Chapter Notes

Introduction to Amines

Amines are a vital class of organic compounds that you can think of as derivatives of the ammonia ($NH_3$) molecule. They are formed when one or more of the hydrogen atoms in ammonia are replaced by alkyl (carbon chain) or aryl (benzene ring) groups.

Amines are everywhere in nature, forming the building blocks of proteins, vitamins, alkaloids, and hormones. They are also crucial in industry for making polymers, dyes, and medicines.

• Adrenaline and Ephedrine: These biologically active compounds contain a secondary amino group and are used to increase blood pressure.
• Novocain: A synthetic amino compound used as a local anesthetic in dentistry.
• Benadryl: A common antihistamine drug that contains a tertiary amino group.
• Quaternary ammonium salts: Used as surfactants (agents that reduce surface tension) in soaps and detergents.

Structure of Amines

Just like in an ammonia molecule, the nitrogen atom in an amine is trivalent, meaning it forms three bonds. It also has an unshared pair of electrons.

• Hybridization: The nitrogen atom in amines is $sp^3$ hybridized.
• Geometry: This hybridization results in a pyramidal geometry. The three $sp^3$ orbitals overlap with orbitals from hydrogen or carbon atoms, while the fourth orbital holds the lone pair of electrons.
• Bond Angle: Because the lone pair of electrons repels the bonding pairs more strongly, the bond angle in amines is slightly less than the standard tetrahedral angle of $109.5^{\circ}$. For instance, in trimethylamine ($(CH_3)_3N$), the C-N-C bond angle is $108^{\circ}$.

Classification of Amines

Amines are classified based on how many hydrogen atoms in an ammonia molecule have been replaced by alkyl or aryl groups.

• Primary (1°) Amines: One hydrogen atom is replaced by an R or Ar group. The general formula is $RNH_2$ or $ArNH_2$.
• Secondary (2°) Amines: Two hydrogen atoms are replaced by R or Ar groups. The general formula is $R_2NH$ or $R-NH-R'$. The groups can be the same or different.
• Tertiary (3°) Amines: All three hydrogen atoms are replaced by R or Ar groups. The general formula is $R_3N$ or $R-N(R')-R''$.

Amines can also be described as:

• Simple Amines: When all the alkyl or aryl groups attached to the nitrogen are identical (e.g., $(C_2H_5)_2NH$).
• Mixed Amines: When the groups attached to the nitrogen are different (e.g., $CH_3NHC_2H_5$).

Nomenclature of Amines

Common System

• For aliphatic amines, the name is formed by prefixing the alkyl group to the word "amine," written as one word.
  • Example: $CH_3NH_2$ is methylamine.
• For secondary or tertiary amines with identical groups, prefixes like di- or tri- are used.
  • Example: $(CH_3)_3N$ is trimethylamine.

IUPAC System

• Primary Amines: These are named as alkanamines. The name is derived by replacing the '-e' from the parent alkane's name with the word 'amine'.
  • Example: $CH_3NH_2$ is methanamine.
• If more than one amino group ($-NH_2$) is present, their positions are numbered, and prefixes like 'di-', 'tri-', etc., are used. The '-e' of the alkane name is retained.
  • Example: $H_2N-CH_2-CH_2-NH_2$ is ethane-1,2-diamine.
• Secondary and Tertiary Amines: The largest alkyl/aryl group is considered the parent chain. The other groups attached to the nitrogen are named as substituents, using the locant N- to indicate they are attached to the nitrogen atom.
  • Example 1: $CH_3NHCH_2CH_3$ is N-methylethanamine.
  • Example 2: $(CH_3CH_2)_3N$ is N,N-diethylethanamine.
• Arylamines: For amines where the $-NH_2$ group is attached to a benzene ring, the IUPAC system replaces the '-e' of the arene with 'amine'.
  • Example: $C_6H_5NH_2$ is named benzenamine. However, its common name, aniline, is also an accepted IUPAC name and is widely used.

Preparation of Amines

Amines can be synthesized through several important methods.

1. Reduction of Nitro Compounds

Nitro compounds can be reduced to primary amines using:

• Hydrogen gas ($H_2$) with a catalyst like finely divided nickel (Ni), palladium (Pd), or platinum (Pt).
• Reduction with metals in an acidic medium, such as tin (Sn) with HCl or iron (Fe) with HCl.

