MCAT Organic Chemistry Review

Isomers

2.3 Relative and Absolute Configurations

The configuration of a stereoisomer refers to the spatial arrangement of the atoms or groups in the molecule. The relative configuration of a chiral molecule is its configuration in relation to another chiral molecule (often through chemical interconversion). We can use the relative configuration to determine whether molecules are enantiomers, diastereomers, or the same molecule. On the other hand, the absolute conformation of a chiral molecule describes the exact spatial arrangement of these atoms or groups, independent of other molecules.

(E) AND (Z) FORMS

(E) and (Z) nomenclature is used for compounds with polysubstituted double bonds. Recall that simpler double-bond-containing compounds can use the cistrans system. To determine the (E)/(Z) designation, one starts by identifying the highest-priority substituent attached to each double-bonded carbon. Using the Cahn–Ingold–Prelog priority rules, priority is assigned based on the atom bound to the double-bonded carbons: the higher the atomic number, the higher the priority. If the atomic numbers are equal, priority is determined by the next atoms outward; again, whichever group contains the atom with the highest atomic number is given top priority. If a tie remains, the atoms in this group are compared one-by-one in descending atomic number order until the tie is broken. The alkene is named (Z) (German: zusammen, “together”) if the two highest-priority substituents on each carbon are on the same side of the double bond and (E) (entgegen, “opposite”) if they are on opposite sides, as shown in Figure 2.15.

Figure 2.15. (E) and (Z) Designations of Alkenes

MNEMONIC

Z = “z”ame sid; E = “e”pposite side

(R) AND (S) FORMS

(R) and (S) nomenclature is used for chiral (stereogenic) centers in molecules. We go through a set sequence to determine this absolute configuration:

Step 1: Assign Priority

Using the Cahn–Ingold–Prelog priority rules described earlier, assign priority to the four substituents, looking only at the atoms directly attached to the chiral center. Once again, higher atomic number takes priority over lower atomic number. If the atomic numbers are equal, priority is determined by the combination of the atoms attached to these atoms; if there is a double bond, it is counted as two individual bonds to that atom. If a tie is encountered, work outward from the stereocenter until the tie is broken. An example is shown in Figure 2.16.

Figure 2.16. Applying the Cahn–Ingold–Prelog Priority Rules to Determine Absolute Configuration Assign priority by the highest atomic number.

KEY CONCEPT

When assigning priority, look only at the first atom attached to the chiral carbon, not at the group as a whole. The higher the atomic number of this first atom, the higher the priority—this same system is used to determine priority for both (E) and (Z) forms, and (R) and (S) forms.

Step 2 (Classic Version): Arrange in Space

Orient the molecule in three-dimensional space so that the atom with the lowest priority (usually a hydrogen atom) is at the back of the molecule. Another way to think of this is to arrange the point of view so that the line of sight proceeds down the bond from the asymmetrical carbon atom (the chiral center) to the substituent with lowest priority. The three substituents with higher priority should then radiate out from the central carbon, coming out of the page, as shown in Figure 2.17.

Figure 2.17. Placing the Lowest-Priority Group in the Back

Step 2 (Modified Version): Invert the Stereochemistry

If it is difficult to visualize rotating three-dimensional structures, one can simplify this process by remembering one simple rule: any time two groups are switched on a chiral carbon, the stereochemistry is inverted. By this logic, we can simply switch the lowest-priority group with the group at the back of the molecule (the substituent projecting into the page). We can then proceed to Step 3, keeping in mind that we have now changed the molecule to the opposite configuration. Therefore, if we use this modified step, we need to remember to switch our final answer (either (R) to (S), or (S) to (R)). This is a strategy we’ll commonly use on Fischer diagrams, as described below.

Step 3: Draw a Circle

Now, imagine drawing a circle connecting the substituents from number 1 to 2 to 3. Pay no attention to the lowest-priority group; it can be skipped because it projects directly into the page. If the circle is drawn clockwise, the asymmetric atom is called (R) (Latin: rectus, “right”). If it is counterclockwise, it is called (S) (sinister, “left”), as shown in Figure 2.18.

