Industrial Organic Chemistry

Chapter 18.

Ether and Epoxides;

Thiols and Sulfides

Instructor: Prof. Junhwan Choi

 Introduction
• Ether: two organic groups bonded to the same oxygen atom.
• Diethyl ether: medicinal use as an anesthetic and industrial use as a solvent.
• Anisole: a pleasant-smelling aromatic ether used in perfumery.
• Tetrahydrofuran: a cyclic ether often used as a solvent.

• : sulfur analog of alcohols.

• : sulfur analog of ethers
 18-1. Names and Properties of Ethers
• Simple ethers with no other functional groups: adding the word ether.
• alkoxy substituent.

• tetrahedral bond angle (112° in

dimethyl ether) and the oxygen atom is sp3-hybridized.
 18-1. Names and Properties of Ethers
• The electronegative oxygen atom gives ethers a slight dipole moment.
• The boiling points of ethers are often slightly higher than those of alkanes.

• Ethers are relatively stable and unreactive in many aspects.

• Some ethers react with the oxygen to give peroxides (contain ). The
peroxides from low-molecular-weight ethers are explosive and dangerous.
 18-2. Preparing Ethers
• Simple symmetrical ethers are prepared by the sulfuric-acid-catalyzed
reaction of alcohols.
• The reaction occurs by SN2 displacement of water from a protonated ethanol
molecule by the oxygen atom of a second ethanol.

• This method is limited to primary alcohols (secondary and tertiary alcohols in

acid-catalyzed reaction: dehydration to yield alkenes).
 18-2. Preparing Ethers
The Williamson Ether Synthesis
• Williamson ether synthesis: an alkoxide ion reacts with a primary alkyl halide
or tosylate in an SN2 reaction. (Alkoxide ion: reaction of an alcohol with a
strong base such as sodium hydride, NaH).

• With Ag2O as a mild base, the free alcohol reacts directly with alkyl halides
(there is no need to preform the metal alkoxide intermediate).
 18-2. Preparing Ethers
• The Williamson synthesis is an SN2 reaction: primary halides and tosylates
E2 elimination can occurs).
• Unsymmetrical ethers should be synthesized by reaction between the more
and less hindered halide
, not vice versa.
 18-2. Preparing Ethers
Alkoxymercuration of Alkenes
• Alkoxymercuration: an alkene is treated with an alcohol in presence of
mercuric compounds (mercuric acetate or mercuric trifluoroacetate).
• Demercuration by reaction with 4 then yields an ether.

• Mechanism: (1) electrophilic addition of Hg2+ to the alkene, (2) reaction of the
intermediate cation with alcohol, (3) reduction 4.

• A variety of alcohols (primary, secondary, tertiary) and alkenes can be used.

 18-2. Preparing Ethers
• Example: How would you prepare ethyl phenyl ether? Use whichever method
you think is more appropriate, Williamson synthesis or the alkoxymercuration
reaction.

• Identify the two groups attached to oxygen.

• Williamson synthesis: SN2 reaction. Requires one of the two groups attached
to oxygen be either secondary or preferably primary.
• Alkoxymercuration reaction: one of the two groups come from an alkene
precursor.
 18-2. Preparing Ethers
• Example: How would you prepare ethyl phenyl ether? Use whichever method
you think is more appropriate, Williamson synthesis or the alkoxymercuration
reaction.

• Ethyl phenyl ether could be made by either method.

 18-3. Reactions of Ethers: Acidic Cleavage
• Ethers are unreactive to many reagents used in organic chemistry: they can be
used as reaction solvents.
• Ethers undergo only one general reaction: they are cleaved by strong acids.
•

• Acidic ether cleavage take place by either SN1 or SN2 mechanism, depending
on the structure of the ether.
 18-3. Reactions of Ethers: Acidic Cleavage
• Ethers with primary and secondary alkyl groups react by an SN2 mechanism.
• Nucleophilic attack occurs at the less hindered site rather than more
hindered site.

• Ethers with a tertiary, benzylic or allylic group cleave by either an SN1 or E1

mechanism (stable carbocation intermediate is formed).
 18-3. Reactions of Ethers: Acidic Cleavage
• Example: Predict the products of the following reaction.

• Acidic cleavage of the ether.

• Identify the substitution pattern of the two groups attached to oxygen.
• An ether with only primary and secondary alkyl groups undergoes cleavage
by SN2 reaction: attack of a nucleophile on the less hindered alkyl group.
• An ether with a tertiary alkyl group undergoes cleavage by SN1 mechanism.
 18-3. Reactions of Ethers: Acidic Cleavage
• Example: Predict the products of the following reaction.

