Substitution, Nucleophilic, Unimolecular

In this section, we shall learn about a new pathway for nucleophilic substitution. Recall that the Sn2 reaction 

In Chapter 6, the kinetics of reaction between halomethanes and nucleophiles revealed a bimolecular transition state The rate of the Sn2 reaction is proportional to the concentration of both ingredients. Similar studies have been carried out by varying the concentrations of 2-bromo-2-methylpropane and water in formic acid (a polar solvent of very low nucleophi-licity) and measuring the rates of solvolysis. The results of these experiments show that the rate of hydrolysis of the bromide is proportional to the concentration of only the starting halide, not the water. 

The hydrolysis of 2-bromo-2-methylpropane is said to proceed by unimolecular nucleophilic substitution, abbreviated SnI. The number 1 indicates that only one molecule, the haloalkane, participates in the rate-determining step The rate of the reaction does not depend on the concentration of the nucleophile. The mechanism consists of three steps. 

Heterolytic cleavage of the carbon-halogen bond separates opposite charges, making this step slow and rate determining. 

Step 1. The rate-determining step is the dissociation of the haloalkane to an alkyl cation and bromide, a process we have already seen in Section 2-2. 

The most synthetically useful nucleophilic substitution reaction is the bimolecular Sn2 reaction, shown in the section 2.7.A. A unimolecular substitution (ionization followed by substitution) is less useful in synthesis in a general sense, but is often the best specific reaction to effect a particular functional group exchange. In Chapter 12 we will see many examples where cationic reactions are very useful. Unimolecular substitution also occurs as a side reaction in aqueous media and can influence both the yield, stereochemistry, and regiochemistry of the final product. 

The SnI Reaction. The mechanistic rationale described above results from many years of experimental observations about the SnI reaction (statements 1-6 below). 25 i i general, the SnI process occurs in those cases where water is present as a solvent or co-solvent, there is a good leaving group and the substrate is tertiary or secondary. A SnI reaction can occur in any polar protic solvent such as methanol, ethanol, or acetic acid, but ionization is much slower in these solvents relative to water because they are not as efficient for, the separation of ions (sec. 2.7.B). If ionization is relatively slow, faster reactions (Sn2 or elimination processes) often predominate. It is convenient to assume that SnI reactions occur only in aqueous media and use this assumption to predict product distributions for a given set of reaction conditions. As with any 

Chapter 2. Acids, Bases, Functional Group Exchanges 

The rate of reaction with tertiary halides that is much faster than with primary halides, 7 which is shown in Table 2.14 for reaction of bromoalkanes with potassium iodide in aqueous media. 

The rate equation can be described using only the concentration of the halide and not that of the nucleophile. The rate determining (slow) step is ionization of the C—Br bond and the fast second step does not greatly influence the overall rate. The rate expression is. Rate = k [RX], for this unimolecular reaction. 2 

Now consider the reaction of acetate ion with rert-butyl chloride  

This reaction looks very similar to the reaction of hydroxide ion with methyl chloride presented earlier, but with the negative oxygen of the acetate anion acting as the nucleophile. (The CH3C02H shown over the arrow is the solvent for the reaction.) However, investigation of this reaction in the laboratory has shown that the reaction rate depends only on the concentration of tert-butyl chloride (r-BuCl). It is totally independent of the concentration of acetate anion. The reaction follows the first-order rate law  

Because the reaction follows a different rate law from the Sn2 mechanism, it must also proceed by a different mechanism. 

The fact that the rate law depends only on the concentration of tert-butyl chloride means that only tert-butyl chloride is present in the transition state that determines the rate of the reaction. There must be more than one step in the mechanism because the acetate ion must not be involved until after the step with this transition state. Because only one molecule pert-butyl chloride) is present in the step involving the transition state that determines the rate of the reaction, this step is said to be unimolecular. The reaction is therefore described as a unimolecular nucleophilic substitution reaction, or an SN1 reaction. 

Free energy versus REACTION PROGRESS DIAGRAM FOR THE SN I REACTION OF TERT-BUTYL CHLORIDE (2-CHLORO-2-METHYLPROPANE) AND ACETATE ANION. 

---

Illustrate the stereochemistry associated with unimolecular nucleophilic substitution by con structmg molecular models of cis 4 tert butylcyclohexyl bromide its derived carbocation and the alcohols formed from it by hydrolysis under S l conditions... 

Section 4.9 The potential energy diagrams for separate elementary steps can be merged into a diagram for the overall process. The diagram for the reaction of a secondary or tertiary alcohol with a hydrogen halide is characterized by two intermediates and three transition states. The reaction is classified as a unimolecular- nucleophilic substitution, abbreviated as SnI. 

The noncatalytic substitution of a 4-diazonium group by nucleophiles, which has proved widely useful in this series, is probably an example of a unimolecular nucleophilic substitution. The first example... 

Because the slowest step of this reaction only involves t-butyl bromide, the overall rate of reaction only depends on the concentration of this species. This is therefore a unimolecular nucleophilic substitution, or SN1, reaction. 

Apart from overcoming coulombic repulsions, 8 2 reactions also proceed with inversion in the face of steric hindrance. By comparison, the stereochemical result of unimolecular nucleophilic substitution SN1 is variable. In fact, nucleophilic substitutions at carbon with retention invariably follow other than SN2 paths. In its broad outlines, the Hughes-Ingold approach swept away the confusions of the period 1895-1933 and has not ceased to stimulate and provoke ideas in the area of substitution reactions. Surprisingly enough, the theoretical foundations of the SN2 process require reexamination and modification, as we shall see. 

Sisl reaction or unimolecular nucleophilic substitution reaction (Section 8.6) A reaction in which the nucleophile replaces the leaving group at an sp3-hybridized carbon in a two-step mechanism that proceeds through a carbocation intermediate. 

---