Rethinking Uncaging: A New Antiaromatic Photocage Driven by a Gain of Resonance Energy

Abstract

Photoactivatable compounds for example photoswitches or photolabile protecting groups (PPGs, photocages) for spatiotemporal light control, play a crucial role in different areas of research. For each application, parameters such as the absorption spectrum, solubility in the respective media and/or photochemical quantum yields for several competing processes need to be optimized. The design of new photochemical tools therefore remains an important task. In this study, we exploited the concept of excited-state-aromaticity, first described by N. Colin Baird in 1971, to investigate a new class of photocages, based on cyclic, ground-state-antiaromatic systems. Several thio- and nitrogen-functionalized compounds were synthesized, photochemically characterized and further optimized, supported by quantum chemical calculations. After choosing the optimal scaffold, which shows an excellent uncaging quantum yield of 28 %, we achieved a bathochromic shift of over 100 nm, resulting in a robust, well accessible, visible light absorbing, compact new photocage with a clean photoreaction and a high quantum product (ϵ⋅Φ) of 893 M^-1 cm^-1 at 405 nm.

Keywords: Baird's rule; excited state aromaticity; photochemistry; photolabile protecting groups; substituent effects.

Figure 1

Uncaging concepts: a) nitrogen‐based push–pull systems (oNB, NDBF), which uncage via an aci‐nitro‐ and subsequent benzisoxazole intermediate, which is shown in the middle. b) Dye‐inspired systems (coumarin, BODIPY) with electron density donation into an antibonding molecular orbital. c) Excited‐state‐aromaticity assisted uncaging investigated here. (LG=leaving group, Nu=nucleophile, R=H, ethynyl, phenyl).

Figure 2

a) Calculated vertical excitation energies of cationic species in water. b) Measured absorption spectra and molar absorption coefficients of the various basic scaffolds and their derivatives with meso‐substitution.

Scheme 1

Synthesis of the para‐thio‐cyclopentadithiophene derivatives: i) NBS, THF, 0 °C, 30 min ; ii) arylboronic acid, Pd(PPh₃)₄, K₂CO₃, toluene/EtOH/H₂O, 100 °C, 24–72 h ; iii) NaBH₄, EtOH/MeOH, RT, 10–30 min ; iv) ethynyl/phenyl MgBr, abs. THF, 0 °C – RT, 2–24 h ; v) Ac₂O, pyridine, room temperature, overnight ; vi) 1,1’‐carbonyldiimidazole, abs. DCM, mw, 45 °C, 60 min and after purification 5‐hydroxytryptamine (5‐HT) hydrochloride, abs. DMF, mw, 50 °C, 60 min. For further experimental details see Supporting Information (Supporting Information).

Figure 3

Absorption spectra and molar absorption coefficients of the various symmetrically and asymmetrically α‐substituted para‐thio compounds. Compound 1a is shown as comparison.

Figure 4

Photolysis for irradiation at 365 nm (11.2 mW) of compound 22 (squares, 37.6 nmol, OD₃₆₅=0.26) and released serotonin 23 (5‐HT, circles) in 1 M PBS buffer with 36 % DMSO at 25 °C.

Figure 5

(a) Light‐induced difference absorption spectra of para‐thio compounds in MeOH before and after 8 minutes of illumination at 365 nm for 1 a, 11 a and 22 and at 420 nm for 20. (b) Absorption spectra of 1 a before and after 8 minutes of illumination at 365 nm (normalized to the main peak of the dark spectrum @ 327 nm).