Unit 5: Sulphur & Nitrogen Containing Functional Groups

1. Sulphur Containing Functional Groups

Thiols (Mercaptans)

Thiols are organic compounds containing the sulfhydryl group (-SH) attached to an alkyl or aryl carbon chain. They are the sulphur analogues of alcohols (R-OH) and are historically referred to as mercaptans due to their strong affinity to capture mercury ions.

Definition: Thiols are organosulphur compounds characterized by the general chemical formula R-SH, where R represents an alkyl or aryl group.

Preparation of Thiols

1. From Alkyl Halides (Nucleophilic Substitution): Heating an alkyl halide with excess sodium hydrosulphide (NaSH) in alcoholic solution yields thiols via an SN2 mechanism.

   R-X + NaSH -> R-SH + NaX

   Example: CH3CH2Br + NaSH -> CH3CH2SH (Ethanethiol) + NaBr.
2. From Grignard Reagents: Reaction of Grignard reagents with elemental sulphur forms a thiolate intermediate, which yields a thiol upon acid hydrolysis.

   R-MgX + S -> R-S-MgX
   R-S-MgX + H3O+ -> R-SH + Mg(OH)X

Reactions of Thiols

• Acidity and Salt Formation: Thiols are significantly more acidic than alcohols because the S-H bond is weaker than the O-H bond, and the thiolate anion (R-S-) is larger and better stabilizes negative charge. Thiols react readily with aqueous bases.

  R-SH + NaOH -> R-SNa + H2O

• Reaction with Heavy Metals: Thiols react with salts of heavy metals such as mercury(II), lead, and arsenic to form insoluble mercaptides.

  2 R-SH + HgCl2 -> (R-S)2Hg + 2 HCl

• Oxidation Reactions: Mild oxidation of thiols with iodine (I2) or hydrogen peroxide (H2O2) produces disulphides. Strong oxidation with nitric acid (HNO3) oxidizes thiols to sulphonic acids.

  2 R-SH + [O] -> R-S-S-R + H2O (Disulphide)
  R-SH + 3 [O] -> R-SO3H (Sulphonic acid)

• Thioester Formation: Reaction of thiols with carboxylic acids or acyl chlorides produces thioesters.

  R-SH + R'-COOH -> R'-CO-S-R + H2O

Thioethers (Alkyl Sulphides)

Thioethers are sulphur analogues of ethers with the general structure R-S-R'. The sulphur atom is sp3 hybridized with two lone pairs of electrons.

Preparation of Thioethers

1. Williamson-Type Reaction (Alkylating Sodium Mercaptides): Treatment of sodium thiolate with an alkyl halide yields a thioether.

   R-S-Na + R'-X -> R-S-R' + NaX

2. From Alkyl Halides and Sodium Sulphide: Heating an excess of alkyl halide with potassium or sodium sulphide produces symmetrical thioethers.

   2 R-X + Na2S -> R-S-R + 2 NaX

Reactions of Thioethers

• Oxidation: Controlled oxidation with hydrogen peroxide (H2O2) yields sulphoxides, while strong oxidation with potassium permanganate (KMnO4) yields sulphones.

  R-S-R + [O] -> R-SO-R (Sulphoxide)
  R-SO-R + [O] -> R-SO2-R (Sulphone)

• Formation of Sulphonium Salts: Due to the nucleophilicity of the sulphur atom, thioethers react with alkyl halides to form trialkylsulphonium salts.

  R-S-R + R'-I -> [R2R'S]+ I-

Sulphonic Acids

Sulphonic acids contain the -SO3H group directly attached to an alkyl or aryl carbon. Aromatic sulphonic acids are highly stable, water-soluble, strong organic acids.

Preparation of Sulphonic Acids

1. Direct Sulfonation of Aromatic Compounds: Benzene reacts with concentrated sulphuric acid or fuming sulphuric acid (oleum) upon heating.

   Ar-H + H2SO4 -> Ar-SO3H + H2O

2. Oxidation of Thiols: Vigorous oxidation of thiols using concentrated nitric acid.

   R-SH + 3 [O] -> R-SO3H

Reactions of Sulphonic Acids

• Acidity: Sulphonic acids are strong organic acids comparable in strength to mineral acids (HCl, H2SO4) due to resonance stabilization of the sulphonate anion across three oxygen atoms.

