Lone Chemist Victor Grignard Biology Essay

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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.

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The French chemist François Auguste Victor Grignard (University of Nancy, France) was awarded the 1912 Nobel 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-

The Grignard reaction is an organometallic chemical reaction where alkyle or aryl magnesium halides (Grignard reagent) act as nucleophiles and attack electrophilic carbon atoms that are present within polar bonds (e.g. in a carbonyl group as in the example shown in scheme 2) to yield a carbon-carbon bond, thus altering hybridization about the reaction centre. The Grignard reaction is very important in the formation of carbon-carbon bonds and for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and many carbon-heteroatom bonds.

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An example of a Grignard reaction

Scheme -2-

Because of the high pKa value 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 with protic solvents (such as water), or with functional groups with acidic protons, 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 magnesium turnings and an alkyl 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 anhydrous diethyl ether or tetrahydrofuran, 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 in nitrogen or argon atmospheres, especially for smaller scales.

THE GRIGNARD REAGENT AND ITS

PROPERTIES

The Grignard Reagent is an

organometallic species formed by the

formal insertion of elemental magnesium

(Mg0) into a carbon-halogen bond R-X

(X = Cl, Br, I) (1), affording an entity

typically written as "RMgX". It is generally

accepted that the metallation reaction

consists of a stepwise path beginning with

a rate determining single electron transfer

(SET) from metallic magnesium to the *

orbital of the C-X bond of the

organohalide (2). This transfer leads to a

radical-anion/radical-cation pair at the

surface of the magnesium (Figure 1).

Transfer of halide anion to Mg•+ to give

XMg•, followed by collapse of XMg• and R•

affords RMgX. The chance diffusion of R•

from a neighboring site can lead to dimer

(R-R) formation (3). This dimer formation

is often generalized as a "Wurtz coupling."

Though it is tempting to accept it as the

actual active species, the formula "RMgX" is

merely a formalism that is useful in

calculating stoichiometry and proposing simple mechanisms. In reality, it is less than

accurate in describing the solvated aggregate structure of the reactive

species (4). Fortunately for Grignard users, large-scale industrial application occurs

safely and reliably without detailed knowledge of the composition of the actual

aggregate structure. First and foremost, the Grignard species is a metallated carbanion and shares many of the properties of other metallated species. It is a nucleophile and a strong base, ranking third behind 1) RNa and 2) RLi in reactivity of the carbanion, based on electronegativity differences (5). Generally, the reactivity of

a carbanionic reagent tends to increase ↑ with increasing ↑p-character (sp<sp2<sp3) and increasing ↑pKa of the conjugate acid. As a nucleophile, a

Grignard reagent bearing a localized (i.e., not resonance-stabilized) carbanion will

generally behave as a hard nucleophile, offering higher relative reaction rates with

hard electrophiles and 1,2-addition as opposed to conjugate addition. This

opposed to conjugate addition. This behavior can be altered to that of a softer

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nucleophile by the addition of Cu(I) salts

to form a cuprate species in situ. Certain

Grignard reagents such as allylic or

benzylic species may have an aptitude for

conjugate or SN2' addition without

transmetallation additives.

Grignard reagents are strong bases

and will react exothermically with a variety

of Lewis and Brønsted acidic species.

Carbon acids such as acetylene,

chloroform, methylene chloride; and

enolizable species, and oxyacids such as

water, alcohols, carboxylic acids; and

inorganic acids such as HX will react

vigorously in contact with a Grignard

reagent. An important point to consider is

that Grignard reagents such as methyl-,

ethyl-, propyl-, or butylmagnesium halides,

when quenched with a proton, may lead

to the rapid formation of methane,

ethane, propane, and butane resulting in

a rapid pressure buildup in a reactor or

storage container. Care must always be

taken to assure that a rapid quench

leading to high vapor pressure products

be avoided.

