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Mechanisms in non-heme iron oxidation catalysisChen, Juan

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CHAPTER 1

Photochemistry of iron complexes

Although iron is the most abundant of the bio-essential metals, and its coordination chemistry

is of central importance to bio-inorganic and bioinspired chemistry, its photochemistry has

been overshadowed by ruthenium polypyridyl complexes since the 1970s. The photochemistry

of iron complexes is nevertheless rich and presents a multitude of opportunities in a wide

range of fields. In this chapter, we review the state of the art and especially recent progress in

the photochemistry of iron complexes, focusing on aspects of relevance to environmental,

biological and photocatalytic chemistry.

Manuscript has been submitted:

Juan Chen, Wesley R. Browne

Chapter 1

2

1.1 Introduction

Photochemistry is an small but essential branch of chemistry, recognized for example, as the

basis for the “molecular-machines” honored by the 2016 Nobel prize for chemistry, and is central

to most life on this planet. At its most basic level, photochemistry is the conversion of

electromagnetic radiation to chemical energy and enables induction of chemical transformations

with spatial and temporal control. The chemical transformations and changes in reactivity form

the basis of “photodynamic therapy” treatments in medicine and in photo(redox)catalysis, and

hence exploring new photochemical processes in both organic and inorganic molecular systems

opens opportunities in medicine, materials and chemical reactivity.

The range of organic and inorganic systems of interest to photochemistry is much more

limited than for thermal reactivity. This is primarily due to the need for a compound to have an

electronically excited state that is sufficiently long lived to engage in energy or electron transfer,

or to react with other compounds. From an inorganic perspective, this demand has limited

attention to transition metal complexes such as those of chromium, ruthenium and iridium. In the

case of iron complexes the lowest excited states are metal centered (e.g., eg t2g) and are

displaced with respect to the ground state facilitating rapid radiationless deactivation, and hence

quenching photochemical reactivity. Given that there are many new iron complexes reported

each year, the challenge is to identify and understand potential approaches to achieving

photoreactivity with iron complexes. In this chapter, we will discuss the known photochemistry of

iron complexes and categorize the various reaction classes to build a picture of the state of the art.

The reported iron complexes are mostly coordinated with organic ligands in an octahedral or,

less often, tetrahedral coordination environment. The photo-processes observed in iron

complexes correlate with formal oxidation states, spin states, as well as the ligand environment.

Hence, we will begin our discussion by introducing electronic structures and the electronic

configurations of iron complexes in their various oxidation states.

The earliest, and perhaps the best-documented, photochemical reactions are the photo-

assisted Fenton and photo-induced decarboxylation reactions, both of which are of relevance to

environmental and materials science (see section 1.3.1 and section 1.3.2). The photochemically

induced release of small molecules, a field of growing importance, is dominated by:

Release of N2, for example, from porphyrin-ligated FeIII azide complexes used to

generate high valent iron complexes.

H2 evolution, for example, through reductive elimination from Fe-hydride complexes,

which holds potential in energy storage.

CO-release, mainly from Fe-CO complexes, which is of importance in CO-related

cytoprotection, anti-inflammation, and vasodilatory therapeutic treatments.

Iron is an essential element and its complexes are well recognized as candidates in

photometallodrugs in cancer treatment, specifically DNA cleavage and photocytotoxicity as

shown by the series of iron complexes discussed in section 1.3.4. Last but not least, photocatalytic

reactions using iron complexes are seeing increasing attention, with both heme and non-heme

iron complex as photo-catalysts in the oxidation of organic substrates, which is discussed in the

penultimate section of this chapter. The contributions made in this thesis are reviewed briefly in

the last section.

Photochemistry of Iron Complexes

3

1.2 Electronic structures and spin states

Iron is the most abundant metal on earth and the known oxidation states of iron range from

Fe0 to FeVI, all of which have been observed experimentally. Its cations have dominated the field

of transition metal oxidation chemistry, due to its great importance in both bioinorganic and

synthetic chemistry. The chemistry if iron is enriched by the number of accessible spin states,

include high-, intermediate-, and low-spin iron complexes, in each of its stable oxidation states. In

bioinorganic and biomimetic chemistry, the majority of iron complexes are in an octahedral or

pseudo-octahedral environment. Scheme 1 illustrates the energetic splitting pattern of d orbitals

and the electron configurations of the oxidation states of FeII to FeIV in octahedral environments.

The states shown are observed in both heme and non-heme iron complexes and photochemistry

involving these complexes has been reported. Fe0, FeV and FeIV are not included due to the lack of

reports on photo activity of their complexes.

Scheme 1. Possible oxidation and spin states of iron complexes in an octahedral geometry (left)

and the splitting patterns for d orbitals of oxo-iron(IV) complex in pseudo-octahedral geometry

with consideration of the ligand environments (right). Both non-heme and heme ligands are

included (structures shown are the representative for each type). All these states are accessible in

both non-heme and heme iron complexes.

The energies of all five d orbitals (𝑑𝑥𝑦, 𝑑𝑥𝑧, 𝑑𝑦𝑧, 𝑑𝑧2 , 𝑑𝑥2−𝑦2) are degenerate in gas phase Fen+

ions. However, in ligand field, the relative energies of the d orbitals are determined by the ligand

environment. In an ideal octahedral complex, the 5d orbitals are split into two degenerate sets,

two of higher energy, 𝑑𝑧2 and 𝑑𝑥2−𝑦2 (eg orbitals) and three of lower energy 𝑑𝑥𝑦, 𝑑𝑥𝑧, 𝑑𝑦𝑧 (t2g

orbitals). Low-spin FeII complexes are the only diamagnetic members of this series of possible

oxidation and spin states with the rest being paramagnetic. Amongst the paramagnetic states,

there is a special case: the antiferromagnetically coupled arrangement of the FeIII dimer, in which

Chapter 1

4

there are five alpha d electrons on one FeIII ion and five beta d electrons on the other. In a

pseudo-octahedral complex, the degeneracy is lifted further. For example, in oxo-iron(IV)

complexes the five d orbitals are different in energy, and the ligands can change the energy

ordering of the orbitals also; the 𝑑𝑥2−𝑦2 orbitals are higher in energy than the 𝑑𝑧2 in a heme

ligand environment (e.g., compound I of P450) and vice versa in most of the non-heme ligand

environments (e.g., N4Py, TMC) (Scheme 1).

The photochemistry of iron complexes was studied extensively prior to the 1970s, but has

been overshadowed by the photophysics and chemistry of ruthenium(II) polypridyl complexes

with hundreds of variants.1 The outstanding physical and chemical properties of these RuII still

play important roles in photochemistry, photophysics, photocatalysis, electrochemistry,

photoelectrochemistry, chemi- and electrochemi-luminescence, and electron and energy transfer.

Iron and ruthenium are in the same Group (VIII) and are similar in octahedral environments, the

metal center and ligand bonding are similar. The most important difference between FeII and RuII

complexes is that almost all the octahedral RuII complex are low-spin with a full filled t2g level.