$Ar-NO_2 \xrightarrow{H_2/Pd \text{ or } Sn/HCl \text{ or } Fe/HCl} Ar-NH_2$

2. Ammonolysis of Alkyl Halides

This method involves the cleavage of a carbon-halogen (C-X) bond by an ammonia molecule. An alkyl or benzyl halide reacts with an ethanolic solution of ammonia in a sealed tube at 373 K. This is a nucleophilic substitution reaction.

$NH_3 + R-X \rightarrow R-NH_3^+X^- \xrightarrow{NaOH} R-NH_2 + H_2O + NaX$

• Disadvantage: The primary amine formed is also a nucleophile and can react further with the alkyl halide to produce a mixture of secondary amines, tertiary amines, and even a quaternary ammonium salt.
• Control: To get the primary amine as the major product, a large excess of ammonia is used.
• Reactivity Order: The reactivity of halides in this reaction is $RI > RBr > RCl$.

3. Reduction of Nitriles

Nitriles (compounds with a $-C \equiv N$ group) can be reduced to primary amines. This is a useful method for increasing the length of a carbon chain, as the resulting amine has one more carbon atom than the starting material. The reduction can be done using:

• Lithium aluminium hydride ($LiAlH_4$).
• Catalytic hydrogenation ($H_2/Ni$).

$R-C \equiv N \xrightarrow{LiAlH_4 \text{ or } H_2/Ni} R-CH_2-NH_2$

4. Reduction of Amides

Amides are reduced to amines using a strong reducing agent like lithium aluminium hydride ($LiAlH_4$).

$R-CONH_2 \xrightarrow{(i) LiAlH_4 \quad (ii) H_2O} R-CH_2-NH_2$

5. Gabriel Phthalimide Synthesis

This is a classic method specifically for preparing pure primary amines. The steps are:

1. Phthalimide is treated with ethanolic potassium hydroxide (KOH) to form its potassium salt.
2. The potassium salt is heated with an alkyl halide (R-X) to form an N-alkylphthalimide.
3. The N-alkylphthalimide is then hydrolyzed with an alkali (like NaOH) to yield the primary amine ($R-NH_2$).

6. Hoffmann Bromamide Degradation Reaction

In this reaction, an amide is treated with bromine ($Br_2$) in an aqueous or ethanolic solution of sodium hydroxide (NaOH).

• Key Feature: This is a degradation reaction, meaning the amine produced has one carbon atom less than the starting amide. An alkyl or aryl group migrates from the carbonyl carbon to the nitrogen atom.
• Usefulness: This method is excellent for decreasing the length of a carbon chain.

$R-CONH_2 + Br_2 + 4NaOH \rightarrow R-NH_2 + Na_2CO_3 + 2NaBr + 2H_2O$

Solution

(i) Amide for Propanamine

Propanamine ($CH_3CH_2CH_2NH_2$) has three carbon atoms. The Hoffmann reaction removes one carbon atom, so the starting amide must have four carbon atoms. The structure is $CH_3CH_2CH_2CONH_2$. The IUPAC name is Butanamide.

(ii) Amine from Benzamide

Benzamide ($C_6H_5CONH_2$) is an aromatic amide. The Hoffmann degradation will remove the carbonyl ($C=O$) group. The amine formed is $C_6H_5NH_2$. The name is Aniline or Benzenamine.

Physical Properties

State and Odor

• Lower aliphatic amines (like methylamine and ethylamine) are gases at room temperature and have a characteristic fishy odor.
• Primary amines with three or four carbon atoms are liquids, and higher members are solids.
• Aniline and other arylamines are typically colorless liquids but can become colored on storage due to atmospheric oxidation.

Solubility

• Lower aliphatic amines are soluble in water because their $-NH_2$ group can form hydrogen bonds with water molecules.
• As the size of the alkyl group (the hydrophobic part) increases, the solubility in water decreases. Higher amines are essentially insoluble in water.
• Amines are generally soluble in organic solvents like alcohol, ether, and benzene.

Boiling Points

• Primary (1°) and secondary (2°) amines can form intermolecular hydrogen bonds with each other because they have hydrogen atoms attached to the nitrogen. This intermolecular association leads to higher boiling points compared to nonpolar compounds of similar mass.
• The extent of hydrogen bonding is greater in primary amines (two H atoms on N) than in secondary amines (one H atom on N).
• Tertiary (3°) amines cannot form intermolecular hydrogen bonds with each other because they have no hydrogen atoms on the nitrogen.
• Therefore, for isomeric amines, the order of boiling points is: Primary > Secondary > Tertiary.
• Alcohols have higher boiling points than amines of similar mass because the O-H bond is more polar than the N-H bond, leading to stronger hydrogen bonds.