RMgX is very polar and consequently

requires a coordinating solvent to keep it

in solution. Ethers are most suitable owing

to the availability of lone-pair electrons for

coordination to the magnesium ion and

resulting solubilization in organic media.

Examples of common solvents include

diethyl ether (Et2O), diisopropyl ether,

dibutyl ether, tetrahydrofuran (THF), and

butyldiglyme. Dimethoxyethane (DME)

and 1,4-dioxane promote precipitation of

MgX2 salts as a result of the Schlenk

equilibrium (more on this later).

tolerated in terms of solubility. An

attempt to dissolve a Grignard species in

a hydrocarbon solvent will have a better

chance for success if the Grignard

species is solvated with an ether.

Grignard reagents are available from

commercial suppliers in drums or

cylinders and are typically offered as THF

or diethyl ether solutions in the range of 1

to 3 Molar. As a practical consideration,

the reagent concentration is limited by the

solubility at temperatures the product is

likely to encounter in transit and storage.

Most Grignard reagents are formulated to

remain soluble at temperatures above

20°C. The issue of solubility requires that

during the cold season, Grignard reagents

must be shipped in heated shipping

containers and be stored at room

temperature off the floor and on pallets. It

is important for freight handlers to clearly

understand that Grignard Reagent formation is usually, though

not exclusively, carried out in ethereal

solvent systems. The presence of

hydrocarbon co-solvents can be

tolerated to varying levels, especially at

elevated temperature and pressure. A

polarizable co-solvent like toluene can

be used in a mixed solvent preparation

of reagent. Furthermore, addition of an

ethereal Grignard solution to a toluene

solution of reactant is often well

products must

not be allowed to sit outside and cool on

the loading dock or in unheated

temporary warehousing. The result of

cooling is precipitation of magnesium

salts. While this does not irreparably harm

the reagent, it does alter its composition

by equilibration. The original composition

is returned by simple dissolution of the

reagent by warming with agitation.

When a Grignard reagent solution gets

cold, solids precipitate and accumulate on

the bottom of the storage container or

vessel. This elementary fact is somewhat

complicated by the Schlenk equilibrium

(Figure 2). This equilibrium describes a

disproportionation property of RMgX

wherein factors that diminish solubility

(i.e., lowered solvent polarity or low

temperature) result in precipitation of the

inorganic salt MgX2 from the organic

solvent medium, thus driving the

equilibrium to the right. Certain ethers

such as DME and 1,4-dioxane drive the

equilibrium to the right by virtue of the

formation of stable coordination

complexes of the

magnesium dihalide salt.

The predominant

characteristic of a

Grignard Reagent is the

anionic aspect of the

carbon attached directly

to the magnesium ion. It

is nucleophilic and usually

quite basic in nature.

These attributes -

nucleophilicity and

basicity - while useful in bond forming

reactions, in fact put some limits on the

types of chemical moieties that can be

present during the formation and use of a

Grignard reagent.

Solvents with electrophilic sites such

as acetonitrile, DMF, acetone, and ethyl

acetate are unsuitable owing to their great

(and irreversible!) reactivity with RMgX.

Reactive moieties on the Grignard

substrate such as aldehydes, ketones,

esters, amides, SO2X, nitriles, epoxides,

hemiacetals, and most halogenated

moieties (i.e., Si-Cl, P-Cl, etc.), must be

protected or absent. Furthermore, the

presence of hetero-atom acids such as

water of hydration, phenols, alcohols,

COOH, N-H, R3N•HCl, as well as carbon

acids like terminal acetylenes and

enolizable groups are quite incompatible

with the formation of an RMgX functional

group on a substrate.

In general, a Grignard reagent is

prepared separately and combined with

the reaction mixture as an ethereal

solution. In some cases a Grignard

reagent can be generated in the presence

of the intended electrophile, which

promptly undergoes addition. This is

referred to as a Barbier reaction or

colloquially as "Barbier conditions".

