B Pharmacy Sem 3: Pharmaceutical Organic Chemistry II

Subject : Pharmaceutical Organic Chemistry II

1. Phenols, Ethers & Epoxides
2. Aldehydes & Ketones
3. Carboxylic Acids & Their Derivatives
4. Amines: Classification, Preparation & Reactions
5. Carbohydrates: Monosaccharides, Disaccharides & Polysaccharides
6. Amino Acids, Peptides & Proteins

Unit 1: Phenols, Ethers & Epoxides

This unit explores three classes of oxygen‑containing organic compounds—phenols, ethers, and epoxides—focusing on their structure, properties, key reactions, synthetic methods, and pharmaceutical relevance.

1.1 Phenols

1.1.1 Structure & Acidity

• General structure: Aromatic ring bearing an –OH substituent.

• Acidity: More acidic (pKa ≈ 10) than aliphatic alcohols due to resonance stabilization of the phenoxide ion.

1.1.2 Electrophilic Aromatic Substitution (EAS)

• Phenolic –OH is a strong ortho/para director and activating group.

• Nitration: Yields ortho‑ and para‑nitrophenol (watch over‑nitration).

• Sulfonation: Gives phenol‑sulfonic acid, reversible by dilute acid.

• Halogenation: Rapid chlorination/bromination in presence of base.

1.1.3 Reactions Specific to Phenols

• Esterification: Phenol + acid chloride → phenyl ester (e.g., aspirin from salicylic acid).

• Etherification: Williamson synthesis (phenoxide + alkyl halide → aryl ether).

• Oxidation: Phenol → quinones under strong oxidants (biologically relevant: coenzyme Q).

1.1.4 Pharmaceutical Examples

• Phenol: Antiseptic.

• Salicylic acid & Aspirin: Analgesic/anti‑inflammatory via phenolic ester.

• Eugenol: Dental analgesic, antiseptic.

1.2 Ethers

1.2.1 Structure & Physical Properties

• General structure: R–O–R′ (R, R′ = alkyl or aryl).

• Boiling points: Lower than alcohols of similar mass (no H‑bonding).

• Solubility: Moderately polar, limited H‑bond acceptor.

1.2.2 Synthesis

• Williamson Ether Synthesis: R–O⁻ + R′–X → R–O–R′ (favours primary halides).

• Acid‑catalyzed dehydration: 2 ROH → R–O–R + H₂O (needs strong acid, high temp).

1.2.3 Reactions

• Cleavage by HX: R–O–R + HBr/HCl → R–Br + R–OH (primary easier than secondary/tertiary).

• Autoxidation: Ethers slowly form peroxides on standing in air (safety hazard).

1.2.4 Pharmaceutical Applications

• Diethyl ether: Historically used as general anesthetic.

• Morphine derivatives: Codeine is a methyl ether of morphine.

1.3 Epoxides (Oxiranes)

1.3.1 Structure & Strain

• Three‑membered cyclic ether; significant ring strain (~27 kcal/mol) → highly reactive.

1.3.2 Synthesis

• Peracid oxidation: Alkene + RCO₃H → epoxide (e.g., mCPBA epoxidation).

• Halohydrin cyclization: Vicinal halohydrin + base → epoxide.

1.3.3 Ring‑Opening Reactions

• Acid‑catalyzed: Nucleophile attacks more substituted carbon (stabilized carbocation-like).

• Base‑catalyzed: Nucleophile attacks less hindered carbon (SN2).

1.3.4 Pharmaceutical Relevance

• Epoxide intermediates in synthesis of β‑blockers, steroids.

• Oxirane‑containing drugs: Epoxide moieties can form covalent bonds with biological nucleophiles (e.g., anticancer agents).

1.4 Key Points for Exams

• Draw resonance structures of phenoxide anion and explain acidity.

• Predict ortho/para vs. meta substitution patterns for phenols.

