Understanding Dioxygen Activation in the Fe(III)-Promoted Oxidative Dehydrogenation of Amines: A Computational Study

Abstract

Hydrogenation and dehydrogenation reactions are fundamental in chemistry and essential for all living organisms. We employ density functional theory (DFT) to understand the reaction mechanism of the oxidative dehydrogenation (ODH) of the pyridyl-amine complex [Fe^IIIL³]³⁺ (L³, 1,9-bis(2′-pyridyl)-5-[(ethoxy-2″-pyridyl)methyl]-2,5,8-triazanonane) to the mono-imine complex [Fe^IIL⁴]²⁺ (L⁴, 1,9-bis(2′-pyridyl)-5-[(ethoxy-2″-pyridyl)methyl]-2,5,8-triazanon-1-ene) in the presence of dioxygen. The nitrogen radical [Fe^IIL³_N8•]²⁺, formed by deprotonation of [Fe^IIIL³]³⁺, plays a crucial role in the reaction mechanism derived from kinetic studies. O₂ acts as an oxidant and is converted to H₂O. Experiments with the deuterated ligand L³ reveal a primary C-H kinetic isotope effect, k^CH/k^CD = 2.30, suggesting C-H bond cleavage as the rate-determining step. The DFT calculations show that (i) ³O₂ abstracts a hydrogen atom from the α-pyridine aliphatic C-H moiety, introducing a double bond regio-selectively at the C₇N₈ position, via the hydrogen atom transfer (HAT) mechanism, (ii) O₂ does not coordinate to the iron center to generate a high-valent Fe oxo species observed in enzymes and biomimetic complexes, and (iii) the experimental activation parameters (ΔH^≠ = 20.38 kcal mol⁻¹, ΔS^≠ = −0.018 kcal mol⁻¹ K⁻¹) fall within in the range of values reported for HAT reactions and align well with the computational results for the activated complex [Fe^IIL³_N8•]²⁺···³O₂.

1. Introduction

Oxidative dehydrogenation (ODH) reactions of alcohols and amines play vital roles in all living organisms. Through evolutionary refinement, nature has evolved enzymes that host transition metals, e.g., iron (Fe), copper (Cu), and zinc (Zn), as well as redox non-innocent ligands at the active site, to oxidize these substrates [1,2,3,4]. Current research focuses on creating affordable biomimetic metal catalysts to functionalize C-H bonds. This task poses a considerable challenge for synthetic chemists, particularly when it comes to controlling regio- and site selectivity during the synthesis and transformation of molecules [5]. Dioxygen (O₂), or hydrogen peroxide (H₂O₂) typically serve as oxidizing agents to perform reactions under mild conditions [6,7]. For example, the Fe(II) complex [Fe(H)(BH₄)(CO)(HN{CH₂CH₂P(iPr)₂}₂] catalyzes the ODH of secondary alcohols to ketones, with good yields in the presence of O₂. A base is necessary to facilitate ligand activation, forming a Fe(II)-amido intermediate that can abstract hydrogen atoms from C-H bonds in alcohols through a concerted outer-sphere mechanism [8]. Similarly, Fe(II) complexes with NNN donor azo-aromatic pincer ligands catalyze the oxidation of benzylic alcohols to carbonyls. In this instance, the ligand undergoes a one-electron reduction initiated by ethoxide N-H deprotonation. This forms an azo-anion radical intermediate, which then reacts by abstracting an H atom from the α-carbon of coordinated alcohol [9] through hydrogen atom transfer (HAT) [10].

We are interested in gaining a deeper understanding of transition metal-promoted ODH reactions in the presence of dioxygen. Specifically, we aim to understand the conversion of the paramagnetic complex [Fe^IIIL³]³⁺ (1) (L³, 1,9-bis(2’-pyridyl)-5-[(ethoxy-2″-pyridyl)methyl]-2,5,8-triazanonane) to the diamagnetic complex [Fe^IIL⁴]²⁺ (2) (L⁴, 1,9-bis(2′-pyridyl)-5-[(ethoxy-2″-pyridyl)methyl]-2,5,8-triazanon-1-ene) characterized by multinuclear NMR spectroscopy and X-ray crystallography (CCDC ref 286407) (Figure 1) [11,12,13].

The Fe(III) complex (1) is unique due to its ODH reactivity in anoxic (Equation (1)) and oxic (Equation (2)) conditions (Figure 1) [12,13].

