Chloromethylation

However, it has been found that a by-product arising from the interaction of formaldehyde and hydrogen chloride is bis(chloromethyl)ether (BCME), which is a potent carcinogen. For this reason the classical chloromethylation route to side-chain halogenated products should not be regarded as a desirable synthetic procedure, and in general should only be used if the required compound cannot be readily prepared by other methods. When used, effective precautions should be taken during the reaction and in the disposal of the reaction residues.12 13 

Recently two alternative procedures have been described. In one case14 methoxyacetyl chloride (MeOCH2 COCl) in the presence of anhydrous aluminium chloride is thought to provide the source of the cation (4), which substitutes in the aromatic nucleus to give the benzyl methyl ether (5), which is subsequently converted into the chloromethylated product (6). 

A wide range of substituted aromatic systems have been chloromethylated by this procedure, the only disadvantage being the expense of the methoxyacetyl chloride. 

In the second alternative method a two-step procedure has been described.15 The first step involves amidomethylation of the aromatic nucleus by reaction with paraformaldehyde and acetamide in the presence of concentrated sulphuric acid. The isolated intermediate is then treated with phosphorus oxychloride in dimethylformamide and xylene and converted into the chloromethylated product [e.g. see 2-(chloromethyl)-4-nitrotoluene, Expt 6.29, for formulation]. The mechanisms of these reactions are currently only speculative. 

2-(Chloromethyl)-4-nitrotoluene. A solution of 6.24 g (0.03 mol) of the foregoing acetamide, 9.67 g (0.063 mol) of phosphorus oxychloride and 2.19 g (0.03 mol) of dimethylformamide in 50 ml of xylene is refluxed for 1 hour. The cooled solution is washed with water and evaporated to give 4.73 g (85%) of product [CAUTION (1)] which after recrystallation from hexane has m.p. 61-62°C. 

The first kinetic study used chloromethyl methyl ether as chlorinating reagent and acetic acid as solvent, viz. reaction (188)381 

Rates were measured at different temperatures between 15 and 100 °C, and relative 

A later study382 using paraformaldehyde and hydrogen chloride as the source of the chloromethyl moiety, reaction (189) 

The reliability of this work has also been questioned by Brown and Nelson339, who could not get any reaction at all with benzene under the conditions quoted by Szmant and Dudek382. If the benzene value is in error it could account for the low selectivities that were observed. By using the competition technique with a deficiency of paraformaldehyde (but an excess of hydrogen chloride) they obtained a toluene benzene reactivity ratio of 112 and partial rate factors of / Me = 117, /mMc = 4.37, /pM = 430. 

Only one detailed kinetic study of chloromethylation involving measurement 

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PoJy (3,3-bis (chloromethyl) oxelane), chlorinated polyether (R CHiCl) is widely used for injection moulding and coaling. 

CHjO), + 3CH,OH + 3HC1 —> 3CH3OCH2CI + 3H,0 Monoalkyl benzene derivatives yield para chloromethjd compounds, frequently accompanied by small amounts of the ortho isomeride. The reaction is similar in some respects to that of Friedel and Crafts. Chloromethylation is of great value in synthetic work as the —CH,C1 group can be converted into other groups such as —CH,OH, —CHO, —CH,OR, —CH,CN, —CH,CH(COOC.,Hs)2 and —CH,. 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

The reaction giving A is chloromethylation, a reliable metliod of adding a CH2OH equivalent to an aromatic ring. You may have been surprised at the use of reagent B to make an acid chloride. B is oxalyl chloride and is often used when pure acid chlorides are wanted - the other products are gases (which ). 

The nitrile is described in a patent tChem. Abs.. 1955, 15963) the last stages were carried out by A. R. Battersby s research group at Cambridge. Chloromethylation is described in Tedder, Vol 2, p.213 and Norman P.372-3. 

Speed manufacturers need only look at the molecules and imagine them without those extra OHs or methylenedioxy ring structures attached to the benzene core. These particular pathways are, however, more uniquely suited for X precursor production because they take advantage of the hindrance that methylenedioxy ring structures and OHs provide on one side of the benzene core. This helps to better assure that mono chloromethylations or bro-minations will occur whereas di- and tri-substitutions are possible on a naked benzene molecule which speed chemists are going to be using (please don t ask). 

