Ch.18: Ethers and Epoxides; Thiols and Sulfides

Dr. Sivappa RasapalliChemistry and BiochemistryUniversity of Massachusetts

Dartmouth

Coverage and ObjectivesCoverage:• The nomenclature of alcohols• Synthesis and Nucleophilic substitution reactions of ethers• Nucleophilic Opening reactions of epoxides• Chemistry of sulfur compoundsLearning objectives:• Provide both IUPAC and common names for ethers, sulfides.• Recognize the physical properties of ethers, epoxides and sulfides• Know the synthesis and chemistry of the functional groups• Write the reaction and electron-pushing (arrow-pushing) mechanism

for the synthesis and reactions of the functional groups• Write the acid-catalyzed ring-opening of epoxides, and explain the

observed stereochemistry of the products.

Nomenclature of Ethers, Epoxides, and Sulfides

18.1 Names and Properties of Ethers 18.1 Names and Properties of Ethers

Ethers, Epoxides, Thiols and sulfides

SS

S

OO

O

SH

OH

Ethers R-O-R or R-O-R´

O

Epoxide

••Ethers (ROR) can be regarded as derivatives ofEthers (ROR) can be regarded as derivatives ofalcohols (ROH).alcohols (ROH).

••Sulfides (RSR) can be regarded as derivatives ofSulfides (RSR) can be regarded as derivatives ofThols (RSH).Thols (RSH).

Nomenclature: Functional Class• simple ethers are named: “alkyl alkyl ether”• name the groups attached to oxygen in alphabetical

order as separate words; "ether" is last word;

• “dialkyl ether” if symmetric

OO

Diethyl Ether

O

diisopropyl etherDiphenyl ether

O

ethyl methyl ether

O Cl

3-chloropropyl ethyl ether

Nomenclature: Substituent• name as alkoxy derivatives of alkanes

CHCH33OOCHCH2 2 CHCH33

methoxymethoxyethaneethane

CHCH33CHCH22OOCHCH2 2 CHCH33

ethoxyethoxyethaneethane

CHCH33CHCH22OOCHCH22CHCH22CHCH22ClCl

1-chloro-3-1-chloro-3-ethoxyethoxypropanepropane

cyclopentyl cyclopentyl methylmethyl sulfide sulfide

Nomenclature: Functional Class• analogous to ethers, but replace “ether” as last

word in the name by “sulfide.”

CHCH33SSCHCH2 2 CHCH33

ethylethyl methyl sulfide methyl sulfide

CHCH33CHCH22SSCHCH2 2 CHCH33

didiethylethyl sulfide sulfide

SSCHCH33

Nomenclature: Substituent• name as alkylthio derivatives of alkanes

CHCH33SSCHCH2 2 CHCH33

methylthiomethylthioethaneethane

CHCH33CHCH22SSCHCH2 2 CHCH33

ethylthioethylthioethaneethane

(methylthio)cyclopentane(methylthio)cyclopentane

SCHSCH33

OxiraneOxirane(Ethylene oxide)(Ethylene oxide)

OxetaneOxetane OxolaneOxolane(tetrahydrofuran)(tetrahydrofuran)

OxaneOxane(tetrahydropyran)(tetrahydropyran)

1,4-Dioxane1,4-Dioxane

Names of Cyclic Ethers OO OO OO

OO

OO

OO

ThiiraneThiirane ThietaneThietane ThiolaneThiolane

ThianeThiane

Names of Cyclic Sulfides SS SS SS

SS

Examples of Nomenclature

O

butyl ethyl ether (common)

1-ethoxybutane (IUPAC)or

OCH3

Br

trans 1-bromo-2-methoxycyclopentane

ethyl (Z) 1-propenyl ether (common)

