Aromatic substitution reactions chlorination

We have already seen that we can substitute bromine and chlorine for hydrogen atoms on the ring of tolnene and other alkylaromatic compounds using electrophilic aromatic substitution reactions. Chlorine and bromine can also be made to replace hydrogen atoms that are on a benzylic carbon, such as the methyl group of toluene. 

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

Two electrophilic aromatic substitution reactions need to be performed chlorination and Friedel-Crafts acylation. The order in which the reactions are carried out is important chlorine is an ortho, para director, and the acetyl group is a meta director. Since the groups are meta in the desired compound, introduce the acetyl group first. 

Leaving groups at C5 of 2-substituted 1,2,3-triazoles are predicted to be the most reactive in nucleophilic aromatic substitution reactions following an AE mechanism (see Section 1.4.2). Accordingly, chlorine at C5 of 360 could be replaced by strong nucleophiles like methanethiolate or methoxide to give 377 or 378. The unactivated 2-phenyl-4-chloro-l,2,3-triazole 380 (R=Ph) was inert toward these nucleophiles (1981JCS(P1)503) (Scheme 115). 

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-... 

IC1 can be represented as I Cl because chlorine is a more electronegative element than iodine. Iodine can act as an electrophile in electrophilic aromatic substitution reactions. 

Intramolecular nucleophilic substitution reactions of chlorine " " or bromine with alco-holates lead to tetrahydropyrans. The alcoholate can be formed in situ by deprotccting an alcohol.Activated aromatic chlorides give in nucleophilic aromatic substitution reactions a six-membered heterocyclc, e.g, reaction of 1 to give 2. ... 

TriCTAs and TeCTAs were prepared by stepwise addition of sulfuryl chloride over 4 h at 60°C. The degree of chlorination was found to be three to four (only tri- and tetrachlorinated thianthrenes were observed as reaction products) when all of the parent compound was consumed. One TriCTA and one TeCTA were obtained as main products. In addition, two other TriCTAs, four TeCTAs, and some PeCTAs were observed in minor concentrations. Because of the ortho- and para-directing properties of sulfur in electrophilic aromatic substitution reactions, 237-TriCTA and 2378-TeCTA, the thio analogue of 2378-TeCDD, were obtained as the main products. Mass spectrometry and H NMR were used in the structure verification. 

To place chlorine on the ring, an electrophilic aromatic substitution reaction must be used. The reaction requires FeCls and can be written as ... 

We have already seen in this chapter that we can substitute bromine and chlorine for hydrogen atoms on the benzene ring of toluene and other alkylaromatic compounds using electrophilic aromatic substitution reactions. We can also substitute bromine and chlorine for hydrogen atoms on the benzylic carbons of alkyl side chains by radical reactions in the presence of heat, light, or a radical initiator like a peroxide, as we first saw in Chapter 10, (Section 10.9). This is made possible by the special stability of the benzylic radical intermediate (Section 15.12A). For example, benzylic chlorination of toluene takes place in the gas phase at 400-600 °C or in the presence of UV light, as shown here. Multiple substitutions occur with an excess of chlorine. 

Polynuclear aromatic hydrocarbons such as naphthalene, anthracene, and phenanthrene undergo electrophilic aromatic substitution reactions in the same manner as benzene. A significant difference is that there are more carbon atoms, more potential sites for substitution, and more resonance structures to consider. In naphthalene, it is important to recognize that there are only two different positions Cl and C2 (see 122). This means that Cl, C4, C5, and C8 are chemically identical and that C2, C3, C6, and C7 are chemically identical. In other words, if substitution occurs at Cl, C4, C5, and C8 as labeled in 122, only one product is formed 1-chloronaphthalene (121), which is the actual product isolated from the chlorination reaction. Chlorination of naphthalene at Cl leads to the five resonance structures shown for arenium ion intermediate 127. 

The functional group transformations are derived from either electrophilic aromatic substitution or nucleophilic aromatic substitution reactions. The electrophilic aromatic substitution functional group transform is shown with a simple X group, where X is chlorine, bromine, nitro, or sulfonyl. The reagents are different, but the basic principle for the formation of such compounds is the same. 

We found that an external chlorinating reagent preferentially passed the chlorine to the template cyclodextrin first, and that the cyclodextrin then relayed the chlorine on to the substrate. Furthermore, this was a catalytic process, and occurred faster than chlorination in the absence of the template. The mechanism involved was established by detailed studies, including reaction kinetics. Modification of the cyclodextrin, and its incorporation into a polymer, have led to the production of highly selective catalysts for this aromatic substitution reaction [22]. In other laboratories an electrochemical adaptation of our reaction has also been made, in which the cyclodextrin molecule is attached to the electrodes [23]. 

We are now able to make a few substituted aromatic compounds, and this capability will shortly prove quite useful. However, much of the interest in synthetic chemistry involves the construction of carbon-carbon bonds. We have made no progress at all in finding ways to make bonds from benzene to carbon. Here and in the next section we do just that by making use of another electrophilic aromatic substitution reaction quite closely related to the bromination and chlorination reactions we have just seen. 

We begin with chlorination of benzene (which is just an electrophilic aromatic substitution reaction), followed by an elimination-addition reaction. When we perform the elimination-addition process, we must carefully choose the reagents. If we use NaOH followed by HsO", the product will be phenol. If we use NaNH2 followed by HsO", the product will be aniline (shown in the scheme above). 

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