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REAGENTS FOR MODERN ORGANIC SYNTHESIS
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Explanation
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GRIGNARD REAGENT & REACTIONS
* The organomagnesium halides are known as Grignard reagents. These are extremely
important reagents developed by the French chemist François Auguste Victor Grignard, who was
awarded the Nobel Prize in 1912 in Chemistry for this work.
The Grignard reagent is represented as R-Mg-X, where
R = alkyl / aryl / alkenyl / allyl group
X = Cl / Br / I
* The reactions involving Grignard reagents, as sources of nucleophiles, are usually referred
to as Grignard reactions.
PREPARATION OF GRIGNARD REAGENT
* The Grignard reagents are prepared by the action of activated magnesium (Rieke
magnesium) on organic halides in suitable solvents like Diethyl ether, Et 2O or Tetrahydrofuran,
THF in anhydrous conditions.
* This is an oxidative insertion of magnesium between carbon and halogen bond, which
involves oxidation of Mg(0) to Mg(II). The mechanism of this reaction if not quiet conclusive.
* The Grignard reagents are in equilibrium with the dialkylmagnesium species R 2Mg and
MgX2 (Schlenk equilibrium).
* In the formation of Grignard reagent, the polarity of carbon attached to the halide group is
reversed. This reversal in polarity is called as umpolung.
REACTION CONDITIONS
Activation of magnesium metal:
* Magnesium metal is usually unreactive due to formation of oxide layer on its surface. Hence
it should be activated by dislodging this layer. It is achieved by adding small amount of iodine or
1,2-dioiodoethane or by using ultrasonic sound.
This problem can also be obviated by using Rieke magnesium, which is in the form of highly
reactive small particles of magnesium with large surface area. It is prepared by reducing
MgCl2 with lithium metal.
Solvent:
* Ether solvents like Diethyl ether, Et2O or Tetrahydrofuran, THF or Dimethoxyethane, DME or
Dioxane are most suitable for the preparation of Grignard reagents. It is because they are not only
unreactive with magnesium but also dissolve and stabilize the Grignard reagents by forming Lewi's
acid base complexes.
* The major disadvantage of Grignard reagents is they react with protic compounds like water,
alcohols, thiols etc. Hence the reaction must be carried out under anhydrous conditions avoiding
moisture.
* These reagents must not be exposed to air as they also react with oxygen by giving peroxide
species which are converted to corresponding alcohols during hydrolytic workup. To avoid this, it
may be preferable to carry out the reaction in nitrogen or argon atmosphere.
PREPARATION OF DIFFERENT TYPES OF GRIGNARD REAGENTS
* The alkyl Grignard reagents are prepared from the corresponding chlorides or bromides or
iodides. The order of reactivity of alkyl halides with magnesium is RCl < RBr < RI. Alkyl fluorides
are seldom used due to much less reactivity.
* The alkenyl and phenyl Grignard reagents are prepared from the corresponding bromides or
iodides in more effective co-ordinating solvent like THF.
E.g. Vinyl bromide and bromobenzene can be converted to corresponding Grignard reagents
by reacting them with magnesium metal in anhydrous THF.
* The alkynyl Grignard reagents are prepared by deprotonating 1-alkynes with another
Grignard reagent like Ethylmagnesium bromide.
E.g. Propyne can be deprotonated with ethylmagnesium bromide to give propynylmagnesium
bromide.
* The allylic Grignard reagents may undergo coupling reactions. Hence they are generated in
situ whenever required in the Grignard reactions.
* Grignard reagents can also be prepared by transmetallation.
E.g. Alkyllithiums can give Grignard reagents when treated with magnesium salts.
REACTIONS OF GRIGNARD REAGENTS
* The Grignard reagents are highly basic and can react with protic compounds like water,
acids, alcohols, 1-alkynes etc., by giving corresponding alkanes.
E.g. Ethylmagnesium bromide liberates ethane gas when treated with water.
The reaction of Grignard reagent with D2O can be used to introduce a deuterium atom
