Weak C–H···π and C–H···F Interactions Form Higher-Order Supramolecular Structures in...

Weak C−H···π and C−H···F Interactions Form Higher-OrderSupramolecular Structures in Cytosine and Uracil(Z)‑4′-Benzamido-2′-butenyl DerivativesMario Cetina,*,† Kresimir Benci,‡ Karlo Wittine,‡ and Mladen Mintas‡

†Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovica 28a,HR-10000 Zagreb, Croatia‡Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulicev trg 20,P.O. Box 177, HR-10000 Zagreb, Croatia

*S Supporting Information

ABSTRACT: In this paper, eight closely related structures of(Z)-4′-benzamido-2′-butenyl cytosine and uracil derivativeswere analyzed to evidence how variations on the molecularlevel affect their supramolecular structures. The N−H···O,N−H···N, and C−H···O hydrogen bonds mainly participate insupramolecular assembling of these molecules, but C−H···Fhydrogen bonds in the molecules containing a fluorine atom atthe 5-position of the pyrimidine ring or the 4-position of thephenyl ring were also observed. Hydrogen bonds in two ofeight structures built two-dimensional network, while in theremaining six structures weak C−H···π or/and C−H···Finteractions expand two-dimensional networks into three-dimensional, thus having a crucial role in the formation ofhigher-order supramolecular structures.

■ INTRODUCTION

Intermolecular interactions are by far the most frequently usedtools in supramolecular chemistry and crystal engineering.1,2

Among the different interactions used for preparation ofdesirable supramolecular structures, the most challenging arevery weak interactions, such as C−H···X (X = halogen atom),3

X···X,4 and halogen interactions.5 The influence of theseinteractions, as well as C−H···π and π···π interactions, onsupramolecular aggregation of the molecules or/and ions canbe evaluated by comparing them with stronger ones, suchas strong (O−H···O, N−H···O, etc.) or weak (C−H···O,C−H···N, etc.) hydrogen bonds.6,7

From several interactions involving halogen atoms, thosecontaining fluorine, the C−H···F and F···F interactions, areespecially interesting due to several reasons. The fluorine atomhas a very important role in medicinal chemistry as an enhancerof the pharmacological properties of drugs. Fluorine is alsointroduced into molecules with the purpose of improving themetabolic stability of compounds, to modulate their phys-icochemical properties, such as lipophilicity or basicity or toenhance their binding affinity to the target protein. Because ofits similar size to hydrogen, the hydrogen atom(s) in themolecule can be substituted by fluorine atom(s), as micro-organisms or enzymes often do not recognize the differencebetween the native or the fluorinated substrate.8 Also, the polarC−F bond−protein interactions play a critical role in the

stabilization of fluorine-containing drugs and their targetproteins. The majority of examples from the protein crystallo-graphic database indicate that although fluorine attached to thecarbon atom serves as a poor hydrogen−bond acceptor, it caninteract with a large number of polarized bonds, as C−F···H−X(X = O, N, S) and C−F···H−Cα (Cα is the α-carbon of theα-amino acid), where the F···H distance is much shorter thanthe hydrogen-bonded contact distance.9 Fluorine may also havea substantial effect on the conformation of the molecule.8a,c,d

Finally, due to its controversial role in supramolecular aggrega-tion, the participation of the fluorine atom in the interactionshas been considered to be a subject of debate. However, it isnow well established that weak C−H···F and F···F interac-tions are realistic and participate in molecular recognition.10 Acharge density study of intermolecular interactions involvingorganic fluorine has established that C−H···F contacts displaycharacteristics of a weak hydrogen bond and has classified F···Fcontacts as a well-defined weak intermolecular interactions.11

Relevant literature has been discussed in a recent Highlightand Perspective.12 However, although these interactions areattractive, it is also known that C−H···F interactions (as wellas the others) can be repulsive3a or that C−H···F interaction

Received: June 6, 2012Revised: September 23, 2012Published: September 26, 2012

Article

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distances can be much longer in order to avoid repulsive F···Fcontacts.10n