2 [Fe^IIIL³]³⁺ + 2 C₂H₅O⁻ → [Fe^IIL⁴]²⁺ + [Fe^IIL³]²⁺ + 2 C₂H₅OH

(1)

4 [Fe^IIIL³]³⁺ + O₂ + 4 C₂H₅O⁻ → 4 [Fe^IIL⁴]²⁺ + 2 H₂O + 4 C₂H₅OH

(2)

Notably, only one double bond is introduced at position C₇N₈ of ligand L³, in contrast to the reports for numerous polydentate amine complexes [14]. Conjugation of the C=N double bond to the pyridine ring stabilizes the Fe^II oxidation state via its π-acceptor capability, consistent with the high redox potential reported [11,12]. The ODH reaction proceeds faster with O₂ and does not show the N-H kinetic isotope effect (KIE) observed in N₂ (k^NH/k^ND = 1.73) [12]. Both reactions, performed in dry ethanol, require a base, C₂H₅O⁻. Deprotonation of complex (1) leads to the nitrogen radical [Fe^IIL³_N8•]²⁺ (2a) which has been suggested to reduce O₂ via four consecutive outer-sphere single electron transfer steps to H₂O [13]. With the deuterated pyridyl-amine ligand L³-D, we observed a C-H KIE k^CH/k^CD with a value of 2.30 for the rate-determining step of the ODH reaction. ²H NMR analysis of the deuterated mono-imine product [Fe^IIL⁴-D]²⁺ (2) indicates regio-selective C-H cleavage by O₂ at the C₇N₈ position through the hydrogen atom transfer (HAT) mechanism, generating the HO₂^● radical [15].

With the results of these kinetic studies in hand, we have proposed that nitrogen N_8• in radical [Fe^IIL³_N8•]²⁺ (2a) transfers charge to the Fe(II) center, lowering the dissociation energy of the C₇-H_a bond. In the transition state (TS) the iron complex exhibits a biradical character and facilitates hydrogen atom transfer (HAT) to ³O₂ in the rate-determining step (Figure 2), consistent with the observed C-H KIE and the experimentally determined third-order rate law in Equation (3). The final product of the ODH reaction, the diamagnetic mono-imine [Fe^IIL⁴]²⁺ (2), has already been characterized by spectroscopic techniques and X-ray crystallography using tetraphenyl borate as a counter anion [12,13,15].

$$-{\displaystyle \frac{\mathrm{d}{\left[{\mathrm{F}\mathrm{e}}^{\mathrm{I}\mathrm{I}\mathrm{I}}{\mathrm{L}}^3\right]}^{3+}}{\mathrm{d}\mathrm{t}}}=k_{\mathrm{O}\mathrm{D}\mathrm{H}}\left[{\left[{{\mathrm{F}\mathrm{e}}^{\mathrm{I}\mathrm{I}\mathrm{I}}\mathrm{L}}^3\right]}^{3+}\right]\left[{\mathrm{O}}_2\right]\left[{{\mathrm{C}}_2{\mathrm{H}}_5\mathrm{O}}^{-}\right]$$

(3)

The current work presents a computational study to validate the proposed reaction mechanism (Figure 2). We aim to understand the pathway of the ODH reaction of Fe(III) complex (1) with external oxidant O₂ and the crucial role of nitrogen radical (2a). We are also interested in identifying the preferred site for the O₂ attack leading to regio-selective dehydrogenation and imine formation. In this study, we describe various calculated structures, geometries, spin states, and conceptual DFT analyses to determine the most favorable configuration for hydrogen atom transfer.

2. Results

2.1. Ligands and Iron Complexes

The pyridyl-amine Fe(III) complex (1) is formed by mixing solutions of ligand L²-H/L²-D (L², 1-[3-aza-4-(2-pyridyl)-butyl]-2-(2-pyridyl)-3-[(2-pyridyl)-methyl] imidazolidine/deuterated analog) and dimethyl sulfoxide complex [Fe^III(C₂H₆OS)₆](NO₃)₃ in ethanol. The imidazolidine ligand L² undergoes a ring-opening reaction to form the low-spin complex [Fe^IIIL³]³⁺ (1) (M = 2; λ_max 366 nm/3390 M⁻¹ cm⁻¹, 582 nm/528 M⁻¹ cm⁻¹) followed by its deprotonation to the nitrogen radical (2a) and the ODH reaction to the mono-imine complex [Fe^IIL⁴]²⁺ (2) (M = 10; λ_max 398 nm/8036 M⁻¹ cm⁻¹, 573 nm/6984 M⁻¹ cm⁻¹) [12,13].

