Three host peculiarities of a cycloalkane-based micelle toward large metal-complex guests

Linear alkanes are essential building blocks for natural and artificial assemblies in water. As compared with typical, linear alkane-based micelles and recent aromatic micelles, we herein develop a cycloalkane-based micelle, consisting of bent amphiphiles with two cyclohexyl frameworks. This uncommon type of micelle, with a spherical core diameter of ~ 2 nm, forms in water in a spontaneous and quantitative manner. The cycloalkane-based, hydrophobic cavity displays peculiar host abilities as follows: (i) highly efficient uptake of sterically demanding Zn(II)-tetraphenylporphyrin and rubrene dyes, (ii) selective uptake of substituted Cu(II)-phthalocyanines and spherical nanocarbons, and (iii) uptake-induced solution-state emission of [Au(I)-dimethylpyrazolate]3 in water. These host functions toward the large metal-complex and other guests studied herein remain unaccomplished by previously reported micelles and supramolecular containers.

L inear alkanes, which are photo-and electrochemically inactive, act as essential building blocks for natural and artificial amphiphilic molecules. Cell membranes 1 and typical micelles 2,3 are micrometer-and nanometer-sized molecular assemblies, respectively, composed of multiple amphiphiles bearing linear alkyl chains (e.g., Fig. 1a). In contrast, the usability of cyclic alkanes for synthetic as well as biological amphiphiles has been obscure so far, except for steroid-based, oligocyclic amphiphiles (e.g., sodium cholate and CHAPS) 4,5 . The rigidity and directionality of the cyclic frameworks are higher than those of the acyclic ones so that the rational incorporation of cycloalkyl groups into amphiphilic molecules would lead to the development of micelles with unusual host functions, such as enhanced and selective guest uptake [6][7][8][9][10][11][12][13][14][15][16] .
We herein report the facile preparation and host functions of cycloalkane-based micelle (CHA) n in water. Bent amphiphiles CHA bearing two hydrophobic cyclohexyl and three hydrophilic ammonium groups assemble into a spherical micelle (Fig. 1c, f), with a core diameter of~2 nm, in a spontaneous and quantitative manner. The flexible cycloalkane-rich cavity demonstrates (i) highly efficient uptake of sterically demanding Zn(II)-tetraphenylporphyrin (ZnTPP) and rubrene (Rub) dyes, (ii) selective uptake of substituted Cu(II)-phthalocyanines (CuPc-Cl) and spherical nanocarbons, and (iii) uptake-induced solution-state emission of [Au(I)-dimethylpyrazolate] 3 (AuPz) in water. These host peculiarities toward the large metal-complex and other guests studied herein remain unreported with previous micelles as well as supramolecular cages and capsules.

Results
Formation of cycloalkane-based micelle (CHA) n . Cycloalkanebased micelle (CHA) n was spontaneously and quantitatively formed from bent amphiphile CHA in water through the hydrophobic effect and van der Waals interactions. The amphiphile was synthesized in four steps starting from the Friedel-Crafts reaction of pyrogallol and chlorocyclohexane, without precious transition-metal catalysts (see "Methods" section). Upon addition of CHA (50 μmol) into water (0.3 ml), micelle (CHA) n was instantly generated at room temperature (Fig. 2a). The concentration-dependent proton nuclear magnetic resonance ( 1 H NMR) spectra of CHA (from 10 to 170 mM) in D 2 O showed the upfield shifts of the phenylene and cyclohexyl signals (H a and H c-e ; Fig. 2b, c), implying the self-assembly of the hydrophobic moieties. Concentration-dependent dynamic light scattering (DLS) analysis further indicated the quantitative formation of small particles (CHA) n at ≥170 mM and provided an average core diameter of 2.3 nm (see Supplementary Fig. 12). The critical micelle concentration of (CHA) n is~170 mM, which is much higher than those of (AA) n (~1 mM) and (SDS) n (~10 mM) 17 , because of the absence of aromatic π-stacking interactions and/or the presence of the three hydrophilic groups. On the basis of the NMR and DLS analyses, molecular modeling studies suggested a spherical (CHA) 12 structure, having a cycloalkane-based, hydrophobic core with diameters of~2 nm (Fig. 2d). The present micelle provides faint ultraviolet (UV)-visible absorption bands at~270 nm (see Supplementary  Fig. 13), in contrast to previous aromatic micelle (AA) n with intense absorption bands in the range of <300 and 310-420 nm 17 .
