20.1 Ketones and Aldehydes
• Common in biomolecules
• Important in the synthesis of many pharmaceuticals
• The basis upon which much of the remaining concepts
in this course will build
• The carbonyl group is common to both ketones and
aldehydes
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20.1 Ketones and Aldehydes –
Relevant Examples
• Identify the following as either an aldehyde or a ketone.
vanilla flavor
cinnamon flavor
spearmint flavor
almond flavor
Vanillin
Cinnamaldehyde
(R)-Carvone
Benzaldehyde
Steroids
Progesterone
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Testosterone
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20.2 Nomenclature of Aldehydes
1. Identify and name the parent chain:
–
–
For aldehydes, replace the e with an al.
Example:
–
–
Be sure that the parent chain includes the carbonyl carbon.
Example:
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20.2 Nomenclature of Aldehydes
1. Identify and name the parent chain:
–
–
Numbering the carbonyl group of the aldehyde takes priority
over other groups.
Example:
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20.2 Nomenclature of Aldehydes
1.
2.
3.
4.
•
Identify and name the parent chain.
Identify the name of the substituents (side groups)
Assign a locant (number) to each substituents.
Assemble the name alphabetically.
Name the following molecule.
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20.2 Nomenclature of Ketones
1. Identify and name the parent chain:
–
–
For ketones, replace the e with an one.
Example:
–
The locant (number showing where the C=O is located) can
be expressed before the parent name or before the suffix.
Example:
–
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20.2 Nomenclature of Ketones
1.
2.
3.
4.
•
Identify and name the parent chain.
Identify the name of the substituents (side groups).
Assign a locant (number) to each substituents.
Assemble the name alphabetically.
Name the following molecule.
•
Practice with SKILLBUILDER 20.1
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20.3 Preparing Aldehydes and
Ketones
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20.4 Carbonyls as Electrophiles
•
What makes the carbonyl carbon a good electrophile?
1. RESONANCE: There is a minor but significant contributor that
includes a formal 1+ charge on the carbonyl carbon.
–
What would the resonance hybrid look like for this carbonyl?
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20.4 Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile?
2. INDUCTION: The carbonyl carbon
is directly
attached to a very electronegative oxygen atom.
3. STERICS: How does an sp2 carbon compare to an sp3?
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20.4 Carbonyls as Electrophiles
•
•
•
Consider the factors: resonance, induction, and sterics.
Which should be MORE REACTIVE as an electrophile,
aldehydes or ketones? Explain WHY.
Example comparison:
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•
20.4 Nucleophilic Attack on a
Carbonyl
We want to analyze how nucleophiles attack carbonyls
and why some nucleophile react and others don’t.
–
•
Example attack:
If the nucleophile is weak, or if the attacking nucleophile
is a good leaving group, the reverse reaction will
dominate.
–
Reverse reaction:
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20.4 Nucleophilic Attack on a
Carbonyl
•
Show the nucleophilic attack for some other
nucleophiles. Nucleophiles to consider include OH–,
CN–, H–, R–, H2O.
•
When the nucleophile attacks, is the resulting
intermediate relatively stable or unstable? WHY?
If a nucleophile is also a GOOD LEAVING GROUP, is it
likely to react with a carbonyl? Explain WHY.
Compare attack on a carbonyl with attack on an alkyl
halide.
•
•
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20.4 Nucleophilic Attack on a
Carbonyl – Nucleophilic Addition
•
If the nucleophile is strong enough to attack and NOT a
good leaving group, then the full ADDITION will occur
(Mechanism 20.1).
•
The intermediate carries a negative charge, so it will
pick up a proton to become more stable.
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20.4 Nucleophilic Attack on a
Carbonyl
•
•
If the nucleophile is weak and reluctant to attack the
carbonyl, HOW could we improve its ability to attack?
We can make the carbonyl more electrophilic:
–
•
Adding an acid will help. HOW?
Consider the factors that make it electrophilic in the
first place (resonance, induction, and sterics).
