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

Abstract

Hypervalent iodine (HVI) compounds are 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 dearomatize electron-poor phenols for the first time. To 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 2-iodoxybenzoic acid (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 disfavor 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. It was identified that trapping in situ-generated triflic acid is a key role played by the bidentate bipyridine ligands in Bi(N)-HVIs as this serves to minimize the decomposition of the ortho-quinone product.

Graphical Abstract

■ 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 co-workers 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 exhibited no reaction at all (entries 3 and 4). The stronger oxidant PhI(O)(OTf)₂ afforded the product quinone in 59% yield after 20 min, which decreased to 27% yield after 4 h because of continued oxidative degradation (entries 5 and 6). Interestingly, Bi(4-OMebipy)-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 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 the desired dearomatization.

Table 1.

Reported Dearomatization of Electron-Deficient Phenols to Ortho-Quinones by Various Iodine(V) Reagents: Selected Results⁵

entry	HVI oxidant	time (h)	yield (%)
1	Bi(4-CO2Etbipy)HVI	0.5	99
2	Bi(4-CO2Etbipy)HVI	4	91
3	IBX	24	12
4	PhI(O)(OAc)2	24	0
5	PhI(O)(0Tf)2	0.66	59
6	PhI(O)(OTf)2	4	27
7	Bi(4-OMebipy)HVI	0.66	38
8	PhI(O)(Py)2(OTf)2	0.66	0

The abovementioned experimental results prompted us to comprehensively investigate the mechanism of the oxidation of p-nitrophenol using the abovementioned iodine(V) oxidants with the aim of answering the following questions: (i) Why are Bi(4-CO₂Etbipy)-HVI and PhI(O)(OTf)₂ potent oxidants in this chemistry, while IBX and PhI(O)(OAc)₂ are not? (ii) Is there a difference between the reactivity of Bi(4-CO₂Etbipy)-HVI compared to PhI(O)(OTf)₂? (iii) If not, why is the reaction efficiency for the former greater than that for the latter? (iv) Why does the replacement of Bi(4-CO₂Etbipy)-HVI with Bi(4-OMebipy)-HVI considerably 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 oxidation. 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. It was found that structure 1, with a distorted octahedral geometry, is the most stable among the four structures. 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 because of 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). The NBO calculations suggest that the I–OTf bonds trans to the oxo and phenyl ligands are mainly ionic in nature; otherwise, they exhibit significant covalent character (Figure S9).

Figure 1.

(a) Stability of different isomers of Bi(4-CO₂Etbipy)-HVI. (b) Reaction free energies for dissociation of the triflate and bipyridine ligands from 1. Free energies calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol.

A recent study investigating the stability of isomers of a related Bi(bipy)-HVI species also 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 to be lower in energy than the other possible systems.

Oxidation of p-Nitrophenol by Bi(4-CO₂Etbipy)-HVI.

Next, we focused on understanding why Bi(4-CO₂Etbipy)-HVI is a suitable reagent for the oxidation of electron-deficient phenols in contrast to IBX (Table 1, entries 1 and 3).⁵ To this end, different mechanistic pathways were explored for the oxidation of PhOH by Bi(4-CO₂Etbipy)-HVI, the results of which are given in the Supporting Information (see Figures S3 and S4). Scheme 1 outlines the most favorable pathway for the phenol oxidation identified from our DFT studies. This reaction involves the following key steps: (i) ligand exchange between phenol and Bi(4-CO₂Etbipy)-HVI, giving adduct 7 stabilized by in situ-generated triflic acid; the bipyridine in this complex acts as a bidentate ligand, which is supported by the NBO analysis (Figure S8), (ii) formation of complex 8 via addition of triflic acid to the bipyridine ligand, (iii) generation of intermediate 10, obtained by the dissociation of 9 from 8, followed by isomerization, (iv) the first redox process, (v) tautomerization assisted by the triflate ligand via sequence 11 → 12 → 13, and finally, (vi) the second redox process that forms ortho-quinone 15.

Scheme 1.

Key Steps for Phenol Oxidation Mediated by 1 Derived from Our DFT Investigation

Figure 2 shows the energy profile calculated for oxidative dearomatization of p-nitrophenol as a model for an electron-deficient substrate based on the mechanism outlined in Scheme 1. Accordingly, the reaction commences by the formation of hydrogen-bonded adduct 16, followed by a ligand exchange involving the concerted interchange associative (CIA) mechanism⁷ through transition structure TS_16–17 to provide adduct 17, which is stabilized by a hydrogen-bonding interaction between in situ-generated triflic acid and the phenolate ligand. This step is calculated to occur with an activation barrier of around 11 kcal/mol and is endergonic by about 8 kcal/mol. Following this, the resulting triflic acid protonates the bipyridine nitrogen trans to the oxo ligand (N^b) in a thermodynamically favorable process to give intermediate 19. Because of the π conjugation within the bipyridine ligand, the addition of the proton to N^b significantly reduces the basicity of N^a, and thus, it binds less strongly to the iodine(V) center in 19. This is consistent with the longer I–N^a distance in 19 (2.426 Å) than in 18 (2.356 Å) (Figure 2). In other words, N^b protonation reduces the coordinative stability of the iodine(V) molecule, and it 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 a more stable structure 21_OTf. Because 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 TS_21–22_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.

