Chemistry: CIX Organic Chemistry -III Lesson: Nitrogen Containing Functional Groups Unit-3: Nitro and Nitroso Compounds, Nitriles and Isonitriles Lesson Developer: Dr. S.P Bhutani College/Dept: Formerly Associate Professor Department of Chemistry Rajdhani College, University of Delhi Lesson Editor:Dr.N.K Gautam Advisor (Sciences) Institute of Lifelong Learning, University of Delhi

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Contents: 1. Nitro Compounds — Introduction 2. Preparation Of Nitro Compounds A. Nitration Of Alkanes B. From Alkyl Halides C. Decarboxylation Of - Nitro Carboxylic Acids D. Nitration Of Aromatic Compounds Mechanism Of Aitration E. By Reaction Of Diazonium Salts With Sodium Nitrite 3. Physical Properties And Reactions Of Nitrocompounds A. Condensation With Aldehydes And Ketones B.Reduction Of Nitro Compounds (I) Reduction In Acid Medium (Ii) Reduction In Neutral Medium (Iii) Reduction Of Nitrobenzene In Alkaline Medium 4. Nitroso Compounds 5. Preparation Of Nitroso Compounds A. By The Addition Of Nocl To Olefins B. By Reduction Of Nitro Compounds C. Oxidation Of Primary Amines D. Nitrosation Of Aromatic Compounds E. N-Nitrosation 6. Reactions Of Nitroso Compounds A. Reduction B. Oxidation 7. Nitriles A. Introduction B. Nomenclature 8. Preparation Of Nitriles A. From Alkyl Halides B. Dehydration Of Amides 9. Reactions Of Nitriles A. Reduction To Primary Amines B. Reduction Of Nitriles To Aldehydes-Stephen’s Method C. Hydrolysis Of Nitriles D. Hydrolysis Of Nitriles To Amides-Mechanism E. Hydrolysis Of Amides To Carboxylic Acids F. Reaction Of Nitriles With Grignard Reagents 10. Isonitriles 11. Preparation Of Isonitriles A. From Alkyl Halides B. From Primary Amines (Carbylamine Test) 12. Reactions Of Isonitriles A. Reduction B. Addition Of Water To Isonitriles

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C. Oxidation Of Isocyanides To Isocyanates D. Hydrolysis Of Isocyanides E. Rearrangement To Cyanides 13. References

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1. NITRO COMPOUNDS — INTRODUCTION Nitroalkanes are relatively rare. Only a few of the simpler ones are commercially available. Examples are nitromethane, nitroethane and 2-nitropropane

Aromatic nitro-compounds are much more common because they are easily prepared by the electrophilic nitration of aromatic compounds. Some examples are given below:

The niroalkanes are named as the nitro derivatives of the corresponding alkane, the positions of the nitro groups being indicated by numbers. For example,

The structure of the nitrocompounds is best represented as a resonance hybrid

2. PREPARATION OF NITRO COMPOUNDS A.Nitration of Alkanes Nitroalkanes are prepared industrially by direct nitration of alkanes

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The reaction can be carried out in the gas phase at about 400°C or in the liquid phase. The reaction is not practical for the preparation of pure products except for nitromethane

With higher alkanes we may get mixture of the mono-, di- and polynitrated products, but extensive chain cleavage also takes place. For example,

B. From Alkyl Halides Some nitro compounds may be prepared in the laboratory by the replacement of alkyl halides with nitrite ion using sodium nitrite. Since nitrite ion is an ambident nucleophile some alkyl nitrite is usually produced as a byproduct.

Yields of the nitroalkanes are higher when silver nitrite is used. But silver nitrite gives nitro compound only when R–X is a primary bromide or iodide.

C. Decarboxylation of - Nitro Carboxylic Acids Nitromethane may be propared by boiling an aqueous solution of sodium nitrite with a halogeno acetic acid.

