Ethers & Epoxides
Reactions of Ethers
Ethers are relatively unreactive.
Ethers are often used as solvents in organic
reactions.
Ethers oxidize in air to form explosive
hydroperoxides and peroxides.
“Crown” ethers are useful as enhancers in
nucleophilic substitution and other reactions
Naming Ethers
• Common names are used frequently:
1. Name each –R group.
2. Arrange them alphabetically.
3. End with the word “ether.”
Naming Ethers
• IUPAC systematic names are often used as well:
1. Make the larger of the –R groups the parent chain.
2. Name the smaller of the –R groups as an alkoxy
substituent.
• SEE: SKILLBUILDER 14.1.
Crown Ethers
Crown Ethers
structure
cyclic polyethers derived from repeating
—OCH2CH2— units
properties
form stable complexes with metal ions
applications
synthetic reactions involving anions
naming
x = total # of atoms in ring: [x] Crown- # of oxygen atoms
18-Crown-6
O
O
O
O
O
O
negative charge concentrated in cavity inside
the molecule
18-Crown-6
O
O
O
K+
O
O
O
forms stable Lewis acid/Lewis base complex
with K+
Ion-Complexing and Solubility
K+F–
not soluble in toluene
Ion-Complexing and Solubility
O
O
O
K+F–
O
O
toluene
O
add 18-crown-6
Ion-Complexing and Solubility
O
O
O
O
F–
O
O
K+
O
O
toluene
O
O
18-crown-6 complex of K+ dissolves
in benzene
O
O
Ion-Complexing and Solubility
O
O
O
O
O
O
K+
O
O
toluene
O
F– carried into toluene
to preserve electroneutrality
O
O
O
+ F–
Application to organic synthesis
Complexation of K+ by 18-crown-6
"solubilizes" potassium salts in toluene
Anion of salt is in a relatively unsolvated state
in toluene (sometimes referred to as a "naked
anion")
Unsolvated anions are very reactive
Only catalytic quantities of 18-crown-6 are
needed
Example
KF
CH3(CH2)6CH2Br
18-crown-6
toluene
CH3(CH2)6CH2F
(92%)
Question
• Which reaction is the best candidate for catalysis by 18crown-6? (Which reaction proceeds faster in the presence of
the crown ether than in its absence?)
•
•
•
•
A)
B)
C)
D)
Bromobutane + KCN (in toluene)
Phenol + Br2 (in water)
Butanol + H2CrO4 (in water)
CH3CH2CH2CHO + H2 (in ethanol)
Ion Size & Crown Ether Complexes
K+
18-Crown-6
Na+
15-Crown-5
Li+
12-Crown-4
Question
• What is the name of the crown ether show at the right?
•
A)
12-crown-4
•
B)
10-crown-5
•
C)
15-crown-5
•
D)
18-crown-6
Question
• Which crown ether would provide the fastest rate for the
following reaction?
•
•
•
•
A)
B)
C)
D)
12-crown-4
10-crown-5
15-crown-5
18-crown-6
The Williamson Ether Synthesis
Just another SN2 reaction 
primary alkyl halide (substrate) + alkoxide (nucleophile)
Example
CH3CH2CH2CH2ONa + CH3CH2I
CH3CH2CH2CH2OCH2CH3 + NaI
(71%)
Another Example
Alkoxide ion can be derived
Alkyl halide must
from primary, secondary, or
be primary
tertiary alcohol
CH2Cl
+
CH3CHCH3
ONa
CH2OCHCH3
CH3
(84%)
1o Halides & Alkoxides
CH3CHCH3
CH2OH
OH
HCl or SOCl2
CH2Cl
+
Na (s)
CH3CHCH3
ONa
CH2OCHCH3
CH3
(84%)
Question
What is the product of the following reaction?
OH
1) NaH 2) ethyl iodide
A.
B.
O
O
?????
C.
D.
O
O
Question
What is the correct order of reagents needed for the
following transformation?
