18: Ethers and Epoxides;

Thiols and Sulfides

醚與環氧乙烷 ; 硫醇與硫醚

Based on McMurry’s Organic Chemistry, 9h edition

 Ethers and Their Relatives
 An ether 醚 has two organic groups (alkyl, aryl, or
vinyl) bonded to the same oxygen atom, R–O–R
 Diethyl ether is used industrially as a solvent
 Tetrahydrofuran (THF) is a solvent that is a cyclic
ether
 Thiols (R–S–H) 硫醇 and sulfides (R–S–R) 硫醚 are
sulfur (for oxygen) analogs of alcohols and ethers

二乙醚 苯甲醚 四氫呋喃 2

 Why this Chapter?

 To finish covering functional groups with C-O

and C-S single bonds

 Focus on ethers and look at thiols and

sulfides before going on to C=O

3
 18.1 Names and Properties of Ethers
 Posses nearly the same geometry as water
 Bond angles of R–O–R bonds are approximately
tetrahedral
 Oxygen atom is sp3-hybridized
 Oxygen atom gives ethers a slight dipole moment
 Relatively stable and unreactive in many aspects
 Very useful as solvents in the laboratory
 IUPAC Names: Alkoxy Alkanes
 Alkoxy alkane: the longest carbon chain is the
alkane parent. Name the OR group as an
alkoxy substituent 烷氧基
CH3 O CH3
CH3 O C CH3
CH3
methoxycyclohexane
2-methoxy-2-methylpropane

5
 Common Names of Ethers
 Alkyl alkyl ether, Name the two alkyl groups
attached to the oxygen and add the word ether.
 Symmetrical: use dialkyl, or just alkyl.

CH3
CH3 O C CH3
CH3CH2 O CH2CH3
CH3
diethyl ether or current: t-butyl methyl ether
ethyl ether old: methyl t-butyl ether (MTBE)
 18.2 Synthesis of Ethers

 Diethyl ether prepared industrially by sulfuric

acid–catalyzed dehydration of ethanol.
 Limited to use with primary alcohols

7
 The Williamson Ether Synthesis
 Reaction of metal alkoxides and primary alkyl halides
and tosylates in an SN2 reaction
 Best method for the preparation of ethers
 Alkoxides prepared by reaction of an alcohol with a
strong base such as sodium hydride, NaH

S N2

8
 The Williamson Ether Synthesis
• 1 RX  substitution

• 3 RX  elimination

9
Silver Oxide-Catalyzed Ether Formation
 Reaction of alcohols with Ag2O directly with alkyl halide
forms ether in one step
 Ag2O as mild base rather than NaH
 Glucose reacts with excess iodomethane in the
presence of Ag2O to generate a pentaether in 85% yield

10
 Alkoxymercuration of Alkenes
烷氧汞化－去汞化

 Alkene is treated with an alcohol in the presence of

mercuric acetate 醋酸汞 or trifluoroacetate 三氟醋酸汞
 Demercuration with NaBH4 yields an ether
 Overall Markovnikov addition of alcohol to alkene

11
 Alkoxymercuration
 Water approaches the mercurinium ion from the side
opposite the ring (anti addition).
 Alcohol adds to the more substituted carbon to form
the Markovnikov product.

12
Ether Syhthesis

13
 18.3 Reactions of Ethers: Acidic Cleavage
 Ethers are generally unreactive
 Strong acid will cleave an ether at elevated temperature
Nucleophilic substitution, SN2 or SN1 depending on the
structure of the subatrate

• Primary and secondary ethers cleave by an SN2

• HI, HBr produce an alkyl halide from less hindered
component by SN2

14
Reactions of Ethers: Acidic Cleavage


Tertiary , benzylic or allylic ethers cleave by an SN1 or E1

15
 Autoxidation of Ethers 補充

 In the presence of atmospheric oxygen, ethers slowly

oxidize to hydroperoxides and dialkyl peroxides.
 Both are highly explosive.
 Precautions:
 Do not distill to dryness.
 Store in small quantities, full bottles with tight caps.

