Aromaticity and Heterocycles

• The material covers the definitions of aromaticity and heterocycles, benzene and its derivatives, heterocyclic aromatic compounds, and heterocyclic non-aromatic compounds.

Aromaticity

• Historically, 'aromatic' compounds were defined by their smell.
• Hückel proposed in 1931 that aromaticity occurs in a cyclic structure under specific conditions.
• Aromaticity requires a planar structure with an uninterrupted conjugated electron system and an odd number of shared electron pairs.
• The Hückel rule states that an unsaturated, cyclic compound is aromatic if it has (4n + 2) shared (pi) electrons in the ring system, where n is a natural number (0, 1, 2, 3, 4, etc.).
• Benzene and pyridine are aromatic because they have 6 pi-electrons, satisfying the Hückel rule when n=1.

Heterocycles

• Heterocycle is derived from "heteros”, meaning "other" or "different" in Greek.
• Heterocycles are cyclic compounds with carbon and at least one other atom in the ring system, such as nitrogen, oxygen, or sulfur in drugs.
• A heteroatom is any atom within a heterocycle structure that isn't carbon or hydrogen.
• Many aromatic and non-aromatic heterocycles exist, as well as aromatic compounds that are not heterocycles.

Benzene Shape and Properties

• Benzene is flat, planar, and aromatic.
• Benzene is quite unreactive and unsaturated.
• Electrons are delocalized in benzene, unlike formal "double bonds".

Benzene Naming

• Benzene refers to the basic six-carbon ring structure without any substitutions.
• Benzyl is used when the benzene ring is attached to another carbon (needs a carbon with at least 2 or 3 hydrogens).
• Phenyl is used, when the benzene ring is a substituent (not H as corner group).
• Phenol is the term for benzene with a directly attached hydroxyl (-OH) group (weak acids that can be ionized/unionized).
• Naming positions on the ring uses ortho-, meta-, and para- prefixes to identify the positions of substituents.
• The numbering system begins at the highest priority substituent.
• If one of the two groups has a 'trivial' name, the compound is named as a derivative of this compound, which becomes the highest priority. E.g. 3-Aminophenol.
• With different groups that don't give a trivial name to the whole molecule, they are named successively, adding the word benzene, using the lowest combination of numbers. E.g. 1-chloro-3-nitrobenzene.

Benzene Reactions

• Benzene is chemically stable and unreactive by itself.
• Aromatic rings can be extensively changed during metabolism inside the body.
• Phenyl derivatives are involved in many metabolic reactions facilitated by enzymes.
• Cytochrome P450, present in the liver, is involved in oxidation.

Important Benzene Derivatives

• Phenol has a pKa of 10 and is a weak acid.
• Phenolic drugs are often delivered as prodrugs with the phenol group masked to render inactivity until metabolized.
• Aniline is covered in lecture 7 and is predominantly unionised at pH 7.4.
• Polycyclic compounds are often fused to heterocyclic aromatics.
• Extended flat compounds are good DNA intercalating agents.

Pyrrole Structure and Properties

• Pyrrole is aromatic: planar and obeys Hückel's rule.
• Because the nitrogen lone pair is shared in the aromatic ring, nitrogen can not act, therefore is not a base, in fact is a very weak acid.
• The pKa of pyrrole is ~23, which means it is considered 'neutral' (unionised) at physiological pH of 7.4.
• Atorvastatin is a drug example and is a synthetic statin, HMGCoA reductase inhibitor, and a lipid-lowering drug.

Imidazole Structure and Properties

• It is aromatic (planar, obeys Hückel's rule).
• One nitrogen's lone pair is shared in the aromatic ring but the other nitrogen's lone pair is not shared in the aromatic ring so can act as a base.
• pKa is about 7
• When pH = pKa, there is 1:1 ionized to unionized species.
• Examples of drugs with the Imidazole structure include Histidine, Histamine and Cimetidine (an antagonist that inhibits acid production in the stomach)

Tetrazole

• Aromatic, weak acid (pKa about 5, similar to RCO₂H pKa).

Pyridine Structure and Properties

• It is aromatic (planar, obeys Hückel's rule).
• Nitrogen's lone pair is not shared in the aromatic ring, these electrons can act as a nucleophile, pyridine is a weak base.
• Drug examples include Rosiglitazone.

Quinoline Structure and Properties

• Aromatic (planar, obeys Hückel's rule).
• Has (4n + 2), where n = 2, (4 x 2) + 2 = 10.
• Nitrogen behaves similarly to pyridine nitrogen – weak base.
• It is found in many biologically active natural products.
• Quinine, found in the bark of Chinchona tree, was found to help with malaria.
• Gin and Tonic was born as a way for soldiers to take quinine by gin with lemon/lime to mask the bitter taste.
• The drug chloroquine is now used to treat malaria.

Indole Structure and Properties:

• It is aromatic (planar, obeys Hückel's rule).
• Has (4n + 2), where n = 2,(4 x 2) + 2 = 10.
• The nitrogen lone pairs are taken up in aromatic resonance so do not act as a base.
• Similar to pyrrole it is neutral (unionised) at physiological pHs
• Has serotonin, pindalol and indomethacin examples

Piperidine (Heterocyclic Non-Aromatic)

• Piperidine acts like an amine base.
• It is non-aromatic, saturated, not planar; electrons not delocalised/shared.
• Similar to an acyclic aliphatic amine, piperidine is a base.
• Workshop (MOW06) with cover some more ionization calculations.
• Is a lone pair that can easily pick up a proton
• above PI so goes in the LHS
• Drug examples: Morphine, Cocaine.

Beta-lactams (Heterocyclic Non-Aromatic)

• A 4 membered ring, strained, a cyclic amide.
• Susceptible to enzymatic hydrolysis by beta-lactamases
• beta-lactam antibiotic
• bacteria over express, bacteria can develop immunity to penicillin

Review Question (Loratadine)

• Loratadine is a second generation antihistamine with pKa of 5.
• If is ionised, its a base and 99% ionised in the stomach.