Fluorinated photoremovable protecting groups: the influence of fluoro substituents on the photo-Favorskii rearrangement (original) (raw)
Related papers
Canadian Journal of Chemistry, 2011
A broadly based investigation of the effects of a diverse array of substituents on the photochemical rearrangement of p-hydroxyphenacyl esters has demonstrated that common substituents such as F, MeO, CN, CO 2 R, CONH 2 , and CH 3 have little effect on the rate and quantum efficiencies for the photo-Favorskii rearrangement and the release of the acid leaving group or on the lifetimes of the reactive triplet state. A decrease in the quantum yields across all substituents was observed for the release and rearrangement when the photolyses were carried out in buffered aqueous media at pHs that exceeded the ground-state pKa of the chromophore where the conjugate base is the predominant form. Otherwise, substituents have only a very modest effect on the photoreaction of these robust chromophores.
The Journal of Organic Chemistry, 2009
Three new trifluoromethylated p-hydroxyphenacyl (pHP) caged γ-aminobutyric acid (GABA) and glutamate (Glu) derivatives have been examined for their efficacy as photoremovable protecting groups in aqueous solution. By replacing hydrogen with fluorine, e.g., a m-trifluoromethyl or a mtrifluoromethoxy vs. m-methoxy substituents on the pHP chromophore, modest increases in the quantum yields for release of the amino acids GABA and glutamate were realized as well as improved lipophilicity. The pHP triplet undergoes a photo-Favorskii rearrangement with concomitant release of the amino acid substrate. Deprotonation competes with the rearrangement from the triplet excited state and yields the pHP conjugate base that, upon reprotonation, regenerate the starting ketoester, a chemically unproductive or "energy wasting" process. Employing picosecond pump-probe spectroscopy, GABA derivatives 2 -5 are characterized by short triplet lifetimes, a manifestation of their rapid release of GABA. The bioavailability of released GABA at the GABA A receptor improved when the release took place from m-OCF 3 (2) but decreased for m-CF 3 (3) when compared with the parent pHP derivative. These studies demonstrate that pK a and lipophilicity exert significant but sometimes opposing influences on the photochemistry and biological activity of pHP phototriggers.
New phototriggers: extending the p-hydroxyphenacyl pi-pi absorption range
Organic letters, 2000
Introducing 3-methoxy or 3,5-dimethoxy substituents on the 4-hydroxyphenacyl (pHP) photoremovable protecting group has been explored with two excitatory γ-amino acids, L-glutamic acid and γ-amino butyric acid (GABA). These substituents significantly extend the absorption range of the pHP chromophore, e.g., the tail of absorption bands of 2a,b extend above 400 nm, well beyond the absorptions of aromatic amino acids and nucleotides. Irradiation releases the amino acids with rate constants of ∼10 7 s -1 and appearance efficiencies (Φ app ) of 0.03−0.04. The photoproducts are formed through the pHP excited triplet and are primarily products of photoreduction and photohydrolysis. 1a,b also rearranged to the phenylacetic acid 3.
Journal of the American Chemical Society, 2000
In our search for a more versatile protecting group that would exhibit fast release rates for peptides, we have designed and developed the p-hydroxyphenacyl (pHP) group as a new photoremovable protecting group. We report the application of this protecting group for the dipeptide Ala-Ala (1) and for the nonapeptide bradykinin (2), two representative peptides that demonstrate C-terminus "caging" and photorelease. The synthesis of these p-hydroxyphenacyl esters was accomplished in good yields by DBU-catalyzed displacement of bromide from p-hydroxyphenacyl bromide. As in the case of caged γ-amino acids 11 (pHP glu) and 12 (pHP GABA) and caged nucleotide 17 (pHP ATP) reported earlier, 1,2 irradiations of the p-hydroxyphenacyl esters of 1 and 2 actuate the release of the peptides with rate constants that are consistently greater than 10 8 s-1 and appearance efficiencies (Φ app) that range from 0.1 to 0.3. Release of the substrate is accompanied by a deep-seated rearrangement of the protecting group into the near-UV silent p-hydroxyphenylacetic acid (6). Quenching studies of pHP Ala-Ala (7) with either sodium 2-naphthalenesulfonate or potassium sorbate gave good Stern-Volmer kinetics yielding a rate constant for release of 1.82 × 10 8 s-1. Quenching of the phosphorescence emission from pHP Ala-Ala (7, E T) 70.1 kcal/mol) and pHP GABA (12, E T) 68.9 kcal/mol) were also observed. The biological efficacy of bradykinin released from pHP bradykinin (9) was examined on single rat sensory neurons grown in tissue culture. A single 337 nm flash (<1 ns) released sufficient bradykinin from the p-hydroxyphenacyl protected nonapeptide to activate cell-surface bradykinin receptors as indicated by a rapid increase in the intracellular calcium concentration. A selective antagonist of type 2 bradykinin receptors blocked the biological response. From these results, it is apparent that flash photolysis of p-hydroxyphenacyl protected peptides provides a powerful tool for the rapid and localized activation of biological receptors.
2009
The p-hydroxyphenacyl (pHP) chromophore is an attractive addition to the family of photoremovable protecting groups in chemistry and biology. Substituent effects on the pHP moiety were explored using cyano substituent at otho and para positions, employing GABA and acetate leaving groups. The quantum yield for GABA release from 3-cyano pHP GABA in water was substantially higher (0.42) than that for the parent. Two novel applications of pHP photochemistry were demonstrated. A light sensitive release of a fluorophore from an almost non-fluorescent pHP fluorophore quencher ensembles resulted in regenerated fluorescence upon exposure to ultraviolet radiation. Carbazole as the quencher leaving group drove the photorelease toward an electron-transfer, radical mechanism. A second application demonstrated that fluorophilic pHP derivatives obtained by attaching a fluorous chain, could be employed to separate the products, often in 95-100% yield, after photorelease from the cage by using fluorous solid phase extraction and fluorous liquid-liquid extraction separation technology. iv TO MY DAD v Acknowledgment I owe my deepest gratitude to several people. Their help and inspiration greatly contributed to the successful completion of this work. First I would like to extend my most heartfelt appreciation to Dr. Givens. He is an exceptional teacher and a mentor. His encouragement, guidance and support led to my better understanding of the subject, while his kindness and thoughtfulness made my graduate life endurable. It is also a pleasure to extent my gratitude to the Givens family for their kind hospitality.
