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					                                E30 ENANTIOMERS
                              Chirality in organic chemistry

THE TASK
To investigate the nature of chirality in organic chemistry.

THE SKILLS
By the end of the experiment you should be able to:
    • use molecular modelling kits and reasoning to study the properties of molecules,
    • measure optical activity using a polarimeter.

OTHER OUTCOMES
    •   You will develop generic scientific skills including the use of models to study molecular
        shapes in organic chemistry.
    •   You will develop an appreciation of the role of chirality in organic chemistry and its
        importance in biology.

INTRODUCTION
The drug thalidomide was developed to treat morning sickness in pregnant women. The
structural formula of thalidomide, shown below, hides the fact that it actually exists in two
molecular forms. The relative positions of the atoms, when viewed in three-dimensions, are
different in the two forms, as shown in the figure below. The two forms may look the same to
you but they are actually non-identical mirror images. The difference may seem subtle, but it is
actually very important. The form on the left is an effective treatment for morning sickness; the
form on the right can cause terrible birth defects.

                                          O

                                            N                  O   thalidomide
                                                        N
                                          O      O




The two forms of thalidomide are termed enantiomers. Enantiomers are pairs of molecules that
are non-identical mirror images. Important biological molecules, including naturally occurring
amino acids and sugars, commonly occur as only one of the possible enantiomer. The other
member of the pair may be completely inactive or, as in the case of thalidomide, have
completely different and deleterious properties.

                                                E30-1
E30-2



A pair of enantiomers is like a left and right hand. Both hands have the same number of fingers
and a thumb, arranged in the same order. They are not identical, however the reflection of a left
hand in a mirror looks just like a right hand and vice versa. A pair of enantiomers are non-
superposable mirror images, and are said to be chiral (pronounced ki'ral to rhyme with spiral,
from the Greek cheir meaning hand).

All other molecules are achiral (i.e. without chirality). In organic chemistry, most chiral
molecules contain an sp3 hybridised carbon atom bearing four different substituents. Such an
atom is known as a stereogenic centre. Chiral molecules have no plane(s) of symmetry.
Molecules can contain more than one stereogenic centre.

LAB-WORK                                                                            20

2-Butanol is an example of a molecule containing one stereogenic centre (marked on the
structures below with asterisks).

                                H                               H
                               *C
                                     OH                HO       C*
                   CH3CH2                                            CH2CH3
                                     CH3                  CH3


•       Construct models of the two forms of 2-butanol and try to superpose them. Make sure
        you are satisfied that the two molecules are different.

Nomenclature of Enantiomers

The four atoms or groups, a, b, c and d, joined to a stereogenic centre are ordered in decreasing
priority such that a > b > c > d. The order of priority is determined by the atomic number of the
atoms directly attached to the carbon atom of interest. Those atoms with higher atomic number
have priority over those with lower atomic number. For example,

                               I > Br > Cl > OH > NH2 > CH3 > H.

When the first atoms of two (or more) groups are of the same kind, then the next atoms along
the chain are considered, and so on until a decision is reached.

The molecule is positioned so that the lowest priority group, d, is remote from the observer who
is looking down the C-d bond. If the sequence a→b→c is clockwise the molecule is labelled
(R) (Latin "rectus" = right), and if the sequence a→b→c is anticlockwise the molecule is
labelled (S) (Latin "sinister" = left).


                                                           b                         b
        b                       b
                                                           C                             d
        C                      d C                    c                              C
            c                                                   d
d                                                     a                         c            a
            a              a         c
                        (R)-configuration                                  (S)-configuration
                                                                                            E30-3



Using the Sequence Rule, label the four groups (a, b, c and d) attached to the stereogenic centre.
Hence assign (R) or (S) configurations to the following compounds.
              OH                           OH                                H

              C H                    H     C                         HO      C
 CH3CH2                                            CH2CH3                          CH2CH3
                   CH3               CH3                               CH3




• Construct a model of a 2-chloropropane molecule.

Identify a plane of symmetry in the molecule. Draw a three-dimensional representation of the
molecule and indicate the location of the plane of symmetry.




                                               C




• Construct a model which is a mirror image of 2-chloropropane and confirm that the molecule
  is superposable on its mirror image.
• Construct two models of a 2-chlorobutane molecule which are mirror images of each other.

Do the molecules contain a plane of symmetry?


Are the molecules superposable on each other?

Draw the three-dimensional representations of the molecules and indicate whether each
stereogenic centre is (R) or (S).




                     C                                                  C




N.B. If one of a pair of enantiomers has an (R) configuration, the other must possess the (S)
configuration. When drawing pairs of enantiomers, swapping the position of two groups
attached to the stereogenic centre will interconvert (R) and (S) configurations.

