Ethers, Sulfides, Epoxides
Variety of ethers, ROR
Aprotic solvent
Reactions of ethers
Ethers are inert to (do not react with)
•Common oxidizing reagents (dichromate, permanganate)
•Strong bases
HX protonates ROH, set-up leaving group
followed by SN2 (10) or SN1 (20 or 30).
•Weak acids. But see below.
Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH.
Look at this reaction and attempt to predict the mechanism…
Characterize this reaction:
Fragmentation
Substitution
Regard as
leaving
group.
Compare to
OH, needs
protonation.
Expectations for mechanism
Protonation of oxygen to establish
leaving group
For 1o alcohols: attack of halide, SN2
For 2o, 3o: formation of carbocation, SN1
Mechanism
H
+
H
R-O-R
H
XO
R
R
O
R
primary R
R
X
Inversion of this
R group
Secondary,
Tertiary R
H
X-
O
R
This alcohol is
protonated, becomes
carbocation and
reacts with halide.
This alcohol will
now be
protonated and
reacted with
halide ion to yield
RX. Inversion will
occur.
R
R
X
Loss of chirality at reacting
carbon. Possible
rearrangement.
Properties of ethers
Aprotic Solvent, cannot supply the H in Hbonding, no ether to ether hydrogen
bonding
Ethers are polar and have boiling points
close to the alkanes.
propane (bp: -42)
dimethyl ether (-24)
ethanol (78)
Hydrogen Bonding
R
Requirements of
Hydrogen Bonding:
Need both H acceptor
and donor.
R
O
H
O
protic
H
H acceptor
Ethers are not protic, no ether to
ether H bonding
However, ethers can function as
H acceptors and can engage in H
bonding with protic compounds.
Small ethers have appreciable
water solubility.
H donor
Synthesis of ethers
Williamson ether synthesis
RO- + R’X
 ROR’
nucleophile electrophile
Characteristics
• RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered)
and a strong base. Both SN2 (desired) and E2 (undesired side product) can
occur.
• Choose nucleophile and electrophile carefully. Maximize SN2 and
minimize E2 reaction by choosing the R’X to have least substituted carbon
undergoing substitution (electrophile). Methyl best, then primary, secondary
marginal, tertiary never (get E2 instead).
• Stereochemistry: the reacting carbon in R’, the electrophile which
undergoes substitution, experiences inversion. The alkoxide undergoes no
change of configuration.
Analysis (devise reactants and be
mindful of stereochemistry)
C2H5
Provide a
synthesis starting
with alcohols.
H3C
H
D
H
Use Williamson ether synthesis.
•Which part should be the nucleophile?
•Which is the electrophile, the compound
undergoing substitution?
O
H
CH3
H
CH3
C2H5
Electrophile should ideally be 1o.
Maximizes subsitution and minimizes
elimination.
We can set it up in two different ways:
C2H5
C2H5
Electrophile, RX
undergoing
1o
substitution
3
H3C
H
D
H
or
O
Nucleophile
H
2o
Nucleophile
H C
H
Remember: the electrophile (RX) will
D inversion.
H
experience
Must1oallow for
that!
O
H
CH3
H
CH3
CH3
H
CH3
C2H5
C2H5
Electrophile, RX
undergoing
substitution
2o
C2H5
C2H5
Electrophile
(RX)
1o
H3C
H
D
H
H3C
H
H
D
SN2
X
Note allowance
for inversion
O
Nucleophile
H
2o
CH3
O
H
CH3
H
CH3
H
CH3
C2H5
Preferably use tosylate as the
leaving group, X. Thus….
C2H5
C2H5
C2H5
C2H5
H3C
H3C
H
H
D
TsCl
H3C
H
H
D
H
D
H
O
H
CH3
H
CH3
C2H5
SN2
{
inversion
retention
Done!
OTs
OH
OH
O
H
CH3
H
CH3
C2H5
K
retention
H
CH3
H
CH3
C2H5
Acid catalyzed dehydration of alcohols to yield
ethers.
H
2 ROH
ROR + H2O
Key ideas:
•Acid will protonate alcohol, setting up good leaving group.
•A second alcohol molecule can act as a nucleophile. The nucleophile
(ROH) is weak but the leaving group (ROH) is good.
Mechanism is totally as expected:
•Protonation of alcohol (setting up good leaving group)
•For 2o and 3o ionization to yield a carbocation with alkene formation as side
product. Attack of nucleophile (second alcohol molecule) on carbocation.
• For 1o attack of nucleophile (second alcohol molecule) on the protonated
alcohol.
Mechanism
For primary alcohols.
RCH2OH
RCH2OH
RCH2OCH2R
RCH2OCH2R
RCH2 - OH2
primary
alcohols
ether
H
For secondary or tertiary alcohols.
ROH
ROH2
H2O + carbocation
ROH
- H+
ether
alkene
E1 elimination
SN1 substitution
H-O-H leaves,
R-O-H attached.
