Grignard reaction

Grignard reactions and reagents were discovered by and are named after the French chemist François Auguste Victor Grignard (University of Nancy, France), who described them in 1900.{{Cite web |last=texte |first=Académie des sciences (France) Auteur du |date=1900-01-01 |title=Comptes rendus hebdomadaires des séances de l'Académie des sciences / publiés... par MM. les secrétaires perpétuels |url=https://gallica.bnf.fr/ark:/12148/bpt6k3086n |access-date=2023-04-23 |website=Gallica |language=EN}} He was awarded the 1912 Nobel Prize in Chemistry for this work.{{cite journal |author=Grignard, V. |author-link=Victor Grignard |year=1900 |title=Sur quelques nouvelles combinaisons organométaliques du magnésium et leur application à des synthèses d'alcools et d'hydrocabures |url=http://gallica.bnf.fr/ark:/12148/bpt6k3086n/f1322.table |journal=Compt. Rend. |volume=130 |pages=1322–25}}

The reaction of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent.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}}. {{doi|10.1351/goldbook}}.

Image:Grignard with carbonyl.png undergo many reactions, the classical Grignard reaction refers only to the reaction of RMgX with ketones and aldehydes, shown in red. X = Cl, Br, I.|center]]

Classically, the Grignard reaction refers to the reaction between a ketone or aldehyde group with a Grignard reagent to form a primary or tertiary alcohol. However, some chemists understand the definition to mean all reactions of any electrophiles with Grignard reagents. Therefore, there is some dispute about the modern definition of the Grignard reaction. In the Merck Index, published online by the Royal Society of Chemistry, the classical definition is acknowledged, followed by "A more modern interpretation extends the scope of the reaction to include the addition of Grignard reagents to a wide variety of electrophilic substrates."{{Cite web |title=Grignard Reaction {{!}} The Merck Index Online |url=https://www.rsc.org/Merck-Index/reaction/r177/ |access-date=2023-04-23 |website=www.rsc.org}} This variety of definitions illustrates that there is some dispute within the chemistry community about the definition of a Grignard reaction.

Shown below are some reactions involving Grignard reagents, but they themselves are not classically understood as Grignard reactions.

File:Grignard_with_others.png

{{See also|Grignard reagents#Reactions of Grignard reagents}}

Because carbon is more electronegative than magnesium, the carbon attached to magnesium acts as a nucleophile and attacks the electrophilic carbon atom in the polar bond of a carbonyl group. The addition of the Grignard reagent to the carbonyl group typically proceeds through a six-membered ring transition state, as shown below.{{cite journal| last1 = Maruyama | first1 = K. | last2 = Katagiri | first2 = T. | year = 1989 | journal = J. Phys. Org. Chem. | doi = 10.1002/poc.610020303 | title = Mechanism of the Grignard reaction | volume = 2 | pages = 205–213 | issue = 3}}

File:Grignard-Reaction Mechanism.pngBased on the detection of radical coupling side products, an alternative single electron transfer (SET) mechanism that involves the initial formation of a ketyl radical intermediate has also been proposed.{{Cite journal |last1=Ashby |first1=E. C. |last2=Goel |first2=A. B. |date=August 1981 |title=Direct evidence supporting a single electron transfer pathway in the reduction of ketones by primary, secondary, and tertiary Grignard reagents |url=https://pubs.acs.org/doi/abs/10.1021/ja00406a070 |journal=Journal of the American Chemical Society |language=en |volume=103 |issue=16 |pages=4983–4985 |doi=10.1021/ja00406a070 |issn=0002-7863|url-access=subscription }} A recent computational study suggests that the operative mechanism (polar vs. radical) is substrate-dependent, with the reduction potential of the carbonyl compound serving as a key parameter.{{Cite journal|last1=Peltzer|first1=Raphael Mathias|last2=Gauss|first2=Jürgen|last3=Eisenstein|first3=Odile|last4=Cascella|first4=Michele|date=2020-02-12|title=The Grignard Reaction – Unraveling a Chemical Puzzle|url=https://pubs.acs.org/doi/abs/10.1021/jacs.9b11829|journal=Journal of the American Chemical Society|language=en|volume=142|issue=6|pages=2984–2994|doi=10.1021/jacs.9b11829|pmid=31951398|issn=0002-7863|hdl=10852/83918|s2cid=210709021|hdl-access=free}}

