Core Concepts
Conformation analysis considers the energetics of possible geometries a molecule can adopt and tries to predict the most likely structure(s). Steric hindrance or strain drives a lot of the selection of the lowest energy conformational isomer or conformer. These conformers are often represented with Newman Projections.
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What is a molecular conformation?
The conformation of a molecule is dependent on the orientation each atom takes with respect to the others due to rotation about a sigma (single) bond. Rotation is only possible around a sigma bond as both double and triple bonds have pi bonds with aligned parallel orbitals. To break these pi bonds would be too energetically costly. When thinking about single bond rotations, different conformations come from various angles of rotation around the single bond. Since some of these angles could bring atoms or functional groups closer together in space, some conformations offer greater stability than others. When two bulky groups come close together during rotation, repulsive forces build up, making states like these less favorable. Conformational analysis often uses an energy diagram to show how the energy of a molecule changes as a bond is rotated. While the plot below accounts for the thermodynamic stability of each conformer, molecules will switch between conformations if given enough activation energy to overcome the steric hindrance that will occur in switching orientations.
The activation energy magnitude varies between the Newman projections or the different possible conformational isomers. The plot above shows butane, with the most thermodynamically stable conformation having the methane groups opposite each other and all the atoms or functional groups are staggered. Moving to the right across the plot requires different amounts of activation energy. Going from the leftmost conformation to the conformation to the right of it requires 16 kJ/mol of energy input. To get to the third conformation from the left from the first, the activation energy of 16 kJ/mol – 12.2 kJ/mol, or 3.8 kJ/mol is required. In this case, the difference in energy between the second and the third conformation is -12.2 kJ/mol. These atoms and functional groups are arranged differently spatially, but the Newman projection is about the same bond.
The diagram above shows an important concept for conformational isomers: eclipsed conformations are less stable than staggered conformations. Every local minimum in the plot above correlates to a staggered conformation. Every local maximum in the plot corresponds to an eclipsed conformation. An eclipsed conformer is also less stable than a gauche conformation: a conformer where two functional groups that are not hydrogen are located near each other. A gauche conformation will require more energy than a staggered conformation, and the energy difference will increase as more bulky groups are present near each other. The most stable conformer will have a staggered conformation with the bulky groups spread out to minimize steric hindrance. In the plot above, this is the leftmost conformer.
Conformational analysis is vital to understanding what structures a molecule may adopt. Sometimes the energy difference between conformers is so great, that a molecule will only ever be expected to be in one energetic minimum. Other times, when the energy differences are small, a molecule may adopt many different conformations and switch between them rapidly. These conformations are in equilibrium, and this property is important for ring structures. Some reactions require a less stable ring conformation for active site availability. Using Le Chatlier’s principle, this will cause the equilibrium to shift as the amount of unstable conformer is depleted. Conformational analysis can be used to rationalize which structures may participate in reactions and can be confirmed with different spectroscopies, such as NMR spectroscopy.
Nuclear Magnetic Resonance
Nuclear Magnetic Resonance spectroscopy, or NMR, can be a sensitive probe of the chemical environment of a specific atom, usually either hydrogen atoms or carbon atoms. Briefly, the spin of each nucleus can be flipped parallel or anti-parallel to the strong magnetic field applied by the instrument with radiowaves. The frequency this transition occurs at is called the chemical shift, and is indicative of the electron density surrounding that nucleus. Each peak in an NMR spectrum comes from a distinct microenvironment. Using the position, intensity, and splitting of the peaks in the spectrum, the structure of a molecule can usually be worked out.
Thinking about using NMR to analyze various conformations of a given molecule, there are a few key structural differences between conformers that will show up in an NMR spectrum. The representative peaks for a sample can be plotted on an NMR spectrum. Increasing the speed of the measurement will allow for an almost instantaneous measurement as opposed to the average of the atom in different conformations. If a fast measurement is performed, then the present state of the sample can be measured: the amount of trans vs. cis isomers. This is due to the reduced time during which the sample can switch between the two conformations. Low temperature decreases molecule kinetic energy and can therefore also be used to separate conformers. The more thermodynamically stable conformers should give the strongest signal in lower temperatures, as they are the most favorable concerning their Gibbs free energy.
Some trans conformers cause additional chemical shifts due to coupling over four carbon atoms. The magnitude of this signal can be compared to the magnitude of cis isomers to find the ratio of the presence of each conformer. The other method to identify the conformers focuses on the interface between solvents and the sample. Different intermolecular forces or steric effects can cause the chemical shift to shift to the right. This solvent is known as a stabilizing solvent. For example, dipole-dipole interactions could be present, which causes the conformer with the most exposed polar groups to give off the strongest signal. This type of solvent would cause the chemical shift peaks to shift to the right much more than hydrophobic or van der Waals interactions would. A solvent may interact with a smaller functional group but this site may not be accessible due to a steric hindrance from a neighboring group. A solvent capable of hydrogen bonding can cause an increased signal corresponding to that conformation if all the conditions are met. The usage of solvents is significant as they can dramatically change the percent yield and product of an organic reaction, given that they can shift the equilibrium between conformers.
The image above shows an example of an NMR spectrum in which different solvents were used, resulting in the appearance of different conformers. Some notable changes are in the region from 2 to 3 and around 7. These regions change in intensity, proton count, and peak value, though some may be hard to see due to the peak overlap or the image resolution. For example, the peak at about 2.2 in part a is shifted to about 2.0 in part b, and to about 1 in part c, showing a more favorable interaction and stability for that chemical group in DMSO-d6 as opposed to Bz-d6. This figure shows that the conformer(s) found in the pure BZ-d6 contribute to the peaks around 7 that are much more abundant in that solvent than in the DMSO-d6 solvent.