Richard F. Daley and Sally J.

Daley
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Organic Chemistry
Chapter 11

Chirality
11.1 Symmetry and Asymmetry 11.2 Nomenclature of Stereocenters 11.3 Properties of Asymmetric Molecules Sidebar - Chiral Recognition 11.4 Optical Isomerism 546 11.5 Fisher Projections 549 11.6 Molecules with Two Stereocenters 11.7 Resolution of Enantiomers 11.8 Stereocenters Other than Carbon Key Ideas from Chapter 11 532 538 544 544

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Copyright 1996-2005 by Richard F. Daley & Sally J. Daley All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the copyright holder.

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Chapter 11

Stereochemistry
Chapter Outline
11.1 11.2 11.3 11.4 11.5 11.6 Symmetry and Asymmetry
Structural features that differentiate between symmetric and asymmetric molecules

Nomenclature of Stereocenters
Naming molecules with stereogenic centers

Properties of Asymmetric Molecules

The various properties of asymmetric molecules

Optical Activity
Optical activity as an indicator of an asymmetric molecule

Fischer Projections
Working with Fischer projections of asymmetric molecules

Molecules with Two Asymmetric Centers

A description of asymmetric molecules with two stereogenic centers

11.7 11.8

Resolution of Enantiomers
Chemical separation of enantiomers from a racemic mixture

Asymmetric Centers Other than Carbon

Stereogenic centers involving atoms other than carbon

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Objectives
Be able to find molecules that are asymmetric and recognize if any stereogenic centers are present Understand that nonsuperimposible mirror image compounds have identical physical and chemical properties in a symmetric environment, but are different in an asymmetric environment Know the nomenclature of stereogenic centers Be able to work with Fischer projections of stereogenic centers Know the difference between enantiomers and diastereomers Recognize the techniques used to separate enantiomers

Th' wurruld has held a lookin'-glass in front iv ye fr'm th' day ye were born an' compelled ye to make faces in it. Finley Peter Dunne Mr. Dooley Says (1910)

hapter 11 continues the study begun in Chapter 3 of the three-dimensional structural features of molecules. This study, known as stereochemistry, is important because the way molecules react with each other depends, in part, on their threedimensional structure. The chemical reactions discussed in Chapter 12, and onward, require an understanding of the stereochemistry of the molecules. Stereochemistry is especially important with biologically significant molecules such as amino acids, proteins, carbohydrates, and nucleic acids because they react and behave in ways highly dependent on their stereochemistry. So far, you have studied two categories of isomers: structural isomers and geometric isomers. Structural isomers differ from each other in the bonding sequences of the atoms they contain. Butane and 2-methylpropane are examples of structural isomers. Geometric isomers have identical bond sequences, but the spatial relationship between those bonds is different. For example, cis-2-butene and trans2-butene are geometric isomers. This chapter introduces a third type of isomer called stereoisomers. Stereoisomers are molecules that have the same bond sequence, but different three-dimensional structures. If you have not yet developed the ability to visualize complex objects in three-dimensions from a two-dimensional representation,

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make molecular models of the examples. Using molecular models helps to clarify the molecular relationships discussed in this chapter.

11.1 Symmetry and Asymmetry

A symmetric molecule can be superimposed on its mirror image. An asymmetric molecule cannot be superimposed on its mirror image.

All three-dimensional objects are either symmetric or asymmetric. When the structure of an object allows you to superimpose it upon its mirror image, that object is symmetric, or identical, to its mirror image. The rectangular box on the left in Figure 11.1 is superimposible upon its mirror image, so the box is symmetric. However, if you take the same box and paint an X in one corner, you can no longer superimpose it on its mirror image. The box is then asymmetric. Note that the difficulty in superimposing the box with the X onto its mirror image is the impossibility of placing one X on top of the other X.

Mirrors

Figure 11.1. The box on the left is superimposible on its mirror image. Painting an X in one corner, as shown on the right, makes the box nonsuperimposible on its mirror image.

A molecule possesses chirality if it cannot be superimposed on its mirror image.

The nonsuperimposibility characteristic of an object upon its mirror image, a trait common to all asymmetric objects, is called chirality. The term chiral comes from the Latin word chiro or chir that means hand or handedness. The most obvious example of chirality is your own hands. Examine them. A typical human hand has four fingers and a thumb. Although all hands have these same basic structural components, hands are asymmetric. That is, a left hand is a nonsuperimposible mirror image of a right hand. Placing your palms together makes this mirror image relationship clearly visible. Many other common objects also have chirality: golf clubs, the threaded base of a light bulb, shoes, and even this book.

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A plane of symmetry is an internal mirror plane.

As with all other three-dimensional objects, organic molecules are either symmetric or asymmetric. A way to determine whether a particular molecule is symmetric or asymmetric is to determine whether the molecule contains a plane of symmetry. If there is a plane of symmetry, then the molecule is symmetric. If there is no plane of symmetry, then the molecule is asymmetric. A plane of symmetry bisects the molecule into two halves that are exact mirror images of each other. Ethyne (or acetylene) contains an infinite number of planes of symmetry. Figure 11.2 shows three of those planes of symmetry, but make a molecular model to help yourself visualize them.

Figure 11.2. Acetylene has an infinite number of planes of symmetry.

Other symmetric molecules have only one or two planes of symmetry. Molecules with a C=C or a C=O double bond have at least one and often two planes of symmetry. Because these functional groups are planar, they impart only symmetry, never asymmetry, to a molecule. However, other portions of the molecule may make a molecule with a double bond or carbonyl group asymmetric. Make a molecular model of propene (Figure 11.3). Rotate the methyl group until you place one of the hydrogens in the same plane as the three hydrogens bonded to the double bonded carbons. Hold the molecule so you are looking at this plane. Notice that the plane bisects all four hydrogens within the plane and that the other two hydrogens are identical mirror images of each other giving the whole molecule a plane of symmetry. This plane is the only plane of symmetry in propene.

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Plane of symmetry H H C H C CH3

Figure 11.3. Propene has a single plane of symmetry.