Figure 2.

Calculated energy profile for the oxidation of p-nitrophenol by Bi(4-CO₂Etbipy)-HVI. Free energies (potential energies) calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol and selected bond distances (green values) in Å.

The second redox process commences with the formation of outer-sphere complex 24 formed by the dissociation of the triflate ligand from 23_OTf. Because of 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-sphere complex 23_OTf. The triflate anion, within 24, is then predicted to act as a base, and through a deprotonation reaction via TS_24–25, it produces zwitterion-type complex 25 with an overall activation barrier of 16.2 kcal/mol. The delivery of the resultant triflic acid to the anionic oxygen of the catecholate ligand within 25 gives 26 (a tautomer of 24), from which the second redox process proceeds via transition structure TS_26–27. The deprotonation of the hydroxy group in 26 by the triflate anion increases the electron density on the catecholate ligand, resulting in two electrons from it being transferred to the I(III) center as represented by the curly arrow mechanism (Figure 2). Notably, because of the weakly coordinating nature of the triflate anion, inner-sphere complex 28 is only 4.0 kcal/mol lower in energy than the outer-sphere complex 26. As such, according to our calculations, the overall activation barrier for the second redox step (via TS_26–27) is only 12.3 kcal/mol. The triflic acid generated in the last step then reacts with 9 and, consistent with the experimental observations,⁵ gives diammonium salt 14 in an exergonic fashion. From the foregoing computational data, we conclude that the rate-determining step of this transformation is the first redox step via sequence 21_OTf→ 22_OTf→ 23_OTf with an activation barrier of 20.8 kcal/mol. This relatively low free energy of activation is in agreement with the experimental observations and explains why the dearomatization reaction by Bi(4-CO₂Etbipy)-HVI occurs at room temperature (Table 1).

Oxidative Dearomatization by PhI(O)(X)₂ (X = OTf, TFA, OAc).

It was demonstrated that PhI(O)(OTf)₂ can mediate the oxidation of p-nitrophenol, while PhI(O)(OAc)₂ exhibits no reaction (Table 1, entries 4 and 5).⁵ Furthermore, it was noted that the ortho-quinone product formed by the 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, 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.

Figure 3.

Calculated energy profile for the first redox process associated with the reaction between 29_X and ArOH, where X = OTf, TFA, and OAc. Free energies (potential energies) calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol, and selected bond distances (green values) are given in Å.

The computed energy profiles given in Figure 3 revealed several noteworthy points.

1. The coordinating ability of the X-ligand decreases in the following order: X = OAc > TFA > OTf, supported by the shortest I–X bond distance in 29_OAc (2.101 Å), and the longest one in 29_OTf (2.141 Å).

2. The overall activation barrier for the oxidative dearomatization increases in the order X = OTf < TFA < OAc. This suggests that the identity of the X-ligand is an important factor in determining the ease of the redox process. Specifically, PhI(O)(OAc)₂, bearing strongly coordinating acetate ligands, has a barrier of 34.5 kcal/mol, while PhI(O)-(OTf)₂, with weakly bound triflate ligands, has a computed activation barrier of only 21.7 kcal/mol. This finding is in agreement with the experimental observations and clearly explains why PhI(O)(OTf)₂ is an appropriate oxidant for the dearomatization reaction, while PhI(O)(OAc)₂ exhibits no reaction.

3. The activation barrier for the ligand exchange via TS_30–31_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, which is evident from the notable elongation of the I–X bond from 29_X to TS_30–31_X (Figure 3). The stronger the I–X bond, the more destabilized is the transition structure TS_30–31_X and the higher is the activation barrier to ligand exchange.

4. 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.

5. 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 X-ligand to occupy a position trans to the strong σ-donor oxo ligand within 22_X.

6. The energy barrier of the redox step (transformation 22_X → TS_22–23_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 natural population analysis (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 (TS_22–23_X), consistent with the shortest C···O distance in TS_22–23_OAc (2.125 Å) and the longest one in TS_22–23_OTf (2.164Å, Figure 3).

