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Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14.1 Introduction to Ethers An ether group is an oxygen atom that is bonded to two carbons. The ether carbons can be part of alkyl, aryl, or vinyl groups. 14.2 Nomenclature of Ethers 1. Name each –R group of the ether 2. Arrange them alphabetically 3. add “ether” to the name – three separate words -or- 1. Make the larger of the –R groups the parent chain 2. Name the smaller of the –R groups as an alkoxy substituent 279 CH 3 CH 2 CH 2 CH 2 OCH 2 CH 3 butyl ethyl ether (1-ethoxybutane O 1-methylethyl 2-methylpropyl ether (isobutyl isopropyl ether) (1-isopropoxy-2-methylpropane) 14.3 Structure and Properties of Ethers The O-atom of ethers is sp 3 hydrbidized Ether can only act as a hydrogen bond acceptor water methanol dimethyl ether In general, the C-O bonds of ethers have low reactivity – this makes then good solvents for other reactions. R O H δ + δ R O H δ + δ H-bond donor H-bond acceptor R O R δ + δ R O H δ + δ H-bond acceptor R O H δ + δ R O R R O R M + δ δ CH 3 CH 2 CH 2 CH 2 CH 3 CH 3 CH 2 CH 2 CH 2 OH CH 3 CH 2 OCH 2 CH 3 MW = 72 MW = 74 MW = 74 bp = 36° C bp = 116° C bp = 35° C diethylether tetrahydrofuran 1,4-dioxane O O O O 280 140

Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14… · Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14.1 Introduction to Ethers – An ether group is an oxygen atom

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Page 1: Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14… · Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14.1 Introduction to Ethers – An ether group is an oxygen atom

Chapter 14: Ethers and Epoxides; Thiols and Sulfides 14.1 Introduction to Ethers – An ether group is an oxygen atom that is bonded to two carbons. The ether carbons can be part of alkyl, aryl, or vinyl groups.

14.2 Nomenclature of Ethers 1. Name each –R group of the ether

2. Arrange them alphabetically

3. add “ether” to the name – three separate words

-or-

1. Make the larger of the –R groups the parent chain

2. Name the smaller of the –R groups as an alkoxy substituent

279

CH3CH2CH2CH2OCH2CH3

butyl ethyl ether (1-ethoxybutane

O

1-methylethyl 2-methylpropyl ether (isobutyl isopropyl ether)

(1-isopropoxy-2-methylpropane)

14.3 Structure and Properties of Ethers The O-atom of ethers is sp3 hydrbidized

Ether can only act as a hydrogen bond acceptor water methanol dimethyl ether

In general, the C-O bonds of ethers have low reactivity – this makes then good solvents for other reactions.

R

OHδ+

δ–

R

OH

δ+δ–

H-bonddonor

H-bondacceptor

R

OR

δ+

δ–

R

OH

δ+ δ–

H-bondacceptorR

OHδ+

δ–R

OR

R

OR

M+

δ–

δ–

CH3CH2CH2CH2CH3 CH3CH2CH2CH2OH CH3CH2OCH2CH3 MW = 72 MW = 74 MW = 74 bp = 36° C bp = 116° C bp = 35° C

diethylether tetrahydrofuran 1,4-dioxane

OO O

O

280

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14.4 Crown Ethers (please read)

Polyethers

Polyethylene glycol (PEG)

HO

OO

OH

n

Monensin – ionophore antibiotic 281

282

16.5: Preparation of Ethers a. Addition of alcohols to alkenes (recall hydration of alkenes in

and oxymercuration from Chapter 9) b. Condensation of alcohols (not very useful)

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283

c. The Williamson Ether Synthesis (the workhorse of ether syntheses) - Reaction of an alkoxide with an alkyl halide or tosylate to give an ether. Alkoxides are prepared by the reaction of an alcohol with a strong base such as sodium hydride (NaH). The Williamson ether synthesis is an SN2 reaction.

284

The Williamson Ether Synthesis: • Few restrictions regarding the nature of the the alkoxide • Works best for methyl- and 1°-halides or tosylates. • E2 elimination is a competing reaction with 2°-halides or

tosylates • 3°-halides undergo E2 elimination • Vinyl and aryl halides do not react

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14.6 Reactions of Ethers – typical ethers are not very reactive Acid Cleavage of Ethers

recall the reaction of an alcohol with HX to give a halide RCH2-OH + H-X RCH2-X + H2O

The mechanism for the acid cleavage of ethers is similar

RCH2-O-CH2R’ + H-X RCH2-X + R’CH2-OH (X)

285

Autoxidation (please read)

14.7 Nomenclature of Epoxides – a reactive cyclic ether

O

OO O

oxirane oxetane oxolane oxane (epoxide) (furan) (pyran)

a.  The ether oxygen is treated as a substituent, and two numbers are given as designate its location; or

b.  Oxirane is used as the parent name

286

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14.8 Preparation of Epoxides a.  Reaction of alkenes with a peroxyacid (Chapter 9.9)

b. Base promoted ring closure of a vicinal halohydrin –this is an intramolecular Williamson ether synthesis.

