Grignard reaction
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The '''Grignard reaction''', named for the French chemist [[François Auguste Victor Grignard]], is an [[organometallic chemistry|organometallic]] [[chemical reaction]] in which [[alkyl]]- or [[aryl]]-[[magnesium]] [[halide]]s ('''Grignard reagents'''), which act as [[nucleophile]]s, attack [[electrophilic]] carbon atoms that are present within polar bonds (e.g., a [[carbonyl]] group, see below) to yield a carbon-carbon bond (compare to [[Wittig reaction]]), thus altering [[hybridization]] about the reaction center.<ref>{{cite journal
| author = [[Victor Grignard|Grignard, V.]]
| title = Sur quelques nouvelles combinaisons organométaliques du magnésium et leur applicatione à des synthèses d'alcools et d'hydrocabures
| journal = Compt. Rend.
| year =1900
| volume = 130
| pages = 1322–1325
| url = http://gallica.bnf.fr/ark:/12148/bpt6k3086n/f1322.table}}</ref> The Grignard reaction is an important tool in the formation of [[carbon-carbon bond]]s<ref>Shirley, D. A. ''Org. React.'' '''1954''', ''8'', 28-58. (Review)</ref><ref>Huryn, D. M. ''Comp. Org. Syn.'' '''1991''', ''1'', 49-75. (Review)</ref> and for the formation of carbon-[[phosphorus]], carbon-[[tin]], carbon-[[silicon]], carbon-[[boron]] and other carbon-heteroatom bonds.
[[Image:Grignard Reaction Scheme.png|center|500px|An example of a Grignard reaction]]
The addition to the nucleophile is irreversible due to the high pK<sub>a</sub> value of the alkyl component (pK<sub>a</sub> = ~45). Grignard reagents [[chemical reaction|react]] with [[electrophilic]] [[chemical compound]]s. It should be noted that such reactions are '''not''' ionic; the Grignard reagent exists as an organometallic cluster (in ether). [[Victor Grignard]] (University Of Nancy, France) was awarded the 1912 [[Nobel Prize in Chemistry]] for the discovery of such reagents. The disadvantage of the Grignard reagents is that they readily react with [[protic solvent]]s (such as water), or functional groups with [[acid]]ic protons, such as alcohols and amines. In fact, atmospheric humidity in the lab can dictate one's success when trying to synthesize a Grignard reagent from magnesium [[swarf|turnings]] and an [[alkyl halide]]. To circumvent this issue, the reaction vessel is often flame-dried to evaporate all moisture, then sealed to prevent more from entering.
An example of the Grignard reaction is a key step in the industrial production of [[Tamoxifen]]:<ref>''Grignard Reagents: New Developments'' H. G. Richey (Editor) ISBN 0-471-99908-3</ref>
[[Image:Tamoxifen synthesis.png|center|300px|Tamoxifen production]]
==Reaction mechanism==
The addition of the Grignard reagent to the carbonyl typically proceeds through a six-membered ring transition state.<ref>Maruyama, K.; Katagiri, T. ''J. Phys. Org. Chem.'' '''1989''', ''2'', 205. ({{DOI|10.1002/poc.610020303}})</ref>
[[Image:Grignard-Reaction Mechanism.png|center|The mechanism of the Grignard reaction.]]
However, with hindered Grignard reagents, the reaction may proceed by single-electron transfer.
In a reaction involving Grignard reagents, it is important to ensure that no water is present, which would otherwise cause the reagent to rapidly decompose. Thus, most Grignard reactions occur in solvents such as anhydrous [[diethyl ether]] or [[tetrahydrofuran]], because the oxygen of these solvents stabilizes the magnesium reagent. The reagent may also react with oxygen present in the atmosphere, inserting an oxygen atom between the carbon base and the magnesium halide group. Usually, this side-reaction may be limited by the volatile solvent vapors displacing air above the reaction mixture. However, it may be preferable for such reactions to be carried out in [[nitrogen]] or [[argon]] atmospheres, especially for smaller scales.
