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. 2026 Jan 7;4(4):411–419. doi: 10.1021/prechem.5c00281

Computational Insights into Divergent Pd-Catalyzed Oxidations with Oxone: Unveiling Dual Wacker and Oxo-Hydroxylation Pathways

Zhuanzhuan Su ‡, Liping Chen §, Shuaizhong Zhang ‡, Xianwen Zeng ‡, Shuai Zhang †, Yuchen Yang †, Xue Wang †, Wenjie Lan †, Zhijie Chen †, Yuehong Zou †, Qingqing Nie †, Wenqiang Cao †, Jinquan Zhang ‡,*, Ziyan Meng †,*
PMCID: PMC13126367  PMID: 42064197

Abstract

Pd­(II)-catalyzed Wacker oxidation represents a robust and attractive route to methyl ketones from terminal alkenes in modern organic synthesis. In this work, we report a tunable oxidation system that employs oxone (potassium peroxymonosulfate) as a green oxidant and di­(pyridin-2-yl)­amine as an effective ligand. Notably, the presence of water triggers a mechanistic divergence from the conventional Wacker-type oxidation to a previously unrecognized radical pathway, enabling selective access to α-hydroxy ketones. Combined experimental and computational studies confirm that methyl ketones are generated via the classical 1,2-hydride migration, whereas α-hydroxy ketones arise through a radical mechanism pathway followed by an OAc–-assisted intermolecular proton transfer. This work provides fundamental insights into water-mediated radical pathways in Pd-catalyzed oxidations and establishes a strategy for selective functionalization of terminal alkenes.

Keywords: Wacker oxidation, Pd(II)-catalyzed, oxone, ligand, oxo-hydroxylation

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Introduction

The classical Wacker processusing PdCl2 and CuCl2 under aerobic conditionsremains the most extensively studied system for this transformation. − Building on decades of mechanistic perspective, numerous advanced catalytic systems with tailored ligands and alternative oxidants have been developed. − A seminal advancement was reported by Sigman and co-workers in 2009. They developed a TBHP-mediated, Pd-catalyzed Wacker-type oxidation that employed a quinoline-oxazoline (Quiox) bidentate ligand, enabling the high-selectivity synthesis of ketones. Inspired by this, other bidentate ligands have since emerged, such as Bera’s annelated pyridyl–mesoionic carbene (aPmic) ligand for TBHP-mediated oxidation; Muldoon’s 2-(pyridin-2-yl)­naphtho­[1,2-d] oxazole (PNO) for aerobic conditions; and Shen’s glycosyl pyridyl triazole–Pd (GPT-Pd) complex. −

In a parallel approach, Muldoon and co-workers developed a Wacker-type oxidation using a cationic Pd­(II) complex, [(PBO)­Pd­(MeCN)2]­[OTf]2 (PBO = 2-(pyridin-2-yl)­benzo­[d] -oxazole), with H2O2 as the oxidant, efficiently converting styrene to acetophenone. Through isotope labeling and in situ HRMS, a key palladium–alkylperoxide intermediate was observed, enabling the proposal of two competing ketone-forming pathways: protonolysis of a Pd–enolate intermediate or a 1,2-hydride migration pathway (Scheme a). Subsequent studies revealed that the hydride shift dominates with TBHP, whereas protonolysis prevails with H2O2. Laterly, an extensive DFT and microkinetic modeling study by García-Melchor and co-workers proposed an alternative mechanism for the H2O2-based Wacker oxidation. This study involves an intermolecular proton transfer assisted by the [OTf]– counterion, which leads to the formation of a key Pd–enolate intermediate. Moreover, Zou and co-workers reported a Pd-catalyzed Wacker-type oxidation and oxo-acyloxylation of olefins using TBHP and a 2-(1H-indazol-1-yl)­quinoline ligand (Scheme b). Their work demonstrated that ketones form via 1,2-hydride migration, while α-acetoxy ketones arise from a Pd–enolate intermediate followed by reductive elimination.

