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

HYDRATES

Addition of Water
O

O H

+
H
+

H2O

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

..

..
O
..

..

..

+ H
:O

:O H

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

an excess of H2O18
shifts the equilibrium
to the right

O H
+H2O18

R C R
18 O

-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
..

:
R O
H

..

O R

R C R

:O
..
acetal

Resonance
stabilized
carbocation

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

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

O
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.

HAWORTH
PROJECTION

CH2OH
O H
H
H
OH H
OH
HO
H
OH

-D-(+)-glucopyranose

Standard Position
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

GLUCOPYRANOSES

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

SOME HAWORTH PROJECTIONS

-CH2OH
up = D

-CH2OH
up = D

cis

CH2OH
O OH
H
H
OH H
H
HO
H
OH
trans
CH2OH
O H
H
H
OH H
OH
HO
H
OH

BOTH OF THESE ARE D-GLUCOSE

D-SUGARS
-D

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

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

O
HO

OH

HO
OH

H
-D-(+)-Glucose
a monosaccharide

HO-Sugar

O
O Sugar

HO
OH

a disaccharide

Since sugars have many -OH groups, this can continue

on to make polysaccharides.

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

O
+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

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

R
+

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

C
R

loss of water
(elimination)

R
G

..
N

R
G

+
N
H

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
C

R + H 2O

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 + H 2O

H3O+

R
C

..
O + H2N

R
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
R

aldehyde
or ketone

..
+ H2N

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

R
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

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

N
H

pyrrolidine

N
H

Water must be removed

morpholine

N
H

SOME SECONDARY
AMINES FREQUENTLY
USED TO FORM
ENAMINES

Enamine Formation
MECHANISM
1)

H
R

H
H-O-H
+

:O :
C

..
+O

H
H-O-H
+
H

..
: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

H
R

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
C

R
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)
R

+N

H
H-O-H
+

N:

+O :

+N

:O
..

slow
R

..
O
..

O-H
H

2)
R

+N

:O
..

R
R

+O
..

R
N
..

continued .

Hydrolysis of Iminium Salts

MECHANISM

3)
R

R
R

+O
..

O-H
H

:O :

+ H3O+

SUBSTRATES FOR ENAMINE ALKYLATION

(and acylation)

X CH2CH3

R
R

N:

R
C

X CH2 CH CH2

R
R

N+
C

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.

O
R C

O
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

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
H

C P(C6H5)3

..

+
ylide

..
P(C 6H5)3
:O
..
+

Br
C

triphenylphosphine
oxide (insoluble)

H H

Muscalure
H

CH3(CH2)6CH2

Sex pheromone of the

common house fly.
Musca Domestica

CH2(CH2)11CH3
(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.

O
CH3(CH2)6

Cl
H

CH2(CH2)12CH3

GRIGNARD REAGENTS

ORGANOMETALLICS FROM
DIVALENT METALS

HALIDE REACTIVITIES
RX + Mg

R-Mg-X

RELATIVE RATES :

FAST

R-I

expensive,
not readily
available

>

R-Br

good
compromise

>

R-Cl

SLOW

less reactive,
but easy to
prepare or buy

FORMATION OF A GRIGNARD REAGENT

CH3

CH3
H3C C H

+ Mg

Cl

ether

H3C C H
MgCl

Ethers are obligatory solvents for the Grignard Reaction.

The reaction doesnt work without an ether solvent.
CH3CH2

O CH2CH3
O

O
THF

Typical ether solvents are:

Diethyl ether (b.p. 35o C)
Tetrahydrofuran (b.p. 65o C)
Dioxane (b.p. 101o C)

Why might you need different solvents?

Consider two different leaving groups:

Br

+ Mg

ether
MgBr
35 C

Cl

+ Mg

THF
MgCl
65 C

Bromine is more reactive than chlorine.

The second reaction is too slow at 35 C,
therefore we use a higher boiling solvent.

We can view the Grignard as a hybrid reagent.