Optical isomers are molecules that rotate a plane of polarized light in opposite directions (see Section 11.3). A center of symmetry is a point in a molecule from which drawing two lines 180o apart will find the same molecular features.

Some stereoisomers lack a plane of symmetry. Without a plane of symmetry, mirror image molecules cannot be superimposed on each other. Molecules that have nonsuperimposible mirror images are called optical isomers. Molecules can be symmetric about a point instead of a plane. These points, called centers of symmetry, are usually found in cyclic molecules. However, even with acyclic molecules, check first to see if it has a plane of symmetry. If it does not, then check for a center of symmetry. To determine whether or not a molecule has a center of symmetry, draw a line from each substituent on the ring through the center of the ring to the substituent opposite it. If the two substituents on either end of each line are identical, then the molecule has a center of symmetry and is symmetric. This concept is illustrated by trans-1,3dibromo-trans-2,4-dimethylcyclobutane in Figure 11.4. Make a model and see for yourself. Check for a center of symmetry by connecting all substituents on the two carbons on opposite sides of the ring. If, in this example, you could not connect both hydrogens and both bromines with a line, then this molecule would not have a center of symmetry.
CH3 H Br CH3
Figure 11.4. Center of symmetry in trans-1,3-dibromo-trans-2,4-dimethylcyclobutane.

Br H

Exercise 11.1 Show any planes of symmetry that you find in the following molecules. a) cis-1,2-Dimethylcyclopropane b) 1-Methylcyclohexanol

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c) Spiro[4.3]octane d) trans-Decalin Sample Solution b) 1-Methylcyclohexanol has one plane of symmetry that bisects the OH and CH3 groups on C-1 as well as C-1 and C-4.
OH CH3

Plane of symmetry

An enantiomer is one of a pair of nonsuperimposible mirror image molecules.

Molecular asymmetry is the result of a molecules shape.

An organic molecule without a plane of symmetry or center of symmetry is asymmetric. A characteristic of all asymmetric molecules is that they possess chirality. That is, for that molecule there exists a nonsuperimposible mirror image molecule. All chiral, or asymmetric, molecules occur in pairs with a right hand and a left hand molecule. Each member of the pair is called an enantiomer. For example, there are two enantiomers of 2,3-pentadiene. To confirm this, make a model of Figure 11.5 and then another of its mirror image. As you examine these two stereoisomers, note that they do not have a plane of symmetry and that you cannot superimpose one molecule upon the other. Their asymmetry is due to their shape, or molecular asymmetry.
H C CH3 C C

H CH3

Figure 11.5. 2,3-Pentadiene is an example of a chiral molecule that does not have a plane or center of symmetry.

A stereogenic center is a specific atom in a molecule that is responsible for some or all of the molecular asymmetry.

Although all chiral molecules have molecular asymmetry, many asymmetric molecules have a stereogenic center or, more specifically, an asymmetric carbon atom. An asymmetric carbon atom is often called a stereocenter. An asymmetric carbon atom is bonded to four nonequivalent substituents. This asymmetry is a property allowed by the tetrahedral structure of a carbon atom.

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A symmetrical molecule has no stereogenic centers and has an internal plane or center of symmetry.

Examining the symmetric properties of the tetrahedral carbon atom will help you understand a stereogenic center. For example, make a molecular model of dibromomethane (Figure 11.6) which is a carbon atom with two pairs of equivalent substituents. Notice that the molecule contains two planes of symmetry. One bisects the carbon atom and lies between the two bromine atoms; the other also bisects the carbon atom, but it lies between the hydrogen atoms. The portions of the molecule on either side of either plane of symmetry are mirror reflections of each other. Construct the mirror image of dibromomethane. Notice that the two are superimposible. That is, dibromomethane is symmetrical.
Planes of symmetry

H C H

Br Br Br

H C H Br

Figure 11.6. Planes of symmetry in dibromomethane.

Now substitute chlorine for one of the bromines and fluorine for one of the hydrogens. The name of the new molecule is bromochlorofluoromethane (Figure 11.7).

H C F

H Cl Br Br C F Cl

Figure 11.7. Two different three-dimensional representations of the same enantiomer of bromochlorofluoromethane. This molecule has no plane of symmetry.

With four different substituents attached to one carbon atom, bromochlorofluoromethane contains no element of symmetry whatsoever. The molecule is asymmetric. Because the molecule is asymmetric, a nonsuperimposible mirror image molecule of bromochlorofluoromethane exists as its enantiomer. Convince yourself that the mirror image molecules of bromochlorofluoromethane are not identical structures by trying to superimpose one model on the other. Orient the two enantiomers into a mirror image position and slide them together placing the hydrogen

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and the fluorine together. As you move the two structures together to superimpose them, note that the bromine and the chlorine point in opposite directions. Next flip the molecules so that the bromine and chlorine are lined up, but now the hydrogen and fluorine point in opposite directions. No matter how you twist, slide or turn the structures, you cannot obtain an overlap of the two isomers. You can make any two of the atoms coincide, but then the other two do not. The structures are asymmetric because they are nonsuperimposible.
Mirror plane H C F Cl Br Cl Br H C F

Mirror images of bromochlorofluoromethane

H H

Cl Br C C F F Br Cl

Attempting to superimpose the enantiomers of bromochlorofluoromethane

Exercise 11.2 Construct each of the following molecules and its mirror image. Then determine whether one is superimposible upon the other. a)
H3C C H CH3 CH2Cl HO CH3

b)

c)
OH

d)
CH3

CH3

e)
H C Br CH3 CH2Cl

f)
CH3 CH3

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Sample solution a) The molecule is symmetrical; therefore the mirror images are superimposible. A plane of symmetry exists between the two methyl groups.
CH3 C H CH2 Cl CH3

11.2 Nomenclature of Stereocenters

After examining several pairs of enantiomers in Section 11.1, you should now know that the structure of each enantiomer within a pair is different. However, based on the rules of nomenclature in Chapter 2, they have the same name. Although the basic name of the two enantiomers is indeed the same, you need a way to differentiate between the two. The most widely accepted procedure, also adopted by the IUPAC committee, is the Cahn-Ingold-Prelog convention. This method designates each stereocenter with a letter, either (R) or (S). To determine whether to use an (R) or an (S) follows this three-step procedure. Step 1 Assign a priority number to each atom, or group of atoms, bonded to the stereocenter. Step 2 Redraw the structure using the Wedge and Dash method. Orient the lowest priority group away from you and the other three groups in the plane of the paper. Step 3 Then draw an arrow from the first priority group, past the second towards the third. If the arrow circles clockwise, call the stereocenter atom (R) (rectus, Latin for right-handed). If the arrow circles counterclockwise, call the stereocenter atom (S) (sinister, Latin for left-handed). To determine the priority numbers, look at the atomic number of the four atomsthe higher the atomic number, the higher the priority number. For example, bromochlorofluoromethane has a Br, Cl, F, and H attached to the carbon. Assign the highest priority number, 1, to Br, as its atomic number is 35. The next priority

The Cahn-IngoldPrelog convention is a method of designating the placement of groups about a stereogenic center.