In some of our previous papers, we have described struc-tures of several purine and pyrimidine derivatives.13 Recently,we showed that small differences on the surface of theN-phthalimide protected (E)- and (Z)-4-amino-2-butenyl5-substituted pyrimidine derivatives influence their supra-molecular aggregation.14 As the number of papers describinginteractions involving fluorine has increased in the past fewyears,15 we extended our previous study on the structures of

sterically constrained (Z)-4′-benzamido-2′-butenyl cytosineand uracil derivatives (Chart 1). The hydrogen-bonded motifsin compounds 1 and 2 we compared with those of the startingcompound 3a (Chart 1) to find out if substituents at the5-position of the pyrimidine ring and/or at the 4-position of thephenyl ring have an impact on the expected N−H···O(C)hydrogen-bonded motif typical of this type of compounds, asthe crystal structure is a result of a delicate balance betweena range of the intermolecular interactions and even a smallchange in the molecular structure may lead to unpredictablechanges in the supramolecular structure.

■ EXPERIMENTAL SECTIONPreparation of 1a−d, 2a, 2b, 2e, 2f, and 3. The syntheses of

(Z)-4′-benzamido-2′-butenyl cytosine derivatives 1a−d and uracilderivatives 2a, 2b, 2e, and 2f, as well as of the starting compound intheir synthesis, 3a, have been described previously.16

Crystal Structure Determination. Colorless single crystals of1a−d, 2a, 2e, 2f, and 3a suitable for X-ray single crystal analysis wereobtained at room temperature by partial evaporation from methanolsolution. A colorless single crystal of 2b was obtained from watersolution. The intensities were collected at 295 K on an OxfordDiffraction Xcalibur2 diffractometer with a Sapphire 3 CCD detectorusing graphite monochromated Mo Kα radiation (λ = 0.71073 Å). TheCrysAlisPro17 program was used for data collection and processing.Details of crystal data, data collection, and refinement parameters aregiven in Table 1.

The crystal structures were solved by direct methods.18 All non-hydrogen atoms were refined anisotropically by full-matrix least-squares calculations based on F2.18 Hydrogen atoms attached to theN4 atom in 1a−d, the N2 atom in 1a−c, the N2 and N3 atoms in 2a,2b, 2e, and 2f, and the N1 atom in 3a, as well as the hydrogen atomsattached to the water oxygen O3 atom in 1d were found in differenceFourier maps, and their coordinates and isotropic thermal parametershave been refined freely. All other hydrogen atoms were included incalculated positions as riding atoms, with SHELXL9718 defaults.Geometric restraint on the N−H bond of the amino group was appliedin the refinement of structures 1b (N4−H4B), 1c (N4−H4A and

Chart 1. Molecular Structures of the (Z)-4′-Benzamido-2′-butenyl Cytosine Derivatives 1 and Uracil Derivatives 2, asWell as Starting Compounds 3

Table 1. Crystallographic Data for Crystals Described in This Paper

1a 1b 1c 1d 2a 2b 2e 2f 3a

formula C15H16N4O2 C15H15FN4O2 C15H15FN4O2 C30H30F4N8O5 C15H15N3O3 C15H14FN3O3 C16H17N3O3 C16H16FN3O3 C11H12ClNO

fw 284.32 302.31 302.31 658.62 285.30 303.29 299.33 317.32 209.67

spacegroup

Pbca Pbca P21/c Pbca C2/c C2/c P21/c P21/c P21/c

a (Å) 8.7354(6) 8.5569(6) 16.4507(9) 14.4861(5) 16.2425(8) 16.9098(7) 11.7837(13) 5.921(2) 4.3098(4)

b (Å) 9.8973(6) 10.0070(6) 8.7236(3) 19.8854(7) 11.2706(5) 11.2132(4) 10.9280(8) 30.199(10) 25.4209(16)

c (Å) 32.784(3) 33.317(4) 9.9629(4) 21.2864(8) 15.9376(9) 15.4936(7) 23.738(2) 10.162(4) 9.7322(5)

β (deg) 90 90 90.171(5) 90 100.630(5) 100.660(5) 100.754(10) 119.67(2) 96.947(7)

V (Å3) 2834.4(4) 2852.9(4) 1429.76(11) 6131.8(4) 2867.5(2) 2887.1(2) 3003.1(5) 1578.8(10) 1058.42(13)

