I Halogen Bonding - ACS Publications - American Chemical Society

DOI: 10.1021/cg100516t

Modulation of N 3 3 3 I and þN-H 3 3 3 Cl- 3 3 3 I Halogen Bonding: Folding, Inclusion, and Self-Assembly of Tri- and Tetraamino Piperazine Cyclophanes

2010, Vol. 10 3638–3646

Kari Raatikainen and Kari Rissanen* Department of Chemistry, Nanoscience Center, University of Jyv€ askyl€ a, P.O. Box 35, FIN-40014, University of Jyv€ askyl€ a, Finland Received April 19, 2010; Revised Manuscript Received May 27, 2010

ABSTRACT: The acidity of the crystallization conditions was successfully employed in modulating the balance between the robust intramolecular hydrogen bonding (HB) and intermolecular halogen bonding (XB) observed in large tri- (1) and tetraamino (2) piperazine cyclophanes. A careful crystallization of the title XB acceptor cyclophanes with a strong bidentate XB donor 1,4-diiodotetrafluorobenzene (F4DIB) from CHCl3:MeOH, dimethylformamide (DMF), or HCl:H2O:EtOH resulted in X-ray quality crystals of 1 3 F4DIB, 2@DMF, 2 3 2@F4DIB, [1H3]Cl3 3 (F4DIB)6, and [2H6]Cl6 3 (F4DIB)2. The intramolecular hydrogen bonding pattern in 1 and 2 was retained in neutral protic and aprotic solvents, and regular N-H 3 3 3 N hydrogen and C-I 3 3 3 N halogen bonding synthons were observed for 1 3 F4DIB, 2@DMF, and 2 3 2@F4DIB. Because of its unaffected Pac-Man (alias Pacman) motif, cyclophane 2 manifested a size-selective complexation of DMF over F4DIB under neutral conditions. Acidic conditions led to the protonation of the cyclophanes, and þN-H 3 3 3 Cl-, CPFC-I 3 3 3 Cl-, and CPFC-I 3 3 3 Cl- 3 3 3 I-CPFC synthons appeared as structural elements. The CPFC-I 3 3 3 Cl- 3 3 3 I-CPFC anion resulted in the first XB rotaxane motif which was observed in [1H3]Cl3 3 (F4DIB)6 where the chloride anion was bound in the center of 1 via EtOH-mediated hydrogen bonding.

Introduction In the past few years, the interest in using halogen bonding (XB) in crystal engineering, in addition to the more traditional noncovalent interactions such as hydrogen bonds and metal ion coordination, has opened new insights in constructing elaborate supramolecular complexes and networks.1 The term “halogen bond” is used to emphasize the characteristics that parallel those of hydrogen bonding (HB) in terms of strength and directionality. The interaction can be schematically described as YX 3 3 3 D, where X represents the electron-deficient halogen atom (Lewis acid/XB donor), D is a donor of electron density (Lewis base/XB acceptor), and Y is any suitable atom such as carbon, nitrogen, halogen, etc.2 In addition to crystal engineering, this novel interaction has lately been applied in other fields of material science, such as supramolecular separations,3 liquid crystals, organic semiconductors, and paramagnetic materials technologies.1 Recently, the important role of halogen bonding in biological systems and its potential in drug development have also been recognized.1,4 Well-defined supramolecular complexes and networks derived from the XB interactions are generally achieved by using those XB donors where a iodine atom is covalently bound to a strongly electron withdrawing atom or molecular moiety.5 The usefulness of these interactions is established in co-crystals of perfluorocarbon (CPFC) iodides and aliphatic (sp3) or aromatic (sp2) amines.1,6 The self-assembly process of the molecular complexes is driven by a strong CPFC-I 3 3 3 N interaction, where the contact distances are about 2.8 A˚, corresponding to a remarkable (ca. 20%) reduction from the sum of the van der Waals (VDW) radii of nitrogen (1.55 A˚) and iodine (1.98 A˚) atoms.6,7 The strong interaction of the highly polarized iodine and the nitrogen atom, manifested by the short and directional *To whom correspondence should be addressed. Tel.: þ358-14-2602672. Fax: þ358-14-2602651. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 06/15/2010