Synthesis of L²-D leads to a 1:1-mixture of the imidazolidine isomers L²-C₇DHC₁₅HH and L²-C₇HHC₁₅DH, and its reaction with [Fe^III(C₂H₆OS)₆](NO₃)₃ results in two Fe(III) complexes (1) mono-deuterated at either carbon C₇ or carbon C₁₅ [15]. As mentioned, only one double bond is introduced at position C₇N₈ of the hexadentate ligand L³ to produce L⁴. Furthermore, there is no evidence for the in situ generation of singlet oxygen, ¹O₂ (M = 1), by EPR spectroscopy employing the trapping agent 2,2,6,6-tetramethyl-4-piperidinol (TEMP) [16], in contrast to reports on the dehydrogenation of Ir(III) amino acid complexes under blue light [17], or the in situ production of ¹O₂ by dioxygen activation on iron phosphide for advanced oxidation processes [18]. Therefore, the primary focus of the computational studies will be on the C₇N₈ region of Fe(III) complex (1) and its reactivity with triplet oxygen, ³O₂ (M = 3).

The optimized structures of Fe(III) complex (1) (Figure A1) and nitrogen radical (2a) (Figure 3) were calculated using the DFT-PBE-Def2SVP method, as implemented in the Gaussian 09 program [19]. The X-ray coordinates of [Fe^IIL⁴][C₆H₅)₄]₂ (CCDC-286407) were chosen for the initial input geometry.

2.2. Nitrogen Radical [Fe^IIL³_N8•]²⁺ and Site for O₂ Attack

First, the total energies for the reactants and products of the ODH reaction (Figure 2) have been calculated. For both the starting Fe(III) complex (1) and Fe(II) radical (2a), a doublet ground state (M = 2) was found to have the minimum energy, and a singlet ground state (M = 1), for the mono-imine Fe(II) complex (2) (

Table 1. Calculated energies (kcal mol⁻¹) for [Fe^IIIL³]³⁺ (1), C₂H₅O⁻, [Fe^IIL³_N8•]²⁺ (2a), C₂H₅OH, O₂, {[Fe^IIL³_{N8• C7•}]²⁺---H_7a---³O₂} (TS), [Fe^IIL⁴]²⁺ (2), and HO₂^•; M, multiplicity; EE, electronic energy; ZPE, zero–point energy; TEC, thermal enthalpy correction; TS, transition state.

Species	M	EE + ZPE (kcal mol−1)	EE + TEC (kcal mol−1)
[FeIIIL3]3+, (1)	2	−1,629,611.901	−1,629,593.709
	4	−1,629,599.929	−1,629,581.205
	6	−1,629,597.183	−1,629,577.986
C2H5O−	1	−96,657.889	−96,654.857
[FeIIL3N8•]2+ (2a)	2	−1,629,517.246	−1,629,499.171
	4	−1,629,500.632	−1,629,481.836
	6	−1,629,495.890	−1,629,476.821
C2H5OH	1	−97,041.209	−97,037.904
O2	3	−94,164.405	−94,162.330
{[FeIIL3N8• C7•]2+---H7a---3O2} (TS)	4	−1,723,662.304	−1,723,642.314
[FeIIL4]2+ (2)	1	−1,629,159.347	−1,629,141.605
	3	−1,629,138.195	−1,629,119.575
	5	−1,629,138.422	−1,629,119.446
HO2•	2	−94,518.050	−94,515.661

).

According to the DFT calculations, complex [Fe^IIIL³]³⁺ (1) undergoes deprotonation of the N₈-H bond with the base C₂H₅O⁻, resulting in the formation of the radical [Fe^IIL³_N8•]²⁺ (2a), with an energy = −1,629,517.246 kcal mol⁻¹. On the other hand, deprotonation of N₁₄-H leads to the formation of radical [Fe^IIL³_N14•]²⁺, which has an energy = −1,629,502.347 kcal mol⁻¹. Thus, the formation of radical [Fe^IIL³_N8•]²⁺ is favored by 14.9 kcal mol⁻¹. One explanation for this result is the intramolecular hydrogen bonding of the oxygen in the OC₂H₅ sidearm with the hydrogens of carbon C₁₃ (2.30 and 2.65 Å), adjacent to nitrogen N₁₄. The angle formed with carbon C₁₅, nitrogen N₁₄, and carbon C₁₃ is 116.08°, while in radical [Fe^IIL³N_8•]²⁺ there is no influence from the OC₂H₅ sidearm, as indicated by the corresponding angle C₇-N₈-C₉, of 121.27°. The nitrogen atom N₈ in the radical [Fe^IIL³N_8•]²⁺ exhibits more sp² character, which favors the formation of this radical [20] (Figure 3).

