What Are the Oxidizing Intermediates in the Fenton and Fenton-like Reactions? A Perspective.

The Fenton and Fenton-like reactions are of major importance due to their role as a source of oxidative stress in all living systems and due to their use in advanced oxidation technologies. For many years, there has been a debate whether the reaction of FeII(H2O)62+ with H2O2 yields OH• radicals or FeIV=Oaq. It is now known that this reaction proceeds via the formation of the intermediate complex (H2O)5FeII(O2H)+/(H2O)5FeII(O2H2)2+ that decomposes to form either OH• radicals or FeIV=Oaq, depending on the pH of the medium. The intermediate complex might also directly oxidize a substrate present in the medium. In the presence of FeIIIaq, the complex FeIII(OOH)aq is formed. This complex reacts via FeII(H2O)62+ + FeIII(OOH)aq → FeIV=Oaq + FeIIIaq. In the presence of ligands, the process often observed is Ln(H2O)5-nFeII(O2H) → L•+ + Ln-1FeIIIaq. Thus, in the presence of small concentrations of HCO3- i.e., in biological systems and in advanced oxidation processes-the oxidizing radical formed is CO3•-. It is evident that, in the presence of other transition metal complexes and/or other ligands, other radicals might be formed. In complexes of the type Ln(H2O)5-nMIII/II(O2H-), the peroxide might oxidize the ligand L without oxidizing the central cation M. OH• radicals are evidently not often formed in Fenton or Fenton-like reactions.

1. General Remarks

In 1894, Mr. Fenton reported that FeII(H2O)62+ catalyzes the oxidation of tartaric acid by H2O2 [1]. No mechanism of this process was suggested by Mr. Fenton. Since then, the reaction FeII(H2O)62+ + H2O2 has been called the Fenton reaction and the reactions MnLm + ROOR’—where M is either Fe or another low-valent transition metal, L is either H2O or another ligand, and R and R’ are either H or another substituent—are called Fenton-like reactions.

The Fenton and Fenton-like reactions are of major importance due to two reasons:

They are considered to be the major source of oxidative stress in all living systems.

They are used in the advanced oxidation technologies/processes that are of major importance in the environmental removal of pollutants.

Due to this prominence, a search in SciFinder for Fenton in 2021 results in 3286 references.

The first mechanisms of the Fenton reaction were suggested in 1932 by two groups in parallel. Bray and Gorin [2] suggested that the mechanism is:Fe whereas Haber and Weiss [3,4] suggested that the mechanism of the Fenton reaction is:Fe

The debate whether the oxidizing intermediate formed in the Fenton reaction is FeIV = O2+aq or OH• has lasted for many decades. Thus, even as recently as this year, it has been suggested that reaction (1) is the correct mechanism, at least in neutral solutions [5], and that (2) is the only process even at pH 5 [6].

The difficulty in differentiating between the two mechanisms stems from the fact that both OH• radicals and FeIV=O2+aq react with organic substrates, usually by abstracting a hydrogen atom, and often form the same, or similar, radicals. Using EPR to quantify the relative yields of the radicals formed in order to decide whether their sources are OH• radicals often fails due to their different lifetimes [7]. This difficulty was overcome by measuring the final products formed when a mixture of two alcohols is present.8 This technique requires that the low-valent metal cation initiating the Fenton-like reaction has a fast ligand exchange rate, i.e., it does not fit FeII(H2O)62+. Using this technique, it was shown that the reaction CrII(H2O)62+ + H2O2 proceeds via a mechanism analogous to reaction (2), whereas the reaction CuIaq+ + H2O2 does not yield OH• radicals or CuIIIaq [8]. Furthermore, thermodynamic arguments [8] and kinetic arguments using the Marcus theory [9] indicate that the Fenton and Fenton-like reactions do not proceed via the outer sphere mechanism. Therefore, an inner sphere mechanism was proposed [8,9]:ML

For simplicity, it will be assumed in that the complex formed is LmM(H2O2)n+. Reaction (3) might be followed by a variety of routes, e.g., [8,9]:→ ML L → ML → ML

Naturally, Lm−1M(H2O2)n+ might also directly oxidize different substrates, e.g., inorganic reducing agents.

It was later discovered that when the central cation M has a too high redox potential, e.g., Co(II) [10], or cannot be oxidized, e.g.: AlIII, GaIII, InIII, ScIII, YIII, LaIII, BeII, ZnII, and CdII [11,12,13], the binding of two or more peroxides to the central cation might lead to the formation of OH• radicals via disproportionation of the peroxides without involving oxidation of the central cation [10,11,12,13]:M M

The observation that ligated H2O2 can oxidize a second ligated peroxide suggests that it might also oxidize other ligands. This was tested theoretically, by DFT [14], and experimentally for the oxidation of a carbonate ligated to CoII [15], thus proving this possibility.