  Ar-SO3H + NaOH -> Ar-SO3Na + H2O

• Conversion to Sulphonyl Chlorides: Treatment with PCl5 or SOCl2 converts sulphonic acids into sulphonyl chlorides.

  Ar-SO3H + PCl5 -> Ar-SO2Cl + POCl3 + HCl

• Desulfonation (Hydrolysis): Heating aromatic sulphonic acids with superheated steam in the presence of dilute acid removes the sulphonic acid group (protodesulfonation).

  Ar-SO3H + H2O + H+ (heat) -> Ar-H + H2SO4

• Nucleophilic Substitution (Phenol Synthesis): Fusion of sodium sulphonates with solid NaOH at high temperatures yields sodium phenoxide, which upon acidification gives phenols.

  Ar-SO3Na + 2 NaOH -> Ar-ONa + Na2SO3 + H2O

2. Nitro Compounds, Nitriles, and Isonitriles

Nitro Compounds

Nitro compounds contain the -NO2 group attached to a carbon atom. They display nitro-aci tautomerism when alpha-hydrogens are present.

Preparation of Nitro Compounds

1. Nitration of Aromatic Rings: Aromatic compounds undergo electrophilic substitution using nitrating mixture (conc. HNO3 + conc. H2SO4).

   Ar-H + HNO3 (H2SO4) -> Ar-NO2 + H2O

2. Reaction of Alkyl Halides with Silver Nitrite: Alkyl halides react with AgNO2 to form nitroalkanes as the major product (due to the nucleophilic attack of the nitrogen atom).

   R-X + AgNO2 -> R-NO2 + AgX

   Exam Note: Reaction with NaNO2 yields alkyl nitrites (R-ONO) as the primary product due to ionic nature.

Important Reactions of Nitro Compounds

• Reduction Reactions: The reduction product depends heavily on the reaction medium:
  • Acidic Medium (Sn/HCl or Fe/HCl): Complete reduction to primary amines.

    R-NO2 + 6 [H] -> R-NH2 + 2 H2O

  • Neutral Medium (Zn/NH4Cl): Reduction yields N-arylhydroxylamines.

    Ar-NO2 + 4 [H] -> Ar-NHOH + H2O

  • Alkaline Medium: Bimolecular reduction of nitrobenzene yields azoxybenzene, azobenzene, or hydrazobenzene depending on the specific reducing agent used (e.g., Zn/NaOH).
• Reaction with Nitrous Acid (Distinction Test for Nitroalkanes):
  • Primary Nitroalkanes (1°): React with HNO2 to produce nitrolic acids, which dissolve in NaOH to yield a blood-red solution.
  • Secondary Nitroalkanes (2°): React with HNO2 to produce pseudonitrols, which are insoluble in base and give a blue color in organic solvents.
  • Tertiary Nitroalkanes (3°): Do not react with HNO2 due to the absence of alpha-hydrogens.

Nitriles (R-CN) and Isonitriles (R-NC)

3. Amines: Basicity, Synthesis, and Key Reactions

Basicity of Amines

Amines act as Lewis bases and Brønsted-Lowry bases due to the presence of an unshared lone pair of electrons on the nitrogen atom.

Basicity Concept: The strength of an amine as a base depends on the availability of the nitrogen lone pair for protonation and the stabilization of the resulting conjugate acid (alkylammonium ion).

Effect of Substituents on Basicity

• Electron-Donating Groups (+I Effect): Alkyl groups release electron density towards nitrogen, increasing lone pair availability and stabilizing the alkylammonium cation. Thus, aliphatic amines are stronger bases than ammonia.
• Electron-Withdrawing Groups (-I, -R Effect): Groups such as -NO2, -CN, and halogens withdraw electron density, reducing basicity.
• Resonance Effect in Aromatic Amines: Aniline is a significantly weaker base than aliphatic amines and ammonia because the nitrogen lone pair is delocalized into the aromatic pi-system via resonance.

