Stereochemistry II Reading: Wade chapter 5, sections 5-8- 5-16 Study Problems: 5-28, 5-29, 5-30, 5-31, 5-35 Key Concepts and Skills: • Draw all stereoisomers of a given structure. • Identify enantiomers, diastereomers, and meso compounds; draw correct Fischer projections of asymmetric carbon atoms. • Explain how the physical properties differ for different types of stereoisomers, and suggest how to separate different types of stereoisomers Lecture Topics: I. Conformational isomerism Consider cis-1,2-dichlorocyclohexane; each chair conformation is chiral, but a ring flip will convert one stereoisomer to its mirror image. Since chair-chair interconversions are rapid at room temperature. A molecule cannot be optically active if its chiral conformations are in rapid equilibrium with their mirror images. different

consider only: Cl Cl

Cl Cl σ mirror image non-superimposable on original molecule ring flip

Cl Cl Cl identical to mirror image: Cl Cl Cl

A correct prediction about whether a molecule is chiral or achiral can be made by analyzing the most symmetrical conformation (in the case of a cyclic molecule, it is the “flat” conformation) Note that trans 1,2-dibromo cyclohexane has chiral chair forms, the mirror images of which cannot be obtained by a ring flip: different

consider only: Cl Cl Cl Cl

mirror image non-superimposable on original molecule ring flip

Cl Cl Cl Cl different from Cl chiral

Cl •Some molecules have no asymmetric carbon atoms (no centers of chirality) yet they are chiral. This is due to locked conformations of a molecule which are chiral and cannot interconvert because of steric hindrance: “axial chirality” •An example is 2,2,2,2’-substituted biphenyls, in which the most symmetrical “flat” conformation cannot be obtained because of a very large degree of steric hindrance to rotation about the central C-C bond: a very high energy is required to rotate past the point of planarity. The molecular conformations are thus locked with the two rings perpendicular to each other. The two conformations are enantiomeric; their mirror images cannot be superimposed.

CH3 I

Very large degree of steric hindrance in most symmetrical planar conformation

I H3C

CH3 H3C I I

H3C CH3 I I

locked conformation non interconvertible conformations ring planes are perpendicular chiral conformations

•Allene is a molecule with one sp-hybridized carbon and two sp2-hybridize carbon atoms. Because of the perpendicular p-orbitals on the central sp-hybridized carbon which overlap to form the pi orbitals, the pi orbitals are also perpendicular, and thus the end groups on the molecule are perpendicular. Substituted allenes are thus chiral molecules with non-superimposable mirror images: mirror plane

CH H3C CH3 H3C 3 C C

H H H H

different compounds enantiomers

II. Fischer Projections Fischer Projections are a shorthand method of drawing stereoisomers to facilitate their comparison when there are multiple asymmetric carbon atoms within a molecule.

• Fischer projections are drawn in cross form with the horizontal bonds coming toward the viewer and the vertical bonds going away from the viewer. For S-lactic acid: COOH COOH COOH

HO H HO H CH3 HO H CH3 CH3

Fischer projection

•Fischer projections that differ by 180° are the same molecule. A 90° rotation, however, is not allowed. Fisher projections also my not be flipped over: they must be kept in-plane. 180° COOH COOH CH3 CH3

HO H HO H H OH H OH in-plane COOH CH3 CH3 COOH

same molecule

90° COOH COOH OH OH

H C COOH HO H HO H 3 H3C COOH

in-plane H CH3 CH3 H

non-superimposable enantiomers • A carbon chain must be drawn along the vertical line of the projection and given IUPAC numbering from top to bottom

• When looking at the mirror image of a Fischer projection, any groups that fail to superimpose after a 180° turn indicates chirality and the two molecules are enantiomers. 1 180° CH OH CH OH CH3 CH2OH 2 2 2 H OH HO H H OH CH3 H in-plane OH 3 CH3 CH3 CH2OH

non-superimposable: enantiomers ALSO:

CH3 CH 3 180° CH3 H Br Br H Br H

Br H H Br in-plane H Br

CH3 CH 3 CH3

not the same molecule! enantiomers

CH3 CH3 CH3 180°

H Br Br H H Br

H Br Br H in-plane H Br

CH3 CH3 CH3

SAME MOLECULES: ACHIRAL

Assigning R and S configurations to Fischer Projections • Same rules apply, but if the low priority group (H) is projecting forward (on a horizontal bond), a counterclockwise rotation indicates R configuration and a clockwise rotation indicates S configuration; if the low priority group is projecting backward (on a vertical bond) the regular Cahn-Ingold Prelog rule applies: 2 2 CHO CHO CHO

H OH 1 H OH 3 H CH2OH CH OH HO CH2OH 2 1 3 projecting forward counterclockwise: clockwise: R R

