Copyright, Arizona State University

Ethers/Epoxides
1 Terminology/Properties
O

Reactions With Brnsted Acids/Bases

(more...)
O

R
R
Symmetric

R'
R
Asymmetric

O
R'
R
~105
Tetrahedral

Epoxide

Generally unreactive although Epoxides are an exception

Good Organic Solvents

2 Nomenclature
Named as substituents (like halides), lowest priority
Substituent is named as the ALKOXY is equivalent to ALKYL, i.e. Me is methyl, thus, -OMe is methoxy etc.
the "main" chain" is according to the usual rules, the longest chain that contains the ,maximum number of
functional groups

Alkoxy substituent

R O
R'

More
2
complex
1
side Alkene

More complex side

is the main chain
3 2 1

1-ethoxybutane

substituent
4

(4S)-tert-butoxycyclohexene

ethoxy
substituent

Some Common Ethers and Common Names

O
diethyl ether

O
oxetane
ethylene oxide
(oxirane)

tetrahydropyran
tetrahydrofuran (THF)

3 Preparation of Ethers
3.1 Williamson Ether Synthesis (SN2 Reaction)
This is just an SN2 reaction, but we will analyze it using retrosynthetic analysis
Retrosynthetic strategy

R O

R O R'

R'

synthons
"put" negative charge on the oxygen and a leaving group on the carbon

Na
alkoxide anion R O

R'

R O R'

synthetic equivalents : reagents

The Williamson ether synthesis consists of Two Steps
Ethers/Epoxides

Copyright, Arizona State University

First Step: preparation of an alkoxide anion (the nucleophile) by deprotonation of an alcohol

which base is useful for this?

R O

R O
Na + H2
sodium alkoxide

Na
H
sodium hydride

sodium hydride is a useful strong base to irreversibly deprotonate an aliphatic alcohol

Example

Na

OH +

Na

H3C OH

Na sodium methoxide

H3C O

Na sodium phenoxide

the conjugate base anions of alcohols are alkoxide anions (organic version of hydroxide)

the phenoxide anion can also be made simply with OH

Stonger acid
faster reaction

OH

Na

OH

Na +

H2O
pKa ~ 15

pKa ~ 10

Second Step; SIMPLE SN2 reaction with a halide (coupling reaction)

RO

R'

SN2

R O R'

preferably primary/allylic halide (SN2)

other good leaving groups will also work (SN2)
Example 1

1. NaH

OH

2. Br

preferred method

1.

NaH

HO

Br 3
2.
doesn't work

(SN2 on a 3 alkyl halide)

Example 2:
only do SN2 at a secondary carbon if you can't avoid it, in this case it can be avoided from the "other" direction

1. NaH

HO
2.

O
Br 1

1.
2.

preferred

Ethers/Epoxides

NaH
Br 2

OH

Copyright, Arizona State University

3.2 Preparation Methods for Ethers/Epoxides Seen Before (Review)

1. Hg(OAc)2/H2O
H
()

Cl

OH

2. NaBH4

MCPBA
O
C OOH

1. Hg(OAc)2/EtOH

OEt

2. NaBH4

the formation of epoxides using MCPBA is described in more detail below

4 Reactions of Ethers/Epoxides (Acids and Bases)

4.1 Cleavage of Ethers Using Acids
Ethers are mainly unreactive, except ONE reaction that we can WORK OUT based on a reaction of alcohols that
we just learned, and reaction principles that we know fairly well
recall conversion of an alcohol to an alkyl bromide

makes a good leaving group

Me O H

H Br

Me O

Br Me

Br
makes a good leaving group
t-Bu O H

H Br

t-Bu O

Br
t-Bu

SN2

t-Bu Br

SN1

protonation of oxygen makes a good leaving group, allows C-O to be broken

SN2 OR SN1, depending upon the substituents on the alcohol
Ether Reaction: Cleavage with Acid

R O R'

Excess HX
Heat

R-X + R'-X + H2O

Mechanism

H
R O R' + H X
L/B Base

L/B Acid

R O R'

SN2
if possible

R-X + R'-OH

H X

R'-OH2

SN1
if SN2

X
R'

IMpossible

R'-X
the first step is related to the alcohol reaction above, the second step IS the alcohol reaction above
this substitution may be by SN2 or SN1 mechanisms, depending upon whether the protonated ether is attached
to a 1, 2 or 3 carbon, as usual

Ethers/Epoxides

Copyright, Arizona State University

Examples

substitute here 3 = SN1

Br
H
O

substitute here 1 = SN2

Br
Excess HBr

Br

SN1

Br

Br
SN1

OH H Br

SN2 at 1
carbon
SN2 FASTER

OH2

Br

NO SN2 at
3 carbon

SN1 SLOWER

protonate the oxygen to create a good leaving group as usual, then

SN2 at the 1 carbon happens FIRST, because SN2 is always faster than SN1
SN1 at the 3 carbon

substitute here 1 = SN2

HBr

OH

Br

Stops here, cannot do

SN2 reaction at sp2 carbon

NO substitution here sp2 carbon

the -OH attached to the sp2 hybridized carbon can not be substituted by either SN1 or SN2 mechanisms

Example with ONE Equivalent of Acid

1 Equiv. HI
O
I

STRONG
LA/Elec.

