CARBONYL COMPOUNDS:

NUCLEOPHILIC ADDITION
REACTION

Lecture 6 ORGANIC CHEMISTRY 2

CARBONYL COMPOUNDS
O O

C C
R H R R'
ALDEHYDE KETON

O O

R OR' R OH
ESTHER CARBOXILIC ACID
 CARBONYL COMPOUNDS

Formalin Ibuprofen Aspirin

Asam cuka Asam semut Perasa buah

 CARBONYL COMPOUNDS

O O O
O

OH OH
H H H OH
Formaldehida asam semut
O
O O
O CH3

H3 C CH3 H3C OH aspirin

Aseton (pembersih kutek) asam cuka
ibuprofen
O
O CH3

C O
O
H2 N NH2
Urea
CH3 O
kantaridin
Preparation of Aldehydes and Ketones

1. Oxidation reactions
2. Hydrolysis of geminal dihalides
3. Hydration of alkynes
4. Reactions with acid derivatives
and nitriles
5. Reaction with carboxylic acids
6. Reaction with thioacetals
1. Aldehydes/Ketones via Oxidation Reactions
a. From Alcohols via PCC
b. From Alkenes via Ozonolysis
c. From Glycols via Periodic Acid Cleavage
PCC
RCH 2 OH R C H
O
PCC R C R
R 2 CHOH
O
R'CH CR 2 R' C H +R C R
ozonolysis
O O
R'
R C CH 2 OH R C R' + H C H
HIO 4
OH O O
Synthesis Mechanism
a.1 Oxidation of 1 alcohols
:Base
O
O
O O
Cr O
H O O O Cr
O H + Cr O
O O
O C
C R H
C C R H
R H R H H
H H
:Base
a.2. Oxidation of 2 alcohols w/ PCC and base
:Base
O
O O O O
H Cr Cr Cr
O O H + O
O O O O
O

C C R
C C
R H R H H R R
R R R
:Base
b.1 Oxidative cleavage of alkenes w/ O3, Zn, CH3COOH
O
O
O
O O
H + O O
O O
H R R
C C
R H H R R H
H R

CH3COO-
CH3COO H
O H
+
O O O O
+ R O O H
R H H R
R H H R
H O R
b.2.Ozonolysis of alkenes, if one of the unsaturated carbon
atoms is disubstituted.
O CH3COO H
O
O
O + O O O O
O O
O
R R O
C C R R R R
R R

CH3COO-

O H
O O + O
O
+
R R R R R R R R
2. Hydrolysis of Geminal Dihalides

H 2O
R CH Cl2 R C H + 2 HCl

O
H 2O
R 2CCl 2 R C R + 2 HCl

O
3. Hydration of Alkynes
a. Markovnikov Addition
b. Anti-Markovnikov Addition

H2O / H2SO4
R C C H R C C H R C CH3
HgSO4
OH H O
9-BBN H2
R C C H R C C H R C C H
-
H2O2 / OH
H OH O
3.a. Hydration of terminal alkynes methyl ketones
H2O

+ H
R C C H R C C +
2+ Hg SO4
Hg SO4

H OH2
+
H O H O H
C C +
H C C
R Hg SO4 R +
Hg SO4

H3O+

O
H O H tautomerization
C C + H2O C CH3
R H R
4. Reactions with Acid Halides
a. Aldehydes via Selective Reduction
Lithium tri-tert-butoxyaluminum hydride
Rosenmund reduction
b. Ketones via Friedel-Crafts Acylation
c. Ketones via reaction with Organometallics
Gilman reagent (organocuprates)
4.a. Aldehydes from Acid Chlorides
Lithium tri-t-butoxyaluminum hydride reduction
Rosenmund reduction

LiAlH(O-t-bu) 3
R C Cl R C H
ether
O O
H 2 / Pd / S
R C Cl R C H
BaSO 4
O Rosenmund catalyst O
4.b. Ketones via Friedel-Crafts Acylation
AlCl3
R C Cl C R + HCl
benzene
O O

AlCl3
R C O C R
benzene C R + RCOOH
O O O

Friedel-Crafts acylation aryl ketones

O
O
O
C
AlCl3 R C
+ C +
H R +
R Cl C
H Cl
AlCl4-
4.c.Ketones via Reaction with Organometallics
Use of Lithium dialkylcuprates

