Grignard Reagents Review

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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
• Schlenk Equilibrium
• Degree of Association in solution
• Alkyl Grignards are most widely studied
• Allyl and cyclic Grignard reagents will also be
  covered

Victor Grignard
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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 IgtBrgtClgtF
• 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.

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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

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Reactions of Grignard reagents
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Mechanism of reaction with ketones2
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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

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Schlenk Equilibrium

• 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

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Mechanism

• Single electron transfer from Mg to organic
  halide
• Shortlived radical anion decays to give organic
  radical R and halide anion X-
• 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

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Structure (solid state)
Alkyl Grignard Reagents

• 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

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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
EtMgCl
EtMgCl
EtMgBr
EtMgBr
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Alkyl Grignard Reagents

• In THF, RMgX (X Cl, Br, I) are monomeric over a
  wide concentration range
• For X F, compounds are dimeric (ie RMgF2)
• 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)

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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

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Alkyl Grignard Reagents
Thermodynamics of Schlenk equilibrium3

• In ether, MgRX is prevalent (K10 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

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NMR Studies4
Alkyl Grignard Reagents

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

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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

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Alkyl Grignard Reagents

• For MeMgBr in Et2O
• At low temperature, two distinct signals are
  seen.
• The lower field signal (t 11.55) is attributed to
  MeMgBr
• The higher field signal (t 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

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Alkyl Grignard Reagents
Further solvent effects5

• Increasing donation by solvent shifts the a-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
• Anisole lt iPr2O lt Et3N lt nBu2O lt Et2O lt THF lt DME

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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.
  p-allyl palladium complexes
• Allylmagnesium bromide has a very simple nmr
  spectrum with only two signals the four a- and
  ?-protons (d 2.5) are equivalent with respect to
  the ß-proton (d6.38)
• The same was found for ß-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

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Allyl Grignard Reagents

• 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

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IR Studies
Allyl Grignard Reagents

• 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

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13C nmr studies
Allyl Grignard Reagents

• 13C spectrum of allylmagnesium bromide has two
  lines of similar width the methylene carbons at
  d58.7 and the methine carbon at d148.1 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

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Cyclic reagents7
Cyclic Grignard Reagents

• As with the Schlenk equilibrium, the bifunctional
  Grignard reagent generated from Br(CH2)5Br could
  exist as
• To establish whether this occurs, firstly the
  magnesiacyclohexane was made in such a way that
  no MgBr2 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

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Association
Cyclic Grignard Reagents

• 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 X-ray structure
• Each Mg has two THF molecules attached

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Cyclic Grignard Reagents

• The degree of association was then measured for
• 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 (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)

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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 for8

• 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

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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

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References

• Magnesium, Calcium, Strontium and Barium, W.E.
  Lindsell, Comprehensive Organometallic Chemistry
  1, 1982, 155
• E.C. Ashby, Quarterly Reviews of the Chemical
  Society, 1967, 21, 259
• M.B. Smith, W.E. Becker, Tetrahedron, 1966, 22,
  3027 1967, 23, 4215
• G.E. Parris, E.C. Ashby, J. Am. Chem. Soc. 1971,
  93, 1206
• G. Westera, C. Blomberg, F. Bickelhaupt, J.
  Organomet. Chem. 155 (1978) C55
• 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
• H.C. Holtkamp, C. Blomberg, F. Bickelhaupt, J.
  Organomet. Chem. 19 (1969) 279.
• B. Denise, J.-F. Fauvarque, J. Ducom, Tetrahedron
  Lett. 5 (1970), 355