• Outline Williamson ether synthesis and acid‑catalyzed dehydration.

• Describe mechanisms for epoxidation of alkenes and epoxide ring‑opening under acidic/basic conditions.

• Cite one pharmaceutical example of each class (phenol, ether, epoxide) and its therapeutic role.

Unit 2: Aldehydes & Ketones

This unit covers the structure, reactivity, key synthetic transformations, and pharmaceutical significance of aldehydes and ketones—two pivotal carbonyl-containing functional groups in drug chemistry.

2.1 Structure, Nomenclature & Physical Properties

2.1.1 Carbonyl Group Characteristics

• Geometry: Planar trigonal (sp²) at the carbonyl carbon; C=O bond length ~1.20 Å, bond dipole significant.

• Polarization: Cδ⁺=Oδ⁻ makes carbonyl carbon electrophilic.

2.1.2 IUPAC Nomenclature

• Aldehydes: Replace –e in parent alkane with –al (e.g., ethanal, benzaldehyde).

• Ketones: Replace –e with –one; indicate position if >3 carbons (e.g., pentan-2-one).

2.1.3 Physical Properties

• Boiling Points: Higher than ethers/alcohols of similar weight due to dipole–dipole interactions, but lower than alcohols of similar size (no H‑bonding).

• Solubility: Lower homologues (≤4 C) dissolve in water; solubility decreases with chain length.

2.2 Common Reactions of Aldehydes & Ketones

2.2.1 Nucleophilic Addition to the Carbonyl

• Hydration: R₂C=O + H₂O ⇌ gem‑diol (reversible; favored for formaldehyde).

• Hemiacetal/Acetal Formation (acid‑catalyzed):

  • R–CHO + R′OH ⇌ hemiacetal → R–CH(OR′)₂ (acetal) + H₂O.

  • Protecting strategy for carbonyls in multi-step synthesis.

• Cyanohydrin Formation: R₂C=O + HCN → R₂C(OH)CN; synthetic precursor to α‑hydroxy nitriles.

• Schiff Base (Imine) Formation: R₂C=O + R′NH₂ → R₂C=NR′ + H₂O; key in forming dyes and enzyme inhibitors.

2.2.2 Redox Transformations

• Reduction:

  • Catalytic hydrogenation (H₂/Pd–C) reduces C=O to alcohol.

  • Metal hydrides (NaBH₄ reduces both; LiAlH₄ stronger—also reduces esters, acids).

• Oxidation (aldehydes only):

  • Mild oxidants (Tollens’, Benedict’s) convert R–CHO to R–COOH.

  • Strong oxidants (KMnO₄, CrO₃) under acidic conditions.

2.2.3 α‑Substitution & Condensation

• α‑Halogenation (acidic/base conditions): introduces halogen at α‑carbon.

• Aldol Condensation: 2 R–CHO/Ketone → β‑hydroxy carbonyl → α,β‑unsaturated carbonyl under heat (C–C bond formation).

• Knoevenagel Condensation: Activated methylene (e.g., malonate) + aldehyde → α,β‑unsaturated product.

2.3 Synthetic Methods

2.3.1 Preparation of Aldehydes

• Partial Oxidation of primary alcohols (PCC, Swern).

• Ozonolysis of alkenes (reductive workup for aldehydes).

2.3.2 Preparation of Ketones

• Oxidation of secondary alcohols (KMnO₄, Jones).

• Friedel–Crafts Acylation: Aromatic + R–COCl/AlCl₃ → aryl ketone.

2.4 Aldehydes & Ketones in Drug Molecules

• Prodrugs: Carbonyl can be reduced/oxidized in vivo to release active species (e.g., prednisone ⇄ prednisolone).

• Reversible covalent inhibitors often use aldehyde warheads (e.g., protease inhibitors).

2.5 Key Points for Exams

• Draw the mechanism of nucleophilic addition (general and specific examples: cyanohydrin, hemiacetal).

