A new photocage is proposed, based on ketoprofen-derived compounds and mediated by carbanions. The new photocage has significant advantages over the widely used o-nitrobenzyl derivatives, including aqueous compatibility, faster photorelease, higher quantum yield, and innocuous byproducts. The photorelease of ibuprofen illustrates the properties of the new photocage.

[reaction: see text]. Photolysis of 3-(hydroxymethyl)benzophenone (1) in aqueous solution (pH < 3) results in clean formation of 3-formylbenzhydrol (2) at dilute (<10(-4) M) conditions. Evidence suggests that the highly efficient (Phi approximately 0.6) reaction involves a unimolecular mechanism and an overall formal intramolecular photoredox process, which requires electronic communication between the 1,3-positions of the benzene ring, an unprecedented example of the photochemical meta effect. The photoredox reaction was not observed in organic solvents, where only photoreduction of the benzophenone moiety was observed.

The photodegradation of nonsteroidal anti-inflammatory drugs (NSAIDs), a class of medications that includes aspirin and ibuprofen, has generated considerable interest since the 1990s, largely because of the phototoxic and photoallergic effects that frequently accompany their therapeutic use. Among NSAIDs, ketoprofen, which contains a benzophenone chromophore, has been extensively studied, reflecting both its notorious adverse effects and the fascination that photochemists have with benzophenone. The photochemistry of ketoprofen involves the intermediacy of an easily detectable carbanion with a remarkable lifetime of 200 ns in water; its life expectancy can in fact be extended to minutes under carefully controlled anhydrous conditions. Over the past decade, we have used some key properties of the ketoprofen carbanion to conduct mechanistic studies on carbanions under various conditions. In particular, its ease of photogeneration provides the temporal control required for kinetic studies, which, combined with its long lifetime and readily detectable visible absorption, have enabled extensive laser flash photolysis work. These studies have led to an intimate understanding of the reaction dynamics for carbanions in solution, including the determination of absolute rate constants for protonation, S(N)2, and elimination reactions. Together they provide excellent exemplars of reactivity patterns that today are part of all introductory curricula in organic chemistry and illustrate the fundamentals of nucleophilic substitution paradigms. More recently, we have begun to exploit the photochemistry of ketoprofenate and have developed the ketoprofenate photocage, a valuable tool for the photocontrolled cleavage of protecting groups and concomitant drug release. The photorelease has been illustrated with ibuprofen, among many other molecules. These photocages have been further improved with the use of the xanthone chromophore; the goal is the release of antiviral agents taking advantage of the improved UVA absorption of xanthone (xanthonate photocages). In this Account, we survey our work of the past few years on the photochemistry of ketoprofen and related chromophores. Beginning with studies on the phototoxicity of ketoprofen, we have made the journey to new prodrug candidates, unraveling mechanistic elements of aroyl-substituted benzyl carbanions along the way.

The photochemistry of 1,1′-bi-2-naphthol (BINOL, 5) has been studied in aqueous solution and found to undergo rapid deuterium incorporation at the 4 and 5 positions (in D2O-CH3CN). All data is consistent with exchange arising via a formal excited state intramolecular proton transfer (ESIPT) from the naphtholic OH to the 4 and 5 positions of the other ring to give quinine methides (QMs) 8 and 9, respectively, both of which subsequently revert to starting material. Photolysis of enantiomerically pure (+)-5 in D2O-CH3CN resulted in racemization concurrent with deuterium incorporation. This is strong evidence to indicate that photoracemization of BINOL is a direct result of ESIPT, in keeping with the invocation of planar QM intermediates. Prolonged irradiation also gave a ring-closed product that is assigned as dihydrobenzoxanthene 7, based on NMR and UV–vis data, and in analogy to known reactions of similar biaryl systems initiated by ESIPT. The formation of 7 is believed to arise via initial ESIPT from the naphtholic OH to the 7 position of the other naphthol ring generating an o-quinone methide intermediate that subsequently undergoes exclusive electrocyclic ring closure to give 7. The deuterium exchange and photocyclization reach maximum quantum efficiency at ~8 mol/L water (in CH3CN). A “water relay” mechanism for ESIPT is proposed that is consistent with the need for water in the photochemical deuterium exchange, racemization, and formation of 7. The photostability and photoracemization of other related BINOL asymmetric catalysts in water should be a concern based on the reported results herein.Key words: BINOL, ESIPT, photoprotonation, photoracemization, photocyclization, quinone methide.

[reaction: see text] Irradiation of 2- and 4-xanthone acetic acid in aqueous buffer (pH 7.4) leads to efficient (Phi = 0.67 and 0.64, respectively) photodecarboxylation to give the corresponding methyl products, consistent with an intermediate benzylic carbanion. Fluorescence and laser flash photolysis (LFP) studies suggest singlet state reactivity, which is unusual for aromatic ketones. 3-Xanthone acetic acid is photoinert under the same conditions. The results suggest that the reactive xanthone acetic acids are promising precursors for carbanion-mediated photocages.