Grignard Reagnt

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Grignard reagent by Ajnish kumar Gupta & Bharti Gupta OrganicChemistry.co.in

Organometallic & Metalloorganic compounds: Those organic compounds in which carbon is directly attached to the metal are called as organometallic compounds while if the compounds are organic in nature but carbon is not directly attached to the metal then they are called as metalloorganic compounds. Examples of organometallic compounds are- Alkyl lithium (RLi), Grignard reagent (RMgX), Gilman reagent (R2CuLi), Dialkylzinc (R2Zn), Et4Pb, R2Cd, R2Hg, R3Al, R2Al-H, R4Sn, R3As, R3Bi etc. The nature of carbon-metal bond varies widely and ranges from essentially ionic to primarily covalent. Ionic character of carbon-metal bond mainly depends on the electropositive character of metal. More will be the electropositive character of the metal, higher will be the ionic character between carbon-metal bond. % ionic character of some carbon-metal bonds: Carbon-Metal bond % ionic character C-Na 65 C-Li 60 C-Mg 52 C-Al 40 C-Zn 38 C-Pb 36 C-Cd 32 C-Sn 28 C-Cu 28 C-Hg 24 C-Na & C-Li bonds are largely ionic in character while C-Zn, C-Pb, C-Cu, C-Hg are

essentially covalent in nature but C-Mg bond is polar covalent in nature and are represented as Cä�Mgä+

Organic part of organometallic compounds always behaves as a nucleophile as well as a base.

Reactivity of organometallic compounds as nucleophile and a base depends mainly on electropositive character of the metal. More will be the electropositive character of metal (i.e. more will be ionic character of C-M bond) more will be the reactivity of organometallic compounds.

Organosodium, Organolithium & Organomagnesium have greater ionic character so they behaves as strong nucleophile and base in the reaction but organozinc, organomercury etc have lesser ionic character so are weaker nucleophile in the reaction.

As these organometallic compounds especially organosodium, organolithium and organomagnesium are very strong base so they react with any acid stronger than alkane from which they are derived.

Ex of metalloorganic compounds are- Sodium OrganicChemistry.co.in alkoxide (RONa), Sodium acetate (CH3COONa), Lead acetate (CH3COO)2Pb etc.

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There are certain compounds that are not considered as an organometallic nor metalloorganic such as (CH3)4Si = Tetramethyl silane =TMS because here carbon is attached to the non metal silicon.

Capsules of Organometallic & metaloorganic compounds C-M bond Organometallic compounds C-N/O/S-M bond Metalloorganic compounds

Grignard reagent (GR) Organomagnesium halides (RMgX) were discovered by Victor Grignard in 1900 and these compounds are now called as Grignard reagent in his honour. This reagent has great use in organic chemistry since then so Grignard was awarded Noble prize for his discovery in 1912.

R Mg X

Ionic bond

Polar covalent bond ( 52% ionic & 48% covalent charecter in bond ) Here R may be saturated (single bonded), unsaturated (double or triple bonded), aliphatic, aromatic, bicyclic, spiro or carbon atom of heterocyclic compound without attachment of any functional group which have acidic H or reactive centre for basic or nucleophilic attack such as

-CH 3, -CH=CH 2, -C R, , , ,

N

Here X may be I, Br, Cl with reativity order RI > RBr > RCl

R Mg I

(More negative charge= good nu-) (less electronegative atom) F is generally not taken due to more electonegativity

R Mg F

(Less negative charge= poor nu-) (Most electronegative atom) Preparation of Grignard reagent: When alkyl or aryl halide is treated with magnesium in presence of ether solution then corresponding RMgX is formed.

