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Chapter 4


Stereoisomers

We have looked at two types of isomers in Chapter 3, conformational isomers (rotational) and configurational isomers.  There are a number of other kinds of isomers and we will be studying several in this chapter.
We will be looking at stereoisomers, compounds which have the same empirical formula, and the same connectivity, but still exhibit several critical differences.  These differences can be detected by the use of polarized light and are critical in the reactions of biological systems.

Stereo isomers are two or more compounds consisting of the same atom, the same groups and the same connectivity, but have different spatial arrangements.  They may be conformational or configurational and in this course we will emphasize the configurational stereoisomers.

The conformational stereoisomers, like ordinary conformers, can be interconverted by rotation about single bonds.  As such, they can exist in appreciable amounts only when the rotational (torsional) barrier is high and/or the temperature is low enough to slow rotation to a near standstill, as in the solid state.

Configurational isomers are those which can be interconverted only by breaking and re-forming of chemical bonds.  They can be separated by the use of appropriate techniques.

Enantiomers are stereo isomers which have the same connectivity, are not superimposable on each other and are also mirror images of each other.

Diastereomers are stereoisomers  which have the same connectivity, but are neither mirror images of each other nor are they superimposable on each other.
{formulas and ball and stick and space filling models of CHFClBr with both enantiomers shown}

The existence of this kind of isomerism is due to the tetrahedral nature of the {sp3 } hybridized
orbitals of carbon.  (There is a type of stereoisomerism, geometric isomerism, which is not centered on single carbon atoms and they will be discussed later.)

Superimposable means that the image of one molecule can be merged with the image of another molecule (in 3-dimensions) so that all parts of one coincide with the other.  This is a convoluted way of saying that the two molecules are identical.

A mirror image of a molecule is exactly that.  Hold up a model of a molecule in front of a mirror and look at its image.  You should also be able to do this without a mirror.  If a molecule is not superimposable (not identical to) its mirror image, then the two non-identical structures are called enantiomers.

Looking at methane and sevral substituted methanes we will introduce the concept of enantiomers (non-superimposable mirror images).

Consider methane.  No matter how you orient two methane molecules they are always identical.  they are perfectly superimposable on their mirror images, in fact, all methane molecules are mirror images of each other.
{methane, ball and stick and space filling}

Monosubstituted Methanes

Next, take a monosubstituted methane molecule like fluoromethane, make a model and its mirror image.
{CH3F, ball and stick and space filling}
If you try to superimpose these two structures, you will see that they are also identical.

Disubstituted Methanes

Consider a disubstituted methane (disubstituted with two different atoms or groups) like {CH2FCl}.
{CH2FCL ball and stick and space filling}
Make the model and its mirror image and try to superimpose them.  You will see that after a bit of manipulation, you can superimpose them and they are identical.

Trisubstituted Methanes

Now consider a methane molecule which has had three of its original hydrogen atoms substituted by three different atoms or groups, like CHFClBr (bromochlorofluoromethane).
{CHFCLBr ball and stick, space filling and mirror images}

If you make a model of this molecule and one of its mirror image, and try to superimpose them, you will find that it cannot be done.  These two are enantiomers.

One way to recognize whether a molecule can exist as a pair of enantiomers is to look for carbon atoms which have four different groups attached.  The groups can be alkyl or any other group as long as there are four single bonds to the carbon in question.  Other atoms beside caarbon can exhibit this property, but because of the ability of carbon to connect in so many different ways, we will concentrate on molecules based on carbon.

A carbon atom with four different groups bonded to it is said to have a chiral center.  A different isotope of some atom can be considered a different group in this definition.  for example, CHDFCl (chlorodeuteriofluoromethane) is considered to have a chiral center at the carbon because the H and D (deuterium) atoms are considered to be different in this case.  There may be more than one chiral center in a molecule as in the sugars.  make models of various molecules with one or two chiral centers and all possible mirror images.

{d and l lactic acid ball and stick and space filling}
{d and l alanine ball and stick, space filling}
{glucose and mirror image, ball and stick, space filling}

Physical Properties of Enantiomers

Most of the physical and chemical properties of two enantimers are identical under non-chiral conditions (this will be defined later).  They have the same boiling points and melting points.  Their solubility in non-chiral solvents is identical.  They react identically with non-chiral reagents.  So why bother identifying them as being somehow different?

