Grignard reagents

Grignard reagents

Preface

In 1900 - the beginning of new century- a short paper by a lone chemist, Victor Grignard, reported a simple procedure for preparing solutions of organomagnesium compounds of composition RMgX.

The Grignard reagent soon became”,,,, the most important of all organometallic compounds encountered in the chemical laboratory” and the organometallic reagent most chemists first encounter in an introductory organic chemistry course, the reason for that were the proprieties which Grignard reagents hold.

A wide variety of organic groups can be used to prepare Grignard reagent solutions and they are relatively inexpensive. Although generally being very stable, Grignard reagents easily undergo many useful reactions with a multitude of organic and inorganic substrates. Despite much of the vast literature concerning Grignard reagent and related organomagnesium compounds concerns synthetic applications; many other features have interested chemists as well. And the reason was the extremely strong propensity of organomagnesium species to form additional bonds- to solvent molecules, to other Rs and Xs, and to substrates-and the usually rapid exchange of groups between magnesiums, establishing their structures has been really a challenge. Deciphering the mechanisms of their reactions has been even more challenging. Chemists were struggling with structures of organomagnesium and their mechanisms at the time envy the seeming simplicity of much transition metal organometallic chemistry.

The French chemistFrançois Auguste Victor Grignard (University of Nancy, France) was awarded the 1912Nobel Prize in Chemistry for this work.

In 1950, kharasch and Reinmuth remarkably successed by attempting to comprehensively survey the knowledge of Grignard reagents in a lengthy monograph (1400 pages). Even at that time the authors noted that in addition to the omission of reactions with metallic substances some additional selection was inevitable. There have been accelerating recent attempts to prepare a comprehensive survey, however the explosive growth of the chemical has made this a more elusive goal year by year.

In 1975, there was estimation that the application of Grignard reagents had appeared in a bit more than 40,000 chemical papers, a number which recently is extremely much larger.

At the close of its first century the Grignard reagent has achieved maturity but exhibits no signs of senescence.

Introduction

More than 100 years have passed since Victor Grignard published his paper on the preparation of ethereal solutions of compounds which was talking about bonding between carbon and magnesium. Since that time Grignard reagents have been a convenient choice for organic chemists in many preparations of complex molecules.

In additional of being extremely useful, Grignard reagents and the way they react have represented a challenge to chemists and physicists. Both the intimate nature of the reagents in various solvents and the detailed mechanisms of their reactions have been under scrutiny by approximately four generations of researches and the work is ongoing. This review will concentrate on advances made in the last thirty years. Since the authors have been engaged in this kind of work during this period of time it is inevitable that the review will focus to a certain extent on their favourite views and topics. Traditionally, Grignard reagents have been seen as potential anions, capable of nucleophilic additions especially to hetero double bonds as in carbonyl compounds. However, in contrast to usual nucleophiles such as amines or sodium alkoxides, catalyst is necessary for Grignard reagents to react with alkyl halides. This fact made the preparation of Grignard reagent easy to accurse. The π bond polarization and the possibility of forming the Carbon-Carbon bond in concert with the formation of the magnesium-oxygen bond are the reasons for the high reactivity of Grignard reagents toward several carbonyl compounds. since the as the established bonds, oxygen - magnesium and carbon -carbon, are much stronger than the broken bonds, Carbon-Magnesium bond and the π-CO bond, The enthalpy (ΔH) of this reaction is highly negative

In 1929 Blicke and powers suggested that some carbonyl compounds may react with Grignard reagents by stepwise, homolytic reaction mechanisms, however more than 40 years passed before this theory was generally accepted. The homolytic mechanism and the polar concerted mechanism are shown in scheme (1)

R2C=­­­­­­

Scheme -1-

TheGrignard reactionis an organometallic chemical reactionwhere alkyle or aryl magnesiumhalides(Grignard reagent) act asnucleophilesand attackelectrophiliccarbon atoms that are present withinpolar bonds(e.g. in acarbonylgroup as in the example shown in scheme 2) to yield a carbon-carbon bond, thus alteringhybridizationabout the reaction centre.The Grignard reaction is very important in the formation ofcarbon-carbon bondsand for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boronand many carbon-heteroatombonds.

