A photoswitchable strapped calix[4]pyrrole receptor: highly effective chloride binding and release

A stiff-stilbene strapped calix[4]pyrrole receptor can be reversibly switched by light between a strong chloride-binding Z-isomer and a very weakly binding E-isomer. The light-induced switching process is monitored by UV-Vis and 1H NMR spectroscopy and chloride binding is studied in detail using both 1H NMR and ITC titrations in DMSO and MeCN. In DMSO, at millimolar concentrations, switching from a fully bound to an almost fully unbound state can be triggered. Quantification of the binding constants in MeCN reveals an extraordinary 8000-fold affinity difference between the Z- and E-isomer. Single crystal X-ray crystallographic analysis gives insight into the structure of the photogenerated E-isomer and the geometry of the chloride-bound receptors is optimized by DFT calculations. The highly effective control of binding affinity demonstrated in this work opens up new prospects for on demand binding and release in extractions and photocontrol of membrane transport processes, among other applications.


Experimental section General methods and materials:
THF, MeCN, and Et2O were dried using a Pure Solve 400 solvent purification system from Innovative Technology. Dry DMSO and DMF were purchased from Acros Organics and DMSO-d6 and CDCl3, were purchased from Eurisotop. DMSO-d6 was stored under N2 over molecular sieves (4Å). The degassing of the solvents was carried out by purging with N2 for 30 min. 6-Carboxy-1-indanone 1 and 6-Hydroxy-2-hexanone 2 were prepared according to procedures reported in the literature. All other chemicals were commercial products and were used without further purification. Column chromatography was performed using silica gel (SiO2) purchased from Screening Devices BV (Pore diameter 55-70 Å, surface area 500 m 2 g -1 ) and thin-layer chromatography (TLC) was carried out on aluminum sheets coated with silica 60 F254 obtained from Merck. Compounds were visualized with UV light (254 nm) or by staining with potassium permanganate. 1 H and 13 C NMR spectra were recorded on Bruker AV 400 and Bruker 500 Ultra Shield instruments at 298 K unless indicated otherwise. Chemical shifts () are denoted in parts per million (ppm) relative to residual protiated solvent (DMSO-d6: for 1 H detection,  = 2.50 ppm; for 13 C detection,  = 39.52 ppm; CDCl3: for 1 H detection,  = 7.26 ppm; for 13 C detection,  = 77.16 ppm. The splitting pattern of peaks is designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet), br (broad). High-resolution mass spectrometry (ESI-MS) was performed on a Thermo Scientific Q Exactive HF spectrometer with ESI ionization. UV-Vis spectra were recorded on an Agilent Cary 8454 spectrometer in a 1 cm or 1 mm quartz cuvette. ITC measurements were performed using a MicroCal VP-ITC MicroCalorimeter. Irradiation of UV-Vis and NMR samples was carried out using a Thorlab model M340F3 LED (0.85 mW) and a Thorlab model M365F1 LED (3.00 mW), positioned at a distance of 1 cm to the sample.
Purification by column chromatography (SiO2, pentane/EtOAc 1:1) afforded compound 2 (1.40 g, 66%) as a pale yellow solid. 1 1,165.9,159.6,137.3,135.4,130.0,127.0,125.2,65.2,36.5,28.4,26.1,22.7;HRMS (ESI)  A similar procedure to the one reported by Boulatov and co-workers was used. 3 TiCl4 (0.98 mL, 8.9 mmol) was added dropwise to a suspension of zinc powder (1.16 g, 17.9 mmol) in dry THF (370 mL). The resulting mixture was stirred under reflux for 1.5 h and subsequently, compound 2 (0.75 g, 1.8 mmol) in dry THF (30 mL) was added to the refluxing mixture over 3 h by syringe pump. After the addition was completed, the mixture was stirred under reflux for a further 1.5 h. The mixture was then allowed to cool to rt, treated with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford (Z)-3 (yield n.d.) as a yellow oil, which was submitted to the next reaction step without further purification. NMR spectroscopic data was identical to that previously reported. 3

NMR dilution experiment of (E)-1
A 1.68 mM solution of (Z)-1 in degassed DMSO-d6 was irradiated with 365 nm light until (E)-1 was fully formed (10 min). Subsequently, 0.5 mL of DMSO-d6 was added three times and after every dilution a 1 HNMR spectrum was recorded.

ITC titration experiments
The titrations were carried out in dry acetonitrile at 25 o C. For the titration with (Z)-1, a 1.20 mM solution was prepared. For (E)-1, a 1.26 mM solution of (Z)-1 was prepared and the sample was irradiated in a 1 mm quartz cuvette until UV-Vis spectroscopy confirmed full conversion

Single crystal X-ray crystallography
All reflection intensities were measured at 110(2) K using a SuperNova diffractometer (equipped with Atlas detector) with Cu Kα radiation (λ = 1.54178 Å) under the program CrysAlisPro (Version CrysAlisPro 1.171.39.29c, Rigaku OD, 2017). The same program was used to refine the cell dimensions and for data reduction. The structure was solved with the program SHELXS-2018/3 (Sheldrick, 2018) and was refined on F 2 with SHELXL-2018/3 (Sheldrick, 2018). Analytical numeric absorption correction based using a multifaceted crystal was applied using CrysAlisPro. The temperature of the data collection was controlled using the The structure is mostly ordered. The atom O3 is disordered over two positions, and the occupancy factor of the major component of the disorder refines to 0.635(4). Figure S23. Displacement ellipsoid shown at the 50% probability level of (E)-1.

Geometry optimization by DFT
Input geometries were generated using ArgusLab. 6 For the energy minimization of (M)-(E)-1⊂Cl -, the single crystal X-ray structure of (M)-(E)-1 was modified and used as the starting geometry. For (P)-(Z)-1⊂Cl -, the calix [4]pyrrole-alkyl and stiff-stilbene-CO2Me fragments were generated and energy minimized first, after which the latter fragment was positioned on top of the first fragment. The Gaussian 09 program 7 was used for further geometry optimization.
Initially, energy minimizations were performed at the semi-empirical PM3 and the DFT B3LYP/STO3G levels of theory using tight convergence criteria. Subsequently, the lowest energy geometries were optimized at the DFT B3LYP/6-31G+(d,p) level of theory using an IEFPCM MeCN solvation model. The DFT-optimized geometry was found to have zero imaginary frequencies. Table S2. Cartesian coordinates of (P)-(Z)-1⊂Cl -.   Table S3. Cartesian coordinates of (M)-(E)-1⊂Cl -.