Grignard Reagents Review

Katharine Goodenough 31/08/05

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

Victor Grignard

Alkyl Grignards are most widely studied

Allyl and cyclic Grignard reagents will also be covered

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, 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
LiR + MgX2 RMgX + LiX

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
dioxane 2RMgX MgX2 MgR2 Mg HgR2

Reactions of Grignard reagents

RH OH R R1 R 1. R1CN 2. H+ R OH R1 R OH R1 2 R R R1 O R CO2Et RMgX
1

H2O

1. CO2 2. 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'

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

2RX

+ Mg RX

R2 R2

+ MgX2 + MgX2

RMgX +

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, 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, concentration, temperature and solvent

Mechanism
1 RX Mg [RX] Mg+ MgX 2 X 3 RMgX R Mg+ 4 Mg2+ 5 MgX+ R

1. Single electron transfer from Mg to organic halide 2. Shortlived radical anion decays to give organic radical R and halide anion X3. 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). R2Mg is not formed directly, but by establishment of the Schlenk equilibrium

Alkyl Grignard Reagents

Structure (solid state)

Dietherates (e.g. [MgBr(Ph)(OEt2)2]) exist as isolated, monomeric units Mg is at centre of a distorted tetrahedron Mg C distance 2.1 2.2 (covalent bond length 1.7 )
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, O-Mg-C = 120.7; Br-Mg-Br = 116.2

S Et

Mg

Et Br Mg Br S

Alkyl Grignard Reagents

Structure (solution)2
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

Association for EtMgCl and EtMgBr in THF 1.3

Association for EtMgCl and EtMgBr in Et2O 3

Association (i)

1.2 1.15 1.1 1.05 1 0 0.5 1 1.5 2 2.5 concentration (M)

Association (i)

1.25

EtMgCl

2.5 2 1.5 1 0.5 0 0

EtMgCl EtMgBr

EtMgBr

0.5

1.5

2.5

concentration (M)

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 Et2O, 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 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

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). 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

Thermodynamics of Schlenk equilibrium3

MgR2 + MgX2 K 2RMgX

Grignard reagent MeMgBr EtMgBr EtMgCl

Solvent Et2O THF Et2O

K 320 3.5 4 480 484

THF
THF

5.09
5.52

In ether, MgRX is prevalent (K~10 103) but in THF (K = 1-10), a more random distribution is seen. Since THF adducts tend to have higher coordination numbers than those of Et2O, differences attributed to degree of solvation. In hydrocarbon solvent, K is very small; in triethylamine it is very large

Alkyl Grignard Reagents

NMR Studies4
MgR2 and RMgX can be distinguished provided exchange is slow on the NMR timescale
-H atoms of magnesium-bound alkyl group R resonate at -2 0 ppm (average under conditions of fast exchange) MgXR is at lower field than MgR2 due to shielding by halogen
MeMgBr -1.55 ppm; MgMe2 -1.70 ppm in Et2O 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

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, 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

 For MeMgBr in Et2O:

Alkyl Grignard Reagents

At low temperature, two distinct signals are seen.

The lower field signal ( 11.55) is attributed to MeMgBr The higher field signal ( 11.70) 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, moving to higher field with lower temperature. It was not possible to observe distinct signals for MeMgBr and Me2Mg as was possible in ether. The Schlenk equilibrium seems to shift towards the dialkylmagnesium at lower temperature, since the spectrum approaches that of Me2Mg at -76 C May be partially due to MgBr2 precipitating

From these data, equilibrium constant was calculated for MeMgBr in THF, K = 4 2.6

Alkyl Grignard Reagents

Further solvent effects5

Increasing donation by solvent shifts the -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] 0.1

[Et2Mg] 0.006

(ppm) -0.468

0.1 0.1

0.1
0.1 -

-0.405
-0.604 -0.655 -0.702

Et2O THF Et3N

nBu O 2

0.1 0.088 0.035

0.129
0.099 0.013

-0.771
-0.500 -0.559 -0.785

Anisole < iPr2O < Et3N < nBu O < Et O < THF < DME 2 2

DME

anisole

0.075

0.025

-0.115

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 1 structure which can then equilibrate, or as the 3 structure, as is known to exist for e.g. -allyl palladium complexes
Allylmagnesium bromide has a very simple nmr spectrum with only two signals: the four and -protons ( 2.5) are equivalent with respect to the -proton (6.38)

MgBr

BrMg MgBr

The same was found for -methylallylmagnesium bromide, which has a methyl group and only one other type of proton

Either rapid interconversion of the 1 structures must make the methylene groups equivalent or the methylene groups of the 3 structure must rotate to make all four of the hydrogens equivalent

H2 H3 R H1Z H1E

Allyl Grignard Reagents

H2 is coupled equally to both of the protons of C1, and these nonequivalent hydrogens could not be frozen out. There must therefore be rapid rotation of the C1-C2 bond on the nmr time scale The value of J12 (~9.5 Hz) shows that this is not an equilibrium between Z and E hydrogens on C1 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 C1-C2 and C1 having significant sp3 character. Mg is localised at C1; its presence controls the geometry at C1

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
R D D a MgBr

Allyl Grignard Reagents

R D BrMg b D

13C

13C

nmr studies

Allyl Grignard Reagents

spectrum of allylmagnesium bromide has two lines of similar width: the methylene carbons at 58.7 and the methine carbon at 148.1 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

Cyclic Grignard Reagents

Cyclic reagents7
As with the Schlenk equilibrium, the bifunctional Grignard reagent generated from Br(CH2)5Br could exist as:

BrMg(CH2)5MgBr

(CH2)5Mg + MgBr2

To establish whether this occurs, 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

Cyclic Grignard Reagents

Association
The monomeric magnesiacyclohexane was found to be in equilibrium with its dimer.
Equilibrium in favour of dimer: K1 (28.25 C) = 531 81 l/mole K1 (48.50 C) = 223 41 l/mole H = -8 kcal/mole (i.e. dimerisation exothermic) i = 1.4 1.7

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

Cyclic Grignard Reagents The degree of association was then measured for:
Br(CH2)5Br Mg, THF BrMg(CH2)5MgBr

Degree of association i = 1.28 1.58 (for BrMg(CH2)5MgBr i = 2) equilibrium between linear and cyclic species exists Schlenk equilibrium constant:
K2 = [BrMg(CH2)5MgBr] [(CH2)5Mg].[MgBr2]

K2 (28.25 C) = 250 65 l/mole K2 (48.53 C) = 300 92 l/mole Magnesium bromide was then added to the previously generated solution of (CH2)5Mg and the same parameters measured: i = 1.49 (28.25 C); i = 1.53 (48.50 C) This is identical to i as measured above solutions are of similar composition K2 (28.25 C) = 299 30 l/mole K2 (48.50 C) = 361 50 l/mole H ~ +2 kcal/mole (endothermic reaction)

Cyclic Grignard Reagents In Et2O, 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
O (CH2)nMg or BrMg(CH2)nMgBr OH + CnH2n+1 b OH

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

Conclusions
Deceptively simple nature of Grignard reactions complicated by behaviour in solution
In Et2O, 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 R2Mg. 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

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