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Solvent Mixing To Induce Molecular Motor Aggregation into Bowl-Shaped Particles: Underlying Mechanism, Particle Nature, and Application To Control Motor Behavior

Control over dynamic functions in larger assemblies is key to many molecular systems, ranging from responsive materials to molecular machines. Here we report a molecular motor that forms bowl-shaped particles in water and how confinement of the molecular motor affects rotary motion. Studying the aggregation process in a broader context, we provide evidence that, in the case of bowl-shaped particles, the structures are not the product of self-assembly, but a direct result of the mixing a good solvent and a (partial) non-solvent and highly independent of the molecular design. Under the influence of the non-solvent, droplets are formed, of which the exterior is hardened due to the increase in the glass transition temperature by the external medium, while the interior of the droplets remains plasticized by the solvent, resulting in the formation of stable bowl-shaped particles with a fluid interior, a glass-like exterior, and a very specific shape: dense spheres with a hole in their side. Applying this to a bulky first-generation molecular motor allowed us to change its isomerization behavior. Furthermore, the motor shows in situ photo-switchable aggregation-induced emission. Strong confinement prohibits the thermal helix inversion step while altering the energy barriers that determine the rotary motion, such that it introduces a reverse trans–cis isomerization upon heating. These studies show a remarkable control of forward and backward rotary motion by simply changing solvent ratios and extent of confinement.

The synthesis started with McMurry coupling of cycloketone 2, which can be prepared according to a reported procedure, 3,4 to form the central olefin bond, giving the dibromo motor as a mixture of trans-and cis-isomers in 3:1 ratio. Palladium-catalyzed carbonylation, as reported, was employed to introduce esters onto the both sides of the motor. 5 At this stage, the two isomers could be separated with a total yield of 80% (60% for trans-4 and 20% for cis -4).The hydrolysis of 4 in the presence of base resulted in the dicarboxylic acid 5 with almost quantitative yield. Compound 5 was then treated with oxalyl chloride with a catalytic amount of DMF, and the corresponding carbonyl chloride was directly used in the next step without any purification. After addition of the aniline 6, of which the synthesis was already reported, 4 the desired molecular motor 1 was isolated.

Compound 3.
To a suspension of zinc powder (2.0 g, 31.3 mmol) in dry THF (60 mL), TiCl 4 (1.63 mL, 14.8 mmol) was added at 0 o C. The resulting mixture was stirred at 65 o C for 2 h. After cooling down to room temperature, compound 2 (2.0 g, 8.0 mmol) was added and the resulting mixture was heated at reflux for another 3 days. The cooled mixture was poured onto silica and washed with DCM to remove the solids. After evaporation of the solvents, the crude product was purified by column chromatography using pentane / DCM (3:1) to give a trans/cis-mixture of compound 3 (1.6 g, 3.5 mmol, 86 % yield, trans:cis = 3:1) as a white solid.  4. Dry methanol (2 mL) was added to the mixture of compound 3 (400 mg, 0.85 mmol, trans:cis = 3:1), potassium carbonate (258 mg, 1.87 mmol), Pd(dpppr)Cl 2 (50 mg, 0.08 mmol), and NMP (10 mL). The mixture was placed in autoclave under 7.5 bar CO, and heated at 110 o C for 2 days. After cooling to room temperature, the resulting mixture was diluted with water (10 mL) and then extracted with ether (2 X 20 mL). The combined organic layer was further washed with water (3 X 20 mL), brine (20 mL), and dried over Na 2 SO 4 . After evaporating the solvent in vacuo, and the residue was purified using column chromatography (pentane:ethyl acetate = 10:1) to give trans-stable 4 (222 mg, 0.52 mmol, 61 %) and cis-stable 4 (68 mg, 0.16 mmol, 19 %) as white solids.

Compound 5.
Compound trans-stable 4 (150 mg, 0.35 mmol) was dissolved in THF (2 mL), Methanol (2 mL), and aqueous NaOH (1M, 2 mL), followed by heating at 65 o C for 18 h. After cooling to room temperature, the mixture was titrated using HCl solution (1 M) to pH 3. Then the mixture was concentrated in vacuo, and the residue was dissolved in THF. The organic phase was collected of which the solvent was removed. The resulting white solid provided trans-stable 5 (142 mg, 0.35 mmol, 99%) without further purification. 1