Chemical Reactions

The chemical reactivity of amines is due to two main features: the unshared pair of electrons on the nitrogen atom and the difference in electronegativity between nitrogen and hydrogen. The lone pair allows amines to act as nucleophiles and bases.

1. Basic Character of Amines

Amines are basic in nature and react with acids to form salts. $R-NH_2 + HX \rightarrow R-NH_3^+X^-$ These amine salts are ionic compounds, soluble in water but insoluble in organic solvents like ether. This property is used to separate amines from non-basic organic compounds.

The basic strength of an amine can be quantified by its base dissociation constant ($K_b$) or its $pK_b$ value. $pK_b = -\log K_b$ A stronger base has a larger $K_b$ value and a smaller $pK_b$ value.

Structure-Basicity Relationship

a) Alkanamines versus Ammonia

• Alkyl groups are electron-releasing (+I effect). They push electron density towards the nitrogen atom, making the lone pair more available to accept a proton.
• Therefore, aliphatic amines are generally stronger bases than ammonia.
• In the gaseous phase, the basicity follows the order predicted by the +I effect: Tertiary > Secondary > Primary > $NH_3$.
• In aqueous solution, the trend is more complex due to a combination of three factors:
  1. Inductive Effect (+I): Favors 3° > 2° > 1°.
  2. Solvation Effect: The substituted ammonium cation formed after accepting a proton is stabilized by hydrogen bonding with water. A primary ammonium ion ($RNH_3^+$) can form more H-bonds than a secondary ion ($R_2NH_2^+$), which in turn forms more than a tertiary ion ($R_3NH^+$). This effect favors 1° > 2° > 3°.
  3. Steric Hindrance: Bulky alkyl groups can hinder the approach of a proton and also interfere with solvation.
• The interplay of these factors leads to the following observed orders of basicity in water:
  • For ethyl groups: $(C_2H_5)_2NH > (C_2H_5)_3N > C_2H_5NH_2 > NH_3$
  • For methyl groups: $(CH_3)_2NH > CH_3NH_2 > (CH_3)_3N > NH_3$

b) Arylamines versus Ammonia

• Aromatic amines are much weaker bases than ammonia.
• In aniline ($C_6H_5NH_2$), the lone pair of electrons on the nitrogen is in conjugation with the benzene ring. It is delocalized into the ring through resonance.
• This delocalization makes the lone pair less available for donation to a proton.
• Furthermore, the anilinium ion formed after protonation has fewer resonance structures than aniline itself, making it less stable.
• Effect of Substituents:
  • Electron-releasing groups (like $-CH_3, -OCH_3$) on the ring increase the basic strength.
  • Electron-withdrawing groups (like $-NO_2, -X, -COOH$) decrease the basic strength.

Solution

The basic strength depends on the availability of the lone pair on the nitrogen atom.

• $(C_2H_5)_2NH$ (diethylamine) is a secondary aliphatic amine with two electron-donating ethyl groups, making it the strongest base.
• $C_2H_5NH_2$ (ethylamine) is a primary aliphatic amine, stronger than ammonia due to the +I effect of the ethyl group.
• $NH_3$ (ammonia) is the baseline.
• $C_6H_5NH_2$ (aniline) is an aromatic amine, where the lone pair is delocalized into the benzene ring, making it the weakest base.

The decreasing order of basic strength is: $(C_2H_5)_2NH > C_2H_5NH_2 > NH_3 > C_6H_5NH_2$

2. Alkylation

Amines can react with alkyl halides to form secondary amines, tertiary amines, and quaternary ammonium salts.

3. Acylation

Primary and secondary amines react with acid chlorides, anhydrides, and esters in a nucleophilic substitution reaction to form amides. This reaction is called acylation. The reaction is often carried out in the presence of a base like pyridine, which is stronger than the amine and neutralizes the HCl formed, shifting the equilibrium to the right. $C_2H_5NH_2 + CH_3COCl \xrightarrow{\text{Pyridine}} C_2H_5NHCOCH_3 + HCl$ The reaction with benzoyl chloride ($C_6H_5COCl$) is specifically called benzoylation.

4. Carbylamine Reaction (Isocyanide Test)

This is a specific test for primary amines (both aliphatic and aromatic). When a primary amine is heated with chloroform ($CHCl_3$) and ethanolic potassium hydroxide (KOH), it forms an isocyanide (or carbylamine), which has an extremely foul smell. $R-NH_2 + CHCl_3 + 3KOH \xrightarrow{\text{Heat}} R-NC + 3KCl + 3H_2O$ Secondary and tertiary amines do not give this test.