O
A. 1) Hg(OAc)2, THF:H2O 2)
NaBH4, OH–
B. 1) BH3:THF 2) H2O2, OH–
C. 1) Hg(OAc)2, CH3CH2OH 2)
NaBH4, OH–
D. 1) MCPBA 2) H+ 3) NaH 4)
Ethyl iodide
Mechanism
Question
• Which of the following best represents the rate-determining
transition state for the reaction shown below?
• A)
• C)
B)
D)
What if the alkyl halide is not primary?
SN2 vs E2
CH2ONa + CH3CHCH3
Br
CH2OH
+
H2C
Elimination produces
the major product.
CHCH3
Question
• The most effective pair of reagents for the preparation of tertbutyl ethyl ether is
•
A)
potassium tert-butoxide and ethyl bromide.
•
B)
potassium tert-butoxide and ethanol.
•
C)
sodium ethoxide and tert-butyl bromide.
•
D)
tert-butyl alcohol and ethyl bromide
Limitation
Preparation of Epoxides
Preparation of Epoxides
Two major methods:
Reaction of alkenes with peroxy acids
Conversion of alkenes to vicinal
halohydrins, followed by treatment
with base.
Preparation of Epoxides
w/ peroxyacids (MCPBA)
.
Conversion of Vicinal Halohydrins
to Epoxides
Example
H
H
OH
NaOH
O
H2 O
H
H
Br
•• –
•• O ••
via:
H
H
•• Br ••
••
(81%)
Epoxidation via Vicinal Halohydrins
Br
Br2
NaOH
H2O
O
OH
anti
addition
inversion
Corresponds to overall syn addition of
oxygen to the double bond.
Epoxidation via Vicinal Halohydrins
H3C
H
Br
H
Br2
H2O
CH3
H3C
H
H
CH3
NaOH
H3C
H
O
OH
anti
addition
H
CH3
inversion
Corresponds to overall syn addition of
oxygen to the double bond.
Question
Which of the following will produce the epoxide below?
A.a, b
B.a, c
C. b, c
D. b, d E. c, d
Stereochemistry / Optical Activity
Epoxidation Stereochemistry
• Epoxidation forms a racemic mixture because
reaction occurs with equal probability on either face
of the double bond.
Enantioselective Epoxidation
• In order to have an optically active product, one of
the reactants, or reagents, or catalyst in a reaction
must be chiral.
• An example is a Sharpless catalyst, which forms
such a chiral complex that favors the formation of
one enantiomeric epoxide versus the other.
• Catalyst:
Enantioselective Epoxidation
• The desired epoxide can be formed in excess by
choosing the appropriate catalyst. Note the position
of the –OH group.
• SEE: CONCEPTUAL CHECKPOINT
14.16.
Question
What is the product of the following reaction?
Reactions of Epoxides
Reactions of Epoxides
All reactions involve nucleophilic attack
at carbon and lead to opening of the ring.
An example is the reaction of ethylene oxide
with a Grignard reagent as a method for the
synthesis of alcohols.
Reaction of Grignard Reagents
with Epoxides
R
MgX
CH2
H2C
O
R
CH2
CH2
OMgX
H3O+
RCH2CH2OH
Example
CH2MgCl
CH2
+ H2C
O
1. diethyl ether
2. H3O+
CH2CH2CH2OH
(71%)
In General...
Reactions of epoxides involve attack by a
nucleophile and proceed with ring-opening.
For ethylene oxide:
Nu—H
+ H2C
CH2
O
Nu—CH2CH2O—H
In General...
For epoxides where the two carbons of the
ring are differently substituted:
Anionic nucleophiles
attack here.
(less hindered)
Nucleophiles attack here
when the reaction is
catalyzed by acids.
R
CH2
C
H
O
Nucleophilic Ring-Opening
Reactions of Epoxides
Question
True (A) / False (B)
Refer to the reaction coordinate diagrams below.
The epoxide reaction is exergonic and the Transition
State resembles the reactants whereas the ether
reaction is slower and the Transition State resembles the
reactants
Ring-opening of Epoxides
• Epoxides can be opened by many strong
nucleophiles.
• Both regioselectivity and stereoselectivity must be
considered.
