Scholar] [CrossRef]
  53. Dunitz, J. Organic fluorine: Odd man out. ChemBioChem 2004, 5, 614–621. [Google Scholar] [CrossRef] [PubMed]
  54. Koller, A.N.; Božilović, J.; Engels, J.W.; Gohlke, H. Aromatic N versus aromatic F: Bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs. Nucleic Acids Res. 2010, 38, 3133–3146. [Google Scholar] [CrossRef] [PubMed]
Crystals 10 00999 sch001 550
Scheme 1. Components of the binary co-crystals of pyrimidine nucleobases/5-fluorosubstituted derivatives showing crystal packing similarity with unsubstituted and 5-fluorosubstituted conformers.
Scheme 1. Components of the binary co-crystals of pyrimidine nucleobases/5-fluorosubstituted derivatives showing crystal packing similarity with unsubstituted and 5-fluorosubstituted conformers.
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Crystals 10 00999 g001 550
Figure 1. Overlay of part of the crystal structure showing crystal packing similarity for: (a) BIRMEU02 and SAVKIM, viewed approximately down a. Bonds of molecules of BIRMEU02 have been colored red, and bonds of molecules of SAVKIM are blue. (b) MEBQEQ and ADAJAT, viewed approximately down a. Bonds of molecules of MEBQEQ have been colored red, and bonds of molecules of ADAJAT are blue. (c) MEBQEQ01 and ADAJAT01, viewed approximately down b. Bonds of molecules of MEBQEQ01 have been colored red, and bonds of molecules of ADAJAT01 are blue. (d) KAMSAS01 and OKATEB, viewed approximately down b. Bonds of molecules of KAMSAS01 have been colored red, and bonds of molecules of OKATEB are blue. For the sake of simplicity, overlay of part of the crystal structure of the pairs DMURAC01/OKATEB and KAMSAS01/DMRAC01, similar to that of the pair KAMSAS01/OKATEB, has been omitted. All atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by red dashed lines.
Figure 1. Overlay of part of the crystal structure showing crystal packing similarity for: (a) BIRMEU02 and SAVKIM, viewed approximately down a. Bonds of molecules of BIRMEU02 have been colored red, and bonds of molecules of SAVKIM are blue. (b) MEBQEQ and ADAJAT, viewed approximately down a. Bonds of molecules of MEBQEQ have been colored red, and bonds of molecules of ADAJAT are blue. (c) MEBQEQ01 and ADAJAT01, viewed approximately down b. Bonds of molecules of MEBQEQ01 have been colored red, and bonds of molecules of ADAJAT01 are blue. (d) KAMSAS01 and OKATEB, viewed approximately down b. Bonds of molecules of KAMSAS01 have been colored red, and bonds of molecules of OKATEB are blue. For the sake of simplicity, overlay of part of the crystal structure of the pairs DMURAC01/OKATEB and KAMSAS01/DMRAC01, similar to that of the pair KAMSAS01/OKATEB, has been omitted. All atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by red dashed lines.
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Crystals 10 00999 sch002 550
Scheme 2. Chemical components of the isomorphic and isostructural co-crystals of 5-fluorocytosine/isocytosine monohydrate, (I), and 5-fluorocytosine/5-fluoroisocytosine monohydrate, PANLAS.
Scheme 2. Chemical components of the isomorphic and isostructural co-crystals of 5-fluorocytosine/isocytosine monohydrate, (I), and 5-fluorocytosine/5-fluoroisocytosine monohydrate, PANLAS.
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Crystals 10 00999 g002 550
Figure 2. The asymmetric unit of (I), showing the adopted atom-numbering scheme. Displacement ellipsoids are at the 50% probability level. The asymmetric unit was selected so that the nucleobase molecules were linked by triple hydrogen bonds. H atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by dashed lines.
Figure 2. The asymmetric unit of (I), showing the adopted atom-numbering scheme. Displacement ellipsoids are at the 50% probability level. The asymmetric unit was selected so that the nucleobase molecules were linked by triple hydrogen bonds. H atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by dashed lines.
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Crystals 10 00999 g003 550
Figure 3. Simulated PXRD patterns for PANLAS (red) and (I) (blue).
Figure 3. Simulated PXRD patterns for PANLAS (red) and (I) (blue).
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Crystals 10 00999 g004 550
