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Organic Chemistry — Pharm D Overview

1. Functional Groups (Most Important for Pharmacy)

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2. Stereochemistry

• Chirality — a molecule with a non-superimposable mirror image (like your hands)
• Enantiomers — same formula, mirror images → often have different biological activity
• R/S configuration — priority rules to name stereocenters
• Pharmacy relevance: Thalidomide disaster — one enantiomer was therapeutic, the other teratogenic

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3. Reaction Mechanisms

• SN1 / SN2 — nucleophilic substitution (affects drug metabolism)
• E1 / E2 — elimination reactions
• Addition reactions — alkenes reacting with HBr, H₂O, etc.
• Markovnikov's rule — major product in addition to unsymmetrical alkenes

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4. Carbonyl Chemistry

• Aldehydes & ketones → nucleophilic addition
• Carboxylic acid derivatives (esters, amides, anhydrides) → hydrolysis in the body
• Ester hydrolysis is key to prodrug activation

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5. Aromatic Chemistry

• Benzene ring — delocalized π electrons, extra stability
• Electrophilic Aromatic Substitution (EAS) — nitration, halogenation, sulfonation
• Ortho/para vs meta directors — substituents on benzene guide incoming groups

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6. Acids & Bases in Organic Chemistry

• pKa — critical for drug absorption (Henderson-Hasselbalch equation)
• Acidic groups: –COOH, –OH (phenol), –SO₃H
• Basic groups: –NH₂, –N (amines)
• Ionization affects solubility and membrane crossing

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Heterocyclic Compounds

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Classification

A. By Ring Size

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B. By Heteroatom

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Key 5-Membered Rings

🔹 Furan

• Contains O
• Aromatic (6 π electrons — O donates lone pair)
• Found in: Furfural, some antifungals

🔹 Pyrrole

• Contains N–H
• N lone pair part of aromatic system → very weakly basic
• Found in: Heme (hemoglobin), Chlorophyll, Atorvastatin

🔹 Thiophene

• Contains S
• More stable than furan
• Found in: Clopidogrel (antiplatelet drug)

🔹 Imidazole

• Contains 2 N (one N–H, one =N–)
• Amphoteric — can act as acid or base
• pKa ~7 → important at physiological pH
• Found in: Histidine (amino acid), Metronidazole, Omeprazole, antifungals (Ketoconazole)

🔹 Pyrazole

• Contains 2 adjacent N
• Found in: Celecoxib (COX-2 inhibitor)

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Key 6-Membered Rings

🔹 Pyridine

• Contains 1 N (like benzene but one CH replaced by N)
• N lone pair NOT part of aromatic system → moderately basic (pKa ~5.2)
• Undergoes Electrophilic Aromatic Substitution with difficulty (N is electron-withdrawing)
• Found in: Nicotinic acid (Vitamin B3), Isoniazid (TB drug), Amlodipine

🔹 Pyrimidine

• Contains 2 N at positions 1,3
• Less basic than pyridine
• Found in: Cytosine, Thymine, Uracil (DNA/RNA bases!), Barbiturates, Trimethoprim

🔹 Purine (Fused Ring — Pyrimidine + Imidazole)

• Found in: Adenine, Guanine (DNA/RNA), Caffeine, Xanthine, Allopurinol

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Fused Bicyclic Heterocycles

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Aromaticity in Heterocycles (Important Concept)

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Pharmacy Relevance Summary

~75–80% of all pharmaceutical drugs contain a heterocyclic ring. Understanding these rings helps you predict drug properties, metabolism, and interactions.

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Indole — Complete Study Notes

Structure

        4   5
       /  \ /  \
      3    C    6
      |    |    |
      2    C    7
       \  / \  /
        N    (benzene)
        H
        1

• Molecular formula: C₈H₇N
• Numbering: N is position 1, then C2, C3 around the pyrrole ring, then C4–C7 on the benzene ring
• Most reactive position: C-3 (electrophilic substitution occurs here preferentially)

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Aromaticity

• 6 from benzene ring carbons
• 2 from pyrrole double bond
• 2 from N lone pair (donated into the π system)

• Very weakly basic (pKa of conjugate acid ~−3.5)
• The N–H proton is mildly acidic (pKa ~17) — can be deprotonated by strong bases

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Physical Properties

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Reactivity — Electrophilic Aromatic Substitution (EAS)

• Attack at C-3 gives an intermediate where the positive charge is stabilized on nitrogen (more stable)
• Attack at C-2 gives a less stable intermediate

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Fischer Indole Synthesis ⭐ (Most Important Reaction)

• Aryl hydrazine + ketone/aldehyde
• Acid catalyst (HCl, ZnCl₂, BF₃)
• Heat

1. Aryl hydrazine + carbonyl compound → arylhydrazone (condensation)
2. [3,3]-sigmatropic rearrangement
3. Re-aromatization and loss of NH₃
4. → Indole product

Exam tip: The carbon at position 2 of indole comes from the α-carbon of the ketone; position 3 comes from the carbonyl carbon.

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Other Synthesis Methods

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Biological Importance

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Pharmaceutical Drugs Containing Indole Ring

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Comparison: Indole vs Isoindole vs Benzimidazole

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Key Exam Points to Remember

1. Indole = benzene fused with pyrrole at C2–C3
2. 10 π electrons → aromatic
3. N lone pair is part of aromatic system → very weakly basic
4. Most reactive position = C-3
5. EAS occurs preferentially at C-3
6. Fischer Indole Synthesis is the classic preparation
7. Tryptophan → Serotonin → Melatonin (all indole-based)
8. Many drugs = indole scaffold (Indomethacin, Sumatriptan, Ondansetron)

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