Biological ChemistryFIRST YEAR ORGANIC CHEMISTRY

Lecture Five

Aromatics, Heterocycles

Amines and Alkaloids

Convenor : Dr. Fawaz Aldabbagh

BenzeneC

CC

C

CC

H

H

H

H

HH

An Aromatic Hydrocarbon is a cyclic compound that does not readily undergo addition reactions Reactivity is different to other unsaturated compounds-Substitution rather than Addition is favoured.

C6H6

Resonance Structure- Rearrange the bonding electrons

Delocalised or Conjugated System – -bonding electrons can move within the molecule

Delocalisation, Resonance-Stabilise molecules, so make them less reactive

High Carbon content – burn with a smoky flame

In aromatic compounds the C atoms are sp2 hybrids, so that each C atom has one remaining p-electron involved in -bonding

C

CC

C

CC

H

H

H

H

HH

Kekul said that he dreamt the structure of benzene – so called Kekul structure of benzene

Three sp2 hybrid orbitals arrange themselves as far apart as possible - which is at 120° to each other in a plane. The remaining p orbital is at right angles to them.

Each carbon atom uses the sp2 hybrids to form sigma bonds with two other carbons and one hydrogen atom.

Each carbon atom uses the sp2 hybrids to form -bonds with two other carbons and one hydrogen atom.

This extensive sideways overlap produces a system of -bonds which are spread out over the whole carbon ring. Because the electrons are no longer held between just two carbon atoms, but are spread over the whole ring, the electrons are said to be delocalised.

= Flat (Planar) MoleculeRegular Hexagon

-Electron Density Rings above and below the plane of the ring – Susceptible to electrophilic attack

Benzene is a colourless odourless liquid that is a suspected carcinogenBenzene and its derivatives are

said to be aromatic - a term coined because of the strong fragrance of some of the derivatives of benzene

Non-aromatic compounds are said to be aliphatic

Michael Faraday first isolated benzene in 1825

Electrophilic Aromatic SubstitutionH

H

H

H

H

H

E

H

H

H

H

HE X+ H X

E EH

EH

EH

Electrophilic attack – Slow Rate Determining Step

E

H

sp3

Delocalised Cyclohexadienyl cation

Transition State

Loss of a proton – fast step

EH

E

Hor

fast E

- H+

Sir Christopher Ingold's ideas (1930s), terminology and nomenclature for reaction mechanisms (e.g. electrophilic, nucleophilic, inductive, mesomeric, SN1, SN2 etc) were generally accepted and employed everywhere.

e.g. The Nitration of benzene

HNO3(c), H2SO4(c)NO2

NO2

H

NO2 NO2

Nitrobenzene

Mechanism

Friedel-Crafts Alkylation

RX+AlCl3 or FeCl3 R

+ HX

Lewis Acid Catalyst is used to activate the alkyl halideA catalyst is usually a molecule which speeds up a reaction, and is required in only a small amount.It is regenerated at the end of the reaction

Friedl-Crafts Alkylation

CH3CH2Cl +AlCl3

CH2CH3

AlCl4

H

CH2CH3H

Al Cl

Cl

Cl

ClCH2CH3

+ HCl

+ AlCl3

Professor Charles Friedeland Professor James Crafts

Cl

BrBr2, FeBr3

Cl2, AlCl3

HALOGENATION

BrFeBr4Br Br FeBr3 H +

The Halogen is polarised

Naming Aromatic HydrocarbonsF CH2CH3 CH3 NH2

OH COH

OCl

Cl

Cl

Cl

Cl

Cl

CH3

NO2

NO2

CH3

CH3O2N

Br

Fluorobenzene

EthylbenzeneToluene Aniline

Phenol

Benzoic Acid1,2-Dichlorobenzene1,3-Dichlorobenzene

-meta

-ortho

-para

1,4-Dichlorobenzene 2,4,6-Trinitrotoluene (TNT)

o-Xylene m-Bromostyrene

1. Must be cyclic 2. Must be planar 3. Each atom of the ring must have a p orbital and these p orbitals must

be perpendicular to the plane of the ring 4. Must contain 4n+2 electrons (where n = 0, 1, 2, ...) –Hückel Rule

Rules for Aromaticity

Naphthalene Anthracene Phenanthrene

n = 1 , 6electrons

10 -electrons 14 -electrons

sp3-carbon NOT Aromatic 6electrons

HETEROCYCLES

N N

H

N

N

H

N

N

S N

H

PyridinePyrrole Imidazole

PyrimidineThiophene

Indole

ALL ARE AROMATIC1. Planar2. Uninterrupted Cycle of p-

orbitals3. All Atoms are sp2 hybridized4. Obey Hückel’s Rule

Most Pharmaceutical compounds are Heterocycles and derivatives

Aromatics with one non-carbon or Heteroatom

N atom in Pyridine, one of the N atoms in Imidazole and both N atoms in Pyrimidine possess a basic lone pair of electrons

Amines are organic bases

H N H

H

R N H

H

R N H

R

R N R

R

Ammonia Primary (1o) Amine

Secondary (2o) Amine Tertiary (3o) Amine

NH2

H Cl

N

H

H

H Cl

Base + Acid = Ammonium Salt

NH Cl

N H Cl

Pyridinium Salt

Aromatic Amine

Aliphatic AminesH2N

NH2

Putrescine(found in decaying meat) NH2

Amphetamine(dangerous stimulant)

N

H Piperidine

N

Triethylamine NH2

Isopropylamine

Alkaloids

Extractions from bark, leaves, berries and fruits yields nitrogen containing bases called alkaloidsName comes from “alkali or base-like” – most react with acids to give soluble salts.Common ending ine, reflecting the fact they are all amines. The names are all non-systematic.Most produce striking physiological effects that vary from alkaloid to alkaloid.

N

N

CH3H

NicotineN

C

O

OH

Nicotinic Acid

small doses its a stimulantlarger doses its a poisonNicotine salts are insecticides

incoperated into NAD+

nicotinamide adenine dinucleotide

N

HH

CH2CH2CH3

Coniine (conium maculatum)poison from hemlock

N

H3C

HOC

O

CPh

H

HOH2C

AtropineIntense Poison0.5-1% solutions are used to dilute the pupilsderivatives used against the common-cold

N

H3C

OH

Cocainesmall doses - stimulantcauses physical addiction and depressionwas used medically as an anesthetic

C

O

Ph

H

OOCH3

Erythroxylum coca1% is cocaine

Professor Marshall Gates – In 1952First Synthesis + Conformation of the structure of morphine

Papaver somniferum (opium poppy)

N

Isoquinoline

N

H3CO

H3CO

H3CO

H3CO

Papaverine

O

HO

RO

NH

H

CH3

Morphine, R = HCodeine, R = CH3

Morphine is a potent analgesicUsed in medicine to relieve “deep” painAddiction + depression + respiratory falure

Alkaloids containing Indole or Reduced Indole Ring

N

O

O

N

H

H

H

H

HN

CH2 N

CH3

CH3

H

GramineStrychnine

Strychnos nuxvomica

Death results from paralysis of the respiratory muscles

Small doses stimulate the respiratory centre, larger doses paralyse it. Juice of the fresh bark is used in cholera and dysentery. The dried bark is given either as a decoction or as a paste. A poultice made of leaves is used for chronic ulcers. The seeds boiled in milk, are pounded into a paste and given to opium addicts: this is believed to be effective in curing addiction