Van der Waals Nanocapsular Complexes of Amphiphilic Calixarenes

Aug 3, 2006 - Synopsis. The inclusion complexes of p-alkanoyl calix[4]arenes with alkanoyl chain lengths from C4 to C10 (C4OH−C10OH) and tetrahydrof...
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CRYSTAL GROWTH & DESIGN

Van der Waals Nanocapsular Complexes of Amphiphilic Calixarenes Ananchenko,*,†

Udachin,†

Gennady S. Konstantin A. Michaela John A. Ripmeester,† Said Jebors,§ and Anthony W. Coleman§

Pojarova,†

Alix

Dubes,†

2006 VOL. 6, NO. 9 2141-2148

National Research Council Canada, Steacie Institute for Molecular Sciences, 100 Sussex DriVe, Ottawa, Ontario K1A 0R6, Canada, and Institut de Chimie et Biologie des Proteins, 7 Passage du Vercors, F-69367 Lyon Cedex 07, France ReceiVed June 21, 2006

ABSTRACT: The inclusion complexes of p-alkanoyl calix[4]arenes with alkanoyl chain lengths from C4 to C10 (C4OH-C10OH) and tetrahydrofuran, dioxane, and some halocarbons as guests were prepared and their structures were studied by single-crystal X-ray diffraction, TGA, DSC, and 13C CP-MAS NMR. The complexes of C6OH are nanocapsules stabilized by van der Waals interactions between the calixarene cavity as extended by the alkanoyl chains and one or more guest molecules. The stability of the nanocapsule compounds depends strongly on the size and saturation vapor pressure of the guests, as well as on the presence of halogen atoms in the guest molecule. In the presence of the latter, the C6OH capsular complexes have markedly lower stability and easily eject the guests. C4OH calixarene prefers to form open-container type complexes, whereas it is possible to prepare quasicapsular complexes of C10OH with dioxane as a guest. In this case, two dioxane molecules are encapsulated by two molecules of calixarene and the third dioxane molecule provides interlayer stabilization of the crystal lattice by hydrogen bonding of dioxane oxygens with OH groups of the neighboring calixarenes. The general trends in the formation and stability of van der Waals capsular complexes of amphiphilic calixarenes are discussed, as well as how they relate to the formation of solid lipid nanoparticles. Introduction Calixarenes are a versatile class of macrocyclic compounds that have been studied extensively, both as host materials and as platforms for the synthesis of designed specific receptors.1 The calixarene structure allows for the complexation of a wide variety of ions, atoms, and small molecules.2 Calix[4]arene can be chemically modified,3 and such modifications are of interest for numerous applications, such as molecular recognition,4 transmembrane transport,5 ion-channel formation,6 self-assembled monolayers at the air-water interface,7 and gas adsorption.8 Amphiphilic calixarenes obtained by Friedel-Crafts acylation of the parent calix[4]arene9 represent a promising class of material for this purpose, because they retain their ability to complex small organic molecules and self-organize as solid lipid nanoparticles (SLNs) in water.10 The use of SLNs as a colloidal transport system is of great interest because of their high stability and high encapsulation loads.10 However, because SLNs are too small for analysis by diffraction, their detailed structures, site distribution, and mode of action remain largely unknown. The crystal structures of host-guest inclusion compounds formed between calixarenes and guests can provide a good basis for the understanding of the guest-induced structural motifs, inclusion propensities, and the molecular recognition capabilities of such amphiphilic derivatives. In a number of preceding papers,11-14 we have described different types of inclusion complexes of p-hexanoyl calix[4]arene,11,14 with the main focus on nanocapsular complexes.12,13 Such nanocapsules have a hydrophobic nanoenvironment constructed from only weak van der Waals interactions. As a result, the calixarene crystal structures exhibit well-defined cavities of near-constant size and shape that can be occupied by a variety of organic guest molecules. The construction of larger capsules * To whom correspondence should be [email protected]. † National Research Council Canada. § Institut de Chimie et Biologie des Proteins.

addressed.

