Chapter 14

Ethers, Epoxides, and Thioethers

游聲盛 (Sheng-Sheng Yu)

成大化工系

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 Why are we here?

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 14-1 Introduction

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 Ethers (醚)

• The formula is R—O—R where R and R are alkyl or

aryl (benzene ring).
• Symmetrical or unsymmetrical
• Most ethers are quite unreactive and used as solvents
for organic synthesis.

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 Ethers

• Diethyl ether was

found to be a much
safer anesthetic than
chloroform.

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 14-2 Physical Properties of Ethers

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 Structure and Polarity

• Oxygen is sp3 hybridized.

• Bent molecular geometry
• Tetrahedral C—O—C angle is 110°. (104.5°for
water)
• Polar C—O bonds
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 Boiling Points

• Similar to alkanes of comparable molecular weight.

• Ethers have large dipole moment, but they can not form hydrogen bonding
by themselves to increase boiling points.

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 Hydrogen Bond Acceptor

• Ethers cannot hydrogen bond with other ether

molecules, so they have a lower boiling point than
alcohols.
• Ether molecules can hydrogen bond with water and
alcohol molecules.
• They are hydrogen bond acceptors.
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 Ethers As Solvents

• Ethers are widely used as solvents because

– they can dissolve nonpolar and polar substances.
– They have low boiling points (simple removal by evaporation).
– they are unreactive toward strong bases.

• Alcohols are not good solvent for strong bases (those stronger than
alkoxide ions). The hydroxy group protonates the base.
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 Solvation of Ions with Ether

• An ionic substance such as lithium iodide is moderately soluble

in ethers because the small lithium cation is strongly solvated by
the ether’s lone pairs of electrons.

• Unlike alcohols, ethers cannot serve as hydrogen bond donors,

so they do not solvate small anions well.

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 Ether Complexes

• Grignard reagents: Complexation

of an ether with a Grignard
reagent stabilizes the reagent and
helps keep it in solution.

• Electrophiles: The ether’s

nonbonding electrons stabilize
the borane (BH3). Recall 8-7,
hydroboration of alkenes.

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 Crown Ether Complexes

• Crown ethers can complex metal cations in the center

of the ring.
• The size of the ether ring will determine which cation it
can solvate better.
• Complexation by crown ethers often allows polar
inorganic salts to dissolve in nonpolar organic solvents
. (Phase transfer agents) 13
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 14-3 Nomenclature of Ethers

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 Common Names of Ethers

• Name the two alkyl groups attached to the oxygen

and add the word ether.
• Name the groups in alphabetical order.
• Symmetrical: Use dialkyl or just alkyl.

C H3
C H C H O C H C H C H3 O C C H3
3 2 2 3
C H3
diethyl ether or
t-butyl methyl ether or
ethyl ether
methyl t-butyl ether
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 IUPAC Names: Alkoxy Alkane Names

• The more complex alkyl group is the alkane name.

The small group (with the oxygen) becomes an
“alkoxy” group.

C H3 O C H3
C H3 O C C H3
C H3
2-Methyl-2-methoxypropane Methoxycyclohexane

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 IUPAC Names

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 Cyclic Ethers (Heterocycles)

• Heterocyclic: Oxygen is part of the ring.

O
• Epoxides (oxiranes) H2C CH2
O
• Oxetanes
• Furans O
(oxolanes )
O

• Pyrans (oxanes )
O O
O
• Dioxanes
O
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 Epoxide

• Epoxides are three-membered cyclic ethers

• Usually formed by peroxyacid oxidation of alkenes

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 Epoxide Nomenclature

• Name the starting alkene and add oxide.

• The oxygen can be treated as a substituent (epoxy) on

the compound. Use numbers to specify position.

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 Epoxide Nomenclature (Continued)

• The three-membered oxirane ring is the parent.

(Oxygen is 1; the carbons are 2 and 3.) Substituents
are named in alphabetical order.

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 Oxetanes

• Least common.
• Strained four-membered ring.

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 Furans

• Five-membered cyclic ethers are named after their aromatic counterparts,

furan.
• Systematic name: Oxolane.
• For example, saturated five-membered cyclic ethers have four additional
hydrogen atoms, so it is called as tetrahydrofuran (THF).
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 Pyrans

• Six-membered cyclic ethers are named after their aromatic counterparts,

pyran.
• Systematic name: Oxane.
• For example, saturated six-membered cyclic ethers have four additional
hydrogen atoms, so it is called as tetrahydropyran (THP).
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 Dioxanes

• Six-membered cyclic ethers with two oxygens: dioxane.

