Most nucleophilic substitutions take place by the S_N2 pathway just discussed. The reaction is favored when carried out with an unhindered substrate and a negatively charged nucleophile in a polar aprotic solvent, but is disfavored when carried out with a hindered substrate and a neutral nucleophile in 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 2-bromo-2-methylpropane (CH₃)₃CBr with H₂O to give the alcohol 2-methyl-2-propanol is more than 1 million times faster than the corresponding reaction of CH₃Br to give methanol.

What’s going on here? A nucleophilic substitution reaction is occurring—a hydroxyl group is replacing a halogen—yet the reactivity order seems backward. These reactions can’t be taking place by the S_N2 mechanism we’ve been discussing, so we must therefore conclude that they are occurring by an alternative substitution mechanism. This alternative mechanism is called the S_N1 reaction, for substitution, nucleophilic, unimolecular.

In contrast to the S_N2 reaction of CH₃Br with OH^–, the S_N1 reaction of (CH₃)₃CBr with H₂O has a rate that depends only on the alkyl halide concentration and is independent of the H₂O concentration. In other words, the process is a first-order reaction; the concentration of the nucleophile does not appear in the rate equation.

To explain this result, we need to know more about kinetics measurements. Many organic reactions occur in several steps, one of which usually has a higher-energy transition state than the others and is therefore slower. We call this step with the highest transition-state energy the rate-limiting step, or rate-determining step. No reaction can proceed faster than its rate-limiting step, which acts as a kind of traffic jam, or bottleneck. In the S_N1 reaction of (CH₃)₃CBr with H₂O, the fact that the nucleophile concentration does not appear in the first-order rate equation means that it is not involved in the rate-limiting step and must therefore be involved in some other, non-rate-limiting step. The mechanism shown in Figure 11.9 accounts for these observations.

Figure 11.9 MECHANISM

The mechanism of the S_N1 reaction of 2-bromo-2-methylpropane with H₂O involves three steps. Step 1—the spontaneous, unimolecular dissociation of the alkyl bromide to yield a carbocation—is rate-limiting.

Unlike what occurs in an S_N2 reaction, where the leaving group is displaced while the incoming nucleophile approaches, an S_N1 reaction takes place by loss of the leaving group before the nucleophile approaches. 2-Bromo-2-methylpropane spontaneously dissociates to the tert-butyl carbocation (CH₃)₃C⁺, plus Br^– in a slow, rate-limiting step, and the intermediate carbocation is then immediately trapped by the nucleophile water in a faster second step. Thus, water is not a reactant in the step whose rate is measured. The energy diagram is shown in Figure 11.10.

Figure 11.10 An energy diagram for an S^N1 reaction. The rate-limiting step is the spontaneous dissociation of the alkyl halide to give a carbocation intermediate. Reaction of the carbocation with a nucleophile then occurs in a second, faster step.

Because an S_N1 reaction occurs through a carbocation intermediate, its stereochemical outcome is different from that of an S_N2 reaction. Carbocations, as we’ve seen, are planar, sp²-hybridized, and achiral. Thus, if we carry out an S_N1 reaction on one enantiomer of a chiral reactant and go through an achiral carbocation intermediate, the product loses its optical activity (Section 8.12). That is, the symmetrical intermediate carbocation can react with a nucleophile equally well from either side, leading to a racemic, 50 : 50 mixture of enantiomers (Figure 11.11).

Figure 11.11 Stereochemistry of the S_N1 reaction. Because the reaction goes through an achiral intermediate, an enantiomerically pure reactant gives an optically inactive racemic product.

The conclusion that S_N1 reactions on enantiomerically pure substrates should give racemic products is nearly, but not exactly, what is found. In fact, few S_N1 displacements occur with complete racemization. Most give a minor (0–20%) excess of inversion. The reaction of (R)-6-chloro-2,6-dimethyloctane with H₂O, for example, leads to an alcohol product that is approximately 80% racemized and 20% inverted (equivalent to 40% R + 60% S).

This lack of complete racemization in S_N1 reactions is due to the fact that ion pairs are involved. According to this explanation, first proposed by Saul Winstein at UCLA, dissociation of the substrate occurs to give a structure in which the two ions are still loosely associated and in which the carbocation is effectively shielded from reaction on one side by the departing anion. If a certain amount of substitution occurs before the two ions fully diffuse apart, then a net inversion of configuration will be observed (Figure 11.12).

Figure 11.12 Ion pairs in an S_N1 reaction. The leaving group shields one side of the carbocation intermediate from reaction with the nucleophile, thereby leading to some inversion of configuration rather than complete racemization.

Problem 11-8

What product(s) would you expect from reaction of (S)-3-chloro-3-methyloctane with acetic acid? Show the stereochemistry of both reactant and product.

Problem 11-9

Among the many examples of S_N1 reactions that occur with incomplete racemization, the optically pure tosylate of 2,2-dimethyl-1-phenyl-1-propanol ([α]D = –30.3) gives the corresponding acetate ([α]D = +5.3) when heated in acetic acid. If complete inversion had occurred, the optically pure acetate would have had [α]D = +53.6. What percentage racemization and what percentage inversion occurred in this reaction?

Problem 11-10

Assign configuration to the following substrate, and show the stereochemistry and identity of the product you would obtain by S_N1 reaction with water (reddish brown = Br):