CHEM 345 Problem Set 16 Key 1.) One way to make 1,3-dicarbonyls is the Claisen condensation. The Claisen condensation is base mediated only. Acid does not work. Draw the mechanism for the following reaction. Why is the Claisen condensation base mediated rather than base catalyzed? What base and solvent should be used?
O O O + base H3O
solvent OMe O The base and solvent should match the ester, otherwise a trans- esterification gives a different product. The reaction is base mediated, because the 1,3-dicarbonyl has a pKa of ~ 10, which consumes the strong base during the reaction.
2.)Why does the following reaction not work?
O NaOH O O + H2O H3O
OMe OH A saponification would occur before the Claisen condensation occurs. The resulting carboxylate would be unlikely to undergo nucleophilic attack.
3.) Predict the product and provide a mechanism for the following reactions:
O O NaOMe C7H10O MeOH
C7H12O2
3.) Predict the product and provide a mechanism for the following reactions:
NaOMe C10H14O MeOH O O
C10H16O2
4.) Fill in the Boxes:
MgBr FeBr3 Br Br2 Mg
O Compound A
+ O CH2O H3O PCC Compound A CH2Cl2 O
Compound B
AlCl3 O LDA Cl O O O
Compound C
O OH H O+ Compound B Compound C 3
O racemic
5.) Breakdown the following molecules into the starting materials that made them. Write the reaction (Aldol and Claisen) that was used. 2 O O Claisen O a. 1 3
OMe
O O O Aldol b. 3 O O O
1 2
O O O c. O 2 1 3 Claisen
MeO
O O O O
O O O O c. 2 1 Claisen
O 3 O O
O OMe O O c. O O O Claisen
1 O 3 O 2 O OMe
d. O Aldol O 3 H H 2 N N HO 1 O
6.) The following molecule does not exist. Or if it did, it would not exist for long. Draw the molecule that this would rapidly and I mean rapidly rearrange to if formed. (Hint: carbonyls are in equilibrium with what other functional group)? O O OH O
tautomerization
O O HO OH
7.) Fill in the boxes to provide a synthesis of the following sets of diastereomers. A.) O LDA O
H O H
O
O OH
H O+ 3 O O H
H
B.) O O LDA
H H O
O
O OH
+ H3O O O H
H
8.) Draw the mechanisms of the following reactions. a. O NaOH O OH
H2O
b. O NaOH O
H2O
c. O NaOH O O
H2O
O d. O NaOH
H2O
e. O + O O NaOMe H3O
OMe MeOH O
f. O + O O NaOEt H3O
OMe EtOH O
9.) The following molecules can be made from an Aldol, Claisen, and/or a Michael. Identify which reaction and the starting materials that could potentially give rise to such a product. Some of the starting materials can be broken down further. Break the molecules down as far as you can.
O a. O O Aldol
H H
b. O OH OH Aldol O O OH
OH OH
Aldol
O O
OH O O Claisen c. O O
MeO
O O Claisen c. O O
OMe
9.) continued. O d. O O Aldol Michael
O O
O O Aldol e. Claisen OMe
O O
O O
Michael
O Aldol O O OMe
O
Michael f. O O
O O
Aldol
O
O 10.) Predict the product of the following sequence. Why is KOtBu/HOtBu used in the third step and not NaOEt/EtOH? Draw the products after each step and the mechanism for the entire sequence.
1.) NaOEt, EtOH 2.) EtI 3.) KOtBu, tBuOH O 4.) MeI 5.) NaOH, H2O O O 6.) HCl, H2O, heat
O
10.) continued KOtBu is used to minimize the reverse Claisen condensation, as KOtBu is less likely to act as a nucleophile to the carbonyl.
11.) Fill in the boxes:
O O O O O + NaOEt H3O
EtOH OEt OEt OEt
O
O O OLi O O MeBr OEt
O
O
O + NaOEt H3O O O
EtO OEt EtOH OEt
O
O O O + NaOEt H3O
H OMe EtOH H
O O NaOEt + OEt H3O EtOH
O O
Chem 345 Reaction Sheets:
Claisen Condensation:
O O O + NaOMe H3O
OMe MeO MeOH
Mechanism: O + NaOMe H3O
OMe MeOH
Breakdown: O O Claisen O O
1 3 MeO 2 O O Claisen O O
3 1 OMe 2 Summary (Key words): Claisen condensation gives a 1,3 dicarbonyl. This is an unfavorable reaction that will only work if there is a proton that can be removed on carbon 2. If an ester is in the product, base/solvent used should match the ester. Breakdown: Break 2,3 bond, C-2 gets hydrogens, C-3 gets an OR group. Since base is consumed in the reaction, you need at least 1.0 eq. of base. Hydroxide does not work as it saponifies the ester. Chem 345 Reaction Sheets:
Aldol Condensation:
O
NaOMe O MeOH O
Mechanism: O
NaOMe
MeOH O
Breakdown: O O O
1 3 2
O OH O O
1 3 2
Summary (Key words): Product is either a 3-hydroxycarbonyl or an a,b unsaturated carbonyl. Breakdown: Break 2,3 bond, C-2 gets hydrogens, C-3 gets a carbonyl. All steps reversible in mechanism. 5,6 member rings form quickly. Mixed Aldols should use LDA.