Stereochemistry

Chapter 4

Stereochemistry I. Stereoisomers

Stereochemistry and stereoisomerism

The science of organic chemistry, we said, is based on the relationship between molecular structure and properties. That part of the science which deals with structure in three dimensions is called stereochemistry (Gr.: stereos, solid). One aspect of stereochemistry is stereoisomerism. Isomers, we recall, are different compounds that have the same molecular formula. The particular kind of isomers that are different from each other only in the way the atoms are oriented in space (but are like one another with respect to which atoms are joined to which other atoms) are called Stereoisomers.

In this chapter, we shall learn how to predict the existence of the kinds of Stereoisomers called enantiomers and diastereomers, how to represent and designate their structures, and, in a general way, how their properties will compare. Then, in following chapters, we shall begin to use what we learn in this one. In Sees. 5.5-5.6. we shall learn about the kind of Stereoisomers called geometric isomers. In Chapter 7, the emphasis will shift from what these Stereoisomers fire, to how they are formed, what they do, and what they can.

Isomer number and tetrahedral carbon

Let us begin our study of stereochemistry with methane and some of its simple substitution products. Any compound, however complicated, that contains carbon bonded to four other atoms can be considered to be a derivative of methane; and whatever we learn about the shape of the methane molecule can be applied to the shapes of vastly more complicated molecules.

The evidence of electron diffraction, X-ray diffraction, and spectroscopy shows that when carbon is bonded to four other atoms its bonds are directed toward the corners of a tetrahedron. But as early as 1874, years before the direct determination of molecular structure was possible, the tetrahedral carbon atom was proposed by J. H. vent Hoff, while he was still a student at the University of Utrecht. His proposal was based upon the evidence of isomer number.

For any atom Y, only one substance of formula CH3Y has ever been found. Chlorination of methane yields only one compound of formula CH3C1; brominating yields only one compound of formula CH3 Br. Similarly, only one CH3 F is known, and only one CH3 I. Indeed, the same holds true if Y represents, not just an atom, but a group of atoms (unless the group is so complicated that in itself it brings about isomerism) ; there is only one CH3OH, only one CH3COOH, only one CH3SO3 H.

What does this suggest about the arrangement of atoms in methane? It suggests that every hydrogen atom in methane is equivalent to every other hydrogen atom, so that replacement of any one of them gives rise to the same product. If the hydrogen atoms of methane were not equivalent, then replacement of one would yield a different compound than replacement of another, and isomeric substitution products would be obtained.

In what ways can the atoms of methane be arranged so that the four hydrogen atoms are equivalent? There are three such arrangements: (a) a planar arrangement (I) in which carbon is at the center of a rectangle (or square) and a hydro.

There is additional, positive evidence for the tetrahedral carbon atom: the finding of just the kind of isomers enantiomers that are predicted for compounds of formula CWXYZ. It was the existence of enantiomers that convinced vent Hoff that the carbon atom is tetrahedral. But to understand what enantiomers are, we must first learn about the property called optical activity.

Optical activity. Plane-polarized light

Light possesses certain properties that are best understood by considering it to be a wave phenomenon in which the vibrations occur at right angles to the direction in which the light travels. There are an infinite number of planes passing through the line of propagation, and ordinary light is vibrating in all these planes. If we consider that we are looking directly into the beam of a flashlight.

An optically active substance is one that rotates the plane of polarized light. When polarized light, vibrating in a certain plane, is passed through an optically active substance, it emerges vibrating in a different.

The polarimeter

How can this rotation of the plane of polarized light this optical activity be detected? It is both detected and measured by an instrument called the polarimeter, which is represented schematically in Fig. 4.2. It consists of a light source, two lenses (Polaroid or Nicol), and between the lenses a tube to hold the substance that is being examined for optical activity. These are arranged so that the light.

The lactic acid (p. 121) that is extracted from muscle tissue rotates light to the right, and hence is known as dextrorotatory lactic acid, or ( i-)-lectic acid. The 2-methyI-l-butanoI than is obtained from fuel oil (a by-product of the fermentation of starch to ethyl alcohol) rotates light to the left and is known as Conrotatory 2-methyl-l-butanol, or ()-2-methyl-l-butanol.