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number, 2, goes to Cl, which has an atomic number of 17. Then comes F, priority number 3, with an atomic number of 9, and finally H, priority number 4, with an atomic number of 1. If the atoms are different isotopes of the same element, prioritize them according to atomic weight, giving the heaviest isotope the highest priority number. For example, tritium (3H) comes before deuterium (2H), which comes before hydrogen (1H). If there is a tie, use the atoms bonded to the tied atoms to determine which gets the higher priority number. For example, consider a stereogenic carbon attached to an isopropyl (CH(CH3)2) group and an ethyl (CH2CH3) group. Before going any further, make a molecular model. For the other two groups attached to the stereocenter, use any two different atoms (H and Br, for example). The name of such a molecule is 3-bromo-2-methylpentane. Br and H get priority numbers 1 and 4 respectively, but because the other two groups begin with a carbon, there is a tie for numbers 2 and 3. To break the tie, you must compare the atomic numbers of the other atoms attached to each of the two carbons. The first carbon of the ethyl group is bonded to two hydrogens and one other carbon. In the isopropyl group, the first carbon is bonded to one hydrogen and two other carbons. Thus, the isopropyl group has the higher priority because it has two other carbons in contrast to only one other carbon in the ethyl group. When considering groups bonded to a stereogenic carbon in a cyclic compound, start one group with the atom immediately to the right of the stereocenter and start another group with the atom immediately to the left of the stereocenter. In the case of a tie in a cyclic compound, continue around the ring until you find a difference. In the example below, the first point of difference is the direction around the ring that comes to the double bond first.
First point of difference 1 2 OH CH3 3

To determine the priority number of atoms involved in a double or triple bond, treat the multiple bond as if it were broken into the corresponding number of single bonds with the atoms at each end of the multiple bond doubled or tripled.

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H C C H

H C C H,
C C H

Thus,
C

becomes

C C

C C C H , and

H C O becomes

H C O O . Thus, for C

becomes

C C

example, a carbon double bonded to another carbon is considered as though it was bonded to two carbons After you have determined the priority of the groups label the group with the highest priority atom 1. The group with the next highest priority label 2, the group with the third highest priority label 3, and the group with the lowest priority label 4. Finally, draw the molecule with the lowest priority group back and the other three groups in front of the plane of the paper.
1 C 2 3 4

When the molecule is drawn with this orientation, add a curved arrow pointing from number 1, past number 2, and on to number 3.
1 C 2 3 4

If the curved arrow is clockwise, the isomer drawn is the (R) isomer. If the arrow curves counterclockwise the isomer is the (S) isomer. The amino acid serine has one stereocenter with NH2, CH2OH, COOH, and H bonded to it. The highest priority group is the NH2 group because nitrogen has the highest atomic number. The carboxylic acid comes next because it has two oxygens, with one of them doubly bonded to carbon. The CH2OH is third with only one oxygen. Last is the hydrogen because it has the lowest atomic number. The figure below shows the two enantiomers of serine, the naturally occurring serine on the left and the synthesized serine on the right. The structure of the naturally occurring serine molecule is (S); the structure of the synthesized serine is (R).

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HOOC C HOH2C H NH2 H H2N C

COOH CH2OH

Natural serine

Synthetic serine

Some groups bonded to a stereocenter carbon are long chains. To determine whether the stereocenter is (R) or (S), continue searching along these chains away from the stereocenter to the first difference between similar chains. Give the chains their priority numbers according to this difference.
Solved Exercise 11.1 Determine whether the following molecule has any stereogenic centers. Mark all asymmetric carbon atoms and determine whether they have an (R) or (S) configuration.

Cl CH3

OH
Solution This molecule has three stereogenic carbon atoms. The carbon bearing the OH group, the one bearing the Cl and the one bearing the CHClCH3 group. These three are starred in the following structure.

Cl * * H * OH
The carbon atom bearing the CHClCH3 has an (R) configuration.

CH3

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Cl CH3

R
OH
You need to rotate the bond between the six-membered ring and the carbon bearing the Cl group. Doing so helps to see that the atom has an (R) configuration.
H Cl H H CH3 CH3 H

R
OH OH

Cl

The carbon bearing the OH group also has an (R) configuration. Flipping the molecule 180o helps to more clearly see the configuration of this carbon atom.
Cl H3C

R
HO H (R,R,R)-3-(1-Chloroethyl)cyclohexanol

Exercise 11.3 For each of the following examples, identify any stereogenic carbon atoms, and then determine whether they have (R) or (S) configurations. a)
H3C C H OH CH2CH3

b)
CH3CH2 C Br CH3 H

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c)
H CH3 H CH3 CH3

d)
Cl

Cl

e)
Cl

f)
O

g)

h)
O

OH H

CH3

Sample solution b) Assign the priority to the four groups this way.
2 CH3CH2 3 CH3

C
1

Br

Then redraw with the lowest priority group back. This structure has an (S) configuration because the arrow curves counterclockwise. The molecule is (S)-2-bromobutane.
3 CH3

Br 1

CH2CH3 2

11.3 Properties of Asymmetric Molecules

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A chiral probe is a technique that uses an instrument or chemical compound to distinguish between individual enantiomers. The chiral probe must be chiral in some fashion. A polarimeter is an instrument that measures the number of degrees a molecule turns a plane of polarized light.