selectively at a particular carbon atom.
* However the Grignard reagents are less basic than organolithiums and hence are more
suitable nucleophiles for carbon-carbon bond formation.
* The Grignard reagents are used as sources of carbon nucleophiles (carbanions) and can
react with electrophilic centers. The addition reactions involving Grignard reagents with
compounds containing polarized multiple bonds like aldehydes, ketones, esters, acid halides,
nitriles, carbon dioxide etc., are termed as Grignard reactions.
* The reactivity of carbonyl compounds with Grignard reagents follow the order: aldehydes >
ketones > esters > amides
MECHANISM OF GRIGNARD REACTION
* The first step in the Grignard reaction is the nucleophilic addition of Grignard reagent to the
polar multiple bond to give an adduct which upon hydrolytic workup gives the final product like
alcohol.
E.g. The mechanism of reaction with a carbonyl compound is shown below.
APPLICATIONS OF GRIGNARD REAGENT
Following is the summary chart of applications of Grignard reagent in modern organic
synthesis.
Grignard reaction
RMg-X +
Product
Formaldehyde ( HCHO )
------->
A primary alcohol: R-CH2-OH
Aldehyde (R'-CHO)
------->
A secondary alcohol: R'-CH(OH)-R
Ketone (R'-CO-R")
------->
A tertiary alcohol: R'-CR"(OH)-R
Ester (R'-COOR")
------->
A tertiary alcohol: R'-CR(OH)-R
Acid halide (R'-COX)
------->
A tertiary alcohol: R'-CR(OH)-R
CO2
------->
A carboxylic acid: R-COOH
CS2
------->
A dithionic acid: R-CSSH
SO2
------->
A sulphinic acid: R-SOOH
SO3
------->
A sulphonic acid: R-SO2OH
nitriles (R'-CN)
------->
A ketone: RCOR'
Hydrogen Cyanide (HCN)
------->
An aldehyde: RCHO
Oxiranes (epoxides)
------->
Alcohols
Weinreb amide
------->
A ketone
cyanogen
------->
A nitrile
choramine
------->
An amine
Iodine
------->
Alkyl iodide
Sulfur
------->
A thiol
halides of B, Si, P, Sn
------->
compounds with C- hetero atom bonds
CdCl2
------->
Dialkyl cadmium
1) The addition of Grignard reagents to formaldehyde furnishes primary alcohols.
E.g. The addition of Ethylmagnesium iodide to formaldehyde followed by hydrolytic workup
furnishes Propyl alcohol, a primary alcohol.
2) The Grignard reaction with aldehydes other than formaldehyde gives secondary alcohols.
E.g. The addition of Methylmagnesium iodide to acetaldehyde gives Isopropyl alcohol.
3) The addition of Grignard reagent to ketones furnishes tertiary alcohols.
E.g. The addition of Methylmagnesium iodide to acetone gives tert-Butyl alcohol.
Stereochemistry:
The carbonyl carbon of an unsymmetrical ketone is a prochiral center. Therefore the addition
of a Grignard reagent can take place on either face of the carbonyl group with equal chance.
Hence a racemic mixture is formed in absence of asymmetric induction.
E.g.
However a mixture of diastereomers is formed when the ketone or aldehyde contains at least
one chiral center. The predominant stereoisomer formed in this case can be predicted by using
Cram's rule.
E.g. The reaction of (R)-2-phenylpropanal with ethylmagnesium bromide, an achiral Grignard
reagent furnishes the (R,R)-2-phenyl-3-pentanol as major product.
Side reactions:
However, the abstraction of an α-hydrogen by Grignard reagent (in this case it acts as a base)
is observed with sterically hindered ketones to furnish an enolate intermediate. The protic workup
of the enolate ends up in the recovery of the starting ketone.
If the Grignard reagent contains a β-hydrogen, reduction of carbonyl compound by hydride
transfer may compete with the desired addition reaction (see below). Hence the Grignard reagent
with smallest possible alkyl group is to be used to avoid this side reaction. Also the use of
corresponding organolithium compounds is advisable to suppress the enolization products.
It is also observed that the tertiary magnesium alkoxides bearing a β-hydrogen, may undergo
a dehydration reaction during protic workup, and thus by giving an elimination product, alkene
instead of alcohol.
E.g.
4) The esters are less reactive than aldehydes and ketones. However they give tertiary
alcohols with excess (2 moles) of Grignard reagent. The initial addition product formed will