Hence, there are only several possible orbital dispositions possible (Scheme 2), (a)the filled metal

t2g orbital lies below the filled orbitals of the ligand (L) and eg orbitals lies above the empty

orbitals of the ligand (L); (b) the fully occupied metal t2g orbitals and empty eg orbitals lie

between the occupied L orbitals and the empty L; (c) the fully occupied t2g orbitals lie between

the filled L orbitals and the empty L; in each of the cases, the lowest energy transitions are the

intraligand-, metal centered- (Laporte forbidden), and metal to ligand charge transfer transitions,

respectively. Scheme 2d shows these four transition types in an octahedral RuII complex with

polypyridyl ligands. However, for iron complexes the energy difference between t2g and eg orbitals

are much less than for ruthenium complexes. This results in excitation populating the eg orbitals,

which means the lowest excitation for iron complex is populated under irradiation and relax to

the ground state much more rapidly than ruthenium complexes.

Scheme 2. (a-c) possible orbital dispositions of d orbitals for octahedral complexes, (d) Electronic

transitions in octahedral RuII complexes with polypyridine ligands.

Photochemistry of Iron Complexes

5

1.3 Photochemistry of iron complexes

Although the excited state transitions in iron complexes under irradiation are not as readily

studied as in ruthenium and osmium complexes, they nevertheless exhibit a rich photochemistry

and show promise in applications in both catalytic oxidation, biochemistry, environmental

chemistry, as well as in material science.

In this chapter, we review the reported photochemistry of iron complexes, including

(1) Photo assisted Fenton Reactions.

(2) Photo induced ligand degradation-decarboxylation.

(3) Photo induced release of small molecules.

(4) Potential anticancer metallodrugs – photocytotoxicity of iron complexes.

(5) Photochemistry of iron complexes in catalytic oxidations.

1.3.1 Photo assisted Fenton Reactions

The photo assisted Fenton reaction is one of earliest reported photochemistry on Iron

complex.2–4 The Fenton reaction (H2O2/FeII)3,5 or Fenton like (H2O2/FeIII), are well known reactions,

which is mainly used to generate reactive radicals (HO• and HOO•) with H2O as by product and is

used widely in the treatment of waste water.6–9 The production of hydroxyl radicals (HO•) is

strongly accelerated under irradiation with UV light compared to thermal reactions due to the

rapid regeneration of Fe2+ through photo reduction of Fe(OH)2+. It should be noted the reactions

1-(1, 2, 3) are not the only reactions involved, the exact mechanism of this reaction is still under

debate due to the fact that the photolysis of H2O2 itself as well as the indistinguishability of Fe4+

and {Fe3+(HO•)}.5

1.3.2 Photo induced ligand degradation - decarboxylation

The photo activity of FeIII carboxylato complexes, is generally more pronounced than the

solvated FeIII ion, due to ligand to metal charge transfer (LMCT) excitations, which induce the

reduction of the transient iron center and oxidative degradation of the organic ligand.10–13 Figure

1 shows one of the most famous examples of such photochemistry, ferrioxalato complexes. The

photo-induced reduction of ferrioxalate was first reported by Parker in 1953,14 followed by the

reporting of similar photo activity in complexes of Ligands bearing a carboxylato group (Figure

2).11,13,15 Among these carboxylato ligands, the ferrioxalato complex is widely used as an

actinometer in quantum yield measurements.16 The mechanism of this photoreduction

accompanied by degradation of the carboxylato ligand was studies by pump/probe transient

absorption spectroscopy and quantum chemical simulations by several groups.17–21 There are two

mechanistic aspects still under discussion; especially the steps that follow photoexcitation.

Pozdnyakov et al. proposed intramolecular charge transfer from oxalate ligand to FeIII center

results in reduction to FeII, which is in contrast to the earlier proposed by Rentzepis and co-

workers that the FeIII−O bond cleaves before electron transfer. With the development of ultrafast

high resolution transient spectroscopy, in 2017, the Gilbert group17 reexamined this reaction,

they propose a mechanism (Figure 1) in which photo absorption and electron transfer (within 0.1

Chapter 1

6

ps) result in formation of an intermediate ferrioxalate radical anion, which then dissociates rapidly

to form thermally excited CO2 and CO2•−. The CO2 relaxes and then leaves the FeII center and the

CO2•− radical anion remains coordination for ~ 10 ns.

Figure 1. Proposed pathways for photoinduced ligand degradation of Ferrioxalate. For

simplification, two oxalates ligands are omitted.15,17

The photochemistry of FeIII-carboxylate complexes in aqueous solutions is highly dependent on

the ligand coordination mode,22 as in oxalate (L1), succinate (L5), citrate (L8), and glutarate (L10),

these di-carboxylato ligands coordinate strongly with FeIII centers and shows intense LMCT bands,

and mostly follow the mechanism in Figure 1. In contrast, complexes of, 2-propanoate (L2), 2-

oxoacetate (L3), gluconate (L9) which are mono-carboxylate ligands, the photo reaction is

dependent on the ligand concentration. Since the carboxylato-complexed FeIII complex is in

equilibrium with FeIII(OH) species and at low concentration of ligands the photolysis of FeIII(OH)

dominates, and produces •OH primarily (equation 1-(1-3)).

Figure 2. Structures of the carboxylate ligands.

In addition to solely carboxylate ligand environment polypyridine amine based tripodal amine

chelated FeIII complexes, [(L11)FeIII-X], with a carboxylate moiety show ligand degradation under

UV irradiation by decarboxylation, proceeding concomitantly with reduction of FeIII to FeII and

formation of CO2 (Figure 3).23

In biochemistry, Siderophores are a wide range of compounds produced by bacteria to

capture iron. They bear an -hydroxy carboxylic acid functionality and coordinate readily to FeIII

ions allowing the passive uptake of iron. Recently, Butler and co-workers24,25 reported

Photochemistry of Iron Complexes

7

photodecarboxylation of Fe(III)-siderophore complexes containing an -hydroxy acid group.

Ligand to metal charge transfer excitation under UV irradiation results in decarboxylation and

oxidation of the petrobactin ligand to form a new ligand (loss of the central carboxylic acid group

with a 3-ketoglutarate group or an enol group remaining on the original citrate backbone, Figure

3).

Figure 3. Examples of ligand decarboxylation of FeIII complex under irradiation.23,24,26

The photo-induced decarboxylation of FeIII complex bearing carboxylato groups (L1-L10) is of

substantial importance in the treatment of environmental pollutants as these small carboxylate

ligands are abundant on earth and frequently invoked in bio-geochemical cycles.22,27–29 Attention

has been directed to the ligand system (L11)23 due to its potential application for catalytic

oxidations and possibilities structural variation rather than the photochemical properties of its

iron complexes. As mentioned above, the photochemistry of siderophore-like FeIII complexes (L12,

L13) holds profound implication for transportation of iron in vivo for phytoplanktonic

communities.25

The application of photo decarboxylation of FeIII complexes in materials was first reported by

Melman and co-workers,30 in which they described gel-sol transitions induced by irradiation of

hydrogel with UV or visible light. This hydrogels consists of alginate cross-linked by iron(III) cations

in the presence of sacrificial small hydroxy carboxylates compounds. This was further developed

by Ostrowski and co-workers,31 in which no sacrificial components were required. They used

photoresponsive coordination hydrogels consisting of Fe(III) irons and the polysaccharides

poly[guluronan-co-mannuronan] (alginate, L14) or poly[galacturonan] (pectate, L15), (Figure 4),

and the photo-induced FeIII-decarboxylation mechanism is proposed. They also revealed that the

photo reactivity was largely influenced by the configuration of the chiral center, which provides

additional control over the stability and photo responsiveness of metal-coordinated materials,

and is of importance for broader application to biological and tissue engineering.32,33

Chapter 1

8

Figure 4. Examples of gelation-solution transition utilizing of the photo-induced FeIII-

decarboxylation reaction. (copy right from ref31).