• Note that the oxygen atoms can be placed in different position.
• The most common one is 1,4-dioxane.

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 Other examples of Dioxanes

• TCDD is a toxic containment in the

herbicide (2,4,5-T). However, TCDD is
often incorrectly called as dioxin.

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 14-4 Spectroscopy of Ethers

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 IR Spectroscopy of Ethers

• IR: The C—O stretch is in the fingerprint

region around 1000–1200 cm–1.

• Many compounds have the C—O stretch.

(Very difficult!)

• If the IR spectrum has the C—O stretch but

does not have a C═O or an OH stretch, then
the compound is most likely an ether.
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 MS Spectrometry of Ethers

• Main fragmentation is the  cleavage to form the

resonance-stabilized oxonium ion.
• Either alkyl group can be cleaved this way.

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 Loss of an Alkyl Group

• The C—O bond can be cleaved to produce a

carbocation.

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 MS Spectra of Diethyl Ether

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 NMR Spectroscopy of Ethers

• The typical chemical shifts for ethers in NMR are

13C—O signal between  65 and 90.
1H—C—O signal between  3.5 and 4.

• Similar to IR, look out for the carbonyl group!

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 14-5 The Williamson Ether
Synthesis

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 Williamson Ether Synthesis

• This method involves an SN2 attack of the alkoxide on

an unhindered primary halide or tosylate.
• Secondary alkyl halides partially works, but
elimination happens to lower the yield.
• The alkoxide is commonly made by adding Na, K, or
NaH to the alcohol.
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 Examples of the
Williamson Synthesis

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 Phenyl Ethers

• Phenoxide ions are easily produced because the

alcohol proton is acidic.
• Phenyl halides or tosylates cannot be used in this
synthesis method.

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 Solved Problem 1
14-1

(a) Why is the following reaction a poor method for the synthesis of t-butyl
propyl ether?
(b) What would be the major product from this reaction?
(c) Propose a better synthesis of t-butyl propyl ether.

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 Solved Problem 1
14-1

(a) The desired SN2 reaction cannot occur on the tertiary alkyl halide (hindered!).

(b) The alkoxide ion is a strong base as well as a nucleophile, and elimination
prevails.

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 Solved Problem 1
14-1

(c) A better synthesis would use the less hindered alkyl group as the SN2
substrate and the alkoxide of the more hindered alkyl group. (The other way
around!)

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 14-6 Synthesis of Ethers by
Alkoxymercuration-Demercuration

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 Alkoxymercuration–Demercuration
Reaction

• Use mercuric acetate with an alcohol. The alcohol will react with
the intermediate mercurinium ion by attacking the more
substituted carbon (more positive charge).
• (Recall Chapter 8-5, 8-6, page 422)
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 14-7 Industrial Synthesis: Bimolecular
Dehydration of Alcohols

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 Industrial Synthesis of Ethers

• Bimolecular condensation of alcohols

• Industrial method, not good lab synthesis
• If temperature is too high or the alcohol is hindered,
alkene forms.
• Recall it is a competition between substitution and
elimination!
H 2S O 4
C H 3C H 2 O H + H O C H 2C H 3 C H 3C H 2 O C H 2C H 3
140 °C

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 14-8 Cleavage of Ethers by HBr
and HI

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 Cleavage of Ethers by
HBr and HI
• Ethers are unreactive, which makes them ideal solvents for a lot of
different reactions.
• They can be cleaved by heating with concentrated HBr and HI.
• Reactivity: HI > HBr >> HCl
• Note that I- and Br- are good nucleophiles, but weak bases. Better for
substitution (SN2) than elimination (E2).

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 Mechanism ofEther Cleavage

• Step 1: Protonation of the oxygen

• Step 2: The halide will attack the carbon and displace the alcohol (SN2).

• Step 3: The alcohol reacts further with the acid to produce another mole of
alkyl halide.
Note: This does not occur with aromatic alcohols (phenols).

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 Phenyl Ether Cleavage

• Phenol cannot react further to become a halide

because an SN2 reaction cannot occur on an sp2
carbon.

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 14-9 Autoxidation of Ethers

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 Autoxidation of Ethers

• In the presence of atmospheric oxygen, ethers slowly oxidize to

hydroperoxides and dialkyl peroxides.
• Both are highly explosive.
• Precautions:
– Do not distill to dryness (concentrated the peroxides).
– Store in full bottles with tight caps.

