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Ethers & Epoxides. Chapter 11. 11.1 Structure, Fig. 11-1. The functional group of an ether is an oxygen atom bonded to two carbon atoms in dialkyl ethers, oxygen is sp 3 hybridized with bond angles of approximately 109.5°. in dimethyl ether, the C-O-C bond angle is 110.3°. Structure.

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Ethers epoxides

Ethers & Epoxides

Chapter 11


11 1 structure fig 11 1
11.1 Structure, Fig. 11-1

  • 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
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


11 2 nomenclature ethers

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)

11.2 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 cyclic ethers
Nomenclature: cyclic 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


11 3 physical properties fig 11 2
11.3 Physical Properties, Fig. 11-2

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


Physical properties fig 11 3
Physical Properties, Fig. 11-3

  • 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


11 4 a preparation of ethers
11.4 A.Preparation of Ethers

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


Preparation of ethers
Preparation of Ethers

  • yields are highest with methyl and 1° halides,

  • lower with 2° halides (competing -elimination)

  • reaction fails with 3° halides (-elimination only)


B preparation of ethers
B. 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 ethers1
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 ethers2
Preparation of Ethers

Step 3: proton transfer to solvent completes the reaction


C preparation of ethers
C. 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 ethers3
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 ethers4
Preparation of Ethers

Step 3: proton transfer to solvent completes the reaction


11 4 reactions a cleavage of ethers
11.4 Reactions, A. 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
Cleavage of Ethers

  • A dialkyl ether is cleaved to two moles of haloalkane


Cleavage of ethers1
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 ethers2
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


B oxidation of ethers
B. 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


11 6 silyl ethers as protecting groups
11.6 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
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 groups1
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 groups2
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 groups3
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 groups4
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 groups5
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 groups6
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


11 7 epoxides

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)

11.7 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


11 8 a synthesis of epoxides

A

g

2

C

H

=

C

H

O

H

C

C

H

2

2

2

2

2

Oxirane

(Ethylene oxide)

11.8 A.Synthesis of Epoxides

  • Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene

2

+

O


B synthesis of epoxides

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)

B. 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
Synthesis of Epoxides

  • Epoxidation of cyclohexene


Synthesis of epoxides1
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 epoxides2
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 epoxides3
Synthesis of Epoxides

  • A mechanism for alkene epoxidation


C synthesis of epoxides
C. Synthesis of Epoxides

  • Epoxides are can also be synthesized via halohydrins

    • the second step is an internal SN2 reaction


Synthesis of epoxides4

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


    D synthesis of epoxides
    D. Synthesis of Epoxides

    • Sharpless epoxidation

      • stereospecific and enantioselective


    Reactions of epoxides
    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


    11 9 a reactions of epoxides

    +

    O

    H

    H

    H

    O

    H

    O

    2

    Oxirane

    1,2-Ethanediol

    (Ethylene oxide)

    (Ethylene glycol)

    11.9 A.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 epoxides1
    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 epoxides2
    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 epoxides3
    Reactions of Epoxides

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


    B epoxides
    B. 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


    Reactions of epoxides4

    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


    11 10 ethylene oxide
    11.10 Ethylene Oxide

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


    Ethylene oxide
    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
    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


    Epichlorohydrin1
    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


    Epichlorohydrin2
    Epichlorohydrin

    • an example of a compound containing the three-carbon skeleton of epichlorohydrin is nadolol, a b-adrenergic blocker with vasodilating activity


    11 11 crown ethers
    11.11 Crown Ethers

    • Crown ether:a cyclic polyether derived from ethylene glycol or a substituted ethylene glycol

      • the parent name is crown, preceded by a number describing the size of the ring and followed by the number of oxygen atoms in the ring


    Crown ethers
    Crown Ethers

    • The diameter of the cavity created by the repeating oxygen atoms is comparable to the diameter of alkali metal cations

      • 18-crown-6 provides very effective solvation for K+


    11 12 a thioethers
    11.12 A.Thioethers

    • The sulfur analog of an ether

      • IUPAC name: select the longest carbon chain as the parent and name the sulfur-containing substituent as an alkylsulfanyl group

      • common name: list the groups bonded to sulfur followed by the word sulfide


    Nomenclature
    Nomenclature

    • Disulfide: contains an -S-S- group

      • IUPAC name: select the longest carbon chain as the parent and name the disulfide-containing substituent as an alkyldisulfanyl group

      • Common name: list the groups bonded to sulfur and add the word disulfide


    B preparation of sulfides
    B. Preparation of Sulfides

    • Symmetrical sulfides: treat one mole of Na2S with two moles of a haloalkane


    Preparation of sulfides
    Preparation of Sulfides

    • Unsymmetrical sulfides: convert a thiol to its sodium salt and then treat this salt with an alkyl halide (a variation on the Williamson ether synthesis)


    C oxidation sulfides
    C. Oxidation Sulfides

    • Sulfides can be oxidized to sulfoxides and sulfones by the proper choice of experimental conditions


    Ethers epoxides

    Ethers

    &

    Epoxides

    End of Chapter 11