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8.1: Introduction to the nucleophilic substitution reaction

Recall from chapter 6 that, in many ways, the proton transfer process in a Brønsted-Lowry acid-base reaction can be thought of as simply a special kind of nucleophilic substitution reaction, one in which the electrophile is a hydrogen rather than a carbon.

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In both reaction types, we are looking at  very similar players: an electron-rich species (the nucleophile/base) attacks an electron-poor species (the electrophile/proton), driving off the leaving group/conjugate base.

In the next few sections, we are going to be discussing some general aspects of nucleophilic substitution reactions, and in doing so it will simplify things greatly if we can use some abbreviations and generalizations before we dive into real examples.

Instead of showing a specific nucleophile like hydroxide, we will simply refer to the nucleophilic reactant as 'Nu'.  In a similar fashion, we will call the leaving group 'X'.  We will see as we study actual reactions that leaving groups are sometimes negatively charged, sometimes neutral, and sometimes positively charged. We will also see some examples of nucleophiles that are negatively charged and some that are neutral. Therefore, in this general picture we will not include a charge designation on the 'X' or 'Nu' species. In the same way, we will see later that nucleophiles and leaving groups are sometimes protonated and sometimes not, so for now, for the sake of simplicity, we will not include protons on 'Nu' or 'X'.  We will generalize the three other groups bonded on the electrophilic central carbon as R1, R2, and R3: these symbols could represent hydrogens as well as alkyl groups. Finally, in order to keep figures from becoming too crowded, we will use in most cases the line structure convention in which the central, electrophilic carbon is not drawn out as a 'C'.

Here, then, is the generalized picture of a concerted (single-step) nucleophilic substitution reaction:

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Examples

In order to provide a more realistic picture, three actual nucleophilic substitution reactions are shown below.  Reactions A and B are biological reactions, while C is a laboratory synthesis reaction (reaction A should be familiar from chapter 6).  In each case, the nucleophilic atom is colored red and the leaving group atom is blue. We will examine each of these reactions in more detail in the next chapter - for now, just make sure that you can relate what is happening in these actual reactions to the general picture shown above.

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Reaction A: Nucleic Acids Research 2000, 28, 3950.  Reaction B: Biochemistry 1998, 37, 16601.  Reaction C: Carbohydrate Research 2004, 339, 51.

Exercise 8.1: Draw the products of the three nucleophilic substitution reactions shown above.  For reactions A and C, assume that a proton is removed from the nucleophilic atom during or after nucleophilic attack.

Solution

 

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