                                                                  Demonstrator’s
                                                                     Initials
E30-4



Molecules may contain more than one stereogenic centre, e.g.

       COOH                         COOH
    HO C* H                       H C* OH
     H C* OH                    HO C* H
          CH3                        CH3
Cyclic molecules may also contain one or more stereogenic centres. 2-chlorocyclobutanol, for
example, contains two stereogenic centres resulting in four possible stereoisomers.

• Construct models of the four possible isomers of 2-chlorocyclobutanol.

Confirm that none of the isomers is superposable on the others. Draw three-dimensional
representations of the molecules and label each stereogenic carbon centre either (R) or (S) as
appropriate. Indicate whether the isomers are cis or trans. Indicate the relationship of each
isomer to each of the others (e.g. A is an enantiomer of B; A is a diastereomer of C; etc.).



 H2C       C                C       CH2          H2C        C                C        CH2


 H2C       C                C       CH2          H2C        C                C        CH2

A                       B                       C                       D
                                Relationship between isomers:
A and B                                         B and C

A and C                                         B and D

A and D                                         C and D


                                                                 Demonstrator’s
                                                                    Initials



• Now break (i.e. remove) the C-C bond between the CH2 carbon atoms and replace it with
  one hydrogen on each carbon. This will convert the models of 2-chlorocyclobutanol into
  models of 3-chloro-2-butanol.
                                                                      CH3
                    H2C       C                                                   C
        "cut"
                              C                                                   C
                    H2C
                                                                      CH3
Confirm that none of the isomers, in any conformational form, is superposable on any of the
others isomers.
Draw three-dimensional representations of the molecules and label each stereogenic carbon as
either (R) or (S) as appropriate. Indicate the relationship of each isomer to each of the others
(e.g. A is an enantiomer of B; A is a diastereomer of C; etc.).
                                                                                         E30-5




A                         B                      C                       D
    CH3                                CH3           CH3                               CH3
             C                    C                         C                     C

             C                    C                         C                     C
    CH3                                CH3           CH3                               CH3

                                 Relationship between isomers:
A and B                                          B and C

A and C                                          B and D

A and D                                          C and D

                                                                 Demonstrator’s
                                                                    Initials


• Convert your four models of 3-chloro-2-butanol into models of 2,3-dichlorobutane by
  replacing all the OH groups with Cl atoms.

Two of your models should now be superposable (i.e. identical). This molecule is known as a
meso-isomer and you should have two models of it. Study these models carefully in order to
answer the following questions.

          Is meso-2,3-dichlorobutane superposable on its mirror image?

    How many stereogenic carbon atoms in meso-2,3-dichlorobutane?

             Does meso-2,3-dichlorobutane have a plane of symmetry?

Draw three-dimensional representations of the three different 2,3-dichlorobutane molecules and
label each stereogenic carbon as either (R) or (S) as appropriate. Indicate the relationship of
each isomer to the other two (e.g. A is an enantiomer of B; A is a diastereomer of C; etc.).
A                                B                               C
           CH3                                        CH3                 CH3
                    C                           C                                  C

                    C                           C                                  C
           CH3                                        CH3                 CH3

                                 Relationship between isomers:
            A and B                         A and C                          B and C



                                                                 Demonstrator’s
                                                                    Initials
E30-6



Optical Activity
In general, enantiomers have identical chemical properties. For example, they have the same
solubilities in water and common solvents. Just as when you try to place your hands in gloves,
right and left handed-molecules react differently to each other with other chiral molecules. All
enzymes in the body are chiral, as are the vast majority of biochemical molecules. The two
enantiomers of thalidomide therefore undergo different reactions within the body and have
different effects on it.

It is often important in the pharmaceutical industry to be able to produce only one enantiomer of
a pair. (This would not work in the case of thalidomide as the two enantiomers interconvert in
vivo). The chemical and physical similarities of enantiomers make them difficult to separate
and to identify. It can be very difficult, and hence expensive, to produce synthetic chiral
molecules from non-chiral starting materials. As living organisms often produce only one
enantiomer, natural products are the most important source of chiral molecules. The extraction
of natural products from plants, explored in E26 and E39, provides the starting point for many
pharmaceutical drugs. In some cases, both enantiomers can be found in Nature. The
(R) enantiomer of limonene, for example, can be extracted from citrus rind whilst the
(S) enantiomer can be extracted from pine resin.

•       The molecular structure of limonene is shown below. Identify the chiral centre and draw
        the (R) and (S) enantiomers in the box below.




