ALDEHYDES AND KETONES I

CHAPTER 16

CHEMISTRY OF THE C=O GROUP

Sections 16.1 and 16.2

Nomenclature of Aldehydes and Ketones

Learn on
your own.

Sections 16.3-16.5
Review and Overview

Read on your own

Section 16.6
Cyanide addition

Lecture

Section 16.7
Addition of Organometallics

Totally review

Section 16.8
Bisulfite Addtion

Read on your own

Sections 16.9-16.11

Lecture

Jump to Sections 16.15-16.19

Lecture

Go Back to Sections 16.12-16-14

Lecture

STRUCTURE

Aldehyde
O
C
R

R = H, alkyl, aryl

Ketone

O
C
R

R'

R and R' = alkyl or aryl

R and R' cannot be hydrogen!

NOMENCLATURE

IUPAC Nomenclature of Ketones

Choose the longest continuous carbon chain that
contains the carbonyl carbon
Number from the end of the chain closest to the
carbonyl carbon
Ketone ending is -one

Do the ketones section of Organic Nomenclature

program!

EXAMPLES
O
C
CH 3

CH 2
CH 2

CH 3

2-Pentanone

O
CH3

CH2

C
CH2

CH

CH3

CH2
CH3
4-Ethyl-3-hexanone

CH

CH3

CH3
3-Isopropylcyclopentanone
or 3-(1-Methylethyl)cyclopentanone

KETONES

Common, or Trivial, Names

Name each group attached to the carbonyl group as an
alkyl group
Combine into a name, according to the pattern:

alkyl alkyl ketone

NOTE:

This is not all one word!

Example of Common Names

O
C
CH 3

CH 2
CH 2

CH 3

Methyl propyl ketone

O
CH3

CH3

C
CH2

CH2

Diethyl ketone

SPECIAL CASES
O

CH3

CH3

dimethyl ketone

diphenyl ketone

acetone

benzophenone

A common laboratory
solvent and cleaning
agent

KNOW
THESE

O
C CH3
methyl phenyl ketone
acetophenone

IUPAC Nomenclature of Aldehydes

Choose the longest continuous carbon chain that contains
the carbonyl carbon
Number from the end of the chain closest to the carbonyl
carbon (carbon #1!)
Aldehyde ending is -al

Do the aldehydes section of Organic Nomenclature

program.

EXAMPLES
H 3C

CH2

CH2

CH2

aldehyde group is
always carbon 1

H
pentanal

Cl
4

CH3

CH

CH
CH3

2-chloro-3-methylbutanal

Common Names of the Aldehydes

CH3

Formaldehyde
1

H3C CH2 C

H3C CH2

Acetaldehyde
2

Propionaldehyde
3

C
H

H3C CH2 CH2 C

Butyraldehyde

Valeraldehyde

O
C
H3C CH2 CH2 CH2 CH2
Caproaldehyde
6

RECOGNIZE
THESE

SPECIAL CASES

C
H

O
C H

formaldehyde

benzaldehyde

C
H

CH3

acetaldehyde

KNOW
THESE

Forming Common Names of Aldehydes

USE OF GREEK LETTERS

C
C
.

is always the end of the chain, no matter how long

CHO

CHO
Cl
-chlorocaproaldehyde
( -chlorohexanal )

Cl
-chlorocaproaldehyde
( -chlorohexanal )

REACTIVITY OF THE C=O GROUP

NUCLEOPHILIC ADDITION

GENERALIZED CHEMISTRY

THE CARBONYL GROUP

nucleophilic
at oxygen

.. O:

H+ or E+

electrophiles
add here

.. :O :

C
+
Nu:

nucleophiles
attack here
electrophilic
at carbon

STEREOCHEMISTRY

THE CARBONYL GROUP IS PLANAR

(SP2 HYBRIDIZED)

Nu:
.

..
..

Nu:
nucleophiles can attack from either top or bottom

LUMO OF FORMALDEHYDE
CH
CO
*(LUMO)

nO

CO
CH

..

C O:
H

Nu:

nucleophiles add
to the larger lobe
(on carbon)

NUCLEOPHILIC ADDITION TO C=O

MECHANISMS
IN ACID AND IN BASE

Nucleophilic Addition to Carbonyl

Basic or Neutral Solution
.. _
:O:

..
O:

-:Nu

slow
C

an
alkoxide
ion

Nu
.. _
:O:

..
:O H
fast

C
Nu

H2O

or on adding acid

Good nucleophiles
and strong bases
(usually charged)

C
Nu

BASIC SOLUTION

Nucleophilic Addition to Carbonyl

Acid Catalyzed
+
:O

..
O:
C

+
H

slow
+

fast

..
:O

.. +
O H

more reactive to
addition than the unprotonated precursor

:Nu

C
Nu

Acid catalysis speeds the rate of

addition of
weak nucleophiles and
weak bases (usually uncharged).

(+)

ACIDIC SOLUTION
pH 5-6

stronger acid
protonates the
nucleophile

CYANOHYDRINS

Addition of Cyanide

:C

N:

.. _
:O :

Buffered to pH 6-8
:O :
_
R

CN

CN
.. _
:O :
R

C
CN

..
:O
R

H2O

H
R

CN

a cyanohydrin

In acid solution there would be little CN-, A cyanohydrin

and HCN (g) would be a problem (poison).

CYANIDE ION BONDS TO HEMOGLOBIN

..
N
CYANIDE IS
Cyanide bonds
IS A POISON
(irreversibly) to the
C
..
CH3
H3C

site (Fe II) where

oxygen usually bonds.

You die of
suffocation lack of oxygen.

Fe
N

N
CH3

H3C

CH2CH2COOH

CH2CH2COOH

HCN is a gas that you can easily breathe into your lungs.

SYNTHESIS OF
-HYDROXYACIDS

SYNTHESIS OF AN -HYDROXYACID
O
CH3

OH

NaCN

C CH3

pH 8

C N

acetophenone

1) NaOH/H2O/
2) H3O+

OH
C CH3
HO
Aldehydes also work unless
they are benzaldehydes,
which give a different reaction
(benzoin condensation).

a cyanohydrin

C O

HYDROLYSIS OF THE
NITRILE GROUP

SYNTHESIS OF NITRILES (AND CYANOHYDRINS)

REVIEW
C=O + NaCN

C-OH
CN
cyanohydrin

R-X + NaCN

acetone

R-CN + NaX

SN2
nitrile
.. both can be hydrolyzed

HYDROLYSIS OF THE CYANO GROUP (NITRILES)

METHOD ONE : strong base + H2O + heat
gas

..

R C N

O:

NaOH
H2O/

R C ..
+
O : Na+

:NH3

..

H3O+

neutralize

..

O:
synthesis of
carboxylic acids

R C ..
O H

OVER ALL

R-CN

..

R-COOH
Nitriles are hydrolyzed to carboxylic acids.

HYDROLYSIS OF THE CYANO GROUP (NITRILES)

METHOD TWO : strong acid + H2O + heat
..

R C N

H2SO4
H2O/

O:
R C ..
O H

..

OVER ALL

R-CN

+ (NH4)2SO4

synthesis of
carboxylic acids

no mechanism
at this time

R-COOH
Nitriles are hydrolyzed to carboxylic acids.

ORGANOMETALLICS

REVIEW FROM CHAPTER 15

Synthesis of Alcohols

Addition of Organometallic Reagents

.. _
+
:O: M

:O :
R

(R-MgBr)

ether

C
R

(R-Li)

:R -

H2O
+
H

These reagents cannot

exist in acid solution

..
:O
R

alcohol

C
R

workup
step

H
R

M (OH)x

Summary of Reactions of
Organometallics with Carbonyl
Compounds
Organometallics with ketones yield
tertiary alcohols
Organometallics with aldehydes yield
secondary alcohols
Organometallics with formaldehyde yield
primary alcohols.
Organometallics with carbon dioxide yield
carboxylic acids.

All review
to you

etc.

HYDRATES

Addition of Water
O

O H

+
H
+

H 2O

R'

aldehyde or ketone
favored

C
O H

O
R'

C
R

R'

O H

a hydrate

hydrates are unstable

and cannot be isolated
in most cases

most hydrates revert to an aldehyde

or ketone as soon as they form
O H

+
R'

H 2O

WATER ADDS TO THE CARBONYL GROUP OF

ALDEHYDES AND KETONES TO FORM HYDRATES
H

catalyzed by a
trace of acid

..