R X + Mg etherR-Mg-X

Mechanism: The mechanism of this reaction is not completely understood but a possible way of writing the mechanism is shown below:

R X

Mg :

R MgX

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Here one thing is certain from experimental result that first interaction is between the metal and the halogen atom and the reaction takes place on the surface of the metal, and how easy it is to make a Grignard reagent can depends on the state of surface- how finally divided the metal is. Magnesium is usually covered by a thin coating of magnesium oxide so Grignard reagent formation generally requires �initiation� to allow the metal to come into contact with alkyl halide. This initiation can be accomplished by adding small amount of I2 or 1,2-Diiodoethane or by using ultra sound to dislodge the oxide layer. Since magnesium becomes bonded to the same carbon that was previously held by halogen, so alkyl group remains intact during the preparation of the reagent. Thus n-propyl chloride yield n-propylmagnesium chloride and isopropyl chloride yields isopropyl magnesium chloride.

CH3 Cl Mg/EtherCH3 MgCl

CH3CH3

Cl

Mg/EtherCH3CH3

MgCl

n-Propyl chloride

iso-Propyl chloride

n-Propylmagnesium chloride

iso-Propylmagnesium chloride Here ether plays an important role as a solvent and stabilizer which stabilizes RMgX so formed by donating its electron pairs to electron deficient Mg.

R Mg X

O R

R

O R

R

Complex between Lewis acidic metal atom and lone pair of ether Ether used may be acyclic, cyclic or polyether but can�t be cyclic ether with 3 or 4 member ring because of its high reactivity. Ex

CH3 O

CH3 ,

Et O

Et ,

Et O

Pr , , ,

O O O

O

H3CO

OCH3

Dimethylether Diethylether Dipropylether THF Dioxane DMEOxine The ether solvent is essential for Grignard reagent formation because ether unlike alcohol, water, Acetone, DMF, DMSO or Dichloromethane will not react with GR and more importantly only in ether Grignard reagent is soluble. Grignard reagent reacts violently with oxygen and vigorously with water so this reagent must be prepared under rigorously oxygen free and moisture free conditions. On standing in contact with air, most aliphatic ethers are converted slowly into unstable peroxides. Although present in only low concentrations, these peroxides are very denserous since they can cause violent explosions during the distillations that normally follow extractions with ether. The presence of peroxides is indicated by formation of red colour when the ether is shaken with an aqueous solution of ferrous ammonium sulphate & potassium thiocyanate.

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Peroxide can be removed from ether in a number of ways including washing with solutions of ferrous ion or distillation from concentrated H2SO4. For the preparation of Grignard reagent, the ether usually is diethyl ether or THF which must be free of traces of water and alcohol. This so-called absolute ether can be prepared by distillation of ordinary ether from concentrated H2SO4 (which removes not only water & alcohol but also peroxide), subsequent storing over metallic sodium. There is available today commercial anhydrous ether of such high quality that only the treatment with sodium is needed to make it ready for Grignard reaction.

Br

Br

Br

Mg/Ether

Mg/Et 2O

Mg/THF

MgBr

MgBr

BrMg

Br FMg/Ether

BrMg F

Cl

CH3

CH3

CH3Mg/Et2O

O

OCl Mg/THF

CH3

CH2 Cl

Mg/Et2O

MgCl

CH3

CH3

CH3

O

OMgCl

CH3

CH2 MgCl

When question is asked by giving molecular formula or by mass such as find the isomers of C5H11MgBr on reaction with water produce n-Pentane as a product, then use the concept of DU and first find if possible structure have acyclic saturation or cyclic or unsaturation then report your answer as

CH3

MgBrCH3

CH3

BrMg

CH3CH3

MgBr

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Reactions of Grignard reagent: Imagine breaking of carbon-metal bond of a Grignard reagent so that metal becomes positively charged and electron deficient as they have less electronegativity and the pair of electrons in the bond end up on carbon forming caranion as carbon have more electronegativity. Grignard reagent do not form true carbanion because they have polar covalent bonds but we can predict there reactivity by treating them conceptually as carbanion. As carbanions are powerful base as well as powerful nucleophile because negative charge is present over carbon which is very much unstable so they either attack over proton or partial positive centre other than proton such as carbon.