CH3

+ Me-I

WEAK Nuc/LB

SN2
FASTEST at
the Me carbon

SN2 would be SLOWER

at this 2 carbon
Note 1 Equivalent of acid, only allows ONE substitution, substitution occurs at the carbon where SN2 is
FASTEST, in the example above it is the methyl carbon atom
Note, H-I is also a strong Bronsted acid, reacts the same way as H-Br
Iodide is a WEAK Lewis base/nucleophile, but the protonated ether is a STRONG Lewis acid/electrophile

4.2 Formation of Epoxides and trans-Diols

New reagent

O
R

Cl

O
O OH

peroxy acid
Ethers/Epoxides

peroxide

OH

carboxylic acid
4

O
C

OH

meta-chloroperbenzoic acid (MCPBA)

Copyright, Arizona State University

Ethers/Epoxides

Copyright, Arizona State University

Mechanism

C
O

H O

carboxylic acid

epoxide
concerted mechanism - all bonds made and broken at the same time
no chance for bond rotation "in the middle" - stereospecific reaction!
Examples

MCPBA

cis-alkene

cis-epoxide formed

reaction is STEREOSPECIFIC
Anti-Addition of two -OH across a C=C bond in an alkene
Synthesis of a trans-Diol
formation of an epoxide followed by ACID CATALYZED HYDROLYSIS of the epoxide
lysis = bond breaking, and hydro = with water, hydrolysis = bond breaking using water

hydrolysis
H3C
cis-alkene
achiral

()

CH3
C

OH
C

HO

CH3

H
ANTI-addition
(R)/(R) and (S)/(S)
stereoisomers formed

CH3
C C

MCPBA

H3C C C CH3
H
LB/BB

H CH3 OH
C C
CH3
H O
H

LA/BA

H
H
WEAK
nucleophile
LB/BB

LA/BA

H3O+ = H2O (solvent)

+ e.g. HCl, H2SO4 (cat.)
H

LA

O
C

H3C
(SN2)

H O

H
H

CH3

oxonium ion

H
LB
backside attack!

when H3O is a reagent, this means aqueous acid (e.g. HCl or H2SO4 in water)
the intermediate is an oxonium ion (onium means more than usual valence, in this case 3 for oxygen), compare
with bromonium etc.,
the driving force for opening the protonated epoxide (oxonium ion) is provided by release of ring strain energy
this reaction sequence makes a trans-diol when cis-/trans-isomers are possible, the overall addition of the two OH is ANTI- in all cases
NOTE: the (R)/(R) and (S)/(S) stereoisomers are formed in the above example (as a pair of enantiomers).
Although cis-/trans-isomers cannot be forme din this case, we still need to distinguish formation of the (R)/(R) and
the (S)/(S) pair of enantiomers from a (R)/(S) and (S)/(R) diastereomers, the addition is ANTI- and we can tell in
this example

Ethers/Epoxides

Copyright, Arizona State University

Recall: 3-membered onium rings are attacked at most substituted carbon

In these reactions the attacking species is a WEAK nucleophile/Lewis base (Br-, H2O, ROH etc.)
smaller contribution to the mix

larger contribution to the mix

Br
Br

H
O

H
O

OAc
Hg
H O
H

H O
H

major

H
O

less minor

H
O

most + charge

intermediate
most minor + charge
"actual"

least +
charge

Example

1. MCPBA
2. H3

achiral

HO

O+

()
Racemic

OH

trans-diol
ANTI-addition
backside attack

Example NOT using aqueous acid

Me
O
H
H

OH

CH3OH

OCH3

HCl (cat.)

