Organometallic compounds used in organic synthesis
Usually Grignard reagents are written as R-Mg-X, but in fact the magnesium(II) centre is tetrahedral when dissolved inLewis basic solvents, as shown here for the bis-adduct of methylmagnesium chloride and THF.
Grignard compounds are popular reagents inorganic synthesis for creating newcarbon–carbon bonds. The carbon-magnesium bond in Grignard reagent is a polar covalent bond. The carbon atom has negative excess charge and acts as a nucleophile.
Grignard reagents are rarely isolated as solids. Instead, they are normally handled as solutions in solvents such asdiethyl ether ortetrahydrofuran usingair-free techniques. Grignard reagents arecomplexes with the magnesium atom bonded to twoetherligands as well as the halide and organyl ligands.
Traditionally Grignard reagents are prepared by treating an organic halide (normally organobromine) with magnesium metal.Ethers are required to stabilize theorganomagnesium compound. Water and air, which rapidly destroy the reagent byprotonolysis or oxidation, are excluded.[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 aninduction period. During this stage, the passivating oxide on the magnesium is removed. After this induction period, the reactions can be highlyexothermic. This exothermicity must be considered when a reaction is scaled-up from laboratory to production plant.[3]Most organohalides will work, butcarbon-fluorine bonds are generally unreactive, except with specially activated magnesium (throughRieke metals).
Typically the reaction to form Grignard reagents involves the use of magnesium ribbon. All magnesium is coated with apassivating layer ofmagnesium 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, andsonication.[4]Iodine,methyl iodide, and1,2-dibromoethane are common activating agents. The use of 1,2-dibromoethane is advantageous as its action can be monitored by the observation of bubbles ofethylene. Furthermore, the side-products are innocuous:
Mg + BrC2H4Br → C2H4 + MgBr2
The amount of Mg consumed by these activating agents is usually insignificant. When treated with small amounts ofmercuric chloride, magnesium pieces become coated with anamalgam, enhancing its reactivity.
Addition of preformed Grignard reagent is often used as the initiator and oxidiser
Specially activated magnesium, such asRieke 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 or1,2-Diiodoethane. Another option is to use sublimed magnesium ormagnesium anthracene.[7]
An alternative preparation of Grignard reagents involves transfer of Mg from a preformed Grignard reagent to an organic halide. Other organomagnesium reagents are used as well.[11] This method offers the advantage that the Mg transfer tolerates many functional groups. An illustrative reaction involvesisopropylmagnesium chloride and aryl bromide or iodides:[12]
i-PrMgCl + ArBr →i-PrCl + ArMgBr
From alkylzinc compounds (reductive transmetalation)
A further method to synthesize Grignard reagents involves reaction of Mg with anorganozinc compound. This method has been used to makeadamantane-based Grignard reagents, which are, due to C-C coupling side reactions, difficult to make by the conventional method from the alkyl halide and Mg. The reductivetransmetalation achieves:[13]
Grignard reagents with chloride, bromide, and iodide are routine reagents. The corresponding fluorides RMgF were not synthesized until 1970.[14] In 1920 Swarts reported the reduction of amyl fluoride to the corresponding hydrocarbon with activated magnesium,[15] while no intermediates were separated. Alkylmagnesium fluoride was first prepared by Ashly and co-workers in 1970, using metal magnesium and catalytic iodine in refluxing tetrahydrofuran or 1,2-dimethoxyethane from the corresponding alkyl fluoride.[16][17]
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 withphenanthroline or 2,2'-biquinoline causes a color change.[18]
Grignard reagents react with a variety ofcarbonyl derivatives.[19]
Reactions of Grignard reagents with carbonyls
Such reactions usually involve an aqueous acidic workup, though this step is rarely shown in reaction schemes.
The most common application of Grignard reagents is the alkylation of aldehydes and ketones, i.e.theGrignard reaction:[20]
Reaction ofCH3C(=O)CH(OCH3)2 withH2C=CHMgBr
Note that theacetal functional group (a protected carbonyl) does not react.
Grignard reagents also react with many "carbonyl-like"electrophiles:
Reactions of Grignard reagents with various electrophiles
Compounds with labile protons are unsuitable electrophiles, because Grignard reagents are strong bases, and protonative quenching occurs much faster than addition.
