Chapter 7: Reactions of Carbonyl Species

7.1 Introduction

In this chapter we explore the structure and reactivity of the carbonyl (C=O) bond and related carbon–heteroatom (C=X) double bonds. These functional groups are ubiquitous in both biological molecules and in the structures of drugs. A prominent example in biological molecules is the amide bond (peptide bond), which serves as the structural backbone of proteins and also helps determine how proteins fold into the specific three-dimensional shapes that lead to function. Other biological molecules containing ketone or thioester functions are involved in cellular metabolism and in sterol biosynthesis in animals and terpene biosynthesis in plants.

Carbonyl-containing functional groups are also found in the structures of many drugs. Often these groups play a structural role, linking and helping to properly orient other functionality for interaction with the drug’s target. These groups can also make direct contact with the target, forming hydrogen bonds and other intermolecular interactions as we have seen in Chapter 2. The chemical reactivity of carbonyl functional groups can also be important in drug action, as is the case for the cyclic amide (β-lactam) present in penicillins and related β-lactam antibiotics. This chapter examines many important classes of carbonyl- containing functional groups and reviews the biologically relevant chemistry of the carbonyl.

7.2 Nature of the Carbonyl Group

Carbonyl-containing functional groups are those possessing a double bond between a carbon and oxygen atom (C=O). The molecular orbital description of a carbonyl involves a σ bond between sp² hybrid orbitals on carbon and oxygen atoms and a π bond involving the 2p orbitals on the bonded atoms. It is the interacting p orbitals of the π bond that prevents rotation about the C=O bond. The two remaining sp² hybrid orbitals on carbon form σ bonds with additional substituents that lie in the plane of the carbonyl bond, and separated by ∼120^o (Figure 7.1). Two electron lone pairs on oxygen project out at a ∼120^o angle and can accept hydrogen bonds or be protonated under acidic conditions.

The bonding between carbon and oxygen in a carbonyl is analogous to that between the carbon atoms of ethylene. The greater electronegativity of oxygen as compared to carbon, however, means that electron density in the carbonyl function is polarized. This polarization can also be understood in resonance terms, the resonance forms shown below implying partial positive character at carbon and partial negative character at oxygen. These partial charges can be indicated as a dipole or using the δ+ and δ+ nomenclature we have used previously (Figure 7.2).