The development of palladium-catalyzed fluorination with biaryl monophosphine ligands has faced two important problems that limit its application for bromoarenes: the formation of regioisomers and insufficient catalysis for heteroaryl substrates as bromothiophene derivatives. Overcoming these problems requires more ligand design. In this work, reliable theoretical calculations were used to elucidate important ligand features necessary for achieving more rate acceleration and selectivity. These features include increasing the ligand-substrate repulsion and creating a negative charge in the space around the fluoride ion bonded to the palladium. The investigated L5 ligand presents these features, and the calculations predict that this ligand completely suppresses the regioisomer formation in the difficult case of 4-bromoanisole. In addition, the free energy barriers are decreased by 2–3 kcal mol⁻¹ in comparison with the catalysis involving the AlPhos ligand. Thus, the present study points out a direction for new developments in palladium-catalyzed fluorination.

中文翻译：

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提高钯催化芳香族氟化反应速率和选择性的新配体的理论设计


钯催化的联芳基单膦配体氟化反应的开发面临着两个限制其在溴芳烃中的应用的重要问题：区域异构体的形成和作为溴噻吩衍生物的杂芳基底物的催化不足。克服这些问题需要更多的配体设计。在这项工作中，使用了可靠的理论计算来阐明实现更多速率加速和选择性所需的重要配体特征。这些特性包括增加配体-衬底排斥力，并在与钯键合的氟离子周围的空间中产生负电荷。所研究的 L5 配体呈现这些特征，计算预测该配体在 4-溴苯甲醚的困难情况下完全抑制区域异构体的形成。此外，与涉及 AlPhos 配体的催化相比，自由能势垒降低了 2-3 kcal ^mol-1。因此，本研究为钯催化氟化的新发展指明了方向。