• Compare NaBH₄ vs. LiAlH₄ reductions and predict products.

• Explain acetal protection/deprotection strategies in peptide synthesis.

• Outline aldol condensation and its utility in constructing carbon–carbon bonds for API scaffolds.

• Name and draw structural formulas of common drug molecules containing aldehyde or ketone functionalities.

Unit 3: Carboxylic Acids & Their Derivatives

This unit examines the chemistry of carboxylic acids and key derivatives (esters, amides, acid chlorides, anhydrides), their interconversions, reaction mechanisms, and importance in drug design and synthesis.

3.1 Structure, Acidity & Nomenclature

3.1.1 Carboxyl Group Characteristics

• Structure: R–C(=O)–OH; planar sp² carbon with resonance between C=O and C–O bonds.

• Acidity: pKa ~4–5; resonance stabilization of the carboxylate anion.

3.1.2 IUPAC Naming

• Parent alkane ending –e becomes –oic acid (e.g., ethanoic acid, benzoic acid).

• Substituents numbered to give –COOH lowest possible locant.

3.2 Key Reactions of Carboxylic Acids

3.2.1 Derivatization

• Esterification (Fischer): R–COOH + R′–OH ⇌ R–COOR′ + H₂O (acid catalyst).

• Amide Formation: R–COOH + R′–NH₂ → R–CONHR′ + H₂O (requires activation or coupling reagent).

• Acid Chloride Formation: R–COOH + SOCl₂ (or PCl₅) → R–COCl + SO₂ + HCl.

3.2.2 Reduction

• LiAlH₄: R–COOH → R–CH₂OH (primary alcohol).

• BH₃·THF: Selective reduction of carboxylic acids over esters/amides.

3.2.3 Decarboxylation

• Thermal or catalytic removal of CO₂ from β‑keto acids and malonic esters.

3.3 Carboxylic Acid Derivatives Interconversions

3.4 Pharmaceutical Applications

• Prodrugs: Esterification to improve lipophilicity and oral bioavailability (e.g., aspirin is acetyl salicylic acid).

• Peptide Bond Formation: Amide linkage between amino acids (activated esters like NHS‑esters).

• Acid Chlorides & Anhydrides: Key intermediates in API synthesis (e.g., acetylation of amines).

• Non‑steroidal Anti‑inflammatory Drugs (NSAIDs): Many contain carboxylic acid moiety (e.g., ibuprofen, naproxen).

3.5 Mechanistic Insight: Nucleophilic Acyl Substitution

1. Nucleophile Attack: Nucleophile (Nu⁻) attacks electrophilic carbonyl carbon → tetrahedral intermediate.

2. Elimination: Leaving group (–OH, –Cl, –OR, –NR₂) departs, reforming the carbonyl.

3.6 Key Points for Exams

• Draw resonance forms of the carboxylate anion and explain acidity.

• Outline Fischer esterification and acid/alkaline hydrolysis mechanisms.

• Compare reactivity order of derivatives: acid chloride > anhydride > ester > amide.

• Describe prodrug ester strategy for improving pharmacokinetics.

• Name common NSAIDs and identify their carboxylic acid functionality.

Unit 4: Amines – Classification, Preparation & Reactions

This unit delves into amines—key nitrogenous bases in medicinal chemistry—covering their structural types, acid–base behavior, major synthetic routes, characteristic reactions, and their roles in pharmaceuticals.

