Other Aromatic Substitutions

Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions, but fluorine is too reactive, and only poor yields of monofluoroaromatic products are obtained by direct fluorination. Aromatic rings react with CI2 in the presence of FeCh catalyst to yield chlorobenzenes. This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the tranquilizer diazepam (Valium). 

Iodine itself is unreactive toward aromatic rings, and an oxidizing agent such as hydrogen peroxide or a copper salt such as CuClz must be added to the reaction. These substances accelerate the iodination reaction by oxidizing I2 to a more powerful electrophilic species that reacts as if it were I. The aromatic ring then attacks I in the typical way, yielding a substitution product. 

Aromatic rings can be nitrated by reaction with a mixture of concentrated nitric and sulfuric acids. The electrophile in this reaction is the nitronium 

The mechanism of electrophilic nitration of an aromatic ring. An electrostatic potential map of the reactive electrophile NO/ shows that the nitrogen atom is most positive (btue). 

Aromatic rings can be sulfonated by reaction with fuming sulfuric acid, a mixture ofH2S04 and SO. The reactive electrophile is either HSO / or neu-i tral SO3, depending on reaction conditions. Substitution occurs by the sar two-step mechanism seen previously for bromination and nitration (Fig 16.7). Note, however, that the sulfonation reaction is readily reversible i can occur either forward or backward, depending on the reaction condition 

There are many other kinds of electrophilic aromatic substitutions besides bromination, and all are thought to occur by the same general mechanism. Let s look at some of these other reactions briefly. 

Nitration of an aromatic ring does not occur in nature but is particularly important in the laboratory because the nitio-substituted product can be reduced by reagents such as iron, tin, or SnCl2 to yield an aryhmwie, ArNH2-Attachment of an amino group to an aromatic ring by the two-step 

Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) is difficult and rarely done in the laboratory., but occurs much more frequently in biological pathways. An example is the hydroxylation of p-hydroxyphenyl acetate to give 3,4-dihydroxyphenyl acetate. The reaction is catalyzed by p-hydroxyphenylacctate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH2. 

How many products might be formed on chlorination of oxylene (odimethyl-benzene), m-xylene, and p-xylene  

Problem 16.3 When benzene is treated with D2SO4, deuterium slowly replaces all six hydrogens in the aromatic ring. Explain. 

Iodine itself is unreactive toward aromatic rings, so an oxidizing agent such as hydrogen peroxide or a copper salt such as CUCI2 must be added to the 

Problem 16.1 Monobromination of toluene gives a mixture of three bromotoluene products. Draw and name them. 

CHAPTER 16 I Chemistry of Benzene Electrophilic Aromatic Substitution 

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For example, direct fluorinations with elemental fluorine are kept imder control in this way, at very low conversion and by entrapping the molecules in a molecular-sieve reactor. As with some other aromatic substitutions they can proceed by either radical or electrophilic paths, if not even more mechanisms. The products are dif ferent then this may involve position isomerism, arising from different substitution patterns, when the aromatic core already has a primary substituent further, there may be changed selectivity for imdefined addition and polymeric side products (Figure 1.31). It is justified to term this and other similar reactions new , as the reaction follows new elemental paths and creates new products or at least new... 

Thiourea, as well as the other thjoamidee, reacts with ethyl phenylglyddat to yield ethyl oinnamate, sulfur and the o-atnide (Eq. 9). This is in accord with the fact that other aromatic-substituted... 

Further insight came from our study of other aromatic substitution reactions. When we blocked the para position of anisole in compound 65, we saw that ortho chlorination was blocked by binding with a-cyclodextrin, so the only reaction was from the substrate that was in free solution, not that which was bound. However, with p-cresol (66) there was still, of course, ortho chlorination but now it was catalyzed by the a-cyclodextrin. When p-cresol binds to the cyclodextrin, the polar phenol or phenoxide group will be out of the cavity, bringing the ortho positions within reach of the cyclo-... 

As with other aromatic substitutions, the substitution step itself can be considered to involve an approximately sps hybridization at the carbon atom under attack (10). In the idealized substitution process shown in Eq. (16), 10 may constitute either an intermediate or a transition state. If proton loss ensues directly, the process is properly called a substitution. In other situations the intermediate 10 may become allied with a radical or an anion, leading thereby to a covalent adduct 11. The final substituted product 12 may then be formed either by the elimination of H—Z (first H, then Z) or by the reversal to 10, followed by proton loss. The first case is a classical example of an addition-elimination halogenation, where the adduct is an essential species in the process. In the second case, structure 10 is a common intermediate for both the substitution and the addition reactions. Being merely a diversion of 10, the addition product is not essential to the substitution. In consequence of this, the isolation of adduct 11 may not mean that addition-elimination is the principal pathway of substitution reversal to 10 may be faster than the elimination of H—Z ( 2, k3>ki). On the other hand, the mere failure to detect adduct 11 does not rule out an addition-elimination process, for dehydrohalogenation of adduct 11 may be much faster than its formation (ki>klt k2). 

Electrophilic substitution, then, like electrophilic addition, is a stepwise process involving an intermediate carbonium ion. The two reactions differ, however, in the fate of the carbonium ion. While the mechanism of nitration is, perhaps, better established than the mechanisms for other aromatic substitution reactions, it seems clear that all these reactions follow the same course. 

Bromination of Aromatic Rings 593 Other Aromatic Substitutions 597 Alkylation of Aromatic Rings The Friedel-Crafts Reaction Acylation of Aromatic Rings 604 Substituent Effects in Substituted Aromatic Rings 605 An Explanation of Substituent Effects 610 Trisubstituted Benzenes Additivity of Effects... 

Silicon and tin are both subject to ipra-replacement by electrophiles, via an electrophilic addition/metal elimination mechanism analogous to other aromatic substitutions, but at a much faster rate than the corresponding replacement of hydrogen. /pra-substitutions also take place on heterocycles and, in the case of electron-rich systems, probably via the same type of mechanism. 

Other aromatic substitutions. Aryl cyanides can be prepared from aryl chlorides in the Pd(0)-catalyzed reaction with Zn-Zn(CN)2, and from aryl bromides and iodides, with CuCN. ... 

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