Figure 2.18. Drawing a Circle to Determine (R)/(S) Designation Clockwise = (R); Counterclockwise = (S)

Remember to correct the stereochemistry if the modified version of Step 2 was used.

MNEMONIC

A clockwise arrangement is like turning a steering wheel clockwise, which makes a car turn Right—so the chirality at that center is (R).

Step 4: Write the Name

Once the (R)/(S) designation has been determined, the name can be written out. (R) and (S) are put in parentheses and separated from the rest of the name by a hyphen. If we have a compound with more than one chiral center, location is specified by a number preceding the R or S within the parentheses and without a hyphen.

KEY CONCEPT

To determine the absolute configuration at a chiral center:

1.    Assign priority by atomic number

2.    Arrange the molecule with the lowest-priority substituent in the back (or invert the stereochemistry by switching two substituents)

3.    Draw a circle around the molecule from highest to lowest priority (1 to 2 to 3)

4.    Clockwise = (R); counterclockwise = (S)

FISCHER PROJECTIONS

On the MCAT, one way to represent three-dimensional molecules is by a Fischer projection. In this system, horizontal lines indicate bonds that project out from the plane of the page (wedges), whereas vertical lines indicate bonds going into the plane of the page (dashes). The point of intersection of the lines represents a carbon atom.

To determine configurations using Fischer projections, we follow the same rules listed above. Once again, we have to make sure that the lowest-priority group projects into the page. A benefit of Fischer projections is that the lowest-priority group can be on the top or bottom of the molecule and still project into the page.

Another advantage is that we can manipulate Fischer projections without changing the compound. As mentioned before, switching two substituents around a chiral carbon will invert the stereochemistry ((R) to (S), or (S) to (R)). Rotating a Fischer projection in the plane of the page by 90° will also invert the stereochemistry of the molecule. By extension, interchanging any two pairs of substituents will revert the compound back to its original stereochemistry, and rotating a Fischer projection in the plane of the page by 180° will also retain the stereochemistry of the molecule. These manipulations are shown in Figure 2.19.

Figure 2.19. Manipulations of Fischer Projections

Again, determining the (R)/(S) designation of a Fischer projection of a compound follows the same rules as described previously. But what if our lowest-priority group is pointing to the side and, as such, pointing out of the page? Just as before, we’ve got a couple of different tricks to help determine the right stereochemistry.

Option 1: Make 0 Switches

Go ahead and determine the order of substituents as normal, drawing a circle from 1 to 2 to 3. Remember, number 4 doesn’t count, so just skip right over it when determining the order. Then, obtain the (R)/(S) designation. The true designation will be the opposite of what you just obtained.

Option 2: Make 1 Switch

Swap the lowest-priority group with one of the groups on the vertical axis. Obtain the (R)/(S) designation and, once again, the true designation will be the opposite of what you just found.

Option 3: Make 2 Switches

In this method, start with option 2, moving the lowest-priority group into the correct position. Then, switch the other two groups as well. Because we made two switches, this molecule will have the same designation as the initial molecule. This is the same as holding one substituent in place and rotating the other three in order.

MCAT EXPERTISE

Determine which option you prefer for Fischer projection (R)/(S) designation and stick with it. It’s more efficient to have a consistent method than to use all three interchangeably.

MCAT Concept Check 2.3:

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

1.    What is the difference between an (E) isomer and a (Z) isomer?

·        (E):

·        (Z):

2.    How is priority assigned under the Cahn–Ingold–Prelog priority rules?

3.    For each of the Fischer projection manipulations listed below, is stereochemistry retained or inverted?

·        Switching a pair of substituents: 

·        Switching two pairs of substituents: 

·        Rotating the molecule 90°: 

·        Rotating the molecule 180°: