Important reactions in organic chemistry for JEE Mains

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CLEMMENSEN REDUCTION

About Clemmensen Reduction

The reduction of carbonyl groups of aldehydes and ketones to methylene groups with amalgamated zinc and concentrated hydrochloric acid is known as [Clemmensen reduction]

The reduction of carbonyl groups of aldehydes and ketones to methylene groups with amalgamated zinc and concentrated hydrochloric acid is known as Clemmensen reduction.

1. The reduction consists in refluxing the carbonyl compounds with amalgamated zinc and excess of concentrated hydrochloric acid.
2. The reduction is useful especially for ketones containing phenolic or carboxylic groups which remain unaffected. Ketones are reducing more often than aldehydes.
3. This reduction is also observed in Wolff-Kishner reduction but Clemmensen reduction is easier to perform.
4. The reduction, however, fails with acid-sensitive and high molecular weight substrates. The α, β-unsaturated ketones undergo reduction of both the olefinic and carbonyl groups.

Reaction Mechanism of Clemmensen Reduction

Exceptional behaviour of clemmensen reductions

Certain cyclic 1,3-diketones give under Clemmensen reduction a fully reduced product along with a monoketone with ring contraction.

The latter probably is formed through a diradical with subsequent intramolecular C – C bond formation and pinacol type rearrangement.

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ALDOL CONDENSATION

About Aldol condensation

Two molecules of an aldehyde or a ketone undergo condensation in the presence of a base to yield a β-hydroxyaldehyde or a β-hydroxyketone. This reaction is called the aldol condensation which may be exemplified by the reaction of acetaldehyde to give acetaldol (3-hydroxybutanal).

The mechanism of this reaction illustrates important characteristics of carbonyl compounds, i.e. the acidity of their α hydrogens and the tendency of their carbonyl groups to undergo nucleophilic addition.Befor moving to mechanism of aldol read the basics of organic chemistry .
Let us see the mechanism now:

Reaction Mechanism of Aldol condensation

Step 1.

Base abstracts a proton from the α carbon of aldehyde to give resonance stabilized enolate ion.

Step 2.

The enolate ion then acts as nucleophile and attacks the carbonyl carbon of a second molecule of aldehyde, producing alkoxide ion.

Step 3.

In step 1, OH– is acting as a base and not as a nucleophile. OH– will act as a nucleophile and attack to the carbonyl group only when there is no acidic hydrogen, i.e. its (OH–) first preference is to act as a base and then as a nucleophile.
This reaction can also be catalysed by acid. Let us see this mechanism and the product formed.

Crossed Aldol Condensation

An aldol condensation between two different carbonyl compounds so called crossed aldol condensation is not always useful as a mixture of four different possible products may be obtained. under certain conditions, a good yield of a single product can be obtained from a crossed aldol condensation.
One reactant contains no α-hydrogens and therefore is incapable of condensing with itself (e.g. aromatic aldehydes or formaldehyde).

Intramolecular Aldol Condensation

When a compound has two carbonyl groups, it can undergo intramolecular aldol condensation in the presence of dilute base (if a-H atoms are present in the compound).
An intramolecular reaction is readily favoured if the reaction leads to the formation of a 5 or 6-membered ring. When one of carbonyl group is an aldehyde and other is a ketone, it’s the ketone, which forms carbanion and this carbanion attack the carbonyl group of an aldehyde in such a manner that 5 or 6-membered ring is formed. For example, 2, 5-hexanedione in presence of dilute OH- undergoes intramolecular aldol condensation to give 2 set of products as there are 2 different types of a-hydrogens. One of the product has a 5-membered ring and the other has a 3-membered ring. The major product of the reaction is a 5-membered ring compound as 5-membered ring has greater stability than 3-membered ring.

Mechanism of Intramolecular Aldol condensation

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ARNDT−ESTER SYNTHESIS

Arndt-Ester synthesis

This method is used to convert lower carboxylic acid into higher carboxylic acid.

RCO2H → RCOCl RCONH2 RCH2CO2H

Arndt-Ester synthesis Mechanism

Nucleophilic attack of diazomethane on the carbonyl carbon of the acid chloride gives an intermediate (i) which eliminates a molecule of HCl to give diazoketone (ii) Diazoketone then splits off a molecule of nitrogen to form a carbene (iii) which rearranges to ketene. The highly reative ketene readily reacts with the nuclephile present (H2O) to form the next higher acid.