Highly efficient uptake of bulky metal-complex and organic dyes. Unexpectedly, micelle (CHA) n exhibited enhanced uptake ability toward highly hydrophobic, large dyes ZnTPP and Rub in water, as compared with previous micelles (AA) n and (SDS) n , and consequently generated well water-soluble host-guest complexes. For the uptake of the metal complex, a mixed solid of CHA (2.0 μmol) and ZnTPP (1.0 μmol) was ground for 6 min using an agate mortar and pestle (Fig. 3a, right). The resultant solid was partially dissolved in H 2 O (2.0 ml) and the subsequent filtration of the suspension yielded host-guest complex (CHA) n • (ZnTPP) m as a clear purple solution. The UV-visible spectrum of the solution displayed intense Soret bands at~420 nm, derived from the incorporated dyes, without overlap with the host absorption (Fig. 3b). The relative band intensity suggested a 5:1 CHA/ZnTPP ratio, which was also confirmed by 1 H NMR analysis in organic solvent (e.g., DMSO-d 6 ) after the lyophilization of the isolated product (see Supplementary Fig. 16). The DLS chart of the product revealed its average core diameter to be 3.8 nm (Fig. 3d, e), suggesting the formation of a (CHA) 45 •(ZnTPP) 9 complex. In the optimized structure, the sterically demanding ZnTPP dyes are fully surrounded by the spherical cycloalkane shell with the multiple hydrophilic pendants (Fig. 3f).
The uptake of ZnTPP dyes by (CHA) n was estimated to be 2.5and 6.7-fold higher than that by aromatic micelle (AA) n and alkane-based micelle (SDS) n , respectively, under the same conditions (Fig. 3a, left and 3b). The result most probably stems from the flexible cycloalkane-based cavity capable of interacting with non-planar, bulky surfaces of (ZnTPP) n clusters, through CH-π interactions, to a high degree. In the same way, Rub dyes were efficiently uptaken by (CHA) n to give an aqueous red solution with the characteristic bands in the UV-visible spectra (see Supplementary Fig. 18). Host-guest complex (CHA) n • (Rub) m , featuring an average core diameter of 2.7 nm (see Supplementary Fig. 19), showed apparent absorption bands at 300 and 420-570 nm (Fig. 3c). Interestingly, the uptake ability of (CHA) n was 2.9 times higher than that of (AA) n toward sterically hindered Rub (see Supplementary Fig. 18). It should be noted that there has been no report on micelles as well as supramolecular containers (e.g., large hydrogen-bonding and coordination capsules) [25][26][27] , accommodating such multiple, bulky metal-complex and organic dyes.
Selective uptake of substituted metal-complexes and spherical nanocarbons. The polyaromatic cavity of (AA) n has been proven to possess non-selective, wide-ranging host capabilities toward various metallophthalocyanines and various nanocarbons through strong π-stacking interactions 28,29 . In contrast, the present micelle (CHA) n displayed the selective uptake of substituted Cu(II)-phthalocyanines and spherical nanocarbons in water. In a manner similar to the preparation of (CHA) n •(ZnTPP) m , simple mixing of CHA and perchlorinated CuPc-Cl (in a 2:1 molar ratio) via manual grinding led to the efficient formation of aqueous host-guest complex (CHA) n •(CuPc-Cl) m (Fig. 4a, right). UV-visible spectrum of the resultant green solution showed Remarkably, neither non-substituted CuPc-H nor perfluorinated CuPc-F was incorporated into (CHA) n under various conditions, for example, with/without grinding and sonication in several amphiphile-substrate ratios (Fig. 4a, left). No absorption bands derived from both CuPc-H and CuPc-F were detectable in the UV-visible spectra (Fig. 4b). Alkane-based micelles (e.g., (SDS) n and its derivative) show poor uptake abilities and no selectivity toward CuPc-Cl under similar conditions 29 . The observed, unusual selectivity is explainable by the self-stacking properties of the planar metal complexes, which are sterically reduced by the slightly larger Cl substituents and distinguished by the cycloalkane-based cavity through multiple CH-π interactions. In the same way, the efficient uptake of bowl-shaped subphthalocyanine (SubPc) dyes was thus accomplished by (CHA) n to afford a violet host-guest complex in water ( Fig. 4b and see Supplementary Methods).