Z 8 8 4 8 8 8 8 4 4

Dcalc 1.333 1.408 1.404 1.427 1.322 1.396 1.324 1.335 1.316

μ (mm−1) 0.092 0.106 0.105 0.116 0.094 0.108 0.093 0.102 0.327

θ (deg) 27.0 25.0 27.0 27.0 27.0 27.0 25.0 25.0 27.0

no. indreflns

3082 2470 3038 6608 3123 3127 5141 2742 2277

no. params 202 211 211 448 198 207 414 217 131

R1 [I >2σ(I)]

0.042 0.066 0.044 0.036 0.056 0.042 0.061 0.066 0.043

wR [I >2σ(I)]

0.063 0.190 0.122 0.058 0.159 0.110 0.148 0.065 0.088

GOF on F2 1.00 1.00 1.00 1.03 1.00 1.00 1.00 0.98 1.00

Δρ max(eÅ−3)

0.10 0.37 0.15 0.13 0.45 0.23 0.55 0.18 0.16

Δρ min(eÅ−3)

−0.13 −0.37 −0.15 −0.15 −0.24 −0.22 −0.28 −0.17 −0.16

Crystal Growth & Design Article

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N4−H4B), and 1d (N4A−H41A, N4B−H41B, and N4B−H42B).Restraints on anisotropic displacement parameters were applied duringthe refinement of the N3 and C2 atoms in 1a, the N3A and C2Aatoms in 1d, as well as the N2B and C10B atoms in 2e. The

PLATON19 and MERCURY20 programs were used for structureanalysis and molecular and crystal structure drawings preparation.

■ RESULTS AND DISCUSSION

All (Z)-4′-benzamido-2′-butenyl cytosine (1) and uracil (2)derivatives (Chart 1) were prepared from (Z)-4-chloro-2-butenylbenzamide (3a) or (Z)-4-chloro-2-butenyl-4-fluoroben-zamide (3b).16 We succeeded in obtaining single crystals ofstarting compound 3a. As expected, the N1···O1 hydrogenbond in 3a generates one of the most common hydrogen-bonded motifs, a C(4)21 N−H···O(C) hydrogen-bondedchain, running parallel to the c axis (Figure 1; Table S1 of theSupporting Information). This hydrogen bond is supportedby the C11···O1 hydrogen bond which forms the C(5)C−H···O(C) hydrogen-bonded chain, thus connecting thesame hydrogen-bonded molecules. A combination of thesetwo hydrogen bonds forms the R2

1(7)21 ring (Figure 1).Neighboring chains of hydrogen-bonded rings run in theopposite directions and are parallel to the c axis.It was anticipated that both hydrogen atoms of the amino

nitrogen N4 atom in cytosine derivatives 1 will be included inthe hydrogen-bonding. Indeed, one of the hydrogen atoms in1a generates the R1

2(4) ring by the N4···O1 and the N4···N3

Figure 1. Crystal packing diagram of 3a, viewed down the a axis,showing the parallel hydrogen bonded chain of rings.

Figure 2. (a) Part of the crystal structure of 1a, showing N−H···O, N−H···N, and C−H···O hydrogen bonds. (b) Part of the crystal structure of 1a,showing the arrangement of hydrogen-bonded molecules. (c) Crystal packing diagram of 1a, viewed down the a axis, showing rows of hydrogen-bonded molecules. (d) Crystal packing diagram of 1a, viewed down the b axis, showing two-dimensional wavelike sheets linked by the C−H···πinteraction (colored in blue) into a three-dimensional network.



hydrogen bonds between the pyrimidine rings of twoneighboring molecules (Figure 2a; Table S2 of the SupportingInformation). The second amino hydrogen atom is alsoinvolved in hydrogen-bonding via the N4···O1 hydrogenbond. Furthermore, the structure of 1a displays the samehydrogen-bonded motif as 3a; that is, two hydrogen bonds, oneN−H···O and one C−H···O, generate a chain of rings. Thisstructure comprises one more ring of the same type formed bytwo C−H···O hydrogen bonds and in which butenyl moietycarbon atoms participate. Overall, each molecule is linked toeight other molecules in such a way that the rows of hydrogen-bonded molecules are intersected with rows of those which areperpendicular to them (Figure 2b and c).The crystal packing diagram along the c axis (Figure 2d)

reveals that hydrogen-bonded molecules form two-dimensionalwavelike sheets which are parallel to the ab plane. Thehydrogen atom of the phenyl ring at the edge of each sheet isdirected to the phenyl ring centroid of the molecule in theneighboring sheet, thus enabling a C−H···π interaction. Thisinteraction links sheets and completes the three-dimensionalnetwork.Compound 1b crystallized in the same space group as 1a and

is isomorphous to it (Table 1).22 In addition, the hydrogen-bonded network is very similar compared to that of 1a. Thus,

both hydrogen atoms of the amino nitrogen atom participate inhydrogen-bonding to oxygen and nitrogen atoms of twoneighboring molecules in a very similar manner (Figure 3a;Table S2 of the Supporting Information).Furthermore, the main hydrogen-bonded motif, the N−

