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Published in final edited form as: Organometallics. 2022 Mar 25;41(22):3161–3166. doi: 10.1021/acs.organomet.2c00017

Thermodynamic-Kinetic Comparison of Palladium(II)-Mediated Alcohol and Hydroquinone Oxidation

David L Bruns 1, Shannon S Stahl 1
PMCID: PMC9916251  NIHMSID: NIHMS1817860  PMID: 36776986

Abstract

Palladium(II) catalysts promote oxidative dehydrogenation and dehydrogenative coupling of many organic molecules. Oxidations of alcohols to aldehydes or ketones are prominent examples. Hydroquinone (H2Q) oxidation to benzoquinone (BQ) is conceptually related to alcohol oxidation, but it is significantly more challenging thermodynamically. The BQ/H2Q redox potential is sufficiently high that BQ is often used as an oxidant in Pd-catalyzed oxidation reactions. A recent report (J. Am Chem. Soc. 2020, 142, 19678-19688) showed that certain ancillary ligands can raise the PdII/0 redox potential sufficiently to reverse this reactivity, enabling (L)PdII(OAc)2 to oxidize hydroquinone to benzoquinone. Here, we investigate the oxidation of tert-butylhydroquinone (tBuH2Q) and 4-fluorobenzyl alcohol (4FBnOH), mediated by (bc)Pd(OAc)2 (bc = bathocuproine). Although alcohol oxidation is thermodynamically favored over H2Q oxidation by more than 400 mV, the oxidation of tBuH2Q proceeds several orders of magnitude faster than 4FBnOH oxidation. Kinetic and mechanistic studies reveal that these reactions feature different rate-limiting steps. Alcohol oxidation proceeds via rate-limiting β-hydride elimination from a PdII–alkoxide intermediate, while H2Q oxidation features rate-limiting isomerization from an O-to-C-bound PdII–hydroquinonate species. The enhanced rate of H2Q oxidation reflects the kinetic facility of O─H relative to C─H bond cleavage.

Graphical Abstract

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Introduction

Palladium(II)-catalyzed oxidation reactions are a versatile class of reactions in organic chemistry that enable diverse transformations, including alcohol oxidation, oxidative coupling of alkenes with heteroatom nucleophiles, oxidative C─C coupling reactions, among others. 1-15 These reactions typically feature two redox half-reactions, consisting of PdII-mediated substrate oxidation and reoxidation of Pd0 to PdII by various oxidants,16 including O217 and benzoquinone (BQ) (Scheme 1).18,19 Ancillary ligands, such as amines and mono- and bidentate pyridine derivatives, are increasingly common in Pd-catalyzed oxidation reactions. These ligands can influence both redox half-reactions, for example, by stabilizing the Pd catalyst, enhancing the rate of catalyst reoxidation, or modulating the chemo-, regio-, or stereoselectivity of substrate oxidation.15

Scheme 1.

Scheme 1.

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Redox Half Reactions in Pd-catalyzed Oxidations with Benzoquinone as the Oxidant.

We recently reported an experimental and computational study of the influence of ancillary ligands on the PdII/0 redox potential.20 This study was made possible by the unexpected finding that certain ligands, such as bathocuproine (bc), increase the PdII/0 potential sufficiently to allow oxidation of hydroquinone (H2Q) by (L)PdII(OAc)2, inverting the typical redox reactivity between PdII/0 and BQ/H2Q.21-23 Analysis of equilibria between (L)PdII(OAc)2/H2Q and (L)Pd0(BQ)/2 AcOH provided the basis for determination of formal redox potentials for various (L)PdII(OAc)2 complexes (Scheme 2A) relative to potentials associated with the BQ/H2Q and PhCHO/PhCH2OH redox reactions (Scheme 2B and 2C) 20,24,25

Scheme 2.

Scheme 2.

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Comparison of Redox Potentials for PdII/0, BQ/H2Q, and PhCHO/PhCH2OH.

Observation of (bc)Pd(OAc)2-mediated oxidation of hydroquinone provides a unique opportunity to compare thermodynamic-kinetic relationships between oxidative dehydrogenation of H2Q and alcohols. The redox potential for BQ/H2Q is ~400-500 mV higher than that of PhCHO/PhCH2OH (Scheme 2),25 but qualitative observations revealed that H2Q oxidation is much more rapid than PhCH2OH oxidation. This contra-thermodynamic kinetic behavior prompted us to pursue a quantitative comparison of the relative rates and probe the mechanisms of these two conceptually similar dehydrogenation reactions. Here, we report an investigation of stoichiometric oxidation of tert-butylhydroquinone (tBuH2Q) to tert-butylbenzoquinone (tBuBQ) and 4-fluorobenzyl alcohol (4FBnOH) to 4-fluorobenzaldehyde, mediated by (bc)Pd(OAc)2 (Scheme 3). Both reactions are conducted in the presence of tert-butylbenzoquinone (tBuBQ) to ensure that they have identical PdII/0 reagents/products, [(bc)Pd(OAc)2]/[(bc)Pd0(BQ)]. This study of stoichiometric alcohol oxidation by PdII complements multiple mechanistic studies of catalytic alcohol oxidation with PdII catalysts,6,26-33 while mechanistic studies of PdII-mediated oxidation of hydroquinone in the absence of a secondary oxidant are unprecedented.22

Scheme 3.

