Chapter 6

6.1 Introduction

The first few chapters of this text were focused on important properties of organic molecules and how these help determine the nature of a drug’s interaction with its biological target. In this chapter and the ones that follow, we will discuss certain reactions of drug molecules and enzymes – biological macromolecules that break and form chemical bonds. In this chapter we discuss substitution, addition, and elimination reactions. The main focus is on substitution reactions, which are prevalent in physiological and metabolic processes, in the action of some drugs, and in the chemical synthesis of nearly all drugs. The topic of addition reactions is introduced here and expanded upon in the following chapter on carbonyl chemistry.

Substitution reactions involve the reaction of nucleophiles with electrophiles. Nucleophiles are “nucleus seekers” that will donate a lone pair of electrons to the new bond that is formed with an electrophile. Electrophiles are “electron seekers” and thus accept a lone pair of electrons from a nucleophile. Some examples of nucleophiles and electrophiles are shown in Figure 6.1. Nucleophiles generally are anionic or neutral with a lone pair of electrons to donate. Electrophiles are positively charged or have a polarized bond with partial positive character. Electrophiles capable of undergoing substitution reactions have a leaving group, a species that can accept and stabilize the pair of electrons that make up the bond being broken.

Figure 6.1

Examples of some good nucleophiles, electrophiles, and leaving groups.

In the sections that follow, we will discuss in more detail the factors that make for a good nucleophile, electrophile, or leaving group. We will also review the various reaction mechanisms by which substitution, addition, and elimination reactions occur. By the end of the chapter you should have developed a sound understanding of the factors that govern these reactions and be able to predict reaction products when provided with the reactants and reaction conditions. You should also be able to write reasonable mechanisms for your reactions, making the proper use of curly arrows to show the movement of electrons as chemical bonds are formed and broken.

6.2 Nucleophiles

In the previous chapter, we used the Brønsted–Lowry definition of acids and bases—species that donate or accept a proton, respectively. A more general description of acids and bases is that first proposed by the chemist Gilbert N. Lewis, who described a covalent bond as the sharing of an electron pair between two atoms. Thus, a Lewis acid is a species that can accept an electron pair and a Lewis base is a species that can donate an electron pair in the formation of a covalent bond. A proton (H+) qualifies as a species that can accept a lone pair of electrons and thus the Lewis description of acids and bases encompasses ...

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