Specific rotation

Since optical rotation of the kind, we are interested in is caused by individual molecules of the active compound, the amount of rotation depends upon how man ileitis's the light encounters in passing through lie lube.

The light will encounter twice as many molecules in a tube 20 cm long as in a tube 10 cm long, and the rotation will be twice as large. If the active compound is in solution, the number of molecules encountered by the light will depend upon the concentration. For a given tube length, light will encounter twice as many molecules in a solution of 2 g per 100 cc of solvent as in a solution containing I g per 100 cc of solvent, and the rotation will be twice as large. When allowances are made for the length of tube and the concentration, it is found that the amount of rotation, as well as its direction, is a characteristic of each individual optically active compound.

Specific rotation is the number of degrees of rotation observed if a 1 -decimeter tube is used, and the compound being examined is present to the extent of Ig cc. This is usually calculated from observations with tubes of other lengths and at different concentrations by means of the equation.

Enantiomeric: the discovery

The optical activity we have just described was discovered in 1815 at the College de France by the physicist Jean-Baptiste Boit.

In 1848 at the Ecole normale in Paris the chemist Louis Pasteur made a set of observations which led him a few years later to make a proposal that is the foundation of stereochemistry. Pasteur, then a young man, had come to the cole normale from the Royal College of Besancon (where he had received his baccalaureni es sciences with the rating of mediocre in chemistry), and had just won his docteur es sciences. To gain some experience in crystallography, he was repeating another chemist's earlier work on salts of tartanc acid when he saw something that no one had noticed before: optically inactive sodium ammonium tartrate existed as a mixture of two different kinds of crystals, which were mirror images of each other. Using a hand lens and a pair of tweezers, he carefully and laboriously separated the mixture into two tiny piles one of right-handed crystals and the other of left-handed crystalsmuch as one might separate right-handed and lefthanded gloves lying jumbled together on a shop counter. Now, although the original mixture was optically inactive, each set of crystals dissolved in water was found to be optical active] Furthermore, the specific rotations of the two solutions were exactly equal, but of opposite sign: that is to say, one solution rotated plane-polarized light to the right, and the other solution an equal number of degrees to the left. In all other properties the two substances were identical.

Since the difference in optical rotation was observed in solution, Pasteur concluded that it was characteristic, not of the crystals, but of the molecules. He proposed that, like the two sets of crystals themselves, the molecules making up the crystals were mirror images of each other. He was proposing the existence Of isomers whose structures differ only hi being mirror images of each other, and whose properties differ only in the direction of rotation of polarized light.

Enantiomers and tetrahedral carbon

Let us convince ourselves that such mirror-image isomers should indeed exist. Starting with the actual, tetrahedral arrangement for methane, let us make a model of a compound CWXYZ, using a ball of a different color for each different atom or group represented as W, X, Y, and Z. Let us then imagine that we are holding this model before a mirror and construct a second model of what its mirror image would look like. We now have two models which look something like this:

The non-superimposable of mirror images that brings about the existence of enantiomers also, as we shall see, gives them heir optical activity, and hence enantiomers arc often referred to as (one kind of) optical isomers. We shall make no use of the Leim optical isomer, since it is hard to define- indeed, is often used undefined - and of doubtful usefulness.

Enantiomeric and optical activity

Most compounds do not rotate the plane of polarized light. How is it that some do? It is not the particular chemical family that they belong to, since optically active compounds are found in all families. To see what special structural feature gives rise to optical activity, let us look closer> at what happens when Polari/ed light is passed through a sample of a single pure compound.

When a beam of polar/ed light passes through an individual molecule, in nearly every instance its plane is rotated a tiny amount by interaction with the charged particles of the molecule; the direction and extent of rotation varies with the orientation of the particular molecule in the beam. For most compounds, because of the random distribution of the large number of molecules that make up even the smallest sample of a single pure compound, for every molecule that the light encounters, there is another (identical) molecule oriented as (he mirrors image of the first i \which exactly cancels its effect. The net result is no rotation, that is, optical inactivity. Thus, optical inactivity is not a property of individual molecules, but rather of the random distribution of molecules that can serve as mirror images of each o(her.

