Rate Accelerations of Bromination Reactions with NaBr and H2O2 via

Sep 30, 2014 - Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, United States...
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Rate Accelerations of Bromination Reactions with NaBr and H2O2 via the Addition of Catalytic Quantities of Diaryl Ditellurides Eduardo E. Alberto, Lisa M. Muller, and Michael R. Detty* Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, United States S Supporting Information *

ABSTRACT: Diaryl ditellurides were oxidized in situ to give aryltellurinic acids, which catalyzed the oxidation of NaBr with H2O2 in buffered aqueous solutions. The aryltellurinic acids were slowly oxidized under the reaction conditions to the corresponding telluronic acids, which did not catalyze oxidation of NaBr with H2O2. Both 4-(methoxyphenyl)tellurinic acid and 4(methoxyphenyl)telluronic acid were characterized in solution by 125Te NMR and for their effectiveness as catalysts in kinetics studies. The effectiveness of the tellurinic acids as catalysts was very sensitive to electron demand in the intermediates present during the course of the reaction. Electron-withdrawing substituents favor the deprotonated tellurinic acid (tellurinate) in solution, while electron-donating substituents favor the protonated tellurinic acid. Of the nine ditellurides screened for their ability to accelerate the oxidation of NaBr with H2O2, diphenyl ditelluride emerged as the most active. The addition of only 0.20 mol % of this ditelluride (relative to substrate) promoted a 240-fold increase in the rate of oxidation of NaBr with H2O2, as measured by the bromination of 4-pentenoic acid. The “Br+” species prepared in situ were trapped by a series of alkenoic acids and activated aryl compounds.

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and tellurinic anhydride derivatives.9 The tellurinic anhydrides have been prepared from diaryl ditellurides and typically are used in stoichiometric quantities. In these studies,8,9 the tellurinic acid has not been identified as the functional catalyst. Herein, we describe the acceleration of bromination reactions with NaBr and H2O2 via the addition of catalytic quantities of diaryl ditellurides 1 (Chart 1). The ditellurides are oxidized to the corresponding tellurinic acid, which is the active catalyst in the bromination reactions.

INTRODUCTION Hydrogen peroxide is thermodynamically powerful as an oxidant yet can be kinetically quite slow. The oxidation of bromide to HOBr or Br2 with H2O2 is one such reaction,1 which limits the utility of bromide/H2O2-based brominations. Bromination reactions with elemental bromine have associated environmental hazards with respect to transport, handling, and storage of bromine. The pursuit of alternatives to the use of bromine is a subject of current research.2 Suitable catalysts for promoting bromide/H2O2-based brominations have been identified in recent years and are an encouraging strategy toward this goal.3 Diorganotellurides have served as catalysts for the activation of H2O2, for the oxidation of halogen salts to positive halogen species,4 and for the oxidation of thiols to disulfides.5 These reactions typically proceed through the Te atom via the telluroxide or the dihydroxytellurane as the oxidized intermediate in the catalytic cycle. While reductive elimination from the telluroxide or the dihydroxytellurane occurs on a kinetically useful time scale, similar reactions from the selenoxide or the dihydroxyselenane are much slower. Consequently, diorganoselenides are oxidized to the selenoxide, which is the actual catalytic species, and the addition of H2O2 to the selenoxide gives the hydroxy(perhydroxy)selenane as the functional oxidant.6 Diaryl diselenides have been examined as additives for the activation of H2O2 in numerous studies,7 and the arylseleninic acid formed by H2O2 oxidation of the diselenide is the actual catalytic species. Surprisingly, similar reactions with diaryl ditellurides have been relatively unexplored. The oxidations of alkenes to epoxides and of thiols to disulfides have been reported with H2O2 and diorganoditellurides8 or with H2O2 © XXXX American Chemical Society

Chart 1. Diaryl Ditellurides Examined as Catalysts for the Activation of Hydrogen Peroxide

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RESULTS AND DISCUSSION Ditelluride Acceleration of Bromination Reactions with NaBr and H2O2. The bromination of 4-pentenoic acid (2) with NaBr and H2O2 in the presence of various catalysts has been a useful model system to compare catalytic activity among various catalysts.4b,c,6,7h Bromination of 2 produces a Received: August 28, 2014

