Objectives for Chapter 22 Readily convert the enol to the keto tautomers and vice versa under both acidic and basic conditions Explain which tautomer is the favored one and understand the exceptions Explain the typical roles adopted by the keto and enol forms in reactivity and apply this information to drawing mechanisms Predict the products and draw the mechanisms for Halogenation under acidic conditions Halogenation under basic conditions Haloform reaction (basic conditions) Malonic ester synthesis (basic conditions) Acetoacetic ester synthesis (basic conditions) Predict the products, draw the mechanism and give the intermediates for The Hell-Volhard-Zelinski reaction Predict the acidity of α-hydrogens, use resonance structures to support your predictions, and relate this to the use of LDA S. Keyser/A.Rosan Chem 350

What is the relationship between the keto and enol forms? 22.1 Keto-enol tautomerism What is the relationship between the keto and enol forms? Resonance forms Constitutional isomers Conformational isomers I’m not sure S. Keyser/A.Rosan Chem 350

22.1 Keto-enol tautomerism Keto-enol tautomers are constitutional isomers S. Keyser/A.Rosan Chem 350

22.1 Keto-enol tautomerism Based on your previous experience, which tautomer is more stable? (Why?) Enol Keto I’m not sure S. Keyser/A.Rosan Chem 350

22.1 Keto-enol tautomerism Keto-enol tautomers are constitutional isomers Typically the keto form is favored Cyclohexanone is 99.9999% keto v 0.0001% enol S. Keyser/A.Rosan Chem 350

22.1 Keto-enol tautomerism: FYI Q: Why might the enol be slightly more favorable? K = 10-6 Energy K = 3.2 K = 1013 Q: Why might the enol be so favorable? S. Keyser/A.Rosan Chem 350

22.1 Keto-enol tautomerism Q: Mechanism under basic conditions? Q: Acidic conditions? (Where should we protonate to get to the keto form??) S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols A double-check: If water acts as an acid, what is the charge for its conjugate base? Negative Positive I’m not sure S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols Which hydrogens are the most acidic? (Where would a negative charge be best stabilized?) Hs at alpha position Hs at beta position Hs at gamma position I’m not sure S. Keyser/A.Rosan Chem 350

The keto form is an okay …. 22.2 Reactivity of enols The keto form is an okay …. Nucleophile Electrophile I’m not sure S. Keyser/A.Rosan Chem 350

The keto form becomes a great electrophile under …. conditions 22.2 Reactivity of enols The keto form becomes a great electrophile under …. conditions Acidic Basic I’m not sure S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols Keto form = electrophile React here Weak Strong S. Keyser/A.Rosan Chem 350

The enol form is a tolerable …. 22.2 Reactivity of enols The enol form is a tolerable …. Nucleophile Electrophile I’m not sure S. Keyser/A.Rosan Chem 350

The enol becomes a great nucleophile under …. conditions 22.2 Reactivity of enols The enol becomes a great nucleophile under …. conditions Acidic Basic I’m not sure S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols Keto form = electrophile Enol form = nucleophile React here Weak Strong React here? OR React here? Weak Strong Enol Enolate S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols Answer the following questions with your group members. Example. Draw the resonance structure for the enolate. Q: Suppose we add BrCH3 to our enolate. Which is the nucleophile and which is the electrophile? Q: Where could our electrophile be added? (Two possibilities!) Q: Which will be preferred? (Which addition is irreversible?) S. Keyser/A.Rosan Chem 350

22.2 Reactivity of enols ChemActivity 25 Answer CTQs #5-6 on p451 (CTQ#6). S. Keyser/A.Rosan Chem 350

LDA is a Great nucleophile only Great base only 22.2 Reactivity of enols LDA is a Great nucleophile only Great base only Great as a nucleophile AND as a base I’m not sure CA25: CTQ#6 S. Keyser/A.Rosan Chem 350

Which of the following reagents will not quantitatively form an enolate anion upon reaction with 2-propanone (pKA = 19) ? 1. 2. 4. 3. Choice One Choice Two Choice Three Choice Four

Which of the following will occur when the following optically active compound is placed in dilute acid? It will form an acetal. It will form a diol. It will become an alcohol. It will lose its optical activity. none of these

What is the predominant enol form of the following molecule? 1. 2. 3. 4. none of these is favored over the others 5. 1 2 3 4 5

S. Keyser/A.Rosan Chem 350

Do Chem Act 25 Model 3 and 4

Let’s complete CTQ 9 Perfect, no errors Only small error(s) At least one major error Not sure

Identify the expected major product of the following reaction. 1. 2. 3. 4. 5. 1 2 3 4 5

Keto and Enol forms are in Equilibrium

Keto and Enol forms are in Equilibrium Note that these changes do not happen stepwise, but molecule by molecule.

