MCAT Organic Chemistry Review

Isomers

2.2 Stereoisomers

Like structural isomers—and all isomers, for that matter—stereoisomers have the same chemical formula. Unlike structural isomers, however, stereoisomers also share the same atomic connectivity. In other words, they have the same structural backbone. Stereoisomers differ in how these atoms are arranged in space (their wedge-and-dash pattern), and all isomers that are not structural isomers fall under this category. The largest distinction within this class is between conformational and configurational isomers. Conformational isomers differ in rotation around single (σ) bonds; configurational isomers can be interconverted only by breaking bonds.

CONFORMATIONAL ISOMERS

Of all of the isomers, conformational isomers, or conformers, are the most similar. Conformational isomers are, in fact, the same molecule, only at different points in their natural rotation around single (σ) bonds.

While double bonds hold molecules in a specific position (as explained with cistrans isomers later), single bonds are free to rotate. Conformational isomers arise from the fact that varying degrees of rotation around single bonds can create different levels of strain. These conformations are easy to see when the molecule is depicted in a Newman projection, in which the molecule is visualized along a line extending through a carbon–carbon bond axis. The classic example for demonstrating conformational isomerism in a straight chain is butane, which is shown in Figure 2.3.

Figure 2.3. Newman Projection of Butane Depiction of different atoms’ positions from the point of view of the C-2 to C-3 bond axis.

Straight-Chain Conformations

For butane, the most stable conformation occurs when the two methyl groups (containing C-1 and C-4) are oriented 180° away from each other. In this position, there is minimal steric repulsion between the atoms’ electron clouds because they are as far apart as they can possibly be. Thus, the atoms are “happiest” and in their lowest-energy state. Because there is no overlap of atoms along the line of sight (besides C-2 and C-3), the molecule is said to be in a staggered conformation. Specifically, it is called the anti conformation because the two largest groups are antiperiplanar (in the same plane, but on opposite sides) to each other. This is the most energetically favorable type of staggered conformation. The other type of staggered conformation, called gauche, occurs when the two largest groups are 60° apart.

MNEMONIC

It’s gauche (unsophisticated or awkward) for one methyl group to stand too close to another group. Groups are eclipsed when they are completely in line with one another—just like a solar or lunar eclipse.

To convert from the anti to the gauche conformation, the molecule must pass through an eclipsed conformation in which the two methyl groups are 120° apart and overlap with the H atoms on the adjacent carbon. When the two methyl groups directly overlap each other with 0° separation, the molecule is said to be totally eclipsed and is in its highest-energy state. Totally eclipsed conformations are the least favorable, energetically, because the two largest groups are synperiplanar (in the same plane, on the same side). The different staggered and eclipsed conformations are demonstrated in Figures 2.3 and 2.4. For compounds larger than butane, the name of the conformation is decided by the relative positions of the two largest substituents about a given carbon–carbon bond.

Figure 2.4. Stability of Straight-Chain Conformational Isomers Degree measurements indicate the angle between the two largest substituents about the carbon–carbon bond.

Figure 2.5 shows the plot of potential energy vs. degree of rotation about the bond between C-2 and C-3 in butane. It shows the relative minima and maxima of potential energy of the molecule throughout its various conformations. Remember that every molecule wants to be in the lowest energy state possible, so the higher the energy, the less time the molecule will spend in that energetically unfavorable state.

Figure 2.5. Potential Energy vs. Degree of Rotation about the C-2 to C-3 Bond in Butane

KEY CONCEPT

Notice that the anti staggered isomer (A and G) has the lowest energy, whereas the totally eclipsed isomer (D) has the highest energy.

These conformational interconversion barriers are small ( between anti staggered butane and totally eclipsed butane) and are easily overcome at room temperature. Nevertheless, at very low temperatures, conformational interconversions will dramatically slow. If the molecules do not possess sufficient energy to cross the energy barrier, they may not rotate at all (as happens to all molecules at absolute zero).

Cyclic Conformations

Cycloalkanes can be either fairly stable compounds, or fairly unstable—depending on ring strain. Ring strain arises from three factors: angle strain, torsional strain, and nonbonded strain (sometimes referred to as steric strain). Angle strain results when bond angles deviate from their ideal values by being stretched or compressed. Torsional strain results when cyclic molecules must assume conformations that have eclipsed or gauche interactions. Nonbonded strain (van der Waals repulsion) results when nonadjacent atoms or groups compete for the same space. Nonbonded strain is the dominant source of steric strain in the flagpole interactions of the cyclohexane boat conformation. To alleviate the strain, cycloalkanes attempt to adopt various nonplanar conformations. Cyclobutane puckers into a slight “V” shape; cyclopentane adopts what is called anenvelope conformation; and cyclohexane (the one you will undoubtedly see the most on the MCAT) exists mainly in three conformations called the chairboat, and twist- or skew-boat forms. These cycloalkanes are shown in Figure 2.6.

