LON-CAPA Sn2

Nucleophilic Aliphatic Substitution Reactions

The Sn2 Mechanism

Substituent Effects

Introduction

We have seen how chemical kinetics offered an insight into the mechanism of the reaction 1.

Specifically, the fact that the transformation is first order in both alkyl halide and hydroxide ion implies that both reactants are involved in the rate determining step of the reaction. This knowledge allowed us to postulate a structure for the transition state of the reaction. Now we are going to see what insights changing the substituents attached to the reaction center can offer. Scheme 1 reiterates the general description of nucleophilic aliphatic substitution reactions.

Scheme 1

Nucleophilic Aliphatic Substitution

Changing Substituents

Figure 1 compares the absolute and relative rate constants of reaction 1 with those of comparable reactions in which the number of methyl groups attached to the electrophilic center increases from one to three.

Figure 1

A Structure-Reactivity Corrleation

The rate of reaction of 2-bromo-2-methylpropane was too small to measure under these conditions.

Exercise 1 As the number of non-hydrogen substituents attached to the reaction center increases, the rate of bimolecular substitution .

Exercise 2 The reaction center in bromoethane is a 1^o 2^o 3^o 4^o carbon atom. The reaction center in 2-bromopropane is a 1^o 2^o 3^o 4^ocarbon atom. The reaction center in 2-bromo-2-methylpropane is a 1^o 2^o 3^o 4^ocarbon atom.

Exercise 4 Assuming that the relative reactivities shown in Figure 1 may be generalized, the order of reactivity of the substrates in Sn2 reactions is

methyl > 1^o > 2^o > 3^o

1^o > methyl > 2^o > 3^o

1^o > 2^o > 3^o>methyl

Exercise 5 The solvent used in the reactions summarized in Figure 2 was a mixture of 80% C₂H₅OH and 20% H₂O. Suggest a reason for not using straight water.

Interactive space-filling models of the four alkyl bromides in Figure 1 are shown in Table 1. The reaction center is colored cyan. Inspect these models to see if you can understand why increasing the number of methyl groups attached to the reaction center decreases the rate of bimolecular nucleophilic aliphatic substitution.

Table 1

Three's a Crowd

bromomethane

bromoethane

2-bromopropane

2-bromo-2-methylpropane

Exercise 6 Given the data in Figure 1 and the structures in Table 1, which of the following diagrams better represents the direction from which the nucleophile must approach the substrate in a bimolecular nucleophilic aliphatic substitution reaction?

Figure 2 presents the relative rates of substitution in a series of primaryl alkyl bromides. Here the number of substituents attached to the reaction center is not changing, but their size is.

Figure 2

Coming at It in a Different Way

Exercise 6 Which compound reacts faster with sodium hydroxide, 1-bromopropane or the isomeric2-bromopropane?

Exercise 7 Which compound reacts faster with sodium hydroxide, 1-bromobutane or the isomeric 2-bromo-2-methylpropane?

Exercise 8 Which change of substituents at the reaction center has a greater effect on the rate of Sn2 reactions, replacing two hydrogens with two -CH₃ groups, or replacing a single hydrogen with a -CH₂CH₃ groups?

Now look at the relative rates of Sn2 reactions for the compounds shown in Figure 3. The non-hydrogen substituent attached to the reaction center is highlighted in red to emphasize the structural similarities between the compounds. The carbon atom bonded to the reaction center is designated by the Greek letter a.

Figure 3

Does This Ring a Bell? (Resonate?)

Exercise 9 Summarize the data presented in Figure 3.

Exercise 10 Complete the following statement: In an Sn2 reaction, when a substituent attached to the reaction center contains a pi bond, the rate of substitution in comparison to a reference compound in which the corresponding substituent does no contain a pi bond.

Exercise 11 If the transition state for an Sn2 reaction looks like this: , draw a picture of the transition state for the reaction of 3-chloro-1-propene, R = -CH=CH₂, which depicts an interaction between the pi system of the double bond and the p orbital of the reaction center.

Exercise 12 The pK_a of ethanol, CH₃CH₂OH, is 16 while that of phenol, C₆H₅OH, is 10. The rate of the Sn2 reaction of C₆H₅CH₂Cl with hydroxide ion is 19 times faster than that of CH₃CH₂Cl. Explain how these two facts are related. Draw pictures that demonstrate the similarity in orbital overlap in the two situations.

To summarize the data we have seen in this topic:

As the number of alkyl groups attached to the reaction center increases, the rate of bimolecular nucleophilic aliphatic substitution decreases. The general order of reactivity of substrates methyl > 1^o > 2^o > 3^o.
The number of alkyl groups attached to the reaction center exerts a larger influence on the rate of bimolecular nucleophilic aliphatic substitution than does the size of the alkyl group.
Compounds in which the a carbon of a substituent is sp or sp² hybridized undergo bimolecular nucleophilic aliphatic substitution reactions faster than analogous compounds in which the a carbon of the substituent is sp³ hybridized.

Now let's take a look at the roles of the nucleophile and the leaving group in Sn2 reactions.