11.4 NUCLEOPHILIC SUBSTITUTION REACTIONS OF EPOXIDES

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1 .4 NUEPII SUBSTITUTIN REATINS F EPXIDES 495 (d When tert-butyl methyl ether is heated with sulfuric acid, methanol and -methylpropene distill from the solution. (e Tert-butyl methyl ether cleaves much faster in Br than its sulfur analog, tert-butyl methyl sulfide. (int: See Sec (f When enantiomerically pure (S--methoxybutane is treated with Br, the products are enantiomerically pure (S--butanol and methyl bromide..6 What products are formed when each of the following ethers reacts with concentrated aqueous I? (a diisopropyl ether (b -ethoxy-,3-dimethylbutane.4 NUEPII SUBSTITUTIN REATINS F EPXIDES A. Ring-pening Reactions under Basic onditions Epoxides readily undergo reactions in which the epoxide ring is opened by nucleophiles. ( 3,-dimethyloxirane (isobutylene oxide 5 ( 3 5 ethanol (solvent Na 5 5 h, 80 -ethoxy--methyl--propanol (83 yield (.9 A reaction of this type is an S N reaction in which the epoxide oxygen serves as the leaving group. In this reaction, though, the leaving group does not depart as a separate entity, but rather remains within the same product molecule. leaving group 3 an S N reaction ( 3 ( 3 5 ( (.30 nucleophile Because an epoxide is a type of ether, the ring opening of epoxides is an ether cleavage. Recall that ordinary ethers do not undergo cleavage in base (Eq..3, p. 49. Epoxides, however, are opened readily by basic reagents. Epoxides are so reactive because they, like their carbon analogs, the cyclopropanes, possess significant angle strain (Sec. 7.5B. Because of this strain, the bonds of an epoxide are weaker than those of an ordinary ether, and are thus more easily broken. The opening of an epoxide relieves the strain of the three-membered ring just as the snapping of a twig relieves the strain of its bending. In an unsymmetrical epoxide, two ring-opening products could be formed corresponding to the reaction of the nucleophile at the two different carbons of the ring. As Eq..30 illustrates, nucleophiles typically react with unsymmetrical epoxides at the carbon with fewer alkyl substituents. This regioselectivity is expected from the effect of alkyl substitution on the

2 496 APTER TE EMISTRY F ETERS, EPXIDES, GYS, AND SUFIDES rates of S N reactions (Sec. 9.4D. Because alkyl substitution retards the S N reaction, the reaction of a nucleophile at the unsubstituted carbon is faster and leads to the observed product. ike other S N reactions, the ring opening of epoxides by bases involves backside substitution of the nucleophile on the epoxide carbon. When this carbon is a stereocenter, inversion of configuration occurs, as illustrated by Study Problem.. Study Problem. What is the stereochemistry of the,3-butanediol formed when meso-,3-dimethyloxirane reacts with aqueous sodium hydroxide? Solution First draw the structure of the epoxide. The meso stereoisomer of,3-dimethyloxirane has an internal plane of symmetry, and its two asymmetric carbons have opposite configurations. S 3 Because the two different carbons of the epoxide ring are enantiotopic (Sec. 0.8A, the hydroxide ion reacts at either one at the same rate. Backside substitution on each carbon should occur with inversion of configuration. 3 meso-,3-dimethyloxirane R inversion of configuration The product shown is the S,3S stereoisomer. Reaction at the other carbon gives the R,3R stereoisomer. (Verify this point! Because the starting materials are achiral, the two enantiomers of the product must be formed in equal amounts (Sec. 7.8A. ence, the product of the reaction is racemic,3-butanediol. (This predicted result is in fact observed in the laboratory. Although the examples in this section have involved hydroxide and alkoxides as nucleophiles, the pattern of reactivity is the same with any nucleophile: The nucleophile reacts at the carbon with no alkyl substituents and opens the epoxide to form an alkoxide, which then reacts in a Brønsted acid base reaction with a proton source to give an alcohol. etting Nuc3 be a general nucleophile, we can summarize this pattern of reactivity with Eq..3: nucleophilic substitution proton transfer R Nuc R Nuc Nuc R Nuc Nuc (.3