16
18.4 Reactions of Ethers: Claisen
Rearrangement
 Specific to allyl aryl ethers, ArOCH2CH=CH2 and allyl vinyl
ethers H2C=HCOCH2CH=CH2
 Heating to 200–250°C leads to an o-allylphenol
 Result is alkylation of the phenol in an ortho position

17
 Claisen Rearrangement Mechanism
 Takes place in a single step through a pericyclic mechanism
 Reorganization of bonding electrons of a six-membered, cyclic transition state
 Mechanism is consistent with 14C labeling

* * * *

18
 18.5 Cyclic Ethers: Epoxides
 Behave like acyclic ethers with the exception of
three-membered ring called epoxides 環氧乙烷
 Strain of the three-membered ring gives epoxides a
unique chemical reactivity
 Dioxane and tetrahydrofuran (THF) are used as solvents

THF
二氧陸圜 bp 101 0C
四氫呋喃 bp 65 0C 19
 Cyclic Ethers: 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 環氧乙烷
 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

20
Preparation of Epoxides Using a Peroxyacid
Synthesis of Epoxides
1. Peroxyacid epoxidation 過氧酸環氧化作用

 Treat an alkene with a peroxyacid 過氧酸

(MCPBA)
間 - 過氧氯苯甲酸

21
•The epoxidation takes place in a one-step concerted
reaction that maintains the stereochemistry of any
substituents on the double bond.

• 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
H3 C CH3 H3 C CH3
RCO 3 H H H
C C C C
H H O
cis-2-Butene cis-2,3-Dimethyloxirane
 Epoxides from Halohydrins
2. Base-Promoted Cyclization of Halohydrin
 Addition of HO-X to an alkene gives a halohydrin 鹵
醇
 Treatment of a halohydrin with base gives an epoxide
 Intramolecular Williamson ether synthesis

Intramolecular
Williamson ether
synthesis 23
18.6 Reactions of Epoxides: Ring-Opening
 Water adds to epoxides with dilute acid at room
temperature
 Product is a 1,2-diol

 Mechanism: acid protonates oxygen and water adds to opposite

side (trans addition)

24
 Halohydrins from Epoxides
 Also can be opened by reaction with acids other than H 3O+
 Anhydrous HF, HBr, HCl, or HI combine with an epoxide
 Gives a trans halohydrins product

25
Regiochemistry of Acid-Catalyzed Opening of Epoxides
 Regiochemistry of acid-catalyzed ring-opening depends on the epoxide’s structure
 Nucleophile preferably adds to less hindered site if primary and secondary C’s 
SN2-like
 Nucleophile preferably adds to more hindered site if tertiary C’s because of
carbocation character ) SN1-like

SN2-like

SN1-like

26
Ring-Opening of 1,2-epoxy-1-methylcyclohexane
with HBr

SN1-like
 Base-Catalyzed Epoxide Opening
 Strain of the three-membered ring is relieved on ring-opening
 Nucleophile preferably adds to less hindered site  SN2-like
 Hydroxide cleaves epoxides at elevated temperatures to give
trans 1,2-diols

SN2-like

SN2-like

28
 Addition of Grignards to Ethylene Oxide

 Amines and Grignard reagents can be used for epoxide opening

 Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain
 Allows conversion of a Grignard reagent into a primary alcohol
 Acyclic and other larger ring ethers do not react

29
 18.7 Crown Ethers
 Large-ring polyethers 環狀聚醚 are commonly known as
crown ethers( 冠醚 ).
 Large rings consisting repeating (-OCH2CH2-) or similar units
 Named as x-crown-y
 x is the total number of atoms in the ring

 y is the number of oxygen atoms

 18-crown-6 ether: 18-membered ring containing 6 oxygen atoms

30
 Crown Ethers
•
Central cavity is electronegative and attracts cations.
e.g. 18-crown-6 ether complexes strongly with K+.
• Complexes between crown ethers and ionic salts are soluble

in nonpolar organic solvent.

