Background  Discovered by Victor Grignard in 1900  Key factors are ethereal solvent and water-free conditions  Awarded Nobel Prize in 1912  By 1975, over papers published using Grignard reagents  Mostly synthetic applications  Physical nature complicated  Important aspects: 1.Schlenk Equilibrium 2.Degree of Association in solution  Alkyl Grignards are most widely studied  Allyl and cyclic Grignard reagents will also be covered Victor Grignard

Formation  Classically formed from an organic halide and magnesium turnings in either ether or THF  Moisture-free conditions and an inert atmosphere are necessary  Magnesium must be of high purity  Activating agent such as iodine or dibromoethane often added  This removes the oxide layer from the Mg and exposes active metal surface  Reactivity of organic halide decreases I>Br>Cl>F  Iodides produce more side products so chloride or bromide usually used.  Other ethers such as DME, THP, anisole, di-n-propyl ether can be used, although solubility of magnesium halide can be a problem  Amine solvents (e.g. triethylamine, N- methyl morpholine) can also be effective for primary alkyl halides. Again, solubility is a problem.

Formation (2)  It is also possible to form a Grignard reagent from an organolithium compound and one equivalent of magnesium halide. This gives access to Grignard reagents which are difficult to prepare directly.  Occurs with retention of stereochemistry so can form chiral Grignard reagents  Dialkyl magnesium compounds obtained by addition of dioxane to ethereal Grignard reagent solution, which results in precipitation of the magnesium halide- dioxane complex that can then be filtered off.  Can also be formed by transmetallation from the diorganomercury compound

Reactions of Grignard reagents

Mechanism of reaction with ketones 2

Wurtz Coupling  The main side-reaction during organomagnesium formation  Most common with larger R-group, organoiodides and especially allylic and benzylic halides  Can be avoided by slow addition of halide or a larger excess of magnesium  May arise by radical coupling or by reaction of the initially formed organometallic with more organic halide

Schlenk Equilibrium  An equilibrium exists in solution between the Grignard reagent RMgX and the diorganomagnesium MgR 2  This equilibrium can be driven to the right by the addition of dioxane  This causes the precipitation of magnesium halide, and the solution can then be filtered off and will contain solely the diorganomagnesium  Useful for formation of diorganomagnesium reagents  Complicates the characterisation of the Grignard reagent  Established using 25 Mg and 28 Mg that exchange occurs readily between labelled MgBr 2 or metallic Mg and both MgEt 2 and MgEtBr  Only occurs with pure forms of magnesium (inhibition may take place by impurities in less pure grades of Mg or exchange may be catalysed by O 2 )  Dependent on nature of X and R, concentration, temperature and solvent

Mechanism 1. Single electron transfer from Mg to organic halide 2. Shortlived radical anion decays to give organic radical R and halide anion X - 3. X - adds to the Mg +, forming MgX. This combines with R to form the Grignard reagent RMgX A second SET may also occur (4), forming R -, which could then combine with MgX + to give RMgX (5). R 2 Mg is not formed directly, but by establishment of the Schlenk equilibrium

Alkyl Grignard Reagents Structure (solid state)  Dietherates (e.g. [MgBr(Ph)(OEt 2 ) 2 ]) exist as isolated, monomeric units  Mg is at centre of a distorted tetrahedron  Mg – C distance 2.1 – 2.2 Å (covalent bond length 1.7 Å)  MgBrMe(THF) 3 crystallises as monomeric trigonal bipyramidal complex with 3 THF ligands  Bromoethylmagnesium crystallises from diisopropyl ether as a dimer [MgBr(Et)(OiPr 2 )] 2 with bridging Br ligands  Each Mg is 4 coordinate, O-Mg-C = 120.7°; Br-Mg- Br = 116.2°

Alkyl Grignard Reagents Structure (solution) 2 EtMgCl EtMgBr The structure of Grignard reagents in solution has been found to be dependent on the solvent used. The degree of association (i) was measured via ebullioscopy, cryoscopy and rates of quasi-isothermal distillation of solvent

