Grignard Reagents – Review
Katharine Goodenough
31/08/05
Background
•
Discovered by Victor Grignard in 1900
–
•
•
Awarded Nobel Prize in 1912
By 1975, over 40000 papers published using
Grignard reagents
–
–
•
Key factors are ethereal solvent and water-free conditions
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
RMgX + LiX
LiR + MgX2
• 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
Mg
dioxane
MgR2
2RMgX
MgX2
HgR2
Reactions of Grignard reagents
RH
OH
R
R
1
R CO2Et
1. R1CN
2. H+
O
R1
H2O
R1
RMgX
R1
RCO2H
R1CHO
OH
R
O
OH
1. CO2
2. H+
R1R2CO
R1
R
OH
R1 2 R
R
R1
R
Mechanism of reaction with ketones2
R'
O
Mg
X
R
O
+ R'MgX
R
R
R
O
R'MgX
Mg
R
R
R'
R'
X
Mg
X
R
OMgX
R
R
R'
+ R'MgX
R
R'
OMgR'
O
Mg R
R
Mg
X
X
R
R'
+ MgX2
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
RMgX +
RX
R2
+ MgX2
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 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
2
[RX]
Mg+
4
R
Mg+
X
MgX
R
Mg2+
5
3
MgX+
RMgX
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 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)(OiPr2)]2 with bridging Br ligands
Each Mg is 4 coordinate, O-Mg-C =
120.7°; Br-Mg-Br = 116.2°
R
OEt2
Mg
X
OEt2
O
O
Mg
Br
O
S
Et
Mg
Me
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
Association for EtMgCl and EtMgBr in Et2O
3
EtMgCl
1.25
Association (i)
Association (i)
1.3
1.2
1.15
1.1
EtMgBr
1.05
EtMgCl
2.5
2
EtMgBr
1.5
1
0.5
1
0
0
0.5
1
1.5
concentration (M)
2
2.5
0
0.5
1
1.5
concentration (M)
2
2.5
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):
X
R
Mg Mg
X
S
R
a
S
R
X
Mg Mg
X
S
R
b
S
S
R
Mg
R
R
Mg
X
S
c
S
X
Mg
X
R
Mg
R
S
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
MgR2 + MgX2
K
2RMgX
Grignard
reagent
Solvent
K
MeMgBr
Et2O
320
THF
3.5 – 4
Et2O
480 – 484
THF
5.09
THF
5.52
EtMgBr
EtMgCl
• 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
• For MeMgBr in Et2O:
Alkyl Grignard Reagents
– 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
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
Anisole < iPr2O < Et3N <
nBu O < Et O < THF < DME
2
2
[EtMgBr]
[Et2Mg]
δ (ppm)
0.1
0.006
-0.468
-
0.1
-0.405
0.1
-
-0.604
-
0.1
-0.655
0.1
-
-0.702
-
0.129
-0.771
Et3N
0.1
-
-0.500
nBu O
2
0.088
0.099
-0.559
DME
0.035
0.013
-0.785
anisole
0.075
0.025
-0.115
iPr
2O
Et2O
THF
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 αand 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 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
Allyl Grignard Reagents
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
R
D
D
D
a
MgBr
BrMg
b
D
13C
•
nmr studies
Allyl Grignard Reagents
13C
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
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
•
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
•
(CH2)5Mg + MgBr2
Mg/THF
[(CH2)5Mg]n
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
∆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
THF
Mg
THF
Mg
Mg
THF
THF
Mg
Mg
THF
THF
a
2
b
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
+
a
RMg or RMgX
Yield a
Yield b
C5H10Mg2Br2
18%
23%
C4H8Mg2Br2
12%
28%
C5H10Mg
6%
35%
C4H8Mg
4%
30%
OH
CnH2n+1
b
•
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