Preparation and Reactions of Stereoisomers

Chapter 7

Stereochemistry II. Preparation and Reactions of Stereoisomers

Stereoisomerism

• Stereoisomers, we have learned, are isomers that differ only in the way their atoms are oriented in space, ^o far, our study has been limited to finding out what the various kinds of stereoisomer's are, how to predict their existence, how to name them, and, in a general way, how their properties compare. In Chap. 4, we learned th.it Stereoisomers exist of the kind called enantiomers (mirror-image isomer. ^, that they can be optically active, and that both their existence and their optical activity are the result of the chirality of certain molecules, that is, of the non supeninposability of such molecules on their mirror images. We learned how to predict, from a simple examination of molecular structure, whether or not a particular compound can display this kind of isomerism. We learned how to specify the configuration of a particular enantiomer by use of the letters R and S.

• On the other hand, from the very practical standpoint of insolubility, geometric isomers are more akin to configurational isomers: interconversion requires bond breaking a IT bond in the case of geometric isomers and hence is always a difficult process. Conformational isomers are interconverted by the (usually) easy process of rotation about single bonds. For convenience, we laid down (Sec. 4.20) the following "ground rule" for discussions and problems in this book: unless specifically indicated otherwise, the terms " stereoisomers" " enantiomers" and " diastereomers" will refer only to configurational isomers, including geometric isomers, and will exclude conformational isomers. The latter will be referred to as "conformational isomers," "'conformers," " conformational enantiomers," and "conformational diastereomer.

Reactions involving stereoisomers

• Now let us go on from the existence of stereoisomers and look at their ///- obligement in chemical reactions: reactions in which stereoisomers are formed, and reactions in which stereoisomers are consumed', reactions in which the reagent is of the ordinary (i.e., optically inactive) kind. and those in which the reagent is optically active. We shall take up: (a) the conversion of an achiral molecule into a chiral molecule, with the generation of a chiral center; (b) reactions of chiral molecules in which bonds to the chiral center are not broken, and see how such reactions can be used to relate the configuration of one compound to that of another; (c) reactions of the kind in (b) in which a second chiral center is generated; (d) reactions of chiral compounds with optically active reagents. Then we shall examine the stereochemistry of several reactions we have already studied free-radical halogenation of alkanes, and electrophilic addition of halogens to aliens -and see how stereochemistry can be used to get information about reaction mechanisms. In doing this, we shall take up: (e) a reaction of a chiral compound in which a bond to a chiral center is broken; (f) a reaction of an achiral compound in which two chiral centers are generated at the same time. 

Generation of a chiral center. Synthesis and optical activity

• One of the products of chlorination of /i-butane is the chiral compound, sec-butyl chloride. It can exist as two enantiomers, I and II, which are specified CH3CH2CH2CH3 c^. heat or light > CH3CH2_cH-CHj + w-Butyl chloride /i-Butane 1. Achiral 5^Butyl chloride.

• Each enantiomer should, of course, be optically active. Now, if we were to put the sec-butyl chloride actually prepared by the chlorination of w-butane into a polarimeter, would it rotate the plane of polarized light? The answer is no, because prepared as described it would consist of the racemic modification. The next question is: why is the racemic modification formed? In the first step of the reaction, a chlorine atom abstracts hydrogen to yield hydrogen chloride and a sec-butyl free radical. The carbon that carries the odd electron in the free radical is s/? 2-hybridized (trigonal, Sec. 2.21), and hence a part of the molecule \slat, the trigonal carbon and the three atoms attached to it lying in the same plane. In the second step, the free radical abstracts chlorine from a chlorine molecule to yield sec-butyl chloride. But chlorine may become attached to either face of the flat radical, and, depending upon which face, yield either of two products: R or S (see Fig. 7.1). Since the chance of attachment to one face is exactly the same as for attachment to the other face, the enantiomers are obtained in exactly equal amounts. The product is the racemic modification.