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Active Oxidant in the Catalytic Cycle. The loss of the typical red color of the ditelluride upon addition of H2O2 to a solution of 1a suggested that 1a was not the active catalyst in this reaction. Through analogy to the reactions of diaryl diselenides with H2O27 and the reported reactions of diaryl ditellurides with H2O2,8,9 tellurinic acid 5a,11 tellurinic anhydride 6a,9a,11 and telluronic acid 7a (Figure 2) are likely candidates to be either the active catalyst in this reaction or the functional oxidant. The reaction of 1a with varying amounts of H2O2 was examined using 125Te NMR spectroscopy to identify oxidized intermediates produced by 1a and H2O2. The 125Te NMR spectrum of ditelluride 1a gave a single peak at δ 450 ppm in THF (Figure 2a). An authentic sample of tellurinic acid 5a was prepared in situ by the hydrolysis of polymeric tellurinic anhydride 6a9a,11 with NaOH.11 The 125Te NMR signal of tellurinic acid 5a was observed at δ 1634 ppm (Figure 2b), which is quite similar to the value of δ 1637 previously reported.11 The addition of 1.0 equiv of H2O2 to a solution of 1a in THF produced a heterogeneous mixture of an aqueous phase and an organic phase. The 125Te NMR spectrum of the aqueous phase displayed one peak observed at δ 1632 ppm (Figure 2c), which was essentially superimposable on the 125Te NMR spectrum of tellurinic acid 5a (Figure 2b). The 125Te NMR spectrum of the organic phase gave only one signal observed at δ 452 ppm (Figure 2d), which is essentially superimposable on the 125Te NMR spectrum of the parent ditelluride 1a (Figure 2a). Tellurenic acid (ArTeOH) was not detected in the reaction of 1a with 1 equiv of H2O2. However, one cannot exclude the initial formation of this product, which might then disproportionate to tellurinic acid 5a and ditelluride 1a. When excess H2O2 (3.0, 5.0, or 10.0 equiv) was added to solutions of 1a in THF, the chemical shift of the 125Te NMR signal was shifted upfield to δ ∼800 ppm (Figure 2e−g, respectively). The product of the addition of 10 equiv of H2O2 to a THF solution of 1a was eventually isolated and characterized as telluronic acid 7a. Telluronic acid 7a was isolated as a high-melting (mp >260 °C), off-white solid in 63% yield. Its high-resolution mass spectrum (ESI, negative mode) gave m/z 284.9407 (calculated for C7H7O4130Te [M − H]− 284.9412). The 1H NMR spectrum of 7a displayed two broadened two-proton singlets at δ 8.13 and δ 7.24, corresponding to the four aromatic protons of 7a, and two broadened singlets at δ 4.06 and δ 4.07, integrating to a total of three protons and corresponding to the methyl singlet of 7a. In solution, two 125Te NMR signals were observed at δ 801 and δ 797 ppm for 7a. A similar result was obtained from the addition of 10 equiv of H2O2 to an aqueous solution of tellurinic acid 5a to give a broadened 125Te NMR signal at δ 801 ppm (Figure 2h). Hydrated telluronic acids are very close in energy to the telluronic acid, which might lead to two signals in the 125Te NMR spectra.12 Both tellurinic and telluronic acids have a propensity to form polymeric chains, which might also lead to averaged signals or multiple signals in the 125Te NMR spectra.13 The 125Te NMR signals for both tellurinic and telluronic acids were only detected in the presence of NaOH, which hydrolyzes the polymeric compounds into smaller oligomers, dimers, and/ or monomers that are soluble in aqueous solutions.11 The abilities of 5a−7a to catalyze the conversion of 4pentenoic acid 2 to brominated products 3 and 4 with NaBr and H2O2 were examined next (Table 1). Tellurinic acid 5a (0.40 mol % relative to 2) was prepared in situ by basic

mixture of products consisting of predominantly bromolactone 3 and smaller amounts of 4,5-dibromopentanoic acid (4), which is converted to bromolactone 3 under the reaction conditions (Figure 1).7h The loss of 2 (and conversion to 3 and 4) is easily followed by 1H NMR spectroscopy, allowing the rate of oxidation of NaBr to be determined indirectly.

Figure 1. Bromination of 0.095 M 4-pentenoic acid (2) with 1.43 M NaBr and 0.14 M H2O2 without and with ditelluride 1a (1.9 × 10−4 M, 0.20 mol % relative to 2) at 298 ± 1 K. Propionic acid (9.5 mM) was used as an internal standard. The starting concentration of 2 ([A]) was set as 3.0 corresponding to an integral of three olefinic protons. All other concentrations are relative to this initial value. Open circles represent the uncatalyzed reaction. Filled circles represent the 1aaccelerated process. The inset shows the 1a-accelerated process with an expanded time scale. Reaction rates are reported as the mean of duplicate runs agreeing within 5%.

The bromination of 0.095 M 2 in pH 6.2 phosphate buffer at 298 ± 1 K with 1.43 M NaBr and 0.14 M H2O2 was quite slow in the absence of catalyst, as shown in Figure 1. The pseudofirst-order loss of 2 gave a kobs value of (5.04 ± 0.06) × 10−7 s−1, as followed by 1H NMR spectroscopy. Bis(4-methoxyphenyl) ditelluride (1a) was our initial ditelluride for study due to its acceptable solubility and to the “handle” that the 4-methoxy substituent gives in 1H NMR studies. The addition of 1a (1.9 × 10−4 M, 0.20 mol % relative to 2) to the reaction mixture described above gave immediate loss of the ditelluride color and formation of a homogeneous solution. In the catalyzed reaction, pseudo-first-order loss of 2 as followed by 1H NMR spectroscopy gave a kobs value of (7.74 ± 0.13) × 10−5 s−1 (Figure 1), which represents a >150-fold enhancement of the reaction rate in comparison to the ditelluride-free experiment.10 These results clearly indicate that the addition of ditelluride 1a accelerates the oxidation of bromide with H2O2 in aqueous solutions at a near-neutral pH of 6.2. After the 1a-accelerated reaction was complete, recharging the reaction with additional 4-pentenoic acid and H2O2 did not give further product formation at the accelerated rate. Additional 3 was produced slowly at the uncatalyzed rate, indicating that the ditelluride or species produced from it were no longer functional as catalysts. B

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Figure 2. 125Te NMR spectra comparing ditelluride 1a, tellurinic acid 5a, tellurinic anhydride 6a, and telluronic acid 7a and varying amounts of H2O2: (a) 1a in 1.0 mL of THF; (b) 6a (25.9 mg, 0.05 mmol) in 2.5 M NaOH in D2O (0.1 mL, 0.25 mmol)/D2O (0.5 mL)/THF (0.3 mL); (c) 1a + H2O2 (83 mM in D2O, 0.6 mL, 0.05 mmol), aqueous phase; (d) 1a + H2O2 (83 mM in D2O, 0.6 mL, 0.05 mmol), organic phase; (e) 1a + H2O2 (0.25 M in D2O, 0.6 mL, 0.15 mmol); (f) 1a + H2O2 (0.42 M in D2O, 0.6 mL, 0.25 mmol); (g) 1a + H2O2 (0.83 M in D2O, 0.6 mL, 0.5 mmol); (h) 6a (25.9 mg, 0.05 mmol) in 2.5 M NaOH in D2O (0.1 mL, 0.25 mmol) + H2O2 (0.83 M in D2O, 0.6 mL, 0.5 mmol). For all experiments carried out with 1a, 23.5 mg of 1a (0.050 mmol) was dissolved in 0.30 mL of THF.