intermolecular contacts, overrides the low attraction between the hydrocarbon and perfluorocarbon moieties and frequently yields stable high melting point crystalline products. Typical packing in these co-crystals is governed by segregated molecular entities with columnar or layered packing8 as a consequence of minimizing the less favorable VDW contacts.9 The potential of perfluorocarbon iodides as XB donors in the construction of supramolecular complexes and networks with simple amines has now been manifested in a number of publications.1-6,8 Because the utilization of more complex and preorganized amines as XB acceptors in crystal engineering has not been explored, we turned our attention to previously designed, structurally reinforced azacrown-type cyclophanes, classified as piperazine cyclophanes.10 These macrocyclic compounds are constructed from piperazine subunits instead of the more commonly used ethylenediamine moiety and are large enough to accommodate a variety of neutral guest molecules. Piperazine subunits provide enhanced preorganization and structural rigidity as well as a multitude of tertiary nitrogen atoms for the XB interactions. Recently, we have shown that 1,4-diiodotetrafluorobenzene (F4DIB) can be used to direct the self-assembly of piperazine cyclophanes into well-defined tubular structures with solvent inclusion.11 In the present study, large piperazine cyclophanes, namely, trimeric tri- and tetrameric tetraamino piperazine cyclophanes 1 and 2 (Scheme 1), were studied as potential XB acceptors. The cyclophanes 1 and 2 are constructed from piperazine and aniline subunits, which results in a rigid macrocyclic skeleton with an unprecedented intramolecular H-bonding seam between the anilinic hydrogens and the piperazine N-atoms. As evidenced by our previous X-ray measurements,12 this intramolecular H-bonding (Scheme 1) induces a unique conformation of trimer 1, where all the amino groups reside on the same side of the macrocycle, which can be specified as an all-syn conformation. The tetramer 2 in turn folds into a very compact shell-like r 2010 American Chemical Society

Article

Crystal Growth & Design, Vol. 10, No. 8, 2010

conformation, a molecular Pac-Man motif, due to its unique conformational appearance, and the ability to form inclusion complexes with a suitably sized guest molecule.12 In addition to the study of 1 and 2 as XB acceptors, the aim of this investigation was to challenge the XB interactions against already existing intramolecular H-bonding in 1 and 2 in order to modulate these contacts and folding, as well as to control the whole self-assembly process. The feature that the cyclophanes 1 and 2 are readily soluble in organic solvents such as dichloromethane and chloroform, but at the same time being amines which are easily converted to the corresponding water-soluble ammonium salts, offers a unique possibility to study the XB behavior in two distinctly different environments. The anion coordination by XB is far less systematically studied than the coordination of neutral ones, despite the fact that the effectiveness of anions in directing the structures via XBs has now been proven in many sophisticated supramolecular systems.13 Some of the simplest examples are heteromeric two-component systems such as halo-anilinium and halo-pyridium salts, where the counteranion functions as the XB acceptor and a halogenated organic cation functions as the XB donor moiety.14 Especially promising examples Scheme 1. The Molecular Structures and the HB Induced Preorganization and Folding in Cyclophanes 1 and 212

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among these are perfluorocarbon iodines and bromides which bind halide anions by a robust CPFC-X 3 3 3 X- synthon.3,13,15 Experimental Section X-ray Crystallography. Suitable crystals of 1 3 F4DIB, [1H3]Cl3 3 (F4DIB)6 3 2@DMF, 2 3 2@F4DIB, and [2H6]Cl6 3 (F4DIB)2 for single crystal X-ray diffraction analysis were selected, and analyses were performed using a Bruker Kappa Apex II diffractometer with graphite-monochromatized Mo-KR (λ=0.71073 A˚) radiation. Collect software16 was used for the data measurement and DENZOSMN17 for the processing. The structures were solved by direct methods with SIR9718 and refined by full-matrix least-squares methods with WinGX-software,19 which utilizes the SHELXL-97 module.20 All C-H hydrogen positions were calculated in the idealized positions by using a riding atom model after the anisotropic refinement of all non-hydrogen atoms of the structure. If possible, all N-H (or þN-H) hydrogens were located from the electron density map and refined with restrained bond distances using isotropic displacement parameters of 1.2Ueq (or 1.5Ueq) of the attached N-atom. Most of the O-H hydrogens were located from the electron density map and refined as a rotating group by using the same (1.2Ueq or 1.5Ueq) isotropic displacement parameters. In the case of [1H3]Cl3 3 (F4DIB)6: one of the three þN-H protons could not be located from the electron density map but was instead deduced from the position of Cl- and refined with a riding atom model. An unusually high residual electron density peak and hole were located near (1.08 A˚ from I103 and 0.59 A˚ from I46) the iodine atoms suggesting errors caused by absorption.21 In the structure of [2H6]Cl6 3 (F4DIB)2, all þN-H (and N-H) were located from the ΔF map except two (N5 and N33), which were refined with a riding atom model to obtain chemically reasonable bond angles. Solvent water hydrogens were poorly resolved from the map and hence were calculated to the idealized H-bond positions. To reduce disorder, 1 3 F4DIB was solved and refined in a polar space group Cc as a racemic twin by using TWIN and BASF [0.49(5)] instructions. Detailed crystallographic data for all structures are summarized in Table 1.