Alkyl Grignard Reagents  In THF, RMgX (X = Cl, Br, I) are monomeric over a wide concentration range  For X = F, compounds are dimeric (ie [RMgF] 2 )  In Et 2 O, RMgX (X = Cl, F) are dimeric over a wide concentration range.  For X = Br, I, association patterns are more complex.  At low concentration, monomeric species exist (in accordance with Schlenk equilibrium)  At high concentration, association increases to greater than 2 (ie dimers and larger present)  Four possible structures for dimer of RMgX (or MgR 2 + MgX 2 ):

Alkyl Grignard Reagents  b should be most stable  Association of Mg through the halogen (MgBr 2 and MgI 2 ) is much stronger than through the alkyl group (Et 2 Mg or Me 2 Mg).  Association of Grignard reagents is predominately through the halogen  Linear structure e is also possible due to the position of the Schlenk equilibrium in Et 2 O towards RMgX

Allyl Grignard Reagents Allylic Grignard reagents 6  Allylic Grignard reagents can give products derived from both the starting halide and the allylic isomer  There is potential for them to exist as the η 1 structure which can then equilibrate, or as the η 3 structure, as is known to exist for e.g. π-allyl palladium complexes  Allylmagnesium bromide has a very simple nmr spectrum with only two signals: the four α- and γ- protons (δ 2.5) are equivalent with respect to the β- proton (δ6.38)  The same was found for β-methylallylmagnesium bromide, which has a methyl group and only one other type of proton  Either rapid interconversion of the η 1 structures must make the methylene groups equivalent or the methylene groups of the η 3 structure must rotate to make all four of the hydrogens equivalent

Allyl Grignard Reagents  H 2 is coupled equally to both of the protons of C 1, and these non-equivalent hydrogens could not be frozen out.  There must therefore be rapid rotation of the C 1 -C 2 bond on the nmr time scale  The value of J 12 (~9.5 Hz) shows that this is not an equilibrium between Z and E hydrogens on C 1 in a planar allylic system, which should have a value of ~12 Hz (average of 9Hz for Z, 15 Hz for E)  The compounds cannot have exclusively the planar structure.  Data supports single bond character in C 1 - C 2 and C 1 having significant sp 3 character.  Mg is localised at C 1 ; its presence controls the geometry at C 1

Conclusions  Deceptively simple nature of Grignard reactions complicated by behaviour in solution  In Et 2 O, Grignard reagents tend to exist as RMgX, but at higher concentrations are highly associated in solution  In THF, there is an equilibrium between RMgX and R 2 Mg. However, the organomagesium reagents tend to be monomeric.  Allylic Grignard reagents are complicated by the nature of their conjugation  Di-Grignard reagents can exist as the cyclic species

Experiment 18: THE GRIGNARD REACTION

Experiment 18: THE GRIGNARD REACTION

Objectives:  To synthesize a 3 o alcohol from an alkyl halide and a ketone using a Grignard reaction.  To determine purity using GC analysis.  To characterize starting materials and products using IR, 1 H-NMR, and 13 C-NMR spectra.

THE GRIGNARD REACTION  Organic halides react with magnesium metal in ether or THF to yield an organomagnesium halide: RMgX ETHER ETHER R-X + Mg > R-Mg-X or THF or THF R= 1 o, 2 o, or 3 o alkyl, aryl or alkenyl X= Cl, Br, I

THE GRIGNARD REACTION  The C-Mg bond is a highly polar covalent bond. The carbon atom is both nucleophilic and basic making it very reactive with a wide variety of E +.  Grignard reagents react with proton donors (Brönsted acids) such as H 2 O, ROH, RCOOH, RNH 2 to yield hydrocarbons. This makes it extremely important to keep the reaction flask and solvent completely dry of water.

THE GRIGNARD REACTION ALCOHOLS FROM GRIGNARD REAGENTS