Chapter 18
Introduction
• Ethers
are compounds with two organic groups
(alkyl, aryl, or vinyl) bonded to the same
oxygen atom, R–O–R’, in a ring or in an
open chain
industrial solvent
anesthetic
perfume
solvent
•
Thiols (R–S–H) and sulfides (R–S–R’) are sulfur
analogs of alcohols and ethers, respectively
– Sulfur replaces oxygen
1.
•
Naming Ethers
Ethers are named according to IUPAC rules:
– Simple ethers with no other functional groups are
named by identifying the two organic substituents
and adding the word ether
– If other functional groups are present, the ether
part is considered an alkoxy substituent
– Simple ethers with no other functional groups are
named by identifying the two organic substituents
and adding the word ether
– If other functional groups are present, the ether part
is considered an alkoxy substituent
Practice Problem: Name the following ethers according to IUPAC
rules
(a) Diisopropyl ether
(b) Cyclopentyl propyl ether
(c) p-Bromoanisole or
4-Bromo-1-methoxybenzene
(d) 1-Methoxycyclohexene
(e) Ethyl isobutyl ether
(f) Allyl vinyl ether
2.
Structure and Properties of Ethers
• The geometry around the O atom of an ether
(ROR) is similar to that of water (HOH)
– R-O-R has an ~ tetrahedral bond angle
(112° in dimethyl ether)
– The O atom is sp3-hybridized
•
The oxygen atom gives ethers a slight dipole moment
•
Ethers have higher boiling points than alkanes with
similar MW
3.
Synthesis of Ethers
•
Ethers can be synthesized by:
i.
Acid-catalyzed dehydration of alcohols
ii. Williamson ether synthesis
iii. Alkoxymercuration of alkenes
i. Acid-catalyzed dehydration of alcohols
•
Symmetrical ethers can be prepared by acid-catalyzed
dehydration of primary alcohols (SN2)
– Example: Diethyl ether is prepared industrially by
sulfuric acid–catalyzed dehydration of ethanol
– Acid-catalyzed dehydration of secondary and tertiary
alcohols yield alkenes (E1)
Practice Problem: Why do you suppose only symmetrical ethers
are prepared by the sulfuric acid-catalyzed
dehydration procedure? What product(s)
would you expect if ethanol and 1-propanol
were allowed to react together? In what ratio
would the products be formed if the two
alcohols were of equal reactivity?
ii. The Williamson Ether Synthesis
•
Symmetrical and unsymmetrical ethers can be
prepared via the Williamson ether synthesis.
– It is a process in which metal alkoxides react with
primary alkyl halides and/or tosylates via SN2
– It is the best method for the preparation of ethers
– Alkoxides are prepared by reaction of an alcohol
with a strong base such as sodium hydride, NaH
Acid
Base
Sodium salt of
the alcohol
•
Silver Oxide-Catalyzed Ether Formation is a variation
of the Williamson ether synthesis
–
Direct reaction of alcohols in Ag2O with alkyl halide forms
ether in one step
–
Example: Glucose reacts with excess iodomethane in the
presence of Ag2O to generate a pentaether in 85% yield
Mechanism of the Williamson Ether Synthesis
•
The Williamson ether synthesis involves SN2 reaction
of an alkoxide ion with a primary alkyl halide
–
An alkoxide nucleophile (RO-) displaces a halide ion (X-)
via SN2
–
Primary halides and tosylates work best for SN2 because
more hindered substrates undergo competitive E2
elimination of HX
–
Unsymmetrical ethers should be synthesized by
reaction between the more hindered alkoxide ion and
less hindered alkyl halide rather than vice versa
Example: Synthesis of tert-butyl methyl ether
Practice Problem: How would you prepare the following ethers
using Williamson synthesis?
a. Methyl propyl ether
b. Anisole (methyl phenyl ether)
c. Benzyl isopropyl ether
d. Ethyl 2,2-dimethylpropyl ether
iii. Alkoxymercuration of Alkenes
•
Ethers can be prepared via Alkoxymercuration of
Alkenes followed by demercuration
– Alkoxymercuration occurs when an alkene reacts with
an alcohol in mercuric acetate or trifluoroacetate
– Demercuration involves reduction of C-Hg by NaBH4
Mechanism of Alkoxymercuration/Demercuration
•
The mechanism involves:
–
Electrophilic addition of Hg2+ to an alkene, followed by
reaction of intermediate cation with alcohol: Overall
Markovnikov addition of alcohol to alkene
–
Reduction of C-Hg by NaBH4
Practice Problem: How would you prepare the ethyl phenyl
ether? Use whichever method you think is
more appropriate, the Williamson synthesis
or the alkoxymercuration reaction.