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 14-10 Thioethers (Sulfides) and
Silyl Ethers

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 Silyl Ethers

• Thioether (sulfide):
– Similar chemistry to ethers, but thioethers undergo oxidation
and alkylation of the sulfur atoms.
• Silyl ether:
– Resistant to some acids, bases, and oxidizing agents
– More easily formed and more easily hydrolyzed
– Used as protecting groups for alcohols
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 Thioethers

• R—S—R, analog of ether

• Name sulfides like ethers, replacing sulfide for ether
in the common name, or alkylthio for alkoxy in the
IUPAC system.

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 Thiols and Thiolates

• Thioethers are easily synthesized by the Williamson ether synthesis using a

thiolate ion as the nucleophile.

• Note that thiols are more acidic than water, so generation of thiolate can
easily be done by aqueous sodium hydroxides.
• Sulfur atom is larger and
more polarizable than
oxygen. Therefore, thiolate
ion is a better nucleophiles
than alkoxides ion.
• Good yield even for
secondary alkyl halide. 54
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 Sulfide Reactions
• Sulfides are easily oxidized to sulfoxides and sulfones. (Sulfur valence
is not filled in sulfide)
• In particular sulfur strongly bonds with oxygen.

Sulfide Sulfoxides
1 equivalent 1 equivalent
peroxide peroxide Sulfones
2 equivalent peroxides
give sulfone,

• The combination of peroxide/acetic acid is a good oxidant for sulfides.

The reaction come from the formation of peroxyacid.

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 Thioethers as Reducing Agents

• Because sulfides are easily oxidized, they are

often used as mild reducing agents.

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 Sulfonium Salts

• Again, sulfur compounds are more nucleophilic than

oxygen compounds.
• Sulfides react with unhindered alkyl halides to give
sulfonium salts.

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 Sulfonium Salts as Alkylating Agents

• Sulfonium salts are strong alkylating agents.

• Sulfonium salts polarizes the carbon atoms and renders it electrophilic.
• The neutral sulfides are excellent leaving groups!

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 Sulfonium Salts as Alkylating Agents
Example in biological systems

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 Alcohol-Protecting Groups

• Example: Grignard reagents fail with alcohols.

• Solution: Protect the hydroxy groups! We may try to convert alcohols to

ethers before the Grignard reagents.
• The protecting groups should be:
– Easy to add and easy to remove.
– Resistant to target reaction.

• However, alkyl ethers are difficult to remove! Usually require

strong acids that might react with other parts of the target
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 Silyl Ethers as Protecting Groups
• Ethers based on silicon (silyl ethers) are much easier to remove than carbon-based
ethers. Fluoride ions remove silyl ethers under gentle condition in organic or
aqueous solution (Strong silicon-fluoride bonding!).

• Example: Using triisopropylsilyl (Tri-Iso-Propyl-Sily, TIPS) protecting group. Bulky

isopropyl groups hinder nucleophilic attack (Better stability).

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 Silyl Ethers as Protecting Groups

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 14-11 Synthesis of Epoxides

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 Synthesis of Epoxides
(Useful intermediates!)

• Peroxyacids are used to convert alkenes to epoxides.

• A concerted reaction: Simutaneous bond formation and breaking. Good to
maintain stereochemistry as the bond has no time to rotate and to change its
cis/trans conformation.
• Most commonly used peroxyacid is meta-chloroperoxybenzoic acid (mCPBA).
• The reaction is carried out in an aprotic acid or neutral pH to prevent the
opening of the epoxide.

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 Synthesis of Epoxides
(Useful intermediates!)

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 Selectivity of Epoxidation

• The most electron-rich double bond reacts faster,

making selective epoxidation possible.

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 Halohydrin Cyclization

• If an alkoxide and a halogen are located in the same

molecule, the alkoxide may displace a halide ion and
form a ring.
• Treatment of a halohydrin with a base leads to an
epoxide through this internal SN2 attack.

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 Epoxides via Halohydrins

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 Epoxides via Halohydrins

• Note that the bases should be strong enough to deprotonate the hydroxy groups,
but not to displace the halide.
• Lutidine is a bulky base that cannot easily attack a carbon atom.

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 14-12 Acid-Catalyzed Ring
Opening of Epoxides

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 Acid-Catalyzed Opening of Epoxides

• Step1: Protonation of the oxygen

• Step 2: Water attacks the protonated epoxide.

