Isoquinoline is a heterocyclic aromatic organic compound that is a structural isomer of quinoline. It consists of a benzene ring fused to a pyridine ring. Isoquinoline derivatives have many pharmaceutical applications including use as antispasmodics, antitussives, anesthetics, and in the production of morphine and related alkaloids. Isoquinoline can be prepared through the Bischler-Napieralski synthesis which involves the condensation and rearrangement of 2-phenylethylamine or through the reaction of cinnamaldehyde with hydroxylamine. Isoquinoline undergoes electrophilic aromatic substitution, oxidation, and reduction reactions.

1. Isoquinoline
Course Title: Organic Pharmacy –II
Course Code: PHARM-1203

2. Contents
1. Description
2. Structure
3. Resonance
4. Preparation
5. Properties
6. Some important chemical reactions
7. Applications of isoquinoline and its derivatives

3. Description:
 Isoquinoline is a heterocyclic aromatic organic compound.
It is a structural isomer of quinoline. Isoquinoline is
benzopyridine, which is composed of a benzene ring fused
to a pyridine ring(β and 𝛾 positions).
In a broader sense, the term isoquinoline is used to make
reference to isoquinoline derivatives. 1-Benzylisoquinoline
is the structural backbone in naturally occurring alkaloids
including papaverine,morphine.
Isoquinoline is one of the very few heterocyclic compounds
in which numbering starts adjacent to benzene ring.
Isoquinoline
Here we can observe that the hetero atom nitrogen is second possition but actually according to the nomencleature of heterocyclic compound . The num
of heterocyclic compound can be started that hetero atom.but here it is exceptional case in consideration of the numbering system of the quinoline here a
numbering system which is given like that and this is some what exceptional case .sothat the nitrogen position is 2nd
Papaverine is an opium alkaloids antispasmodic drug used primarily in the treatment of
visceral spasm and vasospasm and occasionally in the treatment of erevtile dysfunction…
used in the of acute mesenteric…C20H21NO4
Morphine is a pain
medication of
opiate family that is
found naturally in a
dark brown.
Resinous form.
From the poppy
plant
C17 H19NO3
C16H13N

4. Structure:
 In isoquinoline all ring atoms (9 carbons and 1 nitrogen) are SP2 hybridized.
 Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ-
bonds.
 The third SP2 orbital on each carbon atom overlaps with an S orbital of hydrogen and
forms C-H sigma bonds. The third SP orbital of nitrogen is occupied by the nitrogen
lone pair of electrons.
 Each ring atom possess one unhybridized p-orbital containing one electron and those
are perpendicular to the plane containing the σ-bonds. Overlap of these p-orbitals
produces delocalized n-molecular orbital containing σ electrons.
Sigma bond are the strongest type of covalent chemical bond .
They are formed by head on overlaping between atomic
orbitals.
Hybridization is the idea that atomic orbital fuse to form newly hybridized o
which is turn influence molecular geometry and bonding properties
Lone pair reffers to a pair of valence electron that are not shared with another atom in a covalent
bond and sometimes called unshared shared pair or non bonding pair
Delocalization happens when electric charge is spread over more than one atom. Example : bonding
electron may be distributed among severals atom that are bonded together.

5.  Overlap of p orbitals produces delocalized π-molecular orbital containing
10 electrons.
 Isoquinoline shows aromatic properties because the resulting molecular
orbital satisfies the Huckle's rule (4n+2 rule).
 The nitrogen lone pair is not released into the aromatic system because it
is perpendicular to the π system. The nitrogen withdraws electrons by
resonance, resulting in an electron-deficient ring system.
The cyclic pi molecular orbital formed by overlap
p- orbitals must contain (4n+2)pi electron where
n=0.1.2.3.4.5.6….etc. this known as huckel rule.

6. Resonance:
 In the structure of isoquinoline , we can observe that carbon atom is less
electronegative than Nitrogen. So Nitrogen will attract the bond electron
from carbon. So isoquinoline is meta determiner because it decreases
electron density from meta position and in this process electron density
increase at the ortho and para position. So the orientation and resonance
structure of isoquinoline is meta determiner.

