07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 305 7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS 305 The trans diastereomer can exist as a pair of enantiomers, and the two enantiomers of the cis di- astereomer are rapidly equilibrated by the chair interconversion and cannot be separated (Sec. 7.4D). Hence, three potentially separable stereoisomers could be formed: the cis isomer and the two enantiomers of the trans isomer. Because the cis and trans isomers are diastereomers, they are formed in different amounts. (You can’t predict at this point which one predominates, but we’ll re- turn to that issue in Sec. 7.9C.) The two enantiomers of the trans diastereomer must be formed in STUDY GUIDE LINK 7.3 identical amounts. Thus, whatever the amount of the trans isomer we obtain from the reaction, it Analysis of Reaction Stereochemistry is obtained as the racemate—a 50:50 mixture of the two enantiomers. PROBLEMS 7.23 What stereoisomeric products are possible when cis-2-butene undergoes bromine addition? Which are formed in different amounts? Which are formed in the same amounts? 7.24 What stereoisomeric products are possible when trans-2-butene undergoes hydrobora- tion–oxidation? Which are formed in different amounts? Which are formed in the same amounts? 7.25 Write all the possible products that might form when racemic 3-methylcyclohexene reacts with Br2. What is the relationship of each pair? Which compounds should in principle be formed in the same amounts, and which in different amounts? Explain. 7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS At this point, it may seem that stereochemistry adds a complicated new dimension to the study and practice of organic chemistry. To some extent, this is true. No chemical structure is com- plete without stereochemical detail, and no chemical reaction can be planned without consid- ering problems of stereochemistry that might arise. This section examines the possible stere- ochemical outcomes of two general types of reaction: addition reactions and substitution reactions. Then, some addition reactions covered in Chapter 5 will be revisited with particular attention to their stereochemistry. A. Stereochemistry of Addition Reactions Recall that an addition reaction is a reaction in which a general species X Y adds to each end of a bond. The cases we’ve studied so far involve addition to double bonds:L RR RR M M CM A CXM Y R CCR (7.37) + LLL L R R X Y An addition reaction can occur in either of two stereochemically different ways, called syn- addition and anti-addition. These will be illustrated with cyclohexene and a general reagent X Y. LThe stereochemistry of addition to a double bond is discussed with reference to the plane that contains the double bond and its four attached groups. The sides of this plane are called faces. The side of the plane nearest the observer is the top face, and the other side is the bot- tom face. 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 306 306 CHAPTER 7 • CYCLIC COMPOUNDS. STEREOCHEMISTRY OF REACTIONS observer top face (7.38) C C plane of the double bond bottom face In a syn-addition, two groups add to a double bond from the same face: Syn-addition: X X XY (7.39a) y + L ``Y + Y X and Y add from X and Y add from the top face the bottom face In an anti-addition, two groups add to a double bond from opposite faces: Anti-addition: X X XY (7.39b) y + L ``Y + Y X adds from top face; X adds from bottom face; Y adds from bottom face Y adds from top face It is also conceivable that an addition might occur as a mixture of syn and anti modes. In such a reaction, the products would be a mixture of all of the products in both Eqs. 7.39a–b. Examples of both syn- and anti-additions, as well as mixed additions, will be examined later in this section. As Eqs. 7.39a–b suggest, the syn and anti modes of addition can be distinguished by ana- lyzing the stereochemistry of the products. In Eq. 7.39a, for example, the cis relationship of the groups X and Y in the product would tell us that a syn-addition has occurred. Thus, the stere- ochemistry of an addition can be determined only when the stereochemically different modes of addition give rise to stereochemically different products. Thus, when two groups X and Y add to ethylene (H2CACH2), the same product (X CH2 CH2 Y) results whether the re- action is a syn- or an anti-addition. Because this productL can’tL existL as stereoisomers, we can’t tell whether the addition is syn or anti. A more general way of stating the same point is to say that syn- and anti-additions give different products only when both carbons of the double bond become carbon stereocenters in the product. If you stop and think about it, this should make