11.5 Preparation and Oxidative Cleavage of Glycols 503

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11.5 PREPARATION AND OXIDATIVE CLEAVAGE OF GLYCOLS 503

These reactions also provide methods for the formation of carbon–carbon bonds. Reac- tions 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. 11.9.

PROBLEMS 11.21 (a) From what Grignard reagent can 3-methyl-1-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. 11.44. 11.22 Complete the following reactions by giving the structures of the alcohol products. In part (b), show the stereochemistry of the product as well. (a) O Mg + bromocyclopentane H3O

ether .. (b) O .. HHCC + H3C CH3 H3O 2 Ph Li+ CuCN ether

11.5 PREPARATION AND OXIDATIVE CLEAVAGE OF GLYCOLS

Glycols are compounds that contain hydroxy groups on adjacent carbon atoms.

OH OH OH

RR""C C Example: H3C" CH CH2OH LLL LL RR) ) 1,2-propanediol (propylene glycol) general structure of a glycol (R = alkyl, aryl, or H)

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. 11.36). 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

OsO4.

Ph H2O OH OH

NaHSO3 (or other $ reducing agent) $C A CH2 OsO4 Ph ""CCH2 reduced forms of Os (11.46) ++LL H3C "CH3 a glycol (90–95% yield) 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 504

504 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES

The osmium in OsO4 is in a 8 oxidation state. Metals in high oxidation states (such as Mn(VII) and Cr(VI), as you’ve learned)+ are oxidizing agents because they attract electrons. This electron-attracting ability of Os(VIII) results in a concerted (that is, one-step) cycloaddition re-

action between OsO4 and an alkene to give an intermediate called an osmate ester:

O O

S Os accepts O O L S L S S (11.47a) Os(VIII) S Os electrons Os Os(VI) O SO O O 2 L L Further Exploration 11.1 R C CR R2CA CR2 2 2 Mechanism of L OsO4 Addition an osmate ester (The osmate ester is another example of an organic ester derivative of an inorganic acid; Sec. 10.3C.) The curved-arrow notation shows that in this reaction osmium accepts an electron pair. As a result, its oxidation state is decreased to 6. A glycol is formed when the cyclic osmate ester+ is treated with water. Two water mole- cules, acting as nucleophiles, displace the glycol oxygens from the osmium. A mild reducing

agent such as sodium bisulﬁte, NaHSO3, is often added to convert the osmium-containing by- products into reduced forms of osmium that are easy to remove by ﬁltration. (The NaHSO3 is converted into sodium sulfate, Na2SO4.)

O O nucleophilic substitution L

LSOs S at Os by H2O O O OH OH 2 O S O L L S NaHSO3 R2C CR2 2H2O R2""C CR2 Os reduced forms (11.47b) L L L + + HO L OH of osmium 2

Two practical drawbacks to the use of the OsO4 oxidation are that osmium and its compounds are very toxic, and they are quite expensive. However, the reaction of OsO4 with alkenes is so useful that chemists have devised ways for it to be used with very small amounts

of OsO4. This is done by including in the reaction mixture an oxidant that “recycles” the Os(VI) by-product back into OsO4. Among the common oxidants used for this purpose are

amine oxides, which are compounds of the form R3N| O_. Two amine oxides used com-

monly are the following: L 1 1

LO _ (CH ) N| O ON| 1 3 3 3 _ L L 1 3 0 CH3 trimethylamine-N-oxide (TMAO) N-methylmorpholine-N-oxide (NMMO)

In other words, once a small amount of OsO4 is used up, the Os(VI) by-product is oxidized within the reaction mixture by the amine oxide to re-form OsO4. Thus, a catalytic amount of

OsO4 can be used and the amine oxide acts as the ultimate oxidant. "

H C CH HO " OH

3 3 OsO4

" (10 4 mole) " H O C A C (CH ) N| O _ C C (CH ) N 2 $ ) 3 3 _ water/tert-butyl H3C CH3 3 3 + + L L LL + H C CH alcohol 3 ) $ 3 TMAO pyridine H3C CH3 (0.034 mole) 2,3-dimethyl-2-butene 2,3-dimethyl-2,3-butanediol (0.025 mole) (85% yield) (11.48) 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 505

11.5 PREPARATION AND OXIDATIVE CLEAVAGE OF GLYCOLS 505

The OsO4 oxidation is particularly useful because of its stereochemistry. The formation of

glycols from alkenes is a stereospeciﬁc syn-addition. L OH O OsO4 _ (0.3 mole %) H O ON| ONCH (11.49) 2 L acetone/water 3 + y + 0 CH3 ` OH + 0 L cyclohexene NMMO cis-1,2-cyclohexanediol (89% yield)

The mechanism of this reaction provides a simple explanation for the syn stereochemistry.