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Figure 1. Schematic showing the amphiphilic calixarenes. C4OH, R ) C3H7; C6OH, R ) C5H11; C8OH, R ) C7H15; C10OH, R ) C9H19.

that can accommodate several substrates in the cavity could be particularly important. Despite the fact that most frameworks can be constructed using mainly strong covalent and metalligand bonds,15 hydrogen bonds,16 or both,15,16 the case of van der Waals interactions17 is particularly interesting; even these weak interactions collectively can potentially create relatively stable structures, which enable guest exchange12 and chemical transformations13 within the cavity. A more comprehensive understanding of the main trends in complex formation is not possible without extensive studies of the different types of amphiphilic calixarenes with a variety of guests. In this paper, we present a comparative study of crystal structures of the amphiphilic calixarenes (Figure 1) with solvent molecules as guests. The main focus was on tetrahydrofuran (THF), because this is the common solvent for the preparation of SLNs.10 The chain lengths of the amphiphilic calixarenes varied from C4OH (p-butanoylcalix[4]arene) to C10OH (pdecanoylcalix[4]arene), see Figure 1 (excluding C8OH, which was published recently.18) Experimental Section p-Alkanoyl calix[4]arenes were synthesized according to procedures previously described.9 Solvents were purchased from Aldrich. Crystals of complexes were prepared at room temperature by the slow evaporation method, typically, from a solution of ca. 50-300 mg of amphiphilic calixarene in 3-10 mL of the corresponding solvent. Thermogravimetric (TGA) and differential scanning calorimetry (DSC) analyses were performed on TA Instruments equipment with a

10.1021/cg0603826 CCC: $33.50 © 2006 American Chemical Society Published on Web 08/03/2006

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Table 1. XRD Parameters of Inclusion Complexes of Amphiphilic Calixarenes

formula fw color cryst syst space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z Fcalcd (g cm-3) F(000) µ(MoKR) (mm-1) 2θmax (deg) total no. of reflns no. of unique reflns no. of reflns I > 2.5σ(I) no. of variables R wR GOF max ∆/σ (final cycle) residual density (e A-3)

C4OH‚THF

C6OH‚2THF

C6OH‚2HT

C6OH‚HT‚EtOH

C10OH‚1.5dioxane

C48H56O9 776.93 colorless orthorhombic Pna21 17.645(4) 15.371(3) 15.398(3) 90 90 90 4176.3(15) 4 1.236 1664 0.084 59.34 46 122 11 705 9767 542 0.0517 0.1246 1.003 0.059 0.389; -0.274

C58H76O9.5 925.19 yellowish tetragonal P4/nnc 15.4735(12) 15.4765(12) 22.604(3) 90 90 90 5412.2(10) 4 1.290 2232 0.088 56.52 57 351 3355 1884 386 0.076 0.143 1.106 0.040 0.45; -0.22

C54H65BrClF3O8 1014.42 colorless monoclinic P21/n 15.739(3) 21.908(4) 15.847(3) 90 90.59(3) 90 5464.0(19) 4 1.233 2128 0.860 42.48 34 133 6038 4359 825 0.1856 0.5313 2.491 1.199 2.040; -0.980

C56H71BrClF3O9 1060.49 colorless tetragonal P4/nnc 15.4867(13) 15.4867(13) 22.675(3) 90 90 90 5438.2(9) 4 1.295 2232 0.869 56.66 55 831 3390 2190 277 0.1049 0.3049 1.351 0.022 0.580; -1.453

C74H108O11 1173.60 yellowish monoclinic P21/n 15.202(4) 30.187 (7) 15.203(4) 90 90.045 (3) 90 6977 (3) 4 1.117 2560 0.073 49.54 54 951 11 938 6836 940 0.127 0.295 1.047 0.089 0.45; -0.62

Table 2. Changes in 13C NMR Chemical Shifts of Guests in Solid Inclusion Complexes of C4OH, C6OH, C8OH, and C10OH Relative to Liquid Guest complex

