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Organic Chemistry

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


11-1

Ethers & Epoxides


Chapter 11

11-2

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
H

H O

C H

C H

11-3

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
Ethoxyethene CH3 CH2-O-CH=CH2 (Ethyl vinyl ether)

11-4

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
OH CH3 CH2 OCH 2 CH3 OCH2 CH3 Ethoxyethane (Diethyl ether) trans-2-Ethoxycyclohexanol CH3 CH3 OCCH3 CH3 2-Methoxy-2methylpropane (tert-Butyl methyl ether)

11-5

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
2 1O 3

O O

O O O Oxirane Oxetane Oxolane Oxane 1,4-Dioxane (Ethylene oxide) (Tetrahydrofuran) (Tetrahydropyran)

11-6

Physical Properties
Although

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

11-7

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

11-8

Preparation of Ethers
Williamson
CH3

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


CH3 CHO N a Sodium isopropoxide
+

CH3 I

SN 2

CH3 CH3 CHOCH3 2-Methoxypropane (Isopropyl methyl ether)

Na I

+ -

Iodomethane (Methyl iodide)

11-9

Preparation of Ethers
yields are highest with methyl and 1 halides, lower with 2 halides (competing -elimination) reaction fails with 3 halides (-elimination only)
CH3 CH3 SN2 CH3 CO- K+ + CH3 Br CH3 COCH3 + K+ BrCH3 CH3 Potass ium Bromomethane 2-Methoxy-2-methylpropane t ert- bu toxide (Methyl bromid e) (t ert -Butyl methyl ether)
CH3 CH3 CBr + CH3 2-Bromo-2methylprop ane CH3

CH3 O Na

E2

CH3 C=CH2 + CH3 OH + Na Br 2-Methylprop ene

Sodium methoxide

11-10

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)
2 CH3 CH2 OH Ethanol H2 SO4 140C CH3 CH2 OCH2 CH3 + H2 O D iethyl eth er

11-11

Preparation of Ethers
Step 1: proton transfer gives an oxonium ion
O CH3 CH2 -O-H + H-O-S-O-H O fas t and reversib le O + CH3 CH2 -O-H + - O-S-O-H O H An oxon ium ion

Step 2: nucleophilic displacement of H2O by the OH group of the alcohol gives a new oxonium ion
+ SN2 CH3 CH2 -O-H + CH3 CH2 -O-H H + CH3 CH2 -O-CH2 CH3 + O-H H H A new oxonium ion

11-12

Preparation of Ethers
Step 3: proton transfer to solvent completes the reaction
+ CH3 CH2 -O-CH2 CH3 + O-H H H proton tran sfer + CH3 CH2 -O-CH2 CH3 + H O-H H

11-13

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
CH3 CH3 C= CH2 + CH3 OH acid catalyst CH3 CH3 COCH3 CH3 2-Methoxy-2-methyl propane

11-14

Preparation of Ethers
Step 1: protonation of the alkene gives a carbocation
CH3 CH3 C=CH2 + H + O CH3 H CH3 CH3 CCH3 + + O CH3 H

Step 2: reaction of the carbocation (an electrophile) with the alcohol (a nucleophile) gives an oxonium ion
CH3 CH3 CCH3 + HOCH3 + CH3 CH3 CCH3 + O CH3 H

11-15

Preparation of Ethers
Step 3: proton transfer to solvent completes the reaction
CH3 CH3 O H + CH3 CCH3 + O H CH3 CH3 + CH3 O H + CH3 CCH3 H O CH 3

11-16

Cleavage of Ethers
Ethers

are cleaved by HX to an alcohol and a haloalkane


R-O-R + H-X R-O-H + R-X

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-

11-17

Cleavage of Ethers
A

dialkyl ether is cleaved to two moles of haloalkane


O Dibutyl ether + 2HBr heat 2 Br + H2 O 1-Bromobutane

11-18

Cleavage of Ethers
Step 1: proton transfer to the oxygen atom of the ether gives an oxonium ion
CH3 CH2 -O-CH2 CH3 + H + O H H fast an d reversible + CH3 CH2 -O-CH2 CH3 + H A n oxon ium ion O H H

Step 2: nucleophilic displacement on the 1 carbon gives a haloalkane and an alcohol


+ Br: + CH3 CH2 -O-CH2 CH3 H
-

SN2

CH3 CH2 -Br +

O-CH2 CH3 H

the alcohol is then converted to an haloalkane by another SN2 reaction

11-19

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
O + HCl A tert - butyl ether OH + + Cl SN1 Cl

A 3 carbocation intermed iate

11-20

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
O-O-H + O2 O D iethyl ether
+ O2

O A h yd roperoxide
O-O-H O A hydroperoxid e

O D iisopropyl ether

Hydroperoxide:

a compound containing the OOH


11-21

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
OH H 4-Pentyn-1-ol 4-Heptyn-1-ol ? OH