This procedure is called chloromethylation and will not only turn 1,3-benzodioxole into a methyl chloride but will work equally well in converting plain old benzene into benzyl chloride. Both are important stepping stones towards the production of X and meth. For example, benzyl chloride is a schedule I controlled substance because it will beget benzaldehyde and phenylacetonitrile (a precursor for phenylacetic acid). 

To a solution of 0.40 mol of butyllithium in about 280 ml of hexane were added 280 ml of dry THF with cooling below -10°C. Subsequently 0.40 mol of 1,1-diethoxy--2-propyne (see Chapter V, Exp. 28) was introduced in 15 min at -30 to -10°C. To the solution obtained was then added in 15 min with cooling at about -15°C 0.40 mol of chloromethyl ethyl ether (note 2). After the addition stirring was continued for 1 h without cooling. The mixture was then shaken with concentrated ammonium chloride solution and the ethereal layer was separated off. The aqueous layer was extracted twice with diethyl ether. After drying the ethereal solutions over magnesium sulfate the diethyl ether was evaporated in a water-pump vacuum. 

To illustrate the specific operations involved, the scheme below shows the first steps and the final detachment reaction of a peptide synthesis starting from the carboxyl terminal. N-Boc-glycine is attached to chloromethylated styrene-divinylbenzene copolymer resin. This polymer swells in organic solvents but is completely insoluble. ) Treatment with HCl in acetic acid removes the fert-butoxycarbonyl (Boc) group as isobutene and carbon dioxide. The resulting amine hydrochloride is neutralized with triethylamine in DMF. 

Another synthesis avoids the isolation of 6-APA and starts directly with penidllin G. Reaction with chloromethyl pivalate gives its pivaloyloxymethyl ester. This reacts with PCI5 to an imidoyl chloride which may be solvolyzed with propanol. The add chloride of (R)-... 

An uneventful coupling of two hemispherical cavitand molecules — a tetrameth-anethiol and a tetrakis(chloromethyl)precursor (see p. 169) — yielded D.J. Cram s (1988) carcerand . ft entraps small molecules such as THF or DMF, cesium or chloride ions, or argon atoms as permanently imprisoned guests . Only water molecules are small enough to pass through the two small pores of this molecular (prison) cell. 

When butadiene is treated with PdCU the l-chloromethyl-7r-allylpalladium complex 336 (X = Cl) is formed by the chloropalladation. In the presence of nucleophiles, the substituted 7r-methallylpalladium complex 336 (X = nucleophile) is formed(296-299]. In this way, the nucleophile can be introduced at the terminal carbon of conjugated diene systems. For example, a methoxy group is introduced at the terminal carbon of 3,7-dimethyl-I,3,6-octatriene to give 337 as expected, whereas myrcene (338) is converted into the tr-allyl complex 339 after the cyclization[288]. 

The N,N-disubstituted thioureas (135) condensed with a-halocarbonyl compounds give 2-disubstituted aminothiazoies (136) but in lower yields (30 to 70%) (Scheme 65 and Table 11-20) (518). For example, N,N-dialkylthioureas condensed with chloroacetaldehyde or dibromoether lead to Ar,At-dialkyl-2-aminothiazoles in 136, Ri=R2 = methyl (342, 404, 436, 637), ethyl (343, 436), n-propyl (518), n-butyl (518), ally] (518), and benzyl (26, 29). When chloroacetone and dichloroacetone are the carbonyl reactants the corresponding 4-methyl (518) and 4-chloromethyl derivatives (572) were obtained. 

In the case of 4-(chloromethyl)-2-phenylthiazole, chloration in acetic acid yields only theproductsubstitutedat the 5-position ofthethiazolering(247). 

The common names of (di chloromethyl)benzene and (trichloromethyl)benzene are benzal chloride and benzo trichloride respectively... 

Further chlorination of the chloromethyl ketone gives the corresponding trichloromethyl ketone which then undergoes hydrolysis to form chloroform... 

The actual process of solid phase peptide synthesis outlined m Figure 27 15 begins with the attachment of the C terminal ammo acid to the chloromethylated polymer m step 1 Nucleophilic substitution by the carboxylate anion of an N Boc protected C terminal... 

FIGURE 27 14 A section of polystyrene showing one of the benzene rings modified by chloromethylation Indi vidual polystyrene chains in the resin used in solid phase peptide synthesis are con nected to one another at various points (cross linked) by adding a small amount of p divinylbenzene to the styrene monomer The chloromethylation step is carried out under conditions such that only about 10% of the benzene rings bear —CH2CI groups... 

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