Effect of Solvent on Amine Basicity

Basicity trends vary drastically between the gas phase and aqueous medium:

• Gas Phase Order: Pure inductive (+I) effect dominates:

  Tertiary Amine (3°) > Secondary Amine (2°) > Primary Amine (1°) > Ammonia (NH3)

• Aqueous Phase Order: Controlled by a combination of three factors: inductive effect (+I), solvation energy (hydrogen bonding of conjugate acid with water), and steric hindrance.
  • Methyl Substituents (-CH3): Dimethylamine (2°) > Methylamine (1°) > Trimethylamine (3°) > NH3
    Formula Order: 2° > 1° > 3° > NH3
  • Ethyl Substituents (-C2H5): Diethylamine (2°) > Triethylamine (3°) > Ethylamine (1°) > NH3
    Formula Order: 2° > 3° > 1° > NH3

Preparation and Properties: Named Reactions

1. Gabriel Phthalimide Synthesis

A selective method for preparing pure primary aliphatic amines without contamination of secondary or tertiary amines.

• Step 1: Phthalimide is treated with ethanolic KOH to form potassium phthalimide.
• Step 2: Potassium phthalimide undergoes nucleophilic substitution (SN2) with a primary alkyl halide to form N-alkylphthalimide.
• Step 3: Alkaline hydrolysis or hydrazinolysis of N-alkylphthalimide yields the primary aliphatic amine and phthalic hydrazide/salt.

Phthalimide + KOH -> Potassium Phthalimide + H2O
Potassium Phthalimide + R-X -> N-Alkylphthalimide + KX
N-Alkylphthalimide + H2NNH2 -> R-NH2 + Phthalic Hydrazide

Important Limitation: Primary aromatic amines (e.g., aniline) cannot be prepared by Gabriel phthalimide synthesis because aryl halides do not undergo nucleophilic substitution reactions under normal conditions.

2. Carbylamine Reaction (Isocyanide Test)

A specific qualitative test for detecting primary amines (both aliphatic and aromatic).

• Reaction: Heating a primary amine with chloroform (CHCl3) and alcoholic potassium hydroxide (KOH) produces an extremely foul-smelling alkyl/aryl isocyanide (carbylamine).

R-NH2 + CHCl3 + 3 KOH (alc.) (heat) -> R-NC + 3 KCl + 3 H2O

Exam Note: Secondary and tertiary amines do not show this reaction because they lack two hydrogens on nitrogen necessary for the elimination steps.

3. Mannich Reaction

The Mannich reaction involves the condensation of an enolizable compound (containing an active alpha-hydrogen, e.g., ketones), formaldehyde, and a primary or secondary amine (or ammonia) in acidic medium to form a beta-amino carbonyl compound, known as a Mannich base.

CH3-CO-CH3 + HCHO + R2NH + HCl -> R2N-CH2-CH2-CO-CH3 + H2O

4. Hoffmann's Exhaustive Methylation

The process of converting an amine into its quaternary ammonium salt by repeated nucleophilic substitution with excess methyl iodide (CH3I).

R-NH2 + 3 CH3I -> [R-N(CH3)3]+ I- + 2 HI

5. Hofmann Elimination Reaction

When a quaternary ammonium hydroxide is heated, it undergoes an E2 elimination to yield an alkene, a tertiary amine, and water.

• Mechanism & Regioselectivity: Unlike Saytzeff elimination (which yields the most substituted alkene), Hofmann elimination preferentially yields the least substituted (least alkylated) alkene as the major product.
• Reason: Steric bulk of the trialkylamine leaving group (-NR3+) and the acidic nature of the least hindered beta-hydrogen direct the base to abstract a proton leading to the carbanion-like transition state.

[CH3-CH2-CH(CH3)-N(CH3)3]+ OH- (heat) -> CH2=CH-CH2-CH3 (1-Butene, Major) + N(CH3)3 + H2O

4. Distinction Between 1°, 2°, and 3° Amines

Distinction Using Hinsberg Reagent

Hinsberg reagent is benzenesulphonyl chloride (C6H5SO2Cl). It distinguishes primary, secondary, and tertiary amines based on their reaction behavior and solubility of products in alkali (KOH/NaOH).