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The ready decarboxylation of the intermediate nitroacetic acid is due to the electron withdrawing nitro group, which facilitates the loss of carbon dioxide

D. Nitration of Aromatic Compounds Most aromatic compounds, whether of high or low reactivity, can be nitrated. For benzene, the simple alkyl benzenes and less reactive compounds like chlorobenzene, the most common reagent is a mixture of concentrated nitric acid and concentrated sulphuric acid, called the nitrating mixture. For example,

For active substrates the reaction can be carried out with nitric acid alone or in water, acetic acid or acetic anhydride. These milder conditions are necessary for compounds such as amines and phenols since reaction with mixed nitric and sulphuric acids would oxidise these substrates. For example, phenol on nitration with dilute HNO 3 at 25°C gives a mixture of o-nitrophenol and p-nitrophenol whereas nitration with nitrating mixture gives 2,4,6trinitropthenol known as picric acid.

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When aniline is nitrated under strong acid conditions metaorientation is generally observed because the species undergoing nitration is actually the conjugate acid of the amine. Therefore, primary aromatic amines are generally protected before nitration by treatment with acetyl chloride or acetic anhydride. Nitration of the resulting acetanilide avoids all these problems and we get exclusivelyp-nitroacetanilide. Since the NO2 group is deactivating, nitration of nitrobenzene can be carried out only under drastic conditions. We use a mixture of fuming nitric acid and concentrated sulphuric acid at a temperature above 70°C to give m-dinitrobenzene.

When two deactivating groups are present in the benzene nucleus it is very difficult to introduce the third group. Mechanism of Nitration The commonly accepted mechanism for nitration with a mixture of nitric acid and sulphuric acid involves the following sequence of reactions: The first step is the generation of the nitronium ion by following the Lowry-Bronsted approach. Nitric acid acts as a base and accepts a proton from the stronger acid, sulphuric acid. The protonated nitric acid dissociates to produce a nitronium ion. That means, wehave an acid-base equilibrium producing the conjugate acid (NO2+ ) and the conjugate base

(HSO4- ) .

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In the second step,the nitronium ion (NO2+) attacks the -cloud of the benzene ring forming a carbocation (the arenium ion). The carbocation so produced stabilizes by resonance. The actual structure is a resonance hybrid of various resonating structures. This means, the positive charge is not localized on one carbon atom but is distributed over the molecule.

In the third step, proton is abstracted by the conjugate base HSO4- present in the reaction mixture to yield the product.

E.By Reaction of Diazonium Salts with Sodium Nitrite Aromatic nitro compounds can be formed in good yields by treatment of diazonium salts with sodium nitrite in the presence of cuprous ion. The reaction occurs in neutral or alkaline solution.

BF4- is often used as a negative ion to avoid competition from Cl– ion. So, diazoniumfluoborate is first prepared by diazotisation with sodium nirite and fluoboric acid. The diazoniumfluoborate precipitate is filtered. Now the isolated diazoniumfluoborate is

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suspended in aqueous sodium nitrite and treated with copper powder. Nitrogen is evolved and the corresponding nitro compound is produced. For example,

3. PHYSICAL PROPERTIES AND REACTIONS OF NITROCOMPOUNDS Nitro alkanes are colourless (when pure), pleasant smelling liquids, which are sparingly soluble in water. Most of them can be distilled at atmospheric pressure. Nitrobenzene and related nitro compounds are generally high boiling liquids. Nitrobenzene is a pale yellow oil, b.p. 210–11°C. It has a characteristic odour of almonds. At one time it was used in shoe polish, but its use for this purpose has now been discontinued because it is readily absorbed through the skin and is poisonous. The most important property of nitroalkanes is their acidity. The pK a of nitromethane is10.2, that of nitroethane is 8.5 and 2-nitropropane (pKa = 7.8) is so acidic that it is extensively ionised in neutral solution. Nitro compounds owe their acidity to the fact that their conjugate base is resonance stabilised.