Results and Discussion The cyclophanes 1 and 2 were co-crystallized with a strong XB donor F4DIB from three different solvent systems, viz. CHCl3:MeOH, dimethylformamide (DMF), and HCl:H2O: EtOH. The chloroform-methanol mixture is only slightly polar, DMF is polar aprotic, and the hydrochloric acid in water protonates the cyclophanes making them readily soluble in water, while some ethanol reduces the solubility of the Table 1. Crystallographic Data for 1 3 F4DIB, [1H3]Cl3 3 (F4DIB)6, 2@DMF, 2 3 2@F4DIB, and [2H6]Cl6 3 (F4DIB)2 crystal formula space group a [A˚] b [A˚] c [A˚] R [°] β [°] γ [°] V [A˚3] Z T [K] Dcalc μ [mm-1] θ max [°] θ comp [%] no. reflns parameters restraints R1 [I > 2σ(I )] wR2 [I > 2σ(I )] GOF on F2 ΔF max [e A˚3] ΔF min [e A˚3]

1 3 F4DIB C46H67F4I2N9O4 Cc 18.9697(4) 26.6758(9) 10.5487(3) 90 103.455(2) 90 5191.5(3) 4 173(2) 1.458 1.275 25 99.8 4589 615 19 0.0260 0.0496 1.093 0.394 -0.289

[1H3]Cl3 3 (F4DIB)6 C78H72Cl3F24I12N9O3 P21/n 15.0024(2) 28.0603(4) 23.8472(3) 90 91.9240(7) 90 10033.3(2) 4 123(2) 2.164 3.877 27.5 99.6 22959 1168 16 0.0589 0.1442 1.031 4.325 -3.291

2@DMF C51H75N13O I41/acd 36.2670(4) 36.2670(4) 15.7233(2) 90 90 90 20680.8(4) 16 123(2) 1,139 0.071 27.5 99.6 5932 303 8 0.0633 0.1401 1.058 0.481 -0.469

2 3 2@F4DIB C105H142Cl6F4I2N24O P21/c 13.7978(2) 40.2212(6) 20.7248(4) 90 94.356(1) 90 11468.3(3) 4 123(2) 1.331 0.751 25 95.2 19256 1329 16 0.0905 0.1936 1.124 1.325 -1.532

[2H6]Cl6 3 (F4DIB)2 C66H104Cl6F8I4N12O9 P21/m 8.8485(2) 22.9558(5) 21.9893(4) 90 92.028(1) 90 4463.8(2) 2 123(2) 1.549 1.647 27.5 99.7 10482 544 17 0.0438 0.1123 1.056 1.083 -1.316

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Raatikainen and Rissanen

Figure 1. The HB and XB interactions in 1 3 F4DIB (a), the packing view along the c-axis showing the H-bonded MeOH molecules (VDW) in the channel (b), a view parallel to the diagonal of a/c-axes (c). Table 2. Hydrogen and Halogen Bonds in 1 3 F4DIB and [1H3]Cl3 3 (F4DIB)6 [1H3]Cl3 3 (F4DIB)6

1 3 F4DIB XB/HB

[A˚]

[°]

XB/HB

[A˚]

[°]

C-I46 3 3 3 N8 C-I53 3 3 3 N25 N43-H 3 3 3 N39 N43-H 3 3 3 O64 N44-H 3 3 3 N22 N44-H 3 3 3 N11 N45-H 3 3 3 N36 N45-H 3 3 3 O62 O58-H 3 3 3 O64 O60-H 3 3 3 O58 O62-H 3 3 3 O60 O64-H 3 3 3 O62

2.758(8) 2.770(7) 2.882(9) 3.204(8) 2.843(12) 2.880(12) 2.881(9) 3.440(10) 2.764(8) 2.754(7) 2.742(8) 2.774(7)