Figure 4. Cluster overlay of PANLAS and (I), showing crystal packing similarity: (a) hydrogen-bonded ribbons viewed approximately down b; (b) ribbons hydrogen bonded via water molecules viewed approximately parallel to the bc plane. Bonds of molecules of PANLAS have been colored red, bonds of molecules of the title compound are blue. All atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by orange dashed lines.
Figure 4. Cluster overlay of PANLAS and (I), showing crystal packing similarity: (a) hydrogen-bonded ribbons viewed approximately down b; (b) ribbons hydrogen bonded via water molecules viewed approximately parallel to the bc plane. Bonds of molecules of PANLAS have been colored red, bonds of molecules of the title compound are blue. All atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by orange dashed lines.
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Crystals 10 00999 g005 550
Figure 5. Hirshfeld surfaces mapped on dnorm [color scale: −0.6250 (red), 1.2492 a.u. (blue)] and decomposed two-dimensional fingerprint plots for (I). Various close contacts and their proportional contributions are reported. Other (not shown) intermolecular contacts contributed approximately less than 1% to the Hirshfeld surface mapping.
Figure 5. Hirshfeld surfaces mapped on dnorm [color scale: −0.6250 (red), 1.2492 a.u. (blue)] and decomposed two-dimensional fingerprint plots for (I). Various close contacts and their proportional contributions are reported. Other (not shown) intermolecular contacts contributed approximately less than 1% to the Hirshfeld surface mapping.
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Table
Table 1. Crystal data, data collection, and refinement for compound (I).
Table 1. Crystal data, data collection, and refinement for compound (I).
Crystal Data.
Chemical formulaC4H4FN3O·C4H5N3O·H2O
Mr258.23
Crystal system, space groupTriclinic, P-1
Temperature (K)298
a, b, c (Å)5.3363 (9), 8.3389 (17), 12.6501 (12)
a, b, g (°)93.009 (12), 92.037 (11), 100.837 (15)
V (Å3)551.52 (15)
Z2
Radiation typeMo Ka
m (mm−1)0.13
Crystal size (mm)0.10 × 0.08 × 0.07
Data collection
Tmin, Tmax0.702, 1.000
No. of measured, independent, and observed [I > 2s(I)] reflections5277, 2042, 1401
Rint0.037
(sin q/l)max (Å−1)0.606
Refinement
R[F2 > 2s(F2)], wR(F2), S0.063, 0.164, 1.07
No. of parameters195
Drmax, Drmin (e Å−3)0.26, −0.24
Table
Table 2. Packing similarity in matched crystal structures of PANLAS and (I) co-crystals.
Table 2. Packing similarity in matched crystal structures of PANLAS and (I) co-crystals.
Unit-Cell ParametersRMSD (Å)PXSP
PANLAS 0.2120.9430.014
a, b, c (Å)5.4122 (16), 8.447 (2), 12.083 (4)
a, b, g (°)89.454 (5), 85.718 (5), 77.096 (4)
V (Å3)536.9 (3)
(I)
a, b, c (Å)5.3363 (9), 8.3389 (17), 12.6501 (12)
a, b, g (°)93.009 (12), 92.037 (11), 100.837 (15)
V (Å3)551.52 (15)
Table
Table 3. Hydrogen-bond geometry (Å,º) for (I).
Table 3. Hydrogen-bond geometry (Å,º) for (I).
D–H⋯AD–HH⋯AD⋯AD–H⋯A
N2–H2A⋯O1A0.94 (3)1.99 (3)2.920 (3)173 (3)
N2–H2B⋯O1A i0.92 (3)2.09 (3)2.868 (3)142 (2)
N3–H3⋯N3A0.94 (3)2.01 (3)2.946 (3)175 (2)
N2A–H2AA⋯O1 ii0.90 (3)2.03 (3)2.830 (3)147 (2)
N2A–H2AB⋯O10.91 (3)2.03 (3)2.930 (3)171 (2)
N1A–HN1A⋯O20.89 (3)1.93 (3)2.816 (3)171 (2)
C6A–H6A⋯O2 iii0.932.423.267 (3)151
O2–H21W⋯N1 i0.88 (4)1.93 (4)2.807 (3)175 (3)
O2–H22W⋯O1A iv0.87 (4)1.97 (4)2.841 (3)175 (4)
Symmetry codes: (i) −x−1, −y+1, −z+2; (ii) −x−1, −y, −z+1; (iii) −x−3, −y, −z+2; (iv) x−1, y, z.
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Portalone, G. 5-Fluorocytosine/Isocytosine Monohydrate. The First Example of Isomorphic and Isostructural Co-Crystal of Pyrimidine Nucleobases. Crystals 2020, 10, 999. https://0-doi-org.brum.beds.ac.uk/10.3390/cryst10110999

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Portalone G. 5-Fluorocytosine/Isocytosine Monohydrate. The First Example of Isomorphic and Isostructural Co-Crystal of Pyrimidine Nucleobases. Crystals. 2020; 10(11):999. https://0-doi-org.brum.beds.ac.uk/10.3390/cryst10110999

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Portalone, Gustavo. 2020. "5-Fluorocytosine/Isocytosine Monohydrate. The First Example of Isomorphic and Isostructural Co-Crystal of Pyrimidine Nucleobases" Crystals 10, no. 11: 999. https://0-doi-org.brum.beds.ac.uk/10.3390/cryst10110999

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