Preparation of alkyl chlorides from alcohols

The hydroxyl group in tertiary alcohols is most readily replaced, and this is effected by simply allowing the alcohol to react with concentrated hydrochloric add at room temperature. The reaction is a nucleophilic displacement of the SW1 type involving the formation of a relatively stable carbocation intermediate. 

The reaction is illustrated by the preparation of t-butyl chloride (Expt 5.49). 

The hydrochloric acid-zinc chloride reaction may be an Sjv2 type displacement, particularly in the case of primary alcohols. 

The regioselectivity of this latter reaction pathway may be diminished owing to the tendency of carbocations to rearrange, particularly when branching of the carbon chain occurs in the -position. Hence the method is preparatively useful only with secondary alcohols (e.g. butan-2-ol) where one unique secondary carbocation is involved (see also Section 5.5.2, p. 560). 

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Thionyl chloride is the classical reagent for the preparation of alkyl chlorides from alcohols with retention of configuration. This reaction is known to proceed via alkyl chlorosulfinates (7 75) which decompose by an ion pair mechanism, but may be diverted to an SN2 displacement path by addition of pyridine171 Wagner-Meerwein rearrangements have been observed in the course of alkylchlorosulfinate decomposition, e.g. (176) - (777)172). The behavior of the isomeric chlorosulfinates (178) and (179) is consistent with competitive ion pair collapse and 1,2-alkyl shift173. ... 

Alkyl halides. The Vilsmeier reagent has been used to a limited extent to replace an hydroxyl group by chlorine. Actually (1) is a useful reagent for preparation of alkyl chlorides from alcohols without rearrangement. The reaction is conducted at 75-100° in dioxane, DMF, CH3CN, or HMPT. The replacement occurs with inversion. Yields are usually in the range 75-85%. 

Alkyl chlorides. A preparation of alkyl chlorides from the corresponding bromides is accomplished by reaction with Me SiCl in the presence of imidazole. Similarly, alcohols are converted to chlorides with Me SiCl in DMSO. ... 

Why is thionyl chloride preferred over hydrogen halides, in the preparation of alkyl halides from alcohols ... 

Rearrangement may be largely (but not entirely) suppressed by preparing the alkyl chloride from a reaction of the alcohol with thionyl chloride, either (i) alone, or (ii) in the presence of catalytic or equimolar proportions of pyridine, or (iii) in the presence of dimethylformamide.85 In (i) a chlorosulphite is first formed which decomposes via two sequentially formed ion-pair species the second ion pair collapses to yield the alkyl chloride. 

Williamson synthesis of phenyl alkyl and dialkyl ethers. Phenols react with alkyl halides in 20% aqueous NaOH containing 1 equiv. of this surfactant at 80° to form phenolic ethers in 85-97% yield. There is no reaction in the absence of CTAB. This procedure is not useful for preparation of dialkyl ethers from alcohols and alkyl halides. Instead, the alkyl chloride, alcohol, a trace of water, and CTAB are heated in THF at 70° with NaOH (2 equiv.). 

Acid chlorides, alkyl chlorides.1 The combination of dimethylformamide and thionyl chloride has been known for some time to be excellent for preparation of acid chlorides and of alkyl chlorides from acids and alcohols, respectively (1, 286-288). The actual chlorinating agent is considered to be [CICH=N (CH3)2]C1-. The combination of HMPT and thionyl chloride should be capable of forming a similar reagent ... 

Dichloromethyl methyl ether, CH30CHC12, which can be regarded as the ester dichloride of orthoformic acid, does not give homogeneous products from alcohols and is thus, in general, unsuitable for preparation of alkyl chlorides.927... 

A rapid method of preparing alkyl chlorides from alcohols on a laboratory scale consists in reaction with benzoyl chloride in the presence of dimethyl-formamide. During the exothermic reaction lower alkyl chlorides distil off spontaneously and can be purified by subsequent fractionation. 

Chlorosilanes are also converted to siloxanes by reactions not involving hydrolysis. Most are highly exothermic, and appropriate measures for heat dissipation are recommended for safety. Thus chlorosilanes can be converted to siloxanes by reaction with DMSO or with NajCOj or ZnO in suitable solvents such as ethyl acetate or dioxane. Siloxanes can also be obtained by the reaction of alcohols with chlorosilanes, but this is really a kind of hydrolysis in which the water is generated in situ as a by-product of the formation of alkyl chloride from the alcohol and HCl. Siloxanes can of course be prepared from the reaction of HjO with many other kinds of hydrolyzable silanes (e.g., sulfato, iodo, bromo, fluoro, alkoxy, aryloxy, acyloxy, amino, amido, ketoximo) but such intermediates are themselves derived from chlorosilane precursors. Acetoxysilanes undergo thermolysis to yield siloxane bonds. 

Although the reaction of alcohols and mineral acids is usually quite efficient, there are times when the use of mineral acids in chemical reactions must be avoided. Therefore, the availability of alternative methods for the preparation of halides from alcohols is essential. To prepare an alkyl chloride from an alcohol, any reagent must contain chlorine atoms, just as a brominating agent must... 

Alkyl Chlorides from Alcohols and Ethers. The reaction of Ph3PCl2 with alcohols provides an excellent synthetic method for the preparation of alkyl chlorides. Mechanistic studies suggest the rapid initial formation of an alkyloxyphosphonium intermediate which then undergoes slow conversion into Ph3PO and alkyl chloride (eq 1). It is assumed that chlorination takes place by an Sn2 reaction in most cases thus, inversion of configuration is observed in the transformation of (—)-menthol to (+)-neomenthyl chloride (eq 2). As illustrated in eq 1, primary, secondary, and even tertiary alcohols are chlorinated with PhsPCb, although reactions of tertiary alcohols are often accompanied by elimination (10%). 