Use of Mechanistic Principles to Predict Products
acid
C10H22O
OH
H+
H
OH
OH2+
protonate
H
Have set-up leaving
group which would yield
secondary carbocation.
Check for
rearrangements. 1,2 shift
of H. None further.
O
OH
O
H
Carbocation
reacts with
nucleophile,
another alcohol.
deprotonate
H
H
Acid catalyzed addition of alcohol to
alkene
Recall addition of water to an alkene (hydration). Acid catalyzed, yielded
Markovnikov orientation.
Using an alcohol instead of water is really the same thing!!
OH
OR
HOH
ROH
acid
acid
alcohol
ether
Characteristics
Markovnikov
Alcohol should be primary to avoid carbocations being formed from the alcohol.
Expect mechanism to be protonation of alkene to yield more stable
carbocation followed by reaction with the weakly nucleophilic alcohol.
Not presented.
Important Synthetic Technique: protecting
groups. Using Silyl ethers to Protect Alcohols
Protecting groups are used to temporarily deactivate a functional group while
reactions are done on another part of the molecule. The group is then restored.
Example: ROH can react with either acid or base. We want to temporarily
Silyl ether. Does
render the OH inert.
not react with non
Sequence of Steps:
aqueous acid and
bases or moderate
Et3N
aq. acids and
1. Protect:
ROSiR'3
ROH + Cl-SiR'3
bases.
2. Do work:
Alcohol group protected, now do desired reactions.
Bu4N+ F-
3. Deprotect: ROSiR'3
ROH + F-SiR'3
THF
Now a practical example. Want to do this transformation which uses the very basic
acetylide anion:
Replace the H with C2H5
Want to employ this general reaction sequence which we have used before to
make alkynes. We are removing the H from the terminal alkyne with NaNH2.
R'Br
NaNH2
R
H
R
:
R
R'
Problem in the generation of the acetylide anion: ROH is stronger acid than
terminal alkyne and reacts preferentially with the NaNH2!
Solution: protect the OH (temporarily convert it to silyl ether).
Most acidic proton.
Perform desired
reaction steps.
Protect,
deactivate OH
Remove
protection
Alcohol group
restored!!
Revisit Epoxides. Recall 2 Ways to
Make Them
H
Note the
preservation of
stereochemistry
peroxyacid
RCO3H
H
H
H
Epoxide or
oxirane
OH
H
base
H
Cl2
H2O
H
+ enantiomer
H
Cl
anti addition
chlorhydrin
O
Use of Epoxide Ring, Opening in Acid
In acid: protonate the oxygen, establishing the very good leaving group. More
substituted carbon (more positive charge although more sterically hindered) is
attacked by a weak nucleophile.
H
CH3OH
O
H
H
HO
H
CH3
H CH3
H2SO4
H
H
Very similar to opening of
cyclic bromonium ion.
Review that subject.
OCH3
Due to
resonance,
some positive
charge is
located on
this carbon.
Inversion
occurs at this
carbon. Do you
see it?
Classify the
carbons. S
becomes R.
Epoxide Ring Opening in Base
In base: no protonation to produce good leaving group, no resonance but the ring
can open due to the strain if attacked by good nucleophile. Now less sterically
hindered carbon is attacked.
CH3OO
H
H
H
H
OH
H
H
CH3
H3CO
A wide variety of synthetic uses can be made of this reaction…
CH3
Variety of Products can be obtained by varying the nucleophile
Do not memorize
this chart. But be
sure you can figure
it out from the
general reaction:
attack of
nucleophile in
base on less
hindered carbon
H2O/ NaOH
Attack
here
1.
2.
OH
LiAlH4
H2O
An Example of Synthetic Planning
Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably
follow a useful pattern.
:Nu
The epoxide
ring has to have
been located
here
OH
O
Nu
The pattern to be
recognized in the
product is
–C(-OH) – C-Nu
This bond was
created by the
nucleophile
Synthetic Applications
nucleophile
Realize that the H2NCH2- was
derived from nucleophile: CN
N used as
nucleophile
twice.
Formation of
ether from
alcohols.
Epichlorohyrin and Synthetic Planning, same as
before but now use two nucleophiles
Observe the pattern in the product
Nu - C – C(OH) – C - Nu. When you observe
this pattern it suggests the use of epichlorohydrin.
Both of these bonds will be
formed by the incoming
nucleophiles.
Preparation of Epichlorohydrin
Try to anticipate the
products…
OH
Cl2 / H2O
Cl2, high temp
O
base
ClH2C
Cl
Recall
regioselectivity for
opening the cyclic
chloronium ion.
Cl
Cl
Sulfides
Preparation
Symmetric R-S-R
Na2S + 2 RX

Unsymmetric R-S-R’
NaSH + RX
 RSH
RSH + base  RS –
RS- + R’X  R-S-R’
R-S-R
Oxidation of Sulfides
O
S
NaIO4
H2O2 or NaIO4
S
sulfide
O
S
sulfoxide
O
sulfone