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20.4 Nucleophilic Attack on a
Carbonyl – Nucleophilic Addition
•
With a weak nucleophile, the presence of an acid will
make the carbonyl more attractive to the nucleophile
so the full ADDITION can occur (Mechanism 20.2).
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20.4 Nucleophilic Attack on a
Carbonyl – Nucleophilic Addition
•
Is there a reason why acid is not used with strong
nucleophiles?
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20.5 Water as a Nucleophile
•
Is water generally a strong or weak nucleophile?
•
Show a generic mechanism for water attacking an
aldehyde or ketone.
Predict whether the nucleophilic attack is product
favored or reactant favored. WHY?
•
•
Would the presence of an acid improve the reaction?
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20.5 Water as a Nucleophile
•
If water were to attack the carbonyl, what likely
mechanism steps would follow?
•
Will the overall process be fast or slow?
•
Will the overall process be product or reactant
favored?
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20.5 Water as a Nucleophile
Acetone
Formaldehyde
Hexafluoroacetone
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20.5 Water as a Nucleophile
Acetone
Formaldehyde
Hexafluoroacetone
•
How do the following factors affect the
equilibria: entropy, induction, sterics?
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20.5 Water as a Nucleophile
•
To avoid the unstable intermediate with two formal
charges, the reaction can be catalyzed by a base
(Mechanism 20.3).
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20.5 Water as a Nucleophile
•
How does the base increase the rate of reaction? Will
it make the reaction more product-favored?
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20.5 Water as a Nucleophile
•
The reaction can also be catalyzed by an acid
(Mechanism 20.4).
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20.5 Water as a Nucleophile
•
How does the acid increase the rate of reaction? Will it
make the reaction more product-favored?
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20.5 Acetals – Formation
•
An alcohol acts as the nucleophile instead of water.
•
Notice that the reaction is under equilibrium and that
it is acid catalyzed.
Analyze the complete mechanism (Mechanism 20.5)
on the next slide.
Analyze how the acid allows the reaction to proceed
through lower energy intermediates.
•
•
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20.5 Acetals – Formation
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20.5 Acetals – Formation
•
After the hemiacetal is protonated in Mechanism 20.5,
the water leaving group leaves. Why is the water
leaving group pushed out INTRAMOLECULARLY?
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20.5 Acetals – Formation
•
You might imagine an INTERMOLECULAR collision that
causes the water to leave.
•
Why is the INTERMOLECULAR step unlikely?
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20.5 Acetals – Formation
Product favored
Reactant favored
5 and 6-membered cyclic acetals are generally product favored
•
Practice with SKILLBUILDER 20.2.
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20.5 Acetals – Formation
Product favored
Reactant favored
5 and 6-membered cyclic acetals are generally product favored
•
How do entropy, induction, sterics, and
Le Châtelier’s principle affect the equilibrium?
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20.5 Acetals – Equilibrium Control
•
•
Acetals can be attached and removed fairly easily.
Example:
•
Both the forward and reverse reactions are acid
catalyzed.
How does the presence of water affect which side the
equilibrium will favor?
•
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20.5 Acetals – Protecting Groups
•
•
We can use an acetal to selectively protect an
aldehyde or ketone from reacting in the presence of
other electrophiles.
Fill in necessary reagents or intermediates.
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20.5 Acetals – Protecting Groups
•
Fill in necessary reagents or intermediates.
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20.6 Primary Amine Nucleophiles
•
As a nucleophile, are amines stronger or weaker than
water?
–
•
•
•
If you want an amine to attack a carbonyl carbon, will a
catalyst be necessary?
Will an acid (H+) or a base (OH-) catalyst be most likely
to work? WHY?
What will the product most likely look like? Keep in
mind that entropy disfavors processes in which two
molecules combine to form one.
Analyze the complete mechanism
(Mechanism 20.6) on the next slide.
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20.6 Primary Amine Nucleophiles
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20.6 Primary Amine Nucleophiles
•
The mechanism requires an acid catalyst. Note that the
optimal pH to achieve a fast reaction is around 4 or 5.
