Substitution Reactions of Alcohols

Substitution Reactions of AlcoholsWe have looked at substitution reactions that take place via two mechanisms:

SN1 - works for substrates that can form relatively stable carbocations...

SN2 - works best for substrates where the carbon that bears the leaving group is sterically uncluttered.Both mechanisms involve loss of the leaving group in the rate-determining step.

Good leaving groups are...

So, if we want to use alcohols as substrates in these reactions, we must do something to make the –OH group a better leaving group.

OH+N C CN + HO

OH + HO

The problem with alcohols...

Substitution Reactions of Alcohols

3° alkyl halides via SN1

H3C

C

H3CH3C O

HH3C

C

H3CH3C Br

Conc. HBr

Propose a mechanism for this reaction:

1° alcohols are converted into alkyl halides via SN2

CH3CH2CH2CH2OHH2SO4, NaBr

CH3CH2CH2CH2Br

Propose a mechanism for this reaction:


Consider the following reaction. We doesn’t it proceed to products?

CH3CH2CH2CH2OH

H2SO4, NaCN

CH3CH2CH2CH2CNX

OK, so what if we use HCN instead? The reaction still doesn’t proceed. Why?


CH3CH2CH2CH2OH CH3CH2CH2CH2CNXHCN

If we want to make nitriles, we will have to use a different approach. One method is to convert the alcohol into a sulfonate ester. To make a sulfonate ester, you react an alcohol with an appropriate sulfonyl chloride in the presence of an amine (usually pyridine):


OH

SCl

O O

N

OS

O O

N+

HCl–

+ + +

Some common Sulfonate Esters:

O S

O S

O

O

CH3R

O

O

R CH3

O S

O

O

R Br

O S

O

O

CF3R

O S

O

O

CF2CF2CF2CF3R Nonaflate

Triflate

Brosylate

Tosylate

Mesylate

Generic NameEster Abbreviation

R-ONs

R-OMs

R-OTs

R-OBs

R-OTf

Sulfonate EstersAn alternative approach would be to deprotonate the alcohol first, then react it with the sulfonyl chloride:

DMFH2

DMF

OH

S

OO

O

S

OO

ClO

–Cl–

H–O–+

+

+

+

D M F

H2

DMF

OH

S

OO

O

S

OO

ClO

–Cl–

H–O–+

+

+

+

The alkoxides can be made by reacting an alcohol with NaH or with an alkali metal (Na or K):

Sulfonate EstersOnce the alcohols have been converted to the sulfonate ester, it can then be used in an SN2 reaction:

THF

S

OO

O C–

N+ T H F

S

OO

O C–

N+

THFS

OO

OS–+ T H FS

OO

OS–+

Sulfonate esters make good leaving groups because the pKa of their conjugate acids is ~-6.5, roughly the same as that for Cl-. As such, another strategy for making alcohols a better leaving group is to convert them into a halide!

Substitution Reactions of Alcohols – Converting Alcohols to Alkyl Halides

OHPBr3

Br 60%

OHSOCl2

Thionyl chloride

Cl 70%

OHPBr3

Converting Alcohols to Alkyl HalidesPropose a mechanism for the following reaction:

P=O bonds are very strong, making this process favourable.

Converting Alcohols to Alkyl Halides

OHSOCl2

Propose a mechanism for the following reaction:

Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction

R OH HXEtO2C N N CO2Et

PPh3O PPh3R X EtO2C

HN

HN CO2Et

A Mitsonobu reaction involves four main reactants:The alcohol to be substitutedThe conjugate acid of the desired nucleophile (e.g. HCl

for Cl-)Triphenylphosphine (Ph3P = (C6H5)3P)Diethyl azodicarboxylate (DEAD =

CH3CH2OC(O)NNC(O)OCH2CH3)

Converting Alcohols to Alkyl Halides – The Mitsunobu Reaction

Propose a mechanism for the Mitsunobu reaction:

R OH HXEtO2C N N CO2Et

PPh3O PPh3R X EtO2C

HN

HN CO2Et

HX can be a weak acid ...HCN, RCO2H, HN3, ArOH, ArSH

This is a very convenient technique for doing SN2 reactions with alcohols without requiring the alkyl halide.

OH

+ H3CC

SH

O PPh3, DEAD

THF, 25°CS

CCH3

O

The Mitsunobu Reaction

Converting Alcohols to Ethers

C OH

H

H H

C OH

H

H H

+C O

C H

H

HH

H H

If you wanted to make an ether, you could imagine an alcohol reacting with itself. What are the two main reasons why this reaction does not work?

X

The Williamson ether synthesis is a versatile method for making ethers.

O H NaH, DMF O Br ONa

What kind of mechanism does this reaction follow?

Converting Alcohols to Ethers

It is also possible to prepare ethers via SN1 processes.

BrCH3CH2OH

OCH2CH3

Keep in mind that the nucleophilic site and electrophile site don’t necessarily have to be in different molecules. Propose a mechanism for the following reactions:

NaH

DMFHO Cl

O

BrRH

HHH NaOH

H2O

Cleavage of Ethers

The cleavage of ethers also occurs via substitution reactions. Propose a mechanism for the following reaction:

OHI

I2

Cleavage of Ethers

The cleavage of ethers can also be done using trimethylsilyl iodide (TMSI):

OH3C

Si

CH3CH3

I

H3C

OSi

CH3

CH3

H3C

I CH3+

Epoxides – SN2 substrates

With good nucleophiles and under neutral or basic conditions, epoxides are excellent substrates for SN2 reactions.

This type of reaction does not proceed with other ethers. Why?

ONu:

Nu

OH+

Nu

OH

Nu: O no reaction

Like all SN2 reactions, epoxides react with inversion of stereochemistry at the least hindered electrophilic carbon atom.


O

H

H

NaN3, CH3CH3OH, H2O

O

H

H3CPhSH, PhS

Under acidic conditions, epoxides are good SN1 substrates.


O

H3CH3C

CH3OH, H2SO4

Common Leaving Groups RH2C N NLeaving group

NCCH2R N N

NC:

RH2C N N

RH2C S C4F9

O

O

RH2C S CH3

O

O

RH2C I

RH2C Br

RH2C OH

H

RH2C OH

CH3

RH2C Cl

RH2C NCH3

CH3

CH3

Diazonium salt

Class of compound Leaving group

Nonaf late C4F9SO3-

Mesylate

Iodides

Bromides

Protonated alcohols

Protonated ethers

Chlorides

Quaternary Ammonium Salts

Excellentleavinggroups

Good

leavinggroups

N2

CH3SO3-

I-

Br-

H2O

CH3OH

Cl-

N(CH3)3

RH2C F

OC

CH3

O

RH2C

RH2C H

RH2C OH

RH2C NH2

RH2C CH3

Fluorides

Acetates Acetate anion, CH3CO2-

Alcohols Hydroxide, HO-

Hydrides Hydride, H-

Amines Amide, NH2-

Alkanes

Very

poorleavinggroups

F-

CH3-

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Substitution Reactions of Alcohols