Muhammad Aswad

Introduction
Carbonyl compounds are everywhere in nature The majority of biologically important molecules contain carbonyl groups
HO

OH
O

O C

CH3 HO C O

H3C

N H

methyl salicylate

CH3

acetaminophen

acetic acid

Kinds of carbonyl compounds

Many different kinds of carbonyl compounds Depending on what groups are bounded to the C=O unit All contain an acyl bonded to another residue
O C R

The R subtituent of the acyl group may be alkyl, aryl, alkenyl, alkynyl The other subtituent to witch the acyl fragment is bonded may be a Carbon (C), hydrogen (H), Oxygen (O), Halogen (X), Nitrogen (N), Sulfur (S), or the other atom

Classify into two general categories based on the kinds of chemistry they undergo
Ketones and aldehydes Carboxylic acid and their derivatives

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. Hybridization of the oxygen is nominally sp2.

Prochiral
The carbonyl carbon is prochiral. That is, the carbonyl carbon is not the center of chirality, but it becomes chiral as the reaction proceeds.
Nu C :Nu R' C R :Nu R' R C Nu OH O R' R OH

These two products are enantiomers. In general, both enantiomers are formed in equal amount.

Ketone and Aldehyde

2.5 2.5 2.5 ketone 2.1 The R and H in these compounds cant act as a leaving group In subtitution reaction

aldehyde

Carboxylic acid and their derivatives

2.5

Propionic acid (a carboxylic acid)

The OH, OR, Cl, NH2, and OCOR, in these Methyl propionate (an Compounds can act as leaving groups in subtitution 3.5 ester) reaction

Propionyl chloride (an acid chloride)

Propionamide (an amide)

REACTIVITY OF THE C=O GROUP

NUCLEOPHILIC ADDITION

GENERALIZED CHEMISTRY

THE CARBONYL GROUP

nucleophilic at oxygen electrophiles add here H+ or E+

.. O:

.. :O :

C
+

Nu:

nucleophiles attack here electrophilic at carbon

NUCLEOPHILIC ADDITION TO C=O

MECHANISMS IN ACID AND IN BASE

Nucleophilic Addition to Carbonyl Basic or Neutral Solution

.. O: C .. _ :O: C Nu + H2O +

-:Nu

.. _ :O: slow C Nu .. :O H C Nu

an alkoxide ion

fast

or on adding acid Good nucleophiles and strong bases (usually charged)

BASIC SOLUTION

Nucleophilic Addition to Carbonyl Acid Catalyzed

.. O: C + + H fast + :O C H

more reactive to addition than the unprotonated precursor

.. + O H C + :Nu

.. :O slow C Nu

(+)
ACIDIC SOLUTION pH 5-6 stronger acid protonates the nucleophile

Acid catalysis speeds the rate of addition of weak nucleophiles and weak bases (usually uncharged).

Reaction of the Carbonyl Group with Acids

H O C + H+ O C

Typical behavior

Reaction of the Carbonyl Group with Bases

O C + B:
Typical behavior

O C B

The carbocation intermediate has resonance.

H O C O C H

The positive charge character on carbon makes this an excellent site for attack by Lewis bases (nucleophiles).

Once we have the intermediate, what happens to it?

Case 1: The Addition Product is Stable.

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

O C Nu + X

This process is observed when X is a potential leaving group. In this case we have nucleophilic acyl substitution .

ORGANOMETALLICS

Reaction with Organometallic Compounds

O R MgX + R C R

e th e r

R R C R

.. _ + H2O O : M gX ..

R R C R OH

The products of this sequence are always alcohols.

Addition of Organometallic Reagents

:O : R M + R C R R .. _ + :O: M C R H2O + H .. : OH R

(R-MgBr)

The products of the addition are always alcohols.

