**3.1 Hydroxyl radical**

In 1932, Fritz Haber & Joseph Weiss (1932) published in *Naturwissenschaften* (Science of Nature), and again in Proceedings of the Royal Society of London: A (1934), that the hydroxyl radical (HO•) is the oxidative intermediate responsible for Fenton's observation.

The authors proposed that the Fe+2 ion donates an electron to the peroxide molecule, cleaving the O-O bridge producing a hydroxyl radical (HO•) and a hydroxide ion (HO). The hydroxyl radical then attacks another peroxide molecule, forming superoxide, eventually generating oxygen [16, 17].

#### **3.2 Ferryl-oxo ion**

On the other side of the Atlantic Ocean, William Bray & H. M. Gorin published in Journal of the American Chemical Society (1932) that oxygen production after addition of Fe+2 ions to H2O2 in H2O is due to creation of the ferryl-oxo ion (Fe = O)+2 (**Figure 2**). After creation, the ferryl-oxo ion then reacts with another ferryl-oxo molecule to produce oxygen gas, recycling the ferrous ion. The authors proposed that an oxygen atom (•O•) is abstracted by a Fe+2 ion from the peroxide molecule, forming the ferryl-oxo ion (Fe = O+2) (no net change in charge) and H2O [18].

[Bray & Gorin named the molecule 'ferryl ion', but the term is currently used for the Fe+4 ion (without oxygen) [19]. To avoid confusion, the Bray & Gorin molecule is named here 'ferryl-oxo' ion. For similar reason, Barton's 'perferryl ion' will be named 'perferryl-oxo ion'].

These two papers divided the scientific community into partisan camps with sports-like fanaticism that continues today. Champions of the hydroxyl radical theory include: JD Rush, WH Koppenol [20–23], C. Walling [24–26], M. Kremer [27–29], JH Merz, WA Waters, [6, 30, 31], as well as many others. The scientists who argued for the existence of the ferryl-oxo ion included JT Groves [32–35], DA Wink [36–38], and DT Sawyer [39], among many others.

#### **3.3 Oxidative behavior of the hydroxyl radical**

Only exceeded by a fluorine (F<sup>0</sup> ) atom, the powerful hydroxyl (HO•) radical is the second strongest electrophile, and will even oxidize chlorine ion(s) (Cl) to elemental chlorine (Cl<sup>0</sup> ) or gas (Cl2) [40]. A hydroxyl radical will strip an electron from an element (except F) or H• from a hydrocarbon (**Figure 1**).

Hydroxyl radicals (HO•: **Figure 1**) are created by:

1.Donation of an electron to H2O2 from a transition metal ion (**Figure 1a**) (with *exception* of iron and copper ions [41]) produces HO• radicals via secondary electron transfer from the ion to peroxide. The O-O bond of peroxide scissions, producing a hydroxyl ion (HO—) and hydroxyl radical (HO•);

**Figure 1.** *Hydroxyl radical reactions.*

> 2. Splitting H2O2 with UV (λ = 253.7 nm) or γ- radiation (from 60Co) produces two hydroxyl radicals:

$$\begin{array}{c} \text{H-O-O-H} + (\text{UV}) \rightarrow \text{HO}\bullet \\ \text{...} \end{array}$$

Hydrogen Peroxide is Cleaved by UV Rays to Hydroxyl Radicals (2)

(See (Eq. (2)) (**Figure 1d**) [42];

3.UV flash irradiation of oxygen donating molecules, such as N2O to create oxygen atoms (•O•) that react with water molecules:

H2O þ •O• ! 2HO•

Water Molecule and Oxygen Atom Form Hydroxyl Radicals (3)

(Eq. (3)) [43, 44]; or.

