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9 Catalytic Aerobic Oxidation of Phenols

DOI: 10.1055/sos-SD-225-00304

Lumb, J.-P.; Esguerra, K. V. N.Science of Synthesis: Catalytic Oxidation in Organic Synthesis, (20171587.

General Introduction

Phenols are ubiquitous in the chemical industry. Historically, phenol itself was used as a disinfectant to sterilize wounds and medical equipment, and is polymerized to produce plastics. Bakelite, a phenol–formaldehyde polymer, was the first industrial phenolic resin, and served as a key component in insulators for electrical devices, which were fundamentally important to the generation and distribution of electricity.[‌1‌,‌2‌]

In fine-chemical synthesis, phenols are frequently utilized as building blocks. Phenol itself is a solid at room temperature, with a melting point of 40 °C.[‌3‌] As a liquid, it is colorless, and has limited miscibility in water at temperatures below 68 °C.[‌3‌,‌4‌] Substituted derivatives of phenol are readily prepared by standard synthetic transformations, and are generally soluble in organic solvents, including aromatic hydrocarbons, alcohols, ketones, ethers, acids, and halogenated solvents, but somewhat less soluble in aliphatic solvents such as pentanes and hexanes.[‌2‌] Amongst the many methods of functionalizing phenols, those which involve dearomatization have received considerable interest, leading to the development of numerous stoichiometric reagents that are capable of oxidizing phenols by one or two electrons (Scheme 1).[‌5‌‌10‌]

Amongst these oxidants, molecular oxygen (O2) is the most attractive from an economic and environmental perspective.[‌11‌] However, direct oxidation of organic molecules using oxygen is challenged by competitive radical chain reactions, since nonradical pathways are spin-forbidden as a result of molecular oxygen existing in a triplet electronic ground state. Because most organic molecules, including phenols, possess singlet electronic ground states, nonradical aerobic oxidations require activation of molecular oxygen with metal catalysts, or energy in the form of heat or light.[‌12‌‌15‌] Biological systems are well-known to activate molecular oxygen with exceptional fidelity, and, as such, the active sites of metalloenzymes have provided important blueprints for the design and development of synthetic systems capable of selective aerobic oxidations.[‌15‌‌18‌]

Scheme 1 Resonance-Stabilized Radical Species Following Oxidation of meta-Substituted Phenols

Nonenzymatic, catalytic aerobic systems that can oxidize phenols with high selectivity are limited. This stands in stark contrast to the more facile aerobic oxidation of naphthols.[‌19‌‌23‌] Phenols are more difficult to oxidize, as evidenced by their redox potentials (naphthol = 1.87 eV, phenol = 2.10 eV, measured using Ag/AgI electrode referenced to ferrocenium tetrafluoroborate).[‌24‌] In cases where oxidation produces a radical, spin density is more widely distributed to the ortho- and para-positions of the phenol, whereas in 2-naphthols it is more localized to the C1 position. As a result, phenoxyl radicals can undergo a multitude of nonselective C—C or C—O coupling reactions,[‌10‌] in addition to oxygenation to afford either benzo-1,2- or benzo-1,4-quinones (Scheme 2).

Scheme 2 Various Products Arising from Aerobic Oxidation of Phenols[‌10‌]

Phenolic oxidation can take place via a number of different mechanisms. These include: (i) hydrogen atom abstraction (or proton-coupled electron transfer, PCET); (ii) electron transfer–proton loss (ET-PL); or (iii) sequential proton loss electron transfer (SPLET).[‌25‌,‌26‌] PCET is favored for phenols with weaker O—H bonds compared to A—H (i.e., bond dissociation energy of Ar1O—H is lower than that for A—H), where A is any acceptor atom or molecule (Scheme 3).[‌26‌‌28‌] For example, hydrogen atom abstraction of the phenol O—H by hydroxyl radical is thermodynamically favored by 31 kcal · mol−1 (bond dissociation energy of HO—H = 119 kcal · mol−1, and PhO—H = 88 kcal · mol−1). ET-PL is also feasible, as evidenced by studies on the low gas-phase ionization potentials of phenols (Scheme 4, wherein an electron is transferred to A),[‌26‌,‌29‌] and this mode of oxidation tends to occur under acidic conditions. The resulting phenoxonium radical cation (Ar1OH•+) affords the phenoxyl radical (Ar1O) following deprotonation. However, due to the high acidity of ArOH•+, proton transfer is fast, thus blurring the lines between ET-PL and PCET mechanisms. Similarly, phenoxyl radicals, formed via SPLET, can be generated from phenolates (Ar1O) following electron transfer (Scheme 5).[‌30‌] Distinguishing between these mechanisms under the dynamic conditions of catalysis can be difficult, as dramatic changes to the mechanism can occur as a result of subtle changes to the reaction conditions.[‌30‌‌33‌]

Scheme 3 Proton-Coupled Electron Transfer[‌26‌‌28‌]

Scheme 4 Electron Transfer–Proton Loss[‌26‌,‌29‌]

Scheme 5 Sequential Proton Loss Electron Transfer[‌30‌]

The electronic nature of the phenol has a significant effect on the ability of a catalytic system to convert the phenol into a phenoxyl radical, and thus ultimately influences reaction pathways. In general, electron-donating groups favor radical formation, while electron-withdrawing groups tend to slow oxidation.[‌34‌] This has been attributed to a weakening of the O—H bond for phenols bearing electron-donating groups (e.g., calculated bond dissociation energy for p-anisole in water is 78 kcal · mol−1, while for 4-nitrophenol is 92 kcal · mol−1).[‌29‌,‌34‌‌36‌] Moreover, several studies indicate that an intimate association between a metal oxidant and a phenoxyl radical changes the electronic nature of the radical, and plays a pivotal role in controlling reaction trajectories. For example, generation of a metal phenolate is key to ensuring selective C—O bond formation in Hayʼs aerobic polymerization of 2,6-dimethylphenol, whereas free phenoxyl radicals preferentially afford C—C coupled products.[‌37‌‌40‌] Nevertheless, factors that govern the coordination of phenolates or phenoxyl radicals remain poorly understood.

This chapter highlights notable examples of aerobic oxidations of phenols, including C—H functionalization and dearomatization. Phenols containing additional heteroatom substitution, such as catechol, resorcinol, hydroquinone, aminophenols, and benzenethiols display unique reactivity profiles, and are therefore excluded. Likewise, the chemistry of naphthols is not described.