Chirality

•

Stereoisomers

: Isomers with the same connectivity between atoms but have a different arrangement of atoms.

• We have already examined a form of stereoisomerism when we studied geometric isomers, that is, cis-trans isomers in disubstituted cycloalkanes and in alkenes.

• In this chapter, we study isomers where the focus is the arrangement of atoms around one carbon atom rather two neighboring atoms.

• Two stereoisomers, when compared to each other, may be classified as

diastereomers

.

enantiomers

or

Enantiomers

•

Enantiomers

: Two stereoisomers that are nonsuperimposable mirror images of each other.

• As an example, consider 2-butanol, a molecule that exists as a pair of enantiomers.

• One way to see that the mirror image of 2-butanol is not superimposable on the original is to, first, rotate the mirror image.

• Second, try to fit the mirror image on top of the mirror image so that all groups and bonds match exactly.

• The original and mirror image are not superimposable.

• They are different molecules with different properties.

• They are

enantiomers

(nonsuperimposable mirror images).

• Enantiomers: Stereoisomers that are nonsuperimposable mirror images are

chiral

(from the Greek:

cheir

, hand). The term refers to relationship between pairs of objects.

• A person’s left hand is the same as his right hand, except that they are mirror images of each other.

• In a similar way, when molecules are chiral, we say that they show handedness.

• The most common cause of

enantiomerism

organic molecules is the presence of a in

stereocenter

, carbon with four different groups bonded to it.

• Stereocenters are also known as chiral carbons.

• If an object and its mirror image are superimposable, they are identical and there is no possibility of enantiomerism.

• Such an object is

achiral

(without chirality).

• As an example, consider 2-propanol.

• Notice that this molecule has no stereocenter.

Drawing Chiral Molecules

• Below are four different representations for one of the enantiomers of 2-butanol.

• Both (1) and (2) show all four groups bonded to the stereocenter and show the tetrahedral geometry.

• (3) is a more abbreviated line-angle formula; although we show the H atom on the stereocenter, we do not normally show it in line-angle formulas.

• (4) is the most abbreviated representation; you must remember that an H present on this stereocenter.

• On the left is one enantiomer of 2-butanol.

• On the right are two representations for its mirror image.

Naming Enantiomers – 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.

• Before we begin to assign an R or S configuration to a stereocenter, we must assign a priority to each of the atoms that are bonded to the stereocenter.

• We will use the same prioritization rules we used to assign an E or Z configuration to an alkene: 1. Priority is based on atomic number; the higher the atomic number, the higher the priority.

2. If priority cannot be assigned on the basis of the atoms bonded directly to the stereocenter, look to the next set of atoms; priority is assigned at the first point of difference.

3. Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds.

• To assign an R or S configuration : • Assign a priority from 1 (highest) to 4 (lowest) to each group on the stereocenter.

• Orient the stereocenter so that the group of lowest priority is projecting away from you.

• Read the priorities of the three groups projecting toward you in order from (1) to (3).

• If reading these three groups is clockwise, the configuration is

R

(Latin,

rectus

, straight, correct). • If reading these three groups is counterclockwise, the configuration is

S

(Latin:

sinister

, left).

Example

: Assign an R or S configuration to the stereocenter in 2-chlorobutane.

• • • Priorities of atoms attached to stereocenter 1.

2.

3.

4.

chlorine “ethyl” branch “methyl” branch hydrogen When the hydrogen is pointed away the other atoms are arranged 1 – 2 – 3 in the counterclockwise direction.

Therefore, the pictured molecule is (S) –2–chlorobutane.

Example

: Assign an R or S configuration to the stereocenter in 3-cyclohexenol.

• • • Priorities of atoms attached to stereocenter 1.

oxygen (hydroxyl) 2.

3.

4.

carbon in a double bond carbon in a single bond hydrogen When the hydrogen is pointed away the other atoms are arranged 1 – 2 – 3 in the clockwise direction.

Therefore, the pictured molecule is (R) –3–cyclohexenol.

Example

: Assign an R or S configuration to the stereocenter in the amino acid, valine.

• • • Priorities of atoms attached to stereocenter 1.

nitrogen (amine) 2.

3.

4.

carboxylate carbon “isopropyl” carbon hydrogen When the hydrogen is pointed away the other atoms are arranged 1 – 2 – 3 in the counterclockwise direction.

Therefore, the pictured molecule is (S) –valine.

Example

: Name the active enantiomer of ibuprofen.

• • • Priorities of atoms attached to stereocenter 1.

carbon in the carboxyl group 2.

3.

