Transcript Grignard Reagents – Review Meeting - GCG-42

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
Victor Grignard
published using Grignard
reagents
 Mostly synthetic applications
 Physical nature complicated
 Important aspects:
Formation
 Classically formed from an organic halide
and magnesium
turnings
in either ether or
ether RMgX
R X + Mg
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
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
RMgX + LiX
LiR + MgX
which are difficult to prepare directly.
 Occurs with retention of stereochemistry
so can form chiral Grignard reagents
2
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
R
+ MgX
2RX + Mg
or a larger excess of magnesium
+ MgX
RMgX + RX
R
 May arise by radical coupling or by
reaction of the initially formed
organometallic with more organic halide
2
2
2
2
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
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
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)
R
Mg
X
O
Mg
Br
O
Et
as monomeric trigonal
OEt2
O
S
 MgBrMe(THF)3 crystallises
OEt2
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
X
R
S
S
X
R
X
S
R
S
R
R
Mg Mg complex.
Mg Mg
Mg
Mg
more
Mg Mg
X
X
S
S
R
X
S
R
R
S
X
R
c
 At low concentration, monomeric speciesd
exist (in accordance with Schlenk equilibrium)
a
b
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
R
Mg X
Et2O towards RMgX
OEt2
e
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
BrMgto exist for e.g. π-allyl
structure, asMgBr
is known
MgBr
palladium complexes
 Allylmagnesium bromide has a very simple nmr
spectrum with only two signals: the four α- and γprotons (δ 2.5) are equivalent with respect to the βproton (δ6.38)
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
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
THE GRIGNARD REACTION
Experiment 18:
Mg
CH3CH2CH2CH2Br
CH3CH2CH2CH2MgBr
ether
O
CH3
CH3
CH3CH2CH2CH2
C
OMgBr
CH3
H3O
C
CH3
CH3
+
CH3CH2CH2CH2
C
CH3
OH
THE GRIGNARD REACTION
Experiment 18:
Mg
CH3CH2CH2CH2Br
CH3CH2CH2CH2MgBr
ether
O
CH3
CH3
CH3CH2CH2CH2
C
OMgBr
CH3
H3O
C
CH3
CH3
+
CH3CH2CH2CH2
C
CH3
OH
Objectives:
 To synthesize a 3o alcohol from an
alkyl halide and a ketone using a
Grignard reaction.
 To determine purity using GC analysis.
 To characterize starting materials
and products using IR, 1H-NMR, and
13C-NMR spectra.
THE GRIGNARD REACTION
 Organic halides react with magnesium
metal in ether or THF to yield an
organomagnesium halide: RMgX
ETHER
R-X + Mg -------------> R-Mg-X
or THF
R= 1o, 2o, or 3o alkyl, aryl or alkenyl
X= Cl, Br, I
THE GRIGNARD REACTION
 The C-Mg bond is a highly polar
+
MgX
 C
covalent bond. The carbon atom
is both nucleophilic and basic
making it very reactive with a
wide variety of E+.
 Grignard reagents react with
proton donors (Brönsted acids)
such as H2O, ROH, RCOOH,
RNH2 to yield hydrocarbons.
This makes it extremely
important to
keep the reaction
H
MgBr and
flask
solvent completely dry
+
+
HOMgBr
O
of water.
butyl magnesium bromide
H
butane
THE GRIGNARD REACTION
ALCOHOLS FROM GRIGNARD
REAGENTS


 
R MgX +
1
1
R
R
O
R2
 
R 
MgX


R2
MgX
O
H3O
O
2
H
O
+
C
R
1
R
R
2
C
R
R
+
R1
HOMgX