Pharmaceutical Organic Chemistry (PHC 112)

Dr. Minhajul Arfeen

(Assistant Professor)
College of Pharmacy, Qassim University
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Objectives
➢ To develop the understanding of various functional groups
➢ To develop the understanding of various organic reactions and their
Mechanisms
Evaluation methods:
➢ 50 points-(1 Midterm of 20 point each + 20 points for practical + 10
Points for Quiz)
➢ 50 points- Final Exam
Text Book(s):
➢ T.W. Graham Solomon, Organic Chemistry, John Wiley & Sons, Inc.
➢ Ralph J. Fessenden, Organic Chemistry, Brooks Cole.
➢ Ivor L. Finar, Organic Chemistry: The Fundamental Principles, John Wiley
& Sons
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 Course Contents
✓ Aldehydes and Ketones.
✓ Carboxylic Acids.
✓ Carboxylic Acid Derivatives.
✓ Aromatic Compounds (Aromaticity, El Electrophilic Substitution,
Nucleophilic Substitution, Ear And Orientation)
✓ Phenols.
✓ Aromatic Nitro And Related Compounds.
✓ Heterocyclic Chemistry (Antibiotics, Antiviral Agents, Antineoplastic
Agents, Immunotherapy)

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Aldehydes And Ketones

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Functional Groups

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 Structure and Physical Properties

● In aldehydes the carbonyl group is at the end of the carbon chain and so has at
least one hydrogen attached to it
● In ketones the carbonyl group is in the middle of a carbon chain and so has two
alkyl groups attached to it.
● A ketone in which the carbonyl group is attached to benzene is called phenone

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 Structure and Physical Properties
➢ Carbon is sp2 hybridized

➢ The part of the molecule immediately surrounding the carbonyl carbon is flat:
oxygen, carbonyl carbon and the two atoms directly attached to the carbonyl
carbon lie in a plane.
➢ C=O bond is shorter, stronger, and more polar than C=C bond in alkenes and
thus higher boiling point than non polar compounds of similar molecular Wt.
➢ Cannot H-bond to each other, so lower boiling point than comparable alcohol
➢ RCHO and RCOR with less than 5 carbons are soluble in water because of
intermolecular hydrogen bonding between water and solute (Aldehyde and
Ketone), freely soluble in organic solvents

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 IUPAC Nomenclature

1. Identify the longest carbon chain with the functional group of highest priority order
(parent+suffix)
2. Identify the position of the substituent's (prefix) and the position of functional
group
3. Number the carbons of the parent chain from the end that gives the substituents the
lowest numbers
4. If the same substituent occurs more than once, the location of each point on which
the substituent occurs is given.
5. Substituent's are listed in alphabetical order
6. In addition, the number of times the substituent group occurs is indicated by a
prefix (di, tri, tetra, etc.)

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 IUPAC Nomenclature (Aldehydes)

✓ Aldehydes are named using the suffix ‘al’ by replacing ‘e’ of the
corresponding alkane
✓ When two aldehyde functional groups are present, the suffix ‘dial’ is added to
the appropriate alkane name without replacing ‘e’
✓ When a formyl group (-CHO) is attached to a ring, the ring name is followed
by the suffix ‘carbaldehyde’
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 IUPAC Nomenclature (Ketones)

✓ Ketones are named using the suffix ‘one’ by replacing ‘e’ of the corresponding alkane
✓ The IUPAC also permits the naming of the ketones based on the functional class
nomenclature
✓ The groups attached to the carbonyl group are named as separate words followed by the
word ketone
✓ The groups are listed alphabaetically

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 IUPAC Nomenclature (Ketones)

✓ The term ‘oxo’ is used when a functional group of higher status (carboxylic acid, acid
anhydrides, ester, amide, acid hallides, nitriles) is present in the organic compound
containing aldehyde or ketone
✓ The suffix phenone indicates that the acyl group (RCO) is attached to the benzene ring

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General Methods for the Preparation

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1. Oxidation of alcohols in aqueous media

PCC or PDC, which are

used in dichloromethane,
allow the oxidation to be
stopped at the intermed-
iate aldehyde.