(Z) 1-ethoxy-1-propene (IUPAC)or

OHCH3CH2O

CH3CH2O

4,4-diethoxy-2-cyclohexenol

O

O

(E) 2-methyl-3,4-epoxyhexane

(E) 2-methyl-3-hexene oxidetrans 2-ethyl-3-isopropyloxirane

O

OCH3

cis 3-methoxycyclopentene oxide

cis 3-methoxy-1,2-epoxycyclopentane

Periplenone B

OO

O

female cockroach sex pheromone

O

OH

OOHO

OS

NH

Epothilone Banticancer drug from soil bacteria

Structure and Bondingin

Ethers and Epoxides

Bond angles at oxygen are sensitiveto steric effects

HHOO

HH

(CH(CH33))33CCOO

C(CHC(CH33))33

112°112°

105°105° 108.5°108.5°

132°132°

HHOO

CHCH33

CHCH33

OOCHCH33

most stable conformation of diethyl ethermost stable conformation of diethyl ether

resembles pentaneresembles pentane

An oxygen atom affects geometry in much the

same way as a CH2 group

most stable conformation of tetrahydropyranmost stable conformation of tetrahydropyran

resembles cyclohexaneresembles cyclohexane

An oxygen atom affects geometry in much the

same way as a CH2 group

Physical Properties of Ethers

• Boiling points (and melting points) of ethers are lower than corresponding alcohol

– E.g. CH3CH2OH (bp 78°C) vs. CH3-O-CH3 (bp -25°C)• Why? No Hydrogen-bonding for ethers

boiling pointboiling point

36°C36°C

35°C35°C

117°C117°C

Ethers resemble alkanes more than alcohols

with respect to boiling point

Intermolecular hydrogenIntermolecular hydrogenbonding possible in bonding possible in alcohols; not possible alcohols; not possible in alkanes or ethers.in alkanes or ethers.

OO

OHOH

solubility in water (g/100 mL)solubility in water (g/100 mL)

very smallvery small

99

7.57.5

Ethers resemble alcohols more than alkanes

with respect to solubility in water

Hydrogen bonding toHydrogen bonding towater possible for etherswater possible for ethersand alcohols; not and alcohols; not possible for alkanes.possible for alkanes.

OO

OHOH

• • Solubility of acyclic ethers in water is less Solubility of acyclic ethers in water is less than that of than that of corresponding alcohols of equal MW.corresponding alcohols of equal MW.– – Ethers can accept H-bonds, but not donate themEthers can accept H-bonds, but not donate them

Physical Properties-UsesEthers are less dense than water and form the top layer Ethers are less dense than water and form the top layer

when mixed with water.when mixed with water.

• • Note: Note: Diethyl ether (“ether”) is a good general purpose Diethyl ether (“ether”) is a good general purpose

solvent for extracting non-polar and polar organic solvent for extracting non-polar and polar organic compounds from Hcompounds from H22O.O.

• • Its low boiling pt (35 Its low boiling pt (35 ooC) is ideal for recovering organic C) is ideal for recovering organic

solute by evaporation of ether. solute by evaporation of ether.

Solubility of cyclic ethers in water is greater than that of Solubility of cyclic ethers in water is greater than that of

acyclic ethers of equal MW. acyclic ethers of equal MW.

• • Compact shape more easily accommodated by H-Compact shape more easily accommodated by H-

bonding network of water ; Ex: Tetrahydrofuran 1,4-bonding network of water ; Ex: Tetrahydrofuran 1,4-

Dioxane completely miscible with water; important Dioxane completely miscible with water; important

cosolventscosolvents

Solvation

O

OO

O

12-crown-4

OO

O

O

O

15-crown-5

O

O

O

O

O

O

18-crown-6

Crown Ethers• structure

cyclic polyethers derived from repeating —OCH2CH2— units

• propertiesform stable complexes with metal ions

• applicationssynthetic reactions involving anions

OO

OO OO

OO

OO

OO18-Crown-618-Crown-6

OO

OO OO

OO

OO

OO

18-Crown-6

forms stable Lewis acid/Lewis base complex forms stable Lewis acid/Lewis base complex with Kwith K++

K+

Ion-Complexing and Solubility OO

OO OO

OO

OO

OO

++ FF–– OO

OO OO

OO

OO

OO

K+

FF– – carried into benzene to preserve electroneutralitycarried into benzene to preserve electroneutrality

benzenebenzene

18-crown-6 complex of K18-crown-6 complex of K+ + dissolves in benzenedissolves in benzene

Application to organic synthesis

Complexation of KComplexation of K++ by 18-crown-6 by 18-crown-6 "solubilizes" potassium salts in benzene"solubilizes" potassium salts in benzene

