Synthesis

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Synthesis
Making molecules you want from the ones you have.
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Synthesis Requires Two Things
a. a library of reactions
b. a strategy or plan for combining known
reactions to reach the desired target
molecule
c. and a little luck always helps
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A library of reactions
Functional group manipulations
Oxidations, reductions, substitutions etc.
Carbon-carbon bond formations
Used to build the carbon skeleton of the target
molecule
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How does a carbocation react?
Since the carbocation is a Lewis acid It can
react with a Lewis base.
The electron pair on the base attacks
the electron deficient center
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How else can a carbocation gain stability?
Instead of reacting as a Lewis acid it can react
as a Bronstead acid and donate a proton!
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This is called an elimination reaction
Because H is eliminated from the molecule
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Addition
Elimination
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Elimination often competes with substitution.
Just like substitution where there are two forms
SN1 and SN2 there are two forms of elimination,
E1 and E2.
Sorting it all out is pretty complicated, somethin
g we are not going to do.
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But we would like to use elimination as a
synthetic reaction.
So how can you favor elimination?
Use a very strong base that is a poor nucleophile.
For example potassium t-butoxide.
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potassium t-butoxide
very strong base but steric bulk
prevents t-butoxide from readily forming
ethers in a substitution reaction
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The alkene with the most substituents is the most
stable and the most favored product.
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Similar eliminations can take place with alcohols.
Catalyzed by concentrated strong acids
Concentrated acids are hydrophilic and will
remove water from other molecules in order to
dilute themselves.
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But you can get complicated mixtures.
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Alkyne synthesis
Elimination of two moles of HBr from neighboring
carbon atoms will give an alkyne.
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You can reduce alkynes back to alkenes
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Hydrogens come in from the same side.
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You can reduce alkynes back to alkenes
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For the trans isomer use a different reducing
agent. Sodium metal in ammonia. Complicated
mechanism.
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pKa values
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Sodium amide is a very strong base
It can be used to form an acetylide
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Acetylides will give us our first carbon-carbon
bond making reaction.
Acetylides are strong bases and good nucleophiles.
They can undergo substitution reactions with
primary alkyl halides.
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Two ways to make many acetylenes
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Now that we have a carbon-carbon bond forming
reaction we are ready for some real synthesis.
Suppose you wanted to synthesize 3-hexanol
But your only carbon containing
starting materials are compounds with four
carbons or less.
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Analyze carbon framework first.
Which carbon-carbon bonds must be put together in
our synthesis?
We could make the bond between carbons 3 and 4.
But we will chose to make the new C-C bond
between carbons 2 and 3.
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Work backwards
No regiochemistry control
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Work backwards
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One simple reaction you did in the lab.
Ester Synthesis
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Much faster
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Butyl butyrate odor of pineapples
How could you make it from 1-butanol?
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The last reaction we are going to study.
The Grignard Reaction
Reaction of an nucleophilic carbon atom with a
carbonyl group.
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The Grignard Reaction
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The Grignard Reaction converts aldehydes or
ketones to alcohols.
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Reactions with aldehydes give secondary alcohols
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2. H
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Pheromone of the European Bark Beetle
How could you synthesize it from
organic compounds with four carbons or less?
First analyze the carbon skeleton
Then work backwards.
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or
or
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Odor of Rum
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CHE 503 Organic Synthesis
Professor Frank Fowler
Syntheses of Discodermolides Useful for
Investigating Microtubule Binding and
Stabilization Deborah T. Hung, Jennie B.
Nerenberg, and Stuart L. Schreiber Contribution
from the Howard Hughes Medical Institute,
Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts
02138 J. Am. Chem. Soc. 1996, 118, 11054-11080
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For geometric isomers are possible. Only one is
the correct compound.
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How Many Stereoisomers?
isomer choice
216 65,536 isomers
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Possible Grignard?
No, too reactive, use some acetylene chemistry
instead.
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