The physical property which distinguishes between the two enantimers is their interaction with plane polarized light.  The plane of polarization of electromagnetic radiation can be selected by various methods.  If this radiation passes through a pure solution of one of the enantiomers it can rotate the plane of polarization by a certain amount.  If, on the other hand, the same light with the same polarization, is passed through an otherwise identical solution of the other enentiomer (non-superimposable mirror image),  its plane of polarization will be rotated in a direction opposite to that observed for its enantiomer.  The magnitude of the rotation will be identical.

This property is called optical activity.  The magnitude of the rotation is dependent on the number of molecules encountered by the photons and is thus dependent on concentration and path length through the sample.  This is a good way to detect enantiomers and measure their concentration, but of what importance is this property of chirality?  It becomes important when we consider the chemical properties of the molecules.  We will see how one enantiomer may be biologically active as a drug or toxin, while its mirror image may have no biological activity.

We can designate these two enantiomers as being dextrorotatory (rotating the plane to the right or clockwise as we look at the light source) or levorotatory {rotating the plane to the left, or counterclockwise).

We can also designate the rotation in the IUPAC name of the compound by using (+) for dextrorotatory and (-) for levorotatory.
(+) bromochlorofluoromethan and (-) bromochlorofluoromethane

By designating the direction of rotation of the plane of polarized light, we only identify a physical property of the molecule.  We still do not know which configuration is represented by the name.

There is an unambiguous nomenclature which identifies each enantiomer according to its configuration.  This is a system for completely naming the molecule and designating its configuration.

1.  Consider a molecule with a chiral carbon, i.e., four different groups atached to the chiral center.  First, we look at the four atoms bound directly to the chiral carbon and assign certain priority values to each one according to atomic weight.  Lowest atomic weight has lowest priority.  If two of these atoms are the same kind, then assign priority for them based on the next atoms attached to each of them.  (see more detailed description in textbook).

2.  Next, orient the molecule so that the group of lowest priority is pointing directly away from you.  The remaining three groups are now directed toward you and are approximately at the vertices of an equilateral triangle.

3.  Locate the group of highest priority of these three and mentally move from it to the group of next highest priority and from this to the group of lowest priority of these three.

In moving from group to group in this way, note in which direction you have to go.
If the direction is clockwise, this configuration is designated “R”.

If the direction is counterclockwise, this configuration is designated “S”.

The complete names of the compounds would then be:

R-bromochlorofluoromethane and S-bromochlorofluoromethane

If we also know the specific rotation of each molecule, we can add this to the name.

(+) R-bromochlorofluoromethane and (-) S-bromochlorofluoromethane

Problems 4.8, 4.9 4.10
 

Specific Rotation

The optical activity is a property of the individual molecules and we can define a value, called the specific rotation, which is the value of the rotation of an enantiomer under specified conditions of concentration, path length, temprature and wavelength of light.  (see textbook)
 

Problem 4.3, 4.4

{T 17 Schematic diagram of a polarimeter}

Racemic Modification

Since each enantiomer of a pair has exactly the opposite effect on the rotation of plane polarized light, we would imagine that if we have an equal mixture of both enantiomers, the effects would cancel out exactly and no rotation would be observed.  This is the case and such a mixture is called a racemic modification.  For an optically active mixture to racemize, means to lose optical activity and reach a state of zero rotation.

Representations of Chiral Molecules

There must be an unambiguous method for representing chiral structures in 2-dimensions and clearly distinguishing between the configurations.  One way is to use the perspective drawings with the wedge shaped bonds as described earlier in the course.
{show some wedge structures if possible}

Another, simpler, way of representing absolute configurations is the use of cross formulas.
{NT  18 Fischer projections}

{here insert some cross formulas, either from chemdraw if possible or scanned along with ball and stick and space filling models}

Problems   4.5, 4.6

Chemistry of Chiral molecules

Earlier the term “chiral conditions” was mentioned.  Non-chiral conditions are those in which chiralmolecules are not present or are present in equal amounts.  So a chiral molecule in a non-chiral solvent is in a non-chiral environment.  The chiral molecule would also be in a non-chiral environment if the solvent was composed of equal amounts of both enantiomers of some chiral solvent.

