ChemActivity 34
ChemActivity
Base Catalyzed Aldol Reactions
1
34
Part A: Aldol Reaction
(What is the mechanism of the aldol reaction?)
Model 1: Aldol Reaction
new C-C
bond
O
H
OH
OH catalyst
C
C
H
H
H
acetaldehyde
mild conditions:
-room temperature
-dilute base
O
C
C
H3C
C
H
H
H
+ other
products
H
Product I
(aldol)
Critical Thinking Questions
1. Consider the reaction in Model 1.
a) Note that Product I contains two different functional groups. Construct an
explanation for the name “ald-ol.”
“Ald” is for aldehyde and “ol” is for alcohol. An aldol is made by mixing an aldehyde and an alcohol.
b)
c)
d)
e)
How many carbons are there in Product I? 4
Estimate the number of acetaldehyde molecules required to make one
molecule of Product I? 2
Label the “new carbon-carbon bond” in Product I and circle each
acetaldehyde subunit.
Devise a reasonable mechanism for the reaction in Model 1. Be sure to
include important resonance structures of any intermediate products.
ChemActivity 34
O
H
2
O
H
C
C
Base Catalyzed Aldol Reactions
H
H
C
C
O
H
H
O
H
H
O
OH
O
C
H
C
H3C
C
H
H
H
H
C
C
H
H
H
H
OH
O
C
C
H 3C
C
H
H
H
H
OH
ChemActivity 34
Base Catalyzed Aldol Reactions
3
Model 2: Analysis of an Aldol Product Using Retrosynthesis
• Most C-C bond formations are the result of an nucleophilic carbon (Cδ–) joining
with an electrophilic carbon (Cδ+).
• Retrosynthetic analysis can be used to “pull apart” the product (on paper) into two
pieces: the electrophilic piece and the nucleophilic piece.
Step 1: Find the new carbon-carbon bond and draw a line through it.
Step 2: Of the two C’s in this bond, decide which was the Cδ– and which was the Cδ+.
Step 3: Draw real molecules that could have served as the nucleophile and electrophile.
Step 4: Draw in a forward reaction arrow and add any reagents that are required.
Example I: Analysis of a Grignard Reaction
Electrophile
H2C
forward
C
Grignard
Reaction
Product
δ
H2C
H2C
synthesis
MgBr
Cl
δ C
C
Nucleophile
Step 1: Mark the
new C-C bond.
Step 2: Assign
- and + to C's.
Step 3: Choose
real reagents.
Step 4: In this case no extra reagents are needed to make the Nuc– react with the Elec+.
Example II: Analysis of an Aldol Reaction
H
H
and
H
O
O
Aldol
Reaction
Product
C
CH3
C
forward
H
H
HO
C
H
O
δ
C
Electrophile
CH3
CH3
Step 1: Mark the
new C-C bond.
H
Nucleophile
synthesis
H
C
OH
C
H
H
new C-C
bond
HO
O
C
C
CH3
Step 2: Assign
- and + to C's.
Step 3: Choose
real reagents.
Step 4: The nucleophile is prepared by mixing acetaldehyde and a small amount of HO–.
Critical Thinking Questions
2. According to Example 1, name one example of a functional group that makes a C
nucleophilic and one example of a functional group that make a C electrophilic.
Grignard reagents serve as nucleophiles. Alkyl halides serve as electrophiles.
3. For the aldol reaction above, complete Step 1 by marking, on the product, the new
carbon-carbon bond.
4. On an aldehyde, which C is electrophilic and which C is nucleophilic (with addition
of hydroxide)?
The carbonyl carbon is electrophilic. The alpha carbon is nucleophilic.
ChemActivity 34
Base Catalyzed Aldol Reactions
4
5. Follow each step in Model 2 (retrosynthesis) and determine the reagents necessary
to make each of the following aldol products.
O
OH
O
OH
H
O
O
H
H
and
OH
H
O
O
H
O
H
O
OH
H
OH
H
Caution: The next one is tricky!
OH
OH
O
O
O
O
H
H
H
H
and
OH
6. Explain why each of the following aldehydes cannot undergo an aldol reaction
(even in the presence of hydroxide).