R:

MgX

MgX

MgX

RMgX is a source of a carbanion ( R:- ) just like RLi.

Therefore we expect Grignard reagents to be
both a strong base and good nucleophile.

Grignard Reagents give all the same

reactions as alkyllthium compounds.

R-Mg-X

R-Li

Grignard reagents are strong bases and react readily with

any slightly acidic hydrogen ( compare R-Li).
R

MgX

H+

+ MgX+

Li

+ H+

+ Li+

Any source of H+ will bring about this reaction:

water
acids
alcohols

amines
carboxylic acids
atmosperic moisture

alkynes

Any -O-H, -S-H, or -N-H bonds

are sufficiently acidic to react.

SYNTHESIS OF ALCOHOLS AND

CARBOXYLIC ACIDS

Reaction with Carbonyl Compounds

R

O
R

MgX

C
R

.. _ +
:
O
MgX
..

ether
C

R
H 2O

Just as with alkyllithiums ( RLi ):

formaldehyde
other aldehydes
ketones
carbon dioxide

primary alcohols
secondary alcohols
tertiary alcohols
carboxylic acids

R
R

C
R

OH

REACTION WITH CARBON DIOXIDE

O
ether
R-Mg-X

R-C-O- MgX+

O=C=O

H3O+
R-COOH

Mg

1) CO2
CH2 MgBr

CH2 Br
ether

2) H3O+

CH2 COOH

REACTIONS WITH EPOXIDES

PRIMARY ALCOHOLS

Reaction with Oxirane

O
R-Mg-X

H2C

CH2

R
Notice that :
the carbon chain has added two carbons
the product is a terminal alcohol

ether

H3O+

CH2 CH2 OH

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.

REACTIONS OF -HYDROGENS :
ALKYLATION AND HALOGENATION
REACTIONS

REACTIONS OF CARBONYL CONTAINING COMPOUNDS

Until now we have looked at reactions
of the C=O group - nucleophilic additions
and substitutions
Chaps 16, 17, 18, 19

..

O:

Good nucleophiles
react at C=O

C C
Strong bases
remove the
-hydrogens

Chap 21
Now we will look at reactions that
result from the acidity of the alpha
hydrogen

ACIDITY OF -HYDROGENS
ENOLATE IONS

-Hydrogens and Enolate Ions

.. :O :
C C

..

O:

base

C C
H

acidic :

pKa ~ 25

enolate
ion

..
O:

:B

-hydrogen

Major resonance
contributor:
charge is best
on oxygen =

C C

..

However, the
ion is more
nucleophilic
at carbon.

Strong bases will remove a hydrogen on the carbon next to a

carbonyl group (-hydrogen) to make a resonance stabilized
conjugate base.
NaOH, KOH, NaOR, NaH, LDA, etc.

Enolate Ions as Nucleophiles

MORE NUCLEOPHILIC AT CARBON, BUT BEST REPRESENTED AS THE ENOLATE

.. :O :

Mechanisms are often drawn

from the enolate resonance
form like this:

C C
enolate

CH3

..
O:

Rather than from the

ketolate form like this:

C C

CH3

..

ketolate

ALKYLATION OF KETONES
NON-CATALYTIC BASES = NaH, LDA

REACT ONCE

.
one shot

CATALYTIC BASES = NaOH, KOH, NaOR

REACT REPEATEDLY
It just keeps
on going and
going ..

Alkylation of a Ketone

one shot

NON-CATALYTIC BASES REACT ONCE

one mole
NaH

O
C CH3

THF
-hydrogens

one mole
_
..
C CH2 + H
2

CH3-I
one mole

LDA
THF
O

..
C CH2

CH3-I

C CH2 CH3

monoalkylation
_

Sodium Hydride
+

: N : Li
CH CH3
H3C CH
CH3

CH3

NaH

LDA
Lithium Diisopropyl Amide
a strong base

ALKYLATION OF CYCLOHEXANONE
CATALYTIC BASES REACT REPEATEDLY

CH3CH2 I

:O
NaOH

:O

CH2CH3

:-

.. :O:

It just keeps
on going and
going ..

