CHAPTER 5

Stereoisomers

We have already covered two kinds of isomerism:

• Constitutional Isomers (structural isomers)

• Stereoisomers

Examples of Constitutional Isomers:

Examples of Stereoisomers:

Another type of stereoisomerism is called mirror-image stereoisomerism. Mirror-image related stereoisomers are said to be left-handed and right-handed and occur when a molecule and its mirror image are non-superimposable.

Chiral Molecules 5-1 The radical bromination of butane to form 2-bromobutane appears to yield a single product:

Chiral molecules cannot be superimposed on their mirror images.

The two 2-bromobutane molecules formed by the radical bromination of butane are actually non-superimposable and are therefore not identical.

A molecule that is not superimposible on its mirror image is said to be chiral.

In this case each isomer is called an enantiomer.

Compounds whose mirror images are superimposable are called achiral.

Examples of chiral and achiral molecules:

Above all, the chiral examples contain an atom that is connected to 4 different substituent groups. This atom is called an asymmetric atom or a stereocenter.

Often, asymmetric atoms are marked with an asterisk.

Molecules having one stereocenter are always chiral.

The symmetry in molecules helps to distinguish chiral structures from achiral ones.

For most organic molecules, a sufficient test for chirality is absence of a plane of symmetry (mirror plane).

A mirror plane is one that bisects the molecule in such a way that the half of the molecule on one side of the plane is the mirror image of the half on the other side of the plane.

Methane has 6 planes of symmetry, chloromethane has 3, dichloromethane 2, bromochloromethane 1, and bromochlorofluoromethane none:

Optical Activity 5-2 Enantiomers cannot be distinguished on the basis of their physical properties, such as boiling points, melting points, and densities.

Enantiomers can be distinguished by the way they interact with plane-polarized light.

When plane-polarized light is passed through a sample of one of the enantiomers, the plane of polarization is rotated either clockwise or counterclockwise. When the experiment is repeated with the other enantiomer, the plane-polarized light is rotated an equal amount, but in the opposite direction.

If facing the light source:

• Clockwise rotation: enantiomer is dextrorotary (+)

• Counterclockwise rotation: enantiomer is levorotary (-)

This interaction with light is called optical activity and enantiomers are often called optical isomers.

Optical rotation is measured with a polarimeter. Light is electromagnetic radiation that oscillates perpendicular to its direction of motion.

The oscillation of light can be resolved into two perpendicular components.

When light is passed through a polarizer, only one of the two perpendicular components of light is passed through. This light is referred to as plane-polarized light.

When plane-polarized light interacts with a chiral molecule, the plane of polarization of the light is rotated to the left or right.

This effect is called optical rotation and the molecule is said to be optically active.

Optical activity is measured using a polarimeter. This device contains a light source, a polarizer to produce the plane-polarized light, a sample cell, and an analyzer to determine the amount of rotation.

The measured rotation (in degrees) is the observed optical rotation, α, of the sample.

The value of α depends upon:

• Structure of the chiral molecule

• Concentration of the chiral molecule

• Length of the sample cell

• Wavelength of the light

• Solvent used

• Temperature

The specific rotation [α] of a sample is defined for each chiral molecule (the value is solvent dependent):

Specific rotation is a physical constant for a substance, as is melting point, boiling point, density, etc.

Examples of specific rotations:

Optical rotation indicates enantiomeric composition.

A racemic mixture is a mixture of equal amounts of the + and – enantiomers of a chiral compound. It shows no net rotation of plane-polarized light.

When one enantiomer equilibrates with its mirror image, the process is called racemization.

When one of the two enantiomers of a chiral compound is present in a mixture in excess over the other, there will be a net rotation of plane-polarized light.

A 50% enantiomer excess would be defined as a mixture of 75% one enantiomer and 25% of the other (50%+ with 25%+ and 25%-). The mixture would be called 50% optically pure.

The optical purity of an enantiomer is defined:

Absolute Configuration: R-S Sequence Rules 5-3

X-ray diffraction can establish the absolute configuration.