An interesting observation arises from comparing the individual C-H bond lengths in the N₈ and N₁₄ regions (

Table 2. Calculated bond lengths and vibrational frequencies of the nitrogen radicals [Fe^IIL³_N8•]²⁺ and [Fe^IIL³_N14•]²⁺; asymmetric stretching band ν_as, symmetric stretching band ν_s.

Isomer	Bond	Length (Å)	Frequency (cm−1)
[FeIIL3N8•]2+	N8-C7	1.43(8)
	C7-H7a	1.12(2)	2937.73 (H7a-C7-H7b νas)
	C7-H7b	1.11(7)	2873.72 (H7a-C7-H7b νs)
	N14-C15	1.48(2)
	C15-H15a	1.11(1)	3023.81 (H15a-C15-H15b νas)
	C15-H15b	1.11(2)	2976.22 (H15a-C15-H15b νs)
[FeIIL3N14•]2+	N8-C7	1.47(9)
	C7-H7a	1.11(1)	3031.81 (H7a-C7-H7b νas)
	C7-H7b	1.11(1)	2978.06 (H7a-C7-H7b νs)
	N14-C15	1.44(7)
	C15-H15a	1.11(7)	2989.45 (H15a-C15-H15b νas)
	C15-H15b	1.11(2)	2924.56 (H15a-C15-H15b νs)

). A value of 1.12(2) Å was found for the C₇-H_7a bond of radical [Fe^IIL³_N8•]²⁺ (vs. 1.11(7) Å for C₁₅-H_15a in [Fe^IIL³_N14•]²⁺) which is the longest among all the C-H bonds in both [Fe^IIL³_N14•]²⁺ and [Fe^IIL³_N8•]²⁺, and it is this bond that is attacked by dioxygen in the ODH reaction. Analysis of the vibrational frequencies for the methylene groups C₇H_7aH_7b and C₁₅H_15aH_15b reveals that the C₇H_7aH_7b moiety in the radical [Fe^IIL³_N8•]²⁺ has lower frequency values, indicating that this fragment is the most reactive. Note that mono-deuterated carbon atoms C₇ and C₁₅ of Fe(III) complex (1) and corresponding nitrogen radicals (2a) have an asymmetric carbon center, as illustrated for radical [Fe^IIL³_N8•]²⁺ (Figure 4) [15].

Additionally, a Natural Bond Orbital (NBO) population analysis has been conducted for the radical (2a), with the unpaired electron residing on either nitrogen N₈ or N₁₄, to obtain the condensed Fukui indices through vertical calculations. They provide insight into the properties of chemical bonds related to their nucleophilic, electrophilic, or radical reactivity [21,22,23,24,25,26]. The NBO analysis helps us pinpoint the most susceptible site to attack by O₂, showing the dual descriptor Δf for the methylene groups of carbon atoms C₇ and C₁₅ (

Table 3. Fukui indices of selected atoms in radicals [Fe^IIL³_N8•]²⁺ and [Fe^IIL³_N14•]²⁺.

Atom	Fukui Indices
[FeIIL3N8•]2+	f +	f −	Δf
N8•	−0.156	−0.181	0.025
C7	0.017	0.011	0.006
H7b	−0.030	−0.042	0.012
H7a	−0.038	−0.061	0.023
C6	0.010	0.015	−0.005
[FeIIL3N14•]2+	f +	f −	Δf
N14•	−0.200	−0.099	−0.101
C15	0.016	0.011	0.005
H15a	−0.024	−0.025	0.001
H15b	−0.038	−0.026	−0.012
C16	0.006	0.001	0.005