Anion of salt is in a relatively unsolvated Anion of salt is in a relatively unsolvated state in benzene (sometimes referred to as a state in benzene (sometimes referred to as a "naked anion")"naked anion")

Unsolvated anion is very reactiveUnsolvated anion is very reactive

Only catalytic quantities of 18-crown-6 are Only catalytic quantities of 18-crown-6 are neededneededCHCH33(CH(CH22))66CHCH22BrBr

KKFF

18-crown-618-crown-6benzenebenzene

CHCH33(CH(CH22))66CHCH22FF

(92%)(92%)

18. 2 Synthesis of Ethers

Acid–catalyzed dehydration of Alcohols

Diethyl ether prepared industrially by sulfuric acid–Diethyl ether prepared industrially by sulfuric acid–catalyzed dehydration of ethanol – also with other catalyzed dehydration of ethanol – also with other primary alcohols primary alcohols

The Williamson Ether Synthesis

Reaction of metal alkoxides and primary alkyl halides Reaction of metal alkoxides and primary alkyl halides and tosylatesand tosylates

Best method for the preparation of ethersBest method for the preparation of ethers

Alkoxides prepared by reaction of an alcohol with a Alkoxides prepared by reaction of an alcohol with a strong base such as sodium hydride, NaHstrong base such as sodium hydride, NaH

ExampleONa I

O NaI

RORO--, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) , an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) and a strong base. and a strong base. BothBoth S SNN2 (desired) and E2 (undesired side product) can 2 (desired) and E2 (undesired side product) can

occur.occur.

• Choose nucleophile and electrophile carefully. Choose nucleophile and electrophile carefully. Maximize SMaximize SNN2 and 2 and

minimize E2 reactionminimize E2 reaction by choosing the R’X to have least substituted carbon by choosing the R’X to have least substituted carbon undergoing substitution (electrophile). Methyl best, then primary, secondary undergoing substitution (electrophile). Methyl best, then primary, secondary marginal, tertiary never (get E2 instead).marginal, tertiary never (get E2 instead).

• StereochemistryStereochemistry: the reacting carbon in R’, the electrophile which : the reacting carbon in R’, the electrophile which undergoes substitution, experiences inversion. The alkoxide undergoes no undergoes substitution, experiences inversion. The alkoxide undergoes no change of configuration.change of configuration.

Williamson’s Ether Synthesis has Limitations

1. Alkyl halide must be primary (RCH2X)

2. Alkoxides need be derived from primary, secondary or tertiary alcohols

OH

O

O Na

BrSN2

SecondaryAlkoxide

PrimaryAlkyl halide

This reaction worlks particularly well with benzyl and allylhalides, which are excellentalkylating agents

Origin of Reactants

OH Cl

OH O Na

HCl

Na

O

What happens if the alkyl halide is not primary?

O Na

H3C CH3

Br

O OHH3C

H

H

SN2 is sterically disfavored and E2 predominates

Silver Oxide-Catalyzed Ether Formation

Reaction of alcohols with AgReaction of alcohols with Ag22O directly with alkyl halide O directly with alkyl halide

forms ether in one stepforms ether in one stepGlucose reacts with excess iodomethane in the Glucose reacts with excess iodomethane in the presence of Agpresence of Ag22O to generate a O to generate a pentaetherpentaether in 85% yield in 85% yield

HH++

(CH(CH33))22C=CHC=CH22 + CH + CH33OHOH (CH(CH33))33COCHCOCH33

terttert-Butyl methyl ether-Butyl methyl ethertert-Butyl methyl ether (MTBE) was produced on a scale exceeding 15 billion pounds per year in the U.S. during the 1990s. It is an effective octane booster in gasoline, but contaminates ground water if allowed to leak from storage tanks. Further use of MTBE is unlikely.

Addition of Alcohols to Alkenes

Alkoxymercuration

OCH2CH3

H

1. Hg(OAc)2, CH3CH2OH

2. NaBH4

Mechanism of Oxymercuration Hg(OAc)2,

2. NaBH4

OH

Reactions of Ethers:Reactions of Ethers:

Summary of reactions of ethersNo reactions of ethers encountered to this No reactions of ethers encountered to this point.point.