H···O(C) hydrogen bond (supported by the C−H···O(C)hydrogen bond) is identical as in 3a and 1a. However, there aretwo distinct differences between the structures of 1a and 1b.One R2

1(7) ring in 1b is absent, as the C7···O1 hydrogen bondis not formed. Instead, a new interaction is established betweenthe methylene hydrogen atom and fluorine. Each molecule of1b is linked to eight neighboring molecules which are disposedin a similar manner as hydrogen-bonded molecules in 1a. TheC−H···π interaction established between the phenyl ring hydro-gen atom and the phenyl ring of the neighboring molecule is alsopresent in the 1b. Thus, supramolecular subunit in both structures isa two-dimensional hydrogen-bonded sheet which is extendedto a three-dimensional network by one C−H···π interaction.

Figure 3. (a) Part of the crystal structure of 1b, showing N−H···O,N−H···N, C−H···O, and C−H···F hydrogen bonds. (b) Crystalpacking diagram of 1b, viewed down the b axis, showing two-dimensional wavelike sheets linked by one C−H···π interaction(colored in blue) into a three-dimensional network.

Figure 4. (a) Part of the crystal structure of 1c, showing N−H···O, C−H···O, and C−H···F hydrogen bonds. (b) Crystal packing diagram of1c, showing the three-dimensional network formed by C−H···Fhydrogen bonds and π···π interactions (denoted by the red ellipse).



Although different types of interactions built sheets, thesetwo supramolecular structures look very similar (see Figures 2dand 3b), so that they are ipso facto isostructural. However, theconformations of these two molecules differ slightly. The valuesof the C2−N1−C7−C8 and N1−C7−C8−C9 torsion anglesin 1b differ for ca. 25 and 15°, respectively, compared to theequivalent ones in 1a (Tables S3 and S4 of the SupportingInformation). Also, the dihedral angle between the butenylmoiety and the phenyl ring in 1b is slightly bigger than that of 1a.This is clearly seen in the overlapping diagram in which themolecules are overlapped through the butenyl moiety C7−C10

atoms (Figure S1a of the Supporting Information). All thesedifferences in conformation and, in fact, that one C−H···Ointeraction that is absent are possibly caused by the presence ofthe C−H···F hydrogen bond in 1b. The H···F contact of 2.52 Åis slightly shorter than the mean value of 2.55 Å for 5470structures with 9973 H···F contacts found in the CambridgeStructural Database23 (CSD; error-free and disorder-freestructures of organic compounds with R < 0.050 and withdistance shorter than the sum of the van der Waals radii). Thesimilar H···F distance (2.62 Å) was found in only one organicstructure in which this interaction is formed between themethylene hydrogen atom of the 2′-butenyl moiety and thefluorine atom, E-tetraethyl-1,4-diammoniumbut-2-ene bis-(hexafluorophosphate).24 There are also a number of otherC−H···F hydrogen bonds in this structure, some of them veryshort (H···F = 2.40 Å).In 1c, the cytosine derivative with the fluorine atom at the

C-4 position of the phenyl ring, one weak C−H···F hydrogenbond was also observed, but with a slightly longer H···Fdistance (Figure 4a; Table S2 of the Supporting Information).It should be added that the phenyl ring hydrogen atomparticipates in this interaction compared to the situation in 1b,where the butenyl carbon atom acts as a proton donor. Thebutenyl moiety C7 atom is also involved in hydrogen-bonding,thus generating C(5) chains. A distinct difference compared tothe structure of 1b is in the fact that the C−H···F hydrogenbond along with C−H···π interaction participates in three-dimensional net formation. This interaction is also sup-ported by one π···π interaction between phenyl rings ofneighboring molecules (Figure 4b). The rings are mutuallyparallel (α = 0°), the centroid separation is 3.7725(14) Å,the interplanar spacings are 3.5218(9) Å, and the centroidoffset is ca. 1.35 Å.Each molecule of 1c is now linked by seven hydrogen bonds

to ten neighboring molecules. The conformation of 1c is verysimilar to that of 1a (Tables S3 and S4 and Figure S1b of theSupporting Information.Compound 1d crystallized in the same space group as 1a and