2. The Fenton Reaction Is (Fe(H2O)62+ + H2O2)

Efforts to determine whether the reaction Fe(H2O)62+ + H2O2 forms OH• radicals via following the formation of the DMPO-OH• adduct by EPR failed, as it was shown that even mild oxidants, e.g., FeIIIaq, oxidize DMPO via [16]:DMPO + Ox → DMPO DMPO

The rate constant of the Fenton reaction in acidic media is k(Fe(H2O)62+ + H2O2)~50 M−1s−1. The measured rate constants depend on the pH and on the ratio [H2O2]/[Fe(H2O)62+]; the latter dependencies mainly stem from the observation that in the presence of excess H2O2 reactions (9) [17] and (10) [17,18] contribute to the observed rate constants [17]. Fe Fe(H

The nature of the products of reaction (10) were later determined [19] to be FeIIIaq + FeIV=Oaq; thus, clearly in acidic solutions when [H2O2]/[Fe(H2O)62+] > 1, a mixture of OH• radicals and FeIV=Oaq is formed.

Next, Bakac et al. developed a new procedure to differentiate between OH• radicals and FeIV=Oaq based on the different final products formed in the reactions of OH• radicals and FeIV=Oaq with DMSO, (CH3)2SO [20]. This technique can only be used for iron. Using this technique, it was proved that, in acidic solutions, OH• radicals are formed by the Fenton reaction, whereas in neutral solutions, where pH > 6, the product is FeIV=Oaq [20]. This proves that the Fenton reaction under physiological conditions does not form OH• radicals: However, this statement is not correct for the acidic organelles, e.g., lysosomes [21] and some peroxisomes [22]. This conclusion is correct for reactions of Fe(H2O)62+, but not for all Fenton-like reactions of FeIILm, as seen below.

Recently, it was shown that the Fenton reaction is dramatically accelerated in the presence of low concentrations of bicarbonate well below those present in living cells [19]. The oxidizing transient formed under these conditions is the carbonate anion radical, CO3•− [19]. CO3•− is a strong oxidizing agent, E0(CO3•−/CO32−) =1.57 V vs. NHE [23] and is evidently somewhat stronger in neutral media. CO3•− is still a considerably weaker oxidizing agent than OH• radicals and is, therefore, more selective as a ROS [24,25]. The reactions occurring were proposed to be [19]:Fe(H (H Fe(H (H Recent unpublished results [26] suggest that reaction (12) likely proceeds via:(H and reaction (12a) likely proceeds via:(H

The (CO3)FeIVaq thus formed might decompose via:(CO → Fe

Substrate → Fe

The competition between reactions (14a) and (14b) depends on the substrate. Thus, for DMSO k14a >> k14b, but for PMSO (phenyl-methyl-sulfoxide) k14a~k14b.

3. Fenton-like Reactions Involving FeIILm

Two types of Fenton-like reactions have to be considered.

When ligands, L, different from H2O are ligated to The FeII central cation, the effect of HCO3− on the mechanism, discussed above, can be included herein. It should be noted that the technique to distinguish between OH• radicals and FeIV=Oaq, developed by Bakac et al. [20], cannot always be applied here because the mechanism of the reaction LFeIV=O with DMSO is not known. The mechanism of the reactions of FeIILm with H2O2 for the following ligands was studied.

L = PO43−/HPO42− [20]. The results suggest that the Fenton reaction in the presence of phosphate in neutral solutions yields OH• radicals and not (PO43−)mFeIV=Oaq [20].

L = edta [22]. The reaction FeII(edta)2− + H2O2 was studied at pH > 5.5 using the technique developed by Masarwa et al. [8]. The results indicate that OH• radicals are the product of this reaction [27].

L = nta, nta = N(CH2CO2−)33− [28]. The reaction FeII(nta)− + H2O2 was studied. Surprisingly, though edta and nta are very similar ligands, the results differ considerably. The results suggest that the major product of the FeII(nta)− + H2O2 is a (nta)FeIV=Oaq complex [28]. The yields of the final products are pH dependent [28].

L = citrate [29]. The reaction of FeII(citrate)− with H2O2 was studied. This reaction is of importance because FeIII(citrate) is a major component of the non-transferrin iron mobile pool [30]. The results indicate that the reaction FeII(citrate)− + H2O2 in neutral solutions does not yield OH• radicals. The results do not answer the question whether a FeIV(citrate)aq species is a transient formed by this reaction. When low concentration of HCO3− are added to this system, the kinetics and final products are changed dramatically, indicating that the CO3•− radical anion is a major product of the reaction under these conditions [29].

The results presented in this section indicate that the mechanism of the Fenton-like reactions of FeIILm complex dramatically depend on the nature of the ligand. Therefore, one cannot assume that FeII complexes with analogous ligands react via the same mechanism.

