2- chloromethyl-, reactivity

Ghloromethylation. The reactive intermediate, 1-chloromethylnaphthalene [86-52-2] has been produced by the reaction of naphthalene in glacial acetic acid and phosphoric acid with formaldehyde and hydrochloric acid. Heating of these ingredients at 80—85°C at 101.3 kPa (1 atm) with stirring for ca 6 h is required. The potential ha2ard of such chloromethylation reactions, which results from the possible production of small amounts of the powerhil carcinogen methyl chloromethyl ether [107-30-2J, has been reported (21). 

The epoxidation is generally conducted in two steps (/) the polyol is added to epichlorohydrin in the presence of a Lewis acid catalyst (stannic chloride, boron triduoride) to produce the chlorohydrin intermediate, and (2) the intermediate is dehydrohalogenated with sodium hydroxide to yield the aliphatic glycidyl ether. A prominent side-reaction is the conversion of aliphatic hydroxyl groups (formed by the initial reaction) into chloromethyl groups by epichlorohydrin. The aliphatic glycidyl ether resins are used as flexibilizers for aromatic resins and as reactive diluents to reduce viscosities in resin systems. 

According to Section 4.02.3.1.8 substituents removed from the pyrazole ring by two or more saturated carbon atoms and substituents on the benzene ring of indazoles are similar in reactivity to the corresponding aromatic derivatives. For instance, chloromethyl-pyrazoles are comparable to benzyl chlorides and 5-hydroxyindazoles to /3-naphthols in their reactivity. 

Further substitution of 2,4-disubstituted and most 2,3-disubstituted thiophenes occurs in the free a-position, except when a - -M-substituent in the 3-position strengthens the 4-directing power of a —1—M-sub-stituent in the 2-position. Thus methyl 3-methyl-2-thiophenecar-boxylate is brominated in the 4-position and 3-brorao-2-thiophene-aldehyde is nitrated in the 4-position. Recent investigations on the chloromethylation, sulfonation, mercuration, and nitration of 2,4-di-chlorothiophene, which without proof are assumed to occur in the 5-position serves as examples of the reactivity of a 2,4-disubstituted thiophene. Formylation with iV,A-dimethylformamide and... 

The reactivity of the chloromethyl group is illustrated by the reaction of 2,5-dimethyl-3,4-dichloromethylthiophene (174) with water, which gives (175) Another example of ether formation, is the formation of (176) upon normal acidic workup of the reaction product from 2-thiophenemagnesium bromide and 2-thiophenaldehyde. With... 

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 ... 

Electron-rich aromatic substrates can react without a catalyst present. Modern variants of the Blanc reaction use chloromethyl ether" (e.g. (C1CH2)20, ClCH20Me) or methoxyacetyl chloride, since those reagents are more reactive and give higher yields. 

The chloromethylation can be generally employed in aromatic chemistry benzene, naphthaline, anthracene, phenanthrene, biphenyls and many derivatives thereof are appropriate substrates. The benzylic chlorides thus obtained can be further transformed, for example to aromatic aldehydes. Ketones like benzophe-none are not reactive enough. In contrast phenols are so reactive that polymeric products are obtained. ... 

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) ... 

Among the Friedel-Crafts alkylations of aromatic compounds with (chlorinated alkyl)silanes, the alkylation of benzene with (tt>-chloroalkyl)silanes in the presence of aluminum chloride catalyst was generally affected by two factors the spacer length between the Cl and silicon and the electronic nature of substituents on the silicon atom of (w-chloroalkyl)silanes. As the spacer length between the C—Cl and silicon increases from (chloromethyl)silane to (/i-chloroethyl)silane to (/-chloropropyl)silane, the reactivity of the silanes increases. As the number of chloro-groups on the silicon decreases from (chloromethyl)trichlorosilanes to (chloromethyl)methyldichlorosilanes to (chloromethyl)trimethylsilanes, the... 

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible only via a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224— 226], it seemed obvious to react amidines such as isobutyraminidine-HCl 742 with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain 745 directly in one step. Because of the low reactivity of the 4-chlorine in 743, however, reaction of 743, e.g. with isobutyramidine-HCl 742 in the presence of sodium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, in the absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-l,4-dione in nearly quantitative yield [228, 229]. 

A kinetic study of the basic hydrolysis in a water/AOT/decane system has shown a change in the reactivity of p-nitrophenyl ethyl chloromethyl phosphonate above the percolation threshold. The applicability of the pseudophase model of micellar catalysis, below and above the percolation threshold, was also shown [285],... 

There are a number of variations of the Friedel-Crafts reactions that are useful in synthesis. The introduction of chloromethyl substituents is brought about by reaction with formaldehyde in concentrated hydrochloric acid and halide salts, especially zinc chloride.62 The reaction proceeds with benzene and activated derivatives. The reactive electrophile is probably the chloromethylium ion. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

The 6-chloromethyl substituent (series 5 and 6) is required for the inactivation of a-chymotrypsin. Nevertheless, there is only a transient inactivation of HLE and thrombin through the formation of a stable acyl-enzyme in spite of the presence of this group as demonstrated by the spontaneous or hydroxylamine-accelerated reactivation of the treated enzymes (Scheme 11.3, pathway b).21 HLE is specifically inhibited when such an alkylating function is absent (series 7), always through the formation of a transient acyl-enzyme (Table 11.2). 

Even in solution the relative rigidity of the polymer support can play a significant role in the reactivity of attached functional groups. Contrasting studies conducted with chloromethylated derivatives of poly(arylene ether sulfone) (Tg 175°C), phenoxy resin (Tg= 65°C) and polystyrene (Tg= 105°C) allow evaluation of chain rigidity effects. We have shown that the rates of quaternization of chloromethylated poly(arylene ether sulfones) and phenoxy resin deviate from the anticipated second order process at... 

The chloromethylated polymers are very reactive substrates for nucleophilic attach further elaboration can be accomplished under homogeneous conditions In aprotlc solvents, or under heterogeneous conditions In the presence of phase transfer catalysts. The following examples are representative of approaches to functionalized condensation polymers via chloromethylated Intermediates. 

These results suggest that poly[(chloromethyl)thiirane] (PCMT, 4) should be substantially more reactive than polyepichlorohydrin... 

The parent hydrocarbon 4 has been obtained by several routes91-93, with the thermal dehydrochlorination of the readily available 2,4,6-tris(chloromethyl)mesitylene (148, equation 12) being particularly valuable92. The yields of this process (close to 50%) are reproducible, making 4 a readily available, albeit difficult-to-handle, highly reactive starting material for further transformations (see below). 

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