Oxidation of Electron-Deficient Phenols Mediated by Hypervalent Iodine(V) Reagents: Fundamental Mechanistic Features Revealed by a DFT-Based Investigation

Hypervalent iodine(V) (HVI) compounds are highly efficient reagents for the double oxidative dearomatization of electron-rich phenols to o-quinones. We recently reported that an underexplored class of iodine(V) reagents possessing bidentate bipyridine ligands, termed Bi(N)-HVIs, could efficiently dearomatize electron-poor phenols for the first time. To better understand the fundamental mechanistic basis of this unique reactivity, density functional theory (DFT) was utilized. In this way, different pathways were explored to determine why Bi(N)-HVIs are capable of facilitating these challenging transformations while more traditional hypervalent species, such as IBX cannot. Our calculations reveal that the first redox process is the rate-determining step, the barrier of which hinges on the identity of the ligands bound to the iodine(V) center. This crucial process is composed of three steps: (a) ligand exchange, (b) hypervalent twist, and (c) reductive elimination. We found that strong coordinating ligands disfavour these elementary steps and, for this reason, HVIs bearing such ligands cannot oxidize the electron-poor phenols. In contrast, the weakly coordinating triflate ligands in Bi(N)-HVIs allow for the kinetically favorable oxidation of such phenols {e.g., G = ~22 kcal/mol where Bi(N) = Bi(4-CO2Etbipy)}. It was also identified that trapping triflic acid, which is generated in situ, is a key role played by the basic bidentate bipyridine ligands in Bi(N)-HVIs as this serves to minimize decomposition of the sensitive ortho-quinone product.


INTRODUCTION
Hypervalent iodine (HVI) compounds represent a class of important and versatile reagents and reactants in organic synthesis. 1 For example, iodine(V) species, such as 2-iodoxybenzoic acid (IBX), are recognized as effective oxidants for a wide range of synthetic transformations. 2 More specifically, the double oxidation of phenols by IBX or related iodine(V) reagents delivers ortho-quinones in a highly regioselective manner. 3 However, to date, a notable limitation of iodine(V)-mediated phenol oxidation chemistry is that these transformations are typically restricted to electron-rich phenol substrates.
Bidentate nitrogen-ligated iodine(V) compounds, Bi(N)-HVIs, were first reported by Zhdankin and coworkers in 2002. 4 Recently, we demonstrated that these compounds, and specifically Bi(4-CO2Etbipy)-HVI, were uniquely effective at facilitating the highly efficient double oxidative dearomatization of electron-deficient phenols, such as p-nitrophenol (Table 1, entries 1 and 2). 5 In this report, the reactivity of Bi(4-CO2Etbipy)-HVI was benchmarked against a range of other iodine(V) reagents. Specifically, IBX provided very low yields of the target quinone and precursor PhI(O)(OAc)2 gave no reaction at all (entries 3 and 4). The stronger oxidant PhI(O)(OTf)2 afforded the product quinone in 59% yield after 20 minutes, which decreased to 27% yield after 4 hours due to continued oxidative degradation (entries 5 and 6).
Interestingly, Bi(4-OMeEtbipy)-HVI provided the product in much lower yields in comparison to Bi(4-CO2Etbipy)-HVI (entry 7). This revealed that electronic effects within the bipyridine ligand might play a crucial role in the efficiency of the oxidation. It was also interesting to note that the reaction employing pyridine-ligated PhI(O)(Py)2(OTf)2 only returned unreacted starting material, indicating a bidentate ligand may also be required for desired dearomatization. decrease the product yield? Why does the use of pyridine rather than a bipyridine attenuate the reactivity of the iodine(V) reagent? We anticipated that employing Density Functional Theory (DFT) to answer the foregoing questions would provide an enhanced understanding of the fundamental processes involved in iodine(V)-mediated oxidations. Furthermore, by revealing how the structure of Bi(4-CO2Etbipy)-HVI specifically relates to its function, we thought that our study could serve as a platform from which the design of new hypervalent iodine(V) reagents and associated organic transformations would be better enabled.