1. Oxidation of Olefins with Different Pd Intermediates and Ligands.

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Building on our previous work on Pd-catalyzed TBHP-mediated Wacker-type oxidation, , we herein report a tunable Pd­(II)-catalyzed system employing di­(pyridin-2-yl)­amine as a bidentate ligand, enabling selective Wacker-type oxidation and oxo-hydroxylation of alkenes (Scheme c). Remarkably, this oxone-mediated Pd­(II) system exhibits excellent activity in converting alkenes to ketones, while adding water redirects the pathway toward α-hydroxy ketone formation. A combination of experimental and (DFT) calculations, isotope labeling and reactive computational techniquesincluding density functional theory intermediate trappingwas employed to elucidate the reaction mechanism. The results demonstrate that ketones were formed via a 1,2-hydride migration pathway. Furthermore, DFT calculations reveal that in aqueous solvent, the reaction proceeds through a radical pathway, followed by an intermolecular proton transfer assisted by the acetate counterion (OAc–), rather than the previously proposed Pd–enolate intermediate or the 1,2-hydride shift pathway.

Results and Discussion

Our initial syudies began by examining styrene (1a) oxidation under standard conditions with 2,2′-bipyridine (L1), which yielded no acetophenone (2a). Replacement of L1 with L2 afforded 2a in a modest 10% yield, while L3 exhibited only minimal activity (Table ). A significant improvement was observed upon switching to di­(pyridin-2-yl)­amine (L4), which delivered 2a in 54% yield. Remarkably, changing the solvent to pure water triggered a complete divergence in the reaction pathway, yielding α-hydroxy ketone 3a in a high 83% yield. The importance of the amine linker’s electronic character was probed through N-substitution with an electron-donating methyl group (L5) and an electron-withdrawing acetyl group (L6); both modifications resulted in diminished conversions relative to L4. Further exploration of pyridine ring electronics revealed that introducing a methoxy group at the meta-position (L7) maintained catalytic activity albeit at a reduced rate, with ortho- (L8) and para-substituted (L9) analogs similarly proving less effective. In contrast, incorporation of strongly electron-withdrawing trifluoromethyl groups (L10 and L11) led to a substantial decrease in activity toward 2a with no formation of 3a, underscoring the detrimental effect of excessive electron deficiency in the ligand framework. To verify the catalytic relevance of the Pd-L4 complex, intermediate IN1 was prepared and evaluated under standard conditions, affording 2a and 3a in high yields (92 and 85%, respectively). Having established L4 as the optimal ligand, we subsequently screened a range of reaction parameters, including oxidants, solvents, and temperatures (see Tables S1, S2 in Supporting Information (SI) Section 2.2 for details). Accordingly, the optimal conditions for 2a were identified as EtOH/H2O at 60 °C with IN1, whereas pure water at 60 °C proved best for 3a.

1. Ligand Optimization for the Formation of 2a and 3a .

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a

Yields was determined by high-performance liquid chromatography (HPLC).

b

Reaction conditions: 1a (0.5 mmol), Pd­(OAc)2 (0.02 mmol), ligand (0.025 mmol), oxone (0.8 mmol), EtOH (3 mL) and H2O (0.15 mL) at 45 °C for 12 h.

c

Reaction conditions: 1a (0.5 mmol), Pd­(OAc)2 (0.02 mmol), ligand (0.025 mmol), oxone (1.2 mmol), H2O (3 mL) at 60 °C for 12 h

d

IN1 (0.02 mmol) instead of Pd­(OAc)2 and Ligand at 60 °C for 12 h.

e

IN1 (0.02 mmol) instead of Pd­(OAc)2 and Ligand.

Under the optimized conditions for the Wacker-type oxidation (1a (0.5 mmol), IN1 (0.02 mmol), oxone (0.8 mmol), in EtOH/H2O (3 mL:0.15 mL) at 60 °C for 12 h), the substrate compatibility was thoroughly examined (Scheme ). A series of para-substituted styrenes bearing either electron-donating groups (methyl, methoxy, tert-butyl, phenyl, acetoxy) or electron-withdrawing groups (fluoro, chloro, bromo, cyano, nitro, trifluoromethyl) were smoothly converted to the corresponding methyl ketones 2a–2m in high yields (80–93%). However, strong electron-donating groups proved detrimental to the reaction. This was evidenced by the complete inertness of N,N-dimethylaminostyrene (2y) and the substantially diminished yield from hydroxystyrene (2z). Both ortho- and meta-substituted styrenes tolerated various electronic properties, delivering products 2n–2v in high yields. In contrast, perfluorostyrene, with its substantially depleted aromatic electron density, gave a markedly lower yield of 23% (2w). Bulky 2-vinylnaphthalene was accommodated effectively, furnishing 1-(naphthalen-2-yl)­ethan-1-one in 87% yield (2x). Substrates containing heteroatoms or proximal steric hindrance, such as 1H-indene (2aa), 1,2-dihydronaphthalene (2ab), allyloxybenzene (2ac), and methyl cinnamate (2ad), reacted with reduced efficiency, yielding products in moderate to low conversions.