O
O
O
H
H
H
H
None of these aldehydes have alpha hydrogens.
7. Complete the sentence: To undergo an aldol reaction, an aldehyde must have…
(Hint: it is something that the aldehydes in CTQ 6 do not have.)
… alpha hydrogens!
8. Give an example (not appearing in this activity) of an aldehyde that…
a) Cannot undergo an aldol reaction.
b) Can undergo an aldol reaction.
Various answers possible.
OH
ChemActivity 34
Base Catalyzed Aldol Reactions
5
Part B: Mixed Aldol Reactions
(How can steric factors impact the yield of an aldol reaction?)
Review from Part A: In an Aldol Reaction…
• one molecule of aldehyde reacts with base and serves as nucleophile
• a second molecule of aldehyde serves as electrophile.
Model 3: Aldol Reaction with Two Different Aldehydes
O
H
O
C
C
H
H
C
C
H
H
C
H
H
H
acetaldehyde
OH
H
4 different products
H
propanal
Critical Thinking Questions
9. Consider the mixture in Model 3.
a) Circle each α-hydrogen on acetaldehyde and propanal.
b) T or F: Both acetaldehyde and propanal can serve as nucleophile in an aldol.
c) T or F: Both acetaldehyde and propanal can serve as electrophile in an aldol.
d) Draw the two aldol products and two mixed aldol products that result
from the mixture in Model 3. Do not draw the mechanisms.
O
O
OH
OH
H
H
nucleophile = acetaldehyde
electrophile = acetaldehyde
nucleophile = propanal
electrophile = propanal
O
O
OH
OH
H
H
nucleophile = propanal
electrophile = acetaldehyde
nucleophile = acetaldehyde
electrophile = propanal
ChemActivity 34
e)
Base Catalyzed Aldol Reactions
6
For each product on the previous page state whether…
• acetaldehyde enolate ion or propanal enolate ion acted as the
nucleophile to form that product.
• acetaldehyde or propanal acted as electrophile to form that product.
Model 4: “Aldol” Reactions Involving Ketones (“Ketols”?)
• Ketones are also known to participate in aldol reactions.
• The yields of such reactions are generally very low.
O
O
OH
2
OH
(cat.)
Critical Thinking Questions
10. Chemists usually call the product of the reaction in Model 4 an aldol product. A
student rightly objects to this, saying he thinks it should be called a “ketol.”
Explain this student’s reasoning. (Hint: What functional groups are in the product?)
An aldol is a mixture of an aldehyde and an alcohol, therefore a mixture of a ketone and an alcohol
should be called a ketol.
11. The energy diagram for the reaction in Model 4 is shown below.
a) According to this diagram is this reaction up-hill or down-hill in energy?
b) Is your answer consistent with the information given in Model 4? Explain.
O
V.E.
O
OH
O
OH
OH
reaction progress
The reaction is up-hill in terms of potential energy, which is consistent with the fact that the yield of
product is very low.
12. Aldehydes and ketones can both serve as good nucleophiles in aldol reactions
(as long as they have an α-H to remove).
a) Which type of carbonyl compound do you expect will be a better
electrophile in an aldol or mixed aldol reaction: aldehyde or ketone [circle
one]?
b) Explain your reasoning.
Based on both steric and electronic arguments an aldehyde carbonyl carbon is a better electrophile
than a ketone carbonyl carbon. (Assuming alkyl groups are electron donating.)
c) Is your answer consistent with the energy diagram above?
Yes. The energy diagram shows that this reaction, in which a ketone serves as an electrophile, is
unfavorable. (Of course, there could be another reason why the reaction is unfavorable.)
ChemActivity 34
Base Catalyzed Aldol Reactions
7
Model 5: Mixed Aldol with an Aldehyde and a Ketone
O
O
O
C
C
H
C
H
C
H
CH
C
OH
H
H
benzaldehyde
OH
H
acetophenone
Critical Thinking Questions
13. Consider the reactants in Model 5.
a) Explain why benzaldehyde cannot act as a nucleophile in an aldol reaction.
No alpha hydrogens
b)
Which species will better serve as an electrophile in an aldol reaction:
benzaldehyde or acetophenone [circle one]?
c)
Complete the reaction in Model 5 by drawing the single most likely aldol or
mixed aldol product.