Optical inactivity requires, then, that one molecule of a compound act as the mirror image of another. But in the special case of CWXY/, we have found (Sec. 4.7) a molecule whose mirror image is not just another, identical molecule, but rather a molecule of a different, isomeric compound. In a pure sample of a single enations, no molecule can serve as the mirror image of another; there is no exact canceling-out of rotations, and the net result is optical activity Thus, the same non-superimposable of mirror images that gives rise to enantiomers also is responsible for optical activity.

Prediction of enantiomeric. Chirality

Molecules that are not superimposable on their mirror images are chiral. Chirality is the necessary and sufficient condition for the existence Ot enantiomers. That is to say: a compound \\hose molecules are chiral can exist as enantiomers; a compound whose molecules are achiral (mahout chirality) cannot exist as enantiomers.

When we say that a molecule and its mirror image are superimposable, we mean that if in our mind's eye we were to bring the image from behind the mirror where it seems to be, it could be made to coincide in all its parts with the molecule. To decide whether or not a molecule is chiral, therefore, we make a model of it and a model of its mirror image and see if we can superimpose them. This is the safest way, since properly handled it must give us the right answer. It is the method that we should use until we have become quite familiar with the ideas involved; even then, it is the method we should use when we encounter a new type of compound.

After we have become familiar with the models themselves, we can draw pictures of the models, and mentally try to superimpose them. Some, we find, are not superimposable, like these.

The chiral center

So far, all the chiral molecules we have talked about happen to be of the kind CWXYZ; that is, in each molecule there is a carbon (C*) that holds four different groups. H H H C2H5-C*~CH2OH CH3 2-MethyM-butanol CH3 ~-C*-~COOH C2H5 -~C* CH3 OH CI ~CH3 Lactic acid. fee-Butyl chloride a-Dcuterioethylbenzene .

A carbon atom to which four different groups are attached is a chiral center. (Sometimes it is called chiral carbon, when it is necessary to distinguish it from chiral nitrogen, chiral phosphorus, etc.) Many but not all molecules that contain a chiral center are chiral. Many but not all chiral molecules contain a chiral center. There are molecules that contain chiral centers and yet are achiral (Sec. 4.18). There are chiral molecules that contain no chiral centers.

The presence or absence of a chiral center is thus no criterion of chirality. However, most of the chiral molecules that we shall take up do contain chiral centers, and it will be useful for us to look for such centers; if we find a chiral center, then we should consider the possibility that the molecule is chiral, and hence can exist in enantiomeric forms. We shall later (Sec. 4.18) learn to recognize the kind of molecule that may be achiral in spite of the presence of chiral centers; such molecules contain more than one chiral center.

After becoming familiar with the use of models and of pictures of models, the student can make use of even simpler representations of molecules containing chiral centers, which can be drawn much faster. This is a more dangerous method, however, and must be used properly to give the right answers. We simply draw a cross and attach to the four ends the four groups that are attached to the chiral center. The chiral center is understood to be located where the lines cross. Chemists have agreed that such a diagram stands for a particular structure: the horizontal lines represent bonds coming toward us out of the plane of the paper, whereas the vertical lines represent bonds going away from us behind the plane of the paper. That is to say:

In testing the superimposable of two of these flat, two-dimensional representations of three-dimensional objects, we must follow a certain procedure and obey certain rules. First, we use these representations only for molecules that contain a chiral center. Second, we draw one of them, and then draw the other as its mirror image. (Drawing these formulas at random can lead to some interesting but quite wrong conclusions about isomer numbers.) Third, in our mind's eye we may slide these formulas or rotate them end for end, but we may not remove them from the plane of the paper. Used with caution, this method of representation is convenient; it is not foolproof, however, and in doubtful cases models or pictures of models should be.