Example
CH2
H2C
O
NaOCH2CH3
CH3CH2OH
CH3CH2O
CH2CH2OH
(50%)
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
– ••
•• O
••
CH3CH2
CH3CH2
••
O
••
••
O
••
CH2CH2
CH2CH2
•• –
O ••
••
H
••
O
••
CH2CH3
H
– ••
•• O
••
CH2CH3
Example
CH2
H2C
O
KSCH2CH2CH2CH3
ethanol-water, 0°C
CH3CH2CH2CH2S
CH2CH2OH
(99%)
Ring-opening of Epoxides
Environmental Fate?
Propranolol: anti-hypertensive
-Blocker
Stereoselectivity
H
H
NaOCH2CH3
O
CH3CH2OH
OCH2CH3
H
H
OH
(67%)
Inversion of configuration at carbon being
attacked by nucleophile.
Suggests SN2-like transition state.
Regioselectivity
Anionic Nucleophile Attacks Less-crowded Carbon
H3C
CH3
C
C
H
O
NaOCH3
CH3OH
CH3O
CH3
CH3CH
CCH3
OH
CH3
(53%)
Consistent with SN2-like transition state
Question
•
What is the product isolated when the epoxide below reacts
with NaOCH3 in CH3OH?
•
A)
B)
•
C)
D)
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
R
NH3
H2O
H2 N
H
H
S
OH
CH3
(70%)
Inversion of configuration at carbon being
attacked by nucleophile.
Suggests SN2-like transition state.
Stereochemistry
H3C
H
R
CH3
R
R
NH3
H2O
O
H3C H
H2 N
H
H
S
OH
CH3
+
H3N
(70%)
H3C
H
O
H3C
H
-
Question
• What is the product of the reaction shown?
• A)
B)
• C)
D)
Anionic Nucleophile Attacks Less-crowded Carbon
MgBr
+
CHCH3
H2C
O
1. diethyl ether
2. H3O+
CH2CHCH3
OH
(60%)
Question
What are the product(s) of the following reaction?
O
A.
B.
1) CH3MgBr
2) H2O
C.
HO
OH
D.
HO
OH
Lithium Aluminum Hydride Reduces Epoxides
CH(CH2)7CH3
H2C
O
Hydride attacks
less-crowded
carbon
H3C
1. LiAlH4, diethyl ether
2. H2O
CH(CH2)7CH3
OH
(90%)
Acid-Catalyzed Ring-Opening
Reactions of Epoxides
Example
CH2
H2C
O
CH3CH2OH
CH3CH2OCH2CH2OH
H2SO4, 25°C
(87-92%)
CH3CH2OCH2CH2OCH2CH3 formed only on heating
and/or longer reaction times.
Example
CH2
H2C
O
HBr
10°C
BrCH2CH2OH
(87-92%)
BrCH2CH2Br formed only on heating and/or
longer reaction times.
Mechanism
H2C
CH2
H2C
+
O ••
••
••
•• Br
••
•• –
•• Br •
•
••
H
CH2
+
O ••
H
••
• Br •
•
•
CH2CH2
••
O
••
H
Acid-Catalyzed Hydrolysis of Ethylene Oxide
Step 1
H2C
H
+
O ••
••
•• O
+
H
CH2
H
H2C
H
•• O ••
H
CH2
+
O ••
H
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
Step 2
O ••
H
••
H2C
H
+
O ••
H
+ •
H O•
CH2CH2
CH2
••
O
••
H
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
+
H O ••
Step 3
H
H
H
H
O ••
••
•O•
• •
H
CH2CH2
+ •
H O•
CH2CH2
••
O
••
H
••
O
••
H
Acid-Catalyzed Ring Opening of Epoxides
Regioselectivity and Stereoselectivity
Nucleophile attacks more substituted carbon
of protonated epoxide.
Inversion of configuration at site of nucleophilic
attack.
