Loudon Chapter 11 Review: Ethers, Epoxides and Glycols

CHEM 3311, Jacquie Richardson, Spring 2010 - Page 1

This chapter covers four different functional groups, but were only focusing on three of
them: ethers, epoxides and sulfides. Ethers have a central oxygen with an R group to
either side of it. Epoxides are a special kind of ether, where the R groups are linked
together in a three-membered ring. Because theyre strained, epoxides are a lot more
reactive than regular ethers. Glycols, a.k.a. vicinal diols, are a type of alcohol that has
two OH groups on adjacent carbons.
O HO OH
R R R R
R O R
R R R R
Ether Epoxide Glycol
Making ethers: most of these methods are based on reactions we already know.
1. Williamson Ether Synthesis: this is based on getting the molecule set up for an
SN2 reaction, starting with an alcohol and an alkyl halide. You convert the alcohol
into a strong base/good nucleophile first by deprotonating it with a stronger base,
usually sodium hydride. This is usually the best choice for making ethers.
1) NaH
Overall reaction: R O H R O R' (R'X must be SN2-capable)
2) R'X

Mechanism: R O H Na H R O R' X R O R'

2. Alkoxymercuration-reduction: this is very similar to oxymercuration-reduction,

only you bring in an alcohol instead of water.
CH3 H CH3 H
1) Hg(OAc)2, ROH, THF
Overall reaction: H H
2) NaBH4, NaOH
H H OR H
Mechanism:
OAc OAc
Hg OAc OAc
Hg CH3 Hg CH3 Hg CH3 H
OAc CH3 H NaBH4
CH3 H H H H H NaOH H H
H H R O H RO H
H H RO H
H
ROH

3. Alcohol Dehydration: starts by protonating the alcohol, like in chapter 10, which
allows another molecule of alcohol to do either SN1 or SN2 on it, depending on
substrate. This works best for sticking together two molecules of a primary
alcohol, or a tertiary with any other kind of alcohol.
Overall reactions:
H2SO4 H2SO4
H3C OH + HO CH3 H3C O CH3 OH + HO R O R
heat

Mechanisms:

H3C OH H SN2
H3C OH2 HO CH3 H3C O CH3 H3C O CH3
H
HO CH3
SN1
OH H OH2 HO R O R O R
H HO
 Loudon Chapter 11 Review: Ethers, Epoxides and Glycols
CHEM 3311, Jacquie Richardson, Spring 2010 - Page 2

Reactions of ethers:
Like for alcohols, -OR is a bad leaving group. You need to turn it into a good
leaving group, and the only way to do it is with protonation. So you need a strong
acid of some kind. Then, depending on substrate, you can do either SN1 or SN2
with whatever halogen is the conjugate base. This temporarily makes an alkyl
halide and an alcohol, but under these conditions, the alcohol will immediately
turn into another alkyl halide. Normally this isnt a reaction youd do on purpose;
it just happens automatically if you put an ether in acid.
Overall reaction: HX HX
R O R R OH + R X R X + R X

Mechanism:
H
X- does
R O R H X R O R R OH + R X
SN1 or SN2

Making epoxides:
1. With peroxyacids. Usually itll be either mCPBA or MMPP, but peroxyacetic
acid shows up sometimes. Whichever one you use, its normally the only thing
you need to write on the arrow. The starting material is an alkene. The mechanism
happens all in one step, but to understand why things happen the way they do its
helpful to think of it as stepwise at first. The book has a great explanation of this
on page 489.
O
O
OH O
OH O
O Mg+2 OH
O H3C O

O
Cl 2

mCPBA MMPP peroxyacetic acid

Overall reaction: Mechanism: H3C O

CH3 H CH3 O H
mCPBA O H
O O H
H H H H CH3
CH3 H
H H
H H

2. From a halohydrin. We learned how to make halohydrins from alkenes in Ch.5.

Now we can put them to use. The reaction goes by an intramolecular SN2, so its a
lot like Williamson but within the same molecule. Since the alkyl halide is right
there and readily available, you can get away with using a weaker base such as
NaOH, although NaH will still work too.
 Loudon Chapter 11 Review: Ethers, Epoxides and Glycols
CHEM 3311, Jacquie Richardson, Spring 2010 - Page 3

CH H CH3 Br CH3 H
Overall reaction: 3 Br2, H2O NaOH
H H H H
H H OH H O
CH3 Br CH3 Br CH3 H
Mechanism: H H H H H H
O H O H O
Na OH H