179.1(3) 177.6(3) 134(6) 147(7) 138(8) 127(7) 125(6) 175(8) 170(7) 157 164 171

C-I94 3 3 3 Cl1 C-I65 3 3 3 Cl1 C-I53 3 3 3 Cl2 C-I106 3 3 3 Cl2 C-I101 3 3 3 Cl3 C-I82 3 3 3 Cl3 N8-H 3 3 3 O1A N22-H 3 3 3 Cl3 N36-H 3 3 3 Cl2 N43-H 3 3 3 N39 N44-H 3 3 3 N11 N45-H 3 3 3 N25

3.129(3) 3.217(3) 3.289(3) 3.221(3) 3.159(2) 3.229(2) 2.775(7) 3.084(7) 3.158(7) 2.982(9) 2.906(9) 2.856(10)

172.7(3) 170.5(3) 168.7(4) 175.6(3) 173.8(3) 171.8(3) 170(4) 152 163(8) 140 144 143

resulting ammonium salts and helps them to crystallize. Crystallizations were done by dissolving the cyclophane with a 5-20-fold excess of F4DIB in a solvent system and letting it evaporate at RT. Crystallization from the HCl:H2O:EtOH system was done by dissolving/suspending the components first into the ethanol, followed by a dropwise acidification with concentrated HCl and finally tuning the solubility by adding water, thus optimizing the crystallization conditions. As a result, one crystalline product for 1 from CHCl3:MeOH and one from HCl:H2O:EtOH were obtained, while 2 gave crystalline products from all three solvent systems. The HB and XB Interactions in Cyclophane 1 Complexes. Colorless crystals suitable for X-ray diffraction were obtained by a slow evaporation of a chloroform-methanol mixture of cyclophane 1 and F4DIB. One clearly crystalline product 1 3 F4DIB was isolated (Figure 1a). The intramolecular NH 3 3 3 N hydrogen bonding12 of the cyclophane 1 still exists, and the intermolecular N 3 3 3 I-CPFC-I 3 3 3 N halogen bonding (Figure 1a) connects the cyclophanes into a tightly packed lattice with segregated columns of the cyclophanes and the

F4DIB molecules (Figure 1b), similar to the case of the mxylene analogue11 of 1. The shape of the cyclophane is not fully complementary with itself possessing pseudo 2-fold rotational symmetry on the center of the cyclophane. In fact, the structure can also be solved in C2/c but suffers significant disorder. The F4DIB and the hydrogen bonded solvent methanols form a chain (Figure 1b) trapped inside the channels (Figure 1c) in the crystal lattice; the H-bond distances are given in Table 2. Because 1 is constructed from three aniline and piperazine subunits, six XB acceptor sites would be available as the piperazine nitrogens and three as the anilinic nitrogens. However, the 1:1 complex was obtained despite of the used molar ratios of 1 and 4FDIB indicating a very stable and energetically favorable packing motif. The more nucleophilic piperazine N-atoms act as XB acceptors22 resulting in intermolecular CPFC-I 3 3 3 N halogen bonds, yet at the same time the intramolecular N-H 3 3 3 N HBs12 are retained. As a result of this, the cyclophane 1 folds into the conformation where N8 and N25 atoms are optimally oriented for two XB donors. In fact, the resulting I46 3 3 3 N8 and I53 3 3 3 N25 contacts are shorter and

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Figure 2. The asymmetric unit of [1H3]Cl3 3 (F4DIB)6 with a selected numbering scheme (a) and 1D-chain packing motif of the cyclophanerotaxane axle moieties (b) (the other F4DIB’s and irrelevant solvent EtOH’s are excluded for clarity).

closer to 180° (Table 2) than the typical CPFC-I 3 3 3 N (sp3) XB interactions.5,6 The anilinic N-atoms are less nucleophilic22 and are folded or encapsulated inside the cavity of the adjacent cyclophanes and hence are not involved in the halogen bonding. However, all the anilinic hydrogen atoms are involved in hydrogen bonding (Figure 1, Table 2), four as intramolecular N-H 3 3 3 N contacts, while the remaining two form weak N-H 3 3 3 O interactions to the channeled methanol solvates. Even though the intramolecular H-bonding remains, the overall configuration of 1 in 1 3 F4DIB is not anymore the all-syn as observed for the non-XB complexed12 1 but is very similar to the corresponding trinitro analogue of 1.12 Repeating the co-crystallization experiment of 1 and F4DIB in HCl:H2O:EtOH solvent enabled us to control the folding and self-assembly processes of 1 by means of converting the N-H 3 3 3 N and CPFC-I 3 3 3 N interactions to a anion mediated XB-HB synthon. Different molar ratios (1:5 to 1:20) were tested, but the experiments resulted in only one product, a structurally complicated [1H3]Cl3 3 (F4DIB)6. The protonation of the macrocycle clearly alters the balance of the HB and XB interactions and leads to a completely different stoichiometry. Now, one nitrogen in each of the piperazine moieties of 1 is protonated,