4. Ionizing water with electrically produced β-rays to produce radicals

$$\mathrm{H\_2O} + \mathrm{e}^- \rightarrow \mathrm{HO\bullet} + \mathrm{H^-}/\mathrm{H\bullet} + \mathrm{HO^-}$$

Water Molecule is Cleaved by High Energy Electrons to Hydroxyl Radicals, Hydroxyl Ions, Hydride Radicals, and Hydrogen Atoms (4)

(Eq. (4)) [42];

(H• radicals likely combine with each other, as also H� & H+ ions; thus escaping as H2 gas) [42, 45].

Once created, hydroxyl radicals (HO•) will oxidize an element, ion, or compound, by extracting an electron to form HO� and a cation, increase the valence of another ion by +1, or abstract H- from an X-H bond of organic molecule, forming H2O and an organic radical (**Figure 1e**).

*A History of the Fenton Reactions (Fenton Chemistry for Beginners) DOI: http://dx.doi.org/10.5772/intechopen.99846*

#### *3.3.1 Oxidation of hydrocarbons (alkanes) by hydroxyl radicals*

A hydroxyl radical abstracts H• from an alkane to create a C• radical and water (**Figure 1e**) [46, 47]. A second HO• is required to collide with C• to form an alcohol (**Figure 1f**), thus a high HO•/ substrate ratio is required to produce alcohols. Subsequent HO• hydroxyl attacks to the same carbon atom progressively oxidizes and adds oxygen atoms, producing aldehydes/ketones, then organic acids, and finally, carbon dioxide [31, 42, 48]. An example of a hydroxyl radical reaction sequence for oxidation of methane:

$$\begin{aligned} \text{(1)} \text{HO}\bullet + \text{CH}\_{4} &\rightarrow \bullet \text{CH}\_{3} + \text{H}\_{2}\text{O}; \\\\ \text{(2)} \text{HO}\bullet + \bullet \text{CH}\_{3} &\rightarrow \text{CH}\_{3}\text{OH} \\\\ \text{(3)} \text{CH}\_{3}\text{OH} + \text{HO}\bullet &\rightarrow \text{CH}\_{2}\text{O} \\\\ \text{(4)} \text{CH}\_{2}\text{O} + \text{HO}\bullet &\rightarrow \text{HCO}\_{2} \end{aligned} \tag{5}$$

$$\begin{aligned} \text{(5)} \text{HCO}\_{2} + \text{HO}\bullet &\rightarrow \text{CO}\_{2} + \text{H}\_{2}\text{O} \end{aligned}$$

Sequential Oxidation of Methane to Carbon Dioxide by Hydroxyl Radicals

(Eq. (5)) (**Figure 1f**) [25].

There is no guarantee that a second HO• will collide with a carbon radical to make an alcohol.

Under low HO• concentrations, long-lived hydrocarbon radicals fuse to each other to make large complex hydrocarbons via R1C••CR2 fusions (**Figure 1g**). The hydroxyl radical oxidation of methane can also follow:

$$\begin{aligned} \text{(1)} \text{HO} &\text{\textdegree + CH}\_{4} \rightarrow \text{\textdegree CH}\_{3} + \text{H}\_{2}\text{O};\\ \text{(2)} \text{CH}\_{3}\text{\textdegree+ \text{\textdegree CH}\_{3}} &\rightarrow \text{CH}\_{3} - \text{CH}\_{3} \end{aligned} \tag{6}$$

Partial Oxidation of Methane by Hydroxyl Radicals Allow C‐C Fusions

(Eq. (6)) (**Figure 1g**) [25].

Thus carbon–carbon fusions are a hallmark of hydroxyl radical reactions [42, 49]. The HO• radical is: 1) uncharged, and 2) will abstract an electron any atom (except F�) or H• from a molecule it collides with, thus the (HO•) radical is an indiscriminant oxidant. Its oxidation profile determined by accessibility and rate of diffusion. In the oxidation of simple alkanes, the oxidation preference is: 1° H > 2° H > 3 H°.

