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Katharine Goodenough 31/08/05
• • • 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
1. Schlenk Equilibrium 2. Degree of Association in solution
Alkyl Grignards are most widely studied
– Allyl and cyclic Grignard reagents will also be covered
although solubility of magnesium halide can be a problem • Amine solvents (e. triethylamine.Formation • Classically formed from an organic halide and magnesium turnings in either ether or THF ether R X + Mg RMgX • 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. anisole. di-n-propyl ether can be used.g. N-methyl morpholine) can also be effective for primary alkyl halides. Again. . solubility is a problem. THP.
which results in precipitation of the magnesium halide-dioxane complex that can then be filtered off. This gives access to Grignard reagents which are difficult to prepare directly.Formation (2) • It is also possible to form a Grignard reagent from an organolithium compound and one equivalent of magnesium halide. • Occurs with retention of stereochemistry so can form chiral Grignard reagents LiR + MgX2 RMgX + LiX • Dialkyl magnesium compounds obtained by addition of dioxane to ethereal Grignard reagent solution. • Can also be formed by transmetallation from the diorganomercury compound dioxane 2RMgX MgX2 MgR2 Mg HgR2 .
R1CN 2.Reactions of Grignard reagents RH OH R R1 R 1. CO2 2. H+ R OH R1 R OH R1 2 R R R1 O R CO2Et RMgX 1 H2O 1. H+ R1CHO RCO2H O R1 OH R1R2CO R1 R .
Mechanism of reaction with ketones2 R' O + R'MgX R R R R Mg O X R R'MgX R R' Mg X OMgX R R R' + R'MgX R R R' O Mg X Mg R R X R R' OMgR' + MgX2 O Mg X R' .
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 2RX + Mg RX R2 R2 + MgX2 + MgX2 RMgX + .Wurtz Coupling • The main side-reaction during organomagnesium formation • Most common with larger R-group.
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 25Mg and 28Mg that exchange occurs readily between labelled MgBr2 or metallic Mg and both MgEt2 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 O2) • Dependent on nature of X and R. temperature and solvent . concentration.Schlenk Equilibrium 2RMgX MgR2 + MgX2 • • An equilibrium exists in solution between the Grignard reagent RMgX and the diorganomagnesium MgR2 This equilibrium can be driven to the right by the addition of dioxane – This causes the precipitation of magnesium halide.
but by establishment of the Schlenk equilibrium . Single electron transfer from Mg to organic halide 2.Mechanism 1 RX Mg [RX] Mg+ MgX 2 X 3 RMgX R Mg+ 4 Mg2+ 5 MgX+ R 1. Shortlived radical anion decays to give organic radical R• and halide anion X3. This combines with R• to form the Grignard reagent RMgX A second SET may also occur (4). X.adds to the Mg+. forming R-. R2Mg is not formed directly. which could then combine with MgX+ to give RMgX (5). forming MgX.
[MgBr(Ph)(OEt2)2]) exist as isolated.Alkyl Grignard Reagents Structure (solid state) • • • Dietherates (e.7 Å) R Mg X OEt2 OEt2 • MgBrMe(THF)3 crystallises as monomeric trigonal bipyramidal complex with 3 THF ligands O O Mg Br O Me • • Bromoethylmagnesium crystallises from diisopropyl ether as a dimer [MgBr(Et)(OiPr2)]2 with bridging Br ligands Each Mg is 4 coordinate.2 Å (covalent bond length 1.7°. Br-Mg-Br = 116. monomeric units Mg is at centre of a distorted tetrahedron Mg – C distance 2.g.1 – 2.2° S Et Mg Et Br Mg Br S . O-Mg-C = 120.
cryoscopy and rates of quasi-isothermal distillation of solvent Association for EtMgCl and EtMgBr in THF 1.5 concentration (M) Association (i) 1. The degree of association (i) was measured via ebullioscopy.5 2 2.Alkyl Grignard Reagents Structure (solution)2 The structure of Grignard reagents in solution has been found to be dependent on the solvent used.5 1 1.5 1 0.3 Association for EtMgCl and EtMgBr in Et2O 3 Association (i) 1.25 EtMgCl 2.5 concentration (M) .5 1 1.2 1.05 1 0 0.5 2 1.5 2 2.15 1.1 1.5 0 0 EtMgCl EtMgBr EtMgBr 0.
I. compounds are dimeric (ie [RMgF]2) • In Et2O. monomeric species exist (in accordance with Schlenk equilibrium) – At high concentration. association patterns are more complex. RMgX (X = Cl. RMgX (X = Cl. Br.Alkyl Grignard Reagents • In THF. • For X = Br. F) are dimeric over a wide concentration range. association increases to greater than 2 (ie dimers and larger present) • Four possible structures for dimer of RMgX (or MgR2+ MgX2): S X R Mg Mg X S R a S R X Mg Mg X S R b R R Mg X S c S X X R Mg R S d S R Mg Mg . – At low concentration. I) are monomeric over a wide concentration range – For X = F.