). The results indicate that only the hydrogen atom H_7a (or deuterium atom D_7a) of radical [Fe^IIL³_N8•]²⁺ serves as a suitable site for electrophilic attack, with a positive value of Δf, in contrast to hydrogen atoms H_15a and H_15b of radical [Fe^IIL³_N14•]²⁺. The NBO analysis results agree well with our experimental findings, showing that the imine double bond is introduced regio-selectively at position C₇N₈ (Figure 1). Hydrogen atoms H_7a and H_7b are not equivalent; their Δf values indicate that H_7a is the more reactive hydrogen atom (H_7a 0.023 vs. H_7b 0.012). In calculating the attack of ³O₂ on C₇-H_7b, after several collisions, the O₂ molecule will orient itself towards the C₇-H₇a^…3O₂ reaction pathway consistent with the Fukui index analysis (Table 3). The ligand pyridine rings provide electronic repulsion against O₂ attacking C₇-H_b, in favor of the cleavage of the C₇-H_7a bond.

2.3. Hydrogen Atom Transfer [Fe^IIL³_N8•]²⁺ + ³O₂ → [Fe^IIL⁴]²⁺ + HO₂^•

2.3.1. Transition State {[Fe^IIL³_{N8• C7•}]²⁺---H_7a---³O₂}

In the transition state {[Fe^IIL³_{N8• C7•}]²⁺---H_7a---³O₂} (M = 4) (Figure 5), the interaction with ³O₂ (M = 3) defines the C₇H_7a-O₂ angular geometry, with distances Fe-O₂ 4.02 Å, O-O 1.30 Å vs. starting distances Fe-O₂ 4.06 Å, O-O 1.21 Å. The intramolecular hydrogen bond between the oxygen and the methylene C₁₂H_12aH_12b group (distance O---H 2.33 Å, bond angle 98.4°) will enhance the structural stability of the {[Fe^IIL³_{N8• C7•}]²⁺---H_7a---³O₂} transition state. Steric crowding from the peripheral atoms restricts O₂ access to the metal center, inhibiting the formation of high-valent Fe-oxo species (Figure 3).

2.3.2. Spin Density, Charge Density, and Frontier Orbitals

Valuable information on the radical [Fe^IIL³_N8•]²⁺ and its reactivity towards ³O₂ (M = 3) is derived from the spin density population analysis (Figure 6). In the starting complex [Fe^IIIL³]³⁺ (1, state (i)), the spin density of the unpaired electron is entirely localized on the Fe(III) center, with no significant contributions from other atoms in the molecule. In state (ii)/(iii), after deprotonation of the N₈-H bond in complex (1), the radical [Fe^IIL³_N8•]²⁺ (2a) (M = 2) is formed, with the spin density mainly found on the metal via delocalization between Fe(II) and nitrogen atom N₈ (

Table A1. Spin density population for selected atoms of nitrogen radicals [Fe^IIL³_N8•]²⁺ and [Fe^IIL³_N14•]²⁺ shown in Figure 3. Note that the N₁₄ site has a slightly larger spin density (0.379) than N₈ (0.359). However, the Fukui function results indicate that N₈ is the preferred reactive site, consistent with the fact that the [Fe^IIL³_N8•]²⁺ radical is 14.9 kcal mol⁻¹ more stable.

[FeIIL3N8•]2+		[FeIIL3N14•]2+
Atom	Spin Density	Atom	Spin Density
Fe	0.628	Fe	0.638
N8•	0.359	N14•	0.379
C7	−0.021	C15	−0.019
H7a	0.034	H15a	0.021
H7b	0.015	H15b	−0.001
N14	−0.011	N8	−0.008
H14	0.001	H8	0.000
C15	0.002	C7	0.004
H15a	0.000	H7a	0.000
H15b	0.000	H7b	0.003

), with a negative, close to zero, value on the target carbon C₇; O₂ in the vicinity of [Fe^IIL³_N8•]²⁺, with a non-bonding distance of ≈2 Å, does not lead to a significant change in spin density distribution. In state (iv), when O₂ is in the proximity of [Fe^IIL³N_8•]²⁺, the transition state is formed through the hydrogen atom H_7a positioned between carbon C₇ and O₂ (Figure 5); spin density is transferred from O₂ to the Fe(II) radical while H_7a is detached from C₇, which significatively increases the spin density on carbon C₇. Remarkably, in the transition state, the Fe(II) complex shows a biradical character, as outlined in the proposed reaction mechanism (Figure 2). Finally, in state (v), the H_7a atom is no longer bound to C₇, and the diamagnetic final product, mono-imine complex, [Fe^IIL⁴]²⁺, (2) (M = 1) is formed with the consecutive release of HO₂^•. In summary, spin and charge density transfer analysis provides an important contribution to our understanding of the ODH reaction, with ³O₂ as an oxidant, following the HAT mechanism.