Examples of Arndt−Ester synthesis

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BAEYER−VILLIGER OXIDATION

Detail Reaction of Baeyer-Villiger Oxidation

Baeyer-Villiger Oxidation involves the oxidation of ketones to esters by the treatment with peroxyacids.

Cyclic ketones are converted to lactones with ring expansion.

The overall reaction is an insertion of oxygen atom between the carbonyl group and the adjacent carbon atom in ketone. It involves the migration of a group from carbon to the electron−deficient oxygen. Organic solvents (inert) are used such as glacial acetic acid or chloroform, which can dissolve the reactant.

Baeyer-Villiger Oxidation Mechanism

First of all the peroxyacid protonates the ketone and then peroxyacids undergoes nucleophilic attack on this protonated ketone to form an peroxide intermediate (A). This intermediate then undergoes loss of carboxylate anion and migration of a group from carbon to electron deficient oxygen to yield the protonated ester (B). This finally losses a proton to give an ester.

Application of group in Baeyer-Villiger Oxidation

The presence of electron releasing groups in the ketone and electron withdrawing groups in the peroxyacids increases the rate of reaction. In unsymmetrical ketones that group migrates which is more electron releasing, thus the migratory aptitude of alkyl groups is in the order 3° > 2° > 1° > CH3.

Electron releasing substituents in the aryl group facilitate migration. The migratory order of aryl groups is p−anisyl > p−tolyl > phenyl > p−chlorophenyl > p−nitrophenol.

In case of alkyl aryl ketones, it is the aryl group which migrates (except in case of tert butyl groups).

Example of Baeyer−Villiger Oxidation

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BENZOIN CONDENSATION

Reaction Mechanism of Benzoin Condensation

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack is by an anion (-CN) on the carbonyl carbon atom of one molecule, but instead of hydride transfer it is now converted to carbanion which undergoes addition to the carbonyl carbon atom of the second molecule of ArCHO. The rate law commonly observed is

Rate = k [ArCHO]2 [-CN]

and the Benzoin Condensation is believed to follow the general pathway as

Mechanism of Benzoin Condensation

When aromatic aldehyde is treated with alcoholic KCN, the product is not a cyanohydrin but hydroxy aromatic ketone called benzoin. The product of aromatic aldehydes with KCN is different than aliphatic aldehydes because after the attack of CN-, the intermediate (I) in aromatic aldehyde has sufficient acidity (due to -I effect of Ph) so that intramolecular proton exchange takes place to form a carbanion, which is resonance stabilized. This carbanion then attacks another molecule of aromatic aldehyde, which undergoes intramolecular proton exchange and then ejection of CN- to give final product i.e. benzoin. The rate limiting step of the reaction is attack of carbanion on second molecule of aromatic aldehyde.

Example of Benzoin Condensation

In which of the following substrate, rate of Benzoin condensation will be maximum?

Benzoin condensation is due to stability of intermediate (III) when negative charge on C is extensively delocalised in benzene ring, Nitro and CN group. In all other cases, such dispersal is not extensively possible. On the other hand, NO2- is also creating positive charge centre on carbonyl carbon, making it more susceptible to nucleophilic attack of CN-.

Therefor correct answer is (A)

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##VERY VERY IMPORTANT REACTION##

BECKMANN REARRANGEMENT

About Beckmann Rearrangement

The acid-catalyzed conversion of ketoximes to N-substittued amides is known as Beckmann rearrangement. The reaction is catalyzed by acidic reagents like H2SO4, SOCl2, SO3, PCl5, P2O5, C6H5SO2Cl etc. The reaction involves the migration of a group from carbon to the electron deficient nitrogen.The migration of the groups does not depend on the migratory aptitude but upon the orientation of the group is relation to the -OH group. It is found that the migrating group is always anti (trans) to the hydroxyl group. Thus the reaction is stereospecific.