Practice Problem: Write the mechanism of the alkoxymercuration
reaction of 1-methylcyclopentene with ethanol.
Use curved arrows to show the electron flow in
each step.
Practice Problem: How would you prepare the following ethers?
Use whichever method you think is more
appropriate, the Williamson synthesis or the
alkoxymercuration reaction.
a. Butyl cyclohexyl ether
b. Benzyl ethyl ether (C6H5CH2OCH2CH3)
c. sec-Butyl tert-butyl ether
d. Tetrahydrofuran
3.
•
Reactions of Ethers
Ethers undergo:
i.
Acidic Cleavage
ii. Claisen Rearrangement
i. Acidic Cleavage
•
Ethers are generally unreactive to most reagents but
react with strong acids (HI and HBr) at high temperature
–
HI, HBr produce an alkyl halide from less hindered
component by SN2 (tertiary ethers undergo SN1)
Mechanism of the Acidic Cleavage
•
The acidic cleavage reaction takes place:
– via SN2 mechanism at the less highly substituted
site if only primary and secondary alkyl are bonded
to the ether O
– via SN1 or E1 mechanism if one of the alkyl groups
bonded to the ether O is tertiary
•
Ethers with primary and secondary alkyl groups react
with HI or HBr via SN2 mechanism
–
I- or Br- attacks the protonated ether at the less hindered
site
•
Ethers with a tertiary, benzylic, or allylic group react
with HI or HBr via SN1 or E1 mechanism
–
These can produce stable intermediate carbocations
–
Example: tert-Butyl cyclohexyl ether reacts via E1
Practice Problem: Predict the products of the following reaction:
•
•
Ethers with primary and secondary alkyl groups – via SN2
Ethers with a tertiary, benzylic, or allylic group – via SN1 or E1
Practice Problem: Predict the products of each of the following
reactions:
Practice Problem: Write the mechanism of the acid-catalyzed
cleavage of tert-butyl cyclohexyl ether to yield
cyclohexanol and 2-methylpropene
Practice Problem: Why are HI and HBr more effective than HCl
in cleaving ethers?
Nucleophilicity usually increases going down a column
of the periodic table
The halide reactivity order is I- > Br- > Cl-
ii. Claisen Rearrangement
•
Claisen rearrangement is specific to allyl aryl ethers,
ArOCH2CH=CH2
–
–
Heating the allyl aryl ether to 200–250°C leads to an
o-allylphenol
Result is alkylation of the phenol in an ortho position
Mechanism of the Claisen Rearrangement
•
The reaction proceeds via a pericyclic mechanism:
–
•
a concerted reorganization of bonding electrons involving
a 6-electron, 6-membered ring transition state leading to
6-allyl-2,4-cyclohexadienone intermediate
The mechanism is consistent with 14C labelling
Practice Problem: What product would you expect from Claisen
rearrangement of 2-butenyl phenyl ether?
4.
•
Cyclic Ethers: Epoxides
Cyclic ether behaves like an acyclic ether, except if
the ring is 3-membered
–
Dioxane and tetrahydrofuran are used as solvents
Epoxides (Oxiranes)
•
An epoxide is a three-membered ring ether
– It is also called an oxirane (root “ir” from “tri” for 3membered; prefix “ox” for oxygen; “ane” for
saturated)
– It has a unique chemical reactivity (behaves
differently from other open-chain ethers) due to the
strain of the 3-membered ring
•
Ethylene oxide (1,2-epoxyethane) is industrially
important as an intermediate
– It is the simplest epoxide (oxirane)
– It is prepared by reaction of ethylene with oxygen
at 300°C and silver oxide catalyst
•
In the laboratory, epoxides can be prepared by:
i.
