Methyl Radical Addition Reactions to C═X Double Bonds

Yuman Hordijk; Bart Waaijer; Christopher B. Kelly; Trevor A. Hamlin

doi:10.1021/acs.joc.5c01157

Methyl Radical Addition Reactions to C═X Double Bonds

Yuman Hordijk
, Bart Waaijer
, Christopher B. Kelly
, Trevor A. Hamlin^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Radical additions to olefins and related π-systems are essential tools in the modern synthetic toolbox for forging C–C and C–X bonds. We report a systematic DFT study (ZORA-(U)OLYP/TZ2P) on methyl radical (H₃C^•) additions to H₂C═X substrates, where X is varied across elements from the tetrel (group 14: C, Si, Ge), pnictogen (group 15: N, P, As), and chalcogen (group 16: O, S, Se) groups. Our analysis reveals clear periodic trends: addition barriers at carbon decrease, and those at X increase from tetrels to chalcogens; reaction energies become less favorable across a period but more favorable down a group. Regioselectivity favors addition at X except for X = CH₂, NH, and O, where carbon attack dominates─consistent with experimental data. These trends arise from a balance of orbital interactions and Pauli repulsion, with the latter emerging as a key, yet underappreciated, factor governing radical reactivity and regioselectivity in π-systems.

Original language	English
Pages (from-to)	10786-10796
Number of pages	11
Journal	Journal of Organic Chemistry
Volume	90
Issue number	30
Early online date	21 Jul 2025
DOIs	https://doi.org/10.1021/acs.joc.5c01157
Publication status	Published - 1 Aug 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society

Funding

We thank the Netherlands Organization for Scientific Research (NWO) and Microsoft Research for their financial support. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative and VU BAZIS.

Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
VU BAZIS
SURF
Microsoft Research

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title = "Methyl Radical Addition Reactions to C═X Double Bonds",

abstract = "Radical additions to olefins and related π-systems are essential tools in the modern synthetic toolbox for forging C–C and C–X bonds. We report a systematic DFT study (ZORA-(U)OLYP/TZ2P) on methyl radical (H3C•) additions to H2C═X substrates, where X is varied across elements from the tetrel (group 14: C, Si, Ge), pnictogen (group 15: N, P, As), and chalcogen (group 16: O, S, Se) groups. Our analysis reveals clear periodic trends: addition barriers at carbon decrease, and those at X increase from tetrels to chalcogens; reaction energies become less favorable across a period but more favorable down a group. Regioselectivity favors addition at X except for X = CH2, NH, and O, where carbon attack dominates─consistent with experimental data. These trends arise from a balance of orbital interactions and Pauli repulsion, with the latter emerging as a key, yet underappreciated, factor governing radical reactivity and regioselectivity in π-systems.",

author = "Yuman Hordijk and Bart Waaijer and Kelly, \{Christopher B.\} and Hamlin, \{Trevor A.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

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T1 - Methyl Radical Addition Reactions to C═X Double Bonds

AU - Hordijk, Yuman

AU - Waaijer, Bart

AU - Kelly, Christopher B.

AU - Hamlin, Trevor A.

PY - 2025/8/1

Y1 - 2025/8/1

N2 - Radical additions to olefins and related π-systems are essential tools in the modern synthetic toolbox for forging C–C and C–X bonds. We report a systematic DFT study (ZORA-(U)OLYP/TZ2P) on methyl radical (H3C•) additions to H2C═X substrates, where X is varied across elements from the tetrel (group 14: C, Si, Ge), pnictogen (group 15: N, P, As), and chalcogen (group 16: O, S, Se) groups. Our analysis reveals clear periodic trends: addition barriers at carbon decrease, and those at X increase from tetrels to chalcogens; reaction energies become less favorable across a period but more favorable down a group. Regioselectivity favors addition at X except for X = CH2, NH, and O, where carbon attack dominates─consistent with experimental data. These trends arise from a balance of orbital interactions and Pauli repulsion, with the latter emerging as a key, yet underappreciated, factor governing radical reactivity and regioselectivity in π-systems.

AB - Radical additions to olefins and related π-systems are essential tools in the modern synthetic toolbox for forging C–C and C–X bonds. We report a systematic DFT study (ZORA-(U)OLYP/TZ2P) on methyl radical (H3C•) additions to H2C═X substrates, where X is varied across elements from the tetrel (group 14: C, Si, Ge), pnictogen (group 15: N, P, As), and chalcogen (group 16: O, S, Se) groups. Our analysis reveals clear periodic trends: addition barriers at carbon decrease, and those at X increase from tetrels to chalcogens; reaction energies become less favorable across a period but more favorable down a group. Regioselectivity favors addition at X except for X = CH2, NH, and O, where carbon attack dominates─consistent with experimental data. These trends arise from a balance of orbital interactions and Pauli repulsion, with the latter emerging as a key, yet underappreciated, factor governing radical reactivity and regioselectivity in π-systems.

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Methyl Radical Addition Reactions to C═X Double Bonds

Abstract

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