decompose to a ketone which reacts with the second Grignard reagent to furnish the tertiary
alcohol finally.
E.g. Ethyl acetate reacts with two moles of phenylmagnesium bromide and thus by furnishing
1,1-diphenylethanol, a tertiary alcohol.
5) The acid halides also react with 2 moles of Grignard reagent to furnish tertiary alcohols.
Again the reaction proceeds through the intermediate ketone.
E.g. Acetyl chloride reacts with two moles of Ethylmagnesium bromide to furnish 3methylpentan-3-ol.
However, it is also possible to get the ketone in higher yields by using one mole of Grignard
reagent.
6) The Grignard reagents react with carbon dioxide to give carboxylic acids.
E.g. Methylmagnesium chloride gives acetic acid when reacted with carbon dioixide.
An analogous reaction of Grignard reagent is observed with carbon disulphide, CS2, to
give alkanedithionic acid.
E.g. Ethanedithionic acid can be prepared by reacting methylmagnesium chloride with carbon
disulphide, CS2.
Also in another analogous reaction with sulfur dioxide, SO2, an alkanesulphinic acid is
formed.
E.g. Methanesulphinic acid is formed when methylmagnesium chloride reacts with sulfur
dioxide, SO2.
Whereas, alkane sulphonic acids are formed with sulfur trioxide, SO3.
7) The nitriles furnishes ketones with Grignard reagents.
E.g. Acetonitrile gives acetone when reacted with methyl magnesium iodide.
However, aldehydes are obtained with hydrogen cyanide, HCN.
8) The oxiranes (epoxides) furnish alcohols with Grignard reagents.
E.g. Secondary butyl alcohol is obtained when 2-methyloxirane reacts with methylmagnesium
iodide.
The less substituted carbon of oxirane is substituted by the alkyl group of Grignard reagent.
9) Addition of an N-methoxy-N-methyl amide, also known as Weinreb amide,
RCON(Me)OMe, to the Grignard reagent gives a ketone. Initially the Grignard reagent is added to
the Weinreb amide, which further undergoes hydrolysis to furnish ketone.
E.g. The addition of n-butylmagnesium bromide to the following Weinreb amide furnishes 3heptanone.
10) The Grignard reagents are also
with cyanogen or cyanogen chloride.
used
to
prepare
nitriles
by
reacting
them
11) Amines can be prepared by reacting these reagents with Chloramine, NH2Cl.
12) The alkyl iodides can be prepared via Grignard reagents. The alkylmagnesium chlorides or
bromides are treated with Iodine to get corresponding alkyl iodides.
13) A Wurtz like coupling reaction is also possible when the Grignard reagent is treated with
an alkyl halide to furnish an alkane. Indeed it is a side reaction that may be possible during the
preparation of Grignard reagent. This reaction is catalyzed by Cuprous (CuI) ions.
14) Just like oxygen, the sulfur atom is also inserted into the Grignard reagent, which gives a
thiol upon protic workup.
15) The Grignard reagent is also used in the making of bond between a carbon and other
hetero atom like B, Si, P, Sn etc. These applications are depicted in the following reactions.
16) Dialkyl cadmium compounds are formed when the Grignard reagents are made to react
with cadmium chloride.
The dialkyl cadmium compounds furnish ketones upon reacting with acid halides.
< Fetizon's reagent:
Explanation
Reagents for organic synthesis:
TOC
Jones reagent : Explanation >
Or go to: Named organic reactions
From Wikipedia, the free encyclopedia
A solution of a carbonyl compound is added to a Grignard reagent. (See gallery below)
The Grignard reaction (pronounced /ɡriɲar/) is an organometallic chemical reaction in which alkylor aryl-magnesium halides (Grignard reagents) add to a carbonyl group in an aldehyde or
ketone.[1] This reaction is an important tool for the formation of carbon–carbon bonds.[2][3] The reaction
of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent.[4]
Grignard reactions and reagents were discovered by and are named after the French
chemist François Auguste Victor Grignard (University of Nancy, France), who was awarded the
1912 Nobel Prize in Chemistry for this work.[5] Grignard reagents are similar to organolithium
reagents because both are strong nucleophiles that can form new carbon-carbon bonds.
Contents
[hide]

