Question

Show the product of treating \(\gamma\)-butyrolactone with each reagent.

Short answer

Answer: (a) O=C1CCCN1 (amide) (b) HOCC1CCO1 (alcohol) (c) PhC1CO(CC1)OH (secondary alcohol) (d) O=CC1CCO1 (carboxylic acid) (e) MeC1CO(CC1)OH (secondary alcohol) (f) O=CC1CCO1 (aldehyde)

Step-by-step solution

Identify the functional group in \(\gamma\)-butyrolactone

\(\gamma\)-butyrolactone has a five-membered ring containing an ester functional group. The structure can be drawn as follows: O=C1CCCO1

Predict the reaction products with each reagent

(a) NH3 solution: In this reaction, the ester will undergo nucleophilic substitution with NH3, creating an amide. The product is: \(\mathrm{O=C1CCCN1}\) (b) \(\dfrac{1 \cdot \mathrm{LiAlH}_{4}}{2 \cdot \mathrm{H}_{2}\mathrm{O}}\): In this reaction, LiAlH4 will partially reduce the ester to an alcohol: \(\mathrm{O=C1CCCO1 \rightarrow HOCC1CCO1}\) (c) \(\dfrac{1.2 \mathrm{PhMgBr} \text{, ether }}{2 . \mathrm{H}_{2}\mathrm{O}, \mathrm{HCl}}\): In this reaction, the Grignard reagent PhMgBr will attack the ester, followed by acidic hydrolysis, to form a secondary alcohol: \(\mathrm{O=C1CCCO1 \rightarrow PhC1CO(CC1)OH}\) (d) \(\dfrac{\mathrm{NaOH} / \mathrm{H}_{2} \mathrm{O}}{\text{ heat }}\): Here, the ester undergoes saponification with NaOH, converting it into a carboxylic acid salt and then into a carboxylic acid upon acidification: \(\mathrm{O=C1CCCO1 \rightarrow O=CC1CCO1}\) (e) \(\dfrac{1.2 \mathrm{CH}_{3} \mathrm{Li} \text{, ether }}{2 .\mathrm{H}_{2} \mathrm{O}, \mathrm{HCl}}\): Similar to the reaction with the Grignard reagent, the organolithium reagent attacks the ester, and after hydrolysis and acid work-up, a secondary alcohol is formed: \(\mathrm{O=C1CCCO1 \rightarrow MeC1CO(CC1)OH}\) (f) \(\dfrac{\text{ 1. DIBALH, ether, }-78^{\circ}\mathrm{C}}{\longrightarrow}\): In this reaction, DIBALH selectively reduces the ester to an aldehyde at low temperature: \(\mathrm{O=C1CCCO1 \rightarrow O=CC1CCO1}\)

Key concepts

Nucleophilic Substitution

Nucleophilic substitution is a fundamental class of reactions in organic chemistry, where a nucleophile selectively replaces a leaving group in the substrate. In the case of \(\gamma\)-butyrolactone reacting with NH3 (ammonia), the reaction typifies nucleophilic acyl substitution, where the nucleophile NH3 attacks the carbonyl carbon of the ester, leading to the expulsion of the alkoxy group and formation of an amide. The carbonyl carbon's reactivity is due to its partial positive charge, making it an attractive target for nucleophiles like NH3.

This process is pivotal in creating a variety of compounds, such as amides in the synthesis of pharmaceuticals and polymers. Understanding this reaction is also critical for interpreting mechanisms of more complex enzymatic processes in biochemistry.

Ester Reduction

Ester reduction refers to the process of transforming an ester into other less oxidized functional groups, commonly alcohols or aldehydes, through the addition of hydride ions (H-) or other equivalents. In our exercise, we saw that LiAlH4, a powerful reducing agent, can partially reduce an ester to an alcohol. This happens through a two-step mechanism: first, the hydride from LiAlH4 attacks the carbonyl carbon of the ester, and second, an alcohol is formed after the elimination of the alkoxy group.

Ester reductions are particularly important in the preparation of alcohols from esters derived from natural or synthetic sources, and this type of reaction is a staple in medicinal chemistry and the synthesis of complex organic molecules.

Grignard Reaction

Formation of Carbon-Carbon Bonds

The Grignard reaction involves the use of Grignard reagents, which are organomagnesium compounds, to form carbon-carbon bonds. Here, PhMgBr, a Grignard reagent, is introduced to \(\gamma\)-butyrolactone, leading to the formation of a new C-C bond between the phenyl group and the carbonyl carbon of the ester. It is followed by an acidic workup to yield a secondary alcohol.

This reaction has widespread applications in chemistry for extending carbon chains and introducing new functional groups, playing an essential role in the synthesis of diverse organic compounds, including natural products and pharmaceuticals.

Saponification

Saponification is a specific type of hydrolysis where an ester reacts with a base, usually NaOH or KOH, to produce a carboxylate salt and an alcohol. When carried out under heat, the ester in \(\gamma\)-butyrolactone is transformed into a carboxylic acid salt. Further acidic treatment can convert this salt into a free carboxylic acid. The name 'saponification' is derived from the Latin 'sapo', meaning soap, as this reaction is traditionally used in soap making by hydrolyzing fats (triglycerides).

Students should identify saponification as vital in industrial processes for making soaps, as well as in the laboratory for the cleavage of esters in analytical and synthetic chemistry.

Organolithium Reagents

Powerful Carbon Nucleophiles

Organolithium reagents, like CH3Li, are highly reactive species used to form new carbon-carbon bonds in organic synthesis. In our case study, CH3Li reacted with \(\gamma\)-butyrolactone in a fashion similar to the Grignard reagent, forming a new C-C bond and ultimately leading to a secondary alcohol post-acidic workup. Organolithium reagents are considered to be even more reactive than their Grignard counterparts due to the more ionic character of the carbon-lithium bond.

These reagents are frequently utilized in the synthesis of complex molecules, allowing for the precise construction of molecular frameworks in pharmaceuticals, agrochemicals, and advanced materials.

DIBALH Reduction

DIBALH (Diisobutylaluminium hydride) is a selective reducing agent used to reduce esters to aldehydes. It operates effectively at low temperatures, typically -78 °C, to prevent further reduction of the aldehyde formed to an alcohol. This reaction exemplifies the importance of selective reduction, necessary for the stepwise synthesis of complex organic molecules where functional group integrity is crucial.

Understanding the subtleties of this reaction allows organic chemists to strategically manipulate functional groups and orchestrate the synthesis of intricate molecules in disciplines such as drug design and natural product chemistry.