File:Grignard_reagents_with_acidic_protons.png as shown in the figure above.|436x436px]]

The Grignard reaction is conducted under anhydrous conditions.{{Citation |last1=Ouellette |first1=Robert J. |title=15 - Alcohols: Reactions and Synthesis |date=2014-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780128007808000152 |work=Organic Chemistry |pages=491–534 |editor-last=Ouellette |editor-first=Robert J. |access-date=2023-11-06 |place=Boston |publisher=Elsevier |doi=10.1016/b978-0-12-800780-8.00015-2 |isbn=978-0-12-800780-8 |last2=Rawn |first2=J. David |editor2-last=Rawn |editor2-first=J. David|url-access=subscription }} Otherwise, the reaction will fail because the Grignard reagent will act as a base rather than a nucleophile and pick up a labile proton rather than attacking the electrophilic site. This will result in no formation of the desired product as the R-group of the Grignard reagent will become protonated while the MgX portion will stabilize the deprotonated species.

To prevent this, Grignard reactions are completed in an inert atmosphere to remove all water from the reaction flask and ensure that the desired product is formed.{{Cite web |last=Carey |first=Francis A. |title=Grignard reagent |url=https://www.britannica.com/science/Grignard-reaction |website=Britannica}} Additionally, if there are acidic protons in the starting material, as shown in the figure on the right, one can overcome this by protecting the acidic site of the reactant by turning it into an ether or a silyl ether to eliminate the labile proton from the solution prior to the Grignard reaction.

Other variations of the Grignard reagent have been discovered to improve the chemoselectivity of the Grignard reaction, which include but are not limited to: Turbo-Grignards, organocerium reagents, and organocuprate (Gilman) reagents.

Turbo-Grignards are Grignard reagents modified with lithium chloride. Compared to conventional Grignard reagents, Turbo-Grignards are more chemoselective; esters, amides, and nitriles do not react with the Turbo-Grignard reagent.{{cite journal |doi=10.1002/anie.202302489 |title=Comprehensive Study of the Enhanced Reactivity of Turbo-Grignard Reagents* |date=2023 |last1=Hermann |first1=Andreas |last2=Seymen |first2=Rana |last3=Brieger |first3=Lukas |last4=Kleinheider |first4=Johannes |last5=Grabe |first5=Bastian |last6=Hiller |first6=Wolf |last7=Strohmann |first7=Carsten |journal=Angewandte Chemie International Edition |volume=62 |issue=25 |pages=e202302489 |s2cid=257765567 |doi-access=free |pmid=36971042 }}

File:Turbo-Grignard_formation.png

File:Cuprate_conjugate_addition_with_lewis_acid.png

The behavior of Grignard reagents can be usefully modified in the present of other metals. Copper(I) salts give

organocuprates that preferentially effect 1,4 addition.{{Cite journal |last=Woodward |first=Simon |date=2000-01-01 |title=Decoding the 'black box' reactivity that is organocuprate conjugate addition chemistry |url=https://pubs.rsc.org/en/content/articlelanding/2000/cs/b002690p |journal=Chemical Society Reviews |language=en |volume=29 |issue=6 |pages=393–401 |doi=10.1039/B002690P |issn=1460-4744|url-access=subscription }} Cerium trichloride allows selective 1,2-additions to the same substrates. Nickel and palladium halides catalyze cross coupling reactions.

{{Commons category|Grignard reactions}}

• Grignard reagent
• Wittig reaction
• Horner–Wadsworth–Emmons reaction
• Barbier reaction
• Bodroux–Chichibabin aldehyde synthesis
• Fujimoto–Belleau reaction
• Organolithium reagents
• Sakurai reaction
• Indium-mediated allylation
• Alkynylation

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Category:Organometallic chemistry

Category:Carbon-carbon bond forming reactions

Category:Magnesium

Category:Chemical tests

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