287

14.9 Enantioselective Epoxidation (please read) – the previous are stereospecific but not enantiospecific, and give racemic products. Epoxidations useing a chiral catalysts can give epoxides in high enantiomeric excess.

14.10 Ring-opening of Epoxides – epoxides are more reactive than a typical ether do to the strain of the three-membered ring. Epoxides undergo ring-opening reaction with nucleophiles.

288

O + Nu:–Nu

OHthen H2O

Nu:– = HO– (hydroxide) RO– (alkoxides) RS– (thiolates) –CN (cyanide) R–MgBr (Grignard reagents) H– (LAH)

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289

Regio- and stereochemistry of epoxide opening

Epoxides react with anionic nucleophiles (under basic conditions) through an SN2. The nucleophile adds to the less hindered (substituted) carbon of unsymmetrical epoxides and there is inversion of stereochemistry at the carbon undergoing substitution.

290

The regiochemistry of epoxide opening under acidic conditions is dependent on the substitution of the epoxide.

Nucleophiles will preferentially add to a tertiary carbon over primary of secondary under acidic conditions (SN1 like regiochemistry). The ring opening proceeds with inversion of stereochemistry. Nucleophiles will preferentially add to a primary carbon over a secondary (SN2 like regiochemistry).

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291

14.11 Thiols and Sulfides Thiols (mercaptans) are sulfur analogues of alcohols.

Thiols have a pKa ~ 10 and are stronger acids than alcohols.

RS-H + HO– RS– + H-OH (pKa ~10) (pKa ~15.7)

RS– and HS – are weakly basic and strong nucleophiles. Thiolates react with 1° and 2° alkyl halides to yield sulfides (SN2).

CH3CH2-S Na+CH3CH2-SHNaH, THF _ Br

CH3CH2-S-CH2CH2CH2CH3SN2

_HS-CH2CH2CH2CH3HS Na+

SN2Br-CH2CH2CH2CH3

THF+

RS– Na+ +OTs THF

SR

292 292

Oxidation States of organosulfur compounds Thiols can be oxidized to disulfides

2 R-SH[O]

[H]R-S-S-R

disulfidethiols

H3NHN N

HCO2

O2C

OS

O

NH3NH

HNO2C

CO2

OS

O

H3NHN N

HCO2

O2C

O SH

O2

glutathione+2e-, +2H+

-2e-, -2H+

R SH[O]

R S OH[O]

R S OHO [O]

R S OHO

O

2

Thiol sulfenic acid sulfinic acid sulfonic acid

Oxidation of thiols to sulfonic acids

Oxidation of thioethers R S R'

O–[O] [O] R S R'

O–

O–

+2

Thioether Sulfoxide Sulfone

R S R'

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293

Bioactivation and detoxication of benzo[a]pyrene diol epoxide:

P450

O

H2O

P450

OHHO

O

benzo[a]pyreneOH

HO

DNA

glutathione transferase G-S

OHHO

HOSG

NNN

N

NH2

DNA

N

N

N

N

OHHO

HONH

DNA

O2

Glutathione (G-SH)

H3NHN N

HCO2

O2C

O SH

O

294

Sulfides (thioethers) – sulfur analogs of ethers. Reaction of a thiolate anions with 1° and 2° alkyl halides and tosylates (analogous to the Williamson ether synthesis) R-SH + NaOH R-S- Na+ R-S-CH2R’ pKa ~ 11

alcohol or water solvent R’-CH2X

pKa ~ 16-18

Thiolates are more reactive nucleophiles and less basic than alkoxides

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Alkylation of Sulfides to Sulfonium Salts – The sulfur atom of sulfides is much more nucleophilic than the oxygen atom of ethers, and will react with alkyl halides to give stable sulfonium salts.

H3C CH3S H3C I

H3C CH3S

CH3I

dimethyl sulfide trimethyl sulfonium iodide

O N

N

NN

NH2

SH3C

–O2CNH3+ HO OH

S-adenosylmethionine (SAM)

14.12 Synthesis Strategies Involving Epoxides Epoxide ring opening by a nucleophile installs two functional groups on adjacent positions

295

O NaCN OH

NCthen H2O

or extend a carbon chain by 2 (or more)

BrMg(0), THF

O

then H2OMgBr OH

148