*2.1. Crystal Structure*

Crystals of **1** (Figure 1) were obtained from methanol upon slow evaporation, at room temperature. A summary of the crystallographic data and processing parameters is presented in Table 1. Complex **1** (Supplementary Materials: CCDC number 2019464) crystallized in the monoclinic *P*21/*c* space group, with the asymmetric unit containing an iron cation with *N*--acetylpyrazine-2-carbohydrazide acting as a mononegative *<sup>N</sup>*pyrazine *N*amido *O*keto chelate ligand and a *OO'*-donor nitrate anion sharing the equatorial binding region. The axial sites were engaged with two water ligands, and a cationic pentagonal bipyramidal iron complex was thus formed, with its charge being balanced by a nitrate counter anion. The unit cell of **1** contains five non-coordinated and disordered water molecules. The *NN'O* coordination mode of HL− was observed in other cases [45,51] and di ffers from that found in complexes with ligands derived from *N*-acetylsalicylhydrazide [34,52,53]. The HL− ligand in **1** is slightly twisted, as measured by the distance between the least-square plane defined by the pyrazine

ring and the Cmethyl atom (0.539 Å); in **3**, that distance is shorter (0.388 Å) and in **2**, such moieties are coplanar [45]. Due to the water ligands and non-coordinated water molecules, compound **1** is involved in extensive H-bond interactions, which extend the structure to the third dimension. This contrasts with what was found in **2** and **3**, resulting from the kind of contact [45], with the former being assembled in dimers and the latter giving rise to 1D chains.

**Figure 1.** Ellipsoid plot of the complex cation in **1** (drawn at a 30% probability level) with an atom labeling scheme. Selected bond distances (Å) and angles (◦): N3–N4 1.389(3); C5–O2 1.241(3); C6–O1 1.266(3); N1–Fe1 2.2547(19); N3–Fe1 2.034(2); O1–Fe1 2.0707(17); O3–Fe1 1.9998(17); O4–Fe1 1.9910(17); O5–Fe1 2.1163(17); O6–Fe1 2.2508(18); O4–Fe1–O3 167.97(8); O1–Fe1–N1 146.91(7); N3–Fe1–N1 72.68(7); N3–Fe1–O1 74.29(7); and O3–Fe1–N3 95.88(7).

**Table 1.** Crystallographic parameters and structure refinement data for complex **1**.


*a* R = Σ||*Fo*|–|*Fc*||/Σ|*Fo*|; *b* wR(F2) = [Σw(|Fo|<sup>2</sup> − |Fc|2)2/Σw|Fo|4] 12 .

The catalytic properties of **1-3** were investigated and compared for the peroxidative oxidation of cyclohexane, and the e ffect of the type of activating energy input on the catalytic output was also studied.

### *2.2. Peroxidative Oxidation of Cyclohexane*

Using aqueous *tert*-butylhydroperoxide (*t*-BuOOH, 70% aqueous solution) as an oxidant in acetonitrile (NCMe) at 50 ◦C, the homogeneous **1**-**3** were screened for the microwave-assisted (MW) oxidation of cyclohexane (CyH) to cyclohexanone (Cy=O) and cyclohexanol (CyOH) as the final products (Scheme 2). The detection of no other products by Gas Chromatography–Mass Spectrometry (GC-MS) analysis suggests that the catalytic oxidation is very selective. The mechanism involved in the cyclohexane oxidation, involving the generation of cyclohexyl hydroperoxide (CyOOH) as a primary product, was corroborated by the method proposed by Shul'pin [54] and the reaction mixture injected in the gas chromatograph before and after treatment with triphenylphosphine (PPh3). The amount of CyOH had increased significantly after the addition of PPh3 to the reaction mixture, due to the reduction of CyOOH to CyOH and formation of phosphine oxide (PPh3O) (Scheme 2). The results are reported in Table 2 (yield values refer to the samples after treatment with an excess of PPh3).

