CHEM 10109

1
Introduction
CHEM 101/09
Organic Chemistry Origins of the Modern Science
and Structural Aspects
2
What is Chemistry?

• Chemistry Science
• investigation of substances of which matter is
  composed
• study of the elements and of their compounds
• investigation of phenomena of combination and
  change which these substances display
• study of chemical reactions.

Chemist a person trained in, and a practitioner
of, chemistry.
3
What is Chemistry? (cont.)
A chemist - alternative definition - dealer in
medical drugs and seller of medicinal goods -
authorized dispenser of medicine pharmacist
Pharmacy - 'chemist shop' i. the preparation and
dispensing of drugs ii. a pharmacist's
shop Greek 'pharmakeia' 'practice of the
druggist' 'pharmakon' 'drug'
Drug i. A medicinal substance, not necessarily a
pure organic compound may be a plant, or plant
or animal extract. ii. A narcotic, hallucinogen,
stimulant, especially one causing addiction, a
psychotropic substance not necessarily a pure
organic compound
The Canon of Medicine, Avicenna 1025
Oxford English Dictionary
4
What is Chemistry? (cont.)
Organic Chemistry

• Organic - the vital force of living
  organisms

• Ancient use of plants as medicines .
  herbal medicine .Chinese Traditional
  Medicine.

• Organic chemistry originates from the attempts
  to find out why plants possessed medicinal
  properties

• Organic compounds originally considered to be
  compounds from living organisms

5
Historical Overview
Plants and other natural substances since dawn of
history The Ancient World 2100 BC Sumerian
clay tablets- plant extracts, resins, or
spices. Egypt 1600-1550 BC Smith and Ebers
Papyri - 700 prescriptions 'requests for
divine intervention' to treat disease.
Recommended treatments Asthma mixture of herbs
heated on a brick so that the sufferer could
inhale the fumes Cancer A "tumor against the god
Xenus" recommendation - "do thou nothing there
against." Death 'Half an onion and the froth of
beer'!!
Ebers Papyrus
http//www.indiana.edu/ancmed/meso.HTM http//en
.wikipedia.org/wiki/Hieratic http//en.wikipedia.
org/wiki/Ebers_papyrus
6
Historical Overview (cont.)
Ancient Greece 750 BC 146 BC to 'Roman
Greece' 3 AD

• Egyptian remedies incorporated into Greek
  pharmacopoeia.
• Hippocrates (460-370 BC) 'Hippocratic Corpus'
  separated medicine from religion - disease not a
  punishment by gods due to environmental factors,
  diet, living habits concept of preventative
  medicine

• Dioscorides (40-90 AD) 'De Materia Medica' -
• 600 plants, 35 animal products, 90 minerals
• History of herbal science knowledge of herbal
  remedies used by Greeks, Romans, and other
  cultures of antiquity
• Remained in use until 1600.
• Influenced Arabian physicians, and practitioners
  in Renaissance Europe.

http//en.wikipedia.org/wiki/Ancient_Greece
7
Historical Overview (cont.)
Ancient Greece 750 BC 146 BC to 'Roman
Greece' 3 AD
Greek pharmacopoeia (cont.). Galen (129-199?
AD) worked as physician, performed surgery on
gladiators Physician for Marcus Aurelius, Roman
emperor

• 'Humoral' theory - 'internal cause' -
• excess or deficiency of any of the four 'humours'
  (blood,
• phlegm, black bile, yellow bile) countered by
  administration
• of herbs with 'opposing' properties - influenced
  medical
• thinking in Europe for the next 1600 years used
  as basis
• for medical curricula until 18th century..!!!!!

Herbal remedies nomenclature and usage to 16th
century in Europe influenced by Theophrastus,
Dioscorides almond oil, aloes, belladonna,
opium etc.
http//en.wikipedia.org/wiki/Ancient_Greece
http//histowiki.com/mediawiki/index.php/Galen
8
Historical Overview (cont.)
Arabia/Persia Incorporation of Greek and Roman
science into Arab practice. Later, Indian and
Chinese elements also incorporated.

