Contra-Thermodynamic Catalysis and Fluorine Sculpting; Two Counter Cultural Approaches to Synthesis

Project Summary/Abstract The objectives of this proposal are two-fold and include the development and conceptual advancement of contra-

thermodynamic catalysis and fluorine sculpting. The realization of both objectives will elevate the field of synthesis and

positively impact human health through the development of tools for synthesis and chemical biology. While at first blush the directions appear disparate, they both rely heavily on visible light photocatalysis. However, they deviate from one another in the manner in which the excited state photocatalyst is quenched. One by triplet sensitization (Dexter energy

transfer), and the other by SET to or from an excited state catalyst.

Traditional catalysis has the effect of lowering energy barriers and facilitating reactions but ultimately does not alter the

thermodynamics (or spontaneous direction) of the reaction. Our long term objectives are to develop strategies to realize a system that makes formerly impossible, or endergonic, synthesis possible in addition to enabling exergonic synthesis.

Achieving this objective, will result in new tools for the study of large molecules, new synthetic methods. Achieving this

objective will require the development of reactions which are not subject to the principles of microscopic reversibility, i.e. irreversible reactions that can serve to pump energy into the system, and the ability to harness and store the energy thermodynamic currency that can be used to drive reactions. More tangibly we seek to leverage the cis-to-trans

photoisomerization of cycloalkenes to: identify energy pumping reactions, define an energetic currency, and develop

strategies to spend the energetic currency to drive reactions that would be otherwise impossible. Realizing these objectives is expected to both enable synthesis via the development of new endergonic (neglecting the photon energy) reactions and methods as well as the development of biological tools that capitalize on the available energy and the spatio-temporal

controlled associated with light activated processes.

The second direction of this proposal also involves an unorthodox approach to synthesis. Like no other element, fluorine has the ability to modulate the properties of a molecule and its behavior within the human body. Fluorine incorporation

into pharmaceuticals has seen exponential growth in recent years, and yet our synthetic capability to obtain organofluorines

is surprisingly limited. Owing to fluorine’s location on the periodic table, the selective installation of C–F bonds are

exceptionally challenging. Fluorine sculpting is an alternative approach to organofluorine synthesis that begins with a low

cost perfluoroarene and selectively carves out the desired high-value organofluorine. It has shown great promise; providing rapid access to organofluorines. Our long term objective is to advance the concept of fluorine sculpting and provide

expanded access to organofluorines of unprecedented structural complexity. This newfound ability is expected to result in greater understanding of the role fluorine plays in molecules of interest to human health.