7. Preparation:
Bischler-Bapieralski Synththesis:
In this reaction, 2-phenylethylamine is first treated with formyl chloride in the presence of a
base to form N-formyl-2-phenylethylamine. This amide is next heated with phosphorous
pentoxide in pyridine to give 3,4-dihydroisoquinoline which is on oxidation (dehydrogenation)
with palladium or selenium yields isoquinoline.
9H and 8pi
electron
7H and 10pi
electron
Dehydrogenation is the
process by which hydrogen
is removed from an organic
compound to form a new
chemical (to convert
saturated into unsaturated
compounds). It is used to
produce aldehydes and
ketones by
the dehydrogenation of
alcohols.

8.  From Cinnamaldehyde: C6H5CH=CHCHO
This involves condensation of cinnamaldehyde with hydroxylamine to form
the corresponding Oxime. The oxime is then heated wih phosphorus
pentoxide to yield isoquinoline. It is believed that the oxime first undergoes
rearangement which is then followed by ring closure.
An oxime is a chemical compound belonging to
imines with general formula RR; =NOH.. Where R
organic side chain and R; maybe hydrogen . Form
aldoxime or another organic group forming a keto
A rearrangement reaction is broad class of organic reaction where the carbon sketelon of a molecule is
rearranged to give a structural isomer of the orginal molecule.often a substitution moves from one atom
to another atom in the same molecule.

9. Properties:
Isoquinoline is a colorless solid or liquid, mp 23ºC, bp 243ºC. It is
weak base in nature. It is insoluble in water and soluble in most
organic solvents.
Chemical Reactions:
1. Oxidation: On oxidation with permanganate, isoquinoline forms
phthalic(C8H6O4) acid and 3,4-pyridinedicarboxylic acid(cinchomeronic
acid).
Pthalic acid mainly in the form of the
anhydride to produce other chemicals
such as dyes, perfumes, saccharin,
phthalates and many other useful
products.

10. 2. Reduction reaction: Isoquinoline can also converted into 1,2-dihydroisoquinoline
or 1,2,3,4-tetrahydroisoquinoline with diethyl aluminium hydride and sodium
ethanol respectively.
Diethylaluminium hydride
9H
11H
9H

11. 3. Electrophilic Aromatic Substituition: This reaction occurs at the benzene ring at positions
5 and 8.

12. 4. Nucleophilic Substitution reaction: React with sodamide at high
temparature.
Sodium amide commonly ca
sodamide (systematic name so
azanide.) it is a salt compose
sodium ion cation and azan
anion33
Nucleophilic attack take place at possition 1 as it is the only possition which yield a resonance structure in
which the aromatic sixet is presented and nitrogen carries a negative charge.
Chichibabikn
reaction

13. Pharmaceutical Applications of
Isoquinoline and its derivatives:
Anti hyper
tension
Anesthetics Antiretroviral Vasodilators
Topical
Antiseptics
Antitussive
Antispasmodic
Disinfectant

14. Pharmaceutical Applications of
Isoquinoline and its derivatives:
1. Isoquinoline is widely used for the preparation of vanilla spice. This aromatic compound
finds applications in the pharmaceutical industry such as the manufacture of drugs for the
treatment and prevention of schistosomiasis and malaria.
2. Derivatives of isoquinoline like Curare alkaloids, Atracurium, Doxacurium, Mivacurium are
used as neuromuscular blocking agents.
3. Papaverine is used as antispasmodic agent on smooth muscles and as vasodilators.
4. Noscapine are used as antitussive (cough-suppressing agents).

15. 5. Morphine and the related alkaloids are morphinan isoquinoline drugs.
6. Florinated isoquinolines are important components in pharmaceuticals because of their
unique characteristics.
7. Isoquinoline is an important precursor for the discovery of chemicals and drugs.
8. Antihypertension agents, such as quinapril and debrisoquine are derived from 1,2,3,4-
tetrahydroisoquinoline.
9. Antiretroviral agents, such as saquinavir with an isoquinolyl functional group.
10. Dimethisoquin is one of the examples used as anesthetics.

16. Thank You