The distinction between spherical and tubular nanocarbons was also demonstrated by (CHA) n . Like aromatic micelle (AA) n , spherical fullerenes C 60 , C 70 , and Sc 3 N@C 80 were uptaken by (CHA) n in the same way and the resultant, aqueous brown solutions clearly exhibited broadened absorption bands, derived from the incorporated fullerenes ( Fig. 4c and see Supplementary  Fig. 23). Interestingly, the uptake efficiencies of (CHA) n were enhanced by 1.6 times for C 60 and 1.5 times for C 70 , as compared with those of (AA) n under the same conditions. The detailed NMR integral and DLS analyses of the former product suggested the selective formation of a (CHA) 10 •(C 60 ) 4 complex, being different from 1:1 host-guest complex (AA) 5 •C 60 (see Supplementary Fig. 25) 28 . Whereas a huge number of fullerene-based 1:1 host-guest complexes has been reported so far, the facile preparation of host•(fullerene) m complexes (m ≥ 2) remains challenging [30][31][32] . It is worth to note that, unlike (AA) n , singlewalled carbon nanotubes (CNT; 0.7-0.9 nm in diameter and 0.7 μm in length) were not incorporated by (CHA) n so that no aqueous solution in black was obtained even under the optimized procedure for the preparation of (AA) n •(CNT) m (i.e., 6 min grinding and 15 min sonication; Fig. 4d). The difference in selfaggregating ability of the nanocarbones most probably causes its shape-selective uptake by (CHA) n in water.

Uptake-induced solution-state emission of metal-complexes.
Finally, the facile synthesis of water-soluble host-guest complexes with strong red emission was succeeded using CHA and trinuclear Au(I) complexes. AuPz is known for being highly emissive only in the solid state, due to the indispensable intermolecular Au(I)•••Au(I) interactions (Fig. 5a, left) [33][34][35] . To the best of our knowledge, the solution-state emission of trinuclear Au(I) complexes is rare and there has been no report on emissive host-guest complexes including multiple AuPz compounds and its derivatives so far [36][37][38][39][40] . When the standard uptake protocol was applied to a mixture of CHA and AuPz (in a 2:1 molar ratio), colorless host-guest complex (CHA) n •(AuPz) m was obtained as a clear aqueous solution (Fig. 5a, right). The UV-visible spectrum showed broad absorption bands, for (AuPz) m incorporated into (CHA) n , in the short wavelength region (<310 nm; Fig. 5b). DLS analysis of the product (d = 3.1 nm) also indicated the successful uptake of (AuPz) m (m =~12) by (CHA) n in water (Fig. 5c, d).