An enzyme is a large chiral molecule consisting of chiral amino acids, such as serine (page 000), with chiral reactive sites.

Most of the physical properties of both pure enantiomers are identical. For example, both molecules have identical melting points, boiling points, densities, NMR, IR, MS, and indexes of refraction. They do differ, however, in two significant ways. 1) Both enantiomers of a pair rotate a plane of polarized light and rotate it the same number of degrees, but they rotate the light in opposite directions: one clockwise and the other counterclockwise. Thus, they are called optical isomers. 2) Each enantiomer of a pair reacts in an individual way in an asymmetric chemical environment to form another asymmetric compound. Because of their identical physical properties, the only way to distinguish between enantiomers is by using a chiral probe. Polarimeters are chiral probes, as are chiral, or asymmetric, molecules. The two molecules in a pair of enantiomers react differently from each other with another asymmetric compound because of the molecular asymmetry of the pair of enantiomers. Reactions take place when two different molecules physically come in contact with each other. Thus, their shapes determine how they fit together and how or, in some cases, whether or not they will react with each other. Your hands represent a very simplistic example of this principle. As mentioned previously, your hands are chiral objects, so let them represent a pair of enantiomers. React that pair of enantiomers with a symmetric compound, represented by a pair of green flat mittens. Because both mittens will easily fit on either hand, they illustrate how two enantiomers react in the same way with a symmetric compound. Now suppose you react a pair of enantiomers with a pair of asymmetric compounds represented by one red mitten and one green mitten. In this case, either mitten can fit on either hand, but the right hand wearing the green mitten is different than when it is wearing the red mitten. There are four possible combinations with a red or green mitten on the left or right hands. To extend this example further, replace the mittens with gloves. In this case, the right glove fits only on your right hand, and the left glove fits only on your left hand. An example of a glove-like compound is an enzyme. Enzymes catalyze the reactions that take place within the cells of your body and in all other living organisms. Each enzyme is specifically shaped and fits only with the correspondingly shaped enantiomer making up the nutrients from the food you eat, the medicines you take, or the hormones your body produces. This situation is analogous to fitting your hand into a glove. Because the reaction takes place during the time the enzyme and the enantiomer are fitted together, the two won't react if they don't fit.

SIDEBARChiral Recognition

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Open a jar of spearmint oil. Smell it. Then taste it. Next, do the same with a container of caraway seed. As you can observe, their odor and taste are very different. However, the principal component for the flavor and odor of both are enantiomers of each other. (R)-carvone is the principal component of spearmint oil. Its enantiomer, (S)-carvone, is the principal component of caraway oil. The only difference between the two enantiomers is the arrangement of their atoms in space.
CH3 O O CH3

CH3

CH2

CH3

CH2

(R)-Carvone

(S)-Carvone

The distinctive odor of each is the result of the odor receptors in the nose that appear to be based on chiral receptor sites. Thus, the nose perceives odors based on the fit of the odor-causing molecule into the receptor sites located in the nose. This behavior is similar to fitting a key into a lockonly the key designed for a specific lock fits. Likewise, the odor-causing enantiomers fit only into the appropriately shaped odor receptors in the nose. Therefore, (R)-carvone fits into a different receptor than does its enantiomer, (S)-carvone. Biological systems commonly exhibit high levels of chiral recognition. Chiral recognition takes place when a chiral receptor or reagent interacts specifically with one enantiomer of a chiral molecule. A striking example of chiral recognition occurred with the drug thalidomide, a sedative and mild hypnotic introduced to the European marketplace in 1956.
O N H O
Thalidomide

O NH O

Immediately, thalidomide became popular with pregnant women to control morning sickness because, even in large doses, it was not

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lethal and testing had indicated no undesirable side effects. At about the same time, however, the number of congenitally deformed babies increased. The most seriously deformed babies were born with phocomelia, or seal limbs. That is, they either had no limbs or had shortened ones causing the hands and feet to grow close to the body. Other serious defects included absent or malformed external ears, fusion defects of the eye, and the absence of the normal gastrointestinal tract openings. After five years, medical researchers finally traced the problem to the use of thalidomide during the first three months of pregnancy, and thalidomide was removed from the market. Thalidomide had been tested, so what happened to cause this problem? True, the (R) isomer of thalidomide, the medically effective isomer, was made in a laboratory and was tested for negative side effects, and there were none. However, when manufactured under production conditions, the reaction temperature was increased to speed up the reaction time, thus producing a mixture of the (R) and (S) isomers. This was discovered later through more testing along with the fact that the (S) isomer of thalidomide was a teratogen. A teratogen is a chemical substance that causes birth defects. Not all babies whose mothers took thalidomide were born with defects, however. The fetus was susceptible only at specific points in the first three months of its development. Therefore, if the mother did not use the drug at those specific points, there were no problems. If just the pure (R) isomer of thalidomide had been manufactured and ingested, thousands of babies would not have been born deformed.

11.4 Optical Isomerism

One way to differentiate between the two enantiomers in a pair of enantiomers is to observe the differences in how they react with another asymmetric compound. Another way is to contrast their interactions with a plane of polarized light. With ordinary light, the light waves vibrate at all angles in an infinite number of planes of vibration. Passing ordinary light through some polarizing material allows only one of these orientations to pass through. This light is plane-polarized light. See Figure 11.8.

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Slit

Polarizer

Lamp

Cross section of light beam

Figure 11.8. Polarization of a light beam. Before passing through the polarizing filter, the light beam has random orientations of the light waves. After passing through the polarizing filter, the light beam contains only one orientation of the light waves. A polarimeter is an instrument that measures optical activity.

An optically active substance rotates a plane of polarized light. A dextrorotatory isomer rotates a plane of polarized light clockwise or to the right. A levorotatory substance rotates the polarized light counterclockwise or to the left.

