Two Types of Nucleophilic Substitution Reactions

Comparing Two Nucleophilic Substitution Reactions That Clearly Have Different Mechanisms

Experiments tell us that nucleophilic substitution reactions generally fall into two main groups:

In one group:

• The reaction rate depends only on the concentration of substrate (alkyl halide) and not on the concentration of nucleophile
• The reaction rate is fastest for tertiary alkyl halides and slowest for primary (and methyl) alkyl halides
• The stereochemistry of the product, relative to the starting material, is a mixture of retention and inversion

In a second group:

• The reaction rate depends both on the concentration of substrate and nucleophile
• The reaction rate is fastest for primary alkyl halides and slowest for tertiary alkyl halides
• The stereochemistry of the product shows inversion of configuration relative to the stereochemistry of the starting material. 

As we will see, this experimental data points to the fact that there are two distinct mechanisms for substitution reactions, which we will identify as S_N1 (nucleophilic substitution, unimolecular rate-determining step) and S_N2 (nucleophilic substitution, bimolecular rate-determining step).

Table of Contents

1. How Two Nucleophilic Substitution Reactions Vary According To Substrate (Methyl, Primary, Secondary, Tertiary Alkyl Halides)
2. How Two Nucleophilic Substitution Reactions Vary According To Rate Laws (First Order versus Second Order)
3. How Two Substitution Reactions Vary According To Stereochemistry (Inversion versus Retention + Inversion)
4. Given This Information, Come Up With A Hypothesis For Two Substitution Mechanisms

1. How Two Nucleophilic Substitution Reactions Vary According To Substrate (Methyl, Primary, Secondary, Tertiary Alkyl Halides)

The rate of a reaction is something we can readily measure. Some substitution reactions show a definite pattern as we move from primary substrates (substrate here being an alkyl halide) to tertiary substrates.

In the first reaction, the primary alkyl halide gives a faster reaction under otherwise identical conditions than does the tertiary alkyl halide.

However, there are substitution reactions that serve as a counterpoint. In the second example, it is the tertiary substrate that reacts fastest, followed by the primary substrate.

Interesting!

2. How Two Nucleophilic Substitution Reactions Vary According To Rate Laws (First Order versus Second Order)

Measuring the rate also lets us test how dependent it is upon the concentrations of the various reactions. We can try seeing what happens to the rate when we double or quadruple (or octuple – is that a word?) the concentration of the nucleophile or substrate.

In the first reaction, the rate increases linearly as we increase the concentration of either substrate or nucleophile. That is, if we keep the concentration of substrate constant, and double the concentration of nucleophile, we will double the rate.

However, the rate of the second reaction is only sensitive to the concentration of substrate. No matter how much we increase (or decrease) the concentration of nucleophile, the rate does not change!

3. How Two Substitution Reactions Vary According To Stereochemistry (Inversion versus Retention + Inversion)

It’s also possible to measure the optical rotation of a molecule, which is a property of its stereochemistry. As techniques became more refined, we’ve been able to isolate and work with enantiomerically pure compounds.

Interesting observation: if you start with a single enantiomer in the top reaction, you obtain a single enantiomer – except that the absolute configuration has been reversed!

This is called inversion of configuration.

On the other hand, in the bottom reaction, starting with a single enantiomer we tend to get a mixture of retention and inversion.

(If the amount of retention and inversion is equal, we call this “racemization”. Sometimes they’re not exactly equal).

4. Given This Information, Come Up With A Hypothesis For Two Substitution Mechanisms

So given the data that we have (and these are just a few out of countless examples), how do we come up with hypotheses for how these reactions work?

They have to explain:

1. How the bonds form and how they break
2. The dependence on type of substrate
3. The dependence on concentration
4. The observations of stereochemistry

These hypotheses are called mechanisms. Think about how each of these two reactions could potentially work. Then, in the next post, we’ll go through the first type of substitution reaction.

Next Post: The SN2 Mechanism

Notes

Chemistry is an experimental science. There is no great Ramanujan of our discipline, who, starting with a simple set of premises, could derive and predict all of the depth and variety of modern chemistry. No, it is much messier than that.

Chemists have to actively interrogate Nature to learn her secrets. We add substances together and make observations. Given enough reproducible observations, across a number of different variables, we start to see patterns. And once those patterns become apparent, we can then make hypotheses, and test them.  The hypotheses that survive experimental testing eventually become known as “laws”, although they are really just very strong theories that have not been falsified.

This is just a long way of saying that the data comes first, and hypotheses come second – in the act of looking  backwards. Since we’re talking about substitution reactions, let’s go through some interesting, seemingly contradictory data about substitution reactions that have been recorded, and then (in future posts) we can look backwards and talk about what they mean.