(CH2)2O

(CH2)2

C4OH‚THF C6OH‚2THF C8OH‚2THF C10OH‚1.5dioxane

+0.1 -0.6eq, -1.8ax -0.4 -0.3

-2.3 -1.0 -0.9

temperature ramp of 3 °C/min. 13C CP-MAS spectra were recorded on Bruker AMX 300 NMR spectrometer. Single-crystal X-ray diffraction data were collected at 125 K in the ω-2θ scan mode on a Bruker Smart diffractometer equipped with a CCD detector using graphite-monochromatized Mo KR radiation at λ ) 0.71073 Å. The structures were solved by direct methods and refined by full-matrix least squares on F2 using the SHELXTL suite of programs.19 Positions of disordered groups were found from the electron density maps. Disordered fragments were then placed in appropriate positions, and all distances between neighboring atoms and angles were fixed. Site occupancies were refined for the different parts with the same thermal parameters for the same atoms in the various fragments. At the end of the refinement, site occupancies were fixed and hydrogen atoms were placed in calculated positions. Compiled X-ray data are given in Table 1, and corresponding CIF files are given in the Supporting Information.

Figure 2. Packing diagram of the complex of C4OH with THF (hydrogen atoms and disorders are omitted for simplicity).

Results Complex of C4OH with Tetrahydrofuran. The complex of C4OH with THF crystallizes in the orthorhombic Pna21 space group with unit-cell parameters 15.37 and 17.65 Å. The unit cell is represented by two calixarene molecules entrapping one guest molecule each. The connection between calixarene cones is provided by a hydrogen bond formed between a phenolic OH group and the oxygen atom of THF, with a typical distance of ca. 2.7 Å. The hydrocarbon part of THF (Figure 2) is inserted deep in the calixarene cavity, with distances of 3.4-3.8 Å between ipso-carbon atoms of the benzene rings of the host and the CH2 atoms of THF. The two calixarene cones in the unit cell are twisted at an angle of 28.8° with respect to each other. The 13C CP-MAS NMR spectrum of the complex shows no differences between chemical shifts of the CH2-O atoms of entrapped THF as compared with those of liquid tetrahydrofuran (Table 2). On the other hand, the signals of the β-CH2 atoms of THF are shifted upfield by 2.3 ppm, a distinct difference indicating significant shielding of these atoms by the cavity.12,13,17f,20 This agrees with the XRD structure of the complex, where the β-CH2 atoms (Figure 2) are located deeper in the cavity than the CH2-O part of the THF molecule. The complex is stable at ambient temperature and slowly releases THF above 80 °C. Upon release of all THF, the crystal structure changes, probably to a self-included complex, so that a single crystal of the complex does not remain intact after removal of THF. The phase change can be observed on the DSC trace (Figure 3a) as a broad peak around 150 °C. The new phase is stable up to the melting point at ca. 240 °C (Figure 3a). Complexes of C6OH. The complex of C6OH with THF crystallizes in a tetragonal P4/nnc space group with unit-cell parameters 15.47 and 22.60 Å. The asymmetric part contains one phenolic fragment with alkanoyl chains disordered over four proximate positions and two THF molecules that are also disordered. The unit cell contains two calixarene molecules arranged in tail-to-tail pairs to form a hydrophobic capsular complex with a cavity ca. 10 Å wide and ca. 15 Å long, which entraps four molecules of THF (Figure 4). The two calixarene cones of the capsule are twisted at an angle of 32.4° to each other. The unit-cell parameters, as well as the capsular structure,

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guests is ca. 4.0 Å, and both molecules are turned away from each other to alleviate the oxygen’s lone-pair repulsion. Solid-state 13C NMR shows two types of CH2-O atoms of THF captured by the calixarene (Figure 5a): the sharp signal

Figure 5. 13C CP-MAS NMR signals of R-C of THF (a) in freshly prepared complex C6OH‚2THFand (b) after heating for 1 h at 110 °C.