R MgX

Very good Base & Nucleophile

R- + +MgX

(Nucleophile/Base)

(Abstract H+ from substrate which have acidic hydrogen)

(Attack on positive or partial positive centre such as RX, -CO-) As acid-base reaction is generally fast as compare to organic reaction so if there is possibility of both then first acid-base reaction will take place. Grignard reagent is highly reactive reagent. It reacts with numerous inorganic compounds including water, carbondioxide and oxygen and with most kinds of organic compoundssuch as carbonyl compounds, alkyl halide etc. In many a cases this reaction provides the best way to make a particular class of organic compounds so it is very much important for the chemist. Types of reaction of GR � 1. Acid base reaction or reaction with acidic H � As we know that alkyl part of RMgX is a good base so on reaction with any compound which has acidic H, Grignard reagent produce R-H as a product. The compounds which have acidic H can generally identified by looking the attachment of H directly with the other atom such as Z. If Z is O, N, S, X then such compound is acidic in nature. Some exceptional cases of C-H acidity is also seen such as terminal alkyne & cyclopentadiene

RMgXH-Z

R-H + Z-Mg-X

Here H-Z may be H2O, C6H5OH, ROH, H2S, RSH, C6H5SH, RCOOH, RCONH2, NH3, RNH2, R2NH, HX, H2SO4, RSO3H, H3PO4, HCN, R-C≡CH, Cyclopentadiene etc Ex

MgBr

NH4Cl

MgBr

H3O+

H 3 O+

MgBr

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MgBr

OH

O

CH3

CH3 MgI

OH2CH4 + HO MgI

Methane gas is released on heating CH3MgI with a compound containing reactive H atom. This reaction is used for estimation of number of reactive H atom present in a molecule. This method is called as Zerewitinoff method of estimation of reactive H atom.

CH3 MgI6 mole of CH4 gas comes out

Unknown compound

with mol.formola C6H6O6

excess of

Unknown Compound with mol. formula C6H6O6have 6 acidic Hyrdogen

So this unknown compound may have any structure which has 6 acidic hydrogens such as OH

OH

OH

OH

OH

OH

We can�t prepare ordinary hydrocarbon by protonolysis when labeled hydrogen in the form of deuterium D, or tritium T, is present in the reaction container in the form of isotopically labeled water because D or T also behaves as H.

CH3 MgID2O

CH3 D + DO MgI

From the acid base reaction it is clear that Grignard reagent can also be consider as magnesium salt of extremely weak acid R-H as the reaction proceed as such

R MgI R H + OH MgI+ OH2

Stronger acid Weaker acid

Organic reactions: As we have discussed that R of RMgX is also a good nucleophile so it will attack over the centre which has partial positive charge such as carbonyl carbon. Organic reactions of Grignard reagents are generally performed in two steps. In first step substrate on which we want GR reaction is added to the ethereal solution of Grignard reagent at low temperature. In this reaction Grignard reagent attack over the electrophilic centre to give alkoxide which in second step reacts with water in another container to give alcohol as a product.

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Grignard reagent Water

Substrate on which we want GR reactionsuch as carbonyl compounds

Final product in another container

2. Reaction over carbonyl compounds

Carbonyl compounds are those compounds which have presence of C=O group. On the basis of chemical reaction they are divided into two types

a. Aldehydes and ketones b. Carboxylic acid and their derivatives Carbonyl carbon is attached to electronegative atom oxygen which withdraws electron density along sigma bonds and creates partial positive charge over the carbonyl carbon which is a good site for nucleophilic attack. As we know that R of RMgX is a good nucleophile so it will attack over it to give corresponding alcohol. Reaction of aldehyde, ketones are simply one time addition of Grignard reagent attack but reaction of acid halide, anhydride or ester are two time Grignard reagent attack.