:O

O H

..

..

+ H
:O

..
O
..

:O

..

O+
H .. H

:O
..

..
O
..

a hydrate

H
for most compounds the equilibrium
favors the starting materials
and you cannot isolate the hydrate

:O

O H

..

MICROREVERSIBILITY:
In a reaction where all steps are
reversible, the steps in the reverse
reaction are the same as those in
the forward reaction, reversed!

ACID CATALYSIS
RECALL

H
+

O H
..
H
..
+
:O
:O H

..
:O H
+

Acid catalysis enhances the reactivity

of the carbonyl group - nucleophilic
addition proceeds more easily.

:Nu
weak nucleophiles
can react

ISOTOPE EXCHANGE REVEALS THE PRESENCE

OF THE HYDRATE
O18

O
R

+ H2O

H+

18

O H
+H2O18

R C R
18 O

an excess of H2O18
shifts the equilibrium
to the right

-H2O

exchange shows the

presence of a symmetric
intermediate

SOME STABLE HYDRATES

these also indicate that hydrates are possible

Cl

Cl

Cl

+Cl

Cl

O
H

chloral

120o expected
60o required

OH

OH

Cl H
chloral hydrate

OH

O
sp2
cyclopropanone

sp3 OH

109o expected
60o required

cyclopropanone
hydrate

SOME ADDITIONAL STABLE HYDRATES

O

H C C

H
H

glyoxal

O
Ph C C

Ph
H

phenylglyoxal

C C OH
H
O

OH

OH

C C OH
H

ACETALS AND
HEMIACETALS

Addition of Alcohols
TWO MOLES OF ALCOHOL WILL ADD

addition of one mole

H+

R C R' + ROH

O H
R C R'

hemiacetal

O R
addition of second mole

O H
R C R'
O R

H+

ROH

O R
R C R' + H O
O R
an acetal

ACETALS AND HEMIACETALS

R
C O

ROH

H aldehyde

R
C
H

OH ROH
OR

hemiacetal

R
C O
R

ketone

ROH

R
C
R

OH ROH
OR

OR
C

OR

acetal

OR
C

OR

(hemiketal)*

(ketal)*

*older term

*older term

..
R OH

+ H 2S O4

Like a
hydronium
ion

..

H O

:O

..

R C R

ACID CATALYZED
FORMATION OF A
HEMIACETAL

..

:O H
R C R

..
O
..

R C R
H

first
addition

:O
O+

..

..

:
R O
H
..

:O

Normally the starting

material is favored but a second molecule
of alcohol can react
if in excess (next slide)

H
H

R C R
hemiacetal

O
: ..

+ R O+

..

FORMATION OF THE ACETAL ( from the hemiacetal )

remove

H O
..

..

:O H

..

R C R

H
O
+
R C R

:O
..

: O..

..
O
..

: ..
O

second
addition

R C R

R C R

:O +

:O :

SN1

hemiacetal

..

..

+ H

:
R O
H

:O R

R C R

:O
..

O:

..

O R

R C R

:O
..
acetal

Resonance
stabilized
carbocation

WATER SEPARATOR
AZEOTROPE
Two miscible liquids that distill
as a single substance with a
boiling point that is lower than
either of the original liquids.
when cooled,
the azeotrope
separates

benzene 80o C
water 100o C
benzene-water
azeotrope
69.4o C

benzene
water

benzene and water do not mix,

but in the azeotrope the vapors
(gases) mix and distill together
benzene
+ water

Az

REMOVAL OF WATER SHIFTS THE EQUILIBRIUM

( Le Chatelier Principle )

O H

R C R

R C R

2 R O

O R

O H

starting materials
are favored

Removal of water
shifts equilibrium

STABILITY OF ACETALS AND HEMIACETALS

Most hemiacetals are not stable, except for those of sugars
(see later).
Acetals are not stable in aqueous acid, but they are stable to
aqueous base.

AQUEOUS
ACID

AQUEOUS
BASE

OR H2SO4
OR

H2O

OR NaOH
C
OR H2O

ROH

C O +
ROH

no reaction

CYCLIC ACETALS

Formation of 2,2-Dimethoxypropane
THIS IS A NON-CYCLIC ACETAL

O
H3C

CH3

dry acid

+
2 CH3OH

remove
H2O

H3C

CH3

CH3

CH3

gas
dry acid = Dry
HClacid
gas =
or HCl
p-toluenesulfonic
acid
HCl in methanol
O
mp 106oC
HOTs
CH
HCl (g)
S OH
3

(TsOH)

CYCLIC ACETALS
Cyclic acetals can be formed if a bifunctional alcohol is used.
1,2-ethanediol
H2C CH2
H2C

HO OH
O
C

CH2

H+ /benzene

O
C

CH3

H2O

acetophenone

1,3-propanedithiol
O

HS

SH

H+ /benzene
H2O

CH3

PROTECTING GROUP STRATEGY

Functional Group 1
TARGET

Functional Group 2
NON-TARGET

Add
Protecting
Group
TARGET

NON-TARGET

React
Unprotected
Group
NEW
GROUP

NEW
GROUP

Changed

NON-TARGET

Remove
Protecting
Group
NON-TARGET

Unchanged

USE OF A CYCLIC ACETAL AS A PROTECTING GROUP

O

Br

MgBr

Br

The Grignard
Reaction Takes
Place in Basic
Solution - The
Acetal is Stable

H3 O+

COOH

Acetals Hydrolyze
in Acidic Solution

COOMgBr

CARBOHYDRATES
AND SUGARS

Review Sections 5.14-5.17

Carbohydrate Structures
Fischer Projections / D and L

Cyclization of Monosaccharides
only sugars seem to make
stable hemiacetals

a hemiacetal

H
H
HO
H
H

1C

2
3
4

OH

HO

OH

5
6

CH2 OH

glucose

OH

..
O
..

H
H

2
3
4

OH
H
OH

5
6

CH2 OH

glucopyranose

:O:

FURANOSE AND PYRANOSE RINGS

H
4

: O:

O
O

OH

..

O:

H
2

a pyranose
ring

furan

pyran

OH

two anomers
are possible
in each case

a furanose
ring
for clarity no
hydroxyl groups
are shown on the
chains or rings

ANOMERS
-D-(+)-Glucose

H
: O:

O
O

OH
H

anomeric
carbon

H
: O:
H
O
for clarity
hydroxyl groups
on the chain are
not shown

(hemiacetal)

H
OH
-D-(+)-Glucose
anomers differ in configuration
at the anomeric carbon

Glucose

OH

OH

H2C
HO

hemiacetals

H2C

HO

HO

OH

OH

HO

OH
-D-(+)-Glucose

O
OH

H
-D-(+)-Glucose
[] = + 18.7

34%

[] = + 112.2

66%

O
H
H
HO
H
H

OH

2
3
4

OH

H2C

HO

OH

5
6

CH2 OH

..
O
..

Equilibrium mixture:

: O:

[] = + 52.7
O

HO
OH

< 0.001%

open chain

HAWORTH PROJECTIONS
It is convenient to view the cyclic sugars (glucopyranoses)
as a Haworth Projection, where the ring is flattened.
Standard Position

HAWORTH
PROJECTION

CH2OH
O H
H
H
OH H
OH
HO
H

OH

-D-(+)-glucopyranose

upper-right
O back

This orientation is
always used for a
Haworth Projection

WE WILL LEARN HOW TO CONVERT FISCHER PROJECTIONS

TO HAWORTH PROJECTIONS OF EITHER ANOMER

GLUCOSE ENANTIOMERS
CHO
OH

CHO

OH
OH

HO

OH

HO

D-(+)-glucose

CHO

HO

HO

CH2OH

FISCHER

CH2OH
L-(-)-glucose

CH2OH

HAWORTH

HAWORTH PROJECTIONS
HERE ARE SOME CONVENTIONS YOU MUST LEARN
O

1) The ring is always oriented with the oxygen

in the upper right-hand back corner.
CH2OH
O

2) The -CH2OH group is placed

UP for a D-sugar and
DOWN for an L-sugar.