to its poor solubility, tellurinic anhydride 6a was added directly to the reaction mixture and the rate of bromination of 2 in the presence of 6a was slower than reactions with added 1a or with 5a as catalyst (Table 1, entry 4). Telluronic acid 7a was prepared by dissolving anhydride 6a in a NaOH solution (to generate tellurinic acid 5a) followed by the addition of 10 equiv of H2O2 to produce 7a. After this reaction mixture was stirred for 3 h at room temperature, 0.40 mol % of 7a (relative to 2) was added dropwise. Telluronic acid 7a was soluble in the reaction mixture but showed little if any catalytic activity toward the oxidation of bromide. The value of kobs using 7a as catalyst was (4.96 ± 0.08) × 10−7 s−1, essentially identical with the rate of the uncatalyzed reaction ((5.04 ± 0.06) × 10−7 s−1; Table 1, entries 1 and 5). The lack of solubility of tellurinic anhydride 6a made direct comparisons of the different organotellurium species difficult. To prevent the formation of the anhydride, which precipitates from solution at pH 6.2, ditelluride 1a and the tellurinic acid 5a were evaluated in the bromination reactions at pH 7.2. At pH 7.2, the uncatalyzed bromination gave a kobs value of (6.0 ± 0.5) × 10−7 s−1, which is ∼20% faster than the kobs value at pH 6.2 (Table 1, compare entries 1 and 6). At pH 7.2, the catalyst loading was reduced to 0.10 mol % for 1a and 0.20 mol % for 5a to minimize the decomposition of H2O2 to presumably oxygen and water.10 Under these conditions, the addition of 0.10 mol % of 1a and 0.20 mol % of 5a gave comparable rates of bromination of 2 (kobs values of (4.19 ± 0.02) × 10−5 s−1 for 1a and (4.64 ± 0.11) × 10−5 s−1 for 5a (Table 1, entries 7 and 8)), suggesting that 1a is oxidized by H2O2 to give 2 equiv of 5a, which is the actual catalytic species in the reaction or is the

Table 1. Rates of Bromination of 4-Pentenoic Acid (2) with NaBr and H2O2 in the Presence of Catalytic Quantities of Organotellurium Species 1a and 5a−7aa,b

entry

catalyst

pH

1 2 3 4 5 6 7c 8c

none 1a 5a 6a 7a none 1a 5a

6.2 6.2 6.2 6.2 6.2 7.2 7.2 7.2

kobs, s−1 (5.04 (7.74 (4.43 (3.55 (4.96 (6.04 (4.19 (4.64

± ± ± ± ± ± ± ±

0.06) 0.13) 0.10) 0.03) 0.08) 0.46) 0.02) 0.11)

× × × × × × × ×

10−7 10−5 10−5 10−5 10−7 10−7 10−5 10−5

a Reaction conditions (unless specified otherwise): NaBr (1.43 M), 4pentenoic acid (0.095 M in pH 6.2 phosphate buffer), H2O2 (0.14 M), 1a or 6a (0.20 mol % relative to 2, 1.9 × 10−4 M), 5a or 7a (0.40 mol % relative to 2, 3.8 × 10−4 M), and propionic acid (internal standard, 9.5 mM) at 298 ± 1 K. bReaction rates reported as the average of duplicate runs, which agreed within 5%. cDitelluride 1a (0.10 mol % relative to 2, 9.6 × 10−5 M), catalyst 5a (0.20 mol % relative to 2, 1.9 × 10−4 M).

hydrolysis of the anhydride 6a and was then added dropwise to the reaction mixture in pH 6.2 buffer. Even though tellurinic acid 5a precipitated from solution, 5a did catalyze bromination of 2, but the rate of loss of 2 was slower than the rate of reaction from the addition of 1a (Table 1, entries 2 and 3). Due C

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the irreversible reaction of 5a with H2O2 to produce telluronic acid 7a,12 which is inactive toward the oxidation of bromide. The oxidation of 5a to 7a is likely the terminating step in the catalytic process. Stereoelectronic Effects in Diaryl Ditelluride/Aryltellurinic Acid Catalytic Systems. The addition of diaryl ditellurides to solutions of 4-pentenoic acid (2), NaBr, and H2O2 accelerates the bromination of 2. Stereoelectronic effects can affect the rate of bromination by (1) influencing the rate of oxidation of ditelluride to tellurinic acid, (2) influencing the rate of reaction of H2O2 and NaBr with the tellurinic acid, and (3) influencing the rate of oxidation of the tellurinic acid to the telluronic acid. As shown in Scheme 3, the balancing act also includes relative rates for conversion of the pertellurinic acid 11 to the telluronic acid 7 or reaction of the pertellurinic acid 11 with bromide. The diaryl ditellurides 1 (Chart 1), which were prepared by literature procedures,14 were compared for their ability to accelerate the bromination of 4-pentenoic acid (2) with NaBr and H2O2 in pH 6.2 phosphate buffer (Table 2). For 1a−g, values of the Hammett electronic substituent constant, σ,15 for the aromatic substituents are also included in Table 2. In a typical experiment, the reaction rate at 298 ± 1 K was monitored after the addition of 0.20 mol % of ditelluride to an aqueous solution of 0.095 M 2, 0.14 M H2O2, and 1.43 M NaBr. Reaction rates were monitored by 1H NMR spectroscopy and were compared to the rate of the uncatalyzed reaction at 298 ± 1 K. The uncatalyzed bromination of 4-pentenoic acid (2) with H2O2 and NaBr proceeds with kobs of (5.04 ± 0.06) × 10−7 s−1 (Table 2, entry 1). Diphenyl ditelluride 1e, the simplest of the diaryl ditellurides, gave the greatest acceleration among the ditellurides of Chart 1. For 1e, kobs was (1.22 ± 0.01) × 10−4 s−1, which represents a >240-fold rate enhancement relative to the uncatalyzed reaction (Table 2, entry 6). Relative to the phenyl group (with an H atom in both the para and meta positions, σ = 0.0),15 both electron-donating (found in 1a,b,d,f) and electron-withdrawing substituents (found in 1c,g) led to slower rates of bromination. Graphically, this is shown in Figure 3 for a Hammett plot of the catalyzed rate (kcat = kobs(cat) − kobs(uncat)) as a function of σ. As shown in Figure 3, there is a clear change in electron demand for the rate-determining step in the bromination of 2 with NaBr and H2O2 in the presence of 1a−g. As the electrondonating ability of the substituent decreases from p-NMe2 to H, the rate of the reaction increases and the slope of log kcat vs σ is +0.83. As the substituents are changed from being electron donating to electron withdrawing with positive values of σ, there is a dramatic decrease in rate, with the slope of log kcat vs σ being −5.6. The absolute magnitude of the slope with electron-withdrawing substituents is 6−7-fold greater than the slope with electron-donating substituents.

