Question

The following \(\beta\)-diketone can be synthesized from cyclopentanone and an acid chloride using an enamine reaction. CC1CCC(Cl)C1=O (racemic) (a) Propose a synthesis of the starting acid chloride from cyclopentene. (b) Show the steps in the synthesis of the \(\beta\)-diketone using a morpholine enamine.

Short answer

Question: Propose a synthesis of the starting acid chloride from cyclopentene and show the steps in the synthesis of the given β-diketone (SMILES notation: "CC1CCC(Cl)C1=O") using a morpholine enamine. Answer: Starting from cyclopentene, the synthesis follows these steps: 1. Convert cyclopentene to cyclopentanol via hydroboration-oxidation. 2. Convert cyclopentanol to cyclopentanone by oxidation. 3. Perform halogenation on cyclopentanone to form a halo ketone. 4. Replace the hydroxyl group with a chlorine atom using thionyl chloride, resulting in the acid chloride: (CH3)C1CCC(Cl)C1(Cl). 5. Combine cyclopentanone with morpholine to form an enamine. 6. The enamine does a nucleophilic attack on the acid chloride, forming an intermediate. 7. Treat the intermediate with water to facilitate hydrolysis, which forms the β-diketone (CH3)C1CCC(Cl)C1=O and releases morpholine.

Step-by-step solution

Determine the structure of the given β-diketone

The given β-diketone has a SMILES notation of "CC1CCC(Cl)C1=O". We can convert this to the structure: (CH3)C1CCC(Cl)C1=O

Determine the synthesis of the starting acid chloride from cyclopentene

We will convert cyclopentene into the corresponding acid chloride. To do this, follow these steps: a) Perform hydroboration-oxidation: Cyclopentene is converted to cyclopentanol. b) Perform oxidation: Cyclopentanol is converted to cyclopentanone. c) Perform halogenation: Cyclopentanone is converted to a halo ketone by adding a halogen to the alpha carbon. d) Replace the hydroxyl group with a chlorine atom: Treat the halo ketone with thionyl chloride to yield the corresponding compound, which is the acid chloride. The resulting acid chloride is: (CH3)C1CCC(Cl)C1(Cl)

Synthesis of the β-diketone using a morpholine enamine

a) Formation of enamine: Combine cyclopentanone with morpholine to form an enamine. b) Nucleophilic attack: The enamine does a nucleophilic attack on the target acid chloride, resulting in the formation of an intermediate. c) Hydrolysis: The resulting intermediate is then treated with water, which facilitates the hydrolysis reaction to form the β-diketone and releases the morpholine to be used again. From these steps, we successfully synthesized the given β-diketone from cyclopentanone and our converted acid chloride using a morpholine enamine reaction.

Key concepts

Enamine Reaction

The enamine reaction represents an essential process in organic chemistry, where an enamine, a compound formed by the reaction of a secondary amine with a ketone, acts as a nucleophile and attacks an electrophilic center. This type of reaction showcases the versatility of enamines as intermediates in the synthesis of various complex structures.

For instance, if we start with cyclopentanone, we can treat it with a secondary amine such as morpholine. The lone pair on the nitrogen of morpholine attacks the carbonyl group of the ketone to initially form an imine. The imine then undergoes tautomerization, a process where a proton shifts, to an enamine. The double bond between the carbon atoms and the lone pair on the nitrogen make the enamine a good nucleophile. It is this nucleophilicity which allows it to attack the acid chloride in subsequent steps, culminating in the synthesis of the desired \(\beta\)-diketone.

Nucleophilic Attack and Intermediate Formation

After its formation, the enamine then undergoes nucleophilic attack on the acid chloride. The carbon-carbon double bond of the enamine attacks the carbonyl carbon of the acid chloride. The oxygen atom in the carbonyl group of the acid chloride then captures the hydrogen atom from the amine, forming a protonated intermediate.

Hydrolysis of the Intermediate

Finally, water molecules present hydrolyze the protonated intermediate to yield the \(\beta\)-diketone, completing the reaction. Notably, the original amine used to form the enamine, morpholine in this case, is regenerated and can be reused, which is an economic advantage in synthetic chemistry. Thus, the enamine reaction is not only a key transformation in the synthesis of \(\beta\)-diketones but also an exemplar of catalytic cycles in organic synthesis.

Acid Chloride Synthesis

When exploring the pathway to synthesizing \(\beta\)-diketones, we encounter the crucial intermediate of acid chloride. Crafting an acid chloride from a base compound like cyclopentene involves several transformations:

Hydroboration-Oxidation

Initially, cyclopentene undergoes hydroboration-oxidation, a two-step method to convert alkenes into alcohols. During hydroboration, a borane complex adds across the double bond of the alkene, and subsequently, this addition product is oxidized to yield an alcohol, in this case, cyclopentanol.

Oxidation to Ketone

The resulting cyclopentanol is then oxidized to form cyclopentanone. Oxidation generally involves increasing the number of bonds to oxygen, and common reagents for this transformation include chromium-based oxidants or pyridinium chlorochromate (PCC).

Halogenation and Rearrangement

Once we obtain cyclopentanone, it undergoes halogenation. A suitable halogen source is used to add a halogen atom to the alpha carbon of the ketone, adjacent to the carbonyl group. Halogenation effectively creates a halo ketone.

Conversion to Acid Chloride

The final step entails replacing the hydroxyl group with a chlorine atom, converting the halo ketone to an acid chloride. This is typically achieved using thionyl chloride (SOCl2), which facilitates the replacement of the hydroxyl group with chloride, generating the desired acid chloride ready for the enamine reaction. Acid chlorides are highly reactive due to the polarization of the carbonyl group, which makes them excellent electrophiles for various reactions including the enamine reaction to produce \(\beta\)-diketones.

Cyclopentanone Chemistry

Cyclopentanone lies at the heart of the synthesis process for \(\beta\)-diketones, particularly in the reaction under scrutiny. As a five-membered cyclic ketone, cyclopentanone is known for its relative stability and reactivity, playing a central role in organic synthesis.

Simplifying its reactivity, the ketone functionality in cyclopentanone makes it a viable substrate for nucleophilic attack, notably useful in the formation of enamines. The polar bond between the carbonyl carbon and the oxygen atom creates electrophilic character at the carbonyl carbon, making it susceptible to attack by nucleophiles such as secondary amines to form enamines.

Reactivity with Amines

In the context of \(\beta\)-diketone synthesis, cyclopentanone's ability to react with amines to form enamines is crucial. The reaction proceeds by the removal of water (dehydration) and the formation of the double bond in the enamine.

Formation of Different Functional Groups

Furthermore, cyclopentanone's chemistry is integral in the formation of various functional groups through further reaction steps as we have previously seen, including alcohols via hydroboration-oxidation, and the transformation into halo ketones with halogenation. Each of these transformations manipulates the cyclopentanone in ways that tailor it towards the final synthesis goal: creating a \(\beta\)-diketone.

Its versatility and reactivity make cyclopentanone a valuable starting material in synthetic organic chemistry, particularly in the creation of complex molecular structures like \(\beta\)-diketones, which are prevalent in natural products and are useful in a variety of pharmaceutical applications.