D
O

CH2OH

3)

-Sugars have the -CH2OH group and

CH2OH
O

the anomeric hydroxyl group trans.

OH

4)

-Sugars have the -CH2OH group and

the anomeric hydroxyl group cis.

CH2OH
O

OH

GLUCOPYRANOSES

SOME HAWORTH PROJECTIONS

cis

-CH2OH
up = D

CH2OH
O OH
H
H
OH H
H
HO

-CH2OH
up = D

OH

CH2OH
O H
H
H
OH H
OH
HO
H
OH

D-SUGARS
-D
trans
=

BOTH OF THESE ARE D-GLUCOSE

ANOMERS

-D

SOME HAWORTH PROJECTIONS

trans
-CH2OH
down=L

O OH
CH2OH
H HO
H
H
OH H

HO

cis
-CH2OH
down=L

O H
CH2OH
H HO
OH
H
OH H

L-SUGARS
-L

ANOMERS

HO

BOTH OF THESE ARE L-GLUCOSE

-L

CONVERTING
FISCHER PROJECTIONS
TO HAWORTH PROJECTIONS

CONVERTING TO HAWORTH PROJECTIONS

D-(+)-glucose
U
P
1
2

CHO
OH

HO
3
4
5
6

OH
OH
CH2OH

on right
=D

FISCHER
PROJECTION

D
O
W
N

-CH2OH
up = D

cis

=
CH2OH
O OH
H
5
H
4
1
OH H
H
HO 3 2
H
OH
6

trans

BOTH
ANOMERS OF
A D-SUGAR
(D-glucose)

=
CH2OH
O H
H
H
OH H
OH
HAWORTH
HO
PROJECTIONS
H
OH

CONVERTING TO ACTUAL CONFORMATIONS

cis
-CH2OH
up = D

CH2OH
O OH
H
H
OH H
H
HO
H

-D-(+)-glucopyranose
H
HO

OH
CH2 H

OH

HO
H

OH

trans

HAWORTH
O

OH
H

OH
=
CH2OH
H
CH2 H
O H
H
O
H
HO
OH H
H
HO
OH
HO
OH
H
H
OH
OH
H

-D-(+)-glucopyranose

CONFORMATION

HAWORTH PROJECTIONS OF L-SUGARS

L-(+)-glucose
U
P

CHO
HO
OH

HO

HO

CH2OH

on left
=L

FISCHER
PROJECTION

D
O
W
N

-CH2OH
down=L

trans
=

O OH
CH2OH
H HO
H
H
OH H
cis
H
=
O H
HO
CH2OH
H HO
OH
H

HO

OH

BOTH
ANOMERS OF
A L-SUGAR
(L-glucose)

HAWORTH
PROJECTIONS

CONVERTING FISCHER TO HAWORTH PROJECTIONS

CAUTION !
Students often get the erroneous
impression that all the Haworth
rules are reversed for L-sugars
- this is not the case!
LEFT = UP
RIGHT = DOWN

= cis
= trans

These rules
are the same
for both
D- and Lsugars

The only difference when

converting D- and L- sugars
is :
D-sugars -CH2OH = UP
L-sugars -CH2OH = DOWN

AN OPEN CHAIN CAN CONVERT TO EITHER ANOMER

FISCHER

HAWORTH

-ANOMER
OPEN
CHAIN

-ANOMER

You cant tell which anomer will result (predominate)

when you look at the Fischer Projection.
That information is not contained in Fischer Projection.

FRUCTOFURANOSES

standard position

FRUCTOSE

cis =

up = D
1
2

HO

CH2OH
..

O:

HOCH2

O
H HO

6
3
4
5
6

OH
..

OH
..

OH

OH
2

CH2OH

CH2OH

D-(-)-Fructose

anomeric
carbon

-D-(-)-Fructofuranose

MUTAROTATION

Glucose

OH
H2C
HO

OH
O

hemiacetals

H2C

HO

HO

OH

OH

HO

OH
-D-(+)-Glucose

O
OH

H
-D-(+)-Glucose
[] = + 18.7

34%

[] = + 112.2

OH
H2C
HO

Equilibrium mixture:

: O:

[] = + 52.7
O

HO
OH

< 0.001%

66%

open chain

MUTAROTATION
+112o

-D-(+)-glucopyranose1

pure

[]D

+57.2o
66%
34%

+19o

pure

-D-(+)-glucopyranose2

TIME (min)
1 Obtained by crystallization of glucose at room temperature.
2 Obtained by crystallization of glucose at 980 C.

CONVERSION TO AN ACETAL

any alcohol
could be used

hemiacetal

acetal

OH

OH

H2C
HO

excess

OH CH3OH

HO
OH

H2C
HO

O CH3

HO
OH

dry HCl

H
-D-(+)-Glucose

OH
3) + ROH

H2C

1) +H+

HO
2) - H2O

4) -H+

HO
OH

conversion is
via the
carbocation
SN1

THE ALCOHOL USED CAN BE ANOTHER SUGAR

OH

OH
H2C
HO

H2C

HO

OH

HO
OH

H
-D-(+)-Glucose
a monosaccharide

HO-Sugar

O Sugar

HO
OH

a disaccharide

Since sugars have many -OH groups, this can continue

on to make polysaccharides.

DETOXIFICATION BY THE LIVER

In mamalian metabolism, many molecules become glycosylated
in the liver to become glycosides.
The glycosides are more soluble than the original molecule
and can be excreted because they are soluble in blood and urine.

glucose
MOLECULE-OH

MOLECULE-O-Glu
liver enzymes
Glu = glucose
a glycoside

POLYSACCHARIDES

CH2OH

CH2OH
H

O b OH
OH H

HO
H

OH

OH

OH H
H

O
.. :
H

OH

-D-(+)-Glucose

enzyme
mediated

Cellobiose
-1,4-Glycosidic Linkage

CH2OH
H

If continued, you
get cellulose.

CH2OH
H

-1,4

H
H

HO
H

b O

OH H

Humans cant
digest

O a OH
OH H

OH

OH
Cellobiose

CH2OH

CH2OH
H

OH H
OH

HO
H

enzyme
mediated

-D-(+)-Glucose

OH
OH

CH2OH
H

c OH H

OH H

OH

H
Maltose
OH

HO
H

Maltose
-1,4-Glycosidic Linkage

CH2OH
H

OH H

O
.. :
H

OH

OH

Humans can
digest

-1,4

Sucrose
a disaccharide
CH2OH
O

H
H
OH

a H

HO
H

CH2OH

OH

b
..
O
..

HO

CH2OH
OH

OH

-D-(+)-Glucose

-D-(-)-Fructose

Humans can
CH2OH

digest
O

H
H
OH
HO
H

H
OH

CH2OH
a H
b

O
H

(+)-Sucrose

HO

CH2OH
OH

-1,4

Read the remaining material on

polysaccharides on your own.

SUMMARY

ADDITION OF WATER AND ALCOHOLS

WATER

H2O

HO

OH

hydrate

ALCOHOLS
R-O-H

R-O-H

HO

RO

OR

H2O
hemiacetal

RO

OR

OR

H+
H2O
H2O

NaOH

+2 ROH
no reaction

acetal

acetals are
stable to base
but not to
aqueous acid

CYCLIZATIONS
O

H2C CH2
HO OH

cyclic
acetal

OFTEN USED
AS A PROTECTIVE
GROUP

H2O

OH

OR

C
OH

R-O-H

H2O
cyclic hemiacetal
STABLE IF
FORMED FROM A
CARBOHYDRATE

cyclic acetal
A STARCH OR
POLYSACCHARIDE
IF FORMED FROM
CARBOHYDRATES

APPENDIX

These are here for practice

you do not have to learn the
names and structures.

