ChemTalk

Gilman Reagents

Core Concepts

This article serves as a guide to Gilman reagents in organic chemistry. After reading this article, you will be able to understand and describe what they are, their reaction mechanisms, why they are important, their advantages and limitations as reagents, and their real-world applications.

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What are Gilman Reagents?

Gilman reagents, also known as organocuprates, are organometallic compounds containing copper, lithium, and two R groups, which may be alkyl or aryl. They have the general formula of R2CuLi and facilitate a wide variety of reactions, which makes them a versatile and essential tool in organic chemistry. Additionally, it is worth noting that Gilman reagents are similar to Grignard reagents, another category of important compounds in organic chemistry. Both are examples of organometallic compounds, however, Grignard reagents contain magnesium instead of copper. Furthermore, their reaction mechanisms are different and they either react differently with certain compounds or can react with compounds that the other isn’t able to react with.

Preparation and Uses of Gilman Reagents

How Gilman Reagents are Prepared

Organic chemists prepare Gilman reagents by reacting a copper salt with an organolithium compound. For example, lithium dimethyl copper is the most common one and can be prepared by reacting a simple organolithium reagent such as methyllithium (CH3Li) with copper iodide (CuI). Chemists perform the reaction for preparation in the presence of tetrahydrofuran and at the optimal temperature of approximately -78 degrees Celsius.

General reaction:

     \begin{gather*} {2RLi + CuI \rightarrow R_{2}CuLi + LiI} \end{gather*}

Example reaction:

     \begin{gather*} {H_{3}CLi + CuI \rightarrow (H_{3}C)_{2}CuLi + LiI} \end{gather*}

Conjugate Addition Reactions

Organic chemists primarily use Gilman reagents to perform 1, 4 conjugate addition reactions which are important for synthesizing complex molecules. The most common reactions are specifically with α, β (alpha, beta) unsaturated ketones. In α, β unsaturated systems, there is an important resonance form where the beta carbon is positively charged. For context, the beta carbon is the one that is two carbons away from the carbonyl carbon and the positive charge makes it a good electrophile to react with nucleophiles such as Gilman reagents.

gilman reagent conjugate addition

SN2 Reactions

Moreover, they are also useful nucleophiles for SN2 substitution reactions where they form carbon-carbon (C-C) bonds with various electrophiles such as primary alkyl halides. In this case, a coupling reaction takes place and involves the replacement of the halogen atom in the alkyl halide with one of the R groups from the Gilman reagent. This reaction is specifically known as the Corey-House reaction.

general alkyl halide reaction organocuprate
alkyl halide organocuprate reaction

Nucleophilic Acyl Substitution

Finally, Gilman reagents can react with acid halides through a nucleophilic acyl substitution mechanism to form ketones.

acid halide organocuprate

Reaction Mechanism

This article will focus on just the reaction mechanisms for conjugate addition reactions and SN2 reactions with Gilman reagents.

Conjugate Addition Mechanism

For conjugate addition reactions, the pair of electrons in the bond between the R group and copper of a Gilman reagent acts as the nucleophile and forms a bond with an alpha, beta ketone at the beta position. The C-C pi bond then breaks and the alpha carbon becomes negatively charged. From here, resonance allows for the formation of a new C-C pi bond and transfers the negative charge onto oxygen. This specifically is an intermediate known as an enolate which is then protonated by acid next to form the final product.

conjugate addition gilman reagent conjugate addition

SN2 Substitution Mechanism

In the case of SN2 substitution reactions with alkyl halides (R-X), the copper atom in Gilman reagents facilitates nucleophilic attack and the following bond formation. The copper atom loses electrons so that it behaves as a nucleophile, oxidizing from Cu+ to Cu3+. A triorganocopper intermediate with a neutral charge ends up being formed and then undergoes reductive elimination which creates the alkyl coupling product (R-R’).

gilman reagent alkyl halide mechanism

Advantages and Limitations

There are several advantages to using Gilman reagents. For example, they enable the efficient and selective formation of carbon-carbon bonds which makes them greatly versatile. In addition to this, they are compatible with various functional groups in organic chemistry, making them an essential tool. However, there are also several limitations. These include their sensitivity to air and moisture, limited stability, and side reactions that can potentially occur under certain conditions.

Applications of Gilman Reagents

Gilman reagents have many wide-ranging real-world applications from medicine to agriculture. For example, chemists commonly use them to synthesize pharmaceuticals, agrochemicals, and other fine chemicals. Additionally, they play a crucial role in materials science and engineering, where scientists use them to develop new materials and catalysts.

Further Reading