Regioselective Synthesis of Disubstituted Aromatic Compounds

Since the position of electrophilic attack on an aromatic ring is controlled by the directing effects of substituents already present, the preparation of disubstituted aromatic compounds requires that careful thought be given to the order of introduction of the two groups. 

Compare the independent preparations of m-bromoacetophenone and p-bromoace-tophenone from benzene. Both syntheses require a Friedel-Crafts acylation step and a bromination step, but the major product is determined by the order in which the two 

Aluminum chloride is a stronger Lewis acid than iron(lll) bromide and has been used as a catalyst in electrophilic bromination when, as in the example shown, the aromatic ring bears a strongly deactivating substituent. 

When the ortho, para-directing bromine is introduced first, the major product is p-bro-moacetophenone (along with some of its ortho isomer, from which it is separated by distillation). 

PROBLEM 12.18 Write chemical equations showing how you could prepare m-bromonitrobenzene as the principal organic product, starting with benzene and using any necessary organic or inorganic reagents. How could you prepare p-bromonitrobenzene  

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The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

Owing to their numerous applications as fine chemicals for the synthesis of bioactive compounds such as pesticides and pharmaceuticals, isomerically pure chloroaromatics are very valuable materials. /-Butyl hypochlorite/HNa fauja-site in acetonitrile represents an efficient and highly regioselective system of mono-chlorination of a wide range of mono- and disubstituted aromatic substrates in mild conditions (Reaction S). 

The 3,6-diposition-substituted pyridine compounds are important intermediates for industrial synthesis, especially for production of some agricultural chemicals. This compound can be obtained by chemically synthesized from pyridine, but the process is accompanied by some by-products. Microbial hydroxylation of aromatic compounds is a very efficient method of regioselective reaction. Several methods have been reported for the preparation of 3,6-disubstituted pyridine using microorganisms. In 1985, Lehky et al. reported the microbial production of 6-hydroxynicotinic acid (6-HNA) from nicotinic acid (NA) by Achromobacter xylosoxydans Nagasawa et al. also prepared 6-HNA from NA by using Pseudomonas fluorescens TN5. 

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