Figure 3. TGA/DSC of complexes of (a) C4OH with THF, (b) C6OH with THF, and (c) C10OH with dioxane. The sharp peaks at 240, 175, and 134 °C for plots a-c, respectively, correspond to the melting point of the material.

are similar to those of complexes of C6OH with chloroform, dibenzyl ketone, or cis-stilbene described earlier.12,13 Two THF molecules lie on the “poles” of the capsule and two more occupy the “equator”. The polar (i.e., located on the capsule pole) THFs are disordered over two positions each, with the oxygen atoms pointing between two carbonyl groups of the host. The equatorial THF is disordered over three positions that correspond to a significant freedom of the guest at this location. The shortest distance between atoms of equatorial and polar

at 66.9 ppm can be attributed to CH2-O atoms of the equatorial THF molecules, and the broad signal at ca. 65.7 ppm belongs to those of the polar THFs. The comparison with the 13C NMR spectrum of liquid THF (Table 2) reveals that the capsule provides more shielding for the polar guest. It is also clear that the exchange between polar and equatorial positions of THF is very slow and that the mobility of the polar guest is significantly restricted. That is quite different from the C6OH capsules containing chloroform,12 where only one averaged signal from all guests was observed. The β-CH2 atoms of THF are also shielded (1 ppm difference from liquid THF) but less than those in the C4OH‚THF complex. This agrees with the orientation of encapsulated THF found from XRD refinement of the C6OH‚ THF complex and is different from that in the C4OH‚THF complex.

Figure 4. (a) Packing diagram and (b) the capsule of the complex of C6OH with THF. Hydrogen atoms and disorders are omitted for simplicity.

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Table 3. Unit-Cell Parameters and Comparative Stability of Inclusion Complexes of C6OH guest halothane chloroforme tetrahydrofuran pinacolone bromoform

b.p. (°C)a

unit cell

50

P21/n: 15.74, 21.91, 15.85, 90.6 P4/nnc: 15.57, 22.68 P4/nnc: 15.47, 22.61 P4/nnc: 15.61, 22.79 P4/nnc: 15.52, 22.66

61 65 106 150

no. of guest molecules

T (°C) (50%)b

(2)c

30d

(4)c 4 2 4

60, 100d 110, 140 140 80, 120d

a Aldrich Chemical Data. b Release of 50% of the number of guests molecules according to TGA. The second value corresponds to the release of 50% of the number of remaining molecules. c Accepted as the original number of guests per capsule. d Collapse of the nanocapsule. e See ref 12

TGA (Figure 3b) shows that THF can be ejected by heating the substance at ca. 170 °C. Heating at ca. 120 °C removes 3 molecules of THF fairly selectively. The single crystal of the complex survives after such heating and XRD analysis remains possible, although a full refinement of the structure is unreliable because of worse quality of the material. Nevertheless, the unitcell parameters of the complex correspond to those before heating. One can see from the 13C CP-MAS NMR spectrum (Figure 5b) that the chemical shift and shape of the signal of the CH2-O atoms of remaining THF corresponds to those of the polar guests before thermal treatment. Longer heating times remove all of the THF and the capsule collapses, probably into a self-included complex. The original capsular form cannot be restored by placing the guest-free material into THF vapor for several days at room temperature. Aiming to check the ability of C6OH to form capsular inclusion complexes, we prepared complexes of the calixarene with several other guests: bromoform (BF), 1-bromo-1-chloro2,2,2-trifluoroethane (halothane, HT), and pinacolone by crystallization from the corresponding guest. To avoid the problems of very complicated refinements of the highly disordered molecules in the complexes, we measured only unit-cell parameters. Most of the guests form capsular inclusion complexes, as can be deduced from their P4/nnc symmetry and ca. 15.5 and 22 Å unit-cell dimensions (Table 3). The only guest that forms a complex of different symmetry (P21/n) is halothane, so the full refinement of its structure was attempted. However, the quality of the result remained rather poor (R factor was ca. 0.18), which can be explained by the instability of the complex