• In this case, an SN1 cleavage

 18-3. Reactions of Ethers: Acidic Cleavage
•

• Nucleophilicity usually increases going down a column of the periodic table

: The halide reactivity order is I > Br > Cl (Chapter 11-2).
 18-4. Reactions of Ethers: Claisen Rearrangement
• Claisen rearrangement: specific to allyl aryl ethers (H2C=CHCH2
바로이중결합이 L >벤젠리
allyl vinyl ethers (H2C=CHCH2 ).
2

• A Williamson ether synthesis: formation of allyl aryl ether.

• Heating the allyl aryl ether leads an o-allylphenol: alkylation of the phenol in
an ortho position. Claisen rearrangement of allyl vinyl ethers leads unsaturated
ketone or aldehyde.
 18-4. Reactions of Ethers: Claisen Rearrangement
• The Claisen rearrangement reaction takes place in a single step through a
pericyclic mechanism (like Diels-Alder reaction): reorganization of bonding
electrons occurs in a six-membered, cyclic transition state.

• Allyl ether carbon atom (green) is changed to the terminal vinylic carbon.
 18-4. Reactions of Ethers: Claisen Rearrangement
• Example: What product would you expect from Claisen rearrangement of 2-
butenyl phenyl ether?

• Redraw the chemical structure to

reorganize bonding electrons by
pericyclic mechanism.
 18-4. Reactions of Ethers: Claisen Rearrangement
• Example: What product would you expect from Claisen rearrangement of 2-
butenyl phenyl ether?
 18-5. Cyclic Ethers: Epoxides
" 반응성해
• The chemistry of cyclic ethers is the same with open chain ethers.
• Common cyclic ethers (tetrahydrofuran, dioxane) are chemically inert, but they
can be cleaved by strong acids.

• Three-membered-ring compounds called epoxides (or oxiranes) behaves

differently from open-chain ethers: unique reactivity due to the ring strain.

*Ethylene oxide: non-systematic name

(no double bond)
 18-5. Cyclic Ethers: Epoxides
• 3H).

• Epoxides by
• When halohydrin is treated with base, HX is eliminated and an epoxide is
produced by intramolecular Williamson ether synthesis: nucleophilic
alkoxide ion and electrophilic alkyl halides are in the same molecule.
 18-
Acid-Catalyzed Epoxide Opening
• Epoxides are cleaved by treatment with acid but under much mild conditions
because of ring strain (diluted aqueous acid at room temperature).
• The hydrolysis of epoxides gives 1,2-diols, called vicinal glycols.
(vicinal : adjacent / glycol : diol)
 18-
• SN2-like backside attack of a nucleophile on the protonated epoxide, giving
a trans-1,2-diol.
• If anhydrous is used, an epoxide is converted into a trans halohydrin.
 18-
• When both epoxide are either primary or secondary: attack of the nucleophile
occurs at the less substituted site SN2-like result.
• When one of the epoxide carbons is tertiary: nucleophilic attack occurs at the
more substituted site SN1-like result.
 18-
• An SN2-like result: backside displacement of the epoxide oxygen.
• An SN1-like result: nucleophile attacks more hindered tertiary side (the more
stable, tertiary carbocation is involved).
• N1 and SN2 characteristics: SN2-like geometry and SN1-like carbocation
character.
Swl

riter
Sw 2
 18-
• Example: Predict the major product of the following reaction.

• Identify the substitution pattern of the two epoxide carbon atoms.

• no tertiary carbon).
• It will undergo acid-catalyzed cleavage by SN2-like attack of a nucleophile: on
the less hindered carbon.
 18-
• Example: Predict the major product of the following reaction.

SW 2

q
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PrTmary
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 18-
• the strain of the three-membered
ring causes epoxide to react with hydroxide ion at elevated temperature.

1
반응성이높아염기와로반응가능
• -catalyzed epoxide openings: typical SN2 reaction, attack of the
nucleophile takes place at the less hindered epoxide carbon.

:
 18-7. Crown Ethers
• Crown ethers: general format x-crown-y, where x is the total number of atoms
in the ring and y is the number of oxygen atoms.
• Crown ethers sequester specific metal cations in the center. For example, 18-
crown-6 ether binds strongly with potassium ion (K+).
• When the metal cation is strongly solvated, the anion is left bare, thus SN2
reactivity of an anion is enhanced in the presence of a crown ether.
 18-8. Thiols and Sulfides
Thiols
• Thiols (sometimes called mercaptans
mercapto group) are sulfur analogs of alcohols.
• thiol.