RESULTS AND DISCUSSION
We commenced our DFT investigation by evaluating the stability of different isomers of Bi(4-CO2Etbipy)-HVI. The four lower energy isomers of Bi(4-CO2Etbipy)-HVI are shown in Figure   1a. This found that structure 1, with a distorted octahedral geometry, is the most stable of these.
In this complex, the oxo, bipyridine ligand, and a triflate anion occupy equatorial positions, while the second triflate occupies the axial position trans to the phenyl ligand. It is worth noting that due to the strong trans influence of the phenyl ligand, the iodine center binds more weakly to the axial triflate than to the equatorial triflate. This is reflected in the longer I-O b bond distance within 1. Similarly, the strong trans influence of the oxo ligand results in unsymmetrical coordination of bipyridine, which is consistent with the longer distance between the I and N b atoms in comparison to the I and N a atoms. Other isomers are less stable than 1 by 1.6 kcal/mol (isomer 2), 4.7 kcal/mol (isomer 3), and 10.1 kcal/mol (isomer 4). The lower stability of five-coordinate ion pair 4 compared to other isomers indicates that the triflate ligand trans to the phenyl is more likely to remain bound to the iodine center (although weakly). We also found that the most stable structure 1 is resistant to complete dissociation of the bipyridine and triflate ligands. This is supported by the predicted endergonicity of these processes ( Figure   1b). The same is true for other isomers (see Figures S1 and S2).
found that an isomer structure analogous to structure 1 is the most stable. 6 This consistency suggests that regardless of the electronic nature of the bidentate nitrogen ligand, isomer 1 is likely lower in energy than the other possible systems.  changes from a rather inert to a more labile complex. 8 The dissociation of 9 from 19 produces 20 in a thermoneutral fashion which then isomerizes to more stable structure 21_OTf. Since the phenolate provides a weaker trans influence relative to the phenyl, the triflate binds more strongly to the iodine atom in 21_OTf, resulting in this complex being more stable than 20.
This is consistent with the shorter I-OTf bond distance within 21_OTf (2.252 Å) in comparison to the equivalent bond in 20 (2.412 Å) ( Figure 2). It is established that a hypervalent twist must take place for the iodine oxidant to be sufficiently reactive toward the redox process. 9,10 The corresponding twist occurs by overcoming an activation barrier of 8.4 kcal/mol via TS21-22_OTf which forms 22_OTf. The approach of the ortho-carbon of the phenolate to the oxo ligand in 22_OTf promotes the first redox process via an associative mechanism to afford 23_OTf. 10a The formation of this species (23_OTf) is calculated to be exergonic as much as 36.3 kcal/mol, suggesting that the first redox process is not reversible.
The second redox process commences with formation of outer-sphere complex 24 formed by dissociation of the triflate ligand from 23_OTf. Due to the weakly coordinating nature of the triflate anion, the outer-sphere complex 24 is only 9.1 kcal/mol higher in energy than the inner-  (Table 1).  (Table 1, entries 4 and 5). 5 Furthermore, it was noted that the ortho-quinone product formed by reaction with PhI(O)(OTf)2 decomposed as the reaction time increased (Table 1, entries 6). 5 This observation suggests that the presence of the Lewis basic bipyridine ligand in Bi(4-CO2Etbipy)-HVI plays an important role in reducing product degradation. Thus, we employed DFT to investigate and understand the underlying reasons for the reactivity differences between PhI(O)(OTf)2 and PhI(O)(OAc)2. For benchmarking purposes, we also studied the oxidation of p-nitrophenol by PhI(O)(TFA)2 computationally to predict the reactivity of this oxidant. As discussed in the previous section, the first redox process is the rate-determining step of the oxidative dearomatization. Consequently, for these three systems we limited our calculations to studying this part of the reaction mechanism. As shown in Figure   3, the dearomatization commences with the ligand exchange between ArOH and PhI(O)(X)2 (X = OTf, TFA, OAc) via the CIA mechanism, 7 followed by a hypervalent twist and then the redox process via the nucleophilic attack of the ortho-carbon of the phenolate to the oxo ligand.
The computed energy profiles given in Figure 3, revealed several noteworthy points. (iii) The activation barrier for the ligand exchange via TS30-31_X is mainly reliant on the nature of the X-ligand and increases along with the coordinating ability of the X-ligand. This is because it involves a late transition structure, evident from the notable elongation of the I-X bond from 29_X to TS30-31_X (Figure 3). The stronger the I-X bond, the more destabilized the transition structure TS30-31_X, and the higher the activation barrier to ligand exchange.
(iv) The ligand exchange represents an almost thermoneutral process, regardless of the nature of the X-ligand, which is consistent with the small values calculated for ΔG1 listed in Table 2.
(v) The hypervalent twist process is more energetic for a stronger coordinating X-ligand. This is supported by the largest value of ΔG2 for X = OAc and the smallest one for X = OTf (Table   2). This result can be explained by the low tendency of a relatively strong coordinating Xligand to occupy a position trans to the strong σ-donor oxo ligand within 22_X.
