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Home , Addition reaction, Chemical reaction, Diastereomer, Stereochemistry, Syn and anti addition

07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 305

7.9 OF CHEMICAL REACTIONS 305

The trans can exist as a pair of , 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 and the two enantiomers of the trans isomer. Because the cis and trans are , 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 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 . To some extent, this is true. No chemical structure is com- plete without stereochemical detail, and no 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 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 and a general X Y. LThe stereochemistry of addition to a 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 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 of the double bond become 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 , 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 –oxidation is also a substitution reaction in which the 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 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 (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 (Problem 7.23). The meso compound and the enantiomeric pair should be formed in different amounts (Sec. 7.8B). If the enantiomers are formed, they should be formed as the racemate because the starting materials are achiral (Sec. 7.8A). When bromine addition to cis-2-butene is carried out in the laboratory, the only product is the racemate. Bromine addition to trans-2-butene, in contrast, gives exclusively the meso compound. To summarize these results: Experimental facts:

BrL BrL Br (7.45) H C CH A CH CH 2 H C CH CH CH 3 3 CH Cl 3 3 L L 2 2 L L L cis racemate trans meso This information indicates that addition reactions of bromine to both cis- and trans-2-butene are highly stereoselective. Are these additions syn or anti? Because the is not cyclic (as it is in Eq. 7.39), the answer is not obvious. Study Problem 7.6 illustrates how to analyze the result systematically to get the answer.

Study Problem 7.6 According to the experimental results in Eq. 7.45, is the addition of bromine to cis-2-butene a syn- or an anti-addition?

Solution To answer this question, you should imagine both syn- and anti-additions to cis-2- butene and see what results would be obtained for each. Comparison of these results with the experimental facts then shows us which alternative is correct. 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 309

7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS 309

If bromine addition were syn, the Br2 could add to either face of the double bond. (In the fol- lowing structures, we are viewing the alkene edge-on as in Eq. 7.38.) Br Br H3C CH3 H3C CH3 CCA CCA H H H H Br Br

addition to addition to upper face lower face

Br Br CH3 H3C

) H $ H the same $CC) CC (7.46) H3C L CH3 L H H Br Br

meso-2,3-dibromobutane

This analysis shows that syn-addition from either direction gives the meso diastereomer. Because the experimental facts (Eq. 7.45) show that cis-2-butene does not give the meso isomer, the two bromine cannot be adding from the same face of the molecule. Therefore syn-addition does not occur. Because bromine addition is not a syn-addition, presumably it is an anti-addition. Let’s verify this. Consider the anti-addition of the two bromines to cis-2-butene. This addition, too, can occur in two equally probable ways. Br Br H3C CH3 H3C CH3 CCA CCA H H H H Br Br

Br H3C CH3 Br

) H H $ H C $C C enantiomers C C) (7.47) 3 L L CH3 H Br Br H

2S,3S 2R,3R (±)-2,3-dibromobutane

This analysis shows that each mode of addition gives the of the other; that is, the two modes of anti-addition operating at the same time should give the racemate. Because the experi- mental facts of Eq. 7.45 show that bromine addition to cis-2-butene indeed gives the racemate, this reaction is an anti-addition. It is very important that you analyze the addition of bromine to trans-2-butene in a similar manner to show that this addition, too, is an anti-addition.

As suggested at the end of Study Problem 7.6, you should have demonstrated to yourself that the addition of bromine to trans-2-butene is also a stereoselective anti-addition. In fact, the bromine addition to most simple alkenes occurs exclusively with anti stereochemistry. Bromine addition is therefore a highly stereoselective anti-addition reaction. 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 310

