Organic Pharmacy

Organic chemistry is based on structural

theory which separate organic compounds
in families.

ALDEHYDES
KETONES
 Organic Pharmacy
Aldehyde/ketone characteristics:

Aldehydes general formula: RCHO

Ketones general formula: R1R2CO
 Organic Pharmacy
Aldehyde/ketone characteristics:

Both compounds aldehydes and ketones contain

a carbonyl group: C=O

Carbonyl compounds
This group is largely involved in chemistry of
aldehydes and ketones.
Chemistry of both groups are closed but
influenced by the difference in structure.
 Organic Pharmacy
Aldehyde/ketone characteristics:

Aldehydes contain the carbonyl group an organic

group and an hydrogen.
Ketones contain the carbonyl and are substituted
by two organic groups.
Difference regarding oxidation: easy on
aldehydes, difficult on ketones
Nucleophilic addition: aldehydes are more
reactive than ketones
 Organic Pharmacy
Aldehyde/ketone characteristics:

C and O are bond by a sigma and a pi bond.

Due to the difference in electronegativity, electrons
are not equally shared:
The C is holding a partial δ+ charge and O is
holding a partial δ- charge.

R δ+ δ-

C O
R'
 Organic Pharmacy
Aldehyde nomenclature:

Identify the longest continuous chain of

carbons with the acyl or carbonyl carbon as
part of the chain.

Number the carbon chain so that the

carbonyl (acyl: R-CO~) carbon is always
number 1.
 Organic Pharmacy
Aldehyde nomenclature:

Locate and identify alphabetically the

branched groups by prefixing the carbon
number it is attached to.
If more than one of the same type of
branched group is involved use prefixes di
for 2, tri for three, etc.
 Organic Pharmacy
Aldehyde nomenclature:

After identifying the name, number and

location of each branched group, use the
alkane name corresponding to the number of
carbons in the continuous chain
Drop the "e" and add the characteristic
international ending for all aldehydes, "al"
Alkenals involving double bond will require
that the double bond is located but the
ending will still be "al" (al > ene)
 Organic Pharmacy
Aldehyde nomenclature:

If replacing the aldehyde group with a

carboxyl (-COOH) group would yield a
carboxylic acid with a trivial name, the
aldehyde may be named by replacing the
suffix -ic acid or -oic acid in this trivial name
by -aldehyde. For example:
HCHO may be called formaldehyde.
CH3CHO may be called acetaldehyde.
C6H5CHO may be called
benzaldehyde.
 Organic Pharmacy
Aldehyde nomenclature:

H H H H

H C O CH3 C O CH3CH2CH2C O
CH3CH2 C O
Formaldehyde -
Acetaldehyde Propionaldehyde n butyraldehyde
Methanal
Ethanal Propanal Butanal

pentanal H CH 3
valeraldehyde
O CH 3CH CHCH 2CHC O
C
CH3CH 2CH 2CH2C O H

H benzaldehyde 2-methyl-4-hexenal
 Organic Pharmacy
Aldehyde nomenclature:

CH3 H

C O
CH2 CH3
CH3
CH3 C CH CH C O
Br
CH3 Cl H CH2CH3

- - - - - - - -
5 bromo 4 ethyl 2 methyl benzaldehyde
3 chloro 2 4 4 trimethylhexanal
, ,
 Organic Pharmacy
Aldehyde nomenclature:

The aldehyde group is also called the

formyl or methanoyl group.
 Organic Pharmacy
Aldehyde other possible nomenclature:

Branched-chain aldehydes can be named as

derived straight-chain aldehydes, point of
attachment indicated by α, δ, γ, δ…
The α-C being the C holding the CHO.
α-C corresponds to C2
δ γ β α
C C C C CHO
 Organic Pharmacy
Ketone nomenclature:

The simplest ketone: acetone CH3-CO-CH3

For most other ketones, we name the two groups

related by the carbonyl and followed these names
by ketone.

If the carbonyl is attached to a benzene, we can

name it as phenone.
 Organic Pharmacy
Ketone nomenclature:

Identify the parent chain: longest chain

containing the carbonyl.

