Abstract
The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+ cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H.
Highlights
The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission
In the reaction reported by Yu and coworkers the stronger C(sp3)–H bond lactonization is achieved in the presence of the relatively weaker C(sp2)–H bond
We found that the generation of the potassium carboxylate (1, Fig. 2), by the reaction of 2,6-dimethyl benzoic acid with the potassium phosphate, is thermodynamically favorable
Summary
True nature of substrate, and the C–H bond activation step. At first, we used computations to identify the true nature of the used substrate under the reported reaction conditions. Having identified the true natures of substrate (1) and active catalyst (2) of the reaction given, the step of the reaction can be expected to be the complexation, i.e., formation of complex 3: this process is calculated to be exergonic by 2.2 kcal/ mol (Fig. 2). We found that the benzylic C(sp3)–H bond activation in complex 3 occurs via the concerted metalationdeprotonation (CMD) transition state 4-ts, and leads to palladacycle 5 In course of this CMD process, one of the pyridone ligands serves as the deprotonating reagent. In 2009, Ribas and coworkers proposed a concerted C(sp2)–O bond formation from the bimetallic Pd(III)/Pd(III) intermediate[52] All these early reports described the C–O bond formation from the high-valent group 10 transition metals [i.e., Pt(IV), Pd(IV), and Pd(III)]. For the Pd(II)-catalyzed C(sp3)–H lactonization with stoichiometric silver(I) oxidant[36], Martin and coworkers have proposed a concerted reductive elimination from the Pd(II)-intermediate, but ΔGsol (ΔHsol) in kcal/mol
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