Model 6: Controlling Product Formation in a Mixed Aldol
O
O
C
C
H
CH3
C
H
H
benzaldehyde
O
OH
O
OH
H
OH
H
propanal
H
forms preferentially in procedure II
Critical Thinking Questions
14. The reaction in Model 6 normally yields two different aldol/mixed aldol products.
Draw them both.
15. One of the following procedures maximizes formation of one product you drew in
Model 6, and nearly eliminates formation of the other.
I. Benzaldehyde is added very slowly to a mixture of propanal and base.
II. Propanal is added very slowly to a mixture of benzaldehyde and base.
a)
b)
c)
Circle the letter of the successful procedure.
Circle the product in Model 6 that will form preferentially using this
procedure, and cross out the other one.
Explain why the procedure works.
ChemActivity 34
Base Catalyzed Aldol Reactions
8
Procedure II avoids the condition necessary for forming the other product in which a high
concentration of propanal is exposed to base.
Part C: “Condensation Reactions”
(Why are aldol reactions run at high temperature called “condensation” reactions?)
Model 7: Dehydration, the Elimination of Water (HOH)
• When a suitable alcohol is heated in base, the result is an E2 reaction.
OH
CH
CH
H2C
H
C
H
H2C
CH
H2C
CH2
OH
H2C
E2
CH2
HOH
OH
C
H2
C
H2
Critical Thinking Questions
16.
17.
18.
19.
Review: What does the “E” in “E2” stand for? Elimination
Review: Is an E2 reaction, one step or two steps [circle one]?
Use curved arrows to show the mechanism of the reaction in Model 7.
Construct an explanation for why chemists say the alcohol in Model 7 has being
“de-hydrated.”
The starting material lost the components of water.
20. Is hydroxide considered a catalyst in this reaction? Explain.
Yes. It is neither generated, nor consumed, but it facilitates the reaction.
Model 8: Dehydration of an Aldol Product
• At low temperature (below Room T) an aldol product is stable in base.
• At high temperature (above Room T) an aldol product undergoes dehydration.
O
H
C
C
H
H
OH
catalyst
H
H
C
C
H
H
H
OH
catalyst
high Temp.
aldehyde
Critical Thinking Questions
CH3
O
C
OH
catalyst
C
H3 C
C
H
H
H
LOW TEMP.
rxn stops
at the aldol.
H
OH
C
C
C
H
O
H
O
H3 C
low Temp.
H
OH
H
aldol
high Temp.
rxn continues
O
C
H
C
C
H
H
α,β-unsaturated aldehyde
ChemActivity 34
Base Catalyzed Aldol Reactions
9
21. At high temperature an aldol product will react further with base to form an α,βunsaturated aldehyde shown above, right.
a) Use curved arrows to show a mechanism for this further reaction at high T.
b) Construct an explanation for the name "α,β-unsaturated aldehyde."
(Hint: Which C’s will get an H if you treat this product with H2/Pt so as to
“saturate” it with the maximum number of H’s?)
The positions alpha and beta to the carbonyl are unsaturated.
c) Researchers first studying aldol reactions noticed that during the reaction
droplets of water (“condensation”) would form on the inside of the flask. For
this reason chemists call aldols, mixed aldols and similar reactions
“condensation reactions.”
What is the source of these water droplets in an aldol reaction?
(Hint: they only form at high temperatures.)
The water comes from the “dehydration” step in which water is formed from an elimination reaction.
Model 9: Dehydration “Drives” a Condensation Reaction
Below is an energy diagram for the aldol reaction from Model 4, run at high temperature.
O
OH
OH
O
O
V.E.
2
HOH
OH
OH
reaction progress
Critical Thinking Questions
22. Is the reaction in Model 9, overall, up-hill or down-hill in terms of potential
energy?
a)
Do you expect a high yield of α,β-unsaturated product in this reaction? No.
b)
Researchers have found that the reaction in Model 9 (and other condensation
reactions) can be driven to the right to give nearly 100% yield of α,βunsaturated product by boiling off water as steam. Explain.