Enantiomers

Enantiomers have identical chemical properties except toward optically active reagents. The two lactic acids are not only acids, but acids of exactly the same strength; that is, dissolved in water at the same concentration, both ionize to exactly the same degree. The two 2-methyl-l-butanols not only form the same products alkenes on treatment with hot sulfuric acid, alkyl bromides on treatment with HBr, esters on treatment with acetic acid but also form them at exactly he same rate. This is quite reasonable, since the atoms undergoing attack in each case are influenced in their reactivity by exactly the same combination of substituents. The reagent approaching either kind of molecule encounters the same environment, except, of course, that one environment is the mirror image of the other.

Now take the reactions of two enantiomers with an optically active reagent. Again, the reactants are of the same energy. The two transition states, however, are not mirror images of each other (they are diastereomeric), and hence are of different energies; the acts are different, and so are the rates of reaction.

The racemic modification

Anixter ofjeguajj^arls of enantiomers is called a racemjfcjggodificatioii. A racemic modification^ is optically inactive: when enantiomers are mixe3TToge1her, the rotation caused by a molecule of one isomer is exactly canceled by an equal and opposite rotation caused by a molecule of its enantiomer. The prefix is used to specify the racemic nature of the particular sample, as, for example, ( )-lactic acid or ( )-2-methyl-l-butanol. It is useful to compare a racemic modification with a compound whose molecules are superimposable on their mirror images, that is, with an achiral compound. They are both optically inactive, and for exactly the same reason. Because of the random distribution of the large number of molecules, for.

The first resolution was, of course, the one Pasteur carried out with his hand lens and tweezers (Sec. 4.6). But this method can almost never be used, since racemic modifications seldom form mixtures of crystals recognizable as mirror images. Indeed, even sodium ammonium tartrate does not, unless it crystallizes at a temperature below 28. Thus, partial credit for Pasteur's discovery has been given to the cool Parisian climate and, of course, to the availability of tartaric acid from the winemakers of France. The method of resolution nearly always used one also discovered by Pasteur involves the use of optically active reagents and is described in Sec. 7.9. Although popularly known chiefly for his great work in bacteriology and medicine, Pasteur was by training a chemist, and his work in chemistry alone would have earned him a position as an outstanding scientist.

Optical activity: a closer look

We have seen (Sec. 4.8) that, like enantiomers', optical activity results from and only from chirality: the non-superimposable of certain molecules on their mirror images. Whenever we observe (molecular) optical activity, we know we are dealing with chiral molecules.

Is the reverse true? Whenever we deal with chiral molecules with compounds that exist as enantiomers must we always observe optical activity? No. We have just seen that a 50:50 mixture of enantiomers is optically inactive. Clearly, if we are to observe optical activity, the material we are dealing with must contain an excess of one enantiomer: enough of an excess that the net optical rotation can be detected by the particular polarimeter at hand.

detected by the particular polarimeter at hand. Furthermore, this excess of one enantiomer must persist long enough for the optical activity to be measured. If the enantiomers are rapidly interconverted, then before we could measure the optical activity due to one enantiomer, it would be converted into an equilibrium mixture, which since enantiomers are of exactly the same stability must be a 50:50 mixture and optically inactive.

At our present level of study, the matter of speed of interconversion will give us no particular trouble. Nearly all the chiral molecules we encounter in this book lie at either of two extremes, which we shall easily recognized (a) molecules like those described in this chapter which owe their chorally to chiral centers; here interconversion o r enantiomers (configuration^ enantiomers) is so slow because bonds have to be Broken that we need not concern ourselves at all about interconversion; (b) macule's whose enantiomeric forms (conformational enantiomers) are interconvertible Dimply by rotations about single bonds; here for the compounds we shall encounter interconversion is so fast that ordinarily we need not concern ourselves at all about the existence of the enantiomers.

