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.