Reaction Mechanism of Beckmann Rearrangement

The mechanism of the above reaction has been outlined as

In strong acids, the reaction proceeds with the protonation of the OH group of the oxime with subsequent loss of water to yield(A) with electron deficient nitrogen. The migration of alkyl group then gives a carbocation, which is attacked by water molecule followed by the loss of proton gives the amide.
The migrating group retains its configuration and hence the migrating group does not become completely free during the migration, otherwise the reaction cannot be stereospecific. Thus the migration and breaking of N-O bond may be concerted (taking place in one step).For example,

Solved Example of Beckmann Rearrangement

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CANNIZZARO REACTION

About Cannizzaro Reaction

Those aldehydes (aliphatic or aromatic), which do not have a-hydrogen atom on treatment with strong base undergoes a reaction involving its 2 moles, one getting oxidised to yield acid salt and the other getting reduced to primary alcohol. The important condition is that there should not be a good leaving group attached to the carbonyl group.

Reaction Mechanism of Cannizzaro Reaction

This involves hydride transfer from an aldehyde molecule lacking an α-H atom e.g., HCHO, R3CCHO, ArCHO, to a second molecule of either the same aldehyde (disproportionation) or sometimes to a molecule of different aldehyde (crossed Cannizzaro). The reaction requires the presence of strong bases.

The step by step mechanism of Cannizzaro Reaction are

Mechanism of Cannizzaro Reaction at High concentrantion of NaOH

Rapid and reversible addition of -OH to PhCHO yields the hydride donor species, this is followed by slow, rate limiting hydride transfer to the carbonyl carbon atom of a second molecule of PhCHO, and the reaction is completed by rapid proton exchange to yield the more stable pair of carboxylate and alcohol. Mutual oxidation/reduction of two molecules of aldehyde has thus taken place to yield one molecule each of the corresponding carboxylate anion and of the primary alcohol.

Example of Cannizzaro Reaction

Crossed Cannizzaro reaction

The Cannizzaro reaction between two dissimilar aldehyde moelcuels (crossed Cannizzaro reaction) may yield all possible products. However, when one of the aldehydes is formaldehyde the formate ion and the alcohol corresponding to the other aldehyde are formed exclusively. The exclusive formation of the formate ion is due to the high reactivity of formaldehyde which preferentially adds a hydroxide ion before losing one of its two hydrogens as hydride ion to the less reactive aldehyde.

Intramolecular Cannizzaro

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CLAISEN CONDENSATION

Reaction Mechanism of Claisen condensation

Esters with α-hydrogen atom on treatment with a strong base, e.g. C2H5ONa, undergo self condensation to produce β-keto esters.

CH3COCH2COOC2H5

An α-hydrogen in an ester is weakly acidic than the α-hydrogen of aldehydes or ketones, because the carbonyl group helps accommodate the negative charge of the carbanion to a lesser extent.

When ethyl acetate is treated with sodium ethoxide, and the resulting mixture is acidified, ethyl 3-oxobutanoate, generally known as ethyl acetoacetate or acetoacetic ester is obtained.

Mixed Claisen Condensation

A reaction similar to a mixed Claisen condensation is the condensation of the ketone and an ester. Because the α-hydrogens of a ketone are more acidic than those of an ester, primarily one product is formed if the ketone is added slowly to a mixture of the base and excess ester. The product is a β-diketone.

A β-keto aldehyde is formed when a ketone condenses with formate esters.

A β-keto ester is formed when a ketone condenses with diethyl carbonate.

Intramolecular Claisen Condensation

Dieckmann Condensation: The addition of base to a 1,6-diester causes the diester to undergo intramolecular Claisen Condensation, thereby forming a five membered ring β-keto ester. An intramoelcular Claisen Condensation is called a Dieckmann Condensation.

Example of Claisen condensation

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ETARD’S REACTION

About Etard’s Reaction

The reaction involves the oxidation of toluene with chromyl chloride (CrO2Cl2) in CCl4.

In the case of side chains bigger than CH3 group the end carbon atom of the chain is oxidized by CrO2Cl2 to –CHO group.

Reaction Mechanism of Etard’s Reaction

The reaction involves the oxidation of toluene with chromyl chloride (CrO2Cl2) in CCl4.

Examples of Etard’s Reaction

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FRIEDEL-CRAFTS ALKYLATION

About Friedel-Crafts alkylation

French chemist, Charles Friedel, and his American collaborator James M. Crafts, discovered new methods for the preparation of alkylbenzenes (ArR) and acylbenzenes (ArCOR). These reactions are now called the Friedel - Crafts alkylation and acylation reactions.
A general equation for a Friedel–Crafts alkylation reaction is the following:

The mechanism for the reaction (shown in following steps with isopropyl chloride as R–X) starts with the formation of a carbocation (step 1).

