Aromatic Compounds 1

Pharmaceutical Chemistry - Aromatic Compounds (Lecture 1)

• Recommended Reading: Organic Chemistry textbooks by Clayden, Greeves, Warren, and Wothers; Loudon; and Solomon & Fryhle. General and organic chemistry texts also cover aromatic chemistry.

Lecture 1 Content

• History and Importance: Focuses on the historical background, including the discovery of benzene and its relatives. Early aromatic compounds are highlighted.

• Aromatic Compound Definition (Hückel's Rule): Defines aromatic compounds and the properties associated with them based on Hückel's Rule.

• Classification of Aromatic Compounds: Different types of aromatic compounds, including monocyclic, polycyclic, non-benzenoids, macrocyclic, and heterocyclic derivatives are discussed. Examples of compounds within each class are presented, such as benzene, toluene, naphthalene.

• Structure and Limitations of Kekulé's Benzene Structure: Details Kekulé's original model of benzene's structure and outlines the limitations of the model.

• Resonance Theory of Benzene: Describes how resonance theory explains the stability of benzene.

• Molecular Orbital Theory of Benzene: Discusses the MO theory; its connection to the structure and stability of benzene.

• Comparison Between Cyclohexene and Benzene: Explains the differences in reactivity, particularly electrophillic substitution vs. addition reactions between benzene and cyclohexene as an example of aromatic versus non-aromatic reactivity.

Introduction

• Drugs and Aromatic Moieties: Many medications on the market contain aromatic derivatives or have an aromatic moiety.

Pharmaceutically Important Aromatics

• Aspirin: An analgesic and antipyretic drug, highlighting its aromatic composition. Chemical formula and structure will be essential to understand.

• Morphine: A narcotic analgesic drug, demonstrating its aromatic characteristic. The structure is key.

• Valium: A tranquillizer. Chemical structure and category are important to recognize.

• Sulfamethoxazole: An antimicrobial agent that includes aromatic structures. Chemical structure is key here.

Historical Background

• 1826: Michael Faraday discovers benzene and names it.

• 1834: Eilhardt Mitscherlich synthesizes benzene.

• 1865: August Kekulé proposes the first structure of benzene. Crucially, the structure and its limitations of this initial model are essential study points.

Definition: Aromaticity Criteria

• Cyclic Arrangement of p-Orbitals: Aromatic compounds contain one or more rings with a cyclic arrangement of p orbitals.

• P Orbitals per Atom: Each atom in an aromatic ring has a p orbital.

• Planar Rings: Aromatic rings are planar, this concept is critical to applying Huckel's rule.

• Hückel's Rule (4n+2 π electrons): Aromatic compounds must meet the 4n+2 π (pi) electron count (where n is a non-negative integer) for aromaticity.

Classification

• Monocyclic Derivatives (e.g., Toluene): Benzene's derivatives (e.g. toluene).

• Polycyclic Benzenoids (e.g., Naphthalene): Multiple benzene rings bonded together (e.g. naphthalene).

• Non-Benzenoids (e.g., Azulene): Structures not based on benzene rings (e.g. azulene).

• Macrocyclic (e.g., [14]Anulene): Large ring systems, involving 14 π electrons

• Heterocyclic (e.g., Pyridine, Pyrrole): Rings containing atoms other than carbon.

Kekule's Structure of Benzene

• Cyclic Carbon Atoms: The structure of benzene contains six carbon atoms arranged in a ring.

• Alternating Bonds: Alternating single and double bonds are present between the atoms.

• Attached Hydrogen Atoms: Each carbon atom is bonded to a hydrogen atom.

• Equivalence of Atoms: Key observation of the equivalency of the C and H atoms in the structure

Limitations of Kekulé's Structure

• Two 1,2-Dibromobenzenes: Kekulé's model incorrectly predicts two possible 1,2-dibromobenzene isomers; only one isomer has been found in experiments.

• Incorrect Equilibrium: Kekulé suggested the structures were in quick equilibrium; this has been proven incorrect.

Resonance Theory Applied to Benzene

• Representation Through Resonance Structures: Use of multiple Lewis structures to depict the delocalization of electrons in benzene.

• Resonance Hybrid: The actual structure of benzene is a resonance hybrid, which is a combination of all the contributing structures.

• Canonical Forms and Stability: Contributing structures (canonical forms) are used in the model, more stable canonical forms contribute more to the overall structure of the hybrid.

Resonance Energy (or Delocalisation Energy)

• Stability of Hybrid: The resonance hybrid is more stable than the individual contributing structures.

• Energy Difference: The difference in energy value between the resonance hybrid and the most stable canonical forms, a measurable quantity. This is an important measurement of stability.

MO Theory Applied to Benzene

• Bond Angle: Bond angles are 120 degrees, suggesting sp2 hybridization.

• Bond Length: Bond length is between a single and a double bond length value; indicative of delocalization of electrons.

• Individual Sigma Bonds: Each carbon forms one sigma bond to a hydrogen atom and two others to other carbon atoms.

• Remaining p Orbitals: One p electron remains on each carbon atom.

• Electron Cloud: These remaining p electrons form a delocalized electron cloud above and below the plane of the molecule.

• Molecular Orbitals: Six p-orbitals combine to form six molecular orbitals. Three form lower energy 'bonding' orbitals and three 'antibonding' orbitals.

• Crucially, two of the 'bonding' molecular orbital levels are degenerate; that is have the same energy level.

MO Theory Applied to Benzene (cont.)

• Bonding Orbitals: Three molecular orbitals have lower energy than the isolated p orbitals; these are "bonding".

• Antibonding Orbitals: Three molecular orbitals are higher energy than the isolated p orbitals, these are "antibonding".

• Degenerate Orbitals: Two bonding molecular orbitals are degenerate (have the same energy).

• Stability: The closed bonding shell (fully occupied bonding orbitals) contributes significantly to benzene's stability.

Comparison of Cyclohexene With Benzene

• Reactivity Differences: Cyclohexene is a non-aromatic (alkene) compound and undergoes addition reactions, while benzene (aromatic) undergoes substitution reactions.
• The reaction examples demonstrate these fundamental differences in reactivity

Worked Examples

• Aromatic Identification: Apply the criteria determined previously to identify different structures as aromatic. This can involve determining planarity to using rules to count π (pi) electrons.

• Counting π-electrons: Use molecular structures to determine the number of π electrons a molecule contains.