The absolute configuration of an enantiomer is the actual spatial arrangement of the substituent groups around the chiral centers.

There is no straightforward correlation between the absolute configuration of an enantiomer and the sign of rotation of the molecule.

The absolute configuration of an enantiomer can be determined through single crystal X-ray diffraction analysis or through chemical correlation to a molecule whose absolute configuration has already been determined.

Stereocenters are labeled R or S. The convention for naming enantiomers unambiguously was developed by R.S. Cahn, C. Ingold, and V. Prelog.

The four substituents around the chiral carbon must be first ranked in order of decreasing priority.

• a highest priority

• b second-highest priority

• c third-highest priority

• d lowest priority

When the molecule is positioned with the lowest-priority substituent away from the viewer, the remaining three substituents will be arranged in either a clockwise or counterclockwise direction.

If the progression from a to b to c is clockwise, the configuration at the stereocenter is named S (sinister) otherwise the configuration is named R (rectus)

The R or S is added as a prefix in parentheses to the name of the chiral compound.

(R)-2-bromobutane

(S)-2,3-dihydroxypropanal

(R,S)-bromochlorofluoromethane (a racemic mixture)

If known, the sign of rotation of plane-polarized light may also be added, however, there is no correlation between R,S and +,-:

(R)-(+)-2,3-dihydroxypropanal.

Sequence rules assign priorities to substituents. Rule 1:

Look first at the atoms directly attached to the stereocenter.

Precedence is in order of highest atomic number. Hydrogen is always the lowest precedence.

A higher-mass isotope takes precedence over a lower-mass isotope.

Rule 2:

If two atoms are of the same precedence using rule 1, proceed along the two respective substituent chains until you reach a point of difference.

Verify these two examples:

Rule 3:

Double and triple bonds are treated as if they are single and the atoms in them are duplicated or triplicated at each end by the respective atoms at the other end of the multiple bond.

Verify these assignments:

Fischer Projections 5-4 Fischer projection formulas represent 3-D tetrahedral carbon atoms and their substituents in two dimensions.

The molecule is drawn in the form of a cross.

• The tetrahedral carbon is in the plane of the paper at the center of the cross.

• Atoms connected to the tetrahedral carbon by horizontal bonds are behind the plane of the paper.

• Atoms connected to the tetrahedral carbon by vertical bonds are in front of the plane of the paper.

There is more than one correct way to draw a Fischer projection:

Rotating a Fischer projection may or may not change the absolute configuration.

Rotating a Fisher projection formula by 90o converts the structure into that of the enantiomer of the molecule originally represented.

Rotating a Fisher projection formula by 180o keeps the same enantiomer.

Exchanging substituents in a Fischer projection also changes the absolute configuration.

To compare a Fischer projection to another in a different orientation in order to see if they represent the same enantiomer:

• Exchange any two substituents. This turns the molecule into its mirror image.

• Exchange another two substituents. This then turns the molecule back into the original enantiomer.

• Using a series of exchanges, convert one Fisher formula into the other.

• If an odd number of exchanges are required, the two projection formulas represent different enantiomers.

• If an even number of exchanges are required, the two projection formulas represent the same enantiomer.

Fischer projections tell us the absolute configuration.

• Draw any correct Fischer projection formula of a chiral center.

• Assign priorities to all of the substituents.

• Using two consecutive substituent exchanges (to preserve the chirality of the Fischer formula), place group d (lowest priority) on the top.

• If the a,b,c groups are now arranged in a clockwise order, the enantiomer is R: if in a counterclockwise order, the enantiomer is S.

Molecules Incorporating Several Stereocenters: Diastereomers

5-5

Two stereocenters can give four stereoisomers: chlorination of 2-bromobutane at C3.

Consider the chlorination of 2-bromobutane. Several products are formed, but consider only the 2-bromo-3-chlorobutane.

A second stereocenter is formed by the addition of the chlorine atom.

The possible combinations are RR, RS, SR, and SS.

