The Catalyst-Controlled Regioselective Functionalization of Aromatics

With the support of the Chemical Synthesis and Chemical Catalysis Programs in the Division of Chemistry, Professor Jeffrey Gustafson of San Diego State University is studying new approaches to modifying fine chemicals and pharmaceutical intermediates. Aromatic compounds are common building blocks throughout synthetic and pharmaceutical chemistry, however the chemical reactions of aromatic molecules to give value-added commodities is often hindered because it results in the generation of multiple products, necessitating costly purification sequences.

Dr. Gustafson and his team are studying new chemical reactions aimed at controlling the selective modification of both simple and complex aromatic scaffolds, ultimately resulting in more efficient synthetic strategies towards molecules of interest to the academic and pharmaceutical communities. In addition to providing training in organic chemistry for graduate and undergraduate students, this project also impacts the education more broadly in that it proposes to incorporate Virtual Reality experiences to aid students in the 3-dimensional visualization of molecules.

Virtual Reality will also be utilized in outreach programs aimed at SDSU’s general population, as well as local high schools and community colleges.

Professor Gustafson and his team of collaborators and students design ‘organocatalysts’ that affect the regioselective C-H functionalization of simple and complex aromatics through electrophilic aromatic substitution and related aromatic radical functionalization reactions. These transformations traditionally yield poor regioselectivities, often preventing them from being adopted as viable synthetic strategies, particularly in more complex settings.

For the addition of electrophiles into aromatics, the Gustafson group designs bifunctional Lewis basic catalysts that intercept and direct the electrophile, or electrophilic radical to a specific position. The Gustafson group is also exploring similar strategies for the functionalization of aromatics with nucleophiles in the context of nucleophilic aromatic substitution and vicarious nucleophilic substitution.

For the regioselective addition of nucleophiles to aromatics, they utilize a broad array of classic organocatalytic strategies including cation directed catalysis and hydrogen-bonding catalysis. The ability to site-selectively modify simple and complex aromatic systems greatly simplifies the syntheses of molecules and opens the door for these chemistries to be used in the context of late-stage functionalization strategies.

In order to allow for the design of better and more efficient catalysts, the Gustafson group is also performing mechanistic studies with collaborators in computational chemistry and electrochemistry. The site-selective modification of complex intermediates that this work enables has the potential to transform how the late-stage structural optimization of pharmaceuticals, materials and other functional molecules are carried out.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.