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
•Weak acids. But see below.Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH.
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
HX protonates ROH, set-up leaving group followed by SN2 (10) or SN1 (20 or 30).
Look at this reaction and attempt to predict the mechanism…
Mechanism
R-O-RH+
RO
R
H
primary R
X-
RO
R
H
X
Inversion of this R group
This alcohol will now be
protonated and reacted with
halide ion to yield RX. Inversion will
occur.
Secondary, Tertiary R
RO
R
H
X-
R X
This alcohol is protonated, becomes
carbocation and reacts with halide.
Loss of chirality at reacting carbon. Possible rearrangement.
Properties of ethers
Aprotic Solvent, cannot supply the H in H-bonding, 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
RO
H
R
OH
H acceptor H donor
protic
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.
Requirements of Hydrogen Bonding: Need both H acceptor and donor.
Synthesis of ethers
Williamson ether synthesis
RO- + R’X ROR’
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.
nucleophile electrophile
C2H5
H3C H
O
D H
H CH3
C2H5
H CH3
Provide a synthesis starting with alcohols.
Analysis (devise reactants and be mindful of stereochemistry)
Use Williamson ether synthesis.
•Which part should be the nucleophile?
•Which is the electrophile, the compound undergoing substitution?
Electrophile should ideally be 1o. Maximizes subsitution and minimizes elimination.
C2H5
H3C H
O
D H
H CH3
C2H5
H CH3
Electrophile, RX undergoing substitution
Nucleophile or
C2H5
H3C H
O
D H
H CH3
C2H5
H CH3
Electrophile, RX undergoing substitution
Nucleophile
1o
2o
1o
2o
We can set it up in two different ways:
Remember: the electrophile (RX) will experience inversion. Must allow for that!
C2H5
H3C H
O
D H
H CH3
C2H5
H CH3
Electrophile (RX)
Nucleophile
1o
2o
C2H5
H3C H
X
H D
O
H CH3
C2H5
H CH3
SN2Note allowance
for inversion
Preferably use tosylate as the leaving group, X. Thus….
C2H5
H3C H
O
D H
H CH3
C2H5
H CH3
SN2
C2H5
H3C H
OTs
H D
C2H5
H3C H
OH
H D
TsCl
retention
inversion{ O
H CH3
C2H5
H CH3
OH
H CH3
C2H5
H CH3retention
K
Done!
Acid catalyzed dehydration of alcohols to yield ethers.
2 ROH ROR + H2OH
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
RCH2OH RCH2 - OH2
RCH2OHRCH2OCH2R
H
RCH2OCH2R
primaryalcohols
ether
For secondary or tertiary alcohols.
E1 eliminationSN1 substitution
H-O-H leaves, R-O-H attached.
For primary alcohols.
ROH ROH2 H2O + carbocation
ether
ROH
alkene
- H+
Use of Mechanistic Principles to Predict Products
OH
acid
C10H22O
OH
protonate
H+
OH2+
Have set-up leaving group which would yield secondary carbocation.
H
Check for rearrangements. 1,2 shift of H. None further.
H
Carbocation reacts with nucleophile, another alcohol.
OH
H
OH
deprotonate H
O
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!!
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.
HOH
acid
OH
alcohol
ROH
acid
OR
ether
Important Synthetic Technique: protecting groups. Using Silyl ethers to Protect AlcoholsProtecting groups are used to temporarily deactivate a functional group while reactions are done on another part of the molecule. The group is then restored.
Sequence of Steps:
ROH + Cl-SiR'3
Et3NROSiR'3
Alcohol group protected, now do desired reactions.
ROSiR'3Bu4N+ F-
ROH + F-SiR'3THF
1. Protect:
2. Do work:
3. Deprotect:
Example: ROH can react with either acid or base. We want to temporarily render the OH inert. Silyl ether. Does
not react with non aqueous acid and bases or moderate
aq. acids and bases.
Now a practical example. Want to do this transformation which uses the very basic acetylide anion:
R HNaNH2
R'BrR R'R :
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.
Problem in the generation of the acetylide anion: ROH is stronger acid than terminal alkyne and reacts preferentially with the NaNH2!
Replace the H with C2H5
Protect, deactivate OH
Perform desired reaction steps.
Remove protection
Solution: protect the OH (temporarily convert it to silyl ether).
Alcohol group restored!!
Most acidic proton.
Revisit Epoxides. Recall 2 Ways to Make Them
peroxyacidRCO3H
O
Cl2H2O
OH
Cl
base
anti addition
+ enantiomer
chlorhydrin
H
H
H
H
H
H
HH
Epoxide or oxirane
Note the preservation of stereochemistry
Use of Epoxide Ring, Opening in Acid
O
CH3
H
HH
H
CH3OH
CH3H
OCH3
HO
HH
H2SO4
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.
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.
Very similar to opening of cyclic bromonium ion. Review that subject.
Epoxide Ring Opening in BaseIn 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.
O
CH3
HH
H
CH3O-
CH3
H
OH
H3CO
HH
A wide variety of synthetic uses can be made of this reaction…
Variety of Products can be obtained by varying the nucleophile
H2O/ NaOH
1. LiAlH4
2. H2O
OH
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
Attack here
An Example of Synthetic PlanningReactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a useful pattern.
O:Nu OH
Nu
The pattern to be recognized in the
product is –C(-OH) – C-Nu
The epoxide ring has to have
been located here
This bond was created by the
nucleophile
Synthetic Applicationsnucleophile
Realize that the H2NCH2- was derived from nucleophile: CN
Formation of ether from alcohols.
N used as nucleophile twice.
Epichlorohyrin and Synthetic Planning, same as before but now use two nucleophiles
Observe the pattern in the productNu - C – C(OH) – C - Nu. When you observethis pattern it suggests the use of epichlorohydrin.
Both of these bonds will be formed by the incoming nucleophiles.
Preparation of Epichlorohydrin
Cl2, high temp
Cl
Cl2 / H2O
Cl
OH
Cl
base
Try to anticipate the products…
Recall regioselectivity for opening the cyclic
chloronium ion.
O
ClH2C
Sulfides
Symmetric R-S-R
Na2S + 2 RX R-S-R
Unsymmetric R-S-R’
NaSH + RX RSH
RSH + base RS –
RS- + R’X R-S-R’
Preparation
Oxidation of Sulfides
S
sulfide
S
O
sulfoxide
S
O
Osulfone
H2O2 or NaIO4 NaIO4