Configuration

The arrangement of atoms that characterizes a particular stereoisomer is called its configuration. Using the test of superimposable, we conclude, for example, that there are two stereoisomeric sec-butyl chlorides; their configurations are I and IL Let us We have made two models to represent the two configurations of this chloride. We have isolated two isomeric compounds of the proper formula. Now the question arises, which configuration does each isomer have? Does the (-f )-isomer,

Until 1949 the question of configuration could not be answered in an absolute sense for any optically active compound. But in that year J. M. Bijvoet most fittingly Director of the vent Huff Laboratory at the University of Utrecht (Sec. 4.2) reported that, using a special kind of x-ray analysis (the method of anomalous scattering), he had determined the actual arrangement in space of the atoms of an optically active compound. The compound was a salt of (4-) -tartaric acid, the same acid that -almost exactly 100 years before had led Pasteur to his discovery of optical isomerism. Over the years prior to 1949, the relationships* between the configuration of (-f)-tartaric acid and the configurations of hundreds of optically active compounds had been worked out (by methods that we shall take up later, Sec. 7.5); when the configuration of (f )-tartaric acid became known, these other configurations, too, immediately became known. (In the case of the sec-butyl chlorides, for example, the ()-isomer is known to have configuration I, and the (f)-isomer configuration.

Specification of configuration: R and S

Now, a further problem arises. How can we specify a particular configuration in some simpler, more convenient way than by always having to draw its picture? The most generally useful way yet suggested is the use of the prefixes R and S. According to a procedure proposed by R. S. Cahn (The Chemical Society, London), Sir Christopher Ingold (University College, London), and V. Prelog (Eidgenessische Tekniche Hochschule, Zurich), two steps are involved. Step 1. Following a set of sequence rules (Sec. 4.16), we assign a sequence of priority to the four atoms or groups of atoms attached to the chiral center. In the case of Chelbi, for example, the four atoms attached to the chiral center are all different and priority depends simply on atomic number, the atom of higher number having higher priority. Thus I, Br, CI,

Step 2. We visualize the molecule oriented so that the group of lowest priority is directed away from us and observe the arrangement of the remaining groups. If, in proceeding from the group of highcstj^riorityjojlie group unseconds>riojjty and thence to shepherd, our eye travels in a clockwise direction, the configuration is specified R (Catine rectus, right); if counterclockwise, the configuration is specified.

We must not, of course, confuse the direction of optical rotation of a compounder physical property of a real substance, like melting point or boiling point- -\\Ith the direction in which our eve happens to travel when \Ve imagines a molecule held in an arbitrary manner. So far as \\e are concerned, unless \vs. happen to know what has been established experimentally for a specific compound, \\e have no idea \\heather (4) or () rotation is associated \\Ith the (R)- or the (S)-configuration.

Sequence rules

For case of reference and for convenience in reviewing, \\e shall set do\\n here those sequence rules \\e shall have need of. The student should study Rules 1 and 2 now, and Rule 3 later \\hen the need for it arises. Sequence Rule 1. If the four atoms attached to the chiral center are all different, priority depends on atomic number, with the atom of higher atomic number getting higher point>. If two atoms are isotopes of the same element, the atom of higher mass number has the higher priority. For example, in chloroiodomcthanesulfonic acid the sequence is I, Cl, S, H; in -tetramethyl bromide it is Br, C, D, H.

Diastereomers

Next, we must learn what stereoisomers are possible for compounds whose molecules contain, not just one, but more than one chiral center. (In Chapter 34, we shall be dealing regularly with molecules that contain five chiral centers.) Let us start with 2,3-dichloropentane. This compound contains two chiral CH3CH2-CH CH CH3 Cl Cl 2,3-Dichloropentane centers, C-2 and C-3. (What four groups are attached to each of these carbon atoms?) How many stereoisomers are possible?

Using models, let us first make structure I and its mirror image II, and see if these are superimposable. We find that I and II are not superimposable, and hence must be enantiomers. (As before, we may represent the structures by pictures, and mentally try to superimpose these. Or, we may use the simple "cross" representations, being careful, as before (Sec. 4.10), not to remove the drawings from the plane of the paper or blackboard.) Next, we try to interconvert I and II by rotations about carbon-carbon bonds. We find that they are not interconvertible in this way, and hence each of them is capable of retaining its identity and, if separated from its mirror image, of showing optical activity.

