1. Grignard Reagents – Review Katharine Goodenough 31/08/05

2. Background Discovered by Victor Grignard in 1900 –Key factors are ethereal solvent and water-free conditions Awarded Nobel Prize in 1912 By 1975, over 40000 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

3. 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.

4. 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

5. Reactions of Grignard reagents

6. Mechanism of reaction with ketones 2

7. 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

8. 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

9. 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

10. 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°

11. 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

12. 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 ):

13. 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

14. Alkyl Grignard Reagents Thermodynamics of Schlenk equilibrium 3 In ether, MgRX is prevalent (K~10 – 10 3 ) but in THF (K = 1-10), a more random distribution is seen. Since THF adducts tend to have higher coordination numbers than those of Et 2 O, differences attributed to degree of solvation. In hydrocarbon solvent, K is very small; in triethylamine it is very large Grignard reagent SolventK MeMgBrEt 2 O320 THF3.5 – 4 EtMgBrEt 2 O480 – 484 THF5.09 EtMgClTHF5.52

15. Alkyl Grignard Reagents NMR Studies 4 MgR 2 and RMgX can be distinguished provided exchange is slow on the NMR timescale α-H atoms of magnesium-bound alkyl group R resonate at δ-2 – 0 ppm (average under conditions of fast exchange) MgXR is at lower field than MgR 2 due to shielding by halogen –MeMgBr δ -1.55 ppm; MgMe 2 δ -1.70 ppm in Et 2 O at -100 °C Can detect variation in composition –Varies with nature of solvent, organic group, halide, temperature and concentration Alkyl groups undergo exchange under the reaction conditions –Rate of alkyl group exchange determined by structure of alkyl group and secondarily by nature of solvent

16. Alkyl Grignard Reagents For Me 2 Mg in Et 2 O: –The lower field signals are attributed to bridging Me groups in associated dimethylmagnesium –The higher field signal is attributed to terminal methyl groups of the associated molecules, and to monomers In THF: –Signal at 11.76 at +20 °C, shifts to 11.83 at -76 °C –Supports its existence as a monomeric species in THF –At low temp, a small signal was seen at 11.70, attributed to small amounts of associated species

17. For MeMgBr in Et 2 O: –At low temperature, two distinct signals are seen. The lower field signal (τ 11.55) is attributed to MeMgBr The higher field signal (τ 11.70) is Me 2 Mg as before Equilibrium constants for the Schlenk equilibrium cannot be obtained due to precipitation during cooling In THF: –Chemical shifts are very dependant on temperature, moving to higher field with lower temperature. –It was not possible to observe distinct signals for MeMgBr and Me 2 Mg as was possible in ether. –The Schlenk equilibrium seems to shift towards the dialkylmagnesium at lower temperature, since the spectrum approaches that of Me 2 Mg at -76 °C –May be partially due to MgBr 2 precipitating From these data, equilibrium constant was calculated for MeMgBr in THF, K = 4 ± 2.6 Alkyl Grignard Reagents

18. Further solvent effects 5 Increasing donation by solvent shifts the α-H resonance to higher fields Determined for EtMgBr and Et 2 Mg at 40 °C Low concentrations employed to avoid association effects Leads to an order of solvent basicity: Anisole < iPr 2 O < Et 3 N < n Bu 2 O < Et 2 O < THF < DME Solvent[EtMgBr][Et 2 Mg]δ (ppm) i Pr 2 O 0.10.006-0.468 -0.1-0.405 Et 2 O 0.1--0.604 -0.1-0.655 THF 0.1--0.702 -0.129-0.771 Et 3 N0.1--0.500 n Bu 2 O0.0880.099-0.559 DME0.0350.013-0.785 anisole0.0750.025-0.115 Alkyl Grignard Reagents

19. 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

20. 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

21. IR Studies As nmr timescale was found to be too slow to observe the unsymmetrical isomers of allylmagnesium bromide, IR was employed. Two otherwise identical isomers a and b were distinguished by deuterium substitution The mass effect of D directly substituted on a double bond lowers the stretching frequency, remote deuteration has smaller effect Non-deuterated has absorption at 1587.5 cm -1 Deuterated has two peaks at 1559 and 1577.5 cm -1 For methallylmagnesium bromide, one peak at 1584 cm -1 was transformed to two bands at 1566 and 1582 cm -1 Methallyllithium does not undergo similar splitting Allyl Grignard Reagents