7. The overall activation barrier to the first redox process is determined using 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 → TS_22–23_X (redox step) unfavorable, and, as a result, such a ligand is not appropriate for phenol oxidation.

8. 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.

Table 2.

Reaction Free Energies for Transformations 29_X → 21_X (ΔG₁) and 21_X → 22_X (ΔG₂) and Activation Free Energy for the First Redox Step (Transformation 22_X → TS_22–23_X, ΔG^‡₁). Free Energies Calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in Chloroform Are Given in kcal/mol

X	ΔG1	ΔG1	ΔG‡1	ΔG‡t
OTf	0.8	6.7	14.2	21.7
TFA	2.0	11.0	17.6	30.6
OAc	0.8	15.3	18.4	34.5

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 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 Because the carboxylate ligand within IBX coordinates more strongly than the triflate, both the ΔG₂ and ΔG^‡₁ values for IBX are computed to be greater than those for PhI(O)(OTf)₂ (29_OTf). In addition, the larger ΔG₁ 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 the oxidation of electron-deficient phenols. However, it is worth noting that these three key steps become energetically more favorable as phenol becomes more electron-rich (Table S1).

Figure 4.

Reaction free energies for the oxidation of p-nitrophenol by IBX. Free energies calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol.

Oxidation of p-Nitrophenol by PhI(O)(Py)₂(OTf)₂.

It was determined experimentally that substituting the bidentate bipyridine ligand with two pyridine ligands results in deactivation of the Bi(N)-HVI oxidant and recovery of the starting material (Table 1, entry 8).⁵ This can be probed by DFT, which predicts that geometrical isomer 34 is ~12 kcal/mol more stable than active oxidant 36 (Figure 5). The latter is produced only after surmounting an activation barrier as high as 27.7 kcal/mol. The most stable isomer 34 is not reactive toward the ligand-exchange process because the two active sites in this complex are blocked by the pyridine ligands. Specifically, in the most stable structure, the triflate ligands responsible for driving the ligand exchange occupy positions trans to the strong σ-donor phenyl and oxo ligands, which renders this complex incapable of facilitating oxidation. This hypothesis is supported by the highly unstable nature of intermediates 37 and 38, resulting from ligand exchange between 34 and ArOH. To summarize, the high stability of the inactive iodine(V) complex 34 does not allow ligand exchange to easily occur on such a system, and this is the likely reason for no reaction occurring between PhI(O)-(Py)₂(OTf)₂ and p-nitrophenol.¹¹

Figure 5.

Calculated mechanism for the generation of active oxidant 36 from the most stable isomer 34, along with the relative energy of intermediates 37 and 38 achieved by ligand-exchange reaction between 34 and p-nitrophenol (ArOH). Free energies (potential energies) calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol.

Oxidation of p-Nitrophenol by Bi(4-OMebipy)-HVI.

Finally, we wanted to understand why the yield of the oxidative reaction is reduced by replacing the 4,4′-ester substituents within Bi(4-CO₂Etbipy)-HVI with strongly electron-donating 4,4′-dimethoxy moieties (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 the key intermediate 22_OTf. The presence of the electron-donating 4,4′-dimethoxy groups on the bipyridine ligand causes this key step to take place with an activation barrier of 25.1 kcal/mol, which is much more energy-demanding in comparison to the 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 (2.366 Å) than in the latter (2.426 Å) (see Figures 6 and 2a). Consequently, Bi(4-OMebipy)-HVI is less reactive than Bi(4-CO₂Etbipy)-HVI toward phenol oxidation likely because the more strongly coordinated 4,4′-methoxy bipyridine ligand retards the formation of the key intermediate 22_OTf.

Figure 6.

Calculated mechanism for the formation of the key intermediate 22_OTf from the reaction between 1_OMe and p-nitrophenol (ArOH). Free energies calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol.

Oxidation of p-Nitrophenol by Bi(4-NO₂bipy)-HVI.

We previously demonstrated experimentally that replacing Bi(4-CO₂Etbipy)-HVI with Bi(4-NO₂bipy)-HVI, which bears more strongly electron-withdrawing 4,4′-nitro substituents, leads to a reduced 63% yield.⁵ As discussed above, the main role of the bipyridine ligand is to trap two molecules of the in situ-generated triflic acid, thereby reducing the decomposition of the ortho-quinone product. Our calculations indicate that although 4,4′-dinitro-2,2′-bipyridine reacts with the first HOTf in an exergonic fashion, it is not firmly bound to the second one, corroborated by the endergonicity calculated for transformation 9_NO₂ + HOTf → 14_NO₂ (ΔG_rxn = +2.6 kcal/mol, Figure 7). It follows from these results that the reduced yield employing Bi(4-NO₂bipy)-HVI as the oxidant is probably due to the inefficient trapping of HOTf, which leads to the decomposition of the ortho-quinone product. Another reason for this lower reactivity can be ascribed to an issue of solubility of Bi(4-NO₂bipy)-HVI, as discussed by us in a previous study.⁵

Figure 7.