1 Reaction mechanism

2 Preparation of Grignard reagent

o
2.1 Reaction conditions
o
2.2 The organic halide
o
2.3 Magnesium
o
2.4 Solvent
o
2.5 Testing Grignard reagents
o
2.6 Initiation
o
2.7 Industrial production
3 Reactions of Grignard reagents
o
3.1 Reactions with carbonyl compounds
o
3.2 Reactions with other electrophiles

3.2.1 Formation of bonds to B, Si, P, Sn

3.2.2 Reaction with transition metal halides
o
3.3 Carbon–carbon coupling reactions
o
3.4 Oxidation
o
3.5 Nucleophilic aliphatic substitution
o
3.6 Elimination

4 Degradation of Grignard reagents

5 Industrial use

6 Gallery

7 See also

8 References

9 Further reading
[edit]Reaction
mechanism
The Grignard reagent functions as nucleophiles attacking electrophilic carbon atoms that are
present within the polar bond of the carbonyl group. The addition of the Grignard reagent to the
carbonyl typically proceeds through a six-membered ring transition state.[6]
However, with hindered Grignard reagents, the reaction may proceed by single-electron transfer.
Similar pathways are assumed for other reactions of Grignard reagents, e.g., in the formation of
carbon–phosphorus, carbon–tin, carbon–silicon, carbon–boron and other carbon–
heteroatom bonds.
[edit]Preparation
of Grignard reagent
Grignard reagents form via the reaction of an alkyl or aryl halide with magnesium metal. The
reaction is conducted by adding the organic halide to a suspension of magnesium in
an etherialsolvent, which provides ligands required to stabilize the organomagnesium compound.
Empirical evidence suggests that the reaction takes place on the surface of the metal. The
reaction proceeds through single electron transfer:[7][8][9] In the Grignard formation reaction,
radicals may be converted into carbanions through a second electron transfer. [10][11]
R−X + Mg → R−X•− + Mg•+
R−X•− → R• + X−
R• + Mg•+ → RMg+
RMg• + X•- → RMgX
A limitation of Grignard reagents is that they do not readily react with alkyl
halides via an SN2 mechanism. On the other hand, they readily participate
in transmetalation reactions:
RMgX + ArX → ArR + MgX 2
For this purpose, commercially available Grignard reagents are especially
useful because this route avoids the problem with initiation.[12]
[edit]Reaction
conditions
In reactions involving Grignard reagents, it is important to exclude water
and air, which rapidly destroy the reagent by protonolysis or oxidation.
Since most Grignard reactions are conducted in anhydrous diethyl
ether or tetrahydrofuran, side-reactions with air are limited by the protective
blanket provided by solvent vapors. Small-scale or quantitative preparations
should be conducted under nitrogen or argon atmospheres, using air-free
techniques. Although the reagents still need to be dry, ultrasound can allow
Grignard reagents to form in wet solvents by activating the magnesium
such that it consumes the water.[13]
[edit]The
organic halide
Grignard reactions often start slowly. As is common for reactions involving
solids and solution, initiation follows an induction period during which
reactive magnesium becomes exposed to the organic reagents. After this
induction period, the reactions can be highly exothermic. Alkyl and
aryl bromides and iodides are common substrates. Chlorides are also used,
but fluorides are generally unreactive, except with specially activated
magnesium.
[edit]Magnesium
Typical Grignard reactions involve the use of magnesium ribbon. All
magnesium is coated with a passivating layer of magnesium oxide, which
inhibits reactions with the organic halide. Specially activated magnesium,
such as Rieke magnesium, circumvents this problem.[14]
[edit]Solvent
Usually Grignard reagents are written as RMgX, but in fact the magnesium(II) centre is