**Scheme 2.** Microwave (MW)-assisted oxidation of cyclohexane (CyH).

In the presence of **1** and after 3 h under MW-irradiation at 50 ◦C, 14.9% of cyclohexane was converted into ketone-alcohol (KA) oil (cyclohexanol and cyclohexanone mixture), with cyclohexanol as the major product (selectivity up to 86% relative to KA oil after treatment with PPh3), in the absence of any co-catalyst (entry 5, Table 2), with a turnover number of 75 per Fe atom. There was always an increase in the amount of alcohol when the reaction mixture was analyzed after the addition of triphenylphosphine with respect to the existing amount before this treatment. This fact suggests the formation of cyclohexyl hydroperoxide (CyOOH) as a primary product which, after treatment with PPh3, is reduced to cyclohexanol (CyOH). As an example, entries 4 and 5 from Table 2 are presented, and from an initial CyOH yield of 7.5% (before PPh3 treatment), an increment to 13.2% was detected (after PPh3 treatment). Furthermore, a decrease in the amount of cyclohexanone (Cy=O) was observed, although with a less pronounced di fference. For iron complexes **2** and **3**, and for the same reaction conditions, total yields of 10.4% and 14.4% were obtained, with selectivities of 88% and 85% for the alcohol, respectively (Table 2, entries 22 and 25).

The oxidation reaction of cyclohexane was attempted under solvent-free conditions (in the absence of acetonitrile) in the presence of **1** (Table 2, entry 3), without success (the yield did not go beyond 0.74%, despite the high selectivity for the alcohol of 95%). The replacement of compounds **1-3** by their precursor salts, Fe(NO3)3.9H2O and FeCl2, resulted in much lower conversions, with total yields not exceeding 5% (Table 2, entries 28 and 29, respectively), denoting the significance of the *NN'O-*donor ligand *N*--acetylpyrazine-2-carbohydrazide (HL−) in the Fe coordination sphere in the promotion of the catalytic performance of complexes **1-3**. The free pro-ligand did not exhibit any activity. Blank tests

were performed in the absence of any of the Fe(III) compounds **1-3**, but no noteworthy conversion was observed.


**Table 2.** Data *a* for the MW-assisted oxidation of cyclohexane by catalysts **1**-**3** using TBHP (70% aqueous) as an oxidant.

*a* Reaction conditions (unless stated otherwise): cyclohexane (5.0 mmol); 2.5-20 μmol of catalyst; acetonitrile (3 mL); TBHP 70% aqueous solution (10 mmol); 1-9 h; 50 ◦C; microwave irradiation (5 W); yield and Turnover number (TON) determined by gas chromatography upon treatment with PPh3 (see text). *b* Molar yield (%) based on substrate, i.e., moles of product [cyclohexanol (CyOH) or cyclohexanone (Cy=O)] per 100 moles of cyclohexane after PPh3 treatment. *c* Total yield = moles of products [cyclohexanol (CyOH) + cyclohexanone (Cy=O)]/100 moles of cyclohexane. *d* Selectivity to cyclohexanol relative to KA oil mixture, i.e., moles of CyOH/(100 moles of CyOH + Cy=O). *e* Solvent-free conditions. *f* Without PPh3 treatment. *g* Oxidant:substrate = 1:1. *h* Oxidant:substrate = 4:1. *i* n(HNO3)/n(catalyst) = 5. *j* n(HNO3)/n(catalyst) = 10. *k* n(HNO3)/n(catalyst) = 25. *l* n(HNO3)/n(catalyst) = 50. *m* n(HPCA)/n(catalyst) = 25. *n* n(TFA)/n(catalyst) = 25. *o* n(TEMPO)/n(catalyst) = 25.

Complex **1** was chosen for optimizing the reaction conditions and several parameters were explored. The effect of the reaction time is shown in Figure 2a, for the period between 0.5 and 6 h, without any additive and at 50 ◦C (Table 2, entries 1, 2, 5, and 6). There was a gradual increase over time in the amount of KA oil formed, achieving a total yield of ca. 15 and 17% after 3 and 6 h, respectively. During the first hour, the formation of cyclohexanone was not significant (94 and 91% of selectivity for the alcohol, after 0.5 and 1 h reaction, respectively). The yield of cyclohexanone increased (from 0.1 to 1.7%, after 0.5 and 3 h, respectively) and the selectively to the alcohol decreased to 86%, possibly due to the partial oxidation of cyclohexanol.