•
Practice with SKILLBUILDER 20.3.
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20.6 Primary Amine Nucleophiles
•
Why does the reaction slow down below pH 4?
•
Why does the reaction slow down when the pH is
greater than 5?
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20.6 Primary Amine Nucleophiles vs.
Secondary Amine Nucleophiles
•
A proton transfer alleviates
the +1 charge in both
mechanisms. The difference
occurs in the LAST step.
–
–
•
For 1° amines (Mechanism
20.6): the NITROGEN atom loses
a proton directly.
For 2° amines (Mechanism 20.7):
a neighboring CARBON atom
loses a proton.
Practice with SKILLBUILDER
20.4.
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20.7 Wolff-Kishner Reduction
•
Reduction of a carbonyl to an alkane:
•
Hydrazine attacks the carbonyl via Mechanism 20.6 to
form the hydrazone, which is structurally similar to an
imine.
The second part of the mechanism is shown on the
next slide (Mechanism 20.8).
•
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20.7 Wolff-Kishner Reduction
•
In general, carbanions are unstable and reluctant to
form.
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20.7 Wolff-Kishner Reduction
•
•
What drives this reaction forward?
Is OH- a catalyst in the mechanism?
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20.8 Mechanism Strategies
•
Note the many similarities between the acid catalyzed
mechanisms we have discussed:
–
Carbonyl is protonated first:
•
•
–
–
–
•
Makes the carbonyl more electrophilic
Avoids negative formal charge on the intermediate
Avoid high energy intermediate with two formal charges
Acid protonates leaving group so that it is stable and neutral
upon leaving
Last step of mechanism involves a proton transfer forming a
neutral product
Overall: under acidic conditions, reaction
species should either be neutral or have a +1
formal charge.
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20.8 Mechanism Strategies –
Sulfur Nucleophiles
•
Under acidic conditions, thiols react nearly the same
as alcohols. Examples:
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Klein, Organic Chemistry 1e
20.8 Mechanism Strategies –
Alternative to Wolff-Kishner
•
Conditions to convert a ketone into an alkane:
1. A thioacetal is formed via an acid catalyzed nucleophilic
addition mechanism.
2. Raney Ni transfers H2 molecules to the thioacetal converting
it into an alkane.
•
Recall the Clemmenson (Section 19.6) reduction can
also be used to promote this conversion.
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20.9 Hydrogen Nucleophiles
•
•
•
We rarely see hydrogen acting as a nucleophile. WHY?
What role does hydrogen normally play in
mechanisms?
To be a nucleophile, hydrogen must have a pair of
electrons. H:1- is called hydride
Reagents that produce hydride ions include LiAlH4
(LAH) and NaBH4. Hydrides will react readily with
carbonyls.
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20.9 Hydrogen Nucleophiles
•
•
•
•
•
Identify the nucleophile.
Will the reaction be more effective under acidic or
under basic conditions? WHY?
Show a complete mechanism (Mechanism 20.9).
Analyze the reversibility (or irreversibility )of each step.
Describe necessary experimental conditions.
Why are there two steps in the reaction?
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20.10 Carbon Nucleophiles
•
•
Carbon doesn’t often act as a nucleophile. WHY? What
ROLE does carbon most often play in mechanisms?
To be a nucleophile, carbon must have a pair of
electrons it can use to attract an electrophile:
1. A carbanion with a -1 charge and an available pair of
electrons. However, carbanions are relatively unstable and
reluctant to form.
2. A carbon attached to a very low electronegativity
atom such as a Grignard. Analyze the electrostatics
of the Grignard reagent.
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20.10 Grignard Example
•
•
•
•
•
Identify the nucleophile.
Will the reaction be more effective under acidic or
under basic conditions? WHY?
Show a complete mechanism (Mechanism 20.10).
Three equivalents of the Grignard are necessary.
Analyze the reversibility or irreversibility of each step.
Describe necessary experimental conditions.
Why are there two steps in the reaction?
