Grignard reagent

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Usually Grignard reagents are written as RMgX, but in fact the magnesium(II) centre is tetrahedral when dissolved in Lewis basic solvents, as shown here for the bis-adduct of methylmagnesium chloride and THF.

A Grignard reagent or Grignard compound is a chemical compound with the generic formula R–Mg–X, where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride H
3
C–Mg–Cl
and phenylmagnesium bromide (C
6
H
5
)–Mg–Br
. They are a subclass of the organomagnesium compounds

Grignard compounds are popular reagents in organic synthesis for creating new carbon-carbon bonds. For example, when reacted with another halogenated compound R'–X' in the presence of a suitable catalyst, they typically yield R–R' and the magnesium halide MgXX' as a byproduct; and the latter is insoluble in the solvents normally used. In this aspect, they are similar to organolithium reagents.

Pure Grignard reagents are extremely reactive solids. They are normally handled as solutions in solvents such as diethyl ether or tetrahydrofuran; which are relatively stable as long as water is excluded. In such a medium, a Grignard reagent is invariably present as a complex with the magnesium atom connected to the two ether oxygens by coordination bonds.

Synthesis[edit]

Grignard reagents are prepared by treating an organic halide (normally organobromine) with magnesium metal. Cyclic or acyclic ethers are required to stabilize the organomagnesium compound. Water and air, which rapidly destroy the reagent by protonolysis or oxidation, are excluded using air-free techniques.[1] Although the reagents still need to be dry, ultrasound can allow Grignard reagents to form in wet solvents by activating the magnesium such that it consumes the water.[2]

As is common for reactions involving solids and solution, the formation of Grignard reagents is often subject to an induction period. During this stage, the passivating oxide on the magnesium is removed. After this induction period, the reactions can be highly exothermic. This exothermicity must be considered when a reaction is scaled-up from laboratory to production plant.[3] Most organohalides will work, but carbon-fluorine bonds are generally unreactive, except with specially activated magnesium (through Rieke metals).

Magnesium[edit]

Typically the reaction to form Grignard reagents involves the use of magnesium ribbon. All magnesium is coated with a passivating layer of magnesium oxide, which inhibits reactions with the organic halide. Many methods have been developed to weaken this passivating layer, thereby exposing highly reactive magnesium to the organic halide. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication.[4] Iodine, methyl iodide, and 1,2-dibromoethane are common activating agents. The use of 1,2-dibromoethane is advantageous as its action can be monitored by the observation of bubbles of ethylene. Furthermore, the side-products are innocuous:

Mg + BrC2H4Br → C2H4 + MgBr2

The amount of Mg consumed by these activating agents is usually insignificant. A small amount of mercuric chloride will amalgamate the surface of the metal, enhancing its reactivity. Addition of preformed Grignard reagent is often used as the initiator.

Specially activated magnesium, such as Rieke magnesium, circumvents this problem.[5] The oxide layer can also be broken up using ultrasound, using a stirring rod to scratch the oxidized layer off,[6] or by adding a few drops of iodine or 1,2-Diiodoethane. Another option is to use sublimed magnesium or magnesium anthracene.[7]

Mechanism[edit]

In terms of mechanism, the reaction proceeds through single electron transfer:[8][9][10]

R−X + Mg → R−X•− + Mg•+
R−X•− → R + X
R + Mg•+ → RMg+
RMg+ + X → RMgX

Testing Grignard reagents[edit]

Because Grignard reagents are so sensitive to moisture and oxygen, many methods have been developed to test the quality of a batch. Typical tests involve titrations with weighable, anhydrous protic reagents, e.g. menthol in the presence of a color-indicator. The interaction of the Grignard reagent with phenanthroline or 2,2'-bipyridine causes a color change.[11]

Mg transfer reaction (halogen–Mg exchange)[edit]

An alternative preparation of Grignard reagents involves transfer of Mg from a preformed Grignard reagent to an organic halide. This method offers the advantage that the Mg transfer tolerates many functional groups. A typical reaction involves isopropylmagnesium chloride and aryl bromide or iodides:[12]

i-PrMgCl + ArCl → i-PrCl + ArMgCl

Reactions of Grignard reagents[edit]

With carbonyl compounds[edit]

Grignard reagents react with a variety of carbonyl derivatives.[13]

Reactions of Grignard reagents with carbonyls

The most common application of Grignard reagents is the alkylation of aldehydes and ketones, i.e. the Grignard reaction:[14]

Reaction of CH3C(=O)CH(OCH3)2 with H2C=CHMgBr

Note that the acetal function (a protected carbonyl) does not react.

