Nomenclature of Aromatic Compounds

Nomenclature of Aromatic Compounds

• The phenyl substituent is represented as Ph or C6H5-
• Prefixes used for naming disubstituted benzenes are:
  • Ortho (o)
  • Meta (m)
  • Para (p)
• When there are more than two substituents on the benzene ring, the point of attachment is chosen as carbon 1 and numbering is done to give lower locants to the substituents.
• Substituents are presented in alphabetical order when writing the names.

Structure and Stability of Benzene

• The structure of benzene is described by two theories: resonance and molecular orbital theories.
• Empirical formula of benzene is C6H6, with no structure assigned.
• Kekulé proposed the structure of benzene as a six-membered carbon-atom ring with alternating single and double bonds.
• The molecule oscillates between two equivalent structures (A and B) where the single and double bonds continuously interchange positions.
• The actual structure of benzene is a hybrid of the two Kekulé structures (A and B), which leads to the resonance hybrid (C).
• Each of structures (A) and (B) is called a canonical form of benzene.
• Evidence in support of the Kekulé structure of benzene:
  • Monosubstituted benzene always forms only one product (isomer).
  • Disubstituted benzene forms three products (isomers).
• Limitations of the Kekulé structure:
  • Does not explain why benzene fails to undergo addition reactions typical of alkenes.
  • Does not account for the equal length of carbon-carbon bonds (139 pm) in benzene.
  • Does not explain the unusual stability of benzene (150 kJ/mol resonance energy).

Molecular Orbital Theory

• The carbon atoms of the benzene molecule are sp2-hybridized with each C-atom having an unhybridized p-orbital perpendicular to the plane of the benzene ring.
• Each p-orbital overlaps equally well with both neighboring p-orbitals.
• The 6 π electrons of benzene are completely delocalized around the ring, with electron density in all C-C bonds being identical.
• The delocalization of the π system of electrons affords benzene its unusual stability.
• The benzene molecule is conjugated and planar with the shape of a regular hexagon.

Why is Benzene not an Alkene?

• Treatment of cyclohexene with Br2 rapidly leads to the addition product 1,2-dibromocyclohexane.
• However, benzene reacts only slowly and requires a catalyst to produce the substitution product bromobenzene.
• Comparison of heats of hydrogenation of cyclooctatetraene, cyclohexenes, and benzene:
  • When cis-cyclooctene is hydrogenated to cyclooctane, 96 kJ/mol of energy is released.

Electrophilic Aromatic Substitution Reactions

• Aromatic halogenation:
  • Cl2 and Br2 react with benzene in the presence of FeCl3/FeBr3 catalysts to form chloro/bromo benzenes.
  • Iodine is rather unreactive towards aromatic rings, but in the presence of oxidizing agents such as CuCl2 or H2O2, a reaction takes place leading to the formation of iodobenzene.
• Aromatic nitration:
  • A mixture of conc. HNO3 and H2SO4 produces a nitronium ion (NO2+) which reacts as the electrophile.
  • Aromatic nitration does not occur in nature, but the nitro group can be reduced to produce corresponding arylamine (ArNH2) such as aniline.
• Aromatic sulfonation:
  • The electrophile for sulfonation of benzene can be generated when one molecule of H2SO4 protonates another and loses a molecule of water.
  • Aromatic sulfonation can also be achieved when the aromatic ring reacts with fuming sulfuric acid (a mixture of H2SO4/SO3).
  • Aromatic sulfonation does not occur in nature, but it is utilized in the synthesis of dyes and pharmaceuticals such as sulfanilamide.
• Aromatic hydroxylation:
  • Hydrolysis of benzene diazonium salts to produce phenols.
  • Aromatic hydroxylation is an important reaction in drug metabolism leading to excretion of drug metabolites.

Aromatic Alkylation

• Synthesis of aromatic hydrocarbons can be achieved through one of the following named reactions:
  • Friedel-Crafts alkylation reaction
  • Clemensen's reduction
  • Wurtz-Fittig reaction
• Mechanism of aromatic alkylation:
  • Limitations of Friedel-Crafts alkylation reactions:
    • Only alkyl halides can be used for this reaction.
    • The reaction is not feasible with aromatic rings already having electron-withdrawing substituents or amino groups.
    • It is difficult to control polyalkylation.
    • There can be skeletal rearrangement of the alkyl electrophile into a more stable carbocation.
• Aromatic alkylation reactions occur in a number of biosynthetic pathways such as the synthesis of phylloquinone (Vit. K).

Friedel-Crafts Acylation Reactions

• An aromatic compound is treated with an alkyl chloride (RCl) in the presence of AlCl3 catalyst.
• The electrophile is generated by AlCl3-assisted dissociation of an alkyl halide.
• The aromatic ring is acylated with acyl chloride (ROCl) in the presence of AlCl3.

Clemmensen's Reduction

• Reduction of carbonyl compounds to alkanes using Zn/Hg and HCl.

Wurtz-Fittig Reaction

• The reaction involves aryl halides and alkyl halides in the presence of Na in dry ether to form alkyl-substituted benzenes.

Oxidation of Alkyl Benzenes

• Oxidation of alkyl benzenes with strong oxidizing agents such as acidified KMNO4 produces benzoic acid.

Effect of Substituents in Electrophilic Aromatic Substitution Reactions

• Reactivity of the aromatic ring:
  • Activating substituents make the aromatic ring more reactive (e.g. –NH2, -OH, -OCH3, etc.).
  • Deactivating substituents render the aromatic ring less reactive than benzene (e.g. –CHO, -NO2, -CO2H, -CO2R, -NR3+, etc.).
• Substituents influence the orientation of the reaction by being either ortho/para- directors or meta- directors.
• Generally, substituents can be classified into ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators.

Electrophilic Substitution on Phenols

• Benzene reacts with bromine only in the presence of Lewis acid catalysts.
• Phenols react rapidly (3x faster) without a catalyst with bromine to form a product containing three bromine atoms (2,4,6-tribromophenol) at specific positions.

Nitration of Phenol

• Nitration of phenol is problematic under normal nitration conditions since concentrated HNO3 oxidizes phenols.
• Dilute HNO3 is used instead.

Preparation of Paracetamol and Aspirin from Phenol

• How to prepare paracetamol from phenol.
• How to prepare salicylic acid and acetylsalicylic acid (aspirin) from phenol.