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20.10 Cyanohydrin
•
The cyanide ion can act as a nucleophile.
•
Disadvantage: EXTREME toxicity and volatility of
hydrogen cyanide.
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20.10 Cyanohydrin
•
Advantage: synthetic utility
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20.10 Wittig Reaction
•
•
•
•
Like the Grignard and the cyanohydrin, the Wittig
reaction can be very synthetically useful. What do
these three reactions have in common?
Example:
Similar to the Grignard, one carbon is a nucleophile
and the other is an electrophile.
Identify which is which.
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20.10 Wittig Reaction –
Wittig Reagent or Ylide
•
The ylide carries a formal negative charge on a carbon.
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20.10 Wittig Reaction –
Wittig Reagent or Ylide
•
•
In general, carbons are not good at stabilizing a
negative charge. Are there any factors that allow the
ylide to stabilize its formal negative charge?
Why is the charged resonance contributor the major
contributor?
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20.10 Wittig Reaction
•
The Wittig mechanism (Mechanism 20.12):
•
Which of the steps in the reaction is mostly likely the
slowest? WHY?
The formation of the especially stable
triphenylphoshine oxide drives the equilibrium
forward.
•
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20.10 Wittig Reaction –
Formation of an ylide
•
•
•
To make an ylide, you start with an alkyl halide and
triphenylphosphine.
Example:
The first step is a simple substitution. The second step
is a proton transfer.
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20.10 Wittig Reaction –
Formation of an Ylide
•
Is the base used in the second step strong or weak?
Why is such a base used?
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20.10 Wittig Reaction – Overall
•
•
Overall, the Wittig reaction allows two molecular
segments to be connected through a C=C.
Example:
–
–
–
Describe the reagents and conditions necessary for the
reaction to take place.
Give a mechanism.
Note how the colored segments are connected.
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20.10 Wittig Reaction – Overall
•
Overall, the Wittig reaction allows two molecular
segments to be connected through a C=C.
•
Use a retrosynthetic analysis to determine a different
set of reactants that could be used to make the target.
Practice with SKILLBUILDER 20.6.
•
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20.11 Baeyer-Villiger
•
•
An oxygen is inserted between a carbonyl carbon and
neighboring group.
Mechanism 20.13 shows the movement of electrons.
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20.11 Baeyer-Villiger
•
Which step in the equilibrium is most likely the
slowest? WHY?
•
Note the last step is not reversible. WHY?
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20.11 Baeyer-Villiger Example
•
If the carbonyl is asymmetrical, use the following chart
to determine which group migrates most readily.
•
Predict the product of the reaction, and give a
complete mechanism.
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20.12 Synthetic Strategies
•
Recall the questions we ask to aid our analysis1. Is there a change in the carbon skeleton?
2. Is there a change in the functional group?
•
•
Changes to the
carbon skeleton:
C–C bond formation
Name each reaction.
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20.12 Synthetic Strategies
•
Recall the questions we ask to aid our analysis
1. Is there a change in the carbon skeleton?
2. Is there a change in the functional group?
•
•
Changes to the
carbon skeleton:
C–C bond cleavage
Name the reaction.
•
Practice with SKILLBUILDER 20.7.
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20.13 Spectroscopic Analysis –
Infrared Spectroscopy
•
STRONG peak for the C=O stretch:
•
typical carbonyl
typical conjugated carbonyl
Aldehydes also give WEAK peaks around
2700–2800 cm-1 for the C–H stretch.
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20.13 Spectroscopic Analysis –
NMR Spectroscopy
•
Protons neighboring a carbonyl are weakly deshielded
by the oxygen.
•
Aldehyde protons are strongly deshielded, usually
appearing around 9 or 10 ppm.
–
•
Why is the aldehyde proton shifted so far downfield?
In the 13C NMR, the carbonyl carbon generally appears
around 200 ppm.
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20.13 Spectroscopic Analysis –
NMR Spectroscopy
•
Predict 1H NMR shifts, splitting, and integration and 13C
shifts for the following molecule.
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