310 CHAPTER 7 • CYCLIC COMPOUNDS. STEREOCHEMISTRY OF REACTIONS

The study of the stereochemistry of bromine addition to the 2-butenes raises an important philosophical point. To claim that bromine addition to the 2-butenes is an anti-addition requires that the reaction be investigated on both the cis and trans stereoisomers of 2-butene. It is con- ceivable that, in the absence of experimental evidence, anti-addition might have been observed with one stereoisomer of the 2-butenes and syn-addition with the other. Had this been the result, the bromine-addition reactions would still be highly stereoselective, but we could not have made the more general claim that bromine addition to the 2-butenes is an anti-addition. Reactions such as bromine addition, in which different stereoisomers of a starting material give different stereoisomers of a product, are called stereospecific reactions. As the discus- STUDY GUIDE LINK 7.4 sion in the previous paragraph demonstrates, all stereospecific reactions are stereoselective, Sterioselective and Sterospecific but not all stereoselective reactions are stereospecific. To put it another way, all stereospecific Reactions reactions are a subset of all stereoselective reactions. Why is bromine addition a stereospecific anti-addition? The stereospecificity of bromine ad- dition is one of the main reasons that the brominium- mechanism, shown in Eqs. 5.12–5.13 on p. 183, was postulated. Let’s see how this mechanism can account for the observed results. First, the bromonium ion can form at either face of the alkene. (Reaction at one face is shown in the following equation; you should show the reaction at the other face and take your struc- tures through the subsequent discussion.)

Br 3 2 3 "Br 3 1 3 Br| H H 3 3 CCA C $ C Br (7.48) H H _ H3C CH3 L 3 21 3 H3C CH3 Bromonium-ion formation as represented here is a syn-addition because even though only one group has added to the double bond, the methyl groups and have the same (cis) re- lationship in both reactant and product. If formation of the bromonium ion is a syn-addition, then the anti-addition observed in the overall reaction with bromine must be established by the stereochemistry of the reaction be- tween the bromonium ion and the bromide ion. Suppose that the bromonium ion reacts with the bromide ion by backside substitution. This means that the bromide ion donates an pair to a carbon at the face opposite to the bond that breaks, which in this case is the carbon–bromine bond. A backside substitution reaction must occur with inversion of configuration (Sec. 7.9B), because, as the substitution takes place, the methyl and the must swing upwards (green arrows) to maintain the tetrahedral configuration of carbon. Reaction of the bromide ion at one carbon yields one enantiomer; reaction at the other carbon yields the other enantiomer.

Br Br

| H 3 3 H3C $ 3 2 3 C $ C CC$ H L H L H CH3 CH3 Br CH3 3 1 3

Br _ 1 3 12 3 (±)-2,3-dibromobutane (7.49) Br

| Br H 3 3 3 3 $ CH3 C $ C $CC H L H H L CH3 CH3 CH3 Br 3 1 3 Br _ 3 12 3 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 311

7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS 311

Thus, formation of a bromonium ion followed by backside substitution of bromide is a mech-

anism that accounts for the observed anti-addition of Br2 to alkenes. In general, when a nucle- ophile reacts at a saturated carbon in any substitution reaction, backside substitution is observed. (Backside substitution is explored further in Chapter 9.) Might other mechanisms be consistent with the anti stereochemistry of bromine addition? Let’s see what sort of prediction a mechanism makes about the stereochemistry of the reaction.

Imagine the addition of Br2 to cis-2-butene to give a carbocation intermediate. (Bromine addition at the upper face is shown below.) If the carbocation lasts long enough to undergo at least one internal rotation, then both diastereomers of the products would be formed even if a bromonium ion formed subsequently:

Br Br Br _ L Br 3 12 3 Br Br H H H H $ H CH CCA $CC| CC| $CC 3 H H H L CH3 L CH3 L H3C CH3 Br CH3 CH3 CH3 $ Br 3 1 3 _ racemate 180° internal 3 12 3 rotation