3 .4 NUEPII SUBSTITUTIN REATINS F EPXIDES 497 PRBEMS.7 Predict the products of the following reactions. (a 3 N 3 5 (excess ( 3 (b 3 3 Na N- 3 5 / sodium azide.8 From what epoxide and what nucleophile could each of the following compounds be prepared? (Assume each is racemic. (a (b 3 ( 4 N S 3 B. Ring-pening Reactions under Acidic onditions Ring-opening reactions of epoxides, like those of ordinary ethers, can be catalyzed by acids. owever, epoxides are much more reactive than ethers under acidic conditions because of their angle strain. ence, milder conditions can be used for the ring-opening reactions of epoxides than are required for the cleavage of ordinary ethers. For example, very low concentrations of acid catalysts are required in ring-opening reactions of epoxides. ( 3,-dimethyloxirane (isobutylene oxide 3 methanol (solvent S 4 (trace ( 3 (.3 The regioselectivity of the ring-opening reaction is different under acidic and basic conditions. The structure of the product in Eq..3 shows that the nucleophile methanol reacts at the more substituted carbon of the epoxide. ontrast this with the result in Eq..3, in which the nucleophile reacts at the less substituted carbon under basic conditions. In general, if one of the carbons of an unsymmetrical epoxide is tertiary, nucleophiles react at this carbon under acidic conditions. Some insight into why different regioselectivities are observed under different conditions comes from mechanistic considerations. The first step in the mechanism of Eq..3, like the first step of ether cleavage, is protonation of the oxygen. 3 -methoxy--methyl--propanol (76 yield protons come from protonated solvent molecule ( ( 3 protonated epoxide 3 (.33a

4 498 APTER TE EMISTRY F ETERS, EPXIDES, GYS, AND SUFIDES The structural properties of the protonated epoxide show that it can be expected to behave like a tertiary carbocation. long, weak bond d nearly trigonal planar geometry 3 3 d (.33b a large amount of positive charge First, calculations show that the tertiary carbon bears about 0.7 of a positive charge. Second, the geometry at the tertiary carbon is nearly trigonal planar. This means that the tertiary carbon and the groups around it are very nearly flattened into a common plane so that little or no steric hindrance prevents the approach of a nucleophile to this carbon. Finally, the bond between the tertiary carbon and the group is unusually long and weak. This means that this bond is more easily broken than the other bond. In fact, this cation resembles a carbocation solvated by the leaving group (see Fig. 9.3, p. 49. The leaving group blocks the front side of the carbocation so that the nucleophilic reaction must occur from the back side with inversion of stereochemistry. In other words, we can think of this reaction as an S N reaction with stereochemical inversion. Thus, a solvent molecule reacts with the protonated epoxide at the tertiary carbon, and loss of a proton to solvent gives the product. 3 ( 3 ( 3 ( (.33c It is a solvent molecule, not the alkoxide conjugate base of the solvent, that reacts with the protonated epoxide. The alkoxide conjugate base cannot exist in acidic solution; nor is it necessary, because the protonated epoxide is very reactive and because the nucleophile is also the solvent and is thus present in great excess. When the carbons of an unsymmetrical epoxide are secondary or primary, there is much less carbocation character at either carbon in the protonated epoxide, and acid-catalyzed ringopening reactions tend to give mixtures of products; the exact compositions of the mixtures vary from case to case. 3 secondary primary 0.8 S 4 5 (solvent of the product 63 of the product (.34 The mixture reflects the balance between opening of the weaker bond, which favors reaction at the carbon with more substituents, and van der Waals repulsions with the nucleophile, which favors reaction at the carbon with fewer substituents. The regioselectivities of acid-catalyzed epoxide ring opening and the reactions of solvent nucleophiles with bromonium ions are very similar (see Eq. 5.5, p. 84. This is not surprising, because both types of reactions involve the opening of strained rings containing positively charged, electronegative leaving groups.

