Tertiary halides substitution

Primary and secondary allyl halides (R or R = H), all the allyl halides with R = alkyl, aryl and tertiary halides substituted with one or two cyano functions (Y and/or Z = CN) give rise to acetal (295, 296, 297) formation via ring-opening of the non-isolable cyclopropanes by further reaction with the alcohol (equation gg i78,179,181,184,185,188,191,192,206 However, reaction of 2-bromo-2-methyl-l-phenyl-... 

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

Thiols can be prepared by a variety of methods. The most-utilised of these synthetic methods for tertiary and secondary thiols is acid-catalysed synthesis for normal and secondary thiols, the most-utilised methods are free-radical-initiated, alcohol substitution, or halide substitution for mercaptoalcohols, the most-utilised method is oxhane addition and for mercaptoacids and mercaptonitnles, the most-utilised methods are Michael-type additions. 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

In general, substitution reactions of tertiary halides do not find wide use as synthetic methods. 

So the tertiary halide reacts by a different mechanism, which we call SnI- It s still a nucleophilic substitution reaction (hence the S and the N ) but this time it is a unimolecular reaction, hence the 1 . The rate-determining step during reaction is the slow unimolecular dissociation of the alkyl halide to form a bromide ion and a carbocation that is planar around the reacting carbon. 

Problom 7.39 On substitution of one H by a Cl in the isomers of C,H,j, (a) which isomer gives only a primary halide (b) Which isomers give secondary halides (c) Which isomer gives a tertiary halide ... 

With tertiary halides, bimolecular elimination usually occurs if isomeric alkenes can result, the proportions formed depend on the steric requirements of the pyridine because formation of the more substituted alkene (Saytsev Rule) is more sensitive to steric hindrance than formation of the less substituted alkene (Hofmann Rule). Pyridine and r-amyl bromide give 25% of 2-methylbut-l-ene (less... 

Many secondary and tertiary halides undergo El elimination in competition with the SN1 reaction in neutral or acidic solutions. For example, when tert-butyl chloride solvolyzes in 80% aqueous ethanol at 25°, it gives 83% tert-butyl alcohol by substitution and 17% 2-methylpropene by elimination ... 

The order of SN2 reactivity is primary > secondary > tertiary, and branching of the chain close to the site of substitution hinders reaction. The unbranched primary halide n-butyl chloride will be the most reactive and the tertiary halide tert-butyl chloride the least. The order of reactivity will therefore be 1-chlorobutane > l-chloro-2-methylpropane > 2-chlorobutane > 2-chloro-2-methylpropane. 

Tertiary halides undergo a combination of SN1 and Ej reactions. If the reaction is kept cool, and the nucleophile is a relatively weak base, it is possible to get nucleophilic substitution. At high temperatures, or with strong bases, elimination reactions predominate. 

Nucleophilic substitution may occur by two mechanisms. The SN2 mechanism is a one-step process. Its rate depends on the concentrations of substrate and nucleophile. If the halogen-bearing carbon is stereogenic, substitution occurs with inversion of configuration. The reaction is fastest for primary halides and slowest for tertiary halides. 

The SN1 mechanism is a two-step process. In the first step, the alkyl halide ionizes to a carbocation and a halide ion. In the second, fast step, the carbocation combines with the nucleophile. The overall rate is independent of nucleophile concentration. If the halogenbearing carbon is stereogenic, substitution occurs with racemization. The reaction is fastest for tertiary halides and slowest for primary halides. The two mechanisms are compared in Table 6.2. 

On the contrary, in the case of 1-iodonorbomane (a tertiary halide), the result of the reaction with trimethylstannyl reagents (Me3SnM, M = Li, Na), both in the absence and in the presence of trapping agents, confirmed that the nucleophilic substitution process is governed by competition between polar and radical mechanisms133. 

Halides that do not undergo SN2 reactions readily (tertiary, cyclopropyl and bridgehead halides) react by silver-assisted substitution in the presence of silver salts89. Tertiary halides have also been reduced using the in situ generation of cyanoborohydride reagents90. Since primary and secondary halides are apparently unaffected by this reagent, a selective reaction has been developed. 

Different alkyl halides undergo Sn2 reactions at vastly different rates. The structure of the substrate is the most important factor in its reactivity toward Sn2 displacement. The reaction goes rapidly with methyl halides and with most primary substrates. It is more sluggish with secondary halides. Tertiary halides fail to react at all by the Sn2 mechanism. Table 6-5 shows the effect of alkyl substitution on the rate of Sn2 displacements. 

This solvolysis is a substitution because methoxide has replaced bromide on the tert-butyl group. It does not go through the SN2 mechanism, however. The SN2 requires a strong nucleophile and a substrate that is not too hindered. Methanol is a weak nucleophile, and ferf-butyl bromide is a hindered tertiary halide—a poor SN2 substrate. 

Bromocyclohexene is a secondary halide, and benzyl bromide is a primary halide. Both halides undergo SN1 substitution about as fast as most tertiary halides. Use resonance structures to explain this enhanced reactivity. 

Tertiary halides are too hindered to undergo Sn2 displacement, but they can ionize to form tertiary carbocations. Tertiary halides undergo substitution exclusively through the SN1 mechanism. Secondary halides can undergo substitution by either mechanism, depending on the conditions. 

The E2 dehydrohalogenation gives excellent yields with bulky secondary and tertiary alkyl halides, such as ferf-butyl bromide in the preceding example. A strong base forces second-order elimination (E2) by abstracting a proton. The molecule s bulkiness hinders second-order substitution (SN2), and a relatively pure elimination product results. Tertiary halides are the best E2 substrates because they are prone to elimination and cannot undergo Sn2 substitution. 

Amines react with primary alkyl halides to give alkylated ammonium halides. Alkylation proceeds by the SN2 mechanism, so it is not feasible with tertiary halides because they are too hindered. Secondary halides often give poor yields, with elimination predominating over substitution. 

With less hindered alkyl halides hydroxide would not be a good choice as a base for an elimination because it is rather small and still very good at Sn2 substitutions (and even with tertiary alkyl halides, substitution outpaces elimination at low concentrations of hydroxide). So what are good alternatives ... 

Predicting the outcome of substitutions and eliminations is only straightforward in certain cases. For primary halides, S 2 and E2 reactions are predicted. For tertiary halides, SnI, E2 andEl(to a certain extent) are the choices. The possibilities for secondary halides are more complicated. In addition, many reactions yield both substitution and elimination products, and both inversion and retention of configuration may occur in the same reaction. 

The acetylide ion is a strongly basic and nucleophilic species which can induce nucleophilic substitution at positive carbon centres. Acetylene is readily converted by sodium amide in liquid ammonia to sodium acetylide. In the past alkylations were predominantly carried out in liquid ammonia. The alkylation of alkylacetylenes and arylacetylenes is carried out in similar fashion to that of acetylene. Nucleophilic substitution reactions of the alkali metal acetylides are limited to primary halides which are not branched in the -position. Primary halides branched in the P-position as well as secondary and tertiary halides undergo elimination to olefins by the NaNH2. The rate of reaction with halides is in the order I > Br > Cl, but bromides are generally preferred. In the case of a,o)-chloroiodoalkanes and a,to-bromoiodoalkanes. 

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