Applications of p-hydroxyphenacyl (pHP) and coumarin-4-ylmethyl photoremovable protecting groups
Photochemical & Photobiological Sciences, 2012
Most applications of photoremovable protecting groups have used o-nitrobenzyl compounds and their (often commercially available) derivatives that, however, have several disadvantages. The focus of this review is on applications of the more recently developed title compounds, which are especially well suited for time-resolved biochemical and physiological investigations, because they release the caged substrates in high yield within a few nanoseconds or less. Together, these two chromophores cover the action spectrum for photorelease from >700 nm to 250 nm. † This paper is part of a themed issue on photoremovable protecting groups: development and applications.
Synthesis and photochemistry of pH-sensitive GFP chromophore analogs
Tetrahedron Letters, 2011
a b s t r a c t GFP chromophore analogs (7a-e, 8, and 10a,b) containing 2-thienyl-, 5-methyl-2-furyl-, 2-pyrryl, and 6methyl-2-pyridyl-groups were synthesized and their fluorescence spectra recorded in the pH range 1-7. NMR studies showed that protonation of 8 (2-thienyl system) inhibited photoisomerization (Z-E) about the exocyclic double bond but that protonation of 7c (E + Z) (2-pyrryl system) gave only 7cE. Fluorescence studies revealed enhancement of fluorescence intensity of 7c and 7b,e (furyl system) below pH 2.5 and gave a similar result for 10a (pyridyl system) below pH 6. Quantum yields at pH 1 were low, probably due to excited state proton transfer (ESPT).
2-Hydroxyphenacyl ester: a new photoremovable protecting group
Photochemical & Photobiological Sciences, 2012
A 2-hydroxyphenacyl moiety absorbing below 370 nm is proposed as a new photoremovable protecting group for carboxylates and sulfonates. Laser flash photolysis and steady-state sensitization studies show that the leaving group is released from a short-lived triplet state. In addition, DFT-based quantum chemical calculations were performed to determine the key reaction steps. We found that triplet excited state intramolecular proton transfer represents a major deactivation channel. Minor productive pathways involving the triplet anion and quinoid triplet enol intermediates have also been identified.
Dyes and Pigments, 2013
The synthesis, chemical characterization and optical studies of three novel fluorene derivatives is reported. These compounds comprise a DeAeD architecture with fluorene moieties as donor groups and fluorenone or benzothiadiazole derivatives as acceptor groups. Theoretical analysis confirmed the existence and the nature of two principal electronic transitions (p / p* and intramolecular charge transfer). Spectroscopic studies in solution revealed that the intramolecular charge transfer character, and in turn the two-photon activity i.e., the fluorescence induced by two-photon absorption, is strongly affected by solvent polarity. The influence of specific solventesolute interactions over emission properties was also studied through LipperteMataga plot. Evaluation of the two-photon absorption cross-sections, gave a maximum value of 105 GM (1 GM ¼ 10 À50 cm 4 s) in toluene and a minimum value of 23 GM in THF solutions at 750 nm for the fluorenone derivative, a molecule with poor intramolecular charge transfer character and thus weak two-photon absorption; however the benzothiadiazole derivative, with stronger intramolecular charge transfer transition, produced a maximum value of 1000 GM in THF and a minimum value of 236 GM in methanol. Fluorescence quantum efficiency of these compounds was also affected by the medium, with fluorescence quenching in protic solvents such as methanol due to specific solvent interactions (i.e., hydrogen-bonding). Nevertheless, in a more polar medium such as water, nanoaggregates synthesized from the benzothiadiazole derivative exhibited good two-photon activity, i.e., w500 GM and fluorescence quantum efficiency of 0.83. Furthermore, these nanoaggregates exhibited more resistance against photodegradation processes than any of the organic solutions tested.
One- and two-photon photochemical stability of linear and branched fluorene derivatives
Journal of Photochemistry and Photobiology A: Chemistry, 2006
Photochemical decomposition of the fluorene derivatives, 4,4 - [[9,9-bis(ethyl)-9H-fluorene-2,7-diyl]di-2,1-ethenediyl]bis(N,N-diphenyl) benzeneamine (1) and 4,4 ,4 -[[9,9-bis(ethyl)-9H-fluorene-2,4,7-triyl]tri-2,1-ethenediyl]tris(N,N-diphenyl)benzeneamine (2), were investigated in pTHF under one-(UV-lamp) and two-photon (femtosecond laser) excitation. The quantum yields of the photoreactions were determined by absorption and fluorescence methods in air-saturated and deoxygenated solutions. The values of quantum yields were in the range (1.5-2.1) × 10 −6 for both types of irradiation, indicating that similar photobleaching processes occur under both one-and two-photon excitation. Deoxygenation of pTHF increased photostability of 1 and 2 by over an order of magnitude relative to air-saturated solutions. A cursory examination of some of the photochemical products (analyzed by HPLC and APCI-MS spectroscopy techniques) revealed an important role of ground state oxygen in the photoreactions, since no oxidation products were observed upon irradiation in the presence of the well know singlet oxygen sensitizer methylene blue.