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Alkynes to Aldehydes and Ketones: Acid-Catalyzed Hydration

Alkynes to Aldehydes and Ketones: Acid-Catalyzed Hydration

Introduction
Analogous to alkenes, alkynes also undergo acid-catalyzed hydration. While the addition of water to an alkene gives an alcohol, hydration of alkynes produces different products such as aldehydes and ketones.

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The method to achieve α-brominated carboxylic acids using a mixture of phosphorus tribromide and bromine is known as the Hell–Volhard–Zelinski reaction. The reaction is catalyzed by phosphorus tribromide, which can be used directly or produced in situ from red phosphorus and bromine. The mechanism comprises PBr3 catalyzed conversion of acid to acid bromide and hydrogen bromide. The acid bromide enolizes to its enol form in the presence of HBr. The nucleophilic enol attacks the bromine molecule...

ortho–para-Directing Deactivators: Halogens

ortho–para-Directing Deactivators: Halogens

Halogens are ortho–para directors. They are more electronegative than carbon. Therefore, as ring substituents, they can withdraw electrons through the inductive effect and deactivate the aromatic ring towards electrophilic substitution. Halogens also have an electron-donating resonance effect on the ring, which influences the orientation of the incoming electrophile. If an electrophile attacks at the ortho or the para position, the halogen donates electrons and stabilizes the intermediate...

Radical Formation: Homolysis

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A bond is formed between two atoms by sharing two electrons. When this bond is broken by supplying sufficient energy, either two electrons can be taken up by one atom forming ions by the cleavage called heterolysis, or the two electrons are shared by two atoms, with one each creating radicals by the cleavage called homolysis.

Cycloaddition Reactions: MO Requirements for Thermal Activation

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Thermal cycloadditions are reactions where the source of activation energy needed to initiate the reaction is provided in the form of heat. A typical example of a thermally-allowed cycloaddition is the Diels–Alder reaction, which is a [4 + 2] cycloaddition. In contrast, a [2 + 2] cycloaddition is thermally forbidden.

Cycloaddition Reactions: MO Requirements for Photochemical Activation

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Related Experiment Video

Updated: Jun 26, 2026

Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds

Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds

Published on: October 15, 2019

Unlocking pH-responsive dual payload release through hydrazone linkage chemistry.

Heba S Abd-Ellah¹, Dan Zhao², Yayao Zhou²

¹Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.

Bioorganic & Medicinal Chemistry

|March 29, 2025

Summary

This study introduces a novel acid-labile linker for simultaneous intracellular delivery of two payloads. This dual-release system, triggered by acidic conditions, enables targeted combination therapies and cellular function studies.

Keywords:

Acid-labile linkers Acyl hydrazones Dual pathway targeting Nanoparticle endosomal escape

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Published on: May 12, 2023

Area of Science:

Biochemistry
Nanotechnology
Drug Delivery

Background:

Current methods often deliver single payloads, limiting cellular function studies and combination therapies.
Simultaneous intracellular delivery of multiple payloads offers potential for enhanced therapeutic outcomes and deeper biological insights.

Purpose of the Study:

To develop and characterize a novel trifunctional hydrazone linker capable of releasing two distinct payloads (W and Z) in a programmed, acid-triggered manner.
To enable simultaneous, stoichiometric release of payloads via intramolecular cyclization upon initial acid-mediated cleavage.
To incorporate an azide group for potential nanoparticle conjugation, facilitating targeted delivery.

Main Methods:

Synthesis of six target acylhydrazone linkers with varying structures.
Evaluation of linker stability across a range of pH conditions, mimicking physiological and endosomal/lysosomal environments.
Assessment of the dual-release mechanism, including payload stoichiometry and release kinetics.

Main Results:

An acyl acetophenone hydrazone linker (linker 3) demonstrated high stability at physiological pH (7.4) and rapid dual-payload release at acidic pH (4.5-6.5).
The linker successfully mediated a 1:1 stoichiometric release of payload W, subsequently triggering the release of payload Z.
Linker 3 exhibited potential for nanoparticle conjugation due to its built-in azide group.

Conclusions:

Linker 3 represents a feasible and promising platform for dual intracellular drug delivery, particularly for combination therapies.
The linker's pH-dependent release profile makes it suitable for targeted delivery to endosomes, lysosomes, or tumor microenvironments.
This technology could enable novel synergistic treatment strategies using combinations like doxorubicin and nitric oxide donors, or proteins and nucleic acids.