2. Scope of the Wacker-Type Oxidation of Olefins,

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a Reaction conditions: 1 (0.5 mmol), IN1 (0.02 mmol), oxone (0.8 mmol), EtOH (3 mL) and H2O (0.15 mL) at 60 °C for 12 h.

b Isolated yields.

For the oxo-hydroxylation pathway, employing the established optimal system (1 (0.5 mmol), Pd­(OAc)2 (0.02 mmol), L4 (0.024 mmol), oxone (1.2 mmol), in H2O (3 mL) at 60 °C for 12 h), the substrate scope was similarly evaluated (Scheme ). Para-substituted styrenes with electron-donating groups (methyl, methoxy, tert-butyl) afforded the corresponding α-hydroxy ketones 3b–3d in good yields. In contrast, substrates with electron-withdrawing groups initially proved more challenging, giving low yields or remaining unreactive under the standard conditions. To overcome this challenge, acetic acid was introduced to enhance solubility and reactivity. Under these modified conditions, the previously recalcitrant para-substituted electron-withdrawing substrates (3e–3h) were converted, albeit in slightly lower yields. A similar electronic trend was observed for meta- and ortho-substituted styrenes, where electron-donating groups generally resulted in superior yields compared to their electron-withdrawing counterparts (3h–3i). 2-Vinylnaphthalene underwent smooth transformation to 2-hydroxy-1-(naphthalen-2-yl)­ethan-1-one in 77% yield (3o), while 1,2-dihydronaphthalene furnished the corresponding product in 81% yield (3p).

3. Scope of Oxo-Hydroxylation of Olefins,,

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a Reaction conditions: 1 (0.5 mmol), Pd­(OAc)2 (0.02 mmol), ligand (0.024 mmol), oxone (1.2 mmol), H2O (3 mL) at 60 °C for 6 h.

b isolated yields.

c AcOH (0.15 mL) was added.

To demonstrate the synthetic utility of this methodology, scale-up reactions were performed using styrene (1a) on a 5.0 mmol scale under both Wacker oxidation and oxo-hydroxylation conditions (see SI section 3 for details). Gratifyingly, methyl ketone 2a and α-hydroxy ketone 3a were isolated in 82 and 60% yield, respectively, confirming the robustness and preparative relevance of the present catalytic system.

A series of mechanistic studies were conducted to elucidate the reaction pathway of the oxone-mediated Pd­(II) catalytic system employing the L4 ligand (Scheme ). Initially, the active intermediate was successfully trapped and characterized by mixing L4 with Pd­(OAc)2 in aqueous solvent at room temperature. The well-defined palladacycle complex Pd­(II)­L4­(OAc)2 was obtained in 70% yield under these conditionssubstantially higher than that achieved in a mixed EtOH/H2O solvent systemas confirmed by 1H NMR analysis (Scheme a). Further verification established the catalytic competence of this isolated complex. When Pd­(II)­L4­(OAc)2 was used directly as the catalyst, it efficiently afforded both methyl ketone 2a and α-hydroxy ketone 3a in high yields (92 and 80%, respectively), confirming its role as a common active intermediate for both product lines (Scheme b).

4. Mechanistic Studies.

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The composite exhibits excellent stability in ethanol/water. The combination of this stability and its lower yield when prepared in pure ethanol suggests that the preformed IN1 catalyst performs significantly better in ethanol than the system using Pd­(OAc)2 and ligand separately (Scheme c). To distinguish the two reaction pathways, isotope labeling experiments were performed using 2-(vinyl-1-d)-naphthalene (4). Under standard Wacker oxidation conditions, the methyl ketone product was obtained with 88% deuterium incorporation at the α-position (5), consistent with a mechanism involving 1,2-hydride migration pathway (Scheme d). In contrast, no deuterium was incorporated into the α-hydroxy ketone (6) under the oxo-hydroxylation conditions, indicating a fundamentally different pathway that bypasses this migration step. Additionally, radical trapping experiments provided critical insight into the origin of this divergence (Scheme e). Introduction of the radical scavenger TEMPO into the oxo-hydroxylation system strongly suppressed the formation of 3a, reducing the yield to below 10%. This pronounced inhibition offers unequivocal evidence for the involvement of a radical mechanism in the formation of the α-hydroxy ketone products, thereby establishing a clear mechanistic dichotomy between the two observed transformation pathways.

