MM

MEDCHEM7

Medicinal and Pharmaceutical Chemistry – MEDCHEM 7: Aromatic Hydrocarbons I

Course Title: MEDCHEM 7: Aromatic Hydrocarbons I: Structures and ReactionsInstructor: Prof. Andreas HeiseDate: 10/02/2025

Learning Outcomes

  • Recall the structure of benzene.

  • Define ‘resonance’ and understand the bonding in benzene.

  • State Huckel’s rule for aromaticity.

  • Identify both benzenoid and non-benzeneoid aromatic compounds.

  • Describe electrophilic substitution reactions.

  • Recall the products and mechanisms of halogenation, Friedel-Crafts alkylation, Friedel-Crafts acylation, and nitration of aromatic hydrocarbons.

Bonding in Benzene

  • Molecular formula: C6H6.

  • Colorless, toxic, carcinogenic liquid.

  • Boiling point: 80 °C.

  • Composed of six carbon atoms arranged in a ring, each bonded to one hydrogen atom.

  • All carbon-carbon bonds measure 139 pm in length, intermediate between single (154 pm) and double (134 pm) bonds.

  • No formal single or double bonds, leading to a unique bonding structure.

Aromatic Compounds

  • Benzene and its derivatives are classified as aromatic compounds.

  • Viewed as a resonance hybrid of its resonance structures.

  • Important to differentiate between resonance and equilibrium.

Orbital Representation of Bonding in Benzene

  • Each carbon atom has a 2pz orbital.

  • Sidewise overlap results in an extended p cloud with six p electrons.

  • Uniform bond length of 139 pm supports the stability.

Discovery of Benzene

  • Discovered by Michael Faraday in 1825.

  • Significant contributions include electromagnetic induction and battery technology.

Kekule's Contribution

  • F. August Kekule proposed the structure inspired by a dream of a snake seizing its own tail (Ouroboros).

  • Benzene is best represented as a resonance hybrid.

Huckel’s Rule for Aromaticity

  • Aromaticity defined by a planar ring with pz orbitals containing (4n + 2) p electrons.

  • Benzene features an ‘aromatic sextet’ with n = 1.

Aromatic Stability Through Hydrogenation Heats

  • Stability assessed via heat of hydrogenation.

  • Cyclohexene: -118 kJ/mol; Cyclohexadiene: -230 kJ/mol

  • Expected hydrogenation for benzene: -356 kJ/mol, measured: -206 kJ/mol.

  • Increased stability due to aromaticity reduces energy associated with converting benzene to cyclohexane.

Examples of Aromatic Compounds

  • Core examples: benzene, toluene (1,2-dimethylbenzene), aniline, phenol, and hexamethylbenzene.

Naming of Di-substituted Benzenes

  • Common prefixes: ortho- (1,2), meta- (1,3), para- (1,4).

  • Examples: ortho-dibromobenzene, meta-nitrophenol, para-nitrophenol.

Polycyclic and Heterocyclic Aromatic Compounds

  • Examples: naphthalene (10 p electrons), anthracene (14 p electrons).

  • Many drugs derived from these compounds.

Electrophilic Substitution Reactions of Benzene

  • Preserve the aromatic sextet in reactions with electrophiles.

  • F2 reacts violently; Br2 requires AlBr3 as a catalyst.

Mechanism of Chlorination of Benzene

  • Involves generating an electrophile and several steps, including reactions with the electrophile, catalyst regeneration, and loss of H+.

Role of AlCl3 as Catalyst

  • Acts as a Lewis acid to abstract Cl from Cl2, creating Cl +.

  • Can also act as a Lewis base.

Friedel Crafts Alkylation of Benzene

  • Introduces alkyl groups into aromatic compounds and forms new carbon-carbon bonds.

  • Mechanism involves generating electrophile from alkyl halides, electrophilic attack, and sigma complex formation.

  • Significance in medicinal chemistry for synthesizing complex aromatic compounds.

Mechanism of Nitration of Benzene

  • Begins with the formation of the nitronium ion as the electrophile.

  • Subsequent steps mirror those in chlorination and alkylation processes.

Orbital Representation Recap

  • Each carbon’s 2pz orbital overlaps, contributing to benzene’s p cloud, maintaining a stable ring structure.