**Figure 2.** Oxygenated product yield of cyclohexane (CyH) oxidation [cyclohexanol (CyOH) + cyclohexanone (Cy=O)] with respect to the following: (**a**) reaction time (10 μmol of **1**); (**b**) catalyst amount (3 h reaction time); (**c**) acid amount (10 μmol of **1** and 3 h reaction time); and (**d**) reaction time in the presence of acid additive [10 μmol of **1** and n(HNO3)/n-(catalyst) = 25]. Other reaction conditions: CyH (5 mmol); NCMe (3 mL); TBHP (70% aqueous) (10 mmol); 50 ◦C; under MW-irradiation (5 W); and GC analysis after the addition of PPh3.

The amount of catalyst varied between 2.5 and 20 μmol (Figure 2b), and a maximum yield of 19.4% of KA oil was verified for an amount of 20 μmol of **1** (entry 11, Table 2). This parameter does not affect only the yield, which increases from 3.8 to 19.4% with the indicated range amount of catalyst, but also the selectivity which, for cyclohexanol, decreases from 95 to 80% (entries 1 and 9-1, Table 2). In this way, we can conclude that both the increase of the reaction time and the increase in the amount of catalyst favor the formation of ketone.

When performing the oxidation reactions under the typical conditions (3 h, 50 ◦C, and 10 μmol of **1**), the variation in the oxidant/substrate molar ratio also has an important effect on the oxidized product yields (Table 2, entries 5, 7, and 8). The yield of KA oil increased from 8.7 to 14.9 and afterwards to 21.5% when the oxidant/substrate molar ratio was changed from 1:1 to 2:1 and then to 4:1, respectively.

The effect of various additives on the peroxidative microwave-assisted oxidation of cyclohexane was also investigated. In the presence of nitric acid (HNO3), complex **1** exhibited a highly promising effect. The n(HNO3)/n-(catalyst) molar ratio changed from 5 to 50 (Figure 2c). The total yield increased to 37.7%, for n(HNO3)/n-(catalyst **1**) = 25, relative to 14.9% obtained in the absence of any additive (Table 2, entries 5 and 14, respectively). Going beyond this molar ratio does not lead to a significant yield change (37.2% for n/n' = 50) (Table 2, entries 14 and 15).

To investigate the effect of the acid additive over time, catalytic oxidation was performed in the presence of this acid additive (n/n- = 25) for several time periods (1, 3, 6, and 9 h). Firstly, for both cases, in the absence and presence of HNO3 (n/n- = 25) (Figure 2a,d), the quantity of oxygenated products (CyOH + Cy=O) practically reached the maximum after 3 h and then seemed to stabilize.

The positive effect of nitric acid has been observed for other catalytic systems involving the oxidative transformation of alkanes [26,27,55–57]. The presence of a certain amount of acid can promote the catalytic process, either by catalyst activation through the protonation of ligands and unsaturation of the metal center, or by promoting the properties of the oxidant.

The presence of HNO3 affects, apart from the total yield, the product distribution. In the case of **1**, the selectivity for the alcohol was lower in the presence of acid, with the prolongation of time accentuating this effect. In the presence of acid, there was a clear preferential formation of CyOH (selectivity of 85%) in the first hour; a decrease of CyOH selectivity accompanied by an increase of Cy=O selectivity in the 1-3 h period; and beyond 3 h, the ratio between both products seemed to stabilize (Figure 2d).

In the presence of **1,** the influences of the 2-pyrazine carboxylic acid (HPCA), trifluroacetic acid (TFA), and stable free radical 2,2,6,6-tetramethylpiperidin-l-oxyl (TEMPO) were also explored (Figure 3). After 3 h at 50 ◦C under MW-irradiation, the total yield of products dropped in the presence of HPCA (8.8%) and TEMPO (drastically to 1.7%), whereas in the presence of TFA, it increased from 14.9% to 28.3% (Table 2, entries 14, 19, 20, and 21), although not as effectively as for HNO3.

