61st Annual Report on Research 2016

Our grant aimed to understand the mechanisms of aryl-alkyne ring-closure for molecules containing boron-nitrogen (azaborine) bonds. In previous work, attempting to improve the synthesis of BN-pyrene, we found that we could induce an alkyne cyclization at relatively low temperatures without the presence of a catalyst. ¹ This type of transformation is highly endothermic in the parent hydrocarbons. It was proposed that either low temperature carbene formation or electrocyclic closure could lead to improved routes to a number of azaborine bond containing polycyclic aromatic molecules. The mechanism had not been studied with azaborine molecules, and the low-temperature effect appears to be unique these systems. Through isotopic labeling and computational studies, we have been able to gain new insight into this unique closure.

During the first year of our funding we were able to develop an efficient method for isotopic labelling, synthesize isotopically labeled BN-pyrene, and begin computations to confirm our mechanistic hypothesis.² We discovered that not only did the mechanism differ from the process found in the hydrocarbon, but it also was drastically lower in energy.³ With this knowledge in hand, we have spent the second year (1) trying to design new molecules capable of harnessing this mechanism and (2) pursuing an interesting byproduct of one of these reactions.

(1) Developing New Azaborine Chemistry:

Upon finding that reaction barriers were lowered with the presence of boron-nitrogen bonds, we decided to design new structures capable of using this methodology. The fundamental structural motif for this mechanism is an alkyne adjacent to a polycyclic aromatic core containing an azaborine. Rather than limit to one target, we designed a versatile substrate N,N-bis(tolan)amine. Two approaches were used to make this molecule, but the most efficient proved to be a Buchwald-Hartwig coupling to produce N,N-bis(2-bromophenyl)amine. This versatile substrate can then undergo a double Sonagashira cross-coupling to produce the target. With two pendant alkynes, this structure can partake in a number of reactions in an effort to produce a library of polycyclic aromatic hydrocarbons. Our main goal was to insert a boron atom in the center to produce a helicene with an azaborine core. The results of this pursuit are more than just azaborines. We were able to observe several new products depending on our conditions. These included indoles and acridines, which inspired entirely new projects.

(2) Pursuing New Mechanistic Understanding:

One of the new findings was that certain conditions in the synthesis of bis(tolan)amine produced the fused aromatic amine acridine. We have been able to test a number of substrates and each produces acridine in appreciable yields. We do not yet understand this mechanism, but it appears to be an entirely new route to this type of molecule which is used extensively in imaging cells and other applications. We are currently optimizing the reacton and hope to investigate the mechanism more fully in the future.

Impact and Future Work:

This work supported four students over the past year, with two graduating in the spring of 2016. One started his graduate career in chemistry at the University of California – Los Angeles and the other pursuing a medical career. Both of these students presented at local and national conferences and their work with the mechanistic study has been submitted to a journal. The two remaining students worked throughout the summer and one is currently writing her work into a publication for submission later in the Fall of 2016. Both of these students have showed interest in attending graduate school in the future.

We continue to pursue results related to the new molecules and mechanisms with support from my department. Last year, I submitted a grant application for future work related to this concept and will revise the grant for another submission soon. The support of the Petroleum Research Fund has been vital to setting the foundational work in my laboratory and I will continue to build on that foundation for years to come.

References:

Underline indicates undergraduate author:

1. Wadle, J. J.; McDermott, L. B.; Fort, E. H. Microwave assisted synthesis of 10b-aza-10c-borapyrene. Tetrahedron Lett. 2014, 55, 445-447.

2. Gelinas, B. S.; Jaye, J. A.; Mattos, G. R.; Fort, E. H. Rapid and efficient desilylation and deuteration of alkynylpyridines. Tetrahedron Lett. 2015, 56, 4232-4233.

3. Jaye, J. A.; Gelinas, B. S.; McCormick, G. M.; Fort, E. H. Implications of the final ring closure to 10b-aza-10c-borapyrene on aryl-alkyne ring-closing mechanisms. Submitted.