• In the presence of 18-crown-6, KMnO dissolves in benzene
4
• Many other inorganic salts, KF, KCN, NaN , dissolve in
3
organic solvent with help of crown ethers.
冠醚可與特定的陽離子
形成穩定的複合物，使
極性無機鹽類溶於非極
性有機溶劑中

31
 18.8 Thiols and Sulfides
 Thiols (RSH) 硫醇 , are sulfur analogs of alcohols
 Named with the suffix -thiol

 SH group is called “mercapto group” (“capturer of

mercury”)

32
 Preparation of Thiols

 Prepared from alkyl halides by SN2

displacement with a sulfur nucleophile

 Alkylthiol product can undergo further

reaction with the alkyl halide
 Gives symmetrical sulfide, a poorer yield of
the thiol
Using Thiourea to Prepare Alkylthiols
 Thiols can undergo further reaction with the alkyl halide
to give dialkyl sulfides

Pure alkylthiol use thiourea (NH2(C=S)NH2) 硫脲 as the
nucleophile
 This gives an intermediate alkylisothiourea salt, which is
hydrolyzed with an aqueous base to the alkylthio.

34
Oxidation of Thiols to Disulfides
 alkyl thiol (RSH) can be oxidized by Br2 or I2
 Yields disulfides (RSSR’) 二硫化物
 Reaction is reversible
 Key part of numerous biological processes
 disulfides, an important feature of protein

structure
1
oxidation
2 RSH + O2 RS-SR + H2 O
2
A thiol reduction A disulfide
 Disulfide bonds in tertiary Structure
Tertiary structure: the three-dimensional arrangement in
space of all atoms in a single polypeptide chain
 disulfide bonds between the side chains of cysteine

play an important role in maintaining 3° structure

36
Disulfide bonds in tertiary Structure

Human insulin , 51 amino acids

21 amino acids

30 amino acids

37
 Sulfides
 Sulfides (RSR) 硫醚 : sulfur analogs of ethers
 Named by rules used for ethers, with sulfide in
place of ether for simple compounds and alkylthio
in place of alkoxy

38
 Sulfides
 Thiolates (RS) 硫醇陰離子 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

39
 Sulfides as Nucleophiles
 Sulfides and ethers differ substantially in their chemistry
 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 sulfonium
ions(R3S+)

40
 Oxidation of Sulfides
 Easily oxidized through treatment of a sulfide with hydrogen
peroxide H2O2 at room temperature
 Yields sulfoxide 亞碸 (R2SO)
 Further oxidation of the sulfoxide with a peroxyacid yields a
sulfone 碸 (R2SO2)

 Dimethyl sulfoxide (DMSO )is often used as a polar aprotic

solvent

DMSO
 18.9 Spectroscopy of Ethers

 Infrared Spectroscopy
 C–O single-bond stretching 1050 to 1150 cm1 overlaps
many other absorptions.
 Proton NMR:
 H on a C next to ether O is shifted downfield to  3.4 to
 4.5
 In epoxides, these H’s absorb at  2.5 to  3.5 in
their 1H NMR spectra
 Carbon NMR:
 C’s in ethers exhibit a downfield shift to  50 to  80

42
 Infrared Spectrum of of Diethyl Ether

Diethyl ether, CH3CH2OCH2CH3

 1
H NMR Spectrum of Dipropyl Ether

Dipropyl ether
 1
H NMR Spectrum of Epoxides

 In epoxides, these H’s absorb at  2.5 to  3.5

1
H NMR spectrum of 1,2-epoxypropane
 13
C NMR of Ether
13
C absorb at  50 to  80
 Summary

 Compounds that have two organic groups

bonded to the same oxygen atom are called
ethers
 Ethers are prepared either by Williamson ether
synthesis or the alkoxymercuration reaction
 Allyl aryl ethers and allyl vinyl ethers undergo
Claisen rearrangement to give o-allylphenols
and g,d-unsaturated ketones
 Thiols are sulfur analogs of alcohols
 Summary

 Disulfide can be obtained through mild

oxidation of a thiol
 Sulfides are sulphur analogs of ethers
 Alkylation of sulphides with a primary alkyl
halide will yield a sulfonium ion
 Sulfides can also be oxidized to sulfoxides
and to sulfones