In theBruylants reaction, a nitrile can be replaced by the Grignard nucleophile, rather than the Grignard attacking the nitrile to form an imino structure.[21]
Grignard reagents are basic and react with alcohols, phenols, etc. to givealkoxides (ROMgBr).[22] 1,3-Diketones and related substrates are also acidic enough that the Grignard reagent RMgX functions merely as a base, liberating thealkane RH to give a magnesiumenolate.
Most Grignard reactions are conducted in ethereal solvents, especiallydiethyl ether andTHF. Grignard reagents react with1,4-dioxane to give the diorganomagnesium compounds and insoluble coordination polymerMgX2(dioxane)2 and (R = organic group, X = halide):
Grignard reagents donot 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-Ccoupling reactions. For example, nonylmagnesium bromide reacts with methylp-chlorobenzoate to givep-nonylbenzoic acid, in the presence ofTris(acetylacetonato)iron(III) (Fe(acac)3), after workup withNaOH tohydrolyze theester, shown as follows. Without the Fe(acac)3, the Grignard reagent would attack theestergroup over thearyl halide.[25]
4-nonylbenzoicacid synthesis using a grignard reagent
Treatment of a Grignard reagent with oxygen gives the magnesium organoperoxide.[citation needed] Hydrolysis of this material yieldshydroperoxides or alcohol. These reactions involveradical intermediates.
The simple oxidation of Grignard reagents to give alcohols is of little practical importance 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 analkene to an ethylene extendedalcohol.[26] This modification requiresaryl orvinyl 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 asn-butylmagnesium bromide.
In theBoord olefin synthesis, the addition of magnesium to certain β-haloethers results in anelimination reaction to the alkene. This reaction can limit the utility of Grignard reactions.
An example of the Grignard reaction is a key step in the (non-stereoselective) industrial production ofTamoxifen[29] (currently used for the treatment ofestrogen receptor positivebreast cancer in women):[30]
Tetrahydrofuran and a small piece of iodine are added.
A solution of alkyl bromide is added while heating.
After completion of the addition, the mixture is heated for a while.
Formation of the Grignard reagent is complete. A small amount of magnesium still remains in the flask.
The Grignard reagent thus prepared is cooled to0°C before the addition of the carbonyl compound. The solution becomes cloudy as the Grignard reagent precipitates out.
A solution of carbonyl compound is added to the Grignard reagent.
The solution is warmed to room temperature. At this point the reaction is complete.
^Wakefield, Basil J. (1995).Organomagnesium Methods in Organic Chemistry. Academic Press. pp. 21–25.ISBN0080538177.
^Garst, J. F.; Ungvary, F. "Mechanism of Grignard reagent formation". InGrignard Reagents; Richey, R. S., Ed.; John Wiley & Sons: New York, 2000; pp 185–275.ISBN0-471-99908-3.
^Advanced Organic chemistry Part B: Reactions and Synthesis F.A. Carey, R.J. Sundberg 2nd Ed. 1983. Page 435
^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.PMID14502700.
^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.doi:10.1039/C7DT00428A.PMID28443859.
^Krasovskiy, Arkady; Knochel, Paul (2006). "Convenient Titration Method for Organometallic Zinc, Harshal ady Magnesium, and Lanthanide Reagents".Synthesis.2006 (5):890–891.doi:10.1055/s-2006-926345.
^Agami, Claude; Couty, François; Evano, Gwilherm (2000). "Synthesis of α-Substituted Allylic Amines via a Modified Bruylants Reaction".Organic Letters.2 (14):2085–2088.doi:10.1021/ol0059908.PMID10891236.
^Peters, D. G.; Ji, C. (2006). "A Multistep Synthesis for an Advanced Undergraduate Organic Chemistry Laboratory".Journal of Chemical Education.83 (2): 290.Bibcode:2006JChEd..83..290P.doi:10.1021/ed083p290.
Grignard knowledge: Alkyl coupling chemistry with inexpensive transition metals by Larry J. Westrum, Fine Chemistry November/December 2002, pp. 10–13[1]
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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.S2CID94556915.