and each of the three chloride anions are halogen bonded by two F4DIB molecules resulting in I53 3 3 3 Cl2 3 3 3 I106, I82 3 3 3 Cl3 3 3 3 I101, and I65 3 3 3 Cl1 3 3 3 I94 XB interactions. The hydrogens, which now create the ammonium ion moieties, are pointing outward from the macrocycle forming charge-assisted Cl2 3 3 3 HN36 and Cl3 3 3 3 H-N22 HBs and one O1A 3 3 3 H-N8 HB with the solvate ethanol. Thus, Cl2 and Cl3 anions are actually involved in I53 3 3 3 Cl2 3 3 3 H-N36, I106 3 3 3 Cl2 3 3 3 H-N36, I82 3 3 3 Cl3 3 3 3 H-N22, and I101 3 3 3 Cl3 3 3 3 H-N22 interaction patterns, which are combinations of the HBs and the XB interactions, and hence can be classified as a three-component XB-HB synthon (Figure 2a, Table 2). One of the ammonium ion moieties (N8) of the structure is not H-bonded by its counteranion Cl1 but instead bonded by a solvent ethanol (Figure 2a; O1A). The ethanol also forms an O1A-H 3 3 3 Cl3 (3.148(6) A˚ and 145°) HB, and hence is a part of the N22-H 3 3 3 Cl3 3 3 3 H-O1A 3 3 3 H-N8 HB pattern, which further links adjacent cyclophanes resulting in infinite chain motifs (Figure 2b). As mentioned above, Cl1 is coordinated by the XB interactions but is unlike the other chlorines located inside the macrocyclic cavity. As a result, the first reported XB rotaxane-type structure,23 where the

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Figure 3. Crystal structure of 2@DMF with selected numbering scheme (a) of the asymmetric unit (half of the cyclophane). Hydrogen atoms (except anilinic) are omitted for clarity. Hydrogen bonds are shown by dotted red lines. The packing of 2@DMF (b) shows the helical H-bonded DMF chain (VDW) and the encapsulating cyclophanes 2 (capped sticks).

cyclophane 1 acts as the wheel and the CAr-I65 3 3 3 Cl1 3 3 3 I94-CAr as the axle, was obtained. In addition, two other ethanol molecules (Figure 2a; O1B and O1C) are H-bonded to Cl1 and cyclophane through Cl1 3 3 3 H-O1B 3 3 3 H-N and Cl1 3 3 3 H-O1C 3 3 3 H-N HB interactions. The 1D-chains, constituted from the cyclophane-rotaxane axle moieties, linked by the above-described HB pattern, are assembled parallel with the a-axis and further connected to adjacent chains via the XB rotaxane-type synthon. All F4DIB molecules are packed between the 1D-chains with multiple π 3 3 3 π and VDW contacts, resulting in a segregation of hydrocarbon and perfluorocarbon moieties. Similar segregation is usually observed in XB co-crystals of perfluorocarbons and hydrocarbons.8 Despite the triple protonated structure, the conformation of 1 is nearly perfect C3-symmetric bowl-shaped all-syn, similar to the non-XB cyclophane12 1. The low-energy chair conformation24 of the piperazine subunits with proper torsion angles resulted in the seam of intramolecular HBs between aniline hydrogens and nonprotonated piperazine nitrogens. The HB and XB Interactions in Cyclophane 2 Complexes. The cyclophane 2 was dissolved into DMF with an excess of F4DIB. Slow evaporation at room temperature gave