On the other hand, no and low uptake of (AuPz) m were observed with previous micelles (AA) n and (SDS) n , respectively, under the same conditions (see Supplementary Fig. 28). The UV-visible analysis revealed that the AuPz uptake by (CHA) n is 5.3-fold enhanced over that by (SDS) n . The aqueous solution of (CHA) n •(AuPz) m in hand emitted strong red phosphorescence upon irradiation at 290 nm at room temperature, whereas no emission was observed from free AuPz in CHCl 3 (Fig. 5e). The emission spectrum showed intense broad bands at λ max = 711 nm, assignable to typical aurophilic interactions [33][34][35] . The emission bands are slightly hypsochromically shifted (Δλ =~15 nm) as compared with that of AuPz in the solid state. Although the emission quantum yield of solid AuPz (Φ = 84%) is significantly high,~40% of the emissivity was retained even in aqueous solution through efficient uptake of (AuPz) m by (CHA) n (Φ = 32%). The emission band and quantum yield of host-guest complex (CHA) n •(AuPz) m are insensitive to air in water (see Supplementary Fig. 30). The CIE chromaticity diagram of AuPz within and without (CHA) n was used to quantify the total emission color ((x, y = 0.57, 0.33) and (x, y = 0.61, 0.37), respectively; Fig. 5f). The long emission lifetime of (CHA) n •(AuPz) m (τ = 14.4 μs) supported its phosphorescence derived from intermolecular Au(I)•••Au(I) interactions (Fig. 5g). The emission intensity of the product is 3.8 times

Discussion
To explore unusual host functions of micellar systems, we have synthesized a cycloalkane-based bent amphiphile, as a relative of a bent polyaromatic amphiphile. In water, the present amphiphile generated a new micelle, with a flexible cavity surrounded by a cycloalkane-rich spherical shell, in a quantitative manner. Investigation of the host ability toward metal-complex guests successfully elucidated the following three peculiar features: enhanced uptake of bulky Zn(II)-complexes, selective uptake of substituted planar Cu(II)-complexes, and uptake-induced solution-state emission of trinuclear Au(I)-complexes by the cycloalkane-based micelle. The obtained host-guest complexes provide multiple, large metal-complexes in the cavity, which is also uncommon for previously reported micelles and supramolecular containers. On the basis of the present and our previous studies 24 , we herein emphasize that bent frameworks composed of not only (poly)aromatic panels but also cycloalkane groups are of vital importance for the design of micellar systems with intriguing host functions, which will provide further potentials in host-guest chemistry. c DLS chart of (CHA) n •(AuPz) m and d optimized structure of (CHA) 22 •(AuPz) 12 (white: hydrogen; gray, orange, and scarlet: carbon, red: oxygen, blue: nitrogen, yellow: gold). e Emission spectra (room temperature, λ ex = 290 nm) and photographs (λ ex = 254 nm) of (CHA) n •(AuPz) m in H 2 O, and AuPz in CHCl 3 (0.1 mM) and the solid state. f CIE coordinate diagram (H 2 O, room temperature) of (CHA) n •(AuPz) m , (CHA) n •(AuPz′) m , AuPz, and AuPz′. g Emission decay profile (H 2 O, room temperature, λ ex = 280 nm, λ det = 700 nm) of (CHA) n •(AuPz) m .
were synthesized according to previously reported procedures (see Supplementary Methods) 17,28,34 . Synthesis of CHA. 1,5-Dicyclohexyl-2,3,4-trihydroxybenzene (3.308 g, 11.39 mmol), NaOH (4.724 g, 118.1 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (7.412 g, 51.46 mmol), and toluene (50 ml) were added to a two-necked 100-ml glass flask filled with N 2 . The resultant mixture was stirred at 130°C for 12 h. Water (50 ml) was added to the resulting solution and then the two layers were separated. The organic layer was washed with water (2 × 50 ml), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford a brown liquid 17 . This liquid was used directly for the next reaction without further purification. The liquid and CH 3 CN (50 ml) were added to a 50 ml glass flask. CH 3 I (3.5 ml, 56 mmol) was added dropwise to this flask and the resultant mixture was stirred at room temperature overnight. The precipitated crude product was separated and washed with acetonitrile (2 × 20 ml) to afford a white solid (4.884 g, 5.254 mmol). The solid and AgCl (3.001 g, 20.94 mmol) were stirred in H 2 O (20 ml) at 80°C for 12 h. After the addition of CH 3 OH (20 ml), the resultant solution was filtered and concentrated under vacuum to afford CHA (2.643 g, 2.034 mmol; 35% yield) as a white solid 17