+
R' Cu Li
O O
R' Ether
C C
R Cl R R'
5. Aldehydes from Esters and Amides
Diisobutylaluminum hydride (DIBAH or DIBAL-H)
O
R C OR'
or
O
R C NH 2
1. Diisobutylaluminum O
or hydride
R C H
O +
2. H3 O
R C NHR'
or
O
R C NR 2 '
5.a. Partial reduction of certain carboxylic acid
derivatives
O
+
H O H
O C
R H
O H
DIBAH, toluene C +

C H3O+
R O R' +
R OR'
H R'OH
6. Ketones from Carboxylic Acids
Attack by Alkyl Lithium reagents

RLi - +
RCOOH RCOO Li + RH
- +
R O Li
RCOO Li
- + RLi
C
-
R O Li+
- +
R O Li R OH
H 2O
C C
-
R O Li+ R OH

R OH
( H 2O )
C R C R
R OH O
8. Reactions with Nitriles
a. Grignard Addition to give Ketones
b. DIBAH Addition to give Aldehydes

+
R'MgX H
R CN R C N MgX R C R'
H 2O
R' O

DIBAH or DIBAL-H
R CN R C N Al(i-bu)2
diisobutylaluminum hydride
H
R C H +
H /H2 O
O
7. Ketones from Thioacetals
a. Thioacetal formation from an aldehyde precursor
b. Alkylation of the thioacetal intermediate using alkyl lithium
reagents
c. Hydrolysis of the alkylated thioacetal to give ketone product

HSCH 2CH 2SH S S

R C H
BF 3 C (a thioacetal)
O
R H

S S C 4H 9Li S S R'CH 2X
S S
+
C ( C 4H 10 ) C Li C + LiX
R H R R CH 2 R'

S S HgCl 2 / CH3OH / H2O

C R C CH 2 R'
( HSCH 2CH 2 SH )
R CH 2 R' O
 Characteristic Reactions of
Aldehydes and Ketones
1. Reduction reactions
a. Alcohol formation
b. Alkane formation

2. Oxidation reactions

3. Nucleophilic addition reactions

a. Grignard additions to form alcohols
b. Addition of water (hydration) to form gem-diols
c. Addition of alcohols to form acetals/ketals
d. Addition of HCN to form cyanohydrins
e. Addition of ammonia and ammonia derivatives
 Reduction Reactions of Aldehydes & Ketones
1. Alcohol formation
a. Hydrogenation
b. Hydride reduction
2. Alkane formation
a. Clemmensen reduction
b. Wolff-Kishner reduction
H 2 / Pt
R C H R CH 2OH
O
LiAlH4 H 2O
R C H + R CH 2 OH
ether H
O
conc. HCl
R C H R CH 3
Zn(Hg)
O
NH 2 NH 2
R C H - R CH 3
OH / H2 O
O
 Oxidation of Aldehydes & Ketones

1. Conversion of aldehydes to carboxylic acids

2. Oxidation of aromatic aldehydes / ketones to
benzoic acid derivatives
3. Haloform reaction of methyl carbonyls
4. Periodic acid cleavage of vicinal dials/diketones
 Aldehyde / Ketone Oxidations
+
Ag(NH 3)2
1. R C H or Ar C H RCOOH (ArCOOH)
(Tollens reagent)
O O

2. C H

O
KMnO 4 or K2Cr 2O 7
or COOH

C R

O
X2 -
3. CH 3 C R - HCX 3 + RCOO
OH / H2O
O
R C C H RCOOH + HCOOH + HIO 3
4. HIO 4
O O
Nucleophilic
addition
reactions
 Structure of the Carbonyl Group

C O

Hybridization of the carbonyl carbon is sp2.

Geometry of the carbonyl carbon is trigonal planar
Attack by nucleophiles will occur with equal ease from
either the top or the bottom of the carbonyl group.
The carbonyl carbon is prochiral. That is, the carbonyl
carbon is not the center of chirality, but it becomes chiral
as the reaction proceeds.
Prochiral
Nu

C OH
R'
:Nu R
These two products
R'
are enantiomers.
C O
R
:Nu R In general, both
R'
C OH enantiomers are
formed in equal
Nu amount.
Reaction of the Carbonyl Group
1. H
O O
+ H+
C C

2.
O O

C C

+ B

B:
Nucleophilic Addition to Carbonyl:
General Mechanism
+
:OH
1. :O:
fast
+
+ H C
C

..
+ : OH
: OH
slow
+ :Nu C
C
Nu
 .. _
2. :O :
:O:
slow
+ :Nu C
C
Nu

.. _ ..
:O: : OH
fast
C + H2O C

Nu Nu
Relative Reactivity of Aldehydes & Ketones
Aldehydes >>> ketones
1. Steric Reason
nucleophile is able to approach aldehydes more
readily because it only has 1 large substituent
bonded to the C=O carbon, vs. 2 in ketones.
transition state for the aldehyde rxn is therefore less
crowded and has lower energy.