Figure 2.6. Conformations of Cycloalkanes

The most stable conformation of cyclohexane is the chair conformation, which eliminates all three types of strain. The hydrogen atoms that are perpendicular to the plane of the ring (sticking up or down) are called axial, and those parallel (sticking out) are called equatorial. The axial–equatorial orientations alternate around the ring; that is, if the wedge on C-1 is an axial group, the dash on C-2 will also be axial, the wedge on C-3 will be axial, and so on.

Cyclohexane can undergo a chair flip in which one chair form is converted to the other. In this process, all axial groups become equatorial, and all equatorial groups become axial. All dashes remain dashes, and all wedges remain wedges. This interconversion can be slowed if a bulky group is attached to the ring; tert-butyl groups are classic examples of bulky groups on the MCAT. For substituted rings, the bulkiest group will favor the equatorial position to avoid nonbonded strain (flagpole interactions) with axial groups in the molecule, as shown in Figure 2.7.

Figure 2.7. Axial and Equatorial Positions in Cyclohexane During a chair flip, axial components become equatorial and vice-versa. However, components pointing “up” (wedge) remain up and components pointing “down” (dash) remain down.

In rings with more than one substituent, the preferred chair form is determined by the larger group, which will prefer the equatorial position. These rings also have associated nomenclature. If both groups are located on the same side of the ring, the molecule is called cis; if they are on opposite sides of the ring, it is called trans, as shown in Figure 2.8. These same terms are used for molecules with double bonds, as explained later in this chapter.

Figure 2.8. Nomenclature of Rings with Multiple Substituents

CONFIGURATIONAL ISOMERS

Unlike conformational isomers that interconvert by simple bond rotation, configurational isomers can only change from one form to another by breaking and reforming covalent bonds. The two categories of configurational isomers are enantiomers and diastereomers. Both enantiomers and diastereomers can also be considered optical isomers because the different spatial arrangement of groups in these molecules affects the rotation of plane-polarized light.

Chirality

An object is considered chiral if its mirror image cannot be superimposed on the original object; this implies that the molecule lacks an internal plane of symmetry. Chirality can also be thought of as handedness. In fact, one of the easiest visualizations of chirality is to think of your own hands, as shown in Figure 2.9. Although essentially identical, your left hand will not be able to fit into a right-handed glove. Achiral objects have mirror images that can be superimposed; for example, a fork is identical to its mirror image and is therefore achiral.

Figure 2.9. Hands as Examples of Chiral Structures Each hand has a nonsuperimposable mirror image.

KEY CONCEPT

Chirality = handedness

On the MCAT, we will often see this concept tested when there is a carbon atom with four different substituents. This carbon will be an asymmetrical core of optical activity and is known as a chiral center. As mentioned earlier, chiral centers lack a plane of symmetry. For example, the C-1 carbon atom in 1-bromo-1-chloroethane has four different substituents. As shown in Figure 2.10, this molecule is chiral because it is not superimposable on its mirror image.

Figure 2.10. Enantiomers of 1-Bromo-1-Chloroethane

MCAT EXPERTISE

Whenever you see a carbon with four different substituents, think chirality.

Two molecules that are nonsuperimposable mirror images of each other are called enantiomers. Molecules may also be related as diastereomers. These molecules are chiral and share the same connectivity, but are not mirror images of each other. This is because they differ at some (but not all) of their multiple chiral centers.

Alternatively, a carbon atom with only three different substituents, such as 1,1-dibromoethane, has a plane of symmetry and is therefore achiral. A simple 180° rotation around a vertical axis, as shown in Figure 2.11, allows the compound to be superimposed upon its mirror image.

Figure 2.11. Rotation of an Achiral Molecule

Enantiomers

Enantiomers (nonsuperimposable mirror images) have the same connectivity, but opposite configurations at every chiral center in the molecule. Enantiomers have identical physical and chemical properties with two notable exceptions: optical activity and reactions in chiral environments.

KEY CONCEPT

Enantiomers have nearly identical physical properties and chemical properties, but they rotate plane-polarized light in opposite directions and react differently in chiral environments.

A compound is optically active if it has the ability to rotate plane-polarized light. Ordinary light is unpolarized, which means that it consists of waves vibrating in all possible planes perpendicular to its direction of propagation. A polarizer allows light waves oscillating only in a particular direction to pass through, producing plane-polarized light, as shown in Figure 2.12.

Figure 2.12. Polarizer

BRIDGE

While rotation of plane-polarized light can be tested in organic chemistry questions, the polarization of light itself is fair game as a physics question. Be sure to review light polarization, discussed in Chapter 8 of MCAT Physics and Math Review.

Optical activity refers to the rotation of this plane-polarized light by a chiral molecule. At the molecular level, one enantiomer will rotate plane-polarized light to the same magnitude but in the opposite direction of its mirror image (assuming concentration and path lengths are equal). A compound that rotates the plane of polarized light to the right, or clockwise, is dextrorotatory (d-) and is labeled (+). A compound that rotates light toward the left, or counterclockwise, is levorotatory (l-) and is labeled (–). The direction of rotation cannot be determined from the structure of a molecule and must be determined experimentally. That is, it is not related to the absolute configuration of the molecule.

