The Grignard reaction is an organometallic chemical reaction involving alkyl- or aryl-magnesium halides, also called Grignard reagents, with electrophiles.^[1] The Grignard reaction is an important tool in the formation of carbon-carbon bonds^[2][3] and for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatom bonds. n-butyllithium, an organometallic compound. ... Vapours of hydrogen chloride in a beaker and ammonia in a test tube meet to form a cloud of a new substance, ammonium chloride A chemical reaction is a process that results in the interconversion of chemical substances. ... An alkyl is a univalent radical containing only carbon and hydrogen atoms arranged in a chain. ... In the context of organic molecules, aryl refers to any member of the set of functional groups or substituents that are derived from a simple aromatic ring. ... In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. ... A carbon-carbon bond is a covalent bond between two carbon atoms. ... General Name, Symbol, Number phosphorus, P, 15 Chemical series nonmetals Group, Period, Block 15, 3, p Appearance waxy white/ red/ black/ colorless Standard atomic weight 30. ... General Name, Symbol, Number tin, Sn, 50 Chemical series poor metals Group, Period, Block 14, 5, p Appearance silvery lustrous gray Standard atomic weight 118. ... It has been suggested that Silicons ranking be merged into this article or section. ... General Name, Symbol, Number boron, B, 5 Chemical series metalloids Group, Period, Block 13, 2, p Appearance black/brown Atomic mass 10. ...

The addition to the nucleophile is irreversible due to the high pK_a value of the alkyl component (pK_a = ~45). Grignard reagents react with electrophilic chemical compounds. 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 reagent is that they readily react with protic solvents (such as water), or functional groups with acidic 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 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. Image File history File links Download high-resolution version (1407x298, 4 KB) Description: Generalized reaction scheme of the Grignard reaction. ... Vapours of hydrogen chloride in a beaker and ammonia in a test tube meet to form a cloud of a new substance, ammonium chloride A chemical reaction is a process that results in the interconversion of chemical substances. ... In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a substance. ... A chemical compound is a chemical substance consisting of two or more different chemically bonded chemical elements, with a fixed ratio determining the composition. ... François Auguste Victor Grignard (born in Cherbourg, 6 May 1871, died in Lyon, 13 December 1935) was a Nobel Prize-winning French chemist. ... This is a list of Nobel Prize laureates in Chemistry from 1901 to 2006. ... In chemistry a protic solvent is a solvent that carries hydrogen bond between an oxygen as in a hydroxyl group or a nitrogen as in an amine group. ... ACID (Atomicity, Consistency, Isolation, Durability) is a set of properties that guarantee that database transactions are processed reliably. ... Various examples of swarf, including a block of compressed swarf Swarf (or turnings) is shavings and chippings of metal -- the debris or waste resulting from metalworking operations. ... In chemistry, an alkyl halide is an organic molecule of the form R_X, where X is a halide and R contains a carbon atom bonded to other functional groups or hydrogens. ...

An example of the Grignard reaction is a key step in the industrial production of Tamoxifen:^[4] Tamoxifen is an oral selective estrogen receptor modulator which is used in breast cancer treatment, and is currently the worlds largest selling breast cancer treatment. ...

Image File history File links Tamoxifen_synthesis. ...

Reaction mechanism

The addition of the Grignard reagent to the carbonyl typically proceeds through a six-membered ring transition state.^[5]

However, with hindered Grignard reagents, the reaction may proceed by single-electron transfer. Image:Grignard-Reaction Mechanism. ...

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. Diethyl ether, also known as ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic smell. ... For other uses of THF, see THF (disambiguation) Tetrahydrofuran is a heterocyclic organic compound. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... General Name, Symbol, Number argon, Ar, 18 Chemical series noble gases Group, Period, Block 18, 3, p Appearance colorless Atomic mass 39. ...

Synthesis of Grignard reagents

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.^[6] 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. Image File history File links Formation_of_Grignard_reagent. ... General Name, Symbol, Number magnesium, Mg, 12 Chemical series alkaline earth metals Group, Period, Block 2, 3, s Appearance silvery white Standard atomic weight 24. ... Hot metal work from a blacksmith In chemistry, a metal (Greek: Metallon) is an element that readily loses electrons to form positive ions (cations) and has metallic bonds between metal atoms. ... Ether is the general name for a class of chemical compounds which contain an ether group — an oxygen atom connected to two (substituted) alkyl groups. ... Diethyl ether, also known as ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic smell. ... For other uses of THF, see THF (disambiguation) Tetrahydrofuran is a heterocyclic organic compound. ...