Ethers are relatively unreactive.Ethers are relatively unreactive.

Their low level of reactivity is one reason why Their low level of reactivity is one reason why ethers are often used as solvents in chemical ethers are often used as solvents in chemical reactions, and as protecting groups for reactive reactions, and as protecting groups for reactive –OH group.–OH group.

Ethers oxidize in air to form explosive Ethers oxidize in air to form explosive hydroperoxides and peroxides.hydroperoxides and peroxides.

Acid-Catalyzed Cleavage of Ethers

Ethers are generally unreactiveEthers are generally unreactive

Strong acid will cleave an ether at elevated temperatureStrong acid will cleave an ether at elevated temperatureHI, HBr produce an alkyl halide from less hindered HI, HBr produce an alkyl halide from less hindered component by Scomponent by SNN2 (tertiary ethers undergo S2 (tertiary ethers undergo SNN1)1)

CHCH33CHCHCHCH22CHCH33

OOCHCH33

CHCH33BrBrHHBrBr

++

(81%)(81%)

CHCH33CHCHCHCH22CHCH33

BrBrheatheat

ExampleExample

CHCH33

CHCH33CHCHCHCH22CHCH33

OO ••••••••

HH BrBr ••••••••

••••

CHCH33CHCHCHCH22CHCH33

OOCHCH33 HH++

••••

BrBr

––

•••••••• ••••

••••

MechanismMechanism

CHCH33CHCHCHCH22CHCH33

BrBr

HHBrBr

••••

••••••••

CHCH33BrBr

CHCH33CHCHCHCH22CHCH33

OOHH

••••••••

HHII

150°C150°CIICHCH22CHCH22CHCH22CHCH22II

(65%)(65%)

OO

Cleavage of Cyclic EthersCleavage of Cyclic Ethers

OO••••

••••

HHII

HH

OO••••

++

•••• II ••••••••

••••

––

IICHCH22CHCH22CHCH22CHCH22II

HHII HH

OO

•••• II••••

••••••••

••••

MechanismMechanism

Claisen Rearrangement • Specific to allyl aryl ethers, ArOCH2CH=CH2

• Heating to 200–250°C leads to an o-allylphenol• Result is alkylation of the phenol in an ortho

position

Epoxides (Oxiranes)• Three membered ring ether is called an oxirane (root

“ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated)

• Also called epoxides• Ethylene oxide (oxirane; 1,2-epoxyethane) is

industrially important as an intermediate• Prepared by reaction of ethylene with oxygen at 300 °C

and silver oxide catalyst

Epoxides are Extremely Reactive

Preparation of Epoxides Using a Peroxyacid

• Treat an alkene with a peroxyacid

meta chloroperoxybenzoic acid

MCPBA

CO3HCl

O

COR

HO

O

+ RCOHin CH2Cl2

O

H H

O

RCOOH

Epoxide Ring Opening reactions:

1. Epoxide Ring Opening in Acid

O

CH3

H

HH

H

CH3OH

CH3H

OCH3

HO

HH

H2SO4

In In acid:acid: protonate the oxygen, establishing the protonate the oxygen, establishing the very good leaving very good leaving groupgroup. More substituted carbon (more positive charge although more . More substituted carbon (more positive charge although more sterically hindered) is attacked by a sterically hindered) is attacked by a weak nucleophileweak nucleophile..

Due to Due to resonance, resonance,

some positive some positive charge is charge is

located on located on this carbonthis carbon..

Inversion Inversion occurs at this occurs at this

carbon. Do you carbon. Do you see it? see it?

Classify the Classify the carbons. carbons. SS becomes becomes RR..

Very similar to opening Very similar to opening of cyclic bromonium ion. of cyclic bromonium ion. Review that subject.Review that subject.

2. Epoxide Ring Opening in BaseIn In base:base: no protonation to produce good leaving group, no resonance but no protonation to produce good leaving group, no resonance but the ring can open due to the strain if attacked by the ring can open due to the strain if attacked by goodgood nucleophile. Now nucleophile. Now lless sterically hindered carbon is attackedess sterically hindered carbon is attacked..