The D-Aldohexoses
CHO

CHO

CHO

OH

HO

HO

OH

HO

OH

OH

HO

OH

OH

OH

OH

OH

OH

OH

OH

CH2OH
(+)-Allose

(+)-Altrose

OH

HO

OH

OH
CH2OH

(-)-Gulose

CH2OH

(+)-Glucose

(+)-Mannose

CHO

CHO

CH2OH

CH2OH

CHO

HO

CHO

HO
H

CHO

OH

HO

OH

HO

HO

HO

HO

OH
CH2OH
(-)-Idose

OH
CH2OH

(+)-Galactose

OH
CH2OH

(+)-Talose

The L-Aldohexoses
(the other half of the aldohexoses)
CHO

CHO

CHO

HO

CHO

OH

OH

OH

HO

HO

HO

HO

HO

HO

HO

HO

HO

HO

HO

CH2OH
(-)-Allose

(-)-Altrose

HO

HO

HO

H
CH2OH

(+)-Gulose

CH2OH

(-)-Glucose

(-)-Mannose

CHO

CHO

HO

OH

CH2OH

CH2OH

CHO

OH

HO

OH

HO

CHO

OH

OH

OH

OH

OH

OH

H
CH2OH
(+)-Idose

HO

H
CH2OH

(-)-Galactose

HO

H
CH2OH

(-)-Talose

ADDITIONS OF AMINES
TO CARBONYL GROUPS
Aldehydes and Ketones

MANTRA

(Memorization Jingle)

Reactions with C=O :

Primary amines yield imines
Secondary amines yield enamines
Tertiary amines do not react

we will come back to this again and again

AMINES:

R N H

R N H

..

R N R

primary

secondary

tertiary

..

..

PRIMARY AMINES
IMINES

Addition-Elimination:
The Formation of Imines
O

ketone or
aldehyde

C
R

..
NH2

C
R

..
O+

..

N
H

HA

OH

a carbinolamine
intermediate

H 2O

primary
amine
G is a primary
alkyl group

R
C

an imine

Addition of the amine

is followed by a loss
of water (elimination).

Imines are compounds

with a C=N bond

Mechanism of Imine Formation

weak base addition - acid catalyzed

H
H-O
2

..
NH2 +

..
O
.. 1

loss of water
(elimination)

R
G

..
N

+
N

H-O
H

an imine
G

deprotonation

..
OH
..

H
H-O-H
+

proton exchanges

fast

..

..
N

slow

H
H-O-H
+

acid-catalyzed
addition

H R
+
N C O H

..
N

R
C
R

+
H-O-H
H

Formation of Simple Imines

overall result
remove
R

C
R

..
O + H2N

R + H2O

R
an imine

These reactions do not favor the formation of the

imine unless:
- the product is insoluble
(crystallizes or precipitates) or
- water is removed to drive the equilibrium

Hydrolysis of Simple Imines

REVERSAL

In an excess of aqueous acid, simple imines hydrolyze

back to the aldehyde or ketone and the amine from
which they were orginally formed ..
R
C

R + H2O

H3O+

R
C

..
O + H2N

an imine

Imines that are not soluble, however, are difficult to

hydrolyze.

CRYSTALLINE IMINES
HYDRAZONE AND OXIME DERIVATIVES

shown
below

CRYSTALLINE IMINES
There are some special amines that
yield insoluble products (imines)
that are easy to crystallize ..
O

:NH2OH

..
H2N C NHNH2

hydroxylamine

..
R-NH-NH2 various
hydrazine
compounds

semicarbazine

..
NHNH2

O 2N
NO2

2,4-dinitrophenylhydrazine

Formation of Oximes

R
C

aldehyde
or ketone

..
+ H 2N

R
C

OH

OH

hydroxylamine

an oxime

(usually crystallizes)

H 2O

Formation of Hydrazones

R
C

aldehyde
or ketone

..
+ H2N

R
NH

a hydrazine

NH

a hydrazone

H2O

2,4-Dinitrophenylhydrazones
NO2
R
C

..
+ H2N

2,4-dinitrophenylhydrazine

NO2

NH

2,4-dinitrophenylhydrazine

aldehyde
or ketone

NO2
R
C

NO2

NH

insoluble
red,
red orange or yellow
precipitate forms

2,4-dinitrophenylhydrazone
a 2,4-DNP

(precipitates)

H2O

Formation of Semicarbazones
semicarbazine

R
C
R
aldehyde
or ketone

..
+ H2N

NH C

NH2

semicarbazide

R
C

NH C

NH2

H2O

R
a semicarbazone
(usually crystallizes)

DERIVATIVES
CRYSTALLINE IMINES CAN BE USED AS DERIVATIVES
A derivative is a solid compound (formed from the
original compound) whose melting point can help
to identify the original compound.
What you will see in the tables of unknowns:

ketones
2-undecanone
4-chloroacetophenone
4-phenyl-2-butanone

bp
231
232
235

semicarbazone
2,4-dinitrophenylmp
hydrazone
12
12
-

122
204
142

63
236
127

BIOLOGICAL REACTIONS

Pyridoxyl-5-phosphate (P-5-P)
Converts amino acids to -ketoacids, and vice versa.
Biologically important in transamination reactions.

O
O

C H

HO P O CH2

..

OH

H2N C
R

N
H

OH

an amino acid

CH3

pyridoxyl-5-phosphate

- H2O

( P-5-P )

N C
C

OH

OH

formation of
the imine

continued

CH3

first imine

:Enz
Enz-H
H

O O

R CH C

R C C

NH2

N C
C

OH
N
H

converts

OH

OH

OH

tautomerism

H-Enz
O

CH3

H N C
R
H C

Enz:

first imine

OH

-ketoacid

OH

O O

H2 O
N

new imine

NH2 R C C

CH3

CH2
OH

Removing the
amino group

hydrolysis of
the new imine

OH

N
H

CH3

pyridoxamine

TRANSFERRING THE AMINO GROUP

a different -ketoacid
O O
NH2 R C C
CH2

OH

OH

R
N

H N C
R
H C

CH3

OH

OH

R
N

CH3

pyridoxamine

tautomerism
hydrolysis of the imine

These steps are the

reverse of those on
the previous slides.

H
H2N C
R

O
OH

a different
amino acid

SUMMARY

Amino Acid-1 + pyridoxyl-5-phosphate

( takes NH2 group )

-Ketoacid-2 + pyridoxamine
( gives NH2 back )

a different
one reacts
here

-Ketoacid-1 +
pyridoxamine
( has NH2 )

Amino Acid-2 +
pyridoxyl- 5-phosphate

SECONDARY AMINES
ENAMINES

Formation of Enamines
-hydrogen

secondary
amine
H

is required

+
H

..
R

R2NH

benzene

OH

NR2

carbinolamine

NR2

H2O

an enamine

generally removed
by azeotropic
distillation

COMPARISON
carbinolamine intermediates

PRIMARY AMINES

SECONDARY AMINES
hydrogen on the
adjacent carbon

R
C
R

hydrogen
on the
nitrogen

..

N
H

H OH

R C C R

R NR2

..

-H2O

imine

-H2O

no hydrogen
on nitrogen

enamine
When there is no hydrogen on
nitrogen, one is lost from carbon.

piperidine

pyrrolidine

Water must be removed

morpholine

SOME SECONDARY
AMINES FREQUENTLY
USED TO FORM
ENAMINES

Enamine Formation
MECHANISM
1)

H
R

H
H-O-H
+

:O :
C

H
H-O-H
+

..
+O

..
:O

+N

..
:O

2)

..
+O

C
+

H
R

..
+OH2

N:

slow
R

..
N
R

H
R

O-H
H

continued .

Enamine Formation (cont)

MECHANISM
3)

..
+OH2

N:

+
C

N:
R

H
C

+
C

:
N+
R

N+
R

+ H 2O

H2O

H
O-H

4)

N:
R

enamine

HH3O+

water must
be removed
to force the
equilibrium

Nucleophilic Character of Enamines

R

R
:N

R
C
R

..
C

C
R

+N

C
R

nucleophilic
at carbon

X
SN2
2)

Reactions of Enamines as Nucleophiles

R

R
:N

R
R

C
R

SN2

+N

:N

C
+

an iminium salt
R

_
+

hydrolysis

alkylation

ALKYLATION OF A KETONE
pyrrolidine

..

N
H
O

H+

..

CH3I

iminium
salt

+
N

CH3
H2O
remove
water

enamine

H3O+

workup

O
CH3
+

Az

N
H

Hydrolysis of Iminium Salts

MECHANISM

1)

+N

H
H-O-H
+

N:

+O :

R
R

+N

:O
..

slow
R

..
O
..

O-H
H

2)
R

+N

:O
..

R
R

+O
..

N
..

continued .