Such reactions usually involve an aqueous acidic workup, though this step is rarely shown in reaction schemes. In cases where the Grignard reagent is adding to an aldehyde or a prochiral ketone, the Felkin-Anh model or Cram's Rule can usually predict which stereoisomer will be formed. With easily deprotonated 1,3-diketones and related acidic substrates, the Grignard reagent RMgX functions merely as a base, giving the enolate anion and liberating the alkane RH.

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

Naproxen synthesis
Reactions of Grignard reagents with various electrophiles

Reactions as a base[edit]

Grignard reagents serve as a base for protic substrates (this scheme does not show workup conditions, which typically includes water). Grignard reagents are basic and react with alcohols, phenols, etc. to give alkoxides (ROMgBr). The phenoxide derivative is susceptible to formylation paraformaldehyde to give salicylaldehyde.[15]

Alkylation of metals and metalloids[edit]

Like organolithium compounds, Grignard reagents are useful for forming carbon–heteroatom bonds.

Grignard reagents react with many metal-based electrophiles. For example, they undergo transmetallation with cadmium chloride (CdCl2) to give dialkylcadmium:[16]

2 RMgX + CdCl2 → R2Cd + 2 Mg(X)Cl

Schlenk equilibrium[edit]

Most Grignard reactions are conducted in ethereal solvents, especially diethyl ether and THF. With the chelating diether dioxane, some Grignard reagents undergo a redistribution reaction to give diorganomagnesium compounds (R = organic group, X = halide):

2 RMgX + dioxane ⇌ R2Mg + MgX2(dioxane)

This reaction is known as the Schlenk equilibrium.

Coupling with organic halides[edit]

Grignard reagents do not typically react with organic halides, in contrast with their high reactivity with other main group halides. In the presence of metal catalysts, however, Grignard reagents participate in C-C coupling reactions. For example, nonylmagnesium bromide reacts with methyl p-chlorobenzoate to give p-nonylbenzoic acid, in the presence of Tris(acetylacetonato)iron(III) (Fe(acac)3), after workup with NaOH to hydrolyze the ester, shown as follows. Without the Fe(acac)3, the Grignard reagent would attack the ester group over the aryl halide.[17]

4-nonylbenzoicacid synthesis using a grignard reagent

For the coupling of aryl halides with aryl Grignard reagents, nickel chloride in tetrahydrofuran (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 [substituted] styrenes.

Oxidation[edit]

Treatment of a Grignard reagent with oxygen gives the magnesium organoperoxide. Hydrolysis of this material yields hydroperoxides or alcohol. These reactions involve radical intermediates.

The simple oxidation of Grignard reagents to give alcohols is of little practical import as yields are generally poor. In contrast, two-step sequence via a borane (vide supra) that is subsequently oxidized to the alcohol with hydrogen peroxide is of synthetic utility.

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignard reagents with oxygen in presence of an alkene to an ethylene extended alcohol.[18] 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. The 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.

Grignard oxygen oxidation example

Elimination[edit]

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.

Boord olefin synthesis, X = Br, I, M = Mg, Zn

Industrial use[edit]

An example of the Grignard reaction is a key step in the (non-stereoselective) industrial production of Tamoxifen[19] (currently used for the treatment of estrogen receptor positive breast cancer in women):[20]

Tamoxifen production

See also[edit]

Gallery[edit]

References[edit]