Replace the –e of the corresponding alkane by –one

Indicate the position of the carbonyl and

substituent by number and give the lower number
to the C=O.
 Organic Pharmacy
Ketone nomenclature:

acetone, propanone ethyl methyl ketone -

methyl n propyl ketone
butanone -
CH3 C CH 3 2 pentanone
CH 3CH 2 C CH 3
O CH 3CH2CH2 C CH 3
O
O

diethyl ketone benzophenone

acetophenone
-
3 pentanone
C C CH3
CH3CH2 C CH2CH3

O O O
 Organic Pharmacy
Ketone nomenclature:

Aldehyde or ketone takes priority over an –OH

and -ene.
A carbonyl as a substituent is an oxo group
O O O

H2C CH CH2 C CH2 CH3 CH3 C CH2 C H

- - -
5 hexen 3 one -
3 oxobutanal
 Organic Pharmacy
Aldehyde/ketone physical properties:

Polar carbonyl groups makes aldehydes and

ketones polar compounds.

Higher boiling points than non-polar compounds

with comparable molecular weight.

No intermolecular bonding (H bonding)

because the H is related to the C and not to the
O: lower boiling points than comparable
alcohols.
 Organic Pharmacy
Aldehyde/ketone physical properties:

Lower aldehydes and ketones are

appreciably soluble in water (H bonding
between solutes and solvant). Maximum
solubility is reached at 5C.

Aldehydes and ketones are soluble in usual

organic solvents
 Organic Pharmacy
Aldehyde/ketone physical properties:

Formaldehyde is a gas and is handled

either as an aqueous solution (formalin), or as
one of his solid polymer:
paraformaldehyde (-CH2O-)n or trioxane
(CH2O)3
CH 2OCH 2OCH2OCH2OCH 2O

O
H2C CH2

O O

CH2
 Organic Pharmacy
Aldehyde/ketone physical properties:

Keto-enol tautomerism is catalyzed by

either acid or base.
The interconversion of the two forms
involves the movement of a proton and the
shifting of bonding electrons; hence, the
isomerism qualifies as tautomerism
 Organic Pharmacy
Aldehyde/ketone natural occurrence:

Testosterone Vanillin

Cortisone
Organic Pharmacy

ALDEHYDES
KETONES
REACTIONS
 Organic Pharmacy
Aldehyde/ketone reactions:

NUCLEOPHILIC ADDITIONS:
Nucleophilic addition on the C of the
carbonyl.
C=O group provide a site for nucleophilic
addition and increase the acidity of the hydrogen
on the alpha carbon.
The oxygen is able to accommodate a
negative charge.
 Organic Pharmacy
Aldehyde/ketone reactions:

Usually aldehydes are more reactive to

nucleophilic addition than ketones due to both
steric and electronic effects.
steric hindrance is less in aldehydes than
in ketones; aldehydes (H and R), ketones (R
and R’).
Electronically, aldehydes have one R to
provide electrons to the partially positive C,
ketones have two.
 Organic Pharmacy
Aldehyde/ketone reactions:

REVERSIBLE addition of:

Water
Alcohol (hemiacetal/acetal formation)
Ammonia derivatives
Hydrogen cyanide

IRREVERSIBLE addition of:

Organometallic compounds
Cannizaro reaction
 Organic Pharmacy
Aldehyde/ketone reactions:

REDUCTION
Catalytic reduction
Reduction by complex metal hydrides
Reduction to hydrocarbons: Clemmensen and
Wolff-Kishner reduction

OXIDATION
Aldehydes to carboxylic acids
Tollen’s reagent for aldehydes
Haloform reaction on methyl ketones
 Organic Pharmacy
Aldehyde/ketone reactions: addition of water

1. acid as a catalyzer
2. formation of an oxygen cation (oxonium
ion) O+
3. release of H+ and of the instable product

Formation of
hydrates
which are
not stable
 Organic Pharmacy
Aldehyde/ketone reactions: addition of alcohol

Acetal and hemiacetal formation.

 Organic Pharmacy
Aldehyde/ketone reactions: addition of alcohol
 Organic Pharmacy
Aldehyde/ketone reactions: addition of ammonia
derivatives (1º amines)

R2C=O + GNH2

GNH–(R2)C–O–H

R2C=NG + H2O
 Organic Pharmacy
Aldehyde/ketone reactions: addition of ammonia
derivatives (1º amines)

H2N-G could be:

H2N-OH: hydroxylamine oxime

H2N-NH2: hydrazine hydrazone
H2N-NHC6H5: phenylhydrazine phenylhydrazone
H2N-NHCONH2: semicarbazide semicarbazone
 Organic Pharmacy
Aldehyde/ketone reactions: addition of ammonia
derivatives (1º amines)
 Organic Pharmacy
Aldehyde/ketone reactions: addition of cyanide

Cyanohydrine formation: addition of hydrogen

cyanide HCN

RCH=O + H–C≡N RCH(OH)CN(cyanohydrin)