(Table 3). Nevertheless, even such refinement provided the most probable picture of the complex of C6OH with halothane (C6OH‚HT). One can see from Figure 6a that the complex looks like a capsular complex entrapping g2 HT molecules per capsule. The structure is generally similar to that of C6OH with trans-stilbene described earlier.13 The two cones of the calixarene (Figure 6a) in the capsule are not twisted as for the tetragonal P4/nnc complexes. The entire capsule seems more open to the environment and the cones are slightly shifted approximately along the equatorial plane. The positions of the guests were not found precisely enough, but the intensities of the maxima in the electron density map from XRD data allowed us to conclude that the polar guest is turned into the cavity by its bromine atom. TGA analysis showed that the complex should contain two molecules of HT per capsule at room temperature, but because the complex is relatively unstable (see Table 3), one can consider the HT molecule in the equatorial position (found with a site occupancy of ca. 0.1) to be a remaining trace of the original complex C6OH‚2HT, which decomposes at room temperature and ejects halothane. We also prepared a complex of C6OH with halothane by crystallization from an ethanol solution containing the components. The capsular complex obtained under these conditions was of P4/nnc symmetry with two HT and two ethanol molecules per capsule (Figure 6b). The HT molecules occupy polar positions in the capsule with bromine atoms deep in the cavity, and the ethanol molecules occupy the equatorial positions of the capsule. Complex of C10OH. It was not possible to obtain crystals suitable for X-ray diffraction of the complex of C10OH with THF. However, crystallization from dioxane proved to be more successful and afforded square, platelike crystals of the complex, with three dioxane molecules per two calixarene units (Table 1 and Figure 7). The packing diagram (Figure 7a) shows that the C10OH molecules are present in a bilayer structure with calixarenes head to head along the y axes. The bilayers are stabilized by hydrogen bonds connecting molecules of dioxane in the chair conformation to the hydroxyl groups at the lower rim of each calixarene. The average distance between O atoms of hydroxyl groups and oxygen atoms of dioxane is 3.0 Å. The second molecule of dioxane is entrapped inside the cavity of the calixarene in a chair conformation, with a CH2 group deep

Figure 6. X-ray structures of the complex of C6OH with halothane (only atoms with maximal site occupancy are shown for simplicity): (a) P21/n complex obtained from halothane, (b) P4/nnc complex obtained from a 2/1 ethanol/halothane mixture. Atom colors: Br, brown; Cl, green; F, blue; O, red.

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Figure 7. (a) Packing diagram and (b) two nearest capsules of the complex of C10OH with dioxane. Hydrogen atoms and disorders are omitted for simplicity.

in the cavity. The distance between the CH2 group and the nearest ipso-carbon atom on the benzene ring is 3.78 Å. Two alkyl chains (colored yellow in Figure 7b) of the calixarene are included in the cavity of one of the opposite calixarenes and the third alkyl chain (magenta in Figure 7b) is in the other. The fourth chain is situated between these two calixarene molecules. The first two and the last dodecanoyl chains are disordered over two positions. The molecule of dioxane inside the cavity is disordered over three positions. The complex resembles a distorted capsule (in analogy with complexes of C6 with halothane or trans-stilbene13) with two dioxane molecules in polar positions and two chains of the opposite calixarene serving as equatorial guests. On the other hand, the complex can be considered as being self-included, where dioxane guests are pressed deep into the cavity by alkanoyl arms. The complex is not stable and slowly releases dioxane, even at ambient temperature. After the guest has been removed, the complex most likely transforms to a self-included complex in analogy with C4OH and C6OH calixarenes. The phase change can be observed by TGA as being a broad endothermic peak at ca. 70 °C (Figure 3c). Discussion Analysis of the results obtained and a comparison with literature data for calixarenes unsubstituted at the lower rim8,10b,11-14,17a,b,d,f,18 allows us to conclude that the amphiphilic calixarenes may form (i) self-included complexes without guests, or with a guest outside the calixarene cavity (such as the complex of C6OH with methanol11 or C8OH10b; (ii) opencontainer type complexes where the calixarene cavity, like a bowl, contains a guest and is capped by a similar bowl above (the aforementioned complexes of C4OH with THF, as well as C6OH with DMSO, DMF11 or C8OH with THF18); (iii) capsular complexes.12,13 The formation and stability of each type of complex depends on the calixarene, guest type, solvent, and most likely, temperature. Analysis of complexes prepared from the same guests and from calixarenes with gradually increasing alkanoyl chain length gives important information about the interaction preferred for the stabilization of one complex over another. In the series of complexes with tetrahydrofuran, one of the key elements of stability is the ability of the guest to provide a hydrogen-bond link between layers of the crystal lattice. The

