Grignard Reagent

Introduction of Grignard Reagent

Grignard reagent, also known as Grignard compound, refers to a class of hydrocarbon-based magnesium halide organometallic compounds. The chemical formula of Grignard Reagent is R-Mg-X, where X is a halogen and R is an organic group, usually an alkyl or aryl group. Two typical examples are methylmagnesium chloride Cl-Mg-CH3 and phenylmagnesium bromide (C6H5)-Mg-Br. The French chemist François Auguste Victor Grignard first discovered it in 1900, and was therefore 1912 received the Nobel Prize in Chemistry. [1,2]

Grignard reagents are commonly used in organic synthesis to generate new carbon-carbon bonds. For example, when reacted with another halogenated compound R'-X' in the presence of a suitable catalyst, they usually yield R-R' and, as a by-product, magnesium halide MgXX'; and the latter are insoluble in the commonly used solvents. In this respect, they are similar to organolithium reagents.

Pure Grignard reagents are extremely reactive solids. They are usually paired with a solvent (e.g. ether or tetrahydrofuran) and treated as a solution; they are relatively stable as long as water is excluded. In such media, Grignard reagents always exist as complexes, with magnesium atoms linked to two ether oxygens by coordination bonds.

Synthesis
From Mg metal

Traditionally, Grignard reagents are prepared by reacting magnesium metal with an organic halide, usually an organic bromide. Ethers are usually required to stabilize the organomagnesium compounds. Under anhydrous and oxygen-free conditions, they rapidly destroy the reagents by plasmolysis or oxidation. [1] Although the reagents still need to be dried, ultrasound can enable the formation of Grignard reagents in wet solvents by activating the magnesium and thus consuming the water. [2]

Like other solid-liquid reactions, the formation of Grignard reagent usually requires an induction period. At this stage, the passivation oxide on magnesium is removed. After this induction period, the reaction can be exothermic in large quantities. When the reaction expands from laboratory scale to production factory scale, the impact of this heat release must be considered. [3] Most Halocarbon can work, but the carbon fluorine bond is usually inactive, except for magnesium, which is specially activated through Rieke metal.

Magnesium

Typically, reactions for the preparation of Grignard reagents involve the use of magnesium ribbon. All magnesium is coated with a passivation layer of magnesium oxide that will inhibit its reaction with organic halides. A number of methods have been developed to weaken this passivation layer, thereby exposing the highly reactive magnesium to the organic halides. The methods of operation include in situ crushing of magnesium flakes, rapid stirring and ultrasonication.[4] Iodine, methyl iodide, and 1,2-dibromoethane are common activators. Of these, the use of 1,2-dibromoethane is the most advantageous because the process can be monitored by observing bubbles of ethylene. In addition, the by-products are harmless:

Mg + BrC2H4Br → C2H4 + MgBr2

The amount of magnesium consumed by the activator is usually insignificant. Small amounts of mercuric chloride will amalgamate the metal surface and enhance its reactivity. Addition of preformed Grignard reagent is often used as an initiator.

Magnesium that has undergone special activation treatment, such as Rieke magnesium, effectively avoids this problem. [5] The oxide layer can also be broken with ultrasonic wave, scraped off with a stirring rod [6] or added with a few drops of iodine or 1,2-dineneneba iodoethane. Another option is to use sublimed magnesium or magnesium anthracene. [7]

Mechanism

The synthesis reaction of Grignard's reagent proceeds by single electron transfer:[8-10]

R−X + Mg → R−X • − + Mg • +

R−X • − → R • + X −

R • + Mg • + → RMg +

RMg + + X − → RMgX

Mg transfer reaction (halogen-Mg exchange)

Another method of preparation of Grignard reagents is the transfer of magnesium from a preformed Grignard reagent to an organohalide. Other organomagnesium reagents are used as well.[11] The advantage of this preparation method is that a wide range of functional groups can be tolerated by magnesium transfer. Example reactions involving isopropylmagnesium chloride and aryl bromides or iodides are described below. [12]

i - PrMgCl + ArCl → i - PrCl + ArMgCl

From alkylzinc compounds (reductive transmetalation)

