Fluorinated Azobenzenes Switchable with Red Light

Abstract

Molecular photoswitches triggered with red or NIR light are optimal for photomodulation of complex biological systems, including efficient penetration of the human body for therapeutic purposes ("therapeutic window"). Yet, they are rarely reported, and even more rarely functional under aqueous conditions. In this work, fluorinated azobenzenes are shown to exhibit efficient E→Z photoisomerization with red light (PSS_660nm >75 % Z) upon conjugation with unsaturated substituents. Initially demonstrated for aldehyde groups, this effect was also observed in a more complex structure by incorporating the chromophore into a cyclic dipeptide with propensity for self-assembly. Under physiological conditions, the latter molecule formed a supramolecular material that reversibly changed its viscosity upon irradiation with red light. Our observation can lead to design of new photopharmacology agents or phototriggered materials for in vivo use.

Keywords: azobenzene; photoswitches; red-light photoisomerization; therapeutic window.

Figure 1

a) Photochromic compounds 1 a‐c are efficient low‐MW supramolecular hydrogelators (as E‐isomers). Upon optimization of their structure we discovered that compounds 4 and 5 are capable of photoisomerization with red light (>630 nm), which expands the scope of their potential in vivo applications; b) UV‐Vis spectra of the bis‐aldehyde 5 (38 μM in MeCN). The E→Z photoisomerization is more efficient with red (λ_max=660 nm, cut‐off filter <630 nm PSS₆₆₀=82 % Z‐ 5) than with green light (λ_max=532 nm, PSS₅₂₃=67 % Z‐ 5). (see also Table 1); inset: optical demonstration of the photochromism of 5; 407 nm–9 mW/cm², 523 nm–7 mW/cm², 660 nm (with filter)–56 mW/cm².

Figure 2

Band separation of the E‐isomers (black lines) and Z‐isomers (red lines) of the compounds 2–7 in the visible light range (1.5 mM solutions in d₆‐DMSO). Insets show the magnified respective band separation in the range 550–700 nm. In all cases, the y‐axis depicts the molar attenuation coefficient ϵ (M⁻¹ cm⁻¹). The spectra of pure Z‐isomers (red lines) have been calculated from spectra registered for samples irradiated 15 min with 523 nm LED with concomitant determination of the E/Z‐ratio by ¹H NMR (procedure described in Supporting information, pages S77‐S92, Figures S12–S40).

Figure 3

Molecular modelling of the HOMO‐LUMO gap of the bis‐alcohol 3 and the corresponding bis‐aldehyde 5 (PBE0‐D3/def2‐TZVP level of theory). The HOMO‐LUMO gap of 3.670 eV for the E‐5 vs. 4.015 eV for the E‐ 3 (see Table S3) corroborates with the experimentally observed bathochromic shift of the absorption maximum in the E‐5. EWG aldehyde substituents in 5 stabilize all orbitals (π, n, and π*) in comparison to 3. However, the stabilization is most pronounced for the π* (LUMO) orbital, most likely due to the extended conjugation in the π‐orbital system depicted in the orbital contour.

Figure 4

The molecule 8 consisted of two gel‐forming cyclic dipeptide motifs linked with the conjugated TFAB photochromic motif. The gel‐like material formed from E‐ 8 in aqueous conditions can be reversibly dissipated to non‐viscous liquid with red light. This, in turn, solidifies upon thermally induced back‐isomerization.

Figure 5

Electron microscopy of the supramolecular assemblies composed from 8 (1 wt%) under aqueous conditions (Ringer's solution+1 % lead citrate). a) (A) the structure visible as multiple μm long and nm thick fibers; (B) after irradiation at 660 nm (50 min) ‐ the quantity of the described fibers decreases and smaller structures in the nm‐scale are formed; (C) regeneration of fibers occurs after boiling the irradiated gel; (D) upon 1 : 10 dilution of (B) and irradiation at 660 nm – only small fibers visible. b) freeze‐dried samples of hydrogels prepared from 1 wt% 8 in Ringer's solution (E) (no network visible), or from 2 wt% 8 in in water (F) (sponge‐like network revealed); Scalebars: (A) top – 2 μm, bottom 1 μm, (B) – 1 μm, (C) – 2 μm, (D) – 400 nm, (E),(F) – see also Figures S42‐S56.