• Association of Grignard reagents is predominately through the halogen • Linear structure e is also possible due to the position of the Schlenk equilibrium in Et2O towards RMgX R Mg e X OEt2 .Alkyl Grignard Reagents • b should be most stable • Association of Mg through the halogen (MgBr2 and MgI2) is much stronger than through the alkyl group (Et2Mg or Me2Mg).
in triethylamine it is very large . MgRX is prevalent (K~10 – 103) but in THF (K = 1-10). • Since THF adducts tend to have higher coordination numbers than those of Et2O. a more random distribution is seen.09 5. • In hydrocarbon solvent. K is very small.52 • In ether.Alkyl Grignard Reagents Thermodynamics of Schlenk equilibrium3 MgR2 + MgX2 K 2RMgX Grignard reagent MeMgBr EtMgBr EtMgCl Solvent Et2O THF Et2O K 320 3. differences attributed to degree of solvation.5 – 4 480 – 484 THF THF 5.
70 ppm in Et2O at -100 °C • Can detect variation in composition – Varies with nature of solvent.55 ppm. halide. MgMe2 δ -1.Alkyl Grignard Reagents NMR Studies4 • MgR2 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 MgR2 due to shielding by halogen – MeMgBr δ -1. organic group. 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 .
attributed to small amounts of associated species .76 at +20 °C.70. shifts to 11.83 at -76 °C – Supports its existence as a monomeric species in THF – At low temp. and to monomers • In THF: – Signal at 11. a small signal was seen at 11.Alkyl Grignard Reagents • For Me2Mg in Et2O: – 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.
moving to higher field with lower temperature. two distinct signals are seen.• For MeMgBr in Et2O: Alkyl Grignard Reagents – At low temperature. since the spectrum approaches that of Me2Mg at -76 °C – May be partially due to MgBr2 precipitating • From these data.55) is attributed to MeMgBr • The higher field signal (τ 11.6 . – The Schlenk equilibrium seems to shift towards the dialkylmagnesium at lower temperature.70) is Me2Mg 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. K = 4 ± 2. equilibrium constant was calculated for MeMgBr in THF. – It was not possible to observe distinct signals for MeMgBr and Me2Mg as was possible in ether. • The lower field signal (τ 11.
1 [Et2Mg] 0.035 0.785 Anisole < iPr2O < Et3N < nBu O < Et O < THF < DME 2 2 DME anisole 0.604 -0.771 -0.1 - -0.702 Et2O THF Et3N nBu O 2 0.088 0.1 0.655 -0.468 • • • 0.500 -0.075 0.006 δ (ppm) -0.129 0.099 0.025 -0.559 -0.405 -0.1 0.115 .Alkyl Grignard Reagents Further solvent effects5 • Increasing donation by solvent shifts the α-H resonance to higher fields Determined for EtMgBr and Et2Mg at 40 °C Low concentrations employed to avoid association effects Leads to an order of solvent basicity: Solvent iPr 2O [EtMgBr] 0.013 -0.1 0.1 0.
5) are equivalent with respect to the β-proton (δ6. or as the η3 structure.Allyl Grignard Reagents Allylic Grignard reagents6 • • 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 η1 structure which can then equilibrate. π-allyl palladium complexes – Allylmagnesium bromide has a very simple nmr spectrum with only two signals: the four αand γ-protons (δ 2.g. as is known to exist for e.38) MgBr BrMg MgBr – 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 η1 structures must make the methylene groups equivalent or the methylene groups of the η3 structure must rotate to make all four of the hydrogens equivalent .
• Mg is localised at C1. which should have a value of ~12 Hz (average of 9Hz for Z. and these nonequivalent hydrogens could not be frozen out.H2 H3 R H1Z H1E Allyl Grignard Reagents • H2 is coupled equally to both of the protons of C1. • There must therefore be rapid rotation of the C1-C2 bond on the nmr time scale • The value of J12 (~9. 15 Hz for E) • The compounds cannot have exclusively the planar structure. its presence controls the geometry at C1 . • Data supports single bond character in C1-C2 and C1 having significant sp3 character.5 Hz) shows that this is not an equilibrium between Z and E hydrogens on C1 in a planar allylic system.
