Phototriggered Release of a Leaving Group in Ketoprofen Derivatives via a Benzylic Carbanion Pathway, But not via a Biradical Pathway

Abstract

2-Acetoxymethyl-2-(3-benzoylphenyl)propionic acid (KP-OAc) was used as a model to elucidate the solvent-mediated photochemistry mechanism of Ketoprofen (KP). In solutions with a low concentration of water, KP-OAc exhibits a benzophenone-like photochemistry, reacting with water molecules through some reaction to form a ketyl radical intermediate. In neutral solutions with a high concentration of water or acidic solutions, KP-OAc undergoes a photodecarboxylation reaction with the assistance of water molecules or with the catalysis of perchloric acid to directly generate a biradical intermediate that cannot induce the phototrigger reaction to release the AcO(-) group. Therefore, the lifetime of the biradical intermediate of KP-OAc is almost same as that of the biradical intermediate formed from KP in the same kinds of solutions. However, the photodecarboxylation of KP-OAc in phosphate buffer solution directly produces the benzylic carbanion intermediate, which can induce the phototrigger reaction to release the AcO(-) group. Therefore, the lifetime of the biradical intermediate of KP-OAc is significantly shorter than the lifetime of the biradical intermediate of KP in phosphate buffer solution. Interestingly, the investigation of the photochemistry of KP-OAc not only verifies the solvent-mediated photochemistry mechanism of KP but also provides some new insight into the potential of using this kind of platform for phototrigger applications. The biradical intermediate is not the key species leading to the phototrigger reaction but the benzylic carbanion species is the key reactive intermediate that can mediate the phototrigger reaction of KP-OAc. Therefore, a change in the pH of the solutions can be utilized to switch on and switch off the photorelease reactions of KP derivative phototrigger compounds.

Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process

“…Furthermore, the photodissociation will produce highly reactive radical species able to react with biological macromolecules. In addition, and coherently with our scenario, photodissociation of triplet state protonated ketoprofen 51 , 52 , following proton transfer from the carboxylic to the carbonyl group has been reported 80 . However, differently from benzophenone, and due to the influence of the negative charge of its salt form, ketoprofen only exhibits metastable interactions with DNA.…”

Substituent Effects on the Photodeprotection Reactions of Selected Ketoprofen Derivatives in Phosphate Buffered Aqueous Solutions

“…An absorption band at 340 nm gradually decays to 328 nm while another absorption band at 575 nm grows in and shifts to 530 nm. This process is associated with intersystem crossing (ISC) from S 1 to T 1 according to its similarity to results from previous fs-TA studies of ketoprofen derivatives 21 . Then the decarboxylation reaction takes place in the triplet state as is shown in Fig.…”

“…3(b) which demonstrates that the triplet with its maximum absorption bands at 530 nm and 328 nm decay while a longer wavelength broad absorption band at 610 nm grows in at the cost of triplet state from 92 ps to more than 2500 ps. The isosbestic point for this reaction clearly indicates that the KP-ibuprofen triplet anion is the precursor of the 610 nm species which is readily assigned to a KP carbanion species 21 . The corresponding kinetics of the transient absorption at 530 nm and 610 nm are shown in Fig.…”

“…For example, this photodeprotection platform denoted as “ketoprofenate derivatives” (KP-X) have many advantages such as cleanness and efficiency for release of the leaving group, good aqueous solubility and inert and non-absorbing photoproducts. Recently, KP-OAc, one of this new class of KP-X compounds has been used as a model to investigate the highly efficient phototrigger reaction in phosphate buffered aqueous solutions, (PBS) mediated by a carbanion intermediate but not taking place in an acid-assisted decarboxylation reaction 21 22 . However, the mechanism of ketoprofenate release for different substituent groups has not been so well reported and much work is still left to be done to explore how the nature of the leaving groups can influence the photodeprotection reactions of ketoprofenate derivatives.…”

Photodecarboxylation of Adamantane Amino Acids Activated by Phthalimide

“…[9][10][11][12] Photocatalytic decarboxylation reactions have recently experienced a revival in organic synthesis, [13][14][15][16][17][18] and significant progress has been made to elucidate the photodecarboxylation reaction mechanism that leads to anionic species. [19][20][21][22][23][24][25][26][27][28] Photodecarboxylation can be initiated by the phthalimide chromophore in the triplet excited state, which acts as the electron acceptor in the photoinduced electron transfer (PET) reaction. [29,30] The PET-promoted decarboxylation by phthalimides has been used in macrocyclizations, [31] the cyclization of peptides, [32,33] photodecaging strategies, [34] and the enantioselective synthesis of benzodiazepines.…”