Being able to identify which enantiomer of a compound, such as a drug, is present is clearly
important. Enantiomers differ in their optical activity - the ability to rotate the plane of
polarised light.

Normal light consists of waves vibrating in all planes perpendicular to the direction in which the
light is travelling. Filters such as calcite and PolaroidTM transmit light waves vibrating in
parallel planes. If this polarised light is passed through a second filter which is orientated at
right angles, no light can pass through and the image is black. If an optically active material is
placed between the plates, the plane of the light passing through the first one is rotated and the
image is no longer black. By rotating the second (or analysing) filter, the darkness is restored
and the angle required to do this is called the observed rotation.

If the analysing plate needs to be turned to the right (clockwise), the material is dextrorotatory
(from the Latin word dexter meaning ‘on the right side’). If it needs to be turned to the left
(anti-clockwise), the material is levorotatory (from the Latin word laevus meaning ‘on the left
side’).
                                                                                               E30-7




         light source                                                             α
                             polariser


                                               sample tube


                                                                       analyser       viewer
                        Figure 30-1: Schematic diagram of a polarimeter.

Using one of the polarimeter sets in your laboratory, set up the polarimeter following the
procedure described below. Figures 30.2 and 30.3 show views of the polarimeter from the side
and from the top.

(1.1) Remove the sample tube and turn on the light.
(1.2) Take the pair of polarising plates and put them together, with the plate with the line
      drawn on it on top. Hold the plates up to the light and rotate the bottom plate through
      360°. Also try turning each plate over. Find the angle and combination which lets the
      least light through - it should be almost black.
(1.3) Place the plates on the polarimeter with this orientation, making sure that the top plate is
      the one with the line on it. Position it on top of the scale with the line passing through
      zero (and 180) and the cross in the middle. Now make adjustments to the bottom plate so
      that the image is as black as possible.
(1.4) Place the sample tube containing acetone in the clamp. Looking down from the top,
      make minor adjustments to its position so that it is in the centre of the ring.
(1.5) Looking down from the top, rotate the top polarising plate and find the position which
      gives the darkest image. Be careful to keep the cross in the plate over the centre of the
      ring. Record the observed rotation in the box below.
(1.6) There should be two sample tubes containing the enantiomers of limonene with the
      polarimeter set. Make sure that they both have the same concentration.
(1.7) Using the same procedure used for acetone, record the observed rotation for each
      enantiomer. When doing this, it is very important to make sure that the bottom plate does
      not move. Make adjustments, as necessary, to the position of the tube and the top plate,
      ensuring that the cross is kept over the centre of the ring.
(1.8) Label your diagrams of the (R) and (S) enantiomers of limonene (on page E30-6)
      according to their optical activity. Use ‘(+)’ for dextrorotatory and ‘(-)’ for levorotatory.

What is the optical rotation of acetone?

Record the optical rotation, concentration and path length of both enantiomers of limonene.
E30-8




                                                       retort stand



              second polarising plate
              sitting on the ring                                        ring with scale
                                                                         attached to it
                                                                        clamp



                                                                       cell


               f irst polarising plate
               sitting on the ring                                        ring

        Powerpack                                                     light
                                leads


                            Figure 30.2: Side view of polarimeter.




                                                      180

        second polarising
        plate
                                                            scale                 cell

                                         270                             90




                                                        0

                            Figure 30.3: Top view of polarimeter.




                                                               Demonstrator’s
                                                                  Initials
                                                                                             E30-9



Stereochemistry and Chemical Reactions
Reaction at a Stereogenic Centre

Construct separate models of (R)-2-butanol and (S)-2-butanol. Confirm by examination of your
models that they are enantiomers - non-superposable mirror images.

What is the hybridisation of carbon 2 in 2-butanol?

What is the structure(s) of the product(s) when these alcohols are oxidised by an acidified
solution of potassium dichromate? Construct a model of the product. What is the most
appropriate stereochemical description ((R)-, (S)-, chiral or achiral) of the product in each case?

                                         (R)-2-butanol                     (S)-2-butanol



           Product of oxidation



  Stereochemical description

Keep your models to use in the next part.

Formation of a Stereogenic Centre

Examine your models of butanone constructed above.

What is the hybridisation of carbon 2 in butanone?

Place your model of 2-butanone on the desk with carbon 1 to your left and the oxygen atom
oriented away from you. Note that carbons 1, 2 and 3 and the oxygen atom are all in the same
plane, that there is a plane of symmetry through these atoms, and that the molecule is achiral.
The trigonal planar arrangement of these atoms is typical of the atoms adjacent to an sp2
hybridised centre.

