Oxidation of Aromatic Side Chains

Aromatic acids can be prepared by oxidizing an alkyl side chain on an aromatic ring. 

This reaction illustrates the striking stability of aromatic rings it is the alkane-like methyl group, not the aromatic ring, that is oxidized. The reaction involves attack of the oxidant at a C—H bond adjacent to the benzene ring. Longer side chains are also 

If no C—H bond is in the benzylic position, however, the aromatic ring is oxidized, although only under severe reaction conditions. 

With oxidants other than potassium permanganate, this reaction is commercially important. For example, terephthalic acid (Sec. 10.1), one of the two raw materials needed to manufacture Dacron, is produced in this way, using a cobalt catalyst and air for the oxidation. 

Phthalic acid, used for making plasticizers, resins, and dyestuffs, is manufactured by similar oxidations, starting with o-xylene. 

Peroxygen systems have three distinct advantages in industrial side chain oxidation compared to the employment of air. Firstly, the reactions can be conducted at atmospheric pressure, and moderate temperature, which makes this an option for small- to medium-volume production in general purpose (low cost) plant. Secondly, the selectivity to produce alcohols or aldehydes is easier to 

Application of Hydrogen Peroxide for the Synthesis of Fine Chemicals 

Alkaline hydrogen peroxide does not attack alkyl side chains directly, but it can be very useful for the conversion of the aromatic aldehyde to the carboxylic acid in the side chain oxidation sequence. The chemistry is covered in Section 6.1. Peracids usually do not attack alkyl side chains, but can oxidize benzylic alcohols and aldehydes to the carboxylic acids and benzylic ketones to phenyl ester. These reactions are covered in sections on alcohol (5), aldehyde (6.1) and ketone (6.2) oxidation. 

Toluenes can be oxidized by Caro s acid (H2S05) activated by iron(II) salts.286 

The cobalt(II) acetate/acetic acid/sodium bromide (CAB) combination is well known for the autoxidation of alkyl benzenes.287 It is normally employed for the production of terephthalic acid from 1,4-dimethylbenzene.281 However, the use of hydrogen peroxide, as mentioned earlier, means the systems are generally more selective, and can be operated at ambient pressure and relatively low temperatures. 

The power of green chemistry is nicely illustrated by reference to the production of aromatic acids. Classical methods using chlorine or nitric acid have been largely displaced by catalytic oxidations with dioxygen (see Fig. 4.48). This leads to high atom utilization, low-salt technology, no chloro- or nitro-compounds as by-products and the use of a very cheap oxidant. 

Oxidation of hydrocarbons with dioxygen is more facile when the C-H bond is activated through aromatic or vinylic groups adjacent to it. The homolytic C-H bond dissociation energy decreases from ca. 100 kcal mol-1 (alkyl C-H) to ca. 85 kcal mol-1 (allylic and benzylic C-H), which makes a number of autoxidation processes feasible. The relative oxidizability is further increased by the presence of alkyl substituents on the benzylic carbon (see Table 4.6). The autoxidation of isopropylbenzene (Hock process, Fig. 4.49) accounts for the majority of the world production of phenol [131]  

In the Amoco/MC process terephthalic acid (TPA) is produced by aerobic oxidation of p-xylene. This bulk chemical ( 10xl061 a-1) is chiefly used for poly- 

The rather drastic conditions are required because in this particular case the COOH group deactivates the intermediate p-toluic acid towards further oxidation, and some p-carboxybenzaldehyde is found as a side-product, which is hydrogenated back to p-toluic acid. Other than that, a large number of functional groups are tolerated (see Table 4.7) [129]. The combination of cobalt, manganese and bromide ions is essential for optimum performance. The benzylic radicals are best generated with bromine atoms (see above) which in turn are more easily produced 

Complete conversion 90-98% yield Side reactions 30-70% yield Total radical consumption no yield 

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Etard reagents (chromyl chloride and some derivatives) suffer from the problem that occasionally they can exhibit a lack of selectivity and low yields. They are useful in the selective oxidation of aromatic side-chains to a carbonyl group, aldehyde or ketone but in many instances, the formation of the initial complex is slow and yields are low because of difficulties in the work-up which lead to undesired over-reaction. Attempts have been made to solve the problems by the use of sonication [134]. A simple preparation of the liquid reagent was proposed and the Etard reaction itself together with the hydrolytic step were conducted under sonication, with some success (Scheme 3.25). 