tetrahedral when dissolved in Lewis basicsolvents, as shown here for the bis-adduct of
methylmagnesium chloride and THF.
Most Grignard reactions are conducted in ethereal solvents,
especially diethyl ether and THF. With the chelating diether dioxane, some
Grignard reagents undergo a redistribution reaction to give
diorganomagnesium compounds (R = organic group, X = halide):
2 RMgX + dioxane
R2Mg + MgX2(dioxane)
This reaction is known as the Schlenk equilibrium.
[edit]Testing
Grignard reagents
Because Grignard reagents are so sensitive to moisture and oxygen,
many methods have been developed to test the quality of a batch.
Typical tests involve titrations with weighable, anhydrous protic
reagents, e.g. menthol in the presence of a color-indicator. The
interaction of the Grignard reagent withphenanthroline[15] or 2,2'bipyridine[citation needed] causes a color change.
[edit]Initiation
Many methods have been developed to initiate sluggish Grignard
reactions. These methods weaken the passivating layer of MgO,
thereby exposing highly reactive magnesium to the organic halide.
Mechanical methods include crushing of the Mg pieces in situ, rapid
stirring, and sonication[16] of the suspension. Iodine, methyl iodide,
and 1,2-dibromoethane are common activating agents. The use of 1,2dibromoethane is particularly advantageous as its action can be
monitored by the observation of bubbles of ethylene. Furthermore, the
side-products are innocuous:
Mg + BrC2H4Br → C2H4 + MgBr2
The amount of Mg consumed by these activating agents is usually
insignificant. A small amount of mercuric
chloride will amalgamate the surface of the metal, allowing it to
react.
[edit]Industrial
production
Grignard reagents are produced in industry for use in situ, or for
sale. As with at bench-scale, the main problem is that of initiation;
a portion of a previous batch of Grignard reagent is often used as
the initiator. Grignard reactions are exothermic, and this
exothermicity must be considered when a reaction is scaled-up
from laboratory to production plant.[17]
Many Grignard reagents such as methylmagnesium
bromide, methylmagnesium chloride, phenylmagnesium bromide,
and allylmagnesium bromide are available commercially
as tetrahydrofuranor diethyl ether solutions.
[edit]Reactions
of Grignard reagents
[edit]Reactions
with carbonyl compounds
Grignard reagents will react with a variety
of carbonyl derivatives.[18]
The most common application is for alkylation of aldehydes and
ketones, as in this example:[19]
Note that the acetal function (a protected carbonyl) does not react.
Such reactions usually involve an aqueous acidic workup, though
this is rarely shown in reaction schemes. In cases where the
Grignard reagent is adding to a prochiral aldehyde or ketone,
theFelkin-Anh model or Cram's Rule can usually predict which
stereoisomer will be formed. With easily 1,3-diketones and related
substrates, the Grignard reagent RMgX functions merely as a
base, giving the enolate anion and liberating the alkane RH.
[edit]Reactions
with other electrophiles
Grignard reagents will react with other various electrophiles,
serving both as a nucleophile for many and as a base for protic
substrates.
Not shown, the reaction of bromoethane and Mg in ether followed
by the addition of phenol in THF converts the phenol into C 6H5OMgBr. In the presence of paraformaldehyde powder and
triethylamine after the addition of benzene and distillation of the
latter solvents, salicylaldehyde will be the major product after the
addition of 10% HCl. The reaction works also with iodoethane
instead of bromoethane.[20]
[edit]Formation of bonds to B, Si, P, Sn
Like organolithium compounds, Grignard reagents are useful for
forming carbon–heteroatom bonds.
[edit]Reaction with transition metal halides
