Amines

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What are amines?

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Use of amines in nature

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In nature, they occur among proteins, vitamins, alkaloids and hormones. Synthetic examples include Polymers, dyestuffs and drugs. Two biologically active compounds namely adrenaline and ephedrine, both containing secondary amino group, are used to increase blood pressure. Novocaine, a synthetic amino compound, is used as an anaesthetic in dentistry. Benadryl, a well-known antihistaminic drugs also contains tertiary amino group. Quaternary ammonium salts are used as surfactants. Diazonium salts are intermediates in the preparation of a variety of aromatic compounds including dyes.

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Structure of amines

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Like Ammonia, nitrogen atom of amines is trivalent and carries an unshaired pair of electrons. Nitrogen orbitals in amines are therefore SP3 hybridised and the geometry of amines is pyramidal. Each of the three SP3 hybridised orbitals of Nitrogen overlap with orbitals of hydrogen or Carbon depending upon the composition of the amines. Fourth orbital of Nitrogen in all amines contains an unshared pair of electrons. Due to the presence of an unshared pair of electrons, the angle C-N-E (where E is C or H) is less than 109.5°; for instance, it is 108° in case of trimethylamine.

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Classification of amines

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Amines are classified as Primary, secondary and tertiary depending upon the number of hydrogen atoms replaced by alkyl or aryl groups in Ammonia molecule.

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Nomenclature of alkyl group in common system.

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In common system, an aliphatic amine is named by prefixing alkyl group to amine, i.e., alkylamine as one word (example methylamine). In secondary and tertiary amines, when two or more groups are the same, the prefix di and tri is appended before the name of alkyl group.

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Nomenclature of alkyl group in IUPAC system

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Amines are named as alkanamines, derived by replacement of 'e' of alkane by the word 'amine'. For example, CH3 NH2 is named as methanamine. In case, more than 1 amino group is present at different positions in the parent chain, their positions are specified by given numbers to the carbon atoms bearing NH2 groups and suitable prefix such as di, tri, etc. is attached to the amine. The letter 'e' of the suffix of the hydrocarbon part is retained.

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Nomenclature of aryl group

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Nomenclature of some alkyl amines and aryl amines.

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Preparation of amines by reduction of nitro compounds

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Why reduction with iron scrap and hydrochloric acid is preferred

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It is preferred because FeCl2 formed, gets hydrolyzed to release hydrochloric acid during the reaction. Thus, only a small amount of hydrochloric acid is required to initiate the reaction.

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Preparation of amines by ammonolysis of alkyl halides

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Carbon- hydrogen bond in alkyl or benzyl halides can be easily cleaved by a nucleophile. Hence, an alkyl or benzyl halides on reaction with and ethanolic solution of ammonia undergoes nucleophilic substitution reaction in which the halogen atom is replaced by an amino group (-NH2). This process of cleavage of the C-X bond by Ammonia molecule is known as ammonolysis. The reaction is carried out in a sealed tube at 373 Kelvin. The primary amine does obtained behaves as a nucleophile and can further react with alkyl halide to form secondary and tertiary amines, and finally ordinary ammonium salt. The free Aman can be obtained from the ammonium salt by treatment with a strong base.

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Disadvantage of ammonolysis

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Ammonolysis has the disadvantage of yielding a mixture of Primary, secondary and tertiary amines and also quaternary ammonium salt. However, primary amine is obtained as a major product by taking large excess of ammonia.

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Order of reactivity of halides with amines

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RI>RBr>RCl

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Preparation of amines by reduction of nitriles

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Nitriles on reduction with Lithium aluminium hydride (LiAlH4) aur catalytic hydrogeneration produce primary amines. This reaction is used for ascent of amine series, i.e., for preparation of amines containing one carbon atom more than the starting one.

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Preparation of amines by reduction of amides

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The amides on reduction with Lithium aluminium hydride yield amines.

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Preparation of amines by Gabriel phthalimide synthesis.

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Gabriel synthesis is used for the preparation of primary amines. Phthalimide on treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide which on heating with alkyl halide followed by alkaline hydrolysis produces the corresponding primary amine. Aromatic primary amines cannot be prepared by this method because aryl halides do not undergo nucleophilic substitution with the anion formed by phthalimide.

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Preparation of amines by Hoffman bromamide degradation reaction.

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Some physical properties of amines

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The lower aliphatic amines are gases with fishy odour. Primary amines with three or more carbon atoms are liquid and still higher ones are solid. Aniline and other arylamines are usually colourless but get coloured on storage due to atmospheric oxidation.

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What about the solubility of amines in water

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Lower aliphatic amines are soluble in water because they can form hydrogen bonds with water molecules. However, solubility decreases with increase in molar mass of amines due to increase in size of the hydrophobic alkyl part. Higher amines are essentially insoluble in water. Amines are soluble in organic solvents like alcohol, Ether and Benzene.

