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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...

Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule

Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule

If a set of reactants can yield multiple constitutional isomers, but one of the isomers is obtained as the major product, the reaction is said to be regioselective. In such reactions, bond formation or breaking is favored at one reaction site over others.
The hydrohalogenation of an unsymmetrical alkene can yield two haloalkane products, depending on which vinylic carbon takes up the halogen. However, one product usually predominates, where hydrogen adds to the vinylic carbon bearing the...

Base-Promoted α-Halogenation of Aldehydes and Ketones

Base-Promoted α-Halogenation of Aldehydes and Ketones

α-Halogenation of aldehydes and ketones is a reaction involving the substitution of α hydrogens with halogens in the presence of a base. The reaction begins with the abstraction of α hydrogen by the base to produce a nucleophilic enolate ion. This intermediate undergoes a subsequent nucleophilic substitution with the halogen to produce a monohalogenated carbonyl compound. If the starting substrate has more than one α hydrogen, it is difficult to stop the reaction...

Electrophilic Addition to Alkynes: Halogenation

Electrophilic Addition to Alkynes: Halogenation

Introduction
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.

Halogenation of Alkenes

Halogenation of Alkenes

Halogenation is the addition of chlorine or bromine across the double bond in an alkene to yield a vicinal dihalide. The reaction occurs in the presence of inert and non-nucleophilic solvents, such as methylene chloride, chloroform, or carbon tetrachloride.
Consider the bromination of cyclopentene. Molecular bromine is polarized in the proximity of the π electrons of cyclopentene. An electrophilic bromine atom adds across the double bond, forming a cyclic bromonium ion intermediate.

Acid-Catalyzed α-Halogenation of Aldehydes and Ketones

Acid-Catalyzed α-Halogenation of Aldehydes and Ketones

By replacing an α-hydrogen with a halogen, acid-catalyzed α-halogenation of aldehydes or ketones yields a monohalogenated product
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a...

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Related Experiment Video

Updated: May 27, 2025

Constructing Thioether/Vinyl Sulfide-tethered Helical Peptides Via Photo-induced Thiol-ene/yne Hydrothiolation

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Published on: August 1, 2018

Stabilization of a protein by a single halogen-based aromatic amplifier.

Krystel El Hage^1,2, Balamurugan Dhayalan³, Yen-Shan Chen³

¹Department of Chemistry, University of Basel, Basel, Switzerland.

Protein Science : a Publication of the Protein Society

|February 19, 2025

Summary

Halogenation stabilizes insulin by modifying electrostatic interactions. Ortho-substituted analogs show enhanced stability and retain biological activity, improving pharmaceutical formulations.

Keywords:

entropy‐enthalpy compensation free‐energy simulation protein dynamics protein stability unnatural mutagenesis

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Chemical Dimerization-Induced Protein Condensates on Telomeres

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Area of Science:

Protein Engineering
Medicinal Chemistry
Biophysics

Background:

Halogenation is a strategy for protein design.
Understanding electrostatic interactions is key to protein stability.

Purpose of the Study:

Investigate halogenation's utility in protein design.
Enhance the stability of pharmaceutical insulin.

Main Methods:

Quantitative atomistic simulations.
Experimental validation using insulin analogs.
Assays for thermodynamic stability, receptor binding, and fibrillation.

Main Results:

Ortho-halogenation of phenylalanine B24 stabilized insulin (ΔΔG_u = -0.5 to -1.0 kcal/mol).
Ortho-analogs retained biological activity in cellular and animal models.
Enhanced resistance to fibrillation was observed above room temperature.

Conclusions:

Regiospecific halogenation effectively stabilizes insulin.
This approach can improve the shelf-life of insulin formulations.
Potential applications for other therapeutic proteins and vaccines.