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 bromides and iodides are common substrates. Chlorides are also used, but fluorides are generally unreactive, except with specially activated magnesium, such as Rieke magnesium. In thermodynamics, the word exothermic describes a process or reaction that releases energy in the form of heat. ... A bromide is a phrase, or person who uses phrases, which have been used and repeated so many times as to become either insincere in their meaning, or seem like an attempt at trying to explain the obvious. ... An iodide ion is an iodine atom with a −1 (negative one) charge. ... The chloride ion is formed when the element chlorine picks up one electron to form an anion (negatively-charged ion) Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. ... Fluoride is the ionic form of fluorine. ... Rieke metals are a highly reactive metal powders prepared by the methods developed by Reuben D. Rieke. ...

Many Grignard reagents such as phenylmagnesium bromide are available commercially in tetrahydrofuran or diethyl ether solutions. Phenylmagnesium bromide, with the simplified formula C6H5MgBr, is a a magnesium-containing organometallic compound. ... For other uses of THF, see THF (disambiguation) Tetrahydrofuran is a heterocyclic organic compound. ... Diethyl ether, also known as ether and ethoxyethane, is a clear, colorless, and highly flammable liquid with a low boiling point and a characteristic smell. ...

Via the Schlenk equilibrium, Grignard reagents form varying amounts of diorganomagnesium compounds (R = organic group, X = halide): The Schlenk equilibrium is a chemical equilibrium named after its discoverer Wilhelm Schlenk taking place in solutions of Grignard reagents. ...

2 RMgX R₂Mg + MgX₂

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 is also effective. Iodine, methyl iodide, and 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: Sonication is a process of dispersing, disrupting or desactivating various biological materials by the use of sound waves. ... General Name, Symbol, Number iodine, I, 53 Chemical series halogens Group, Period, Block 17, 5, p Appearance violet-dark gray, lustrous Standard atomic weight 126. ... Iodomethane, commonly called methyl iodide, is a dense volatile liquid. ... 1,2-Dibromoethane is a manufactured chemical. ... Ethylene (or IUPAC name ethene) is the chemical compound with the formula C2H4. ...

Mg + BrC₂H₄Br → C₂H₄ + MgBr₂

The amount of Mg consumed by these activating agents is usually insignificant.

The addition of a small amount of mercuric chloride amalgamates the surface of the metal, allowing it to react. Mercury chloride is a white poisonous soluble crystalline sublimate of mercury, used as a pesticide or antiseptic or wood preservative. ... the word amalgamation, see Amalgamation. ...

These methods weaken the passivating layer of MgO, thereby exposing highly reactive magnesium to the organic halide. Passivation is the process of making a material passive in relation to another material prior to using the materials together. ... Magnesium oxide Magnesium oxide, or magnesia, is a white solid mineral that occurs naturally as periclase and is a source of magnesium. ...

Variations

Grignard reagents will react with a variety of carbonyl derivatives.^[7] Carbonyl group In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom : C=O. The term carbonyl can also refer to carbon monoxide as a ligand in an inorganic or organometallic complex (a metal carbonyl, e. ...

In addition, Grignard reagents will react with other various electrophiles. Image File history File links Download high-resolution version (1730x1163, 48 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Grignard reaction ...

Also the Grignard reagent is very useful for forming carbon-heteroatom bonds. Image File history File links Download high-resolution version (1470x1166, 37 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Grignard reaction ...

Coupling reactions

A Grignard reagent can also be involved in coupling reactions. For example, nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid.^[8] A coupling reaction in organic chemistry is a catch-all for a range of reactions in Organometallic chemistry where two hydrocarbon radicals are coupled with the aid of a metal containing catalyst. ...