10.

Which of the above carbonyl compounds is most acidic?

Rank the above from least to most acidic. A < B < C < D D < B < A < C D < A < C < B D < A < B < C C < B < A < D

22.3 α-halogenation of aldehydes and ketones Q: Under basic conditions, which form predominates: enol or enolate? Q: Categorize the three reactants as electrophiles or nucleophiles. Which will react with which? Q: What should the first step of the mechanism below be? BASIC CONDITIONS Example. Draw the mechanism for the following transformation. Note to self: Don’t erase this mechanism until the next group slide. S. Keyser/A.Rosan Chem 350

22.3 α-halogenation of aldehydes and ketones Q: Under acidic conditions, which form predominates: enol or enolate? ACIDIC CONDITIONS Example. Draw the mechanism for the following transformation. Note to self: Don’t erase this mechanism until the next group slide. S. Keyser/A.Rosan Chem 350

Which statement is true? 22.3 α-halogenation of aldehydes and ketones Which statement is true? Multiple halogenations occur under acidic conditions only Multiple halogenations occur under basic conditions only Multiple halogenations occur under both acidic and basic conditions I’m not sure S. Keyser/A.Rosan Chem 350

Which alpha hydrogen will be more acidic? 22.3 α-halogenation of aldehydes and ketones Which alpha hydrogen will be more acidic? propanal’s 2-bromopropanal’s I’m not sure S. Keyser/A.Rosan Chem 350

22.3 α-halogenation of aldehydes and ketones Example. Halogenation occurs multiple times under basic conditions and only once under acidic conditions. In your groups, explain why halogenation occurs multiple times under basic conditions. Then explain why only one halogenation can occur under acidic conditions. (Which mechanistic step will be difficult to do?) S. Keyser/A.Rosan Chem 350

Predict the product. I’m not sure 22.3 α-halogenation of aldehydes and ketones Predict the product. I’m not sure S. Keyser/A.Rosan Chem 350

22.6 Halogenation/reactivity of enolates Now we’ll be investigating this reaction specifically in lab. Make sure to fill this in after you’ve completed it! For now, we’ll wait! Example. Predict the product for this reaction. S. Keyser/A.Rosan Chem 350

Let’s talk about halogenation of carboxylic acids… First, we must evaluate the ease of forming the enol/enolate from carboxylic acids… Worldofstock.com S. Keyser/A.Rosan Chem 350

22.4 Alpha bromination of carboxylic acids Which α protons are more acidic or easier to remove: those of carboxylic acids or ketones? (Reasoning?) Carboxylic acids Ketones I don’t know S. Keyser/A.Rosan Chem 350

22.4 α-bromination of carboxylic acids Carboxylic acids  α-brominated carboxylic acids The enols of carboxylic acids are more difficult to access than those of aldehydes/ketones; specific reaction conditions are required = Hell-Volhard-Zelinskii reaction (HVZ). 1) PBr3, Br2; 2) H2O Q: What does PBr3 give as a product? Example. Draw the mechanism for the reaction. Know reagents and products. Be able to figure out mechanism if given the intermediates! HBr is floating around now S. Keyser/A.Rosan Chem 350

Now for acidity trends for carboxylic acids, aldehydes and ketones, and other functional groups! Worldofstock.com S. Keyser/A.Rosan Chem 350

Which α protons are more acidic? (Why?) 22.5 Acidity of α-hydrogens Which α protons are more acidic? (Why?) Ketones β-diketones I don’t know S. Keyser/A.Rosan Chem 350

Which α protons are more acidic? (Why?) 22.4 Alpha bromination of carboxylic acids Which α protons are more acidic? (Why?) Amides Ketones I don’t know S. Keyser/A.Rosan Chem 350

Which is the stronger base? 22.2 Reactivity of enols REVIEW Which is the stronger base? Sodium hydroxide (NaOH) LDA I’m not sure S. Keyser/A.Rosan Chem 350

