Transcript Project Overview

Chapter 12
Alcohols from
Carbonyl Compounds
Oxidation-Reduction &
Organometallic
Compounds
Created by
Professor William Tam & Dr. Phillis Chang
Ch. 12 - 1
About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor
William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in
1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an
NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard
University (USA). He joined the Department of Chemistry at the University of
Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and
Associate Chair in the department. Professor Tam has received several awards
in research and teaching, and according to Essential Science Indicators, he is
currently ranked as the Top 1% most cited Chemists worldwide. He has
published four books and over 80 scientific papers in top international journals
such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her
M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She
lives in Guelph with her husband, William, and their son, Matthew.
Ch. 12 - 2
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 - 3

Structure
~ 120o O
C
~ 120o
~ 120o
● Carbonyl carbon: sp2 hybridized
● Planar structure
Ch. 12 - 4

Polarization and resonance structure
O


C
O
C
Ch. 12 - 5
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 - 6

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 - 7
2.

Oxidation-Reduction Reactions in
Organic Chemistry
Reduction of an organic molecule usually
corresponds to increasing its hydrogen
content or decreasing its oxygen content
oxygen content
decreases
O
R
carboxylic
acid
O
O
[H]
OH reduction
hydrogen content
decreases
R
H R
aldehyde
OH
[H]
H
reduction
R
H
H
Ch. 12 - 8

The opposite reaction of reduction is
oxidation. Increasing the oxygen
content of on organic molecule or
decreasing its hydrogen content is
oxidation
OH
[O]
RCH3
lowest
oxidation
state
[H]
R
H
O
[O]
H
[H]
R
O
[O]
H
[H]
R
OH
highest
oxidation
state
Ch. 12 - 9

Ar
Oxidation of an organic compound may
be more broadly defined as a reaction
that increases its content of any
element more electronegative than
carbon
CH3
[O]
[H]
Ar
CH2Cl
[O]
[H]
Ar
CHCl2
[O]
Ar
CCl3
[H]
Ch. 12 - 10
2A. Oxidation States in Organic Chemistry
 Rules
● For each C–H (or C–M) bond  -1
● For each C–C bond  0
● For each C–Z bond  +1
(where M = electropositive element and is
equivalent to H, e.g. Li, K, etc.; Z =
electronegative heteroatom, e.g. OR, SR,
PR2, halogen, etc.)
 Calculate the oxidation state of each carbon
based on the number of bonds it is forming
to atoms more (or less) electronegative
than carbon
Ch. 12 - 11

Examples
H
(1) H
C
H
Bonds to C:
4 to H = (- 1) x 4 = - 4
H
Total = - 4
Oxidation state of C = - 4
Ch. 12 - 12

Examples
H
(2) H
C
H
Bonds to C:
OH
3 to H = - 3
1 to O = +1
Total = - 2
Oxidation state of C = - 2
Ch. 12 - 13

Examples
O
(3)
H
C
Bonds to C:
H
2 to H = - 2
2 to O = +2
Total = 0
Oxidation state of C = 0
Ch. 12 - 14

Examples
O
(4)
H
C
Bonds to C:
OH
1 to H = - 1
3 to O = +3
Total = +2
Oxidation state of C = +2
Ch. 12 - 15

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 - 16
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 - 17
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 - 18

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 - 19

Mechanism
H
O
R
OR'
+ H
O
Al H
R
H
OR'
H
O
R'O +
H
OH
R
H
H
H
O
H
O
H
R
H
H
R
H
Al H
H
o
Esters are reduced to 1 alcohols
Ch. 12 - 20
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 - 21

Examples
O
(1)
R
H
O
H2O
R
R'
H2O
H
H
OH
NaBH4
(2)
R
OH
NaBH4
R
H
R'
Ch. 12 - 22

Mechanism

O


R
R'
O
H
+ H
B
H
R
H
OH
R
H
R'
H
H
O
H
R'
Aldehydes are reduced to 1° alcohols
& ketones are reduced to 2° alcohols
Ch. 12 - 23
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 - 24
4. Oxidation of Alcohols
4A. Oxidation of Primary Alcohols to
Aldehydes
R
OH
1o alcohol


O
[O]
R
O
[O]
H
aldehyde
R
OH
carboxylic
acid
The oxidation of aldehydes to carboxylic
acids in aqueous solutions is easier than
o
oxidation of 1 alcohols to aldehydes
It is, therefore, difficult to stop the oxidation
o
of a 1 alcohol to the aldehyde stage unless
specialized reagents are used
Ch. 12 - 25

PCC oxidation
● Reagent
PCC =
N
[CrO3Cl]
H
(Pyridinium chlorochromate)
CrO3 + HCl +
N
Pyridine
(C5H5N)
N
H [CrO3Cl]
Pyridinium
chlorochromate
(PCC)
Ch. 12 - 26

PCC oxidation
R
OH
OH
R
R'
CH2Cl2
PCC
R'
R
CH2Cl2
R
CH2Cl2
H
O
PCC
OH
R
O
PCC
R
R'
No Reaction
Ch. 12 - 27
4B. Oxidation of Primary Alcohols to
Carboxylic Acids
KMnO4, OH
H2O, heat
O
-
R
H3O+
O
K
O
R

OH
H2CrO4
(chromic acid)
R
OH
Chromic acid (H2CrO4) usually prepared by
[CrO3 or Na2Cr2O7] + aqueous H2SO4
Jones reagent
Ch. 12 - 28

