Review
Highvalent 3d metal-oxo mediated C–H halogenation: Biomimetic approaches

https://doi.org/10.1016/j.ccr.2019.213174Get rights and content

Highlights

  • Biomimetic halogenation by metal-oxo complexes resembling active sites of halogenase.

  • High-valent manganese-porphyrins show superior reactivity towards halogenation.

  • Manganese-salens exhibit similar reactivity to manganese-porphyrins for halogenation.

  • There is a greater scope for improvement in activity of non-heme biomimetic models.

  • Vanadium-oxo-peroxo complexes are efficient catalyst for electrophilic halogenation.

Abstract

Enzymes are most efficient catalyst for organic transformations including halogenation of C–H bonds. Most of the halogenating enzymes utilize high valent metal-oxo intermediates for hydrogen atom abstraction (HAA) and subsequent haloalkane formation. Due to high demand of organohalide compounds, many attempts have been made to mimic the active sites of halogenating enzymes in order to achieve efficacy of enzymes. Different first row transition metals complexes have been synthesized using various ligand systems. In this review, we have summarized the efforts made towards development of halogenation using high valent metal-oxo complexes and understanding the mechanism of their activity.

Introduction

Halogen substituted organic compounds are of immense importance both in biology and industry. More than 5000 natural compounds are known to be containing halogens [1]. Amongst the highly valued bioactive molecules vancomycin, salinosporamide A, rebeccamycin etc. are examples containing carbon-halogen bonds [2], [3]. Synthetically, many of the new generation coupling reactions require halogen containing substrates. Therefore pharmaceutical and other industries consumes tons of substrates having C–X (X = halogen) bond at specific positions and with specific spatial arrangements [1].

Nature has unique ability to synthesize all biomolecules in most efficient way and synthesis of organohalogen compounds are not exception. There exist several classes of halogenating enzymes in biosystems that deals with production of halogenated compounds, namely a) heme–iron haloperoxidases, b) vanadium dependent haloperoxidases, c) flavin dependent halogenases and d) non-heme iron halogenases. Examples of halogenating enzymes include chloroperoxidase (CPO), vanadium-dependent bromoperoxidase (V-HPO), syringomycin halogenase (SyrB2) etc [3], [4], [5]. Except flavin dependent halogenases, these enzymes carry out regiospecific halogenation of specific substrates at biological temperature and pH using first row transition metal centers present in the active sites; a condition highly desirable in synthetic chemistry [6]. The protein cavity provided in enzymatic systems is responsible for regiospecificity as the secondary interactions allow exposure of site of concern to the active site [7], [8]. The active site of heme and non-heme iron based halogenating enzymes employ high valent metal-oxo intermediate to incorporate C–X bond selectively into the required carbon center of a biomolecule.

In the last century, enormous efforts have been made to fully understand and mimic mechanistic insights of enzyme reactivity [9]. Among those, structural and functional mimic of high valent metal-oxo systems have been studied mostly. Although reasonable success has been achieved with these systems for several transformations such as hydroxylation and epoxidation, metal-oxo driven functional mimic for halogenation is inadequate in the literature [10]. Strong reactivity of the high valent metal-oxo is considered responsible for this limitation. The metal-oxo species has high affinity towards hydrogen abstraction from saturated substrate to form reactive radical intermediate. The absence of protein chain in biomimetic systems analogous to enzymes creates challenge in controlling the forward reaction of the radical intermediate. In particular, during attempt for halogenation a competitive hydroxylation also occur simultaneously because of comparable rate of hydroxyl transfer from metal hydroxo species to substrate radical. Despite these shortcomings, several attempts have been made by chemists to achieve selective halogenation over other functionalizations utilizing high valent metal-oxo intermediates in both heme and non-heme domain. In this perspective, we have summarized structural and functional mimics of metal-oxo mediated halogenation. For clear understanding the literature has been divided into four parts, i) heme based systems, ii) salen based systems, iii) non-heme based systems and iv) vanadium-oxo-peroxo based systems.

Section snippets

Heme based systems

Chloroperoxidase is one of the most studied heme based halogenating enzymes found in nature. The active site of chloroperoxidase is a heme–iron center with +3 oxidation in its native state. The metal center upon oxidation forms Fe(IV)double bondO (2) intermediate, which in turn is converted to Fe(III)-OX (3) in presence of halide (Scheme 1). The substrate then interacts with this intermediate to give away the halogenated product [1], [11]. Even though iron-porphyrin based oxidation reaction are thoroughly

Salen based metal oxo mediated halogenation

The fluorination strategy by manganese porphyrin afforded expected fluorinated products selectively at benzylic position. Unfortunately, equal proportion of oxidized products viz. alcohol and carbonyl products were also observed in the reaction mixture. Benzyl radical, having low ionization potential, rebounds faster with Mn–OH intermediate which inhibits fluorination partially. Jacobson and co-workers in 1991, replaced manganese porphyrin with manganese-salen complex in order to achieve

Non-heme based systems

The active site of α-ketoglutarate (α-KG) dependent SyrB2 halogenase is based on iron(II) ion, co-ordinated with two histidine residue, one aspartate residue, one halide and a water molecule (Scheme 8). During oxidation, the water is replaced by an oxo ligand with a cis configuration to chloride co-ordination. The metal-oxo complex 28 is formed from 27 by series of transformations promoted by various enzymes in biological systems [3]. Then the usual hydrogen abstraction from substrate forms the

Vanadium-oxo-peroxo based systems

Vanadium dependent haloperoxidase is most abundant compared to the other two types [3]. The active site of V-XPO (vanadium dependent haloperoxidase) is unique in various aspects. The redox inactive VV ion is co-ordinated to protein through a single histidine residue in addition to hydrogen bonding with co-ordinated oxygen atoms. This vanadate ion forms a μ -peroxo complex in presence of H2O2, which in turn captures halide to form hypohalite. This intermediate acts as electrophilic halogen

Conclusion

In conclusion, there exist various methods for synthesis of organohalide compounds, but none energetically as efficient as enzymes. Moreover enzymes use abundant first row transition metals inside a specifically confined space. In the journey to mimic these reactivities, only manganese-porphyrin and manganese-salen complexes showed more promising results than the others. Although non-heme iron-oxo-halide complexes can be synthesized with structural similarity of corresponding enzyme active

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

This activity was supported by SERB, India (CRG/2018/003951). Financial support received from CSIR-India (fellowship to JPB) is gratefully acknowledged.

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