active oxidant. If tellurinic acid 5a were the active oxidant, then tellurenic acid 8a would be the actual catalyst, as shown in Scheme 1. Scheme 1. Possible Catalytic Cycle with Tellurinic Acid 5a as Active Oxidant and Tellurenic Acid 8a as Catalyst

In order to address this query, tellurinic acid 5a was examined as an oxidant for the bromination of 1,3,5trimethoxybenzene (9) with NaBr. One equivalent of tellurinic acid 5a (0.25 mmol), prepared as described above, was added dropwise to a solution of 9 (0.25 mmol) dissolved in a mixture of 1,4-dioxane and pH 6.2 phosphate buffer containing NaBr (3.75 mmol, Scheme 2). After 4 h, the products were examined Scheme 2. Bromination of 9 using a Stoichiometric Quantity of 5a and NaBr (15 equiv) in pH 6.2 Phosphate Buffer and 1,4-Dioxane without and with H2O2 (5 equiv)

by 1H NMR spectroscopy. No brominated products were observed and the starting 1,3,5-trimethoxybenzene (9) was recovered in 89% yield. Conversely, when 1 equiv of 5a was added dropwise to a solution of 9 in 1,4-dioxane/buffer containing 5.0 equiv of H2O2, 2-bromo-1,3,5-trimethoxybenzene (10) was isolated in 64% yield after 4 h, as well as 23% of unreacted 9. These results suggest that tellurinic acid 5a (1) is not the active oxidant in the reaction and (2) is actually the catalyst for the bromination reactions with H2O2 and NaBr. The catalytic cycle shown in Scheme 3 is consistent with the experimental observations for oxidation of ditelluride 1a with H2O2 and with bromination of 2 with H2O2 and NaBr. Initially, ditelluride 1a reacts with excess H2O2 to produce tellurinic acid 5athe true catalyst in this process. Tellurinic acid 5a reacts with H2O2 to produce pertellurinic acid 11a as the intermediate oxidant, which in turn reacts with bromide in the buffered system to give hypobromous acid and tellurinic acid 5a. Reaction of 5a with additional H2O2 continues the catalytic cycle, while HOBr brominates 4-pentenoic acid (2). In competition with the formation of pertellurinic acid 11a is

Scheme 3. Proposed Reaction Mechanism for the Oxidation of Bromide with H2O2 Activated by Ditelluride 1a

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Table 2. Bromination of 2 with NaBr and H2O2 Catalyzed by Ditellurides 1a−ia

entry 1 2 3 4 5 6 7 8 9 10

catalyst none 1a 1b 1c 1d 1e 1f 1g 1h 1i

kobs, s−1c

σb −0.27 −0.83 0.23 −0.17 0.0 −0.21 0.43

(5.04 (7.74 (2.29 (2.43 (8.59 (1.22 (4.16 (5.26 (3.09 (3.99

± ± ± ± ± ± ± ± ± ±

0.06) 0.13) 0.02) 0.03) 0.20) 0.01) 0.08) 0.12) 0.04) 0.09)

× × × × × × × × × ×

kcat, s−1d −7

10 10−5 10−5 10−6 10−5 10−4 10−5 10−7 10−6 10−6

(7.69 ± 0.13) (2.24 ± 0.02) (1.83 ± 0.03) (8.54 ± 0.20) (1.22 ± 0.01) (4.11 ± 0.08) (2.2 ± 1.8) × (2.59 ± 0.04) (3.49 ± 0.09)

× 10−5 × 10−5 × 10−6 × 10−5 × 10−4 × 10−5 10−8 × 10−6 × 10−6

krele 1 153 45 5 170 242 83 1 6 8

a

Conditions: 4-pentenoic acid (2; 0.095 M in pH 6.2 phosphate buffer), catalyst (0.20 mol % relative to 2), H2O2 (0.14 M), NaBr (1.43 M), and propionic acid (9.5 mM, internal standard) at 298 ± 1 K. bValues of σp and σm from ref 15. cAverage of duplicate runs, which agreed within 5%. dkcat = kobs(cat.) − kobs(uncat.). ekrel = kobs(cat.)/kobs(uncat.).