1.3.3 Photo-induced releasing of small molecules

1.3.3.1 Photo-induced N-N cleavage – N2 releasing

The photo-induced release of N2 from a porphyrin-ligated (L16-17) FeIII azide complex (thin

film), under irradiation of UV-visible (406.7- 514.5 nm) light in frozen dichloromethane (30 K) was

reported by Wagner and Nakamoto in 1989.34 Heterolytic cleavage of the N-N bond was

accompanied by oxidation of the iron center to form an iron nitrido complex (L)FeV≡N with

concomitant evolution of N2 (Figure 5). The formation of the (L)FeV≡N complex was confirmed by

resonance Raman spectroscopy with the (Fe-N) band at 876 cm-1 and 873 cm-1 for (L16,

L18)FeV≡N and (L17)FeV≡N, respectively.34 Due to the substantial electron deficiency of (L)FeV≡N,

the photochemistry could only be studied in a cryogenic inert matrix or thin film. However, similar

to the non-innocence of the porphyrin ligand in oxo-iron(IV) enzymes (P450 compound I),35 the

d3-configured iron(V) center, the closed shell dianionic ligand, the d4-configured iron(IV) center

and the ligand radical monoanion are resonance structures by virtue of magnetic coupling. Hence,

the possibility of similar photolysis in redox-innocent non-heme ligand environment is an

important question.

Figure 5. Examples of photo-induced oxidation of porphyrin-ligated FeIII azide complex with a

release of N2.

Photochemistry of Iron Complexes

9

This photo-induced cleavage of N-N bond was reported by Wieghardt and co-workers36 in a

non-heme ligand environment (L19, Figure 6), in which the FeIII center was located in a pseudo-

octahedral ligand environment with azide ligands at its two axial positions while its four equatorial

sites were occupied by a the redox-innocent macrocyclic ligand. High valent FeV intermediates

were observed at 4 and 77 K by EPR and Mӧssbauer spectroscopy and in contrast to heme

systems, a five-coordinate ferrous species has also been observed in the same reaction which

originated from Fe-N homolytic cleavage and coordination of “solvent” acetonitrile. Although the

detailed photo excitation mechanism is not established, femtosecond mid-infrared spectroscopy

provides insight into the overall dynamics of the photo-induced release of N2 and formation of FeV

process.37–40 266 nm excitation of the FeIII azide precursor results in mainly the non-adiabatic

cooling (internal conversion, vibrational energy relaxation), and the “productive” channel of N-N

cleavage and buildup of the iron(V) product are due to in the “localized” excitation of low

frequency N3 modes, and population of excited states leading to N-N cleavage. Furthermore, due

to the relatively high barrier for rebound of FeV with N2 back to FeIII again, the formed dinitrogen

collides with its surroundings and diffuses out of the reaction cage readily.37

Figure 6. Examples of photo-induced oxidation (or reduction) of non-heme FeIII azide complexes

with a release of N2.36–38,41

The photolysis pathways are highly dependent on reaction conditions and ligand environment.

Vӧhringer and co-workers38 found, in contrast to the studies in cryogenic inert matrises,42 that

irradiation of the FeIII azide precursor (L20) with one nitrogen atom replaced by an acetate group

coordinated to the Fe ion in an axial position, trans to the N3 group, in acetonitrile at room

temperature almost exclusively forms the solvent-stabilized ferrous complex by Fe-N cleavage at

266 nm.38 L21 was pre-oxidized from ferric to ferryl states by electrochemistry, photo-irradiation

of L21 at 650 nm at 77 K results in similar N-N cleavage and evolution of N2, with formation of the

higher oxidation state (L21)FeVI≡N which is the only identified FeVI complex to date.41

Chapter 1

10

This section is limited to discussion, only a few illustrative examples of the photolysis of Fe-N3

complexes are discussed. There are an increasing number of ligands developed, incorporating of,

for example, pyridine moiety into the amine-based ligand backbone by Costas and co-wokers,43,44

show similar photo reactivity to the complexes discussed above. It should be noted that, up to

now, photo-induced N-N cleavage is still the most common way to convert FeIII-azido precursor to

FeV or FeVI complex, with only a few reports of the thermal reactions yielding these species.39

1.3.3.2 Photo-induced replacement of labile ligand – CO releasing

Carbon monoxide (CO) is a key molecule in biochemistry; in vivo, it is a natural metabolite and

produced mainly by heme oxygenase-1.45,46 certain levels of CO have a positive effect on the body

including cytoprotectian, anti-inflammation, vasodilation and are used in therapeutic

treatments.47 However, due to the highly affinity to iron of hemoglobin, excess CO can shut down

oxygen transportation.48 Hence, the controlled release of CO from carbon monoxide releasing

molecules (CORMS) is a promising strategy in delivering CO to target tissues in therapies.

Photo-induced CO-release, with precise spatial and temporal control during the treatment is

essential and has considerable interest in recent decades. Metal-CO complexes have seen the

most attention due to labile coordination of CO metal centres, which under irradiation M-CO

bond cleavage and releasing of CO. There are several recent reviews published on this topic49–54

and here the field will be mentioned only briefly. Iron, in particular, generates great interests in

CORMs studies, and we only focus on the reported Fe-CO photoCORMs here.

Figure 7. Examples of photo-induced carbon monoxide releasing molecules (photoCORMs).

The first Fe-CO photoCORMs for biological application were reported by Motterlini and co-

workers in 2002.53 However, an iron pentacarbonyl [Fe0(CO)5] complex, which shows photo-

induced release of CO of [Fe0(CO)5] and related complexes was reported before 1970s.55,56

Typically [Fe0(CO)5] was exposed to a cold light source, the releasing CO was detected by

measuring the conversion of deoxymyoglobin to carbonmonoxymyoglobin. The CO release

proceeds in a step-wise manner, accompanieD with a change in the complex’s symmetry. For

example, at low temperature (< 20 K), one CO is released to form C2v symmetric Fe(CO)4,

prolonged irradiation results in the second release of CO to from Fe(CO)3. the formed Fe(CO)3 and

Fe(CO)4 can recombine with CO or the matrix molecules, (e.g., CH4, Xe) depending on the

Photochemistry of Iron Complexes

11

irradiation conditions.57–61 The detailed mechanism of photolysis was studied using picosecond

and nanosecond time-resolved infrared spectroscopy by George and co-workers.57 More

functional ligands were incorporated into the Fe-CO complex, to control the steric and electronic

properties of iron centre through subtle changes introduced by the ligand structure. Lynam and

co-workers62 developed a series of tricarbonyl complexes containing 2-pyrone ligands (L22CO-2),

tuning of the substitution on the backbone significantly affects the CO releasing properties.62 Late

In 2010 Westerhausen and co-workers reported a biogenic dicarbonyl bis(aminoethylthiolato)

iron (II) (L22CO-3) complex (Figure 7a), which shows more advantageous properties towards the

potentials therapeutic applications. It’s solubility in water, and the CO release triggered by

irradiation with visible light ( > 400 nm), has very minor adverse effect in physiological test.63

Drawing Inspiration from hydrogenases,64 which produce hydrogen, biomimetic models (L22CO-4,

L22CO-5)65–69 with an diiron centre with thiolate ligands environment, releases CO under

irradiation to generate a solvent coordinated complex (Figure 7b). The CO-releasing rate is

sensitive to the thiolates structures, with two monothiolates (“open” form) being more photo

reactive than a dithiolate (“closed” form).70 The dimercaptopropanoate-bridged diiron

hexacarbonyl complex reported by Fan and co-workers68 shows rapid CO-release with six CO

ligands disassociated within 30 minutes hour and formation of the final product as a water soluble

iron thiolate salt.68 Epithelial cell tests did not show obvious cytotoxicity. As a common feature of

these Fe0 and Fe1 complexes is that they always undergo full decomposition under irradiation.

