Halides, alkyl reaction with ethers

Reaction with Alkyl Halides The gas inlet tube is replaced by an addition funnel, and 10 ml of HMPT is added rapidly with stirring. The mixture is cooled to 10-15°, and a solution of the alkyl halide (0.1 mole) in 20 ml of THF is added dropwise over a period of 30-40 minutes. The mixture is then heated to 40° for 2-3 hours. The thick white suspension of the sodium halide is cooled and dilute cold hydrochloric acid is carefully added until the mixture is clear. The organic layer is separated, and the aqueous layer is extracted three times with 20-ml portions of ether, the ethereal extracts then being combined with the organic material. The ethereal solution is washed twice with saturated sodium chloride solution and dried. The ether and THF are removed under reduced pressure (rotary evaporator), and the alkyne is distilled. 

It is these reactions that are thought to provide some justification for equation (vii) [in Section VI B3] according to which p-phenethylbi-guanide in methanol exists to some extent as biguanidium methoxide. This being so, the reaction with alkyl halides is the nucleophihc displacement of the halogen ion by methoxide with formation of the methyl ether and the salt of the biguanide. 

The hfs-lactim ether (190) was metallated with BuLi regiospecifically in the alanine part of the molecule to produce, after the reaction with alkyl halides, the (3R)-adducts... 

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. 

When ethoxide is used as a base to abstract a-proton, it could react with the alkyl halide (Sn2) to form ether. However, the acid-base equilibrium with the diketone prefers the more stable, less basic enolate over the ethoxide, essentially consuming the ethoxide. Thus, the very stable enolates from 1,3-dicarbonyl compounds are able to undergo Sn2 reactions with alkyl halides without competition from the alkoxide catalyst. 

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. 

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. ... 

Cesium fluoride. 13,68 14 Ethers. A direct tran< reaction with alkyl halides ii as methyl glycerate via dibui As base. Both sulflde CsF as a base. A route to c malonic ester and glycidyl n... 

Cesium fluoride. 13,68 14,79 15,75-76 16,69-70 17,68 18,88-89 19,70-72 Ethers. A direct transformation of aryl silyl ethers to aryl alkyl ethers is by their reaction with alkyl halides in the presence of CsF-DMF. Monobenzylation of glycols such as methyl glycerate via dibutylstannylene acetals. ... 

Reactions with Alkyl Halides.— The in situ generation and reaction of chlorodi-phenylphosphine (2) with a-chloro-ethers gives good yields of a-alkoxyalkylphosphine oxides (20). The phosphine (2) is made from phosphorus trichloride and benzene, and the sequence looks like a very convenient one-pot procedure - the dangers of certain chloro-ethers aside ... 

Reaction with alkyl halides and sulfonates. Previously this reagent found little use in organic chemistry because it is unstable in protic solvents and insoluble in aprotic solvents. However, three laboratories have now reported that addition of crown ethers, particularly 18-crown-6, permits preparation of solutions of KO2 in various solvents DMSO, DMF, DME, and even benzene and ether. In DMSO, a crown ether is unnecessary. ... 

There are two major reactions of organocuprates, and both give products reminiscent of a carbon nucleophile (1) reaction with alkyl halides and (2) conjugate addition with a,p-unsaturated ketones. Conjugate addition to a, 3-unsaturated ketones is promoted when ether is used as a solvent.381 The substitution reaction is promoted by the use of THF or ether-HMPA as a solvent. l As mentioned earlier, the mechanism of these reactions probably involves a one-electron transfer, although other mechanistic proposals are in the literature,but the synthetic result is that expected of a carbon nucleophile. 85 The general reactivity of organocuprates with electrophiles follows the order ... 

In ether and THF, 0-alkylation is a much less serious problem in reactions with alkyl halides. With the possible exception of iodomethane, the use of lithium enolates in ether solvents leads to C-alkylation as the major product in virtually all cases. When the enolate carbanion center is sterically hindered, however, O-alkylation can be a problem, even in THF or ether. There are some reagents that prefer 0-alkylation, with silyl halides, and anhydrides being the most common. Both of these O-alkylation reactions will be discussed in Section 9.3.C. 

The mechanism of the reaction with various alkyl halides in NMP is believed to involve nucleophilic attack by both the solvent-separated ion-pairs Na2[Fe(CO)J (kj) and [Na(Fe(CO)J (k j) (where k 2 = O.lSdm mol s and Atj < t 2) evidenced by the non-linear dependence of the observed rate constant on the concentration of complex. In THF the dissociation of the ions is less extensive, and the rate of reaction with alkyl halides is correspondingly slower. However, the addition of polar solvents or crown ethers increases the rate of the reaction, and this has been ascribed to the kinetically more reactive, more dissociated species. 

Phenoxides can be used in a Williamson ether synthesis by reaction with alkyl halides (Sjj2 process) to create aUg l-aryl ethers. 

Alkoxides are readily formed from partially substituted polyols and sugars by treatment with sodium naphthalenide 19) in 1,2-dimethoxy-ethane solution and subsequent reaction with alkyl halides then produces ethers 20). The reaction sequence is simple to apply, and the method deserves further investigation. 

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