Next, the Natural Bond Order approach has been used to study the transfer of charge from [Fe^IIL³_N8•]²⁺ (M = 2) to ³O₂ (M = 3) (Figure 7). Analysis of the initial Fe(III) complex (1, state (i)) shows a large charge value located on Fe(III) (+0.657e). Notably, Fe(III) induces the polarization of the coordinated amine N₈ (−0.592e)-H₈ (+0.432e), with H₈ susceptible to deprotonation. The nitrogen radical (ii)/(iii) shows the delocalization of the electron density over the methylpyridine fragment, with the larger values on Fe(II) (+0.447e) and the coordinated N atoms (−0.418e/−0.425e); additionally, carbon C₇ shows a value of −0.274e, which indicates its tendency to donate electrons. At a distance of 2.0 Å between ³O₂ and radical (2a) the partial charges do not change. In transition state (iv) (Figure 5), charge transfer occurs from (2a) to ³O₂; this process begins through the C₇-H_7a moiety. As a result, both the carbon atom C₇ and the hydrogen atom H_7a become more positively charged. The negative charge on the oxygen atoms increases significantly (−0.223e, −0.152e) showing a partial reduction of the O₂ molecule, while N₈ becomes more negative. As H_7a is detached from C₇ in the transition state, the values on C₇ and H_7a increase, showing the electron density donation from the C₇-H_7a fragment towards O₂. Note that part of the initial electron density of the C₇-H_7a bond shifts towards nitrogen N₈. Finally, in stage (v), the H_7a atom is no longer bound to C₇, and HO₂^● is formed. In summary, spin and charge density transfer analysis provides an important contribution to our understanding of the ODH reaction, with ³O₂ as an oxidant, following the HAT mechanism.

An important aspect highlighted in the NBO charge population analysis (Figure 7) concerns the charge transfer from C₇H_7a to ³O₂ in the transition state (M = 4), involving 0.37 electrons. The HOMO orbitals of the [Fe^IIL³_N8•)]²⁺ radical (A) exhibit signatures in the C₇H_7a region, which is where ³O₂ interacts (Figure 8). As an open-shell system, [Fe^IIL³_N•]²⁺ (M = 2) has two different possibilities for the molecular orbitals arising from its spin configuration. These are α and β, giving two pairs of frontier molecular orbitals HOMO-α/LUMO-α and HOMO-β/LUMO-β, with an energy difference of 0.11 eV (2.5367 kcal mol⁻¹) between HOMO-α and HOMO-β. Thus, both orbitals might contribute to transferring electrons of C₇H_7a to ³O₂ in the transition state. For the LUMO-α and LUMO-β orbitals, we observe an energy gap of 0.84 eV (19.37 kcal mol⁻¹), with LUMO-β showing a greater propensity to accept electrons from O₂ in the region where the imine bond is formed. The significantly lower energy gap of 1.21 eV (27.90 kcal mol⁻¹) for HOMO-β and LUMO-β, compared to 1.94 eV (44.74 kcal mol⁻¹) for HOMO-α and LUMO-α, suggests that HOMO-β and LUMO-β play a major role in charge transfer. This transfer occurs from C₇H_7a to O₂ and from O₂ back to C₇H_7a during the imine formation process.

3. Discussion

Extensive kinetic studies have led to the development of a mechanism for the oxidative dehydrogenation (ODH) of [Fe^IIIL³]³⁺ (1), using O₂ as the oxidant. This mechanism identifies the radical [Fe^IIL³_N8•]²⁺ as a crucial component and follows the hydrogen atom transfer (HAT) pathway (see Figure 2; kinetic equations including the final third-order rate law can be found in A2) [15]. As mentioned, a C-H KIE k^CH/k^CD with a value of 2.30 was observed for the rate-determining step of the ODH reaction when using the deuterated pyridyl-amine ligand L³-D.

