SYNTHESIS
Make me a molecule
“Chemists make molecules… they study the
properties of these molecules; they analyze, they
form theories as to why molecules are stable, why
they have the shapes and colors they do; they
study mechanisms, trying to find out how
molecules react.”
“At heart of their science is the molecule that is
made.”
― Roald Hoffmann―
In
the beginning synthesis was unnecessary. Chemistry was
founded upon the study of those materials which were available
from natural sources. Many of the materials we use today are
made by chemical synthesis.
Organic Chemistry
Organic Compounds
Most of the new compounds made today are organic, that is,
they are composed largely of carbon. This element has a unique
ability to form strong chemical bonds between not only carbon
atoms but also many other elements.
The chemistry of life is largely a result of the incredible versatility
of carbon and is, of course, why carbon chemistry is called
organic chemistry.
C
C
H
C
C O
C
C
C H
N
C
C
N
O O
Cl
C
C
C
stable and versatile
C
C
unstable
N
O
NH4
OCN
Ammonium cyanate
Heat
H2N
C
NH2
Urea
Like most people of his time, the chemist
Friedrich Woehler believed that living
things had a special mysterious “life force”
that enabled them to make “living
chemicals” like urea. This notion later
came to be known and derided as
“vitalism.”
When Woehler made a discovery that shocked him and overturned the
reigning concept of vitalism: he made the substance "urea" out of
inorganic chemicals in 1828 in a test tube and the life force theory was
proven false.
Product
e.g. paint and pigment
vitamin
synthetic fiber
pesticide
plastic
explosive pharmaceutical
Synthesis involves breaking and making new chemical bonds
to create new chemical structures.
O
C OH
O H
Saliciyic acid
CH2OH
O glucose
Salicin
CH2OH
O H
Salicyl alcohlol
O
O
H3C C O C CH3
O
C OH
O C CH3
O
Acetylsalicylic acid
(Asprin)
In 400 B.C., the Greek physician Hippocrates recommended
chewing bark of the willlow tree to alleviate the pain of
childbirth and to treat eye infections. The active component of
willow bark was later founded to be salicin.
 Hydrolysis of salicin in aqueous acid gives salicyl alcohol,
which can be oxidized to salicylic acid. Salicylic acid proved to
be an even more effective pain reliever. Unfortunately, it causes
severe irritation of stomach.
 In 1883, chemists at Bayer division of I. G. Farben in
Germany prepared aspirin. It proved to be less irritating to the
stomach than salicylic acid and also more effective in relieving
the pain and inflammation of rheumatoid arthritis.
Organic Synthesis:
1. Carbon-Carbon Bond Formation
2. Functional Group Interconversion
CH3
CH3
H
+
H3O
CH3CH2MgBr
CH3
CH2CH3
O
OH
OH
3
H
Br
H3C
I
H3C
CH3
C
C
CO2H
CH3
I
H3C
CH3
HO2C
C
C
H
H
OH
HO2C
CO2H
CO2H
enantiomers
H
fumarase
(enzyme)
:
1
OH
H2O
CO2H
H3C
Br
1
HO2C
1
CH3
OH
H2O
:
Br
H
Br
HO2C
CH2CH3
HO2C
CO2H
Efficiency and selectivity are important characteristics that have to be
taken into account.
Efficiency: yields, number of steps
Selectivity: chemoselectivity, regioselectivity, stereoselectivity
Louis Pasteur was born on December 27,
1822 in Dole, in the region of Jura, France.
Resolution of enantiomers
Louis Pasteur
Chemist
1822-1895
“Chance favors only prepared mind.”
-Louis Pasteur
Chiral Compounds
CH2CH3
CH3CH2
H C
I
C HI
CH3
CH3
(+)-2-iodobutane
(bp: 119 oC)
(-)-2-iodobutane
(bp: 119 oC)
[ ]D = +15.9
[ ]D = -15.9
Enatiomers
Optical isomers
They are optically active.
HO
H NH 2
HO
(S) 도파 (R)
N
H2N H
OH
심각한 부작용
파킨슨병 치료
H3C
OH
HOOC
COOH
H
H
N
CH3
(S) 케타민 (R)
Cl O
O Cl
환각제
마취제
H3C CH3
H3C
COOH
(S) 페니실아민 (R)
H3C CH3
HOOC
H2N H
H
OH
결핵치료
HO
OH
N
H
NH 2
돌연변이유도
관절염치료
H
N
CH3
(S,S) 에탐부톨 (R,R)
N
H
H
N
HO
시력상실
O
O
H
H
O
N
N
H
O
O
(S) 탈리도미드 (R)
O
N
N
O
H
기형아 생성
HO
O
O
진정제
H O
H
N
H NH 2H
O
(S,S) 아스파탐 (R,R)
O
¾´¸À
O
H2N
O
OH
(S) 아스파라진 (R)
N H
H2
NH 2
HO
H N O
H2
¾´¸À
´Ü¸À
CH3
CH3
(S) 리모넨 (R)
·¹ ¸ó Çâ
O
N
H
H2N H
O
O
´Ü¸À
O
O
¿À·» ÁöÇâ
OH
MAKING COMPLEX MOLECULES
Fischer achieved the first synthesis of the
first truly complicated organic molecules, the
sugar molecule D-glucose in 1890.
H
O
C
H
C OH
HO C H
Hermann Emil Fischer
Germany
(1852-1919)
The Nobel Prize
in Chemistry 1902
H
C OH
H
C OH
CH2OH
D-Glucsoe
Fischer’s work on the total synthesis of D-glucose is
regarded as the catalyst for the development of
synthetic organic chemistry in the 20th century.
O
I
Br
Br
NMe 2
Br
Br
NMe 2
NMe 2
Br
Br
Br
NMe
NMe
NMe
H
( II )
O
NMe
NMe
Willstatter’s synthesis of tropine
COOH
COOH
CHO
+
The Nobel Prize
in Chemistry 1947
OH
H
OH
Sir Robert Robinson
United Kingdom
(1886-1975)
Br
H2NMe +
O
NMe
O
NMe
O
CHO
COOH
COOH
Robinson’s synthesis of tropinone in 1917
The Robinson’s synthesis of tropinone was hailed as revolutionary.
This was to look at the target molecule and try to imagine how the
molecule could be constructed from simpler chemical units.
As the result of
better
understanding of
the mechanistic
principles of
organic reactions,
by the 1940s and
1950s the field of
total synthesis
really took off.
In 1965
Professor R. B.
Woodward was
awarded the
Nobel Prize for
his
contribution to
‘The Art of
Organic
Synthesis.’
The organic
synthesis is
like the game
of chess.
Robert Burns Woodward
Some of the Complex Molecules Made by Woodward
“There is
excitement,
adventure, and
challenge, and
there can be
great art in
organic
synthesis.”
Quinine (1944)
anti-malarial drug
- Woodward
Vitamin B12 (1973)
Strychnine (1954)
pesticide
Prostaglandins
Corey, Elias James
1928–, American organic chemist
and educator, b. Methuen, Mass.,
grad. Massachusetts Institute of
Technology (B.S. 1948, Ph.D.
1951). In 1990, he was awarded
the Nobel Prize in Chemistry.
Some prostaglandins affect human blood pressure
at concentrations as low as 0.1 microgram per
kilogram of body weight.
Substances that inhibit prostaglandin synthesis
may be useful in controlling pain, asthma attacks,
and anaphylactic shock and in reducing the
clotting ability of blood.
Retrosynthetic Analysis by Corey
“The organic chemist
is more than a
logician and
strategist; he is an
explorer strongly
influenced to
speculate, to imagine,
and even to create.”
- Corey