increase the pKa values of the tellurinic acids relative to phenyltellurinic acid (5e) and minimize the equilibrium concentration of A in the reaction, while electron-withdrawing substituents would decrease the pKa values of the tellurinic acids and increase the equilibrium concentration of A. Electrondonating substituents increase the pKb values of the tellurinic acids and increase the equilibrium concentration of intermediate B in the reaction. The nucleophilic addition of H2O2 to the Te atom of A will be less favored than the nucleophilic addition of H2O2 to protonated intermediate B. Protonated B is an electrophile, and H2O2 addition would lead to intermediate C and then to pertellurinic acids 11a−g as the actual oxidant in the bromination reactions. The nucleophilic addition of H2O2 to the Te atom of intermediate A will be less favored due to the net negative charge on the tellurinate moiety. The intermediate B must solve a different conundrum to give the pertellurinic acids 11a−g. More strongly electron donating groups stabilize the intermediate B and raise the pKb value of the tellurinic acid more than more weakly electron donating groups. However, the rate of addition of H2O2 to intermediate B is inversely correlated with its stability! Thus, the simplest tellurinic acidphenyltellurinic acid (5e)is the best catalyst among those studied herein. The intermediate B can be explored via tellurinic acids 5h,i, which are formed from diaryl ditellurides 1h,i, respectively, upon treatment with H2O2. 5h,i should both be quite similar electronically to the p-tolyl tellurinic acid 5di.e., have weakly electron-donating substituentsbut can affect intermediate B

Figure 3. Hammett plot of kcat for ditellurides 1a−g as a function of the Hammett electronic substituent constant, σ. Values of kcat are calculated via kcat = kobs(cat.) − kobs(uncat.).

The substituent dependence on the rate-determining step can be rationalized as shown in Scheme 4. The addition of all the ditellurides 1a−g gave an immediate loss of the red ditelluride color in solution. Furthermore, no induction period was noticed in the kinetic plots of reaction. These results suggest that the oxidation of the ditelluride is not the ratedetermining step of the reaction and that the substituent effects exert their influence in the tellurinic acids 5a−g. The tellurinic acids at pH 6.2 can exist as the neutral tellurinic acid form 5a−g, as the deprotonated, anionic form shown as A in Scheme 4, or as the protonated, cationic form shown as B in Scheme 4. Electron-donating substituents would

Scheme 4. Intermediates Favored by Electron-Withdrawing Substituents (A) and Electron-Donating Substituents (B) in the Conversion of Tellurinic Acids to Pertellurinic Acids

E

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Scheme 5. Chelating (Intermediate Bh) and Steric Interactions (Intermediate Bi) Hindering Conversion of Tellurinic Acids to Pertellurinic Acids

withdrawing substituents on the catalyst slow the rate of reaction (Figure 3). What is unknown, at this time, is the difference in pKa values between seleninic and tellurinic acids and the differences in magnitude of substituent effects (the “ρ” value)15 for the seleninic and tellurinic acids. General Scope of Brominations of Alkenoic Acids and Activated Aromatic Substrates with NaBr and H2O2 and Catalytic Quantities of Diphenyl Ditelluride (1a). Diphenyl ditelluride (1e) is oxidized to phenyltellurinic acid (5e), which is the best tellurinic acid catalyst for the activation of H2O2 among the ditellurides 1 of Chart 1. We examined bromination reactions of the substrates shown in Table 3 to explore the scope and tolerances of these reaction conditions. For the pentenoic acid substrates of Table 3, bromolactonizations were conducted in a 1/1 mixture of pH 6.2 phosphate buffer and 1,4-dioxane for solubility (0.05 M overall in substrate), 0.25 mol % of 1e (producing 0.50 mol % of 5e), 1.5 equiv of H2O2, and 15 equiv of NaBr. After 16 h at room temperature, bromolactone products were isolated in 78−88% yield (Table 3, entries 1−4). In the absence of 1e, ≤4% brominated products were observed. For alkenoic acids 2, 12, 14, and 16, only the five-membered-ring-containing bromolactone regioisomer was formed, as evidenced by 1H and 13C NMR analysis of the product mixture. In the reaction of racemic 2-methyl-4-pentenoic acid 14, a 1.7/1.0 mixture of diastereoisomeric bromolactones 15 (by 1H NMR) was obtained. Bromination of alkenoic acid 16 gave a 7.3:1 mixture of bromolactone 17 and 4,5-dibromo-4-methylpentanoic acid 17′ (Table 3, entry 4). For 5-hexenoic acid (18), the highest bromination yields were obtained using pH 4.2 buffer solution and 24 h of reaction. The six-membered bromolactone 19 and 5,6dibromohexanoic acid (19′) were produced in a 1.0:3.4 ratio in a combined 78% yield (Table 3, entry 5). The ratio of these products did not change upon standing under the conditions of the reactioni.e., 17′ did not cyclize to give lactone 17. Activated aromatic compounds were also brominated under similar conditions. Using 1.1 equiv of H2O2 for the bromination of 9 limited the formation of 2,4-dibromo-1,3,5-trimethoxybenzene and gave monobrominated 10 in 93% yield (entry 6). Bromination of N-phenylmorpholine gave N-(4-bromophenyl)morpholine (21) in 93% yield (Table 3, entry 7). In the absence of catalyst, 10 and 21 were produced in 5 and 1% yields, respectively.

in two different ways. Tellurinic acid 5h can stabilize intermediate B via chelation, as shown in Scheme 5 (intermediate Bh), while the mesityl tellurinic acid 5i can hinder approach to the Te atom of intermediate B via steric interactions from the two o-methyl substituents (intermediate Bi). Chelation in Bh slows the addition of H2O2, and the kobs value for bromination of 2 via the addition of ditelluride 1h is only 6-fold greater than that for the uncatalyzed reaction (Table 2, entry 9, kcat = (2.59 ± 0.04) × 10−6 s−1). Similarly, the addition of H2O2 to intermediate Bi is slowed through the steric interactions of the two o-methyl substituents, and kobs for bromination of 2 via the addition of ditelluride 1i is only 8-fold faster than the uncatalyzed reaction (Table 2, entry 10, kcat = (3.49 ± 0.09) × 10−6 s−1). Intermediates related to A and B have been postulated for oxidations of sulfides with H2O2 catalyzed by cyclic seleninate esters, as shown in Scheme 6.16 In this study, both an electronScheme 6. Proposed Intermediates from Ref 16 Formed in Oxidations with H2O2 Catalyzed by Seleninate Esters

donating methoxy substituent and an electron-withdrawing fluoro substituent in the seleninate ester accelerated the reaction relative to the unsubstituted seleninate catalyst. The unsubstituted seleninate ester was the poorest catalyst of those examined. The catalytic oxidations were accelerated by the addition of trifluoroacetic acid and slowed in the presence of hydroxide. The authors proposed intermediates A and B in Scheme 6 to account for this behavior, with the electrophilic character of B determining the rate of the catalyzed reaction. In the current study, the unsubstituted phenyltellurinic acid 5a is the best catalyst and both electron-donating and electronF