The ﬁve-membered osmate ester ring is easily formed when two oxygens of OsO4 are added to the same face of the double bond by a concerted mechanism. This process closely resem- bles the concerted cycloaddition mechanism of ozonolysis. (See Eq. 5.34, p. 197.) Hydrolysis of the osmate ester gives the glycol.

O S O O O L

S LSOs S S Os S O O OH OH O O 2 syn-addition H O R R L L 2 $ CCA R CCR RRCC) (11.50) R R L L RR R R an osmate ester a 1,2-glycol

On the other hand, an anti-addition by a concerted mechanism would be very difﬁcult, if not

impossible: the two reacting oxygens of OsO4 cannot simultaneously reach opposite faces of the p bond.

The hydrolysis of epoxides and the OsO4 oxidation are complementary reactions because they provide glycols of different stereochemistry. This point is explored in Study Problem 11.4.

Study Problem 11.4 Outline preparations of cis-1,2-cyclohexanediol and (Ϯ)-trans-1,2-cyclohexanediol from cyclohexene.

Solution As Eq. 11.49 shows, the direct oxidation of cyclohexene by OsO4 yields cis-1,2- cyclohexanediol by a syn-addition. In contrast, conversion of cyclohexene into the epoxide with a peroxycarboxylic acid (see Problem 11.11a), followed by acid-catalyzed hydrolysis (Eq. 11.36), gives the trans-diol. Epoxide hydrolysis gives the trans-diol because it occurs with inversion of conﬁguration.

RCO3H OH (for example, mCPBA) H3O , H2O | O (occurs with (11.51) y ` inversion) ` OH cyclohexene cyclohexene ( )-trans-1,2-cyclohexanediol | oxide _

(Remember the following convention: Although we draw a single enantiomer of the product for convenience, it should be understood to be the racemate; Sec. 7.8A.) 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 506

506 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES

Glycol formation from alkenes can also be carried out with potassium permanganate

(KMnO4), usually under aqueous alkaline conditions. This reaction is also a stereospeciﬁc syn-addition, and its mechanism is probably similar to that of OsO4 addition. OH

H2O, OH _ (11.52) KMnO4 acetone OH MnO2 ++(purple (brown ppt) solution) (45% yield)

Although the use of KMnO4 avoids the expense of OsO4, a problem with the use of KMnO4 is that yields are low in many cases because over-oxidation occurs; that is, the glycol product is oxidized further. Conditions have to be carefully worked out in each case to avoid this side reaction.

The manganese in MnO_4 is in the 7 oxidation state. It is converted into Mn(IV) as a result of the reaction. Visually, when oxidation+ occurs, the brilliant purple color of the permanganate

ion is replaced by a murky brown precipitate of manganese dioxide (MnO2). This color change can be used as a test for functional groups that can be oxidized by KMnO4.

PROBLEMS 11.23 What organic product is formed (including its stereochemistry) when each of the following

alkenes is treated with NMMO in the presence of H2O and a catalytic amount of OsO4? (a) 1-methylcyclopentene (b) trans-2-butene

11.24 From what alkene could each of the following glycols be prepared by the OsO4 or KMnO4 method? (a) OH (b)OH (c) meso-4,5-octanediol

CH CH OCH CH "CHCH OH " CH2OH 3 2 2 2 2 L V 11.25 Show a curved-arrow mechanism for the ﬁrst step, and the structure of the cyclic intermedi-

ate formed, when an alkene is treated with KMnO4. A Lewis structure for the permanganate

1 ion is as follows: 1

O S O 3 S 3 SMn L O O _ 3 1 3 1 3 permanganate ion

B. Oxidative Cleavage of Glycols The carbon–carbon bond between the OH groups of a glycol can be cleaved with periodic acid to give two carbonyl compounds: L

OH OH O O S S H IO Ph "CH "C CH Ph CH H C C CH 2H O HIO H O 5 6 3 dilute HOAc 3 3 2 3 2 + LLL anLL aldehyde + aL ketoneL ++8 periodic "CH (77–83% yield) acid 3 a glycol (11.53)

Periodic acid (pronounced PURR-eye-OH-dik) is the iodine analog of perchloric acid.