4.1 Classification of Amines

4.1.1 By Substitution Level

• Primary (1°) Amines: R–NH₂

• Secondary (2°) Amines: R₂NH

• Tertiary (3°) Amines: R₃N

• Quaternary Ammonium Salts: R₄N⁺X⁻ (fully substituted; permanently charged)

4.1.2 By Structure

• Aliphatic Amines: open‑chain (e.g., methylamine, ethylenediamine)

• Aromatic Amines: nitrogen attached to an aromatic ring (e.g., aniline)

• Heterocyclic Amines: nitrogen in a ring (e.g., pyridine, imidazole)

4.2 Physical & Chemical Properties

4.2.1 Basicity

• Amines are Brønsted bases: RₙNH + H₂O ⇌ RₙNH₂⁺ + OH⁻

• pKₐ of conjugate acids (RNH₃⁺) typically ~9–11 for aliphatic, ~4–5 for aniline (aromatic) due to resonance.

4.2.2 Solubility & Boiling Point

• 1° and 2° amines form H‑bonds → higher boiling points, water‑soluble if low molecular weight.

• 3° amines lack N–H bonds → lower boiling points than 1°/2°.

• Quaternary ammonium salts are ionic → water‑soluble, no volatility.

4.3 Preparation of Amines

4.3.1 Aliphatic Amines

• Reductive Amination:

  1. Aldehyde/ketone + NH₃ or RNH₂ → imine/Schiff base

  2. Reduction (NaBH₄, H₂/Pd–C) → amine

• Gabriel Synthesis (for 1° amines):

  1. Phthalimide + KOH → potassium phthalimide

  2. Alkylation with R–X → N‑alkyl phthalimide

  3. Hydrazinolysis → R–NH₂

• Nitrite Reduction: R–NO₂ + H₂/Pd→ R–NH₂

4.3.2 Aromatic Amines

• Reduction of Nitroarenes: Ar–NO₂ + Fe/HCl or Sn/HCl → Ar–NH₂

• Hofmann Degradation (for converting amides to 1° amines with one fewer carbon): R–CONH₂ + Br₂/NaOH → R–NH₂ + CO₂

4.4 Reactions of Amines

4.4.1 N‑Alkylation & N‑Acylation

• Alkylation: R–NH₂ + R′–X → R–NHR′ (risk of over‑alkylation)

• Acylation: R–NH₂ + R′COCl → R–NHCO–R′ (amide bond formation in peptides)

4.4.2 Diazotization (Aromatic Amines)

• Ar–NH₂ + NaNO₂/HCl (0–5 °C) → Ar–N₂⁺Cl⁻ (diazonium salt)

• Subsequent Transformations:

  • Sandmeyer reactions (Ar–Cl, Ar–Br, Ar–CN)

  • Phenol formation (Ar–OH)

  • Azo coupling (Ar–N=N–Ar′)

4.4.3 Hofmann Elimination

• R₃N → R₃N⁺X⁻ (methylation) → heat → alkene + R₂NH₂⁺X⁻

4.4.4 Schiff Base Formation

• R–NH₂ + R′–CHO ⇌ R–N=CH–R′ + H₂O; useful for linking drugs to carriers or as intermediates.

4.5 Pharmaceutical Significance

• Protonation state in vivo affects absorption, distribution, and receptor binding.

• Amine-containing prodrugs (e.g., codeine → morphine) rely on metabolic dealkylation.

4.6 Key Points for Exams

• Classify an amine given its structure (1°, 2°, 3°, quaternary; aliphatic vs. aromatic).

• Compare basicity (pKₐ) of aliphatic vs. aromatic amines and explain resonance effects.

• Outline Gabriel synthesis and Hofmann degradation mechanisms.

• Write the diazotization mechanism for aniline and predict products of Sandmeyer reactions.

• Identify the role of the amine group in drug–receptor interactions for at least two pharmaceuticals.

Unit 5: Carbohydrates – Monosaccharides, Disaccharides & Polysaccharides

This unit explores the structure, stereochemistry, reactions, and pharmaceutical applications of carbohydrates—from simple sugars to complex polysaccharides used as excipients and drug delivery materials.

5.1 Monosaccharides

5.1.1 Definition & General Formula

• Simple sugars with formula CₙH₂ₙOₙ (n = 3–7).