The carbocation then acts as an electrophile (step 2) and attacks the benzene ring to form an arenium ion. The arenium ion (step 3) then loses a proton to generate isopropyl benzene.

Reaction Mechanism of Friedel Crafts alkylation

Reaction Mechanism of Friedel-Crafts alkylation involve formation of carbocation by the help of lewis acid. The following reaction mechanims of Friedel-Crafts alkylation explain for isopropyl chloride.

When R–X is a primary halide, a simple carbocation probably does not form. Rather, the aluminum chloride forms a complex with the alkyl halide and this complex acts as the electrophile. The complex is one in which the carbon-halogen bond in nearly broken–and one in which the carbon atom has a considerable positive charge.

δ+ δ–
RCH2 ---- Cl : AlCl3

Even though this complex is not a simple carbocation, it acts as an electrophilic it transfers a positive alkyl groups to the aromatic ring. These complexes are so carbocation like that they also undergo typical carbocation rearrangements.

Order of reactivity of Friedel-Crafts alkylation

The order of reactivity of some catalysts is AlBr3 > AlCl3 > FeCl3 > SbCl5 > SnCl4 > BCl3 > BF3 etc. The alkylating agents may be alkyl halides, alcohols or alkenes. For more reactive halides, a less active catalyst (e.g. ZnCl2) and for less reactive halides, a highly active catalyst (e.g. AlCl3) is used. Commonly used solvents are nitrobenzene, ether, carbon disulphide etc.

Limitation of Friedel Crafts alkylation

(i)Polyalkylation: As we know alkyl group activates the ring towards electrophilic substitution, it is clear that product of Friedel-Crafts alkyation will be more reactive and can undergo further alkylation. So, we get monoalkylated as well as polyalkylated products. However, polyalkylation may be minimized by taking aromatic compound in large excess.

(ii)Rearrangement: As we know, carbocations can undergo rearrangements easily to more stable carbocations, sometime the carbocation produced during Friedel-Crafts alkylation undergo rearrangement before attack on aromatic ring. This leads to the formation of product, substituted by rearranged carbocation.

(iii)Effect of already present substituent on Aromatic Rings: Electron-withdrawing substituents inhibit the reaction while highly activating groups (like - OH, -NH2, -NHR) reacts with the catalyst to retard the reaction. Hence aromatic compounds having strong activating and strong deactivating groups give poor yield. Naphthalene and heterocylic compounds are also very reactive and react with the catalyst, thereby giving very poor yield of substituted product.

(iv)Isomerisation and Disproportionation: In presence of excess catalyst and at high temperature, isomerisation and disproportionation can also take place.

(v) Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily.

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FRIEDEL CRAFTS ACYLATION

About Friedel-Crafts Acylation

Substitution of hydrogen by acyl group in aromatic compound is known as Friedel-Crafts Acylation. The most commonly used catalyst is anhydrous AlCl3, although other Lewis acids can also be used. The acylating reagents are either acid halides or acid anhydrides.The Mechanism of Friedel-Crafts acylation involves following steps.The generation of attacking species may follow two different mechanisms.

Reaction Mechanism of Friedel-Crafts Acylation

The attacking species may also be 1 : 1 complex of AlCl3 with the acid halide. With acid anhydrides, free acyl cation is the attacking reagent generated by the attack of AlCl3.The substitution mechanism may be written as In either case the catalyst is required in considerable extent as the catalyst also forms complex with the ketone produced as a result of Lewis acid-base reaction.

The product ketone is then extracted with ice-cold dilute acidic solution.In presence of activating groups, the reaction takes place easily with good yield, whereas, deactivating groups inhibit the reaction. Hence, nitrobenzene is the commonly used solvent.

Reduction of Acyl to Alkene

When cyclic anhydrides are used as one of the component, Friedel-Crafts acylation provides a means of adding a new ring to an aromatic compound.

Factors Determining mechanism of alkylation :

(i) Nature of alkyl groups

If the alkyl group is simple CH3- or CH3CH2-, then a complex between alkyl halide and Lewis acid is the electrophile as shown in second mechanism. But because of the relative stability of s-and t- carbonium ions, the adducts with s- and t- alkyl halides ionise and it is now the s- and t- carbonium ion that is predominantly the active species. e.g.