A. Condensation with Aldehydes and Ketones The anions obtained from nitroalkanes are nucleophilic and enter into typical nucleophilic reactions. They undergo Aldol type of addition reactions with aldehydes and ketones. The reaction is known as Henry Reaction, which is analogous to the aldol addition reactions of aldehydes and ketones.

Since intro compounds are quite acidic, only weakly basic catalysts are required.

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In case of aromatic aldehydes, dehydration of the intial -hydroxy nitro compound usually results. With benzaldehydeniromethane condenses to give -nitrostyrene.

The mechanism is similar to Aldol condensation as given below:

B.Reduction of Nitro Compounds The nitro group is relatively stable to many reagents. It is generally inert to acids and most electrophilic reagents. Hence, it may be present in a ring when reactions with such reagents are used. The most important reaction of the nitro group in aromatic compounds is reduction, but the reduction product depends on the reaction conditions used. Catalytic hydrogenation and reduction in acidic media yields the corresponding amine. (i) Reduction in Acid Medium Both aliphatic and aromatic nitro compounds can be reduced to amines. The reaction has been applied more often to aromatic nitro compounds owing to their greater availability. Many reducing agents have been used to reduce aromatic compounds, the most common being Zn, Sn, Fe and acid.

The reduction of nitrobenzene to aniline in the acidic medium is a classic example of reduction with metal and acid. Thus, nitrobenzene is reduced to aniline by Sn and HCl, The amine is obtained as its salt. On treatment with NaOH the saltdecomposes to free aniline.

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LiAlH4 reduces aliphatic nitro compounds to amines but with aromatic nitro compounds, the products are azo compounds. Treatment of aromatic nitro compounds with NaBH 4 has resulted in reduction of the ring to a cyclohexane ring with –NO2 group still intact. The course of the reduction of nitro compounds has been shown to take place through the following stages:

Nitroso compounds, which are supposed to be intermediates, are too reactive to be isolated. But hydroxylamine has been isolated in certain conditions. Reduction by metals in mineral acids cannot be stopped, it always produces the amine. The mechanisms of these reactions have not been fully studied, but the formation of nitroso compounds and hydroxylamines as intermediates is definite. Both of these compounds give amines when reduced with the above reducing agents. With metals and acid the following mechanism has been suggested.

In strongly acid solution, the product is p-aminophenol. It is formed by rearrangement of phenyl hydroxyl amine.

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The mechanism involved is given below:

Electrolytic Reduction When nitrobenzene is reduced by electrolysis in dilute sulphuric acid solution NPhenylhydroxylamine is produced first undergoes an intramolecular rearrangement to yield p-aminophenol. The mechanism of rearrangement has already been given. (ii) Reduction in Neutral Medium (Reduction of Nitro Compounds to Hydroxylamine) When nitrobenzene is reduced under neutral conditions, we get phenyl-hydroxylamine. Among the reagents used the most common is zinc dust and ammonium chloride.

Nitro compounds have also been reduced electrochemically to hydroxylamines. Nitroso compounds and hydroxylamines can be reduced to amines by the same reagents that reduce nitro compounds e.g., with Zn/HCl.

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(iii) Reduction of Nitrobenzene in Alkaline Medium Nitrobenzene on reduction with zinc dust and methanolic sodium hydroxide gives a mixture of products. The first product of reduction is nitrosobenzene which may react with N-phenylhydroxylamine to give azoxybenzene. Azoxybenzene may be further reduced to form azobenzene and hydrazobenzene. Thus, nitrobenzene on reduction gives a mixture of azobenzene, azoxybenzene and hydrazobenzene. It is also believed that azobenzene is obtained first which then gets converted into azoxybenzene and hydrazobenzene.

All the above products can be obtained separately by choosing the appropriate conditions.

(i) Azoxybenzene is produced by direct reduction of nitrobenzene in alkaline medium with sodium arsenite.