According to LeChatelier’s principle, removal of water from this reaction will drive it toward products
since water is a product.
ChemActivity 34
Base Catalyzed Aldol Reactions
10
ChemActivity 34
Base Catalyzed Aldol Reactions
11
Review:
• The alpha (α) carbon of a carbonyl compound can be made nucleophilic by the
addition of a base to form the enolate ion.
O
H
O
C
C
C
H
H
O
C
H
H
O
H
H
H
C
H
C
H
H
nucleophilic
carbon
Enolate Ion
• In acid or base, a keto compound is in equilibrium with its enol form.
• Using 2nd order resonance structures we can demonstrate that the alpha (α) carbon
of an enol is nucleophilic (as shown below).
O
H
C
C
H
acid
or
base
nucleophilic
carbon
O
H
C
H
H
C
H
C
H
H
H
Keto
C
H
H
H
O
1st Order
Resonance Structure
2nd Order
Resonance Structure
of Enol
of Enol
Model 10: α,β-Unsaturated Carbonyl Compounds
O
H
C
H
O
2nd
order
H
C
H
H
H
C
C
H
H
O
H
C
C
C
O
H
C
C
C
H
H
H
H
C
C
H
H
these two are not nearly as important as
the one with the neg. charge on oxygen!
Note: Oxygen must always have an octet, even in 2nd order resonance structures!
Critical Thinking Questions
23. Draw any reasonable 2nd order resonance structures for the α,β-unsaturated
carbonyl compound in Model 10.
a) Use these to predict whether the alpha (α) carbon of an α,β-unsaturated
carbonyl compound will be nucleophilic or electrophilic.
b) Use these to predict whether the beta (β) carbon of an α,β-unsaturated
carbonyl compound will be nucleophilic or electrophilic.
ChemActivity 34
Base Catalyzed Aldol Reactions
12
Exercises for Part A
1. For each of the following aldehydes, draw the aldol product that will result when the
aldehyde is treated with a catalytic amount of base (e.g. KOH).
O
OH
H
O
OH
F3C
H
O
Cl
OH
H
O
OH
H
2. The reactants from Model 1 are drawn below. Hydroxide is both a strong base and
an excellent nucleophile. As a result, hydrate formation is in competition with aldol
formation.
OH
O
O
OH
H
aldol product
H2O
HO
OH
OH
H
acetaldehyde
H2O
H
hydrate product
(starting material)
V.E.
aldol formation
Reaction Progress
hydrate formation
a)
Use curved arrows to show the mechanism of hydrate formation.
b)
Hydrate formation is faster than aldol formation (as shown by the energy
diagram), yet the amount of hydrate found in the reaction at any given time
is below the detection limit. Explain this observation.
ChemActivity 34
Base Catalyzed Aldol Reactions
13
3. Draw the aldol product that results from an intramolecular aldol reaction involving a
base catalyst and the following dialdehyde.
O
H
OH
H
O
a) Explain why the intramolecular product you drew above is more likely to
form than the following product (assume a dilute solution of dialdehyde).
O
H
H
O
H
HO
O
b) In the lab you treat a concentrated solution of this dialdehyde with hydroxide
and the result is long polymer chains. Explain this finding.
4. Draw the two different aldol products that result from intramolecular aldol reactions
involving the di-aldehyde 3-methylhexandial and base.
5. In an aldol reaction one molecule of aldehyde reacts with base and becomes a
nucleophile, and one molecule of aldehyde serves as electrophile. For each product
you drew in the previous question indicate which aldehyede of the dialdehyde acted
as Nuc– and which acted as Elec+. Call the ends the 1-aldehyde and the 6-aldehyde.
6.
Read the assigned pages in your text and do the assigned problems.
Exercises for Part B
7. Draw the mechanism of the reaction in Model 4.
8. Draw the aldehydes or ketones that could be used to make the following aldol
products. (Note: Some of these products may not be formed in high yield due to the
fact that ketones are poor electrophiles.) Use Retrosynthesis-described in Model 2.
OH
O
O
HO
OH
O
target 1
target 2
target 3
OH O
target 4
9. Draw a new example of two different reactants (use aldehydes or ketones or one of
each) that would give a high yield of a single aldol product regardless of the way
they are mixed. And draw the product.