 Organic Pharmacy
Aldehyde/ketone reactions: addition of
organometallic compounds

Formaldehyde primary alcohol

Aldehyde secondary alcohol
Ketone tertiary alcohol
 Organic Pharmacy
Aldehyde/ketone reactions: addition of
organometallic compounds
 Organic Pharmacy
Aldehyde/ketone reactions: Cannizzaro reaction

Cannizzaro reaction: disproportionation of

an aldehyde with no αH in carboxylic acid and
alcohol under the influence of a base.
 Organic Pharmacy
Aldehyde/ketone reactions:

REDUCTION / OXIDATION:
Reduction to alcohol by catalytic
hydrogenation or by using reducing agent
(LiAlH4, NaBH4) and reduction to
hydrocarbons by Clemmensen and Wolff-
Kishner reduction.

Oxidation to acids by KMnO4, K2Cr2O7

and Tollen’s reagent for aldehydes and haloform
reactions on methyl ketones.
 Organic Pharmacy
Aldehyde/ketone reactions:

REDUCTION TO ALCOHOLS:
+
H2 Ni, Pt or Pd

C O C OH

LiAlH4 or NaBH4
+
then H
 Organic Pharmacy
Aldehyde/ketone reactions:

REDUCTION TO HYDROCARBONS:
Clemmensen reduction: amalgamated Zinc in
acidic medium

Wolff-Kishner: hydrazine in basic medium

 Organic Pharmacy
Aldehyde/ketone reactions:

OXIDATION:
Aldehydes:

Tollen’s reagent
Reaction of aldehydes with silver ion to release
acid and and free silver (silver mirror).
 Organic Pharmacy
Aldehyde/ketone reactions:

OXIDATION: ketones generally do not go easily further

oxidation
Haloform reaction of methylketones:
OH-
R-CO-CH3 + X2 → RCOO− + CHX3 + 2OH-
X2 + OH− → XO− + X− + H+ (X = Cl, Br, I)
R-CO-CH3 + 3 OX- → RCOO− + CHX3 + 2OH-

(1) R-CO-CH3 + 3 OX- → R-CO-CX3 + 3 OH−

(2) R-CO-CX3 + OH− → RCOOH + −CX3
(3) RCOOH + −CX3 → RCOO− + CHX3
 Organic Pharmacy
Aldehyde/ketone reactions:

REACTION ON THE α-H OF THE α-C:

The carbonyl activate the carbon-hydrogen

bond nearby.
α hydrogens (H on the αC) can react with
base or acid and give the enol form.
The unusual acidity of α hydrogens can be
explained by both the electron withdrawing
ability of the carbonyl group and resonance
in the anion that forms.
 Organic Pharmacy
Aldehyde/ketone reactions:

REACTION ON THE α-H OF THE α-C:

 Organic Pharmacy
Aldehyde/ketone reactions:

REACTION ON THE α-H OF THE α-C:

The anion formed by the loss of an α hydrogen can be

stabilized by resonance to form the enol or enolate
(anion form).

keto Carbanion: carbon wich gain e- enolate

 Organic Pharmacy
Aldehyde/ketone reactions:

REACTION ON THE α-H OF THE α-C:

 Organic Pharmacy
Aldehyde/ketone reactions:

REACTION ON THE α-H OF THE α-C:

Haloform reaction (iodoform test for methyl

ketone)
Halogenation of ketones: substitution reaction
Aldol condensation : addition reaction
 Organic Pharmacy
Aldehyde/ketone reactions on the α-C: haloform

Haloform (trihalomethane) reaction of

methylketones: OH-
R-CO-CH3 + X2 → RCOO− + CHX3 + 2OH-
hypohalite
X2 + OH− → XO− + X− + H+ (X = Cl, Br, I)
R-CO-CH3 + 3 OX- → RCOO− + CHX3 + 2OH-

(1) R-CO-CH3 + 3 OX- → R-CO-CX3 + 3 OH−

(2) R-CO-CX3 + OH− → RCOOH + −CX3

(3) RCOOH + −CX3 → RCOO− + CHX3

 Organic Pharmacy
Aldehyde/ketone reactions: halogenation of ketones

Acid or base catalyzed: formation of an α-

haloketone.