Treatment of an alkene with a peroxyacid
ii. Treatment of a halohydrin with base
i. Preparation of Epoxides Using a Peroxyacid
•
An epoxide is prepared by treatment of an alkene with a
peroxyacid (RCO3H)
–
m-chloroperoxybenzoic acid is a common peroxyacid used
•
The mechanism of epoxidation by treatment of an alkene
with a peroxyacid (RCO3H):
–
is a one-step process in which peroxyacids transfer oxygen
to the alkene with syn stereochemistry (no intermediates)
ii. Preparation of Epoxides from Halohydrins
•
An epoxide is prepared by treatment of a halohydrin
with base
–
Addition of HO-X to an alkene gives a halohydrin
–
Treatment of a halohydrin with base eliminates HX and
gives an epoxide
•
The mechanism of epoxidation by treatment of a
halohydrin with a base is an intramolecular Williamson
ether synthesis:
–
The nucleophilic alkoxide ion and the electrophilic alkyl
halide are in the same molecule
Practice Problem: What product would you expect from reaction
of cis-2-butene with m-chloroperoxybenzoic
acid? Show the stereochemistry
Practice Problem: Reaction of trans-2-butene with m-chloropero
-xybenzoic acid yields an epoxide different
from that obtained by reaction of the cis
isomer. Explain.
5.
•
Ring-Opening Reactions of Epoxides
There are two types of ring-opening reactions of
epoxides:
i.
Acid-Catalyzed Epoxide Opening
ii. Base-Catalyzed Epoxide Opening
i. Acid-Catalyzed Epoxide Opening
•
Water adds to epoxides with dilute acid at room
temperature
– The product is a 1,2-diol, also called vicinal glycol
(on adjacent C’s: vicinal)
– Epoxides react under milder conditions because of
ring strain
Ethylene Glycol
• 1,2-ethanediol is synthesized from acid catalyzed
hydration of ethylene oxide
– Widely used as automobile antifreeze (lowers
freezing point of water solutions)
•
The mechanism of acid-catalyzed epoxide cleavage
involves:
– Protonation: Acid protonates oxygen
– Backside attack of a nucleophile: water adds to
opposite side (trans addition)
The mechanism of acid-catalyzed epoxide cleavage is
similar to the final step of alkene bromination
Halohydrins from Epoxides
• Anhydrous HF, HBr, HCl, or HI also combines with
an epoxide
– This gives a trans product (halohydrin)
Regiochemistry of Acid-Catalyzed Opening of Epoxides
– When both epoxide carbon atoms are either primary or
secondary, the nucleophile preferably attacks the less
highly substituted site (less hindered site)
– When one of the epoxide carbon atoms is tertiary, the
nucleophile attacks the more highly substituted site
• The mechanism is neither purely SN1 nor SN2.
– more stable, tertiary carbocation T.S character (SN1-like)
– back-side displacement of leaving group (SN2-like)
Practice Problem: Predict the major product of the following
reaction:
Practice Problem: Predict the major product of each of the
following reactions:
Practice Problem: How would you prepare the following diols?
ii. Base-Catalyzed Epoxide Opening
• Unlike other ethers, epoxides can be cleaved by base
as well as by acid
– Strain of the three-membered ring is relieved on ringopening
– Hydroxide ion cleaves epoxides at elevated
temperatures to give trans 1,2-diols
Addition of Grignards to Ethylene Oxide
• Grignard reagents cleave the ring of epoxides
– Reaction of ethylene oxide with Grignard reagent
adds –CH2CH2OH to the Grignard reagent’s
hydrocarbon chain
• Acyclic and other larger ring ethers do not react
Grignard reagent
• Base-catalyzed epoxide opening is SN2-like
– Attack of the nucleophile takes place at the less
hindered epoxide carbon
Practice Problem: Predict the major product of the following
reactions:
6.