Hydroxyl radicals (HO•) [17] can be created by H2O2 receiving an electron from a transition metal ion [41], or by splitting an oxygen donating molecule, either H2O2, with UV light or radiation [42, 50] or N2O (aq.) with UV light [43, 44]. Hydroxyl radicals can be quenched/scavenged by reducing agents [51] including aliphatic alcohols [50], DMSO [52], acetate ions [22], polyols [53], H2S [54], and NO [55]. These reagents are included as radical traps where HO• radical oxidations are undesirable.

#### *3.3.2 Hydroxyl radical oxidation of alcohols*

Waters (1946) reported that HO• radical oxidation of ethylene glycol (CH2(OH)- CH2(OH)) produced both glycoaldehyde (CH(O)-CH2(OH)) and formaldehyde (2x: CH2O). To determine which H• abstraction caused C-C bond cleavage, Waters

#### **Figure 2.**

*Ferryl-Oxo ion reactions.*

oxidized pinacol, which has no available O-**C-H** bonds, to acetone ((CH3)2C=O) as the only product. Thus, Waters (1946) proved that H• abstraction from the hydroxyl oxygen (H-C-*O-H*) bond of a 1-, 2-, diol causes C-C bond cleavage, and H• abstraction from an *H-C*-O-H bond of a 1-, 2-, diol causes localized C=O bond formation [56] (see ferryl-oxo ion: **Figure 2c** and **d**).

Droege & Tully (1986a,b) oxidized gaseous ethane (<sup>1</sup> H, <sup>2</sup> H, and mixed) (46)] and propane (<sup>1</sup> H, <sup>2</sup> H, and mixed) [47] with UV-activated N2O&H2O to compare oxidation rates of the terminal vs. center carbons, and test the isotope effect on HO• oxidation for different positions of the ethane and propane molecules. The authors found that there was no difference in positional abstraction for hydrogen vs. deuterium at 1° (ethane & propane) or 2° positions (propane only); however C-C chain fusions increased with temperature.

Baxley & Wells (1998) oxidizing tertiary alcohols with HO• radicals in air. HO• radicals were generated by UV activation of CH3ONO, NO, and O2 gases. H-abstraction from the sole -OH group caused C-C cleavage producing a ketone, a hydrocarbon and water. Abstractions from C-H bonds produced either addition of a second hydroxyl group or fusions producing long chain diols, however the authors noted that the hydroxyl group of 2-butanol was targeted more frequently than of 2-pentanone [48].

#### *3.3.3 Hydroxyl radical oxidation of diols, polyols, and carbohydrates*

Gilbert and King (1981, 1984) oxidized glucose with HO• generated by Ti+3/H2O2. Using electron spin resonance (ESR) the authors concluded that HO• radical produced *A History of the Fenton Reactions (Fenton Chemistry for Beginners) DOI: http://dx.doi.org/10.5772/intechopen.99846*

carbon (C•) radicals at all positions in equal ratios, indicating distributed attack by HO• toward all carbon positions in glucose, the established signature of HO• oxidations [57, 58].

Dizdaroglu & Von Sonntag reacted glucose [43] and cellobiose (44) with HO• generated from UV irradiation of N2O saturated H2O. By mass spectroscopy, the authors identified several 6-carbon derivatives of glucose including gluconic and glucuronic acids, several hexosuloses, hexodialdose, and. Several dehydrohexoaldoses, proposing that addition of H• or HO• radicals occurred after abstraction of –H or –OH groups from glucose. The authors determined for both carbohydrates, all carbons were oxidized equally.

In addition to 6-carbon molecules, Von Sonntag and coworkers reported fragmentation of glucose into various aldoses, formaldehyde, formic acid, carbon dioxide, and carbon monoxide, representing different C-C bond cleavages. The authors did not explain the origins of the C-C bond cleavage products.

In summary, the hydroxyl radical (HO•) is a powerful but non-selective oxidant. It can abstract electrons from any molecule or element with exception of fluorine. Hydroxyl radicals will abstract hydrogen atoms (H•) from organic molecules from any accessible C-H, O-H, or N-H (59) bond at rates proportional to accessibility by simple diffusion [43, 46, 57].