**Figure 3.** Effects of different additives on the oxidation of cyclohexane catalyzed by **1**. Reaction conditions: CyH (5 mmol); **1** (10 μmol); TBHP (70% aq.) (10 mmol); NCMe (3 mL); 50 ◦C; 3 h; under MW-irradiation (5 W).

The effects of the presence of HNO3 (n(HNO3)/n-(catalyst **2** or **3**) = 25) and TEMPO additives were also analyzed for compounds **2** and **3**. In the case of the acid additive, although an increase in the amount of oxygenated products was observed, this effect was not so accentuated for these catalysts as for **1** (Table 2, entries 23 and 26, for **2** and **3**, respectively). The presence of the TEMPO radical resulted, for both catalytic systems, as in the case of **1**, in a drastic decrease in the yields (Table 2, entries 24 and 27, for **2** and **3**, respectively).

The peroxidative oxidation of cyclohexane was also performed, for comparative purposes, using different types of energy inputs, apart from microwaves, namely conventional heating and ultrasound (US) irradiation. Reactions were performed for compounds **1**-**3**, during 3 h at 50 ◦C and in the presence of HNO3 as an additive (n(HNO3)/n-(catalyst) = 25), and in the case of compound **1**, for different periods of time.

If we consider the period of 3 h, compounds **1**-**3** responded differently to the different energy stimuli. It can be observed that **1** exhibits a better performance when the reaction is promoted by microwave radiation (Table 3, entry 8), conceivably due to its ionic character and larger dipole, which promote microwave energy absorption [31,48,58–60]. Accordingly, the effect of MW irradiation (in comparison with conventional heating) in the case of catalyst **3**, with a symmetrical apolar molecule, is negligible (Table 3, entries 17 and 18). In this case, a different driving force, i.e., acoustic cavitation in sonochemistry, shows a more effective role (Table 3, entry 19), which is consistent with the known ultrasonic cleavage of a metal-ligand bond [61]. For the dinuclear catalyst **3**, this can lead to the formation of more active mononuclear catalytic species. The reaction catalyzed by **2** does not seem to be favored by any of the radiations (MW and US), which may be due to its possible decomposition into less active or inactive species when it is under these energy inputs. It is also noteworthy to mention that, for the same period, the selectivity does not vary much when we compare the catalytic activity of **1**-**3** under the effect of different energy inputs (Table 3). For example, for the period of 3 h, and in the presence of **1**, the selectivity for cyclohexanol varies between 66 and 69% for different energy sources. In the case of **2** and **3**, only the MW stands out and the selectivities reach values higher than 90%.


**Table 3.** Effect of different energy inputs for the oxidation of cyclohexane by catalysts **1**-**3** using TBHP (70% aq.) as an oxidant *a.*

*a* Reaction conditions (unless stated otherwise): cyclohexane (5.0 mmol); 10 μmol of catalyst; acetonitrile (3 mL); TBHP 70% aqueous solution (10 mmol); n(HNO3)/n-(catalyst) = 25; 0.5-6 h; 50 ◦C; microwave irradiation (5 W); yield and TON determined by gas chromatography upon treatment with PPh3. *b* Molar yield (%) based on substrate, i.e., moles of product [cyclohexanol (CyOH) or cyclohexanone (Cy=O)] per 100 moles of cyclohexane after PPh3 treatment. *c* Total yield = moles of products [cyclohexanol (CyOH) + cyclohexanone (Cy=O)]/100 moles of cyclohexane. *d* Selectivity to cyclohexanol relative to KA oil mixture, i.e., moles of CyOH/(100 moles of CyOH + Cy=O). *e* Data from Table 2 (entries 14, 16, and 17). CONV = under conventional heating with oil bath; MW = under MW-assisted condition; US = under ultrasound irradiation.

In addition, compound **1** was exposed to different types of energy input for different reaction times and, in all of the cases, a maximum selectivity for cyclohexanol was observed in the first 30 min of the reaction (Figure 4, Table 3). Thereafter, the selectivity decreased, conceivably due to the conversion of the cyclohexanol into cyclohexanone.

