Nucleophilic Substitution in Benzylic Halides

Primary benzylic halides are ideal substrates for Sn2 reactions, since they are very reactive toward good nucleophiles and cannot undergo competing elimination. 

Benzylic halides that are secondary resemble secondary alkyl halides in that they undergo substitution only when the nucleophile is weakly basic. If the nucleophile is a strong base such as sodium ethoxide, elimination by the E2 mechanism is faster than substim-tion. 

PROBLEM 11.8 Give the structure of the principal organic product formed on reaction of benzyl bromide with each of the following reagents  

SAMPLE SOLUTION (a) Benzyl bromide is a primary bromide and undergoes Sn2 reactions readily. It has no hydrogens (3 to the leaving group and so cannot undergo elimination. Ethoxide ion acts as a nucleophile, displacing bromide and forming benzyl ethyl ether. 

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

Like allylic halides, benzylic halides undergo nucleophiUc substitution, both SnI and Sn2, faster than simple alkyl halides and for similar reasons. 

Relative Sj l Rates Hydrolysis of the tertiary benzylic halide 2-chloro-2-phenylpropane occurs 620 times faster than hydrolysis of iert-butyl chloride under the same conditions (90% acetone-10% water at 25°C). 

Because S l rates reflect the activation energy for carbocation formation, we conclude that a phenyl substituent stabilizes a carbocation more than a methyl group does. 

1-Methyl-1-phenylethyl cation tert-Bntyl cation 

As measured by their first-order rate constants, the compound shown (R = CH3) undergoes hydroiysis 26 times faster than 2-chloro-2-phenyipropane (R = H) in 90% acetone-10% water at 25°C. Offer a resonance expianation for this rate difference. 

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To account for these unusual results and the role of the free-radical character, a mechanism that implies that NH—CO—PTM- is a good leaving group in 8, 2 reactions has been proposed. It is based on the quantum-mechanical approach used to account for the kinetics of nucleophilic substitution in benzyl halides, which involves a diradicaloid configuration in the relevant transition state. The latter would be particularly stabilized by the radical character of the labelled glycine. 

It is not immediately obvious how to carry out this synthesis, so let s use retrosynthetic analysis to find a way. The only method you know for introducing a C=N group into a molecule is nucleophilic substitution. The alkyl halide for that substitution reaction can be obtained from die addition of HBr to an alkene in the presence of a peroxide. The alkene for that addition reaction can be obtained from an elimination reaction using an alkyl halide obtained by benzylic substitution. 

The solubility of ionic substances in relatively nonpolar aprotic solvents can be greatly enhanced by using catalytic quantities of macrocyclic polyethers, such as 18-crown-6, the structure of which is shown in Fig. 5.5. These macrocyclic ethers selectively solvate the cation, both enhancing solubility and also leaving the anion in a very weakly solvated state. The anions behave under these conditions as highly reactive species, sometimes termed naked anions. A study of the relative rates of nucleophilic substitution on benzyl tosylate by potassium salts in acetonitrile in the presence of 18-crown-6 revealed a pronounced leveling effect. " All the potassium halides (fluoride, chloride, bromide, and iodide) were approximately equal in their reactivity. Potassium acetate was observed to be almost ten times more reactive than potassium iodide under these conditions—a reversal of the normal reactivity of acetate ion versus iodide ion in nucleophilic substitution reactions. As measured by cHji values in Table 5.5, iodide is 3 log units, i.e., 10 times, more reactive than acetate ion in the protic solvent methanol. 

Nucleophilic Substitution on Alkyl Halides by Heteroatoms. A number of more or less activated alkyl halides, such as benzyl halides and allyl halides, undergo substitution reactions mediated by AgBp4 in the presence of a heteroatom nucleophile. For example, treatment of pentamethylcyclopentadienyl bromide with AgBp4 in the presence of a nucleophile gives the corresponding substituted product (eq 2). Thiols, amines, and alcohols have been used as nucleophiles. ... 

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/ ... 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

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). 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

The possibility that substitution results from halogen-atom transfer to the nucleophile, thus generating an alkyl radical that could then couple with its reduced or oxidized form, has been mentioned earlier in the reaction of iron(i) and iron(o) porphyrins with aliphatic halides. This mechanism has been extensively investigated in two cases, namely the oxidative addition of various aliphatic and benzylic halides to cobalt(n) and chromiumfn) complexes. 

You have read (Unit 10, Class Xll) that the carbon - halogen bond In alkyl or benzyl haUdes can be easily cleaved by a nucleophile. Hence, an allqrl or ben l haUde on reaction with an ethanollc solution of ammonia undergoes nucleophilic substitution reaction m which the halogen atom Is replaced by an amino (-NHJ group. This process of cleavage of the C-X bond by ammonia molecule Is known as ammonolysis. The reaction Is carried out In a sealed tube at 373 K. The primary amine thus obtained behaves as a nucleophile and can further react with allqrl halide to form secondary and tertiary amines, and finally quaternary ammonium salt. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

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