Grignard reaction

The Grignard reaction, named for the French chemist François Auguste Victor Grignard, is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides (Grignard reagents), which act as nucleophiles, attack electrophilic carbon atoms that are present within polar bonds (e. François Auguste Victor Grignard ( May 6, 1871 in Cherbourg - December 13, 1935 in Lyon) was a Nobel Prize Organometallic chemistry is the study of Chemical compounds containing bonds between Carbon and a Metal. A chemical reaction is a process that always results in the interconversion of Chemical substances The substance or substances initially involved in a chemical reaction are called An alkyl is a Univalent radical consisting of Carbon and Hydrogen atoms arranged in a chain In the context of organic molecules aryl refers to any Functional group or Substituent derived from a Simple aromatic ring, may it be Phenyl Magnesium (mægˈniːziəm is a Chemical element with the symbol Mg, Atomic number 12 Atomic weight 24 A halide is a Binary compound, of which one part is a Halogen Atom and the other part is an element or radical that is less In Chemistry, a nucleophile (literally nucleus lover as in nucleus and phile) is a Reagent that forms a Chemical bond to In Chemistry, an electrophile (literally electron-lover) is a Reagent attracted to Electrons that participates in a chemical reaction by accepting g. , a carbonyl group, see below) to yield a carbon-carbon bond (compare to Wittig reaction), thus altering hybridization about the reaction center. In Organic chemistry, a carbonyl group is a Functional group composed of a Carbon Atom double-bonded to an Oxygen The Wittig reaction is a Chemical reaction of an Aldehyde or Ketone with a triphenyl phosphonium ylide (often called a Wittig reagent ^[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. A carbon-carbon bond is a Covalent bond between two Carbon Atoms. Phosphorus, (ˈfɒsfərəs is the Chemical element that has the symbol P and Atomic number 15 Tin is a Chemical element with the symbol Sn (stannum and Atomic number 50 Silicon (ˈsɪlɪkən or /ˈsɪlɪkɒn/ silicium is the Chemical element that has the symbol Si and Atomic number 14 Boron (ˈbɔərɒn is a Chemical element with Atomic number 5 and the chemical symbol B.

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. A chemical reaction is a process that always results in the interconversion of Chemical substances The substance or substances initially involved in a chemical reaction are called In Chemistry, an electrophile (literally electron-lover) is a Reagent attracted to Electrons that participates in a chemical reaction by accepting A chemical compound is a substance consisting of two or more different elements chemically bonded together in a fixed proportion by Mass. 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. François Auguste Victor Grignard ( May 6, 1871 in Cherbourg - December 13, 1935 in Lyon) was a Nobel Prize The Nobel Prize in Chemistry (Nobelpriset i kemi is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of Chemistry. The disadvantage of the Grignard reagents is that they readily react with protic solvents (such as water), or functional groups with acidic protons, such as alcohols and amines. In Chemistry a protic solvent is a Solvent that has a Hydrogen atom bound to an Oxygen as in a Hydroxyl group or a Nitrogen In Computer science, ACID ( Atomicity Consistency Isolation Durability) is a set of properties that guarantee that Database transactions are 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. Swarf (or turnings or chips are shavings and chippings of metal—the debris or waste resulting from Metalworking operations The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of Chemical compounds consisting of Alkanes such as Methane 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:^[4]

1 Reaction mechanism
2 Synthesis of Grignard reagents
- 2.1 Practical tips
3 Variations
4 Grignard degradation
5 References
6 See also

Reaction mechanism

The addition of the Grignard reagent to the carbonyl typically proceeds through a six-membered ring transition state. Tamoxifen is an orally active Selective estrogen receptor modulator (SERM that is used in the treatment of Breast cancer and is currently the world's largest ^[5]

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. Diethyl ether, also known as ether and ethoxyethane, is a clear colorless and highly Flammable liquid with a low Boiling point and a "THF" redirects here For other uses see THF (disambiguation. 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. Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 This article pertains to the chemical element For other uses see Argon (disambiguation.

Synthesis of Grignard reagents

Grignard reagents are formed via the action of an alkyl or aryl halide on magnesium metal. Magnesium (mægˈniːziəm is a Chemical element with the symbol Mg, Atomic number 12 Atomic weight 24 The M acro E xpansion T emplate A ttribute L anguage complements TAL, providing macros which allow the reuse of code across ^[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. Ether is a class of Organic compounds which contain an ether group — an Oxygen Atom connected to two (substituted Alkyl In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally The organometallic chemistry of group 2 elements is relevant to Organic chemistry, though in some cases the interest is strictly academic Typical solvents are diethyl ether and tetrahydrofuran. Diethyl ether, also known as ether and ethoxyethane, is a clear colorless and highly Flammable liquid with a low Boiling point and a "THF" redirects here For other uses see THF (disambiguation. Oxygen and protic solvents such as water or alcohols are not compatible with Grignard reagents. The reaction proceeds through single electron transfer. A one-electron reduction in Organic chemistry involves the transfer of an electron from a Metal to an organic substrate.

