Organic Chemistry Second Edition Chapter 20 David Klein

Organic Chemistry Second Edition Chapter 20 David Klein
Aldehydes and Ketones Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.1 Relevant Examples Identify the following as either an aldehyde or a ketone Shows relevant examples and gives students practice recognizing the structural difference between aldehydes and ketones Steroids Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.3 Preparing Aldehydes and Ketones
Some of the text from tables 20.1 and 20.2 could be removed so that the structures could be larger. Instructor could briefly explain these reactions. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.4 Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile? 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? It helps to get a detailed understanding of what makes molecules reactive before looking at the specific reactions they undergo Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

What makes the carbonyl carbon a good electrophile? Induction – The carbonyl carbon is directly attached to a very electronegative oxygen atom Sterics - How does an sp2 carbon compare to an sp3? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Consider the factors: resonance, induction, and sterics Which should be more reactive as an electrophile, aldehydes or ketones? Explain WHY! Example comparison: Instructor would explain how the sterics and induction of the R groups attached to the ketone makes the carbonyl less electrophilic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.4 Nucleophilic attack on a Carbonyl
We want to analyze how nucleophiles attack carbonyls and why some nucleophile react and others don’t If the nucleophile is weak, or if the attacking nucleophile is a good leaving group, the reverse reaction will dominate Example attack: Reverse reaction: Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Students should get a sense for how the properties of the nucleophile can affect whether the attack is likely to take place with emphasis on the quality of the nucleophile as a leaving group. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.4 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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! Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics) Adding an acid will help. HOW? It is nice to show how the addition of the acid makes the carbonyl more electrophilic by emphasizing the reasons that explained why it was electrophilic to begin with. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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) After giving students a chance to think about it, the question at the bottom of the slide can be answered by the instructor: the acid would most likely protonate the nucleophile if the nucleophile were strong, which would decrease its ability to attack the carbonyl Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Is there a reason why acid is not used with strong nucleophiles? After giving students a chance to think about it, the question at the bottom of the slide can be answered by the instructor: the acid would most likely protonate the nucleophile if the nucleophile were strong, which would decrease its ability to attack the carbonyl Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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? These questions will help the class to walk through the analysis whereby they can predict an overall mechanism, analyze the kinetics and thermodynamics of the process, and predict that the intermediate will form infrequently because of its formal charges (high activation energy to form) and that the overall process is probably reactant favored due to entropy. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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? See next slide for examples These questions will help the class to walk through the analysis whereby they can predict an overall mechanism, analyze the kinetics and thermodynamics of the process, and predict that the intermediate will form infrequently because of its formal charges (high activation energy to form) and that the overall process is probably reactant favored due to entropy. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Water as a nucleophile Acetone Formaldehyde Hexafluoroacetone

20.5 Water as a nucleophile Acetone Formaldehyde
How do these factors affect the equilibria: entropy, induction, sterics? Acetone Formaldehyde Hexafluoroacetone Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Water as a nucleophile How does it increase the rate of reaction? Will it make the reaction more product favored? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Water as a nucleophile How does the acid increase the rate of reaction? Will it make the reaction more product favored? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal Formation Klein, Organic Chemistry 2e

20.5 Acetal Formation After the hemiacetal is protonated in mechanism 20.5, the water leaving group leaves. Why is the water leaving group pushed out intramolecularly? Instructor could describe how sterics prevents attack at the crouded carbon, which is essentially tertiary. Also, because the OR group can intramolecularly donate electrons pushing out the leaving group, that intramolecular reaction may happen more often as it won’t require a specifically oriented intermolecular collision. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal Formation You might imagine an intermolecular collision that causes the water to leave Why is the intermolecular step unlikely? Instructor could describe how sterics prevents attack at the crouded carbon, which is essentially tertiary. Also, because the OR group can intramolecularly donate electrons pushing out the leaving group, that intramolecular reaction may happen more often as it won’t require a specifically oriented intermolecular collision. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal Formation Practice with SkillBuilder 20.2 Product favored
Reactant favored 5 and 6-membered cyclic acetals are generally product favored Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal 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? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.5 Acetal Protecting Groups
Fill in necessary reagents or intermediates Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 These questions will help the class to walk through the analysis to compare amines to nucleophiles we have already talked about in detail (water) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.6 Primary Amine nucleophiles
These questions will help the class to walk through the analysis to compare amines to nucleophiles we have already talked about in detail (water) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.6 Secondary vs. Primary Amines
A proton transfer alleviates the +1 charge in both mechanisms. The difference occurs in the last step 1 ° AMINE (mechanism 20.6): the NITROGEN atom loses a proton directly 2 ° AMINE (mechanism 20.7): a neighboring CARBON atom loses a proton Practice with SkillBuilder 20.4 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.6 Wolff-Kishner Reduction
Reduction of a carbonyl to an alkane Hydrazine attacks the carbonyl via mechanism 20.6 to form the hydrozone, which is structurally similar to an imine The second part of the mechanism is shown on the next slide (mechanism 20.8) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 condition, reaction species should either be neutral or have a +1 formal charge Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.7 Hydrolysis of Acetals, Imines, and Enamines
Hydrolysis (using water to break bonds) can occur with an acid catalyst See mechanism on next slide Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Hydrolysis of imines and enamines undergoes a very similar mechanism under acidic conditions Hydrolysis is not effective when a base is used as the catalyst Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.8 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 and NaBH4. Hydride will react readily with carbonyls Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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?) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Examples: A carbanion with a -1 charge and available pair of electrons. However, carbanions are relatively unstable and reluctant to form A carbon attached to a very low electronegativity atom such as a Grignard. Analyze the electrostatics of the Grignard reagent c Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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?) Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.10 Cyanohydrin The cyanide ion can act as a nucleophile
Disadvantage: EXTREME toxicity and volatility of hydrogen cyanide Forming a C-C bond allows us to build complexity in the molecule. Also, CN group can later be used to give a variety of other functional groups such as amines or carboxylic acids Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.10 Cyanohydrin Advantage: synthetic utility
Forming a C-C bond allows us to build complexity in the molecule. Also, CN group can later be used to give a variety of other functional groups such as amines or carboxylic acids Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Emphasis on how reactions that form new C-C bonds are useful to build up complex molecules Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.10 Wittig Reagent or YLIDE
The ylide carries a formal negative charge on a carbon The nearby formal + charge and the resonance act to help stabilize the carbanion. Note the difficulty in overlapping orbitals between carbon and phosphorus due to their different sizes. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.10 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? The nearby formal + charge and the resonance act to help stabilize the carbanion. Note the difficulty in overlapping orbitals between carbon and phosphorus due to their different sizes. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Note the rare 4-membered ring intermediate Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.10 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.11 Baeyer-Villiger Which step in the equilibrium is most likely the slowest? WHY? Note the last step is not reversible. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Predict the product of the reaction, and give a complete mechanism

20.12 Synthetic Strategies Recall the questions we ask to aid our analysis Is there a change in the carbon skeleton? Is there a change in the functional group? Changes to carbon skeleton: C-C bond formation Name each reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

20.12 Synthetic Strategies Recall the questions we ask to aid our analysis Is there a change in the carbon skeleton? Is there a change in the functional group? Changes to carbon skeleton: Carbon-Carbon bond cleavage – name the reaction Practice with SkillBuilder 20.7 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems
Give a reasonable name for the molecule with both an aldehyde and ketone below. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Give necessary reagents to make the carbonyl below from an alkyne and also from an alkyl halide without altering the number of carbons Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Organic Chemistry Second Edition Chapter 20 David Klein

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