X2
C C C C + HX
H+ or OH - O
H O X

alpha haloketone
 Organic Pharmacy
Aldehyde/ketone reactions: halogenation of ketones

Electrophilic substitution of an alpha hydrogen by

bromine (acid catalyzed, intermediate is enol).
 Organic Pharmacy
Aldehyde/ketone reactions: halogenation of ketones

Electrophilic substitution of an alpha hydrogen by

bromine (base catalyzed, intermediate is enolate).
 Organic Pharmacy
Aldehyde/ketone reactions: ALDOL CONDENSATION

Reaction in which an enolate/enol reacts

with a carbonyl compound to form a β-
hydroxyketone or β-hydroxyaldehyde (Aldol
product), followed by dehydration to give a
conjugated enone (or alkenal).
 Organic Pharmacy
Aldehyde/ketone reactions: ALDOL CONDENSATION
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION:
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION:

nucleophile
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION:
Addition of the enolate (or enol=nucleophile)
on the carbonyl (or protonated carbonyl).
Important reaction because it can be used to
construct new C-C bonds.
Carbonyl compounds without alpha
hydrogen can not form enolate/enol form, then
they will not undergo aldol reaction.
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION: the most simple with

ethanal (acetaldehyde)
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION:
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

ALDOL REACTION:
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

CROSSED ALDOL REACTION:

An aldol reaction between two different
carbonyl compounds is a crossed aldol reaction.
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation

CONDENSATION ON ALDOL PRODUCTS:

A condensation reaction is a reaction in which
water or another small molecule (methanol) is
formed by reaction between two organic
molecule
Formation of a double bond between the alpha
and beta carbon.
 Organic Pharmacy
Aldehyde/ketone reactions: aldol condensation
Organic Pharmacy

ALDEHYDES
KETONES
PREPARATION
 Organic Pharmacy
Aldehydes preparation:

• Oxidation reactions:
oxidation of primary alcohols: aliphatic
aldehydes
oxidation of methylbenzene: aromatic
aldehydes

• Reduction reaction:
Reduction of acid/acyl chlorides (aliphatic
or aromatic)
 Organic Pharmacy
Ketones preparation:

• Aliphatic ketones:
oxidation of secondary alcohols
reaction between an acid/acyl chloride with
an organocopper compounds

• Aromatic ketones: Ar-CO-R or Ar-CO-Ar

reaction between an acid/acyl chloride and
an organocopper compounds
Friedel-Crafts acylation (no rearrangement)
 Organic Pharmacy
Aldehydes preparation:

For both aldehydes and ketones preparation, an

important material is the acid or acyl chlorid.

O
R C
Cl

Obtained by reaction of an carboxylic acid

RCOOH with SOCl2, PCl3 or PCl5.
 Organic Pharmacy
Aldehydes / ketones preparation:

Alcohol
R’
Primary: RCH2-OH Secondary: R-CH-OH
oxidation

Aldehydes Ketones
 Organic Pharmacy
Aldehydes / ketones preparation:

Ketones
+ organocopper
compounds

(Ar or R) Acyl chloride

+ Ar-H (Friedel-
Reduction
Crafts acylation)

Aldehydes Ketones
 Organic Pharmacy
Aldehydes preparation:

Pyridinium chlorochromate PCC is a

reddish orange solid reagent used to oxidize
primary alcohols to aldehydes and secondary
alcohols to ketones.
 Organic Pharmacy
Ketones preparation: Friedel-Crafts acylation
Organic Pharmacy

BACK-UP
 Organic Pharmacy
Aldehydes preparation:

alcohol

oxidation R-CH2OH
R-CHO
R-COOH R-COCl
Acid/Acyl chlorid
reduction

oxidation Ar-CH3
Ar-CHO
Ar-COOH Ar-COCl
Aromatic acid/acyl chlorid

reduction
 Organic Pharmacy
Aldehydes preparation:

Oxidation of primary alcohol:

1-butanol butanal (n-butyraldehyde)

Pyridinium
chlorochromate

Oxidation of aromatic compounds:

methylbenzene
Cl2, heat Ar-CHCl2 H2O

Ar-CH3 Ar-CHO
CrO3 Ar-CH(OAc)2 H2O
Acetic anhydre
 Organic Pharmacy
Ketones preparation:

R-CH-R’
OH
R-C-R’
RCOOH RCOCl O
R2’-CuLi
 Organic Pharmacy
Ketones preparation:

Ar-H
RCOCl / Ar’COCl, AlCl3

Ar-C-R’
Ar-Br Ar-Li Ar2-CuLi O
RCOCl / Ar’COCl
Ar-C-Ar’
Ar-COOH Ar-COCl O
R2’-CuLi / Ar2CuLi