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. In Thermodynamics, the word exothermic "outside heating" describes a process or reaction that releases Energy usually in the form of Heat, but Alkyl and aryl bromides and iodides are common substrates. A bromide Ion is a Bromine atom with charge of −1 Compounds with bromine in formal Oxidation state −1 are called bromides An iodide Ion is an iodine atom with a &minus1 charge. Compounds with iodine in formal Oxidation state &minus1 are called iodides Chlorides are also used, but fluorides are generally unreactive, except with specially activated magnesium, such as Rieke magnesium. The chloride Ion is formed when the element Chlorine picks up one Electron to form an Anion (negatively-charged ion Cl&minus Fluoride is the reduced form of Fluorine. Both organic and Inorganic compounds containing the element fluorine are considered fluorides Rieke metals are highly reactive Metal powders prepared by the methods developed by Reuben D

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. "THF" redirects here For other uses see THF (disambiguation. Diethyl ether, also known as ether and ethoxyethane, is a clear colorless and highly Flammable liquid with a low Boiling point and a

Via the Schlenk equilibrium, Grignard reagents form varying amounts of diorganomagnesium compounds (R = organic group, X = halide):

2 RMgX $\overrightarrow{\leftarrow}$ R₂Mg + MgX₂

Practical tips

Many methods have been developed to initiate sluggish Grignard reactions. The Schlenk equilibrium is a Chemical equilibrium named after its discoverer Wilhelm Schlenk taking place in solutions of Grignard reagents The Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication of the suspension. Sonication is the act of applying sound (usually Ultrasound) energy to agitate particles in a sample for various purposes Iodine, methyl iodide, and 1,2-dibromoethane are commonly employed activating agents. Iodine (ˈaɪədaɪn ˈaɪədɪn or /ˈaɪədiːn/ from ιώδης iodes "violet" is a Chemical element that has the symbol I and Atomic Iodomethane, commonly called Methyl iodide and commonly abbreviated "MeI" is the Chemical compound with the formula CH3I The use of 1,2-dibromoethane is particularly advantageous as its action can be monitored by the observation of bubbles of ethylene. Structure This Hydrocarbon has four Hydrogen Atoms bound to a pair of Carbon atoms that are connected by a Double bond. Furthermore, the side-products are innocuous:

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(II chloride or mercuric chloride (formerly corrosive sublimate) is the Chemical compound with the formula HgCl sub>2

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, or magnesia, is a white solid Mineral that occurs naturally as Periclase and is a source

Variations

Grignard reagents will react with a variety of carbonyl derivatives. In Organic chemistry, a carbonyl group is a Functional group composed of a Carbon Atom double-bonded to an Oxygen ^[7]

In addition, Grignard reagents will react with other various electrophiles.

Also the Grignard reagent is very useful for forming carbon-heteroatom bonds.

Coupling reactions

A Grignard reagent can also be involved in coupling reactions. A coupling reaction or oxidative coupling in Organic chemistry is a catch-all for a range of reactions in organometallic chemistry where two Hydrocarbon 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. In Organic chemistry, a halogenoarene, haloarene, or aryl halide, is an organic compound in which a Halogen atom is bonded to a Carbon ^[8]

For the coupling of aryl halides with aryl Grignards, nickel chloride in THF is also a good catalyst. Nickel(II chloride (or just nickel chloride) is the Chemical compound NiCl2 "THF" redirects here For other uses see THF (disambiguation. 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. Lithium chloride is a Chemical compound with the formula Li[[Chlorine Cl]] Copper(II chloride is the Chemical compound with the formula CuCl2 The Kumada-Corriu coupling gives access to styrenes. A Kumada coupling or Kumada-Corriu coupling is a Cross coupling reaction in Organic chemistry between a Alkyl or Aryl Grignard

