Chapter 15 Chirality: The Handedness of Molecules

Isomers Types of isomers In this chapter we study enantiomers and diastereomers.

Enantiomers Enantiomers: Nonsuperposable mirror images. As an example of a molecule that exists as a pair of enantiomers, consider 2-butanol.

Enantiomers One way to see that the mirror image of 2-butanol is not superposable on the original is to rotate the mirror image.

Enantiomers Now try to fit one molecule on top of the other so that all groups and bonds match exactly. The original and mirror image are nonsuperposable. They are different molecules. Nonsuperposable mirror images are enantiomers.

Enantiomers Objects that are nonsuperposable on their mirror images are chiral (from the Greek: cheir, hand). They show handedness. The most common cause of enantiomerism in organic molecules is the presence of a carbon with four different groups bonded to it. A carbon with four different groups bonded to it is called a stereocenter.

Enantiomers If an object and its mirror image are superposable, they are identical and there is no possibility of enantiomerism. We say that such an object is achiral (without chirality). As an example of an achiral molecule, consider 2-propanol. notice that it has no stereocenter.

Enantiomers To see the relationship between the original and its mirror image, rotate the mirror image by 120°. When we do this rotation, we see that all atoms and bonds of the mirror image fit exactly on the original. This means that the original and its mirror image are the same molecule. They are just viewed from different perspectives.

Enantiomers To summarize; Objects that are nonsuperposable on their mirror images are chiral (they show handedness). The most common cause of chirality among organic molecules is the presence of a carbon with four different groups bonded to it. We call a carbon with four different groups bonded to it a stereocenter. Objects that are superposable on their mirror images are achiral (without chirality). Nonsuperposable mirror images are called enantiomers. Enantiomers always come in pairs.

The R,S System Because enantiomers are different compounds, each must have a different name. Here are the enantiomers of the over-the-counter drug ibuprofen. The R,S system is a way to distinguish between enantiomers without having to draw them and point to one or the other. HW:1- What is a racemic mixture?; 2- Why is ibuprophen sold as a racemic mixture?; 3- What would be the effect if it weren’t? *expect a test question on this!

The R,S System The first step in assigning an R or S configuration to a stereocenter is to arrange the groups on the stereocenter in order of priority. Priority is based on atomic number. The higher the atomic number, the higher the priority. *Note: a double bond is treated as 2 single bonds to the element. EX: C=O would be C-O-O when assigning priority

R,S Priority of Some Groups

The R,S System Example: Assign priorities to the groups in each set.

The R,S System Example: Assign priorities to the groups in each set. Solution:

The R,S System To assign an R or S configuration: 1. Assign a priority from 1 (highest) to 4 (lowest) to each group bonded to the stereocenter. 2. Orient the molecule in space so that the group of lowest priority (4) is directed away from you. The three groups of higher priority (1-3) then project toward you. 3. Read the three groups projecting toward you in order from highest (1) to lowest (3) priority. 4. If reading the groups 1-2-3 is clockwise, the configuration is R. If reading them is counterclockwise, the configuration is S.

*Get a kit and construct the following 2 molecules The R,S System *Get a kit and construct the following 2 molecules Example: Assign an R or S configuration to each stereocenter.

The R,S System Example: Assign an R or S configuration to each stereocenter.

The R,S System Returning to our original three-dimensional drawings of the enantiomers of ibuprofen.

Two or More Stereocenters For a molecule with n stereocenters, the maximum number of possible stereoisomers is 2n. We have already verified that, for a molecule with one stereocenter, 21 = 2 stereoisomers (one pair of enantiomers) are possible. For a molecule with two stereocenters, a maximum of 22 = 4 stereoisomers (two pair of enantiomers) are possible. For a molecule with three stereocenters, a maximum of 23 = 8 stereoisomers (four pairs of enantiomers) are possible, and so forth.

Two Stereocenters 2,3,4-Trihydroxybutanal Two stereocenters; 22 = 4 stereoisomers exist (two pairs of enantiomers). Diastereomers: Stereoisomers that are not mirror images. (a)-(c) and (b)-(c), for example, are diastereomers.

Stereoisomers Example: Mark all stereocenters in each molecule and tell how many stereoisomers are possible for each.

Stereoisomers Example: Mark all stereocenters in each molecule and tell how many stereoisomers are possible for each. Solution:

Stereoisomers The 2n rule applies equally well to molecules with three or more stereocenters.

Optical Activity Ordinary light: Light waves vibrating in all planes perpendicular to its direction of propagation. Plane-polarized light: Light waves vibrating only in parallel planes. Polarimeter: An instrument for measuring the ability of a compound to rotate the plane of plane-polarized light. Optically active: Showing that a compound is capable rotating the plane of plane-polarized light. *NOTE: D,L will not be on this test (slides 24-26). The designation is primarily used with carbs and amino acids, so we will wait until that unit to cover it.

Polarimeter Figure 15.6 Schematic diagram of a polarimeter with its sample tube containing a solution of an optically active compound.

Optical Activity Dextrorotatory: Clockwise rotation of the plane of plane-polarized light. Indicated by (+). Levorotatory: Counterclockwise rotation of the plane of plane-polarized light. Indicated by (-). Specific rotation: The observed rotation of an optically active substance at a concentration of 1 g/mL in a sample tube 10 cm long.

Chirality of Biomolecules Except for inorganic salts and a few low-molecular-weight organic substances, the molecules in living systems, both plant and animal, are chiral. Although these molecules can exist as a number of stereoisomers, almost invariably only one stereoisomer is found in nature. Instances do occur in which more than one stereoisomer is found, but these rarely exist together in the same biological system.

Chirality of Biomolecules How an enzyme distinguishes between a molecule and its enantiomer. Figure 15.7 A schematic diagram of an enzyme surface that can interact with (R)-glyceraldehyde at three binding sites but with (S)-glyceraldehyde at only two of the three sites.

Chirality of Biomolecules Enzymes (protein biocatalysts) all have many stereocenters. An example is chymotrypsin, an enzyme in the intestines of animals that catalyzes the digestion of proteins. Chymotrypsin has 251 stereocenters. The maximum number of stereoisomers possible is 2251! Only one of these stereoisomers is produced and used by any given organism. Because enzymes are chiral substances, most either produce or react with only substances that match their stereochemical requirements.

Chirality of Biomolecules Because interactions between molecules in living systems take place in a chiral environment, a molecule and its enantiomer or one of its diastereomers elicit different physiological responses. As we have seen, (S)-ibuprofen is active as a pain and fever reliever, while its R enantiomer is inactive (although the body can convert R to S, but it takes time). The S enantiomer of naproxen is the active pain reliever, but its R enantiomer is a liver toxin!