Organomagnesium compounds (Grignard reagent-RMgX)

Introduction

Organometallic compounds are the compounds where at least one carbon metal bond is
present. There are many types of organometallic compounds. Many metals can form Carbon
metal bond and generates organometallic compounds. Among the metals Lithium (Li)
Magnesium (Mg), Copper (Cu), Zinc (Zn) are widely used since the beginning of 19th century.
Many other Organometallic compounds are also known where Silicon (Si), Tin (Sn), Cadmium
(Cd) etc are used as a metal. In this connection it has to be mentioned that all carbon metal bonds
are covalent in [Link] in this case we will focus our discussion on organomagnesium
compounds which is known as Grignard Reagent (G.R).

Francois August Victor Grignard was an organic chemist who reported Organomagnesium
compound first where carbon magnesium covalent bond is present in 1899 and awarded Nobel
Prize in 1912. Grignard reagent is a widely used reagent for the synthesis of different functional
group containing organic molecules and also used as a reagent for higher homologation of
carbon. This reagent is very much relevant till today.

Preparation
1. We can prepare Grignard reagent starting from Magnesium metal (Mg) and organic halides
(RX):
RX + Mg RMgX

Common solvent is diethlyether (Et2O), for preparation of vinylmagnesium bromide THF is

preferred.

In this context it is very important to note that, if we give a close look towards the reaction,
we find a reversal of polarity occurs which is known as Umpolung. Here in this particular
case, alkyl group (R) possesses +ve formal charge in RX which changes to -ve formal charge
over RMgX.
Pictorial diagram of Umpolung

+ − − + −
In RX the polarity is: R X In RMgX the polarity is: R Mg X
By this method an accepter centre is transformed to a donor centre.
 In this case X is preferably I>Br>Cl and R is preferably 1⁰>2⁰>3⁰ because 3⁰ suffers from
elimination.
Again, Preparation of G.R becomes difficult with increasing number of carbons in alkyl
group. i.e, CH3X> C2H5X.>C3H7X…… and so on.
When the preparation of Grignard reagent is difficult some methyl iodide added to overcome
this problem, which is known as entrainment method. For this method ethylene dibromide (3
molecule or more) and Mg in excess (6 molecule or more) is used.
Precaution during preparation of Grignard Reagent

Solvent should be perfectly dry or anhydrous and alcohol free, because Grignard
Reagent forms alkane after taking one hydrogen from HOH or ROH.

RMgX + HOH/ROH RH + Mg(OH/R)X

i. Reaction should be carried out under Nitrgen or Argon atmosphere. Because in presence
of oxygen it forms R-O-O-MgX which undergo following type of reaction.
RMgX
RMgX + O2 R-O-O-MgX ROMgX
ROMgX then hydrolysed further to ROH in presence of water.

ii. In course of preparation of Grignard Reagent, Mg should be oxide free because due to the
coating of MgO over Mg will cause difficulties since reaction occurs from the surface
area of the Mg
2. Transfer of Magnesium (Mg):
We can synthesize a number of Grignard reagents simply by exchanging the position of
Magnesium and halogen. This can be done since magnesium can tolerate different
functional groups.
i-PrMgCl + ArCl ArMgCl + i-PrCl

3. Allyl and benzyl ethers and thio ethers are reported to yield Grignard Reagent with Mg.
 CH2=CHCH2OCH3 + Mg CH2=CHCH2OMgCH3

+ Mg (Reike)
SC6H5 S MgSC6H5
S

Reike: highly reactive metal powder

4. The preparation of Grignard Reagent free from halide impurities was achieved using dialkyl
mercury with Mg.
R2Hg + Mg R2Mg + Hg

Structure
Grignard reagent remains in complex structure with many species in equilibrium known
as Schlenk equilibrium.
X X
R
R2Mg + MgX2 R2Mg2X2 Mg
2RMgX RMg Mg
MgR
R X
X

etc Dimer 2RMgX R2Mg + MgX2 Dimer etc

The extent of association depends on the concentration and is extensive above about
0.3M. In solution Grignard Reagent is coordinated with ether molecule.