Oxidative cleavage of olefins, terminal alkynes, or aromatic rings 9-11 Oxidation of aromatic side chains 9-21 Oxidation of amines 9-22 Oxidation of primary alcohols or ethers... 

Potassium nitrosodisulfonate, 258 Trimethylsilyl chlorochromate, 327 By hydrolysis of acetals or thioacetals Amberlyst ion-exchange resin, 152 Methylthiomethyl p-tolyl sulfone, 192 By isomerization of allylic alcohols N-Lithioethylenediamine, 157 By oxidation of aromatic side chains Trimethylsilyl chlorochromate, 327 From oxidative cleavage of alkenes [Bis(salicylidene-7-iminopropyl)-methylamine]cobalt(II)... 

A good yield of p-nitrobenzoic acid2 is obtained from p-nitrotoluene if a lead peroxide anode be employed in a mixture of sulphuric and acetic acids. Investigations upon the oxidation of aromatic side-chains have been conducted by Smith3 and also by Law and Perkin.4... 

Fig. 4.51 Mechanism for the aerobic oxidation of aromatic side-chains.

Nickel peroxide, an undefined black oxide of nickel, is prepared from nickel sulfate hexahydrate by oxidation in alkaline medium with an ozone-oxygen mixture [929] or with sodium hypochlorite [930, 931, 932, 933]. Its main applications are the oxidation of aromatic side chains to carboxyls [933], of allylic and benzylic alcohols to aldehydes in organic solvents [929, 932] or to acids in aqueous alkaline solutions [929, 930, 932], and of aldehydes to acids [934, the conversion of aldehyde or ketone hydrazones into diazo compounds [935] the dehydrogenative coupling of ketones in the a positions with respect to carbonyl groups [931] and the dehydrogenation of primary amines to nitriles or azo compounds [936]. 

Benzylic oxidation of aromatic side-chains is also a well established technology in the bulk chemicals arena, e. g. toluene to benzoic acid and p-xylene to ter-ephthalic acid [1,2]. These processes involve homogeneous catalysis by, e. g., cobalt compounds, however, and also fall outside the scope of this book. Ammoxi-dation of methyl-substituted aromatic and heteroaromatic compounds is performed over heterogeneous catalysts in the gas phase but this reaction is treated elsewhere (Section 9.5). Transition metal-substituted molecular sieves have been widely studied as heterogeneous catalysts for oxidation of aromatic side-chains in the liquid phase, but there are serious doubts about their heterogeneity [5,6]. Here again, a cursory examination of the literature reveals that supported palladium seems to be the only heterogeneous catalyst with synthetic utility [4]. 

Similarly, the CrAPO-5- and chromium silicalite-1 (CrS-l)-catalyzed oxidation of aromatic side-chains with TBHP or O2 as the primary oxidant [27-31] almost certainly arises as a result of soluble chromium(VI) leached from the catalyst. The same probably applies to benzylic oxidations with TBHP catalyzed by chromium-pillared montmorillonite [32]. More recently, a chromium Schiff s base complex tethered to the mesoporous silica, MCM-41, was claimed [33] to be an active and stable catalyst for the autoxidation of alkylaromatic side-chains. It would seem unlikely, however, that Schiff s base ligands can survive autoxidation conditions. Indeed, on the basis of our experience with chromium-substituted molecular sieves we consider it unlikely that a heterogeneous chromium catalyst can be developed that is both active and stable to leaching under normal oxidizing conditions with O2 or RO2H in the liquid phase. Similarly, vanadium-substituted molecular sieves are also unstable towards leaching under oxidizing conditions in the liquid phase [6,34]. 

Perhaps the most familiar and useful hydrocarbon oxidation is the oxidation, of aromatic side chains. Two factors enter into making this a high-yield procedure despite the use of powerful oxidants First, the benzylic site is activated to oxidation. Either radical or carbonium intermediates can be especially easily formed here because of the potential resonance stabilization. Second, the aromatic ring is inert to attack by the Mn(VII) and Cr(VI) oxidants that attack the alkyl side chain. 

Several examples of oxidation of aromatic side chains are given in Scheme 9.16. Entries 3 and 5 are cases where the oxidation is terminated at stages short of the carboxylic acid oxidation state. 

Oxidation of Aromatic Side Chains and Aromatic Ring System Some examples are given (Scheme 79). 

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