1b (Table 1), but with two independent molecules of the titlecompound (A and B) and one water molecule in theasymmetric unit. We recrystallized this compound from driedmethanol several times, but we always got a hemihydrate, aseven a small amount of moisture was enough for inclusion ofthe water molecule into the crystal lattice. The presence of thewater molecule resulted in a structure comprising a completelydifferent hydrogen-bonded network. The hydrogen-bondedmotifs characteristic for 3a (and structures 1a−1c) are absent,as amide hydrogens in both independent molecules arehydrogen-bonded to the water molecule. Both molecules Aand B are overall linked to eight neighboring molecules andto the water molecule. It should be noted that C−H···F andF···F interactions were not observed in this structure. Thecrystal packing diagram along the a axis reveals that thesupramolecular structure of 1d is a two-dimensional network(Figure 5b). However, the molecules are packed very tightly(Figure S2a of the Supporting Information). Such tight packingis established by general appearance but also by the higherdensity value of all the structures described in this paper (seeTable 1). The water molecule is entrapped by two independentmolecules displaced in the opposite direction, thus forming anegglike structure (Figure S2b of the Supporting Information.Consequently, such a structure shows remarkable differences inthe conformation compared to previously described structures

Figure 5. (a) Part of the crystal structure of 1d, showing N−H···O,O−H···O, N−H···N, and C−H···O hydrogen bonds. (b) Crystalpacking diagram of 1d, viewed down the a axis, showing rows ofparallel hydrogen bonded molecules that form a two-dimensionalnetwork.



(Tables S3 and S4 of the Supporting Information). Themolecules of 1a−1c are almost linear, whereas the molecule of1d is folded (Figure S1 of the Supporting Information). Theconformation of two independent molecules does not differsignificantly (Figure S1c of the Supporting Information).As expected, the molecules of uracil derivatives are assembled

by N−H···O hydrogen bonds into dimers via R22(8) rings. This

is one of the most common motifs in structures of similarpyrimidine derivatives. Besides an eight-membered ring, thehydrogen-bonded motifs of 3a formed by N−H···O(C)and C−H···O(C) hydrogen bonds are also present in 2a(Figure 6a and Table S5 of the Supporting Information). Thecombination of R2

2(8) and R12(7) rings forms tapes which

run parallel to the b axis (Figure S3a of the SupportingInformation). In such a way, each molecule is linked tooverall three neighboring molecules. It is also obvious fromFigure 6b that butenyl moiety hydrogen atoms are directedto the neighboring phenyl rings. Thus, one C−H···π inter-action participates also in supramolecular assembling, thuslinking tapes into a stairlike three-dimensional network(Figure 6c).Compound 2b crystallized in the same space group as 2a and

is isomorphous to it (Table 1).22 The conformations of thesetwo molecules are also very similar (Tables S6 and S7 andFigure S4a of the Supporting Information). Compared to 2a,each molecule is hydrogen-bonded to six neighboringmolecules, and two C−H···F hydrogen bonds were alsoobserved (Figure 7a and Table S5 of the SupportingInformation). While the C14···F1 hydrogen bond generatesC(14) chains, the C7···F1 hydrogen bond forms dimers viaR22(12) rings. The former interaction, together with N−H···O

and C−H···O hydrogen bonds, participates in the formationof hydrogen-bonded sheets, thus forming a supramolecularstructure very similar to that of 2a (Figure 7b). The laterinteraction, together with one C−H···π interaction, links sheetsinto a three-dimensional network (Figure 7b). This C−H···π

interaction, with a H···Cg distance of 2.67 Å, is the shortest onein all structures presented in this paper and can be classified as amodest interaction. The interaction in 2a is almost identical inlength [H···Cg = 2.71 Å] and also linear [C−H···Cg ≈ 180°].It is interesting to note that in both of them the same ethenylcarbon atom participates as a donor. Two organic structureswith the same motif and similar values of H···Cg distances werefound in CSD.23 In the first one, (4Z)-(6-(2RS,4RS,5SR)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl)hex-4-enoic acid,25 the H···Cg distance of 2.73 Å is approximatelyequal to those in 2a, while in the second one, (Z)-9-(4-benzamido-2-buten-1-yl)adenine monohydrate,16 it is slightlylonger [2.77 Å]. There are also a number of other examples ofmodest interactions in which the H···Cg distances range from2.63 to 2.76 Å.26