Scheme 3.

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(bc)Pd(OAc)2-Mediated Oxidation of tBuH2Q and 4FBnOH.

Results and Discussion

Kinetic investigation of (bc)Pd(OAc)2-mediated hydroquinone oxidation.

We initiated our investigation with a kinetic analysis of (bc)Pd(OAc)2-mediated oxidation of tBuH2Q at −30 °C in chloroform by UV-visible spectroscopy (monitoring appearance of an absorption band at 420 nM; see Figure S7 in the Supporting Information). This hydroquinone derivative was used instead of the parent H2Q because of its higher solubility in chloroform. The reaction forms the known complex, (bc)Pd0(tBuBQ).20 The concentration of (bc)Pd(OAc)2 was varied from 0.25-1.25 mM, with [tBuH2Q] fixed at 4 mM and [tBuBQ] at 1 mM. Then, [tBuH2Q] was varied from 1-10 mM, with [(bc)Pd(OAc)2] and [tBuBQ] fixed at 1 mM each. Comparison of the initial rates under each of these conditions revealed a first-order dependence on [(bc)Pd(OAc)2] and [tBuH2Q] (Figures 1a and 1b). The reaction was unaffected by changes to [tBuBQ] over a range of 1-8 mM concentration (See Supporting Information, Figure S9). No deuterium kinetic isotope effect was evident from independent rate measurements with tBuH2Q and tBuD2Q (kH/kD = 1.0 ± 0.2, Figure 1c; care was taken to avoid O─D exchange with sources of "H" in the glassware; see section 8 in the Supporting Information for details).

Figure 1.

Figure 1.

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Kinetic analysis of (bc)Pd(OAc)2-mediated oxidation of tBuH2Q, including (a) [(bc)Pd(OAc)2] dependence, (b) [tBuH2Q] dependence, and (c) kinetic isotope effect obtained via independent rate measurement. See sections 7 and 8 in the Supporting Information for experimental details.

Kinetic investigation of (bc)Pd(OAc)2-mediated alcohol oxidation.

Similar kinetic analysis was conducted for (bc)Pd(OAc)2-mediated oxidation of 4FBnOH. Use of this substrate facilitated analysis of the reaction by 19F NMR spectroscopy, although most kinetic data were acquired by UPLC analysis of reaction aliquots. The concentration of (bc)Pd(OAc)2 was varied from 2-12 mM, [4FBnOH] and [tBuBQ] fixed at 40 mM and 10 mM. Then, [4FBnOH] was varied from 10-160 mM, while fixing [(bc)Pd(OAc)2] and [tBuBQ] at 10 mM each. Comparison of the initial rates under each of these conditions revealed a first-order dependence on [(bc)Pd(OAc)2] and [4FBnOH] (Figures 2a and 2b). The reaction was unaffected by changes to [tBuBQ] (see Supporting Information, Figure S3). A deuterium kinetic isotope effect of kHkD = 2.0 ± 0.3 was observed from the comparison of independent rates measured with 4FBnOH and 4FPhCD2OH as the substrate. An intramolecular kinetic isotope of kHkD = 2.8 ± 0.3 was obtained from oxidation of 4FPhC(H)(D)OH (Figure 2c and 2d). These KIEs are similar to those observed for Pd-catalyzed alcohol oxidation with bc-ligated Pd catalysts.26 Hammett analysis of 4-substituted benzyl alcohols revealed that the reaction is slightly faster with more electron-rich alcohols (ρ = −0.33) (see Figure S6 in the Supporting Information).

Figure 2.

Figure 2.

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Kinetic analysis of (bc)Pd(OAc)2-mediated oxidation of 4FBnOH, including (a) [(bc)Pd(OAc)2] dependence (b) [4FBnOH] dependence, and kinetic isotopic effects determined by (c) independent rate measurements of 4FBnOH and 4FPhCD2OH and (d) an intramolecular competition experiment with 4FPhC(H)(D)OH. See sections 2 and 3 in the Supporting Information for experimental details.

Carboxylate electronic and steric effects and temperature analysis of hydroquinone and alcohol oxidation rates.