Hydrolysis of Iminium Salts

MECHANISM

3)

R
R

+O
..

O-H
H

:O :

+ H3O+

SUBSTRATES FOR ENAMINE ALKYLATION

(and acylation)

X CH2CH3

R
R

N:

X CH2 CH CH2

R
R

N+

alkylation

X CH2 C CH3

X = Cl, Br, I

O
_

X CH2 C O CH3

..
C

enamine

acyl compounds
may be used O
R C

primary
secondary
allylic

O
Cl

acylation

C CH3
O

O
Cl RO C Cl

Cl

C O CH2CH3

CHLORIDES, BROMIDES AND IODIDES

In SN2 reactions you learned the rate sequence R-I > R-Br > R-Cl
and that iodides are better substrates than chlorides.
This is true.
Based on this knowledge ..
many students assume that if acid chlorides are good
the acid bromides and iodides must be better.
However acid bromides and iodides are difficult to
prepare, and the iodides are quite unstable
.. you should use the chlorides.

R C

Cl RO C Cl

They are easily prepared

from the acid by:
R-COOH + SOCl2

Enamine Reactions -- Summary

O

secondary
amine

+N
R

R2NH
H

alkyl or
acyl
halide

H2O
H+
O
R

TERTIARY AMINES
DO NOT REACT

COMPARISON

PRIMARY AMINE

You need to lose two Hs,

one to form the intermediate,
one to eliminate water.

loses H from N
O

N R

..

N
H

C
R

SECONDARY AMINE

H is lost to form intermediate

loses H from C

H OH

N R

R C C R

TERTIARY AMINE

H is lost
.. H

: N-R
R

H :O

R N R
R
no H to lose

R C C R
R

N-R
+
R

unstable
reverses

The tertiary amine cant

form the carbinolamine
intermediate because
it lacks an H on N.

FORMING RINGS
SOME GUIDELINES

DILUTE SOLUTION AND EXACT STOICHIOMETRY

FAVOR RING FORMATION
Problem 16-18 in
NH2

H
+

NH2

Also remember
that unstrained
5- and 6-rings
form easily,
other sizes are
difficult.

in your textbook.

O C
pH = 5

NH
CH2
NH

1:1 molar ratio and

dilute solution favor
the ring formation

H
Excess formaldehyde (>2:1)
and a more concentrated
solution favor the diimime.

N CH2
N CH2
In dilute solution the molecule is more
likely to react internally with itself
because encounters with other molecules
will be less frequent.

HINT ON THE MECHANISM ..

C=N can undergo additions just like C=O
protonation
first

H
CRUCIAL
STEP

Both are polar multiple bonds

and both can undergo acidcatalyzed nucleophilic addition.

N CH2

..

NH2

forms ring
pH 5
mildly
acidic

.. see if you can figure out the rest of the mechanism

for Problem 16-18 on your own.

WITTIG REACTION

Ylide
A compound or intermediate
with both a positive and a
negative charge on adjacent
atoms.

- ..

Y
BOND

Betaine or Zwitterion
A compound or intermediate
with both a positive and a
negative charge, not on
adjacent atoms, but in different
parts of the molecule.

MOLECULE

-:

Preparation of a Phosphorous Ylide

( WITTIG REAGENT )
precipitates
R2
R1

benzene

(C6H5)3P :

R1

+
(C6H5)3P

heat

R2

- ..

: O-CH
.. 3

..
P Ph

ether

strong base

Ph
+
Triphenylphosphine
( Ph = C6H5 )

Ph

(C6H5)3P

- ..

R1

C
R2

an ylide

Resonance in Ylides
+
(C6H5)3P

..
C

R
(C6H5)3P

R
d-p BACKBONDING

..

Remember that Phosphorous

is a Period III element (d orbitals).

P C
3d

2p

Backbonding to phosphorous
reduces the formal charges
and stabilizes the negative
charge on carbon.

The Wittig Reaction

MECHANISM
R1
C

O +

-..

+
(C6H5)3P

R3

R2
R4

R2

ylide

R3

R1
C
R2

betaine

C
R4

synthesis of
an alkene

P(C6H5)3

INSOLUBLE
very thermodynamically
stable molecule

R2

R1

R3

: O:
.. _

P(C6H5)3
+

R1

R3

:O
..

R4

R4

P(C6H5)3

oxaphosphetane
(UNSTABLE)

SYNTHESIS OF AN ALKENE - WITTIG REACTION

H3C

CH2CH3

H3C

Br

CH2CH3

H3C

H3C

H3C

:P(C6H5)3

O
H3C
+

+
(C6H5)3P CH2CH3
ylide

(C6H5)3P
CH3ONa

CH2CH3
H

ANOTHER WITTIG ALKENE SYNTHESIS

H

+
Br
C P(C6H5)3

CH2Br

H
:P(C6H5)3

PhLi

H
C

C P(C6H5)3

..

+
ylide

..
P(C6H 5)3
:O
..
+

Br
C

triphenylphosphine
oxide (insoluble)

H H

Muscalure
H

Sex pheromone of the

common house fly.
Musca Domestica

CH2(CH2)11CH3

CH3(CH2)6CH2

(Z)-9-tricosene
Wittig

The reaction can be made to give the

cis alkene (Z) by correct choice of
solvent and temperature, or by the
separation of a mixture of cis and trans.

CH3(CH2)6

Cl

CH2(CH2)12CH3

ALDEHYDES AND KETONES II.

Oxidation and Reduction;
and Synthesis

CATALYTIC REDUCTION

OXIDATION AND REDUCTION

REDUCTION OF ALDEHYDES AND KETONES

C O

+ 2H+ + 2e-

C O
H H

OXIDATION OF ALCOHOLS

C O

- 2H+ - 2e-

C O

H H
These two reactions are the inverse of each other!

MANTRA
REDUCTION OF ALDEHYDES AND KETONES

Aldehydes react with one mole of reducing

agent to give a
Primary Alcohol
Ketones react with one mole of reducing
agent to give a
Secondary Alcohol
R

C O
H R
C O
R

CH OH
H R
CH OH
R

CATALYTIC REDUCTION
CH2

H2, 40 o C

C O Ni, 2 atm

. H. H.
H.

CH2
H

C O

H H
syn
addition

Reduction of a C=O group

is more difficult than the
reduction of a C=C double
bond.

A specially prepared
catalyst called
Raney Nickel
is often used for C=O.

. and reduction of a
benzene ring is more
difficult yet.

Often heat and pressure

are required.

SELECTIVE HYDROGENATIONS
H

OH

20O C
1 atm

Pd/C

Hydride
reagents

easy

H2

OH

Ni 40O C
2 atm
O

PtO2
100o C
5 atm
Conditions will vary
with the specific
compound.

OH

more
difficult
most
difficult

CATALYTIC HYDROGENATION AT 1 ATM

Hydrogen gas is just bubbled through
the solution

H2
solvent +
compound

magnetic
stir bar

suspended
catalyst

ROCKING BOTTLE HYDROGENATION

NOT SHOWN
perforated screen
surrounds the bottle

Good for pressures

up to about 2 atm.

H2

HYDROGENATION BOMB
pressure
gauge

stirrer

H2

inlet

head bolts
heavy steel
shield
threaded

heater

thick steel
walls

Good to pressures
of 5-10 atm.

HYDRIDE REDUCING REAGENTS

Another Method of Reduction

HYDRIDE REAGENTS

.. _
: O:

..
O:
R C R

H:

H3O+

R C R

R C R

OH

simplified mechanism

+ H B- H

Na

sodium borohydride

Li

+ H Al - H
H

lithium aluminum hydride

THERE IS A DIFFERENCE IN REACTIVITY

more overlap
period 2
element

2sp3 - 1s

H
more
diffuse

period 3
element

Al

NaBH4
shorter, stronger bond
LESS REACTIVE
less overlap

3sp3 - 1s

LiAlH4
longer, weaker bond
MORE REACTIVE

COVALENT / IONIC CHARACTER

+

The Al-H bond has

more ionic character
and is a stronger base.
MORE REACTIVE

The B-H bond has more

covalent character.
LESS REACTIVE

Al

:H

SODIUM BOROHYDRIDE
REDUCTIONS

SODIUM BOROHYDRIDE IS SELECTIVE

NaBH4 only reduces aldehydes and ketones
aldehyde

ketone

C O
H R
C O
R

CH OH or R-CH2-OH
H R
CH OH
secondary
R
alcohol

OH

The double bond

and the ester are
not touched.

