SYNTHESIS

1
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?
2
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.
3
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.
unstable
stable and versatile
4
Product e.g. paint and pigment vitamin
synthetic fiber pesticide plastic
explosive pharmaceutical
5
Organic Synthesis

1. Carbon-Carbon Bond Formation
2. Functional Group Interconversion

enantiomers
Efficiency and selectivity are important
characteristics that have to be taken into
account. Efficiency yields, number of
steps Selectivity chemoselectivity,
regioselectivity, stereoselectivity
6
???              
??????(Stereoisomers)
cis-1,2-dichloroethylene (bp 60 oC)
trans-1,2-dichloroethylene (bp 48 oC)
cis
trans
()-2-iodobutane (bp 119 oC)
(-)-2-iodobutane (bp 119 oC)
Chiral compounds
Enantiomer
7
Conformations of Ethane
conformation the different arrangements of atoms
that result from rotation about a single
bond conformers a specific conformation
(conformational isomer) same connections of atoms
Eclipsed conformation
Staggered conformation
8
Conformational Mobility of Cyclohexane
Hax
Heq
Heq
Hax
- Energy barrier of interconversion 45 kJ/mol
(10.8 kcal/mol) (20 kcal/mol available at 25
?) - Hax and Heq are indistinguishable
9
Twist-Boat Cyclohexane
10
Chirality

• If an object has a plane of symmetry it is the
  same as its mirror image.
• The lack of a plane of symmetry is called
  handedness, chirality

Chiral Greek cheir (hand) al Crystals,
molecules, or three-dimensional objects that are
not superimposable with their mirror images are
said to be chiral. (cf. achiral)
Chiral Objects Achiral Objects
baseball glove pencil
golf club tennis racket
Chiral object (molecule) A is different object
(molecule) from its mirror image object
(molecule) A.
11
Chiral Molecules and Achiral Molecules
Enantiomers and the Tetrahedral Carbon
Mirror Images
identical (superimposable)
achiral
identical (superimposable)
achiral
enantiomers (nonsuperimposable)
chiral
12
Chirality Centers

• A point in a molecule where four different groups
  (or atoms) are attached to carbon is called a
  chirality center (asymmetric center or
  stereogenic center).

• Note that chirality is a property of the entire
  molecule, whereas a chirality center is a
  structural feature within the molecule that
  causes chirality.

13
Pasteurs Discovery of Enantiomers

• Louis Pasteur discovered that sodium ammonium
  salts of tartaric acid crystallize into right
  handed and left handed forms such an event is
  rare.

Resolution of enantiomers
Louis Pasteur Chemist
1822-1895
Chance favors only prepared mind. -Louis
Pasteur
14
Optical Activity

• Light restricted to pass through a plane is
  plane-polarized.

• Solutions of chiral compounds rotate
  plane-polarized light and the molecules are
  said to be optically active.

15
Chiral Compounds
(-)-2-iodobutane (bp 119 oC)
()-2-iodobutane (bp 119 oC)
? D 15.9
? D -15.9
Enatiomers Optical isomers
They are optically active.
16
(No Transcript)
17
(No Transcript)
18
MAKING COMPLEX MOLECULES
Fischer achieved the first synthesis of the first
truly complicated organic molecules, the sugar
molecule D-glucose in 1890.
Hermann Emil Fischer Germany
(1852-1919)
D-Glucsoe
The Nobel Prize in Chemistry 1902
Fischers work on the total synthesis of
D-glucose is regarded as the catalyst for the
development of synthetic organic chemistry in the
20th century.
19
Willstatters synthesis of tropine
Sir Robert Robinson United Kingdom
(1886-1975)
The Nobel Prize in Chemistry 1947
Robinsons synthesis of tropinone in 1917
The Robinsons 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.
20
Sir Christopher Kelk Ingold
(1893-1970)
21
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.
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.
22
Robert Burns Woodward
23
Some of the Complex Molecules Made by Woodward
There is excitement, adventure, and challenge,
and there can be great art in organic
synthesis. - Woodward
Quinine (1944) anti-malarial drug
Vitamin B12 (1973)
Strychnine (1954) pesticide
24
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.
25
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
26
Chiral Compounds
(-)-2-iodobutane (bp 119 oC)
()-2-iodobutane (bp 119 oC)
? D 15.9
? D -15.9
Enatiomers Optical isomers
They are optically active.
Separation of enantiomers Resolution or
Optical
resolution
27
To obtain one pure enantiomer, resolution is
required.
Only one enantiomer is obtained by asymmetric
synthesis.
28
Asymmetric Synthesis
Synthesis of One Enantiomer using a Chiral
Auxiliary

Chiral Auxiliary
29
Asymmetric Synthesis
Synthesis of an Enantiomer using a Chiral Reagent
Hebert C. Brown (1912- )
The Nobel Prize in Chemistry 1979
30
(No Transcript)
31
Asymmetric Synthesis
Synthesis of an Enantiomer using a Chiral Catalyst
32
Asymmetric Synthesis
Synthesis of an Enantiomer using a Chiral Catalyst
33
The anticancer drug, Taxol
Synthesis K. C. Nicolaou at The Scripps
Research Institute Robert
Holton at Florida State University
34
Carbon Species
carbocation
stable (neutral)
carbene
carbanion
radical
unstable species
relatively stable complex
35
1. Stabilize unstable organic compounds
- strained, unstable - does not exist at normal
temperatures and pressures - reacts with itself
to form larger ring
- stable - well-behaved and easily-manipulated -
readily seperated - a convenient source of
cyclobutadiene
36
2. Change characters of organic compounds
- surrounded by a cloud of negative electrons -
prefer to interact with positively-charged
molecules - reacts with itself to form larger ring
- Cr(CO)3 sucks away electrons from benzene -
prefer to interact with negatively-charged
molecules
37
Combinatorial Chemistry
Combinatorial Library
4 ?? monomer
Nn Combinations
44 256? tetramer
38
Solid Phase Synthesis? ????
resin monomer
shake
resin cleavage
wash
wash
39
Split-Mix Process
Mix-Split Couple
33 27
tag each bead!
Mix-Split Couple
40
Solid Phase Library
In 1991s, Houghten Lam synthesis of a huge
peptide library
20 amino acids
Solid-phase synthesis
202 400 dipeptides
DNA fully automatic (solution)
peptide
203 8000 tripeptides
carbohydrate
small molecule (drug-like)
204 160,000 tetrapeptides
ln 1992, Jon Ellman synthesis of non-peptide
drug-like molecules by solid phase synthesis
41
Supramolecular Chemistry
??? ??
1. Molecular chemistry- Covalent bond
2. Supramolecular chemistry- Chemistry beyond
molecules Assembly of molecules Molecular
recognition
Non-covalent bonds - electrostatic forces -
hydrogen bonds - van der Waals interactions -
dipole interactions - hydrophobic interactions,
etc
1987 ????? ????? Charles Pedersen, Jean-Marie
Lehn, and Donald J. Cram
42
The Binding between Drug and Bilogical
Receptors through Non-Covalent Bonds
physiological response
recognition
Drug Molecule
Biological Effects
Biological Receptor
Supramolecular complex
43
DNA Double Helix
44
(No Transcript)
45
Carcerand
46
Chemosensors
Signals - fluorescence - color - electric
signal...
47
(No Transcript)