Me3C-Cl + AlCl3 —> . Me3C+ + . AlCl4

(ii) Nature of Lewis acid as catalyst

The order of effectiveness of Lewis acid catalysts has been shown to be

AlCl3 > FeCl3 > BF3 > TiCl3 > ZnCl2 > SnCl4

The action of Me3CCH2Cl/AlCl3 on benzene is found to yield almost completely the rearranged product, PhCMe2CH2Me, which can be explained on the basis of the initial electrophilic complex being polarized enough to allow the rearrangement of [Me3CCH2]d±----Cl----AlCl3d- to the more stable [Me2CCH2Me]d+ -----Cl-----AlCl3d-. By contrast Me3CCH2Cl/FeCl3 on benzene is found to yield almost completely the unrearranged product, Me3CCH2Ph. This is due to the fact that the complex with the weaker Lewis acid, FeCl3, is not polarized enough to allow the rearrangement.

(iii) Temperature

Not only nature of the alkyl group, but also temperature determines the nature of electrophile. e.g. n-alkyl group can be introduced to a fair extent without rearrangement at low temperatures, because ionisation of the adduct is retarded. But at higher temperatures, carbonium ion is formed which rearranges and the product is rearranged alkyl benzene. Thus n-propylchloride gives isopropyl benzene.

Limitations of Friedel−Crafts Acylation

(i)Acylation requires more catalyst as the product ketone forms complex with the catalyst.
(ii)Acylation in presence of strong deactivating groups (like -NO2, -COCl, -SO3H, -CCl3 etc.) is not recommended as it gives very poor yield.
(iii)Acylation is not recommended in presence of -OH, -NH2, -NHR and -NR2 groups as they give O-acylated and N-acylated products.

The Friedel - Crafts acylation reaction is an effective means of introducing an acyl group into an aromatic ring. The reaction is often carried out by treating the aromatic compound with an acyl halide. Unless the aromatic compound is one that is highly reactive, the reaction requires the addition of at least one equivalent of a Lewis acid (such as AlCl3) as well. The product of the reaction is an aryl ketone. Moreover these groups also forms complexes with the catalyst thereby inhibiting the reaction.

Questions based on Friedel−Crafts Acylation

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FRIES REARRANGEMENT

About Fries Rearrangement

Phenylacetate undergoes the Fries rearrangement with AlCl3 to form ortho and para hydroxy acetophenone. The ortho isomer is separated from the mixture by its volatility with steam.The phenyl ester formed from the reaction of phenol and acid anhydride undergoes rearrangement when treated with anhydrous AlCl3 to yield ortho and para-hydroxyketones. The o-isomer is separated from the mixture by steam-distillation.Generally low temperature (60°C or less) favours the formation of the p-isomer whereas high temperature (above 160°C) favours the o-isomer.

The ortho isomer has higher vapour pressure because of chelation, O–H—O = C and is steam volatile. In the para isomer, there is intermolecular H-bonding with H2O. The para isomer (rate-controlled product) is the exclusive product at 25°C because it has a lower ΔH and is formed more rapidly. Its formation is reversible, unlike that of the ortho isomer which is stabilized by chelation. Although it has a higher ΔH, the ortho isomer (equilibrium-controlled product) is the chief product at 165°C because it is more stable

Reaction Mechanism of Fries Rearrangement

Examples of Fries Rearrangement

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GATTERMANN-KOCH REACTION

About Gattermann-Koch Reaction

Benzaldehyde and many aromatic aldehydes are conveniently synthesized by treating benzene (or other aromatic compounds) with a mixture of carbon monoxide and hydrogen chloride (compounds of formyl chloride) in the presence of an equimolecular quantity of Lewis acid and a trace of copper (I) chloride. The initially formed cation (C+HO) adds to the benzene nucleus to give the σ complex which yields the aldehyde.

