An alternative to making the halide: ROH ROTs

p-toluenesulfonyl chloride

Tosyl chloride

TsCl

ROH +S OO

Cl

S OO

O

CH3 CH3

R Tosylate group, -OTs, good leaving

group, including the

oxygen.

The configuration of the R group is unchanged.

Preparation from alcohols.

Example

CH3

H OH

C2H5

C3H7 CH3

TsCl

CH3

H OTs

C2H5

C3H7 CH3

Preparation of tosylate.

Retention of configuration

Substitution on a tosylate

The –OTs group is an excellent leaving group

Acid Catalyzed Dehydration of an Alcohol, discussed earlier as reverse of hydration

Protonation, establishing of good leaving group.

Elimination of water to yield carbocation in rate determining step.

Expect tertiary faster than secondary.

Rearrangements can occur.

Elimination of H+ from carbocation to yield alkene.

Zaitsev Rule followed.

Secondary and tertiary alcohols, carbocations

Primary alcohols

Problem: primary carbocations are not observed. Need a modified, non-carbocation mechanism.

Recall these concepts:

1. Nucleophilic substitution on tertiary halides invokes the carbocation but nucleophilic substitution on primary RX avoids the carbocation by requiring the nucleophile to become involved immediately.

2. The E2 reaction requires the strong base to become involved immediately.

Note that secondary and tertiary protonated alcohols eliminate the water to yield a carbocation because the carbocation is relatively stable. The carbocation then undergoes a second step: removal of the H+.

The primary carbocation is too unstable for our liking so we combine the departure of the water with the removal of the H+.

What would the mechanism be???

Here is the mechanism for acid catalyzed dehydration of Primary alcohols

1. protonation

2. The carbocation is avoided by removing the H at the same time as H2O departs (like E2).

As before, rearrangements can be done while avoiding the primary carbocation.

Principle of Microscopic Reversibility

Same mechanism in either direction.

Pinacol Rearrangement: an example of stabilization of a carbocation by an adjacent lone

pair.

Overall:

MechanismReversible protonation.

Elimination of water to yield tertiary carbocation.

1,2 rearrangement to yield resonance stabilized cation.

Deprotonation.

This is a protonated

ketone!

Oxidation

Primary alcohol

RCH2OH RCH=O RCO2H

Na2Cr2O7

Na2Cr2O7

Na2Cr2O7 (orange) Cr3+ (green) Actual reagent is H2CrO4, chromic acid.

Secondary

R2CHOH R2C=O

Tertiary

R3COH NR

KMnO4 (basic) can also be used. MnO2 is produced.

The failure of an attempted oxidation (no color change) is evidence for a tertiary alcohol.

Na2Cr2O7

OH

CH2OH

HO

Na2Cr2O7

acid

OH

CO2H

O

Example…

Oxidation using PCC

Primary alcohol

RCH2OH RCH=OPCC

PCCSecondary

R2CHOH R2C=O

Stops here, is not oxidized to carboxylic acid

Periodic Acid Oxidation

OH

OH

glycol

HIO4

O

O

two aldehydes

+ HIO3

OH

O HIO4

O

O

aldehydes

HO

carboxylic acid

+ HIO3

O

O HIO4

O

OHO

carboxylic acidcarboxylic acid

OH + HIO3

OH

O 2 HIO4

OH

O

OH

OHO

O

+ 2 HIO3

Mechanistic Notes

Cyclic structure is formed during the reaction.

Evidence of cyclic intermediate.

Sulfur Analogs, Thiols

Preparation

RI + HS- RSH

SN2 reaction. Best for primary, ok secondary, not tertiary (E2 instead)

Acidity

H2S pKa = 7.0

RSH pKa = 8.5

Oxidation

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-R

H+

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

R

O

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

RCH2OH

RCH2OCH2R

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

O

H

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