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
R X + Mg ether 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 Mg
2RMgX MgR2 HgR2

MgX2
Reactions of Grignard reagents

RH

OH
R1 H2O
R 1. CO2
R 1 RCO2H
R CO2Et 2. H+

1. R1CN RMgX R1CHO

O 2. H+ OH

R1 R O R1R2CO R1 R
OH R1
R
R1
OH

R1 2 R
R
 Mechanism of reaction with ketones2

R' X
Mg
R O
O O R'MgX R'
+ R'MgX Mg
R
R R R R
R' X
Mg

R OMgR'
OMgX
R O Mg R + MgX2
+ R'MgX R R'
R R' R' R
R Mg X
X
 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 R2 + MgX2

RMgX + RX R2 + MgX2
 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 25 Mg and 28 Mg 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 2 4
RX [RX] R R

Mg Mg+ X Mg+ Mg2+

3 5 MgX+
MgX

RMgX

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).

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 R OEt2
isolated, monomeric units Mg
• Mg is at centre of a distorted tetrahedron X OEt2
• Mg – C distance 2.1 – 2.2 Å (covalent bond
length 1.7 Å)

• MgBrMe(THF)3 crystallises as monomeric O

trigonal bipyramidal complex with 3 THF O
Mg
ligands Br Me
O

• Bromoethylmagnesium crystallises from

diisopropyl ether as a dimer [MgBr(Et)(OiPr2)]2
with bridging Br ligands S Br Et
Mg Mg
• Each Mg is 4 coordinate, O-Mg-C = 120.7°; Et Br S
Br-Mg-Br = 116.2°
 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 Association for EtMgCl and EtMgBr in Et2O

1.3 3
Association (i)

Association (i)
1.25 2.5
EtMgCl EtMgCl
1.2 2

1.15 1.5
EtMgBr
1.1 1

1.05 0.5
EtMgBr
1 0
0 0.5 1 1.5 2 2.5 0 0.5 1 1.5 2 2.5
concentration (M) 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 R X S X R S R R S R X
Mg Mg Mg Mg Mg Mg Mg Mg
R X S R X S R X S X R S
a b c d
 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 X
OEt2
e
 Alkyl Grignard Reagents

Thermodynamics of Schlenk equilibrium3

K
MgR2 + MgX2 2RMgX

Grignard Solvent K
reagent
MeMgBr Et2O 320
THF 3.5 – 4
EtMgBr Et2O 480 – 484
THF 5.09
EtMgCl THF 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

• 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 -1.55 ppm; MgMe2 δ -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
 Alkyl Grignard Reagents
• For MeMgBr in Et2O:
– 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 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 Solvent [EtMgBr] [Et2Mg] δ (ppm)
shifts the α-H resonance to i
Pr2O 0.1 0.006 -0.468
higher fields
- 0.1 -0.405
• Determined for EtMgBr and
Et2Mg at 40 °C Et2O 0.1 - -0.604
• Low concentrations employed - 0.1 -0.655
to avoid association effects THF 0.1 - -0.702
• Leads to an order of solvent - 0.129 -0.771
basicity:
Et3N 0.1 - -0.500
Anisole < iPr2O < Et3N <
n
Bu2O 0.088 0.099 -0.559
n
Bu2O < Et2O < THF < DME
DME 0.035 0.013 -0.785
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 η1 structure which can then
equilibrate, or as the η3 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)

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
 Allyl Grignard Reagents
H2
H3 H1Z

R H1E

• H2 is coupled equally to both of the protons of C1, and these non-

equivalent 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
 Allyl Grignard Reagents
IR Studies
• As nmr timescale was found to be too
slow to observe the unsymmetrical R R
D
isomers of allylmagnesium bromide, IR D D
was employed.
MgBr BrMg D
• Two otherwise identical isomers a and b a 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
13
C nmr studies
• C spectrum of allylmagnesium bromide has two lines of similar
13

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
 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:

Mg/THF [(CH2)5Mg]n
[(CH2)5Hg]4
high vacuum

• 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
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

Mg Mg
2

THF
THF THF
Mg
Mg Mg
Mg THF
THF
a b
THF
 Cyclic Grignard Reagents
• The degree of association was then measured for:

Mg, THF
Br(CH2)5Br 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:
[BrMg(CH2)5MgBr]
K2 =
[(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
ΔH ~ +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 OH OH
BrMg(CH2)nMgBr
+

CnH2n+1
a b

RMg or RMgX Yield a Yield b

• Less reduction to alcohol
C5H10 Mg2Br2 18% 23% seen for cyclic
organomagnesium reagent
C4H8Mg2Br2 12% 28%
• Reduction takes place via
C5H10 Mg 6% 35% a 6-centre transition state
in an elimination of MgH by
C4H8Mg 4% 30% 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