#### **3.4 Oxidative behavior of the ferryl-oxo ion**

The ferryl-oxo [(Fe = O)+2] ion, a less powerful oxidant than the HO• radical, is created by oxygen abstraction from H2O2 (**Figure 2a**). The oxidizing power of the (Fe = O)+2 ion is moderately stronger than the strength of C-H bond of an alkane and roughly equivalent to the C-H bond strength of benzene; the (Fe = O)+2 ion is reported not to abstract H• from anhydrous acetonitrile (CH3-C N) [59]. Though weaker than the HO• radical, the (Fe = O)+2 ion is a discriminatory oxidant, abstracting H from the weakest X-H bond in a molecule and oxidizing molecules with the weakest X-H bonds in a mix of molecules (**Figure 2b**) [32–35]. In the oxidation of simple alkanes, the oxidation preference is: 3° H > 2° H > 1° H (**Figure 2**).

#### *3.4.1 Ferryl-oxo ion oxidation of hydrocarbons (alkanes)*

Groves & coworkers demonstrated that oxidation of alkanes by (Fe = O)+2 in nonaqueous environments produced alcohols without carbon–carbon fusions. Addition of -OH groups to alkanes was both *regio-* and *stereo-*selective. Using isotopic H2 18O2 / H2 16O, Groves and coworkers found that the peroxyl oxygen was incorporated as the hydroxyl oxygen 90% of the time. Groves et al. termed the effect 'oxygen rebound' [32–35].

Groves et al. proposed a two-step mechanism to explain their results (**Figure 2b**):


Unlike HO•, the [Fe = O]+2 is both stereo- and regio- selective. For hydrocarbons, the H-C oxidation preference order is: 3° C-H > 2° C-H > 1° C-H. The basis of the rebound effect is likely due to attraction of the electrophile C• radical and the nucleophile oxygen (•O•) of the (Fe-OH)+3 ion. The oxygen is added to the same bond position on the oxidized carbon.

[Fenton's original reaction: (Eq. (7)) violates Groves' model because tartaric acid oxidation follows a different pathway:

$$\text{C}\_4\text{H}\_6\text{O}\_4 + \text{FeSO}\_4 + \text{H}\_2\text{O}\_2 + \text{H}\_2\text{O} \rightarrow \text{C}\_4\text{H}\_4\text{O}\_4 + 2\text{H}\_2\text{O}$$

Fenton's First Reaction: Oxidation of Tartaric Acid by FeSO4*=*H2O2 (7)

Erik Hückel's double bond resonance theory states that molecules with 4N + 2 unpaired electrons in conjugated (staggered) double bonds are extraordinarily stable. In the oxidation of tartaric acid, the abstraction of the first H• from C2 is followed by ejection of the second H• from C3 to form a C=C bond, because the central C=C bond is conjugated to the flanking C=O bonds of the terminal carboxylic acids. Thus, Fenton's molecule was resistant to further oxidations, allowing him to discover it].

#### *3.4.2 Ferryl-oxo ion oxidization of alcohols*

Ferryl-oxo ion [(Fe = O)+2] oxidation of oxygen-containing organic molecules behaves differently from hydrocarbon oxidations (**Figure 2c** and **d**). Carbon and hydrogen have similar affinity for electrons, therefore the electron pair is shared equally and in a hydrocarbon, hydrogen-carbon all bonds are about equal strengths. Oxygen (O) heteroatoms have a higher affinity for electrons than carbon or hydrogen atoms, making the C-O bond stronger than a C-C bond, while weakening other bonds extending from the hydroxyl carbon significantly [19, 60–62].