RMgX

CH3 H/R

O

CH3 H/R

O-

R

H2O/H+

CH3 H/R

OH

R(Substrate) The class of alcohol that is obtained from a Grignard synthesis depends upon the type of carbonyl compounds used i.e. formaldehyde,HCHO, yield primary alcohol; other aldehyde whether aliphatic or aromatic yield secondary alcohol but ketone yield tertiary alcohol as a products.

RMgX

H H

O

H H

O-

R

H2O/H+

H H

OH

R(Formaldehyde)1* alcohol

RMgX

R1 H

O

R1 H

O-

R

H2O/H+

R1 H

OH

R(Any other aldehyde except formaldehyde) 2* alcohol

RMgX

R1 R2

O

R1 R2

O-

R

H2O/H+

R1 R2

OH

R(Ketone)3* alcohol

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In case of acid halide, anhydride and ester when Grignard reagent attacks it form alkoxide first in which same carbon have two electronegavive atoms, which is very much unstable so X/OCOR/OR which are also a good leaving groups, leaves from the alkoxide to first form aldehyde or ketone first. As we know that reactivity of aldehyde and ketone is more as compared to acid halide, anhydride or ester so next Grignard reagent attacks over this aldehyde or ketone to give a new alkoxide which have only one electronegative atom so it will be formed as a stable adduct at the last which later react with water to form alcohol as a product. So in case of acid halide, anhydride and ester, 2 GR will attack to form first substitution product followed by addition product.

R X/OCOR/OR

O R'MgBr

R R'

OR'MgBr

R R'

OMgBr

R'

H2O/H+

R R'

OH

R'

(Less reactive due to positive M of O/X)(More reactive as I-effect is less powerful)

Ist attack 2nd ttack

alcohol In case of acyclic ester two separate alcohols are obtained but in case of cyclic ester two alcohols are obtained in same compounds similarly in case of acyclic anhydride one alcohol and one carboxlic acid are obtained separately but in case of cyclic anhydride alcohol and caboxlic acids are obtained in same compounds. In the above type of reaction substrate may be aldehydes, ketones, acid halide, anhydride or ester etc but not be carboxylic acid or amide as they have acidic Hydrogen so acid base reaction will take place instead of Organic reaction.

CH3 O

O

CH3 CH3

OH

CH3CH3

O

CH3

O

EtMgBr

H2O/H+

EtMgBr

H2O/H+

+ CH3 OH

OH

CH3

OH

Et

Et

CH3 O

O O

CH3

O

CH3

O

O

EtMgBr

H2O/H+

EtMgBr

H2O/H+

CH3

OH

EtEt

O

CH3OH

+

CH3

OH

OH

O

Et

Et

Reactivity of Grignard Reagent with different compounds: As we know that general acid �base reaction are fast and organic reactions are slow so reactivity order of Grignard reagent for different compounds generally follow: Compounds with acidic H>Aldehyde>Ketone>Acid halide>Anhydride>Ester>Alkyl halide

BrO

O

CH3MeMgBr

H2O/H+

BrCH3

OHCH3

2 mole

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O

O

CH3OH

O

MeMgBr O

O

CH 3BrMgO

O

MeMgBr O

O

CH 3BrMgO

BrMgO

CH 3

CH 3

O

BrMgO

BrMgO

CH3

MeMgBr

CH3

OMgBr

BrMgO

BrMgO

CH3CH 3

MeMgBr

O

CH3 O

O

CH3CH 3MgBr( 1 eq)

H2O/H+

OH

CH3 O

O

CH3CH3 If there is possibility of both inter and intramolecular reaction then intramolecular reactions are generally faster as compared to intermolecular reaction.

F

I

O

C l

Mg/Ether F

IMg

O

C l

F

O

As carbonyl carbon is planner in shape so Grignard reagent can attack from both sides if steric hindrance is absent to give a pair of enentiomer i.e. racemic mixture will be formed. But if chiral centre is already present in the carbonyl compound then a pair of diastereomers will be obtained.