R R R
OEt2
Et2O Mg X Mg X
Mg
X OEt2 Et2O Et2O

monomer dimer

Reactivity of Grignard Reagent

As a Base:

Grignard Reagent acts as a base and produces an alkane after abstracting a proton from any
compound which contains active hydrogen. (Anhydrous condition should be maintained)
 RMgX + ZH RH + ZMgX
(Z= R'O, OH, RCO2, X, R2N)

Uses:

i. For deuterium incorporation

RMgX + D2O RD + Mg(OD)X

ii. For synthesis of acetylene magnesium bromide

EtMgBr, Et2O HC CMgBr C6H6
HC CH

EtMgBr, Et2O PhC CMgBr C6H6

Ph C CH

iii. Determination of presence of active hydrogen in any compound which is known as

Zeriwitinoff active hydrogen determination.

O O OH O OMgX O OMgX O
RMgX H3O+

H3C C CH3 H3C CH3 H3C CH3 H3C CH3

H2
From the used amount of Grignard Reagent we can determine the presence of active
hydrogen in any compound.

As a Nucleophle:
Grignard Reagent acts as a nucleophile and used for the preparation of different type of
compounds containing different functional groups:
i. Alcohols:
A. 1° alcohols
a. 1° alcohols of + 0 carbon
RMgX
RMgX + O2 R-O-O-MgX ROMgX
ROMgX then hydrolysed further to ROH in presence of water or acid.

b. 1° alcohols of + 1 carbon homologation

 R-++CH2OH HCHO
RMgX RCH2OH

RMgX
Et2O H3O+
RMgX + HCHO RCH2OMgX RCH2OH

This reaction proceeds via 6 membered T.S where one mole Grignard reagent acts
as Lewis acid and another mole acts as carbanion. Although after completion of
reaction one mole of Grignard reagent gets back which supports our mechanism
of involvement of only one mole Grignard reagent for this reaction.

X X X
R
Mg Mg Mg
O R O
R
Mg O
H
Mg CH2 Mg C X
R
X R
X
R H

c. 1° alcohols of 2 carbon homologation (reaction with ethylene oxide)

O
- +
RMgX RCH2CH2OH R + CH2CH2OH

O RMgX
Et2O H3O+
RMgX + RCH2CH2OMgX RCH2CH2OH
Example:
O
i. Mg/THF
PhBr PhOH
ii.. H3O+
d. 1° alcohols of 3 carbon homologation
O
i. THF
RMgX R OH
ii. H3O+

B. 2° alcohols
a. When aldehydes are treated with Grignard reagent 2° alcohols are formed.

RMgX R2CHOH R-++CH(R)OH RCHO

RMgX
H3O+/NH4Cl
RMgX + RCHO R2CHOMgX R2CHOH

Example:
OH

CHBr i. Mg/ Ether

ii. CH3CHO CH-CH-CH3
iii. dil H2SO4

b. When ethyl formate is treated with Grignard reagent 2° alcohols are formed. 2
Equivalent RMgX required here. This is a process for the synthesis of a 2°
alcohol containing two similar alkyl groups.

RMgX R2CHOH R-++CH(R)OH RCHO

RMgX
H3O+ R-++CHO
RMgX + RCHO R2CHOMgX R2CHOH
RMgX HCOOEt
+
H3O
HCOOEt + RMgX RCH(OMgX)OEt RCH(OH)OEt RCHO

RMgX
H3O+
R2CHOH R2CH(OMgX)

Example:
R = C4H7 and X = Br
 C. 3° alcohols
a. When ketones are treated with Grignard reagent 3° alcohols are formed.