• El-Razi (860-925) use of minerals - salts of
  copper, mercury, arsenic and gold.
• Abulcasis (936 - 1013) Spain - 'Liber
  Servitorus' - preparation of medicines by
  sublimation and distillation purification of
  minerals for medical applications - earliest
  reference to use of pure chemicals in therapy.
• Ibn Sina - Avicenna (980-1037) 'The
• Canon of Medicine'- contagious nature
• of infectious diseases use of
• quarantine, evidence-based medicine,
• clinical trials steam distillation to isolate
• essential oils

http//en.wikipedia.org/wiki/Avicenna
9
Historical Overview (cont.)
Post-Renaissance Europe Jewish physicians
reintroduce medical lore associated with
Dioscorides, Galen and contemporaries Paracels
us (1493-1541) challenges use of herbal
remedies - looks for chemical remedies, e.g.
based on antimony, gold and mercury,
('diseases from the stars') - toxicology - "All
things are poison and nothing is without
poison, only the dose permits something not
to be poisonous." Herbal remedies still
universally used.
10
Historical Overview (cont.)
China Traditional Chinese Medicine (TCM)
'Shen Nong' 3-5000 years ago - the
'beginning'.. the 'holy farmer' the
'inventor' of agriculture tested hundreds of
herbs and was poisoned 70 times a day! an
allegory of the origin of Chinese materia medica
by trial and error - 'Shen Nong Ben Cao
Jing 'Divine Farmer's Materia Medica' lists
various herbs e.g. rei shi, discovered by
Shennong, given grade and rarity ratings -
earliest Chinese pharmacopoeia medicines from
minerals, plants, and animals. Huang Di Nei
Jing ???? 'Yellow Emperor's Inner Canon of
Internal Medicine' - 300 BC - diagnosis and
treatment concepts used as basis of texts for
the following two millennia
??
?????
11
Historical Overview TCM
'Shen Nong Ben Cao Jing' ????? - 'The Divine
Farmers Materia Medica ' (probably compiled
about 300 BC-200 AD) effects of some 365
substances (252 from plants, 67 from animals, and
46 mineral substances) - classified into ranks-
- upper rank non toxic, can be taken as tonics
for long periods renshen (Panex ginseng),
gouqizi (Lycii chinense), liquorice
(Glycyrrhiza uralensis).
Lycii chinense
Panex ginseng
Glycyrrhiza uralensis
12
Historical Overview TCM (cont.)
'Shen Nong Ben Cao Jing' - ????? 'The Divine
Farmers Materia Medica ' classified into ranks
(cont.) - upper rank non toxic, can be taken
as tonics for long periods - middle rank dose
related toxicity, intended to treat the
sick mahuang (Ephedra sinicae), ganjiang
(ginger, Zingiberis officinalis) peonies,
cucumber etc. - low rank toxic chuanwu
(Aconiti carmichaeli), rhubarb, various fruits
Aconiti carmichaeli
Zingiberis officinalis
Ephedra sinicae
13
Historical Overview TCM (cont.)
'Tang Ben Cao' - 657-659 AD - most famous first
official pharmacopoeia written by medical experts
of Tang Dynasty (618-907) 'Ben Cao Gang Mu'-
????- 1596 - Li Shi Zhen - 30 years to complete,
1892 entries, 60 on plants 24 animals, and
minerals contains 11,000 prescriptions
Philosophy Body composed of two complementary
forces Yin and Yang - inseparable in the unit,
but separable in identity negative and positive,
moon and sun, weak and strong, cold and hot
etc. - in healthy state, Yin and Yang are in
dynamic equilibrium - imbalance leads to
disease. - logical to restore equilibrium of Yin
and Yang (cf. humoral theory!) TCM expresses
disease concepts in the context of symptoms
expressed by the whole body.
"The Chinese Materia Medica A Practical
English-Chinese Library of Traditional Chinese
Medicine", Publishing House of Shanghai
Collection of Traditional Chinese Medicine "The
English-Chinese Encyclopedia of Practical
Traditional Chinese Medicine Pharmacology of
Traditional Chinese Medical Formulae" Higher
Education Press Beijing, China.
14
Historical Overview TCM (cont.)
Philosophy (cont.) Drugs - cold, hot, warm and
cool - 'cold and cool' - zhimu (Anemarrhena
asphodeloides), huanglian (Coptidis chinensis),
huangbai (phellodendri amurensis) etc 'clear
away heat and toxic material' - treatment of hot
flushes, thirst, fast strong pulse. - 'warm and
hot' - fuzi (Aconiti carmichaeli), ganjiang
(Zingiberis officinalis) etc treatment of cold
feelings, cold extremities, pale looks, weak
pulse.
Anemarrhena asphodeloides
phellodendri amurensis
Coptidis chinensis
"The Chinese Materia Medica A Practical
English-Chinese Library of Traditional Chinese
Medicine", Publishing House of Shanghai
Collection of Traditional Chinese Medicine "The
English-Chinese Encyclopedia of Practical
Traditional Chinese Medicine Pharmacology of
Traditional Chinese Medical Formulae" Higher
Education Press Beijing, China.
15
Historical Overview TCM (cont.)