SOME SYNTHETIC APPLICATIONS

OF GRIGNARD REAGENTS

noteworthy developments from the

literature will be discussed. But before

proceeding with reaction specifics, some

basics are in order.

FINE CHEMISTRY

complexes of the

magnesium dihalide salt.

The predominant

characteristic of a

Grignard Reagent is the

anionic aspect Although Grignard reactions trace back

more than 100 years, the development

of new reaction chemistry is far from

static. Several relatively recent and

of the

carbon attached directly

to the magnesium ion. It

is nucleophilic and usually

quite basic in nature.

These attributes -

nucleophilicity and

basicity - while useful in bond forming

reactions, in fact put some limits on the

types of chemical moieties that can be

present during the formation and use of a

Grignard reagent.

Solvents with electrophilic sites such

as acetonitrile, DMF, acetone, and ethyl

acetate are unsuitable owing to their great

(and irreversible!) reactivity with RMgX.

Reactive moieties on the Grignard

substrate such as aldehydes, ketones,

esters, amides, SO2X, nitriles, epoxides,

hemiacetals, and most halogenated

moieties (i.e., Si-Cl, P-Cl, etc.), must be

protected or absent. Furthermore, the

presence of hetero-atom acids such as

water of hydration, phenols, alcohols,

COOH, N-H, R3N•HCl, as well as carbon

acids like terminal acetylenes and

enolizable groups are quite incompatible

with the formation of an RMgX functional

group on a substrate.

In general, a Grignard reagent is

prepared separately and combined with

the reaction mixture as an ethereal

solution. In some cases a Grignard

reagent can be generated in the presence

of the intended electrophile, which

promptly undergoes addition. This is

referred to as a Barbier reaction or

colloquially as "Barbier conditions".

The preparation of a Grignard reagent

By mixing the halogenoalkane to small amount of magnesium in a conical flask containing ethoxyethane (commonly known as diethyl ether or just "ether") Grignard reagents will be made. The flask has to be fitted to a reflux condenser, and then the mixture will be warmed over a water bath for approximately 30 minutes.

http://www.chemguide.co.uk/organicprops/haloalkanes/padding.gifhttp://www.chemguide.co.uk/organicprops/haloalkanes/makegrignard.gif

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:

http://www.chemguide.co.uk/organicprops/haloalkanes/padding.gifhttp://www.chemguide.co.uk/organicprops/haloalkanes/grignardh2o.gif

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:

http://www.chemguide.co.uk/organicprops/haloalkanes/grignardco2a.gif

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):

http://www.chemguide.co.uk/organicprops/haloalkanes/grignardco2b.gif

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:

http://www.chemguide.co.uk/organicprops/haloalkanes/carbonyl.gif

R and R' can be the same or different, and can be an alkyl group or hydrogen.

f one (or both) of the R groups are hydrogens, the compounds are called aldehydes. For example:

http://www.chemguide.co.uk/organicprops/haloalkanes/aldehydes.gif

If both of the R groups are alkyl groups, the compounds are calledketones. Examples include:

http://www.chemguide.co.uk/organicprops/haloalkanes/ketones.gif

The general reaction between Grignard reagents and carbonyl compounds

The reactions between the various sorts of carbonyl compounds and Grignard reagents can look quite complicated, but in fact they all react in the same way - all that changes are the groups attached to the carbon-oxygen double bond.

