ch20 - laney college · 4/18/2012 3 • show the nucleophilic attack for some other nucleophiles....

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• Common in biomolecules

• Important in the synthesis of many pharmaceuticals

• The basis upon which much of the remaining concepts in this course will build

20.1 Ketones and Aldehydes

• The carbonyl group is common to both ketones and aldehydes

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e20 -1

20.1 Ketones and Aldehydes –Relevant Examples


1. Identify and name the parent chain:– For aldehydes, replace the e with an al.

– Example:

20.2 Nomenclature of Aldehydes

– Be sure that the parent chain includes the carbonyl carbon.

– Example:


1. Identify and name the parent chain:– Numbering the carbonyl group of the aldehyde takes priority

over other groups.

– Example:



1. Identify and name the parent chain.

2. Identify the name of the substituents (side groups)

3. Assign a locant (number) to each substituents.

4. Assemble the name alphabetically.


p y

• Name the following molecule.


1. Identify and name the parent chain:– For ketones, replace the e with an one.

– Example:

20.2 Nomenclature of Ketones

– 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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1. Identify and name the parent chain.

2. Identify the name of the substituents (side groups).

3. Assign a locant (number) to each substituents.

4. Assemble the name alphabetically.

20.2 Nomenclature of Ketones

p y

• Name the following molecule.

• Practice with SKILLBUILDER 20.1


20.3 Preparing Aldehydes and Ketones


• 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.

20.4 Carbonyls as Electrophiles

– What would the resonance hybrid look like for this carbonyl?


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?


• Consider the factors: resonance, induction, and sterics.

• Which should be MORE REACTIVE as an electrophile, aldehydes or ketones? Explain WHY.

• Example comparison:



• We want to analyze how nucleophiles attack carbonyls and why some nucleophile react and others don’t.

– Example attack:

20.4 Nucleophilic Attack on a Carbonyl

• 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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• 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.


• If the nucleophile is strong enough to attack and NOT a good leaving group, then the full ADDITION will occur (Mechanism 20.1).

20.4 Nucleophilic Attack on a Carbonyl – Nucleophilic Addition

• The intermediate carries a negative charge, so it will pick up a proton to become more stable.


• 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).


• 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).



• Is there a reason why acid is not used with strong nucleophiles?



• Is water generally a strong or weak nucleophile?

• Show a generic mechanism for water attacking an aldehyde or ketone.

20.5 Water as a Nucleophile

• 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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• 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?



Acetone

Formaldehyde


Formaldehyde

Hexafluoroacetone


Acetone

Formaldehyde

• How do the following factors affect the equilibria: entropy, induction, sterics?


Formaldehyde

Hexafluoroacetone

• To avoid the unstable intermediate with two formal charges, the reaction can be catalyzed by a base (Mechanism 20.3).




• How does the base increase the rate of reaction? Will it make the reaction more product‐favored?


• The reaction can also be catalyzed by an acid (Mechanism 20.4).



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• How does the acid increase the rate of reaction? Will it make the reaction more product‐favored?


• An alcohol acts as the nucleophile instead of water.

20.5 Acetals – Formation

• 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.




• After the hemiacetal is protonated in Mechanism 20.5, the water leaving group leaves. Why is the water leaving group pushed out INTRAMOLECULARLY?



• You might imagine an INTERMOLECULAR collision that causes the water to leave.


• Why is the INTERMOLECULAR step unlikely?



• Practice with SKILLBUILDER 20.2.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e20 -30

5 and 6-membered cyclic acetals are generally product favored

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• How do entropy, induction, sterics, and Le Châtelier’s principle affect the equilibrium?


5 and 6-membered cyclic acetals are generally product favored

• Acetals can be attached and removed fairly easily.

• Example:

20.5 Acetals – Equilibrium Control

• Both the forward and reverse reactions are acid catalyzed.

• How does the presence of water affect which side the equilibrium will favor?


• 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.

20.5 Acetals – Protecting Groups


• Fill in necessary reagents or intermediates.

20.5 Acetals – Protecting Groups


• 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‐) catal st be most likel

20.6 Primary Amine Nucleophiles

• 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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• 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.


• Why does the reaction slow down below pH 4?


• Why does the reaction slow down when the pH is greater than 5?


• A proton transfer alleviates the +1 charge in both mechanisms. The difference occurs in the LAST step.