An example of a Grignard reaction

Scheme -2-

Because of the high pKavalue of the alkyl component which is approximately 45, the nucleophilic organometallic addition reaction is then irreversible. such reactions are not ionic; the Grignard reagent exists as an organometallic cluster (in ether).

If there are disadvantages we need to mention about the Grignard reagents is that they easy react withprotic solvents(such as water), or with functional groups withacidicprotons, such as alcohols and amines. In fact, atmospheric humidity in the laboratory can dictate one's success when attempting to synthesize a Grignard reagent from magnesiumturningsand analkyl halide. One of several methods used to exclude water from the reaction atmosphere is to flame-dry the reaction vessel to evaporate all moisture, which is then sealed to prevent moisture from returning.

Another disadvantage of Grignard reagents is that they do not readily form carbon-carbon bonds by reacting with alkyl halides via an SN2 mechanism.

Mechanism reaction

The reaction of the Grignard reagent with the carbonyl typically proceeds through a six-membered ring transition state as shown in scheme (3).

The mechanism of the Grignard reaction.

Scheme-3-

However, with hindered Grignard reagents, the reaction may proceed by single-electron transfer.

As has been mentioned earlier, in any reaction involving Grignard reagents, it is really important to make sure that no water is present, which would otherwise cause the reagent to rapidly decompose. Therefore, most Grignard reactions occur in solvents such as anhydrousdiethyl etherortetrahydrofuran, because the oxygen of these solvents stabilizes the magnesium reagent. Another problem the reaction might face which is the ability of reagents to react with oxygen present in the atmosphere, inserting an oxygen atom between the carbon base and the magnesium halide group. Usually, the volatile solvent vapours will limited this side reaction by displacing air above the reaction mixture. However, it may be preferable for such reactions to be accurse innitrogenorargonatmospheres, especially for smaller scales.

THE GRIGNARD REAGENT AND ITS

PROPERTIES

Scheme-4-

The reaction must be completely dry because Grignard reagents react with water as we going to explain later.
All reactions accurse with the Grignard reagent are carried out with the mixture produced from this reaction. It's impossible to separate it out in any way.

Reactions of Grignard reagents

Grignard reagents and water

Grignard reagents will produce alkanes when reacting with water and this is the main reason that everything in the reaction has to be very dry throughout the preparation above.

For example:

Scheme-5-

The inorganic product on the reaction above, Mg(OH)Br, is referred to as a "basic bromide". We can assume it as a kind of middy-way level between magnesium bromide and magnesium hydroxide.

Grignard reagents and carbon dioxide

In two levels, Grignard reagents will react with carbon dioxide first stage will be the addition of the Grignard reagent to the carbon dioxide.

Dry carbon dioxide is bubbled through a solution of the Grignard reagent in ethoxyethane, made as described above.

For example:

Scheme-6

Second stage will be the hydrolization of the product (reaction with water) in the presence of a dilute acid. Typically, you would add dilute sulphuric acid or dilute hydrochloric acid to the solution formed by the reaction with the carbon dioxide.

A carboxylic acid is produced with one more carbon than the original Grignard reagent.

The usually quoted equation is (without the red bits):

Almost all sources quote the formation of a basic halide such as Mg(OH)Br as the other product of the reaction. That's actually misleading because these compounds react with dilute acids. What you end up with would be a mixture of ordinary hydrated magnesium ions, halide ions and sulphate or chloride ions - depending on which dilute acid you added.

Grignard reagents and carbonyl compounds

What are carbonyl compounds?

Carbonyl compounds contain the C=O double bond. The simplest ones have the form:

It is much easier to understand what is going on by looking closely at the general case (using "R" groups rather than specific groups) - and then slotting in the various real groups as and when you need to.

The reactions are essentially identical to the reaction with carbon dioxide - all that differs is the nature of the organic product.

In the first stage, the Grignard reagent adds across the carbon-oxygen double bond:

Dilute acid is then added to this to hydrolyse it. (I am using the normally accepted equation ignoring the fact that the Mg(OH)Br will react further with the acid.)

An alcohol is formed. One of the key uses of Grignard reagents is the ability to make complicated alcohols easily.