Nucleophile Attacks More-substituted Carbon
H3C
CH3
C
C
H
O
CH3OH
H2SO4
CH3
OCH3
CH3CH
OH
CCH3
CH3
(76%)
Consistent with carbocation character at
transition state
Stereochemistry
H
H
OH
O
HBr
H
H
Br
(73%)
Inversion of configuration at carbon being
attacked by nucleophile
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
CH3OH
H2SO4
R
CH3O
H
H
S
OH
CH3
(57%)
Inversion of configuration at carbon being
attacked by nucleophile
Stereochemistry
H3C
H
R
CH3
R
R
CH3OH
O
CH3O
H2SO4
H3C H
H
H
S
CH3
+
CH3O
H
H3C
H
+
H3C
H
+
O H
OH
Question
•
What is the product isolated when the epoxide at the right
reacts with CH3OH and H2SO4?
•
A)
•
C)
B)
D)
anti-Hydroxylation of Alkenes
H
O
H
CH3COOH
O
H
H
H2O
H
OH
H
(80%)
OH
HClO4
Question
What is the product of the following reaction?
O
HBr
OH
A.
OH
C.
Br
Br
Br
B.
OH
OH
D.
Br
Thiols & Thio Ethers
Thiols
• Sulfur appears just under oxygen on the periodic
table.
• Sulfur appears in THIOLS as an –SH group
analogous to the –OH group in alcohols.
Thiols / Mercaptans
• Thiols are also known as mercaptans.
• The –SH group can also be named as part of a side
group rather than as part of the parent chain.
• The mercaptan name comes from their ability to
complex mercury.
• 2,3-dimercapto-1-propanol is used to treat
mercury poisoning.
Thiols / Mercaptans
• Thiols are known for their unpleasant odor.
• Skunks use thiols as a defense mechanism: (E)-2butene-1-thiol, 3-methyl-1-butanethiol, and 2quinolinemethanethiol, and acetate thioesters of these.
• Methanethiol is added to natural gas (methane) so that
gas leaks can be detected.
• The hydrosulfide ion (HS–) is a strong nucleophile and
a weak base.
• HS– promotes SN2 rather than E2.
Thioethers / Sulfides
• Sulfur analogs of ethers are called SULFIDES or
THIOETHERS.
• Sulfides can also be named as a side group.
Thioethers / Sulfides
• Sulfides are generally prepared by nucleophilic
attack of a thiolate on an alkyl halide.
Question
What is the correct order of reagents needed for the
following transformation?
A.a, b, f
B.a, b, g
C.a, b, h
D.a, b, i
E.a, c, g
Thioethers / Sulfides
Sulfide reactions:
Nucleophilic substitution of an alkyl halide:
The process produces a strong alkylating reagent that can
add an methyl group to a variety of nucleophiles such
as genetic bases and histones, as noted in the
Epigenetics bonus Webinar
Thioethers / Sulfides
Sulfide reactions:
Nucleophilic substitution of an alkyl halide:
The process produces a strong alkylating reagent that can
add an methyl group to a variety of nucleophiles such
as genetic bases and histones, as noted in the
Epigenetics bonus Webinar
Thioethers / Sulfides
Methylation of cytosine, a genetic base:
Nucleophilic substitution of SAM-CH3
(SAM = S-adenosylmethionine)
Where cytosine is the nucleophile.
Thioethers / Sulfides
Sulfide reactions:
Oxidation: sodium meta-periodate produces a sulfoxide.
Thioethers / Sulfides
Consider the IR of dimethylsulfoxide (DMSO) and the resonance structures
below it. An S=O bond has a strong peak @ ~1050 cm-1 and an S-O
bond @ 700-900 cm-1. Which resonance form should predominate?
Thioethers / Sulfides
Sulfide reactions:
Oxidation: hydrogen peroxide produces a sulfone.
Question
What is the correct order of reagents needed for the
following transformation?
Br
O
A.
Mg, diethyl ether
B.
1) LAH 2) H2O
F.
G.
C.
1) NaBH4 2) H2O
D.
Na2Cr2O7, H2SO4, H2O
E.
H2O
H.
O
O
O
A.
B.
C.
D.
E.
a, f, e, d
a, g, e, d
a, h, e, d
b, f, e, d
b, g, e, d