Another method of synthesizing Grignard reagents is the reaction of magnesium with organic zinc compounds. This method has been used to make adamantyl Grignard reagents, which are difficult to prepare from alkyl halides and magnesium by conventional methods due to C-C coupling side reactions, and thus need to be obtained by reducing the metal. [13]

AdZnBr + Mg → AdMgBr + Zn

Testing Grignard reagents

Since Grignard reagent is very sensitive to water and oxygen, many methods have been developed to test the quality of a batch of reagents. The typical Grignard reagent concentration determination methods mainly include acid-base titration, spectral measurement, gas chromatography measurement and electrochemical titration. In order to increase the convenience of reaction, acid-base titration is often used. For example, when Menthol is used with a color indicator, the color change caused by the interaction between Grignard reagent and 1,10-phenanthroline is used to calculate the concentration of Grignard reagent. [14]

Reference

1. Goebel, M. T.; Marvel, C. S. (1933). "The Oxidation of Grignard Reagents". Journal of the American Chemical Society. 55 (4): 1693–1696. https://doi.org/10.1021/ja01331a065

2. Smith, David H. (1999). "Grignard Reactions in "Wet" Ether". Journal of Chemical Education. 76 (10): 1427. Bibcode:1999JChEd..76.1427S. https://doi.org/10.1021/ed076p1427

3. Philip E. Rakita (1996). "5. Safe Handling Practices of Industrial Scale Grignard Ragents" (Google Books excerpt). In Gary S. Silverman; Philip E. Rakita (eds.). Handbook of Grignard reagents. CRC Press. pp. 79–88. ISBN 0-8247-9545-8.

4. Smith, David H. (1999). "Grignard Reactions in "Wet" Ether". Journal of Chemical Education. 76 (10): 1427. Bibcode:1999JChEd..76.1427S. https://doi.org/10.1021/ed076p1427

5. Lai Yee Hing (1981). "Grignard Reagents from Chemically Activated Magnesium". Synthesis. 1981 (9): 585–604. https://doi.org/10.1055/s-1981-29537

6. Clayden, Jonathan; Greeves, Nick (2005). Organic chemistry. Oxford: Oxford Univ. Press. pp. 212. ISBN 978-0-19-850346-0.

7. Wakefield, Basil J. (1995). Organomagnesium Methods in Organic Chemistry. Academic Press. pp. 21–25. ISBN 0080538177.

8. Garst, J. F.; Ungvary, F. "Mechanism of Grignard reagent formation". In Grignard Reagents; Richey, R. S., Ed.; John Wiley & Sons: New York, 2000; pp 185–275. ISBN 0-471-99908-3.

9. Advanced Organic chemistry Part B: Reactions and Synthesis F.A. Carey, R.J. Sundberg 2nd Ed. 1983. Page 435

10. Garst, J.F.; Soriaga, M.P. "Grignard reagent Formation", Coord. Chem. Rev. 2004, 248, 623 - 652. https://doi.org/10.1016/j.ccr.2004.02.018

11. Arredondo, Juan D.; Li, Hongmei; Balsells, Jaume (2012). "Preparation of t-Butyl-3-Bromo-5-Formylbenzoate Through Selective Metal-Halogen Exchange Reactions". Organic Syntheses. 89: 460. https://doi.org/10.15227/orgsyn.089.0460

12. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. (2003). "Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange". Angewandte Chemie International Edition. 42 (36): 4302–4320. https://doi.org/10.1002/anie.200300579

13. Armstrong, D.; Taullaj, F.; Singh, K.; Mirabi, B.; Lough, A. J.; Fekl, U. (2017). "Adamantyl Metal Complexes: New Routes to Adamantyl Anions and New Transmetallations". Dalton Transactions. 46 (19): 6212–6217. https://doi.org/10.1039/C7DT00428A

14. Krasovskiy, Arkady; Knochel, Paul (2006). "Convenient Titration Method for Organometallic Zinc, Harshal ady Magnesium, and Lanthanide Reagents". Synthesis. 2006 (5): 890–891. https://doi.org/10.1055/s-2006-926345