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Chapter 12
Alcohols from
Carbonyl Compounds
Oxidation-Reduction &
Organometallic
Compounds
1. Structure of the Carbonyl Group

Carbonyl compounds
O
R
O
H
R
Aldehyde
R'
Ketone
O
R
O
O
OH
Carboxylic acid
R
O
OR'
Ester
R
N
R'
Amide R"
Ch. 12 - 2

Structure
~ 120o O
C
~ 120o
~ 120o
● Carbonyl carbon: sp2 hybridized
● Planar structure
Ch. 12 - 3

Polarization and resonance structure
O


C
O
C
Ch. 12 - 4
1A. Reactions of Carbonyl Compounds
with Nucleophiles

One of the most important reactions of
carbonyl compounds is nucleophilic
addition to the carbonyl group
O
Nu


C
O
nucleophilic
addition
Nu
C
Ch. 12 - 5

Two important nucleophiles:
● Hydride ions (from NaBH4 and
LiAlH4)
● Carbanions (from RLi and RMgX)

Another important reactions:
OH
R
H
O
oxidation
H
1o alcohol
reduction
R
C
H
aldehyde
Ch. 12 - 6

Overall order
H
H
C
H
H
<
H
oxidation - 4
state
lowest
oxidation
state of
carbon
H
C
H
-2
O
OH
<
H
C
0
O
H
<
H
O
C
OH
+2
<
C
O
+4
highest
oxidation
state of
carbon
Ch. 12 - 7
3. Alcohols by Reduction of
Carbonyl Compounds
H
R
[H]
O
OH
R
OR'
H
OH
(1o alcohol)
[H]
O
O
R
R
O
R
H
[H]
[H]
R'
HO
R
H
R'
Ch. 12 - 8
3A. Lithium Aluminum Hydride

LiAlH4 (LAH)
● Not only nucleophilic, but also very
basic
● React violently with H2O or acidic
protons (e.g. ROH)
● Usually reactions run in ethereal
solvents (e.g. Et2O, THF)
● Reduces all carbonyl groups
Ch. 12 - 9

Examples
O
(1)
R
OH
O
OR'
O
R
2. H+, H2O
H
2. H+, H2O
H
H
OH
R
H
H
+ HOR'
OH
1. LiAlH4, Et2O
(3)
R
2. H+, H2O
1. LiAlH4, Et2O
(2)
R
OH
1. LiAlH4, Et2O
R
H
H
Ch. 12 - 10
3B. Sodium Borohydride

NaBH4
● less reactive and less basic than
LiAlH4
● can use protic solvent (e.g. ROH)
● reduces only more reactive carbonyl
groups (i.e. aldehydes and ketones)
but not reactive towards esters or
carboxylic acids
Ch. 12 - 11

Examples
O
(1)
R
H
O
H2O
R
R'
H2O
H
H
OH
NaBH4
(2)
R
OH
NaBH4
R
H
R'
Ch. 12 - 12
3C. Overall Summary of LiAlH4 and
NaBH4 Reactivity
reduced by LiAlH4
reduced by NaBH4
O
O
O
<
<
R
O
O
R
OR'
<
R
R'
R
H
ease of reduction
Ch. 12 - 13
5. Organometallic Compounds

Compounds that contain carbon-metal
bonds are called organometallic compounds
C
M
primarily ionic
(M = Na or K)
 
C : M
(M = Mg or Li)
C
M
primarily covalent
(M = Pb, Sn, Hg or Tl)
Ch. 12 - 14
6.
Preparation of Organolithium &
Organomagnesium Compounds
6A. Organolithium Compounds

Preparation of organolithium
compounds
R

X
+
2 Li
Et2O
(or THF)
Order of reactivity of RX
● RI > RBr > RCl
RLi
+
LiX
Ch. 12 - 15

Example
(80% - 90%)
Et2O
Br
+
2 Li
-10oC
Li
+
LiBr
Ch. 12 - 16
6B. Grignard Reagents

Preparation of organomagnesium
compounds (Grignard reagents)
R
Ar

X
X
+
+
Mg
Mg
Et2O
Et2O
RMgX
ArMgX
Order of reactivity of RX
● RI > RBr > RCl
Ch. 12 - 17
7B. Reactions of Grignard Reagents
with Epoxides (Oxiranes)

Grignard reagents react as nucleophiles
with epoxides (oxiranes), providing
convenient synthesis of alcohols
RMgBr
+
O
then H2O
R
OH
Ch. 12 - 18

Via SN2 reaction
R
O
R
O
H+, H2O
R
OH
(1o alcohol)
Ch. 12 - 19

Also work for substituted epoxides
RMgBr +
O
H
then H2O
RMgBr +
H
(2o alcohol)
R"
R'
OH
R'
R'
O
R
then H2O
R
OH
R"
R'
(3o alcohol)
Ch. 12 - 20
7C. Reactions of Grignard Reagents
with Carbonyl Compounds
O
+
R
R"MgX
R'
OH
1. Et2O
+
2. H3O
R
R'
R"
R' = H (aldehyde)
R' = alkyl (ketone)
Ch. 12 - 21

