Polycaps: Reversibly formed polymeric capsules (calixareneyself-assemblyymolecular recognitionyhydrogen bonding)

Described are assemblies consisting of polymeric capsules, ‘‘polycaps,’’ formed from two calix[4]arene tetraureas covalently connected at their lower rims. In these structures self-assembly leads to reversibly formed capsule sites along a chain, reminiscent of beads on a string. Their dynamic behavior is characterized by 1H NMR spectroscopy through encapsulation of guest species, reversible polymerization, and the formation of sharply defined hybrid capsules. Molecule-within-molecule complexes represent an unusual arrangement of matter (1) with promising applications in mechanistic and physical organic chemistry (2, 3). More complicated synthetic systems that begin to resemble complexes found in biology are molecules that assemble through weak intermolecular forces. Specifically, cup-shaped molecules with hydrogen bonding sites on their larger rims have interesting capacities for molecular assembly. When the hydrogen bonding sites are self-complementary, the molecules dimerize to form capsules. These assemblies reversibly encapsulate smaller guest species of suitable size and shape, but show dynamic qualities (4): the capsules form and dissipate at rates that vary from microseconds to hours—long enough for chemical reactions to occur within them (5). Several such systems derived from resorcinarenes and calixarenes have been extensively characterized (6–8). In the calix[4]arenes (Fig. 1) the cup-like shape provides half of each capsule, while the ureas on its larger (upper) rim provide the hydrogen bonds that permit the molecules to assemble. The alkyl (R1) groups on the phenolic oxygens of the lower rim maintain (on average) the cup-like conformation (9), and the R2 groups on the distal urea nitrogen (Nb) provide for reasonable solubility in organic media. Their ready synthetic accessibility has raised the possibility (8, 10) that covalent connection at their lower rims could lead to polymeric capsules, or polycaps, on assembly (Fig. 2). MATERIALS AND METHODS General. All chemicals were used without further purification unless otherwise specified. p-Heptylphenyl isocyanate was prepared from the corresponding acid based on a literature procedure (11). 5,11,17,23-Tetraoctylurea-25,26,27,28tetrapropoxycalix[4]arene (1, R1 5 n-propyl, R2 5 n-octyl) was prepared from the known tetraamine (12) by treatment with octyl isocyanate in a manner similar to 6 and 7. The 5,11,17,23tetra-tert-butyl-25,26,27-tripropoxy-28-hydroxycalix[4]arene 2 was prepared according to the literature (13). Proton (1H) NMR spectra were recorded on Bruker (Billerica, MA) DRX600 (600 MHz) or AM-300 (300 MHz) spectrometers. Carbon (13C) spectra were recorded on a Bruker DRX-600 (151 MHz) spectrometer. IR spectra were recorded on a Perkin–Elmer Paragon 1000PC FT-IR spectrometer. The fast atom bombardment (FAB) positive ion mass spectra were obtained on a VG ZAB-VSE double-focusing high resolution mass spectrometer equipped with a cesium ion gun. Matrix-assisted laser desorption ionization mass spectrometry experiments were performed on a PerSeptive Biosystems (Cambridge, MA) Voyager-Elite mass spectrometer with delayed extraction. Melting points (mp) were obtained on a Thomas Hoover (Philadelphia) capillary melting point apparatus and are uncorrected. 5,11,17,23-Tetrater t-butyl-25,26,27-tr ipropoxy-28(ethoxycarbonyl)methoxycalix[4]arene (3). The alcohol 2 was suspended in anhydrous N,N-dimethylformamide (DMF; 50 ml) under N2 prior to the addition of 0.23 g (5.8 mmol) of NaH (60% dispersion in mineral oil). The mixture was heated between 55 and 60°C for 1 h to effect complete deprotonation. To the pale yellow, cloudy mixture was added ethyl bromoacetate (480 ml, 4.32 mmol), and stirring was continued at the above temperature for 14 h. The cooled mixture was added to 300 ml of water and extracted with CHCl3 (2 3 150 ml). The organic layer was separated, washed with water (2 3 200 ml) and dried over MgSO4. Following filtration and concentration, the resulting oily solid was triturated with methanol affording a white powder. The solid (2.27 g, 2.64 mmol, 92%) was filtered and washed with methanol: mp 189–191°C. 1H NMR (CDCl3) d 6.90 (s, 2H), 6.89 (s, 2H), 6.66 (s, 4H), 4.82 (s, 2H), 4.65 (d, 2H, J 5 12.7 Hz), 4.40 (d, 2H, J 5 12.4 Hz), 4.21 (q, 2H, J 5 7.1 Hz), 3.85–3.71 (m, 6H), 3.17 (d, 2H, J 5 13.0 Hz), 3.12 (d, 2H, J 5 12.6 Hz), 2.10 (m, 2H), 1.97 (m, 4H), 1.29 (t, 3H, J 5 7.2 Hz), 1.17 (s, 9H), 1.16 (s, 9H), 1.08–0.96 (m, 9 H), 0.99 (s, 18H). 13C NMR (CDCl3) 170.87, 154.08, 153.53, 153.48, 144.89, 144.59, 144.25, 134.64, 134.12, 133.28, 133.09, 125.50, 125.14, 124.85, 124.79, 76.83, 70.91, 60.21, 33.79, 33.62, 31.46, 31.41, 31.25, 30.91, 23.25, 23.19, 14.10, 10.35, 10.00. IR (thin film) 2961, 2874, 1765, 1480, 1389, 1361, 1300, 1201, 1125, 1070, 910, 870, 734 cm21. High-resolution mass spectrometry (HRMS) (FAB; M 1 Cs1) calculated for C57H80O6Cs 993.5009, found 993.5035. 5 , 1 1 , 1 7 , 2 3 T e t r a n i t r o 2 5 , 2 6 , 2 7 t r i p r o p o x y 2 8 (ethoxycarbonyl)methoxycalix[4]arene (4). Calixarene 3 (2.26 g, 2.62 mmol) was dissolved in CH2Cl2 (55 ml) and glacial acetic acid (27 ml). To this colorless solution was added fuming HNO3 (16.5 ml), resulting in a color change to an opaque purpleyblack. After 1.5 h the clear yellowyorange solution was added to 300 ml of water and further diluted with CH2Cl2 (100 ml). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (50 ml). The combined organic extracts were washed with water (300 ml), dried over MgSO4, and The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact. © 1997 by The National Academy of Sciences 0027-8424y97y947132-6$2.00y0 PNAS is available online at http:yywww.pnas.org. Abbreviations: DMSO, dimethyl sulfoxide; DMF, N,N-dimethylformamide; FAB, fast atom bombardment; HRMS, high-resolution mass spectrometry; PyBOP, 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; THF, tetrahydrofuran. ‡To whom reprint requests should be addressed at: The Scripps Research Institute, 10550 North Torrey Pines Road, MB-26, La Jolla, CA 92037. e-mail: [email protected].