• Isopentane is allowed to undergo free-radical chlorination, and the reaction mixture is separated by careful fractional distillation, (a) How many fractions of formula C5HnCl would you expect to collect? (b) Draw structural formulas, stereochemical were pertinent, for the compounds making up each fraction. Specify each enantiomer as R or S. (c) Which if any, of the fractions, as collected, would show optical activity? (d) Account in detail just as was done in the preceding section for the optical activity or inactivity of each fraction.

Reactions of chiral molecules. Bond

• Having made a chiral compound, sec-butyl chloride, let us see what happens when it, in turn, undergoes free-radical chlorination. A number of isomeric dichlorobutanes are formed, corresponding to attack at various positions in the molecule. (Problem: What are these isomers?) 

• We carry out free-radical chlorination of (S)-jeer-butyl chloride, and by fractional distillation isolate the various isomeric products, (a) Draw stereochemical formulas of the 1,2-, 2,2-, and 1,3-dichlorobutanes obtained in this way. Give each enantiomer its proper R or S specification, (b) Which of these fractions, as isolated, \\ill be optically active, and which will be optically inactive? Now, let us see how the axiom about bond breaking is applied in relating i ne configuration of one chiral compound to that of another.

Reactions of chiral molecules. Relating configurations

• We learned (Sec. 4.14) that the configuration of a particular enantiomer can be determined directly by a special kind of x-ray diffraction, which was first applied in 1949 by Biomet to ( -I )-tartaric acid. But the procedure is difficult and time-consuming and can be applied only to certain compounds. In spite of this limitation, however, the configurations of hundreds of other compounds are now known, since they had already been related by chemical methods to (+)- tartaric acid. Most of these relationships were established by application of the axiom given above; that is, the configurational relationship between two optically active compounds can be determined by converting one into the other by reactions that do not involve breaking oj a bond to a chiral center, Let us take as an example (-)-2.-methyl-l-butanol (the enantiomer found in fuel oil) and accept, for the moment, that it has configuration III, which we would specify S. We treat this alcohol with hydrogen chloride >and obtain the alkyI chloride, l-chloro-2-methylbutane. Without knowing the mechanism of this reaction, we can see that the carbon-oxygen bond is the one that is broken. No bond to the chiral center is broken, and therefore configuration is retained, with 

• The three compounds all happen to be specified as S, but this is simply because CH2C1 and COOH happen to have the same relative priority as CH2OH. If we were to replace the chlorine with deuterium (Problem: How could this be done?), the product would be specified R, yet obviously it would have the same configuration as the alcohol, halide, and acid. Indeed, looking back to sec-butyl chloride and 1 ,2-dichlorobutane, we see that the similar configurations I and II are specified differently, one S and the other R; here, a group ( CH3) that has a lower priority than ~C2 H5 is converted into a group ( CH2C1) that has a higher priority. We cannot tell whether two compounds have the same or opposite configuration by simply looking at the letters used to specify their configurations; we must work out and compare the absolute configurations indicated by those letters.

Optical purity

• 
  Reactions in which bonds to chiral centers are not broken can be used to get one more highly important kind of information: the specific rotations of optically pure compounds. For example, the 2-methyl-l-butanol obtained from fuel oil (which happens to have specific rotation -5.756) is optically pure like most chiral compounds from biological sources that is, it consists entirely of the one enantiomer, and contains none of its mirror image. When this material is treated with hydrogen chloride, the l-chloro-2-methylbutane obtained is found to have specific rotation of -f 1.64. Since no bond to the chiral center is broken, every molecule of alcohol with configuration III is converted into a molecule of chloride with configuration IV; since the alcohol was optically pure, the chloride of specific rotation -f 1.64 is also optically pure. Once this maximum rotation has been established, anyone can determine the optical purity of a sample of l-chloro-2-methylhutane in a few moments by simply measuring its specific rotation. If a sample of the chloride has a rotation of +0.82, that is, 50% of the maximum, we say that it is 50 % optically pure. We consider the components of the mixture to be (+)-isomer and ()-isomer (not (+)-isomer and (-)-isomer). (Problem: What are the percentages of (-f)-isomer and (-)-isomer in this sample?) Problem 7.6 Predict the specific rotation of the chloride obtained by treatment with hydrogen chloride of 2-methyl-l-butanol of specific rotation -f 3.12.