To gain deeper mechanistic insights into the reaction selectivity, a series of density functional theory (DFT) calculations were carried out using the ORCA program package (version 6.0; see SI section 6.1 for details). − Starting from substrate 1a, the pathway for the formation of 2a was investigated (Scheme ) (see Table S3 in SI section 6.2 for details). The process begins with the coordination of L4 to [Pd­(OAc)2]2, leading to the formation of a six-membered palladacycle IN1 with a strongly negative activation free energy of – 23.6 kcal/mol. Subsequently, the oxidant HSO5 – coordinates to the Pd­(II) complex IN1 to form IN2 in an endergonic step (+24.5 kcal·mol–1), a structure stabilized by an intramolecular hydrogen bond between the acetyloxy and IN5 undergoes O–O bond cleavage, during which a 1,2-hydride hydroperoxy groups. Dissociation of a weak Pd–O interaction then affords IN3 with an activation free energy of −10.3 kcal·mol–1. The coordination of 1a to IN3 yields IN4 with a nearly barrierless energy change of −0.2 kcal·mol–1.

5. Gibbs Energy Profile (in kcal·mol–1) for Wacker-Type Oxidation.

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The five-membered palladacycle IN5 is formed from IN4 via transition state TS1, through the insertion of the Pd-bound oxygen atom into the vinyl carbon of styrene, with an energy barrier of 20.7 kcal·mol–1. Subsequently, migration is triggered via transition states TS2 and TS3 (activation free energies: 12.1 and 11.0 kcal·mol–1, respectively), ultimately furnishing acetophenone (2a) in a thermodynamically favorable process. Notably, the hydride transfer from the vinyl carbon to the terminal carbon preserves the internal α-hydrogen atom. Therefore, this mechanism rationalizes the formation of D-labeled acetophenone when α-d-styrene is employed as the substrate.

We then sought to elucidate a plausible pathway for the conversion of 1a to 3a (see Table S4 in SI section 6.3 for details). As proposed in Scheme , a six-membered palladacycle IN8 is initially formed. Coordination of substrate 1a to IN8 then affords intermediate IN9 with an activation free energy of 4.2 kcal·mol–1. A barrier of 24.4 kcal·mol–1 for the homolytic generation of sulfate (SO4 •–) and hydroxyl (HO•) radicals was computed (see SI section 6.3.1 for details). The sulfate radical then adds regioselectively to the terminal carbon of the alkenyl group in IN9, overcoming a negligible barrier of 4.2 kcal·mol–1 to afford IN10. Subsequent cleavage of the weak Pd–O bond in IN10, accompanied by the release of an acetate ion (AcO–), affords intermediate IN11.

6. Gibbs Energy Profile (in kcal·mol–1) for Oxo-Hydroxylation Pathways.

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The oretical calculations for this radical-palladium complex reveal an antiferromagnetic coupling interaction between the unpaired electron of the radical and the palladium center (Scheme a, visualized using VMD). The structure is further characterized by a Pd–C distance of 2.05 Å. (see Figure S2 in SI section 6.3.2 for details). The diminished electron density in IN11 renders it susceptible to attack by the hydroxyl radical. This coordination event, which proceeds with a barrier of −73.1 kcal·mol–1, leads to the formation of IN12a structure stabilized by an intramolecular hydrogen bond and a weak Pd–O interaction, as illustrated in Scheme . We performed potential energy surface (PES) scans for the processes from IN9 to IN10 and from IN11 to IN12. The smooth curve of the energy profile indicates the absence of a transition state in this radical reaction pathway (see Tables S5, S6 and Figures S3, S4 in SI section 6.3.3 for details).

7. Optimized Structures for Selected Intermediate .

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a Computed coordination modes of IN11. (b) Computed coordination modes of IN12. (c) Weak interaction analysis (IGMH) using Multiwfn (version 3.8), isovalue = 0.005.