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.IR Studies • As nmr timescale was found to be too slow to observe the unsymmetrical isomers of allylmagnesium bromide. remote deuteration has smaller effect Non-deuterated has absorption at 1587. IR was employed.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 R D D a MgBr Allyl Grignard Reagents R D BrMg b D • • • • • • .5 cm-1 Deuterated has two peaks at 1559 and 1577.
while the methine signal remained constant. • As temperature was reduced. the methylene resonance broadened and disappeared into baseline noise. • At the lowest temperatures studied (~180K at 62.1 ppm.9 MHz) there was no sign of the appearance of separate high.and low-field methylene resonances.13C • 13C nmr studies Allyl Grignard Reagents spectrum of allylmagnesium bromide has two lines of similar width: the methylene carbons at δ58. 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 .7 and the methine carbon at δ148.
firstly the magnesiacyclohexane was made in such a way that no MgBr2 could contaminate the cyclic compound: [(CH2)5Hg]4 Mg/THF high vacuum [(CH2)5Mg]n • 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 . the bifunctional Grignard reagent generated from Br(CH2)5Br could exist as: BrMg(CH2)5MgBr (CH2)5Mg + MgBr2 • To establish whether this occurs.Cyclic Grignard Reagents Cyclic reagents7 • As with the Schlenk equilibrium.
7 • • Established that 12-membered dimer was present by crystallisation and Xray structure Each Mg has two THF molecules attached K Mg Mg 2 THF Mg Mg THF a THF Mg THF b Mg THF THF . dimerisation exothermic) i = 1.4 – 1.Cyclic Grignard Reagents Association • The monomeric magnesiacyclohexane was found to be in equilibrium with its dimer. – Equilibrium in favour of dimer: K1 (28.50 °C) = 223 ± 41 l/mole ΔH = -8 kcal/mole (i.25 °C) = 531 ± 81 l/mole K1 (48.e.
28 – 1.53 °C) = 300 ± 92 l/mole Magnesium bromide was then added to the previously generated solution of (CH2)5Mg and the same parameters measured: i = 1.[MgBr2] • K2 (28.53 (48.25 °C) = 250 ± 65 l/mole K2 (48.25 °C) = 299 ± 30 l/mole K2 (48.50 °C) This is identical to i as measured above → solutions are of similar composition K2 (28.58 (for BrMg(CH2)5MgBr i = 2) → equilibrium between linear and cyclic species exists Schlenk equilibrium constant: K2 = [BrMg(CH2)5MgBr] [(CH2)5Mg].25 °C).49 (28. THF BrMg(CH2)5MgBr • • • Degree of association i = 1.Cyclic Grignard Reagents • The degree of association was then measured for: Br(CH2)5Br Mg.50 °C) = 361 ± 50 l/mole ΔH ~ +2 kcal/mole (endothermic reaction) • • • • . i = 1.
e. i = 2 i. Schlenk equilibrium lies to the left in diethyl ether and monomer is present Influence of cyclic structure on reactivity was investigated for:8 O (CH2)nMg or BrMg(CH2)nMgBr OH + CnH2n+1 b OH • a RMg or RMgX C5H10Mg2Br2 C4H8Mg2Br2 C5H10Mg C4H8Mg Yield a 18% 12% 6% 4% Yield b 23% 28% 35% 30% • 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 E2 cis mechanism .• • Cyclic Grignard Reagents In Et2O.
but at higher concentrations are highly associated in solution • In THF.Conclusions • Deceptively simple nature of Grignard reactions complicated by behaviour in solution • In Et2O. However. the organomagesium reagents tend to be monomeric. Grignard reagents tend to exist as RMgX. • Allylic Grignard reagents are complicated by the nature of their conjugation • Di-Grignard reagents can exist as the cyclic species . there is an equilibrium between RMgX and R2Mg.
B) D. 5 (1970). W. Westera. Chem. K. Chem. Ashby. Parris. 1967. 19 (1969) 279. Chem. Am. 1967. Hill. Smith. Soc. 1966. G. Soc. Chem.C. 21. Am. M. Hutchison. Calcium. Denise. 1206 5. Organomet. J. 4215 4. Beck. 23. 1971. Fauvarque.E. E. Blomberg. Benkeser.A. B. Bivens. C. 1973. J. Lindsell. L.References 1. R. Bickelhaupt. F. Organomet. J.E. Ashby.B. 22. Desai. Quarterly Reviews of the Chemical Society. Comprehensive Organometallic Chemistry 1. 155 (1978) C55 6.A. 355 . Chem. H. C. 514 (1996) 1. Holtkamp. Becker.A.A. Blomberg. 8.R. Darki. J.C. J. 95. A) E.E. Strontium and Barium. 259 3. G. W. 3027.-F. F. W. 7075 7. A. Magnesium. H. Ducom.C. Tetrahedron. 1982. 155 2. J. Bickelhaupt. J. Boyd. 93. Tetrahedron Lett. Organomet. E.
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