Reactions of epoxides: These can happen under acidic or basic conditions, or with
organometallics like Grignards. In all cases, it acts like an SN2 reaction in terms of
geometry its a backside attack, which gives inversion of configuration.
1. Under acidic conditions, the mechanism looks a lot like opening the bromonium
ion opening from chapter 5. Just like in that case, the attack happens at the more
substituted carbon due to charge density. But you have to protonate the oxygen
first.
Overall reactions: Mechanism:
H
O H CH3 OH CH3 OH
CH3 H2O O H H CH3 O H
H H CH3
H2SO4 H H
H H OH H H H Nu H
H H
O H CH3 OH Nu
CH3 ROH
H H
H2SO4
H H OR H
CH3 OH
CH3 O H HX
H H
H H X H

2. Under basic conditions, the oxygen doesnt get protonated, but the nucleophile
just goes straight in for the attack. The attack happens at the less substituted
carbon now, since the only concern is sterics. I only put a couple of examples here
but most of the other nucleophile/bases we saw in chapter 9 can do this under the
right conditions.

Overall reactions: Mechanism:

O H OH H O H O H HO H
CH3 NaOH CH3 H Nu
CH3 H CH3 H CH3 H
H2O
H H H OH H H H Nu H Nu
Nu
O H OH H
CH3 NaOR
ROH CH3 H
H H H OR

3. With organometallics, the alkyl group attacks the less substituted carbon just like
under regular basic conditions. Theoretically you could use a Grignard or
organolithium to do the attack but theres a problem: these are such strong bases
that theyre more likely to pull off a H if theres one available. So about the only
time you can safely use these organometallics is if there are no other carbons
attached to the epoxide ring.
 Loudon Chapter 11 Review: Ethers, Epoxides and Glycols
CHEM 3311, Jacquie Richardson, Spring 2010 - Page 4

Overall reaction: Mechanism is same as above for first rxn. For second rxn, it's E2:
1)RLi or RMgBr R Li
OH H
H O H THF or ether
+ H H H
2) H3O O
H H H R H2C O H H2C
1)RLi or RMgBr H
CH3 O H THF or ether H2C OH H H H R
H
H H 2) H3O+ H R
Problem!

To get around this problem, theres a new type of organometallics: cuprates. First,
you need to know how to make them. You start with two molecules of an
organolithium and react them with copper (I) chloride.
CuCl R Cu R or R2CuLi
Making cuprates: 2 R Li
THF
Li
These are weaker bases than Grignards or organolithiums, so theyll behave
nicely and add an R group to the molecule without doing anything else.
Overall reaction: Mechanism is same as in basic conditions, for both rxns.
1)R2CuLi
OH H
H O H THF or ether
H H
2) H3O+
H H H R
1)R2CuLi
OH H
CH3 O H THF or ether
CH3 H
H H 2) H3O+
H R
No problem!

Making glycols: There are two different methods depending on what stereochemistry
you want.
1. From an epoxide, like we saw above. Since this goes by backside attack, youll
always have one OH bold and one dashed. This is called an anti diol. It works in
either acidic or basic conditions.
Overall reactions:
OH OH O H H2O, H+ OH OH
CH3 O H NaOH CH3
CH3 H
CH3 H
H2O
H H H H H H H H
2. From an alkene. This is a new reaction that involves osmium tetroxide. Here, both
oxygens add to the same face at the same time, so it gives a syn diol. Often, other
reagents are included to recycle the osmium and allow it to be used in much
smaller amounts, though theyre not required. You also have the option of using
KMnO4, although it can oxidize further and is not ideal.
Overall reaction:
OH OH
CH3 H OsO4
CH3 H
H2O
H H H H
 Loudon Chapter 11 Review: Ethers, Epoxides and Glycols
CHEM 3311, Jacquie Richardson, Spring 2010 - Page 5

Reactions of glycols:
Mostly they can do anything that regular alcohols can do. There is one important,
unique reaction. You can split them in half between the OH group using IO4- in
some form. The end result of this looks a lot like ozonolysis on an alkene, only
you start with a glycol (which you can get to from an alkene by two different
ways). For this to work, the molecule has to be capable of getting its two OHs
pointing in the same direction, whether it starts that way or whether it gets there
by rotating around the bond between the two carbons.
OH OH
HIO4, NaIO4 H3C H
Overall reaction: CH3 H O O
or H5IO6
H H H H