C R

M (OH)x

Crude outline of the mechanism of organometallic addition

R "R: "
-

R C O slow R C R' O

+ R'

(from R-MgX)

R, R' = H, alkyl, or aryl

R R C R'

H+

OH

Synthesis of Alcohols

Addition of Organometallic Reagents

:O : R M + R C R .. :O R C R .. _ + :O: M
ether

C R

(R-MgBr)

(R-Li)
:R

These reagents cannot exist in acid solution

H2O + H H R

workup step

M (OH)x

alcohol

Whatever is attached to the carbonyl group will be attached to the resulting alcohol carbon.
H R M + H formaldehyde R R M + H other aldehydes R R M + R' ketones C O R C O R C O R H C OH (M = Li or MgX) H primary alcohol R C OH

H secondary alcohol R C OH

R' tertiary alcohol

Example
O CH3 CH2 C CH2 CH3 CH3MgI ether O CH3 CH2 C CH3 H2O, H+ MgI CH2 CH3

O
Organometallics react with ketones to yield tertiary alcohols.

H CH2 CH3

CH3 CH2 C CH3

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 C R R'
aldehyde or ketone favored

H2O

+ H
R

O H C O H a hydrate R'

most hydrates revert to an aldehyde or ketone as soon as they form

O H R C O H R' R O C + R' H2O

hydrates are unstable and cannot be isolated in most cases

ACID CATALYSIS
RECALL

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

.. :O H
+

Acid catalysis enhances the reactivity of the carbonyl group - nucleophilic addition proceeds more easily.

:Nu
weak nucleophiles can react

Water is a weak nucleophile.

WATER ADDS TO THE CARBONYL GROUP OF ALDEHYDES AND KETONES TO FORM HYDRATES
H

:O

..

O H

..

catalyzed by a trace of acid + H :O

:O H
C H H

..

:O
C

..

.. O ..

.. .. O ..

O+

H H H

:O .. ..
+

a hydrate

O H

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

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 .. .. + H :O :O
+

.. :O H
+

Acid catalysis enhances the reactivity of the carbonyl group - nucleophilic addition proceeds more easily.

:Nu
weak nucleophiles can react

Alcohols are weak nucleophiles.

Addition of Alcohols
TWO MOLES OF ALCOHOL WILL ADD

addition of one mole

O R C R' + ROH
addition of second mole

O H R C R' hemiketal O R

O H R C R' O R + ROH

O R R C R' + H O O R
an aketal

The equilibria normally favor the aldehyde or ketone starting material, but we will show how they can be made.

ADDITION OF WATER AND ALCOHOLS

WATER

O C

H2O

HO

OH
hydrate

ALCOHOLS

O C

R-O-H

HO

OR

R-O-H H2O

RO

OR

hemiacetal

acetal

RO

OR

H H2O
+

O +2 ROH
no reaction

H2O NaOH

acetals are stable to base but not to aqueous acid

Nucleophilic Acyl Subtitution Reaction of Carboxylic Acid and Derivatives

AlphaSubtitution Reaction
Subtitution of an Hydrogen by an Electrophilic (E+) and involves the formation of an intermediate enol or enolate ion

 Since they are negatively charged, enolate ions behave as nucleophiles and undergo many of reactions. For example, enolates react with primary alkyl halides in the SN2 reaction The nucleophilic enolate ion displaces halida ion and a new CC bond forms

 The SN2 alkylation reaction between and enolate ion and alkyl halida is one of the most powerful method available for making CC bonds thereby building up larger molecules for smaller precursors

 Take place when two carbonyl compounds react with each other For example, when acetaldehyde is treated with base, two molecules combine to yield the hydroxy aldehyde product known as aldol (aldehyde + alcohol)

Carbonyl Condensation Reactions

References
1. Mc. Murry, J., 2000, Organic Chemistry, Fifth Edition, Brooks/Cole 2. Fessenden, R. J., Fessenden, J. S., 1986, Kimia Organik Jilid I dan II, Terj. A. H. Pudjaatmaka, Penerbit Erlangga