Kodanko and co-workers71 found the non-heme [(N4Py)FeII(CO)] complex (L22CO-6, Figure 7c),

which shows similar photo-induced CO release but with extraordinary thermal stability in aqueous

solution and the more functionalized polyprindine ligand environment opens possibilities for

ligand modification. Furthermore, this complex was modified with a peptide, which promises

advantages for photoCORM transportation to a target tissue and further for the therapeutic

treatment.71

1.3.3.3 Photo-induced reductive elimination Fe-hydride – H2 evolution

In contrast to CO-release via a labile ligand coordination, H2 is generally produced by photo-

induced reductive elimination from a Fe-hydride complex which was reviewed by Perutz and

Procacci recently.72 There are two main classes: monohydride and dihydride complexes. The

biomimetic hydrogenase complex (L23H2-1), a representative example for the Fe-monohydrides,

was reported by Rauchfuss and co-workers,73 which give four turnovers for H2 evolution under

irradiation in the presence of triflic acid (Figure 8a).73 The Fe dihydride complexes, are mainly

based on Fe-carbonyl (Figure 8b) and Fe-phosphine structures (Figure 8c). Sweany74 noted that

the H2Fe(CO)4photolysis results in a characteristic CO stretching band appears for the totally

symmetric mode of Fe(CO)4 by matrix-isolation combined FTIR spectroscopy,. The recombination

of Fe(CO)4 with the released H2 was inferred from the reappearance of IR bands for H2Fe(CO)4. In

contrast to Fe-carbonyl complexes, Fe-phosphine dihydrides are more photo reactive and have

been extensively studied towards the activation of strong C-H bonds under irradiation. Notably

the first step under irradiation is still the photo reductive elimination of molecular H2 (Figure 8c),

which leaves a vacant site on the iron centre for small molecule oxidative addition and hence C-H

or C-S activation of substrates.75–77

Chapter 1

12

Figure 8. Examples of photo-induced H2 evolution by Fe-containing complexes.

In addition to the above mentioned complexes, the so called ““Janus intermediate”, which has

the active site of 4[Fe-S] core with two bridging Fe hydrides (E4(4H)) was studied by Hoffman and

co-workers by in situ EPR and ENDOR spectroscopy. This complex shows photo-induced reductive

elimination of H2 at 20 K, and reverts to (E4(4H)) by oxidation of H2 at 175 K.

1.3.4 Potential anticancer metallodrugs – photocytotoxicity of iron complexes

Rosenberg78 first reported cispldin as an anticancer chemotherapy stimulating the

development of several platinum-based metal complexes as metallodrugs. However, drug

resistance and severe side effects stimulates the search for new non-platinum alternatives.79 The

successful application of Bleomycin,80 an iron-containing natural antibiotic for cancer treatment

draws attention to iron complexes and a series of bio-mimic model complexes with a variety of

ligand environments have been reported. Pre-clinical testing towards cytotoxicity were carried

out in many cases.81 As candidates for chemotherapy, metallodrugs should have as little negative

affect on healthy cells.

Photoactivated or photodynamic treatment (PDT), in which the anticancer drugs is only active

under irradiation and non-cytotoxic in the dark, appears to be a promising approach due to its

highly spatially selective for the target tumor.82,83 There are a few papers reviews covering the

cytotoxicity of iron complexes towards anticancer treatments.81,84–86 Here we focus only on the

photocytotoxicity of reported iron complexes in recent years.

In order to increase the photo-induced DNA cleavage activity and further the photocytotoxicity

(Table 1 lists some cell lines examined in photocytotoxicity studies), there are several aspects that

need to be considered: (a) binding properties with DNA, a strong interaction with targets or

related proteins for transportation, (b) transport into cells, which is closely related to the

lipophilicity of the complex structures, (c) strong absorptivity in the PDT window, (d) proper

oxidation states of the metal center considering the reducing environment in the cell, which is

capable of generating reactive oxygen species under irradiation for DNA cleavage. The first three

Photochemistry of Iron Complexes

13

properties can be achieved by ligand modification, while the last plays a central role for in

reactive oxygen species generation. Hence, we categorized reported iron complexes by oxidation

state of the iron center here.

Table 1. Abbreviations of cell types mentioned in this section.

Abbreviation Cell type Abbreviation Cell type

HeLa Human cervical carcinoma,

HaCaT Human keratinocytes, MCF-7 Human breast cancer

Hep G2 Human hepatocellular carcinoma MRC‐5 Human fibroblast

HPL1D Nontransformed human epithelial

lung cells

A549 Human non-small cell lung

carcinoma

1.3.4.1 Photocytotoxicity of FeII complex

The earlier reports were about several FeII complexes (Figure 9). Roelfes and co-workers87

reported the DNA cleavage activity of a polypyridyl amine-based pentadentate FeII complex (L24),

which is a functional biomimic of Fe-Bleomycin. Its activity was enhanced by irradiation. A series

of ligands modified with the covalently attached chromophores were synthesized and these iron

complexes show similar photo-activity, in which the photoactivity was enhanced by attachment of

the 9-aminoacridine moiety (L25) and reseeded by 1,8-naphthalimide moieties (L26-28). The

cleavage of DNA was attributed to the generation of reactive oxygen species (ROS), HO•, O2•-, 1O2,

under irradiation (355, 400.8, 473 nm).87 In contrast to covalent attachment, the influence of

chromophores in photo-enhancing the DNA cleavage activity of L24 was studied with presence of

A 9-aminoacridine moiety and A 1,8-naphthalimide. A significant synergistic effect (except few

cases) was not observed. ROS are generally accepted as THE actual species responsible for DNA

cleavage. However, surprisingly, addition of ROS scavengers (Na3N, DMSO and superoxide

dismutase), significantly increased DNA cleavage activity. This unexpected result revealed the

complexity of the ROS mechanism. That ROS could be the reactive species for DNA cleavage, but

the positive effect of scavengers implied the importance of maintaining steady state

concentration of ROS for DNA cleavage.88 The photocytotoxcity of these complexes towards living

cells were also studied and compared with the natural antibiotics Bleomycin, complexes L24 and

L25 both show comparable efficiency to nuclear DNA cleavage with Bleomycin. However, via

apoptosis and different to the cell cycle arrest induced mitotic catastrophe by Bleomycin.89 Lately,

Chakravarty and co-workers90 reported another FeII complex (L29), bearing two planar

phenanthroline groups which provide for the strong binding to DNA, which show significant

photocytotoxcity to HaCaT and MCF-7 cells under visible light irradiation (400 - 700 nm) and only

very minor dark toxicity. Very recently, Tabrizi91 reported an FeII pincer complex (L30), which

incorporates a NCN pincer and boron dipyrromethene group, which also showed

photocytotoxicity to HeLa and MCR-5 cells under irradiation (500 nm) with minor dark toxicity.

