Chlorination of anisole

The complex kinetic expression for chlorination of anisole by hypochlorous acid (p. 577) becomes simpler for both less reactive and more reactive substrates. For benzene, the expression is... 

Rather different experimental results were obtained by de la Mare et a/.208, 209, who studied chlorination by hypochlorous acid in 51, 75 and 98 % aqueous acetic acid. With the latter medium, the chlorination of anisole or m-xylene (at an unspecified temperature) was independent of the concentration of aromatic, and catalysed by perchloric acid to a much greater extent than an equimolar amount of lithium perchlorate the reaction was also catalysed by the base, sodium acetate. The reactive species was postulated as chlorine acetate produced... 

Figure 5.3. The selective chlorination of anisole in the presence of cyclodextrin (Breslow, 1982).

Breslow et al. (13) have prepared an insolubilized cyclodextrin resin by crosslinking with epichlorohydrin. The resin was used for the chlorination of anisole via a three-step process. The column was loaded with anisole, that is, the available cycloclextrin cavities were filled with anisole. Aqueous HOCl was passed through and the product, 99% / -chloroanisole, was eluted with tetrahydrofuran. 

Aryloxymethyl chlorides may be prepared by the reaction of sodium aryloxymethanesulfonates with phosphorus pentachloride. The chlorination of anisole does not, as previously reported, give phenoxymethyl chloride, but rather a mixture of p- and o-chloroanisoles. Similarly, anisole and other unsubstituted methyl aryl ethers undergo ring chlorination with phosphorus pentachloride and chlorine, whereas ring-chlorinated anisoles, such as />-chloroanisole, undergo chlorination at the methyl group with chlorine at 190-195° in the presence of a catalytic amount of phosphorus pentachloride. ... 

Regioselective chlorination of aromatics. Phenol undergoes regioselective chlorination at the orf/io-position with 1, but selectivepara-chlorinationwith2. Chlorination of anisole by either reagent results exclusively in para-chlorination, because of steric effects.2 Chlorination of naphthol with 1 and 2 is more regioselective than that of phenol.1... 

Chlorination of benzaldehyde anils with A-chlorobenzenesulfonamide is catalyzed by Ru(III) in aqueous methanol994. RuC13 catalyzes the chlorination of anisole by ICI in aqueous acetic acid995. 

In a pioneering work, Breslow and his colleagues have used a-cyclodextrins as enzyme models in the chlorination of anisole and obtained almost exclusive para chlorination1004-1006. Another approach is the application of micellar solutions1007. 

Microsolvent effects in the cyclodextrin cavity have also been observed in hypochlorite chlorination of acetophenone1029. Higher para selectivity has been observed in the bromination of acetanilide and benzanilide in presence of cyclodextrins or amylose1030 and in the anodic chlorination of anisole with cyclodextrin-modified electrode1031. 

The chlorination of anisoles present in the cork occurs during the hypochlorite wash, which has been a part of cork processing for many years, results in the formation of TCA. Equally significant is the potential methylation of chlorophenols... 

Modified carbon and graphite electrodes have been found adequate for producing a mixture of optically active isomers and stereoselective addition reactions such as the chlorination of anisole at an a-cyclodextrine-modified graphite electrode [45]. 

A variety of methods for the selective chlorination of anisole have appeared. A solution of anisole in chlorobenzene treated with cupric chloride supported on neutral alumina followed by vigorous stirring at 100°C for 3 hours afforded... 

