The Grignard Reactions (pronounced /? Ri? Ar/) is an organologous chemical reaction in which alkyl, vinyl, or aryl -magnesium halides ( Grignard reagents ) are added to the carbonyl group in the aldehyde or ketone. This reaction is an important tool for the formation of carbon-carbon bonds. The reaction of the organic halide with magnesium is not the Grignard reaction, but provides the Grignard reagent.
Grignard reactions and reactions are discovered by and named after the French chemist FranÃÆ'§ois Auguste Victor Grignard (University of Nancy, France), who published it in 1900 and was awarded the 1912 Nobel Prize in Chemistry for this work. Grignard reagents are similar to organolytic reagents because they are strong nucleophiles that can form new carbon-carbon bonds. Nucleophilicity increases if the alkyl substituents are replaced by the amido group. This magnesium halide amide is called Hauser base.
Video Grignard reaction
Reaction mechanism
Grignard reagents function as nucleophiles, attacking electrophilic carbon atoms present in the polar bonds of the carbonyl group. The addition of Grignard reagents to carbonyl usually takes place through the six-membered transition state of the ring.
However, with Grignard reagents being blocked, the reaction can proceed with a single electron transfer. Similar pathways are assumed for other reactions of Grignard reagents, for example, in the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatomic bonds.
Maps Grignard reaction
Grignard reagent preparation
Grignard reagents are formed by the reaction of alkyl or aryl halides with magnesium metal. The reaction is carried out by adding an organic halide to the magnesium suspension in the etherial solvent, which provides the necessary ligands to stabilize the organomagnesium compound. Empirical evidence indicates that the reaction occurs on the metal surface. The reaction takes place through a single electron transfer: In Grignard's formation reaction, the radical can be converted into karbanion via a second electron transfer.
- R-X Mg -> R-X o - Mg o
- R-X o - -> R o X -
- R o Mg o -> RMg
- RMg X - -> RMgX
The limitation of Grignard reagents is that they do not readily react with alkyl halides via the S N 2 mechanism. On the other hand, they are ready to participate in the transmetalation reaction:
- RMgX AlX -> AlR MgX 2
For this purpose, commercially available Grignard reagents are useful because they avoid problems with initiation.
Reaction conditions
In reactions involving Grignard reagents, it is important to exclude water and air, which rapidly destroy the reagents by protonolysis or oxidation. Since most Grignard reactions are carried out in diethyl ether or anhydrous tetrahydrofuran, the side reactions with air are limited by the protective blanket provided by the solvent vapor. Small or quantitative preparations should be performed under nitrogen or argon atmospheres, using aerial techniques. Although the reagents must still be dry, ultrasound can allow Grignard reagents to form in wet solvents by activating magnesium to consume water.
Organic halide
Grignard's reaction often begins slowly. As is usual for reactions involving solids and solutions, the initiation follows the induction period during which the reactive magnesium becomes exposed to the organic reagent. After this induction period, the reaction can be very exothermic. Alkyl and aryl bromide and iodide are common, with chloride also visible. However, fluoride is generally not reactive, except with special activated magnesium (via Rieke metal).
Magnesium
A typical Grignard reaction involves the use of magnesium bands. All magnesium is coated with a passive layer of magnesium oxide, which inhibits the reaction with an organic halide. Special magnesium activated, such as Rieke magnesium, avoids this problem. The oxide layer can also be broken down using ultrasound, using a stir bar to scratch the oxidized layer, or by adding a few drops of iodine or 1,2-Diiodoethane.
Solvent
Most Grignard reactions are performed in fine solvents, especially diethyl ether and THF. With dieter dieter chelating, some Grignard reagents underwent a redistribution reaction to produce a diorganomagnesium compound (R = organic group, X = halide):
- 2 RMgX dioxane? R 2 Mg MgX 2 (dioxane)
This reaction is known as Schlenk's equilibrium.
Test the Grignard reagent
Because Grignard reagents are highly sensitive to moisture and oxygen, many methods have been developed to test batch quality. The typical test involves titration with anhydrous anhydrous reagent, anhydrous, eg. mentol in the presence of color indicators. The interaction of Grignard reagents with phenanthroline or 2,2'-bipyridine causes discoloration.
Initiation
Many methods have been developed to start slow Grignard's reaction. These methods weaken the MgO passive layer, thereby exposing highly reactive magnesium to organic halides. Mechanical methods include destroying Mg pieces in situ, rapid stirring, and sonication of suspension. Iodine, methyl iodide, and 1,2-Dibromoethane are common activating agents. The use of 1,2-dibromoethane is very advantageous because its action can be monitored by observations of ethylene bubbles. Furthermore, harmless byproducts:
- Mg BrC 2 H 4 Br -> C 2 H 4 MgBr 2
The amount of Mg consumed by this activating agent is usually insignificant. A small amount of mercury chloride will unite the metal surface, allowing it to react.
Industrial production
Grignard reagents are manufactured in industry for use in situ, or for sale. Like bench scale, the main problem is initiation; some of the earlier Grignard reagents are often used as initiators. The Grignard reaction is exothermic, and this exothermicity should be considered when the reaction is increased from the laboratory to the production plant.