Compound 2e crystallizes in monoclinic space group P21/cwith two independent molecules (A and B) in the asymmetricunit, which are linked by two N−H···O hydrogen bonds intodimers (Figure 8a). This structure includes two C−H···Ohydrogen bonds which are absent in the previously describedstructures of uracil derivatives, both of them forming a finitepattern. The C10A···O1B hydrogen bond, together with twomuch stronger interactions, N−H···O hydrogen bonds,generates hydrogen-bonded rings (Figure S5 of the SupportingInformation), while the C7B···O1A hydrogen bond expandsthese chains of rings into a two-dimensional network (Figure 8b).Two independent molecules are mutually linked by hydrogenbonds to overall six other molecules. One C−H···π interactionlinks the two-dimensional network into a three-dimensionalnetwork. Surprisingly, although the conformation of the twoindependent molecules is very similar (Tables S6 and S7 andFigure S4b of the Supporting Information), the butenyl moietybond lengths C7C8, C8C9, and C9C10 in molecule Bdiffer from equivalent ones in molecule A, other structuresdescribed in this paper (please see CIF file in the SI) and struc-tures of similar derivatives.13c,14 Thus, the C7C8 and C9C10

Figure 6. (a) Part of the crystal structure of 2a, showing N−H···O and C−H···O hydrogen bonds. (b) Crystal packing diagram of 2a, viewed downthe b axis, showing tapes formed by N−H···O and C−H···O hydrogen bonds. (c) Part of the crystal structure of 2a, showing a stairlike three-dimensional network formed by one C−H···π interaction (colored in blue).



bonds in molecule B are shorter for ca. 0.06 and 0.08 Å, re-spectively, while the C8C9 bond is longer for ca. 0.07 Å.These differences in bond lengths may be an artifact of thethermal librations and other molecular movements that are veryactive at room temperature.The chain of rings observed in 3a and the motif of the

N−H···O hydrogen bonded dimer is maintained also in 2f(Figure 9a). Each molecule of 2f is linked overall to five othermolecules. In contrast to the other structures of the uracilderivatives, one C−H···N hydrogen bond in 2f forms C(5)chains parallel to the a axis. This interaction is perpendicularto the chain of rings formed by all other hydrogen bonds(Figure 9b). The two-dimensional network formed in such away is spreading along the ac plane (Figure S6 of theSupporting Information) and is markedly different from thoseof the other structures of uracil derivatives. The fluorine atom isnot included in any type of intermolecular interaction, and theC−H···π interaction is not involved in the formation of thesupramolecular architecture. The conformation of the molecule

also differs slightly compared to the other structures, as theC2−N1−C7−C8 torsion angle is ca. 17° smaller than that in theother structures and the phenyl ring is coplanar with the amidecarbonyl bond defined by the O3−C11−C12−C13 torsionangle (Table S6; Figure S4c; see the Supporting Information).As expected, uracyl derivatives were found to have slightly

lower melting points compared to cytosine derivatives.16 Thiscan be explained by the fact that the number of stronginteractions in uracyl derivatives with two strong hydrogenbond donors and three strong acceptors in the molecule issmaller compared to that in cytosine derivatives which possessthree strong hydrogen bond donors and three strong acceptors.The comparison of the melting points of isomorphous crystals1a and 1b can allow a conclusion to be made about the relativestrength of hydrogen bonds. Seven identical intermolecularinteractions participate in supramolecular assembling of 1aand 1b: three N−H···O, one N−H···N, two C−H···O, and oneC−H···π. Compound 1a with one additional C−H···O hydro-gen bond has a slightly higher melting point (for ca. 20 °C)than compound 1b, in which a weaker C−H···F hydrogen bondwas observed. Such a conclusion cannot be made in the case ofisomorphous crystals 2a and 2b, as their melting points are verysimilar. Furthermore, it was found earlier that, in the case ofisomers, the compound with higher melting point could havesometimes lower density of packing, i.e. unit cell volume permolecule (V/Z).27 In the case of two isomers, compounds 1band 1c, the melting points are identical, as well as the density ofpacking amounting to 357 Å3.