Formation of Ethers. Very high ether yields can be obtained from alcohols and phenols with dialkyl sulfates in CH2CI2 and concentrated NaOH—tetrabutylammonium chloride at room temperature or slightly elevated temperature within 1—5 h (18). Using excess aqueous caustic—N(C4H2)4HS04, unsymmetrical aUphatic ethers can be prepared with alkyl chlorides at 25—70°C in 3—4 h (19) (see Ethers). 

No details are given for scheme A. Presumably one could use the phosphoryl chloride instead of the fluoride. Scheme B, in which ethyl chloride is formed, was run in boiling xylene using equimolar quantities of the reactants. Michaelis (33) has partially described the preparation of starting materials from secondary amines with phosphorus oxychloride and also ethyl dichlorophosphate. Schrader (38) obtained alkyl and amido fluophosphates by reaction of the corresponding chlorophosphates with sodium fluoride in aqueous or alcoholic solution. 

The preparation of alkyl methyl ethers may be readily effected under PTC conditions from the alcohol, dimethyl sulphate and 50 per cent w/w aqueous sodium hydroxide, employing tetrabutylammonium hydrogen sulphate as catalyst.95 The usefulness of this procedure has been extended, and optimum conditions have been described for the alkylation of a range of aliphatic alcohols using, for example, 1-chlorobutane or benzyl chloride.96 The PTC preparative examples described in Expt 5.73 are for the methylation, allylation, but-2-enylation and benzylation of, for example, 2-hydroxymethyl-l,4-dioxaspiro[4.5]decane (Expt 5.63), and have been developed in the editors laboratories. These methods have also been applied to the alkylation of protected monosaccharide derivatives (p. 652). 

A more efficient method of preparing alkyl halides from alcohols involves reactions with thionyl chloride (SOCL). 

Alcohols and aldehydes are also suitable materials for the creation of an alkyl amine. In addition to the aforementioned formation of alkyl chloride as an intermediate, alcohols can be directly converted to amines under hydrogenation conditions in the presence of ammonia while aldehydes are prereacted to form imine followed by hydrogenation [13]. Selectivity of the primary amine with these techniques is difficult and this process is more typically utilized for the preparation of tertiary amines where the reaction can be driven to completion. In certain cases, alcohols and aldehydes provide structural elements which are not attainable from natural sources. An example is the formation of a hydrogenated tallow 2-ethyl hexyl amine. The amine is prepared as shown below in eqn 6.1.8 using a hydrogenated tallow amine reacted with 2-ethyl hexanal [14, 15] ... 

In the plant, alkylations are carried out in large horizontal or upright kettles (see chrysophenine). The alkyl chlorides are prepared from hydrochloric acid, zinc chloride (ferric chloride can be used equally well in place of zinc chloride) and alcohol, and are transported in large iron cylinders and stored in reservoirs. For use, the material is trans-... 

For a variety of reasons, we chose to design our sensitizers around the alkyl sulfonates. We found that both 5-alkyl and aryl sulfonates of 1 can conveniently be prepared in excellent yields from the corresponding sulfonyl chloride through the use of catalytic amounts of sulfonyl transfer reagents such as 4-dimethylaminopyridine (DMAP) in the presence of triethylamine. This procedure is more convenient then the more traditional Schotten-Baumann conditions or those employing pyridine and allowed the preparation of sulfonate derivatives from both 1° and 2° aliphatic alcohols in high yield. 

Direct substitution of F for OH by means of HF has no preparative importance. All the methods of preparing alkyl fluorides from alcohols proceed in principle by way of esters the alcohol is converted into the alkyl chloride, bromide, iodide, or / -toluenesulfonate, and then the halogen atom (see page 204) or the tosyloxy group (see page 229) is replaced by fluorine. 

The reaction is particularly advantageous for preparation of alkyl bromides and iodides from sterically hindered or unsaturated alcohols. For preparative purpose it is especially useful when R X is benzyl bromide, methyl iodide, bromine (Br2), or iodine (I2), but use of benzyl chloride and chlorine (Cl2) is also significant R can usefully be H only when R X is HC1. When the alcohol is sensitive to heat, the quasi-phosphonium compound should be prepared first and then allowed to react with the alcohol. Also, for use with unsaturated alcohols in cases when R X is Cl2, Br2, or I2 the crude (C6H50)3PX2 should be prepared as a separate stage. In general, however, the three reactants can be allowed to react together, as in (a). 

Sulfonate Formation. The preparation of an alkyl methane-sulfonate from an alcohol can be achieved by treatment of an alcohol with methanesulfonic anhydride in the presence of pyridine or 2,4,6-collidine (eq 1). The use of methanesulfonic anhydride rather than methanesulfonyl chloride eliminates the formation of small amounts of alkyl chlorides which occurs when... 

Synthesis of Disaccharides and their Derivatives.—K method has been devised for the preparation of alkyl a-glycosides of reducing disaccharides. Conversion of the peracetylglycosyl bromides to the j3-iV,JV-dialkyldithiocarba-mates was followed by deacetylation and treatment with the alcohol (methanol and benzyl alcohol were used) in the presence of mercury(ii) chloride and cadmium carbonate. Good yields of products containing mainly a-glycosides were obtained from cellobiose, lactose, and maltose. ... 

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