(ii) Azobenzene is formed by reduction of nitrobenzene with zinc and methanolic sodium hydroxide.

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(iii) With

excess of hydrazobenzene.

zinc

and

sodium

hydroxide

nitrobenzene

is

reduced

to

4. NITROSO COMPOUNDS The nirosoalkanes contain a nitroso group, - N == O directly attached to a carbon atom. They are named as the nitroso derivatives of the corresponding alkane. For example,

Secondary amines when treated with nitrous acid give N-niroso compounds.

In aromatic systems, a nitroso compound can be substituted in the benzene nucleus. An example is of p-nitrosodimethylaniline.

5.PREPARATION OF NITROSO COMPOUNDS A.By the Addition of NOCl to Olefins

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NOCl adds to alkenes to give alkene nitrosohalide.

There are three possible products when NOCl is added to olefins. The initial product is always the -halo nitroso compound, but these are stable only if the carbon bearing the nitrogen has no hydrogen. If it has, the nitroso compound tautomerises to the oxime.

B. By Reduction of Nitro Compounds When nitro compounds are treated with most reducing agents, nitroso compounds are either not formed or react further under the reaction conditions and cannot be isolated. However, certain aromatic nitroso compounds can be obtained in good yields by irradiation of the corresponding niro compounds in 0.1 M aqueous KCN with UV light.

C. Oxidation of Primary Amines Primary aromatic amines can be oxidised to nitroso compounds. Most often the conversion is accomplished by Caro’s acid (H2SO5) or with H2O2 in acetic acid

Hydroxylamines, which are probably intermediates in most cases, can sometimes be isolated, but under the reaction conditions they are generally oxidised to the nitrosocompound. Primary aliphatic amines can be oxidised in this manner, but the nitroso compound is stable only if there is no -hydrogen. If there is a -hydrogen the compound tautomerises to the oxime.

Aromatic hydroxylamines are easily oxidised to nitroso compounds, most commonly by acid dichromate

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D.Nitrosation of Aromatic Compounds Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions when treated with nitrous acid and secondary amines give N-nitroso rather than C-nitroso compounds. Hence, the reaction is limited to phenols and tertiary amines. We have already seen the formation ofp-nitrosodimethylaniline from dimethylaniline

E. N-Nitrosation When secondary amines are treated with nitrous acid, N-nitroso compounds (also called nitrosamines) are formed. The reaction can be accomplished with dialkyl, diaryl or alkylaryl amines.

6.REACTIONS OF NITROSO COMPOUNDS A. Reduction Nitroso compounds can be reduced to amines using the common reagents, metal/ acid (the most common being Zn, Sn or Fe and acid) and catalytic hydrogenation.

N-Nitroso compounds are reduced to hydrazines

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B. Oxidation Nitroso compounds may be oxidised to the nitro compounds by nitric acid. There should not be any α - hydrogen present. For example,

Aromatic nitroso compounds are easily oxidised to nitro compounds by many oxidising agents.

Nitroso compounds exist as such only when the nitroso group is attached to a tertiary charbon atom. If the nitroso group is attached to a primary or secondary carbon atom, the nitroso compound is generally unstable and rearranges to the oxime

7.NITRILES A. Introduction Nitriles contain the cyano group, –CN. They are classified as acid derivatives because they hydrolyse to give carboxylic acids and can be synthesised by dehydration of amides. Hydrolysis to an acid

Synthesis from an acid

Both the carbon atom and the nitrogen atom of the cyano group are sphybridised and the R—CN bond angle is 180° i.e., the molecule is linear.