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 Acid-Catalyzed Opening of Epoxides

• Step 3: Deprotonation of the trans-1,2-diol

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 Acid-Catalyzed Opening of Epoxides in
Alcohol Solution

• A molecule of alcohol acts as

the nucleophile and attacks
and opens the epoxide.
• This reaction produces an
alkoxy alcohol with anti
stereochemistry.
• Good way to synthesize
compounds with adjacent
hydroxy and ether groups.

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 Ring Opening with Hydrohalic Acids

• After protonation the halide ion attacks the

protonated epoxide.
• The halohydrin initially formed reacts further with HX
to give a 1,2-dihalide.

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 Biosynthesis of Steroids

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 Biosynthesis of Steroids

• The reaction to cyclic intermediate is mainly achieved by enzyme.

• pi bond act as the nucleophile.
• The nucleophilic attack and transfer of carbocation produce a ring.
• A series of these steps convert achiral and acyclic starting materials to a
compound with four rings and four asymmetric carbon atoms!

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 14-13 Base-Catalyzed Ring
Opening of Epoxides

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 Base-Catalyzed Opening of Epoxides

• The hydroxide ion attacks and opens the ring.

• The diol is obtained after protonation of the alkoxide
with water.

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 Ring Opening in Base

• Usually, ethers do not under nucleophilic substitution or elimination under

basic condition because alkoxides ion is a poor leaving group.
• An epoxide is higher in energy than an acyclic ether by about 25 kcal/mol
ring strain.
• Release of the ring strain makes the opening of an epoxide
thermodynamically favored.
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 Ring Opening in Base

• Both acid and base catalyzed epoxy ring opening give

the same product, but acid-catalyzed reaction occurs
at milder conditions.

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 Amines also opens epoxides

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 14-14 Orientation of Epoxide Ring
Opening

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 Regioselectivity of Epoxidation

• So far, we only considered symmetrically

substituted epoxides and they give the same
products under acidic and basic conditions.

• For unsymmetrical epoxides, the results from

acids and bases catalysts are quite different.

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 Regioselectivity of Epoxidation

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 Regioselectivity of Epoxidation

• Under basic condition, the alkoxide ion simply

attacks the less hindered carbon atom in an SN2
displacement.

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 Under acidic condition

• Under acidic condition, the balancing between ring strain and the
energy cost to put positive charges on different carbons should be
considered.

Protonated epoxides
• Tertiary carbons can better
stabilize positive charges and
are more electrophilic.
• The bond between tertiary
carbon and oxygen is weaker. 86
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 Under acidic condition

• For weak nucleophiles (like ethanol), the electrophilicity is quite

important.
• Therefore, in acidic conditions, the nucleophilic attack occurs at the
more electrophilic carbons.

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 A short summary

Although the acid-catalyzed ring opening may

look like SN1 reaction, it comes with the inversion
of stereochemistry!

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 14-15 Reactions of Epoxides with
Grignard and Organolithium Reagent

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 Reaction of Epoxides with
Grignard and Organolithiums

• Strong bases, such as Grignards and organolithiums, open the epoxide ring
by attacking the less hindered carbon. Organolithiums are more selective
than Grignard reagents.

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 Reaction of Epoxides with
Grignard and Organolithiums

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 14-16 Epoxy Resins: The Advent
of Modern Glues

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 Glues

• Old glues are made from carbohydrates or proteins (biological sources).

Sometimes, they are too viscous to use. They may also have low stability,
low solvent resistance.

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 Epoxy Resins

• Epoxies polymerize in place, so they match the shape

of the joint perfectly.
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 Epoxy Resins

1. Base-catalyzed
ring opening

2. Halohydrin
cyclization

3. Continuous
polymerization

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 Epoxy Resins

• What happens here is the polymerization of epoxy resins.

• Under basic condition, a second epoxides form from the initial reaction between
bisphenol A and epichlorohydrin. One bisphenol A can react with two molecules of
epichlorohydrin.
• The reaction can keep going to give molecules with high molecular weight
(Polymers) and eventually solidified.

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 Epoxy Resins

Large production of epoxy/carbon fiber composites for aircrafts (strong and

lightweight).
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 Epoxy Resins

• The commercial epoxy glues comes with two

parts.
• Prepolymers.
• Hardeners.

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 Hardeners act as nucleophiles

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 Hardeners act as base catalysts
that promote the crosslinking (Network)

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 Take away of Chapter 14

• What are ethers?

• How can we synthesize ethers?

• How about epoxy?

– Synthesis
– Ring-opening reaction

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