The nitrogen radical reacts with ³O₂, resulting in the transition state denoted as {[Fe^IIL³_{N8• C7•}]²⁺---H_7a---³O₂}. In this state, the spin density is observed on nitrogen N₈ (0.274) and carbon C₇ (0.308) (Figure 6A). This is followed by the formation of a C₇N₈ double bond in the final mono-imine product [Fe^IIL⁴]²⁺, along with the release of HO₂^•. In the transition state, the hydrogen atom H_7a is intermediate between C₇ and O₂, defining the reaction coordinate C₇---H_7a---O₂, with an associated stretching imaginary vibrational frequency of −390 cm⁻¹. It’s important to emphasize that the transition state has just one imaginary frequency, as this is precisely what we anticipate in such cases.

There is no evidence for the formation of a high-valent iron-oxo species, likely because the metal center in [Fe^IIIL³]³⁺ and [Fe^IIL³_N8•]²⁺ is deeply buried (Figure A1). This species is a key player in nonheme iron dioxygenases that perform C-H oxidation reactions by transferring hydrogen atoms to the [Fe^IV=O]²⁺ site [27,28,29,30,31].

The data compiled in Table 1 allow us to calculate the energy profile of the ODH reaction, including the activation parameters for the formation of the mono-imine [Fe^IIL⁴]²⁺ by the HAT mechanism (Figure 9). The activation energy, E_a (Δ EE + ZPE TS—reactants) = 19.34 kcal mol⁻¹, and the activation parameters ΔH^≠ (Δ EE + TEC TS—reactants) = 19.19 kcal mol⁻¹ and ΔS^≠ (ΔS TS—reactants) = −0.034 kcal mol⁻¹ K⁻¹. These estimated values are close to the experimental results, E_a = 21.04 kcal mol⁻¹, ΔH^≠ = 20.38 kcal mol⁻¹ and ΔS^≠ = −0.018 kcal mol⁻¹ K⁻¹ (Figure 9) [15].

The amine-imine oxidation reaction discussed in this work (Figure 1) starts with the deprotonation of the N₈-H bond in [Fe^IIIL³]³⁺ (1), resulting in the formation of the nitrogen radical [Fe^IIL³_N8•]²⁺ (2a), a key player in the process. The main themes of this process are typical to many amine-imine oxidations involving Ru(II) and Fe(III) complexes. Two basic types of mechanisms have been proposed for the amine-imine 2e⁻/2H⁺ transfer process [14]: (i) 2e⁻-step reactions involving high-valent metal centers [27,28,29,30,31], and (ii) 1e⁻-step reactions involving ligand-radical intermediates [32,33,34,35,36]. Nevertheless, the reaction from [Fe^IIIL³]³⁺ (1) to [Fe^IIL⁴]²⁺ (2) was noted as novel since it occurred spontaneously without requiring an external oxidant, and it appeared representative of similar systems involving fundamental proton and electron transfer steps [37].

The interest in the (bio)chemistry of radicals, transient or stable, has skyrocketed over the past four decades [38,39]. In particular, the chemistry of nitrogen-centered radicals has found plentiful applications in organic synthesis, which is not surprising since the nitrogen atom is common in many important (bio)molecules and is essential for fine-tuning their physicochemical properties [20,40,41]. Metal-coordinated nitrogen-centered radicals are generally more stable than free organic nitrogen-centered radicals; thus they open the door to powerful catalytic applications [42,43]. In metal radical complexes, the localization of the unpaired electron can take on distinct forms. It may reside predominantly at the nitrogen atom, resulting in aminyl radicals (designated as LM^m+-N^•R₂), or it may be associated with the metal itself, as seen in amidyl radicals (indicated as LM^m+1-N^••R₂). This key distinction is exemplified in the aminyl radical Rh(I) complex, which shows reactivity with a variety of hydrogen atom donors [42]. The topic has been meticulously discussed by Kaim, shedding light on the nuances of these fascinating complexes with redox-active ligands showing non-innocent behavior [44].

The computational analysis of the Fe(III)-promoted oxidative dehydrogenation of amines supports the findings of the kinetic results [15]. We demonstrate that the cleavage of the C-H bond occurs through a hydrogen atom transfer (HAT) mechanism. The nitrogen radical [Fe^IIL³N_8•]²⁺ (2a) plays a crucial role in the regio-selective abstraction of hydrogen atoms by O₂, leading to the subsequent formation of the hydroperoxyl radical, HO₂^●. In summary, understanding the Fe(III)-promoted ODH reaction enhances catalyst development for controlled C-H bond activation and functionalization, which remains a major challenge in synthetic chemistry.