Now consider the reaction of 2-butanone with the hydride ion, H , to produce 2-butanol. This
reaction proceeds via a nucleophilic addition as shown in the following mechanism.


                                                             O
                                                         H       H                             OH
       O                                       O                                     OH
       C                                CH3    C CH2CH3
CH3         CH2CH3                                                             CH3    C CH2CH3
                                               H                                     H
  H

The arrows represent the movement of electron pairs. The nucleophilic hydride ion attacks the
positively charged end of the polarised carbonyl group and causes the π-bond to break. As a
result, the hybridisation of carbon 2 changes from sp2 to sp3.
E30-10



When a nucleophile (N:) attacks an sp2 hybridised carbon to generate a tetrahedral sp3
hybridised carbon, the stereochemistry of the product is determined as shown below.
   N                                                                             Y                 X       Y
                                   N                                 X C                                    Z
         Y                                                                                             C
                                   C                                             Z
   X C                                  Y                                                              N
         Z                     X
                                       Z                            N
                                                                                                           (II)
                                            (I)

What is the stereochemical relationship between the products (I) and (II)?


Which enantiomer of 2-butanol will be formed if the H nucleophile
approaches from the top most side of your model?

Which enantiomer of 2-butanol will be formed if the H nucleophile
approaches from the underneath side of your model?

Statistically, what relative percentage of each
enantiomer would you expect to be produced
when this reaction is performed in the laboratory?

A 50/50 mixture of a pair of enantiomers is called a racemic mixture or a racemate.

Label the starting material and product as “chiral” or “achiral” and indicate the stereochemistry
of the products from the following reactions. Choose from (R)-enantiomer, (S)-enantiomer,
racemic mixture or achiral.
                   Starting Material                                         Product
                                                  Br2
                      CH3    CH CH2                           CH3       CH CH2         Br
                                                                        Br




         CH3       CH CH2      CH CH2             H2 / Pd      CH3       CH CH2          CH2 CH3
                   OH       (R)-enantiomer                               OH



                                                        2
             CH3    CH CH2      CH CH2            Cr2O7 / H     CH3          C CH2       CH CH2
                    OH      (S)-enantiomer                                   O




                                                   HCl
                     CH3    CH CH      CH3                    CH3       CH CH2         CH3
                                                                        Cl




                                                                             Demonstrator’s
                                                                                Initials
                                                                                        E30-11



Resolution of Enantiomeric Mixtures

• Construct two models of (R)-2-bromo-2-chloroacetic acid. Check that they are superposable.
  Using one of these models and your model of (R)-2-butanol as starting points, construct a
  model of the ester that would be formed from the reaction of these two compounds.
  (Remove the H from the alcohol and the OH from the acid.)

Draw the constitutional structure of the product, indicating all the stereogenic centres in the
molecule. Label all the stereogenic centres as either (R) or (S).




• Using your remaining (R)-2-bromo-2-chloroacetic acid model and your model of
  (S)-2-butanol as starting points construct a model of the ester that would be formed from the
  reaction of these two compounds.

Draw the constitutional structure of the product, indicating all the stereogenic centres in the
molecule. Label all the stereogenic centres as either (R) or (S).




Examine your two ester models.
Are they mirror images of each other?


Are they superposable on each other?


What is the stereochemical relationship of your two models?

How could a mixture of these two compounds be separated? What would be the significance of
effecting such a separation?




                                                               Demonstrator’s
                                                                  Initials
E30-12



FURTHER EXERCISES
                                                                                   3
The constitutional formula of 2-methylamino-1-phenyl-1-propanol is                 CH3
shown at the right. Complete the three-dimensional representations
                                                                                   2
of the four stereoisomers of 2-methylamino-1-phenyl-1-propanol.           HO   1
                                                                                       NHCH3




                 NHCH3                   NHCH3                    NHCH3                    NHCH3
         C   C                 C     C                 C      C                C       C




Indicate which of the isomers has the (1R,2S) configuration - this is ephedrine, used medicinally
as a bronchodilator for the treatment of asthma. Indicate which of the isomers has the (1S,2S)
configuration - this is pseudoephedrine, which has pharmacological properties quite distinct
from ephedrine, being used as a nasal decongestant.

What is the stereochemical relationship between
this pair of isomers?


Which isomer is the enantiomer of ephedrine?


Which isomer is the enantiomer of pseudoephedrine?

Would you expect two enantiomers to have similar pharmacological properties to each other?
Give reasons for your answer.
                                                                                    E30-13



Suggest a method by which a racemic mixture of ephedrine and its enantiomer may be resolved
into separate samples.




                                                             Demonstrator’s
                                                                Initials

				
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