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Boiling points of amines

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Primary and secondary amines are engaged in intermolecular association due to hydrogen bonding between nitrogen of one and hydrogen of another molecule. This intermolecular association is more in primary amine than in secondary amines as there are two hydrogen atoms available for hydrogen bond formation in it. Tertiary amines do not have intermolecular Association due to the absence of hydrogen atom available for hydrogen bond formation. Therefore, the order of boiling points of isomeric amines is : primary> secondary> tertiary. Boiling points of amines, alcohols and alkanes of almost the same molar mass are shown in the table.

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What makes amines reactive

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Difference in electronegativity between nitrogen and hydrogen atoms and the presence of an unshared pair of electrons over the nitrogen atom makes amines reactive. The number of hydrogen atoms attached to nitrogen atom also decides the course of reaction of amines; that is why primary, secondary and tertiary amines differ in many reactions. Moreover, amines behave as nucleophile due to the presence of unshared electron pair.

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Basic character of amines

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Amines, being basic in nature, react with acids to form salts. Amine salts on treatment with a base like NaOH regenerate the parent amine.

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Solubility of amine salts

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Amine salts are soluble in water but insoluble in organic solvents like ether. This reaction is the basis for the separation of amines from the non basic organic compounds insoluble in water.

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Why do amines act as Lewis base

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Amines have an unshared pair of electrons on nitrogen atom due to which they behave as Lewis base. The reaction of amines with mineral acids to form ammonium salts shows that these are basic in nature.

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pKb values of amines in aqueous phase

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Larger the value of Kb or smaller the value of pKb, stronger is the base. pKb value of ammonia is 4.75. Aliphatic amines are stronger bases than Ammonia due to +I effect of alkyl groups leading to high electron density on nitrogen atom. There pKb values lie in the range of 3 to 4.22. on the other hand, aromatic amines are weaker base than Ammonia due to the electron withdrawing nature of aryl group.

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Structure-basicity relationship of amines

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Basicity of amines is related to their structure. Basic character of an Amine depends upon the ease of formation of the cation by accepting a proton from the acid. The more stable the cation is relative to the amine, more basic is the amine.

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Basicity of alkyl amines versus ammonia

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Order of basicity of aliphatic amines

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Why pKb value of aniline is quite high

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It is because in alanine or other arrangements, the -NH2 group is attached directly to the benzene ring. It results in the unshared electron pair on nitrogen atom to be in conjugation with the benzene ring and thus making it less available for protonation.

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Resonating structures of aniline

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Resonating structures of anilinium ion obtained by accepting a proton

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Only two resonating structures

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Stability of aniline versus anilinium ion

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Greater the number of resonating structures, greater is the stability. Thus, aniline is more stable than anilinium ion. The proton acceptability or the basic nature of aniline or other aromatic amines would be less than that of ammonia. In case of substituted aniline, it is observed that electron releasing groups like -OCH3 -CH3 increases basic strength whereas electron withdrawing groups like -NO2, -SO3H, -COOH, -X decrease it.

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Alkylation

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Amines reacts with alkyl halides to form amines of higher class. In this reaction, amines acts as nucleophile.

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Acylation

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Aliphatic and aromatic primary and secondary amines react with acid chlorides, anhydrides and esters by nucleophilic substitution reaction. This reaction is known as acylation. Replacement of hydrogen atom of -NH2 or -NH group by the acyl group. The products obtained by acylation reaction are known as amides. The reaction is carried out in the presence of a base stronger than the amine, like pyrimidine, which removes HCl so formed and shifts the equilibrium to the right hand side.

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Benzoylation

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When amines react with benzoyl chloride(C6H5CoCl), this reaction is known as benzoylation.

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Product of reaction of amines with Carboxylic acids

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They form salts with amines at room temperature.

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Carbylamine reaction

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Reaction of amines with nitrous acid

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Secondary and tertiary amines react with nitrous acid in a different manner.

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Reaction of amines with arylsulphonyl chloride

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Maximum electron density in resonating structure of aniline

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Aniline is a resonance hybrid of five structures. Ortho and para position to the NH2 group become centres of high electron density. Thus, NH2 group is Ortho and para directing and a powerful activating group.

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Bromination

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Aniline reacts with bromine water at room temperature to give a white precipitate of 2,4,6-tribromoaniline.

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How do we prepare monosubstituted aniline derivative.

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Main problem encountered during electrophilic substitution reactions of aromatic amines is that of their very high reactivity. Substitution tends to occur at Ortho and para positions. So, controlling the activating effect of NH2 group to prepare monosubstituted aniline derivative can be done by protecting the NH2 group by acetylation with acetic anhydride, then carrying out the desired substitution followed by hydrolysis of the substituted amide to the substituted amine.

