CONVERSION OF

1
CONVERSION OF ALCOHOLS TO HALIDES
2
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
3
ALCOHOLS ARE UNREACTIVE TO SN1 / E1
AND SN2 / E2 .. EXCEPT IN ACID
4
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
5
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.
6
METHODS FOR THE CONVERSION OF ALCOHOLS TO
HALIDES OR TOSYLATES
7
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
8
CONCENTRATED HCl, HBr, HI
9
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.
10
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.
11
REARRANGEMENTS ARE COMMON WHEN THE MECHANISM IS
SN1 (CARBOCATION)
conc.
HCl
ionization
rearranges
expected
some E1 will occur
found
alkene
12
ALTERNATE CONDITIONS
13
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
14
ALL THREE REACTIONS GIVE ESSENTIALLY THE SAME
RESULT
1-butanol (primary alcohol)
All examples above are acid-assisted SN2
mechanisms.
15
STEREOCHEMISTRY
16
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
17
PHOSPHOROUS HALIDES
18
PHOSPHOROUS HALIDES
PCl5 and PBr5 ,
the pentachloride and pentabromide, also work in
a similar fashion


phosphorous trichloride
phosphorous tribromide
P X2
PX3
Synthesis
The iodides are less frequently used, since they
are unstable, but PI3 is a known reagent.
19
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)
20
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.
21
THIONYL CHLORIDE
22
THIONYL CHLORIDE
..
..
-



..
..
..
..

..



..

..
..
..
..
Nu
nucleophiles attack sulfur
Electron-deficient at sulfur due to the S-O
dipole and the inductive effects of the two
chlorines.
23
PYRIDINE SOLUTION
INVERSION
24
ALCOHOLS REACT WITH THIONYL CHLORIDE TO
MAKE CHLOROSULFITE ESTERS

pyridine
MECHANISM IN PYRIDINE SOLUTION
lots of free chloride ions
25
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
26
ETHER SOLUTION
RETENTION
27
ALCOHOLS REACT WITH THONYL CHLORIDE TO
MAKE CHLOROSULFITE ESTERS

MECHANISM IN ETHER SOLUTION
gas escapes solution
chloride ion is lost
28
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
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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.
30
TOSYLATES
31
CONVERSION TO A TOSYLATE WITH TsCl AND PYRIDINE
TsCl
Poor leaving group
..

..


-
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.
32
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
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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.
34
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.
35
BROSYLATES
36
BROSYLATES WORK LIKE TOSYLATES
p -bromobenzenesulfonyl chloride

Brosyl Chloride
pyridine
BsCl
a p -bromobenzensulfonate
Brosylate
R-OBs
a good leaving group
37
NATURES WAY ...
ADENOSINE TRIPHOSPHATE
ATP
38
ADENOSINE TRIPHOSPHATE (ATP)
adenine
ribose
adenosine adenine ribose
triphosphate tail
Natures way of modifying alcohols.
39
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
40
PHOSPHATES (MONO, DI, AND TRI) ARE GOOD LEAVING
GROUPS FOR BOTH SN1 AND SN2 REACTIONS
Nu
SN2
SN1 (ionization)
..
..
..
..







..
..
..
..
..
..
..

..




..
..
..
..
..
..
..







..
..
..
..
resonance stabilized ion
41
SUMMARY
42
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)
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PROBLEMS
44
PROBLEM 1
Give a method to accomplish this conversion.
45
PROBLEM 2
Give a method to accomplish this conversion.