Aldehydes Ketones
2. Electronic Reason
greater polarization of aldehyde carbonyl group
aldehyde is more electrophilic and more reactive than
ketones.
H H
+ +
C C
R H R R'
1 carbocation 2carbocation
(more stable, less reactive)
(less stable, more reactive)
- -
O O
+
C
+ +
+
R H C
R R'
Aldehyde Ketone
(less stabilization of +, (more stabilization of
more reactive) +, less reactive)
Relative Reactivity of Aldehydes & Ketones
Aliphatic aldehydes >>> Aromatic aldehydes
The electon-donating resonance effect of the aromatic ring
makes the carbonyl group less electrophilic than the carbonyl
group of the aliphatic aldehyde.
The carbocation intermediate
H H
O O The positive charge character on
carbon makes this an excellent site
for attack by Lewis bases
C C
(nucleophiles).

Nucleophile attacks the electrophilic C=O carbon from a

direction ~45 to the plane of the carbonyl group
At the same time: Rehybridization of the carbonyl carbon from
sp2 to sp3 occurs.
 Once we have the
intermediate, what
happens to it?
Case 1: The Addition Product is Stable.
OH

R C R

Nu

The reaction stops here. This happens most often when

the nucleophilic atom is carbon, oxygen, or sulfur.
Case 2: Addition-Elimination

OH
R R
R C R C + O
H H
Nu Nu
H

The addition product is unstable with respect to loss

of a molecule of water. This is observed most often
when the nucleophilic atom is nitrogen or
phosphorus.
Case 3: Loss of Leaving Group

O O

R C X R C + X

Nu Nu

This process is observed when X is a potential

leaving group. In this case we have nucleophilic
acyl substitution.
 Nucleophilic Addition of H2O: Hydration

Nucleophilic addition of water is catalyzed by acid and base.

1. Base-catalyzed

1. O slow O-

OH
:OH-

O
2, H H
O- OH
fast
+ OH-
OH OH
2. Acid-catalized
H H
1) O O
O

C + H+ C C

Resonance places greater positive charge

character on the carbonyl carbon.
2)
H
H
O O
slow
C C

O O
H H
H H

3)
H H
O O

C C + H+

O O
H H H
 Important only for low-molecular-weight aldehydes
Examples:

C in water 20 C >99.99% hydrate

H H
O

C 58%
CH3 H

C ca. 0%
CH3 CH3
 Nucleophilic Addition of Alcohols:
Acetal Formation
Acetals and Ketals are formed by reacting two equivalents
of an alcohol with an aldehyde or ketone, in the presence of
an acid catalyst.
Hemiacetals and Hemiketals are formed by reacting only
one equivalent of alcohol with the aldehyde or ketone in the
presence of an acid catalyst. Further reaction with a second
alcohol forms the acetal or ketal.
A diol, with two OH groups on the same molecule, can be
used to form cyclic acetals.
All steps in acetal/ketal formation are reversible.
 O O H
+
H
C + ROH R C R'
R R'
O R
a hemiacetal
Aldehydes form hemiacetals faster than ketones

O H O R
+
H
R C R' + ROH R C R' + H 2O

O R O R
an acetal
(or ketal)
This reaction is also reversible. But, in this case, the equilibrium can
be driven to the right by an application of Le Chteliers Principle.
 OR OR

R H R R
OR OR

OH OH

R H R R
OR OR
Mechanism of Acetal Formation:
H Cl + H H
: O: :O
:O
+ +
R
O:
aldehyde/ketone
.. .. H
O
R H .. ..
O
H H

+
Cl H H
+ R H
H :O
:O + OH2 O
.. R
O
R
+ H3O
+
O
Hemiacetal/
.. .. Hemiketal
O
R H

R R
:O
:O
+ R +
O: R + H3O
O
H .. .. Acetal/
O Ketal
H H
Example Nucleophilic Addition of Alcohols
1. Formation of 2,2-Dimethoxy-propane
O Dry acid =
CH3 C CH3 O CH3 HCl gas
dry acid HCl in methanol
+ CH3 C CH3 HOTs