• Examples: trioses (glyceraldehyde), tetroses, pentoses (ribose), hexoses (glucose, fructose).

5.1.2 Stereochemistry & Isomerism

• Chirality: Every carbon bearing –OH and –H is a stereocenter (except terminal –CH₂OH).

• D/L Nomenclature: Configured relative to glyceraldehyde; most naturally occurring hexoses are D‑form.

• Epimers: Differ at one stereocenter (e.g., glucose vs. galactose at C‑4).

• Anomers: Cyclic hemiacetal formation yields α/β forms (e.g., α‑D‑glucose vs. β‑D‑glucose).

5.1.3 Ring Structures

• Furanose (five‑membered) vs. Pyranose (six‑membered) rings.

• Mutarotation: Interconversion between α and β anomers in aqueous solution via open‑chain form.

5.1.4 Reducing vs. Non‑Reducing Sugars

• Reducing: Free anomeric –OH (e.g., glucose, maltose) can open to aldehyde → Tollens’/Benedict’s positive.

• Non‑Reducing: Anomeric carbons locked in glycosidic bond (e.g., sucrose).

5.2 Disaccharides

5.2.1 Formation & Glycosidic Linkages

• Two monosaccharides join via O‑glycosidic bond between anomeric carbon of one and –OH of another.

• Bond nomenclature: e.g., α(1→4), β(1→2).

5.2.2 Key Examples

5.2.3 Properties & Digestion

• Enzymes: sucrase, lactase, maltase cleave respective linkages in the gut.

• Clinical relevance: lactose intolerance (β‑galactosidase deficiency), diagnostic tests using reducing sugar assays.

5.3 Polysaccharides

5.3.1 Classification

• Homopolysaccharides: single monosaccharide type (e.g., starch, glycogen, cellulose).

• Heteropolysaccharides: two or more types (e.g., hyaluronic acid, chondroitin sulfate).

5.3.2 Structure & Function

• Starch: Amylose (linear α(1→4)) and amylopectin (α(1→4) with α(1→6) branches) → energy storage in plants.

• Glycogen: Highly branched α(1→4) with α(1→6) branches every ~8–12 units → animal energy reserve.

• Cellulose: β(1→4) linear → structural rigidity in plant cell walls; indigestible by human enzymes.

5.3.3 Pharmaceutical Applications

• Excipients:

  • Microcrystalline cellulose: tablet binder/filler.

  • Starch derivatives: disintegrants.

• Polysaccharide-based Drug Delivery:

  • Alginate beads for controlled release (calcium‑crosslinked).

  • Chitosan nanoparticles for mucoadhesive delivery.

• Biomedical Uses:

  • Hyaluronic acid: viscosupplementation in osteoarthritis, dermal fillers.

  • Heparin: anticoagulant glycosaminoglycan.

5.4 Key Reactions & Analysis

• Hydrolysis: Acidic or enzymatic cleavage of glycosidic bonds → monosaccharides.

• Oxidation: Aldonic acids (e.g., gluconic acid) from primary –OH oxidation; uronic acids (e.g., glucuronic acid) from terminal –CH₂OH oxidation.

• Derivatization for Analysis:

  • TLC or HPLC of alditol acetates for sugar profiling.

  • Periodic acid‑Schiff stain for polysaccharide visualization in tissues.

5.5 Key Points for Exams

• Draw Fischer and Haworth projections for D‑glucose, indicating α/β anomers.

• Differentiate reducing vs. non‑reducing sugars and give examples.

• Describe linkage types in starch vs. cellulose and relate to digestibility.

• List three pharmaceutical applications of polysaccharides and explain their functional role.

• Outline enzymatic hydrolysis pathways for disaccharides in the human intestine.

Unit 6: Amino Acids, Peptides & Proteins

This unit covers the building blocks of proteins—amino acids—through to peptide bond formation and higher‑order protein structures, with emphasis on their chemical behavior, synthesis, analysis, and pharmaceutical relevance.