EtMgBrCH 3 O

H H 2 O/H+ +

CH 3 O H

HEt

CH 3 O H

HEt

EtMgBrO

H

HEt

H 2 O/H+

O H

H

HEt

Et

O H

H

HEt

Et+

Questions may be asked about the choice of selection of carbonyl compounds and Grignard reagent in a preparation of a particular alcohol. To solve this type of questions always the concept of backward reaction keeping steric hindrance over carbonyl carbon. Let us suppose we have to prepare 2-Methylhexan-2-ol. For this, As we know that it is tertiary alcohol so it must be prepared from the reaction of ketone with Grignard reagent. But the question is- which ketone, and by which Grignard reagent. So possible combination will be

C H 3

O HC H 3

CH 3

2 -Methylhexan- 2 -ol

C H 3

O HC H 3

CH 3

2 -Methylhexan- 2 -ol

CH 3

MgBr+ C H 3

O

CH 3n-Butylmagnesium bromide acetone

CH 3 MgBr + CH 3C H 3

O

Methylmagnesium bromide Hexan- 2 -one

1 st way

2 nd way

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Both combinations are correct but combination 1st will give better yield because of the reason that carbonyl compound have less steric hindrance.

O

C H 3

C H 3CH 3 MgBr

OH

C H 3

C H 3

CH 3

C H 3OC H 3

C H 3

BrMg

MgBr

O

C H 3

C H 3

C H 3

Route 1 st

Route 2 nd Route 3 rd

Nerolidol Out of these three, 2nd route will yield maximum product formation because of less steric hindrance over carbonyl carbon. 3. Reaction with RX: As we know that R of RMgX is a strong nucleophile so it will attack over carbon directly attach to the halogen in alkyl halide to give substitution product. As the nature of nucleophile is strong so it will show SN2 reaction to give product.

XMg R + R' XSN 2

R R'

If stereochemistry is present over the carbon directly attach to halogen then inversion in configuration will be observed.

H

D

Et Br

CH3MgBr1.

2. OH2

(S)

Et

D

CH3 H(R)

If stereochemistry is present in alkyl part of RMgX then no change of stereochemistry is observed i.e. retainsion in configuration is seen in alkyl part of RMgX because it is the attacking site and not the site over which attack occur.

MgBr

D

Et H

CH3BrCH3

D

Et H R or S nomenclature may be same or different in the reactant and product because it is based on high priority of atomic number. In case of substrate MgBr (1), Et (2), D (3) & H (4) but in case of product Et (1), CH3 (2), D (3) & H (4). So in solving such question be careful in deciding the product i.e. inversion in configuration of substrate occur but may or may not lead to change in R/S nomenclature.

Br

D

Et H

(R)

D

CH3 H H

D

Et

(R)

MgBr

D

Et H

(R)

+

(S)

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As the nature of reaction is SN2 , so steric hindrance in alkyl part of R-X is very much important in deciding the rate of formation of product. It is also important to note that steric hindrance of alkyl part of RMgX is not so important as compare to steric hindrance of alkyl part of R-X. When there is comparision of rate of reaction also, think for the steric hindrance of alkyl part of alkyl halide only

Br

CH3

CH3 Br

CH3 MgBr

MgBr

CH3

CH3

CH3

CH3

CH3

r1

r2

r2 > r 1

R

MgBr

R' CH 3 Br

CH 3 CH 2 Br

R

C H 3

R'

R R'

C H 3

r1

r2

r1 > r 2

(4) Reaction with epoxide � As we know that R of RMgX is a strong nucleophile so it will over the carbon directly attach to oxygen in three & four member cyclic ethers which bears partial positive charge. Reactivity of three & four member cyclic ether lies in the fact that they have angle strain. They react easily with any nucleophile to open the ring to be strain free molecule. When alkyl part of RMgX attack over the cabon directly attached to oxygen it first form alkoxide which may attack over proton of water to give final alcohol as a product or may attack over any other partial positive centre such as alkyl halide to give ether as a product.

