Synthesis, Characterization, and Mechanistic Insights into the Oxidation Reactions by Heme Compound I and Compound II Model Systems

Abstract

지난 수 십년 동안 많은 수의 헴성 및 비헴성 리간드를 포함하는 금속-산소 중간체들이 O2-활성화를 통하거나 인공 산화제를 사용하여 합성되었다. 상세한 반응성 연구와 분광학적 조사를 통해 금속-산소 중간체의 전자적 및 입체적 특성이 중간체의 반응성에 미치는 영향을 잘 이해할 수 있었다. 본 학위논문은 주로 Compound I (Cpd I) 및 Compound II (Cpd II)라고 알려진 포르피린 리간드(헴)가 배위된 고-산화가 철-옥소 중간체의 생성, 분광학적 특성 및 반응성 연구에 중점을 두고 있다. 첫째, Cpd I 의 모델화합물로서 고산화가 Fe(IV)-옥소 포르피린 π-양이온 라디칼 종인 [(TMP+•)FeIV(O)(Cl)] (1)에 의한 시클로헥센의 산화에서 반응 속도 상수를 –40 to –80 oC 범위의 다양한 온도에서 측정하였다. 다양한 온도에서 관찰된 속도 상수와 생성물 분포는 단순히 온도를 낮춤으로써 반응 경로가 C=C 이중 결합 에폭시화에서 알릴 C-H 하이드록실화로 바뀐다는 사실을 확인할 수 있었다. 그러므로 본 연구를 통하여 반응 온도의 변화와 같은 환경 요인의 작은 변화가 한 반응 경로로부터 다른 반응 경로로 전환될 수 있음을 확인할 수 있었다. 둘째, 우리는 전자가 풍부한 포르피린 리간드 및 전자가 부족한 포르피린 리간드가 배위된 Cpd II 모델 화합물에의한 시클로헥센의 산화에 대한 연구를 수행하였다. 이 연구로부터 헴성 Cpd II 모델의 화학 선택성이 포르피린 리간드의 전자적 특성에 따라 다르다는 것을 입증하였다. 흥미롭게도, 전자 결핍 포르피린 리간드를 포함하는 Cpd II 모델 화합물에 의한 시클로헥센의 산화는 높은 반응속도론적 동위원소 효과(KIE)와 더불어 2-cyclohexenol 을 생성물로 얻었다. 반면, 전자가 풍부한 포르피린을 포함하는 Cpd II 모델 화합물에 의한 시클로헥센의 산화반응에서는 KIE 값은 1 이였으며, C=C 에폭시화 경로가 유리함을 입증할 수 있었다. 전자가 풍부한 포르피린을 포함하는 Cpd II 모델 화합물의 경우, 불균등화 반응을 통하여 Cpd I 및 Fe(III)-OH 포르피린이 생성되며, Cpd I 이 활성 산화제임을 확인할 수 있었다. 마지막으로, Cpd II 의 모델화합물인 [(TPFPP)FeIV(O)]에 의한 나프탈렌 및 그 유도체의 방향족 하이드록실화 반응에 대한 연구를 수행하였다. 나프탈렌에서 Cpd II 로의 전자 전달을 통하여 1-나프톨이 생성되며, 이 전자 전달 단계가 속도 결정 단계임을 규명하였다. ;Over the past several decades, a large number of synthetic metal-oxygen intermediates bearing heme and nonheme type ligands have been synthesized through O¬2 activation or by using artificial oxidants. Through detailed reactivity studies and spectroscopic investigations, researchers have been able to better understand how these metal-oxygen intermediates electronic and steric properties play a role in determining their reactivity. This thesis mainly focuses on the generation, spectroscopic characterization, and reactivity studies of high-valent iron-oxo intermediates supported by porphyrin ligand (heme) commonly known as Compound I (Cpd I) and Compound II (Cpd II). Firstly, the rate constants of cyclohexene (CHE) oxidation by a high-valent Fe(IV)-oxo porphyrin π-cation radical species, [(TMP+•)FeIV(O)(Cl)] (1), commonly known as Cpd I was determined at various temperatures ranging from –40 to –80 ºC. The rate constants and product distribution observed during the reaction of CHE by 1 at various temperatures, led us to conclude that the reaction pathway changed from the C=C double bond epoxidation to the allylic C–H hydroxylation by simply lowering the temperature. The epoxidation pathway was seen to be dominating irrespective of the temperature upon replacement of CHE-h10 to CHE-d10. The dependence of temperature on the rate constants of the allylic C–H hydroxylation pathway in the reactions of CHE-h10 and CHE-d10 by 1 suggested a remarkable tunneling effect on the hydrogen atom abstraction of allylic C–H bonds of CHE by 1. This leads us to propose that the tunneling effect is the determining factor for the interchange of the reaction pathway between C=C double bond epoxidation and the C–H hydroxylation by varying the reaction temperature. We observed similar energy barriers for epoxidation and hydroxylation reactions in CHE oxidation by 1 by performing DFT calculations. Further, this study confirmed that small adjustments to environmental factors, such as a change in reaction temperature, can result in preferences for one reaction pathway over another. Secondly, we extended our research to study the electronic effect of porphyrin ligand on the oxidation of CHE by Cpd II model complexes. The chemoselectivity of nonheme Fe(IV)-oxo intermediates is described to be very distinct from that of heme Cpd I intermediates in the CHE oxidation. In general nonheme Fe(IV)-oxo models favor allylic C–H bond activation, whereas, heme Cpd I models usually prefer the C=C epoxidation reaction (with few exceptions). In this chapter, we demonstrated that the chemoselectivity of heme Cpd II intermediates differs depending on the electronic nature of the ligands. High-valent Fe(IV)-oxo porphyrins, such as [(TPFPP)FeIV(O)] (1a) and [(TMP)FeIV(O)] (2a), were prepared, characterized, and explored their reactivity in CHE oxidation. Interestingly, oxidation of CHE by 1a having an electron-withdrawing porphyrin ligand occurred at the allylic position with a large kinetic isotope effect (KIE), and 2-cyclohexenol was obtained, as seen in nonheme Fe(IV)-oxo species. Whereas, as shown in heme Cpd I intermediates, the CHE oxidation by 2a having an electron-donating porphyrin yielded epoxide product and no KIE, indicating that 2a favors the C=C epoxidation. This result can be explained by the disproportionation of 2a, which gives rise to the formation of [(TMP+•)FeIV(O)]+ (2b) and FeIII-complex and 2b is the true oxidant that results in the epoxidation of the C=C double bond in CHE. However, disproportionation of 1a was not observed under the present reaction conditions. Theoretical calculations support that heme Cpd II intermediates prefer allylic hydroxylation of CHE over epoxidation, as described in the nonheme Fe(IV)-oxo species, and also prove that disproportionation of Cpd II intermediates is highly affected by the electronic structure of the ligand. Also, the effect of acid and base on reaction mechanism has been discussed as well. Lastly, we studied aromatic hydroxylation of naphthalene and its derivatives by Cpd II complex, [(TPFPP)FeIV(O)] (1a). The results indicated that electron transfer from naphthalene to Cpd II is the rate-determining step leading to the generation of 1-naphthol. Further, 1,4-naphthoquinone is generated as the final product by fast oxidation reactions of 1-naphthol. Mechanistic studies revealed the involvement of an initial electrophilic attack on the π-system of the aromatic ring to generate a tetrahedral radical or cationic σ-complex as suggested by inverse KIE and a large negative Hammett ρ value. The oxygen atoms in the product (1,4-naphthoquinone) were observed to be derived from the iron-oxo species by the 18O-labelling experiments.