B Pharmacy Sem 4: Pharmaceutical Organic Chemistry III

Subject: Pharmaceutical Organic Chemistry III

1. Aromatic Electrophilic Substitution Reactions (Nitration, Sulfonation, Halogenation, Friedel–Crafts)
    2. Aromatic Nucleophilic Substitution Reactions
    3. Heterocyclic Chemistry (Five‐ and Six‐Membered Rings; Synthesis & Reactions of Pyrrole, Furan, Thiophene, Pyridine, Quinoline)
    4. Chemistry of Steroids and Antibiotics (Structural Features & Key Synthetic Steps)
    5. Pharmaceuticals: NSAIDs, Sulfa Drugs & Their Mechanisms
    6. Named Organic Reactions & Mechanisms (Wurtz, Sandmeyer, Reimer–Tiemann, etc.)

Unit 1: Aromatic Electrophilic Substitution Reactions

This unit delves into the principles, mechanisms, and pharmaceutical relevance of electrophilic substitution on aromatic rings, covering nitration, sulfonation, halogenation, and Friedel–Crafts reactions.

1.1 Overview & General Mechanism

1.1.1 Definition

• Reactions in which an electrophile (E⁺) replaces a hydrogen atom on an aromatic ring without disrupting aromaticity.

1.1.2 Mechanistic Steps

1. Formation of Electrophile: Generation of a strong electrophile (e.g., NO₂⁺, SO₃H⁺, Cl⁺).

2. σ‑Complex (Wheland Intermediate): Electrophile attacks the π‐system, forming a resonance‑stabilized arenium ion.

3. Deprotonation & Aromaticity Restoration: A base removes H⁺ from the σ‑complex, regenerating the aromatic system.

1.1.3 Factors Affecting Reactivity & Orientation

• Activating vs. Deactivating Groups:

  • Activators (–OH, –OCH₃) increase rate, direct ortho/para.

  • Deactivators (–NO₂, –C≡O) decrease rate, direct meta (unless strongly deactivating).

• Steric Effects: Bulky substituents can hinder approach at ortho positions.

1.2 Nitration

1.2.1 Generation of Electrophile

• Mixed acid: HNO₃ + H₂SO₄ → NO₂⁺ + HSO₄⁻ + H₂O.

1.2.2 Reaction Conditions & Regioselectivity

• Temperature control (0–30 °C) to minimize poly‑nitration.

• Activating groups favor ortho/para; deactivators favor meta.

1.2.3 Pharmaceutical Applications

• Sulfa Drug Precursors: p‑Aminobenzoic acid nitration → p‑nitrobenzoic acid, reduced to p‑aminobenzoic acid.

• Aryl Nitro Intermediates: Building blocks for aniline derivatives in antihistamines.

1.3 Sulfonation

1.3.1 Electrophile Formation

• Fuming sulfuric acid (oleum): SO₃ + H₂SO₄ ↔ HSO₃⁺ + HSO₄⁻.

1.3.2 Equilibrium & Reversibility

• High temperature drives desulfonation; low temperature (25–50 °C) favors sulfonation.

1.3.3 Uses in Drug Synthesis

• Water‑Soluble Salts: Sulfonic acids (e.g., sulfonamide antibiotics) improve aqueous solubility.

• Protecting Group Strategy: Temporary sulfonation to block positions during multi‑step syntheses.

1.4 Halogenation

1.4.1 Chlorination & Bromination

• Catalyst: FeCl₃ or AlCl₃ for Cl₂; FeBr₃ for Br₂ → generates Cl⁺ or Br⁺.

• Selectivity: Activators direct ortho/para; deactivators meta.

1.4.2 Iodination & Fluorination

• Iodination: I₂ + oxidizer (HNO₃ or H₂O₂) → I⁺.

• Fluorination: More challenging; often uses electrophilic reagents like Selectfluor.

1.4.3 Medicinal Chemistry Relevance

• Halogenated Analogs: Modulate lipophilicity, metabolic stability, and receptor binding (e.g., chlorpromazine).

• Radiolabeling: I‑131 or F‑18 incorporation for diagnostic imaging.

1.5 Friedel–Crafts Reactions

1.5.1 Alkylation

• Electrophile: RCl + AlCl₃ → R⁺.

• Limitations: Rearrangement of carbocations; polyalkylation; deactivated rings unreactive.

