Photochemical Strategies to Decage Organic Compounds

Citation

Regan, Clinton Joseph (2016) Photochemical Strategies to Decage Organic Compounds. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9C53HTF. https://resolver.caltech.edu/CaltechTHESIS:06082016-025813806

Abstract

This dissertation primarily describes new photochemical decaging systems that are activated by visible light. Such systems are expected to be useful as chemical biology tools or as drug delivery systems in a therapeutic context. A primary motivation for the development of these systems is for the treatment of traumatic brain injury, where a decaging strategy would require activation by low energy near-infrared light. Since most photochemical reactions are initiated using ultraviolet light, a primary challenge in developing these systems is overcoming the low energy efficiency of typical photochemical processes. Initial model systems are designed to address this challenge through use of the photoacidic effect. While many hydroxyaromatic compounds are known to become much more acidic in their excited state, the effect has never been utilized to accelerate an acid-catalyzed chemical reaction. Investigations are carried out in Chapter 2 to probe for the possibility of this unprecedented photochemistry. Ultimately, the results suggest that the acid-catalyzed decaging processes are too slow to be useful in a photochemical context. This finding led to the development of decaging strategies that utilize a phototriggered approach. In Chapter 2, a system is described where decaging occurs through rapid lactonization of a photogenerated hydroquinone. Formation of the hydroquinone results from an intramolecular photoreduction of the benzoquinone due to activation by violet light. Detailed mechanistic studies carried out on this system ultimately establish the importance of the triplet state in the overall reaction. While most benzoquinones form the triplet with unit efficiency, the system studied here forms the triplet in less than 10% yield. However, when the triplet is formed, it proceeds cleanly to products with high efficiency. Although the benzoquinone system has been useful for mechanistic studies, its application as a therapeutic decaging strategy has been challenging. Efforts to extend the wavelength toward the near-infrared have led to loss in photochemical reactivity. Ultimately, this challenge was overcome through the use of methylene blue. Methylene blue is a common organic dye that is activated by red light and undergoes photoreduction to a colorless form, similar to the benzoquinone systems. In Chapter 4, derivatives of methylene blue that are capable of undergoing photoreductive cyclization are designed and synthesized. Ultimately, these systems are found to be capable of rapidly decaging alcohols using red light.

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