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Table 3. Bromination with NaBr and H2O2 Catalyzed by Diphenyl Ditelluride (1e)a

a Reaction conditions (unless specified otherwise): substrate (1.00 mmol), H2O2, NaBr (15 mmol) in pH 6.2 phosphate buffer/1,4-dioxane mixture (1/1 v/v, 20 mL total), and 0.25 mol % of PhTeTePh (1e), 16 h at room temperature. bIsolated yield reported as the average of duplicate runs, yields in parentheses are for the catalyst-free experiments. c1.7/1.0 mixture of 15 diastereoisomers. dpH 4.2 phosphate buffer/1,4-dioxane mixture (1/1 v/v, 20 mL total), 24 h at room temperature.

The tert-butyldimethylsilyl protecting group of N,N-dimethylaminoaniline 22 was stable to the conditions of the reaction, and brominated 23 was isolated in 92% yield (Table 3, entry 8) using 2.0 equiv of H2O2, pH 4.2 phosphate buffer, and a 24 h reaction time. Esters also survived the reaction conditions, as 24 and 26 gave brominated esters 25 and 27, respectively, each in 95% isolated yield (Table 3, entries 9 and 10) using conditions identical with those for the bromination of 22. The lower pH favors the formation of Br2 from NaBr with H2O2.17 In the absence of catalyst, the bromination products 23, 25, and 27 were produced in ≤6% yields after 24 h of reaction. In comparison to the other substrates of Table 3, the bromination of anisole (28) with NaBr and H2O2 was quite slow in the presence of 1e. With less activated aryl substrates such as 28, a classic conundrum with respect to H2O2 oxidations of bromide emerges. If concentrations of Br2 and/ or HOBr build up in solution, then either of these species can react with H2O2 to give bromide, O2, and 1 equiv of protons.17,18 Bromination of anisole (28) proceeded at a slower rate in comparison to those for the other substrates of Table 3, giving rise to the undesired disproportionation of H2O2 assisted by HOBr and/or Br2 (evidenced by evolution of

bubbles of presumably oxygen). Consequently, 4-bromoanisole (29) was isolated in only 23% yield after 24 h of reaction (Table 3, entry 11). Attempted Chlorination of 1,3,5-Trimethoxybenzene (9). We also examined the chlorination of 1,3,5-trimethoxybenzene (9) using 1e as a catalyst with NaCl and H2O2. Less than 1% chlorination of trimethoxybenzene was observed after 24 h of reaction using NaCl (15 equiv), 0.25 mol % of 1e, and H2O2 (1.1 equiv) in pH 4.2 buffer.

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CONCLUSIONS Aryltellurinic acids are effective catalysts for the activation of H2O2 for the oxidation of bromide to electrophilic bromine species (HOBr/Br2). Diaryl ditellurides generate the tellurinic acids in situ upon reaction with H2O2. The catalyst-terminating step in the tellurinic acid catalyzed reactions is likely oxidation of the tellurinic acid to the telluronic acid. The scope of the bromination reactions with alkenoic acids and with activated aromatic substrates was explored using 0.25 mol % of diphenyl ditelluride (1e) as a precursor to 0.50 mol % of phenyltellurinic acid in a solvent system of 1/1 by volume 1,4-dioxane and pH 6.2 or pH 4.2 phosphate buffer. The bromolactonization of a series of alkenoic acids (entries 1−5, G

