Organic Exam 3

What is the first step in fatty acid biosynthesis starting from acetyl-CoA, and what enzyme/cofactor is required?

Acetyl-CoA is converted into malonyl-CoA using Acetyl-CoA carboxylase. Step adds a carboxyl group to form a highly reactive β-keto acid derivative (malonyl-CoA), which provides the driving force for carbon-carbon bond formation.

In fatty acid biosynthesis, what is the thermodynamic driving force that allows the enolate-like nucleophile to attack the growing chain?

Decarboxylation of malonyl-CoA. Loss of CO2 gas generates a reactive enolate nucleophile without requiring a harsh environment. This then attacks the thioester (E-S-acyl) of the growing chain.

Sketch the electron-pushing arrows for the chain elongation step in fatty acid biosynthesis. What is the result of this?

Result: a new β-keto acyl-CoA chain elongated by 2 carbons.

Why is the alpha-hydrogen of diethyl malonate so acidic, and what base is typically used to deprotonate it?

The alpha-hydrogen is situated between two carbonyl groups. The resulting conjugate base (enolate) is highly stabilized through resonance delocalization across both carbonyl oxygens. Sodium ethoxide is used, which matches the ester groups to prevent transesterification side reactions.

What type of mechanism occurs when the diethyl malonate enolate reacts with an alkyl halide? What are the structural limitations?

SN2 substitution - nucleophilic alpha-carbon attacks the alkyl carbon bearing the halogen, kicking off the halide leaving group; it works best with primary or methyl halides because it is an SN2 pathway

Can malonic ester synthesis be used to add two alkyl groups to the alpha carbon? Explain.

After the first alkylation, there is still one acidic alpha-hydrogen remaining. Can add a second equivalent of base to form a second enolate, followed by a second alkyl halide

What is the purpose of treating an alkylated malonic ester with LiOH (or NaOH/H2O), and what functional group is formed?

Ester saponification (hydrolysis); converts the diester into a substituted malonic acid. Hydrolysis cleaves the ester bonds, replacing ethyl groups with hydrogens for decarboxylation.

What happens when a substituted 1,3-dicarboxylic acid is heated?

Decarboxylation

why is lithium diisopropylamide (LDA) used at low temperatures to form an enolate from an ester, rather than using a standard alkoxide base?

LDA is an incredibly strong, non-nucleophilic base. Bulky isopropyl groups prevent it from acting as a nucleophile and attacking the ester carbonyl. The alpha-hydrogen is exposed on the outside and accessible for the bulky molecule (easy acid-base reaction)

Draw the structure of LDA

Centra nitrogen atom bonded to two isopropyl groups. The nitrogen bears a negative formal charge stabilized by a lithium counter-cation.

What is the starting material for acetoacetic ester synthesis, and what is the final product category after alkylation, hydrolysis, and decarboxylation?

Ethyl acetoacetate (a β-keto ester) as starting material. A substituted methyl ketone derivative as product

While malonic ester synthesis yields…acetoacetic ester synthesis yields…

Substituted acetic acids; substituted methyl ketones

How can a dialkylation product be synthesized from ethyl acetoacetate, and what are the specific stepwise requirements?

It must be done sequentially. Treat with 1 equivalent of base followed by 1 equivalent of the first alkyl halide. Treat monoalkylated intermediate with a second equivalent of based followed by a second alkyl halide.

Draw the resonance contributors of an alpha, β-unsaturated carbonyl compound. Based on this, which two carbons are electrophilic?

Creates a resonance contributor with a positive charge on the β-carbon and negative charge on the oxygen. Both the carbonyl carbon and the β carbon bear partial positive charges and can be attacked by nucleophiles.

Define a “Michael Reaction.” What specific pathway does it follow?

A Michael reaction is a conjugate addition (1,4 addition) where the nucleophile is a carbon-based stabilized enolate (a Michael donor) attacking an a,β-unsaturated carbonyl compound (a Michael acceptor).

Regiochemistry of a Michael reaction

Nucleophile selectively attacks at the β-carbon, breaking the carbon-carbon pi bond

Conditions/descriptions for a 1,2 addition to an a,β-unsaturated system

Fast and reversible, kinetic pathway (carbonyl carbon more sterically accessible and has higher localized positive charge density), strong/hard/localized nucleophiles

What nucleophiles would be used for a 1,2-addition to an alpha,β-unsaturated system?

Grignard reagents, organolithiums

Conditions/descriptions for a 1,4-addition to an alpha,β-unsaturated system?

Slow and irreversible, thermodynamic pathway (retains CO double bond which is stronger than CC), weaker/softer/polarizable nucleophiles

Examples of nucleophiles used for 1,4-addition?

NaCN, enolates, organocuparates