(23) session 23 heterocyclic compounds (self-study!)

5/2/2012

1

Session 23

Organic Chemistry, UNAM School of Medicine1

Heterocyclic CompoundsHeterocyclic CompoundsHeterocyclic CompoundsHeterocyclic Compounds

Dr L.H.A. Prins (Ph.D.)

Dept. of Pharmacy

UNAM

Learning Outcomes

2

� By the end of this session, the student should be able to:

�Understand the importance of heterocyclic compounds

�Recognise & name selected heterocyclic compounds

�Describe the structure of heterocyclic compounds

�Describe some chemical properties of heterocyclic

compounds

Organic Chemistry, UNAM School of Medicine

5/2/2012

2

Definitions??Definitions??Definitions??Definitions??

3

� Heterocycles = Ring compounds with elements other than C in

the ring

- Most common elements to appear in heterocyclic compounds:

oxygen (O), nitrogen (N) & sulphur (S)

- Aliphatic heterocycles are similar to the open chain

analogues (ethers, amines & sulphides)

- Unsaturated heterocycles have unique & interesting properties


Importance??Importance??Importance??Importance??

4

� Two thirds of all organic compounds are aromatic heterocycles.

Most pharmaceuticals are heterocycles.

�Quinine & sildenafil: Examples of heterocycles used as

pharmaceuticals


Quinine

Pfizer: Viagra ®

Treatment of malaria for 400 years Erectile dysfunction

Sildenafil

5/2/2012

3

Importance??Importance??Importance??Importance??

5 Organic Chemistry, UNAM School of Medicine

N

N

Me

N NHMe

NNC

H

H

Ovarian & lung cancer

GSK - TopotecanPfizer - Irinotecan

Treating stomach & intestinal ulcers

Cimetidine

Definitions??Definitions??Definitions??Definitions??

6

� Natural product = Compound synthesised by a plant or an

animal

� Alkaloids = Natural products that contain one or more N

heteroatoms


5/2/2012

4

Nomenclature of Nomenclature of Nomenclature of Nomenclature of heterocyclesheterocyclesheterocyclesheterocycles

7

� Saturated cyclic amine - named as a cycloalkane, using the prefix “aza” to denote the N atom- Heterocyclic rings are numbered so that the heteroatom has

lowest possible #- Some common names are acceptable according to IUPAC

� Examples:



8

� Saturated heterocycles:- Heterocycles with O & S heteroatoms are named similarly

- Prefix for O is “oxa” - Prefix for S is “thia”

• Examples:


5/2/2012

5


9

� Saturated heterocycles:

- Lowest # assigned to heteroatom with the highest precedence:

O > S > N

• Example:



10

� Heterocyclic names you should know:


5/2/2012

6


11




12



5/2/2012

7


13




14



5/2/2012

8

6666----membered membered membered membered heterocyclesheterocyclesheterocyclesheterocycles: Pyridine: Pyridine: Pyridine: Pyridine


N NH

pyridine piperidine

In pyridine the CH of benzene is replaced by a N at om (& a pair of electrons)

Hybridisation = sp 2 with similar resonance stabilisation as benzene

Lone pair of electrons not involved in aromaticity

Pyridine is a weak base

Pyridine is ππππ electron deficient

Electrophilic aromatic substitution is difficult

Nucleophilic aromatic substitution is easy

6666----membered membered membered membered heterocyclesheterocyclesheterocyclesheterocycles: Pyridine: Pyridine: Pyridine: Pyridine


Pyridine (p Ka = 5 .25) is a weaker base than alkylamines

Reason: Lone-pair e - on pyridine N are in an sp 2 orbital, while those on alkylamine

N are in an sp 3 orbital

Because s orbitals have maximum e - density at the nucleus but p orbitals have a

node at the nucleus, e- in an orbital with more s character are held more cl osely

to the + charged nucleus & are less available for b onding ( ∴∴∴∴ less basic)

sp2 hybridised N atom (33% s character) in pyridine is less basic than sp3 hybridised N

in analkylamine (25% s character )

5/2/2012

9

5555----membered membered membered membered heterocyclesheterocyclesheterocyclesheterocycles: : : : PyrrolePyrrolePyrrolePyrrole


Pyrrole is aromatic: 6 ππππ electrons

Lone pair tied up in aromatic ring

Pyrrole is ππππ electron excessive

Electrophilic aromatic substitution is easy

Nucleophilic aromatic substitution is difficult



N atom in pyrrole is less e - rich, less basic & less nucleophilic than N in

an aliphatic amine

C atoms of pyrrole are more e - rich & more nucleophilic than typical =

bond C’s

∴∴∴∴ Pyrrole ring – very reactive toward electrophiles

5/2/2012

10



Electrostatic potential maps – pyrrole N is e- poor (less red) compared

with N in its saturated counterpart pyrrolidine

Pyrrole C atoms are e- rich (more red ) compared with C’s in 1,3-

cyclopentadiene

5555----membered membered membered membered heterocyclesheterocyclesheterocyclesheterocycles with 2 or more with 2 or more with 2 or more with 2 or more

NitrogensNitrogensNitrogensNitrogens


Diazoles

ImidazolePyrazole

Triazoles

NN

N

H

NN

NH

N

NN

H

N

NN

H

1,2,3-Triazole1,2,4-Triazole

pKa = 10.3

pKa = 14.5(imidazole)pKa = 16.5 (pyrrole)

Imidazole is more basic than pyridine,

but more acidic than pyrrole

Weakly basic like pyridine, but more acidic than imidazole

5/2/2012

11

5555----membered membered membered membered heterocyclesheterocyclesheterocyclesheterocycles with 2 or more with 2 or more with 2 or more with 2 or more

NitrogensNitrogensNitrogensNitrogens


Tetrazoles

NN

NN

H

RN

N

NNH

R

NN

NN

H

RN

N

NN

R NN

NN

R_

_

etc

pKa ~ 5 ~ RCOOH

Polycyclic Polycyclic Polycyclic Polycyclic heterocyclesheterocyclesheterocyclesheterocycles: : : : IndoleIndoleIndoleIndole


Indole is aromatic: 10 ππππ electronsHas a non-basic, pyrrole-like N & undergoes electro philicsubstitution more easily than benzeneBenzene part is non-reactiveElectrophilic aromatic substitution occurs at C3 of the e - richpyrrole ring

N

H

Indole

5/2/2012

12

Polycyclic Polycyclic Polycyclic Polycyclic heterocyclesheterocyclesheterocyclesheterocycles: : : : IndoleIndoleIndoleIndole


Quinoline & isoquinoline are aromatic: 10 ππππ electrons

Have basic, pyridine-like N atoms

Undergo electrophilic substitutions, although less easily than

benzene

Reaction occurs on the benzene ring rather than on t he

pyridine ring

Quiz: Heterocycles

Review of General Chemistry, UNAM School of Medicine24

� Which N atom in the hallucinogenic indole alkaloid, N,N-

dimethyltryptamine is more basic? Explain.

5/2/2012

13

Thank you

25

END



�Quiz answer:

� The side-chain N atom of N,N-dimethyltryptamine is more basic

than the ring N atom because its lone pair electrons is more

available for donation to a Lewis acid.

� The aromatic N lone pair electrons is part of the ring π electron

system.

5/2/2012

14


� Additional reading on aromaticity:

� Organic Chemistry, John McMurry (7th Ed)

� Sections 15.3 – 15.5

� Page 523 - 530

Health & Medicine

(23) session 23 heterocyclic compounds (self-study!)