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Te NMR spectrum of the remaining aqueous phase was recorded (Figure 2c). To the residual red oil was added 1.0 mL of CDCl3, and the 125Te NMR spectrum of the organic-soluble materials was recorded (Figure 2d). Experiments with Tellurinic Anhydride 6a. Methoxyphenyl tellurinic anhydride (6a) was prepared as previously described.9a,11 Tellurinic anhydride 6a (25.9 mg, 0.050 mmol) was dissolved in 0.10 mL of 2.5 M NaOH in D2O (0.25 mmol of NaOH) to hydrolyze the anhydride to give tellurinic acid 5a.11 The 125Te NMR spectrum of 5a was acquired by diluting the solution with 0.5 mL of D2O and 0.3 mL of THF. For the acquisition of the 125Te NMR spectrum of telluronic acid 7a, 0.83 M H2O2 in D2O (0.60 mL, 0.50 mmol) was added dropwise to tellurinic anhydride 6a (25.9 mg, 0.050 mmol) dissolved in 0.10 mL of 2.5 M NaOH in D2O and the 125Te NMR spectrum was then recorded (Figure 2h). Data for 5a:11 1H NMR (D2O, 500 MHz) δ 7.63 (d, 2H, J = 8 Hz), 7.05 (d, 2H, J = 8 Hz), 3.75 (s, 3H); 13C NMR (D2O, 75.5 MHz) δ 161.7, 140.1, 130.8, 115.0, 55.7; 125Te NMR (D2O, 126.2 MHz) δ 1635. Preparation of (4-Methoxyphenyl)telluronic Acid (7a). Bis(4methoxyphenyl) ditelluride (1a, 0.47 g, 1.0 mmol) was dissolved in 8 mL of THF and the reaction flask placed in an ice bath. Hydrogen peroxide (8.8 M, 1.14 mL, 10 mmol) dissolved in 4 mL of THF was then added dropwise. The reaction mixture was stirred at 0 °C for 1 h and then warmed to room temperature. The solvent was evaporated at ambient temperature, and an orange solid was obtained. The solid was washed with ether (3 × 10 mL) with stirring, the solids were allowed to settle, and the solvent was removed with a pipet. The resulting solid was dissolved in 15 mL of 0.2 M NaOH at 80 °C and was then acidified to pH 4 with 10 M acetic acid. The precipitate that formed was collected by filtration, washed with water (50 mL), and dried under vacuum until constant weight to give telluronic acid 7a as an offwhite solid (356 mg, 63% yield), mp >260 °C. The product was soluble in polar organic solvents such as DMF and DMSO and in aqueous solutions of NaOH and NH4OH: 1H NMR (0.2 M NaOH in D2O, 60 °C, 500 MHz) δ 8.13 (br s, 2H), 7.24 (br s, 2H), 4.07 and 4.06 (two overlapped singlets, 3H); 13C NMR (0.2 M NaOH in D2O, temperature 60 °C, 100 MHz) δ 160.0 (br), 132.6, 132.5, 113.9 (br), 55.9, 55.8; 125Te NMR (0.36 M NaOH in D2O/THF 2.3/1, 126 MHz) δ 801.5, 797.9; HRMS (ESI, negative mode, HRDFMagSec) m/z calculated for C7H7O4130Te [M − H]− 284.9412, found 284.9407. Bromination of 1,3,5-Trimethoxybenzene (9) with Stoichiometric Tellurinic Acid 5a. Sodium hydroxide (0.1 M, 2.75 mL, 0.275 mmol) was added to tellurinic anhydride 6a (65 mg, 0.125 mmol). After 15 min of stirring at ambient temperature, the resulting solution was added dropwise to a stirred solution of 9 (42 mg, 0.25 mmol) in 5.0 mL of 1,4-dioxane and 1.5 M NaBr (2.5 mL, 3.75 mmol) in pH 6.2 phosphate buffer (PO4 0.5 M). In a separate experiment, 8.8 M H2O2 (142 μL, 1.25 mmol) was also added. After 4 h, 5.0 mL of 0.5 M NaOH was added and the mixture extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with 0.5 M NaHSO3 (1 × 10 mL) and brine (1 × 10 mL), dried over MgSO4, and concentrated. In the reaction without H2O2, 37 ± 1 mg of starting material (89% yield, average of two runs) was recovered after workup. The reaction performed using H2O2 gave 49 ± 1 mg after workup (average of two runs). 1H NMR analysis of the crude product revealed a mixture of starting material (23% yield) and 2-bromo-1,3,5trimethoxybenzene (10, 64% yield). Kinetic Experiments for Bromination of 4-Pentenoic Acid: General Considerations. Stock solutions of 4-pentenoic acid (2, 0.10 M) containing propionic acid (0.01 M) as an internal standard were prepared in pH 6.2 or pH 7.2 phosphate buffer (0.23 M in PO4) in D2O. Serial dilution with D2O of commercially available H2O2 8.8 M was employed to prepare 4.0, 4.8, and 5.6 M solutions of H2O2. Sodium bromide was added directly to the reaction vessel. Ditellurides 1a−i were added to the reaction mixture as freshly made 10 mM solutions in distilled 1,4-dioxane. After the addition of all the reaction components, the vessels were immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. Periodically the reaction mixture was sampled and the progress of the reaction

Table 3) gave products in 78−84% isolated yields. In the absence of ditelluride 1e, bromination of the alkenoic acids under identical conditions gave ≤4% reaction. Activated aromatic substrates (entries 6−10, Table 3) gave monobromination products in 92−95% isolated yields in the presence of ditelluride 1e. In the catalyst-free reactions, ≤6% bromination was observed under otherwise identical conditions. Furthermore, the tellurinic acid catalyzed brominations did not deprotect tert-butyldimethylsilyl ethers (entry 8, Table 3) and did not hydrolyze ethyl esters (entries 9 and 10, Table 3). The effectiveness of the tellurinic acids as catalysts is very sensitive to electron demand in the intermediates present during the course of the reaction (Figure 3). Electronwithdrawing substituents decrease the pKa value of the tellurinic acids, increasing the equilibrium concentration of the tellurinate intermediate A shown in Scheme 4. Electron-donating substituents favor the electrophilic intermediate B of Scheme 4. The rate of catalysis is dependent upon the rate of addition of H2O2 to A and B. We have also shown that chelation and steric interactions affect the Te center of intermediates A and B. The further oxidation of the tellurinic acid to the telluronic acid stops catalysisthe telluronic acid does not activate peroxide. The use of ditellurides/tellurinic acids to catalyze bromination reactions has promise. The reactions described here have all been conducted in the presence of a 15-fold excess of NaBr. Further work on the design of catalysts should focus on (1) increasing the rate of reaction of bromide with the functional oxidant to regenerate tellurinic acid while producing HOBr/Br2 and (2) slowing the rate of oxidation to the telluronic acid, which stops the catalytic process.