RMgX R3COH R-++CR2OH R2CO

RMgX
H3O+
RMgX + R2CO R3COMgX R3COH

Example:

EtMgBr, Et2O Ph2CO

Ph C CH Ph C CMgBr

Ph OH
Ph OMgBr
aquous NH4Cl
C
C
Ph C C Ph
Ph C C Ph

b. When ethyl chloroformate is treated with Grignard reagent 3°alcohols are

formed.

RMgX R3COH R-++CR2OH R2CO

RMgX
R-++RCO
aquous NH4Cl R COH
RMgX + R2CO R3COMgX 3

ClCOOEt RMgX RCOOEt

RMgX R-++CO(OEt)
 Here aq. Ammonium chloride is used to prevent dehydration.
H3O+
ClCOOEt + RMgX RC(Cl)(OMgX)OEt RC(Cl)(OH)OEt RCOCl

RMgX
i. RMgX RCOR H3O+
R3COH R2C(Cl)OH R2C(Cl)(OMgX)
ii. H3O+

c. Reactions with esters give 3° alcohols with two similar alkyl group
OMgX
R' R A
R'CO2Et i. RMgx (2 Eq)
ii. Aq. NH4Cl C
OEt
R OH R
R'
Mechanism for the reaction with esters involve the intermediate A which
further reacts to give alcohol. However, if this reaction is quenched at this
stage then there is a possibility to get ketone. This is also possible since it is
more reactive than ester.
However under general conditions (during direct addition) we add
substrate to the Grignard reagent so there is a large excess of Grignard reagent
which is very reactive and so less selective. So it react with both ester and A.
But if we ad Grignard reagent to ester then there is a possibility to stop
reaction at A since the more reactive ester is in excess. This process is known
as inverse addition.
So for synthesis of a ketone from an ester using Grignard reagent we
follow inverse addition procedure.

d. Reaction with diethylcarbonate give 3° alcohols with three similar alkyl group
EtO

RMgBr C O i. Ether R3COH

[Link]. NH4Cl
EtO
Example:
Synthesis of Ph3CO:
 (OEt)2CO + PhMgBr (3 eq.) Ph2CO + PhMgBr
Ph3COH

PhCO2Et + PhMgBr (2 eq.)

ii. Carbonyl Compounds

Aldehyde (RCHO):

During the formation of 2° alcohol we have used RMgX and HCOOEt where
aldehyde was formed as an intermediate. But after formation of aldehyde it becomes
more reactive than HCOOEt and reaction does not stop here and further reaction
takes place. So it is difficult to prepare aldehydes from ethyl formate and reaction
ended with 2° alcohol. So we can think about reverse addition (i.e, addition of
Grignard reagent to the ester). Again Reverse addition in this case is not such
effective.
RCHO R-++CHO

RMgX HCOOEt
Preparation of aldehydes are readily obtained from ethyl orthoformate instead of
ethyl formate by direct addition. When Grignard reagent reacts with ethyl
orthoformate it forms acetal which prevent the formation of 2° alcohol since they are
stable towards nucleophiles. Acetals on hydrolysis forms aldehydes. This is the most
useful process for producing aldehydes by using GR.
RCHO RCH(OEt)2 R-++CH(OEt)2
Acetal

RMgX HC(OEt)3
 OEt
R-MgX RCH(OEt)2 Mg(OEt)X
H C OEt
OEt H3O+

RCHO

Ketone (R2CO):

a. Like aldehydes we can think about ketones which can be prepared through
ketals. But the availability of RC(OEt)3 is very poor because of heavy cost of
product.
b. Ketones can also be prepared by Grignard reagent (1mole) using RCOCl
(1mole) via inverse addition, but then also tertiary alcohol formed.
c. The best process to produce ketones by using GR is the reaction of RMgX
(Grignard reagent) with RCN (alkyl cyanide) by direct addition. If we use
HCN instead of RCN aldehydes are formed.