If you pass this plane-polarized light through a polarimeter containing a solution of a pure enantiomer, the plane of polarization visibly rotates a certain number of degrees. If you place a solution of the other enantiomer with the same concentration in the same instrument, the plane of polarized light rotates the same number of degrees in the opposite direction. The amount of rotation stays constant for a given pair of enantiomers with the same concentration, using polarimeters of the same wavelength of light and the same tube length. Substances that exhibit this type of behavior are optically active, and the number of degrees that the plane of polarized light rotates is a measure of optical activity. An enantiomer that rotates light clockwise, as you look toward the light source is dextrorotatory. Designate a dextrorotatory enantiomer as a d or (+) isomer. An enantiomer that rotates light counterclockwise is levorotatory. Designate a levorotatory enantiomer as an l or () isomer. For example, the d form of 2bromobutane has a rotation of +39.4o when you measure it with the 589 nm wavelength band of a sodium vapor lamp. This wavelength is called the sodium D line. Its enantiomer, l-2-bromobutane, has a rotation of 39.4o. Remember, there is no connection between the d or l isomers and the (R) and (S) designations. The d or l designation comes from the experimental observation of the sign of the optical rotation and the (R) or (S) designation comes from the Cahn-Ingold-Prelog rules.

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Specific rotation is how much a plane of polarized light rotates under certain conditions.

The normalized measurement of the optical activity of an optical isomer is called its specific rotation. Normalization is necessary to provide a constant measurement of a molecule's optical activity because not all polarimeters use the same tube length and different concentrations of the isomers are used. The specific rotation of a molecule is a physical property of that molecule; thus, its measurement is always the same. The symbol used to indicate specific rotation is [] . The [] is the specific rotation, the T is the temperature of the solution, and the is the wavelength of light being used. Use the following expression to calculate the specific rotation of a molecule: [] T [] = l [X] Where [] is the observed rotation, l is the length of the tube in decimeters (1 dm = 10 cm), and [X] is the concentration of the solute in g/mL. Although [] is the term used for specific rotation, another symbol commonly used is []D. This symbol indicates the sodium D line as the light source at a temperature of 25oC. Exercise 11.4 Researchers isolated a pure enantiomer of an unknown chemical structure from a rare flower. They then dissolved it in chloroform at a concentration of 0.22 g/mL. When they placed the mixture in a polarimeter, it gave a rotation of +2.697o in a 1 dm cell using the sodium D line. Calculate the value of []D. An equimolar mixture of two enantiomers has no effect on a plane of polarized light because the two isomers have an identical but opposite effect on the plane of polarized light. An equal mixture of a pair of enantiomers is called a racemic mixture, or a racemate. When doing a chemical reaction that produces a molecule with a stereocenter using symmetrical materials, you always obtain a racemic mixture of the product. In other words, you cannot produce asymmetric compounds directly from symmetric starting materials. For example, reacting phenyl magnesium bromide with 2-butanone produces racemic 2-phenyl-2-butanol.
T T

A racemic mixture, or racemate, is a mixture containing equal amounts of both enantiomers.

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MgBr O 1) 2) H3O OH Racemic 2-phenyl-2-butanol HO +

Exercise 11.5 A series of solutions contains mixtures of the two enantiomers of 2bromobutane. The specific rotations for these compounds are +39.4o for the d isomer and 39.4o for the l isomer. Calculate the observed rotations of [] using a 1 dm cell at 25oC for each of the following solutions. a) 0.1 g/mL of d and 0.1 g/mL of l b) 0.01 g/mL of d and 0.1 g/mL of l c) 0.5 g/mL of d and 0.3 g/mL of l d) 1.0 g/mL of d and 1.5 g/mL of l Sample solution b) The rotation of the d isomer is = 39.4o x 1 x 0.01 = 0.394o For the l isomer, the rotation is = 39.4o x 1 x 0.1 = 3.94o Because the observed rotation would be the sum of the two, then = 0.394o + (3.94o) = 3.55o

11.5 Fischer Projections

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To this point, you have used only the wedge-and-dash structures to indicate a three-dimensional perspective when drawing molecules. As the complexity of the molecules you study increases, these drawings will become more difficult to understand and more time consuming to draw. Similarities and differences between complex stereoisomers are difficult to see with the wedge-and-dash stereochemical drawings. Around 1900, as Emil Fischer studied the stereochemistry of sugars that contain up to seven stereocenters each, he began developing a simple way to represent these complex molecules so he could draw them more rapidly. Later, Victor Meyer worked to simplify Fischer's method of drawing molecules. This method of representing molecules is called Fischer projections. Fischer projections also facilitate the comparison of stereoisomers by emphasizing the differences in the complex stereochemistry of enantiomers with more than one stereocenter. Fischer projections use perpendicular lines to represent a stereocenter. The point where the lines intersect represents the asymmetric carbon. The horizontal lines represent the bonds that project forward, and the vertical lines represent the bonds that project backward. For example, to convert a wedge-and-dash representation of (R)-bromochlorofluoromethane to a Fischer projection begin by making a model to help yourself visualize the conversion. Rotate the model until the atoms projecting back in the wedge-and-dash representation, the hydrogen and the fluorine, are in the vertical positions, as in Figure 11.8, and the atoms projecting forward, the bromine and the chlorine, are in the horizontal positions. (The center drawing shows why this representation is sometimes called the bow tie representation.) Replace the wedges and dashes with a pair of perpendicular lines.

H Br C Cl F Br

H Cl F
Fischer projection

C Cl Br F

Wedge-and-dash projections

Figure 11.8. Converting a wedge-and-dash structure to a Fischer projection. The Fischer projection uses perpendicular lines to represent a stereogenic carbon atom. The horizontal lines project toward the viewer, and the vertical lines project away from the viewer.

When working with a Fischer projection, you may rotate the projection 180o in the plane of the paper because the vertical (dashed) lines are still vertical and the horizontal (wedge) lines are still horizontal.