Distinction Using Nitrous Acid (HNO2)

Nitrous acid (prepared in situ: NaNO2 + HCl at 0–5 °C) reacts differently with 1°, 2°, and 3° amines:

5. Diazonium Salts: Preparation and Synthetic Applications

Preparation of Diazonium Salts (Diazotization)

Arenediazonium salts are prepared by reacting a primary aromatic amine (such as aniline) with nitrous acid (NaNO2 + HCl) at cold temperatures (273 K to 278 K or 0 °C to 5 °C).

Ar-NH2 + NaNO2 + 2 HCl (0–5 °C) -> Ar-N2+ Cl- + NaCl + 2 H2O

Crucial Reaction Condition: Temperature must be strictly maintained between 0 °C and 5 °C. Above 5 °C, diazonium salts hydrolyze rapidly to form phenol with the evolution of nitrogen gas.

Synthetic Applications of Diazonium Salts

Diazonium salts are extremely versatile synthetic intermediates because the -N2+ group is an excellent leaving group.

A. Reactions Involving Replacement (Displacement) of Nitrogen

1. Sandmeyer Reaction (Replacement by -Cl, -Br, -CN): Treatment with cuprous salts dissolved in corresponding halogen acids or KCN.

   Ar-N2+ Cl- + CuCl / HCl -> Ar-Cl + N2
   Ar-N2+ Cl- + CuBr / HBr -> Ar-Br + N2
   Ar-N2+ Cl- + CuCN / KCN -> Ar-CN + N2

2. Gattermann Reaction: Modification of Sandmeyer reaction using copper powder in presence of halogen acid.

   Ar-N2+ Cl- + Cu / HCl -> Ar-Cl + N2 + CuCl

3. Replacement by Iodine (-I): Warming diazonium salt solution with potassium iodide (KI) solution.

   Ar-N2+ Cl- + KI (warm) -> Ar-I + N2 + KCl

4. Schiemann Reaction (Replacement by Fluorine -F): Treatment with fluoroboric acid (HBF4) precipitates diazonium fluoroborate, which yields aryl fluoride upon dry heating.

   Ar-N2+ Cl- + HBF4 -> Ar-N2+ BF4- (heat) -> Ar-F + N2 + BF3

5. Deamination / Replacement by Hydrogen (-H): Reduction with hypophosphorous acid (H3PO2) or ethanol (CH3CH2OH) yields parent aromatic hydrocarbon.

   Ar-N2+ Cl- + H3PO2 + H2O -> Ar-H + H3PO3 + N2 + HCl
   Ar-N2+ Cl- + CH3CH2OH -> Ar-H + CH3CHO + N2 + HCl

6. Replacement by Hydroxyl Group (-OH): Boiling or warming the aqueous diazonium salt solution with dilute sulphuric acid.

   Ar-N2+ Cl- + H2O (boil with H2SO4) -> Ar-OH + N2 + HCl

7. Replacement by Nitro Group (-NO2): Reacting diazonium fluoroborate with aqueous NaNO2 in the presence of copper powder upon heating.

   Ar-N2+ BF4- + NaNO2 (Cu, heat) -> Ar-NO2 + N2 + NaBF4

B. Reactions Retaining Nitrogen (Coupling Reactions)

Diazonium salts act as weak electrophiles and react with electron-rich aromatic compounds like phenols and aromatic amines to form bright colored azo dyes (-N=N- linkage).

• Coupling with Phenol: Reaction in weakly alkaline medium (pH 9–10) produces an orange dye (p-hydroxyazobenzene).

  Ar-N2+ Cl- + C6H5OH (pH 9-10) -> Ar-N=N-C6H4-OH (p-hydroxyazobenzene) + HCl

• Coupling with Aniline: Reaction in weakly acidic medium (pH 4–5) produces a yellow dye (p-aminoazobenzene).

  Ar-N2+ Cl- + C6H5NH2 (pH 4-5) -> Ar-N=N-C6H4-NH2 (p-aminoazobenzene) + HCl