2. Oxidation alcohols in dichloromethane

✓ 1° alcohol + oxidation→ Aldehyde→ carboxylic acid

✓ 2° alcohol + oxidation→ Ketone,
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3. Ozonolysis

4. Treatment of Glycols with periodic acid

✓ 1,2- or vicinal diols are cleaved by periodic acid, HIO4, into two
carbonyl compounds.
✓ The reaction is selective for 1,2-diols
✓ The reaction occurs via the formation of a cyclic periodate ester
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5. Hydrolysis of Geminal Dihalides

5. Hydration of Alkynes

✓ Markovnikov Addition
✓ Anti-Markovnikov Addition

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5. From Acid Chlorides

✓ Reduction with Lithium tri-t-butoxyaluminum hydride

✓ Rosenmund Reduction

✓ Ketones can be prepared by the use of lithium dialkylcuprate (R2CuLi),

formed by the reaction of 2 moles of R-Li with cuprous iodide.

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6. Aldehydes from Esters and Amides

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7. Ketones via Friedel-Crafts Acylation

8. From Nitriles

9. Gatterman-Koch Formylation

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9. Synthesis Using 1,3-Dithiane
✓ Thioacetal formation from an aldehyde precursor
✓ Alkylation of the thioacetal intermediate using alkyl lithium reagents
✓ Hydrolysis of the alkylated thioacetal to give ketone product

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Characteristic Reactions of
Aldehydes and Ketones

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Characteristic Reactions of Aldehydes and Ketones
1. Oxidation reactions
2. Nucleophilic addition reactions
✓ Grignard additions to form alcohols
✓ Addition of water (hydration) to form gem-diols
✓ Addition of alcohols to form acetals/ketals
✓ Addition of HCN to form cyanohydrins
✓ Addition of ammonia and ammonia derivatives
3. Reduction reactions
✓Alcohol formation
✓Alkane formation

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Oxidation Reactions
✓CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids (acidic
conditions)

Tollens’ reagent Silver oxide, Ag2O, in aqueous ammonia oxidizes aldehydes

(basic conditions)

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Oxidation Reactions of Ketones
✓ Ketones Oxidize with Difficulty
✓ Undergo slow cleavage with hot,
alkaline KMnO4
✓ C–C bond next to C=O is broken to
give carboxylic acids
✓ Reaction is practical for cleaving
symmetrical ketones

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Oxidation Reactions of Methyl Ketones (Haloform Reaction)
✓ Characteristic reaction of methyl ketones
✓ Excessive halogenation takes place at the
methyl carbon in presence of base
✓ The haloform reaction is synthetically
useful as a means of converting methyl
ketones to carboxylic acids

Step I Step II

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Reduction Reaction
1. Alcohol formation
✓ Hydrogenation
✓ Hydride reduction

✓ Aldehydes and ketones can be hydrogenated to 1° and 2° alcohol

respectively in presence of hydrogen gas and metal catalyst ( Pt, Ni and Pd)

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 Hydride reduction

Mechanism

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Reduction Reaction of Carbonyl Compounds

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2. Alkane formation
Clemmensen reduction

✓ Clemmensen reduction is a chemical reaction described as a reduction of

ketones (or aldehydes) to alkanes using zinc amalgam and hydrochloric acid

Wolff-Kishner Reduction reaction

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Mechanism

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 Nucleophilic Addition Reactions
✓ Nu- approaches 75° to the plane of C=O and adds to ‘C’
✓ An electron pair from the nucleophile attacks electrophilc
carbonyl carbon, thus pushing an electron pair from the
C=O bond onto the oxygen atom resulting into the
formation of alkoxide ion intermediate.
✓ The hybridization state of carbonyl carbon changes from
sp2 to sp3
✓ Protonation of alkoxide ion resulting into the formation
neutral alcohol addition product

Negatively Charged Nucleophile Neutrel Charged Nucleophile

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Nucleophilic Addition Reactions (Variation)

Negatively Charged
Nucleophile

Neutrel Nucleophile

Nucleophilic addition under acidic condition (Weak Nucleophile)

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 Relative Reactivity of Aldehydes and Ketones
✓ Formaldehyde is more reactive than aldehydes followed by ketones towards
nucleophilic addition reactions
(i) Carbonyl carbon is more electrophilic in formaldehyde followed by
aldehydes and ketone due to the iductive effect of the alkyl groups
(ii) The transition state for addition is less crowded in formaldehyde followed by
aldehyde and ketone due to the alkyl group
(iii) Thus the transition state is lower in energy for formaldehyde followed
aldehyde and ketone respectively.

