In this chapter, we will review fundamental concepts of chemical structure and bonding in the organic molecules that make up drugs and their biological targets. By “organic,” we mean molecules that are constructed primarily from the element carbon (C). Carbon exhibits striking versatility in its ability to form various different bonding arrangements with other carbon atoms as well as with other biologically relevant elements such as nitrogen (N), oxygen (O), sulfur (S), and phosphorus (P). It is this versatility that allowed carbon-based life to emerge on our planet. Thus, to understand the molecules of life—proteins, lipids, nucleic acids, hormones, etc.—and the drugs that interact with them, we must start with a solid understanding of structure and bonding in organic molecules. In this chapter, we will begin by contrasting the nature of ionic and covalent bonding and will describe the polarization of covalent bonds. We will then dive deeper into the nature of the covalent bond, discussing atomic and molecular orbitals, the “hybridization” of orbitals, and aromaticity. Finally, we will review some important functional groups and organic ring systems that figure prominently in the structures of biological molecules and drugs.
In the chapters that follow we will learn more about the intermolecular interactions, mostly non-covalent, that govern the binding of a drug molecule to its intended (and sometimes unintended) biological targets. For now, it is important to recognize that a drug molecule’s particular structure—its shape and the nature and connectivity of its atoms—determines what biological activities it will have. If a molecule’s structure leads to interactions in the body that correct an abnormality, restore normal function of a cell, or kill a pathogenic or cancerous cell, a new medicine is born. The seemingly endless ways in which organic molecules can be assembled has allowed scientists to create our current pharmacopeia and affords confidence that still more new medicines will be developed to address currently unmet medical needs.
1.2 The Nature of Covalent and Ionic Bonds
Atoms are comprised of a nucleus containing positively charged protons and uncharged neutrons surrounded by negatively charged electrons. On account of their very low mass, electrons behave as both particles and waves. The peculiar wave-like nature of the electron is what prevents this negatively charged particle from simply “falling” into the positively charged nucleus, to which it is clearly attracted. Wave-like electrons are spatially confined to specific atomic “orbitals” surrounding the nucleus. While atomic and molecular orbitals (Sections 1.4 and 1.5) underlie our current understanding of chemical bonding, their existence was hinted at much earlier by a certain periodicity in the chemical reactivity of the elements. It was this observation that allowed Mendeleev to construct his periodic table of the elements. A partial periodic table including just the first three “periods” (rows) of elements most relevant to organic chemistry is provided here (Figure 1.1).
Periodic table of the first ...