Due to its specific localization in mitochondria in HeLa, it is a potential candidate for

mitochondria-targeted theranostic agents.91 Notably, Chakravarty and co-workers reported a

dipyridoquinoxaline (dpq) FeII complex capable of cleaving DNA under irradiation at 365 nm, but is

photo-inactive under visible light. In contrast, its FeIII complex is photoactive on DNA cleavage in

visible light, which shifted their attention to the studies of photocytotoxicity of FeIII with a variety

of ligands.92,93

Chapter 1

14

Figure 9. Examples of FeII complex showing photocytotoxicity.

1.3.4.2 Photocytotoxicity of FeIII complex

Chakravarty and co-workers reported a new group of ternary FeIII complexes between 2009 –

2012 with several ligands (L31-L36) (Figure 10),94–96 the tetradentate phenolate-based ligand was

designed to bind to FeIII to generate strong LMCT absorption bands in the visible region, the tert-

butyl group was attached to increase the lipophilicity and the phenanthroline-based group was

attached to increase the DNA binding strength. As a result, all complexes (L31-L36) show strong

binding propensity to calf thymus DNA and some proteins (the extent dependent on the

substituents on the dipyridophenazine ring), in which the complex of L31 shows remarkable high

photocytotoxicity to HeLa and HaCaT cells under visible irradiation and low dark toxicity. The

mechanism is similar to that of previously reported FeII complexes; cell death is through

apoptosis,94 extension of dipyridophenazine with an extra benzene ring (L36) results in even

higher photocytotoxicity to HeLa cells.95 Biotin (vitamin H or B7) is a biomarker overexpressed by

some tumor cells and can be used to increase the cytotoxic selectivity. The binding ability to

streptavidin to biotin is unaffected by the addition of the iron complex, however, the selective

enhancement of photocytotoxicity toward to HepG2 cells over HeLa and HEK293 cells was

observed for biotin-attached complexes (L33 and L35).96 Iron complexes of schiff base phenolate

ligands (L37 - L45) show photocytotoxicity with irradiation with red light. L37 – L40 complexes are

all avid binders to calf thymus DNA and shows strong pUC19 DNA cleavage activity under

irradiation. In contrast to non-sugar appendant (L37), the sugar (carbohydrate moiety, the

biomarker in some tumor cells) appendant complexes L38 and L39 show significant

photocytotoxicity towards HeLa and HaCat cells and no dark cytotoxicity.97

Progress in activity against other cellular organelles (endoplasmic reticulum), other than DNA,

was made with tridentate Schiff base pyridoxal ligands derived of vitamin B6 such as in L41-43.

Complexes of L44 and L45 show less photocytotoxicity compared to those of complexes of

pyridoxal vitamin B6 ligands (L42 and L43). It is likely to be due to the greater uptake into the

endoplasmic reticulum in the case of vitamin modified complexes than non-vitamin based

complexes.98 Another notable example related to vitamin B6 corporation was reported by Hussain

and co-workers.99 The vitamin B6 modified complex of L40 is photocytotoxic while non-vitamin B6

modified analogue is not.99

Another group of iron complexes were reported by Chakravarty and co-workers in 2011

broaden the PDT window to the near IR region.100 It is important in PDT treatment that light in

this region is used as it has the greatest penetration in human tissue. In addition to a

dipicolyamine ligand, they introduced a series of catecholate ligands which gave rise to intense

Photochemistry of Iron Complexes

15

LMCT bands in near IR region 620 – 850 nm (L46 – L49) (Figure 10). The tridentate dipocolylamine

group functions as a planar aromatic group with a strong propensity for interaction with DNA. The

bidentate dianionic catechol (cat) ligands enhance lipophilicity and the permeability of the cell

membrane to the complexes. The order of photocytotoxicity was L48 > L47 > L49 ≈ L46. L48

shows the highest photocytotoxicity due to the tert-butyl group, which increase lipophilicity. In

contrast to L49, which contains the dopamine group that increases aqueous solubility but

decreases lipophilicity. As in previous studies, the cytotoxicity is due to the apoptosis. By binding

to DNA and, under irradiation, DNA cleavage due to formation of reactive oxygen species.101 Later

salicylates were also used as a ligand for FeIII complexes (L51), and also showed photocytotoxicity

to HeLa and MCF-7 cells under visible light irradiation with the help of the photoactive

anthracenyl group, in contrast to the photo-inactive phenyl complex (L50).102

Figure 10. Examples of FeIII complex showing photocytotoxicity.

Chapter 1

16

1.3.4.3 Photocytotoxicity of FeIII-oxo dimer complex

As a photo-metallodrug, an iron complex should have as low as possible dark toxicity to

healthy cells. In contrast to the FeII and FeIII oxidation states, complexes in the oxidation states Fe0

and Fe1 are generally unstable at ambient or physiological conditions. Complexes in the oxidation

states FeIV or higher although also invoked as reactive intermediates in oxidation reactions, are

not considered for PDT treatments. Diiron(III) complexes, however, are possible candidates.

The first report of photo-induced DNA cleavage by oxo-bridged diiron(III) complexes was by

Chakravarty IN 2008,103,104 in which the almost linear Fe-O-Fe centers were coordinated by L-

histidine and phenanthroline based ligands (L53- L54) (Figure 11). These complexes display

double-strand DNA cleavage under visible light irradiation. The dipyrido quinoxaline (dpq) group

(L54) was proposed to bind the DNA through groove binding. What was interesting is that the

complexes were flipped when binding with DNA, the two dpq planar groups rotate via the Fe-O-

Fe center to a trans confirguration in order to reduce the steric effect for binding. In addition, in

contrast to the dpa group the phenanthroline (L53) diiron complex showed only single-strand

DNA cleavage activity under visible light irradiation. Phenanthroline ligands in complexes L53 and

L54 are not only the DNA binder but also the photosensitizer. In contrast, the complex L52. Lacks

the photosensitizer group making it photo-inactive towards the DNA cleavage.103 Later another

group of diiron complexes were reported, which do not have the L-histidine group but another

dpq (L56 and L58) or phenanthroline (L55 and L57) ligands attached,105 which as predicted103 bind

more strong to DNA than complexes L52-L54. The near linear oxo-bridged diiron complexes, L55

and L56 are better than the acetate bridged complexes L57 and L58, which is due to the rotation

via Fe-O-Fe bond was hindered in acetate bridged diiron complexes (L57 and L58). Photo-induced

DNA cleavage activity is wavelength dependent for these complexes: complex L58 shows

particular red light activity and the other two are shorter-visible light active, complex L55 is

photo-inactive. All the DNA cleavage mechanism of all photo-active complexes mention above

(L53, L54, L57, L58) are partially attributed to the Fe-carboxylate group present, as we discussed

in section 1.3.2, under irradiation decarboxylation produce reactive radical species, which is

responsible for the oxidative DNA cleavage.

Figure 11. Examples of diiron(III) complex showing photocytotoxicity.