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 (Li₂CuCl₄), prepared by mixing lithium chloride (LiCl) and copper(II) chloride (CuCl₂) in THF. The Kumada-Corriu coupling gives access to styrenes. Image:4nonylbenzoicacid2. ... Nickel(II) chloride, or nickelous chloride or just nickel chloride, is the chemical compound NiCl2. ... Tetrahydrofuran, also known as THF, hydrofuran, oxolane, oxacyclopentane, or furanidine, is a heterocyclic organic compound. ... Lithium chloride behaves as a fairly typical ionic compound, although the Li+ ion is very small. ... Copper(II) chloride is the higher chloride of copper, with the formula CuCl2. ... A Kumada coupling or Kamuda-Corriu coupling is a cross coupling reaction in organic chemistry between a alkyl or aryl Grignard reagent and an aryl or vinyl halocarbon catalysed by nickel or palladium. ...

Oxidation

The oxidation of a Grignard reagent with oxygen takes place through a radical intermediate to a magnesium hydroperoxide. Hydrolysis of this complex yields hydroperoxides and reduction with an additional equivalent of Grignard reagent gives an alcohol. In chemistry, radicals (often referred to as free radicals) are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. ... Organic peroxides are organic molecules containing the peroxide functional group ROOR If the R is hydrogen, the compound is called organic hydroperoxide. ... Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. ... Functional group of an alcohol molecule. ...

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.^[9] 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 File history File links Download high-resolution version (1026x174, 3 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Grignard reaction ... The chemical structure of ethylene, the simplest alkene. ... Functional group of an alcohol molecule. ... In the context of organic molecules, aryl refers to any member of the set of functional groups or substituents that are derived from a simple aromatic ring. ... Chemical structure of the vinyl functional group. ...

Image File history File links Grignard_oxidation_example. ...

Nucleophilic aliphatic substitution

Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production: In chemistry, a nucleophile (literally nucleus lover) is a reagent which is attracted to centres of positive charge. ... In chemistry, nucleophilic substitution is a class of substitution reaction in which an electron-rich nucleophile attacks a molecule and replaces a group or atom, called the leaving group. ... In chemistry, an alkyl halide is an organic molecule of the form R_X, where X is a halide and R contains a carbon atom bonded to other functional groups or hydrogens. ... Naproxen (trade names: Aleve, Anaprox, Naprogesic, Naprosyn, Naprelan) is a non-steroidal anti-inflammatory drug (NSAID) commonly used for the reduction of mild to moderate pain, fever, inflammation and stiffness caused by conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, injury, menstrual cramps, tendinitis, bursitis, and the...

Image File history File links Download high-resolution version (896x132, 3 KB) Naproxen synthesis I, the creator of this work, hereby grant the permission to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1. ...

References

1. ^ Grignard, V. Compt. Rend. 1900, 130, 1322.
2. ^ Shirley, D. A. Org. React. 1954, 8, 28-58. (Review)
3. ^ Huryn, D. M. Comp. Org. Syn. 1991, 1, 49-75. (Review)
4. ^ Grignard Reagents: New Developments H. G. Richey (Editor) ISBN 0-471-99908-3
5. ^ Maruyama, K.; Katagiri, T. J. Phys. Org. Chem. 1989, 2, 205. (DOI:10.1002/poc.610020303)
6. ^ Lai, Y. H. Synthesis 1981, 585-604. (Review)
7. ^ Butyric acid, α-methyl- Henry Gilman and R. H. Kirby Organic Syntheses, Coll. Vol. 1, p.361 (1941); Vol. 5, p.75 (1925). (Article)
8. ^ 4-Nonylbenzoic Acid A. Fürstner, A. Leitner, G. Seidel. Org. Syn. 2004, 81, 33-42. (Article)
9. ^ 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)

François Auguste Victor Grignard (born in Cherbourg, 6 May 1871, died in Lyon, 13 December 1935) was a Nobel Prize-winning French chemist. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... Organic Syntheses is a scientific journal that Since 1921 has provided the chemistry community with annual collections of detailed and checked procedures for the organic synthesis of organic compounds. ... Organic Syntheses is a scientific journal that since 1921 has provided the chemistry community with annual collections of detailed and checked procedures for the organic synthesis of organic compounds. ... The Journal of the American Chemical Society (usually abbreviated as , or JACS), is a peer-reviewed scientific journal, published since 1879 by the American Chemical Society. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ...

See also

• Barbier reaction
• Bodroux-Chichibabin aldehyde synthesis
• Fujimoto-Belleau reaction
• Gilman reagent
• Organolithium reagents
• Sakurai reaction