Non-innocent Additives in a Palladium(II)-Catalyzed C-H Bond Activation Reaction: Insights into Multimetallic Active Catalysts Megha Anand, † Raghavan B. Sunoj,* ,‡ and Henry F. Schaefer, III* ,† † Center for Computational Quantum Chemistry, University of Georgia Athens, Georgia 30602, United States, ‡ Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India * S Supporting Information ABSTRACT: The role of a widely employed additive (AgOAc) in a palladium acetate-catalyzed ortho-C-H bond activation reaction has been examined using the M06 density functional theory. A new hetero-bimetallic Pd-(μ- OAc) 3 -Ag is identified as the most likely active species. This finding could have far-reaching implications with respect to the notion of the active species in palladium catalysis in the presence of other metal salt additives. O ver the years, a broad range of methodologies has become available for making functionalized aromatic compounds using transition metal-catalyzed C-H bond activation. 1 The approach, in general, involves the use of a suitable transition metal catalyst on substrates bearing a directing group. 2 One of the quintessential examples in this genre is the palladium acetate-catalyzed ortho-functionalization of aryl amides as well as 2-phenylpyridines. 3 A quick perusal of literature spanning over a decade reveals that several such methods resort to the use of additives to improve the efficiency of the catalytic processes. 2a,4 Typical additives are metal salts, such as a terminal oxidant, that help regenerate the transition metal catalyst back to its native oxidation state toward the later part of the catalytic cycle. 3a,c,d,5 It is important to recognize that a large number of C aryl -C and C aryl -heteroatom bond formation reactions for aryl functionalizations have been achieved using Pd(OAc) 2 as the catalyst. 1,2a,b,6 While the examples for C aryl -C coupling reactions are available in abundance, reactions for C aryl -O and C aryl -N coupling remained relatively less reported until recently. 1a,b,5a,6a,7 One of the most recent breakthroughs in direct aryl amination came from the Yu group (Scheme 1). 8 The resulting product aryl amines are known to be useful in many biological processes. 9 The Yu reaction employs silver acetate and cesium fluoride as additives besides palladium acetate as the catalyst. The use of multiple additives under homogeneous reaction conditions is obviously expected to increase the mechanistic complexities. In particular, the nature of the catalytic species in the presence of such additives could be different from the conventionally proposed monomeric Pd(OAc) 2 . Clearly, this hypothesis warrants careful scrutiny. As a part of our continuing investigations toward under- standing the mechanisms of transition metal-catalyzed carbon- heteroatom bond formation reactions, 10 we became interested in examining the mechanism of the Pd(OAc) 2 -catalyzed amination of N-arylbenzamides, as shown in Scheme 1. 8 That reaction brings forth some intriguing questions concerning the role of additives such as AgOAc and CsF. However, the molecular origin and the mode of action of such additives in the catalytic cycle still remain to be established. The reaction relies on C-H functionalization, where the amide acts as the directing group for ortho-C-H bond activation. In this Communication, we intend to capture the first molecular insights into the potential involvement of some novel multimetallic catalytic species in the vital C-H bond activation step. Our discussion is presented in terms of the Gibbs free energies computed with the M06 density functional theory in 1,2-dichloroethane (DCE) as the continuum solvent. 11 The reaction shown in Scheme 1 can be envisaged to begin with the coordination of the catalyst to the amido nitrogen. 12 The role of different additives has been probed by explicitly including them in the C-H activation transition state. Among the different possibilities considered, energetically the most preferred only are discussed, whereas alternatives are used for cogent comparisons. To begin, a conventional pathway wherein a molecule of Pd(OAc) 2 functions as the sole catalyst is examined. Similar to the other known systems, the N-H activation by Pd(OAc) 2 is considered as the first step after the combination of catalyst with the substrate. 13 The resulting intermediate is poised to undergo ortho-C-H bond activation owing to the proximity between the metal and the aryl C-H bond. The ensuing acetate-assisted C-H activation via TS1 or TS2, as shown in Figure 1, will provide a palladacycle Received: December 18, 2013 Published: April 3, 2014 Scheme 1. Palladium Acetate-Catalyzed ortho-Amination of N-Arylbenzamide 8 Communication pubs.acs.org/JACS © 2014 American Chemical Society 5535 dx.doi.org/10.1021/ja412770h | J. Am. Chem. Soc. 2014, 136, 5535-5538