Grignard reaction

The Grignard reactions are a class of organometallic chemical reactions in which alkyl, allyl, vinyl, or aryl magnesium halides (Grignard reagents) are added to the carbonyl group of an aldehyde or ketone. [1,2] The reaction is an important tool for carbon-carbon bond formation in organic chemistry.[3,4]

(R2 can also be hydrogen)

The Grignard reaction and Grignard's reagent were discovered by and named after the French chemist François Auguste Victor Grignard, who published the results of this research in 1900 [5] and was awarded the 1912 Nobel Prize in Chemistry for it [6]. The reaction of organic halides with magnesium is not a Grignard reaction, but provides a Grignard reagent [7].

 

Although the Grignard reagent can initiate many reactions, the classical Grignard reaction refers only to the reaction of RMgX with ketones and aldehydes, shown in red.

Reaction mechanism

Due to carbon is more electronegative than magnesium, the carbon attached to magnesium acts as a nucleophilic reagent and attacks the electrophilic carbon atoms within the polar bond of the carbonyl group. The addition process of Grignard reagent to the carbonyl group usually proceeds through the six-membered ring transition state. [8]

Based on the detection of free radical coupling by-products, another single electron transfer (SET) mechanism involving the initial formation of ketyl radical intermediates has also been proposed. A recent computational study has shown that the mechanism of reaction operation (polarity versus radical) depends on the substrate, with the reduction potential of the carbonyl compound being one of the key parameters that play a decisive role. [9]

Other reactions using Grignard reagents

The classical Grignard reaction usually refers only to the formation of a primary or tertiary alcohol between a ketone or aldehyde group and a Grignard reagent. [5] And some chemists understand the definition to mean all reactions of electrophilic molecules with Grignard reagents.[10] As a result, there is still some controversy today regarding the definition of a Grignard reaction.

March's Advanced Organic Chemistry defines it as "the addition of Grignard reagents to aldehydes and ketones ......."[1] Its definition in the IUPAC Goldbook, on the other hand, does not address either aspect.[7] In the Merck Index, published online by the Royal Society of Chemistry, the classic definition is recognized, followed by "more modern interpretations expanding the range of applications of the Grignard reaction to include the addition of Grignard reagents to a variety of electrophilic substrates."[10]

Some organic chemical reactions involving Grignard reagents but not classical Grignard reactions are shown below.

 

Reactions as a base

Grignard reagent can be used as a base to deprotonate to produce enol intermediates. Grignard reagent is basic and reacts with alcohols, phenols, etc. to form alcohol salts (ROMgBr). Phenoxy derivatives are readily formylated by paraformaldehyde to give salicylaldehyde.[17]

Alkylation of metals and metalloids

As with organolithium compounds, Grignard reagents can be used to form carbon-heteroatom bonds.

 

Grignard reagents react with many metal-based electrophiles. For example, they undergo metal transfer with cadmium chloride (CdCl2) to give dialkyl cadmium. [18]

2 RMgX + CdCl2 → R2Cd + 2 Mg(X)Cl

Schlenk equilibrium

Most Grignard reactions are generally carried out in ether solvents, with ether and tetrahydrofuran being particularly common. Grignard reagents react with 1,4-dioxane to form diorganomagnesium compounds (R2Mg) and the insoluble coordination polymer MgX2 (dioxane)2.

2 RMgX + dioxane ⇌ R2Mg + MgX2(dioxane)2

The reaction utilizes the Schlenk equilibrium, pushing it to the right.

