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Reports: UR152993-UR1: Aromatic Donor-Acceptor Organocatalysis: Noncovalent Activation of Aryl Halides in Green Palladium Cross-Coupling Reactions

Joseph J. Reczek, PhD, Denison University

Over the past year, we have made several advances towards our overall goal of using aromatic donor-acceptor interactions (ADA) as organic co-catalysts in coupling reactions with aryl halides. Specifically, we are working to generate a general catalytic approach for facilitating the reaction of electron-rich (deactivated) aryl chlorides in Palladium-type cross-coupling reactions. We plan to lower the activation energy of the rate limiting oxidative addition step by adding an electron-poor aromatic co-catalyst. In aqueous solvents, the complementary electrostatics of the aromatics will lead to face-centered stacking (solvophobic effect), possibly decreasing the C-Cl bond strength of the aryl chloride and driving the reaction (Figure 1).
Figure 1. Illustration of the first oxidative addition step in aryl halide cross-coupling reactions, highlighting the transition state energy for: a) a standard aryl halide palladium coupling, b) the proposed ADA-activated aryl halide coupling. 
In initial studies, we observed a modest rate enhancement of a Heck coupling reaction in the presence of an electron-poor naphthalene diimide (NDI) co-catalyst (Figure 2).  While promising, reaction times in this system were not conducive to timely study of conditions. Additionally, the poor water miscibility of the reagents (no reaction observed at 50% water) limited the solvophobic driving force for potential ADA catalysis that could be leveraged for this system.
Figure 2. a) Scheme for Heck reaction with NDI co-catalyst. b) Graph of GC-MS data following % conversion of six Heck reactions with and without the co-catalyst.
We next moved to exploring ADA catalysis in Sonogashira coupling reactions, which generally have significantly shorter reaction times compared to the similar-type Heck reactions. In the presence of the same NDI co-catalyst, we found conditions in which a rate enhancement trend was observed for the Sonogashira coupling in a reasonable time frame (Figure 3). However, solubility is still limited in this system, and the % conversion measured showed a high degree of variability, leading us to believe that we were not collecting homogeneous reaction samples.

Figure 3. a) Sonogashira coupling reaction initially explored. b) Percent conversation with and without NDI co-catalyst. The data sets shown are the average of 5 independent reactions under the same conditions. While promising, error bars indicate the high level of variation in our system, and limit the statistical significance of the observed rate enhancement.

We have recently moved towards synthesizing model reagents with better water solubility in order to maximize solvophobic interactions and increase the consistency of our reactions set up and analysis (Scheme 1a). We have recently synthesized and purified the PEG-appended aryl chloride and alkene shown below, and are now beginning studies on the ADA assisted coupling of these reagents in 100% water as solvent (Scheme 1b).

Scheme 1.

As we continue to develop model reaction set-ups to illustrate general ADA organocatalysis, we have also been working towards the syntheses of electron-poor aromatic catalysts other than NDI. This includes core-substituted NDI (cNDI) derivatives with greater electro-positive surfaces (Figure 4a). These cNDI derivatives are all derived from a common intermediate, the corresponding dibromo-NDI. Surprisingly, when we began working on the target cNDI ADA catalysts, we found that there was no good synthetic procedure available for the key dibromo-NDI intermediate, with literature preps giving actual yields from 12-15%. This led us to develop an optimized synthetic procedure for the dibromo-NDI (Figure 4b). By monitoring the brominating with 1H NMR, and using concentrated microwave heating for the imidization, we were able to more than double the efficiency of isolating pure dibromo-NDI. This work is currently accepted for publication in Synthetic Communications.

Figure 4. a) Target core-substituted NDI derivatives to serve as ADA catalysts. All derived from the dibromo-NDI intermediate. b) Scheme for the optimized synthesis of dibromo-NDI.

Impact:

In addition to the progress discussed above, this PRF funding has had a significant impact on Denison's department of Chemistry and Biochemistry. This grant has funded two full-time undergraduate researchers, Alex Sterdjevich and Lovely Abocado, in summer research. Alex is currently applying to graduate programs, and Lovely will be returning for a second summer of research on this project. Both of these students are currently scheduled to present their work at the 2015 spring national ACS meeting in Colorado. This funding has also contributed to chemicals and supplies for these and two other undergraduate students participating in semester-research for the past year. Importantly, this grant has made it possible for me to recruit students as sophomores to do research, and already two more are committed for the summer of 2015 on this project. This significantly enhances the research culture of the department at Denison, raises the visibility of the chemical sciences among students, and enhances the likelihood of students continuing in the sciences. Finally, this funding has helped provide the resources for the recently accepted publication mentioned above, and played a significant role in my positive tenure decision last year. On behalf of my students, and myself, I thankful to PRF for the invaluable support of undergraduate research.