RMgX + O

R'SN 2

R

O-Mg+X

R' H 2O/H+

R"-X

R

OH

R'

R

O-R"

R'

acid-base reaction

SN 2 reactionAlkoxideEpoxideGrignard reagent

Here again the rate of reaction is SN2, in which R of RMgX attack over the carbon of three or four member cyclic ether directly attach to oxygen which have less steric hindrance. Alkoxide so formed after the attack of alkyl part of RMgX is again a good base and good nucleophile that�s why it further attack over proton or attack over other alkyl part of another alkyl halide via SN2 mechanism to give alcohol or ether as a product.

RMgX +SN 2

O-Mg+

X

R 1R H 2O/H+

R"-X

OH

R 1R

O-R"

R 1R

acid-base reaction

SN 2 reactionAlkoxideGrignard reagent

O

R 1

Four member cyclic ether

It is interesting to note here that Grignard reagent on reaction with ethylene oxide (CH2)2O make primary alcohol containing two more carbons than the Grignard reagent.

RMgX + O

SN 2R

O-Mg+

X

H 2O/H+

R

OHacid-base reactionAlkoxideEpoxideGrignard reagent

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(5) Reaction with oxygen: Grignard reagent reacts with molecular oxygen to give either hydroperoxide or alcohol.

RMgX + O2 R-O-O-Mg-X H2O/H+

R-OH

RMgX

2 R O-MgXH2O/H

+

2 R-OH

Main product This reaction can be used to convert alkyl halides to alcohol without side reactions. It is observed that with aryl Grignard reagent yields are lower and only phenols are obtained with no hydroperoxides. The mechanism of this reaction is uncertain but some chemist proposed free radical mechanism on the basis of paramagnetic behavior of oxygen.

Br

Br

Mg/THF

Mg/THF

MgBr

MgBr

1. O2

1. O2

2. H2O/H+

2. H2O/H+

OH

OH

(6) Reaction with CO2

Grignard reagents adds to one C=O bonds of CO2 exactly as they do to an aldehyde or a ketone to form a salt of a carboxylic acid. This reaction is usually performed by adding the Grignard reagent to dry ice. This method is very much important as it increases the chain by one unit without affecting any other alkyl group. Since labeled CO2 is commercially available so this is a good method for preparation of carboxylic acid labeled in the carboxyl group. The formation of the salt of a carboxylic acid after the addition of CO2 to a reaction mixture is regarded as a positive test for the presence of a carbanion or of a reactive organometalic intermediate in that reaction mixture.

RMgX + CO2 R-C-O-Mg-X H2O/H+

R-C-OH

O O

Br

Mg/THF

MgBr

CO2

H2O/H+

COOH

Similar to the reaction of GR with CO2, CS2 can also react with GR to give dithiocarboxylic acid as a product.

RMgX + CS2 R-C-S-Mg-X H2O/H+

R-C-SH

S S

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(7) Reaction with nitriles, R-CN Grignard reagent reacts with alkyl or aryl nitrile to give ketone as a product. Many ketones have been made in this manner and yield can be further improved by the use of Cu(I) salt or by benzene containing one equivalent of ether as the solvent rather than ether alone.

RMgX + R'

N

H2O/H+

R'

N-Mg+X

R

R'

O

R

The ketimine salt does not generally react with Grignard reagent, hence tertiary alcohol or tertiary alkyl amines are not formed as a product. By careful hydrolysis of the salt it is also possible to isolate ketimine R-CRÐ=NH, especially when R & RÐ are aryl groups. It is also noted that the addition of Grignard reagent to C≡N group is normally slower than to the C=O group.

CH3

O

CH3

CH3MgBr

CH3 NCH3MgBr

CH3

OH

CH3

CH3

CH3

O

CH3

OH2

OH2

1.

2.

1.

2.

