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Conversion of Alcohols into Alkyl Halides

Hydroxyl groups are poor leaving groups, and as such, are often converted to alkyl
halides when a good leaving group is needed
Three general methods exist for conversion of alcohols to alkyl halides, depending on
the classification of the alcohol and the halogen desired
Reaction can occur with phosphorus tribromide, thionyl chloride or hydrogen halides

Sec. 11 -alcohols 1
Alkyl Halides from the Reaction of Alcohols with PBr3 and SOCl2

These reagents only react with 1° and 2° alcohols in SN2 reactions


In each case the reagent converts the hydroxyl to an excellent leaving group
No rearrangements are seen

Reaction of phosphorous tribromide to give alkyl bromides

Sec. 11 -alcohols 2
Reaction of thionyl chloride to give alkyl chlorides
Often an amine is added to react with HCl formed in the reaction

Sec. 11 -alcohols 3
Tosylates, Mesylates, and Triflates: Leaving Group
Derivatives of Alcohols
The hydroxyl group of an alcohol can be converted to a good leaving
group by conversion to a sulfonate ester

Sulfonyl chlorides are used to convert alcohols to sulfonate esters


Base is added to react with the HCl generated

Sec. 11 -alcohols 4
A sulfonate ion (a weak base) is an excellent leaving group

If the alcohol hydroxyl group is at a stereogenic center then the overall


reaction with the nucleophile proceeds with inversion of configuration
The reaction to form a sulfonate ester proceeds with retention of configuration

Sec. 11 -alcohols 5
Alcohols by Reduction of Carbonyl Compounds
with LiAlH4 and NaBH4

R-OH

The carbonyl group is susceptible to


nucleophilic attack.

Nucleophile Electrophile
(base) (acid)

Sec. 11 -alcohols 6
Mechanism with LiAlH4 and NaBH4
Electrophile H
(acid) O R C R
O R
+ 3 C R O R
C H C OAlH3 Li R R H C O Al O C H
R R
R R O R
+ R H3O +
R C R
Li H3Al- H
H C OH H
Nucleophile
(base) R a tetra-alkyl aluminate

Electrophile
(acid)
O
H2O
C δ+
R R

+
Na H3B- H
Nucleophile
(base)
Sec. 11 -alcohols 7
Examples Reduction - gain of electrons
or add hydrogens
O 1) LiAlH4/Et2O
2) H3O+
H or
OS = +1 NaBH4/H2O

O
NaBH4/H2O
OS = +3 O
HO OS = +2

O
OS = +2 O 1) LiAlH4/Et2O
2) H3O+
O OS = +3

O
1) LiAlH4/Et2O
2) H3O+
OH
OS = +3
Sec. 11 -alcohols 8
Oxidation of Alcohols Oxidation - loss of electrons
or add oxygens
OS = -1 very hard to
KMnO4 / OH¯ / heat stop oxidation
CH3CH2CH2OH
or
propanol NaCr2O7 / H2SO4
or
H2CrO4 or CrO3  Jones reagent

OH OH
H2CrO4 H2CrO4

acetone acetone
OS = -1

O
CH2Cl2
CH3CH2CH2OH + PCC CH3CH2CH
Cl
stops at aldehyde C
H Cl
H
aprotic solvent

Sec. 11 -alcohols 9
Organometallic Compounds

+
δ δ+
C M - C M C M

M = Na+ or K+ M = Mg or Li M = Pb, Sn, Hg, or Tl


Primarily ionic polar covalent Primarily covalent
explosive with water relative stable in ether much less reactive

Organolithium Compounds

ether Li
Br + 2 Li + LiBr

ether Li + LiBr
Br + 2 Li

Sec. 11 -alcohols 10
Grignard Reagents

Br ether MgBr
+ Mg

ether
Br + Mg MgBr

General Reactions

The actual structure of the Grignard reagents are more complex than the formula
2 RMgX R2Mg + MgX2

It also forms a complex with the solvent, ether

For convenience we will represent


the Grignard reagent as RMgX

Sec. 11 -alcohols 11
Grignard reagents as well as organolithium compounds are very strong
bases. They act as if they have free carbanions. Organolithium
compounds will react as a Bronsted-Lowry base or as a nucleophile.

CH3MgBr + CH3CH2O-H

carbon with a negative charge is a stronger base than an oxygen with a negative charge

C C H +

SN2 O

dilute HCl

Sec. 11 -alcohols 12
Grignard Reagents and Carbonyl Compounds

Step One
Mechanism
nucleophilic attack
R on carbonyl carbon
R MgX + C O
nucleophile ether
R
(base)
electrophile halomagnesium alkoxide
Step Two (acid)

R H
+

R C O H O X
Mg2+ X
H
R
alcohol

Order of Reactivity RI > RBr > RCl


RI and RBr mostly used RCl reacts sluggishly
Sec. 11 -alcohols 13
General Reactions

δ δ+ δ H HBr
δ+ δ ether
-R1MgBr- + (dilute)
C -O + MgBr2
H
formaldehyde 1° alcohol

R2
δ δ+ δ HCl
δ+ δ ether
-R1MgBr- + (dilute)
C -O + MgBrCl
H
an aldehyde 2° alcohol

R2
δ δ+ δ HCl
δ+ δ ether
-R1MgBr- + (dilute)
C -O + MgBrCl

R3
a ketone
3° alcohol
Sec. 11 -alcohols 14
General Reactions
R2
δ δ+ δ δ+ δ
-R1MgBr- ether
+ C -O

R3O
δ δ+
a ester
-R1MgBr

HCl
(dilute)

3° alcohol

Grignard Reagent add twice because a ketone is created as an intermediate that can
react with the second equivalence of the Grignard Reagent

Sec. 11 -alcohols 15
Sec. 11 -alcohols 16
Sec. 11 -alcohols 17
Examples
 Because Grignard reagents are very strong bases they can not be made from
compounds that have acidic hydrogens → -OH, -NH2, -SH, -CO2H, -SO3H etc.

 Limited to alkyl halides or organic compounds containing carbon-carbon


double bonds, internal triple bonds, ether linkages and -NR3 groups.

 Although we can make acetylenic Grignards through an acid base reaction and
use it to our advantage. δ O
-δ+ OH
CH3MgBr 1)
CH3CH2C CH CH3CH2C CMgBr H
ether
+ CH4(g) 2) H3O+

H3C
O 1) CH CH2Li
H3 C

2) H3O+ OH

Sec. 11 -alcohols 18
Examples
Sometimes a Grignard reaction can be completed with a compound containing an
acidic hydrogen if two equivalents of the reagent is used

O
ether CH3MgBr
CH3MgBr + HOCH2CH2CCH3
2) H3O+

C
Na NH2 1) H3C CH3
CH3CH2C CH
2) NH4Cl, H2O
H
+
H N H

H Cl
H2 / Pd
acid

a lot missing Sec. 11 -alcohols 19

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