O NH
R2CN
C C
R1 R2 R1 R2

R1MgX
R1
R2 +
H3O
R2 C N R1MgX C NMgX C O

R1
R2

iii. Carboxylic acids (RCOOH):

The reaction is carried out by adding Grignard reagent to a large excess of dry ice
(Solid CO2). Large excess of dry ice is used due to following reasons.

a. To maintain refrigeration i.e, low temperature

 b. To prevent the initially formed RCO(OMgX) further to yield the unwanted
ketones.

This reaction is useful to synthesis of acids with same three alkyl group (R 3CCOOH
type).

O
CO2
C H
R O

RMgX

R R
H3O+
RMgX O C O O C O C
OMgX
OH

iv. Ester
Esters can be prepared via inverse addition of Grignard reagent to the ethyl
chloroformate or diethyl carbonate.
O O

RMgX
EtO X R OEt

If inverse addition is not performed reaction does not stop here at the stage of ester.
Further reaction takes place and ester forms ketone first and then the final product
becomes 3° alcohol.
v. Alkyl cyanide
When ClCN or cyanogen gas (CN-CN) treated with GR it forms alkyl cyanide.

RMgX ClCN RCN + MgXCl

vi. Amine
 R-NH2 R- + NH2+ NH2Cl OR NH2OMe

RMgX NH2Cl RNH2 + MgXCl

RMgX
vii. Ether
R-O-CH2Cl + CH3MgBr R-O-CH2CH3

viii. Alkane
R-X + R'MgX R-R'

1. Abnormal behavior of Grignard reagent

I. When ketones are treated with Grignard reagent generally 3° alcohols are formed.
But if alkyl groups of ketones are bulky (eg. isopropyl) then normal reaction
procedure does not follow and following type of reaction takes place.
Br

Br
Mg
H
O Mg H
O
CH3 O C
C CH3
C H C
H

MgBr
OH O
H
H3O+
C C
H CH3
H

Thus hindered ketones undergo reduction with Grignard reagent which have −H. We
observe reduction of ketone to 2° alcohol.

ii. Ketones having -H sometimes form enolates instead of normal reaction.
 O O OMgBr O
CH3MgBr

iii. Another abnormal behavior of Grignard reagent was observed when PhMgBr reacts with
PhCHO. At first benzaldehyde forms 2° alcohol which further reacts with another molecule of
PhCHO to yield ketone and 1° alcohol.

Br

Br
Mg
O O
Mg
Ph O O
C
PhMgBr Ph
PhCHO Ph H
H C C
Ph
Ph H H
Ph

MgBr
OH O
Ph
H3O+ O
C C
Ph Ph Ph
H H
Ph
H

iv. Mg is not so hard like Li (always 1,2 addition) and not so soft like Cu (always 1,4
addition).
With - unsaturated aldehydes Grignard reagent undergoes facile addition to C=O
(1,2 addition).
C2H5
i.. C2H5MgX
O ii. H3O+ OH

But with - unsaturated ketones there is a competition between 1,2 and 1,4
addition.
 Et Et
i.. C2H5MgX

O ii. H3O+
O OH
1,4 addition 1,2 addition

Kumada Coupling

The Kumada Coupling was the first Pd or Ni-catalyzed cross coupling reaction, developed in
1972.

The coupling of Grignard reagents with alkyl, vinyl or aryl halides under Ni-catalysis provides an
economic transformation, but the reaction is limited to halide partners that do not react with
organomagnesium compounds. One example is in the industrial-scale production of styrene derivatives,
and the Kumada Coupling is the method of choice for the low-cost synthesis of unsymmetrical biaryls.

Pd(0) Or Ni(II)
RMgX + ArX Ar R
Ligand

X = I, Br, Cl, OTf, OTs (Rare)

Reaction mechanism:
L ArX
Ar R
Pd0
L Oxidative Addition
Reductive elimination

L Ar L Ar
PdII PdII
L R X L

Tr ans-/ Cis- isomerization L Ar RMgX

PdII Transmetallation
R L