Reports: UNI150347-UNI1: Toward Greater Understanding and Expanded Utility of the Palladium-Catalyzed Activation of Carbon-Carbon Single Bonds

Jeffrey B. Johnson, PhD, Hope College

The activation and functionalization of carbon-carbon single bonds remains an unrealized facet of organic chemistry. A generalized transition metal-catalyzed methodology allowing for the selective cleavage of carbon-carbon bonds has nearly boundless potential, yet efforts to date have primarily relied upon specialized substrates for the achievement of this unusual reaction.[1] Likewise, subsequent functionalization of the resulting organometallic species has also proven to be a significant challenge.

To date, there are very few examples of mechanistic investigations into transition metal-catalyzed carbon-carbon bond activation processes. To remedy this dearth of information, our group has pursued the mechanistic investigation of two such reactions: the palladium-catalyzed β-aryl elimination of triarylmethanols (Scheme 1)[2] and the rhodium-catalyzed alkene carboacylation using quinolinyl ketones (Scheme 2).[3] The intent of each of these studies is to identify factors that influence the carbon-carbon bond step of each process and subsequently utilize this information for the extension of known reactivity.

Palladium-Catalyzed β-Aryl Elimination

Our efforts to discern between two mechanistic hypotheses (Scheme 3) utilized two. Two students (one supported by a Moissan Undergraduate Fellowship sponsored by the American Chemical Society Division of Fluorine Chemistry) were involved in preparing a number of substituted triarylmethanols for the identification of factors, if any, that influenced the relative propensity of β-aryl elimination. A third student performed reactions of a more mechanistic nature to examine the reversibility of various steps throughout the catalytic reaction.

Approximately 30 aryldiphenylmethanol compounds containing variable substitution were prepared and subjected to the standard reaction conditions. As indicated in Scheme 4, several products are possible in these reactions, and the relative ratio of these products was determined utilizing GC/MS methods thus providing the means to examine the cleavage propensity of each substituent.

Notably, variation of the electronics of an aryl group had only subtle influence on selectivity (Table 1), and the results demonstrated no clear trends of reactivity both more electron deficient and electron rich substituents appeared to increase the rate of β-aryl elimination versus the phenyl substituent.

A clearer picture was obtained with the preparation and testing of a series of fluorine substituted substrates (Table 2). The significant influence of an ortho-fluorine is readily apparent. Beyond the ortho-substitution, additional electron withdrawing substituents result in greater selectivity, and the inclusion of multiple fluorine atoms results in cumulative effects.

Investigation of aryl bromides was performed by simultaneously utilizing two aryl bromides. The reaction was stopped short of complete conversion and the product ratios were determined via GC/MS. Results from these competition reactions demonstrated that electron deficient aryl bromides proceeded more rapidly than electron rich aryl bromides (Scheme 5). These results indicate that oxidative addition either limits the rate of catalyst turnover or lies in a reversible step that precedes the turnover limiting step.

Additional information implicating initial oxidative addition has been obtained by determining the influence of β-aryl elimination. As illustrated in Scheme 6, more electron rich aryl bromides result in greater preference for cleavage of the electron deficient fluorinated aryl substituent, while the use of an electron deficient aryl bromide results in a decrease and eventual reversal in the selectivity of aryl group transfer. These results provide significant support for the premise that the selectivity of aryl transfer can be controlled by tuning the electronic character of the palladium catalyst.

To date, this work has provided significant insight into factors influencing β-aryl elimination, including the effects of electronics on the C-C activation step and the nature of the active palladium species. The results described above are currently under consideration for publication. Research efforts will continue with the expansion of this known methodology toward more widely applicable coupling methodologies utilizing carbon-carbon bond activation as an entry point into high energy organometallic species.

Rhodium-Catalyzed Carboacylation of Alkenes

Carbon-carbon single bond activation may also occur via an oxidative addition process, a process exemplified by the intramolecular carboacylation of quinolinyl ketones. In order to compare and contrast various methods of C-C bond activation, our group has also investigated the mechanism of this transformation.

Although this project was primarily funded via other sources, two students supported by the PRF assisted in the synthesis and characterization of quinolinyl ketone species that were utilized in the study. The determination of the rate law, 12C/13C kinetic isotope effect, and rate variations with substrates ultimately uncovered a mechanism in which the turnover limiting step of catalysis varied with the nature of the substrate. With small alkenes, carbon-carbon bond activation is the highest activation barrier, while larger alkenes are limited by alkene insertion. These results have been published.[4]

Student and PI Impact

The student involved in the various aspects of this program have combined to provide 16 oral and poster presentations to date, including presentations at the 241st National ACS Meeting in Anaheim, CA, the 42nd National Organic Symposium in Princeton, NJ, and the 243rd National ACS Meeting in San Diego, CA. Of the five students who have worked on this project, one will be attending graduate school in chemistry at the University of California-Irvine in the fall of 2012, two are rising seniors who intend to pursue graduate studies in the fall of 2013, and two are prospective dental students. All remain active in the research laboratory.

The results above have led to one publication, as well as an additional submitted manuscript. These results have also provided the foundation for additional ongoing studies into the development of methodologies for the selective activation of carbon-carbon bonds. The preliminary results obtained from this work contributed to the recent acquisition of an NSF-CAREER award that will support this work through 2017.


[1]) Murakami, M.; Ito, Y. Topics in Organometallic Chemistry 1999, 97-129.

[2]) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407.

[3]) Dreis, A. M.; Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412.

[4]) Lutz, J. P.; Rathbun, C. M.; Stevenson, S. M.; Powell, B. M.; Boman, T. S.; Baxter, C. E. Zona, J. M.; Johnson, J. B. J. Am. Chem. Soc. 2012, 134, 715-722.