Aromatic substitution chloromethylation

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

In a first reaction step the formaldehyde 2 is protonated, which increases its reactivity for the subsequent electrophilic aromatic substitution at the benzene ring. The cationic species 4 thus formed loses a proton to give the aromatic hydroxymethyl derivative 5, which further reacts with hydrogen chloride to yield the chloromethylated product 3 ... 

The Lewis acid ZnCl2 effects formation of an oxonium ion which is reactive in electrophilic aromatic substitution. The intermediate zinc alkoxide reacts with the arene to form the chloromethylated product and zinc oxides ... 

In an analogous reaction, where anisole (0.5 mole), chloromethyl ether (0.1 mole), and REX catalyst (2 gm) were stirred for 14 hours at room temperature, a 28% yield of a mixture of 2,2 -dimethoxydiphenyl-methane, 2,4 -dimethoxydiphenylmethane, and 4,4 -dimethoxydi-phenylmethane in the ratio of 1 5.7 5.4 was obtained. No 1 1 adduct (chloromethyl- or methoxymethylanisole) was observed. The lower reaction temperatures required with anisole reflect the activating effect of an electron-donating substituent in electrophilic aromatic substitution. 

Issues of regioselectivity in the Blanc chloromethylation and related Friedel-Crafts reactions have been studied extensively. As is common with a majority of electrophilic aromatic substitution reactions, substitution typically occurs ortho or para to electron-donating substituents, with issues of steric strain playing a role in the relative ratio of ortho and para products. The Blanc reaction is t3q)ically somewhat regioselective, favoring the para-isomer but accompanied by lesser amounts of the ortho product. ... 

Functionalization of sytrene polymers involves electrophilic substitution on the aromatic ring. Chloromethylation has been the most widely used reaction (Merrifield, 1963). Chloromethylation of styrene polymers is carried out using a Lewis acid catalyst and chloromethyl methyl ether as the solvent [Eq. (1)]. Carbon disulfide or chloroform have also been employed as cosolvents. 

Polystyrene is a polymer (Section 12-15) whose subunits are derived from ethenylbenzene (styrene). Although beads of polystyrene are insoluble and rigid when dry, they swell considerably in certain organic solvents, such as dichloromethane. The swollen material allows reagents to move in and out of the polymer matrix easily. Thus, its phenyl groups may be functionalized by electrophihc aromatic substitution. For peptide synthesis, a form of Friedel-Crafts alkylation is used to chloromethylate a few percent of the phenyl rings in the polymer. 

Aromatic Substitution. Several important classes of aromatic substitutions are mediated by ZnCU, including the Hoesch reaction (eq 56) and the Fischer indole synthesis (eq 57). Haloalky-lation of aromatic rings using Formaldehyde or Chloromethyl Methyl Ether is readily accomplished through the agency ofZnCb and wanning (eq 58). ... 

An important side reaction is the formation of diaryl methane derivatives ArCHaAr. Moreover poly substituted products may be obtained as minor products. Aromatic compounds have been treated with formaldehyde and hydrogen bromide or hydrogen iodide instead of hydrogen chloride. The formaldehyde may be replaced by another aldehyde the term Blanc reaction however stands for the chloromethylation only. 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

Finally, a series of 2-chloromethyl-5-aryl-1,3,4-oxadiazoles 82 were prepared by reaction of aromatic hydrazides 81 and a chloromethylorthofor-mate used as the solvent under microwave activation [62]. Potentially, the chloromethyl group could imdergo nucleophiUc substitution expanding the scope of this reaction (Scheme 28). 