1.5.2 Acylation

• Electrophile: RCOCl + AlCl₃ → RCO⁺.

• Advantages: Deactivating acyl group prevents poly‑substitution; can be reduced later to alkyl.

1.5.3 Pharmaceutical Examples

• Ketone Intermediates: Acylation to introduce benzoyl motifs in analgesics.

• Spiro and Bicyclic Scaffolds: Friedel–Crafts cyclizations in steroid and alkaloid synthesis.

1.6 Key Mechanistic Insights & Named Reactions

1.6.1 Arenium Ion Stability

• Resonance forms; substituent effects critical for transition‐state stabilization.

1.6.2 Common Pitfalls

• Over‑reaction (polysubstitution), catalyst poisoning (deactivator groups), carbocation rearrangements.

1.6.3 Named Transformations

• Gattermann–Koch Formylation (CO + HCl, AlCl₃/CuCl): Introduce –CHO on benzene.

• Vilsmeier–Haack Reaction (DMF + POCl₃): Formylation of activated aromatics.

1.7 Key Points for Exams

1. Draw Mechanisms: Full curved‐arrow mechanism for nitration and Friedel–Crafts acylation.

2. Predict Products & Orientation: Given substituents, identify major isomer(s).

3. Pharma Applications: Cite two examples where each type of reaction is used in drug synthesis.

4. Compare Reactions: Advantages of Friedel–Crafts acylation vs. alkylation.

5. Troubleshooting: Explain why polyalkylation occurs and strategies to avoid it.

Unit 2: Aromatic Nucleophilic Substitution Reactions

This unit examines how nucleophiles replace leaving groups on aromatic rings, focusing on the two main mechanisms—addition–elimination and benzyne pathways—and their relevance in pharmaceutical synthesis.

2.1 Overview & General Concepts

2.1.1 Definition

• Replacement of an aromatic “leaving group” (commonly –NO₂, –Cl, –F) by a nucleophile (Nu⁻) under conditions that preserve or restore aromaticity.

2.1.2 Two Principal Mechanisms

1. Addition–Elimination (SₙAr): Requires strong electron‑withdrawing groups ortho/para to the leaving group to stabilize the σ‑complex.

2. Benzyne Mechanism: Occurs under harsh conditions when no activating groups are present; involves elimination to form a highly reactive benzyne intermediate.

2.2 Addition–Elimination (SₙAr)

2.2.1 Mechanistic Steps

1. Nucleophilic Attack: Nu⁻ attacks the carbon bearing the leaving group, forming a non‑aromatic σ‑complex (Meisenheimer complex).

2. Elimination: Departure of the leaving group (e.g., Cl⁻, F⁻) restores aromaticity.

2.2.2 Structural Requirements

• Activating Groups: Strong electron‑withdrawing substituents (–NO₂, –CN, –SO₂R) at ortho/para positions increase reactivity.

• Leaving Groups: Fluoride is often most reactive in SₙAr due to its strong inductive stabilization of the intermediate.

2.2.3 Reaction Conditions

• Polar aprotic solvents (DMF, DMSO) to stabilize the nucleophile.

• Elevated temperatures (80–150 °C) or phase‑transfer catalysis for sluggish systems.

2.2.4 Pharmaceutical Applications

• Sulfonamide Synthesis: Nucleophilic displacement of chlorobenzenes to yield aryl sulfonamides (e.g., sulfamethoxazole).

• Radiolabeling: ^18F–fluoride incorporation into aromatic rings for PET tracers via SₙAr on nitroarenes.

2.3 Benzyne Mechanism

2.3.1 Formation of Benzyne

• Strong base (NaNH₂, t‑BuOK) induces elimination of HX (often H and a leaving group) to generate a triple‑bonded benzene intermediate.

2.3.2 Nucleophilic Capture

• Nu⁻ adds to one of the benzyne carbons; protonation completes substitution, yielding a mixture of regioisomers.

2.3.3 Conditions & Limitations

• Requires very strong bases and high temperatures (>200 °C).

• Poor regioselectivity—often yields ortho and meta substituted isomers.

2.3.4 Drug Industry Examples

• Aniline Synthesis: Historical route to aniline derivatives via benzyne from chlorobenzene; largely supplanted by milder methods.

• Polymer Precursors: Manufacturing of specialty monomers where traditional SₙAr fails.