A series of bc-supported Pd carboxylate complexes, (bc)Pd(O2CR)2, were used to probe steric and electronic effects for oxidation of tBuH2Q and 4FBnOH. The carboxylate ligands included 4-trifluoromethylbenzoate, benzoate, 4-tert-butylbenzoate, acetate, and pivalate. Electronic parameters correspond to the pKa values of the conjugate acids of the carboxylates, which range from 10.1 to 12.6 (DMSO values).34-37 Relative steric effects were assessed by using a proxy value corresponding to the percent buried volume reported for PR3 groups (R = 4CF3Ph, Ph, 4tBuPh, Me, tBu) at 2 Å in (R3P)AuCl complexes.38,39

Initial rates of tBuH2Q oxidation were obtained with the different (bc)Pd(O2CR)2 complexes. A plot of log(rate) versus carboxylate pKa values revealed a slope of 0.06 with a poor correlation (R2 = 0.04) (Figure 3a), indicating the rate is not strongly correlated with the basicity of the carboxylate ligand. A relatively good correlation was observed, however, between log(rate) versus the buried volume parameter for the carboxylate ligands (R2 = 0.86) (Figure 3b), indicating that the rate of tBuH2Q oxidation by (bc)Pd(O2CR)2 is sensitive to the steric profile of the carboxylate ligand.

Figure 3.

Figure 3.

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Rate dependence of 4FBnOH oxidation by (bc)Pd(O2CR)2 on (a) pKa (DMSO) of RCO2H and (b) on percent buried volume. Rate dependence of tBuH2Q oxidation by (bc)Pd(O2CR)2 on (c) pKa (DMSO) of RCO2H and (d) on percent buried volume. ‡Percent buried volume values obtained from PR3 ligands (see text for details).

An analogous set of experiments was performed for 4FBnOH oxidation. In this case, the Brønsted plot exhibits a much better correlation (R2 = 0.99) with a positive slope (0.37) (Figure 3c), indicating that the reaction is promoted by more basic carboxylate ligands. On the other hand, the corresponding assessment of steric effects (Figure 3d) exhibits a very poor correlation (R2 = 0.02), indicating that steric effects of the carboxylate ligand play little role in 4FBnOH oxidation.

The studies described thus far have employed different temperatures for investigation of tBuH2Q and 4FBnOH oxidation reactions, −30 °C and 60 °C, respectively. These different temperatures highlight the faster rate of tBuH2Q oxidation. In order to permit quantitative comparison at a single temperature, both reactions were analyzed over a range of temperatures, from −40 – 0 °C for tBuH2Q and +30 – +60 °C for 4FBnOH. The resulting data were then subjected to Eyring analysis to obtain activation free energies at 298 K: ΔG‡tBuH2Q(298 K) = 17.1 kcal/mol and ΔG‡4FBnOH(298 K) = 23.1 kcal/mol. The values, which quantify the kinetic facility of tBuH2Q over 4FBnOH oxidation may be compared to the overall reaction free energies of reaction with (bc)Pd(OAc)2, which strongly favor 4FBnOH over tBuH2Q oxidation: ΔG°tBuH2O(298 K) = −2.9 kcal/mol20 and ΔG°4FBnOH(298 K) = approx. −22 kcal/mol (the latter estimated from the difference in reported reduction potentials of tBuBQ and benzaldehyde24,25). Both sets of energetic values are depicted in the energy diagram in Figure 4.

Figure 4.

Figure 4.

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Free energy diagram for (bc)Pd(OAc)2-mediated oxidation of 4FBnOH and tBuH2Q.

Mechanistic analysis.

The kinetic data elaborated above provide a foundation for understanding the origin of the contra-thermodynamic outcome depicted in Figure 4. The data reveal both similarities and differences between (bc)Pd(OAc)2-mediated oxidation of tBuH2Q and 4FBnOH. Both reactions feature a first-order dependence on [(bc)Pd(OAc)2] and [substrate], but they exhibit different KIEs and show different electronic and steric effects. Mechanisms that rationalize these observations are depicted in Scheme 4A.

Scheme 4.

Scheme 4.

