Definitions

Scope: Most of this analysis will be applied to a series of simple organic (although the analysis can also be applied to inorganic) compounds ranging from straight-chain hydrocarbons, functionalised straight chain molecules such as alkenes, aldehydes and ketones, esters and amides, through small and medium ring cycloalkanes and related saturated oxygen heterocycles, and ending with some examples of atropisomerism.

The terms conformation and conformational analysis will be defined and illustrated. Conformation should be distinguished from the configuration.

• configuration is normally taken to mean a fixed geometrical arrangement around an atom or several atoms and which is prevented from exchanging with other configurations at "chemical temperatures" by the presence of high kinetic barriers, normally resulting from the need to actually break bonds to do so. This normally means that geometrical and optical confgurational isomers can be separated at room temperatures.
• In contrast, any one conformation is more likely to easily exchange with other conformations as part of an equilbrium process, due to much smaller kinetic barriers which are normally the result of not needing to break any bonds. These changes normally occur at one or more single bonds which are presumed to rotate about their axes with relatively low kinetic barriers. This means that, except for a few special cases called atropisomers, we cannot separate and isolate individual conformational isomers at room temperature (although it might be possible at low temperatures). A conformer of a molecule is thus regarded as synonymous with a rotamer about one or more bonds.

If we take a molecule containing a single bond bearing groups, X and Y, attached to the atoms A and B at either end of that bond then we can consider a number of isomers caused simply by rotation about that bond:

Of course, we need not choose a 90° rotation as in the above example but, rather, any degree, or fraction of a degree, between 0 and 360°. If the energy of the system is plotted as function of this rotation, one or more minima will emerge as a result. These minima can sustain molecular vibrations (i.e. they have a finite lifetime) and hence also an associated zero-point energy, entropy and free energy. We give each pose with these properties the name conformational isomers (or conformers) or just conformations.

Conformational analysis: Conformational analysis can therefore be regarded as the analysis of the poses (shapes) that molecules can adopt as a result of single bond rotations. A molecule can adopt an equilibrium between several such poses, the relative abundance of which is determined by the Boltzmann distribution, and which in turn is merely determined by the relative free energy of each pose. Conformational analysis is the study of how some properties (particularly the free energy and reactivity) of a molecule are related to its shape. The shape of a molecule is not static but is a dynamic equilibrium between a number of conformations, the preferred ones being those we would encounter more times than any other if we were to take a series of snapshots of the population, because they have lower free energies. Conformational analysis can be considered to consist of two parts.

1. Analysis of why the preferred conformations adopt the shapes that they do. This is the the thermodynamic part of the subject and it concentrates on the free energies:
   • ΔG = -RT Ln K_eq; R the gas constant = 1.98 cal/mol per K, T = temp and K_eq is the equilibrium constant between any two conformations differing in free energy by ΔG
2. The second part concentrates on reactivity, and may be considered the kinetic part of the subject since it depends on the free energy of activation.
   • Ln(k/T) = 23.76 - ΔG/RT gives the rate (of a unimolecular) reaction, where ΔG^‡ is the free energy barrier for the process and k is the rate constant (in s^-1).

The theory of conformational analysis: Two concepts from quantum mechanics will be borrowed to build a framework for understanding the factors influencing the free energies of conformations.

1. The Stereoelectronic theory of structure describes how interactions between electrons in covalent bonds and lone pairs controls the relative energies of conformations.
2. The second describes how atoms in molecules interact at non-bonded distances rather longer than that of the covalent bond, being a more quantitative model for what is often called steric effects, or van der Waals dispersion effects.

A Note on energies. Throughout these notes, you will find energies expressed in kcal/mol rather than kJ/mol (1 kcal= 4.1868 kJ). This is because the computer programs used all show kcal, as does much of the literature you might read on the topic.

© Henry S. Rzepa, 2010-2014. Hide|show Toolbar.