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The structure of a nitrile is similar to that of a terminal alkyne. The nitrogen of the nitrile has a lone pair of electrons in place of the acetylenic hydrogen of the alkyne as shown below:

Although a nitrile has a lone pair of electrons on nitrogen, it is not very basic. A concentrated solution of mineral acid is required to protonate the nitrile. We can explain this lack of basicity, by observing that the nitrile’s lone pair resides in ansp-hybrid orbital with 50% s character. This orbital is drawn closer to the nucleus. Therefore, these electrons are tightly bound and relatively unreactive. B.Nomenclature Although niriles are sometimes named as cyanides or as cyano compounds, they generally derive their names from the acids they yield upon hydrolysis. They are named by dropping –ic from the commonname of the acid and adding nitrile after inserting ‘o’ between the root and the ending. For example, nitrile corresponding to acetic acid is named as acetonitrile and benzonitrile from benzoic acid and so on.

In the IUPAC system, they are named by adding the suffix-nitrile to the name of the alkane correspondingto the longest carbon chain in the molecule including the nitrile carbon.

8.PREPARATION OF NITRILES A.From Alkyl Halides Aliphatic niriles are prepared by treatment of alkyl halides with sodium cyanide in a solvent that will dissolve both the reactants. Generally dimethylsulphoxide is used. The reaction is exothermic and occurs readily at room temperature

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The reaction of alkyl halide with cyanide ion is nucleophilic substitution. Cyanide ion is a good nucleophile, the reaction goes by S N2. As cyanide ion is a strong base, it can abstract hydrogen ion from the alkyl halide causing elimination as well as substitution. With tertiary halides elimination is the principal reaction. Even with secondary halides the yield of the substitution product is poor. Therefore, primary halides can be converted into nitriles.

We shall see that aromatic nitriles are prepared from diazonium salts, not from unreactive aryl halides

B.Dehydratution of Amides Amides react with P2O5 or POCl3 orwith boiling acetic anhydride to form nitriles

This is a useful method for preparing nitriles that are not available by nucleophilic substitution reactions by alkyl halides and cyanide ion.

9.REACTIONS OF NITRILES A. Reduction to Primary Amines Nitriles are reduced to primary amines by LiAlH4 or by catalytic hydrogenation.

This gives us a method for obtaining primary amines from alkyl halides with one more carbon. When —CN group is added and reduced, the resulting amine has an additional carbon atom e.g., we can get 1-butanamine from 1-bromopropane.

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B. Reduction of Nitriles to AldehydesStephen’s Method The reduction of nitriles to aldehydes is known as Stephen’s method. The nitrile is dissolved in ether and treated with stannous chloride and hydrochloric acid.

The nitrile with HCl forms

This is reduced with SnCl 2 to R — CH NH, which precipitates as a complex with SnCl 4. The complex is hydrolysed to the corresponding aldehyde.

This method is not applicable for the synthesis of ketones. The Stephen reduction is most successful when R is aromatic but it can be done with aliphatic R up to about six carbons. C.Hydrolysis of Nitriles Nitriles are hydrolysed to amides and further to carboxylic acids by heating with acid or base. Complete hydrolysis of a nitrile produces a carboxylic acid or a carboxylate ion. However, mild conditions can hydrolyse nitriles to amides. For example, alkaline hydrolysis of pentanenitrile gives pentanamide.

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Basic Hydrolysis

Acid Hydrolysis

D.Hydrolysis of Nitriles to Amides-Mechanism In both acidic and basic hydrolysis, nitriles are first hydrolysed to amides and then they get converted to carboxylic acids or carboxylate ion. In acidic hydrolysis, the first step is the protonation of the nitrogen atom. Subsequent nucleophilic attack by water and loss of a proton gives the tautomeric form of an amide. In the presence of concentrated H2SO4 the reaction stops at the protonated amide.

