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{{Short description|Organometallic coupling reaction}} {{Use American English|date=January 2019}} {{Use mdy dates|date=January 2019}} {{Reactionbox | Name = Classical Grignard reaction | Type = Coupling reaction | NamedAfter = [[Victor Grignard]] | Section3 = {{Reactionbox Identifiers | OrganicChemistryNamed = grignard-reaction | RSC_ontology_id = 0000014 }} |Reaction={{Reactionbox Reaction | Reactant1 = [[Methanal]]/Higher [[aldehyde]]/[[Ketone]] | Reactant2 = [[Grignard reagent|R-MgX]] | Reagent1= (H<sub>3</sub>O<sup>+</sup>) | Product1 = Primary/Secondary/Tertiary alcohols }}|BoxWidth=25%}}[[File:Grignard reaction experiment 07.jpg|thumb|right|A solution of a carbonyl compound is added to a Grignard reagent. (See [[Grignard reagent#Gallery|gallery]])|206x206px]] [[File:Grignard_reaction_scheme.svg|thumb|center|524x524px|An example of a Grignard reaction (R<sub>2</sub> or R<sub>3</sub> could be hydrogen)]] The '''Grignard reaction''' ({{IPA|fr|ɡʁiɲaʁ|lang}}) is an [[organometallic chemistry|organometallic]] [[chemical reaction]] in which, according to the classical definition, carbon [[alkyl]], [[allyl group|allyl]], [[vinyl group|vinyl]], or [[aryl]] magnesium [[halide]]s ([[Grignard reagent]]) are added to the [[carbonyl]] groups of either an [[aldehyde]] or [[ketone]] under anhydrous conditions.<ref name=":1">{{March6th}}</ref><ref>[http://www.mhhe.com/physsci/chemistry/carey/student/olc/ch19reactioncarboxylicacids.html Chapter 19: Carboxylic Acids]. Organic Chemistry 4e Carey. mhhe.com</ref><ref name=":12" /> This reaction is important for the formation of [[carbon–carbon bond]]s.<ref>{{cite journal|last = Shirley|first = D. A.|year = 1954|title = The Synthesis of Ketones from Acid Halides and Organometallic Compounds of Magnesium, Zinc, and Cadmium|journal = [[Org. React.]]|volume = 8|pages = 28–58}}</ref><ref>{{cite book|last = Huryn|first = D. M.|year = 1991|title = Comprehensive Organic Synthesis, Volume 1: Additions to C—X π-Bonds, Part 1|pages = 49–75|chapter = Carbanions of Alkali and Alkaline Earth Cations: (ii) Selectivity of Carbonyl Addition Reactions|editor1-last = Trost|editor1-first = B. M.|editor2-last = Fleming|editor2-first = I.|isbn = 978-0-08-052349-1|editor1-link = Barry Trost|editor2-link = Ian Fleming (chemist)|publisher = [[Elsevier Science]]|doi = 10.1016/B978-0-08-052349-1.00002-0}}</ref> ==History and definitions== 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.<ref name=":0">{{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}}</ref> He was awarded the 1912 [[Nobel Prize in Chemistry]] for this work.<ref>{{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}}</ref> The reaction of an organic halide with magnesium is ''not'' a Grignard reaction, but provides a Grignard reagent.<ref name=":2">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}}.</ref> [[Image:Grignard with carbonyl.png|thumb|560x560px|Although [[Grignard reagent#Reactions of Grignard reagents|Grignard reagents]] 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.<ref name=":1" /> However, some chemists understand the definition to mean all reactions of any electrophiles with Grignard reagents.<ref name=":3" /> 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."<ref name=":3">{{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}}</ref> 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 reagent]]s, but they themselves are not classically understood as Grignard reactions. [[File:Grignard_with_others.png|alt=Reactions of Grignard reagents with various electrophiles|center|494x494px|Additional reactions which involve Grignard reagents, but are not considered to be Grignard reactions by the classical definition. X = Cl, Br, I.]] ==Reaction mechanism== {{See also|Grignard reagents#Reactions of Grignard reagents}} Because carbon is more [[Electronegativity|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.<ref>{{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}}</ref> [[File:Grignard-Reaction Mechanism.png|center|715x715px|The mechanism of the Grignard reaction.]]Based 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.<ref>{{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 }}</ref> A recent computational study suggests that the operative mechanism (polar vs. radical) is substrate-dependent, with the [[reduction potential]] of the [[Carbonyl group|carbonyl]] compound serving as a key parameter.<ref>{{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}}</ref> ==Conditions== [[File:Grignard_reagents_with_acidic_protons.png|thumb|If a Grignard reaction is performed in the presence of water, or any labile proton, the labile proton will quench the [[Grignard reagent]] as shown in the figure above.<ref name=":12" />|436x436px]] The Grignard reaction is conducted under [[anhydrous|anhydrous conditions]].<ref name=":12">{{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 }}</ref> Otherwise, the reaction will fail because the Grignard reagent will act as a base rather than a nucleophile and pick up a [[Lability|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 [[Air-free technique|inert atmosphere]] to remove all water from the reaction flask and ensure that the desired product is formed.<ref>{{Cite web |last=Carey |first=Francis A. |title=Grignard reagent |url=https://www.britannica.com/science/Grignard-reaction |website=Britannica}}</ref> 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. ==Variants== 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=== Turbo-Grignards are Grignard reagents modified with [[lithium chloride]]. Compared to conventional Grignard reagents, Turbo-Grignards are more [[chemoselectivity|chemoselective]]; [[ester]]s, [[amide]]s, and [[nitrile]]s do not react with the Turbo-Grignard reagent.<ref>{{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 }}</ref> [[File:Turbo-Grignard_formation.png|none|thumb|320x320px|An example reaction of forming a Turbo-Grignard with an ester group.]] ===Heterometal-modified Grignard reagents=== [[File:Cuprate_conjugate_addition_with_lewis_acid.png|none|thumb|405x405px|A conjugated 1,4 addition using a Gilman reagent with an arbitrary R group]] The behavior of Grignard reagents can be usefully modified in the present of other metals. Copper(I) salts give [[Gilman reagent|organocuprates]] that preferentially effect [[nucleophilic conjugate addition|1,4 addition]].<ref name=":4">{{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 }}</ref> Cerium trichloride allows selective 1,2-additions to the same substrates. Nickel and palladium halides catalyze [[cross coupling reaction]]s. ==See also== {{Commons category|Grignard reactions}} * [[Grignard reagent]] * [[Wittig reaction]] * [[Horner–Wadsworth–Emmons reaction]] * [[Barbier reaction]] * [[Bodroux–Chichibabin aldehyde synthesis]] * [[Fujimoto–Belleau reaction]] * [[Organolithium reagent]]s * [[Sakurai reaction]] * [[Indium-mediated allylation]] * [[Alkynylation]] ==References== {{Reflist}} {{organometallics}} {{Authority control}} [[Category:Organometallic chemistry]] [[Category:Carbon-carbon bond forming reactions]] [[Category:Magnesium]] [[Category:Chemical tests]] [[Category:Name reactions]]
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