Iron-catalyzed Aromatic Substitutions

Jette Kischel, Kristin Mertins, Irina Jovel, Alexander Zapf, and Matthias Belter 

Functionalization of C—H bonds via aromatic substitution is an important means of adding functional groups to all kinds of arenes and as such is of significant relevance to many areas of chemistry. Notably, the key step in several industrially important reactions is an electrophilic attack on aromatic Jt-systems by carbocations or other strong electrophiles. 

Typically, in electrophilic aromatic substitutions, the electrophilic attack results from the high electron concentration on both sides of the aromatic ring [ 1 ]. For the 

With respect to iron catalysts, iron(III) chloride is one of the most common catalysts known for electrophilic aromatic substitutions and has been widely used in the past. In genera], it is an inexpensive and eco-friendly reagent featuring a higher catalytic activity than other metal chlorides [5, 6]. 

Iron Catalysis in Organic Chemistry. Edited by Bernd Plietker Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31927-5 

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Since aromatic substitutions, aliphatic substitutions, additions and conjugate additions to carbonyl compounds, cycloadditions, and ring expansion reactions catalyzed by Fe salts have recently been summarized [17], this section will focus on reactions in which iron salts produce a critical activation on unsaturated functional groups provided by the Lewis-acid character of these salts. 

The direct arylation of arenes with stannaries ArSnCls is similarly catalyzed by PdCl2 and proceeds with CuCh as oxidant [152]. In this instance, a different mechanism was suggested based on the transmetallation between the stannane and a Pd(lV) salt, followed by an electrophilic aromatic substitution and reductive elimination. Arylzinc reagents also arylate 2-arylpyridines in the presence of iron catalysts [153]. 

The high-valent iron-oxo sites of nonheme iron enzymes catalyze a variety of reactions (halogenation and hydroxylation of alkanes, desaturation and cyclization, electrophilic aromatic substitution, and cis-dihydroxylation of olefins) [lb]. Most of these (and other) reactions have also been achieved and studied with model systems [Ic, 2a-c]. With the bispidine complexes, we have primarily concentrated on olefin epoxidation and dihydroxylation, alkane hydroxylation and halogenation, and sulfoxidation and demethylation processes. The focus in these studies so far has been on a thorough analysis of the reaction mechanisms rather than the substrate scope and catalyst optimization. 

The reaction should not be done in a steel reactor because of corrosion issues. But there is another reason. Even the slightest bit of corrosion in the presence of chlorine will give iron (III) chloride. This serves as a Lewis acid and catalyzes electrophilic aromatic substitution. The reaction is drawn showing the formation of the para isomer but other isomers are also formed. Ring-chlorinated toluene is an unwanted and difficult-to-remove impurity if you are making benzyl chloride. 

In 2010, Zhu and coworkers first reported the direct intramolecular C(sp )-H amination of Af-arylpyridine-2-ammes using a combination of Cu(OAc)2 and Fe(N03)3 as a bimetalUc catalytic system to furnish pyrido[l,2-a]benzimidazoles in satisfactory yields [13]. The authors believe that a Cu(lll)-catalyzed electrophilic aromatic substitution (SEAr) pathway is operating in this process according to the results of mechanistic studies, wherein iron(lll) acts a unique role to facilitate the formation of the more electrophilic Cu(III) species because in the absence of iron(III), a much less efficient and reversible Cu(II)-mediated SEAr process takes place. 

Tris (triphenylphosphine) nickel, tris (tri-p-tolylphosphine) nickel, and bis (1,3-diphenylphosphinepropane) nickel proved to be good catalysts, the first being slightly more effective. The tricyclohexylphosphine complex was a very poor catalyst, and bis (cyclooctadiene) nickel did not catalyze cyanation. Cyanation of several substituted aromatic halides in the presence of Ni[P(C6H5)3]3 prepared by reducing dichlorobis (triphenylphosphine) nickel (II) 2 with a powdered manganese iron (80 20) alloy (Reaction 3) is reported in Table II. 

Selective reduction to hydroxylamine can be achieved in a variety of ways the most widely applicable systems utilize zinc and ammonium chloride in an aqueous or alcoholic medium. The overreduction to amines can be prevented by using a two-phase solvent system. Hydroxylamines have also been obtained from nitro compounds using molecular hydrogen and iridium catalysts. A rapid metal-catalyzed transfer reduction of aromatic nitroarenes to N-substituted hydroxylamines has also been developed the method employs palladium and rhodium on charcoal as catalyst and a variety of hydrogen donors such as cyclohexene, hydrazine, formic acid and phosphinic acid. The reduction of nitroarenes to arylhydroxyl-amines can also be achieved using hydrazine in the presence of Raney nickel or iron(III) oxide. ... 

Cycloaddition, Diels-Alder reactions, epoxidation of aromatic aldehydes, isomerization of aryl-substituted epoxides, and aziridination catalyzed by the iron Lewis acid [(j 5-C5H5)Fe(CO)2(THF)] 03ACA3. 

Monooxygenation of aromatics, alicyclic and linear alkanes with molecular oxygen is catalyzed by nonheme iron complexes in the anhydrous organic solvents in the presence of hydroquinones as electron and proton donors. Iron complexes are prepared in situ by stirring FeCla, pyrocatechol, and pyridine (mole ratio is 1 1 2) in acetonitrile or in pyridine. Isolated catecholatoiron complex is also used. Catalytic activity is greatly dependent on the kinds of hydroquinone and increases in the order of 2,5-di-t-butyl- t-butyl->methyl->H-hydroquinone. Non-substituted hydroquinone hardly exhibits activity, and the activity is controlled by the oxidation potential and steric effect of hydroquinones. 

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