sense, because the question of syn- and anti-addition is a question of the relative stereochem- istry at both carbons, and the relative stereochemistry cannot be determined if both carbons aren’t stereocenters. B. Stereochemistry of Substitution Reactions In a substitution reaction, one group is replaced by another. In the following substitution re- 1 action, for example, the Br is replaced1 by OH: 1 1 H3C Br_ OH H3C OH Br _ (7.40) L 1 3 + 3 1 L+1 3 1 3 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 307 7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS 307 The oxidation step of hydroboration–oxidation is also a substitution reaction in which the boron is replaced by an OH group. _OH 3HO OH (CH3CH2)3B 3CH3CH2 OH _B(OH)4 (7.41) ++L L + A substitution reaction can occur in two stereochemically different ways, called retention of configuration and inversion of configuration. When a group X9 replaces another group X with retention of configuration, then X and X9 have the same relative stereochemical posi- tions. Thus, in the following example, if X is cis to Y, then X9 is also cis to Y. Substitution with retention of configuration: X XЈ replace X with XЈ (7.42a) ` Y ` Y Substitution with retention also implies that if X and X9 have the same relative priorities in the R,S system, then the carbon that undergoes substitution will have the same configuration in the reactant and the product. Thus, if this carbon has (for example) the R configuration in the start- ing material, it has the same, or R, configuration in the product. When substitution occurs with inversion of configuration, then X and X9 have different relative stereochemical positions. Thus, if X is cis to Y in the starting material, X9 is trans to Y in the product: Substitution with inversion of configuration: X XЈ replace X with XЈ (7.42b) ` Y ` Y Substitution with inversion also implies that if X and X9 have the same relative priorities in the R,S system, then the carbon that undergoes substitution must have opposite configurations in the reactant and the product. Thus, if this carbon has (for example) the R configuration in the starting material, it has the opposite, or S, configuration in the product. As with addition, it is also possible that a reaction might occur so that both retention and inversion can occur at comparable rates in a substitution reaction. In such a case, stereoiso- meric products corresponding to both pathways will be formed. Examples of substitution re- actions with inversion, retention, and mixed stereochemistry are all well known. As Eqs. 7.42a–b suggest, analysis of the stereochemistry of substitution requires that the carbon that undergoes substitution must be a stereocenter in both the reactants and the prod- ucts. For example, in the following situation, the stereochemistry of substitution cannot be determined. not a stereocenter XЈ substitution by XЈ with retention X ` same compound (7.43) ` XЈ substitution by XЈ with inversion ` Because the carbon that undergoes substitution is not a stereocenter, the same product is ob- tained from both the retention and inversion modes of substitution. 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 308 308 CHAPTER 7 • CYCLIC COMPOUNDS. STEREOCHEMISTRY OF REACTIONS A reaction in which particular stereoisomers of the product are formed in significant excess over others is said to be a stereoselective reaction. Thus, an addition that occurs only with anti stereochemistry, as shown in Eq. 7.39b, is a stereoselective reaction because only one pair of enantiomers is formed to the exclusion of a diastereomeric pair. A substitution that occurs only with inversion, as shown in Eq. 7.42b, is also a stereoselective reaction because one di- astereomer of the product is formed to the exclusion of the other. This section has established the stereochemical possibilities that might be expected in two types of reactions: additions and substitutions. The remaining sections apply these ideas in dis- cussing the stereochemical aspects of several reactions that were first introduced in Chapter 5. C. Stereochemistry of Bromine Addition The addition of bromine to alkenes (Sec. 5.2A) is in many cases a highly stereoselective reac- tion. The addition of bromine to cis- and trans-2-butene can be used to apply the ideas of Sec- tion 7.9B to a noncyclic compound as well as to show how the stereochemistry of a reaction can be used to understand its mechanism. When cis-2-butene reacts with Br2, the product is 2,3-dibromobutane. BrL BrL H3C CH3 $CCA ) Br2 H3C CH CH CH3 (7.44) + L L L HH) $ 2,3-dibromobutane cis-2-butene You should now realize that three stereoisomers of this product are possible: a pair of enan- tiomers and the meso compound (Problem 7.23).