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CONVERSION OF ALCOHOLS TO HALIDES. CHAPTER 12. 12.1 Nomenclature of Alcohols 12.2 Nomenclature of Ethers. learn on your own. 12.4 Conversion of Alcohols to Alkyl Halides. lecture. some review read on your own. Tosylates Review Section 10.3 pp 916-917

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CONVERSION OF

ALCOHOLS TO HALIDES


CHAPTER 12

12.1 Nomenclature of Alcohols

12.2 Nomenclature of Ethers

learn on your own

12.4 Conversion of Alcohols to Alkyl Halides

lecture

some review

read on

your own

Tosylates Review Section 10.3 pp 916-917

and 12.3 (end) just before Section 12.4

& lecture

12.7 Synthesis of Ethers

review

read on your own

not much new here

12.8 Epoxides

12.14 Synthesis of Alkynes using Acetylide Ions

lecture

12.15 Synthesis of Nitriles using Cyanide Ion


ALCOHOLS ARE UNREACTIVE TO

SN1 / E1 AND SN2 / E2

….. EXCEPT IN ACID


strong

base

ALCOHOLS

Alcohols are frequently the best starting point for a synthesis.

Many alcohols are available from chemical suppliers,

and they are relatively inexpensive.

Unfortunately, alcohols have a drawback in that they are not reactive

in nucleophilic substitution or elimination reactions since hydroxide

is a poor leaving group.

-

+

R + OH

R OH

SN1

-

R Nu + OH

SN2

Nu: + R OH

no reaction in

either case

poor leaving

group


R O H

O H

H

Acid conditions must be used to

change the leaving group to

water, a neutral group.

+ H+

SN2

R Nu + O H

Nu: + R O H

+

H

H

SN1

neutral

R+

+

Alternatively, the hydroxyl group can be converted to a

different functional group through chemical reaction.

R OH

R Cl

R OTs

or

Often the hydroxyl group is converted to a halide, or a tosylate which

can then react readily in elimination and substitution reactions.


METHODS FOR THE CONVERSION OF

ALCOHOLS TO HALIDES OR TOSYLATES


METHODS FOR THE CONVERSION OF ALCOHOLS

TO ALKYL HALIDES OR TOSYLATES

We will examine several methods to convert alcohols to more

reactive groups (slides follow).

concentrated

haloacids

RCl

1.

ROH + conc HCl

( also HBr and HI )

H2SO4

halide salts +

sulfuric acid

2.

ROH + NaCl

RCl

( also NaBr and NaI )

3.

ROH + PCl3

RCl

phosphorous

halides

( also PCl5, PBr3, PBr5 ,PI3 )

4. ROH + SOCl2

RCl

thionyl chloride

tosylates

5. ROH + TsCl

ROTs

ROTs + NaX

RX



CONCENTRATED HYDROCHLORIC ACID

HCl - strong acid - completely ionized in water

alcohol

1.

primary

slow

2.

alkyl chloride

primary substrate

acid-assisted SN2

The mechanism depends on

the nature of the substrate.


CONCENTRATED HYDROCHLORIC ACID

tertiary

1.

slow

2.

rearrangement

is possible with

some alcohols

3.

some E1

will occur

tertiary substrate

acid-assisted SN1

The mechanism depends on

the nature of the substrate.


REARRANGEMENTS ARE COMMON WHEN

THE MECHANISM IS SN1 (CARBOCATION)

conc.

HCl

ionization

rearranges

expected

some E1

will occur

found

+ alkene



AN EQUIVALENT METHOD TO USING

CONCENTRATED HX IS TO USE NaX + H2SO4

NaX + H2SO4 conc HX

H2O

H2O

=

H3O+ + X-

H3O+ + X-

+ Na+ + SO42-

spectator ions


ALL THREE REACTIONS GIVE

ESSENTIALLY THE SAME RESULT

1-butanol (primary alcohol)

All examples above are acid-assisted SN2 mechanisms.



STEREOSPECIFICITY

The reactions of alcohols in strong acid solutions

are rarely stereospecific.

Other reactions are used when a stereospecific

result is required, usually

phosphorous halides (PX3) or

inversion

we will

discuss

these next

thionyl chloride (SOCl2)

1. retention - ether solvent

2. inversion - pyridine solvent



PHOSPHOROUS HALIDES

PCl5 and PBr5 ,

the pentachloride

and pentabromide,

also work in a

similar fashion

:

:

phosphorous

trichloride

phosphorous

tribromide

Synthesis:

P + X2

PX3

The iodides are less frequently used, since they are

unstable, but PI3 is a known reagent.


SN2 displacement

at phosphorous

the phosphorous group

is a better leaving group

than OH

..

-

:

:

..

+

SN2 displacement

at carbon

the remaining

two chlorines

can also react

(inversion if a stereocenter)


CONVERSION OF AN ALCOHOL TO A HALIDE WITH PCl3

SN2

inversion of

configuration

ether

Benzene or ethers or can be used as a solvent.

If the alcohol is a liquid, frequently no solvent

at all is used ( a “neat” reaction = w/o solvent ).

This SN2 reaction works best with primary and

most secondary alkyl halides. Tertiary halides

are a bad choice.



THIONYL CHLORIDE

..

..

-

:

:

:

..

