Nucleophilic substitution with 2-methyl-2-propanol

El eliminations begin with the same uni molecular dissociation we saw in the Sfsjl reaction, but the dissociation is followed by loss of H+ from the adjacent carbon rather than by substitution. In fact, the El and SN1 reactions normally occur together whenever an alkyl halide is treated in a protic solvent with a non-basic nucleophile. Thus, the best El substrates are also the best SN1 substrates, and mixtures of substitution and elimination products are usually obtained. For example, when 2-chloro-2-methylpropane is warmed to 65 °C in 80% aqueous ethanol, a 64 36 mixture of 2-methyl-2-propanol (Sjql) and 2-methylpropene (El) results. 

The regiochemistry of acid-catalyzed ring opening depends on the epoxide s structure, and a mixture of products is usually formed. When both epoxide carbon atoms arc cither primary or secondary attack of the nucleophile occurs primarily at the less highly substituted site. When one of the epoxide carbon atoms is tertiary,however nucleophilic attack occurs primarily at the more highly substituted site. Thus, L,2-epoxypropane jeac t with HCl to give primarily l-chloro-2-propanol, but 2-methyl 1,2-cpoxypropane gives 2-chloro-2-methyl-l-propanol as the major product. 

We ve now seen that the Sn2 reaction is worst when carried out with a hindered substrate, a neutral nucleophile, and a protic solvent. You might therefore expect the reaction of a tertiary substrate (hindered) with water (neutral, protic) to be among the slowest of substitution reactions. Remarkably, however, the opposite is true. The reaction of the tertiary halide (CHn) )CBr with H2O to give the alcohol 2-methyl-2-propanol is more than 1 million times as fast as the corresponding reaction of the methyl halide CHsBr to give methanol. 

In Section 11.2.2, the rate of reaction for a tertiary halide in an Sn2 reaction is shown to be prohibitively slow, due to steric hindrance in the requisite pen-tacoordinate transition state. When 2-bromo-2-methylpropane (64) is heated in anhydrous THF (no water) with KI, for example, only unreacted 65 and KI are isolated. There is no reaction (see Chapter 7, Section 7.12, for a definition of no reaction ). Many different experiments have been done with this reaction, including using different nucleophiles, different solvents, and different reaction conditions. Interestingly, when 64 is heated in water, 2-methyl-2-propanol (65) is isolated in low yield. This is clearly a substitution reaction (Br for OH), but it cannot be an S 2 reaction. The reaction occurred with a tertiary halide, which is contrary to the requirement of a high-energy pentacoordinate transition state such as 13 (see Figure 11.5). Many experiments have demonstrated that this reaction follows first-order rather than second-order kinetics and there is an intermediate in an overall two-step reaction. 

When 2-methyl-2-propanol tert-hvXyl alcohol, 65) is treated with concentrated HCl, 2-chloro-2-methylpropane (2-chloro-2-methylpropane ter -butyl chloride, 93) is isolated in 90% yield. Similarly, when 1-butanol (94) is treated with 48% HBr in the presence of sulfuric acid, a 95% yield of 1-bromobutane (96) is obtained. In both reactions, the oxygen of the alcohol reacts as a Br0nsted-Lowry base in the presence of the protonic acids, HCl, or sulfuric acid. The fact that alkyl halides are produced clearly indicates that these are substitution reactions. In previous sections, tertiary halides gave substitution reactions when a nucleophilic halide ion reacted by an Sfjl mechanism that involved ionization to a carbocation prior to reaction with the halide. Primary halides react with a nucleophilic halide ion by an 8 2 mechanism. It is reasonable to assume that tertiary alcohols and primary alcohols will react similarly, i/the OH unit is converted to a leaving group. 

For example, when 2-bromo-2-methylpropane (tert-butyl bromide) is mixed with water, it is rapidly converted into 2-methyl-2-propanol (tert-butyl alcohol) and hydrogen bromide. Water is the nucleophile here, even though it is poor in this capacity. Such a transformation, in which a substrate undergoes substitution by solvent molecules, is called solvolysis, such as methano-lysis, ethanolysis, and so on. When the solvent is water, the term hydrolysis is applied. 

The acid-catalyzed substitution reaction of 2-methyl-2-propanol occurs in two steps from the alkyl-oxonium ion with the formation of an intermediate carbocation. The carbocation forms in the ratedetermining step, which does not involve the nucleophile. In the second, fast step, the carbocation reacts with a nucleophile such as a halide ion to form the product. 

---