4.

carbon in the benzene ring “methyl” carbon hydrogen When the hydrogen is pointed away the other atoms are arranged 1 – 2 – 3 in the counterclockwise direction.

Therefore, the active enantiomer is (S) –ibuprofen.

Enantiomers and Diastereomers

• • For a molecule with 1 stereocenter,

2 1 = 2

stereoisomers are possible.

• For a molecule with 2 stereocenters, a maximum of

2 2 = 4

stereoisomers are possible.

• For a molecule with

n

of

2

n

stereocenters, a maximum stereoisomers are possible.

Diastereomers

enantiomers.

are stereoisomers that are not • A stereoisomer has one enantiomer and 2 n – 2 possible diastereoisomers.

• Consider 2,3,4-trihydroxybutanal as an example

.

• Two stereocenters;

2 2 = 4

enantiomers) are possible.

stereoisomers (two pairs of • Erythrose and threose are diastereomers.

Meso Compounds

•

Meso compound

: an achiral compound possessing two or more stereocenters.

• Tartaric acid contains two stereocenters.

• Two stereocenters; 2

n

= 4, but only three stereoisomers exist, one meso compound and one pair of enantiomers.

• • Meso compounds can be identified because they have a plane of symmetry.

Plane of Symmetry

: An imaginary plane passing through an object and dividing it such that one half is the mirror image of the other half.

• Molecules with a plane of symmetry are achiral.

• Thus a meso compound is it’s own mirror image.

Chirality in Cyclic Molecules

• 2-Methylcyclopentanol • 2 stereocenters; according to the 2

n

of

2 2 = 4

stereoisomers are possible.

rule, a maximum • Neither molecule has a plane of symmetry; therefore, no meso stereoisomer exists.

• 2-methylcyclopentanol has a total of 4 stereoisomers, two pairs of enantiomers.

• 1,2-Cyclopentanediol • 2 stereocenters = a maximum of 4 potential stereoisomers.

• However, the cis isomer has a plane of symmetry; therefore, it is meso compound.

• Thus 1,2-cyclopentanediol has only 3 stereoisomers: one meso compound (the cis isomer) and one pair of enantiomers (the trans isomer).

• The cis and the trans isomers are diastereoisomers of each other.

• 4-Methylcyclohexanol • Note the molecule has 2 stereocenters.

• However, both the cis isomer and the trans isomer have a plane of symmetry.

• That is, both the cis and trans isomers are meso compounds .

• Therefore, 4-methylcyclohexanol has two stereoisomers and yet is not chiral.

• 3-Methylcyclohexanol • The molecule has 2 stereocenters.

• Neither the cis isomer nor the trans isomer have a plane of symmetry.

• Therefore, 4-methylcyclohexanol has four stereoisomers.

Molecules with Three Or More Stereocenters

• We need to be able to identify the stereocenters in larger molecules so that we can be aware of the different stereoisomers.

• Menthol • 3 stereocenters • 2 3 = 8 potential stereoisomers .

• Only one of the stereoisomers is the flavoring.

• Cholesterol • 8 stereocenters • 2 8 = 256 potential stereoisomers .

• Only one of the stereoisomers is made by the human body.

• Cholesterol has one enantiomer and 254 diastereoisomers.

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

: A compound that rotates the plane of plane-polarized light.

Schematic diagram of a polarimeter

• The angle of rotation for plane-polarized light is measured from the perspective of the light coming toward you rather than going away.

•

Dextrorotatory (D)

: Clockwise rotation of the plane of plane-polarized light.

•

Levorotatory (L)

: Counterclockwise rotation of the plane of plane-polarized light.

• Often chiral molecules are distinguished from each other based on their optical activity, that is, (L or D) is used rather than (R or S).

• Biological amino acids have the (S) configuration; however, they are almost always refer to by their optical activity (L) as in L-valine rather than (S) valine.

• The angle of rotation depends on concentration and the wavelength of light; therefore, a specific standard has been created to be able to compare the angle of rotation for different molecules to each other.

•

Specific rotation

: The observed rotation of plane polarized light at 589 nm of an optically active substance at a concentration of 1 g/100 mL in a sample tube 10 cm long.

Chirality in Biochemicals

• 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.

• It's a chiral world!

• Enzymes have gazillions  of potential stereoisomers.

• Only one will have biological activity.

• Because living systems depend on chiral environments, a molecule and its enantiomer or one of its diastereomers elicit different physiological responses.

• (

S

)-ibuprofen is active as a pain and fever reliever, whereas its R enantiomer is inactive.

• The S enantiomer of naproxen is the active pain reliever, whereas its R enantiomer is a liver toxin!