As an example, when (HO•) oxidizes ethanol, H• abstraction occurs indifferently from any of the six C-H positions, producing roughly 50% ethylene glycol and 50% acetaldehyde yield. On the other hand, when ethanol is oxidized by (Fe = O)+2 ion, the bond strengths of the methyl C-H bonds are �96 kCal/mole, whereas the hydroxyl C-H bond strengths are �81.6 kCal/mol and the O-H bond strength is �104 kCal/mole (60). Because the (Fe = O)+2 ion has the higher probability of abstracting H• from a hydroxyl carbon (due to bond strength) or hydroxyl oxygen (due to charge attraction) rather methyl carbons, acetaldehyde will be formed in preference to ethylene glycol [60, 63–66].

#### *3.4.3 Ferryl-oxo ion oxidation of diols, polyols, and carbohydrates*

Following the Coon & White (1977) discovery of the Fe+3-heme core in cytochrome P450 and its ability to sever the O-O bond, and oxidize NADPH2 [67, 68], Okamoto et al. (1985) mimicked the ability of enzyme P450scc to split a C-C bond of a diol in 1-, 2-, bis-(4-methoxyphenyl)ethane-l,2-diol using Fe+3 ion, O2, and a reductant (N-benzyl-3-carbamoyl-1,4-dihydropyridine) [69].

Okamoto et al. (1988) found that Fe+2 + H2O2 could substitute for Fe+3 and O2 to cleave diols to paired aldehydes. Using various inhibitors and/or substituting ferric for ferrous ion, the authors concluded that (Fe = O)+2 was created and was the oxidant that cleaved the 1-, 2-, diols (**Figure 2c**). The authors also discovered that when one

*A History of the Fenton Reactions (Fenton Chemistry for Beginners) DOI: http://dx.doi.org/10.5772/intechopen.99846*

hydroxyl group was substituted, paired aldehydes formed, but when both hydroxyl groups were blocked, no aldehydes were produced (**Figure 2d**) [70].

Sugimoto and Sawyer (1985a) reported that Fe+2 and two moles of H2O2 oxidized alkenes (hydrocarbons with double bonds) to paired aldehydes formed by (Fe = O)+2. The authors proposed that Fe+2 ion and H2O2 caused dioxygen addition to a double bond, forming a dioxetane, that then scissioned to a diol; a second oxidation (Fe = O)+2 scissioned the diol to paired aldehydes. The authors saw similar oxidative behavior when CH3-O-O-H and *p*-Cl-Ph-O-O-H were substituted for H2O2 [71].

Thus 1-, 2-, diols produce the same products when oxidized by either HO• (56) or (Fe = O)+2 [68] oxidants indicating that the formation of paired aldehydes is faster than oxygen addition reactions of alkanes. [Though contemporary, the Sawyer's and Oka's research teams did not appear to be aware of each other, or of Waters (1946)].

The rationale for asymmetric cleavage of diols (**Figure 2c** and **d**) is due to the additive weakening of the C-C bond between the two hydroxyl groups [19, 60, 61, 65]. When H• is abstracted from a hydroxy oxygen of a diol pair, the weakest bond of the oxygen-centered (H-C-O•) carbonyl radical is the C-C bond between the diol pair (•O-R1CH R2CH-OH); electron abstraction from the C C bond produces paired aldehydes (**Figure 2c**). However, when H• is abstracted from a C-H bond of a hydroxyl carbon, the weakest bond of the diol group is the O-H bond opposite the C• radical (H O-R1C•); the hydrogen atom is ejected from carbon-centered (H O-C•) carbonyl radical to form the carbonyl bond. Abstraction of H• from a tertiary -OH group can cause ejection of a C• radical to form the C=O bond (**Figure 2d**) [60–66].

[Fenton's oxidation of tartaric acid should have produced two products: 2-, 3-, dihydroxy-, maleic acid [HOOC-C(OH) = C(OH)-COOH] *and* glyoxalic acid [HO-C(O)-C(O)H. Waters (1946), Okamoto et al. (1988), and Sugimoto et al. (1984, 1985a) indicates that Fenton could have discovered both oxidation products].

