Unconventional mechanism and selectivity of the Pd-catalyzed C–H bond lactonization in aromatic carboxylic acid

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.

Roles of Ligand and Oxidant in Pd(II)-Catalyzed and Ligand-Enabled C(sp3)–H Lactonization in Aliphatic Carboxylic Acid: Mechanistic Studies

“…Despite the broader application of these synthesis protocols in late-stage functionalization, we anticipate that elucidation of the mechanisms of C–H bond oxidation (by internal oxidant, as in C–H lactonization in carboxylic acids, or external oxidant, as in C–H hydroxylation in heterocyclic carboxylic acids by O 2 molecule), as well as the roles of the utilized catalyst, substrate, ligand, base, and oxidant, undoubtedly broadens the scope of these synthesis protocols and enables the discovery of more efficient, environmentally benign, and highly practical novel C–H oxidation reactions. Based on these anticipations, recently, we have studied the mechanism and controlling factors of Pd­(II)-catalyzed and pyridone ligand-assisted C­(sp 3 )–H lactonization in 2,6-dimethyl benzoic acid (Scheme b, referred to as the reaction rBA) . Briefly, we observed the following (see Scheme ).…”

“…In 2011, Martin and co-workers proposed a concerted reductive elimination mechanism for Pd­(II)-catalyzed C­(sp 3 )–H lactonization with a stoichiometric silver­(I) oxidant; however, they did not rule out a stepwise mechanism including the dissociation of the carboxylate ligand, followed by C–O bond formation. Recently, our group proposed and validated a stepwise intramolecular S N 2 nucleophilic substitution mechanism of Pd­(II)-catalyzed and pyridone ligand-enabled lactonization in o -methyl benzoic acid, which utilizes K 2 HPO 4 as a base and O 2 as an oxidant …”

“…Our analyses show that the transition-state 8-ts and 10-ts lacks the stabilizing η 3 -(π-benzylic)–Pd­(II) interaction. This could be (as emphasized previously) one of the reasons for the large calculated C–O bond formation barrier. Thus, the reaction rAA, most likely, proceeds via a different mechanistic pathway compared to the intramolecular S N 2 nucleophilic substitution pathway previously reported for the reaction rBA …”

“…From the generated palladacycle 5 , the lactonization process is expected to proceed via the C 1 –O 2 bond formation. As previously discussed, the C–O bond formation from Pd­(II) and/or high-valent Pt and Pd-complexes is a complicated process. − The success of this process is not only dependent on the nature and oxidation state of the used transition metals but also on the nature of the auxiliary ligands, oxidant, and base. For example, multiple experimental groups − have provided evidence that C–O bond formation in the Pd­(IV) and Pt­(IV)-complexes may proceed via either direct reductive elimination or/and stepwise S N 2 nucleophilic substitution mechanisms.…”

“…Herein, we extend our previous joint computational and experimental efforts and aim to establish the mechanism of the β-C­(sp 3 )–H bond lactonization in aliphatic carboxylic acid, previously reported by Yu and co-workers . We aim to identify reasons why the use of MPAA ligand and TBHP oxidant (below, this reaction is referred to as rAA) was critically important for the success of this reaction.…”