Reaction Mechanism of Gattermann Reaction

@akashmg @Dr.NishantJangra @MentorGeetanjali @Mayank1 @Omprakash @Rajpoot

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GRIGNARD REAGENT

Reaction Mechanism of Grignard Reagent

The Grignard reagent, we recall, has the formula RMgX, When a solution of an alkyl halide in dry ethyl ether, (C2H5)2O, is allowed to stand over turnings of metallic magnesium, a vigorous reaction takes place. The solution turns cloudy, begins to boil and the magnesium metal gradually disappears. The resulting solution is known as a Grignard reagent. It is one of the most useful and versatile reagents known to the organic chemists… This halide can be alkyl (1o, 2o, 3o), allylic, aryl alkyl (e.g. benzyl), aryl (phenyl) or substituted phenyl. The halogen may be –Cl, –Br or –I, (Arylmagnesium chlorides must be made in the cyclic ether tetrahydrofuran instead of ethyl ether.)
Aldehydes and ketones resemble each other closely in most of their reactions. Like the carbon-carbon double bond, the carbonyl group is unsaturated, and like the carbon-carbon bond, it undergoes addition. One of its typical reactions is addition of the Grignard reagent.
The carbon-magnesium bond of the Grignard reagent is a highly polar bond, carbon being negative relative to electropositive magnesium. It is not surprising, then, that in the addition to carbonyl compounds, and the organic group becomes attached to carbon and magnesium to oxygen. The product is the magnesium salt of the weakly acidic alcohol and is easily converted into the alcohol itself by the addition of the stronger acid, water. Since the Mg(OH)X thus formed is a gelatinous material difficult to handle, dilute mineral acid (HCl, H2SO4) is commonly used instead of water, so that water-soluble magnesium salts are formed.

The action of Grignard’s reagent on aldehydes, ketones and esters

Grignard Reagent use

The Grignard reagent is the best-known member of a broad class of substances called organometallic compounds, in which carbon is bonded to a metal like lithium, potassium, sodium, zinc, mercury, lead, thallium or to almost any metal known. Each kind of organometallic compound has, of course, its own set of properties and its particular uses depend on these. But whatever the metal, it is less elctronegative than carbon, and the carbon-metal bond-like one in the Grignard reagent - is highly polar. Although the organic group is not a full-fledged carbanion–an anion in which carbon carries negative charge, nevertheless has considerable carbanionic character. As we shall see, organometallic compounds owe their enormous usefulness chiefly to one common quality, they can serve as a source from which carbon is readily transferred with its electrons.

The Grignard reagent, we recall, has the formula RMgX, and is prepared by the reaction of metallic magnesium with the appropriate organic halide. This halide can be alkyl (1°, 2°, 3°), allylic, aryl alkyl (e.g. benzyl), or aryl (phenyl) or substituted phenyl. The halogen may be –Cl, –Br or –I, (Arylmagnesium chlorides must be made in the cyclic ether tetrahydrofuran instead of ethyl ether).
Aldehydes and ketones resemble each other closely in most of their reactions. Like the carbon-carbon double bond, the carbonyl group is unsaturated and like the carbon-carbon bond, it undergoes addition. One of its typical reactions is addition of the Grignard reagent.
Since the electrons of the carbonyl double bond hold together atoms of quite different electronegativity, we would not expect the electrons to be equally shared, in particular, the mobile π cloud should be pulled strongly towards the more electronegative atom, oxygen. Whatever the mechanism involved, addition of an unsymmetrical reagent is oriented so that the nucleophilic (basic) portion attaches itself to carbon and the electrophilic (acidic) portion attaches itself to oxygen.
The carbon-magnesium bond of the Grignard reagent is a highly polar bond, carbon being negative relative to electropositive magnesium. It is not surprising, that in the addition to carbonyl compounds, the organic group attached to carbon and magnesium to oxygen.

The product is the magnesium salt of the weakly acidic alcohol and is easily converted into the alcohol itself by the addition of the stronger acid, water. Since the Mg(OH)X thus formed is a gelatinous material difficult to handle, dilute mineral acid (HCl, H2SO4) is commonly used instead of water, so that water-soluble magnesium salts are formed. Exceptional behavior of Grignard Reagent In certain cases, a Grignard reagent does not react with compounds containing functional group normally capable of reaction. Generally the branching of the carbon chain near the functional group prevents the reaction, the cause is probably the steric effect. For example, methyl magnesium bromide or iodide does not react with hexamethyl acetone (CH3)3CCOC(CH3)3. It has also been found that if Grignard reagent contains large alkyl groups, reaction may be prevented. For example, isopropyl methyl acetone reacts with methyl magnesium iodide but not with t-butyl magnesium chloride. In other cases, abnormal reaction may take place. For example, when isopropyl magnesium bromide is added to diisopropyl ketone, the expected tertiary alcohol is not formed, instead the secondary alcohol, di-isopropylcarbinol is obtained resulting from the reduction of the ketone.