(vi) The energy barrier of the redox step (transformation 22_X  TS22-23_X) is particularly sensitive to the nature of the X-ligand. As the coordinating ability of the X-ligand increases, the activation barrier to this step increases (see the ΔG ‡ 1 values in Table 2). Consequently, a strong coordinating X-ligand alleviates the electron deficiency of the iodine(V) center in 22_X, making it less susceptible to be involved in the redox step. This hypothesis finds support from the inspection of the NPA charge on the iodine atom in 22_X, which increases along the series from +2.544 in 22_OAc to +2.568 in 22_OTf ( Figure 3). Also, this feature causes the redox step for a relatively strong coordinating X-ligand to take place via a later transition structure (TS22-23_X), consistent with the shortest C … O distance in TS22-23_OAc (2.125 Å) and the longest one in TS22-23_OTf (2.164 Å, Figure 3).
(vii) The overall activation barrier to the first redox process is determined by the following formula: ΔG ‡ t = ΔG1 + ΔG2 + ΔG ‡ 1 ( Table 2). As discussed above, ΔG1 is mainly independent from the nature of the X-ligand and thus only ΔG2 and ΔG ‡ 1 contribute to the ease of the dearomatization process. A strong coordinating X-ligand makes both transformations 21_X  22_X (hypervalent twist) and 22_X  TS22-23_X (redox step) unfavorable, and as a result such a ligand is not appropriate for the phenol oxidation.
(viii) The first redox process by PhI(O)(OTf)2 proceeds with an overall activation energy of 21.7 kcal/mol (Figure 3a), which is comparable to that of 20.8 kcal/mol where the process is driven by Bi(4-CO2Etbipy)-HVI (Figure 2a). This result implies that these two reagents should have a very similar reactivity and the presence of the bipyridine ligand in the latter does not attenuate the oxidizing capacity of the iodine(V) center. This suggests that the presence of the bipyridine ligand allows for trapping of the in-situ-generated triflic acid, which considerably reduces the rate of decomposition of the sensitive ortho-quinone product, as shown in Table 1.  Oxidation of p-nitrophenol by IBX. We recently investigated the mechanism of the double oxidation of phenols by IBX. 10a Figure 4 depicts the free energy changes for the three key steps outlined in Table 2. The complete energy profile for the IBX-mediated the oxidation of p-nitrophenol is provided in the Supporting Information ( Figure S5). Consistent with the experimental findings (Table 1), we found that unlike PhI(O)(OTf)2, the oxidation of p-nitrophenol by IBX requires a high overall activation barrier (30.9 kcal/mol). 11 Since the carboxylate ligand within IBX coordinates more strongly than the triflate, both the ∆G2 and ∆G ‡ 1 values for IBX are computed to be greater than those for PhI(O)(OTf)2 (29_OTf). In addition, the larger ∆G1 value for IBX than PhI(O)(OTf)2 indicates that the former is thermodynamically more resistant to ligand exchange. It follows from these results that all three key steps (ligand exchange, hypervalent twist, and the redox step) contribute to the much lower reactivity of IBX toward oxidation of electron-deficient phenols.   (Table 1, entries 1 and 7). 5 From the DFT-derived mechanism illustrated in Scheme 1, we posit that the reaction between p-nitrophenol and Bi(4-OMebipy)-HVI should commence with the ligand exchange followed by protonation of the bipyridine ligand to give 19_OMe ( Figure 6). The overall activation free energy for these two key steps is computed to be only 10.1 kcal/mol. 11 Based on the proposed mechanism, for the redox process to proceed, the protonated bipyridine ligand needs to dissociate from 19_OMe to give key intermediate 22_OTf.
The presence of the electron-donating 4,4'-dimethoxy groups on the bipyridine ligand cause this key step to take place with an activation barrier of 25.1 kcal/mol, which is much more energy demanding in comparison to analogous process from 19 (18.8 kcal/mol, Figure 2a). The stronger coordination of the bipyridine ligand within 19_OMe than in 19 is evident from the shorter I-N bond distance in the former (2.336 Å) than in the latter (2.426 Å) (see Figures 6 and 2a).

CONCLUSION
In summary, our comprehensive computational investigation reveals how the key structural and electronic properties of Bi(4-CO2Etbipy)-HVI facilitate its enhanced oxidation capacity relative to more traditional hypervalent iodine(V) species. We anticipate that these findings will assist in the design and development of new hypervalent iodine(V) reagents and synthetic transformations.

COMPUTATIONAL METHODS
Gaussian 16 12 was used to fully optimize all the structures reported in this paper at the M06-2X level 13 of density functional theory (DFT). For all the calculations, solvent effects were considered using the SMD solvation model for CHCl3 solvent. 14 The effective core potential of Hay and Wadt with a double-ξ valence basis set (LANL2DZ) 15 was chosen to describe iodine.
Polarization functions were also added for I (ξd= 0.289). 16 The 6-31G(d) basis set was used for other atoms. 17 This basis set combination will be referred to as BS1. Frequency calculations were carried out at the same level of theory as those for the structural optimization. Transition structures were located using the Berny algorithm. Intrinsic reaction coordinate (IRC) calculations 18 were used to confirm the connectivity between transition structures and minima.
To further refine the energies obtained from the SMD/M06-2X /BS1 calculations, we carried

Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.

Notes
The authors declare no competing financial interest.