colorless X-ray quality crystals. Instead of a co-crystal with F4DIB, the X-ray structure revealed a 1:1 inclusion complex with DMF (2@DMF) in a very compact Pac-Man conformation.12 The hydrogen bonding and the structure of the inclusion complex are depicted in Figure 3a. The included DMF molecules form a -CdO 3 3 3 H-CdO hydrogen bonded helical chain leading to chiral wire-type columns which run through the crystal lattice in the direction of the c-axis (Figure 3b). Even in a competing solvent such as DMF, the fully saturated hydrogen bonding system in 2 is so robust that even the strong XB donor F4DIB cannot break it and only the 1:1 Pac-Man complex is observed. This is probably due to the better fit of the DMF over F4DIB into the cavity of 2, yet changing the solvent system will change the inclusion mode (see below). Cyclophane 2 is constructed from four aniline and piperazine subunits, which corresponds to about 1.33 times the overall size of the smaller trimer 1. In general, bulky groups or structural moieties greatly reduce the conformational freedom of cyclic structures, but macrocycles with a large enough size and some degree of flexibility and suitable intramolecular interactions, such as intramolecular hydrogen bonding, can lead to a unique folding behavior.25 For instance, the conformation shown in Scheme 1 and in Figure 3 results when all the anilinic hydrogens in 2 participate in intramolecular H-bonds with the piperazine moieties forming eight intramolecular N-H 3 3 3 N HBs (Table 3), and at the same time, all piperazines adopt energetically the most favorable conformations with horizontally oriented N-methylene substituents.24 Because of the rigidity of 2, the average N-H 3 3 3 N contact distance and angle are about 2.93 A˚ and 134°. This complete set of intramolecular interactions leads to a highly symmetrical structure with a cyclic H-bonding pattern. Similar phenomena in other quite rigid macrocyclic structures suggest that this kind of cyclic pattern of intramolecular forces would provide additional stabilization through the co-operative effects as observed in self-folding cavitands.26 In addition to pure DMF as the solvent, cyclophane 2 with F4DIB in ratios varying between 1:5 to 1:20 was also crystallized from mixtures of chloroform and methanol. Like in the other cases discussed above, only one type of X-ray quality crystals was obtained, after careful evaporation of the solvent mixture. The X-ray structure determination revealed the ratio of 2 to F4DIB to be 2:1 (Figure 4a). The most striking feature of this structure was the formation of a 2@F4DIB inclusion complex, which seems to be a consequence of the same Pac-Man-like conformation that was found in 2@DMF. Interestingly, the 45 A˚3 cavity of the other cyclophane is empty, indicating that while F4DIB can be encapsulated by 2, the CHCl3 and MeOH solvent molecules are not suitable for encapsulation, chloroform being too large and MeOH too small for a snug fit into the cavity. The crystal packing is governed by the XB-induced dimer formation, 2 3 2@F4DIB 3 3 3 2 3 2@F4DIB shown in Figure 4b. The conformation of 2 remains intact despite the changed molecular composition and halogen bonding. While the conformation is maintained by the intramolecular hydrogen bonding, the F4DIB molecules are actually integrated into the structure as guest molecules forming a host-guest complex but leaving both halogen bond donor and acceptor sites available. Because of the folding, induced by the intramolecular hydrogen bonding, the only possible XB acceptors are the weakly nucleophilic aniline nitrogens resulting in two quite weak intermolecular N60 3 3 3 I128 and N120 3 3 3 I121 contacts. The XB distances are about 10% longer than in 1 3 F4DIB,

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Table 3. Specified Hydrogen- and Halogen Bonds in 2@DMF, 2 3 2@F4DIB, and [2H6]Cl6 3 (F4DIB)2 2@DMF XB/HB N8-H 3 3 N23-H 3 N23-H 3 N8-H 3 3

3 N10 3 3 N13 3 3 N25 3 N28

XB/HB C-I34 3 3 3 Cl1 C-I41 3 3 3 Cl2 N5-H 3 3 3 N7 N33-H 3 3 3 N25 N10-H 3 3 3 Cl1 N22-H 3 3 3 Cl2 N20-H 3 3 3 Cl3 N20-H 3 3 3 Cl4

2 3 2@F4DIB

[A˚]

[deg]

XB/HB

[A˚]

[deg]

2.981(3) 2.868(3) 2.922(3) 2.963(3)

132(2)° 136(2)° 134(2)° 135(2)°

C-I121 3 3 3 N120 C-I128 3 3 3 N60 N57-H 3 3 3 N8 N57-H 3 3 3 N53 N58-H 3 3 3 N11 N58-H 3 3 3 N22 N59-H 3 3 3 N25 N59-H 3 3 3 N36 N60-H 3 3 3 N50 N60-H 3 3 3 N39 N117-H 3 3 3 N68 N117-H 3 3 3 N113 N118-H 3 3 3 N71 N118-H 3 3 3 N82 N119-H219 3 3 3 N96 N119-H319 3 3 3 N85 N120-H220 3 3 3 N99 N120-H320 3 3 3 N110