3 3 CH2OH CH OH 2 CH2OH

H C 1 2 Cl Br 1 Cl Br 3 Br Cl CH 3 CH3 2

clockwise R clockwise: R projecting backward III. Diastereomers Diastereomers are stereoisomers that are not mirror images; they are geometric isomers (like cis-trans isomers about a double bond) and usually compounds containing at least two centers of chirality. Examples: CH3 CH3 S S H Br H Br H H3C H H R S H Cl Cl H

H3C H H3C CH3 CH3 CH3

Diastereomers Diastereomers Stereoisomers but not enantiomers Relationships:

enantiomers enantiomers

CH CH3 3 CH3 CH3 R S S R H Br Br H H Br Br H R S S R H Cl Cl H Cl H H Cl

CH CH3 3 CH3 CH3

2S, 3R 2R, 3S 2S, 3S 2R, 3R Diastereomers

Diastereomers

Diastereomers

Diastereomers

• If the number of stereogenic carbon atoms in a molecule is n, there are a maximum of 2n possible stereoisomers. Thus, for two stereogenic carbon atoms, there are a maximum of 22 or 4 possible stereoisomers. There are many cases where less than the maximum number of stereoisomers may be found, especially in symmetrical molecules. Example: Same molecule enantiomers

CH CH3 3 CH3 CH3 S R H Br Br H H Br Br H σ S R H Br Br H Br H H Br

CH CH3 3 CH3 CH3

2S, 3S 2R, 3R "meso-diastereomer" (±)-diastereomers

2-stereogenic carbon atoms; a total of 3 stereoisomers for 2,3-dibromobutane! •A meso compound is one that is achiral despite having centers of chirality: it usually has some element of symmetry, like an internal mirror plane IV. Absolute and Relative Configuration

Absolute configuration is the detailed stereochemical picture of a molecule, specifying how the atoms are arranged in space through designating R or S configurations at each chirality center. Relative configuration is the experimentally determined relationship between the configuration of two molecules or two stereogenic carbon atoms within a molecule, even though we may not know the absolute configuration of either. Example: O

H3C trans 2,4-dimethylcyclohexanone relative configuration: trans configuration of two methyl groups determined by NMR

CH3

however, we don't know absolute stereochemistry:

O O S H3C R H3C or

S R

CH3 CH3

V. Physical Properties of diastereomers

•Diastereomers, unlike enantiomers, have different physical properties: melting points, boiling points, etc. Diastereomers can thus be separated by ordinary means: chromatography, distillation, crystallization, etc.

•Enantiomers, which are mirror-image molecules, have virtually identical physical properties and are thus very difficult to separate..

•Pure enantiomers of optically active compounds are often obtained by isolation from natural sources. Examples: carbohydrates (D-(+)-glucose) and amino acids (L-(+)- alanine)

•Many chemical reactions involve achiral reagents and thus can yield racemic mixtures as products. How can one separate (resolve) enantiomers of a given molecule?

Resolution of Enantiomers

•Column Chromatography can be employed using a chiral stationary phase as an adsobent: different enantiomers form diastereomeric complexes with the chiral column packing and move through the column at different rates. In this way separation can be achieved without chemical modification of a racemic mixture.

•A racemic mixture can also be resolved by reacting the mixture of enantiomers with a chiral resolving agent, which generates diasteromers that are easily separated. The pure enantiomers can then be obtained by hydrolysis of the respective diastereomers. We illustrate this process for the formation of diastereomeric esters by reaction of a racemic diacid with a chiral alcohol: separable inseparable Diastereomers Racemic mixture Resolving agent CH3 O COOH C O S CH3 H+ H Br H Br + 2 S HO Br H Br H -H2O CH3

COOH S-phenyl ethanol C O O

COOH (S,S,S,S) CH R 3 CH3 Br H O + 2 + R HO H C O H Br H Br COOH -H2O Br H S-phenyl ethanol CH3

C O O

hydrolysis: (S,R,R,S)

CH3 O C O COOH + H Br H S H Br

Br H CH3 S +H2O Br H C O O COOH

pure enantiomer (S,S,S,S) Additional Problems for practice:

1.) Draw a three-dimensional picture that corresponds to each of the following Fisher projections: COOH COOH CHO

H OH HO H HO H a b c HO H HO H HO H

CH2OH CH2OH H OH

HO H

CH2OH 2.) State the relationship between each of the following pairs of structures (identical, enantiomers, diasteromers, constitutional (structural) isomers, or different compounds that are not isomeric)

CH3 CH3 a

CH3 CH3

OH OH b OH OH

Cl Br

c

Br Cl

Cl Cl d

Cl Br Cl Br

Cl Cl

d

Cl Br Br Cl