Jones oxidation
● Reagent: CrO3 + H2SO4
● A Cr(VI) oxidant
R
OH
OH
R
H2SO4
(orange solution)
+
R
R'
R'
H2SO4
(orange solution)
CrO3
R"
H2SO4
OH
Cr(III)
(green)
O
CrO3
OH
R
O
CrO3
+
R
R'
Cr(III)
(green)
No Reaction
Ch. 12 - 29
4D. Mechanism of Chromate Oxidations

Formation of the Chromate Ester
H
H
H3C
H3C
O
C
H
O
+ HO
H
Cr
O
H3C
O
H
O
O
H
H
O
O
Cr
C
H3C
H
O
O
O
H
H
H
H
O
+
O
O
H3C
H3C
O
C
H
Cr
OH
H
H
H
H
O
O
H3C
H3C
Cr
O
C
H
O
O
O H
H
H Ch. 12 - 30

The oxidation step
O
H3C
O
C
H3C
H
+
H
H
Cr
OH
O
H3C
O
C
O +
Cr
H3C
+ H
O
OH
O
H
H
O
Ch. 12 - 31
4E. A Chemical Test for Primary and
Secondary Alcohols
R
OH
OH
R
H2SO4
(orange solution)
+
R
R'
R'
H2SO4
(orange solution)
CrO3
R"
H2SO4
OH
Cr(III)
(green)
O
CrO3
OH
R
O
CrO3
+
R
R'
Cr(III)
(green)
No Reaction
Ch. 12 - 32
4F. Spectroscopic Evidence for Alcohols
Alcohols give rise to broad O-H stretching
absorptions from 3200 to 3600 cm-1 in IR spectra
 The alcohol hydroxyl hydrogen typically produces
a broad 1H NMR signal of variable chemical shift
which can be eliminated by exchange with
deuterium from D2O
 Hydrogen atoms on the carbon of a 1o or 2o
alcohol produce a signal in the 1H NMR spectrum
between  3.3 and  4.0 ppm that integrates for 2
and 1 hydrogens, respectively
 The 13C NMR spectrum of an alcohol shows a
signal between  50 and  90 ppm for the alcohol
carbon

Ch. 12 - 33
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 - 34
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 - 35

Example
(80% - 90%)
Et2O
Br
+
2 Li
-10oC
Li
+
LiBr
Ch. 12 - 36
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 - 37

Example
Br
+ Mg
THF
MgBr
Ch. 12 - 38
7.
Reactions of Organolithium and
Organomagnesium Compounds
7A. Reactions with Compounds Containing Acidic Hydrogen Atoms
 
 
RMgX ~ R:MgX

RLi ~ R:Li
Grignard reagents and organolithium
compounds are very strong bases
 
 
R MgX + H Y
(or RLi)
R
(Y = O, N or S)
H + Y + Mg2+ + X
Ch. 12 - 39

Examples
● As base
(1) CH3MgBr + H2O
H3C
H + OH
+ Mg2+ + Br
MgBr
(2)
+ CH3OH
+ CH3O
+ Mg2+ + Br
Ch. 12 - 40

Examples
● As base
(3)
H + H3C
MgBr
MgBr + H
CH3
A good method for the preparation
of alkynylmagnesium halides
Ch. 12 - 41
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 - 42

Via SN2 reaction
R
O
R
O
H+, H2O
R
OH
(1o alcohol)
Ch. 12 - 43

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 - 44
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 - 45

Mechanism
O

+
R

R"
O


MgX
R
R'
H
OH
R
O
MgX
R"
R'
H
H
R"
R'
Ch. 12 - 46
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 - 47

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 - 48

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 - 49

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 - 50

Reaction with esters
o
● 3 alcohol
O
+
R
OR'
R"MgX
OH
1. Et2O
2. H3O
+
R
R"
R"
+ R'OH
Ch. 12 - 51

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 - 52

Examples
MgBr
(1)
O
Et2O
+
H
OH
H
OMgBr
H3O+
H
H
(1o alcohol)
Ch. 12 - 53

Examples
MgI
(2)
O
Et2O
+
H3C
H
OH
OMgI
CH3
H3O+
CH3
H
(2o alcohol)
Ch. 12 - 54

Examples
O
(3)
MgBr +
Ph
Ph
OH
(3o alcohol)
Ph
Et2O
Ph
H3O+
Ph
Ph
OMgBr
Ch. 12 - 55

Examples
O
(4)
MgI
Et2O
+
Ph
Ph
OMe
MgI
OMgI
O
MgI
OMe
O
Ph
Ph
OH
H3O+
Ph
(3o alcohol)
Ch. 12 - 56
8A. How to Plan a Grignard Synthesis

Synthesis of
OH
Me
Me
Ch. 12 - 57

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 - 58

Method 2
● Retrosynthetic analysis
OH
Me
Me
MeMgBr
O
Me
+
disconnection
● Synthesis
MeMgBr +
O
OH
Me
1. Et2O
2. H3O+
Me
Me
Ch. 12 - 59

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 - 60
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 - 61

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 - 62

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 - 63
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 - 64
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 - 65
9. Protecting Groups
HO
I
OH
How?
HO
Ch. 12 - 66

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 - 67

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 - 68

TBSCl
imidazole
DMF
Synthesis
Br
HO
(protection)
Br
TBSO
Me
TBSCl = tBu
Si
Mg, Et2O
Cl
Me
Imidazole =
N
N
H
MgBr
TBSO
O
DMF = H
N
O
Me
1.
Me
(a polar aprotic solvent)
OH
HO
2. H3O+
OH
Bu4N F
THF
(deprotection)
TBSO
Ch. 12 - 69
 END OF CHAPTER 12 
Ch. 12 - 70