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:

http://www.chemguide.co.uk/organicprops/haloalkanes/padding.gifhttp://www.chemguide.co.uk/organicprops/haloalkanes/grigcarbgena.gif

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.)

http://www.chemguide.co.uk/organicprops/haloalkanes/grigcarbgenb.gif

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.

http://www.chemguide.co.uk/organicprops/haloalkanes/methanal.gif

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

http://www.chemguide.co.uk/organicprops/haloalkanes/genalcohol.gif

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

http://www.chemguide.co.uk/organicprops/haloalkanes/makeprimoh.gif

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.

http://www.chemguide.co.uk/organicprops/haloalkanes/ethanal.gif

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

http://www.chemguide.co.uk/organicprops/haloalkanes/genalcohol.gif

So this time the final product has one CH3 group and one hydrogen attached:

http://www.chemguide.co.uk/organicprops/haloalkanes/makesecoh.gif

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 CH3CH2 group into some other alkyl group;

changing the nature of the aldehyde - which would change the CH3 group 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.

http://www.chemguide.co.uk/organicprops/haloalkanes/propanone.gif

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

http://www.chemguide.co.uk/organicprops/haloalkanes/maketertoh.gif

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 CH3CH2 group into some other alkyl group;

changing the nature of the ketone - which would change the CH3 groups 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.

http://www.chemguide.co.uk/organicprops/haloalkanes/grigpolar.gif

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 a nucleophilebecause 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.

A nucleophile is 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 in coupling reactions. For example, nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid, in the presence of iron(III) acetylacetonate. Ordinarily, the Grignard reagent will attack the ester over the aryl halide.[11]

For the coupling of aryl halides with aryl Grignards, nickel chloride in 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) andcopper(II) chloride (CuCl2) in THF. The Kumada-Corriu coupling gives access to styrenes.

4-nonylbenzoicacid synthesis using a grignard reagent

Oxidation

The oxidation of a Grignard reagent with oxygen takes place through a radical intermediate to a magnesium hydroperoxide. Hydrolysis of this complex yields hydroperoxides and reduction with an additional equivalent of Grignard reagent gives an alcohol.

Grignard oxygen oxidation pathways

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignards with oxygen in presence of an alkene to an ethylene extended alcohol.[12] This modification requires aryl 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.

Grignard oxygen oxidation example

Nucleophilic aliphatic substitution

Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:

Naproxen synthesis

[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.

Boord olefin synthesis, X = Br, I, M = Mg, Zn

64.

Grignard Degradation

W. Steinkopf et al., Ann. 512, 136 (1934); 543, 128 (1940).

Stepwise dehalogenation of a polyhalo compound through its Grignard reagent which on treatment with water yields a product containing one halogen atom less:

https://themerckindex.cambridgesoft.com/TheMerckIndex/NameReactions/3794402.gif

V. Grignard, Compt. Rend. 130, 1322 (1900); F. F. Blicke, Heterocycl. Compd. 1, 222 (1950); K. Nützel, Houben-Weyl 13/2a, 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. This hydrolysis method allows the determination of the number of halogen atoms in an organic compound. In modern usage Grignard degradation is used in the chemical analysis of certain triacylglycerols.[15]

CHEM 286L - Organic Chemistry Laboratory II

Grignard Reaction (Part 1)

The Grignard reaction, named for the French chemist François Auguste Victor Grignard, is a

chemical reaction in which alkyl- or aryl-magnesium halides (Grignard reagents), which act as

nucleophiles, attack electrophilic carbon atoms that are present within polar bonds (a carbonyl

group, for example) to yield a carbon-carbon bond. The hybridization of the carbon being

attacked changes from sp2 to sp3. The Grignard reaction is an important tool in the formation of

carbon-carbon bonds.

In the first step of your experiment, you will prepare a Grignard reagent by reacting

bromobenzene with magnesium metal in ether as solvent. The Grignard reagent,

phenylmagnesium bromide, will then react with benzophenone and after the acidic work-up a

tertiary alcohol, triphenylmethanol, will be isolated.