Decreasing order of electrophilicity for

carbonyl carbon TS, Aldehydes TS, Ketone
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 Relative Reactivity of Aromatic Aldehyde
(i) Aromatic Aldehydes Less reactive in nucleophilic addition reactions than
aliphatic aldehydes
(ii) Electron-donating resonance effect of aromatic ring makes C=O less
electrophilic and thus less reactive than the carbonyl group of an aliphatic
aldehyde

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 Nucleophilic Addition of Grignard Reagents
✓ Treatment of aldehydes or ketones with Grignard reagents yields an alcohol
✓ RMgX is called as Grignard reagent, R= Alky, vinyl and Aryl group, X=
hallogens
✓ Examples of Grignard reagent CH3MgBr, PhMgBr, CH2CHMgBr
✓ A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts
for all practical purposes as R : − MgX +
✓ A negatively charged carbon center is called as carbon anion or carbanion

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 Nucleophilic Addition of Grignard Reagents
✓ Reaction of grignard reagent
with formaldehyde leads to
the formation of primary
alcohol

✓ Reaction of aldehyeds with

grignard reagents lead to the
formation of secondary
alcohol

✓ Reaction of grignard reagent

with Ketones lead to tertiary
alcohol

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Nucleophilic Addition of Grignard Reagents

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Nucleophilic Addition of 1° and 2° Amine

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Imine Formation

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Imine Formation (General Mechanism)

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Nucleophilic Addition of Ammonia derivatives

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Enamine Formation (General Mechanism)

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Nucleophilic Addition of Alcohols: Formation of Acetals

✓ The alcohols attach to the carbonyl carbon of the aldehydes to form acetals
✓ The formation of acetal is acid catalyzed reaction and is reversible
✓ The steps in the formation of acetals are reversible in nature and thus acetals
can be hydrolyzed back to obtain aldehydes
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Formation of Acetals: Mechanism

✓ Cyclic acetals is favored

when a ketone or an
aldehyde is treated with
excess of 1,2-diol and a
trace of acid
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Nucleophilic Addition of Phosphorus Ylides:
The Wittig Reaction
✓ The aldehyde and ketones react with Phosphorus Ylides to yield alkene and
triphenyl phosphine oxide (a by-product). The reaction is known as Wittig
reaction.
✓ The Wittig reaction is important for the synthesis of Alkenes
✓ The ylide required in the reaction has no net negative charge, but acts as the
source of negative carbon atom, which reacts with carbonyl carbon atom of
aldehydes and ketones
✓ The phosphorus ylides is used in the Wittig reaction are also known as
Phosphoranes

An ylide or ylid (/ˈɪlɪd/ or /ˈɪlaɪd/) is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion)
directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur)

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The Wittig Reaction:
Mechanism

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The Wittig Reaction: Mechanism

Cannizzaro Reaction
✓ Aldehydes that have no α-hydrogen, undergo an intermolecular oxidation-
reduction (disproportionation reaction) called the cannizaro reaction, when
they are treated with concentrated base

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Cannizzaro Reaction (Mechanism)

Aldol Reaction
✓ In presence of dilute base or acid, two molecules of aldehyde or ketones
combine tor form β-hydroxy aldehyde or β-hydroxy ketone. This reaction is
called as Aldol Condensation reaction
✓ Shown by aldehydes and ketones with α-
hydrogen atom

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Aldol Reaction (Mechanism)

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Cross Aldol Reaction
✓ In a crossed aldol reaction, two
different aldehydes and ketones are
used.

Dehydration of Aldol Product

✓ The β-hydroxy aldehyde or ketone undergo dehydration on heating to form the
carbon carbon double bond between α and β-carbon atoms (enone )

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Dehydration of Aldol Product (Mechanism)

Acid catalyzed Aldol Condensations

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Acid catalyzed Aldol Condensations (Mechanism)

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Reformatsky Reaction
✓ Aldehyde or ketone is treated with α-halo ester in presence of zinc to obtain β-
hydroxy ester is known as Reformatsky reaction

Mechanism

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Nucleophilic Addition of HCN: Cyanohydrin Formation
✓ Aldehydes and unhindered ketones react with HCN to yield cyanohydrins,
RCH(OH)C≡N
✓ Addition of HCN is reversible and base-catalyzed, generating nucleophilic
cyanide ion, CN-

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Uses of Cynohydrins

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Addition of Bisulfite

Bisulfite

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Thank You

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