#### **3.5 Comparison of ferryl-oxo ion and hydroxyl radical oxidizations**

Though HO• radical and (Fe = O)+2 ion both create a C• radical, the differences between the two oxidants is: 1) HO• is a 1 e oxidant, whereas (Fe = O)+2 ion is a 2 e oxidant, thus two independent HO• oxidations are required to make a hydroxyl group; and 2) reducing agents that trap HO• radicals and thus halt HO•-based oxidations, do not disrupt ferryl-oxo ion oxidations. The most likely explanation radical quenching by the ferryl-oxo ion is the proximate distance of Fe+3-O-H and C• radical is coupled with likely nucleophile / electrophile attraction, allowing rapid re-reaction to occur [36–38].

The noted crypto-HO• positional effect seen in Fe+2/H2O2 catalyzed oxidations is likely due to localized binding of Fe+2 ions to a substrate that has O heteroatoms when it added to the substrate prior to H2O2 [22, 23, 72] addition.

### **4. Perferryl-oxo ion**

#### **4.1 Early history of the perferryl-oxo ion**

Fenton conducted Fe+3/H2O2 experiments but did not note any reactions and assumed that no reaction(s) had occurred [5, 7]. However, on the other side of the English Channel, Fenton's contemporaries found contrary evidence.

Spring (1895) mixed H2O2 solutions with different pure chemical substances noting which substances caused oxygen gas release. Spring noted that both ferrous and ferric chlorides decomposed H2O2 and released oxygen gas [40].

Ruff (1898) used basic ferric acetate and H2O2 to oxidize gluconic acid to arabinose and carbon dioxide, a C1-C2 bond cleavage with oxidations of both C1 and C2, the reaction now known as 'Ruff's degradation' [73].

Bohnson (1921) noted that a solution of a ferric salt in water, dilute enough to show only very slight color, turns brightly lavender with '1 or 2 drops' of 30% H2O2 followed by O2 gas release from the solution. After bubbling ends, no residual H2O2 remained in the solution, indicating complete decomposition. The author observed that when H2O2 is added to Fe+3 salts, a lavender color appears briefly. Bohnson speculated that the color represented a transient higher Fe oxidation state. Bohnson trapped the lavender pigment with cold KOH coloring the solution red, then Ba(OH)2, forming a red gelatinous precipitate. Washing the precipitate with HCl released chlorine gas. Bohnson determined the empirical formula of the precipitate: barium ferrate (BaFeO4), thus isolating the Fe+6 oxidation state as FeO4 <sup>2</sup> (ferrate) ion. Bohnson also prepared potassium ferrate (K2FeO4) by bubbling chlorine gas through a solution of Fe(OH)3/KOH solution, producing a deep lavender color; addition of Ba(Cl)2 to the lavender solution again formed the red precipitate: BaFeO4 [74].

Bohnson (1921) also demonstrated direct conversion of ethanol to acetic acid. Bohnson noted that addition of Fe+3 ions to an H2O2 solution produced oxygen gas, but addition of ethanol to the H2O2 solution prior addition of Fe+3 ions disrupted oxygen evolution, leading the author speculated that ethyl alcohol was oxidized to acetaldehyde or acetic acid. Bohnson also compared of oxidation by ethanol by Fe+2/ H2O2 vs. Fe+3/H2O2 and found that Fe+2/H2O2 produces acetaldehyde, then acetic acid, whereas Fe+3/H2O2 oxidized ethanol to acetic acid primarily, with only trace amounts of acetaldehyde detected. Bohnson proposed that Fe+3/H2O2 oxidized ethanol directly to acetic acid, bypassing acetaldehyde formation [74].

Walton & Christensen (1926) compared the oxidation of ethanol with FeSO4/H2O2 or Fe2(SO4)3/H2O2 under anhydrous conditions. Separately assaying for acetaldehyde and acetic acid, the authors noted that when ethanol is oxidized with FeSO4/H2O2 acetaldehyde appeared before acetic acid, whereas when ethanol is oxidized by Fe2(SO4)3/H2O2 acetic acid appears long before acetaldehyde, proving that Fe+3/H2O2 oxidation exhibits non-Fenton-like behavior, thus confirming Bohnson (1921) [75].