What sort of alcohol you get depends on the carbonyl compound you started with - in other words, what R and R' are.

The reaction between Grignard reagents and methanal

In methanal, both R groups are hydrogen. Methanal is the simplest possible aldehyde.

Assuming that you are starting with CH3CH2MgBr and using the general equation above, the alcohol you get always has the form:

Since both R groups are hydrogen atoms, the final product will be:

A primary alcohol is formed. A primary alcohol has only one alkyl group attached to the carbon atom with the -OH group on it.

You could obviously get a different primary alcohol if you started from a different Grignard reagent.

The reaction between Grignard reagents and other aldehydes

The next biggest aldehyde is ethanal. One of the R groups is hydrogen and the other CH3.

Again, think about how that relates to the general case. The alcohol formed is:

So this time the final product has one CH3group and one hydrogen attached:

A secondary alcohol has two alkyl groups (the same or different) attached to the carbon with the -OH group on it.

You could change the nature of the final secondary alcohol by either:

* changing the nature of the Grignard reagent - which would change the CH3CH2group into some other alkyl group;

* changing the nature of the aldehyde - which would change the CH3group into some other alkyl group.

The reaction between Grignard reagents and ketones

Ketones have two alkyl groups attached to the carbon-oxygen double bond. The simplest one is propanone.

This time when you replace the R groups in the general formula for the alcohol produced you get a tertiary alcohol.

A tertiary alcohol has three alkyl groups attached to the carbon with the -OH attached. The alkyl groups can be any combination of same or different.

You could ring the changes on the product by

* changing the nature of the Grignard reagent - which would change the CH3CH2group into some other alkyl group;

* changing the nature of the ketone - which would change the CH3groups into whatever other alkyl groups you choose to have in the original ketone.

* Why do Grignard reagents react with carbonyl compounds?

* The mechanisms for these reactions aren't required by any UK A level syllabuses, but you might need to know a little about the nature of Grignard reagents.

* The bond between the carbon atom and the magnesium is polar. Carbon is more electronegative than magnesium, and so the bonding pair of electrons is pulled towards the carbon.

* That leaves the carbon atom with a slight negative charge.

The carbon-oxygen double bond is also highly polar with a significant amount of positive charge on the carbon atom. The nature of this bond is described in detail elsewhere on this site.

The Grignard reagent can therefore serve as anucleophilebecause of the attraction between the slight negativeness of the carbon atom in the Grignard reagent and the positiveness of the carbon in the carbonyl compound.

Anucleophileis a species that attacks positive (or slightly positive) centres in other molecules or ions.

Carbon-carbon coupling reactions

A Grignard reagent can also be involved incoupling reactions. For example, nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid, in the presence ofiron(III) acetylacetonate. Ordinarily, the Grignard reagent will attack the ester over thearyl halide.[11]

For the coupling of aryl halides with aryl Grignards,nickel chlorideinTHFis also a good catalyst. Additionally, an effective catalyst for the couplings of alkyl halides isdilithium tetrachlorocuprate(Li2CuCl4), prepared by mixinglithium chloride(LiCl) andcopper(II) chloride(CuCl2) in THF. TheKumada-Corriu couplinggives access to styrenes. 4-nonylbenzoicacid synthesis using a grignard reagent

Oxidation

The oxidation of a Grignard reagent with oxygen takes place through aradicalintermediate to a magnesium hydroperoxide. Hydrolysis of this complex yieldshydroperoxidesandreductionwith an additional equivalent of Grignard reagent gives analcohol.

Grignard oxygen oxidation pathways

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignards with oxygen in presence of analkeneto an ethylene extendedalcohol.[12]This modification requiresarylorvinylGrignards. 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.

Grignard oxygen oxidation example

Nucleophilic aliphatic substitution

Grignard reagents arenucleophilesinnucleophilic aliphatic substitutionsfor instance withalkyl halidesin a key step in industrialNaproxenproduction:

Naproxen synthesis

V. Grignard,Compt. Rend.130,1322 (1900); F. F. Blicke,Heterocycl. Compd.1,222 (1950); K. Nützel,Houben-Weyl13/2a,128 (1973).