==Synthesis of Grignard reagents==
[[Image:Formation of Grignard reagent.gif|right|300px|Idealized cartoon for the formation of a Grignard reagent]]
Grignard reagents are formed via the action of an alkyl or aryl halide on [[magnesium]] [[metal]].<ref>Lai, Y. H. ''Synthesis'' '''1981''', 585-604. (Review)</ref> The reaction is conducted by adding the organic halide to a suspension of magnesium in an [[ether]], which provides [[ligands]] required to stabilize the [[organomagnesium compound]]. Typical solvents are [[diethyl ether]] and [[tetrahydrofuran]]. Oxygen and protic solvents such as water or alcohols are not compatible with Grignard reagents. The reaction proceeds through [[single electron transfer]].
Grignard reactions often start slowly. As is common for reactions involving solids and solution, initiation follows an induction period during which reactive magnesium becomes exposed to the organic reagents. After this induction period, the reactions can be highly [[exothermic]]. Alkyl and aryl [[bromide]]s and [[iodide]]s are common substrates. [[Chloride]]s are also used, but [[fluoride]]s are generally unreactive, except with specially activated magnesium, such as [[Rieke metals|Rieke magnesium]].
Many Grignard reagents such as [[phenylmagnesium bromide]] are available commercially in [[tetrahydrofuran]] or [[diethyl ether]] solutions.
Via the [[Schlenk equilibrium]], Grignard reagents form varying amounts of diorganomagnesium compounds (R = organic group, X = halide):
:2 RMgX <math>\overrightarrow{\leftarrow}</math> R<sub>2</sub>Mg + MgX<sub>2</sub>
===Practical tips===
Many methods have been developed to initiate sluggish Grignard reactions. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and [[sonication]] of the suspension. [[Iodine]], [[methyl iodide]], and [[1,2-Dibromoethane|1,2-dibromoethane]] are commonly employed activating agents. The use of 1,2-dibromoethane is particularly advantageous as its action can be monitored by the observation of bubbles of [[ethylene]]. Furthermore, the side-products are innocuous:
: Mg + BrC<sub>2</sub>H<sub>4</sub>Br → C<sub>2</sub>H<sub>4</sub> + MgBr<sub>2</sub>
The amount of Mg consumed by these activating agents is usually insignificant.
The addition of a small amount of [[mercuric chloride]] [[amalgam]]ates the surface of the metal, allowing it to react.
These methods weaken the [[passivation|passivating]] layer of [[magnesium oxide|MgO]], thereby exposing highly reactive magnesium to the organic halide.
==Variations==
Grignard reagents will react with a variety of [[carbonyl]] derivatives.<ref>{{OrgSynth | title = Butyric acid, α-methyl- | author = Henry Gilman and R. H. Kirby | collvol = 1 | collvolpages = 361 | year = 1941 | prep = cv1p0361}}</ref>
[[Image:Grignard with carbonyl.png|center|600px|Reactions of Grignard reagents with carbonyls]]
In addition, Grignard reagents will react with other various electrophiles.
[[Image:Grignard with others.png|center|500px|Reactions of Grignard reagents with various electrophiles]]
Also the Grignard reagent is very useful for forming carbon-heteroatom bonds.
<!-- This image is missing! [[Image:OrganoelementGrignard.png|center|400px|Reactions of Grignard reagents with non carbon electrophiles]]-->
===Coupling reactions===
A Grignard reagent can also be involved in [[coupling reaction]]s. For example, nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid, in the presence of [[iron(III) acetylacetonate]]. Ordinarily, the Grignard reagent will attack the ester over the [[aryl halide]].<ref>{{OrgSynth | title = 4-Nonylbenzoic Acid | author = A. Fürstner, A. Leitner, G. Seidel | year = 2004 | volume = 81 | pages = 33-42 | prep = v81p0033}}</ref>
[[Image:4nonylbenzoicacid2.gif|center|4-nonylbenzoicacid]]
For the coupling of aryl halides with aryl Grignards, [[nickel chloride]] in [[THF]] is also a good catalyst. Additionally, an effective catalyst for the couplings of alkyl halides is [[dilithium tetrachlorocuprate]] (Li<sub>2</sub>CuCl<sub>4</sub>), prepared by mixing [[lithium chloride]] (LiCl) and [[copper(II) chloride]] (CuCl<sub>2</sub>) in THF. The [[Kumada-Corriu coupling]] gives access to styrenes.