..

..

..

+

..

:

:

:

..

:

..

..

..

..

:Nu

nucleophiles

attack sulfur

Electron-deficient at sulfur due to the S-O dipole

and the inductive effects of the two chlorines.



ALCOHOLS REACT WITH THIONYL CHLORIDE

TO MAKE CHLOROSULFITE ESTERS

+

pyridine

MECHANISM

IN PYRIDINE

SOLUTION

lots of free

chloride ions


:

:

O

:

:

O

..

..

S

..

..

:

:

C

l

C

l

..

S

..

:

C

l

..

:

..

O

..

..

C

H

:

O

H

C

H

3

C

-

H

..

:C

l

:

C

H

3

..

(S)

..

..

O

S

O

..

..

H

C

H

3

C

-

..

:

C

l

:

..

:

C

l

:

..

(R)

IN PYRIDINE, THE HIGH CONCENTRATION OF

CHLORIDE ION LEADS TO AN SN2 MECHANISM

..

..

lots of free

chloride ions

“fragmentation”

SN2

inversion

PYRIDINE =

SN2 MECHANISM

INVERSION


ETHER SOLUTION

RETENTION


ALCOHOLS REACT WITH THONYL CHLORIDE

TO MAKE CHLOROSULFITE ESTERS

+

MECHANISM

IN ETHER

SOLUTION

gas

escapes

solution

chloride

ion is lost


IN ETHER, THE CONCENTRATION OF CHLORIDE ION

IS LOW, DECOMPOSITION (SNi) OCCURS BEFORE SN2

ETHER = RETENTION

thermal

decomposition

(S)

“SNi”

solvent

shell

..

no dissociation

both ions are trapped

in solvent cavity


SNi

SN2

(R)

(S)

SUMMARY

chlorosulfite

ester

(R)

(R)

+

pyridine

ether

THE SOLVENT

IS THE THING

inversion

retention

(g)

+

In pyridine - the chlorosulfite ester is attacked by Cl-,

SN2 with inversion.

In ether - the chlorosulfite ester undergoes thermal decomposition,

SNi with retention.



CONVERSION TO A TOSYLATE WITH TsCl AND PYRIDINE

Poor leaving

group

TsCl

..

+

..

*

:

-

Cl

..

R-OTs

pyridine

*

-

+

Cl

Good leaving group

for both SN1 and SN2

If the alcohol is

chiral, the conversion

to a tosylate retains

configuration.


EXAMPLE OF THE USE OF A TOSYLATE

(R)

(R)

TsCl

CH3-CH-OH

CH3-CH-OTs

pyridine

Ph

Ph

RETENTION

NaCN

acetone

SN2

INVERSION

(S)

CH3-CH-CN

Ph


EXPLANTION OF STEREOCHEMISTRY

Same configuration

as the starting alcohol.

..

:

pyridine

NaCN

acetone

The first reaction step

does not involve the

carbon stereocenter -

the atom oxygen reacts.

This step is an

SN2 reaction

with inversion

of configuration.


CAUTION

A COMMON STUDENT ERROR

Do not mix up or confuse :

pyr.

ROH + TsCl ROTs

Ts-Cl / pyridine

makes a tosylate

and

pyr.

ROH + SOCl2

RCl

/ pyridine

SOCl2

makes an inverted

alcohol

These are two different reagents.



BROSYLATES WORK LIKE TOSYLATES

p -bromobenzenesulfonyl

chloride

+

“Brosyl Chloride”

pyridine

BsCl

a p -bromobenzensulfonate

“Brosylate”

R-OBs

a good leaving group


NATURE’S WAY ……...

ADENOSINE TRIPHOSPHATE

ATP


ADENOSINE TRIPHOSPHATE (ATP)

adenine

ribose

adenosine = adenine + ribose

triphosphate “tail”

Nature’s way of modifying alcohols.


..

..

..

:O-R

:O-R

:O-R

H

H

H

R-O-H + ATP R-O-P or R-O-P-P or R-O-P-P-P

triphosphate

monophosphate

All 3 are more

reactive than

alcohols.

diphosphate


PHOSPHATES (MONO, DI, AND TRI) ARE GOOD LEAVING

GROUPS FOR BOTH SN1 AND SN2 REACTIONS

Nu:

SN2

SN1 (ionization)

..

..

..

..

:

:

:

:

:

:

:

..

..

..

..

..

..

..

+

..

:

:

:

:

..

..

..

..

..

..

..

:

:

:

:

:

:

:

..

..

..

..

resonance stabilized ion



METHODS FOR SYNTHESIS OF HALIDES

Mechanism

depends on

substrate but

generally not

stereospecific.

Rearrangements can

occur with primary or

secondary substrates.

conc. HX

or

NaX + H2SO4

Tertiary work well.

Inversion of

configuration

(SN2)

Best for primary and

secondary substrates.

PX3, PX5

neat or ether

or benzene

Best for primary or

secondary substrate,

some tertiary OK.

SOCl2, ether

Retention of

configuration

(SNi)

SOCl2 pyridine

Inversion of

configuration

Best for primary or

secondary substrate.

(SN2)



PROBLEM 1

Give a method to accomplish this conversion.


PROBLEM 2

Give a method to accomplish this conversion.


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