It is very much important to note that nitrile on reaction with GR give ketone as a product and not the alcohol. So only one equivalents of GR is needed for preparation of ketone from nitrile. (8) Reaction with terminal alkynes followed by organic reactions As we have discussed earlier that terminal alkyne have acidic hydrogen so GR reacts with terminal hydrogen by acid-base reaction, but the important part of this reaction is that a new GR with generally more number of carbon with unsaturation is formed which can easily react with any partial positive centre similar to any other Grignard reagent.

RMgX + R'

CH

R'-XR'

C-Mg+X

- R-H R'

R' It is mainly used to increase the number of carbon atom of alkynes by reaction with alkyl halide, but other reactions are also possible.

CH3

CH3 CH3

CH

CH3

CH3 CH3 MgBr CH3 CH3

CH3

OH

EtMgBr/Et2O

40*C

1. CH2O

2. H2O

Similar to Grignard reagent other Organometalic compounds also give similar reactions.

CH3

CH

Hex-1-yne

n-Bu LiCH3

Li + n-Bu HTHF/- 78* C

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CH3 CHEt MgBr

CH3 MgBr + Et HTHF/ 20* C

CH CH CH Na +THF/ 20* C

NaNH2NH3

CHCH3LiCH3THF

BuLi

O

CH3 CH3

OH2

OH

CH3 CH3

CH3

OCH3

OHOestrone

CH Li1.

2. H3O+

OHCH3

OH

CH

Ethyloestradiol (9) Reaction of C=S bond Grignard reagent can attack over partial positive carbon of C=S bond to give thioalcohol as a product similar to carbonyl compounds.

RMgX + R' R"

S

R' R"

S-

R

+MgX

H2O/H+

R' R"

SH

R (10) Reaction with R-N=O Grignard reagent can also attack over partial positive nitrogen of N=O bond to give alkyl substituted hydroxyl amine as a product similar to carbonyl compounds.

RMgX + NR'

O

H2O/H+

NR'

O-

R

+MgX

NR'

OH

R

(11) Reaction with R-S=O Grignard reagent can attack over partial positive sulpher of S=O bond to give corresponding product similar to carbonyl compounds.

RMgX + SR'

O

R'H2O/H

++MgX

SR'

O-

R'R

SR'

OH

R'R

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Capsule of Grignard reagent R MgX

Very good Base & Nucleophile

R- + +MgX

(Nucleophile/Base)

(Abstract H+ from substrate which have acidic hydrogen)

(Attack on positive or partial positive centre such as RX, -CO-) Preparation of diGR When monohaloalkane reacts with Mg in presence of dry ether corresponding Grignard reagent, RMgX is formed. So we can think for the preparation of diGrignard reagent by the help of dihaloalkane similar to monohaloalkane. But following experimental results are obtained in the preparation of diGR under similar condition of preparation of monoGR.

X X Mg/Ether No reaction

XX Mg/Ether

CH2 CH2

X X Mg/Ether

XX Mg/Ether

MgX MgX

diGR From above equations it is clear that atleast 4 atom distance must be present between the two halogens to form diGR. This diGR is very reactive and are formed under reaction condition to give intramolecular reaction to form cyclic product on reaction with acid halide, ester, anhydride etc.

Br BrMg/THF

BrMg MgBrMeO-C-OMe

O

O

+ 2 MeOH

Limitation of Preparation of Grignard reagent

1. As RMgX is a powerful base so substrate containing acidic H in R part of alkyl group can�t be used in preparation of RMgX. So R containing �OH,-NH2,-NHR,-COOH,-SO3H,-SH,-C≡C-H are not used.

2. As RMgX is a powerful nucleophile so substrate containing reactive centre for nucleophilic attack in R part of alkyl group can also not be used in preparation of RMgX. So R containing �CHO,-COR,-COOR,-CONR2,-NO2,-C≡N, epoxide,four membered cyclic ether are not used. Preparation or RMgX is limited to alkyl halide or analogous organic halides containing C=C, internal C≡C, ether linkage, -NR2 group.