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CHO H C OH H

CHO OH CH2OH Rotate 180o HO

CH2OH H CHO HO

CH2OH C H

CH2OH

CHO

However, rotating the projection by 90o is NOT allowed, as it changes the configuration of the projection. A 90o rotation no longer fits the convention of horizontal lines forward and vertical lines backward. A 90o rotation reverses this convention.
CHO H C OH H CHO OH CH2OH Rotate HOH2C 90o OH H CHO / HOH2C H C OH CHO

CH2OH

You may not turn the figure over, because this also gives an incorrect representation of the structure.
CHO H C OH H CHO OH CH2OH Flip HO CHO H CH2OH / HO CHO C H

CH2OH

CH2OH

Both the 90o rotation and flip operations drawn above actually are drawing the enantiomers of the initial structures. When drawing a longer chain with the stereocenter in the middle of a chain, the convention is to arrange the chain vertically with the longer part of the chain at the bottom of the structure.
CH3 H C OH H CH3 OH CH2CH3
Not CH3 OH H CH2CH3

CH2CH3
Solved Exercise 11.2

Consider the following pairs of Fischer projections. What operation was done to go from one projection to another: flip or rotate 90o, 180o, or 270 o. Are the two structures the same molecule or are they enantiomers? a)

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CH3 H Br CH2CH3 (S)-2-Bromobutane ? CH3CH2

H CH3 Br

Solution The structure on the right is rotated clockwise by 90o compared to the structure on the left. Converting the structure on the right to a threedimensional structure shows it is (R)-2-bromobutane. Thus, they are enantiomers.

H CH3CH2 Br CH3 CH3CH2

H CH3 Br (R)-2-Bromobutane

b)
CH2CH3 Br CH CH3 CH2 ? H3C Br CH2CH3 CH CH2

(R)-3-Bromo-3methyl-1-pentene

Solution This molecule is rotated 180o and thus the two Fischer projections are identical.

Exercise 11.6 For each of the following sets of structures, state how the first structure relates to each of the following structures in the set. Make models to help yourself. The relationships may include being the same compound, a structural isomer, or an enantiomer. a)
CH3 H NH2 COOH H
NH2

CH3 COOH
NH2

COOH H CH3 H

COOH
NH2

CH3

b)

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C OOH H OH C H3 H3C

H C OOH OH C H2 C H3 Cl H C H3
CH3 H CH2CH3 H OCH3

C H3 H OH C OOH C H3 H Cl C H2 C H3
CH3 OCH2CH3 CH3 H

C OOH H3 C H C H2C H3 H Cl C H3
CH2CH3 CH3 OCH3

OH

c)
C H3 Cl H C H2C H3

d)
OCH3 H CH3 CH2CH3

Sample Solution a) The first and second structures are enantiomers, the first and third are identical, and the first and fourth are enantiomers.

11.6 Molecules with Two Stereocenters

The atoms in stereoisomers bond in the same sequence but have different spatial arrangements. Enantiomers are stereoisomers that are mirror images of each other. All stereoisomers that are not enantiomers are diastereomers. When a molecule contains more than one stereocenter, its stereoisomers exist in pairs that exhibit an enantiomeric relationship; that is, they are mirror images of each other. They also exist in pairs that exhibit a diastereomeric relationship. That is, they are not mirror images of each other. Consider the following two structures of 3-chloro-2-butanol.
CH3 H H CH3 OH Cl H Cl CH3 CH3 OH H

Diastereomers are stereoisomers that are not mirror images of each other.

To follow this discussion, make molecular models of the two structures shown above. In these structures, both C2 and C3 are stereocenters. The atoms making up these two molecules have the same bonding order yet are different in their spatial arrangement, therefore they are

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stereoisomers. They are not enantiomers, however, because they are not mirror images of each other. C2 has an (S) configuration in both structures, and C3 has an (R) configuration in the structure on the left and an (S) configuration on the right. Carbon C3 has a mirror image relationship in the molecules, but C2 does not. Because these two molecules are stereoisomers, but they do not have a mirror-image relationship, they are diastereomers. Both diastereomers are stereogenic, and each has an enantiomer giving a total of four stereoisomeric 3-chloro-2-butanols. To help visualize this, make molecular models of the two mirror-image molecules.
CH3 H H CH3 OH HO Cl Cl CH3 CH3 H H H Cl CH3 CH3 OH H HO H CH3 CH3 H Cl

With the 2n rule you can calculate the maximum possible number of stereoisomers with n stereogenic centers.

You now have two pairs of enantiomers, and either member of one pair of enantiomers is a diastereomer of both members of the other pair. Because each stereocenter can have the atoms in an (R) or an (S) configuration arrangement, a molecule with n stereocenters has 2n possible stereoisomers. This rule, called the 2n rule, allows you to calculate the maximum number of stereoisomers possible for a molecule. However, not all molecules have this maximum number of stereoisomers. 2,3-Butanediol, for example, does not. It has two stereocenters, C2 and C3 and, according to the 2n rule, it should have four stereoisomers.
CH3 H H CH3 OH HO OH HO CH3 CH3 H H H HO CH3 CH3 OH H HO H CH3 CH3 H OH

However, if you draw all four of the isomers, or make molecular models of them, you will find that the apparent enantiomeric pair on the left above is actually different representations of the same molecule. (Remember that rotating a Fischer projection 180o in the plane of the page is acceptable.)

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CH3 H H CH3 OH OH HO HO

CH3 H H CH3
Rotate 180o H in the plane of the page

CH3 OH OH

Apparent pair of enantiomers

CH3 Identical to the structure on the left.

These two structures are the same because there is an internal plane of symmetry in the Fischer projection. This internal plane of symmetry reflects one half onto the other half. The molecule has two stereogenic centers: one is (R) and the other is (S). It is almost as if the molecule were a racemic mixture within itself.
CH3 H H CH3 OH OH
Internal plane of symmetry

A meso compound contains stereogenic centers and an internal plane of symmetry.

Compounds, such as 2,3-butanediol, which exhibit an internal plane of symmetry and are symmetrical, even though they have stereocenters, are called meso compounds. Meso compounds are symmetric structures with the two halves of the molecule having identical substituents, but opposite configurations. The symmetric diastereomer is called the meso diastereomer. A meso compound is an example of a compound with stereogenic centers, but does not exhibit optical activity. The compounds that are diastereomers of the meso compound and are enantiomers of each other are called the () or dl pair. Exercise 11.7 For the following compounds mark any stereocenters and determine whether they are (R) or (S). Mark any meso compounds. Determine which are optically active. a)
C H3 H Br Cl H C H3
C H3

b)
C H3

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c)
H3 C C H3

d)

OH

OH

e)
C H3 H H HO HO C H3 OH OH H H

f)
Br

Cl

Sample Solution b) Redraw the structure as a Fischer projection using your models to help you see the transformation.