Br _ Br Br Br 3 12 3 CH3 CH3 $ CH3 H $CC| CC| $CC H L H H L H H L Br CH CH CH3 $ 3 3 Br 3 1 3 _ meso (7.50) 3 12 3 The reaction, then, would not be stereoselective. Because this result is not observed (Eq. 7.45), a carbocation mechanism is not in accord with the data. This mechanism also is not in accord with the absence of rearrangements in bromine addition. The bromonium-ion mechanism, however, accounts for the results in a direct and simple way. The credibility of this mechanism has been enhanced by the direct observation of bromonium under special conditions. In 1985, the structure of a bromonium ion was determined by X-ray . Does the observation of anti stereochemistry prove the bromonium-ion mechanism? The answer is no. No mechanism is ever proved. deduce a mechanism by gathering as much information as possible about a reaction, such as its stereochemistry, the presence and absence of rearrangements, and so on, and ruling out all mechanisms that do not fit the experimental facts. If someone can think of another mechanism that explains the facts, then that mechanism is just as good until someone finds a way to decide between the two by a new experiment.

PROBLEMS 7.26 Assuming the operation of the bromonium-ion mechanism, give the structure of the product(s) (including all stereoisomers) expected from bromine addition to cyclohexene. (See Study Problem 7.5 on p. 304.) 7.27 In view of the bromonium-ion mechanism for bromine addition, which of the products in your answer to Problem 7.25 (p. 305) are likely to be the major ones? 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 312

312 CHAPTER 7 • CYCLIC COMPOUNDS. STEREOCHEMISTRY OF REACTIONS

D. Stereochemistry of Hydroboration–Oxidation Because hydroboration–oxidation involves two distinct reactions, its stereochemical outcome is a consequence of the stereochemistry of both reactions. Hydroboration is a stereospecific syn-addition.

CH3 CH3 H H BR2 M L (7.51) y ` BR2 H (racemate) Notice again the structure-drawing convention used here: Even though just one enantiomer of the product is shown, the product is racemic because the starting materials are achiral (Sec. 7.8A). The syn-addition of borane, along with the absence of rearrangements, is the major evi- dence for a concerted mechanism of the reaction.

R2B H L R2B H concerted C A C syn-addition (7.52a)

Occurrence of an anti-addition by the same concerted mechanism would be virtually impossi- ble, because it would require an abnormally long B H bond to bridge opposite faces of the alkene p bond. L

R2B R2B concerted anti-addition would require an C C unrealistic B H (7.52b) bond length L H H The oxidation of organoboranes is a stereospecific substitution reaction that occurs with re- tention of stereochemical configuration.

H3C H3C H H H O /OH 2 2 _ (7.53) ` ` BR2 OH H H trans-2-methylcyclohexanol

We won’t consider the mechanism of this substitution in detail here, but we can certainly con- clude that it does not involve backside nucleophilic substitution. (Why?) (The mechanism is Further Exploration 7.4 Stereochemistry of shown in Further Exploration 7.4.) Organoborane The results from Eqs. 7.51 and 7.53 taken together show that hydroboration–oxidation of Oxidation an alkene brings about the net syn-addition of the elements of H OH to the double bond. L H3C H3C CH3 H H H BR H O /OH M 2 2 2 _ (7.54) syn-additionL retention of y ` configuration ` BR2 OH H H 1-methylcyclohexene (±)-trans-2-methylcyclohexanol 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 313

7.9 STEREOCHEMISTRY OF CHEMICAL REACTIONS 313

As far as is known, all hydroboration–oxidation reactions of alkenes are stereospecific syn- additions.

Notice carefully that the H and OH are added in a syn manner. The trans designation in the name of the product of Eq.L 7.54 hasL nothing to do with the groups that have added—it refers to the relationship of the , which was part of the alkene starting material, and the OH group. Notice again the drawing convention: only one enantiomer of each chiral molecule is drawn,L but it is understood that the racemate of each is formed.

