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Thiourea-Mediated Halogenation of Alcohols

Amar R. Mohite, Ravindra S. Phatake, Pooja Dubey, Mohamed Agbaria, Alexander I. Shames, N. Gabriel Lemcoff* and Ofer Reany*

*Ben-Gurion University of the Negev, Beer-Sheva 8410501; The Open University of Israel, Ra'anana 4353701, Israel, Email: lemcoffbgu.ac.il, oferreopenu.ac.il

A. R. Mohite, R. S. Phatake, P. Dubey, M. Agbaria, A. I. Shames, N. G. Lemcoff, O. Reany, J. Org. Chem., 2020, 85, 12901-12911.

DOI: 10.1021/acs.joc.0c01431


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Abstract

Substoichiometric amounts of thiourea additives mediate the halogenation of alcohols under mild conditions. In the the absence of thiourea, oxidation of the alcohol is observed, whereas the substrate can be recovered when excess thiourea is used. Both bromination and chlorination were highly efficient for primary, secondary, tertiary, and benzyl alcohols and tolerate a broad range of functional groups.


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Details

The article discusses a novel methodology for the halogenation of alcohols using thiourea additives and N-halosuccinimides (NXS) under mild conditions. The process is efficient for primary, secondary, tertiary, and benzyl alcohols, tolerating a wide range of functional groups. The amount of thiourea added is crucial, as it dictates the reaction pathway: substoichiometric amounts favor halogenation, while excess thiourea inhibits the reaction. The method is highly atom-economic, using inexpensive and recyclable reagents, making it appealing for both academic and industrial applications. Detailed studies, including electron paramagnetic resonance (EPR) and isotopic labeling, suggest a radical-based mechanism. The reaction proceeds efficiently in nonpolar solvents, and radical scavengers like butylated hydroxyl toluene (BHT) suppress bromination, supporting the radical mechanism. The methodology offers a sustainable alternative to classical halogenation methods, with advantages such as simplicity, cost-effectiveness, and broad applicability. The article also highlights the potential for further research, including the use of chiral thioureas for asymmetric halogenation and expanding the methodology to other halogens. This approach represents a significant advancement in the field of organic synthesis, promoting more sustainable chemical processes.


Key Words

alkyl bromides, alkyl chlorides, benzyl bromides, benzyl chlorides, NBS, NCS, photochemistry


ID: J42-Y2020