Alkyl halide reaction with alcohols

Alkylation is a very broad reaction type and it can, depending on the nature of the alkylating agent, proceed either as a substitution or as an addition reaction. The alkylation by substitution of, for example, aromatic hydrocarbons, phenols or amines is based on the reaction with alkyl halides or alcohols. Some evidence indicates that, at least partly, the alkylation proceeds through the intermediate formation of alkenes from the alkylating agent when the reaction is conducted at atmospheric pressure and at high temperature. 

The products were isolated as esters by reaction of the acylcobalt carbonyls with an alcohol and iodine. In the case of the alkyl halides, carbon monoxide was normally absorbed, but under nitrogen, acylcobalt tricarbonyls must be formed. The reaction with alkyl halides was slow and some isomerization was noted using M-propyl iodide (formation of n-butyrates and isobutyrates). Absence of carbon monoxide promoted the isomerization. Isopropyl iodide gave no reaction. When ethyl a-bromopropionate was used, no isomerization was found at — 25 °C under carbon monoxide, but the isomerized product, diethyl succinate, was the major product at 25° C under carbon monoxide or nitrogen. Under the conditions of the experiments no isomerization of the alkyl halide itself was found. 

Thus reaction with alkyl halides such as allyl bromide or pro-pargyl bromide allow for the introduction of oleflnlc2. . or acetylenic side groups onto the phosphazene ring VI, while alcohol leads to the formation of hydrido-phosphazene complexes VII. The hydrogen in these compounds can be replaced with halogen to yield the first series of iodor-phosphazene compounds VIII. 

Phenols can be converted into esters by reaction with acid chlorides or acid anhydrides and into ethers by reaction with alkyl halides in the presence of base (Following fig.). These reactions can be done under milder conditions than those used for alcohols due to the greater acidity of phenols. Thus phenols can be converted to phenoxide ions with sodium hydroxide rather than metallic sodium. 

Epoxides react cleanly with amines to give amino-alcohols. We have not so far featured amines as nucleophiles because their reactions with alkyl halides are often bedevilled by overreaction (see the next section), but with epoxides they give good results. 

Some examples of industrially important uses are the following reactions With alkyl halides or alcohols amines or imines can be manufactured. For example, inethanol forms mono- through trimethylamine dichloromethane yields ethylene imine in the presence of calcium oxide. Amines can also be produced by reacting ammonia with alkyl halides in multistage processes [1425]. 

The typical reactions of the alcohol group include their conversion to ethers and esters by reaction with alkyl halides and with acid chlorides or anhydrides, respectively (Scheme 6.2). The benzyl ether group is readily cleaved by hydrogenolysis and is often used as a protecting group for alcohols. Primary alcohols are oxidized initially to the aldehyde and then to the carboxylic acid. 

The reduction of benzoic acids affords the dienolate (77) which may be alkylated in situ by a variety of electrophiles to afford 1-substituted derivatives. Clearly, the addition of alcohol must be avoided or limited to small quantities. It may also be necessary to remove the ammonia before adding the electrophile. The vast majority of applications have been based on reactions with alkyl halides to form (78), but additions of (77) to formaldehyde, epoxides and a,p-unsaturated esters to form the range of adducts (79) to (81) have also been reported (Scheme 14). 

Similar information is available for other bases. Lithium phenoxide (LiOPh) is a tetramer in THF. Lithium 3,5-dimethylphenoxide is a tetramer in ether, but addition of HMPA leads to dissociation to a monomer. Enolate anions are nucleophiles in reactions with alkyl halides (reaction 10-68), with aldehydes and ketones (reactions 16-34, 16-36) and with acid derivatives (reaction 16-85). Enolate anions are also bases, reacting with water, alcohols and other protic solvents, and even the carbonyl precursor to the enolate anion. Enolate anions exist as aggregates, and the effect of solvent on aggregation and reactivity of lithium enolate anions has been studied. The influence of alkyl substitution on the energetics of enolate anions has been studied. ... 

With /V-acylthioamides the reaction proceeds very slowly and the products are difficult to purify. Therefore, the Af-acylthioamides 32 are first converted into the S -alkyl derivatives 33 by the reaction with alkyl halides under strongly basic conditions. The resulting A -acylthioimi-dates 33 react with amidines and guanidines in alcoholic solution in the presence of sodium alkoxide to form 2,4,6-trisubstituted 1,3,5-triazines 34 in moderate to good yields.438,439 This procedure is an extension of the synthesis of trisubstituted 1,3,5-triazines from A -acylimidates 17 and amidines (vide supra).325... 

The value of thiourea for the preparation of thiols is that on reaction with alkyl halides,271 mixtures of hydrogen bromide and alcohols,272 or suitable aromatic273 or heterocyclic halides274 it readily yields S-alkyl- or S-aryl-thiouronium salts, from which the thiols are usually obtained in good yield by alkaline hydrolysis or by aminolysis with high-boiling, strongly nucleophilic... 

Kosolapoff (182), who prepared tri- cr -butyl phosphite from phosphorus trichloride and er -butyl alcohol, claimed that This phosphite could not be made to undergo the Michaelis-Arbuzov reaction with alkyl halides at temperatures under 80-90°, while above that temperature it began to decompose with evolution of isobutylene. Further support for the concept that the tertiary ester group is unreactive was provided by the... 

As noted above, alkyne anions are very useful in Sn2 reactions with alkyl halides, and in acyl addition reactions to a carbonyl.46 Alkyl halides and sulfonate esters (tosylates and mesylates primarily) serve as electrophilic substrates for acetylides. A simple example is taken from Kaiser s synthesis of niphatoxin B, in which propargyl alcohol (36) is treated with butyllithium and then the OTHP derivative of 8-bromo-1-octanol to give a 47% yield of 37.48... 

For efficient action of Y as cocatalysts, it is necessary that in reactions with alkyl halides they behave as bases abstracting proton not as nucleophiles entering undesired nucleophilic substitution. From a variety of possible Y-H, only OH acids—alcohols and phenols, and to smaller extent some NH acids—are shown to be proper cocatalysts. In a model studies of base-induced PTC j8-elimination of HBr from cyclohexyl bromide, it was shown that benzyl and benzhydryl alcohols, 2,2,2-trifluoroethanol, trifluoromethylphenyl carbinol, and mesitol are particularly efficient cocatalysts (71) as shown in equation 159. 

In the synthesis of propargylic alcohols, we saw the reaction of an alkynyl nucleophile (either the anion RC=CNa or the Grignard RC CMgBr, both prepared from the alkyne RC CH) with a carbonyl electrophile to give an alcohol product. Such acetylide-type nucleophiles will undergo Sn2 reactions with alkyl halides to give more substituted alkyne products. With this two-step sequence (deprotonation followed by alkylation), acetylene can be converted to a terminal alkyne, and a terminal alkyne can be converted to an internal alkyne. Because acetylide anions are strong bases, the alkyl halide used must be methyl or 1° otherwise, the E2 elimination is favored over the Sn2 substitution mechanism. 

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