• Philosophy (cont.)
• Complex prescriptions
• 'emperor' or 'monarch' - the principle ingredient
  against the disease
• 'higher official' or 'minister' - auxilliary to
  increase effect of 'emperor'
• 'assistant' - relieves the minor symptoms or as
  an antidote
• 'guide' - transports the drug to the desired
  tissue or organ.
• Importance on drug interactions - the 'seven
  modes' describe the influence of one drug over
  the other by effects such as promoting,
  decreasing, inhibiting or eliminating activity or
  toxicity.

"The Chinese Materia Medica A Practical
English-Chinese Library of Traditional Chinese
Medicine", Publishing House of Shanghai
Collection of Traditional Chinese Medicine "The
English-Chinese Encyclopedia of Practical
Traditional Chinese Medicine Pharmacology of
Traditional Chinese Medical Formulae" Higher
Education Press Beijing, China.
16
Historical Overview (cont.)

• The Modern Era
• Realisation that active principles in plants
  may be due to chemical substances, and their
  actual isolation from medicinally-active plants
• The science of organic chemistry increasing
  availability of solvents , equipment etc.,
  ability to 'extract' active principles'
• - Scheele (1742-1786) isolation of tartaric,
  gallic, uric,
• lactic, citric and malic acids
• Modern organic chemistry ultimately used to
  demonstrate
• possible merit, or worthlessness, of many
  remedies