The photocytotoxicity of these complexes, under specific conditions (excess H2O2), are

established to be more toxic to cancer cells than healthy cells and this difference is amplified by

visible light irradiation.106 Another photocytotoxic diiron(III) complex (L60) was reported, which

does not bear the FeIII-carboxylate group but curcumin, this complex shows enhanced stability

Photochemistry of Iron Complexes

17

and photocytotoxicity towards HeLa and MCF-7 cells under irradiation. Curcumin is proposed to

be the photo-active group since the analogous complex L57 is photo-inactive.107

From this section we can conclude that iron (bio-essential metal and low heavy-metal toxicity

in vivo cells) complexes have considerable potential to be the photo-metallodrugs, although

photocytotoxicity studies as the anticancer medication are still in early stages. The significant

effect on photocytotoxicity due to ligand modification is highly attractive for the inorganic

chemists since the abundance of small molecules, which are already well-documented in clinic

studies for anticancer treatment or reagent transportation, could be readily incorporated into

ligand structures. This increases the possibilities for iron complex as the photometallodrugs in

PDT. However, the mechanisms are still unclear with the lack of the information on the photo-

activity of the iron complexes themselves limits understanding of the cytotoxic mechanisms,

hence, the close examination of the photoreactivity iron complex will be the essential topic for

the further development of this field.

1.3.5 Photochemistry of iron complex in catalytic oxidation reaction

Beyond doubt catalysis has changed the world, the most famous and perhaps most important

are the Haber-Bosch (Nitrogen fixing process) and Fisher-Tropsch (converting synthesis gas into

hydrocarbons) processes. In both cases heterogeneous iron-based catalysts are applied.108

Recently, the developments in organic synthesis for ligand design have opened many

opportunities in controlling the reactivity of iron-based homogenous catalyst. Metal/ligand

cooperation opens opportunities for the replacement of noble metals by iron in homogenous

catalysis. Furthermore, modern spectroscopy provides extensive information about the catalyst

structure and mechanism, which has enabled biomimetic approaches to ligand design and

achieve new and better reactivity for the iron complexes.

High-valent iron-oxo species are frequently invoked as the reactive species in the substrates

the oxidation of organic substrates in both biocatalytic enzymes and catalytic reactions. There are

several ways to access high oxidation states, such as: sacrificial oxidants (e.g., H2O2, PhIO, m-CPBA

etc.),109 electrochemical oxidation,110 and photo excitation.111 Photochemistry benefits in being

non-invasive and atom economic and is drawing more attention in recent years. In this section,

we focus on the application of photochemistry in catalytic oxidations by iron complexes. As the

photo-induced generation of higher oxidation states or reactive oxygen species can be achieved

by two different ways: the direct excitation and the indirect excitation with the use of a

photosensitizer.

1.3.5.1 Photoinduced catalytic reaction-----the use of a photosensitizer

The use of a photosensitizer to introduce extra energy to a reaction is recently affording

considerably attention. In regard to iron catalysis, the most widely used photosensitizer are RuII

complexes (e.g., [Ru(bpy)3]2+) due to the outstanding photophysical and photochemical properties.

The excited state of [Ru(bpy)3]2+* generated under visible light irradiation can engage in electron

transfer to form [Ru(bpy)3]3+, which is a strong oxidant (1.26 V vs SCE, Figure 12) and can oxidize

most iron complexes to their higher oxidation states. This approach is a so-called “multi-catalyst

strategy” (Figure 12).

Chapter 1

18

Figure 12. Photochemistry of [Ru(bpy)]2+ (a) and a multi-catalyst strategy in catalytic oxidation

with iron complex (b).

1. The application of photosensitized heme-based catalytic systems

Gray and coworkers112 reported the photoinduced generation of high-valent metalloenzyme

intermediates in a heme system using the photosensitizer [Ru(bpy)3]2+ as electron donor (Figure

13) in 1995. The reaction was studied by nanosecond transient absorption method with

[Ru(bpy)3]2+ promoted to its excited state [Ru(bpy)3]

2+*, followed by the electron transfer to

[Ru(NH3)6]3+ (electron acceptor, EA) to form the strong oxidant [Ru(bpy)3]

3+. It can directly oxidize

ferric microperoxidase-8 (MP8) [(P)FeIII-OH2] ( L59) to its cation radical ferric form [(P•+)FeIII-OH2],

this cation radical species is in equilibrium with its ferryl MP8 [(P)FeIV=O] (Compound II). Under

acidic conditions (pH < 6) the equilibrium shifts to the left and ferryl MP8 is not observed. At

alkaline pH, deprotonation shifts the equilibrium to right and the radical ferric species is not

osberved. This studies show that the porphyrin ligand centered oxidation is the rate limiting step

are not the metal center.112 Later, the same concept was applied to the heme Horseradish

Peroxidase (HRP).113 In this reaction, [Co(NH3)5Cl]2+ was used as the electron acceptor. The HRP

ferryl species (Compound II) is formed via a ferric -cation porphyrin radical species [(P•+)FeIII-OH2]

intermediates at alkaline pH. Notably, ferryl porphyrin radical species [(P•+))FeIV=O] (Compound I)

by oxidation of Compound II was also observed.113

Figure 13. Examples of generation of high-valent metalloenzyme by multi catalyst strategy.

Photochemistry of Iron Complexes

19

As discussed above, the rate determining step is the porphyrin-based ligand oxidation and

hence this approach is unsuitable for the thiolate-ligated heme cytochromes P450 since the heme

is buried deep inside the enzyme. Cheruzel and co-workers114 reported a new strategy, in which

the photosensitizer [(IA-phen)Ru(bpy)2]2+ (IA-phen = 5-iodoacetamino-1,10-phenanthroline) was

covalently bound to cytochrome P450 BM3 (RuIIK97C−FeIII

P450) (Figure 14). Under irradiation three

species with well-defined transient absorption spectra were observed, first *RuIIK97C−FeIII

P450,

second RuIIIK97C−FeIII

P450 and returning back to the initial RuIIK97C−FeIII

P450. Kinetic studies reveal

three transient species assigned as RuIIK97C−(P•+)FeIII

P450(A)(OH2), RuIIK97C−[(P•+)FeIII

P450(B)(OH2) and

RuIIK97C−[(P)FeIV

P450(OH) (Compound II). The conversion of RuIIK97C−(P•+)FeIII

P450(A)(OH2) to

RuIIK97C−[(P•+)FeIII

P450(B) (OH2) was rationalized by solvent or polypeptide confirmational changes,

similar with MP8 and HRP. The conversion from ferric radical cation RuII−[(P•+)FeIII(OH2) to ferryl

RuIIK97C−[(P)FeIV

P450(OH) is pH dependent, both of which are present transiently and a fast recovery

to the initial complex RuIIK97C−FeIII

P450 is observed.114 Similarly, Farmer and co-workers115 reported

another example in which the photosensitizer [Ru(bpy)3]2+ was attached covalently to a heme

enzyme via a –(CH2)7− linker (L62). In contrast to RuIIK97C−FeIII

P450 I, the distance between

photosensitizer and heme unit was large enough to prevent recovery from the ferric porphyrin

radical species RuII−( P•+))FeIII to the initial RuII−FeIII state. The fate of this ferric radical either

oxidizing the iron center to form the ferryl form (Compound II) or oxidize a surrounding amino

acid residue, which is in contrast to HRP in L60 (Figure 13). The oxidation of the protein

surroundings also suggested that the protein environment significant influenced the reaction.115

This linking strategy was already reported by Oishi and co-workers as earlier as 1999, who

demonstrated that it facilitated intramolecular electron transfer with observation of the ferric–

porphyrin cation radical spectroscopically.116

Chapter 1

20

Figure 14. Examples of generation of high-valent metalloenzyme by modified multi catalyst

strategy.

