Gilman Reagent: Preparation and reactions with easy mechanism

What is Gilman reagent?

Gilman reagent is an organometallic reagent containing lithium (Li), copper (Cu), and two alkyl or aryl groups. The Gilman reagent is also known as lithium dialkylcuprate or lithium diarylcuprate and is represented by R2CuLi. The Gilman reagent reacts with alkyl bromides, chlorides, and iodides in ether or tetrahydrofuran (THF) as a solvent to give a significant amount of cross-coupling products.

Gilman reagent

Preparation of Gilman reagent

Generally, Gilman reagent is prepared in two steps:

  1. In the first step, alkyl halide (R-X) is treated with lithium (Li) in the presence of dry ether to get alkyl lithium (R-Li).
  2. In the second step, the alkyl lithium (R-Li) is treated with cuprous iodide (CuI) in tetrahydrofuran (THF) solvent at -78 °C to get lithium dialkyl cuprates (Gilman reagent).
Preparation of Gilman reagent

Gilman reagent is usually prepared at a temperature below 0 °C due to the thermal instability of the dialkyl cuprate containing hydrogen atoms on the carbon beta to Cu.

Structure of Gilman Reagent

In diethyl ether solution, lithium dimethyl cuprate exists as a dimer, forming an 8-membered cyclic structure. Likewise, lithium diarylcuprate also crystallizes as dimer etherate.

Structure of Gilman Reagent

But, if the Li+ ion forms a complex with crown ether like 12-crown-4, the diorganocuprate anion exists in a linear structure.

Structure of Gilman Reagent

Coupling Reaction with Gilman Reagent

The coupling reaction of Gilman reagent with alkyl halides is of wide scope and R in R2CuLi may be primary alkyl, allylic, benzylic, aryl, vinyl, or allenic and may contain keto, COOH, COOR, or CONR2 group.

Coupling Reaction with Gilman Reagent

Gilman Reagent Mechanism

The mechanism of the coupling reaction probably involves the formation of Cu(III) intermediate and proceeds in two steps. In the first step, the Gilman reagent acts as a nucleophile, and the copper atom of the Gilman reagent undergoes an SN2-type substitution reaction with an alkyl halide to give Cu(III) intermediate. Thus, the formed neutral tricopper intermediate undergoes reductive elimination to give the coupling product. During the reductive elimination, the copper (III) complex is reduced to Cu(I). The general reaction mechanism of the Gilman reaction is outlined below:

Gilman Reagent Mechanism

Stereochemistry of Gilman Reagent

The coupling reaction with allylic substrates usually proceeds via an SN2-type reaction with high selectivity for the γ-position.

The coupling reaction of Gilman reagent (Ph2CuLi) with 2-bromobutane proceeds via retention of configuration but the same reaction with 2-iodobutane proceeds via racemization.

The reaction at a vinylic substrate is stereospecific and usually proceeds with the retention of configuration.

Generally, gem-dihalides do not react with the Gilman reagent, but when two halogens are present on the carbon α to an aromatic ring or on a cyclopropane ring both halogens can be replaced by R. However, 1,2-dibromides exclusively give an elimination product.

Application of Gilman Reagent

Gilman reagent is widely used for the preparation of new compounds having carbon-carbon bonds from alkyl, aryl, acyl, vinyl, and allyl halides and also from α,β-unsaturated ketones.

Reaction of Gilman reagent with acid chloride

Gilman reagent (lithium dialkylcuprate) reacts with acid chlorides to produce ketones.

Reaction of Gilman reagent with acid chloride

Mechanism of Gilman reagent with acid chlorides

Gilman reagent (lithium dialkylcuprate) acts as a nucleophile and attacks the carbonyl center to form a tetrahedral intermediate. The tetrahedral intermediate loses chloride ion to form a ketone.

Mechanism of Gilman reagent with acid chlorides

Reaction of Gilman reagent with α,β-unsaturated ketones

Gilman reagent reacts with α,β-unsaturated ketones to give 1,4-addition products.

Reaction of Gilman reagent with α,β-unsaturated ketones

Mechanism of Gilman reagent with α,β-unsaturated ketones

Initially, the nucleophile from the Gilman reagent attacks the carbon-carbon double bond of the α,β-unsaturated ketones, forming resonance-stabilizeded enolate ion. The enolate ion on acidification gives a 1,4-addition product.

Mechanism of Gilman reagent with α,β-unsaturated ketones

Reaction with epoxide

Gilman reagent attacks at the least substituted carbon atom of epoxide to give corresponding alcohol by SN2 type mechanism.

Reaction of Gilman reagent with epoxide

Since the reaction proceeds through the SN2 type mechanism, in disubstituted epoxide inversion of configuration is observed at ring carbon.

Gilman 17

Reaction with vinyl halide

The Alkyl group from the Gilman reagent replaces the halogen attached to the alkene and aromatic ring to give a coupling product. This reaction is generally impossible with SN1 and SN2 reactions but the mechanism of the reaction is still unknown and is supposed to occur through free radical reaction.

Reaction of Gilman reagent with vinyl halide

Gilman reagent versus Grignard reagent

Since the C-Cu bond is less polarized than the C-Mg bond, the Gilman reagent is a strong nucleophile and less reactive compared to the Grignard reagent.

1. The Grignard reagent gives addition product with ketones and other carbonyl compounds but the Gilman reagent is a weak nucleophile compared to the Grignard reagent and does not react with ketones.

Gilman reagent versus Grignard reagent

2. Grignard reagent gives tertiary alcohol with acyl chloride but Gilman reagent gives ketones with acyl chlorides.

Gilman 13

3. Grignard reagent gives 1,2-addition products with α,β-unsaturated ketones but Gilman reagent gives 1,4-addition products.

Gilman 12 1

Which one is more nucleophilic Gilman reagent or Grignard reagent?

Gilman reagent is a strong nucleophile compared to Grignard reagent and gives coupling product with alkyl halides, whereas Grignard reagent does not react with alkyl halides.

Which one is more nucleophilic Gilman reagent or Grignard reagent?

Gilman reagent practice problem

Complete the following reactions.

Gilman reagent practice problem


Gilman reagent form carbon-carbon bonds through coupling with

Organochlorides, bromides, and iodides.

Published by: Siddha Raj Upadhyaya(Gurudev)

Gilman reagent video


  1. The Preparation of Methylcopper and some Observations on the Decomposition of Organocopper Compounds
    Henry Gilman, Reuben G. Jones, and L. A. Woods
    The Journal of Organic Chemistry 1952 17 (12), 1630-1634
  2. Chemistry of carbanions. XVII. Addition of methyl organometallic reagents to cyclohexenone derivatives
    Herbert O. House and William F. Fischer Jr.
    The Journal of Organic Chemistry 1968 33 (3), 949-956
    DOI: 1021/jo01267a004
  3. Conjugate Addition Reactions of Organocopper Reagents
    Gary H. Posner
    React. 197219, 1-114
  4. Carbon-carbon bond formation by selective coupling of n-alkylcopper reagents with organic halides
    Elias J. Corey and Gary H. Posner
    Journal of the American Chemical Society 1968, 90 (20), 5615-5616
  5. Reaction of lithium dialkyl- and diarylcuprates with organic halides
    George M. Whitesides, William F. Fischer Jr., Joseph San Filippo Jr., Robert W. Bashe, and Herbert O. House
    Journal of the American Chemical Society 196991 (17), 4871-4882

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