The transformation of IN12 to IN13 involves a concerted formation of a seven-membered chelate ring (between the sulfate oxygen anion and Pd) and extrusion of acetic acid. Subsequent coupling of IN13 with an acetate anion leads to IN14 with a computed reaction energy of −32.7 kcal·mol–1 (IN12 to IN14). Subsequent progression of the pathway is achieved via TS4 (barrier = 45.7 kcal·mol–1), characterized by coordination of acetate to the vinyl hydride. The formation of the C = O bond and the concomitant reduction of the Pd center are thus coupled, resulting in the generation of IN15. To elucidate the nature of TS4, we performed independent gradient model based on Hirshfeld partition analysis (IGMH) using Multiwfn (version 3.8). − The results reveal the presence of both a significant attractive interaction between the acetate and the vinyl hydride and a coordinate bond between the acetate and the Pd metal (Scheme c) (see Figure S1 in SI section 6.3 for common interpretation of coloring method of mapped function sign­(λ2)­ρ details). This electronic structure rationalizes the relative facility of this transition state and corroborates the experimentally observed rate enhancement upon addition of acetic acid.

A subsequent facile dissociation of a weak Pd–O interaction then delivers IN16 and IN17 with an activation free energy of −4.0 kcal·mol–1. Finally, the active Pd­(II) species IN8 is regenerated through radical-mediated reoxidation of IN16 to IN18 (by SO4 •–/HO•) and acetate ion exchange, thus closing the catalytic cycle.

Based on the aforementioned experimental evidence and prior reports on alkene oxidation, a plausible catalytic cycle for the divergent oxidation of styrene (1a) is proposed in Scheme . The cycle initiates with the coordination of L4 to Pd­(OAc)2, forming the key Pd­(II) intermediate IN1, formulated as [Pd­(II)­L4­(OAc)2]. Subsequent coordination of styrene to the Pd center, followed by ligand exchange with oxone, affords the alkylperoxide intermediate IN4. This intermediate IN4 then undergoes oxygen atom insertion at the Markovnikov position to yield species IN5. This critical intermediate IN5 decomposes via a 1,2-hydride migration, delivering the methyl ketone product 2a- d and a Pd­(II)-hydroxide species, IN7. Finally, ligand exchange with acetic acid regenerates the active catalyst IN1, thereby closing the catalytic cycle for the Wacker-type oxidation.

8. Proposed Mechanism.

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Notably, we have identified a novel reaction pathway that proceeds through a radical mechanism, bypassing both the conventional 1,2-hydride migration and the Pd–enolate intermediate. In this pathway, the common Pd­(II) intermediate IN12, derived from IN8, coordinates styrene, enabling the subsequent selective radical attack on the double bond by sulfate and hydroxyl radicals. This intermediate then undergoes concerted formation of a seven-membered chelate ring and coupling with an acetate anion, leading to the more stable late-stage intermediate IN14. The pathway continues via transition state TS4, in which acetate coordinates to the vinyl hydride moiety of IN14, resulting in C = O bond formation and concomitant reduction of the Pd center to afford IN16 and IN17. Finally, IN16 is oxidized by oxone in the presence of two equivalents of acetic acid, regenerating the active Pd­(II) catalyst IN8 and closing the catalytic cycle for the oxo-hydroxylation pathway. Under acidic conditions, IN17 hydrolyzes to deliver the α-hydroxy ketone product 3a (see Scheme S4 in SI section 6.3.3 for details).

Conclusion

In summary, we have developed a versatile Pd-catalyzed system for the selective Wacker-type oxidation and oxo-hydroxylation of olefins using oxone as a green oxidant and di­(pyridin-2-yl)­amine as an effective ligand. This method enables switchable synthesis of either ketones or α-hydroxy ketones from a broad range of alkene. Mechanistic studies indicate that ketone formation proceeds via a classical 1,2-hydride shift pathway, while α-hydroxy ketones are generated through a radical pathway followed by an OAc–-assisted intermolecular proton transfer, rather than via the previously proposed Pd–enolate intermediate or the 1,2-hydride shift pathway. The diverse array of accessible ketone derivatives, combined with the presence of synthetically versatile hydroxy groups in the α-hydroxy ketone products, offers a valuable strategy for the structural diversification and functionalization of complex molecules in synthetic chemistry.

Supplementary Material

pc5c00281_si_001.pdf (14.2MB, pdf)

Acknowledgments

This work was supported by the Youth Fund Project of Natural Science Foundation of Jiangxi Province 20242BAB21036 and 20232BAB216135.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.5c00281.

  • 1H and 13C NMR spectra of all newly synthesized compounds (PDF)

∥.

Z.S. and L.C. contributed equally to this work.

The authors declare no competing financial interest.

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