(CH3)2CHCOCH(CH3)2 (CH3)2CHCH(OH)CH(CH3)2 + CH3CH = CH2
α, β unsaturated carbonyl compounds react with Grignard reagent in the 1,2-or 1,4-positions.

1,2 addition In Grignard Reagent

1,4 addition:

The extent of 1,4 addition can be made greater by the use of Cu2Cl2 or (CH3COO)2Cu. In this case, reaction is initiated by the free radical mechanism.The reaction of dihalides of the type Br(CH2)nBr with magnesium depends on the value of n. For n = 1-3, no Grignard reagent is formed. For example,

When n ≥ 4, the Grignard reagent can be possibly made with dibromo compound viz, Br(CH2)nBr.

Products of the Grignard Synthesis

The class of alcohol that is obtained from a Grignard synthesis depends upon the type of carbonyl compound used. Formaldehyde (HCHO) yields primary alcohols, other aldehydes (RCHO) yield secondary alcohols and ketones (R2CO) yield tertiary alcohols.This relationship arises directly from our definitions of aldehydes and ketones and our definitions of primary, secondary and tertiary alcohols. The number of hydrogens attached to the carbonyl carbon defines the carbonyl compound as formaldehyde, higher aldehyde or ketone. The carbonyl carbon is the one that finally bears the –OH group in the product and the number of hydrogen defines the alcohol as primary, secondary, or tertiary.

For example,

Planning a Grignard Synthesis

How do we decide which Grignard reagent and which carbonyl compound to use in preparing a particular alcohol ? We have only to look at the structure of the alcohol we want. Of the groups attached to the carbon bearing the –OH group, one must come from the Grignard reagent, the other two (including any hydrogens) must come from the carbonyl compound.
Most alcohols can be obtained from more than one combination of reagents. We usually choose the combination that is most readily available. For example, consider the synthesis of
2-phenyl-2-hexanol.

As shown, we could make this either from the four-carbon Grignard reagent and the aromatic ketone, or from the phenyl Grignard reagent and the six-carbon aliphatic ketone. As we know, the first route uses the more readily available carbonyl compound and is the one actually used to make this alcohol.
Grignard reagent from a compound (e.g., HOCH2CH2Br) that contains, in addition to halogen, some group (e.g.,–OH) that will react with a Grignard reagent. If the preparation of Grignard from this were tried, as fast as a molecule of Grignard reagent formed, it would react with the active group (–OH) in another molecule to yield an undesired product (HOCH2CH3).
We must be particularly watchful in the preparation of an arylmagnesium halide, in view of the wide variety of substituents that might be present on the benzene ring. Carboxyl (-COOH), hydroxyl (-;OH), amino (-NH2) and -SO3H all contain hydrogen atom attached to oxygen or nitrogen and therefore are so acidic that they will decompose a Grignard reagent.
The nitro (-NO2) group oxidizes a Grignard reagent. It turns out that only a comparatively few groups may be present in the halide molecule from which we prepare a Grignard reagent, among these are -R, -Ar, -OR and -Cl (of an aryl chloride).The aldehyde (or other compound) with which a Grignard reagent is to react may not contain other groups that are reactive towards a Grignard reagent. For example, a Grignard reagent would be decomposed before it could add to the carbonyl group of following compounds

A related synthesis utilizes ethylene oxide to make primary alcohols containing two more carbons than the Grignard reagent.

Here, too, the organic group attaches to carbon and magnesium to oxygen. In this reaction breaking of carbon-oxygen σ bond takes place in the highly strained three-membered ring. For example,’

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HELL-VOLHARD-ZELINSKY REACTION

About Hell-Volhard-Zelinsky Reaction

In the presence of phosphorus, aliphatic carboxylic acids react smoothly with chlorine or bromine to yield a compound in which α-hydrogen has been replaced by halogen such reaction is know as Hell-Volhard-Zelinsky Reaction

The function of the phosphorus is ultimately to convert a little of the acid into acid halide so it is the acid halide, not the acid itself, that undergoes this reaction.