1 NaBH4
2
O

primary alcohol

OMe

H3O+
O

OMe

SELECTIVE HYDROGENATIONS
H

OH

1) NaBH4
2) H3O+

20O C
1 atm
Pd/C

H2

OH

Ni 40O C
2 atm
PtO2

?
Protective
group!

100o C
5 atm

OH

C
A, B, and C
progressive

Sodium Borohydride Reduction of

Aldehydes and Ketones
aldehyde
and ketones

NaBH4
R

+ Na
BH3
O

R C R

H
H

BH3

H3O+
workup
step

OH
R

H
alcohol

ADDITION IS CONCERTED
AND SYN STEREOSPECIFIC
..

..

C O:

C O:

H BH3

H BH3

reacts three
more times

Sodium Borohydride Reduction

of Norcamphor
exo attack

1 NaBH4
2

H3O+

O
bicyclo[2.2.1]heptan-2-one
(norcamphor)

OH
endo alcohol
(86%)

+
OH
H
exo alcohol
(14%)

Sodium Borohydride
Reduction of Camphor
hindered

CH3

H3C

CH3

H 3C

H3C

CH3

1 NaBH4

CH3

H3O+

O
camphor

endo attack

CH3

OH

(exo)

OH

CH3

(endo)

borneol
(15%)

isoborneol
(85%)

LITHIUM ALUMINUM HYDRIDE

REDUCTIONS

LiAlH4 (LAH) IS NOT SELECTIVE

LiAlH4 reduces anything with a polar multiple bond!
+

or

C=Y:
..

C Y:

As with NaBH4 these compounds give alcohols:

CH OH

C O

aldehyde

CH OH

C O

ketone

LiAlH4 IS NOT SELECTIVE (cont)

These acid derivatives also give alcohols

CH OH

C O

ester

CH OH

C O

acid chloride

Cl

CH OH

C O
HO

ROH

RO

carboxylic
acid

LiAlH4 IS NOT SELECTIVE (cont)

These compounds give amines:

R
amide

nitrile

R CH2 NH2

C O
NH2

+
nitro
compound

R N O
O-

R CH2 NH2

R NH2

SIMPLE ALKENES DO NOT REACT

alkenes

or

alkynes

they are
not polar !

.. unless they are conjugated with a polar group.

.. which polarizes them.

Lithium Aluminum Hydride

Reduction of Aldehydes and Ketones
O
LiAlH4

ether
R

R
H C O

Al Li
4

O H

H C O

Al Li
4

4 H2O

R + Al(OH)3

H
+ LiOH

REACTION OF HYDRIDES WITH WATER

LiAlH4 Reacts Explosively With H2O, Causing Fire
LiAlH4 + 4 H2O
LiOH + Al(OH)3 + 4 H2 + heat
Ether solvents are used: diethyl ether, THF, etc.

NaBH4 Reacts With H2O (or methanol) Very Slowly

NaBH4 + 4 H2O
NaOH + B(OH)3

+ H2

Water and alcohols can be used as solvents.

no fire

DISSOLVING METAL REDUCTIONS

THERMODYNAMIC CONTROL
O

OH eq

Na

eq

EtOH

major

ax

OH
H

locked in
eq position
H

minor

sodium donates electrons and the alcohol donates protons

..
:O
C

. Na.
+e-

.. :O :
C

radical
anion

HO Et
+H+

stereocenters can invert

..

..

:O H

+e-

+H+

radical

:O H

. Na

- ..

OH
C

anion

HO Et

More Thermodynamic Control

Dissolving Metal

CH3

H3C

H3C

CH3

Na

CH3

OH

EtOH

CH3

major
product

exo

compare NaBH4 results on slides 18 and 19

major
product

Na

OH

EtOH

exo

EPIMERIZATION
A stereoisomer that has changed configuration at only one
stereocenter (a type of diastereomer) is called an EPIMER

strong
base

A
H
endo

NaOtBu

epimer
of A

OH

tBuOH

OH

exo

Epimerization generally gives the lowest energy stereocenter,

the one that is most thermodynamically stable.
endo
epimerization

:
OH

..

OH

HO-tBu

E
N
E
R
G
Y

exo

REDUCTION

COMPARISON OF METHODS

THREE DISTINCT METHODS

REDUCTION

All methods add two electrons 2e(gain of electrons = reduction)

and two protons 2H+.

CATALYTIC REDUCTION

two radicals

H.

H.

= 2e and 2H+ are added as two H

HYDRIDE REDUCTION
H+ proton
C

hydride

H:

= 2e and 2H+ are added as H: and H+

DISSOLVING METAL REDUCTION

C
M

metal gives
electron

.
C
M+

.. O:
..

etc.
H-S

solvent gives
proton

= 2e and 2H+ are added

sequentially as e , H+ , e , H+

COMPLETE REMOVAL OF
THE CARBONYL GROUP

REMOVAL OF C=O
O

THREE METHODS
1) Clemmensen Reduction

Zn(Hg) + conc. HCl

strong acid conditions

2) Wolff-Kishner Reduction

NH2NH2 + KOH

strong base conditions

3) Desulfurization

Thioacetal + H2 + Ni
somewhat milder, but also reduces C=C

Clemmensen Reduction
Removes the C=O Group

O
R C

Zn(Hg)

R C H
HCl (conc.)

Cl
possibly via :

R C Cl
R

ZnCl2
+

Exact mechanism
is not known.
Obviously Zn gives
up electrons to Cl
(reduction).

Hg
H2O

Wolff-Kishner Reduction
Removes the C=O Group
190 - 200 C
KOH

O
+

R C

NH2 NH2

CH2 CH2
HO OH
high-bp
solvent

goes via the hydrazone

R
R

C N NH2

R C H
R

+ N2
+ H2O

MECHANISM OF THE WOLFF-KISHNER REACTION

(you are not required to memorize this mechanism)

..
:O
R C

..

..

NH2 NH2

NaOH
high bp solvent

..
- :O
..

.. ..

C N NH2
hydrazone

ketone

- :..O

..

..

C N NH

..

R H

R
H O

..

C N N:

R H

..

R
C:
R H

H O
H

H
R

.. .. C N NH
..

: N N:
gas

R H
C
R H

C=O
removed
alkane

Desulfurization
Removes the C=O Group
O
R

+
R

BF3

HS CH2 CH2 SH

S + HO
2
C
diethyl ether
R
R
S

Raney Ni

H2
Exact mechanism is not known.

C S

. H. H.
H.

C S
H H

Hydrogenation is known
to break C-S bonds
( hydrogenolysis ).

H
R

H
R

+ H3C CH3
+ 2 NiS + H2S

HOW WOULD YOU DO THESE ?

O
Wolf-Kishner (base)
Clemmensen (acid)

Cl

Cl

Desulfurization

O
Wolf-Kishner (base)
Clemmensen (acid)

CH2 OH

CH2 OH

Desulfurization

SYNTHESIS OF
ACID CHLORIDES

ACID CHLORIDE SYNTHESIS

THIONYL CHLORIDE
RECALL THIONYL CHLORIDE:

Chapter 12, Section 12.4, pp. 12-24 to 12-27.

R-OH + SOCl2

benzene

R-Cl + SO2 + HCl

alcohol

alkyl chloride

The -OH group of an acid reacts the same way.

O
R C
acid

+ SOCl2

benzene

OH

RLi + CO2

Recall how to
make an acid?

O
R C
acid
chloride

Cl

+ SO2 + HCl

REDUCTIONS OF
ACID CHLORIDES

LiAlH4 with Acid Chlorides

ACID CHLORIDES REACT TWICE
two hydrides react

Acid Chloride
O
R C

X
cleaves

O H
LiAlH4

R C H

+ LiCl + AlCl3

COLLAPSE OF THE INTERMEDIATE

bond is highly polar
- not strong

O
R C
Cl

AlH3
FIRST
ADDITION

O
R C H
SECOND
ADDITION

reacts again

- ..

:O:

AlH3
Cl- is lost

R C
H
Cl
The tetrahedral intermediate
collapses easily, because the
bond to Al is not strong.