OH

STRONG Elec./LA

reaction is REGIOSPECIFIC
-OCH3 attached to the most
substituted carbon

O
H3C

H
WEAK Nuc/LB

H
H3C

H3C

NOTE, the solvent here is NOT water, this is not hydrolysis, it is "methanolysis" (bond breaking using methanol)
+
The acid catalyst is NOT H3O (there is no water), HCl dissolved in methanol will dissociate (not quite as much
as in water, but substantially)
Other strong organic acid catalysts (catalysts that can be dissolved in organic solvents) that can be used here
+
(when H3O cannot be used) include

TFA

O
S OH TsOH
O

trifluoroacetic acid: TFA

p-toluene sulfonic acid: TsOH

F3C C
OH

Ethers/Epoxides

Copyright, Arizona State University

Related example (you should be able to extrapolate to examples such as this by knowing the mechanism)

Cl

HO

HCl

H Ether (inert solvent)

Me

STRONG Elec./LA
backside attack
Walden inversion

-H still dashed
-Me still wedged
but now both point "up"

Me

Cl

(SN2)

H
O

dashed -H and wedged

-Me are "pushed up"

H
Me

Cl

WEAK Nuc/LB

In his case the acid is the reagent, it ADDS to the epoxide, it is not just a catalyst
+
Obviously H3O can't be used here since we do not have water as the solvent
when the chloride anion acts as the nucleophile/LB it is doing an SN2 reaction on the carbonatom, the SN2
proceeds with a Walden inversion, the wedged -Me and the dashed -H change from both pointing "down" to both
pointing "up", but the wedged bond remains wedged and the dashed bond remains dashed when we look at the
reaction from the perspective shown

4.3 Formation of cis-Diols

This is normally part of CHM 233, we skipped this section last semester, it fits quite well here.
The are TWO sets of reagents that will accomplish this reaction
The reaction

cold KMnO4/-OH/H2O
OR

OH

syn-addition
(same side)

OH

OsO4 / H2O2
The mechanisms

+7 oxidation state
metal gets
reduced here

+5 oxidation state

O O
Mn

Mn

OH

+4 oxidation state

HO

OH

+ MnO2

syn-addition!
-OH
O

HO Mn

don't need to know!!

O

O O
HO Mn
O
O

HO Mn OH
O
O
-OH

aqueous
workup
O

radical
reduction

O
+ MnO2(OH)2

addition/elimination mechanism
although this is obviously complex, the important part is that the MnO4 ion starts the reaction by adding to both
ends of the alkene at the same side, which is why a cis-diol must be formed
note that in mechanisms involving metal atoms, the metal has enough electrons and empty orbitals to give and
take electrons on its own, almost at will (almost like cheating to an organic chemist!!)
Ethers/Epoxides

Copyright, Arizona State University

metal gets
reduced here

+8 oxidation state
O

O
Os

+6 oxidation state

O O
Os

H2O2

HO

OH

+ OsO4
catalyst
syn-addition! regenerated!

H2O2
don't need to know.....

why TWO reagents?

KMnO4 - inexpensive, used for large scale reactions, variable yields
OsO4 - expensive, extremely toxic! good yields, is catalytic, used in small scale syntheses
This illustrates the principle that in general there will always be more than one reagent to accomplish any
transformation even if we only discuss one in this course
Examples

cold KMnO4/-OH/H2O

achiral

* *

OH

HO

H3C
CH3
C C
achiral
H
H

OsO4 / H2O2

H3C
H
C C
achiral
H
CH3

OsO4 / H2O2

H3C
*C
H
HO

solution not
optically active
meso compound

cis-diol

solution not
optically active
meso compound

CH3

C*

H OH
H

H3C
*C
H
HO

OH
()

H3C OH

HO

()

solution not
optically active
racemic mix.

Compare

1. MCPBA
trans-diol
H

2. H3

OsO4
H2O2

O+

cis-diol
H

OH

HO
OH
meso compound!

H
HO
() racemic mixture

4.4 Base Catalyzed Opening of Epoxides

Recall

Nu
Ethers/Epoxides

RNu
9

O-R

Poor leaving group

Copyright, Arizona State University

Compare

Nu

better "leaving group",

release of ring strain

Nu
reaction works, driven by release of ring strain energy
only have an oxygen anion leaving group when you have high energy electrons in the Nucleophile/Lewis base
reactant, and in this case the strain energy of the epoxide helps a lot too
when NOT PROTONATED, strong nucleophiles attack epoxides at the least substituted carbon for steric
reasons, this is essentially an SN2 reaction and SN2 is fastest at the least substituted carbon
this is the OPPOSITE of what happens when the epoxide is protonated, when protonated the nucleophile
electron energy decreases more andf faster when it approaches the carbin with the larger partial positive charge,
so that charge effects "win" over the steric effect, but when the epoxide is NOT protonated, there are no charge
effects and the steric effect wins
a STRONG Lewis/Bronsted base is required to attack a non-protonated epoxide, but we have seen several of
these already

oxygen NOT
protonated!