Many Grignard reagents such as methylmagnesium bromide, methylmagnesium chloride, phenylmagnesium bromide, and allylmagnesium bromide are commercially available as a solution of tetrahydrofuran or diethyl ether.
Transfer reaction Mg (halogen-Mg exchange)
An alternative preparation of Grignard reagents involves removal of Mg from Grignard reagents already formed to organic halides. This method offers the advantage that Mg transfers tolerate many functional groups. Typical reactions involve isopropylmagnesium chloride and aryl bromide or iodide.
Grignard reagent reaction
With carbonyl compounds
Grignard reagents react with various carbonyl derivatives.
The most common applications of Grignard reagents are aldehyde and ketone alkylation, Grignard's reaction:
Note that the acetyl function (protected carbonyl) does not react.
Such a reaction usually involves the examination of aqueous acid, although this step is rarely shown in the reaction scheme. In cases where Grignard reagents add aldehyde or projected ketones, the Felkin-Anh model or Cram Rule can usually predict which stereoisomers will be formed. With 1,3-dicetones and a deprotonated acid substrate, the RMgX Grignard reagent serves only as a base, providing anion enolate and freeing RH alkanes.
Grignard reagents are the nucleophiles in a nucleophilic aliphatic substitution for example with alkyl halides in key steps in the production of industrial Naproxen:
Reaction as base
Grignard reagents serve as a basis for the protic substrate (this scheme does not indicate the condition of the exercise, which usually includes water). Grignard reagents are basic and react with alcohol, phenol, etc. to provide alkoxides (ROMgBr). Phenoxide derivatives are susceptible to paraformaldehyde formation to provide salicylaldehyde.
Bond formation to B, Si, P, Sn
Grignard reagents react with many metal-based electrophiles. For example, they undergo transmission with cadmium chloride (CdCl 2 ) to provide dialkylcadmium:
- 2 RMgX CdCl 2 -> R 2 Cd 2 Mg (X) Cl
Dialkylcadmium reagents are used for the preparation of ketones from acyl halides:
- 2 R'C (O) Cl R 2 Cd -> 2 R'C (O) R CdCl 2
With an organic halo
Grignard reagents usually do not react with organic halides, in contrast to their high reactivity with other major group halides. In the presence of metal catalysts, however, Grignard reagents participate in the C-C coupling reaction. For example, nonylmagnesium bromide reacts with methyl p-chlorobenzoate to give p -nonylbenzoic acid, in the presence of Tris iron (acetylacetonato) (III) (Fe (acac) 3 ), after working with NaOH to hydrolyze the ester, is shown as follows. Without Fe (acac) 3 , the Grignard reagent will invade the ester group above the aryl halide.
For the coupling of aryl halides with Grignard aryl reagents, nickel chloride in tetrahydrofuran (THF) is also a good catalyst. In addition, an effective catalyst for alkyl halide coupling is dilithium tetrachlorocuprate (Li 2 CuCl 4 ), prepared by mixing lithium chloride (LiCl) and copper (II) chloride (CuCl 2 ) in THF. Kumada-Corriu clutch gives access to styrene [substitution].
Oxidation
The simple oxidation of Grignard reagents to provide alcohol is not very practical because the crops are generally poor. In contrast, the two-step sequence through boran ( supra vide ) which is then oxidized to alcohol with hydrogen peroxide is a synthetic utility.
The synthetic utility of Grignard oxidation can be increased by the reaction of Grignard reagents with oxygen in the presence of an alkene to an ethylene-extended alcohol. This modification requires aril or vinyl Grignards. Adding only Grignard and alkene does not produce a reaction that indicates that the presence of oxygen is very important. The only drawback is the requirement of at least two Grignard equivalents although this is partly inevitable with the use of a dual Grignard system with a cheaper Grignard reducer such as n-butylmagnesium bromide.
Elimination
In the synthesis of the Boord olefin, the addition of a particular resultant magnesium to the reaction resulted in an elimination reaction to the alkene. This reaction can limit the usefulness of Grignard's reaction.
Grignard reagent degradation
At one time, the formation and hydrolysis of Grignard reagents was used in the determination of the number of halogen atoms in organic compounds. In modern use, Grignard degradation is used in certain triacylglycerol chemical analyzes.
Industrial use
Examples of Grignard reactions are a key step in the production of Tamoxifen (non-stereoselective) industries (currently used for the treatment of estrogen receptor positive breast cancer in women):
Gallery
See also
- Wittig's Reaction
- The Barbier Reaction
- Bodroux-Chichibabin aldehyde synthesis
- Fujimoto-Belleau's Reaction
- Organolithium reagents
- Sakurai reaction
- Indium mediation allylation
- Alkynylation
References
Further reading
-
ed. by Gary S. Silverman.... (1996). Rakita, Philip E.; Silverman, Gary, eds. Grignard reagent handbook . New York, N.Y: Marcel Dekker. ISBNÃ, 0-8247-9545-8. Ã, CS1 maint : Additional text: author list (link) - Mary McHale, "Grignard Reactions," Connexions, http://cnx.org/content/m15245/1.2/. 2007.
- Grignard Knowledge: chemical alkyl coupling with cheap transition metal by Larry J. Westrum, Fine Chemistry November/December 2002, pp. 10-13 [1]
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