Because all of the horizontal bonds in a Fischer projection formula point towards the viewer and all vertical bonds away from the viewer, a Fischer projection formula represents the molecule in its eclipsed conformation.

In order to convert a Newman or dashed-wedged representation into a Fischer representation, first rotate the molecule to form an eclipsed rotomer.

Treat each stereocenter separately and regard the group containing the other stereocenter as a simple substituent.

When a chiral molecule has two stereocenters, four stereoisomers are possible: RR, RS, SR, and SS.

The RR and SS isomers are mirror images of each other and are therefore enantiomers.

The RS and SR isomers are also mirror images of each other and are enantiomers.

The RR and RS stereoisomers are not mirror images of each other; nor are the SS and SR stereoisomers.

Stereoisomers not related as object and mirror image are called diastereomers.

Diastereomers are distinct molecules with different physical and chemical properties.

They can be separated by fractional distillation, crystallization, or chromatography.

They have different melting points, boiling points, densities, and specific rotations.

Cis and trans isomers are cyclic diastereomers. Consider 1-bromo-2-chlorocyclobutane:

There are 4 stereoisomers: RR, SS, RS, and SR. The two cis isomers, SR and RS, are enantiomers and the two trans isomers, RR and SS are enantiomers.

A cis isomer and a trans isomer are diastereomers of each other.

More than two stereocenters means still more stereoisomers.

A compound containing 3 stereocenters will exist as 8 stereoisomers which can be grouped into 4 pairs of enantiomers:

RRR | SSS

SRR | RSS

RSR | SRS

RRS | SSR

In general, a compound having n stereocenters can have a maximum of 2n stereoisomers.

Meso Compounds 5-6

Two identically substituted stereocenters give rise to only three stereoisomers.

Consider the radical bromination of 2-bromobutane:

Since there are 2 chiral centers in the product, we might expect 4 distinct stereoisomers: RR, RS, SR, and SS.

These could then be organized into enantiomeric pairs: RR | SS and RS | SR.

A closer look at the RS and SR pair of molecules, however, shows that they are superimposable molecules and are therefore identical.

A compound containing 2 or more stereocenters that is superimposable with its mirror image is called a meso compound.

Meso compounds contain an internal mirror plane which divides the two halves of the molecule which are mirror images of each other.

The presence of a mirror plane in any energetically accessible conformation of a molecule is sufficient to make it achiral.

2,3-Dibromobutane exists as three stereoisomers only: a pair of enantiomers and an achiral meso diastereomer.

Examples of meso compounds having multiple chiral centers:

Cyclic compounds may also be meso. 1,2-Dicyclobutane exists in the cis and the trans form. The cis form, however, contains a mirror plane and is therefore an achiral meso compound.

For the purpose of identifying a mirror plane, cyclic compounds can usually be treated as if the ring were planar since the out-of-plane conformers are all generally interconvertable at room temperature.

Stereochemistry in Chemical Reactions 5-7

The radical mechanism explains why the bromination of butane results in a racemate.

When a hydrogen atom is extracted from butane by an attacking bromine atom, it does not matter which hydrogen is extracted, an achiral planar sp2 radical is formed:

The two lobes of the p orbital are equally susceptible to attack by bromine in the second step. The two transition states are energetically equivalent to each other, so equal amounts of the two enantiomeric products are formed.

The formation of chiral compounds from achiral reagents yields racemates (optically inactive reactants yield optically inactive products).

The presence of a stereocenter affects the outcome of the reaction: chlorination of (S)-2-bromobutane.

Chlorination of (S)-2-bromobutane at a terminal methyl group can proceed at either C1 or at C4:

Both products are optically active. The original stereocenter remains unchanged.

In the case of C1 chlorination, the sequence of priorities about the stereocenter changes, which changes the configuration at C2 from S to R.

In the case of C4 chlorination, the carbon chain must be renumbered to maintain the lowest possible substituent numbering.