17
Historical Overview (cont.)
Morphine Opium - the dried latex of the opium
poppy, cultivation since neolithic times
4000 BC Sumerians images of euphoria the
flower of joy. 1300 BC Egyptians poppy
cultivation, widespread use. 330 BC Alexander
the Great brings opium to Persia, India. 300 BC
onwards Greeks, Romans, Muslin Empire -
sedative, soporific (anaesthetic?) Modern times
Persia, India, China, Europe, and the Americas
- 'recreational', sedative, anaesthetic. 1753
Linnaeus Papaver somniferum - 'sleep- inducing'
"Not poppy, nor mandragora, nor all the drowsy
syrups of the world, shall ever medicine thee to
that sweet sleep which thou owedst yesterday.
Ibid - Sc. 3. - Othello, Moor of Venice -
Shakespeare (1603)
18
Historical Overview. Morphine (cont.)
17th Century Sydenham uses opium in clinical
practice.
1803 Sertürner morphine (Latin Morpheus God
of Dreams) the first pure bioactive compound
isolated from a plant conducts tests in humans
(Setürner, three sons!) 1832 Robiquet codeine
from opium 1853 Conversion of morphine into
quaternary salts which are biologically active
first demonstration that a natural product
derivative has biological activity 1874 Wright
Conversion of morphine into diacetylmorphine
injection into dogs and rats to evaluate
activity
(-)-Morphine R R' H Codeine R Me, R' H
1897 Hoffmann Bayer Elberfeld -
diacetylmorphine 'heroin' marketed as cough
suppressant, non-addictive morphine
substitute!
Molecular Interventions 2001, 1, 189-191
19
Morphine (cont.)
Morphine R R' H
Codeine R Me, R' H
Morphine (Greek Morpheus God of Dreams) the
most important alkaloid of opium
20
Morphine (cont.)
1853 Conversion of morphine into quaternary
salts which are also biologically active first
demonstration that a derivative of a natural
product has biological activity
21
Historical Overview Atropine
Deadly nightshade (Atropa belladonna) (Greek
Atropos - one of the Fates who held the shears to
cut the thread of human life)
Theophrastus (371 287 BC) treatment of
wounds, gout, and sleeplessness, love potion.
Cleopatra (69-30 BC) used to dilate pupils of
her eyes for beauty enhancement. Dioscorides
(40-90 AD) anaesthetic for pain, sleeplessness,
given prior to surgery.
Renaissance Europe (14-17 Century) juice of the
berries to dilate the pupils of eyes ? Italian
bella donna - beautiful lady To 19 century
combination with opium for anaesthesia in
Roman, Islamic Empires, in Europe until
superseded by modern anesthetics.
22
Historical Overview Atropine (cont.)
1820 Mydriatic effects of belladonna examined by
Runge. 1831 Mein - isolates atropine
1880 Ladenburg - synthesis of atropine and proof
of structure 1901 Willstätter - synthesis of
tropinone 1917 Robinson - tropininone - first
'biomimetic' or 'biogenetic-like' synthesis
-'according to how enzymes in the plant make
the compound'
Atropine racemic mixture of L- and
D-hyoscyamine racemization occurs during
isolation L- (or S-)-hyoscyamine has the
biological activity. - a 'classic drug' which
markedly assisted evolution of the 'lock and
key' hypothesis' of receptor binding -
structurally related alkaloids referred to as
tropane alkaloids - e.g. scopolamine
scopolamine
23
Historical Overview Atropine (cont.)

• A classic drug which has assisted in
  understanding how modern drugs work in the body

24
Historical Overview Salicin and Aspirin
Bark from the willow tree (Salix alba)..
3000 BC Sumerians - list willow bark in medical
texts 1543 BC Egyptians - Ebers Papyrus lists
pain reducing, ani-inflammatory properties 400
BC Hippocrates - 'Hippocratic Corpus' -willow
bark for pain in childbirth, reduction of
fevers 300 BC onwards Greek, Roman, Muslim
Empires -pain reducing, anti-inflammatory
properties 1763 Stone - reports to Royal Society
London that willow bark is effective in
Reducing fever, relieves shortage of 'Peruvian
bark' (quinine - see later), but does not cure
'fever' To 19th Century widespread usage of
willow-bark preparations 19th Century efforts to
extract 'active principle' commence'
25
Historical Overview Salicin and Aspirin (cont.)
1828-1829 Buchner, Leroux, Piria isolate
crystalline salicin from willow bark 1838 Piria
isolates salicylic acid more potent than
salicin. 1830-1899 widespread use of extracts,
problems with gastric irritation
1898 Hoffmann at the Bayer Chemical Company,
Germany makes aspirin (acetyl salicylic acid)
from phenol - in vivo tests in animals clinical
trials. 1899-onwards marketing - the most
successful drug ever developed 50,000 tons
produced each year - analgesic
anti-inflammatory anticoagulant-low dose level -
protection against myocardial infarction
Largest Aspirin pack in the world 120 m x 65 m
x 19 m Bayer Leverkusen administration wrapped
(1999) Guinness Book of Records
26
Historical Overview Quinine
Mal aria . Bad air
(nuè jí)
Treatment of Malaria From the New World
Jesuits Bark
1630 Local Spanish Official in Peru cured of
malaria by a Jesuit missionary with native
remedy made from bark of a local tree
1632 Contessa de Chinchòn in Lima cured
introduces the Polva de la Contessa into
Spain ..
.. a romantic fairy tale!
1638 Father Antonia de la Calancha introduces
Jesuits Bark into Europe ..
27
Historical Overview Quinine
28
Historical Overview Quinine (cont.)
Transmission of infective parasites Plasmodium
species - via Anopheles mosquitoes which cause
malaria
29
Historical Overview Quinine (cont.)
Jesuits Bark
Cinchona ledgeriana
30
Treatment of Malariain China
1692 Emperor Kanxi (1661-1722) treated for
malaria with Jesuits Bark by Jesuit
missionaries.
31
Historical Overview Quinine (cont.)
1819 Runge
concentrated an alcoholic extract of the bark of
the fever tree ?white powder
1820 Pelletier and Caventou
1903 Rabe
Deduces correct structure for major constituent
- quinine
an alkaloid
World supply Bark of Cinchona ledgeriana (to
11 dry weight)
32
Organic Chemistry