LiAlH4 Reduction of an Acid Chloride

Li +
O

LiAlH4

R C

Li

Cl

.. - AlH3
: O:

R C
Cl
H

tetrahedral
intermediate
collapses

- AlH3

R C
H
H
H3O+
workup
OH
R C
H
H

LiAlH4

O
R C
aldehyde

+ Li+ Cl-

leaving
group

H
reaction doesnt
stop here

TWO HYDRIDES REACT

REDUCTIONS OF ESTERS

.. ESTERS ALSO REACT TWICE

LiAlH4 with Esters

ESTERS REACT TWICE
two hydrides react

Ester
O
R C

O R'
cleaves

O H
LiAlH4

R C H + R'

O H

two alcohols

LiAlH4 Reduction of an Ester

Li +
O
R C

Li

LiAlH4
OR'

.. - AlH3
: O:

R C
H
H
H3O+
workup

LiAlH4

two
alcohols

+
R-OH

tetrahedral
intermediate
collapses

R C
OR'
H

O
R C
aldehyde

OH
R C
H
H

.. - AlH3
: O:

RO

leaving
group

H
reaction doesnt
stop here

TWO HYDRIDES REACT

workup

ROSENMUND REDUCTION
Converts Acid Chlorides to Aldehydes

This reaction allows you to stop the reduction at

the aldehyde stage and not continue to the alcohol
(which would be the result with LiAlH4).

Acid Chloride

Aldehyde

stops here
one stage of
reduction

X
Alcohol

second step
does not occur

This is an older method. Yields are not always

adequate, but it is sometimes a useful method.

Rosenmund Reduction
O
R C Cl + H2
SOCl2

Pd/BaSO4
sulfur
quinoline

Rosenmund catalyst

O
R C H
Ordinary catalysts
would continue and
reduce the aldehyde.

O
R C OH

R C Cl

R C Cl

. H. H.
H.

H H

DIBAL-H
A Newer Method ...

DIISOBUTYL ALUMINUM HYDRIDE

( DIBAL-H )

SYNTHESIS

two moles

H3 C
LiAlH4 + 2
CH CH2 OH
H3 C

OiBu

H Al OiBu + 2 H2
H

( iBuOH )
isobutyl alcohol

Remember:
H:- + H-O-R
strong
base

DIBAL-H
less active than LiAlH4

gas

H-H +

..
:O-R
..

takes the place

of hydride

Reduction of Esters to Aldehydes

DIBALH is soluble in hydrocarbon solvents because of the isobutyl groups;
ethers must be used for LAH.

O
R C
O R'
esters

DIBAL-H
toluene

H2O
HCl

R C
+

- 70o C

some carboxylic
acids may be
reduced

R'

H
OH

RCOOH

NOTE

Sometimes LiAlH4 will also stop at the aldehyde if the temperature

is below -60o C. DIBAL-H is more consistent.

At 20o C,
LiAlH4 will
reduce the
aldehyde,
DIBAL-H

stops at the
aldehyde at
the lower
temperature.

DIBAL-H ALSO REDUCES

ACID CHLORIDES TO ALDEHYDES
O
R C Cl + H2

DIBAL-H
Pd/BaSO4

R C H

o
-70sulfur
ether

quinoline

This method gives better yields than the

Rosenmund reduction.
stable
at -70o

Apparently the tetrahedral

intermediate does not collapse
at -70o C (expel the leaving
group). This doesnt happen
until you warm the solution
and add aqueous acid which
destroys the DIBAL-H.

Li

+
O

- Al
H

R C
Cl
H

does not
react again

HYDROLYSIS OF THE INTERMEDIATE

Aqueous acid breaks the
complex apart.

Li

+
O

- Al

H3 O+

.. H
:O

R C
Cl
H

R C
Cl
H

O
R C

+ LiCl

DIBALH ALSO REDUCES ALDEHYDES AND KETONES

The main feature of DIBALH is that it reacts only

ONCE to form a stable tetrahedral complex.
Since the complex doesnt fall apart until workup,
a second reduction is avoided.

Aldehydes and ketones only need one hydride to be

fully reduced ...
therefore, DIBAL-H reduces aldehydes and ketones.
With esters, acid chlorides and acids, more than one
hydride is required. Since DIBAL-H reacts only once,
they are not fully reduced, stopping at the aldehyde.

ORGANOMETALLIC COMPOUNDS
WITH ESTERS AND ACID CHLORIDES

RLi with Esters and Acid Chlorides

( also RMgX )

REACT TWICE
two RLi react

Acid Chloride
O
R C
Cl

RLi
ether

O H
R C R'
R'

Ester
O
R C

cleaves

O H
RLi

O R" ether

R C R'

R" O H

R'
two alcohols

RMgX with Esters and Acid Chlorides

( also R-Li )
O
R C

RO

R"MgX
OR'

.. MgX
: O:
R C
R"
R"
H3O+
OH

R-OH

R C
R"
R"

R"MgX

DECOMPOSES

.. MgX
:O:

Tetrahedral
complex not
stable weak O-Mg
bond.

R C
OR'
R"

O
R C

ketone

RO

R"
doesnt
stop here

Reacts Twice !

COLLAPSE OF THE INTERMEDIATE

bond is highly polar
- not strong

- ..

Li

:O:

R C
OR
R'
breaks down and
yields a ketone which
reacts again

DECOMPOSES & REACTS AGAIN

The tetrahedral intermediate
collapses easily, because the
bond to Li+ is not strong.
The leaving group RO- is
expelled.

The complexes formed from

Grignard reagents react in
the same way. The bond to
Mg is not strong.

ORGANOCADMIUM
REAGENTS

Ketone Synthesis
Organocadmium Reagents
2 R MgX + CdCl2

R Cd R

+ 2 MgXCl

organocadmium
compound R2Cd

2 R C Cl + R Cd R
Less active than
RLi or RMgX

2 R C R + Cd Cl2
reacts once

ORGANOCADMIUM REAGENTS
DO NOT REACT TWICE WITH ESTERS
O
C O CH
3

..

reacts
once

Cd-R

:O

C O CH3

STOPS
HERE

CH3
CH3 Cd CH3

workup

H3 O+

ketone

C CH
3

+
Acid chlorides also react this way.

:O-CH
3
..

HO-CH3

STABLE TETRAHEDRAL COMPLEX

The bond has more covalent
character than a bond to Li
or Mg - it is stronger.

Cd OR
O

R C
OR
R'
The complex is
stable and does
not break down
and react again.

Apparently the tetrahedral

intermediate does not collapse
(expel the leaving group)
during the reaction. It only
breaks down on hydrolysis,
and then the leaving group
is expelled.

HYDROLYSIS OF THE INTERMEDIATE

Aqueous acid breaks the
complex apart.

Cd R

.. H
:O

H3 O+

R C
OR
R

R C
OR
R
O
R C

+ LiCl

Ketone is isolated.

LITHIUM DIALKYL CUPRATES

Ketone Synthesis
Lithium Dialkylcuprates
O

R C Cl + R2CuLi
Less active than
RLi or RMgX

0
ether

ketone

R C R

R Cu

LiCl

SUMMARY

MANTRA
Aldehydes react with one mole of reducing
agent to give a
Primary Alcohol
Ketones react with one mole of reducing
agent to give a
Secondary Alcohol

Acid Chlorides react with two moles of reducing

agent to give a
Primary Alcohol
Esters react with two moles of reducing
agent to give a
Primary Alcohol
+ a second alcohol

BIOLOGICAL
REDUCING REAGENTS

Nicotinamide Adenine Dinucleotide

NADH
adenine

..
N

..
NH2

H H

N:
O

:N

..
N

N
.. H C O P O P O CH
2 O
O 2
O_
H
H
H
H
_O
H
H
H
H
HO
OH
HO
OH
diphosphate
ribose

ribose

..
C NH2

nicotinamide

biological
COENZYME
works with
an enzyme

Reduction of Acetaldehyde
in Fermentation
O

+
H

H3C C H
acetaldehyde

H H

RED

OH
H3C C H
H

hydride
transfer

ethanol

O
C NH2

C NH2

..
N
R
NADH

OX

REVERSIBLE
This coenzyme
can also oxidize
depending on the
associated enzyme.