A useful application in the manufacture of ion-exchange resins may well be possible which avoids the use of carcinogenic chloromethyl ether. Here, a polymer of p-methyl styrene is chlorinated on the side chain with aqueous NaOCl and a phase-transfer catalyst. Sasson et al. (1986) have shown how stubborn . substituted aromatics like nitro/chlorotoluenes can be oxidized to the corresponding acids by using aqueous NaOCl containing Ru based catalyst. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

More specific evidence came from affinity labeling with molecules which could react with specific amino acid group sat or adjacent to the substrate site. These labels were substrate analogues and competitive inhibitors. Substituted aryl alkyl ketones were used. TV-p-toluene-sulphonyl-L-phenylalanine chloromethyl ketone (TPCK) blocked the activity of chymotrypsin. Subsequent sequence analysis identified histidine 57 as its site of binding (see Hess, 1971, p 213, The Enzymes, 3rd ed.). Trypsin, with its preference for basic rather than aromatic residues adjacent to the peptide bond, was not blocked by TPCK but was susceptible to iV-p-toluenesulphonyl-L-lysine chloromethyl ketone (TLCK) (Keil, ibid, p249). 

Aromatic electrophilic substitution is used commercially to produce styrene polymers with ion-exchange properties by the incorporation of sulfonic acid or quaternary ammonium groups [Brydson, 1999 Lucas et al., 1980 Miller et al., 1963]. Crosslinked styrene-divinyl-benzene copolymers are used as the starting polymer to obtain insoluble final products, usually in the form of beads and also membranes. The use of polystyrene itself would yield soluble ion-exchange products. An anion-exchange product is obtained by chloromethylation followed by reaction with a tertiary amine (Eq. 9-38) while sulfonation yields a cation-exchange product (Eq. 9-39) ... 

We note from Table VIII a strong interest in halogenated resists, particularly those substituted with chlorine. The addition of chlorine to the aromatic structure of polystyrene has a marked effect on cross-linking efficiency. Monodisperse polystyrene, for example, has a sensitivity on the order of 50 p C/cm2, yet with as little as 20% chloromethyl groups substituted on the ring, the sensitivity is improved to 2 C/cm2 for comparable molecular weight and distribution. 

Nondestructive reactions of trisacetylacetonates of chromium(lll), cobalt(lll), and rhodium(lll) are reviewed. Halogenation, nitration, thiocyanation, acylation, formylation, chloromethylation, and aminomethylation take place at the central carbon of the chelate rings. Trisubstituted chelates were obtained in all cases except acylation and formylation. Unsymmetrically and partially substituted chelates have been prepared. Substitutions on partially resolved acetylacetonates yielded optically active products. NMR spectra of unsymmetrically substituted, diamagnetic chelates were interpreted as evidence for aromatic ring currents. Several groups were displaced from the chelate rings under electrophilic conditions. The synthesis of the chromium(lll) chelate of mal-onaldehyde is outlined. 

The photodissociation of aromatic molecules does not always take place at the weakest bond. It has been reported that in a chlorobenzene, substituted with an aliphatic chain which holds a far-away Br atom, dissociation occurs at the aromatic C-Cl bond rather than at the much weaker aliphatic C-Br bond (Figure 4.30). This is not easily understood on the basis of a simple picture of the crossing to a dissociative state, and it is probable that the reaction takes place in the tt-tt Si excited state which is localized on the aromatic system. There are indeed cases in which the dissociation is so fast (< 10-12 s) that it competes efficiently with internal conversion. 1-Chloromethyl-Np provides a clear example of this behaviour, its fluorescence quantum yield being much smaller when excitation populates S2 than when it reaches Figure 4.31 shows a comparison of the fluorescence excitation spectrum and the absorption spectrum of this compound. This is one of the few well-documented examples of an upper excited state reaction of an organic molecule which has a normal pattern of energy levels (e.g. unlike azulene or thioketones). This unusual behaviour is related of course to the extremely fast dissociation, within a single vibration very probably. We must now... 

Exercise 22-21 a. Substitution of a chloromethyl group, —CH2CI, on an aromatic ring is called chloromethylation and is accomplished using methanal, HCl, and a metal-halide catalyst (ZnCI2). Write reasonable mechanistic steps that could be involved in this reaction ... 

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