In addition to the photoxidation strategy in Figure 12b, there is also a photoreductive strategy,

in which the electron acceptor ([Ru(NH3)6]3+, [Co(NH3)5Cl]2+) is replaced by electron donor (e.g.,

diethyldithiocarbamate = DTC). As an excitation quencher DTC reduces the excited [Ru(bpy)3]2+*

to [Ru(bpy)3]+, which is a strong reductant (-1.26 V vs SCE). As with the modified photooxidative

strategy, a polypyridyl Ru(II) moiety was attached covalently to a heme enzyme, however, the fate

of the intermediate Ru(I)-Fe(III) species is not as clear as in the photo oxidative strategy.

Nevertheless, C-H functionalization studies show higher total turnover numbers under irradiation

with visible light than control reactions,117 which further emphasizes that reactivity can be

controlled both by the varying the nature of photosensitizer and modification of the heme

structure.118 In short, several successful attempts to induce photochemistry at the iron center of

heme metalloenzyme have been described and the field can expect further developments.119,120

2. Photosensitized non-heme based catalytic systems

The number of heme and non-heme iron dependent enzymes involved in oxidations make

mimicking such systems highly attractive in biomimetic catalyst design. Several high-valent

complexes of bioinorganic relevance have been reported generated with oxidants and there are

recently several reports of their photochemical generation. Fukuzumi and co-workers111 reported

the first photochemical generation of a high-valent iron-oxo complex with the pentadentate

polypyridyl ligand N4Py (L63) in 2010 using a photoinduced oxidative pathway (Figure 12b). The

photosensitizer [Ru(bpy)3]2+ when excited with visible light is oxidized by the electron acceptor

[Co(NH3)5Cl]2+ to form [Ru(bpy)3]3+, which in turn oxidizes the non-heme FeII complex (L63) to the

FeIV=O complex (with water as the oxygen source) in a step-wise manner (Figure 15).111

Photochemistry of Iron Complexes

21

Figure 15. Examples of the photosensitized catalytic reactions in non-heme systems.

Later in 2014, Dhar and co-worker121 reported the first photochemical generation of iron(V)-

oxo with tetra-amidoma-crocyclic TAML ligands (L64 and L65). In this case, they started with FeIII

complex as in heme system, and S2O82- was used as electron acceptor. The FeIII state was oxidized

to FeIV=O state first, which is different from the previous case as the [Ru(bpy)3]3+ formed in

photoinduced electron transfer is not strong enough to oxidize FeIV state to FeV state. The

formation of FeV was attributed to the SO4•− radical oxidation (Figure 15)121 and this reactive is

intermediate responsible for water oxidation. In 2017, the complex L64 was also studied for its

photocatalytic hydroxylation and epoxidation reaction by Sen Gupta and co-workers.122 Notably,

in this photocatalytic reaction there is no SO4•− radical species present due to the use of

[Co(NH3)5Cl]2+ as electron acceptor instead of S2O82- and formed (L64)FeIV monomer immediately

form a dimer [{(L64)FeIV}2(-O)]2+ as an active oxidant. 122

As with heme systems, the covalent linking strategy binding photosensitizer to the iron

complex was also used in non-heme systems. Banse and co-workers123 reported a chromophore-

catalyst complex L65 (Figure 16), in which the non-heme iron complex was attached covalently to

the photosensitizer ([Ru(bpy)3]2+) as in the heme systems (L61 and L62). The complex [RuII-

FeII(OH2)]2+ was promoted to the excited state [*RuII-FeII(OH2)]

2+ under irradiation ( = 450 nm),

which then formed [RuIII-FeII(OH2)]2+ by oxidation with [Ru(NH3)6]

3+, followed by intramolecular

Chapter 1

22

electron transfer from iron(II) center to ruthenium(III) center to form [RuII-FeIII(OH)]2+. The high-

valent of [RuII-FeIV(O)]2+ complex was formed by a second cycle (Figure 16).123

Figure 16. Examples of the modified photosensitized catalytic reaction in non-heme systems.

In addition to the photosensitized oxidative formation of high-valent iron complexes, a

photosensitized reductive pathway to form a high-valent iron complex was reported, it shows

catalytic oxidation of PPh3 with several turnovers.124 Instead of an electron acceptor Et3N was

used as an electron donor, the formed excited state [Ru(bpy)3]2+* was quenched to form Ru(I)

complex [Ru(bpy)3]+ which is a strong reductant (-1.26 V vs SCE). It reduces the diiron(III) complex

to mononuclear Fe(II) and subsequently reacts with molecular oxygen to form -peroxo diiron(III)

complex and then even higher oxidation states of form two iron(IV)-oxo moieties, which is

responsible for substrate oxidation (Figure 17). Notably, the modified linked complex L67 shows

lower photo-efficiency than the a non-covalently connected Ru/iron system, presumably due to

deactivation of the ruthenium complexes excited state by deprotonation of the imidazole

linker.124 In this studies dioxygen activation and formation of -peroxo diiron(III) complex were

demonstrated, however, the formation of iron(IV)=O species was not confirmed.

Figure 17. Examples of photo-induced reductive formation high-valent iron complex.

In summary, in both heme and non-heme systems, the use of photosensitizers dramatically

increase the reactivity of the iron complexes/enzyme. Covalent linking of the photosensitizer and

iron complex further contributes to efficiency through intramolecular electron transfer. However,

in these systems there is still an obvious question remaining: how are the photoactivity of these

Photochemistry of Iron Complexes

23

iron complex themselves? These latter systems open opportunities for photo-driven oxidation

with a single catalyst.

1.3.5.2 Photo-catalytic reactions through direct photo-excitation of iron complexes

1. Direct photo activation of mononuclear heme iron complexes

Direct photoactivation of a heme complex was reported by Newcomb and co-workers in

2005.125 In which the photooxidiation of Compound II (a neutral iron(IV)-oxo porphyrin compound)

to Compound I (a radical iron(IV)-oxo porphyrin compounds) occurs when under UV irradiation (

= 355 nm, Figure 18b), including the complex L68, horseradish peroxidase (HRP) (L69) and horse

skeletal Myoglobin. Usually, compound I models are formed by addition of terminal oxidants

(H2O2, PhIO, m-CPBA) to its porphyrin-iron(III) precursor, followed by reaction with substrates to

form the relatively stable compound II. Under irradiation, compound II forms compounds I

manifested in a change in the UV-vis absorption spectrum which shows that compound I persists

for several seconds in the absence of substrates.125

Figure 18. Examples of photolysis reaction on heme system.

Later, the same group reported photochemical generation of even higher oxidation states, i.e.

an iron(V)-oxo porphyrin complex (Figure 18c).126 The porphyrin(IV)=O complex has a axial

substituent (NO2, ClO2), which under UV irradiation ( = 350 nm) undergoes heterolytic cleavage

to form iron(V)-oxo compounds, which react more than 100 times more rapidly with substrates

oxidation than the corresponding iron(IV) compound.126

2. The direct photo activation of dinuclear heme iron complexes

The light-driven catalytic oxidation of substrates using a single iron-containing catalyst is an

elusive goal. In this regard, photoinduced disproportionation of porphyrin diiron(III) complexes is

one of most promising pathways. Richman and co-workers127 reported the first example of

photoinduced hetero-cleavage of the oxo-bridge of a -oxo porphyrin diiron(III) [(FeTPP)2O]4+

complex (L70) with formation of 2 equiv. of FeIITPP as the final product under UV-irradiation

(O→Fe LMCT band) accompanied by the oxidation of the substrate PPh3. The Fe(III)-Fe(III)

complex was regenerated by oxidation by molecular oxygen. Formation of high-valent iron(IV)-

oxo intermediates (FeIVOTPP) via disproportionation was proposed based on substrate oxidation

outcomes as well as the quantum yield measurements.127,128 The water soluble complex (L71)

showed similar photoinduced disproportionation reactions.129

Chapter 1

24

Figure 19. Examples of photo-induced disproportionation of diiron(III) porphyrin complexes.

