A regioselective Pd-mediated C–H bond arylation methodology for tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated tryptophan derivatives, in several cases quantitatively. The reactions proceed in air, without base, and at room temperature in EtOAc. The synthetic methodology has been evaluated and compared against other tryptophan derivative arylation methods using the CHEM21 green chemistry toolkit. The behavior of the Pd catalyst species has been probed in preliminary mechanistic studies, which indicate that the reaction is operating homogeneously, although Pd nanoparticles are formed during substrate turnover. The effects of these higher order Pd species on catalysis, under the reaction conditions examined, appear to be minimal: e.g., acting as a Pd reservoir in the latter stages of substrate turnover or as a moribund form (derived from catalyst deactivation). We have determined that TsOH shortens the induction period observed when [ArN2]BF4 salts are employed with Pd(OAc)2. Pd(OTs)2(MeCN)2 was found to be a superior precatalyst (confirmed by kinetic studies) in comparison to Pd(OAc)2.

Manganese‐catalyzed C−H bond activation chemistry is emerging as a powerful and complementary method for molecular functionalization. A highly reactive seven‐membered MnI intermediate is detected and characterized that is effective for H‐transfer or reductive elimination to deliver alkenylated or pyridinium products, respectively. The two pathways are determined at MnI by judicious choice of an electron‐deficient 2‐pyrone substrate containing a 2‐pyridyl directing group, which undergoes regioselective C−H bond activation, serving as a valuable system for probing the mechanistic features of Mn C−H bond activation chemistry.

The ability of carboxylate groups to promote the direct functionalization of C−H bonds in organic compounds is unquestionably one of the most important discoveries in modern chemical synthesis. Extensive computational studies have indicated that this process proceeds through the deprotonation of a metalcoordinated C−H bond by the basic carboxylate, yet experimental validation of these predicted mechanistic pathways is limited and fraught with difficulty, mainly as rapid proton transfer is frequently obscured in ensemble measures in multistep reactions (i.e., a catalytic cycle consisting of several steps). In this paper, we describe a strategy to experimentally observe the microscopic reverse of the key C−H bond activation step underpinning functionalization processes (viz. M−C bond protonation). This has been achieved by utilizing photochemical activation of the thermally robust precursor [Mn(ppy)(CO) 4 ] (ppy = metalated 2-phenylpyridine) in neat acetic acid. Time-resolved infrared spectroscopy on the picosecond−millisecond time scale allows direct observation of the states involved in the proton transfer from the acetic acid to the cyclometalated ligand, providing direct experimental evidence for the computationally predicted reaction pathways. The power of this approach to probe the mechanistic pathways in transition-metal-catalyzed reactions is demonstrated through experiments performed in toluene solution in the presence of PhC 2 H and HOAc. These allowed for the observation of sequential displacement of the metal-bound solvent by the alkyne, C−C bond formation though insertion in the Mn−C bond, and a slower protonation step by HOAc to generate the product of a Mn(I)-catalyzed C−H bond functionalization reaction.

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Insights into the factors controlling the site selectivity of transition metal-catalyzed C−H bond functionalization reactions are vital to their successful implementation in the synthesis of complex target molecules. The introduction of fluorine atoms into substrates has the potential to deliver this selectivity. In this study, we employ spectroscopic and computational methods to demonstrate how the "ortho-fluorine effect" influences the kinetic and thermodynamic control of C−H bond activation in manganese(I)mediated reactions. The C−H bond activation of fluorinated N,Ndimethylbenzylamines and fluorinated 2-phenylpyridines by benzyl manganese(I) pentacarbonyl BnMn(CO) 5 leads to the formation of cyclomanganated tetracarbonyl complexes (2a−b and 4a− e), which all exhibit C−H bond activation ortho-to-fluorine.Corroboration of the experimental findings with density functional theory methods confirms that a kinetically controlled irreversible σ-complex-assisted metathesis mechanism is operative in these reactions. The addition of benzoic acid results in a mechanistic switch, so that cyclomanganation proceeds through a reversible AMLA-6 mechanism (kinetically and thermodynamically controlled). These stoichiometric findings are critical to catalysis, particularly subsequent insertion of a suitable acceptor substrate into the C−Mn bond of the regioisomeric cyclomanganated tetracarbonyl complex intermediates. The employment of time-resolved infrared spectroscopic analysis allowed for correlation of the rates of terminal acetylene insertion into the C−Mn bond with the relative thermodynamic stability of the regioisomeric complexes. Thus, more stable manganacycles, imparted by an ortho-fluorine substituent, exhibit a slower rate of terminal acetylene insertion, whereas a para-fluorine atom accelerates this step. A critical factor in governing C−H bond site selectivity under catalytic conditions is the generation of the regioisomeric cyclomanganated intermediates, rather than their subsequent reactivity toward alkyne insertion.