11-22

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
pK a 16-18 pK a 25 H OH + Na+ NH 2 H O-Na+ + NH3

11-23

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

11-24

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
O=Si=O S ilicon dioxide H H-Si-H H Silane CH3 CH3 -Si-CH3 CH3 Tetramethylsilane CH3 CH3 -Si-Cl CH3 Ch lorotrimethylsilane

11-25

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
CH3 RCH2 O-Si-CH3 + Et 3 NH+ ClCH3 A trimeth yls ilyl Triethylether ammonium chloride

CH3 RCH2 OH + Cl-Si-CH3 + Et 3 N CH3 Chlorotri- Triethylmethylsilane amin e

11-26

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
Me Me Si Cl Me Trimethylsilyl chlorid e (TMSCl) Et Et Si Cl Et Me Si Cl Me Si Cl Triis op ropylsilyl chloride (TIPS Cl)

Trieth yls ilyl t -Butyldimethylsilyl chlorid e chloride (TESCl) (TBD MS Cl)

11-27

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
RCH2 O Si A TBDMS-protected alcohol + F
-

Bu4 N+ FTHF

RCH2 OH + F Si

11-28

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
OH H 4-Pentyn-1-ol CH3 O Si CH3 CH3 4 . Bu4 N+ FOH 4-Hep tyn -1-ol CH3 + F Si CH3 CH3 1 . ( CH3 ) 3 SiCl H CH3 O Si CH3 CH3 2 . Na+ NH2 Br 3.

11-29

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
2 3

H2 C
1O

CH 2

H3 C

H C C

CH 3

H O

Oxirane (Ethylene oxide)

O cis-2,3-Dimethyloxirane (cis-2-Butene oxide)

H 1,2-Epoxycyclohexane (Cyclohexene oxide)

11-30

Synthesis of Epoxides
Ethylene

oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene
2 CH2 = CH2 + O2 Ag 2 H2 C CH2 O Oxirane (Ethylene oxide)

11-31

Synthesis of Epoxides
The

most common laboratory method is oxidation of an alkene using a peroxycarboxylic acid (a peracid)
O CO O H O CO O H O CH 3 CO O H Peroxyacetic acid (Peracetic acid)

Cl meta-chloroperoxybenzoic acid (MCPBA)

CO O

Mg

2+

Magnesium monoperoxyphthalate (MMPP)

11-32

Synthesis of Epoxides
Epoxidation

of cyclohexene
O RCOOH H CH2 Cl2 O + O RCOH

+ Cycloh exene

A p eroxycarboxylic acid

H 1,2-Ep oxycyclohexan e A carboxylic (Cycloh exene oxide) acid

11-33

Synthesis of Epoxides
Epoxidation

is stereospecific:

epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane epoxidation of trans-2-butene gives only trans-2,3dimethyloxirane
H C H3 C C H CH3 RCO3 H H H3 C C CH3 H + C O H H3 C C C H CH3

trans- 2-Buten e

O t rans- 2,3-D imethyloxirane (a racemic mixture)

11-34

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

11-35

Synthesis of Epoxides
A

mechanism for alkene epoxidation


R O
3

R O C O O C C

C
2

H
4

O
1

O C C

11-36

Synthesis of Epoxides
Epoxides

are can also be synthesized via halohydrins


CH3 CH=CH2 Propene Cl2 , H2 O OH O NaOH, H2 O CH3 CH-CH2 CH3 CH CH2 SN 2 Cl A chlorohydrin Meth yloxiran e (racemic) (racemic)

the second step is an internal SN2 reaction


O C C Cl O internal S N 2 C C + Cl

An epoxide

11-37

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-2butene to an epoxide by the halohydrin method gives only cis-2,3-dimethyloxirane
H H3 C 1 . Cl 2 , H 2 O C C CH 3 2 . N a O H , H O 2 cis-2-Butene H H3 C H C C

H CH 3

O cis-2,3-Dimethyloxirane

11-38

Synthesis of Epoxides
Sharpless

epoxidation
T i( O-iPr) 4

stereospecific and enantioselective


R2 R3 (-)-D iethyl tartrate + OH A n allylic alcoh ol tert -Bu tyl h yd roperoxid e OOH
T i( O-iPr) 4

R2 R3 A R2 R3 B

R1 O + OH OH

R1

R1 O + OH OH

(+)-D iethyl tartrate

OH Et OOC COOEt Et OOC OH (2S,3S)-(-)-D iethyl tartrate

OH COOEt OH (2R ,3R)-(+)-D iethyl tartrate

11-39

Reactions of Epoxides
Ethers

are not normally susceptible to attack by nucleophiles Because of the strain associated with the threemembered ring, epoxides readily undergo a variety of ring-opening reactions
Nu C O C

