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Download Author Version (PDF) Organic & Biomolecular Chemistry Experimental evidence for the formation of cationic intermediates during iodine(III)-mediated oxidative dearomatization of phenols Journal: Organic & Biomolecular Chemistry Manuscript ID OB-COM-07-2018-001652.R3 Article Type: Communication Date Submitted by the Author: 30-Aug-2018 Complete List of Authors: Tang, Ting; Texas Tech University, Department of Chemistry & Biochemistry Harned, Andrew; Texas Tech University, Department of Chemistry & Biochemistry Page 1 of 4 OrganicPlease do not adjust margins & Biomolecular Chemistry Journal Name COMMUNICATION Experimental evidence for the formation of cationic intermediates during iodine(III)-mediated oxidative dearomatization of phenols Received 00th January 20xx, a a Accepted 00th January 20xx Ting Tang and Andrew M. Harned * DOI: 10.1039/x0xx00000x www.rsc.org/ 6,7,8 Iodine(III)-based oxidants are commonly used reagents for the catalysts. Trying to design a chiral environment around an oxidative dearomatization of phenols. Having a Better intermediate that reacts through a unimolecular pathway is a understanding of the mechanism through which these reactions very different challenge than one involving a bimolecular pathway. proceed is important for designing new iodine(III)-based reagents, Path A: bimolecular redox decomposition catalysts, and reactions. We have performed a Hammett analysis of the oxidative dearomatization of substituted 4-phenylphenols. OH (R2OH) O O 1 This study confirms that iodine(III)-mediated oxidative OAc R + Ph–I + Ph I Ph I dearomatizations likely proceed through cationic phenoxenium + AcOH OAc OAc + ions and not the direct addition of a nucleophile to an iodine- AcOH 1 2 R1 2 R OR bound phenol intermediate. 1 3 Phenyliodine(III) diacetate (PIDA) and its congeners are powerful organic oxidants that have been employed in a wide range of interesting transformations.1 One of the more 2 common applications of these reagents is in the oxidative O (R OH) O = irreversible step dearomatization of phenols to give cyclohexadienones (e.g., + Ph–I + H 1→3, Figure 1).2 Curiously, despite the wide use of this + AcO transformation, its mechanistic details are shrouded in 1 2 R1 R OR mystery. It is widely accepted that there is an initial ligand 4 3 exchange between phenol 1 and PIDA to generate an 3 Path B: unimolecular redox decomposition intermediate aryl-λ -iodane (2). What happens next is subject (predicted by DFT calculations) to some debate, and two mechanistic proposals are usually encountered in the literature.3 One involves a bimolecular 3.222 redox decomposition pathway (Path A, 2→3) in which a 3.172 2 nucleophile (in this case R OH) attacks the aromatic ring of the 3.239 4 3.242 “activated” phenol. This SN2´-like mechanism is proposed to 3.250 3.282 2.643 directly form dienone 3 through a single transition state. 2.650 3 9.27 Alternatively, aryl-λ -iodane 2 follows a unimolecular redox 10.02 3.375 2.829 3.367 2.646 14.10 decomposition pathway (Path B, 2→4→3). This SN1-like 13.87 5 TS1 mechanism involves forms phenoxenium ion 4, which is then 2.502 2.477 rapidly trapped by the nucleophile to give dienone 3. TS2 Although pathways A and B both result in the same Figure 1. Mechanistic picture for iodine(III)-mediated oxidative product, having a better understanding of how these reactions dearomatizations. proceed is important for the development of new reactions. Answering this mechanistic question is also of critical Recently, we reported a series of DFT calculations, using importance for developing next generation chiral aryl iodide water as a nucleophile, aimed at probing the likelihood of pathways A and B.9 Briefly, we were able to locate transition states (TS1 and TS2, Figure 1) corresponding to the unimolecular redox decomposition of iodane 2. Transition state TS2, in which the acetate group of iodane 2 is protonated, represents an attempt account for potential hydrogen bonding effects10 during the decomposition of the This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 1 Please do not adjust margins OrganicPlease do not adjust & Biomolecular marginsChemistry Page 2 of 4 COMMUNICATION Journal Name ‡ ‡ iodane and is lower in energy (ΔG TS1 ~29 kcal/mol; ΔG TS2 ~10 be detrimental to a reaction mechanism that involves direct kcal/mol). In contrast, we were unable to locate a transition addition of a nucleophile to iodane 2. state representing the direct addition of a nucleophile (H2O) to Comparing our results to literature reports of relevant the phenolic ring of iodane 2. The reason for this failure was reactions was quite instructive. Hammett plots for the attributed