Wieland & Franke (1928) reported that under strong acidic conditions Fe+3/H2O2 oxidized formic acid (HCOOH) to CO2 and H2O, and dihydroxymaleic acid (HOOC- (OH)C=C(OH)-COOH) to 2,3 dioxo-propanoic acid (HOOC-C(O)-C(O)-COOH) and CO2 [76].

Goldschmidt & Pauncz (1933) investigated the Fe2(SO4)3/H2O2/ethanol reaction and confirmed that ethanol was oxidized directly to acetic acid. The authors also explained that Fenton & Jackson (1899) and Fenton & Jones (1900) did not detect aldehydes from aliphatic alcohols because the 1:1 molar ratio of H2O2 and alcohol was sufficient to oxidize all the alcohol to organic acids [77].

Even as late as 1989, Fe+3/H2O2 oxidation articles appeared noting unusual oxidations. Sanderson et al. (1989) submitted a patent for co-synthesis of *t*-butanol and *t*-butyl peroxide from *t*-butane by Fe+3/H2O2, showing addition of either a hydroxyl or a peroxyl group to the 3° carbon without explanation of mechanism [78].

#### **4.2 Oxidative behavior of the perferryl-oxo ion**

White & Coon (1977) summarized the discovery of the mechanism of respiration by mitochondrial enzyme cytochrome P450. Cytochrome P450 uses a Fe+3 ion chelated in a heme ring to conduct the reduction: (Eq. (8)) [67, 68].

*A History of the Fenton Reactions (Fenton Chemistry for Beginners) DOI: http://dx.doi.org/10.5772/intechopen.99846*

$$\text{P450}-\left(\text{Fe}^{+3}\right) + \text{NADPH}\_2 + \nu\_i\text{O}\_2 \rightarrow \text{P450}-\left(\text{Fe}^{++}\right) + \text{NADP}^+ + \text{H}\_2\text{O}$$

$$\text{Cytochrone P450 Reduction of NADPH}\_2 \text{ with Oxygen} \tag{8}$$

Responding to the discovery that the critical enzyme of respiration forms a Fe+3 = O intermediate to split the dioxygen molecule, Barton et al. (1983) sought to mimic the biological reaction using chelated Fe+3 ions and peroxide ion (O2 �2 ) instead of oxygen as a new process to oxidize hydrocarbons to alcohols. Working with alkanes (R1-CH2-R2), Barton expected that pyridine-chelated Fe+3 ions and potassium peroxide (K2O2) would produce alcohols (**Figure 3**) [54].

What Barton did not expect was that the reaction produced a mix of alcohols [R1-HC(OH)-R2] *and ketones* (R1-(C=O)-R2). Direct oxidation of hydrocarbons to ketones, a single step 4e� oxidation and oxygen addition, was new to organic chemistry. For the oxidation of simple alkanes, the oxidation preference of the Fe+3/H2O2 oxidant is: 3° H > 2° H > 1 H°. Barton et al. (1983) also found that they could manipulate the alcohol/ketone ratio by choosing iron chelators with different N/O ratios.

To understand the reaction mechanism, Barton and co-workers studied the oxidation of adamantine (C10H16, 4 tertiary, 6 secondary, 0 primary C-H groups). Despite the preponderance of secondary carbons, Barton's reactant favored oxidation of tertiary vs. secondary carbons by a 5:1 margin indicating that the oxidant behaved similar to the ferryl-oxo ion, but single step ketone addition was never reported for (Fe = O)+2 oxidations [54].

Sugimoto & Sawyer (1985b) confirmed and extended Barton's findings by using Fe+3 and H2O2 to oxidize hydrocarbons molecules with double and triple bonds, isolating epoxides (R1-C-O-C-R2) and oxetanes (R1-C-O�O-C-R2) [79].

Seven years elapsed until Barton and coworkers resolved the perferryl-oxo structure and oxidation mechanism (**Figure 3**).


