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

Abstract

The mechanism of Pd­(II)-catalyzed, mono-N-protected amino acid (MPAA) ligand and TBHP oxidant-mediated lactonization of β-C­(sp3)–H bond in aliphatic carboxylic acid has been studied. We have shown that the combination of TBHP oxidant and MPAA ligand is very critical: the reaction proceeds via MPAA ligand-mediated Pd­(II)/Pd­(IV) oxidation by TBHP, followed by C–O reductive elimination from the Pd­(IV) intermediate. While Pd­(II)/Pd­(IV) oxidation is a rate-limiting step, C–H bond activation is the regioselectivity-controlling step. MPAA ligand acts not only as an auxiliary ligand to stabilize the catalytic active species but also as a proton acceptor in C–H bond deprotonation and as a proton donor during Pd­(II)/Pd­(IV) oxidation by TBHP. The use of a peroxide-based oxidant with the hydroxyl group is required: in the rate-limiting Pd­(II)/Pd­(IV) oxidation transition state, the H-atom of the OH group participates in the 1,2-hydrogen shift to facilitate proton-shuttling between MPAA ligand and peroxide. Thus, lactonization of the C­(sp3)–H bond in aliphatic carboxylic acid occurs via the Pd­(II)/Pd­(IV) catalytic cycle, unlike the previously reported Pd­(II)-catalyzed pyridone ligand and O2 oxidant-assisted benzylic C–H lactonization in aromatic o-methyl benzoic acid, which occurs via the Pd­(II)/Pd(0) catalytic cycle and an intramolecular SN2 nucleophilic substitution mechanism. A comparison of these findings for C­(sp3)–H bond lactonization in aliphatic and aromatic carboxylic acids enabled us to identify the roles of catalyst, substrate, ligand, and oxidant.

Mechanistic Details of the Pd‐catalyzed and MPAA Ligand‐Enabled β‐C(sp3)‐H Acetoxylation of Free Carboxylic Acid

“…Similar to our previously reported [25] transition state TS2_ Cs L2 for the L2 ligand mediated Pd(II)/Pd(IV) oxidation by TBHP, in TS2_Na_L3 not only the t BuOÀ OH bond is breaking and the PdÀ OH bond is forming, but also the 1,2-hydrogen shift within the TBHP takes place (see Figures 1, 3 and 5). Simultaneously of these transformations, the hydrogen atom of hydroxyl group of the previously protonated MPAA ligand is transferring to the Pd-coordinated OH-group.…”

“…[25] However, the CÀ H bond activation for reaction (1c) occurring via the transition state TS1_Na_L3 (see Figures 3 and 4) and leading to the palladacycle 3_Na_L3 requires a free energy barrier of 24.4 kcal/mol, which is significantly larger than 11.2 kcal/mol barrier previously reported for the L2 mediated reaction (1b). [25] Overall reaction Pd(AcO) 2 + L3 + AA2!3_Na_L3 is calculated to be exergonic by 13.1 kcal/mol, while the formation of 3_Na_L3 from the pre-reaction intermediate 2_Na_L3 is endergonic by 3.1 kcal/mol.…”

“…The above described steps of the reaction, i. e. Pd(AcO) 2 + L + sub + TBHP!1 + sub + TBHP!2_M_L + 2AcOH + TBHP!3_ M_L + 2AcOH + TBHP!4_M_L + 2AcOH!5_M_L + 2AcOH were previously reported [25] for Cs-based base and ligand L2 mediated Pd(II)/Pd(IV) oxidation by TBHP then the CÀ O reductive elimination mechanism of the Pd(II)-catalyzed β-C(sp 3 )À H lactonization reaction (1b), in the absence of Ac 2 O.…”

“…[24] Astoundingly, our following computational analysis of this reaction revealed that the use of TBHP oxidant, in combination with the MPAA ligand L2, is critically important and opens energetically more favorable reaction path, which we called as MPAA ligand mediated Pd(II)/Pd(IV) oxidation by TBHP then the CÀ O reductive elimination from the Pd(IV) intermediate pathway (see Figure 1 for the generated Pd(IV) intermediate and the Pd(II)/Pd(IV) oxidation transition state). [25] To our best knowledge, this was first identification of TBHP as a 2-electron oxidant. The use of MPAA ligand in the reaction (1b) is critically important, as well.…”

“…Based on our previous studies, [22,25] here we are proposing the multistep mechanism (see Figure 2) of the Pd-catalyzed β- C(sp 3 )À H acetoxylation in aliphatic carboxylic acid AA2 (i. e., reaction (1c)) that starts by complexation of Pd(OAc) 2 and MPAA ligand (in Figure 2 we used L3 as a ligand) that leads to formation of intermediate 1_L, and follows via the: (a) acetic acid to substrate (AA2) exchange to generate intermediate 2_ M_L, (b) the CÀ H bond activation via the CMD mechanism to form palladacycle 3_M_L, and (c) the MPAA ligand-mediated Pd(II)/Pd(IV) oxidation by TBHP to produce intermediate 4_M_ L. From this Pd IV intermediate, reaction may proceed via two distinct pathways leading to lactonization and acetoxylation products, in the absence and presence of acid anhydride. The lactonization from the palladacycle 4_M_L occurs via direct CÀ O bond formation transition state and leads to product 5_ M_L.…”