KEY CONCEPT

The system for labeling optical activity always uses d- or (+) to refer to clockwise rotation of plane-polarized light, while l- and (–) always go together and refer to counterclockwise rotation of plane-polarized light. Do not confuse this with D- or L- labels on carbohydrates or amino acids, which are based on the absolute configuration of glyceraldehyde. (R) and (S) also refer to absolute configuration, which is determined by structure. Optical activity does not consistently align with the other systems.

The amount of rotation depends on the number of molecules that a light wave encounters. This depends on two factors: the concentration of the optically active compound and the length of the tube through which the light passes. Chemists have set standard conditions of  for concentration and 1 dm (10 cm) for length to compare the optical activities of different compounds. Rotations measured at different concentrations and tube lengths can be converted to a standardized specific rotation using the following equation:

Equation 2.1

where [α] is specific rotation in degrees, αobs is the observed rotation in degrees, c is the concentration in  and l is the path length in dm.

When both (+) and (–) enantiomers are present in equal concentrations, they form a racemic mixture. In these solutions, the rotations cancel each other out, and no optical activity is observed. If enantiomerism is analogous to handedness, racemic mixtures are the equivalent of ambidexterity. These solutions possess no handedness overall and will not rotate plane-polarized light.

KEY CONCEPT

A racemic mixture displays no optical activity.

Diastereomers

Diastereomers are non-mirror-image configurational isomers. Diastereomers occur when a molecule has two or more stereogenic centers and differs at some, but not all, of these centers. This means that diastereomers are required to have multiple chiral centers. For any molecule with nchiral centers, there are 2n possible stereoisomers. Thus, if a compound has two chiral carbon atoms, it has a maximum of four possible stereoisomers, as shown in Figure 2.13.

Figure 2.13. 2n Possible Stereoisomers (n = chiral centers) Four stereoisomers with two chiral centers; enantiomers = I/II and III/IV pairs, and all other combinations are diastereomers.

In this image, one can see that I and II are mirror images of each other and are therefore enantiomers of each other. Similarly, III and IV are enantiomers. However, I and III are not. These are stereoisomers that are not mirror images and are thus diastereomers. Notice that other combinations of non-mirror-image stereoisomers are also diastereomers: I and IV, II and III, and II and IV.

Diastereomers have different chemical properties. However, they might behave similarly in particular reactions because they have the same functional groups. Because they have different arrangements in space, they will consistently have different physical properties. Diastereomers will also rotate plane-polarized light; however, knowing the specific rotation of one diastereomer gives no indication of the specific rotation of another diastereomer. This is in stark opposition to enantiomers, which will always have equal-magnitude rotations in opposite directions.

Cis–Trans Isomers

Cis–trans isomers (formerly called geometric isomers) are a specific subtype of diastereomers in which substituents differ in their position around an immovable bond, such as a double bond, or around a ring structure, such as a cycloalkane in which the rotation of bonds is greatly restricted. In simple compounds with only one substituent on either side of the immovable bond, we use the terms cis and trans. If two substituents are on the same side of the immovable bond, the molecule is considered cis. If they are on opposite sides, it is considered trans, as shown in Figure 2.8 earlier. For more complicated compounds with polysubstituted double bonds, (E)/(Z) nomenclature is used instead, as described in the next section.

MCAT EXPERTISE

While the MCAT is up-to-date with science, it is still possible to see older terms for some concepts on Test Day. Thus, it’s important to know not only the name cis–trans isomers, but also the older name, geometric isomers.

Meso Compounds

For a molecule to have optical activity, it must not only have chiral centers within it, but must also lack a plane of symmetry. Thus, if a plane of symmetry exists, the molecule is not optically active, even if it possesses chiral centers. This plane of symmetry can occur either through the chiral center or between chiral centers. A molecule with chiral centers that has an internal plane of symmetry is called a meso compound, an example of which is shown in Figure 2.14.

Figure 2.14. Example of a Meso Compound

As shown in this image, D- and L-tartaric acid are both optically active, but meso-tartaric acid has a plane of symmetry and is not optically active. This means that even though meso-tartaric acid has two chiral carbon atoms, the molecule as a whole does not display optical activity. Mesocompounds are essentially the molecular equivalent of a racemic mixture.

KEY CONCEPT

Meso compounds are made up of two halves that are mirror images. Thus, as a whole they are not optically active.

MCAT Concept Check 2.2:

Before you move on, assess your understanding of the material with these questions.

1.    What is the difference between a conformational and a configurational isomer?

·        Conformational:

·        Configurational:

2.    Briefly summarize the differences between enantiomers and diastereomers:

3.    What is a meso compound?