PROBLEMS 7.28 What products, including their stereochemistry, should be obtained when each of the following alkenes is subjected to hydroboration–oxidation? (D 2H.) (a) H3C CH3 (b) H3CD = = $CCA ) $CCA )

D) $D D) $CH3 7.29 Contrast the results in Problem 7.28 with those to be expected when cis- and trans-2-butene (not isotopically substituted) are subjected to the same reaction conditions.

E. Stereochemistry of Other Addition Reactions Catalytic Catalytic hydrogenation of most alkenes (Sec. 4.9A) is a stereo- specific syn-addition. The following example is illustrative; the products are shown in eclipsed conformations for ease in seeing the stereochemical relationships. H H Ph CH3 Pd/C CCA H CC (7.55a) 2 acetic Ph $ $ CH H3C Ph + () L 3 H3C Ph racemate

H H Ph Ph Pd/C CCA H CC (7.55b) 2 H C $ $ CH H3C CH3 + (solvent) 3 L 3 Ph Ph meso isomer Results like these show that the two hydrogen atoms are delivered from the catalyst to the same face of the double bond. The stereospecificity of catalytic hydrogenation is one reason that the reaction is so important in .

Oxymercuration–Reduction Oxymercuration of alkenes (Sec. 5.4A) is typically a stereo- specific anti-addition. HO H H H Hg(OAc) , H O CH CCA 2 2 $CC 3 (7.56) THF H H3C CH3 L H3C $HgOAc (racemic) 07_BRCLoudon_pgs5-1.qxd 12/8/08 12:13 PM Page 314

314 CHAPTER 7 • CYCLIC COMPOUNDS. STEREOCHEMISTRY OF REACTIONS

(What result would you expect for the same reaction of trans-2-butene? See Problem 7.30.) Because this reaction occurs by a cyclic-ion mechanism (Eqs. 5.20c–d, p. 188) much like bromine addition, it should not be surprising that the stereochemical course of the reaction is

the same. In the reaction of the mercury-containing product with NaBH4, however, the stere- ochemical results vary from case to case. In this example, a deuterium-substituted analog,

NaBD4, was used to investigate the stereochemistry, and it was found that mercury is replaced by hydrogen with loss of stereochemical configuration.

HO H HO H HO D

CH3 NaBD4, OH CH3 $CC _ $CC $CC (7.57) H $ H H L H L + L H3C $HgOAc H3CH$D 3C CH3 (equal amounts of each) Hence, oxymercuration–reduction is in general not a stereoselective reaction. Despite its lack of , the reaction is highly regioselective and is very useful in situations in STUDY GUIDE LINK 7.5 which stereoselectivity is not an issue, such as those in which both carbons of the double bond When Stereoselectivity in the alkene starting material are not simultaneously converted into stereocenters as a result Matters of the reaction.

PROBLEMS 7.30 (a) Give the product(s) and their stereochemistry when trans-2-butene reacts with Hg(OAc)2 and H2O. (b) What compounds result when the products of part (a) are treated with NaBD4 in aqueous NaOH? Contrast these products (including their stereochemistry) with the products of Eq. 7.57. 7.31 For which of the following alkenes would oxymercuration–reduction give (a) a single di- astereomer; (b) two diastereomers; (c) more than one constitutional isomer? Explain.

H3C CH3

CH3 H

CH3 AB C D

KEY IDEAS IN CHAPTER 7

I Except for cyclopropane, the have puck- tions. Cyclohexane and substituted cyclohexanes un- ered carbon skeletons. dergo the chair interconversion, in which equatorial groups become axial, and vice versa. The twist-boat I Of the cycloalkanes containing relatively small rings, conformation is a less stable conformation of cyclo- cyclohexane is the most stable because it has no hexane derivatives. Twist-boat conformations are in- angle and it can adopt a conformation in which terconverted through boat transition states. all bonds are staggered. I A cyclohexane conformation with an axial I The most stable conformation of cyclohexane is the is typically less stable than a conformation with the chair conformation. In this conformation, hydrogens same substituent in an equatorial position because of or substituent groups assume axial or equatorial posi-