===Oxidation===
The oxidation of a Grignard reagent with oxygen takes place through a [[radical (chemistry)|radical]] intermediate to a magnesium hydroperoxide. Hydrolysis of this complex yields [[hydroperoxide]]s and [[organic reduction|reduction]] with an additional equivalent of Grignard reagent gives an [[alcohol]].
[[Image:Grignard oxygen oxidation.png|center|600px|Grignard oxygen oxidation pathways]]
The synthetic utility of Grignard oxidations can be increased by a reaction of Grignards with oxygen in presence of an [[alkene]] to an ethylene extended [[alcohol]].<ref>''Air-Assisted Addition of Grignard Reagents to Olefins. A Simple Protocol for a Three-Component Coupling Process Yielding Alcohols'' Youhei Nobe, Kyohei Arayama, and Hirokazu Urabe ''[[J. Am. Chem. Soc.]]'' '''2005''', 127(51), 18006 - 18007. ({{DOI|10.1021/ja055732b}})</ref> This modification requires [[aryl]] or [[vinyl]] Grignards. Adding just the Grignard and the alkene does not result in a reaction demonstrating that the presence of oxygen is essential. Only drawback is the requirement of at least two equivalents of Grignard although this can partly be circumvented by the use of a dual Grignard system with a cheap reducing Grignard such as n-butylmagnesium bromide.
[[Image:Grignard oxidation example.png|center|400px|Grignard oxygen oxidation example]]
===Nucleophilic aliphatic substitution===
Grignard reagents are [[nucleophile]]s in [[nucleophilic aliphatic substitution]]s for instance with [[alkyl halide]]s in a key step in industrial [[Naproxen]] production:
[[Image:Naproxen synthesis.png|center|550px|Naproxen synthesis]]
===Elimination===
In the [[Boord olefin synthesis]], the addition of magnesium to certain β-haloethers results in an [[elimination reaction]] to the alkene. This reaction can limit the utility of Grignard reactions.
[[Image:BoordReactionOverview.png|300px|center|Boord olefin synthesis, X = Br, I, M = Mg, Zn]]
==Grignard degradation==
'''Grignard degradation''' <ref>''Studien in der Thiophenreihe. XXVI. Isomere Bromthiophene und die Konstitution der Thiophendisulfonsäuren'' (p 136-164) Wilhelm Steinkopf, Hans Jacob, Herbert Penz Justus [[Liebig's Annalen der Chemie]] '''1934''' Volume 512, Issue 1 , Pages 136 - 164 {{DOI|10.1002/jlac.19345120113}}</ref> <ref>''Studien in der Thiophenreihe. LII. Abkömmlinge des 3-Brom- und 2,3-Dibrom-thiophens'' [[Justus Liebig's Annalen der Chemie]] Volume 543, Issue 1, Date: 1940, Pages: 128-132 Wilhelm Steinkopf {{DOI|10.1002/jlac.19405430110}}</ref> at one time was a tool in structure elucidation in which a Grignard RMgBr formed from a heteroaryl bromide HetBr reacts with water to Het-H (bromine replaced by a hydrogen atom) and MgBrOH. This [[hydrolysis]] method allows the determination of the number of halogen atoms in an [[organic compound]]. In modern usage Grignard degradation is used in the chemical analysis of certain triacylglycerols <ref>''Stereospecific analysis of triacylglycerols via racemic phosphatidylcholines and phospholipase C.'' Myher,J.J. and Kuksis,A., Can. J. Biochem., 57, 117-124 ('''1979'''). </ref>.
==References==
{{Reflist}}
==See also==
* [[Barbier reaction]]
* [[Bodroux-Chichibabin aldehyde synthesis]]
* [[Fujimoto-Belleau reaction]]
* [[Organolithium reagent]]s
* [[Sakurai reaction]]
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