E30 ENANTIOMERS Chirality in organic chemistry

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1 E30 ENANTIMERS hirality in organic chemistry TE TASK To investigate the nature of chirality in organic chemistry. TE 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. TER UTMES 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. INTRDUTIN 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. N N thalidomide 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

2 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 nonsuperposable 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 sp 3 hybridised carbon atom bearing four different substituents. Such an atom is known as a stereogenic centre. hiral molecules have no plane(s) of symmetry. Molecules can contain more than one stereogenic centre. LAB-WRK 20 2-Butanol is an example of a molecule containing one stereogenic centre (marked on the structures below with asterisks). * * onstruct 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 > l > > N 2 > 3 >. 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 -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). d b c a d a b c c a b d c b d a (R)-configuration (S)-configuration

3 E30-3 Using the Sequence Rule, label the four groups (a, b, c and d) attached to the stereogenic centre. ence assign (R) or (S) configurations to the following compounds onstruct 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. onstruct a model which is a mirror image of 2-chloropropane and confirm that the molecule is superposable on its mirror image. onstruct 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). 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.

4 E30-4 Molecules may contain more than one stereogenic centre, e.g. * * * * 3 3 yclic molecules may also contain one or more stereogenic centres. 2-chlorocyclobutanol, for example, contains two stereogenic centres resulting in four possible stereoisomers. onstruct models of the four possible isomers of 2-chlorocyclobutanol. onfirm 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 ; etc.) A B D Relationship between isomers: A and B B and A and B and D A and D and D Now break (i.e. remove) the - bond between the 2 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. "cut" onfirm 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 ; etc.).

5 E30-5 A B D A and B A and A and D Relationship between isomers: B and B and D and D onvert your four models of 3-chloro-2-butanol into models of 2,3-dichlorobutane by replacing all the groups with l 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? ow 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 ; etc.). A B Relationship between isomers: A and B A and B and

6 E30-6 ptical 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 Polaroid TM 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 ).

7 E30-7 light source polariser α sample tube Figure 30-1: Schematic diagram of a polarimeter. analyser viewer 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. old 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.

8 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 leads light Figure 30.2: Side view of polarimeter. 180 second polarising plate scale cell Figure 30.3: Top view of polarimeter. 0

9 E30-9 Stereochemistry and hemical Reactions Reaction at a Stereogenic entre onstruct separate models of (R)-2-butanol and (S)-2-butanol. onfirm 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? onstruct 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 entre 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 sp 2 hybridised centre. Now consider the reaction of 2-butanone with the hydride ion,, to produce 2-butanol. This reaction proceeds via a nucleophilic addition as shown in the following mechanism 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 sp 2 to sp 3.

10 E30-10 When a nucleophile (N:) attacks an sp 2 hybridised carbon to generate a tetrahedral sp 3 hybridised carbon, the stereochemistry of the product is determined as shown below. N X Y Z X N Y Z What is the stereochemical relationship between the products (I) and (II)? (I) N X Y Z X N Y Z (II) Which enantiomer of 2-butanol will be formed if the nucleophile approaches from the top most side of your model? Which enantiomer of 2-butanol will be formed if the 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. hoose from (R)-enantiomer, (S)-enantiomer, racemic mixture or achiral. Starting Material Product 3 2 Br Br Br / Pd 3 2 (R)-enantiomer r 2 7 / 2 (S)-enantiomer l l 3

11 E30-11 Resolution of Enantiomeric Mixtures onstruct two models of (R)-2-bromo-2-chloroacetic acid. heck 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 from the alcohol and the 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? ow could a mixture of these two compounds be separated? What would be the significance of effecting such a separation?

12 E30-12 FURTER EXERISES The constitutional formula of 2-methylamino-1-phenyl-1-propanol is shown at the right. omplete the three-dimensional representations of the four stereoisomers of 2-methylamino-1-phenyl-1-propanol N 3 N 3 N 3 N 3 N 3 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.

13 E30-13 Suggest a method by which a racemic mixture of ephedrine and its enantiomer may be resolved into separate samples.