O

CH3

HH

H

CH3O-

CH3

H

OH

H3CO

HH

A wide variety of synthetic uses can be A wide variety of synthetic uses can be made of these reactions as shown in the made of these reactions as shown in the following slidesfollowing slides

Base-Catalyzed Epoxide Opening • Strain of the three-membered ring is relieved on

ring-opening• Hydroxide cleaves epoxides at elevated temperatures

to give trans 1,2-diols

O

NaOCH3 in CH3OH

OH

OCH3

OCH3

O Na

OCH3H

regenerates base catalyst

In In base:base: no protonation to no protonation to

produce good leaving group, no produce good leaving group, no

resonance but the ring can open resonance but the ring can open

due to the strain if attacked by due to the strain if attacked by

goodgood nucleophile. Now l nucleophile. Now less ess

sterically hindered carbon is sterically hindered carbon is

attackedattacked..

18.6 Reactions of Epoxides: Ring-Opening

• Water adds to epoxides with dilute acid at room temperature

• Product is a 1,2-diol (on adjacent C’s: vicinal)• Mechanism: acid protonates oxygen and water adds

to opposite side (trans addition)

Halohydrins from Epoxides• Anhydrous HF, HBr, HCl, or HI combines with an

epoxide• Gives trans product

Epoxides from Halohydrins• Addition of HO-X to an alkene gives a halohydrin• Treatment of a halohydrin with base gives an epoxide• Intramolecular Williamson ether synthesis

OHO

Br

Br2+ HBr

Addition of Grignards to Ethylene Oxide

• Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain

• Acyclic and other larger ring ethers do not react

+ enant.

RCO3HO

CH3MgBr

MgBrO

CH3H3O+

OH

CH3

Different isomers

Variety of products can be obtained by varying the

nucleophiles

HH22O/ NaOHO/ NaOH

1.1. LiAlHLiAlH44

2.2. HH22OO

OH

Do not memorize Do not memorize this chart. But be this chart. But be sure you can figure sure you can figure it out from the it out from the general reaction: general reaction: attack of attack of nucleophile nucleophile in in basic mediabasic media on on less hindered less hindered carboncarbon

An Example of Synthetic Planning

Reactions of a nucleophile (basic) with an epoxide/oxirane ring Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a reliably follow a useful pattern.useful pattern.

O:Nu OH

Nu

The The patternpattern to to be recognized in be recognized in the product is the product is ––C(-OH) – C-NuC(-OH) – C-Nu

The epoxide The epoxide ring has to ring has to have been have been located herelocated here

This bond This bond was created was created by the by the nucleophilenucleophile

Synthetic Applications

nucleophilenucleophile

Realize that the HRealize that the H22NCHNCH22- -

was derived from was derived from nucleophile: CNnucleophile: CN

Formation of ether from Formation of ether from alcohols.alcohols.

N used as N used as nucleophile nucleophile twice.twice.

Epichlorohyrin and Synthetic Planning, same as before but now use two

nucleophiles

Observe the Observe the pattern in the productpattern in the productNu - C – C(OH) – C - Nu. When you observeNu - C – C(OH) – C - Nu. When you observethis pattern it suggests the use of epichlorohydrin.this pattern it suggests the use of epichlorohydrin.

Both of these bonds will Both of these bonds will be formed by the be formed by the incoming nucleophiles.incoming nucleophiles.

Why does Acid Catalyzed Opening Give Inversion?

CH2OH

HO

CH3CH2

CH3

O

CH3

CH3CH2

NaOH, H2OCH2OH

HO

CH3

CH3CH2

H3O+

(S) (S)

(R)

Propose a Mechanism

Br

O

1) NaOCH3

2) heat OCH3OCH2+ NaBr

2 Successive SN2 Reactions

Br

O

1) NaOCH3

2) heat OCH3OCH2+ NaBr

OCH3

Br

O

CH3O

Provide a Mechanism

O

H+, H2O

OH

OH

• Sulfur-containing amino acids• • Methionine and Cysteine

• Important in protein secondary and tertiary structure

NH2

S

O

OH

Methionine

NH2

HS

O

OH

Cysteine

HN

O N

S

OCO2H

H

penicillin

MeO N

HN

S

O

N

OMe

omeprazole

S

H2N NH

SO3

O O

Na

dapsone

Physical Properties• Thiols and sulfides are more volatile (lower bp) than

corresponding alcohols or ethers. Stench! Skunky!