Copyright © 2006 by Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.
Grignard degradation

Grignard degradation[13][14]at one time was a tool in structure elucidation in which a Grignard RMgBr formed from a heteroaryl bromide HetBr reacts with water to Het-H (bromine replaced by a hydrogen atom) and MgBrOH. Thishydrolysismethod allows the determination of the number of halogen atoms in anorganic compound. In modern usage Grignard degradation is used in the chemical analysis of certain triacylglycerols.[15]

• 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 α- and γ-protons (δ 2.5) are equivalent with respect to the β-proton (δ6.38)

- 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

• 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

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

13C nmr studies

• 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

• Grignard Synthesis of Benzoic Acid

• Organometallic compounds are versatile intermediates in the synthesis of alcohols,

• carboxylic acids, alkanes, and ketones, and their reactions form the basis of some of the most

• useful methods in synthetic organic chemistry. They readily attack the carbonyl double bonds of

• aldehydes, ketones, esters, acyl halides, and carbon dioxide. The use of organometallic reagents

• can produce the synthesis of highly specific carbon-carbon bonds in excellent yields.

• Among the most important organometallic reagents are the alkyl- and arylmagnesium halides,

• which are almost universally called Grignard reagents after the French chemist Victor Grignard,

• who first realized their tremendous potential in organic synthesis. Their importance in the

• synthesis of carbon-carbon bonds was recognized immediately after the report of their discovery

• in 1901. Grignard received the 1912 Nobel Prize in chemistry for applications of this reagent to

• organic synthesis. The Grignard reagent is easily formed by reaction of an alkyl halide, in

• particular a bromide, with magnesium metal in anhydrous diethyl ether. Although the reaction

• can he written and thought of as simply

• R - Br + Mg → R - Mg - Br (RMgX) it appears that the structure of the material in solution is rather more complex. There is evidence that dialkylmagnesium is present

2 R-Mg-Br R-Mg-R + MgBr 2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

and that the magnesium atoms, which have the capacity to accept two electron pairs from donor molecules to achieve a four-coordinated state, are solvated by the unshared pairs of electrons on diethyl ether:

Grignard reagents, like all organometallic compounds, are substances containing carbonmetal bonds. Because metals are electropositive elements, carbon-metal bonds have a high degree of ionic character, with a good deal of negative charge on the carbon atom. This ionic character gives organometallic compounds a high degree of carbon nucleophilicity.

δ- δ+ δ-

R - Mg - R

The Grignard reagent is a strong base and a strong nucleophile. As a base it will react with all protons that are more acidic than those found on alkenes and alkanes. Thus, Grignard reagents react readily with water, alcohols, amines, thiols, etc., to regenerate the alkane. Such reactions are generally undesirable and are referred to as reactions that “kill” the Grignard. In the absence of acidic protons, Grignard reagents undergo a wide variety of nucleophilic addition reactions, especially with compounds containing polar C=0 bonds. The resulting carbon-carbon bond formation yields larger and more complex molecules; and because a variety of different organic (R or Ar) groups can be introduced into organic structures, a wide array of organic compounds can be produced. Some reactions of Grignards are shown below.

Formation of a Grignard reagent takes place in a heterogeneous reaction at the surface of solid magnesium metal, and the surface area and reactivity of the magnesium are crucial factors in the rate of the reaction. It is thought that the alkyl or aryl halide reacts with the surface of the metal to produce a carbon-free radical and a magnesium-halogen bond. The free radical R•, then reacts with the • MgX to give the Grignard reagent, RMgX.

Grinding a few of the magnesium turnings with a mortar and pestle promotes the formation of the Grignard reagent by exposing an unoxidized metallic surface and providing a larger reactive surface area. For an alkyl halide, this procedure will usually be all that is necessary to initiate the reaction quickly; and, in many instances, breaking just one magnesium turning suffices.

When an aryl halide is used, grinding a few magnesium turnings and adding a small iodine crystal can promote the heterogeneous reaction at the surface of the magnesium. There is some question about iodine's exact function; it may react with the metal surface to provide a more reactive interface or it may activate the aryl halide. Some of the color changes that one sees are due to the presence of iodine.

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