Molecular motor 1.
To a solution of trans-stable 5 (200 mg, 0.5 mmol) in THF (5 mL), DCM (5 mL), and DMF (1 drop) was add oxalyl chloride (0.21 mL, 2.5 mmol) at 0 o C under nitrogen. After warming up to room temperature, the mixture was stirred for another 1 h. The resulting solution was concentrated to yield acid chloride, which was subsequently dissolved in dry DCM (20 mL) and triethylamine (0.14 mL, 1 mmol). To the aforementioned solution of acid chloride, compound 6 (620 mg, 1.1 mmol) was added at 0 o C. After stirring at room temperature for 18 h, the resulting solution was washed with water (20 mL), brine (20 mL), and dried over Na 2 SO 4 . The solvents was evaporated in vacuo, and the resulting residue was purified by column chromatography (pentane:DCM = 1:1) to yield trans-stable 1 (449 mg, 0.3 mmol, 60 %) as a white solid. 1 Figure S1. 1    Cis-stable 1 was obtained as a white solid with the same procedures and had a yield of 65 %. 1   (R,R)-(P,P)-trans-5 and (R,R)-(P,P)-cis-5 were prepared following a previous reported procedure. 3 Then, the same process was employed to synthesize (R,R)-(P,P)-trans-1 and (R,R)-(P,P)-cis-1 as that of the racemic material.

Freezing bath beads
As proof of principle of the proposed mechanism (figure 5) of bowl-shaped particle formation, we froze bath beads in liquid nitrogen to create similar bowl-shaped particles at a macroscopic-scale (Supplementary Movie 1). Upon freezing, the outer shell of the oil goes through the glass transition temperature and shrinks against the pressure from the still liquid interior resulting in a macroscopic bowl-shaped particle. S8 Figure S5. Solvent induced aggregation of 0.5 mg/ml Styrofoam in chloroform with 50% methanol (A) and of 0.6 mg/ml Nile Red in tertiary butanol with 75% water (B). Figure S6. Spheres from the molecular motor 1 at 10 -4 M in THF at φ w 60% (A, B) and φ w 90% (C, D), and their evolution over time. Panels B and D are images of samples A and C, respectively, after 4 days of aging. Scalebars represent 1 μm (black) and 500 nm (white), respectively. Figure S7. Particle size distribution of trans-stable 1 in THF/water mixture with φ w = 60% and φ w = 90% (c = 1 x 10 -4 M)。At 60% φw, a particle radius of 392 nm with a poly-dispersity of 64% is measured, whereas at 90% φw the radius is 130 nm with a polydispersity of 35% φ w 60% φ w 90% S11

Phase separation
In order to gain insight in the mechanism of bowl-shaped particle formation, we used Nile Red fluorescence to monitor the polarity dependent fluorescence maximum in different solvent-water mixtures 2 ( Figure S8). Measurements started at pure solvent (methanol, ethanol (not shown for figure clarity), propanol, tert-butanol and THF) and water was added stepwise. Only in methanol-water the absorption maximum keeps shifting linearly towards 660 nm (close to pure water 2 ). In the other solvents at critical water content (CWC), the fluorescence spectrum suddenly broadened, showing a second population of Nile Red that experienced a much lower polarity. The hydrophobic Nile red does not tolerate the polarity of the water and initiates phase separation into droplets. As soon as the concentration of Nile Red is increased for TEM measurements, however, the CWC seems specific for the nature and concentration of the molecule and the nature of the initial solvent, rather than the water content. The fact that Nile Red does not cause precipitation into droplets in methanol underlines that not only the non-solvent, but also the solvent quality plays a role. While infinitely diluted Nile-Red results in droplets from the solvent being gathered around the hydrophobic Nile-Red, higher concentrations of Nile-Red in THF-water result in bowl-shaped particles at 75% φ w ( Figure 2B), indicating the role of hydrophobic interactions as well as a strong effect of molecular concentration. Figure S8. Nile Red fluorescence maxima, which change with polarity, of different solvent-water mixtures. Water acts as precipitator for Nile Red in all mixtures except methanol-water, inducing lowpolarity droplets. At the CWC, the fluorescence spectra can not be explained with a single peak and are solved with convolution into two peaks (1 and 2), each peak representing a sub-population of the Nile Red.   Figure S17. 1 H NMR spectrum of cis-unstable 1 in the aggregates (φ w = 90%) after heating. Transstable 1 was irradiated to PSS in THF which was followed by adding water. The resulting mixture was heated at 50 o C for 48h. The aggregates were then centrifuged and dissolved in CDCl 3 for NMR.