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