2.4 Practical Considerations & Variations

2.4.1 Leaving‑Group Effects

• Order of reactivity: F > Cl > Br > I for SₙAr (opposite to electrophilic halogenations).

2.4.2 Nucleophile Types

• Common nucleophiles: alkoxides (–OR), amines (–NH₂), thiolates (–SR), cyanide (–CN).

2.4.3 Catalytic & Phase‑Transfer Methods

• Use of crown ethers or quaternary ammonium salts to transport inorganic nucleophiles into organic phase.

2.5 Key Points for Exams

1. Mechanism Diagrams: Draw curved‑arrow mechanisms for both addition–elimination and benzyne pathways.

2. Predict Reactivity: Given a substituted aryl halide, rank its susceptibility to SₙAr.

3. Regioselectivity Rationale: Explain how ortho/para nitro groups direct and stabilize the Meisenheimer complex.

4. Pharma Examples: Cite one SₙAr route to an important sulfonamide and one ^18F‑labeling procedure.

5. Compare Mechanisms: List pros and cons of addition–elimination vs. benzyne in drug synthesis.

Unit 3: Heterocyclic Chemistry

A comprehensive exploration of five‐ and six‐membered heterocycles—focusing on their structures, methods of synthesis, characteristic reactions, and roles in pharmaceutical compounds.

3.1 Introduction to Heterocyclic Chemistry

3.1.1 Definition & Importance

• Heterocycles are ring systems containing one or more heteroatoms (N, O, S) alongside carbon.

• Over 75% of small‐molecule drugs feature heterocyclic scaffolds—crucial for binding specificity, solubility, and metabolic stability.

3.1.2 Classification

• By Ring Size:

  • Five‑membered: Pyrrole, Furan, Thiophene

  • Six‑membered: Pyridine, Quinoline (fused benzopyridine)

• By Saturation: Aromatic vs. partially or fully saturated analogs (e.g., piperidine, tetrahydrofuran).

3.1.3 Aromaticity Criteria

• Planarity, cyclic conjugation, and Huckel’s rule (4n + 2 π‑electrons) determine aromatic stability.

3.2 Pyrrole

3.2.1 Structure & Properties

• Formula C₄H₅N; 6 π‑electron aromatic ring with the lone pair on N delocalized into the π‑system.

• Relatively acidic N–H (pKa ≈ 17) and highly activated at the 2‑ and 5‑positions for electrophilic substitution.

3.2.2 Key Syntheses

1. Paal–Knorr Synthesis

   • 1,4‑Diketone + ammonia or primary amine → pyrrole (acid‐catalyzed cyclization).

2. Hantzsch Synthesis Variation

   • α‑Amino ketone + α,β‑unsaturated carbonyl → pyrrole under acidic conditions.

3.2.3 Reactions

• Electrophilic Substitution:

  • Nitration, halogenation occur at C‑2/C‑5 under mild conditions.

• Metalation:

  • Lithiation at C‑2 allows for further cross‑coupling or alkylation.

• Oxidation:

  • Over‐oxidation yields maleimide derivatives; controlled oxidation leads to functionalized pyrroles.

3.2.4 Pharmaceutical Relevance

• Prostaglandins: Contain a 5‑membered ring related to pyrrole.

• Anticancer Agents: E.g., select kinase inhibitors use substituted pyrrole cores.

3.3 Furan

3.3.1 Structure & Properties

• Formula C₄H₄O; oxygen’s lone pair partly participates in aromatic sextet.

• More reactive than benzene toward electrophiles; instability under strong acid or heat.

3.3.2 Syntheses

1. Paal–Knorr Furan Synthesis

   • 1,4‑Diketone cyclodehydration under acid or base.

2. Feist–Benary Reaction

   • α‑Halocarbonyl + β‑dicarbonyl + amine catalysis yields substituted furans.

3.3.3 Reactions

• Diels–Alder Donor:

  • Acts as a diene in cycloadditions to build complex ring systems.

• Electrophilic Substitution:

  • Occurs at C‑2, yielding 2‑substituted furans (e.g., formylation, halogenation).

• Ring Opening:

  • Acidic or catalytic hydrogenation can open the ring to 1,4‑dicarbonyls.

3.3.4 Pharmaceutical Uses

• Antimicrobials: Nitrofurans (e.g., nitrofurantoin) rely on furan’s redox chemistry.

