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Radical Formation: Homolysis

Radical Formation: Homolysis

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.

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Orthogonal Cleavage of the HMPB Linker from Solid Support Using HFIP.

Michael Desgagné¹, Dennis A Kutateladze¹, Bradley L Pentelute^1,2,3,4

¹Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Organic Letters

|December 8, 2025

Summary

Hexafluoroisopropanol (HFIP) enables efficient cleavage of the HMPB linker for peptide synthesis at low concentrations. This method provides yields comparable to traditional trifluoroacetic acid conditions.

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Area of Science:

Organic Chemistry
Peptide Synthesis
Biochemistry

Background:

Hexafluoroisopropanol (HFIP) is a common hydrogen-bond-donor solvent in chemical synthesis.
4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB) is a widely used linker for C-terminal peptide synthesis.
Current peptide cleavage methods often require harsh conditions, such as concentrated acids.

Purpose of the Study:

To investigate the cleavage efficiency of the HMPB linker using varying concentrations of HFIP in dichloromethane.
To determine if lower HFIP concentrations can achieve comparable yields to traditional cleavage methods.
To elucidate the chemical mechanism behind the observed HMPB linker cleavage.

Main Methods:

Solid-phase peptide synthesis utilizing the HMPB linker.
Cleavage experiments using a gradient of HFIP concentrations in dichloromethane.
Analysis of cleavage yields and comparison with trifluoroacetic acid (TFA) cleavage standards.
Computational analysis to explore the electronic effects of substituents on the cleavage mechanism.

Main Results:

The HMPB linker cleaves effectively from the solid support at HFIP concentrations as low as 20% in dichloromethane.
Peptide yields obtained using 20% HFIP were comparable to those achieved with concentrated trifluoroacetic acid.
The presence of a para-methoxy substituent on the phenoxy ring was identified as a key factor in enhancing cleavage efficiency.
A proposed mechanism involves stabilization of the benzylic carbocation intermediate through an added resonance structure.

Conclusions:

Low concentrations of HFIP in dichloromethane offer an efficient and potentially milder alternative for cleaving HMPB-linked peptides.
The methoxy substituent on the HMPB linker plays a crucial role in facilitating cleavage by stabilizing the carbocation intermediate.
This finding has implications for optimizing peptide synthesis protocols, potentially reducing side reactions and improving overall yields.