Thus, the presence of two chiral centers can lead to the existence of as many as four stereoisomers. For compounds containing three chiral centers, there could be as many as eight stereoisomers'; for compounds containing four chiral centers, there could be as many as sixteen stereoisomers, and so on. The maximum number of slcrcoisomers that can exist is equal to 2", where n is the number of chiral centers. (In any case where miso compounds exist, as discussed in the following section, there will be fewer than this maximum.

Mezo structures

Now let us look at 2,3-dichlorobutane, which also has two chiral centers. Does this compound, too, exist in four stereoisomeric forms? CH3 -CH-CH-CH3 i i Cl Cl 2,3-Dichlorobutane Using models as before, we arrive first at the two structures V and VI. These are mirror images that are not superimposable or interconvertible; they are therefore enantiomers, and each should be capable of optical activity.

Specification of configuration: more than one chiral center

Now, how do we specify the configuration of compounds which, like these, contain more than one chiral center? They present no special problem; we simply specify the configuration about each of the chiral centers, and by use of numbers tell which specification refers to which carbon. Consider, for example, the 2,3-dichloropentanes (Sec. 4.17). We take each of the chiral centers, C-2 and G-3, in turn ignoring for the moment the existence Cl Cl 2,3-Dichloropentane of the other and follow the steps of Sec. 4.15 and use the Sequence Rules of Sec. 4.16. In order of priority, the four groups attached to C-2 are Cl, CH3CH2CHC1~, CH3 , H. On C-3 they are CI, CH3 CHC1-, CH3CH2-, H. (Why is CH3CHC1- "senior" to CH3 CH2-?) Taking in our hands or in our mind's eye a model of the particular Stereoisomer we are interested in, we focus our attention first on C-2 (ignoring C-3), and then on C-3 (ignoring C-2). Stereoisomer I (p. 134), for example, we specify (2S,3S)-2,3-dichloropentane. Similarly, II is (2R,3R), III is (2S,3R), and IV is (2R,3S). These specifications help us to analyze the relationships among the stereoisomers. As enantiomers, I and II have opposite that is, mirror-image configurations about both chiral centers: 2S,3S and 2R,3R. As diastereomers, I and III have opposite configurations about one chiral center, and thus same configuration about the other: 2S,3S and 2S,3R. We would handle 2,3-dichlorobutane (Sec. 4.18) in exactly the same way. Here it happens that the two chiral centers occupy equivalent positions along the CH3 -CHCH~CH3 Cl Cl 2,3-Dichlorobutane.

chain, and so it is not necessary to use numbers in the specifications. Enantiomer's V and VI (p. 136) are specified (S, S)- and (R, R)-2,3-dichlorobutane; respectively. The meson isomer, VII, can, of course, be specified either as (R, S)- or (S, R)-2,3- dichlorobutane the absence of numbers emphasizing the equivalence of the two specifications. The mirror-image relationship between the two ends of this molecule is consistent with the opposite designations of R and S for the two chiral centers. (Not all (R, S)-isomers, of course, are miso structures only those whose two halves are chemically equivalent.)

Conformational some

we saw that there are several different staggered conformations of w-butane, each of which lies at the bottom of an energy valley at an energy minimum separated from the others by energy hills . Different conformations corresponding to energy minima are called conformational isomers, or conformers. Since conformational isomers differ from each other only in the way their atoms are oriented in space, they, too, are stereoisomers. Like stereoisomers of any kind, a pair of conformers can either be mirror images of each other or not. -Butane exists as three conformational isomers, one aim and two gauche (Sec. 3.5). The gauche conformers, II and III, are mirror images of each other, and hence are (conformational) enantiomers. Conformers I and II (or I and III) are not mirror images of each other, and hence are (conformational) diastereomers. Although the barrier to rotation in w-butane is a little higher than in ethane, it is still low enough that at ordinary temperatures, at least interconversion of conformers is easy and rapid. Equilibrium exists and favors a higher population of the more stable anti conformer; the populations of the two gauche conformers mirror images, and hence of exactly equal stability are, of course, equal. Put differently, any given molecule spends the greater part of its time as the aim conformer and divides the smaller part equally between the two gauche conformers. As a result of the rapid interconversion, these isomers cannot be separated.