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Nomenclature of Aromatic Compounds with Multiple Substituents01:11

Nomenclature of Aromatic Compounds with Multiple Substituents

When more than one substituent is present on the benzene ring, the IUPAC nomenclature depends on the number of substituents present.
For disubstituted benzene derivatives, with two groups attached to the benzene ring, three constitutional isomers are possible. For example, consider dimethyl benzene, often called xylene, where the second methyl group can be substituted at the second, third, or fourth carbon. The relative position of the substituents is represented by prefixes ortho, meta, or...
Nomenclature of Aromatic Compounds with a Single Substituent01:23

Nomenclature of Aromatic Compounds with a Single Substituent

Benzene is the simplest aromatic hydrocarbon or arene. The IUPAC names for simple monosubstituted benzene derivatives are derived by adding the substituent's name as a prefix to the parent benzene. For example, halobenzene, where the halogen could be fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH301:11

ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3

All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
Electrophilic Aromatic Substitution: Chlorination and Bromination of Benzene01:15

Electrophilic Aromatic Substitution: Chlorination and Bromination of Benzene

Chlorination and bromination are important classes of electrophilic aromatic substitutions, where benzene reacts with chlorine or bromine in the presence of a Lewis acid catalyst to give halogenated substitution products. A Lewis acid such as aluminium chloride or ferric chloride catalyzes the chlorination, and ferric bromide catalyzes the bromination reactions. During the bromination of alkenes, bromine polarizes and becomes electrophilic. However, in the bromination of benzene, the bromine...
Directing and Steric Effects in Disubstituted Benzene Derivatives01:18

Directing and Steric Effects in Disubstituted Benzene Derivatives

When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the more strongly...
Directing Effect of Substituents: ortho–para-Directing Groups01:14

Directing Effect of Substituents: ortho–para-Directing Groups

Ortho–para directors are substituent groups attached to the benzene ring and direct the addition of an electrophile to the positions ortho or para to the substituent. All electron-donating groups are considered ortho–para directors. They donate electrons to the ring and make the ring more electron-rich. The ring is therefore susceptible to the addition of electrophiles. Substituents such as amino, hydroxy, or alkoxy, containing lone pairs on the atom adjacent to the ring, donate electrons...

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Updated: May 31, 2026

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes
05:34

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Published on: December 16, 2019

Ladderanes: Stepping Up as Nonclassical ortho-Substituted Benzene Bioisosteres.

Souvik Adak1, Verónica Muñoz-Canales2, Surya Sekhar Manna1

  • 1Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, United States.

Journal of the American Chemical Society
|May 28, 2026
PubMed
Summary

[2]-Ladderane derivatives offer a novel solution for replacing ortho-substituted aromatic rings in drug discovery. These simplified analogs of 1,2-disubstituted cubanes improve API properties, aiding medicinal chemistry efforts.

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Area of Science:

  • Medicinal Chemistry
  • Organic Synthesis
  • Drug Discovery

Background:

  • Modulating physicochemical properties of active pharmaceutical ingredients (APIs) is crucial in drug discovery.
  • Saturated isosteres for aromatic rings can improve API properties, but ortho-substituted rings remain challenging to replace.
  • 1,2-Disubstituted cubanes are ideal but difficult to synthesize.

Purpose of the Study:

  • To validate [2]-ladderane derivatives as simplified analogs and bioisosteres of ortho-substituted benzene.
  • To establish [2]-ladderanes as effective tools for medicinal chemistry.

Main Methods:

  • Gram-scale synthesis of versatile [2]-ladderane building blocks.
  • Functionalization of building blocks via medicinal chemistry-relevant transformations.
  • Synthesis and comparison of matched pairs of bioactive compounds.

Main Results:

  • Demonstrated gram-scale synthesis of [2]-ladderane derivatives.
  • Showcased functionalization of [2]-ladderanes using relevant chemical transformations.
  • Evaluated physicochemical, biochemical, and cellular properties of matched pairs, establishing [2]-ladderanes' efficacy.

Conclusions:

  • [2]-Ladderane derivatives serve as effective bioisosteres for ortho-substituted benzene rings.
  • These compounds offer a viable alternative to challenging cubane analogs.
  • The study establishes [2]-ladderanes as valuable tools for improving API properties in medicinal chemistry.