**Figure 3.** *Perferryl-Oxo ion reactions.*

Couching their model on the accepted behavior of Fe+3 nucleus of cytochrome P450 [80–82], Barton et al. (1990) proposed (Fe = O)+3 as the reaction product of Fe+3 and H2O2 or Fe+2 and O2 • � (superoxide anion) (**Figure 3a**). [Barton et al. (1990–8) wrote the structure of the perferryl-oxo ion as [FeV=O]. The (FeV=O(�2)) and (Fe = O)+3 formulas are equivalent for atoms, bonds, and net charge].

Barton et al. (1990): 1) proposed a bifurcated pathway leading either to alcohol or ketone formation, showing that the alcohol/ketone ratio could be varied with addition of dianisyl telluride, and 2) determined that both alcohol and ketone formation occurred in two steps, choosing different non-reversible paths at the second reaction [83, 84].

Barton and Doller (1992) mapped out steps of the pathway of perferryl-oxo ion oxidation of hydrocarbons (**Figure 3b**–**d**):

Step 1 (**Figure 3b**): Formation of Fe+4-C-R intermediate. Using diphenyldiselenide (Ph-Se-Se-Ph), or phenyl selenol (Ph-Se-H), Barton trapped the Fe+4-C-R intermediate as a stable (Fe+3-Ph-Se-C-R) intermediate as detected by mass spectroscopy (structure not specified).

Step 2 (**Figure 3c**): Oxygen Insertion to form Fe+3-O-O-C-R intermediate. Comparing 16O2 and 18H2O2, the authors detected primarily 16O-labeled alcohols and ketones indicating that O2 (not O2 �2 ) formed the dioxygen bridge. The authors proposed that in an anoxic environment, peroxide is oxidized to dioxygen by ferric ions in sufficient quantities to complete the reaction as follows: [Eq. (9)]

$$2\,\text{Fe}^{+3} + \text{O}\_2\text{}^{-2} \to 2\,\text{Fe}^{+2} + \text{O}\_2$$

$$\text{Reduction of }\text{H}\_2\text{O}\_2 \text{ to }\text{O}\_2\text{by Fermi Jones} \tag{9}$$

Step 3 (**Figure 3d** (1 & 2)): Bifurcated Pathways Arise from Differential Cleavage of the O-O Bridge. The Fe+3-O-O-C-R intermediate is the branch point between the 2e- and 4e- oxidative pathways: a) scission of the Fe+3-O-|-O-R bond produces an alkoxide (R-O―) and the (Fe = O)+3 ion (**Figure 3d**.1); b) scission of the Fe+3-|-O-O-R bond produces Fe+3 ion and a peroxyl (―O-O-R) ion which then degrades to a ketone (R = O), and an oxide ion (O�<sup>2</sup> ) (**Figure 3d**.2).

Barton and Doller (1992) trapped the ferric-peroxy-carbon (Fe+3-O-O-C-R) cleavage intermediates with tri-methoxy phosphine (P(OMe)3). P(OMe)3 reacted with either oxygen (R-C-O\*-O-Fe+3 or R-C-O-O\*-Fe+3) trapping potential oxygen bridge cleavage products as R-C-O-P(OMe)3 and R-C-O-O-P(OMe)3 respectively. Thus Barton and Doller (1992) explained the mechanism of bifurcated production of alcohols or ketones from alkanes by perferryl-oxo (Fe = O)+3 ion (85). Barton's oxidation scheme was confirmed by Schuchardt et al. (2001) [55].

Barton's perferryl-oxo ion oxidation theory explains Ruff's oxidation gluconic acid to arabinose (1898) [71] the one-step conversion of ethanol to acetic acid observed by Bohnson (1921) [72], Walton & Christensen (1926) [75], Goldschmidt & Pauncz (1933) [75], and the co-synthesis of *t*-butanol and *t*-butyl peroxide from *t*-butane by Sanderson (1989) [76].