Nocera and co-workers130 reported a strategy for selective oxidation of substrates using -oxo

porphyrin diiron(III) complexes under photo catalytic conditions. Cofacial bisporphyrine -oxo

diiron(III) complexes bearing dibenzofuran (DPD, L74) and xanthene (DPX, L75) (Figure 19), in

which the two ‘Pacman’ moieties were used as a pillar to build up a molecular spring architecture,

confined the attack on the substrates to favor a side-on geometry. The size of the two spacers

controls the pocket size for the substrates and prevents recombination to form the -oxo

diiron(III) states. The photocatalytic oxidation of substrates (dimethyl sulfoxide) was studied and

compared with the complex with such a spacer (L72). The DPD-bridged complex L74 shows similar

quantum efficiency with non-bridged complex L72, but much higher oxidation efficiency towards

substrates oxidation and hence is a superior photo-catalyst.130,131 Later, this spring-loaded

complex was further modified in the porphyrin ring with 3 pentafluorophenyl groups (L73), which

showed higher turnover numbers towards sulfide,132 olefin,132 and hydrocarbon oxidation133

under visible light irradiation with molecular oxygen as terminal oxidation and without use of a

co-reductant. An ethane linked cofacial diiron(III) -oxo porphyrin reported by Rath and co-

workers134 showed photocatalytic oxidation of P(OR3) (R: Me, Et) via a photoinduced

disproportionation reaction mechanism. The pillar linked cofacial diiron(III) -oxo porphyrin

complexes show an common feature in that they have much smaller Fe-O-Fe angles (150-160◦)

compared to the 170-178◦ of non-linked complexes and favor attack on substrates in a side-on

manner.134

The first systems with inequivalent ligands (i.e. heme/Nonheme) was the -oxo diiron(III)

[(L)FeIII-O-FeIII(L’), L77] complex reported by Karlin and co-workers in 2004 (Figure 19c),135 which

shows photoinduced catalytic oxidation of a series of substrates, PPh3 to OPPh3, tetrahydrofuran

to γ-butyrolactone, and toluene to benzaldehyde. Transient absorption spectroscopy indicates

that the photoinduced disproportionation of the -oxo diiron(III) to form an FeIV=O/FeII pair

Photochemistry of Iron Complexes

25

occurs, in which the FeIV=O is the reactive towards substrate oxidation.135 Notably, photoinduced

disproportionation of diiron(III) is not the only case reported, with an even higher oxidation state,

iron(V) generated by photoinduced disproportionation of a bis-corrole-diiron(IV)-µ-oxo dimer

together with one equiv. iron(III). The reactivity of the iron(V) intermediates is greater than that

of the corresponding iron(IV) complex.136

Form the discussion above, we can conclude that the photo-induced disproportionation of -

oxo diiron(III)/diiron(IV) is a promising strategy in photocatalytic oxidations with iron complexes.

The intermediate high-valent iron complexes formed are key reactive species. However,

limitations remain; the quantum yield in these heme systems is quite low due to the large driving

force for recombination of Fe(IV)=O and Fe(II) units, which shuts down productive oxidation

pathways. Compared to heme system, non-heme iron complex have more flexibility in terms of

ligand modification and also the thermal reactivity toward to a variety of substrates with non-

heme high-valent iron-oxo complexes has been studied extensively. Hence it is worthwhile to

study the possibility of driving non-heme iron complex oxidations photo chemically.

3. The direct photo activation of non heme iron complexes

The potential application of non-heme iron complexes under photochemical conditions

requires that they are stable under catalytic conditions (e.g., FeII, FeIII and FeIV in some cases). The

FeI and FeV complexes are highly reactive at ambient conditions. Although non-heme iron

photochemistry is dominated by photo-induced decarboxylation of iron(III) complexes, discussed

in section 1.3.1, 1.3.2, and more recent reports of the photochemistry of iron(II) complexes in

relation to the activation of dioxygen (see below), direct activation is not apparent from the

literature.

The photo-induced oxidation of non-heme iron(II) complex in the presence of molecular

oxygen as the terminal oxidant (L78 and L79 in Figure 20a) was reported first in 2009.137 A non-

heme iron(II) complex (L78), designed as a functional biomimic of iron bleomycin and studied

extensively in its reactivity with oxidants such as H2O2, forms reactive high-valent iron-oxo

species.138 Irradiation of the iron complex of L78 in aerobic methanol or H2O results in the

formation of corresponding solvent-coordinated iron(III) complex. The reactivity is not observed

under anaerobic conditions and the highly favorable coordination of acetonitrile to the FeII center

precludes such reactivity in acetonitrile. Later, Bartlett and co-workers reported a non-heme

iron(II) complex bearing a tetradentate (bpmcn) ligand (L80 in Figure 20b). This complex

undergoes similar photo-induced oxidation from the iron(II) to iron(III) states by activation of

dioxygen. In this case, there are two labile coordination sites on the iron center compared with

the one site available in the L78 based complex and hence O2 coordination is expected to be more

facile. Hence photo-induced oxidation also occurs in acetonitrile.139

Chapter 1

26

Figure 20. Examples of photo-induced oxidation of non-heme iron(II) complexes with molecular

oxygen as terminal oxidants.

1.4 Photochemistry of non-heme iron complexes and an overview of the

thesis

In this thesis, we focus mainly on the photo activation non-heme iron complexes, as well as

mechanisms of thermal reactions of non-heme iron complex with H2O2. Chapter 2, 3 and 4, focus

on photochemically induced activation of iron complexes in the Fe(IV) and Fe(III) oxidation states.

In chapter 2, the direct activation of non-heme iron(IV)-oxo complexes and the mechanisms

involved are explored. In chapter 3 the photo-catalytic oxidation of methanol under aerobic

conditions reveals the involvement of a photo-active non-heme -oxo bridged diiron(III) complex

and its mechanism for photo-induced disproportionation. In chapter 4, the photo-induced

oxidative degradation of the non-heme iron polypyridyl complexes under basic conditions are

explored and the implications the conclusions reached hold in regard to ligand design is discussed.

Chapters 5 and 6 focus on the mechanism of thermal generation of high-valent iron(IV)-oxo

complexes by reaction of non-heme iron(II) complexes with H2O2. In chapter 5 , the generation of

an iron(IV)-oxo complex via heterolysis of an O-O bond in an Fe(II)-OOH species formed with

stoichiometric H2O2 is focused on. In chapter 6, a novel reaction pathway for the reaction of

iron(III)-hydroperoxo species with H2O2, which is kinetically incompetent in the homolytic

cleavage of its O-O to form high-valent iron(IV)-oxo species, is shown to react with H2O2 directly

under catalytic conditions to produce oxygen and water. The reaction pathways described are

shown to be detrimental to the efficiency of the complexes in the catalytic oxidation of organic

substrates.

Photochemistry of Iron Complexes

27

1.5 References

(1) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev.

1988, 84, 85–277.

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