Calculated reaction free energy for the reaction between 4,4′-dinitro-2_,2′-bipyridine and two molecules of HOTf. Reaction free energies calculated by SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) in chloroform are given in kcal/mol.

■ CONCLUSIONS

In this study, DFT calculations were exploited to better understand the mechanistic nuances that underpin the oxidative dearomatization of electron-deficient phenols by hypervalent iodine(V) compounds to ortho-quinones. We found that the corresponding oxidation proceeds with a low activation barrier if the ligands bound to the iodine(V) center are weakly coordinating triflate anions. In this case, the reaction generates two equivalents of triflic acid as a side product. The acid-sensitive ortho-quinone product undergoes decomposition in the presence of triflic acid, thereby decreasing the yield of the reaction. To minimize this, the in situ-generated triflic acid needs to be trapped using a base. We found that the bipyridine ligands are the most efficient bases to this end. However, the electronic nature of the 4,4′-substituents on the bipyridine plays a crucial role in controlling the efficiency of the iodine(V) oxidant. A bipyridine with electron-donating substituents (4,4′-dimethoxy-2,2′-bipyridine) binds relatively strongly to the iodine(V) center, attenuating the oxidizing capacity of the oxidant. While a bipyridine with strongly electron-withdrawing substituents (4,4′-dinitro-2,2′-bipyridine) binds relatively weakly to the iodine(V) center, it is not sufficiently basic to completely trap all the in situ-generated triflic acid. In comparison, a bipyridine with less electron-withdrawing substituents (4,4′-diester-2,2′-bipyridine) features the necessary balance between the two crucial aforementioned roles, resulting in it being the most appropriate base for this purpose. In this way, our DFT study reveals how the key structural and electronic properties of Bi(4-CO₂ Etbipy)-HVI facilitate its enhanced oxidation capacity relative to other 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.

■ EXPERIMENTAL SECTION

Computational Methods.

Gaussian 16¹² was used to fully optimize all the structures reported in this study at the M06-2X level¹³ of DFT. For all the calculations, solvent effects were considered using the SMD solvation model for the 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) calculations¹⁸ 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 out single-point energy calculations using the M06-2X functional method¹⁹ for all the structures with a larger basis set (BS2). BS2 utilizes the def2-TZVP²⁰ basis set on all atoms. A strong convergence criterion was also employed to increase the accuracy of the single-point calculations. All thermodynamic data were calculated at the standard state (298.15 K and 1 atm).

In this work, the free energy for each species optimized by SMD/M06-2X/BS1 in solution was calculated using the formula: G = E(BS2) + G(BS1) − E(BS1) + ΔG^{1atm → 1M}, where ΔG^{1atm → 1M} = 1.89 kcal/mol is the free-energy change for compression of 1 mole of an ideal gas from 1 atm to the 1 M solution-phase standard state. NPA was carried out using the NBO6 software integrated into Gaussian 16.²¹

The free-energy barriers for ligand dissociation via TS_19–20,TS_34–35, TS_18–20, and TS_19–22_OMe were estimated according to the protocol presented by Hall and Hartwig.²² In this protocol, for example, the Gibbs free-energy barrier for a dissociation reaction such as A-B → A + B is estimated as ΔG^‡ ≈ ΔH = H_A + H_B − H_A−B.

To validate the accuracy of the SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d) calculations in determining the relative energies of species, we optimized key structures related to the PhI(O)(OAc)₂-mediated oxidation of p-nitrophenol using the triplezeta def2-TZVP Ahlrich’s basis set (BS2); this basis set was recently reported by Sun et al. as a suitable one for the optimization of species formed during oxidative reactions mediated by IBX.²³ These additional results demonstrate that the basis set dependence of the geometries is insignificant in affecting the final results. For example, using SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ(d),6-31G(d), the relative free energies of 21_OAc, TS_21–22_OAc, 22_OAc, TS_22–23_OAc, and 23_OAc are 0.8, 19.8, 16.1, 34.5, and −21.5, respectively. Using SMD/M06-2X/def2-TZVP, the relative free energies are 0.7, 19.9, 15.4, 34.1, and −20.5, respectively (for details, see Table S1). It should be noted that the latter method takes 5–10 times longer for the optimizations and restricts the ability to explore the potential energy surface or to consider larger systems. Given that there is very little change in the relative free energies, we generally use the single-point method with BS2 rather than complete optimization. It follows from these results that the methodology used for studying the title reaction is adequately reliable.