alkanoyl chain lengths in C4OH and C8OH18 calixarenes prove to be suitable for the entrapping of one and two THF molecules, respectively, and yield the link that stabilizes the entire lattice. It is generally similar to complexes of C6OH with DMF, DMSO, and nitrobenzene described earlier.11 An unexpected stabilization and interlayer stretching found for the complex of C10OH with dioxane clearly indicates the prevalence of hydrogen bonding over van der Waals interactions even involving multi-CH2 alkanoyl chains. On the other hand, if the alkanoyl chains of the host are longer than required to entrap a single guest molecule but at the same time not long enough for two THF guests, the stabilization chain (cavity rf guest r(H-bond)f lower rim) becomes distorted; interlayer stabilization through van der Waals interaction begins to play the key role and yields the capsular complexes such as those of C6OH. The ability to form capsular complexes, which preferably entrap an even number of guest molecules, seems to be solely the property of C6OH. The first requirement for capsule formation is the relatively low polarity of the guest and an inability to form strong hydrogen bonds with OH groups at the lower rim of the neighboring calixarene, therefore preventing the formation of the open-container complex. The second requirement is the size (and molecular shape21) of the potential guest and the solvent.22 Any molecule of a size smaller than the cavity dimensions potentially can be encapsulated, as for chloroform, bromoform, stilbenes,13 and dibenzyl ketone.12 However, the size of the guest probably affects the structure of the capsule, transforming it from P4/nnc symmetry to P21/n (vide infra). The third requirement is an appropriate crystallization medium. The best method for obtaining the capsular complex is the crystallization of C6OH from its solution in the guest. However, because this is not possible in many cases, a third component, solvent, is needed to carry out the complexation. The method is designed on the basis of the guest template effect and has been described for complexes of resorcinarenes.23 The solvent used should not give the capsular complex, with alcohols appearing to be the best choice. In this case, there is a competition between formation of the capsular complex with dissolved guests and formation of a self-included structure, as expected from pure alcohols.11 The driving force for both processes is the hydrophobic interaction,17c,24 with some restric-

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Figure 8. Square bipyramidal capsular complexes: P4/nnc symmetry (left) and P21/n symmetry (right).