Precursors to magnesiates

Grignard reagent reacts with organolithium compounds to form ate complexes (Bu = butyl).[19]

BuMgBr + 3 BuLi → LiMgBu3 + BuBr

Coupling with organic halides

Grignard reagents do not normally react with organic halides, in contrast to their high reactivity with other main group halides. However, in the presence of a metal catalyst, Grignard reagents can participate in C-C coupling reactions. For example, after esters are hydroesterified with NaOH under alkaline conditions, magnesium nonylbromide reacts with methyl p-chlorobenzoate in the presence of Fe(acac)3 to give p-nonylbenzoic acid as follows. Without the presence of Fe(acac)3, the Grignard reagent attacks the ester group on the aryl halide. [20]

 

For the coupling reaction of aryl halides with aryl Grignard reagents, tetrahydrofuran (THF) solution of nickel chloride is also an efficient catalyst.In addition, the Gilman catalyst lithium tetrachlorocuprate (Li2CuCl4) tetrahydrofuran solution prepared by mixing lithium chloride (LiCl) and copper chloride (CuCl2) is an effective catalyst for alkyl halide coupling.Kumada-Corriu coupling provides substituted styrene.

Industrial Application

An example of an industrial application of the Grignard reaction is the involvement of phenylmagnesium bromide in the industrial production of Tamoxifen, an anti-breast cancer drug used for the treatment of estrogen-progestogen receptor-positive expression. [22,23]

Reference

1. Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.),New York:Wiley-Interscience,ISBN 978-0-471-72091-1

2. Chapter 19: Carboxylic Acids. Organic Chemistry 4e Carey. mhhe.com

3. Shirley, D. A. (1954). "The Synthesis of Ketones from Acid Halides and Organometallic Compounds of Magnesium, Zinc, and Cadmium". Org. React. 8: 28-58.

4. Huryn, D. M. (1991). "Carbanions of Alkali and Alkaline Earth Cations: (ii) Selectivity of Carbonyl Addition Reactions". In Trost, B. M.; Fleming, I. (eds.). Comprehensive Organic Synthesis, Volume 1: Additions to C-X π-Bonds, Part 1. Elsevier Science. pp. 49-75. https://doi.org/10.1016/B978-0-08-052349-1.00002-0

5. texte, Académie des sciences (France) Auteur du (January 1, 1900). "Comptes rendus hebdomadaires des séances de l'Académie des sciences/publiés. par MM. les secrétaires perpétuels". Gallica. Retrieved April 23, 2023.

6. Grignard, V. (1900). "Sur quelques nouvelles combinaisons organométaliques du magnésium et leur application à des synthèses d'alcools et d'hydrocabures". Compt. Rend. 130: 1322-25.

7. IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). ISBN 0-9678550-9-8. https://doi.org/10.1351/goldbook

8. Maruyama, K.; Katagiri, T. (1989). "Mechanism of the Grignard reaction". J. Phys. Org. Chem. 2 (3): 205–213. https://doi.org/10.1002/poc.610020303

9. Peltzer, Raphael Mathias; Gauss, Jürgen; Eisenstein, Odile; Cascella, Michele (February 12, 2020). "The Grignard Reaction-Unraveling a Chemical Puzzle". Journal of the American Chemical Society. 142 (6): 2984–2994. https://doi.org/10.1021/jacs.9b11829

10. "Grignard Reaction | The Merck Index Online". www.rsc.org. Retrieved April 23, 2023.

11. "Unit 12 Aldehydes, Ketones and Carboxylic Acids". Chemistry Part II Textbook for class XII. Vol. 2. India: National Council of Educational Research and Training. 2010. p. 355. ISBN 978-81-7450-716-7. Archived from the original on September 20, 2018. Retrieved March 9, 2019.

12. Arredondo, Juan D.; Li, Hongmei; Balsells, Jaume (2012). "Preparation of t-Butyl-3-Bromo-5-Formylbenzoate Through Selective Metal-Halogen Exchange Reactions". Organic Syntheses. 89: 460. https://doi.org/10.15227/orgsyn.089.0460

13. A.Fürstner, A. Leitner, G. Seidel (2004). "4-Nonylbenzoic Acid". Organic Syntheses. 81: 33–42.

14. Richey, Herman Glenn (2000). Grignard Reagents: New Developments. Wiley. ISBN 0471999083.

15. Jordan VC (1993). "Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer". Br J Pharmacol. 110 (2): 507–17. https://doi.org/10.1111/j.1476-5381.1993.tb13840.x