CHE 3332 – Organic Chemistry 2 – Spring 2021 Week 13 Resource Hello everyone! Virtual group tutoring for this class will be every Tuesday from 6-7 pm, and you can reserve your spot by making an appointment at www.Baylor.edu/Tutoring. This week, we’ll

cover Chapter 22: Alpha Carbon Chemistry: Enols & Enolates. Keywords: enol, enolate, Claisen, Michael Reaction, Stork Enamine Synthesis

Enols & Enolates Alpha vs beta carbon notation: Reactivity of positions:

The alpha carbon is one carbon away from the carbonyl while the beta carbon is two carbons away from the carbonyl. The carbonyl carbon is cationic because it can be attacked by a nucleophile. The carbonyl oxygen has resonance due to its double bond and is anionic because of its lone pairs. The alpha carbon is anionic and can attack an electrophile because of its closeness to the carbonyl. The alpha hydrogen is cationic and can be pulled off by a base.

The alpha-carbon can only act as a nucleophile if the carbonyl is in enol or enolate reactive form. Enols are made either through acid or base tautomerization. Enolates are more reactive than enols because they’re charged. A strong base, such as EtO or LDA, is needed to make an enolate. Example:

Alpha-Halogenation of Enols & Enolates – Add halogen to alpha-carbon On an unsymmetrical ketone, put the halide on the more substituted alpha carbon. An additional step can be done using a base to do an elimination and leaving a double bond.

• Alpha-Halogenation in Basic Conditions - Add halogen on less substituted alpha-carbon

Alpha-Bromination of Carboxylic Acids - Add bromine on alpha-carbon of carboxylic acid

Aldol Condensation – Aldehyde treated with base reacts with a second (same) aldehyde to make an aldol

• Crossed Aldol Reaction – Two different aldehydes are used. This works if one aldehyde has no alpha-protons.

• Intramolecular Aldol – Two carbonyls cyclize. The product has one intact carbonyl and the alpha carbon has a double bond on it. The other carbonyl tautomerizes and the carbonyl becomes the beta carbon of the product.

Claisen Condensation – Two of the same esters react via their enolate. Ester has to have 2 alpha-protons to react. The base’s substituent group (OR-) must match the original ester’s substituent group. The product has two carbonyls.

• Crossed Claisen – Two different esters react. One must either have no alpha-protons or one must be made into an enolate with LDA first.

• Intramolecular Claisen – Two esters cyclize. One ester stays intact and is connected to a carbonyl at the beta carbon position. The second ester’s carbonyl stays intact but the substituent is replaced by a bond to the alpha carbon.

Kinetic vs Thermodynamic Alkylation – Alkylate at the alpha-carbon position. The kinetic product favors the cold and a large base like LDA. The large base favors alkylating at the less substituted alpha-carbon. The thermodynamic product favors the heat and a small base like NaH. The small base favors alkylating at the more substituted alpha-carbon.

Malonic Ester Synthesis - Transforms alkyl halide into carboxylic acid with 2 new carbons. It always begins with diethylmalonate. It can also be done twice so then the carboxylic acid will have two R groups on it instead of one.

Acetoacetic Ester Synthesis Transforms alkyl halide into ketone with 3 new carbons. It always begins with ethyl acetoacetate. It can also be done twice so then the ketone will have two R groups on it instead of one. Michael Reaction If a double bond is adjacent to the carbonyl, you have an alpha, beta-unsaturated carbonyl that has two reactive spots. The #1 is the oxygen and adjacent carbons are numbered subsequently.

• Grignards favor 1,2-addition.

• Gilmans favor 1,4-addition.

Stork Enamine Synthesis Enamine adds with 1,4-addition to a ketone. The nitro group is replaced by a carbonyl. The enamine’s alpha carbon bonds to the #4 position of the ketone.

Quiz: Name the reaction and predict the products

1.

2.

3. Answers: Notes & questions sourced from Wiley Organic Chemistry Second Semester textbook.

1. Alpha-Halogenation of Enols & Enolates

2. Intramolecular Aldol

3. Acetoacetic Ester Synthesis