tions because of the nonaqueous media. The prevalence of one process over the other strongly depends on the molar ratio of the components in solution as well as on the rate of crystallization: slow crystallization seems to favor the formation of capsular complexes. Of course, under special conditions, such as crystallization from an ethanol/halothane mixture, the ethanol can also be encapsulated; this likely reflects some specific interaction between HT and ethanol, enabling entrapping of both. It should be noted that pH of the crystallization medium may also play some role in the capsules formation; however, this role seems to be less important than for the case H-bonded capsules.16,25 Generally, there are two types of capsular complexes: those of P4/nnc symmetry and those of P21/n symmetry. Schematically, both types of complexes can be represented by square bipyramids (Figure 8), where the components of the capsule are either twisted or shifted, respectively. One can find a parallel between C6OH and p-tert-butylcalixarene,17f when the latter forms the corresponding P4/nnc and P21/c (as well as P2/n and P4/n) complexes.17,26,27 In the P4/nnc one, the structure represents a “pure” type of the capsule; the second type can be said to be a distorted or transient capsule, which resembles the “open capsule” reported for p-sulfonatothiacalix[4]arene complexes.28 And this is generally similar to the relationship among the phases of p-tert-butylcalixarene inclusion complexes,17f though C6OH has its own distinct features. It is worth remembering that P21/n capsules of C6OH are formed under conditions that are generally not favorable for capsule formation, such as the large guest trans-stilbene from ethanol13 or the large guest halothane with destabilizing interactions between halogen atoms and the benzene rings of calixarene (vide infra).27 The stability of the capsular inclusion complexes of C6OH correlates with the boiling point (or vapor pressure) of the guest (Table 3). However, as one can see from Table 3, the capsules are generally halophobic, i.e., for two guests with similar boiling points and vapor pressures, such as THF and chloroform, the less-stable complex forms with the latter. This is likely to be a general feature of calixarenes, as pointed out in previous publications.27 Moreover, any electronegative group (oxygen in THF, dioxane in the corresponding complexes, as well as the carbonyl group27d,29) avoids being in the deep pocket. The “halophobicity” has been observed earlier and discussed in terms of soft acid-base properties of halogen atoms and the benzene rings of the calixarene cavity.27a,b,d In our opinion, the reason is the electronegativity of the combined four electron-rich benzene rings of the calixarene. The calixarene pocket preferably accepts more acidic CH and similar groups,30-33 as well as easily polarizable groups.32 The case of HT-calixarene interaction can be considered as being an example of a weak halogen bond,34 where the halothane plays the role of halogen (Br) donor and the π-system of the pocket becomes the acceptor of the bromine, because the latter is the most polarizable and least electronegative atom (except H) in halothane. However, this Br-π

Ananchenko et al.

interaction is weaker than the potential CH3-π one27 if such a group were to be present in the molecule. Thus, amphiphilic calixarenes SLNs are likely to lose aliphatic halocarbons during transport. The C6OH capsule with tetrahydrofuran remains stable even if only one molecule of THF has been encapsulated. The stability can be attributed to favorable interactions of THF CH2s (vide supra) with the deep cavity, in analogy with many guests in p-tert-butylcalix[4]arene.17a,b,d,f,26,27 The THF molecule is deeply and almost perfectly inserted in the pocket, with distances between the CH2 carbon of the guest and C-ipso atoms of the host of ca. 3.5-3.8 Å. A particular electrostatic (nucleophilic) (CH2)2Oδ-‚‚‚δ+CdO interaction probably yields an additional contribution to the stabilization, as can be seen from a comparison of THF positions in the cavities of different calixarenes, from C4OH (vide supra) to C8OH.18 Among these three calixarenes, the most stable complex is the one with C6OH and only here does the orientation of THF differ from those in C4OH and C8OH.18 It is worth noting that the position of THF in C4OH or deep in C8OH resembles that of THF entrapped in cucurbit[6]uril;35 hence, the orientations of THF in C6OH‚2THF seem to be unique and it is not yet clear why. It was mentioned above that the mobility and exchange between polar and equatorial positions of THF in the cavity are restricted. The different stability of the capsule with various guests should enable controlled release and refill of this nanocontainer. On the other hand, the ability of THF (and probably similar molecules) to re-enforce the capsule can be exploited for such applications as gas adsorption or chemical transformations of guests. C6OH is probably the only calixarene in this series (C4OHC10OH) that can form stable nanocapsular complexes. Shorter chain lengths cannot provide strong enough van der Waals interactions between chains to form stable capsular structures. Our attempts to crystallize a capsular complex of C4OH with cyclohexane or with 1,4-dimethylcyclohexane from ethanol failed. On the other hand, p-tert-butylcalix[4]arene easily forms such van der Waals complexes.17a,b,d,26,27 The reason for their stability is the enhanced number of possible interactions due to tBu‚‚‚tBu contacts, i.e., about 2-3 CHn‚‚‚CHn contacts per pair of arms. For the case of C6OH, this number can easily be achieved (Figure 4b), but the alkanoyl chains of C4OH are too short. C10OH already contains too many CH2 groups that give strong van der Waals interactions, so the interaction with the guest cannot compete. An additional force (such as hydrogen bonding here) is needed to pull the calixarene cavities away from each other, resembling in this case the structures of koilates36 with interlayer dioxane as a fragile connector. The complex 2C10OH‚3dioxane can be considered as being a transient capsule in analogy to C6OH‚HT, and the former remains stable only while the external dioxane molecule connects the neighboring layers. The complex’s 13C CP-MAS NMR spectrum looks similar to that of capsular P4/nnc complexes of C6OH (Figure 9) despite the relatively low symmetry of the structure (P21/n vs P4/nnc). However, the marked instability of this structure, the difficulties in preparing the complex, and the small effective available volume of the cavity despite the large size of this dimeric structure do not give good opportunities for its potential applications. Concluding Remarks The general ability of amphiphilic calixarenes to form inclusion complexes of different types is of great interest for