5 .4 NUEPII SUBSTITUTIN REATINS F EPXIDES 499 Acid-catalyzed ring-opening reactions of epoxides, like base-catalyzed ring-opening reactions, occur with inversion of stereochemical configuration. ` 3 (solvent inversion of configuration cyclohexene oxide When water is used as a nucleophile in acid-catalyzed epoxide ring opening, the product is a,-diol, or glycol. Acid-catalyzed epoxide hydrolysis is generally a useful way to prepare glycols. ` (solvent cyclohexene oxide S 4 catalyst l 4 (trace 30 min ` ` (.36 Notice the trans relationship of the two hydroxy groups in the product, which results from the inversion of configuration that occurs when water reacts with the protonated epoxide. It follows that cis-,-cyclohexanediol cannot be prepared by epoxide opening. owever, in Sec..5A, you will learn how this stereoisomer can be prepared by another method. Although base-catalyzed hydrolysis of epoxides also gives glycols (see Study Problem., polymerization sometimes occurs as a side reaction under the basic conditions (see Problem.68. onsequently, acid-catalyzed hydrolysis of epoxides is generally preferred for the preparation of glycols. 3 ( -trans--methoxycyclohexanol (8 yield ( -trans-,-cyclohexanediol (a glycol; 80 yield (.35 PRBEM.9 Predict the major product(s of each of the following transformations. (a 5 5 (optically active 3 (solvent S 4 (trace (b The enantiomer of the epoxide in part (a 3 (solvent S 4 (trace et s summarize the facts about the regioselectivity and stereoselectivity of epoxide ringopening reactions:. Nucleophiles react with unsymmetrical epoxides under basic conditions at the less branched carbon, and inversion of configuration is observed if reaction occurs at a stereocenter.. Nucleophiles react with unsymmetrical epoxides under acidic conditions at the tertiary carbon. If neither carbon is tertiary, a mixture of products is formed in most cases. Inversion of configuration is observed if reaction occurs at a stereocenter. These facts are applied in Study Problem.3.

6 500 APTER TE EMISTRY F ETERS, EPXIDES, GYS, AND SUFIDES Study Problem.3 Predict the major product in each case that would be obtained when the following epoxide is hydrolyzed under (a basic conditions; (b acidic conditions. (The epoxide carbons are numbered for reference in the solution. ( 3 3 Solution As the preceding summary suggests, when attempting to predict the products of an epoxide ring-opening reaction, first decide whether the conditions of the reaction are basic or acidic. If basic, the nucleophile reacts at the less substituted carbon of the epoxide; if acidic, the nucleophile reacts the tertiary carbon of the epoxide. Then determine whether the carbon at which the reaction occurs is a stereocenter. If so, make sure to predict the product that results from inversion of configuration. (a Under basic conditions, the hydroxide ion nucleophile will react at the less substituted carbon (carbon- of the epoxide. (If you have difficulty seeing why this is the less substituted carbon, re-read Study Guide ink 9.. Because this carbon is not a stereocenter, the stereochemistry of the substitution does not matter. onsequently, the reaction is ( 3 3 ( 3 3 (.37 ( 3 3 (b Under acidic conditions, the nucleophile is water, which reacts with the protonated epoxide at the more branched carbon (carbon-. Notice that carbon- is a stereocenter (even though it is not an asymmetric carbon; reaction of the nucleophile at carbon- occurs with inversion of configuration. onsequently, the product of the reaction under acidic conditions is a diastereomer of the product obtained under basic conditions. S 4 (catalyst ( 3 3 (.38 PRBEM.0 (a Suppose,-dimethyloxirane is hydrolyzed in water that has been enriched with the oxygen isotope 8. Indicate how the hydrolysis product would differ under acidic and basic conditions. (b Show how the stereochemistry of the products will differ (if at all when the following enantiomerically pure epoxide is hydrolyzed under acidic and basic conditions. 3 D 3 D. Reaction of Epoxides with rganometallic Reagents Grignard reagents (Sec. 8.8 react with ethylene oxide to give, after a protonation step, primary alcohols:

7 .4 NUEPII SUBSTITUTIN REATINS F EPXIDES 50 3 MgBr hexylmagnesium bromide (a Grignard reagent ethylene oxide ether, heat 3 3 -octanol (7 yield (.39 Br Mg R This reaction is another epoxide ring-opening reaction. To understand this reaction, recall that the carbon in the Mg bond of the Grignard reagent has carbon-anion character and is therefore a very basic carbon (Sec. 8.8B. This carbon is the nucleophile that reacts with the epoxide. At the same time, the magnesium of the Grignard reagent, which is a ewis acid, coordinates to the epoxide oxygen. (Recall that Grignard reagents associate strongly with ether oxygens; see Eq. 8.3, p. 36. Just as protonation of an oxygen makes it a better leaving group, coordination of an oxygen to a ewis acid also makes it a better leaving group. onsequently, this coordination assists the ring opening of the epoxide in much the same way that Brønsted acids catalyze ring opening (Sec..4B. R MgBr R 3 Mg R MgBr Br R 3 MgBr RMgBr a bromomagnesium alkoxide (.40a As Eq..40a shows, this reaction yields an alkoxide, which is the conjugate base of an alcohol (Sec. 8.6A. After the Grignard reagent has reacted, the alkoxide is converted into the alcohol product in a separate step by the addition of water or dilute acid: R MgBr Mg Br R 3 (.40b It would be reasonable to suppose that Grignard and organolithium reagents would react with epoxides other than ethylene oxide, and they do. owever, many reactions of Grignard and lithium reagents with epoxides are unsatisfactory because they give not only the expected products of ring opening but also rearrangements and other side reactions as well. (Grignard reagents and organolithium reagents have some ewis acid character that promotes such side reactions. owever, another type of organometallic reagent, the lithium organocuprate, undergoes useful ring-opening reactions with epoxides. Two types of organocuprates are used most commonly in organic chemistry. The first type is formed from the reaction of two equivalents of an alkyllithium reagent with copper(i halide in an ether solvent. The first equivalent reacts to form an alkylcopper reagent plus a lithium halide. The driving force for the reaction is the greater tendency of lithium, the more electropositive metal, to exist as an ion. 3 i u l 3 u i l (.4 Because the copper is a ewis acid, the alkylcopper reagent reacts with a second equivalent of the alkyllithium to give a lithium dialkylcuprate. 3 i u 3 i u( 3 lithium diethylcuprate (a lithium dialkylcuprate (.4