..

..

enolate
ion

difficult to stop
at monoalkylation
with NaOH or KOH
(catalyst, not used up)

O
CH3CH2
CH3CH2

CH2CH3
CH2CH3

Sequence of Alkylation - Cyclohexanone and Base

It is difficult to stop at monoalkylation
even if one mole of CH3I is used.

Alkylation follows the sequence

shown below.

KOH
CH3I

Large or bulky groups may follow a

different sequence than this one.

O
CH3

This enolate has

SAME lower energy SIDE the double bond is
FIRST more substituted.
Steric hindrance
is not a problem.

O
CH3 H3C

CH3

H3C

CH3

CH3

CH3

H3C

CH3

O-

OCH3

CH3

CH3-I

This enolate has

higher energy.

ALKYLATION OF KETONES
NON-CATALYTIC BASES = NaH, LDA

Monoalkylation is Obtained by Using

Non-Catalytic Bases
A non-catalytic base is used up, and not regenerated.

..

:H -

:O

..

:O

H
NaH

.. :O :

Na+

H2
gone

CH3I

one
mole
stoichiometric base

.
one shot

..

:O

CH3
H

+ NaI

Lithium Diisopropyl Amide

.
one shot

: N : Li
H3C CH
CH3

CH CH3
CH3

LDA
Lithium Diisopropyl Amide
a strong base

LDA is also a non-catalytic base.

It is too strong a base to be regenerated after it is
used to remove a proton from an aldehyde or ketone.
.. (iPr)2N :
+ -H

..

(iPr)2NH

X
difficult

.. (iPr)2N :

(need to add Lio)

ALKYLATION OF KETONES
ENAMINES

ALKYLATION OF CYCLOHEXANONE
ENAMINES ALSO GIVE MONOALKYLATION

..

CH3CH2 I

+
N

CH2CH2

Alkylates once
and stops !

.
one shot

To perform a second alkylation

you must make the enamine all
over again!

O
CH2CH3

Sequence of Alkylation: Enamine

( pyrrolidine + CH3I )
O

O
first
time

Alkylations go one-at-a-time.
You must make a new enamine
each time.

CH3

Notice the different order of

methylation from that with base.

CH3

CH3 H3C

Difficult to go beyond dialkylation

because of steric hindrance.

second
time

Steric hindrance
N

This enamine
is favored.

N
CH3

CH3

This enamine
is not favored.
yellow area
is planar

-BROMINATION
OF KETONES

Bromination
It just keeps
on going and
going ..

..

.. ..
: Br Br :
.. ..

:O

KOH

.. :O:

Br2
O

O
Br

O
Br
Br

Br

Br

Br

Br

Br

Br

Br

Difficult to stop at monobromination

IODOFORM REACTION

Iodoform Reaction
O

NaOH

R C O Na + CHI3

R C CH I2
3

yellow

precipitate

NaOH

NaOH

H2O

..
R C CH
2

-: C

R C OH

I
good
leaving
group

I2
It just keeps
on going and
going ..

O
O
R C CH I
2

2x more

R C C

..-

H O:
..

REACTIONS OF -HYDROGENS :
ALDOL AND CLAISEN
CONDENSATION REACTIONS

TYPES OF REACTIVITY FOR

ALDEHYDES AND KETONES
O
C CH

nucleophilic
addition

C CH
Nu H

Nu:

OH

:B
removal
of -H

Good nucleophiles add.

C CH

..

Strong bases remove -hydrogens.

Often, both processes compete.