+ HN u :
HO

11-40

Reactions of Epoxides
Acid-catalyzed

ring opening

in the presence of an acid catalyst, such as sulfuric acid, epoxides are hydrolyzed to glycols
O + H2 O Oxirane (Ethylene oxide) H+ HO OH

1,2-Ethanediol (Ethylene glycol)

11-41

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
H H
2

O
3

H2 C O
1

CH2 H O H
(1)

H2 C +

CH2 O+ H
2

H H +O 3 CH2 CH2 OH

OH CH2 CH2 + H3 O+ OH

11-42

Reactions of Epoxides
Attack

of the nucleophile on the protonated epoxide shows anti stereoselectivity


hydrolysis of an epoxycycloalkane gives a trans-1,2diol
O + H2 O H
+

OH +

OH

1,2-Epoxycyclop entan e (Cyclopen tene oxide) (achiral)

OH OH trans- 1,2-Cyclop entaned iol (a racemic mixtu re)

11-43

Reactions of Epoxides
Compare

the stereochemistry of the glycols formed by these two methods


H RCO3 H O H OH OsO4 , t-BuOOH OH cis -1,2-Cyclopentan ediol (ach iral) H H2 O
+

OH +

OH

OH OH t rans- 1,2-Cyclopen tanediol (formed as a racemic mixtu re)

11-44

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
CH3 HSCH2 CHOH A -mercaptoalcohol Na SH / H2 O H2 C Na+C N- / H2 O CH3 N CCH2 CHOH A -hydroxynitrile
+ -

CH3 HOCH2 CHOH A glycol H2 O/ H3 O CH3 CH O Methyloxiran e


+

CH3 HC CCH2 CHOH A -alk yn ylalcoh ol


+ 1 . HC C Na 2 . H2 O

NH3 CH3 H2 NCH2 CHOH A -aminoalcohol

11-45

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:CH CH 2 1 . L i A l H4
2 . H2 O CH - CH 3 OH 1-Phenylethanol

O Phenyloxirane (Styrene oxide)

11-46

Ethylene Oxide
ethylene oxide is a valuable building block for organic synthesis because each of its carbons has a functional group
OH N C (1) O Na CN
+ -

H2 / M (2) O (4)

OH H2 N OH CH3 N OH (5) H2 SO4 CH3 N O SOCl2 (6) CH3 N Cl (7) NH3 CH3 N N-H Cl

OH

CH3 NH2 (3)

CH3 N H
+

(8) CH3 C C Na

OH

11-47

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
O O H2 N Procaine O Eth ylen e oxide + N H D iethylamine N H2 N O OH + HO N

11-48

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
Cl + HCl + Cl2 500C Prop ene 3-Chlorop ropen e (Allyl chloride) OH Step 2: Cl Cl Cl + HCl + Cl2 / H2 O Step 1: OH Step 3: Cl Cl + Ca(OH) 2 Cl O

+ CaCl2 Ep ichloroh yd rin (racemic)

11-49

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
Cl O Nu Nu O OH Nu Nu Nu

Epichlorohydrin

11-50

Epichlorohydrin
an example of a compound containing the threecarbon skeleton of epichlorohydrin is nadolol, a adrenergic blocker with vasodilating activity
Cl O HO HO N adolol (racemic) N OH H OHO HO a nu cleophile d erived b y removal of th e acidic H from an -OH group H2 N the nitrogen nu cleophile of a 1 amin e O

11-51

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

O O O O 18-Crown -6 O O

11-52

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+

11-53

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
S Ethylsulfanylethan e (D ieth yl s ulfide) S 2-Eth yls ulfanylprop ane (Eth yl is op ropyl su lfid e)

11-54

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
S Ethyldis ulfanylethane (Diethyl disulfide) S

11-55

Preparation of Sulfides
Symmetrical

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


2 RX + Na2 S
SN 2

RSR + 2 NaX A sulfide


+ 2Na Cl
+ -

Cl

Cl

+ Na2 S

1,4-Dichlorobutane

S Thiolane (Tetrahydrothiophen e)

11-56

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)
CH3(CH2)8CH2S Na Sodium 1-decanethiolate
+

+ CH3I

SN2

CH3(CH2)8CH2SCH3 + Na+ I1-Methylsulfanylde cane (De cyl meth yl sulfide)

11-57

Oxidation Sulfides
Sulfides

can be oxidized to sulfoxides and sulfones by the proper choice of experimental conditions
S- CH3 Methyl phenyl sulfide H2 O2
25 oC

O NaIO 4 S- CH3 o Methyl phenyl sulfoxide

25 C

O S- CH3 O Methyl phenyl sulfone

2CH3 -S-CH3 + O2 Dimethyl su lfid e

oxides of nitrogen

O 2CH3 -S-CH3 Dimethyl su lfoxide

11-58

Ethers & Epoxides


End of Chapter 11
11-59