2.993(7) 2.946(7) 2.916(10) 2.969(11) 2.938(10) 2.898(10) 2.929(11) 2.875(11) 2.879(10) 2.853(9) 2.908(10) 2.918(10) 2.926(11) 3.097(11) 2.859(10) 2.869(10) 2.898(10) 2.985(10)

169.2(3) 175.6(3) 149(8) 135(8) 127(8) 132(8) 134(8) 148(9) 137(8) 137(8) 137(8) 141(8) 124(8) 134(8) 137(8) 130(8) 138(8) 152(9)

[2H6]Cl6 3 (F4DIB)2 [A˚] 3.117(1) 3.087(1) 2.754(4) 2.729(4) 3.096(4) 3.109(4) 3.427(5) 3.547(5)

[°] 178.2(2) 179.8(2) 140.6 140.9 174(5) 167(5) 165(5) 152(5)

Figure 4. The asymmetric unit of 2 3 2@F4DIB with selected numbering scheme. All non-anilinic hydrogen atoms and solvate methanol and chloroform molecules are omitted for clarity (a). The packing showing 2 3 2@F4DIB 3 3 3 2 3 2@F4DIB dimer connected by two XBs (b). Solvent methanol and chloroform molecules are omitted for clarity and XB and HB interaction are represented by dotted lines.

which reflects the weaker XB attraction due to the lower nucleophilicity of aniline nitrogens.22 The hydrogen and halogen bond distances and angles are presented in Table 3. Because of the inclusion of F4DIB inside 2, the average contact distance and angle for all four N-H 3 3 3 N H-bonds are 2.93(8) A˚ and 134(8)°, which is very close to those in 2@DMF (Table 3). For the apohost in 2 3 2@F4DIB, the average of the corresponding N-H 3 3 3 N contacts is changed to 2.91(4) A˚ and 137(8)°, which manifests only marginal squeezing of the conformation. Because of such a robust and preorganized binding cavity in cyclophane 2, a high size selectivity toward guest molecules is expected. While 2 with F4DIB was crystallized from a chloroform-methanol mixture, none of the solvent molecules were encapsulated. In the

case of the smaller-sized and polar methanol, the nonpolar interior of the cavity does not offer any stabilizing H-bond acceptors and is thus not favored by a guest; on the other hand, the quite nonpolar chloroform is too large to fit into the cavity and is thus unsuitable. The large empty voids inside the crystal lattice are generally assumed to be unfavorable in terms of energy, and hence, both the weak halogen bonding and the packing forces contribute to the encapsulation of F4DIB into the cavity of 2. As shown by the structure of 2@DMF, it is obvious that cyclophane 2 is selective toward DMF over F4DIB, CHCl3, and MeOH present in the solvent system. To illustrate the excellent size match with the cavity of cyclophane 2, the structures of 2@MeCN,12 2@DMF, and 2 3 2@F4DIB are illustrated in Figure 5.

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Following the same strategy as in [1H3]Cl3 3 (F4DIB)6, cyclophane 2 was crystallized with F4DIB from acidified waterethanol mixtures. Unlike 1, significant conformational changes were expected to occur in 2 due to the larger structural flexibility, as the intramolecular H-bonding pattern would be broken down by the protonation of the piperazine nitrogens, and subsequent strong charge-assisted hydrogen bonding to the chloride anions would occur. After a few careful crystallization attempts using different ratios of 2 and F4DIB, the hexa-protonated structure [2H6]Cl6 3 (F4DIB)2 was obtained. The crystal structure, depicted in Figure 6, shows that the Pac-Man motif has opened into a shallow crown-type conformation (possessing a mirror plane through N5 Cl4, Cl3 and N33) due to the protonation of four piperazine N-atoms (N10, N10#, N22 and N22#, #=x, 1/2 - y, z) and two aniline nitrogens (N5 and N33). The four hydrogens, which now create an ammonium ion moiety on each piperazine subunit, are pointing outward from

Figure 5. VDW representation of the size-match in 2@MeCN,12 2@DMF, and 2 3 2@F4DIB.