ALDOL CONDENSATION

The Aldol Condensation

ald
+
ol

O
R CH2 C H

OH
+

base

R CH2 C CH C H

H R

an aldol
(-hydroxyaldehyde)

R CH2 C H
H3O+

- H2O

O
aldols easily lose
water to form a
double bond

R CH2 CH C C H
R

,-unsaturated aldehyde

Aldol Condensation -- Mechanism

:O :

_ ..
+ :O
.. H

CH3 C H

CH3 C H
..
CH2

slow

CH3 C H

:O:

.. _
: O:

: O:
_
..
CH2 C H

: O:

H
+ H2O

: O:

fast

..
:O H

:O:

CH3 C CH2 C
H

C H

forms new
C-C bond

CH2 C H

C H

CH3 C CH2 C H

H2C

enolate ion

.. _
: O:

: O:

fast

.. _
: O:

_ ..
+ :OH
..

The Bond Forming Step

carbonyl
(acceptor)

H
H3C

_
O

+
C

H
H3C

_
O

..
CH2
C
H
enolate

CH2
O

nucleophile
(donor)

C
H

Ketones Also Give Aldol Condensations

OH

C CH
3

..

CH2

CH

C O

C O

- CH2

NaOH

CH3

-H2O

C O

aldol

CH3

CROSSED ALDOL
CONDENSATIONS

Crossed Aldol Condensations

KETONE + ALDEHYDE

aldehyde

OH

C H

.. -

CH2

CH2

NaOH

C O

C O

ketone
- H2O
Works best to if an aldehyde is
the acceptor, since they are
more reactive; and works really
well if the aldehyde has no -H.
The ketone should have the -H.

O
CH CH C

a chalcone

IMPORTANT GUIDELINES
1.

Aldehyde carbonyl groups are more reactive toward

nucleophilic addition than ketone carbonyl groups.
C +

+I

Nu:
MORE
REACTIVE

C +

+I

R +I

Alkyl groups
deactivate the
carbonyl ( +I )
to addition.

RELATIVE REACTIVITY OF C=O GROUPS

THE EFFECT OF ALKYL SUBSTITUTION
Density - LUMO plots ( color scale 0.000 to 0.030 )

O
H-C-H
MORE
REACTIVE

O
CH3-C-H

O
CH3-C-CH3
LESS
REACTIVE

2.

Ketones form enolate ions more easily than aldehydes.

.. .. :O :
:O :
R

C C H

R
aldehyde enolate

ketone enolate
more stable
.. :O :

..
:O

Which enolate will

form fastest?
CH3CH2

C CH2
..

O
CH3CH2

C C R
R

More
substituents
on the
double bond

C CH3

..
:O
CH3CH C CH3
..

CH3CH2

C CH2

monosubstituted

.. :O :
H3C CH C CH3
disubstituted

ALDEHYDE + KETONE ?
In mixed reactions the ketone enolate
usually adds to the aldehyde.

The ketone forms the lower energy enolate (forms faster)

and it adds to the aldehyde (more reactive C=O).

WHAT ABOUT
TWO DIFFERENT KETONES ?

HOW MANY PRODUCTS WITH THIS ONE ?

A
a

H3C C CH2

x2

CH3CH2

C CH3

x2

four mixed products

aB, bB, cA, dA

two different self dimers

two different self dimers

aA, bA

cB, dB

8 POSSIBLE PRODUCTS !
.. which enolate do you think will form preferentially?

FORMATION OF RINGS

Formation of Rings
1

2
O

H3C C CH2CH2CH2 C CH3

NaOH

CH3

CH3

OH

CH3

- :CH2
O

Why dont 2 hydrogens react ?

TETRAPHENYLCYCLOPENTADIENONE
O
Ph CH2

O
CH2 Ph

Ph

Ph

KOH

EtOH

Ph
Ph

Ph

Ph

An Interesting Sequence
O
1) O3
2) H3O+

O
KOH
Aldol

OH
H2SO4
- H2O

OH-

CLAISEN CONDENSATIONS

The Claisen Ester Condensation

O
R CH2 C O CH2 CH3
+
O

NaOCH2CH3
CH3CH2OH

R CH2 C O CH2 CH3

R CH2 C CH C O CH2 CH3

R

a -ketoester

+
CH3 CH2 O H

Notice that
the base, the solvent and the leaving group

CH3CH2O- Na+, CH3CH2OH, CH3CH2Oall match (this is required in most cases).