5. Reaction with Nitrous Acid ($HNO_2$)

Nitrous acid is unstable and is prepared in situ by reacting sodium nitrite ($NaNO_2$) with a mineral acid like HCl. Different classes of amines react differently.

• Primary Aliphatic Amines: React to form an unstable aliphatic diazonium salt, which immediately decomposes to liberate nitrogen gas and form an alcohol. $R-NH_2 + HNO_2 \rightarrow [R-N_2^+Cl^-] \xrightarrow{H_2O} ROH + N_2 + HCl$
• Primary Aromatic Amines: React at low temperatures (273-278 K) to form a relatively stable arenediazonium salt. This reaction is called diazotisation. $C_6H_5-NH_2 + NaNO_2 + 2HCl \xrightarrow{273-278 \text{ K}} C_6H_5-N_2^+Cl^- + NaCl + 2H_2O$

6. Reaction with Arylsulphonyl Chloride (Hinsberg's Test)

This reaction is used to distinguish between primary, secondary, and tertiary amines using benzenesulphonyl chloride ($C_6H_5SO_2Cl$), also known as Hinsberg's reagent.

• Primary Amine: Reacts to form an N-alkylbenzenesulphonamide. The hydrogen attached to the nitrogen in this product is acidic, so the product dissolves in alkali (like KOH).
• Secondary Amine: Reacts to form an N,N-dialkylbenzenesulphonamide. This product has no hydrogen attached to the nitrogen, so it is not acidic and is insoluble in alkali.
• Tertiary Amine: Does not react with Hinsberg's reagent.

7. Electrophilic Substitution in Aromatic Amines

The $-NH_2$ group is a powerful activating group and is ortho- and para-directing. It increases the electron density at the ortho and para positions of the benzene ring, making aromatic amines highly reactive towards electrophilic substitution.

a) Bromination Aniline reacts with bromine water at room temperature to give a white precipitate of 2,4,6-tribromoaniline immediately. To obtain a monosubstituted product (like p-bromoaniline), the high reactivity of the amino group must be controlled. This is done by protecting the $-NH_2$ group through acetylation (reacting it with acetic anhydride). The resulting acetanilide ($-NHCOCH_3$) group is still ortho-, para-directing but is much less activating. After bromination, the acetyl group can be removed by hydrolysis to get the desired product.

b) Nitration Direct nitration of aniline with a mixture of concentrated $HNO_3$ and $H_2SO_4$ is problematic because:

1. It leads to tarry oxidation products.
2. In the strongly acidic medium, aniline gets protonated to form the anilinium ion ($-NH_3^+$), which is a meta-directing group. This results in a significant amount of m-nitroaniline (47%) along with the expected para (51%) and ortho (2%) isomers. To get the p-nitro derivative as the major product, the amino group is first protected by acetylation, followed by nitration and then hydrolysis.

c) Sulphonation Aniline reacts with concentrated sulphuric acid to form anilinium hydrogensulphate. On heating at 453-473 K, this rearranges to form p-aminobenzenesulphonic acid, commonly known as sulphanilic acid. Sulphanilic acid exists as a dipolar ion or zwitterion.

Diazonium Salts

Diazonium salts are a class of organic compounds with the general formula $ArN_2^+X^-$, where Ar is an aryl group and X⁻ can be an anion like $Cl^-, Br^-, HSO_4^-$, etc. The $N_2^+$ group is called the diazonium group.

• Example: $C_6H_5N_2^+Cl^-$ is named benzenediazonium chloride.

Preparation of Diazonium Salts

Aromatic diazonium salts are prepared by treating a primary aromatic amine, dissolved or suspended in a cold aqueous mineral acid, with sodium nitrite at a low temperature (273-278 K). This process is known as diazotisation. $C_6H_5NH_2 + NaNO_2 + 2HCl \xrightarrow{273-278 \text{ K}} C_6H_5N_2^+Cl^- + NaCl + 2H_2O$

Stability

Arenediazonium salts are more stable than alkyldiazonium salts due to the delocalization of the positive charge over the benzene ring through resonance. However, they are still unstable and are typically used immediately after preparation without being isolated.

Chemical Reactions

The reactions of diazonium salts are incredibly useful in synthesis and can be divided into two main categories.