Scheme shud be here,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

One of the characteristic reactions of aldehydes and ketones is the nucleophilic addition

reaction. When a nucleophile adds to the carbonyl group of an aldehyde or a ketone, a

tetrahedral compound is formed. If the nucleophile is a strong base, the tetrahedral compound

does not have a group that can be expelled (see nucleophilic addition-elimination reaction)

therefore the tetrahedral compound is the final product of the reaction

1. All glassware and the magnesium used in a Grignard synthesis should be scrupulously dry.

Even apparently dry glassware can contain moist air and a surprisingly large amount of water

adhered to the walls of the glass equipment. This can greatly lower your yield or even prevent

the reaction from starting. Your instructor will help you flame dry parts of your equipment

required for your reaction so please PAY ATTENTION to the prelab lecture.

2. Due to the occurrence of side reactions in this procedure the reactants for the Grignard

procedure will not be used in strictly stoichiometric amounts.

Magnesium: 0.160 g (6.6mmole) (Balance room)

Bromobenzene: 0.7 mL (6.6 mmole) (Provided by TA)

Benzophenone: 1.10 g (6.00 mmole) (Balance room)

Diethyl ether is extremely volatile and its vapors are flammable and explosive. No flames can be

present when any ether is being used in the room.

Procedure

Step 1

Step 2

Step 3

Step 4

Step 5

Place 0.160 g of magnesium turning and a magnetic stirring bar into a 10 ml round-bottom flask

fitted with a drying tube containing CaCl2, and have your instructor flame dry them (remove the

plastic cap and o-rings first). Once this operation is completed, quickly assemble the set-up

illustrated at the end of this procedure. Do not waste anytime doing so as the longer you take

the more moisture will condense in your flask.

Obtain a vial of bromobenzene from your TA and carefully fill it to the top with anhydrous

diethyl ether provided in the central hood.

Add all the alkyl halide to the magnesium in the round-bottom flask (without using a pipette,

simply pour the solution from the vial onto the flask), Stir the reaction mixture for several

minutes while carefully observing the mixture for signs of reaction. If after a few minutes no

reaction seems to be occurring, carefully remove the round-bottom flask and using a stirring rod,

start scratching the magnesium turnings, until a cloudy/milky solution appears (consult your

instructor for help in initiating the reaction if you still do not observe any change). When the

reaction has started the ether solvent will begin to reflux vigorously, as this reaction is

exothermic, so make sure that you have cold water running through your reflux condenser.

When the ether no longer refluxes on its own, use a warm water bath (~40°C tap water is good

enough!) to heat the reaction mixture under gentle reflux for an additional 15 minutes to

complete the formation of the phenylmagnesium bromide. (Note: the phenylmagnesium bromide

solution in diethyl ether is a dark brown smelly mixture!)

While your phenylmagnesium bromide solution is gently refluxing, weigh 1.10 g of

benzophenone into a clean, dry 3 ml conical vial (previously rinsed with one ml of anhydrous

diethyl ether). Add 2 ml of anhydrous diethyl ether to the benzophenone and make sure to

dissolve it completely.

After your phenylmagnesium bromide reaction is complete, it is time to add your freshly

prepared benzophenone solution. Using the provided clean syringe and needle, begin a dropwise

addition of the benzophenone solution through the septum on your Claisen head. After all of the

ketone has been added, gently reflux the mixture for 15 minutes using a warm water bath. At this

DEPARTMENT OF CHEMI STRY

Step 6

Step 7

point the reaction might be really thick and stirring it might be a problem, no worries, the

reaction has occurred already.

After addition of the ketone, cool the reaction mixture to room temperature, open your Claisen

side arm, and using a pipette, carefully add 1 ml of water dropwise; a gelatinous mixture of

magnesium salts should start forming, and stirring might still be a challenge. Slowly add enough

6M HCl to completely dissolve the magnesium salts (no more than 3 ml are needed). At this

point you can remove your flask from your set-up and using your spatula break up any remaining

solid. You should now observe two phases (organic and aqueous) in the flask, but little or no

solid.