Chlorination of (S)-2-bromobutane at C2, the stereocenter, leads to 2-bromo-2-chlorobutane. The molecule remains chiral, however a racemic mixture is formed.

Hydrogen abstraction at C2 leads to a planar, sp2-hybridized, achiral radical.

Chlorination occurs equally at either lobe of the p orbital leading to equal amounts of the R and S enantiomers and thus a racemic mixture.

Chlorination of (S)-2-bromobutane at C3, forms a second stereocenter and gives rise to diastereomers

In this case, the two faces of the radical transition state are not mirror images of each other, due to the stereocenter at C2.

Attack by chlorine at the two faces of the radical will occur at different rates (due to steric reasons) and the two diastereomers are formed at different rates.

Stereoselectivity is the preference for one stereoisomer.

A reaction that favors the formation of one of several possible stereoisomeric products is said to be stereoselective.

Chlorination of (S)-2-bromobutane at C3 is stereoselective, whereas chlorination at C2 is not (a racemate is formed).

100% stereoselectivity is usually obtained in nature when enzymes (chiral molecules themselves) convert achiral compounds into chiral ones.

Resolution: Separation of Enantiomers 5-8 Pure enantiomers can be obtained by first synthesizing a racemic mixture and then separating the enantiomers formed by a process called resolution.

Resolution is best carried out by converting a racemate into a mixture of diastereomers by adding an enantiomerically pure reagent. The resulting diastereomers can then be separated by standard techniques.

Each pure diastereomer can then be separated into one of the original enantiomeric molecules and the optically active reagent, which can be used again to resolve further racemic mixtures.

A popular reaction employed in the resolution of racemic mixtures is salt formation between acids and bases.

(+) Tartaric acid can be used to resolve racemic amines.

Chiral chromatography can be used to resolve racemic mixtures without first isolating diastereomers. In this method, an optically active compound is attached to a solid support in a column, and the racemic mixture is allowed to pass through it.

Each of the two enantiomeric molecules in the mixture will interact differently with the attached chiral molecule and will have different retention times on the column.

Important Concepts 5

1.  Isomers – Same molecular formula, different compounds:

•  Constitutional – Individual atoms are connected differently •  Stereoisomers – Same connectivity, different 3D arrangement. •  Mirror-Image Stereoisomers – Related as image

2.  Chiral Molecule – Not superimposable on its mirror image

3.  Stereocenter – Carbon atom bearing 4 different substituents

4.  Enantiomers – Two stereoisomers, each a non-superimposable mirror image of the other

Important Concepts 5

5.  Racemate – A one-to-one mixture of enantiomers 6.  Mirror Plane – Chiral molecules cannot contain a

mirror plane. 7.  Diastereomers – Stereoisomers not related to each

other as mirror images (i.e. cis/trans). 8.  Two Stereocenters In A Molecule – Create up

to 4 stereoisomers: 2 diastereomerically related pairs. If the 2 stereocenters generate a mirror plane in the molecule, the molecule is known as a meso compound and is achiral.

9.  Physical Properties of Stereoisomers – Most are the same except for the rotation of plane-polarized light. One enantiometer rotates the plane of polarization to the right, the other to the left. This rotation is expressed as the specific rotation [α].

Important Concepts 5

10. Absolute Configuration – Determined by X-ray diffraction. Assignment of R or S, as determined by the Cahn, Ingold, and Prelog sequence rules

11.  Fischer Projections – Standard 2-D representation of 3-D molecules containing stereocenters

12. Radical Halogenation – Can introduce chirality into an achiral compound. Racemic mixtures are often produced.

13. Radical Halogenation of a Chiral Molecule Containing 1 Stereocenter –

•  Gives a racemate if the reaction occurs at the stereocenter •  Gives 2 diastereomers in unequal amounts if the reaction

occurs elsewhere

Important Concepts 5

14. Stereoselectivity – Preference for the formation of one stereoisomer when several are possible

15. Resolution – Separation of enantiomers •  Reaction with a pure enantiomer of a second chiral

compound and separation of the diastereomers •  Chiral chromatography