Fluorinated photoremovable protecting groups: the influence of fluoro substituents on the photo-Favorskii rearrangement

Abstract

To further explore the nature of the photo-Favorskii rearrangement and its commitment to substrate photorelease from p-hydroxyphenacyl (pHP), an array of ten new fluorinated pHP γ-aminobutyric acid (GABA) derivatives was synthesized and photolyzed. The effects of fluorine substitution on the chromophore and the photophysical and photochemical properties of these new chromophores were shown to be derived primarily from the changes in the ground state pK a of the phenolic groups. The quantum yields and rate constants for release are clustered around Φ dis = 0.20 ± 0.05 and k r = 8 ± 7 × 10 7 s −1 (H 2 O), respectively. The triplet lifetimes of the pHP GABA derivatives were concentrated in the range of 0.4-6.0 ns (H 2 O). The corresponding deprotonated conjugate bases displayed reduced efficiencies by 50% or more (one exception) and exhibited a weak fluorescence in pH 8.2 buffer. Pump-probe spectroscopy studies have further defined the rates of intersystem crossing and the lifetimes of the reactive triplet state of the fluoro pHP chromophore.

Competing Pathways in the Photo-Favorskii Rearrangement and Release of Esters: Studies on Fluorinated p-Hydroxyphenacyl-Caged GABA and Glutamate Phototriggers

“…In 1-octanol, 2 and 3 had quantum yields for disappearance of 0.14 and 0.10, respectively. In aqueous-organic mixed solvents, the quantum yields increased with increasing water content in accord with earlier observations with mixed acetonitrile:H 2 O solvent mixtures, 14,15,21,23 Typically, for biologically benign solvents like CH 3 CN or DMSO, the quantum yield for 2 increased by a factor of 4 upon addition of 10% (v:v) H 2 O, i.e., increasing from 0.03 in dry CH 3 CN to 0.12 in 10% H 2 O:CH 3 CN. Above 25% H 2 O, the quantum yields remained relatively constant.…”

“…As reported earlier, water plays a significant role on the rate and quantum yield. 21 For example, the triplet lifetime of pHP diethyl phosphate with its better leaving group, decreases dramatically as the proportion of water in acetonitrile is increased (Table 3 and Figure 4). 14,15,23a Nevertheless, the quantum yields for the disappearance of the pHP phosphate and appearance of the rearranged phenylacetic acid remain significantly below unity.…”

“…Benzyl protection of commercially available 4-bromo-2-trifluoromethylphenol ( 9 ) with BnBr/K 2 CO 3 /CH 3 CN, followed by acetylation with a Stille protocol 20 using Pd(PPh 3 ) 4 /tributyl(1-ethoxyvinyl)-stannane in toluene, and hydrolysis of the resulting enol ether gave the fluorinated acetophenone 10 . The Stille coupling of protected p -bromophenols to stannyl vinyl ethers served as a high yielding, general route for us to synthesize a variety of p- hydroxyacetophenones 21 as opposed to traditional acylation methodology. α-Bromination with dioxane dibromide in dichloromethane (DDB/CH 2 Cl 2 ), followed by esterification with N-Boc protected GABA and deprotection of the phenol and amine groups with Pd/C (10% w/w)/H 2 in EtOAc and 1:1 TFA/CH 2 Cl 2 , respectively, afforded CF 3 -pHP GABA ( 3 ) in 55% overall yield from 9 .…”

“…The carboxylate leaving group, e.g. GABA release, is less effective than phosphates, 5,14-16,21-23 for example, as expressed by the higher quantum yields for phosphate release. In fact, carboxylates are among the least efficient substrates (φ d = 0.04 – 0.20) we have reported.…”

Two-Photon Activation of p-Hydroxyphenacyl Phototriggers: Toward Spatially Controlled Release of Diethyl Phosphate and ATP

“…28,44,45 Preliminary work that is currently in progress suggests that the quantum efficiency for releasing phosphate esters like the ones studied here is similar, or possibly even larger, than for the protonated chromophore. Furthermore, both the extinction coefficient and the 2PA cross section increase upon deprotonation of the pHP chromophore, adding to the favorable properties of the conjugate base as a one-and two-photon PPG.…”