Organic Chemistry

Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson

Ethers & Epoxides Chapter 11

Structure • The functional group of an ether is an oxygen atom bonded to two carbon atoms • in dialkyl ethers, oxygen is sp3 hybridized with bond angles of approximately 109.5°. • in dimethyl ether, the C-O-C bond angle is 110.3°

Structure • in other ethers, the ether oxygen is bonded to an sp2 hybridized carbon • in ethyl vinyl ether, for example, the ether oxygen is bonded to one sp3 hybridized carbon and one sp2 hybridized carbon

C H O H 3 C H O C C H C H C H O C H C H 3 3 3 2 2 3 C H O C H C H 3 2 3 Ethoxyethane trans- 2-Ethoxy- 2-Methoxy-2- (Diethyl ether) methylpropane cyclohexanol ( tert- Butyl methyl ether) Nomenclature: ethers • IUPAC: the longest carbon chain is the parent • name the OR group as an alkoxy substituent • Common names: name the groups bonded to oxygen in alphabetical order followed by the word ether

Nomenclature: ethers • Although cyclic ethers have IUPAC names, their common names are more widely used • IUPAC: prefix ox- shows oxygen in the ring • the suffixes -irane, -etane, -olane, and -ane show three, four, five, and six atoms in a saturated ring

Physical Properties • Although ethers are polar compounds, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state

Physical Properties • Boiling points of ethers are • lower than alcohols of comparable MW • close to those of hydrocarbons of comparable MW • Ethers are hydrogen bond acceptors • they are more soluble in H2O than are hydrocarbons

Preparation of Ethers • Williamson ether synthesis:SN2 displacement of halide, tosylate, or mesylate by alkoxide ion

Preparation of Ethers • yields are highest with methyl and 1° halides, • lower with 2° halides (competing -elimination) • reaction fails with 3° halides (-elimination only)

Preparation of Ethers • Acid-catalyzed dehydration of alcohols • diethyl ether and several other ethers are made on an industrial scale this way • a specific example of an SN2 reaction in which a poor leaving group (OH-) is converted to a better one (H2O)

Preparation of Ethers • Step 1: proton transfer gives an oxonium ion • Step 2: nucleophilic displacement of H2O by the OH group of the alcohol gives a new oxonium ion

Preparation of Ethers Step 3: proton transfer to solvent completes the reaction

Preparation of Ethers • Acid-catalyzed addition of alcohols to alkenes • yields are highest using an alkene that can form a stable carbocation • and using methanol or a 1° alcohol that is not prone to undergo acid-catalyzed dehydration

Preparation of Ethers • Step 1: protonation of the alkene gives a carbocation • Step 2: reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion

Preparation of Ethers Step 3: proton transfer to solvent completes the reaction

Cleavage of Ethers • Ethers are cleaved by HX to an alcohol and a haloalkane • cleavage requires both a strong acid and a good nucleophile; therefore, the use of concentrated HI (57%) and HBr (48%) • cleavage by concentrated HCl (38%) is less effective, primarily because Cl- is a weaker nucleophile in water than either I- or Br-

Cleavage of Ethers • A dialkyl ether is cleaved to two moles of haloalkane

Cleavage of Ethers • Step 1: proton transfer to the oxygen atom of the ether gives an oxonium ion • Step 2: nucleophilic displacement on the 1° carbon gives a haloalkane and an alcohol • the alcohol is then converted to an haloalkane by another SN2 reaction

Cleavage of Ethers • 3°, allylic, and benzylic ethers are particularly sensitive to cleavage by HX • tert-butyl ethers are cleaved by HCl at room temp • in this case, protonation of the ether oxygen is followed by C-O cleavage to give the tert-butyl cation

Oxidation of Ethers • Ethers react with O2 at a C-H bond adjacent to the ether oxygen to give hydroperoxides • reaction occurs by a radical chain mechanism • Hydroperoxide: a compound containing the OOH group

Silyl Ethers as Protecting Groups • When dealing with compounds containing two or more functional groups, it is often necessary to protect one of them (to prevent its reaction) while reacting at the other • suppose you wish to carry out this transformation

Silyl Ethers as Protecting Groups • the new C-C bond can be formed by alkylation of an alkyne anion • the OH group, however, is more acidic (pKa 16-18) than the terminal alkyne (pKa 25) • treating the compound with one mole of NaNH2 will give the alkoxide anion rather than the alkyne anion

Silyl Ethers as Protecting Groups • A protecting group must • add easily to the sensitive group • be resistant to the reagents used to transform the unprotected functional group(s) • be removed easily to regenerate the original functional group • In this chapter, we discuss trimethylsilyl (TMS) and other trialkylsilyl ethers as OH protecting groups

Silyl Ethers as Protecting Groups • Silicon is in Group 4A of the Periodic Table, immediately below carbon • like carbon, it also forms tetravalent compounds such as the following

Silyl Ethers as Protecting Groups • An -OH group can be converted to a silyl ether by treating it with a trialkylsilyl chloride in the presence of a 3° amine

Silyl Ethers as Protecting Groups • replacement of one of the methyl groups of the TMS group by tert-butyl gives a tert-butyldimethylsilyl (TBDMS) group, which is considerably more stable than the TMS group • other common silyl protecting groups include the TES and TIPS groups