3. If alkyl group of alkyl halide have presence of some functional group which have hydrogen such as alcohol then it must be protected first before the preparation of Grignard reagent. This protection of acidic Hydrogen can be done generally by help of bulky triphenylmethylchloride, Ph3Cl or more commonly trimethylsilyl chloride, Me3SiCl.

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Trimethylsilyl chloride on reaction with alcohol first form trimethylsilyl ether, Me3Si-OR. Now the alkyl part of Me3Si-OR do not have acidic hydrogen so we can make Grignard reagent from it and can performed whatever reaction of Grignard reagent we want and at the last we use acid hydrolysis, H2O/H+ for deprotection or removal of Me3Si group.

Br OHMg/THF

BrMg OH

Not the product

Br OH Br OSiMe3

Me3SiCl Mg/THF

BrMg OSiMe3

CH3 Br

CH3 OSiMe3

H2O/H+

CH3 OH

CH3

O

CH3

1.

2. H2O/H+

O1.

2. H2O/H+

1. CO2

2. H2O/H+

OH

OHOH

CH3

OH

CH3

HOOC OH

4. If alkyl group of alkyl halide have presence of some functional group which have partial

positive charge as that of aldehyde or ketone then it must be protected first before the preparation of Grignard reagent. This protection of aldehyde or ketone can be done generally by help of reaction with alcohols or thioethers. Alcohols on reaction with aldehyde or ketone first form acetal. Now the alkyl part of acetal can be used to make Grignard reagent. This acetal containing Grignard reagent reacts similar to that one which do not have acetal linkage, so it will give many reaction and at the last we use acid hydrolysis, H2O/H+ for deprotection or removal of acetal group.

Br CH3OMg/THF

BrMg CH3O

Not the product

Br CH3O Br CH3H3CO

H3CO

CH3OH Mg/THF

BrMg CH3H3COH3CO

CH3 Br

CH3 CH3H3CO

OCH3

H2O/H+

CH3 CH3O

CH3

O

CH3

1.

2. H2O/H+

O1.

2. H2O/H+

1. CO2

2. H2O/H+

CH3

OH

O

CH3

CH3

OH

CH3

O

HOOC CH3O

Page 17


General inorganic & organic reactions of GR

CH 3 MgBr

HCHO

RCHO

RCOR

RCOCl

RCOOR

RCOOCOR

CO 2

CS 2

SO 2

(CH 2 )2O

R-CN

R-X

O 2

C HRPh-CH 2X

RSOR

OH 2

ROH

NH 3

RNH 2

R 2NH

PhNH 2

NH 4+

Cl

RCOOH

HX

H 3PO 4

SH 2

RSH

OH

RCONH 2

RCONHR

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

C H 4

CH 3CH 2OH

C H 3

OH

RR

OH

R C H 3

C H 3

OH

R C H 3C H 3

OH

R C H 3

C H 3

OH

R C H 3

RCOOH

CH 3

S H

S

CH 3 S

O H

O

CH 3CH 2CH 2OH

CH 3COR

CH 3R

CH 3OH

S R

OH

R C H 3

CH 3CH 2Ph

* Second step is assumed to be protonation

Acid-base reaction Organic reactions

Page 18


Last but not the least once again I m telling you to focus on this very important topic of Organic Chemistry i.e. �Grignard Reagent�. It is the one which is very much important to prepare nearly all types of organic compounds by suitable reaction condition. My best wishes are always with you,

Always yours

Ajnish Kumar Gupta (AKG)

M.Sc. CSIR-NET-2006 Lecturer of Organic chemistry

Resonance Eduventures Pvt. Ltd.

Bharti Gupta (BRG)

M.Sc. UGC-JRF-2010 Lecturer of Organic chemistry

Resonance Eduventures Pvt. Ltd. For more information about notes, solutions of various competitive exam, videos related to

organic reactions log on to my website-

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