Chapter 20 Aldehydes and Ketones Suggested Problems –

Ketones and Aldehydes Common in biomolecules Important in the synthesis of many pharmaceuticals The carbonyl group is common to both ketones and aldehydes

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

Nomenclature of Aldehydes 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

Nomenclature of Aldehydes Identify and name the parent chain Numbering the carbonyl group of the aldehyde takes priority over other groups Example:

Nomenclature of Aldehydes 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 Example: Name the following molecule E-7-hydroxy-3-propylhept-4-enal

Nomenclature of Ketones 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

Nomenclature of Ketones 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 Example: Name the following molecule Practice with SkillBuilder 20.1 E-1-hydroxy-5-propyloct-3-en-2,6-dione

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.

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

Carbonyls as Electrophiles 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?

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: Induction and sterics

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:

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

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! Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics) Adding an acid will help. HOW?

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)

Nucleophilic attack on a Carbonyl Is there a reason why acid is not used with strong nucleophiles?

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? Product disfavored by both entropy and enthalpy (formation of charges). YES, it would activate the carbonyl

Water as a nucleophile If water were to attack the carbonyl, what likely mechanism steps would follow? Will the overall process be product or reactant favored? See next slide for examples

Water as a nucleophile Acetone Formaldehyde Hexafluoroacetone

Water as a nucleophile Acetone Formaldehyde How do these factors affect the equilibria: entropy, induction, sterics? Acetone Formaldehyde Hexafluoroacetone

Water as a nucleophile The reaction can be catalyzed by a base (mechanism 20.3)

Water as a nucleophile The reaction can also be catalyzed by an acid (mechanism 20.4)

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

Acetal Formation

Acetal Formation Product favored Reactant favored Practice with SkillBuilder 20.2 5 and 6-membered cyclic acetals are generally product favored

Acetal Formation How do entropy, induction, sterics, and LeChateleir’s Principle affect the equilibrium? Product favored Reactant favored 5 and 6-membered cyclic acetals are generally product favored

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?

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

Acetal Protecting Groups Fill in necessary reagents or intermediates

Acetal Protecting Groups Fill in necessary reagents or intermediates

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

Primary Amine nucleophiles

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

Primary Amine nucleophiles Why does the reaction slow down at pH below 4? Why does the reaction slow down at pH greater than 5?

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

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)

Wolff-Kishner Reduction In general, carbanions are unstable and reluctant to form

Wolff-Kishner Reduction What drives this reaction forward? Loss of N2

Hydrolysis of Acetals, Imines, and Enamines Hydrolysis (using water to break bonds) can occur with an acid catalyst See mechanism on next slide

Hydrolysis of Acetals, Imines, and Enamines How can the equilibrium be controlled to give either acetal formation or hydrolysis?

Hydrolysis of Acetals, Imines, and Enamines 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

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

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

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

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) Describe necessary experimental conditions

Carbon nucleophiles Carbon doesn’t often act as a nucleophile. WHY? 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

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 Describe necessary experimental conditions (why are there two steps in the reaction?)

Cyanohydrin The cyanide ion can act as a nucleophile Disadvantage: EXTREME toxicity and volatility of hydrogen cyanide

Cyanohydrin Advantage: synthetic utility

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

Wittig Reagent or YLIDE The ylide carries a formal negative charge on a carbon

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?

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

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

Formation of an ylide Is the base used in the second step strong or weak? Why is such a base used?

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

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

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

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

Baeyer-Villiger An oxygen is inserted between a carbonyl carbon and neighboring group

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

Baeyer-Villiger Example Use the following chart to determine which group migrates most readily Predict the product, and give a complete mechanism

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

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

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

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

Additional Practice Problems Give a reasonable name for the molecule with both an aldehyde and ketone below. (S)-3,3-dichloro-4-cyclohexyl-heptan-6-oneal

Additional Practice Problems Give necessary reagents to make the carbonyl below from an alkyne and also from an alkyl halide without altering the number of carbons

Additional Practice Problems Predict the major product and give a complete mechanism.

Additional Practice Problems Predict the major product and give a complete mechanism.

Additional Practice Problems Predict the structure of the enamine product in the reaction below and show the last step of the mechanism.

Additional Practice Problems Give necessary Wittig reagents to synthesize the molecule below and show a complete mechanism.

Additional Practice Problems Give necessary Wittig reagents to synthesize the molecule below and show a complete mechanism.

Additional Practice Problems Give reagents necessary for the synthesis below

Additional Practice Problems Give reagents necessary for the synthesis below Alternative synthesis