In this chapter we will consider the conformations, or three-dimensional shapes, that organic molecules can adopt via rotations about single bonds in their structures. These rotations occur rapidly at physiological temperatures and so most molecules can readily adopt several distinct conformations that are in equilibrium with each other. These various conformations will have different free energies, which will determine the relative abundance of the different conformations. Two energetic extremes in the conformations of ethane are shown below, with the staggered conformation being lowest in energy (most favored) and the eclipsed conformation highest in energy (Figure 4.1). When a drug molecule interacts with its biological target, it must adopt a conformation (shape) that is compatible with binding to the target. The conformation of organic molecules is therefore a topic of great relevance to the action of drug molecules.
Staggered and eclipsed conformations of ethane represented as stick (left) and space-filling models (right). (Reproduced, with permission, from Carey FA, Giuliano RM. Organic Chemistry. 9th ed. New York: McGraw-Hill Education; 2014.)
It is important at this stage to clarify the distinction between the terms configuration and conformation. As we learned in Chapter 3, configuration relates to the connectivity of atoms. A molecule might exist with either the S or R configuration at a chirality center but these two possibilities represent different molecules—they cannot interconvert without breaking and reforming chemical bonds. In contrast, two different conformations (or conformers) of a given molecule may have different shapes but they are still the same molecule—their interconversion requires only rotations about certain bonds. These rotations usually occur rapidly on the human timescale and so many different conformers are in equilibrium. To study the conformations of organic molecules then, we must imagine freezing time so that the different conformers can be compared and analyzed. This is what we will learn to do in this chapter.
4.2 Newman Projections and Dihedral Angles
To study the conformations of a simple organic molecule like ethane it is helpful to visualize rotations about single C–C bonds. Traditional structural drawings are less than ideal in this regard because they depict bonds from the side. An end-on view down the axis of a bond as it rotates provides a much better picture of what is happening. Consider the three different drawings of ethane below (Figure 4.2). All three drawings illustrate a “staggered” conformation but the Newman projection provides the clearest view of how the C–H bonds on the respective carbon atoms are staggered. A Newman projection represents a view looking exactly down the C–C bond axis. The carbon “in front” from this perspective appears with three C–H bonds separated by 120° (i.e., at 2, 6, and 10 o’clock). The carbon “behind” is shown as a circle with C–H bonds ...