A chiral molecule is in a chiral environment if it is in a chiral solvent composed of only one enantiomer or even if one enantiomer of the solvent was present to a greater extent than the other enantiomer.  A chiral environment could be the surface of a solid material (such as a catalyst) composed of one enantiomer.

In some cases, chiral environments were produced by the application of directed electric and/or magnetic fields, gravitational fields (centrifugation), or circularly polarized radiation.

Diastereomers

Diastereomers are stereoisomers which are not mirror images and are not superimposable.  Tn this chapter, we will consider diastereomers which have chiral centers.  In Chapter 8 we will study another kind of diastereomer, geometric isomers.  For our current purposes, we can consider diastereomers which have two chiral centers.  Our examples will be compounds in which the two chiral carbons are attached to each other, but this is done for simplicity and clarity.  Chiral centers do not have to be next to each other to form diastereomers.

Consider the following compound.

{2,3 dichloro pentane} {structural formula, fisher diagrams of all four stereoisomers, 4 ball and stick and 4 space filling models}

You can see that there are two DIFFERENT chiral centers in this molecule.  For practice, make a list of the four groups attached to each chiral center.

This diastereomer has 4 different stereoisomers.  They are shown as two pairs of enantiomers.

To simplify the relationship between these four structurees, note that the two molecules from one of the enantiomer pairs are neither mirror images nor superimposable on either of the structures of the other enantiomer pair.  This relationship is diastereomerism.

Physical Properties

Selecting any two molecules which are diastereomers, their physical properties are similar, not necessarily identical.  boiling points, melting points, solubility in achiral solvents, etc. may be close, but you should not be surprised if they are different.

The reason for this is that these properties are determined by interactions with other molecules, dipole-dipole interactions, VDW forces, etc.  These interactions are dependent on geometry.  Two diastereomers reacting with some achiral molecules will form some kind of interaction complexes.  These complexes will also be diastereomers and not mirror images or superimposable so their interaction energies will not be the same and neither will most of their properties.  This situation will also occur if the diastereomers interact with chiral molecules.

Chemical Properties

Chemical interactions occur when molecules come together.  When two diastereomers interact with an achiral molecule, the interaction complexes are also diastereomers of each other.  The achiral molecule does not necessarily approach the two diastereomers in the same way.  thus, the energy of the two interactions is not necessarily the same and reaction rates can differ.  In some cases, one diastereomer may react much more rapidly than the other.  In other cases each diastereomer may yield different products for a given reaction.  We will see more of this in greater detail in Chapter 10 when we study stereospecificity and stereoselectivity.

When interacting with chiral molecules, the differences can be much more pronounced.  We will look at the various kinds of reactions which can occur later in this chapter.

Meso Compounds

For our purposes, meso compounds will be those which have two identical chiral centers and therefore have a plane of symmetry through some point between those centers.

{2,3 dichloro butane}  {structural formula, 4 Fisher diagrams showing that one pair of mirror images are mutually superimposable, 4 ball and stick, 4 space filling}
 

Problem 4.12

Nomenclature and Specification of Configuration

Diastereomers can be named unambiguously using the R and S notation as described earlier.  When there are several chiral center, however, the process is carried out separately for each chiral center, designating each as either R or S.  The number of the carbon atom is added to indicate which chiral center is being specified.  (2R, 3S) or (2S, 3S) etc.

The R and S notation, once assigned, can help dealing with enantiomers and diastereomers easier.  Remember that R is the mirror image of S.

For a molecule with two chiral centers  designated (2R, 3S), its mirror image is (2S, 3R) and for its diastereomer designated (2R, 3R) there is a mirror image (2S, 3S).

Chemical Reactions of Chiral Molecules Under Various Conditions

* Achiral reagent with two enantiomers

In this case, the achiral reagent will interact with each of the enantiomers to form a transition state structure.  Since each transition state still has only one chiral center, the two transition states will be mirror images of each other and thus be of equal energy (activation energy).  So the reaction rates for the enantiomers will be identical.  If bonds to the chiral centers are not broken during the reaction (the reaction occurs at some other part of the molecule) then the products formed will be enantiomers.  If the initial mixture is racemic, the product will also be racemic.

* If you start with an achiral system, your product will be achiral.