– For 1° amines (Mechanism

20.6 Primary Amine Nucleophiles vs. Secondary Amine Nucleophiles

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.



• Reduction of a carbonyl to an alkane:

20.7 Wolff‐Kishner Reduction

• 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).


• In general, carbanions are unstable and reluctant to form.



• What drives this reaction forward?

• Is OH‐ a catalyst in the mechanism?



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• 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

20.8 Mechanism Strategies

– 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.


• Under acidic conditions, thiols react nearly the same as alcohols. Examples:

20.8 Mechanism Strategies –Sulfur Nucleophiles


• Conditions to convert a ketone into an alkane:

20.8 Mechanism Strategies –Alternative to Wolff‐Kishner

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.


• 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 l H 1 i ll d h d id

20.9 Hydrogen Nucleophiles

electrons. H:1‐ is called hydride

• Reagents that produce hydride ions include LiAlH4

(LAH) and NaBH4. Hydrides will react readily with carbonyls.


• Identify the nucleophile.

• Will the reaction be more effective under acidic or

20.9 Hydrogen Nucleophiles

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?


• 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:

20.10 Carbon Nucleophiles

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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• Identify the nucleophile.

• Will the reaction be more effective under acidic or d b i diti ? WHY?

20.10 Grignard Example1)

2) dilute HCl (aq)

OH

O

O

BrMg3 equivalents

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?


• The cyanide ion can act as a nucleophile.

20.10 Cyanohydrin

• Disadvantage: EXTREME toxicity and volatility of hydrogen cyanide.


• Advantage: synthetic utility

20.10 Cyanohydrin


• Like the Grignard and the cyanohydrin, the Wittig reaction can be very synthetically useful. What do these three reactions have in common?

• Example:

20.10 Wittig Reaction

• Similar to the Grignard, one carbon is a nucleophile and the other is an electrophile.

• Identify which is which.


• The ylide carries a formal negative charge on a carbon.

20.10 Wittig Reaction –Wittig Reagent or Ylide


• In general, carbons are not good at stabilizing a

20.10 Wittig Reaction –Wittig Reagent or Ylide

g , g gnegative 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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• The Wittig mechanism (Mechanism 20.12):

20.10 Wittig Reaction

• 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.


• To make an ylide, you start with an alkyl halide and triphenylphosphine.

• Example:

20.10 Wittig Reaction –Formation of an ylide

• The first step is a simple substitution. The second step is a proton transfer.


• Is the base used in the second step strong or weak? Why is such a base used?

20.10 Wittig Reaction –Formation of an Ylide


• Overall, the Wittig reaction allows two molecular segments to be connected through a C=C.

• Example:

20.10 Wittig Reaction – Overall

O

– Describe the reagents and conditions necessary for the reaction to take place.

– Give a mechanism.

– Note how the colored segments are connected.


Br

• Overall, the Wittig reaction allows two molecular segments to be connected through a C=C.

20.10 Wittig Reaction – Overall

retro1.

• Use a retrosynthetic analysis to determine a different set of reactants that could be used to make the target.

• Practice with SKILLBUILDER 20.6.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e20 -59

2.

• An oxygen is inserted between a carbonyl carbon and neighboring group.

• Mechanism 20.13 shows the movement of electrons.

20.11 Baeyer‐Villiger


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• Which step in the equilibrium is most likely the slowest? WHY?

20.11 Baeyer‐Villiger

• Note the last step is not reversible. WHY?


• 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

20.11 Baeyer‐Villiger Example

complete mechanism.


• 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?

20.12 Synthetic Strategies

• Changes to the carbon skeleton: C–C bond formation

• Name each reaction.


• 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

20.12 Synthetic Strategies

carbon skeleton: C–C bond cleavage

• Name the reaction.



• STRONG peak for the C=O stretch:

20.13 Spectroscopic Analysis –Infrared Spectroscopy

typical carbonyl typical conjugated carbonyl

• Aldehydes also give WEAK peaks around 2700–2800 cm‐1 for the C–H stretch.


• Protons neighboring a carbonyl are weakly deshielded by the oxygen.

20.13 Spectroscopic Analysis –NMR Spectroscopy

• 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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• Predict 1H NMR shifts, splitting, and integration and 13C shifts for the following molecule.

20.13 Spectroscopic Analysis –NMR Spectroscopy

O


O

HO

ch20 - laney college · 4/18/2012 3 • show the nucleophilic attack for some other nucleophiles....

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