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or some ordering of the structure, i.e., it leads to the appearance of a second phase within the nanoparticle (particularly, it has been pointed out in the paper37). This new phase is expected to be a capsular complex, because this type of structure was the only one observed for C6OH and molecules of low polarity. Clearly, such treatment of as-produced SLNs, as yet of unknown structure, can be very useful for improving the properties of SLNs based on C6OH. For higher calixarenes, however, a similar workup is likely to be less effective because the formation of capsules is much more difficult. However, the flexible nature of the CnOH class of substituted calixarenes, both as molecules and as solid materials, clearly is an important feature in being able to organize SLNs for improved carrying capacity. Acknowledgment. This work was supported in part by the CNRS-NRC collaborative program. G.S.A. gratefully acknowledges financial support in the form of a Visiting Fellowship in the Canadian Government Laboratories. Color figures were prepared with the program MOLMOL.38 Supporting Information Available: Crystallographic information files (CIF); figures of asymmetric parts of complexes displaying thermal ellipsoids (except C6OH‚HT). This material is available free of charge via the Internet at http://pubs.acs.org.

References

Figure 9. 13C CP-MAS NMR spectra of solid complexes of (a) C4OH with THF, (b) C6OH with THF, and (c) C10OH with dioxane. Spinning sidebands are marked with an asterisk.

the purposes of producing materials capable of encapsulation for transport and release, reactions in controlled environments, and gas storage and separation. The C6OH nanocapsules provide a relatively large void volume and can be filled under controlled conditions by many appropriate guests. Unfortunately, larger void space for inclusion (C10OH and probably higher) likely is not achievable because the van der Waals interactions responsible for stabilization of the self-included complexes are too large to be overcome by most guest species. However, it is possible that some guests may still form inclusion complexes, and this would be indicative of a special selectivity for a number of specific guest materials. However, for the common guests discussed in this paper, only C6OH is able to form capsular complexes. The simple consideration of the structures of calixarenes allows one to conclude that the ability of a calixarene to form a capsule depends on the ratio of sizes of rigid (four Ar-CO groups in alkanoyl calixarenes) and flexible ((CH2)nCH3) parts of the molecule. Therefore, the design of calixarenes, which potentially will be able to form van der Waals nanocapsules with larger void spaces, may be possible simply by appropriately expanding the rigid and flexible fragments. The results obtained above for the crystalline materials can be compared to those known for solid lipid nanoparticles (SLNs).10,37 Moreover, some predictions can be made related to the potential adsorption properties of SLNs. It is known10 that solid lipid nanoparticles based on amphiphilic calixarenes are amorphous materials, which, however, may show some crystalline order in the inner core.10a It is also known that exposure of C6OH nanoparticles to vapors of solvents changes the structure of these materials, improving their adsorption properties. One can assume that solvent vapor (such as that of dichloromethane37) evokes a particular crystallization of SLNs

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