O
HC

Me MgBr

HO

Nuc/LB attacks the LEAST

substituted carbon when the
oxygen is not protonated

These are STRONG Lewis bases/nucleophiles (actylide. Grignard, -OH, -OR etc.)
Hydrolysis example (recall, hydrolysis means breaking bonds using water, here, bonds in the epoxide ring)

WEAK LA/Elec.

OH

NaOH
H2O
OH
STRONG LB/nuc
O

H O
OH

HO

Example with different strong LB/nucleophile

Na OCH3
HOCH3
OCH3

(SN2)
backside attack

OCH3

CH3

OH

+
OCH3

OCH3

reaction is REGIOSPECIFIC
-OCH3 attached to the LEAST substituted carbon

the STRONG LB/nucleophile methoxide attacks the least substituted side for steric reasons (seen previously!)
RECALL: a different product (structural/REGIO isomer) is formed in the corresponding from acid catalyzed
reaction!

Ethers/Epoxides

10

Copyright, Arizona State University

OH

CH3OH

reaction is REGIOSPECIFIC
-OCH3 attached to the
MOST substituted carbon

HCl (cat.)
H3CO
H

OH

O
H

H O CH
3

H3C

an abbreviated mechanism is shown here, you can solve problems using an ALGORITHMIC APPROACH,
where if you follow the correct algorithm (the mechanism in this context) you MUST get the correct answer
OR, you develop HEURISTIC PROBLEM solving skills that allow you to "jump" to the answer without writing out
the entire mechanism, this is much faster and the way that "real" chemists work out the products of reactions
the more problems you solve the better developed your heuristic problem solving becomes

4.5 Examples in Synthesis

Example

Br

()
+

Na OH
DMF
OH

1. BH3.THF
2. OH/H2O2

B
O

Br
O

NaH

best synthons from

bond B (not bond A)

Na

in this case the C-O bond that we are tempted to make to construct the ether (bond A) is not as good as bond B,
since to make bond A we would need to do an SN2 reaction on a secondary carbon atom
in ether synthesis you need to select the BEST C-O bond to make in an SN2 reaction
Example

OH

MCPBA

Na/NH3(l)
OH

O
()

1. Na+ C

2. H3O+

()

OH

CH3
()

H
OH

too difficult to
ensure transstereochemistry

can't make required C-C bond in last step, need to do a FGI that will allow the C-C bond to be made
convert (backwards) into an alkyne, NOW can make the C-C bond
Ethers/Epoxides

11

Copyright, Arizona State University

Ethers/Epoxides

12

Copyright, Arizona State University

5 Summary of Reactions (more)

Do NOT start studying by trying to memorize the reactions here!
Work as many problems as you can, with this list of reactions in front of you if necessary, so that you can get
through as many problems as you can without getting stuck on eth reagents/conditions, and so that you can learn
and practice solving reaction problems. Use this list AFTER you have worked all of the problems, and just before
an exam. By then you will have learned a lot of the reagents/conditions just by using them and you will only have
to memorize what you haven't learned yet. Then do the following:
Cover the entire page of reagents/conditions with a long vertical strip of paper, see if you can write down the
reagents/conditions for each reaction, check to see which you get correct, if COMPLETELY correct, circle Y, if
incorrect or even slightly incorrect, circle N. In this way you keep track of what you know and what you don't know.
Keep coming back to this list and so the same thing only for those reactions you circled N, until all are circled Y.
Knowing the reagents/conditions on this page is INSUFFICIENT to do well on an exam since you will ALSO need
to recognize how to use and solve reaction problems in different contexts, this page ONLY helps you to learn the
reagents/conditions that you have not YET learned by working problems.

Na+ H
OH

NaOH can NOT be used here

Na+ OH

OH

NaH could also be used here

Br
O

Na

(SN2)

Williamson ether synthesis

1. Hg(OAc)2 / CH3OH
2. NaBH4
MCPBA
1. MCPBA
2. H3O+
HBr / heat

O
O

CH3OH
H+ (cat.)

Y/N

Na

Y/N

Na

Y/N

()

Y/N

OCH3
O

Y/N
OH

Y/N

()

HO

Br + Br

Y/N

HO
Y/N
OCH3

must be an organic acid, HCl, TsOH etc.

OH

O
()

CH3OH
NaOCH3

Ph

Y/N
CH3O

Ph
OH

OsO4/H2O2
OH

cold KMnO4/-OH/H2O
Ph

Ethers/Epoxides

Ph

13

HO

OH

Ph

Ph

Copyright, Arizona State University