• Hydrogen bonding less important for thiols compared to alcohols

• Dipoles are less pronounced

Thiols are more acidic than alcohols (pKa)– Size mismatch between small hard proton and large,

polarizable sulfur atom favours formation of thiolate anion.

Thiols: Formation and Reaction• From alkyl halides by displacement with a sulfur

nucleophile such as –SH – The alkylthiol product can undergo further

reaction with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol

Using Thiourea to Form Alkylthiols• Thiols can undergo further reaction with the alkyl

halide to give dialkyl sulfides• For a pure alkylthiol use thiourea (NH2(C=S)NH2) as

the nucleophile• This gives an intermediate alkylisothiourea salt,

which is hydrolyzed cleanly to the alkyl thiourea

Use an alkyl halide and HUse an alkyl halide and H22S or AcSHS or AcSH

BrH2S, KOH, EtOH

SH

i, (COCl)2, DMF, CH2Cl2, r.t.N Ph

OH

N Ph

SHii, KSAc, DMF, r.t.iii, KOH, EtOH, r.t. then HCl pH 5

J. Am. Chem. Soc.J. Am. Chem. Soc., , 20052005, , 127127, 15668, 15668

NH2

OH

Br

i, NaNO2, HCl

ii, KS OEt

S

, H2O

SH

OH

Br

iii, LiAlH4

J. Org. Chem.J. Org. Chem., , 19901990, , 5555, 2736, 2736

For palladium coupling of AcSFor palladium coupling of AcS–– and ArX, see and ArX, see Tetrahedron Lett.Tetrahedron Lett., , 20072007, , 4848, 3033, 3033

Preparation of Thiols

Oxidation of Thiols to Disulfides• Reaction of an alkyl thiol (RSH) with bromine or

iodine gives a disulfide (RSSR)• The thiol is oxidized in the process and the halogen is

reduced

Sulfides• Thiolates (RS) are formed by the reaction of a thiol

with a base• Thiolates react with primary or secondary alkyl

halide to give sulfides (RSR’)• Thiolates are excellent nucleophiles and react with

many electrophiles

Sulfides as Nucleophiles• Sulfur compounds are more nucleophilic than their

oxygen-compound analogs– 3p electrons valence electrons (on S) are less

tightly held than 2p electrons (on O)• Sulfides react with primary alkyl halides (SN2) to

give trialkylsulfonium salts (R3S+)

Sulfides as Nucleophiles

Oxidation of Sulfides• Sulfides are easily oxidized with H2O2 to the

sulfoxide (R2SO)• Oxidation of a sulfoxide with a peroxyacid yields a

sulfone (R2SO2)• Dimethyl sulfoxide (DMSO) is often used as a polar

aprotic solvent

Oxidation of Sulfides

Good nucleophilesGood nucleophiles

Tetrahedron Lett.Tetrahedron Lett., , 20052005, , 4646, 8931, 8931

HOSH

PhCH2Cl, Cs2CO3 HOS Ph

DMF, Bu4NI, r.t.

73%

SH

BrCH2CO2tBu, Cs2CO3

DMF, Bu4NI, r.t.

97%

MeO

S

MeO

CO2tBu

SHBuBr, Cs2CO3

SDMF, Bu4NI, r.t.

93%

Suitable for alkyl-alkyl and aryl-alkyl thioethersSuitable for alkyl-alkyl and aryl-alkyl thioethers

Successful for secondary alkyl iodides (Successful for secondary alkyl iodides ( iiPrI) but not tertiary halidesPrI) but not tertiary halides

No racemization using No racemization using LL-cysteine methyl ester-cysteine methyl ester

Reaction of Thiols

18.9 Spectroscopy of Ethers • Infrared: C–O single-bond stretching 1050 to 1150

cm1 overlaps many other absorptions.• Proton NMR: H on a C next to ether O is shifted

downfield to 3.4 to 4.5– The 1H NMR spectrum of dipropyl ether shows

this signal at 3.4– In epoxides, these H’s absorb at 2.5 to 3.5 d in

their 1H NMR spectra• Carbon NMR: C’s in ethers exhibit a downfield shift

to 50 to 80