CH3 CH3

H Plane of symmetry H

This compound does have an internal plane of symmetry making it a meso compound with no optical activity. The top stereocenter is (S) and bottom one is (R). When naming a molecule with two stereocenters, consider each center separately and assign each stereocenter the appropriate (R) or (S) designation along with the appropriate carbon number. For example, the name of the compound in Exercise 11.7d is (1R,2R)-1,2cyclopentanediol. Another common way of naming molecules with two stereocenters is to use the terms erythro and threo. The terms erythro and threo are derived from the simple sugar molecules 2,3,4trihydroxybutanal that are commonly known as erythrose and threose.

An erythro molecule has two stereocenters with similar groups next to each other in the eclipsed conformation. A threo molecule has two stereocenters with two pairs of the similar groups on opposite sides of the molecule.

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CHO H H OH OH CH2OH Erythrose HO H

CHO H OH CH2OH Threose

Use the term erythro when the similar groups are adjacent to each other on the molecule. When these groups are identical, the molecule is meso. Then name the molecule with the meso name. Use the term threo when the similar groups are on opposite sides of the molecule. When these groups are identical, they are () or dl molecules. Then use (), or dl. For example, the terms meso and dl are appropriate for symmetric molecules such as 2,3-dichlorobutane or tartaric acid.
COOH H H OH OH COOH meso-Tartaric acid HO H COOH H OH COOH (dl)-Tartaric acid H HO COOH OH H COOH

For molecules such as 2-bromo-3-chlorobutane or 3-chloro-2-butanol, erythro and threo are more appropriate. While the threo, erythro, meso, and dl terms are widely used, none of these terms are a part of IUPAC nomenclature rules.

CH3 H
H

CH3 Cl Cl H
H

CH3 H HO CH3 Cl H Cl H

CH3 H OH CH3

OH HO CH3 CH3

Erythro 3-chloro-2-butanol Solved Exercise 11.3

Threo 3-chloro-2-butanol

There are two stereocenters in 1,3-dimethylcyclohexane and thus, according to the 2n rule, there are four stereoisomers. Two of these stereoisomers have the methyl groups cis and in the other two the methyl groups are trans. What is the stereochemical relationship between the two chair conformations of cis1,3-dimethylcyclohexane? What about trans-1,3-dimethylcyclohexane?

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Solution The two chair forms of cis-1,3-dimethylcyclohexane are a pair of nonsuperimposible nonmirror images. Thus, they are diastereomers.

The two chair forms of trans-1,3-dimethylcyclohexane are a pair of nonsuperimposible mirror images. Thus, the two are enantiomers.

Exercise 11.8 Draw the threo and erythro isomers of 2-bromo-3-chlorobutane.

11.7 Resolution of Enantiomers

Resolving enantiomers is a method of separating a pair of enantiomers. A resolving agent is a chiral compound or apparatus used as an aid in separating enantiomers.

Because enantiomers have identical physical and chemical properties in a symmetric environment, separating, or resolving, them using normal separation methods such as distillation, chromatography, or crystallization do not work. Resolution of enantiomers requires the use of a resolving agent. The first resolution of a pair of enantiomers occurred in 1848, and the resolving agents were a microscope and a pair of tweezers. After crystallizing salts of () tartaric acid, Louis Pasteur observed through his microscope that there were two forms of crystals.
C OOH H HO OH H C OOH HO H C OOH H OH C OOH

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See Section 1.7, page 000, for more on vant Hoff and Le Bel.

Section 7.7, page 000 discusses the reaction of a ketone with a hydride nucleophile.

Then, while looking through the microscope, he used a pair of tweezers to separate the crystals into two piles. When he compared the properties of the two piles, the only difference he found was their interaction with a plane of polarized light. The crystals in one pile turned the light clockwise; the crystals in the other pile turned the light counterclockwise. He had managed to affect the first separation of enantiomers. It was this work by Pasteur that led to van't Hoff's and Le Bel's suggestion in 1874 that four atoms bonded to carbon resulted in a tetrahedral structure. Enantiomers rarely crystallize in different forms, as does tartaric acid, so chemists must use other methods to separate them. The most common method is to react the racemic mixture with a single pure enantiomer. Single pure enantiomers of optically active compounds are generally isolated from biological sources because biological systems usually contain only one enantiomer of a pair. This reaction produces a pair of diastereomers that is separated by physical methods. The synthesis of (R)-2-butanol shows the resolution of a pair of enantiomers. A convenient synthetic method for the synthesis of (R)-2butanol is the addition of hydrogen to the carbonyl group of 2butanone. The product is a racemic mixture of 2-butanol because neither starting material nor reagents are asymmetric. Unless you use an optically active starting material or reagent when synthesizing an asymmetric compound, the result is a racemic mixture of enantiomers.
O CH3CH2CCH3 1) LiAlH4 2) H3O H CH3 OH + HO CH2CH3 (S)-2-Butanol CH3 H CH2CH3 (R)-2-Butanol

To resolve this racemic mixture, you need an asymmetric reagent that reacts with the alcohol to produce a pair of diastereomers. An asymmetric carboxylic acid, such as Louis Pasteurs (+)-tartaric acid, is a logical choice because it will react with the alcohol to form a pair of diastereomeric esters which can then be separated and hydrolyzed. Additionally, (+)-tartaric acid is readily available because wineries produce large quantities of it as a side product.