Reactions of chiral molecules. Generation of a second chiral center

• Let us return to the reaction we used as our example in Sec. 7.4, free -radical chlorination of sec-butyl chloride, but this time focus our attention on one of the other products, one in which a second chiral center is generated: 2,3-dichlorobutane. This compound, we have seen (Sec. 4.18), exists as three stereoisomers', tonka's and a pair of enantiomers. <:H3CH2 ~~CH-CH3 H2JJL5LM ^ CH3 -CHCH-CH3 -h other products I i i CI O Cl c-But> 1 Chloi I Jc 2,3-Dichlorobutan Let us suppose that we take optically active .\vs.-butyl chloride (the (S)-isomer, s i^, carry out the chlorination, and by fractional distillation scopulate the 2,3- dichlorobutanes from all the other products (the 1,2-isomer, 2,2-is>omen, etc.). Which stereoisomers can we expect to have.

• Suppose (as is actually the case) that the products from (S)-.you\ i chloride >how a Symes ratio of 29:71. What would we get from chlorination of (RJ-vat- 'Mittl chloride? We would get (R, R-) and /we-products, and the R, R:/mast> ratio would be exactly 29:71. Whatever factor favors mew-product over (S, S)-product villa favor myo-product over (R, R) ~product, and to exactly the same.

• In we said that attachment of chlorine to either face of the isobutyl radical is equally likely. This is in effect true but deserves closer examination. Consider any conformation of the free radical: I, for example. It is clear that attack by chlorine from the top of I and attack from the bottom are no

• Preferred attack from, say, the bottom of conformation III a likely preference since this would keep the two chlorine atoms as far apart as possible in the transition state would yield /w^o-2,3-dichlorobutane. A rotation of 180 about the single bond would convert III into IV. Attack from the bottom of IV would

Reactions of chiral molecules with optically active reagents. Resolution

• So far in this chapter we have discussed the reactions of chiral compounds only with optically inactive reagents. Now let us turn to reactions with optically active reagents and examine one of their most useful applications: resolution of a racemic modification, that is, the separation of a racemic modification into enantiomers. We know. that when optically inactive reactants form a chiral compound, the product is the racemic modification. We know that the enantiomers making up a racemic modification have identical physical properties (except for direction of rotation of polarized light), and hence cannot be separated by the usual methods of fractional distillation or fractional crystallization. Yet throughout this book are frequent references to experiments carried out using.

• What is the relationship between these two salts? They are not superimposable, since the acid portions are not superimposable. They are not mirror images, since the base portions are not mirror images. The salts are stereoisomers that are not enantiomers, and therefore are dianthrones. 

• Compounds other than organic bases, acids, or alcohols can also be resolved. Although the particular chemistry may differ from the salt formation just described, the principle remains the same: a racemic modification is converted by an optically active reagent into a mixture of diastereomers which can then be separated.

Reactions of chiral molecules. Mechanism of free-radical chlorination

• So far, we have discussed only reactions of chiral molecules in which bonds to the chiral center are not broken. What is the stereochemistry of reactions in which the bonds to the chiral center are broken? The answer is: it depends. It depends on the mechanism of the reaction that is taking place; because of this, stereochemistry can often give us information about a reaction that we cannot get in any other way. For example, stereochemistry played an important part in establishing the mechanism that was the basis of our entire discussion of the halogenation of alkanes (Chap. 3). The chain-propagating steps of this mechanism are: (2a) X- + RH > HX + R- (3a) R- + X2 > RX + X

• Until 1940 the existing evidence was just as consistent with the following alternative steps: (2b) X- + RH > RX + H- (3b) H- + X2 > HX + X To differentiate between these alternative mechanisms, H. C. Brown, M. S. Kharasch, and T. H. Chao, working at the University of Chicago, carried out the photochemical halogenation of optically active S-(H-)-1-chloro-2-methylbutanc. A number of isomeric products were, of course, formed, corresponding to attack at various positions in the molecule. (Problem: What were these. products?) They focused their attention on just one of these products: j,2-dichloro-2-mcthylbutane, resulting from substitution at the chiral center (C-2). CH3 CH3CH2CHCH2C1 h , light CH3 CH3 CH2CCH2C1 (S)-(4-)-l-Chloro-2-methylbutane ()-l,2-Dich1oro-2-mcthylbutane.