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Why activating effect of NHCOCH3 group is less than that of amino group.

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The Lone pair of electrons on nitrogen of acetanilide interacts with oxygen atom due to resonance. Hence, the lone pair of electrons on nitrogen is less available for donation to benzene ring by resonance. Therefore, activating effect of -NHCOCH3 group is less than that of amino group.

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Nitration

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Direct Nitration of aniline builds its oxidation products in addition to the nitro derivatives. Moreover, in the strongly acidic medium, aniline is protonated to form the anilinium Ion which is meta directing.

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How do we obtain a nitro derivative ,in Nitration reaction, as the major product?

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By protecting the NH2 group by acetylation reaction with acetic anhydride, the nitration reaction can be controlled and the p-nitro derivative can be obtained as the major product.

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Sulphonation

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Aniline reacts with concentrated sulphuric acid to form anilinium hydrogensulphate which on heating with sulphuric acid at 453 to 473 Kelvin produces p-aminobenzene sulphonic acid, commonly known as sulphanilic acid, as the major product.

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Why does aniline does not undergo Friedel-Craft's reaction.

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It does not undergo Friedel-Craft's reaction (alkylation and acylation) due to salt formation with aluminium chloride, the Lewis Acid, which is used as a catalyst. Due to this, nitrogen of aniline acquires positive charge and hence acts as a strong deactivating group for further reaction.

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Diazonium salt and their nomenclature

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Stability of diazonium salts

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Primary aliphatic amines form highly unstable alkyl diazonium salts. Primary aromatic amines for Marine diazonium salts which are stable for a short time in solution at low temperatures (273-278 K). The stability of Aaron diazonium iron is explained on the basis of resonance.

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Preparation of diazonium salts

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Physical properties of diazonium salts

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Benzenediazonium chloride is a colourless crystalline solid. It is readily soluble in water and is stable and cold but reacts with water when warmed. It decomposes easily in the dry state. Benzenediazonium fluoro borate is water insoluble and stable at room temperature.

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Chemical properties of diazonium salts

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The reactions of diazonium salts can be broadly divided into two categories, namely (A) reactions involving displacement of Nitrogen and (B) reactions involving retention of diazo group.

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Reactions involving displacement of Nitrogen

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Diazonium group being a very good leaving group, is substituted by other groups such as Cl-, Br-, I-, CN- and OH- which displace nitrogen from the aromatic ring. The nitrogen formed escapes from the reaction mixture as a gas.

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Replacement of Nitrogen by halide or cyanide ion

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The Cl-, Br- and CN- nucleophiles can easily be introduced in the benzene ring in the presence of Cu(I) ion. This reaction is called Sandmeyer reaction.

Alternatively, chlorine or bromine can also be introduced in the benzene ring by treating the diazonium salt solution with corresponding halogen acid in the presence of copper powder. This is referred as Gattermann reaction.

The yield in Sandmeyer reaction is found to be better than Gattermann reaction.

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Replacement of Nitrogen by iodide ion

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Iodine is not easily introduced in the benzene directly, but, when the diazonium salt solution is treated with potassium iodide, iodobenzene is formed.

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Replacement of Nitrogen by fluoride ion

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When arenediazonium chloride is treated with fluoroboric acid, arenediazonium fluoroborate is precipitated which on heating decomposes to yield aryl fluoride.

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Replacement of Nitrogen by hydrogen

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Certain mild reducing agents like hypophosphorous acid (phosphinic acid) or ethanol reduce diazonium salts to arenes and themselves get oxidised to Phosphorus acid and ethanal, respectively.

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Replacement of Nitrogen by hydroxyl group and replacement of Nitrogen by -NO2 group.

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Reactions involving retention of diazo group coupling reactions

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The azo products obtained have an extended conjugate system having both the aromatic rings joined through the nitrogen nitrogen double bond. These compounds are often coloured and are used as dyes. Benzenediazonium chloride reacts with phenol in which the phenol molecule at its para position is coupled with the diazonium salt to form p-hydroxyazobenzene. This type of reaction is known as coupling reaction. Similarly the reaction of diazonium salt with aniline yields p-aminoazobenzene. This is an example of electrophilic substitution reaction.

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Importance of diazonium salts in synthesis of aromatic compounds

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Diazonium salts are very good intermediates for the introduction of -F, -Cl, -Br, -I, -CN, -OH, -NO2 groups into the aromatic ring. Aryl fluorides and iodides cannot be prepared by direct halogenation. The cyano group cannot be introduced by nucleophilic substitution of chlorine in chlorobenzene but cyanobenzene can be easily obtained from diazonium salt. Thus, the replacement of diazo group by other groups is helpful in preparing those substituted aromatic compounds which cannot be prepared by direct substitution in Benzene or substituted Benzene.