6.1 Structure & Classification of Amino Acids

6.1.1 General Structure

• Backbone: H₂N–CH(R)–COOH

• Zwitterion at physiological pH: –NH₃⁺ and –COO⁻

6.1.2 Stereochemistry & Chirality

• All proteinogenic amino acids (except glycine) are L‑configuration.

• Cα is a stereocenter bearing four different substituents.

6.1.3 Side‑Chain Classification

6.1.4 Acid–Base Properties

• pKₐ values: COOH ~2.0; NH₃⁺ ~9.0; side chains vary (e.g., His ~6.0, Cys ~8.3, Tyr ~10.1).

• Isoelectric point (pI): pH at which net charge = 0; critical for solubility and separation techniques.

6.2 Reactions of Amino Acids

6.2.1 Peptide Bond Formation

• Condensation: Carboxyl of one amino acid + amino of another → amide (peptide) + H₂O.

• Activation: DCC, EDC or activated esters (NHS‑esters) used to drive coupling.

6.2.2 Modifications & Derivatizations

• Decarboxylation: R–CH(NH₂)–COOH → R–CH₂–NH₂ + CO₂ (bioactive amines like serotonin).

• Transamination: Amino group transfer via pyridoxal phosphate (PLP) cofactor.

• Protection/Deprotection: Boc, Fmoc strategies in solid‑phase peptide synthesis.

6.2.3 Side‑Chain Chemistry

• Disulfide Bond Formation: 2 Cys –SH → Cys–S–S–Cys stabilizes tertiary structure.

• Phosphorylation: Ser/Thr/Tyr –OH → –OPO₃²⁻ regulates activity in signaling.

6.3 Protein Structure & Folding

6.3.1 Levels of Organization

1. Primary: linear sequence of amino acids.

2. Secondary: local conformations—α‑helix, β‑sheet, β‑turn.

3. Tertiary: 3D folding via hydrophobic interactions, H‑bonds, disulfides.

4. Quaternary: assembly of multiple polypeptide chains (e.g., hemoglobin).

6.3.2 Forces Stabilizing Structure

• Hydrophobic Effect drives core formation.

• Electrostatic Interactions & salt bridges.

• Hydrogen Bonding in backbone and side chains.

• Covalent Disulfide Bonds in oxidizing environments.

6.4 Analytical Techniques

• Chromatography:

  • HPLC (reverse‑phase for peptide purity).

  • Ion‑exchange (separation by charge; pI determination).

• Electrophoresis: SDS‑PAGE for molecular weight; isoelectric focusing for pI.

• Spectroscopy: UV at 280 nm (Trp/Phe/Tyr content); CD for secondary‑structure estimation.

• Mass Spectrometry: Peptide mapping, sequencing (MALDI‑TOF, ESI-MS).

6.5 Pharmaceutical Applications

• Peptide Drugs:

  • Insulin (51‑amino‑acid peptide) for diabetes management.

  • Glucagon‑like peptide‑1 (GLP‑1) analogs in type 2 diabetes.

• Protein Therapeutics:

  • Monoclonal antibodies (e.g., trastuzumab) targeting specific antigens.

  • Enzyme replacement (e.g., imiglucerase for Gaucher’s disease).

• Excipients & Delivery:

  • Albumin‑based carriers for poorly soluble drugs.

  • PEGylation of peptides/proteins to enhance half‑life.

6.6 Key Points for Exams

• Draw general amino acid structure and label pKₐ’s of –COOH and –NH₃⁺.

• Classify amino acids by side‑chain properties and predict pI.

• Outline mechanism of peptide bond formation using activating agents.

• Describe α‑helix and β‑sheet H‑bonding patterns.

• List two analytical methods for purity and two for structural characterization of peptides/proteins.

• Cite examples of peptide or protein drugs and the role of sequence/structure in their function.