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11.5 PREPARATION AND OXIDATIVE CLEAVAGE OF GLYCOLS 507

Periodic acid is commercially available as the dihydrate, HIO4 2H2O, often abbreviated, as in Eq. 11.53, as H5IO6 (sometimes called para-periodic acid). Its sodium8 salt, NaIO4 (sodium metape- riodate), is sometimes also used. Periodic acid is a fairly strong acid (pKa 1.6). The periodate cleavage reaction has been used as a test for glycols as well as for synthesis.= The - formulas HIO4 or H5IO6 are used interchangeably for periodic acid. The cleavage of glycols with periodic acid takes place through a cyclic periodate ester inter-

mediate (Sec. 10.3C) that forms when the glycol displaces two OH groups from H5IO6. L H H

OH Ph ) OH $ O

Ph OH C"

" " HO OH OH

"C %

"I $ % "I 2H O (11.54a) ) " ) 2 + HO $ O "C O + H3C " "C " OH # O ) # "OH H3C "OH "CH3 CH3 H5IO6 a glycol contains iodine (VII) a cyclic periodate ester; contains iodine (VII)

The cyclic ester spontaneously breaks down by a cyclic ﬂow of electrons in which the iodine accepts an electron pair. (The direction of electron ﬂow is arbitrary.)

iodine accepts an electron pair

H $ ) $C O Ph O OH OH

C" OH OH

% Ph

$ % "I "I (11.54b) " ) )

"C O H3C + 3 O ) # $ # H C O "OH "OH 3 C O CH3 $ H3IO4 (or HIO3 H2O) H3C contains iodine8 (V) aldehydes and/or ketones

A glycol that cannot form a cyclic ester intermediate is not cleaved by periodic acid. For example, the following compound is not cleaved because it is impossible for both oxygens to be part of the same cyclic periodate ester. (If you can’t see why, build a model and try connect- ing the two oxygens with one other atom.)

"OH

Do not confuse osmium tetroxide, permanganate, and periodate oxidations, all of which occur through cyclic ester intermediates (Sec. 11.4A). Periodate oxidizes glycols, but the other two reagents oxidize alkenes to give glycols. In all of these reactions, oxidation occurs because an atom in a highly positive oxidation state can accept an additional pair of electrons. In the periodate oxidation, the reduction of the iodine occurs during the breakdown of a cyclic ester; in the permanganate and osmium tetroxide oxidations, the metals are reduced during the formation of a cyclic ester. 11_BRCLoudon_pgs4-4.qxd 11/26/08 8:56 AM Page 508

508 CHAPTER 11 • THE CHEMISTRY OF ETHERS, EPOXIDES, GLYCOLS, AND SULFIDES

PROBLEMS 11.26 Give the product(s) expected when each of the following compounds is treated with periodic acid. (a) OH OH (b) OH (c) OH "CH CH PhCH "CHCH OH 3 2 2 ` L OH V 11.27 What glycol undergoes oxidation to give each of the following sets of products?

(a) H3C (b) O $ S $C AAOO + H3C S O

11.6 OXONIUM AND SULFONIUM SALTS

A. Reactions of Oxonium and Sulfonium Salts If the acidic hydrogen of a protonated ether is replaced with an alkyl group, the resulting compound is called an oxonium salt. The sulfur analog of an oxonium salt is a sulfonium salt:

H R CH3 O O O "| "| "| _BF4 RR3 RR3 H C 3 CH % % % % 3 % % 3 a protonated a trialkyloxonium trimethyloxonium ether ion tetrafluoroborate (an oxonium salt)

H R CH3 "S "S "S | | | NO_3 R 3 R R 3 R H C 3 CH % % % % 3 % % 3 a protonated a trialkylsulfonium trimethylsulfonium sulfide ion nitrate (a sulfonium salt)

Oxonium and sulfonium salts react with nucleophiles in SN2 reactions:

1 1 CH3 1 HO H CO BF HO CH (CH ) O BF _ 3 |" _4 3 3 2 _4 (11.55) 1 3 + L 3 1 ++(89% yield)3

"CH3

1 1 heat (11.56) Ph CH S| CH3 Br _ Ph CHS CH3 CH3Br LLL2 3 1 3 LLL2 + 1 3 "CH3 "CH3 "CH3 2

| (CH3)3N(CH3)3S| NO_3 (CH3)4N NO_3 (CH3)2S (11.57) 33++2 2 Oxonium salts are among the most reactive alkylating agents known, and they react very rapidly with most nucleophiles. Because of their reactivity, oxonium salts must be stored in the absence of moisture. For the same reason, these salts are stable only when they contain