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Nucleophilic Substitution Reactions

Nucleophilic Substitution Reactions

Historical perspective
In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids through a series of reactions. This conversion suggested the involvement of optical inversion during the substitution reaction. Further, in 1930, Sir Christopher Ingold described for the first time two different forms of nucleophilic substitution reactions, which are known as SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution...

Reaction Mechanisms

Reaction Mechanisms

Chemical reactions often occur in a stepwise fashion, involving two or more distinct reactions taking place in a sequence. A balanced equation indicates the reacting species and the product species, but it reveals no details about how the reaction occurs at the molecular level. The reaction mechanism (or reaction path) provides details regarding the precise, step-by-step process by which a reaction occurs.
For instance, the decomposition of ozone appears to follow a mechanism with two steps:

Multi-Step Reactions

Multi-Step Reactions

Chemical reactions often occur in a stepwise fashion involving two or more distinct reactions taking place in a sequence. A balanced equation indicates the reacting species and the product species, but it reveals no details about how the reaction occurs at the molecular level. The reaction mechanism (or reaction path) provides details regarding the precise, step-by-step process by which a reaction occurs. Each of the steps in a reaction mechanism is called an elementary reaction. These...

Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism

Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism

The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring...

Radical Reactivity: Overview

Radical Reactivity: Overview

Radicals, the highly reactive species, gain stability by undergoing three different reactions. The first reaction involves a radical-radical coupling, in which a radical combines with another radical, forming a spin‐paired molecule. The second reaction is between a radical and a spin‐paired molecule, generating a new radical and a new spin‐paired molecule. The third reaction is radical decomposition in a unimolecular reaction, forming a new radical and a spin‐paired...

Radical Anti-Markovnikov Addition to Alkenes: Mechanism

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The reaction of hydrogen bromide with alkenes in the presence of hydroperoxides or peroxides proceeds via anti-Markovnikov addition. The radical chain reaction comprises initiation, propagation, and termination steps.
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Related Experiment Video

Updated: Sep 17, 2025

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

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Published on: November 9, 2019

Novel Mannich-Type Multicomponent Reactions: Discovery, Mechanism, and Application.

Xianjing Zhou¹, Zhencheng Lai¹, Jiaming Li¹

¹Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Accounts of Chemical Research

|July 1, 2025

Summary

This summary is machine-generated.

This study introduces novel multicomponent reactions (MCRs) for synthesizing complex molecules, particularly enabling Mannich reactions with unactivated C-H bonds for drug discovery and natural product modification.

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Area of Science:

Organic Chemistry
Medicinal Chemistry
Synthetic Methodology

Background:

Multicomponent reactions (MCRs) are crucial for efficient synthesis of complex molecules.
The Mannich reaction, a key MCR, typically involves activated C-H bonds.
Developing Mannich reactions for unactivated C-H bonds, especially C(sp³)-H, is challenging.

Purpose of the Study:

To develop novel Mannich-type multicomponent reactions involving unactivated C-H bonds.
To explore the application of these MCRs in scaffold evolution of natural products and drug discovery.
To elucidate the mechanistic pathway of the novel Mannich reactions.

Main Methods:

Investigated a serendipitous discovery leading to a double Mannich alkylamination.
Conducted mechanistic studies involving multiple Mannich, retro-Mannich, and dehydrogenation steps.
Developed Mannich-type MCRs utilizing benzofurans/indoles, formaldehyde, and alkylamine hydrochlorides.

Main Results:

Achieved unprecedented alkylamination in both C(sp²)-H and unactivated benzylic C(sp³)-H bonds.
Successfully synthesized piperidine-fused benzofurans/indoles and indole-fused seven-membered heterocycles.
Demonstrated broad compatibility with medicinally relevant functionalities and successful scaffold evolution of tanshinones.

Conclusions:

Developed a powerful synthetic toolbox for scaffold evolution of natural products and drug discovery.
Pioneered chemical evolution of tanshinones, leading to potent NLRP3 inflammasome inhibitors and effective ALI treatments.
Generated promising drug candidates, including novel HDAC, P-gp, and STAT3 inhibitors, highlighting the MCRs' therapeutic potential.