  1. ^ Goebel, M. T.; Marvel, C. S. (1933). "The Oxidation of Grignard Reagents". Journal of the American Chemical Society. 55 (4): 1693–1696. doi:10.1021/ja01331a065.
  2. ^ Smith, David H. (1999). "Grignard Reactions in "Wet" Ether". Journal of Chemical Education. 76 (10): 1427. Bibcode:1999JChEd..76.1427S. doi: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. doi:10.1021/ed076p1427.
  5. ^ Lai Yee Hing (1981). "Grignard Reagents from Chemically Activated Magnesium". Synthesis. 1981 (9): 585–604. doi:10.1055/s-1981-29537.
  6. ^ Clayden, Jonathan; Greeves, Nick (2005). Organic chemistry. Oxford: Oxford Univ. Press. p. 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. doi:10.1016/j.ccr.2004.02.018.
  11. ^ Krasovskiy, Arkady; Knochel, Paul (2006). "Convenient Titration Method for Organometallic Zinc, Magnesium, and Lanthanide Reagents". Synthesis. 2006 (5): 890–891. doi:10.1055/s-2006-926345.
  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. doi:10.1002/anie.200300579. PMID 14502700.
  13. ^ Henry Gilman and R. H. Kirby (1941). "Butyric acid, α-methyl-". Organic Syntheses.; Collective Volume, 1, p. 361
  14. ^ Haugan, Jarle André; Songe, Pål; Rømming, Christian; Rise, Frode; Hartshorn, Michael P.; Merchán, Manuela; Robinson, Ward T.; Roos, Björn O.; Vallance, Claire; Wood, Bryan R. (1997). "Total Synthesis of C31-Methyl Ketone Apocarotenoids 2: The First Total Synthesis of (3R)-Triophaxanthin" (PDF). Acta Chemica Scandinavica. 51: 1096–1103. doi:10.3891/acta.chem.scand.51-1096. Retrieved 2009-11-26.
  15. ^ Peters, D. G.; Ji, C. (2006). "A Multistep Synthesis for an Advanced Undergraduate Organic Chemistry Laboratory". Journal of Chemical Education. 83 (2): 290. doi:10.1021/ed083p290.
  16. ^ "Unit 12 Aldehydes, Ketones and Carboxylic Acids" (PDF). Chemistry Part II Textbook for class XII. 2. India: National Council of Educational Research and Training. 2010. p. 355. ISBN 978-81-7450-716-7.
  17. ^ A. Fürstner, A. Leitner, G. Seidel (2004). "4-Nonylbenzoic Acid". Organic Syntheses. 81: 33–42.CS1 maint: multiple names: authors list (link)
  18. ^ Youhei Nobe; Kyohei Arayama; Hirokazu Urabe (2005). "Air-Assisted Addition of Grignard Reagents to Olefins. A Simple Protocol for a Three-Component Coupling Process Yielding Alcohols". J. Am. Chem. Soc. 127 (51): 18006–18007. doi:10.1021/ja055732b. PMID 16366543.
  19. ^ Richey, Herman Glenn (2000). Grignard Reagents: New Developments. Wiley. ISBN 0471999083.
  20. ^ Jordan VC (1993). "Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer". Br J Pharmacol. 110 (2): 507–17. doi:10.1111/j.1476-5381.1993.tb13840.x. PMC 2175926. PMID 8242225.

Further reading[edit]

  • ed. by Gary S. Silverman .... (1996). Rakita, Philip E.; Silverman, Gary (eds.). Handbook of Grignard Reagents. New York, N.Y: Marcel Dekker. ISBN 0-8247-9545-8.CS1 maint: extra text: authors list (link)
  • Mary McHale, "Grignard Reaction," Connexions, http://cnx.org/content/m15245/1.2/. 2007.
  • Grignard knowledge: Alkyl coupling chemistry with inexpensive transition metals by Larry J. Westrum, Fine Chemistry November/December 2002, pp. 10–13 [1]

Specialized literature[edit]

  • Rogers, H. R.; Hill, C. L.; Fujiwara, Y.; Rogers, R. J.; Mitchell, H. L.; Whitesides, G. M. (1980). "Mechanism of formation of Grignard reagents. Kinetics of reaction of alkyl halides in diethyl ether with magnesium". Journal of the American Chemical Society. 102 (1): 217. doi:10.1021/ja00521a034.
  • De Boer, H.J.R.; Akkerman, O.S; Bickelhaupt, F. (1988). "Carbanions as intermediates in the synthesis of Grignard Reagents". Angew. Chem. Int. Ed. 27 (5): 687–89. doi:10.1002/anie.198806871.
  • Van Klink, G.P.M.; de Boer, H.J.R; Schat, G.; Akkerman, O.S.; Bickelhaupt, F.; Spek, A. (2002). "Carbanions as Intermediates in the Formation of Grignard Reagents". Organometallics. 21 (10): 2119–35. doi:10.1021/om011083a. hdl:1874/14334.
  • Shao, Y.; Liu, Z.; Huang, P.; Liu, B. (2018). "A unified model of Grignard reagent formation". Physical Chemistry Chemical Physics. 20 (16): 11100–08. doi:10.1039/c8cp01031e.