Transfer this reaction mixture to a centrifuge tube and separate the layers, putting aside the

aqueous phase while you continue to work with the organic phase. (If your organic layer is too

small, add a few mL of diethyl ether, as it is easier to work with good size layers for better

separations). Wash the organic phase with 3 mL of 10 % sodium bicarbonate solution followed

by 3 mL of a saturated sodium chloride solution. Place the ether solution in a small Erlenmeyer

and add anhydrous sodium sulfate (or anhydrous magnesium sulfate), to dry it for few minutes.

Decant the ether solution from the drying agent into a small beaker and remove the ether using

the air outlet in your hood or by placing the beaker on a warm hot plate. When the ether is

largely gone cover the top of your beaker with parafilm, punch a few holes into it and store it in

your locker until your next lab

NMR study

MgR2 and RMgX can be distinguished provided exchange is slow on the NMR timescale

α-H atoms of magnesium-bound alkyl group R resonate at δ-2 - 0 ppm (average under conditions of fast exchange)

MgXR is at lower field than MgR2 due to shielding by halogen

MeMgBr δ -1.55 ppm; MgMe2 δ -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

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

Further solvent effects5

Increasing donation by solvent shifts the α-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 < iPr2O < Et3N < nBu2O < Et2O < THF < DME

Solvent

[EtMgBr]

[Et2Mg]

δ (ppm)

iPr2O

0.1

0.006

-0.468

-

0.1

-0.405

Et2O

0.1

-

-0.604

-

0.1

-0.655

THF

0.1

-

-0.702

-

0.129

-0.771

Et3N

0.1

-

-0.500

nBu2O

0.088

0.099

-0.559

DME

0.035

0.013

-0.785

anisole

0.075

0.025

-0.115

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.

Scheme shud be here ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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.

The proper selection of solvent is crucial in carrying out a reaction involving a Grignard

reagent. Diethyl ether is the most frequently used solvent because it is inexpensive and promotes

good yields. The yields of Grignard reagents are highest when a large amount of ether is present

and when pure, finely divided magnesium metal is used.

The magnesium atom in a Grignard reagent has a coordination number of four. The alkyl

magnesium halide already has two covalent bonds to magnesium. The other two sites can be

occupied by ether molecules (See structure on page 1). These complexes are quite soluble in

ether. In the absence of the solvent, the reaction of magnesium and the alkyl halide takes place

rapidly but soon stops because the surface of the metal becomes coated with the

organomagnesium halide. In the presence of a solvent, the surface of the metal is kept clean and

the reaction proceeds until all of the limiting reagent is consumed.

As indicated earlier, the presence of water or other acids inhibits the initiation of the

reaction and destroys the organometallic reagent once it forms. All glassware and reagents must

be thoroughly dry before beginning a Grignard experiment. Oven-drying of the glassware is

essential when the laboratory atmosphere is humid. When the humidity in the laboratory is low,

as it is during the winter heating season, air-drying the glassware overnight will usually be

sufficient for macroscale preparations. The glassware for microscale reactions must always be

dried in an oven just prior to beginning the reaction because even trace amounts of moisture

become significant at this scale.

Commercially available anhydrous ether, alkyl halides, and aryl halides are sufficiently pure for

most Grignard reactions. Keep the ether container tightly closed except when actually pouring

the reagent, and do not let your ether stand in an open container, because water from the air will

dissolve into it.

The mechanism of the Grignard reaction with aldehydes and ketones is actually quite

complex, but it can easily be rationalized as a simple nucleophilic addition reaction:

The hydrolysis step is important in a Grignard synthesis. It is common to use an aqueous

mineral acid, such as sulfuric or hydrochloric acid, to expedite hydrolysis. Not only does this

cause the reaction to go more readily, but Mg(II) is converted from the much less manageable

hydroxide or alkoxide salts to water-soluble sulfates or chlorides. For preparing labile products,

such as tertiary alcohols, the weaker acid ammonium chloride is an excellent alternative. Strong

acids, such as sulfuric acid, may cause tertiary alcohols to dehydrate.