the macrocycle and are bound by their counter-anions resulting in charge-assisted Cl1 3 3 3 H-N10, Cl1# 3 3 3 H-N10#, Cl2 3 3 3 H-N22, and Cl2# 3 3 3 H-N22# HBs (Table 3). Consequently, C-I 3 3 3 N XB contacts, which are characteristic in 2 3 2@F4DIB and 1 3 F4DIB, were replaced by the three-component XB-HB synthons N10-H 3 3 3 Cl1 3 3 3 I34-C35, N22-H 3 3 3 Cl2 3 3 3 I41C40, as well as their symmetry equivalents, similar to what was found in [1H3]Cl3 3 (F4DIB)6. The two remaining protonated sites, viz. the NH3þ-groups on the opposite aniline moieties, form intramolecular N25 3 3 3 H-N33-H 3 3 3 N25# and N7 3 3 3 H-N5-H 3 3 3 N7# HB-patterns, while the third þ N-H is H-bonded to the ethanol solvates trapped between the macrocycles. Anions Cl3 and Cl4 are included inside the cavity coordinated by N20-H 3 3 3 Cl3 3 3 3 H-N20# and N20-H 3 3 3 Cl4 3 3 3 H-N20# HB patterns with the aniline NH2-groups and H-bonds with the solvent H2O (Figure 6b). Finally, a complicated but well-resolved pattern of six water and three ethanol solvents, while being disordered due to the mirror symmetry of 26þ, connects all chlorides (as well as protonated N5 and N33) into a complex HB network. Bisfunctional halogen bond donors form extended supramolecular chain structures.6,8 In the case of 26þ, strong linear Cl 3 3 3 I-CPFC-I 3 3 3 Cl- and tetrahedral CPFC-I 3 3 3 Cl- 3 3 3 H-Nþ XB interactions link the protonated cyclophanes together as caterpillar tread-type chains. The cyclophane chains are aligned on top of each other thus forming infinite tubular structures (Figure 7a). In addition to the intramolecularly

Figure 6. The structure of [2H6]Cl6 3 (F4DIB)2. Solvate ethanol and water molecules are omitted for clarity. XB and HB interactions are represented by dotted lines (a). The HB network of five H2O and three EtOH on the mirror plane (gray), where symmetry-related atoms are shown by the same color (b).

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Figure 7. The packing of the 26þ and F4DIB molecules along the c-axis (a) and a-axis (b). The solvent ethanol and water molecules are omitted for clarity. The XB and HB interactions are illustrated by dotted lines.

encapsulated chloride anions, the interstices of the parallel chains (Figure 7b) are filled with a HB-network of ethanol and water molecules. In addition to the concerted halogen and hydrogen interactions, the crystal structure is further stabilized by offset π 3 3 3 π stacking between the F4DIB molecules. Consequently, a segregated packing of hydro- and perfluorocarbon moieties, similar to [1H3]Cl3 3 (F4DIB)6, is obtained. Conclusions It is generally suggested that the assembly of crystalline solids results from the balance of all intermolecular interactions in the crystal by maximizing the attractive interactions and minimizing the repulsive ones, generally leading to the closest packing. The co-crystals of piperazine cyclophanes 1 and 2 with F4DIB clearly show that both halogen and hydrogen bonding have a marked role as the main inter- and intramolecular interactions. The apparent competition between the XB and HB donors for the same acceptor sites is strongly influenced by the bulk environment. Marked differences in inter- and intramolecular interactions were observed when the crystallization environment was changed from neutral-liphophilic to acidic-aqueous conditions. A strong control of the intramolecular H-bonding and the overall self-assembly of cyclophanes 1 and 2 was achieved. The potential of halogen bonding based anion coordination is far less systematically studied than that of the neutral XB acceptors; in our investigation this strategy was further extended to large amine macrocycles 1 and 2, and the resulting structures [1H3]Cl3 3 (F4DIB)6 and [2H6]Cl6 3 (F4DIB)2 are now the first examples of large molecular weight cyclic polyammonium chlorides where the self-assembly is driven by anion-mediated threecomponent CPFC-I 3 3 3 Cl- 3 3 3 H-Nþ XB-HB synthons. In addition, the first halogen bonded rotaxane motif was observed as a structural element in [1H3]Cl3 3 (F4DIB)6. Halogen bonding combined with hydrogen bonding offers an excellent route to complex, elaborate, and potentially functional 3-D structures. Acknowledgment. We thank the Academy of Finland (KRi. proj. no. 212580 and 218325) and the National Graduate School of Organic and Bioorganic Chemistry (KRa) for financial support Supporting Information Available: X-ray data with details of refinement procedures (CIF). This information is available free of charge via the Internet at http://pubs.acs.org.

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