When different peroxides are used as oxidants in the Fenton-like reaction, such as in biological systems, the most important peroxides are the ROOH compounds, where R is an alkyl. The ROOH peroxides are formed in biological systems, mainly in lipids, via the chain reaction [30,31]:RH + Ox → R R RH + RO

Therefore, the mechanism of the reaction (CH3)3COOH + Fe(H2O)62+ was studied. The results indicate that in this system FeIV=Oaq is also formed in neutral solutions in the absence of bicarbonate. In the presence of low concentrations of bicarbonate, CO3•− radical anions are the product of this Fenton-like reaction [32].

The S2O82− and HSO5− peroxides are of major importance in advanced oxidation technologies [33,34,35,36]. Therefore, the mechanisms of the reactions Fe(H2O)62+ + HSO5−/S2O82− were studied. The results indicate that in acidic media, SO4•− radical anions are the active oxidizing species formed, in neutral solutions, FeIV=Oaq is formed, and in the presence of low concentrations of bicarbonate, CO3•− is the oxidizing intermediate formed [26].

4. Other Fenton-like Reactions

Fenton-like reactions are reported for most low-valent transition metals and even for cations that are not involved in redox processes [11,12,13]. Herein, only Fenton-like reactions involving CuI [37] and ZnII [38,39,40,41] that are of biological importance and CoII, due to its role in advanced oxidation technologies [15], are discussed.

The reaction of CuI with H2O2 was long thought to yield OH• radicals [42], but it was later shown that the active oxidizing agent is CuI(H2O2) [8] or CuIIIaq [43]. It was also proposed that the reaction of CuI with S2O82− yields CuIIIaq [44]. Conversely, it was proposed that the reactions of Cu(II) with HSO5−and S2O82− yield CuIIIaq and SO4•− [45].

Surprisingly, Zn2+aq and ZnII-complexes were shown to be involved in the formation of reactive oxygen species (see references [38,39,40,41] for example.). However, no chemical mechanism initiating this process was forwarded. One possible mechanism is that suggested by Shul’pin et al. [13]. According to this mechanism, the reactions involved are:Zn Zn Zn

As the steady state concentration of H2O2 in biological media is very low, the probability that two H2O2 will bind to the same Zn2+aq is low. Therefore, it is tempting to propose that the process leading to the formation of reactive oxygen species catalyzed by Zn2+aq is:Zn Zn Zn

These two plausible mechanisms must be studied experimentally to prove one or both of them.

The reaction Co(H2O)62+ + H2O2 to yield OH• radicals is endothermic due to the high redox potential of the CoIII/II couple [10]. However, it was shown that the following reactions replace the simple Fenton-like reaction [14]:Co(H (H

In the presence of bicarbonate, the complex cyclic-(CO)CoII(HO2−)2(H2O) is formed. This complex decomposes via [15]:

The reaction of HSO5− with Co(H2O)62+ and with CoII(P2O7)(H2O)22− require more than one peroxymonosulfate to form radicals [46].

Finally, it should be pointed out that it is likely that ligands other than carbonate, with the proper redox potential, might also be oxidized directly by peroxides [14].

5. Heterogeneous Fenton-like Processes

A variety of heterogeneous catalysts react with H2O2 in Fenton-like processes. Thus, ZnO-nanoparticles induce the formation of reactive oxygen species in biological systems. However, this is attributed to the dissolved Zn2+aq ions [39] and is, therefore, not truly heterogeneous.

The most important heterogeneous catalysts of Fenton-like processes have iron atoms/cations as the active participants, e.g., zero-valent iron [47], MFe2O4 (e.g., Fe3O4 [48] and MgFe2O4 [49]), and LaFeO3 [50]. These systems are used in advanced oxidation processes and not in biological ones. Therefore, their mechanisms are not discussed herein.

6. Concluding Remarks

The major conclusions of this perspective are:

The reaction FeII(H2O)62+ + H2O2 yields OH• radicals as the active oxidizing agent in acidic solutions when [FeII(H2O)62+] > [H2O2], a mixture of OH• radicals and FeIV=Oaq in acidic solutions when [FeII(H2O)62+] < [H2O2], FeIV=Oaq in neutral solutions, and CO3•− in solutions containing even low concentration of HCO3−, i.e., under physiological conditions.

It is important to note that mechanisms of the reactions H2O2 + FeIILm(H2O)k, where L are ligands different than water, depend dramatically on the properties of L. Thus, one must study the mechanism for each ligand separately.

The study of the mechanisms of Fenton-like reactions with other peroxides requires separate studies.

The mechanisms of Fenton-like reactions of other low-valent metal cations differ from each other and thus require separate studies.

Therefore, it must be concluded that the mechanism of each Fenton-like reaction should be studied before concluding which oxidizing transient is formed in that reaction.