•
Crown Ethers
Crown ethers are large rings consisting of repeating
(-OCH2CH2-) or similar units
–
They were discovered by Charles Pedersen (Dupont;
early 1960’s)
•
•
Crown ethers are named as x-crown-y
–
–
x is the total number of atoms in the ring
y is the number of oxygen atoms
–
Example: 18-crown-6 ether: 18-membered ring
containing 6 oxygens atoms
Central cavity is electronegative and attracts cations
Uses of Crown Ethers
• Complexes between crown ethers and ionic salts
are soluble in nonpolar organic solvents
– This allows reactions to be carried out under aprotic
conditions
– It thus creates reagents that are free of water that
have useful properties
• Inorganic salts (eg. KF, KCN, and NaN3) dissolve
in organic solvents with the help of crown ethers
– This leaves the anion dissociated, enhancing
reactivity
Purple benzene
Practice Problem: 15-Crown-5 and 12-crown-4 ethers complex
Na+ and Li+, respectively. Make models of
these crown ethers, compare the sizes of the
cavities.
7.
•
Thiols and Sulfides
Thiols (RSH), also known as mercaptans, are sulfur
analogs of alcohols
– They are named with the suffix –thiol
– SH group is called “mercapto group” (“capturer of
mercury”)
Sulfides
• Sulfides (RSR’) are sulfur analogs of ethers
– They are named by rules used for ethers, with sulfide in
place of ether for simple compounds and alkylthio in
place of alkoxy
Thiols: Formation and Reaction
• Thiols are prepared from alkyl halides by SN2
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
• For a pure alkylthiol, thiourea (NH2(C=S)NH2) is used
as the nucleophile
– This gives an intermediate alkylisothiourea salt, which is
hydrolyzed cleanly to the alkyl thiourea
– This avoids the problem of thiols undergoing further
reaction with the alkyl halide to give dialkyl sulfides
Oxidation of Thiols to Disulfides
• Reaction of an alkylthiol (RSH) with bromine (Br2)
or iodine (I2) gives a disulfide (RSSR’)
– The thiol is oxidized in the process and the halogen is
reduced
– It is reversed when the disulfide is reduced back to
thiol by treatment with Zn and H+
– Disulfide “bridges” form the cross-links between
protein chains (stabilize the three dimensional
conformations of proteins)
Sulfides: Formation and Reaction
Thiolate ions (RS-)
– are formed by the reaction of a thiol with a base
– react with primary or secondary alkyl halide to give
sulfides (RSR’)
– are excellent nucleophiles and react with many
electrophiles via SN2 mechanism
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 via SN2
to give trialkylsulfonium salts (R3S+)
– This is unlike dialkyl ethers
• Trialkylsulfonium salts are useful alkylating agents:
– A nucleophile can attack one of the groups bonded to
the positively charged sulfur, displacing a neutral
sulfide as leaving group
Oxidation of Sulfides
• Unlike ethers, sulfides are easily oxidized.
– 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
Practice Problem: Name the following compounds:
Practice Problem: 2-Butene-1-thiol is one component of skunk
spray. How would you synthesize this
substance from methyl 2-butenoate? From
1,3-butadiene?
8.
Spectroscopy of Ethers
• Infrared: C–O single-bond stretching 1050 to 1150
cm1 overlaps many other absorptions.
• Proton NMR: H on a C next to ether O are shifted
downfield to 3.4  to 4.5 
– The 1H NMR spectrum of dipropyl ether shows the
these signals at 3.4 
– 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
Infrared Spectroscopy
• Ethers are difficult to distinguish by IR spectroscopy
– C–O single-bond stretching 1050 to 1150 cm1 overlaps
many other absorptions.
IR spectrum: CH3CH2OCH2CH3
Nuclear Magnetic Resonance Spectroscopy
• Proton NMR: H on a C next to ether O are shifted
downfield to 3.4  to 4.5 
– The 1H NMR spectrum of dipropyl ether shows the these
signals at 3.4 
• Proton NMR: H on a C next to ether O are 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
– Example: 1,2-epoxypropane
• Carbon NMR: C’s in ethers exhibit a downfield shift
to 50  to 80 
– Example: These C’s in methyl propyl ether absorb at 58.5
and 74.8 
– Example: These C’s in anisole absorb at 54.8 
Practice Problem: The 1H NMR spectrum shown is that of an
ether with the formula C4H8O. Propose a
structure.
Chapter 18