2 CH3OH O CH3

+ H2 O
2. Formation of a Cyclic Acetal
O CH2
O
CH2
dry HCl O
+ H 2O
+

HO CH2 CH 2 OH a 1,3-dioxolane

Ethylene glycol
1,2-Ethanediol
3. Cyclization of Monosaccharides
Carbohydrates contain the functional groups of alcohols and aldehydes or
ketones in the same molecule. They are polyhydroxyaldehydes or
polyhydroxyketones.
Thus they can form acetal-type products through the intramolecular
interaction of these functional groups.
As a model, consider the reaction:

H OH
O C
H+ CH 2 O
CH 2 CH 2 C
HO CH 2 CH 2 H CH 2 CH 2
CH 2
 O OH
H
1
H C 1C

2 2
H OH H OH

3 3 :O:
HO H HO H

4 4
H OH H OH

5 .. 5
H O H
..
6 H 6
CH 2 OH CH 2 OH

H
: O: O
a pyranose
O OH
ring
H H
6
H
.. O
O: H
H
a furanose
O ring
5 OH
Nucleophilic Addition of HCN

1)
O
O
C slow
R C R
R R

C
C N
N
2)

O O H

R C R + H+ R C R

C C

N N

A cyanohydrin
Example
O O
Na2CO3
+ C N C N
(NaCN)

H2O, H+
Notice that the cyanide ion and
the acid are added in two
OH
separate steps!
Sodium carbonate is used to C N

keep the reaction medium basic.

So, whats it good for?

OH
CHCH2NH2
1. LiAlH4,THF

2. H2O
O OH
2-Amino-1-phenylethanol
CHCN
HCN

OH
CHCO2H
H3O, heat

Mandelic Acid
 Addition of Organometallic Reagents
R R

-
slow
"R: " + C O R C O

R' R'
(from R-MgX)

H+
R, R' = H, alkyl, or aryl

R C OH

R'

The products of the addition are always alcohols.

Whatever is attached to the carbonyl group will be attached
to the resulting alcohol carbon.

H H

R M + C O R C OH

(M = Li or MgX) H H
formaldehyde primary alcohol

R R

R M + C O R C OH

H H
other aldehydes secondary alcohol

R R

R M + C O R C OH

R' R'
ketones tertiary alcohol
Nucleophilic Addition of Grignard (R-MgX)

+ MgX R MgX MgX

O O O
R
R

Tetrahedral intermediate

OH2 OH
+ HOMgX
R

An Alcohol
 Addition of Hydride Reagents

O
OH
O
":H-" H3O
C
R R' R C
fr:NaBH4 H R
R' H
R'
 Compounds that bear an amino group

G NH 2

Form Imines
The G group can be one of many different possibilities
 Addition-Elimination:
The Formation of Imines

R R
.. HA
G NH2 + C O C N G + H2 O
R R

an imine

All of the imine reactions, regardless of G, go by the

same mechanism.
Mechanism of Imine Formation:
Step 1
R H R R
.. .. slow
+ .. _ .. ..
G NH2 + C O
.. G N C .. :
O G N C OH
..
R H R H R

Step 2

R R
.. fast _
.. +
G N C OH + HA G N C + H2O + A
..
H R H R

Step 3

R R
+ _ fast ..
G N C + A G N C + H A

H R R
 Formation of Simple Imines
A. Simple primary amines
R R
.. acid
C O + H2N R C N R + H2O
R R
an imine

Aldehydes and ketones react with simple primary amines

to yield imines.
The equilibrium is unfavorable; the products are much
less stable than the reactants.
B. Simple secondary amines
When secondary amines are allowed to react with
aldehydes or ketones, dehydration of the type shown in the
elimination step cannot take place (there is no labile
hydrogen on the nitrogen atom of the addition product).

OH

R C R

N
R' R'
 If the starting aldehyde or ketone has an -hydrogen,
however, dehydration toward the -carbon can occur,
yielding an enamine.
H O H OH
+
H
R C C R + R2NH R C C R

R R NR2

+ R NR2
H
C C + H2O

R R
an enamine

The acid catalyst is generally a dry acid, such as p-toluene

sulfonic acid (HOTs)
Amines that are used typically to form enamines:

CH3 CH2

N H

CH3 CH2 N
Diethylamine
H
Piperidine

H N

Pyrrolidine H
Morpholine
Enamine Formation
.. ..
1) H :O : H + OH H :OH
+
R C C R + H R C C R R C C R
+
R R R

2) .. .. ..
H + OH H :OH H +OH2
slow
R C C R R C C R R C C R

R .. R +N H R N:
N H
R R R R
R R
3)
+ ..
H OH2 H H
+
R C C R R C C R R C C R

R N: R N: R N+

R R R R R R
+ H2O
4)