to the overall negative charge of the phenolic ionization of phenols (ρ = +1.819–3.197) and anilinium ions (ρ portion of iodane 2 and the ability of this partial negative = +2.767–3.558)18 have positive ρ values. This indicates that charge to repel an incoming nucleophile. These results strongly our results are not a direct measure of the suggested that path B was not only the favored pathway for stabilization/destabilization of the partial negative charge in the decomposition of iodane 2, but was likely the only iodane 2. We are aware of only one other Hammett study productive pathway available.11 Although these results put a involving an iodine(III)-mediated oxidation. This report used crack in the mechanistic black box, we recognized that a more substituted phenyliodine(III) diacetates [RC6H4I(OAc)2] for the substantial experimental result was needed in order to give oxidative cleavage of vicinal diols.19 The resulting Hammett weight to this prediction. Herein, we report such a result. plot had a positive slope (ρ = +1.475 vs σ). This result is Based on the computational prediction that these consistent with a reaction in which the iodine center is reactions proceed through a phenoxenium ion, we reasoned reduced (iodine become less positive). A ρ value of opposite 12 that a Hammett study of the oxidative dearomatization of sign should be expected when monitoring the oxidation of a 13 substituted 4-phenylphenols (5→6) would be an ideal substrate. solution (Figure 2A). However, the rapid reaction rates (A) OH OH O PhI(OAc)2 typically seen during iodine(III)-mediated oxidative (0.1 mmol) + dearomatization reactions preclude the measurement of naphthalene individual rate constants by traditional means. Instead, we (int. std.) 14 H X MeOH Ar OMe turned to the "one-pot" method reported by Harper, in 25±0.5 ºC 5a 5b-g 6a-g which the necessary relative rates (kX/kH) are obtained using a X = OMe, CH , F, Br, CO Et, CF competition experiment15 and are related, by equation 1, to 3 2 3 (0.2 mmol) (0.2 mmol) the amount of each compound present at the beginning of the (B) experiment and at the time of the analysis. Compared to 0.500 traditional methods of obtaining rate data, this model has 0.400 many practical benefits,14 not least of which is that accurate 0.300 OMe measurements of substrate or product concentrations is not 0.200 0.100 ) necessary. Only the ratio at the beginning and end of the H CH3 k / 0.000 sigma-p◆ σ X p reaction is needed. k -0.100 sigma++ y = -0.5965x - 0.083 F ■ σ ! log ( – ! -0.200 R² = 0.96348 sigma-̖ !"( ) CO Et σ !! !!,!!! Br 2 -0.300 y = -0.7261x + 0.0223 = !! (1) !! !"( ) R² = 0.88358 !!,!!! -0.400 y = -0.9224x + 0.0209 CF3 16 -0.500 R² = 0.95289 In our study, naphthalene was used as an internal -0.600 standard to measure the ratio (by HPLC) of phenols 5a and 5b- -1.00 -0.80 -0.60 -0.40 -0.20 0.00 0.20 0.40 0.60 0.80 g at the beginning and end of the reaction. Each reaction was sigma run to partial conversion, by using a limiting amount of PIDA, (C) in order to ensure some of each starting material remained. 0.400 + – 0.300 OMe The resulting Hammett plots, with respect to σp, σ , and σ 17 0.200 y = -0.5106x + 0.0576 values, are shown in Figure 2B. As can be seen, plotting R² = 0.14932 against + gave the best linear fit. The plots using and – 0.100 σ σp σ CH3 ) 0.000 H both displayed significant curvature. Importantly, the linear fit k / X -0.100 for all three of the plots returned negative ρ values, which is k F -0.200 consistent with the development of positive charge in the log ( Br phenolic ring of iodane 2 during the rate determining step. -0.300 y = -0.7693x - 0.2272 R² = 0.54784 CO2Et In order to gauge whether resonance or inductive effects -0.400 sigmaR◆ σR -0.500 sigmaI■ σI are more important, we plotted the relative rate data against CF3 17 σR and σI values (Figure 2C). Neither gave a very good -0.600 2 -0.80 -0.60 -0.40 -0.20 0.00 0.20 0.40 0.60 correlation (R value), but visual inspection of the plot sigma σI reveals it is very scattered, compared to the corresponding σR Figure 2. (A) Competition experiment used to measure relative rate plot. Resonance effects are expected to be more important for data. (B) Hammett plots of relative rate data. (C) Evaluation of stabilizing/destabilizing a developing charge, but will not be as resonance and inductive effects on relative rates. important for nucleophilic attack on a "neutral" molecule. Our We also performed a series of DFT calculations in order to results also show that the methoxy substituent, a resonance 16 donating group, facilitates the reaction. It is difficult to imagine further corroborate our experimental results.
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