ChemActivity 34
Base Catalyzed Aldol Reactions
14
10. Draw a new example of two different reactants (use aldehydes or ketones or one of
each) that would give a high yield of a single aldol product only when one is slowly
added to the other.
a) Specify the correct procedure (e.g. add A to B or B to A)
b) Draw the product.
11. Draw a new example of two different reactants (use aldehydes and/or ketones) that
would give a mixture of four different aldol products and draw each product.
12. The structures shown below are called β-keto carbonyl compounds. Construct an
explanation for this name.
O
O
O
O
O
O
O
O
H
O
H
H
H
O
a)
O
Which H is the most acidic on the following β-keto carbonyl compound?
O
H
b)
Draw the conjugate base of the compound from a) including all important
resonance structures.
c)
Which of the following compounds do you expect to be more acidic?
Explain your reasoning.
O
Cmpd X =
O
O
Cmpd Y =
H
d)
Is your answer above consistent with the following pKa data for these
compounds: pKax = 9 and pKay = 17?
e)
When compounds X and Y are mixed with hydroxide, one mixed aldol-type
product is generated. Draw this product and show the mechanism of
formation. (Hint: consider which compound is more likely to react with base
and become the enolate nucleophile.)
13. Read the assigned pages in your text and do the assigned problems.
ChemActivity 34
Base Catalyzed Aldol Reactions
15
Exercises for Part C
14. Explain the following results. When cyclohexanone is treated with base at room
temperature a product with molecular formula C12H20O2 is recovered in 22% yield.
However, when cyclohexanone is treated with acid at room temperature a product
with molecular formula C12H18O is recovered in 92% yield.
15. In some cases the dehydration step is very down hill so it is nearly impossible to
isolate the aldol product. The reaction below is such an example:
O
O
OH
H
dilute, room temp.
(or acid)
acetone
benzaldehyde
a) Draw the aldol product and the α,β-unsaturated carbonyl products-E and Z
(dehydration products).
b) Construct an explanation for why the α,β-unsaturated carbonyl products are
much more stable than the aldol product. (The aldol product cannot be
isolated in this case, even if the reaction is run at very low temperature.)
16. Even in harsh basic conditions the following pair of carbonyl compounds gives a
very low yield of a single aldol product.
O
O
hot concentrated
base or acid
H
benzaldehyde
2,4-dimethyl-3-pentanone
a) Draw the most likely aldol product that results from this mixed aldol reaction.
b) Construct an explanation for why, in this case, the α,β-unsaturated carbonyl
compound cannot form under any conditions.
c) Explain why this reaction give as very low yield of aldol product.
d) Explain why, in this case, attempting to drive the reaction to the right by
boiling off water does not work.
17. The preparation of α,β-unsaturated carbonyl compounds is a subject of great interest
among synthetic organic chemists. The aldol method is perhaps the most elegant
way to form a new carbon-carbon bond, but there are other ways. Propose a
synthesis of the following target from the starting material given.
O
H
O
H
starting material
target
ChemActivity 34
Base Catalyzed Aldol Reactions
16
18. Certain compounds re-arrange in acidic or basic basic solution to form α,βunsaturated carbonyl compounds. Use curved arrows to construct a mechanism for
the following re-arrangement in base (HO–), then in acid (H3O+).
acid or base
O
O
catalysis
19. According to the equilibrium arrows, the rearrangement above is down hill. What is
the driving force for this reaction? (Explain why the product is lower in potential
energy/more stable than the reactant.)
20. Draw products that form when 2-butanone is heated in base at 50o C (RT = 25oC).
21. Design an efficient synthesis of each of the following target molecules. All carbon
atoms must come from the starting material/s given. Be sure to specify the
conditions of any aldol reactions.
O
Target
Starting
material
N
O
Cl
O
Br
Br
cyclohexanone
formaldehyde
O
O
H
acetone
benzaldehyde
methyl amine
toluene
acetaldehyde
hint: an acid chloride can be
made from a carboxylic acid
22. Read the assigned pages in your text and do the assigned problems.
ChemActivity 34
Base Catalyzed Aldol Reactions
17