• Cardiovascular Drugs: Some calcium‐channel blockers incorporate furan units.

3.4 Thiophene

3.4.1 Structure & Properties

• Formula C₄H₄S; sulfur contributes two electrons to aromatic sextet, conferring high stability.

• Electron‐rich yet less reactive than furan; resistant to strong acids.

3.4.2 Synthetic Routes

1. Paal–Knorr Thiophene Synthesis

   • 1,4‑Diketone + P₄S₁₀ (thionation) → thiophene.

2. Gewald Reaction

   • α‑Cyano ketone + elemental sulfur + base → 2‑aminothiophenes.

3.4.3 Characteristic Reactions

• Electrophilic Substitution:

  • Predominantly at C‑2; nitration, sulfonation, and halogenation under controlled conditions.

• Metal‑Catalyzed Coupling:

  • Suzuki, Stille, or Negishi cross‑coupling at halogenated thiophenes to build conjugated systems.

3.4.4 Drug Applications

• Antipsychotics & Antidepressants: E.g., many carry substituted thiophene rings for CNS activity.

• Anti‑inflammatories: Some COX‑2 inhibitors include thiophene moieties.

3.5 Pyridine

3.5.1 Structure & Properties

• Formula C₅H₅N; six‑membered aromatic ring where N’s lone pair resides in an sp² orbital (not part of π‑system)—accounts for basicity (pKa of conjugate acid ≈ 5.2).

• Deactivated toward electrophiles, activated toward nucleophiles at ortho/para positions.

3.5.2 Synthesis Methods

1. Hantzsch Dihydropyridine Synthesis

   • Aldehyde + two β‑ketoesters + ammonia → dihydropyridine → oxidized to pyridine.

2. Bönnemann Cyclization

   • 1,5‑Diketones + ammonia/trityl salts under heat.

3.5.3 Reaction Chemistry

• Electrophilic Substitution:

  • Requires strong Lewis acids; often leads to N‑oxide intermediates for further functionalization.

• Nucleophilic Substitution:

  • 2‑ and 4‑positions can undergo SₙAr when converted to N‑oxide or with strong leaving groups.

• Quaternization:

  • Formation of pyridinium salts—used as phase‑transfer catalysts or medicinal scaffolds.

3.5.4 Pharmaceutical Significance

• Antituberculars: Isoniazid analogs feature hydrazide‐pyridine cores.

• Cardiovascular Agents: Nicotinic acid (niacin) is a pyridine‐3‐carboxylic acid.

3.6 Quinoline

3.6.1 Structure & Properties

• Fused benzene–pyridine system (C₉H₇N); aromatic in both rings with resonance across the bicyclic structure.

• Basicity similar to pyridine; electrophilic and nucleophilic reactivity localized to the pyridine ring.

3.6.2 Synthetic Strategies

1. Skraup Synthesis

   • Aniline + glycerol + H₂SO₄ + oxidant (nitrobenzene) → quinoline.

2. Friedländer Synthesis

   • 2‑Aminoaryl ketone + carbonyl compound with α‑methylene → quinoline under acidic/basic catalysis.

3.6.3 Reactions & Functionalization

• Electrophilic Substitution:

  • Occurs primarily on the benzene ring; directed by pyridine nitrogen’s -I effect.

• Nucleophilic Addition at C‑2:

  • Grignard or organolithium reagents attack C‑2 of N‑oxide derivatives.

3.6.4 Role in Drug Design

• Antimalarials: Quinine and chloroquine belong to quinoline family.

• Antibacterials & Antineoplastics: Many exhibit intercalating or enzyme‑inhibitory activity through planar quinoline cores.

3.7 Comparative Summary & Applications

3.8 Key Points for Exams

1. Mechanism Sketches: Show Paal–Knorr pyrrole synthesis, Skraup quinoline formation, and a Diels–Alder with furan.

2. Reactivity Trends: Rank five heterocycles by ease of electrophilic substitution.

3. Synthetic Design: Propose a route to 2‑aminothiophene using the Gewald reaction.

4. Pharmaceutical Context: Match five heterocycles to their corresponding drug example and discuss why that ring was chosen.

5. Aromaticity Rationalization: Explain why pyrrole’s lone pair contributes to aromaticity, whereas pyridine’s does not.