Figure 7. (a) Part of the crystal structure of 2b, showing N−H···O,C−H···O, and C−H···F hydrogen bonds. (b) Crystal packing diagramof 2b, viewed down the b axis, showing two-dimensional sheets linkedby one C−H···F hydrogen bond into a three-dimensional network.

Figure 8. (a) Part of the crystal structure of 2e, showing N−H···O andC−H···O hydrogen bonds. (b) Crystal packing diagram of 2e, vieweddown the b axis, showing the two-dimensional network which is linkedby one C−H···π interaction (colored in blue) into a three-dimensionalnetwork.



■ CONCLUSIONSIn this paper we showed that supramolecular the structuresof cytosine and uracil derivatives differ with respect to thesubstituents at the 5-position of the pyrimidine and at the4-position of the phenyl ring. Even the main hydrogen-bondedmotif observed in starting compound 3a, NH···O(C)hydrogen-bonding chain (in combination with the CH···O(C) hydrogen bond), was not found in all structures.In 1d, the cytosine derivative with the fluorine atom at the5-position of the pyrimidine ring and at the 4-position of thephenyl ring, this motif is absent. This structure is markedlydifferent on the molecular and supramolecular level comparedto the structures of other cytosine derivatives. Moisture in thesolvent used for recrystallization and thus inclusion of a watermolecule into the crystal lattice dramatically influences itsmolecular packing and conformation. The absence of C−H···Fand/or possible F···F interactions expected in this structureis a consequence of other strong interactions which overruledweaker ones. Hydrogen bonds in 1a and 1b form two-dimensional sheets which are extended into a three-dimensionalnetwork by one C−H···π interaction. These two structures areipso facto isostructural. However, there is one very importantdifference between them. The C−H···F hydrogen bond in 1binfluences the conformation of the molecule. One C−H···Fhydrogen bond in 1c is responsible for the formation of a three-dimensional network. As a result of this interaction, neighboringsheets are slightly closer, and therefore one π···π interactionparticipates also in the formation of a three-dimensionalnetwork. Thus, the fluorine atom at the C-4 position of thephenyl ring in 1c plays a crucial role in the formation of ahigher-order supramolecular architecture.

In the case of uracil derivatives, the molecules are assembledby a N−H···O hydrogen bond into dimers. The structures of2a, 2b, and 2e are very similar as neighboring tapes or sheetsare expanded to a three-dimensional network by one C−H···πinteraction. In 2b, one C−H···F hydrogen bond supports thisinteraction in the sheets’ linking. The supramolecular structureof 2f is markedly different from the others, as C−H···F andC−H···π interactions are absent, and a three-dimensionalnetwork is not formed. A new type of interaction appeared(C−H···N hydrogen bond) and is possibly responsible for thedifferent supramolecular aggregation of 2f.In all structures, with the exception of 1d and 2f, weak

C−H···F and C−H···π interactions form higher-order supra-molecular structures.

■ ASSOCIATED CONTENT*S Supporting InformationTables of intermolecular interaction geometries, torsion angles,and dihedral angles; additional figures; and X-ray crystallo-graphic information file (CIF) for the structures presented inthis paper (CCDC Nos. 885155−885163). This material isavailable free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*Tel.: ++385 1 3712 590. Fax: ++385 1 3712 599. E-mail:[email protected] authors declare no competing financial interest.

■ ACKNOWLEDGMENTSSupport for this study was provided by the Ministry of Science,Education and Sports of the Republic of Croatia (Projects #125-0982464-2922 and # 119-1193079-3069). M.C. thanksAcad. Prof. Kari Rissanen for discussions.

■ DEDICATIONThis paper is dedicated to Professor Ante Nagl on the occasionof his 70th birthday.

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Figure 9. (a) Part of the crystal structure of 2f, showing N−H···O,C−H···O, and C−H···N hydrogen bonds. (b) Crystal packing diagramof 2e, viewed down the a axis, showing the two-dimensional networkformed by hydrogen bonds.



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