• They had planned the experiment on the following basis. The two mechanisms differed as to whether or not a free alkyl radical is an intermediate. The most likely structure for such a radical, they thought, was /to as, it turns out, it very probably islands

•  the radical would lose the original chirality. Attachment of chlorine to either face would be equally likely, so that an optically inactive, racemic product would be formed. That is to say, the reaction would take place wife racemization.

Stereoselective and stereospecific reactions* syn- and anti-Addition

• As our second example of the application of stereochemistry to the study of reaction mechanisms, let us take another familiar reaction: addition of halogens to alkenes. In this section we shall look at the stereochemical facts and, in the next, see how these facts can be interpreted. Addition of bromine to 2-butene yields 2,3-dibromobutane. Two chiral centers are generated in the reaction, and the product, we know, can exist as a meson compound and a pair of enantiomers. CH3 CH=CHCH3 + Br2 > CH3-CH CH-CH3 2-Butene ^ ^ 2,3-Dibromobutan.

• The reactant, too, exists as diastereomers: a pair of geometric isomers. If we start with, say, caw r-2-butene, which of the stereoisomeric products do we get? A mixture of all of them? No. cw-2-Butene yields only racemic 2,3-dibromobutane; none of the mesa compound is obtained. A reaction that yields predominantly one stereoisomer (or one pair of enantiomers) of several diastereomeric possibilities is called a Stereoselective reaction. Now, suppose we start with f/my-2-butene. Does this, too, yield the racemic dibromide? No. mm.? -2-Butene yields only /ner0-2,3-dibromobutane. A reaction in which stereochemical different reactants give stereochemical different products is called a stereospecific reaction. 

• To describe stereospecificity in addition reactions, the concepts of jaw-addition and anti-addition are used. These terms are not the names of specific mechanisms. They simply indicate the stereochemical facts: that the product obtained is the one to be expected if the two portions of the reagent were to add to the same face of the alkene (Syri) or to opposite faces. 

• Starting with rraws-2-butene, we can again attach the bromine atoms to opposite faces of the alkene in two ways but, whichever way we choose, we obtain the Whall encounter other examples of stereospecific additions, both anti and \vs. We shall find that other reactions besides addition can be

Mechanism of halogen addition

• We saw earlier (Sec. 6.13) that addition of halogens to alkenes is believed to proceed by two steps: first, addition of a positive halogen ion to form an organic cation; then combination of this cation with a negative halide ion. We saw some of the facts that provide evidence for this mechanism.

• In the last section, we learned another fact: halogens add to simple alkenes with complete stereospecificity, and in the anti-sense. Let us reexamine the mechanism in the light of this stereochemistry and focus our attention on the nature of the intermediate cation. This intermediate we represented simply as the carbonium ion. A part of a carbonium ion, we remember (Sec. 5.16), is flat: the carbon that carries the positive charge is s/? 2-hybridized, and this trigonal carbon and the three atoms attached to it lie in the same plane. Now, is the observed stereochemistry consistent with a mechanism involving such an intermediate? Let us use addition of bromine to c/j-2-butene as an example. A positive bromine ion is transferred to, say, the top face of the but this picture of the reaction is not satisfactory, and for two reasons. First, to account for the complete stereospecificity of addition, we must assume that attack at the bottom face of the cation is not just preferred, but is the only line of attack: conceivable, but especially in view of other reactions of carbonium ions (Sec. 14.13) not likely. Then, even if we accept this exclusively bottom-side attack, we are faced with a second problem. Rotation about the carbon-carbon bond would convert cation I into cation II; bottom-side attack on cation II would.