• Thiols are weakly acidic like alcohol, but thiols does not form hydrogen
bonds because the sulfur atoms is not sufficiently electronegative.
• The most striking characteristics of thiols is their appalling odor: volatile thiols
are added to natural gas and liquefied propane to serve as an easily detectable
warning in case of leaks.
 18-8. Thiols and Sulfides
• Thiols are usually prepared from alkyl halides by SN2 displacement with a
sulfur nucleophile such as hydrosulfide anion, SH.

• An excess nucleophile is needed because the product thiol can undergo a

second SN2 reaction with alkyl halide to give a .
 18-8. Thiols and Sulfides
• To circumvent the formation of sulfide by-product, 2 2C=S is used
as the nucleophile.
• The reaction occurs by displacement of the halide ion to yield an intermediate
alkyl isothiourea salt.
• Alkyl isothiourea salt is hydrolyzed by subsequent reaction with aqueous base.
 18-8. Thiols and Sulfides
• Thiols can be oxidized 2 or I2 to yield .
• Disulfide can be easily reduced back to a thiol by treating with zinc and acid.

• The thiol-disulfide interconversion is a key part of numerous biological processes.

 18-8. Thiols and Sulfides
Sulfides
• Sulfides are the sulfur analogs of ethers.
• is used for simple compounds, alkylthio is used for complex substances.

• Treatment of a thiol with a base gives the corresponding thiolate ion (RS ,
which undergoes reaction with a primary or secondary alkyl halides to give a
sulfide by an SN2 mechanism.
 18-8. Thiols and Sulfides
• Sulfides and ethers differ in their chemistry.
• less
tightly bound than those in oxygen (3p electrons vs. 2p electrons), sulfur
compounds are more nucleophilic.
• Dialkyl sulfides react rapidly with primary alkyl halides by an SN2 mechanism to
give sulfonium ions (R3S+ .
 18-8. Thiols and Sulfides
• Sulfonium ions are useful alkylating agents.
• Nucleophile can attack one of the groups bonded to the positively charged
sulfur, displacing a neutral sulfide as leaving group.

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알컬그룹 제공
 18-8. Thiols and Sulfides
• Sulfides are easily oxidized (ethers are not easily oxidized).
• Treatment of a sulfide with H2 2 yields the corresponding sulfoxide (R2 , and
further oxidation yields sulfone (R2SO2 .

• is a particularly well-known sulfoxide as a solvent.

 18-8. Thiols and Sulfides
• Example: 2- -1-thiol is one component of skunk spray. How would you
synthesize this substance from methyl 2-butenoate? From 1,3-butadiene?

• Thiols can be prepared from alkyl halides by SN2 displacement with a sulfur
nucleophile. 2 2C=S is used as the nucleophile.
 18-8. Thiols and Sulfides
• Example: 2- -1-thiol is one component of skunk spray. How would you
synthesize this substance from methyl 2-butenoate? From 1,3-butadiene?

• Making alkyl halide from alcohol or electrophilic addition and SN2 displacement
with thiourea (NH2)2C=S will give thiol.
에스터 > 알코올 D

브
 Summary of Chapter 18
• Ethers are compounds that have two organic groups bonded to the same
oxygen atom, .

Preparation of ethers
• Williamson ether synthesis: SN2 reaction of an alkoxide ion with a primary
alkyl halides.
• Alkoxymercuration reaction: Markovnikov addition of an alcohol to an alkene.

Reaction of ethers
• Ethers are inert to most reagents but react with strong acids
• If only primary and secondary alkyl groups are bonded to the ether oxygen,
reaction takes places by an SN2 mechanism at the less substituted site.
• If one of the alkyl groups is tertiary, it takes places by an SN1 or E1 mechanism.
• Claisen rearrangement: allyl aryl ethers and allyl vinyl ethers.
 Summary of Chapter 18
• Epoxide: cyclic ethers with a three-membered, oxygen-containing ring.
• less substituted site occurs if both epoxide
carbons are primary or secondary.
• more substituted site occurs if one of the
epoxide carbons is tertiary.
• -catalyzed epoxide ring-opening occurs at the less hindered epoxide carbon.

• Thiols: sulfur analogs of alcohols, prepared by SN2 reaction of an alkyl halide

and thiourea. Mild oxidation of a thiol yields a disulfide.
• Sulfides: sulfur analogs of ethers, prepared by SN2 reaction between a
thiolate anion and a primary or secondary alkyl halide.
• Sulfides are more nucleophilic than ethers and can be alkylated to a
sulfonium ion.
• Sulfides can be oxidated to sulfoxides and sulfones.