• Derived from organic - the vital force of
  living organisms

Organic Chemistry

• Examples compounds from living organisms-
  can be converted into other organic compounds.

• Now, consider urea ... crystallized from urine!

? However
1828 Friedrich Wöhler heated ammonium cyanate
an inorganic compound, to obtain urea, an
organic compound.
(NH4)(NCO)-? H2NCONH2
33
Revision of Definition of Organic Chemistry
?Apply generally to the chemistry of carbon in
reactions and compounds with non-metals H, N,
O, S, P, X (X F, Cl, Br, I), etc.
Organic Chemistry
?Also generally include reactions and compounds
of carbon with non-metals and metals
organometallic chemistry!
alkanes, alkenes, alkynes, alcohols, ethers,
alkyl amines, carboxylic acids, esters, amides,
nitriles, thiols, thioethers, phosphines, alkyl
halides, aromatic hydrocarbons, aromatic halogen
compounds, aromatic amines, phenols, amino acids,
peptides, proteins, nucleic acids, terpenes,
steroids, alkaloids, waxes, fats, oils,
organometallic compounds
Exclude metal carbonates, cyanides, cyanates
34
Number of Organic Compounds?

• Approximately 30 million compounds in Chemical
• Abstracts journal published by the American
• Chemical Society which abstracts information
• from most primary scientific journals

Organic Chemistry
However..
- Probably over 100 million separate organic
compounds have been prepared (synthesized) in
a laboratory, or isolated from a natural source
over the past 120 years.
- Theoretical limit is much, much larger .
1050 compounds in 'chemical space'.

• Fortunately the number of known reactions which
  give these compounds is much, much less!

Why are there so many organic compounds??
35
Covalent Bonding with Carbon

• Covalent bonds with
• H C, Si, Sn, Ge .. N, P, As, Sb, Bi.. O, S,
  Se,Te.. F, Cl, Br, I..
• Mg, Ca.. B, Al, Ga other metals
  (organometallic compounds)

chains
rings
Carbon forms
single bonds
rings and chains
double bonds
triple bonds
36
Covalent Bonding with Carbon (cont.)
Chains, rings, rings and chains with C, H ..
.. hydrocarbons
Carbon forms chains, rings, rings and chains with
C, H .. and other atoms . N, S, X (X F, Cl,
Br, I), P, .. etc.
'heteroatoms'
Heterocyclic compound
37
Conventions for Structural Formulas
Structural formula defines constitution
sequence of bonds and nature of bonding
connecting atoms in a molecule.
C4H10
C10H8
Thick wedge bond to atom above plane of
paper
Hashed or dashed wedge bond to atom below
paper
Even bond bond in plane of paper
38
Conventions for Structural Formulas (cont.)
For heteroatoms C and H first in formula,
followed by symbols for heteroatoms in
alphabetical order
C2H2BrClF2
39
3-D Representations of Molecules
Methane
Ethylene
Molecular models
Tube provides rapid sighting of bond lengths
and angles
Ball and Wire or Framework shows bonds
connecting atoms
Ball and spoke directs attention to bonds and
atoms
Space Filling emphasizes 'volume' occupied by
atoms
40
Molecular Models
Androsterone
Naphthalene
Ladenburg Benzene
41
Molecular Models (cont.)
Morphine
Quinine