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COOH H HO OH H COOH (+)-Tartaric acid

Figure 11.9 shows the esterification reaction of the resulting diastereomeric esters. Because diastereomers generally have different physical properties, they can be separated easily via distillation, chromatography, crystallization, or other physical methods. For example, the two diastereomeric esters of tartaric acid have melting points that differ by about 20oC. They also have different water solubilities and different acid strengths. These differences allow separation using ordinary physical methods. The separation is so complete that you end up with each of the diastereomeric esters in the pure form.
O C CH3 HO H CH2CH3 CH3 H OH CH2CH3 Racemic 2-butanol (+)-Tartaric acid + H HO COOH OH H COOH H H H HO O OH H COOH (R)-2-Butyl (+)-tartrate CH3 O CH2CH3 H HO O C OH H CH3 H CH2CH3

COOH (S)-2-Butyl (+)-tartrate

Figure 11.9. Reaction of (R)- and (S)-2-butanol with (+)-tartaric acid to produce (R)and (S)-2-butyl (+)-tartrate. The two diastereomeric esters of tartaric acid can be separated because they have different physical properties.

A hydrolysis reaction is a good way to isolate the enantiomeric alcohols. Hydrolysis of (R)-2-butyl tartrate gives (R)-2-butanol.

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O C H HO O OH H COOH

CH3 H CH2CH3 OH HO CH3 H CH2CH3

+

COO H HO OH H COO

Hydrolysis of the (S)-2-butyl tartrate gives (S)-2-butanol, completing the resolution of the enantiomers.
CH3 H O CH2CH3 H HO O C OH H COOH OH H CH3 OH CH2CH3
+

COO H HO OH H COO

Exercise 11.9 The same concept of resolution of enantiomers also applies to amines. An amine reacts with a carboxylic acid to produce a salt.
R'COOH + RNH2 Carboxylic Amine acid

R'COO NH3R Salt

Using (+)-tartaric acid, accomplish the resolution of 2-aminobutane. Draw the diastereomeric salts that result from this reaction.

11.8 Stereocenters Other than Carbon

Although carbon is the most commonly found stereocenter in a molecule, a number of other atoms can be stereocenters, too. One of these atoms is silicon. Silicon forms the same sort of tetrahedral structure as carbon; thus, a silicon atom with four different groups bonded to it can be asymmetric, and indeed there are many examples of compounds with silicon stereocenters.

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H3C CH3CH2 Si H CH3CH2

H Si Cl CH3

(R)-Ethyl methyl phenyl silane

(S)-Ethyl methyl silyl chloride

Another possible stereocenter atom is nitrogen. Nitrogen forms amines that are derivatives of ammonia (NH3) in which carboncontaining groups replace one or more of the hydrogens. For example, ethylmethylamine has four different groups around the nitrogen: an ethyl group, a methyl group, a hydrogen, and an electron pair. Because the geometry of this molecule is nearly tetrahedral, ethylmethylamine should be an asymmetric molecule with nitrogen as its stereocenter.

C H3 C H3C H2

C H3 C H2C H3

Amine inversion flips the groups about the amine nitrogen from one enantiomer to the other.

A pair of enantiomers should exist, but they don't because a process called amine inversion prevent them from being separated. If you compare the amine structure to an umbrella, then amine inversion is similar to an umbrella turning inside out in the wind. At room temperature, this inversion process proceeds so rapidly that resolution of the enantiomers is impossible.

C H3 C H3C H2

C H3C H2 C H3

Nitrogen is a stereocenter when ammonia forms derivatives with cyclic structures and bulky groups. In these cases, inversion does not occur making it possible to separate the enantiomers. Some steric arrangements of the atoms within a compound also make amine
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inversion impossible. For example, 1-azabicyclo[3.2.1]octane cannot undergo amine inversion, thus allowing the enantiomers to be separated.

N
1-Azabicyclo[3.2.1]octane

Phosphorus is in the same group on the periodic table as nitrogen and, like nitrogen, it also forms trigonal pyramidal structures. However, unlike the amines formed by nitrogen, phosphines do not undergo rapid inversion. Thus, phosphorus is a stereocenter that can form a number of optically active phosphines. For example, ethyl methyl phenyl phosphine is asymmetric and has been resolved.

CH3 CH2 CH3

Ethyl methyl phenyl phosphine

When sulfur has three different substituents, it also forms compounds that are asymmetric. The rate of inversion for asymmetric sulfur compounds is quite slow, allowing for ready resolution of the enantiomers. An example of a compound with sulfur as the stereocenter is a dialkyl sulfoxide such as the ethyl methyl sulfoxide shown below.

CH3 CH3CH2

S O

Ethyl methyl sulfoxide

The Cahn-Ingold-Prelog priority rules specify the absolute configuration of any of these centers. These rules assign the unshared pair of electrons a lower priority than hydrogen. Application of these priority rules to ethyl methyl sulfoxide is shown below.

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CH3 CH3CH2 2

S O 1

(S)-Ethyl methyl sulfoxide

Exercise 11.10 What is the isomeric relationship between the two forms of the following compound that are interconverted by amine inversion? Could you isolate this compound in an optically active form?
H CH3 CH3CH2 C N

H CH3 CH2CH3 C CH3 CH3CH2 N

CH2CH3 CH3

Key Ideas from Chapter 11

All three-dimensional objects are either symmetric or asymmetric. You can superimpose a symmetric object onto its mirror image, but you cannot superimpose an asymmetric object onto its mirror image. Stereoisomers are molecules that have the same sequence of bonds, but have a different arrangement of the atoms in space. There are two types of stereoisomers. 1. Enantiomers: Compounds that have a mirror image relationship. 2. Diastereomers: Stereoisomers that are not enantiomers.

A carbon atom bonded to four different groups is stereogenic center. A molecule with a single stereogenic center is asymmetric. Molecules with more than one stereocenter may be chiral molecules or they may be meso molecules. Meso molecules are symmetrical molecules with even numbers of stereogenic center. Meso isomers occur with molecules that have an internal plane of symmetry.

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The pure components of an enantiomeric pair have the same melting points, boiling points, and other physical properties, but they rotate the plane of polarized light in equal but opposite directions. Diastereomers, in general, differ in their physical properties. That is, they have different melting points, boiling points, etc. A chemical reaction capable of producing an asymmetric product from a symmetric substrate produces both enantiomers equally with symmetric reagents. Asymmetric reagents usually prefer one enantiomer rather than the other. Atoms other than carbon (e.g. nitrogen, phosphorus, and sulfur) can also be stereocenters. The four different groups can include a non-bonding pair of electrons as one of the groups.

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