Acidity Model 5 It’s not just about carboxylic acids anymore

22.5 Acidity of α-hydrogens Example. Rank the following compounds in order of acidity of the alpha hydrogens. (1 = most acidic) pKa: 9 19 13 24 Example. Provide an explanation for the order of acidity. S. Keyser/A.Rosan Chem 350

22.5 Acidity of α-hydrogens Example. Rank the following compounds in order of acidity of the alpha hydrogens. (1 = most acidic) pKa: 9 19 13 24 Example. Provide an explanation for the order of acidity. Q: Which enolates can be formed with NaOH? Which can be formed with LDA? (CQ!) Note to self: Don’t explain anything yet! S. Keyser/A.Rosan Chem 350

22.5 Acidity of α-hydrogens Which α protons can be deprotonated under aqueous basic (NaOH) conditions? Those of ketones Those of β-diketones I don’t know LDA needed! S. Keyser/A.Rosan Chem 350

Which alpha hydrogens are more acidic? 22.5 Acidity of α-hydrogens Which alpha hydrogens are more acidic? alpha H of ester alpha H of amide I’m not sure S. Keyser/A.Rosan Chem 350

Which blue hydrogens are more acidic? 22.5 Acidity of α-hydrogens Which blue hydrogens are more acidic? alpha H of diketone H of propanol I’m not sure S. Keyser/A.Rosan Chem 350

22.5 Acidity of α-hydrogens See ChemActivity 25 On page 454, answer CTQs #’s 13 -16. S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions MALONIC ESTER SYNTHESIS Step 1. Alkylation Step 2. Hydrolysis Step 3. Decarboxylation S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions MALONIC ESTER SYNTHESIS Q: What is your reactant? Q: What is the sequence of reagents? Q: What is your product? Q: Can you add on a second alkyl group at the α-position? S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions Q: Could you use the malonic ester synthesis to give the following products? If so, give the synthetic steps! (CQ) S. Keyser/A.Rosan Chem 350

The Malonic Ester Synthesis Creates Substituted Acetic Acids S. Keyser/A.Rosan Chem 350

Could you use the malonic ester synthesis to give the desired product? 22.7 Alkylation of enolate ions Could you use the malonic ester synthesis to give the desired product? Yes No I’m not sure S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions Could you use the malonic ester synthesis to give the other desired product? Yes No I’m not sure S. Keyser/A.Rosan Chem 350

Chem Act 25 CTQ 16

Chem Act 25 CTQ 17

Chem Act 25 CTQ 17

Problem 22.25

How many protons with a pKa < 22 exist in the following molecule? 1 2 3 4

Which of the following explains why protons α to a carbonyl group show enhanced acidity? An inductive effect from the adjacent carbonyl weakens the C-H bond. The conjugate base is stabilized by resonance. The charge that results after deprotonation is delocalized. An inductive effect from the adjacent carbonyl weakens the C-H bond; and the conjugate base is stabilized by resonance. all of these

Which of the following reagents will not form an enolate anion upon reaction with a ketone? 1. 2. 3. 5. 4. Choice One Choice Two Choice Three Choice Four Choice Five

22.7 Alkylation of enolate ions Example. Predict the product and draw the mechanism for the following reaction. Provide all relevant resonance structures, arrows, and charges. S. Keyser/A.Rosan Chem 350

22.6 Reactivity of enolate ions Q: We determined that LDA was needed for the irreversible conversion of ketones to enolates. However, we used NaOH with the halogenation of ketones. Why do we expect to obtain significant amounts of product? S. Keyser/A.Rosan Chem 350

S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions ACETOACETIC ESTER SYNTHESIS Q: How does your product change when you change your starting material but leave everything else the same? Step 1. Alkylation Step 2. Hydrolysis Step 3. Decarboxylation S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions ACETOACETIC ESTER SYNTHESIS PRODUCES SUBSTITUTED ACETONE Q: How does your product change when you change your starting material but leave everything else the same? Step 1. Alkylation Step 2. Hydrolysis Step 3. Decarboxylation S. Keyser/A.Rosan Chem 350

22.7 Alkylation of enolate ions Other direct alkylations Other α-hydrogens are also acidic and can be removed with strong base like LDA. Example. Predict the products for the following reactions. S. Keyser/A.Rosan Chem 350

Problem 22.37 S. Keyser/A.Rosan Chem 350