Mechanism
O

+
R

R"
O


MgX
R
R'
H
OH
R
O
MgX
R"
R'
H
H
R"
R'
Ch. 12 - 22
8.
Alcohols from Grignard Reagents
O
+
R
R"MgX
R'
OH
1. Et2O
+
2. H3O
R
R'
R"
R' = H (aldehyde)
R' = alkyl (ketone)
Ch. 12 - 23

R, R’ = H (formaldehyde)
o
● 1 alcohol


R

MgX
O
O

MgX
+
R
H
H
formaldehyde
H
H3O+
OH
R
H
H
H
1o alcohol
Ch. 12 - 24

R = alkyl, R’ = H (higher aldehydes)
o
● 2 alcohol


R

MgX
O
O

MgX
+
R
R'
H
higher
aldehyde
H
H3O+
OH
R
R'
R'
H
2o alcohol
Ch. 12 - 25

R, R’ = alkyl (ketone)
o
● 3 alcohol


R

MgX
O
O

+
R
R'
R"
ketone
R'
R"
NH3Cl
H2O
OH
R
MgX
R'
R"
3o alcohol
Ch. 12 - 26

Reaction with esters
o
● 3 alcohol
O
+
R
OR'
R"MgX
OH
1. Et2O
2. H3O
+
R
R"
R"
+ R'OH
Ch. 12 - 27

Mechanism
O


+ R"
R
O


MgX
R
OR'
MgX
OR'
R"
O
R'O
+
R
H
OH
R
R"
R"
O
H
O
H
R
MgX

R"
R"

MgX
R"
R"
Ch. 12 - 28

Examples
MgBr
(1)
O
Et2O
+
H
OH
H
OMgBr
H3O+
H
H
(1o alcohol)
Ch. 12 - 29

Examples
MgI
(2)
O
Et2O
+
H3C
H
OH
OMgI
CH3
H3O+
CH3
H
(2o alcohol)
Ch. 12 - 30

Examples
O
(3)
MgBr +
Ph
Ph
OH
(3o alcohol)
Ph
Et2O
Ph
H3O+
Ph
Ph
OMgBr
Ch. 12 - 31

Examples
O
(4)
MgI
Et2O
+
Ph
Ph
OMe
MgI
OMgI
O
MgI
OMe
O
Ph
Ph
OH
H3O+
Ph
(3o alcohol)
Ch. 12 - 32
8A. How to Plan a Grignard Synthesis

Synthesis of
OH
Me
Me
Ch. 12 - 33

Method 1
● Retrosynthetic analysis
OH
MgBr
Me
Me
O
+
Me
Me
disconnection
● Synthesis
MgBr
+
Me
OH
O
1. Et2O
+
Me 2. H3O
Me
Me
Ch. 12 - 34

Method 2
● Retrosynthetic analysis
OH
Me
Me
MeMgBr
O
Me
+
disconnection
● Synthesis
MeMgBr +
O
OH
Me
1. Et2O
2. H3O+
Me
Me
Ch. 12 - 35

Method 3
● Retrosynthetic analysis
OH
disconnection
Me
Me
O
OEt
+ 2 MeMgBr
disconnection
● Synthesis
O
OEt
OH
1. Et2O
+
2.
H
O
3
+ 2 MeMgBr
Me
Me
Ch. 12 - 36
8B. Restrictions on the Use of
Grignard Reagents
Grignard reagents are useful
nucleophiles but they are also very
strong bases
 It is not possible to prepare a Grignard
reagent from a compound that
contains any hydrogen more acidic
than the hydrogen atoms of an alkane
or alkene

Ch. 12 - 37

A Grignard reagent cannot be prepared
from a compound containing an –OH
group, an –NH– group, an –SH group,
a –CO2H group, or an –SO3H group

Since Grignard reagents are powerful
nucleophiles, we cannot prepare a
Grignard reagent from any organic
halide that contains a carbonyl, epoxy,
nitro, or cyano (–CN) group
Ch. 12 - 38

Grignard reagents cannot be prepared
in the presence of the following groups
because they will react with them:
OH,
NH2,
SO3H,
SH,
O
O
C
R,
NO2,
C
OR,
N,
C
H,
O
O
H,
CO2H,
NHR,
NH2,
O
Ch. 12 - 39
8C. The Use of Lithium Reagents
 
R Li +
O
OLi
R
organolithium
reagent

aldehyde
or
ketone
lithium
alkoxide
H3O+
OH
R
alcohol
Organolithium reagents have the
advantage of being somewhat more
reactive than Grignard reagents
although they are more difficult to
prepare and handle
Ch. 12 - 40
8D. The Use of Sodium Alkynides

Preparation of sodium alkynides
R

NaNH2
H
R
-NH3
Reaction via ketones (or aldehydes)
O
R
Na
ONa
Na +
R
OH
H3O+
R
Ch. 12 - 41
9. Protecting Groups
HO
I
OH
How?
HO
Ch. 12 - 42

Retrosynthetic analysis
OH
O
HO
MgBr +
HO
disconnection
Br
HO

However
Br
HO
Mg
Et2O
BrMg
O

MgBr
H
O
acidic proton
H

powerful
base
Ch. 12 - 43

Need to “protect” the –OH group first
HO
Br
(protection)
OH
"P"O
"P"O
Mg, Et2O
O
1.
2. H3O+
Br
"P"O
MgBr
(no acidic OH group)
(deprotection)
OH
HO
Ch. 12 - 44