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Proposed Mechanisms for (A) Hydroquinone and Benzyl Alcohol Oxidation Mediated by (bc)Pd(OAc)2 and (B) Oxidation of Pd0 by Benzoquinone in the Presence of Acid21

Oxidation of tBuH2Q by (bc)Pd(OAc)2 (Scheme 4A, top) is proposed to begin with formation of a PdII-(O-hydroquinonate) species 1a via proton-coupled ligand exchange30 between acetate and tBuH2Q, followed by rate-limiting isomerization to the PdII-(C-hydroquinonate) species 1b. These steps rationalize (a) the rate law, with a first order dependence on [Pd] and [tBuH2Q], and (b) the lack of a primary kinetic isotope effect, since H/D reactivity is incorporated in an equilibrium step expected to have negligible equilibrium isotope effect. The lack of systematic correlation between the rate and carboxylate pKa suggests proton transfer steps are not involved in the rate-limiting step, while the carboxylate steric influence, favoring less sterically hindered carboxylates, is rationalized by rate-limiting isomerization of the hydroquinonate to the more hindered C-bound isomer 1b. The reaction concludes with an intramolecular redox reaction involving proton transfer from the phenolic O─H of 1b to the carboxylate, coupled to two-electron transfer to Pd. This step forms the (bc)Pd0(BQ) product 3. This mechanism corresponds to the microscopic reverse of the mechanism proposed by Bäckvall for acid-promoted oxidation of well-defined Pd0(BQ) complexes (Scheme 4B).21

The oxidation of 4FBnOH (Scheme 4A, bottom) is similarly proposed to begin with proton-coupled exchange of 4FBnOH with acetate at (bc)Pd(OAc)2 to generate Pd-alkoxide 1b. The kinetic isotope effect data, however, suggest that β-hydride elimination to generate PdII-hydride 2b is rate-limiting. The electronic dependence on the carboxylate ligand suggests that formation of the PdII-alkoxide 2a also contributes the reaction rate.6 Subsequent loss (formally, reductive elimination) of acetic acid from 2b in the presence of tBuBQ forms the Pd-quinone product 3. The kinetic facility of this step,40 enhanced further by the ability of quinones to promote H─O2CR reductive elimination from PdII(H)(O2CR) complexes,41 rationalizes the zero-order dependence of the reaction rate on [tBuBQ].

To summarize, 4FBnOH oxidation has a significantly higher kinetic barrier than tBuH2Q oxidation, even though the net reaction of 4FBnOH is more favorable by approximately 20 kcal/mol. At least two factors support faster rates of tBuH2Q oxidation. The first step in both reactions involves proton-coupled ligand substitution between the substrate and a carboxylate ligand, and H2Q is significantly more acidic than benzyl alcohol (aqueous pKa value of H2Q is ~5 units lower than the pKa of benzyl alcohol).42,43 Thus, the pre-equilibrium formation of a PdII-hydroquinonate intermediate will be strongly favored relative to formation of a PdII-alkoxide. The difference in relative rates, however, ultimately arises from the difference in relative energies of the rate-limiting transition states. The data indicate that the transition state for hydroquinonate isomerization is lower in energy than the transition state for PdII-alkoxide β-hydride elimination. Net hydride transfer from the hydroquinonate intermediate, involving proton transfer to carboxylate and two-electron transfer to Pd, is sufficiently facile that it proceeds after the rate-limiting isomerization step. This step is undoubtedly facilitated by the polarity of the O─H bond of the hydroquinonate, which facilitates proton transfer, relative to cleavage of the C─H bond involved in β-hydride elimination from the alkoxide.44

Conclusions

The mechanistic studies of (bc)Pd(OAc)2-mediated oxidation of 4FBnOH and tBuH2Q outlined above illuminate the kinetic and thermodynamic relationships between these reactions. The oxidation of 4FBnOH is approximately 20 kcal/mol more favorable than the oxidation of tBuH2Q. Nonetheless, the activation energy for 4FBnOH oxidation is substantially higher than that for tBuH2Q oxidation (ΔΔG‡ = 6 kcal/mol), resulting in tBuH2Q oxidation proceeding several orders of magnitude faster than 4FBnOH oxidation at room temperature. Mechanistic data provide insights into the different rate-limiting steps for these reactions, which feature β-hydride elimination for 4FBnOH oxidation and isomerization from an O-to-C-bound hydroquinonate in tBuH2Q oxidation. This study represents the first mechanistic analysis of hydroquinone by PdII complexes, and it was made possible by the identification of ancillary ligands that increasing the PdII/0 redox potential sufficiently to support oxidation of hydroquinones.

Supplementary Material

SI

ACKNOWLEDGMENT

This article is dedicated to Maurice Brookhart on the occasion of his 80th birthday. We have been inspired by Brook's leadership in the field of organometallic chemistry and homogeneous catalysis throughout his career. Funding for the experimental work was provided by the National Science Foundation (CHE-1953926; SSS). Spectroscopic instrumentation was supported by a gift from Paul J. Bender, NSF (CHE1048642), and the NIH (1S10 OD020022-1).

Footnotes

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website: Experimental details and compound characterization data (PDF).

The authors declare no competing financial interests.

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Supplementary Materials

SI
NIHMS1817860-supplement-SI.pdf (704.2KB, pdf)

RESOURCES