Hydrolysis of benzyl halides

The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Since each of these nucleophiles can also act as a base, reaction conditions are selected to favor substitution over elimination. Usually, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformation is not used extensively for synthesis. The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good yield. This can be a useful synthetic transformation because benzyl halides are available either by side chain halogenation or by the chloromethylation reaction (Section 11.1.3). 

Aromatic alcohols are obtained by the hydrolysis of benzyl halides and by the reduction of aromatic aldehydes and ketones. 

The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good... 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

Many of the common laboratory methods for the preparation of alcohols have been discussed in previous chapters or will be considered later thus to avoid undue repetition we shall not consider them in detail at this time. Included among these methods are hydration (Section 10-3E) and hydroboration (Section 11-6D), addition of hypohalous acids to alkenes (Section 10-4B), SN1 and Sn2 hydrolysis of alkyl halides (Sections 8-4 to 8-7) and of allylic and benzylic halides (Sections 14-3B and 14-3C), addition of Grignard reagents to carbonyl compounds (Section 14-12), and the reduction of carbonyl compounds (Sections 16-4E and 16-5). These methods are summarized in Table 15-2. 

Hydrolysis of alkyl halides is severely limited as a method of synthesizing alcohols, since alcohols are usually more available than the corresponding halides indeed, the best general preparation of halides is from alcohols. The synthesis of benzyl alcohol from toluene, however, is an example of a useful application of this method. 

Krohnke aldehyde synthesis. Transformation of benzyl halides into aldehydes via their pyri-dinium salts which, on treatment with p-nitrosodi-methylaniline, give nitrones. Hydrolysis of the nitrones yields aldehydes. 

The Sommelet reaction, also known as the Sommelet oxidation, is the oxidation of benzyl halides (1) to the corresponding aldehydes (3) using hexamethylenetetramine (HMTA) followed by hydrolysis of the hexaminium salt 2.1-3 This reaction is closely related to the Delepine amine synthesis, the Duff aldehyde synthesis, and the Krtihnke reaction (see Section 7.10.3). 

In 1913, Marcel Sommelet (1877-1952) of the Faculty de Pharmacie of Paris University published his seminal article in Comptes Rendus with the title Decomposition of Alkyl Halide Addition Products of Hexamethylenetetramine, where he delineated the formation of aldehydes by treatment of benzyl halides followed by hydrolysis.4,5 In 1954, S. J. Angyal published a review in Organic Reactions, where he summarized the mechanism, scope, and limitations of the Sommelet reaction.1 Angyal s review ignited a flurry of research and the Sommelet reaction became a well-known standard for the transformation of benzyl halides to the corresponding benzaldehydes. 

The present Grignard-type addition may be reasonably explained by smooth oxidative addition of benzyl halides to nickel in the metallic state to give benzylnickel halide intermediates, and the insertion of 1,2-diketone into the carbon-nickel bond would afford the corresponding hydroxy ketones after hydrolysis. 

The hydrolysis of benzyl chloride is catalyzed by the presence of Hg" salts. The electrophilic salts are here behaving as acids and react with the organic halide to form a carbonium ion ... 

By the hydrolysis of nitriles. The nitriles may be easily prepared either from amines by the Sandmeyer reaction (Section IV,66) or by the action of cuprous cyanide upon aryl halides (compare Section IV,163). Benzyl cyanide... 

Benzylic halides resemble allylic halides m the readiness with which they form carbocations On comparing the rate of S l hydrolysis m aqueous acetone of the fol lowing two tertiary chlorides we find that the benzylic chloride reacts over 600 times faster than does tert butyl chloride... 

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

This method is particularly applicable to the more reactive benzyl halides which are easily hydrolyzed in the aqueous media usually employed for the metathetical reaction with alkali cyanides. For example, anisyl chloride treated with sodium cyanide in aqueous dioxane gives, as a by-product, 5-10% of anisyl alcohol as determined by infrared analysis. The use of anhydrous acetone not only prevents hydrolysis to the alcohol but also decreases the formation of isonitriles. This method was also applied successfully by the submitters to the preparation of -chlo-rophenylacetonitrile in 74% yield. 

In an alternate synthesis of the intermediate ketone, the benzylic halide, 69, is used to alkylate sodium phenoxide. Cyclization of the acid (70) obtained on hydrolysis of the ester by means of trifluoroacetic anhydride again gives 67... 

Both sides of acetone have been alkylated with different alkyl groups, in one operation, by treatment of the Al,lV-dimethylhydrazone of acetone with n-BuLi, followed by a primary alkyl, benzylic, or allylic bromide or iodide then another mole of n-BuLi, a second halide, and finally hydrolysis of the hydrazone. ... 

Alkylation of saturated 5(4//)-oxazolones at C-4 is a well-known reaction that can be achieved under a wide variety of conditions. Numerous articles have described this reaction as a means to prepare 4,4-dialkyl-5(477)-oxazolones 147 that are valuable intermediates to prepare ot,ot-disubstituted a-amino acids. For instance,2-phenyl-5(4//)-oxazolone 146 readily obtained from hippuric acid and A,A -dicyclohexylcarbodiimide (DCC), is alkylated at C-4 with allyl, benzyl, or phenacyl halides if the reaction is conducted in dipolar aprotic solvents in the presence of weak bases. Hydrolysis of the resulting 5(477)-oxazolones leads to a,a-dialkylglycines 148 (Scheme 7.43). 

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