Silyl Ethers as Protecting Groups • silyl ethers are unaffected by most oxidizing and reducing agents, and are stable to most nonaqueous acids and bases • the TBDMS group is stable in aqueous solution within the pH range 2 to 12, which makes it one of the most widely used -OH protecting groups • silyl blocking groups are most commonly removed by treatment with fluoride ion, generally in the form of tetrabutylammonium fluoride

Silyl Ethers as Protecting Groups • we can use the TMS group as a protecting group in the conversion of 4-pentyn-1-ol to 4-heptyn-1-ol

C H H C 3 H C C H 3 2 2 Oxirane cis- 2,3-Dimethyloxirane 1,2-Epoxycyclohexane (Ethylene oxide) ( cis- 2-Butene oxide) (Cyclohexene oxide) Epoxides • Epoxide: a cyclic ether in which oxygen is one atom of a three-membered ring • simple epoxides are named as derivatives of oxirane • where the epoxide is part of another ring system, it is shown by the prefix epoxy- • common names are derived from the name of the alkene from which the epoxide is formally derived H H 1 H 2 3 O C C O O 2 1 H

A g 2 C H = C H O H C C H 2 2 2 2 2 Oxirane (Ethylene oxide) Synthesis of Epoxides • Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene 2 + O

C O O H C O O H 2 + C H C O O H M g 3 - C O Peroxyacetic acid C l (Peracetic acid) meta- chloroperoxy- Magnesium benzoic acid monoperoxyphthalate (MCPBA) (MMPP) Synthesis of Epoxides • The most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid) O O O O 2

Synthesis of Epoxides • Epoxidation of cyclohexene

Synthesis of Epoxides • Epoxidation is stereospecific: • epoxidation of cis-2-butene gives only cis-2,3-dimethyloxirane • epoxidation of trans-2-butene gives only trans-2,3-dimethyloxirane

Synthesis of Epoxides • A mechanism for alkene epoxidation must take into account that the reaction • takes place in nonpolar solvents, which means that no ions are involved • is stereospecific with retention of the alkene configuration, which means that even though the pi bond is broken, at no time is there free rotation about the remaining sigma bond

Synthesis of Epoxides • A mechanism for alkene epoxidation

Synthesis of Epoxides • Epoxides are can also be synthesized via halohydrins • the second step is an internal SN2 reaction

C H H C 3 1 . C l , H O 3 2 2 H C C H 2 . N a O H , H O 3 3 2 cis- 2-Butene cis- 2,3-Dimethyloxirane Synthesis of Epoxides • halohydrin formation is both regioselective and stereoselective; for alkenes that show cis,trans isomerism, it is also stereospecific (Section 6.3F) • conversion of a halohydrin to an epoxide is stereoselective • Problem: account for the fact that conversion of cis-2-butene to an epoxide by the halohydrin method gives only cis-2,3-dimethyloxirane H H H H C C C C O

Synthesis of Epoxides • Sharpless epoxidation • stereospecific and enantioselective

Reactions of Epoxides • Ethers are not normally susceptible to attack by nucleophiles • Because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions

+ O H H H O H O 2 Oxirane 1,2-Ethanediol (Ethylene oxide) (Ethylene glycol) Reactions of Epoxides • Acid-catalyzed ring opening • in the presence of an acid catalyst, such as sulfuric acid, epoxides are hydrolyzed to glycols + O

Reactions of Epoxides Step 1: proton transfer to oxygen gives a bridged oxonium ion intermediate Step 2: backside attack by water (a nucleophile) on the oxonium ion (an electrophile) opens the ring Step 3:proton transfer to solvent completes the reaction

Reactions of Epoxides • Attack of the nucleophile on the protonated epoxide shows anti stereoselectivity • hydrolysis of an epoxycycloalkane gives a trans-1,2-diol

Reactions of Epoxides • Compare the stereochemistry of the glycols formed by these two methods

Epoxides • the value of epoxides is the variety of nucleophiles that will open the ring and the combinations of functional groups that can be prepared from them

1 . L i A l H 4 C H C H C H - C H 2 3 2 . H O 2 O H Phenyloxirane (Styrene oxide) Reactions of Epoxides • Treatment of an epoxide with lithium aluminum hydride, LiAlH4, reduces the epoxide to an alcohol • the nucleophile attacking the epoxide ring is hydride ion, H:- O 1-Phenylethanol

Ethylene Oxide • ethylene oxide is a valuable building block for organic synthesis because each of its carbons has a functional group

Ethylene Oxide • part of the local anesthetic procaine is derived from ethylene oxide • the hydrochloride salt of procaine is marketed under the trade name Novocaine

Epichlorohydrin • The epoxide epichlorohydrin is also a valuable building block because each of its three carbons contains a reactive functional group • epichlorohydrin is synthesized from propene

Epichlorohydrin • the characteristic structural feature of a product derived from epichlorohydrin is a three-carbon unit with -OH on the middle carbon, and a carbon, nitrogen, oxygen, or sulfur nucleophile on the two end carbons

Organic Chemistry