+
N
R
NAD

Reduction of Pyruvic Acid

in Muscle Tissue
O O
CH3 C C OH

+
H

pyruvic acid

H H

formed when
muscles contract

HO O

CH3 C C OH

lactic acid

O
C NH2

C NH2

..

+
N

NADH

+
NAD

OXIDATIONS OF ALCOHOLS

OXIDATION OF AN ALCOHOL
( LOSS OF 2H+ and 2e- )

carbon

- 2H
OXIDATION

REDUCTION

+ 2H

H
hydrogen

LOSS OF TWO
HYDROGENS
one an -H

Oxidations
The alcohol must
have -hydrogens.

H
R C OH
R

H
H

OH

R C OH
R

R'

R'

R''

R C OH

no reaction

R'
Remember: A dehydrogenation (loss of hydrogen)
is also a form of oxidation!

MANTRA
Primary alcohols oxidize to give
Carboxylic acids (via aldehyde)*
Seconday alcohols oxidize to give
Ketones
Tertiary alcohols do not oxidize
no oxidation
Aldehydes oxidize easily to give
Carboxylic acids
* With special reagents, the oxidation of a primary alcohol
can be stopped at the aldehyde.

PRIMARY ALCOHOLS

Oxidation of Primary Alcohols

with KMnO4
R CH2 OH

KMnO4
heat

REQUIRES
HEAT

O
R C H
KMnO4
heat

two -hydrogens

O
R C OH

+ MnO2
precipitate

C=C Double bonds are also oxidized by this reagent.

Oxidation of Primary Alcohols

with K2Cr2O7
CHROMIC ACID
TEST

K2Cr2O7
R CH2 OH

H2SO4

O
R C H

K2Cr2O7
H2SO4
O
R C OH + Cr3+

SECONDARY ALCOHOLS

Oxidation of Secondary Alcohols

CHROMIC ACID
TEST

OH

R C R
H

K2Cr2O7
H2SO4

R C R

Jones Oxidation

3+
Cr

JONES REAGENT

CHROMIC ACID
EQUILIBRIA

H2SO4
CrO3 + H 2O

H 2SO4
H 2CrO4
O

H O Cr O H
O
Chromic acid

x2

H2Cr2O7 + H2O
O

H O Cr O Cr O H
O

Dichromic acid

ALL OF THESE ARE CHROMIC ACID SPECIES

CrO3

H2CrO4

NaCr2O7

H2SO4

H2SO4

H2SO4

oxidizing
agents

MECHANISM

O
HO Cr OH
O
H2 O

H2SO4

HO Cr O :
+
H
H
O
..
R C O:
H
H
Primary alcohol
has two -H

Alcohols react with

chromic acid to form
chromate esters.

..
..
R C O
.. Cr O
.. H
Chromate ester

MECHANISM

( continued )

..
:Cr O
.. H

aldehyde

..
..
R C O Cr O H
..
..
H

R C O:

..

H O:
H

..

H
Loss of two
electrons

H O:
+
H

Loss of
-hydrogen
FIRST OXIDATION

Oxidation
continues
(next slide)

The two lost

electrons
end up here.

MECHANISM

( continued )

Requires
water and acid

hydrate
(an alcohol !)

R C O

R C O
H 2O

O
H

Oxidation continues because

the aldehyde forms a hydrate.
The hydrate is an alcohol (diol)
that has an -hydrogen.

Oxidation
continues

MECHANISM
O

( continued )
H

:O
.. H

HO Cr O :
+
H
H
O
..
R C O:
:..O H
H

O
..
..
R C O Cr O H
..
..
OH

hydrate

Carboxylic
acid

Chromate
ester

R C O:

..

OH

Loss of -hydrogen,
loss of 2 electrons.

..
: Cr O
.. H
O

SECOND OXIDATION

.. H
H O+
H

HOW CAN WE

STOP OXIDATION OF THE ALDEHYDE ?

Oxidation of the aldehyde requires the hydrate to form.
H

R C O

H
R C O

H 2O

O
H

Formation of the hydrate requires acid and water.

What if we do the reaction in

basic medium with no water ?

SARRETT AND PCC REAGENTS

Oxidation with
Chromic Oxide and Pyridine
OH

CrO3 .
N

R C R
H

R C R

CH2Cl2
aldehydes do not
oxidize further

Sarett Oxidation

Oxidation with
Pyridinium Chlorochromate
CrO3Cl .
OH

R C R

O
R C R

CH2Cl2
aldehydes do not
oxidize further

PCC Oxidation

except in DMF
which enhances
reactivity

MEERWEIN-PONNDORF-VERLEY
REDUCTION

MEERWEIN-PONNDORF-VERLEY REDUCTION
aluminum
isopropoxide

O
R

OH
R

+ H C
3

Al(OiPr)3

C CH3
H

OH

R C R
H

isopropyl alcohol

EQUILIBRIUM
Use an excess of isopropyl alcohol to reduce a ketone.
Use an excess of acetone to oxidize an alcohol.

O
+

H3C

acetone

CH3

O
O
R

HYDRIDE
DONOR

Al O
O
CH3
H

CH3

The alcohol complexes with the

aluminum isopropoxide and acts
as a hydride donor to the ketone.

TOLLENS TEST

The Tollens Test

O
R

2 Ag(NH3)2OH
H

aldehyde

Ketones do
not react.

Remember that aldehydes

are easily oxidized.

metallic
silver

O NH4 +

2 Ag

+ H2O + NH3

silver mirror

CARBOHYDRATES
AND THE TOLLENS TEST
aldehyde

H
OH
H2C
HO

H
O
OH

HO
OH

-D-(+)-glucopyranose
Pyranose and open-chain
forms are in equilibrium
in solution.

HO

O
OH

The open chain form

is an aldehyde and
gives a Tollens test.

OH

OH
CH2 OH

D-(+)-glucose

REDUCING SUGAR

CARBOHYDRATES
AND THE TOLLENS TEST
ketone

aldehyde

TAUTOMERIZATION

HO

CH2 OH

CH OH

C O

C OH

HO

* CH OH

HO

OH

OH

OH

OH

OH

OH

CH2 OH
D-(-)-fructose

CH2 OH
enediol

CH2 OH
* both diastereomers
REDUCING SUGAR

-D-(-)-fructofuranose
Ketoses also give the test because they tautomerize! in solution.

CARBOHYDRATES
AND THE TOLLENS TEST
hemiacetals open in solution
= REDUCING SUGAR
H

OH
H2C
HO

HO

OH

HO
OH

HO

aldehyde

OH
H

OH

OH
CH2 OH

OH
H2C

O
OMe

HO
OH

acetals do not open in solution unless hydrolyzed in acid

= NONREDUCING SUGAR

ketoses
tautomerize
to reducing
sugars

CARBOHYDRATES
AND THE TOLLENS TEST
Any polysaccharide which has a hemiacetal ring will
give a positive Tollens test = reducing sugar.
CH2OH
O

H
H
OH

CH2OH
O

H
b

H
HO

HO
H

CH2OH
OH

OH

CH2OH

c OH H

OH

OH

Maltose
reducing sugar

OH

O
H

Neither sugar is in a
hemiacetal link.

CH2OH

OH H

HO

(+)-Sucrose
non-reducing

Hemiacetal link at a.

SYNTHESIS PROBLEMS

A Simple Synthesis Problem

O

C CH
2

Make from benzyl alcohol

complete synthesis on board

A Synthesis Problem
O

CH3

C OH

CH3

C CH3

complete synthesis on board

Another Synthesis Problem

O
C H

C CH2

complete synthesis on board

Yet Another Conversion

H3C
CH OH

H3C

H3C
C CH CH2 CH3

H3C
+ H3C CH2 CH2 OH

complete synthesis on board

PHARMACEUTICALS
Mexican Yams

HO

OH

the pill

C CH

Norethisterone

must be
injected

CH3

better absorbed through

the stomach and intestines
than progesterone

STEROID
O

progesterone

A B

C D

Mexican Yams
OH

OH
HOCH2CH2OH

CrO3
pyridine

H+ (-H2O)
O

O
O

acetal

Na C CH
NH3(liq)
O Na

protecting group
HO

C CH

H3

C CH

O+

O
O

norethisterone