H
+ +
R C C R R C C R + H

R N: R N:

R R R R
 Formation of Oximes
R R
.. acid
C O + H2N OH C N OH + H2O
R R
hydroxylamine an oxime

Aldehydes and ketones react with hydroxylamine to yield

oximes.
Oximes are important derivatives in qualitative organic
analysis.
 Formation of Hydrazones
R R
.. acid
C O + H2 N NH R C N NH R + H2O
R R
a hydrazine a hydrazone

Aldehydes and ketones react with substituted hydrazines to

yield substituted hydrazones.
The equilibrium is generally unfavorable.
Exception: when R is an aromatic ring.
Wolff-Kishner Reaction: Nu- Addition of Hydrazine

N H
N

R R'
O NH2
N -OH
+ H2NNH2 + OH2
R R' R R'
N H
N
C
R R'

OH2
H OH2 N H
C N
OH + OH2 + N N+ R H OH
R H R'
R' R H
alkane R'
 Formation of Semicarbazones
R O
.. acid
C O + H2N NH C NH2
R semicarbazide

R O

C N NH C NH2 + H2 O
R

a semicarbazone

Aldehydes and ketones react with semicarbazide to yield

semicarbazones.
Semicarbazones are the second-most important of the derivatives
of aldehydes and ketones.
 The enamine is quite nucleophilic,
owing to resonance of the type:

R' R'

R N R' R N R'

C C C C

R R R R

As a consequence of this resonance, the -carbon

of an enamine has a great deal of carbanion-like
(nucleophilic) character.
Reactions of Enamines as Nucleophiles

R R R R R

R :N R R +N R :N

C C R C C R R C C R
+
R R R R
an iminium salt

R X
_
+ X
SN2
Hydrolysis of Iminium Salts
1)
R R R R R R

R +N R N: R +N H
slow
R C C R R C C R R C C R

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

2)
R R

R +N H R R R

R C C R R C C R + N H
..

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

3)
R R
+
R C C R R C C R + H

R +O H R :O :
..
Enamines can react with alkyl halides -- Heres an example.
O O

N N O

CH3 CH3
H2O
+ CH3 I
H+

from cyclohexanone
 Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
Converts an aldehyde/ketone into an alkene.
A phosphorus ylide(aka phosphorane), acts as the Nu-
Ylide : A compound or intermediate with both a positive and
a negative formal charge on adjacent atoms.

R _ R
+ ..
(C6H5)3P C (C6H5)3P C
R R

The ylide is nucleophilic, owing to the negative charge

character on carbon (structure on the right).
A phosphorus ylide(aka phosphorane), acts as the Nu- to attack the
carbonyl carbon and yields a four-membered ring, dipolar intermediate called
the betaine.
The betaine decomposes spontaneously to yield an alkene and a
triphenylphosphine oxide.
Can produce monosubstituted, disubstituted, and trisubstituted alkenes.
R1 R3 R1 R3

C O + (C6H5)3P C R2 C C R4
R2 R4
: O: P(C6H5)3
an ylide .. _ +
a betaine

R1 R3
C C + O P(C6H5)3
R2 R4
This is a type of condensation reaction -- we use it to dock to large
structures together.
This is another example of addition-elimination.
Mechanism of the Witting Reaction:

: O:
+
P
+ -: ..: P
:
- O +
ketone/aldehyde R R'
R'
ylide R
betaine

P O R' ..
+ :O P
R
alkene
R'
R
 Conjugate Nucleophilic Addition to
--Unsaturated Aldehydes and Ketones
Direct addition (aka 1,2 addition) occurs when a nucleophile attacks
the carbon in the carbonyl directly.
Conjugate addition (aka 1,4 addition) occurs when the nucleophile
attacks the carbonyl indirectly by attacking the second carbon away
from the carbonyl group, called the beta carbon, in an unsaturated
aldehyde or ketone.
Conjugate addition reactions form an initial product called an enolate,
which is protonated on the carbon next to the carbonyl, the alpha
carbon, to give the final saturated aldehyde/ketone product.
Conjugate addition can be carried out with nucleophiles such as
primary amines, secondary amines, and even alkyl groups like in
organocopper reactions.
It is the carbonyl that activates the conjugated C=C double bond for
addition which would otherwise not react.
 Conjugate (1,4) addition mechanism:

-: ..:
O

Nu
: O: O
-
: Nu
Nu
H H H
O+
alpha,beta-unsaturated Saturated
aldehyde or ketone H aldehyde or ketone
:O:
- ..
Nu

Enolate ion