Cyclodextrins exhibit remarkable ortho-para selectivity in the chlorination of aromatic compounds by hypochlorous acid (HOCl) [22] (Scheme 5). Chlorination takes place via formation of a covalent intermediate, a hypochlorite ester of cyclodextrin. In the chlorination of anisole by hypochlorous acid, pura-chlorination occurs almost exclusively in the presence of sufficient cyclodextrin, although in control experiments maltose had no effect on the product ratio. For example, selectivity for para-chlorination in the presence of 9.4 X 10 M a-cyclodextrin is 96%, which is much larger than that in the absence of a-cyclodextrin (60%). In the proposed mechanism, one of the secondary hydroxyl groups reacts with HOCl to form a hypochlorite ester, which attacks the sterically favorable para position of the anisole molecule included in the cyclodextrin cavity in an intracomplex reaction. The participation of one of the secondary hydroxyl groups at the C-3 position in the catalysis was shown by the fact that dodecamethyl-a-cyclodextrin, in which all the primary hydroxyl groups and all the secondary hydroxyl groups at the C-2 positions are methylated, exhibited equal or larger ortho-para specificity than native a-cyclo-... 

The chlorination of anisole by HOCl in aqueous solution produces both p- and o-chloro-anisole, in a ratio of 60 40 [63]. By contrast, in the presence of a-cyclodextrin (cyclo-hexaamylose) the para chlorination dominates, so that with 10 mM cyclodextrin the product is 96% p- and 4% o-chloroanisole. In water solution anisole binds into the cyclodextrin cavity. The simplest idea would be that this binding blocks chlorination at the ortho positions, which are inside the cavity, while the para position of the anisole is still exposed to solution. The true situation is more interesting. When the reaction shows 96% selectivity for para chlorination, the anisole is only 72% bound, so the bound anisole must be more reactive, not just more selective, than that in solution. The data indicate that ortho chlorination is indeed completely blocked for the anisole/cyclodextrin complex, but that the para position is 5.6 0.8 times more reactive in the complex than in solution. It was suggested that the chlorine was being delivered to the para position of bound anisole by a hydroxyl group of the cyclodextrin, which had been converted to a hypochlorite group (Scheme 6-10). Later work confirmed this idea. 

Scheme 6-10 Selective para-chlorination of anisole complexed by a-cyclodextrin.

Table IX. Product Distribution in the Chlorination of Anisole by Hypochlorous Acid in the Presence of a-Cyclodextrin...

Figure 19. Proposed mechanism for chlorination of anisole catalyzed by a-cyclodex-trin...

Another important pioneering work in CyD chemistry was reported by Breslow and Campbell [7] on the chlorination of anisole with HOCl. In the presence of a-CyD, the chlorination occurs exclusively at the para-position of anisole. This reaction also takes advantage of covalent catalysis. Here, HOCl first reacts with the secondary OH group of CyD, and the chlorine atom is selectively transferred to the para-position of anisole. Since the anisole penetrates into the cavity with the methoxy group first, the para-position of anisole is located near the secondary OH group (and thus near the CyD-OCl group). Apparently, the product selectivity comes from a proximity effect , as is often observed in enzymatic reactions. 

In our earlier study we saw that we could achieve geometric selectivity in the chlorination of anisole by HOCl in water solution. In simple water solution we saw a 1.5 ratio of para chlorination to ortho chlorination of the anisole, while in a 9mM concentration of a-cyclodextrin the para- to ortho-tatio was 29.6. Under these conditions the anisole was only 72% bound into the cavity, so these results indicated that the cyclodextrin not only covered the ortho positions, it also actively catalysed the para chlorination. The most reasonable idea about this was that one of the hydroxyl groups of the cyclodextrin reacted with HOCl to become a hypochlorite group, and that this then deUvered the chlorine to the para position of the bound anisole (Figure 2.2). 

Figure 2.2 a-Cyclodextrin catalyses the para chlorination of anisole by hypochlorous acid... 

Fig. 10. a Structural representation of a-cyclodextrin, b re-gioselective chlorination of anisole encapsulated in a cyclodextrin cavity [48]... 

As an example of a well-studied biomimetic process, consider the chlorination of anisole ... 

As a result, we can expect para (or ortho) substitution to occur more rapidly than the other two reactions (Fig. 14.67). In fact, the chlorination of anisole gives only... 

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