Transcript No Slide Title
Synthesis
Making molecules you want from the ones you have.
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
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
How does a carbocation react?
CH
3
CH
3
C CH
3 Br
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
CH 3 CH 3 CH 3 C Br
How else can a carbocation gain stability?
CH
3
CH
3
C CH
3
Instead of reacting as a Lewis acid it can react as a Bronstead acid and donate a proton!
CH 3 CH 3 C C H H H
This is called an elimination reaction Because H + is eliminated from the molecule
OH CH 3 CH 3 C C H H
+ H
2
O
CH 3
Addition
CH 3 C C H H H Br OH CH 3
Elimination
CH 3 CH 3 CH 3 C Br CH 3 C C H H
+ H
2
O
Elimination often competes with substitution.
Just like substitution where there are two forms S N 1 and S N 2 there are two forms of elimination, E1 and E2.
Sorting it all out is pretty complicated, something we are not going to do.
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.
HO + K
potassium t-butoxide very strong base but steric bulk prevents t-butoxide from readily forming ethers in a substitution reaction
K O + 1/2 H 2
Br + K O H O + + KBr
K O Br + major minor
The alkene with the most substituents is the most stable and the most favored product.
Br Br K O + major minor K O major minor
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.
O H H 2 SO 4 hot
OH H 2 SO 4 hot 56% 32% 12%
But you can get complicated mixtures.
Alkyne synthesis
Br K O Br
Elimination of two moles of HBr from neighboring carbon atoms will give an alkyne.
H
Br Br
K O
You can reduce alkynes back to alkenes
H 2 Pd H 2 Pd H H or H H
Pd CH 3 Pd H Pd C Pd H H C Pd H Pd H Pd CH 3 H C C H H H Pd H CH 3 H H C H H Pd H H 3 C H H Pd C H H H
Hydrogens come in from the same side.
You can reduce alkynes back to alkenes
H 2 Pd H 2 Pd H H or H H
For the trans isomer use a different reducing agent. Sodium metal in ammonia.
Complicated mechanism.
Na NH 3 Na NH 3 H H or H H
H 2 O
pKa values
H NH 3 H H H H H CH 3 CH 3 HO H NH 2 H H H CH 3 CH 2 15.7
25 38 44 51
Sodium amide is a very strong base
Na + NH 3 Na + NH 2 + 1/2 H 2
It can be used to form an acetylide
H Na + NH 2 Na
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.
H Na + NH 2 Na + Br Na
1.
Na/NH 3 2.
Br H
Two ways to make many acetylenes
H 1. Na/NH3 2. Br 2.
H 1. Na/NH3 Br
Now that we have a carbon-carbon bond forming reaction we are ready for some real synthesis.
Suppose you wanted to synthesize 3-hexanol
O H
But your only carbon containing starting materials are compounds with four carbons or less.
four carbons O H three carbons O H two carbons
Analyze carbon framework first.
three carbons
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.
Work backwards
O H H 2 O H 2 SO 4
No regiochemistry control
H 2 O H 2 SO 4 H 2 Pd H H
Work backwards
O H H 2 O H 2 SO 4 1. Na/NH 3 2.
Br H H 2 Pd H H
H H H 2 Pd H 1. Na/NH 3 2. CH 3 CH 2 Br CH 3 1. Na/NH 3 2. CH 3 Br H
One simple reaction you did in the lab.
Ester Synthesis
R O O H + H O R' O R O R' + H 2 O
R O O H
SOCl
2 R O Cl Much faster H O R'
O O H SOCl 2 H O CH 3 O Cl H O O O CH 3 O O
O O Butyl butyrate odor of pineapples How could you make it from 1-butanol?
O O O Cl + H O SOCl 2 O O H CrO 3
O
The last reaction we are going to study.
The Grignard Reaction
Reaction of an nucleophilic carbon atom with a carbonyl group.
O
The Grignard Reaction
Br Mg Mg Br
O Br Mg O Mg Br
The Grignard Reaction converts aldehydes or ketones to alcohols.
Mg Br O H H + O
Br Mg Br Mg Br Mg BrMgCH 3 BrMg BrMg Mg Br
1.
BrMg 2. H + O O H O 1.
BrMgCH 3 2. H + 1. BrMg 2. H + O
Reactions with aldehydes give secondary alcohols
O O H H 1.
BrMg 2. H + O Mg Br 1.
H 2. H + H O H
HBr O H ?
Br Mg O 1.
H 2. H + H O H Mg Br
OH
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.
OH O H + Br
OH Br + H O
HBr O H Br
or
HBr
or
MgBr + H O H + BrMgCH 3 O
MgBr H 1.
2. H + O O H 1.
H O 2. H + Mg O H HBr Br
O PCC OH BrMg 1.
2. H + MgBr 1.
O H 2. H + H
Odor of Rum
O PCC H OH
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
Me Me Me O Me O HO Me Me OH OH Me Me OH OCONH 2
Isolated from a marine sponge
OH OH or OH or For geometric isomers are possible. Only one is the correct compound.
OH or OH or
Me Me Me O Me O HO Me Me OH OH Me Me OH OCONH 2
Isolated from a marine sponge
Me Me Me O Me O HO Me Me OH OH Me Me OH OCONH 2
How Many Stereoisomers?
= isomer choice
2
16
= 65,536 isomers
Me Me Me O Me O HO Me Me OH OH Me Me OH OCONH 2 Ph S O O H Y Me Me OTBS Me Me OTBS X Me Me Me Me O OCONH 2
Possible Grignard?
Ph S Me O H Y Me O Me OTBS Me OTBS
No, too reactive, use some acetylene chemistry instead.
X Me
O H R I Ni R' H 2 Pd HO R R'
Me Me Me O Me O HO Me Me OH OH Me Me OH OCONH 2
Isolated from a marine sponge