8 50 APTER TE EMISTRY F ETERS, EPXIDES, GYS, AND SUFIDES (Aryllithium reagents such as phenyllithium, Phi, can also be used to prepare lithium diarylcuprates. If copper(i cyanide, un, is used instead of a copper(i halide, the cyanide group, which is much more basic than halide, remains bound to the copper, and a more complex reagent is formed: 3 i un ( 3 u(ni a higher-order organocuprate (.43 Although Eq..43 describes the stoichiometry of the reagent, it exists in a state (or states of higher aggregation. Such reagents are called higher-order organocuprates. Both types of organocuprate reagents are useful in organic chemistry, and both react with epoxides. owever, the higher-order organocuprates are the preferred reagents for use with epoxides because they react with a wider variety of epoxides and give fewer side reactions. (We ll see some important uses of lithium dialkylcuprates in later chapters. An organocuprate reagent reacts at the carbon of the epoxide with fewer alkyl substituents to give products of ring opening. Protonolysis gives the alcohol. ( 3 u(ni 3 0 TF 3 i u(n i un i (S,S--ethyl--methyl--cyclopentanol (96 yield (.44 Notice that the alkyl group from the reagent reacts at the epoxide carbon with inversion of stereochemical configuration. We can think of the reaction as an S N process in which a carbon anion nucleophile is delivered from the copper to the epoxide carbon electrophile with stereochemical inversion. Epoxide opening is assisted by lithium ion, which is a built-in ewis acid: i i R R R u(ni R 3 u(ni (.45 This mechanism doesn t take into account the aggregated structure of the reagent, but it correctly predicts the chemical and stereochemical outcome of the reaction. The reactions of organometallic reagents with epoxides provide other methods for the synthesis of alcohols that can be added to the list in Sec You should ask yourself what limits the types of alcohols that can be prepared by each method.

9 .5 PREPARATIN AND XIDATIVE EAVAGE F GYS 503 These reactions also provide methods for the formation of carbon carbon bonds. Reactions that form carbon carbon bonds are especially important in organic chemistry because they can be used to lengthen carbon chains. We ll explore this point further in Sec..9. PRBEMS. (a From what Grignard reagent can 3-methyl--pentanol be prepared by reaction with ethylene oxide, then aqueous acid? (b From what epoxide and what higher-order cuprate reagent can 3-ethyl-3-heptanol be prepared? (c Give the structure of another epoxide and another higher-order cuprate that could be used to prepare the alcohol in Eq omplete the following reactions by giving the structures of the alcohol products. In part (b, show the stereochemistry of the product as well. (a Mg bromocyclopentane 3 ether (b Ph i un ether PREPARATIN AND XIDATIVE EAVAGE F GYS Glycols are compounds that contain hydroxy groups on adjacent carbon atoms. R R R R general structure of a glycol (R = alkyl, aryl, or Example: 3,-propanediol (propylene glycol Although glycols are alcohols, some glycol chemistry is quite different from the chemistry of alcohols. Some of this unique chemistry is the subject of this section. A. Preparation of Glycols You have already learned that some glycols can be prepared by the acid-catalyzed reaction of water with epoxides (Eq..36. This is one of two important methods for the preparation of glycols. The other important method for the preparation of glycols is the oxidation of alkenes with s 4. Ph $ NaS 3 (or other reducing agent A s 4 Ph $ 3 3 a glycol (90 95 yield reduced forms of s (.46