A. Reactions Involving Displacement of Nitrogen

The diazonium group ($-N_2^+$) is an excellent leaving group (as stable $N_2$ gas) and can be replaced by a variety of nucleophiles.

1. Replacement by Halide or Cyanide Ion (Sandmeyer Reaction): The $Cl^-, Br^-$, or $CN^-$ ion can be introduced into the benzene ring by treating the diazonium salt solution with the corresponding copper(I) salt ($CuCl/HCl, CuBr/HBr, CuCN/KCN$). $ArN_2^+X^- \xrightarrow{CuCN/KCN} ArCN + N_2$
2. Gattermann Reaction: This is an alternative to the Sandmeyer reaction for introducing chlorine or bromine, using copper powder and the corresponding halogen acid. The yield is generally better with the Sandmeyer reaction.
3. Replacement by Iodide Ion: Iodobenzene is formed by simply warming the diazonium salt solution with potassium iodide (KI). $ArN_2^+Cl^- + KI \rightarrow ArI + KCl + N_2$
4. Replacement by Fluoride Ion: An arenediazonium salt is treated with fluoroboric acid ($HBF_4$) to precipitate arene diazonium fluoroborate, which upon heating decomposes to yield an aryl fluoride.
5. Replacement by H (Deamination): The diazonium group can be replaced by a hydrogen atom, effectively removing the amino group from the ring. This is done using mild reducing agents like hypophosphorous acid ($H_3PO_2$) or ethanol ($C_2H_5OH$). $ArN_2^+Cl^- + H_3PO_2 + H_2O \rightarrow ArH + N_2 + H_3PO_3 + HCl$
6. Replacement by Hydroxyl Group: Phenol is formed when the diazonium salt solution is warmed to about 283 K, causing it to hydrolyze. $ArN_2^+Cl^- + H_2O \xrightarrow{\text{Warm}} ArOH + N_2 + HCl$

B. Reactions Involving Retention of Diazo Group (Coupling Reactions)

In these reactions, the diazonium salt acts as an electrophile and attacks another electron-rich aromatic ring (like phenol or aniline) to form brightly colored azo compounds (containing the $-N=N-$ bond). This is an electrophilic substitution reaction.

• Reaction with Phenol: Benzenediazonium chloride reacts with phenol in a mildly alkaline medium (pH 9-10) to form p-hydroxyazobenzene, an orange dye.
• Reaction with Aniline: It reacts with aniline in a mildly acidic medium (pH 4-5) to form p-aminoazobenzene, a yellow dye.

Importance of Diazonium Salts in Synthesis

Diazonium salts are extremely valuable intermediates in organic synthesis. They allow for the introduction of functional groups ($-F, -Cl, -Br, -I, -CN, -OH, -NO_2$) onto an aromatic ring, many of which are difficult or impossible to introduce by direct substitution. For example, aryl fluorides and iodides cannot be made by direct halogenation, but are easily prepared via diazonium salts. This makes them a cornerstone of aromatic chemistry.

Solution

This is a multi-step synthesis that showcases the utility of different reactions.

1. Reduction of the Nitro Group: The starting material is 4-nitrotoluene. First, reduce the nitro group to an amino group using Sn/HCl or Fe/HCl to get 4-methylaniline (p-toluidine).
2. Protection of the Amino Group: To avoid side reactions during oxidation, protect the highly activating amino group by acetylation with acetic anhydride. This forms N-(4-methylphenyl)ethanamide.
3. Oxidation of the Methyl Group: The methyl group can now be oxidized to a carboxylic acid group using a strong oxidizing agent like alkaline $KMnO_4$, followed by acidification. This yields 4-acetamidobenzoic acid.
4. Bromination: Now, perform bromination. The acetamido group is ortho-, para-directing. Since the para position is blocked by the carboxyl group, bromine will add to an ortho position. Reacting with $Br_2$ in acetic acid gives 2-bromo-4-acetamidobenzoic acid.
5. Deprotection (Removal of Acetyl Group): Hydrolyze the acetamido group back to an amino group by heating with aqueous acid or base. This gives 2-bromo-4-aminobenzoic acid.
6. Deamination (Removal of Amino Group): The final step is to remove the amino group. This is done via diazotisation followed by reduction.
   • React with $NaNO_2/H_2SO_4$ at 0-5°C to form the diazonium salt.
   • Treat the diazonium salt with hypophosphorous acid ($H_3PO_2$) to replace the diazonium group with hydrogen.

This sequence of reactions yields the final product, 2-bromobenzoic acid.