Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Inorg Chem. 2023 Dec 4;62(48):19758-19770. doi: 10.1021/acs.inorgchem.3c03215. Epub 2023 Nov 16.
Selective halogenation is necessary for a range of fine chemical applications, including the development of therapeutic drugs. While synthetic processes to achieve C-H halogenation require harsh conditions, enzymes such as nonheme iron halogenases carry out some types of C-H halogenation, i.e., chlorination or bromination, with ease, while others, i.e., fluorination, have never been observed in natural or engineered nonheme iron enzymes. Using density functional theory and correlated wave function theory, we investigate the differences in structural and energetic preferences of the smaller fluoride and the larger chloride or bromide intermediates throughout the catalytic cycle. Although we find that the energetics of rate-limiting hydrogen atom transfer are not strongly impacted by fluoride substitution, the higher barriers observed during the radical rebound reaction for fluoride relative to chloride and bromide contribute to the difficulty of C-H fluorination. We also investigate the possibility of isomerization playing a role in differences in reaction selectivity, and our calculations reveal crucial differences in terms of isomer energetics of the key ferryl intermediate between fluoride and chloride/bromide intermediates. While formation of monodentate isomers believed to be involved in selective catalysis is shown for chloride and bromide intermediates, we find that formation of the fluoride monodentate intermediate is not possible in our calculations, which lack additional stabilizing interactions with the greater protein environment. Furthermore, the shorter Fe-F bonds are found to increase isomerization reaction barriers, suggesting that incorporation of residues that form a halogen bond with F and elongate Fe-F bonds could make selective C-H fluorination possible in nonheme iron halogenases. Our work highlights the differences between the fluoride and chloride/bromide intermediates and suggests potential steps toward engineering nonheme iron halogenases to enable selective C-H fluorination.
选择性卤化对于一系列精细化学品应用是必要的，包括治疗药物的开发。虽然实现 C-H 卤化的合成过程需要苛刻的条件，但非血红素铁卤化酶等酶可以轻松地进行某些类型的 C-H 卤化，例如氯化或溴化，而其他类型的卤化，例如氟化，从未在天然或工程化的非血红素铁酶中观察到。使用密度泛函理论和相关波函数理论，我们研究了在整个催化循环中较小的氟化物和较大的氯或溴化物中间体在结构和能量偏好上的差异。尽管我们发现氟化物取代对限速氢原子转移的能垒影响不大，但与氯和溴化物相比，氟化物在自由基回弹反应中观察到的更高能垒导致 C-H 氟化的困难。我们还研究了异构化在反应选择性差异中可能起作用的可能性，我们的计算揭示了关键 ferryl 中间体的异构能学之间的关键差异，氟化物和氯/溴化物中间体之间存在差异。虽然认为参与选择性催化的单齿异构体的形成对于氯和溴化物中间体是可能的，但我们发现我们的计算中不可能形成氟化物单齿中间体，因为缺乏与更大蛋白质环境的额外稳定相互作用。此外，发现较短的 Fe-F 键会增加异构化反应的能垒，这表明形成与 F 形成卤素键并延长 Fe-F 键的残基的掺入可能使非血红素铁卤化酶中的选择性 C-H 氟化成为可能。我们的工作强调了氟化物和氯/溴化物中间体之间的差异，并提出了潜在的步骤，以工程化非血红素铁卤化酶，从而实现选择性 C-H 氟化。