• P + X2 ⎯→ PX3
• R – CH2 – COOH + PX3 ⎯→ RCH2 – COX

Reaction Mechanism of Hell-Volhard-Zelinsky Reaction

Application of Hell-Volhard-Zelinsky Reaction

The halogen of these halogenated acids undergoes nucleophilic displacement and elimination much as it does in the simple alkyl halides. Halogenation is therefore the first step in the conversion of a carboxylic acid into many important substituted carboxylic acid.

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HUNSDIEKER REACTION

Reaction-Hunsdieker reaction

silver salts of carboxylic Acid react with halogen to give RX .

• RCOOAg + X2 RX + AgX + CO2
• (X2 = Cl2 or Br2)

Reaction Mechanism of Hunsdieker reaction

The mechanism is uncertain but probably in the first step acyl hypohalite is formed which then decomposes into free radicals.
RCOOAg + X2 RCOOX + AgX
RCOOX RCOO∙ + X∙
RCOO∙ R∙ + CO2
R∙ + X2 RX + X∙
R∙ + RCOOX RX + RCOO∙ etc.
In Hunsdieker reaction, Br2 in CCl4 gives better yield than Cl2 in CCl4.
The yield and ease of formation of R -X is
1°RX > 2°RX > 3°RX
If I2 is used in Hunsdieker reaction in CCl4, then a ester is formed. This is known as Birnbaum−Simonini Reaction.

But if acids are used with I2 and red mercuric oxide, alkyl iodides are obtained.
2RCO2H + 2I2 + HgO 2RI + 2CO2 + HgI2 + H2O

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HOFFMANN BROMAMIDE DEGRADATION

About Hoffmann Bromamide Degradation

Amides with no substituent on the nitrogen when treated with a solution of Br2 or Cl2 in KOH yield only primary amines having one carbon atom less than the amides.

Reaction Mechanism of Hoffmann Bromamide Degradation

The reaction mechanism involves base-promoted N-bromination yielding N-Bromo amide as an intermediate. The N-Bromo amide then reacts with the hydroxide ion to produce N-bromamide anion, which rearranges with the migration of R group and loss of Br- ion to produce isocyanate.
Base catalyzed hydrolysis of isocyanate formed in the reaction mixture produces carbamate ion, which undergoes spontaneous decarboxylation resulting in the formation of amine.

[Vamshi]

JONES REAGENT

Jones reagent (chromic acid in aqueous acetone solution)

Chromic acid, H2CrO4 , is a strong acid in presence of acetone it act as good oxidising agent also know as Jones oxidising agents and is a reagent for oxidizing alcohols to ketones and carboxylic acids.

In place of comic acid we can use Na2CrO4 (sodium chromate), Na2Cr2O7 (sodium dichromate), KCrO4 (potassium chromate), K2Cr2O7 (potassium dichromate), and CrO3 (chromium trioxide) are alike in one crucial manner: when they are combined with aqueous acid, each of them forms H2CrO4 , and ultimately it is H2CrO4 that is involved in the important chemistry.

Application of Jones Reagent

This is a sufficiently mild oxidising agent, so that it oxidises alcohols without oxidising or rearranging double bonds. MnO2 can oxidise 1° allylic or 1° benzylic alcohols selectively into aldehydes.

Example of Jones reagent (chromic acid in aqueous acetone solution)

CH3–CH=CH–CH2OH CH3–CH=CH–CH=O

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KOLBES REACTION

About Kolbes Reaction

Sodium phenoxide is heated with carbon dioxide at 120-140°C under pressure to yield sodium salicylate, which upon acidification produces salicylic acid is know as Kolbes reactions

A small amount of p− derivative is also formed. If the temperature rises above 140° C, the p− isomer is the main product.

Mechanism of Kolbe’s Reaction

Salicylic acid is used for the preparation of Aspirin, oil of wintergreen (methyl salicylate), and salol (phenyl salicylate).

[Vamshi]

KNOEVENAGEL REACTION

About Knoevenagel Reaction

Condensation of aldehydes and ketones with compounds having active methylene group in the presence of basic catalyst to form α, β-unsaturated compounds is called Knoevenagel Reaction. The basic catalyst may be ammonia or its derivative. Thus 1°, 2°, 3° amines i.e., aniline, di-or tri-alkyl amines, pyridine or piperidine are used.

Reaction Mechanism of Knoevenagel Reaction

High reactivity of the methylene group of the active methylene compound prevents self-condensation of the aldehyde.