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The mechanism for the basic hydrolysis begins with attack by hydroxide on the electrophilic carbon of the cyano group. Protonation gives the unstable enol tautomer of an amide. Removal of the proton from oxygen and reprotonation on nitrogen gives the amide. Attack by hydroxide and reprotonation

E.Hydrolysis of Amides to Carboxylic Acids Amides undergo hydrolysis when they are heated with aqueous acid or aqueous base. (i) Acidic Hydrolysis

(ii) Basic Hydrolysis

F.Reaction of Nitriles with Grignard Reagents Ketones can be synthesised by using niriles as the starting materials. Since nitrogen is more electronegative than carbon, the –C≡N triple bond is polarised like the >C=O bond of

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the carbonyl group. Nucleophiles can add to the –C≡N bond by attacking the electrophilic carbon atom. A Griguard or organolithium reagent attacks a nitrile to give the magnesium salt of an imine. Acid hydrolysis of the imine leads to the formation of a ketone.

Some examples are as follow:

10.ISONITRILES In alkyl isonitriles, nitrogen is attached to carbon of the alkyl group. They also called isocyanides.

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For examples

11.PREPARATION OF ISONITRILES A. From Alkyl Halides We have seen that alkyl halides on reaction with sodium cyanide give alkyl cyanides. However, with silver cyanide in aqueous ethanolic solution alkyl halides give isocyanides or isonitrile. The above reaction takes place by SN1 mechanism. As soon as we add silvercyanide, AgX is precipitated and a carbocation is generated. CN– ion is an ambidentnucleophile, negative charge shifts from carbon to nitrogen. The ion C == N attacks the carbocation so generated and we get the formation of isonitriles

B. From Primary Amines (Carbylamine Test) Isonitriles, also known as carbylamines, are obtained by heating a mixture of a primary amine and chloroform with ethanolic potassium hydroxide.

The mechanism of this reaction is uncertain. Robisonsuggested that the reaction may proceed via intermediate formation of dichlorocarbene, which is produced from chloroform in alkaline solution

Dichlorocarbene reactswith primary amines to give isonitriles.

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For example

This method is used as a test for detecting the presence of primary amines. The test is known as Carbylamine Test: Isocyanides are most unpleasant smelling liquids with lower boiling points. If anyone performs this test, the smell immediately spreads in the whole laboratory—it smells of rotten dead mice.

12.REACTIONS OF ISONITRILES A. Reduction Alkyl isonitriles are reduced to N-methylamines, i.e., secondary amines, either by LiAlH4 or by catalytic hydrogenation.

B. Addition of Water to Isonitriles Formamides are obtained by the acid-catalysed addition of water to isocyanides

The probable mechanism is given below:

C. Oxidation of Isocyanides to Isocyanates Isocyanides have been oxidised to isocyanates with HgO and with O 3 as well as with a halogen and dimethylsulphoxide.

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In the latter case, the oxidising agent is the halogen, which converts isocanide to, R—N

== CCI2which is hydrolysed to isocyanate.

Isocyanides can also be converted to isothiocyanates by treating with a disulphide, PhCOSSCOPh and thallium or with sulphur

D. Hydrolysis of Isocyanides Alkyl isocyanides are hydrolysed to an amine and formic acid by dilute acids but are not hydrolysed by alkalis.

E. Rearrangement to Cyanides Isocyanides when heated in the gas phase or in nonpolar solvents, undergo a 1, 2,intramolecular shift to cyanides.

REFERENCES: 1.Organic Chemistry by Morrison, R.T. and Boyd, R.N. Darling Kindersley (India) Pvt. Ltd. (Pearson Education). 2. Organic Chemistry by Graham Solomons, T.W. John Wiley and Sons. 3. Introduction to organic chemistry by Andrew Streitwieser, Jr. and Claylon H. Heathcock Macmillan Publishing Company. 4. Organic Chemistry by Seyhan Ege A.I.T.B.S. Publishers and Distributers J5/6, Krishan Nagar, Delhi- 110051. 5. Advanced Organic Chemistry by Jerry March John Wiley and Sons. 6. Organic Chemistry by L.G. Wade, Jr. Pearson Education. 7. A Guide Book to Mechanism in Organic Chemistry by Peter Sykes – Pearson Education.

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