Claisen Ester Condensation Mechanism

1)

O
CH3 C OC2H5
+
_ ..
: O C2H5
..

2)

_
: CH2

C OC2H5

.. _
:O :

O
CH3 C OC2H5

CH3 C OC2H5
O

O
_
: CH2 C OC2H5
3)

.. _
: O:

.. _
: O:
H2C C OC2H5

CH2 C OC2H5
: O:

CH3 C OC2H5
O
CH2 C OC2H5

CH3 C
O
CH2 C OC2H5

_ ..
: O C2H5
..

Dieckmann Condensation
A CYCLIC CLAISEN CONDENSATION

MeOOC CH2CH2CH2CH2 COOMe

NaOMe
MeOH
O
C O CH
3

O
O
C O CH3

..

CH C O CH3
O

PATTERNS
HO
R CH2 C

(H)

-hydroxy to C=O

O
CH C R

3-hydroxyaldehyde or
(H)

Type of
Condensation
Reaction

ALDOL

3-hydroxyketone

-H2O

R CH2 C

O
R CH2 C

,-unsaturated C=O

C R

2-propen-1-al or
2-propen-1-one

O
CH C OR
R

-keto ester

ALDOL
(with loss of H2O)

CLAISEN

CONJUGATE ADDITION
MICHAEL ADDITION

Addition of Nucleophiles to Enones

Conjugate Addition or Michael Addition
..

:O

.. :O:

.. : O:

C C +

C C

C C
+

:Nu

:Nu

1,2-addition

1,4-addition

OH
C
C C

Nu

H C
C C
Nu

conjugate
addition

CONJUGATE ADDITION
..

.. : O:

O:
H

C
C C

H
:N C

H
CH3

H C C
:N C

CH3

H
H-OH

..

O:
H C
CH3
H C C
H
:N C

In conjugate addition
the nucleophile adds
and then picks up a
hydrogen from the
solvent medium.

CONJUGATE ADDITION
GENERALIZATION

conjugated ketone

C C
H

stereochemistry
also matters

C R
H

weak
nucleophiles/bases
conjugate addition
1,4-addition

strong
bases

direct to C=O
1,2-addition

Strong Bases : 1,2-Addition

Strong bases give direct addition to C=O (1,2-addition) unless
the C=O group is sterically hindered by large groups

Organolithium compounds

RLi

Grignard reagents

RMgX

Lithium Aluminum Hydride

LiAlH4

Weak Bases : 1,4-Addition

Good nucleophiles and weak bases give conjugate addition
(1,4-addition), also known as Michael Addition, especially if
the C=O group is hindered.
Amines
Alcohols

..
R-NH2
..
R-O-H
..

Water

..
H-O-H..

Enolates
Organocopper and cadmium compounds
( RMgX + CuCl or CdCl2 )
Lithium dialkylcuprates
( RLi + CuCl )
Cyanide ion

:C

N:

ADDITION TO CARBONYL
CH3MgI

HO

CH3

strong bases add

by 1,2 addition

CH3Li

(CH3)2CuLi

or
CH3MgI

or
(CH3)2Cd

_
:CH3

CuCl

CH3
weaker bases add
by 1,4 addition

_
:CH3

+
C-Li and C-Mg bonds are
more ionic (stronger bases)

R-Cu and R-Cd bonds are

more covalent (weaker bases)

STEREOCHEMISTRY ALSO MATTERS

LARGE GROUPS ON EITHER SIDE OF THE CARBONYL FAVOR CONJUGATE ADDITION
large groups here
promote 1,4 addition

O
H

C
C C

CH3
CH CH3

CH3MgBr

STERIC HINDRANCE

H
H C C

CH3

large groups here can

also promote 1,4 addition

OH
CH3
C
CH CH3
H
major product

O
H
C C
H

C H

OH

CH3MgBr

H
large groups here
promote 1,2 addition

C H
C C

CH3
major product

small groups here

make 1,2 addition
more probable