Grignard reagents react with many metal-based electrophiles. For
example, they undergo transmetallation with cadmium
chloride (CdCl2) to give dialkylcadmium:[21]
2 RMgX + CdCl2 → R2Cd + 2 Mg(X)Cl
Dialkylcadmium reagents are used for preparation of ketones
from acyl halides:
2 R'C(O)Cl + R2Cd → 2 R'C(O)R + CdCl2
[edit]Carbon–carbon
coupling reactions
A Grignard reagent can also participate in coupling
reactions. For example, nonylmagnesium bromide reacts
with methyl p-chlorobenzoate to give p-nonylbenzoic acid,
in the presence
ofTris(acetylacetonato)iron(III) (Fe(acac)3), after workup
with NaOH to hydrolyze the ester, shown as follows.
Without the Fe(acac)3, the Grignard reagent would attack
the ester group over the aryl halide.[22]
For the coupling of aryl halides with aryl Grignards, nickel
chloride in tetrahydrofuran (THF) is also a good catalyst.
Additionally, an effective catalyst for the couplings of alkyl
halides is dilithium tetrachlorocuprate (Li2CuCl4), prepared
by mixing lithium chloride (LiCl) and copper(II)
chloride (CuCl2) in THF. The Kumada-Corriu
coupling gives access to [substituted] styrenes.
[edit]Oxidation
Treatment of a Grignard reagent with oxygen gives the
magnesium organoperoxide. Hydrolysis of this material
yields hydroperoxides or alcohol. These reactions
involve radical intermediates.
The simple oxidation of Grignard reagents to give alcohols
is of little practical import as yields are generally poor. In
contrast, two-step sequence via a borane (vide supra) that
is subsequently oxidized to the alcohol with hydrogen
peroxide is of synthetic utility.
The synthetic utility of Grignard oxidations can be
increased by a reaction of Grignard reagents with oxygen
in presence of an alkene to an ethylene
extended alcohol.[23] This modification
requiresaryl or vinyl Grignards. Adding just the Grignard
and the alkene does not result in a reaction demonstrating
that the presence of oxygen is essential. Only drawback is
the requirement of at least two equivalents of Grignard
although this can partly be circumvented by the use of a
dual Grignard system with a cheap reducing Grignard
such as n-butylmagnesium bromide.
[edit]Nucleophilic
aliphatic substitution
Grignard reagents are nucleophiles in nucleophilic
aliphatic substitutions for instance with alkyl halides in a
key step in industrial Naproxen production:
[edit]Elimination
In the Boord olefin synthesis, the addition of magnesium
to certain β-haloethers results in an elimination reaction to
the alkene. This reaction can limit the utility of Grignard
reactions.
[edit]Degradation
of Grignard reagents
At one time, the formation and hydrolysis of Grignard
reagents was used in the determination of the number of
halogen atoms in an organic compound.[24] In modern
usage Grignard degradation is used in the chemical
analysis of certain triacylglycerols.[25]
[edit]Industrial
use
An example of the Grignard reaction is a key step in the
industrial production of Tamoxifen[26] (currently used for
the treatment of estrogen receptor positive breast cancer
in women):[27]
[edit]Gallery

Magnesium turnings placed on a flask.

Covered with THF and a small piece of iodine added.

A solution of alkyl bromide was added while heating.

After completion of the addition, the mixture was heated for a
while.

Formation of the Grignard reagent had completed. A small
amount of magnesium still remained in the flask.

The Grignard reagent thus prepared was cooled to0°C before
the addition of carbonyl compound. The solution became cloudy
since the Grignard reagent precipitated out.

A solution of carbonyl compound was added to the Grignard
reagent.

The solution was warmed to room temperature. The reaction
was complete.
[edit]See
also