**Figure 4.** Effect of different energy stimuli on the oxidation of cyclohexane catalyzed by **1**. Reaction conditions: CyH (5 mmol); **1** (10 μmol); TBHP (70% aqueous) (10 mmol); NCMe (3 mL); n(HNO3)/n-(catalyst) = 25; 50 ◦C; 0.5-6 h. CONV = under conventional heating with oil bath; MW = under MW-assisted condition; US = under ultrasound irradiation.

The present Fe(III) catalytic system is more effective for the oxidation of cyclohexane under MW conditions in terms of yields, compared to Cu(II) or V(V) catalytic systems with hydrazone-based ligands [27,35,42]. In the presence of an additive (HNO3), the current Fe(III) catalytic system shows significant increase in the total yield, whereas the V(V) systems are effective under additive-free conditions [27,42]. The total yield under US conditions is also higher than that shown by a hydrazone Cu(II) catalytic system under MW conditions [27]. The selectivity towards CyOH of the current catalytic system is moderate in comparison with the hydrazone V(V) system [35,42].

From radical trapping experiments (addition of 2,2,6,6-tetramethylpiperidin-l-oxyl free radical to the reaction medium), in the presence of **1**, **2**, or **3** (Table 2, entries 21, 24, and 27, respectively), an extensive product yield inhibition (over 80%), relative to the total yield obtained when the reactions were carried out without any additive (Table 2, entries 5, 22, and 25, respectively), was observed. This suggests that the cyclohexane oxidation catalysed by complexes **1**-**3** proceeds through a radical mechanism, as proposed in other cases, depicted in Equations (1)–(9) [27,35,36,54,62]. Firstly, the reaction proceeds through the iron-catalyzed decomposition of the oxidant, leading to the formation of *t-*BuOO• and *t*-BuO• radicals upon the reduction of Fe(III) and oxidation of Fe(II) species, according to reactions (1) and (2), respectively. Then, cyclohexyl radical (Cy•) formation takes place due to H-abstraction from CyH by *t-*BuO• (reaction (3)). Upon the reaction with dioxygen, Cy• forms CyOO• (reaction (4)), and then upon H-abstraction from TBHP by CyOO•, CyOOH is formed (reaction (5)). In the reactions (6) and (7), the Fe-assisted decomposition of CyOOH produces CyO• and CyOO•, which leads to the formation of cyclohexanol (CyOH) and cyclohexanone (Cy=O) (the desired products), according to reactions (8) and (9).

$$\text{[Fe}^{\text{III}}\text{]} + \text{t-BuCOH} \rightarrow \text{t-BuCO}^{\bullet} + \text{H}^{+} + \text{[Fe}^{\text{II}}\text{]}\tag{1}$$

$$\text{[Fe}^{\text{II}}\text{]} + \text{t-BuCOH} \rightarrow \text{t-BuO}^{\bullet} + \text{[Fe}^{\text{III}}\text{]} + \text{HO}^{\bullet} \tag{2}$$

$$\text{t-BuO}^{\bullet} + \text{CyH} \rightarrow \text{t-BuOH} + \text{Cy}^{\bullet} \tag{3}$$

$$\text{Cy}^{\bullet} + \text{O}\_{2} \rightarrow \text{CyOO}^{\bullet} \tag{4}$$

$$\text{CyCO}^{\bullet} + \text{t-BuOOH} \rightarrow \text{CyOOH} + \text{t-BuOO}^{\bullet} \tag{5}$$

$$\text{CyCOOH} + \text{[Fe}^{\text{II}}\text{]} \rightarrow \text{CyO}^{\bullet} + \text{HO}^{-} + \text{[Fe}^{\text{III}}\text{]} \tag{6}$$

$$\text{CyOOH} + \text{[Fe^{III}]} \rightarrow \text{CyOO}^{\bullet} + \text{H}^{+} + \text{[Fe^{II}]} \tag{7}$$

$$\text{CyO}^{\bullet} + \text{CyH} \rightarrow \text{CyOH} + \text{Cy}^{\bullet} \tag{8}$$

$$2\text{CyOO}^{\bullet} \rightarrow \text{CyOH} + \text{Cy=O} + \text{O}\_2 \tag{9}$$