22. 13 C nmr studies 13 C spectrum of allylmagnesium bromide has two lines of similar width: the methylene carbons at δ58.7 and the methine carbon at δ148.1 ppm. As temperature was reduced, the methylene resonance broadened and disappeared into baseline noise, while the methine signal remained constant. At the lowest temperatures studied (~180K at 62.9 MHz) there was no sign of the appearance of separate high- and low-field methylene resonances; only the broadening of the average signal The allylic rearrangement is the only process that could be taking place with a large enough shift difference to account for the observed broadening Similar behaviour is also observed for methallylmagnesium bromide Allyl Grignard Reagents

23. Cyclic reagents 7 As with the Schlenk equilibrium, the bifunctional Grignard reagent generated from Br(CH 2 ) 5 Br could exist as: To establish whether this occurs, firstly the magnesiacyclohexane was made in such a way that no MgBr 2 could contaminate the cyclic compound: Titration of a hydrolysed aliquot of the reaction product gives a ratio for basic Mg/total Mg of 1/1 as required for dialkylmagnesium compounds Cyclic Grignard Reagents

24. Association The monomeric magnesiacyclohexane was found to be in equilibrium with its dimer. –Equilibrium in favour of dimer: K 1 (28.25 °C) = 531 ± 81 l/mole K 1 (48.50 °C) = 223 ± 41 l/mole ΔH = -8 kcal/mole (i.e. dimerisation exothermic) i = 1.4 – 1.7 Established that 12-membered dimer was present by crystallisation and X- ray structure Each Mg has two THF molecules attached Cyclic Grignard Reagents

25. The degree of association was then measured for: Degree of association i = 1.28 – 1.58 (for BrMg(CH 2 ) 5 MgBr i = 2) → equilibrium between linear and cyclic species exists Schlenk equilibrium constant: K 2 (28.25 °C) = 250 ± 65 l/mole K 2 (48.53 °C) = 300 ± 92 l/mole Magnesium bromide was then added to the previously generated solution of (CH 2 ) 5 Mg and the same parameters measured: i = 1.49 (28.25 °C); i = 1.53 (48.50 °C) This is identical to i as measured above → solutions are of similar composition K 2 (28.25 °C) = 299 ± 30 l/mole K 2 (48.50 °C) = 361 ± 50 l/mole ΔH ~ +2 kcal/mole (endothermic reaction) Cyclic Grignard Reagents

26. RMg or RMgXYield aYield b C 5 H 10 Mg 2 Br 2 18%23% C 4 H 8 Mg 2 Br 2 12%28% C 5 H 10 Mg6%35% C 4 H 8 Mg4%30% In Et 2 O, i = 2 i.e. Schlenk equilibrium lies to the left in diethyl ether and monomer is present Influence of cyclic structure on reactivity was investigated for: 8 Less reduction to alcohol seen for cyclic organomagnesium reagent Reduction takes place via a 6-centre transition state in an elimination of MgH by an E 2 cis mechanism Cyclic Grignard Reagents

27. 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

28. References 1.Magnesium, Calcium, Strontium and Barium, W.E. Lindsell, Comprehensive Organometallic Chemistry 1, 1982, 155 2.E.C. Ashby, Quarterly Reviews of the Chemical Society, 1967, 21, 259 3.M.B. Smith, W.E. Becker, Tetrahedron, 1966, 22, 3027; 1967, 23, 4215 4.G.E. Parris, E.C. Ashby, J. Am. Chem. Soc. 1971, 93, 1206 5.G. Westera, C. Blomberg, F. Bickelhaupt, J. Organomet. Chem. 155 (1978) C55 6.A) E.A. Hill, W.A. Boyd, H. Desai, A. Darki, L. Bivens, J. Organomet. Chem. 514 (1996) 1. B) D.A. Hutchison, K.R. Beck, R.A. Benkeser, J. Am. Chem. Soc. 1973, 95, 7075 7.H.C. Holtkamp, C. Blomberg, F. Bickelhaupt, J. Organomet. Chem. 19 (1969) 279. 8.B. Denise, J.-F. Fauvarque, J. Ducom, Tetrahedron Lett. 5 (1970), 355