* Chiral Reagent with Two Enantiiomers

Suppose you have a chiral reagent with configuration R and react it with a racemic modification of two enentiomers R and S.  When the molecules collide, they will form transition states with two chiral centers (diastereomers) as folloes:
R + R  -->  R,R
R + S --> R,S

These two transition states are diastereomers  and thus of different energy.  The activation energies will be different, so one reaction will occur more rapidly than the other.  If no bonds to the chiral centers are broken during the reaction, the products will be diastereomers.

This property can be employed to separate a racemic modification into two pure enantiomers.  using either an appropriate chiral reagent or a column containing a chiral packing, or a chiral solvent, the energy differences between diastereomeric transition states can be employed to resolve the mixture.

{T 21 Conversion of racemic 2-butanol to diastereomeric esters}

{T 22 Chromatographic resolution of enantiomers}

Molecules making up biological systems are largely chiral and as a result form highly chiral environments.  Nearly all the naturally occuring amino acids which constitute proteins and peptides, are of one configuration.  Only certain diastereomers of sugars will have appropriate biological activity.  So enzymes, which are protein catalysts, will react correctly only with one enantiomer or diastereomer.  Other stereoisomers may be unreactive or may even be toxic to the biological system.  If this is the case, then how did the first living organisms select only one set of stereoisomers?

{T 18 Chiral recognition by an enzyme}

* Reactions that Form New Chiral Centers

Consider the free radical chlorination of n-butane.  We will only look at the 2-chlorobutane (sec-butyl chloride) products.

{CH3CH2CH2CH3  +  Cl2  -->  CH3-CHClCH2CH3} {structural formulas and ball and stick and space filling models}

In this reaction a new chiral center is generated at carbon 2.  This follows the mechanism we studied in Chapters 2 and 3.  Recall that the step in which the carbon-chlorine bond is formed, has a chlorine molecule approach the alkyl free radical.  As we saw, this radical is nearly flat and the chlorine can approach equally from either side of the plane.  Approach from one side yields the R configuration while approach from the other side yields the S configuration.  Since both are eaually likely, R and S are formed in equal amounts yielding the racemic modification.  Work this out with models until you understand it thoroughly.

When we say that attack from either side is equally likely, what we mean is that the energy barrier along the paths to R and S products are equal.

{T 19 Formation of racemic 2-butanol from 2-butanone}

* Generation of a Second Chiral Center.

Consider the free radical chllorination of (S) 2-chlorobutane which has a chiral center and is enantiomerically pure.

{(S) 2-chlorobutane + Cl2 --> (2S, 3R) and (2S, 3S) 2,3-dichlorobutane} {structural formula, ball and stick, space filling}

We will only look at the 2,3-dichloro butanes formed.

In this reaction, the free radical is formed at carbon 3 and this can then be attacked from either side by chlorine, forming both R and S configurations at carbon 3.  The products will have configurations (2S, 3R) and (2S, 3S).  But is attack from either side equally likely in this case?

Since there is a chiral center adjacent to the reaction site, the transition states of the step in which the carbon-chlorine bond is formed, will be diastereomers for attack from the two sides.  Thus, their energies will not be equal and the products will also be diastereomers and not necessarily formed in equal amounts.

The free energy of activation for the two reaction paths will be unequal and thus proceed at different rates, yielding different amounts of the two products.

* Reaction without Breaking Bonds to Chiral Center or Generating New Chiral Center.

Consider the previous reaction, but now focus on a different product.

{(s) 2-chlorobutane + Cl2 --> 1,2-chlorobutane} (structural formulas, ball and stick, and space fillling}

A new chiral center is not formed and the old chiral center is retained.  The product will therefore be chiral, but the addition of chlorine to one of the groups attached to the chiral center will change the priority of that group in our naming process and the product will have the opposite configuration (r).  This is only a nomenclature matter.  No bonds to the chiral center were broken, but one of the substituent groups was modified, giving it a higher priority than it had in the original reactant.
 

If a bond to the chiral center is broken in any reaction, then an optically pure compound may racemize to some extent or even completely.  this will depend on the mechanism of the reaction occuring.  If we carefully design our experiments, this behavior can give us insights into the mechanism being followed.  We will see this in chapter 5.

{T 20 Summary of types of isomers}

Problems 1, 2, 3, 6, 7, 8, 9, 12,