4. Materials and Methods

The Fe(III)-promoted ODH reaction in the presence of O₂ as oxidant, and the radical [Fe^IIL³_N8•]²⁺ (2a) as key intermediate, was analyzed using density functional theory (DFT). All electron calculations were performed at the PBE level of theory [45,46,47], coupled with Def2SVP basis sets and including GD3 empirical dispersion correction [48,49,50]. The quantum chemical software Gaussian 09 was used [19]. The geometry of the radical (2a) was established based on the X-ray structure of [Fe^IIL⁴][B(C₆H₅)₄]₂ (2) [12,13], CCDC reference number 286407. This initial structure was relaxed using a geometry optimization procedure. A strict convergence criterion was applied for the total energy minimized to 10⁻⁸ a.u.; structures were relaxed with 10⁻⁵ eV/Å as a threshold criterion for force convergence. The interaction of ³O₂, (M = 3), with [Fe^IIL³_N8•]²⁺ (2a) (M = 2) was analyzed for structures of different geometries and multiplicities. Several pathways of O₂, approaching the C-H/C-D groups, were investigated to identify the most energetically favorable configuration for H/D atom transfer [Fe^IIL³_N8•]²⁺ → ³O₂, resulting in the formation of the Fe(II) imine complex (2) and the O₂H/D radical. We employed conceptual DFT to study the electronic and structural properties and the chemical reactivity of the systems of interest (atomic charge, condensed Fukui index, Natural Bond Orbital population analysis, dual descriptor, and HOMO-LUMO gap, SI). To test and calibrate the procedure, we calculated (i) the structure and ground state of the Fe(II) imine complex (2) and (ii) the molecular geometry of the hydroperoxyl radical HO₂^●, with results in excellent agreement with the reported experimental data [12,13,51].

5. Conclusions

Many biological and chemical processes employ dioxygen as an oxidant, involving metal-dependent C−H activation and functionalization as critical steps. One prime example is the heme-dependent enzyme cytochrome P450, a catalyst with a remarkable substrate range and an enormous potential for industrial applications [52]. Exploring its reaction mechanism through chemical, spectroscopic, and computational methods has resulted in significant research aimed at developing efficient catalytic systems [53]. Non-heme iron complexes, particularly those with pyridyl-alkylamine ligands, have received significant attention due to their inspiration from the active sites of metalloenzymes [27,28,29,30]. In this research, we have performed a DFT theoretical study to enhance our understanding of the oxygen-dependent dehydrogenation of the Fe(III) pyridyl-amine complex (1) into the stable Fe(II) mono-imine complex (2). Before the computational studies, the reaction was thoroughly investigated using kinetic methods, multinuclear NMR spectroscopy, and X-ray crystallography. It has been proposed that the cleavage of the C-H bond occurs via hydrogen atom transfer (HAT) [15]. High-valent Fe oxo species are not observed in the dehydrogenation reaction because steric hindrance from surrounding atoms prevents the direct coordination of O₂ with the iron center. The preferred site for the O₂ attack on the nitrogen radical [Fe^IIL³_N8•]²⁺ has been identified, which plays a crucial role in the hydrogen atom transfer (HAT) mechanism. It allows for regio-selective hydrogen atom abstraction by O₂, ultimately resulting in the formation of the hydroperoxyl radical HO₂^● in line with the experimental findings. The theoretical results regarding the transition state indicate significant effects related to the transfer of spin density from the O₂ molecule to [Fe^IIL³_N8•]²⁺, which defines the reactive site in the hydrogen atom transfer (HAT) mechanism. Additionally, the charge transfer to the O₂ molecule also is important in the reaction HAT step. The calculated transition state is characterized by notable spin populations on the C₇ atom and the N₈ atom of the ligand, suggesting the formation of a biradical species. The calculated parameters align closely with the experimental values: activation energy (E_a) is 19.34 kcal mol⁻¹ vs. 21.04 kcal mol⁻¹; the enthalpy of activation (ΔH^≠) is 19.19 kcal mol⁻¹ vs. 20.38 kcal mol⁻¹; and the entropy of activation (ΔS^≠) is −0.034 kcal mol⁻¹ K⁻¹ vs. −0.018 kcal mol⁻¹ K⁻¹. These results underscore the reliability of the computational approach and convincingly document the role of computational chemistry as an integral and essential component of chemical research [54].