Oxidation

The oxidation of a Grignard reagent with oxygen takes place through a radical intermediate to a magnesium hydroperoxide. In Chemistry, radicals (often referred to as free radicals) are atoms molecules or ions with Unpaired electrons on an otherwise Open shell Hydrolysis of this complex yields hydroperoxides and reduction with an additional equivalent of Grignard reagent gives an alcohol. Organic peroxides are Organic compounds containing the Peroxide Functional group (ROOR' Organic reductions or organic oxidations or organic redox reactions are Redox reactions that take place with Organic compounds In Organic In Chemistry, an alcohol is any Organic compound in which a Hydroxyl group ( - O[[hydrogen H]]) is bound to a Carbon

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. In Organic chemistry, an alkene, olefin, or olefine is an unsaturated Chemical compound containing at least one Carbon In Chemistry, an alcohol is any Organic compound in which a Hydroxyl group ( - O[[hydrogen H]]) is bound to a Carbon ^[9] This modification requires aryl or vinyl Grignards. In the context of organic molecules aryl refers to any Functional group or Substituent derived from a Simple aromatic ring, may it be Phenyl A vinyl compound is any Organic compound that contains a vinyl group (also called ethenyl) &minus C[[Hydrogen H]] =CH sub>2 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.

Nucleophilic aliphatic substitution

Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:

Elimination

In the Boord olefin synthesis, the addition of magnesium to certain β-haloethers results in an elimination reaction to the alkene. In Chemistry, a nucleophile (literally nucleus lover as in nucleus and phile) is a Reagent that forms a Chemical bond to In organic and Inorganic chemistry, nucleophilic substitution is a fundamental class of Substitution reaction in which an "electron rich" The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of Chemical compounds consisting of Alkanes such as Methane Naproxen ( INN) (nəˈprɒksən is a Non-steroidal anti-inflammatory drug (NSAID commonly used for the reduction of moderate to severe Pain, Fever The Boord olefin synthesis is an Organic reaction forming Alkenes from Ethers carrying a Halogen atom 2 carbons removed from the oxygen atom (β-halo-ethers An elimination reaction is a type of Organic reaction in which two Substituents are removed from a molecule in either a one or two-step mechanism. This reaction can limit the utility of Grignard reactions.

Grignard degradation

Grignard degradation ^[10] ^[11] 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. Hydrolysis is a Chemical reaction during which one or more water molecules are split into hydrogen and hydroxide ions which may go on to participate in further reactions An organic compound is any member of a large class of Chemical compounds whose Molecules contain Carbon. In modern usage Grignard degradation is used in the chemical analysis of certain triacylglycerols ^[12].

References

^ Grignard, V. (1900). François Auguste Victor Grignard ( May 6, 1871 in Cherbourg - December 13, 1935 in Lyon) was a Nobel Prize "Sur quelques nouvelles combinaisons organométaliques du magnésium et leur applicatione à des synthèses d'alcools et d'hydrocabures". Compt. Rend. 130: 1322-1325.
^ Shirley, D. A. Org. React. 1954, 8, 28-58. (Review)
^ Huryn, D. M. Comp. Org. Syn. 1991, 1, 49-75. (Review)
^ Grignard Reagents: New Developments H. G. Richey (Editor) ISBN 0-471-99908-3
^ Maruyama, K. ; Katagiri, T. J. Phys. Org. Chem. 1989, 2, 205. (doi:10.1002/poc.610020303)
^ Lai, Y. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. H. Synthesis 1981, 585-604. (Review)
^ Henry Gilman and R. H. Kirby (1941). "Butyric acid, α-methyl-". Org. Synth.; Coll. Organic Syntheses is a Scientific journal that since 1921 has provided the Chemistry community with annual collections of detailed and checked procedures Vol. 1: 361.
^ A. Fürstner, A. Leitner, G. Seidel (2004). "4-Nonylbenzoic Acid". Org. Synth. 81: 33-42. Organic Syntheses is a Scientific journal that since 1921 has provided the Chemistry community with annual collections of detailed and checked procedures
^ 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. The Journal of the American Chemical Society (usually abbreviated as J (doi:10.1021/ja055732b)
^ Studien in der Thiophenreihe. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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
^ Studien in der Thiophenreihe. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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
^ Stereospecific analysis of triacylglycerols via racemic phosphatidylcholines and phospholipase C. Official title Annalen der Chemie, 1832–1839 Annalen der Chemie und Pharmacie, 1840–1872 (ISSN 0075-4617 CODEN JLACBF A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. Myher,J. J. and Kuksis,A. , Can. J. Biochem. , 57, 117-124 (1979).

**Chemical bonds to carbon**
Core organic chemistry	many uses in chemistry. The Barbier reaction is an Organic reaction between an Alkyl halide and a Carbonyl group as an Electrophilic substrate in the presence of The Bodroux-Chichibabin aldehyde synthesis is a Chemical reaction whereby a Grignard reagent is converted to an Aldehyde one carbon longer The Fujimoto-Belleau reaction is a Chemical reaction that forms cyclic α-substituted αβ-unsaturated Ketones from Enol Lactones The reaction An organolithium reagent is an Organometallic compound with a direct bond between a Carbon and a Lithium atom The Sakurai reaction (also known as the Hosomi-Sakurai reaction) is the Chemical reaction of Carbon Electrophiles (such as a Ketone shown here A carbon-hydrogen bond also known as a C-H bond is a single bond between Carbon and Hydrogen atoms most commonly found in Organic compounds An organolithium reagent is an Organometallic compound with a direct bond between a Carbon and a Lithium atom The organometallic chemistry of group 2 elements is relevant to Organic chemistry, though in some cases the interest is strictly academic Organoborane or organoboron compounds are Chemical compounds that are organic derivatives of BH3 for example trialkyl boranes A carbon-carbon bond is a Covalent bond between two Carbon Atoms. A carbon-nitrogen bond is a Covalent bond between Carbon and Nitrogen and one of the most abundant in Organic chemistry and Biochemistry A carbon-oxygen bond is a Covalent bond between Carbon and Oxygen and one of the most abundant in Organic chemistry and Biochemistry Fluorocarbons are chemical compounds that contain Carbon - Fluorine bonds The relatively low reactivity and high polarity of the carbon-fluorine bond imparts The Grignard reaction, named for the French chemist François Auguste Victor Grignard, is an organometallic Chemical reaction in which Alkyl - organoaluminium compound is an Organometallic compound with a Carbon to Aluminium bond Organosilicon compounds are organic compounds containing Carbon Silicon bonds. Organophosphorus compounds are Chemical compounds containing Carbon - Phosphorus bonds. Organosulfur compounds are Organic compounds that contain Sulfur (sulphur Applications The simplest form of organochlorides are chlorinated Hydrocarbons These consist of simple Hydrocarbons in which one or more hydrogen atoms have The organometallic chemistry of group 2 elements is relevant to Organic chemistry, though in some cases the interest is strictly academic Organotitanium compounds in Organometallic chemistry contain Carbon to Titanium Chemical bonds Organotitanium chemistry is the science Organochromium chemistry is a branch of Organometallic chemistry that deals with Organic compounds containing a Chromium to Carbon bond and their Organonickel chemistry is a branch of Organometallic chemistry that deals with Organic compounds feature Nickel - Carbon bonds Organocopper compounds in Organometallic chemistry contain Carbon to Copper Chemical bonds Organocopper chemistry is the science of Organozinc compounds in Organic chemistry contain Carbon to Zinc Chemical bonds Organozinc chemistry is the science of organozinc Organogermanium compounds are Organometallic compounds containing a Carbon to Germanium or Hydrogen to germanium Chemical bond. An organoarsenic compound in Organic chemistry is an Organic compound containing a Chemical bond between Arsenic and Carbon. Organoselenium compounds are Chemical compounds containing Carbon to Selenium Chemical bonds Organoselenium chemistry is the corresponding Halocarbon compounds are Chemicals in which one or more Carbon Atoms are linked by Covalent bonds with one or more Halogen Atoms Organozirconium compounds are Organometallic compounds containing a Carbon to Zirconium Chemical bond. Organopalladium chemistry is a branch of Organometallic chemistry that deals with organic Palladium compounds and their reactions An organocadmium compound is a Organometallic compound containing a Carbon to Cadmium Chemical bond. Organotin compounds or stannanes are Chemical compounds based on Tin with Hydrocarbon substituents Organotellurium chemistry in Chemistry describes the synthesis and properties of Chemical compounds containing a Carbon to Tellurium Chemical Halocarbon compounds are Chemicals in which one or more Carbon Atoms are linked by Covalent bonds with one or more Halogen Atoms Organomercury refers to the group of organometallic compounds that contain mercury. Organolead compounds are Chemical compounds containing a Chemical bond between Carbon and Lead. Organouranium compounds are Organometallic compounds containing a Carbon to Uranium Chemical bond. A chemical bond is the physical process responsible for the attractive interactions between Atoms and Molecules and which confers stability to diatomic and polyatomic Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6
Academic research, but no widespread use	Bond unknown / not assessed.

Dictionary

-noun

(chemistry) The reaction of a Grignard reagent (an organo-magnesium halide) with aldehydes or ketones to form secondary or tertiary alcohols

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