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EXPERIMENTAL SECTION

Preparation of Bis[3,5-bis(trifluoromethyl)phenyl] Ditelluride (1g). Elemental tellurium (1.28 g, 10 mmol) was added in one portion to 10 mL of a 1.0 M solution of (3,5-bis(trifluoromethyl)phenyl)magnesium bromide in THF (freshly prepared from 1-bromo3,5-bis(trifluoromethyl)benzene (2.99 g, 10.2 mmol), magnesium (0.243 g, 10 mmol), and 10 mL of THF). The resulting mixture was stirred for 15 h at ambient temperature and was then added to an aqueous solution of K3Fe(CN)6. The products were extracted with CH2Cl2, and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was filtered through a small pad of silica with hexanes as eluent to give the product as an orange solid (1.98 g, 58% yield), mp 58−60 °C: 1H NMR (CDCl3, 500 MHz) δ 8.20 (s, 4H), 7.76 (s, 2H); 125Te NMR (CDCl3, 126 MHz) δ 504.4; HRMS (EI, positive mode) m/z 685.8394 (calcd for C16H6F12130Te2+ 685.8397). Acquisition of 125Te NMR Spectra. Samples were prepared in 5 mm NMR tubes. The 125Te NMR spectra were recorded at 126.18 MHz and 25 °C with an acquisition time of 0.82 s and a spectral width for data acquisition of 192 kHz. The data were collected for 16k transients, with a pulse width of 9 μs and a relaxation delay of 0.5 s. The FIDs were transformed with an exponential line broadening function of 15−50 Hz. Samples were referenced relative to diphenyl telluride as an external standard with a chemical shift of δ 688 in CDCl3 relative to Me2Te (δ 0.0).19 125 Te NMR Experiments with Ditelluride 1a or Tellurinic Acid 5a and H2O2. Experiments with Ditelluride 1a. To a stirred solution of bis(4-methoxyphenyl) ditelluride (1a, 23.5 mg, 0.050 mmol; Figure 2a) in 0.3 mL of THF was added 0.60 mL of a stock solution of H2O2 (0.83 M in D2O (0.5 mmol, Figure 2g), 0.42 M H2O2 in D2O (0.25 mmol, Figure 2f), 0.25 M H2O2 in D2O (0.15 mmol, Figure 2e), or 0.083 M H2O2 in D2O (0.050 mmol)) dropwise. Subsequently, 0.10 mL of 2.5 M NaOH in D2O (0.25 mmol) was added and the collection of 125Te NMR data commenced. When 1.0 equiv of H2O2 was added, a dark red oil formed and separated from solution. The H

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Organometallics

Article

monitored by 1H NMR spectroscopy, suppressing the H2O/HOD and 1,4-dioxane signals. The consumption of 4-pentenoic acid was measured by assessing the changes between the relative integral values of the internal alkene proton of 4-pentenoic acid (δ 5.8 ppm) and the methylene protons of propionic acid (δ 1.1 ppm). In general, experiments were followed through the first two half-lives and the results were plotted as pseudo-first-order reactions (ln [A] vs time in seconds, where [A] is the integral of the alkene proton). The results shown in Figure 1 and compiled in Tables 1 and 2 represent an average of duplicate runs that agreed within 5% between runs. Kinetic Experiments Employing Ditellurides 1a−i in pH 6.2 Buffer. Sodium bromide (772 mg, 7.5 mmol, 1.43 M final concentration) was added to a solution of 0.10 M 4-pentenoic acid (2) in pH 6.2 buffer (5.0 mL, 0.5 mmol, 95 mM final concentration) followed by the addition of 4.8 M H2O2 (156 μL, 0.75 mmol, 0.14 M final concentration). Then, 100 μL of a 10 mM solution of ditellurides 1 in 1,4-dioxane (1.0 μmol, 0.20 mol % relative to 2, 190 μM final concentration) was added at once. The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. The contents of the NMR tube were returned to the reaction vessel following compilation of the 1H NMR spectra. Kinetic Experiment Employing Catalytic Tellurinic Acid 5a in pH 6.2 Buffer. Tellurinic anhydride 6a (12.9 mg, 0.025 mmol) was dissolved in 0.1 M NaOH in D2O (2.5 mL, 0.25 mmol), and the resulting solution was stirred at room temperature until the solid was completely dissolved (∼15 min). The tellurinic acid solution (100 μL, 2.0 μmol, 0.40 mol % relative to 2, 380 μM final concentration) was added dropwise to a 1.43 M solution of NaBr (772 mg, 7.5 mmol) in 0.10 M 4-pentenoic acid (2) in pH 6.2 buffer (5.0 mL, 0.5 mmol of 2, 95 mM final concentration) followed by the addition of 4.8 M H2O2 (156 μL, 0.75 mmol, 0.14 M final concentration). The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. After the NMR spectra were recorded, the contents of the NMR tube were returned to the reaction vessel. Kinetic Experiment Employing Catalytic Telluronic Acid 7a in pH 6.2 Buffer. Tellurinic anhydride 6a (12.9 mg, 0.025 mmol) was dissolved in 0.1 M NaOH in D2O (2.47 mL, 0.25 mmol), and the resulting solution was stirred for 15 min at room temperature. Then, 8.8 M H2O2 (28 μL, 0.25 mmol) was added. The resulting solution was stirred for 3 h, and then an aliquot of this solution (100 μL, 2.0 μmol of 7a, 0.40 mol % relative to 2, 380 μM final concentration) was added dropwise to a 1.43 M solution of NaBr (772 mg, 7.5 mmol) in a stock solution of 0.10 M 2 in pH 6.2 buffer (5.0 mL, 0.5 mmol of 2, 95 mM final concentration) containing H2O2 (156 μL of a 4.8 M stock solution, 0.75 mmol, 0.14 M final concentration) to produce a homogeneous solution. The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. After the NMR spectra were recorded, the contents of the NMR tube were returned to the reaction vessel. Kinetic Experiment Employing Catalytic Tellurinic Anhydride 6a in pH 6.2 Buffer. Tellurinic anhydride 6a (1.0 mg, 2 μmol, 0.20 mol % related to 2, 190 μM final concentration) was added to a solution of 1.43 M NaBr (1.54 g, 15.0 mmol) in a 0.10 M stock solution of 4-pentenoic acid (2) in pH 6.2 buffer (10.0 mL, 1.0 mmol, final concentration 95 mM), H2O2 4.8 M (313 μL, 1.5 mmol, final concentration 0.14 M), and 200 μL of D2O. The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. After the NMR spectra were recorded, the contents of the NMR tube were returned to the reaction vessel. Kinetic Experiment Employing Ditelluride 1a in pH 7.2 Buffer. A 1.44 M solution of NaBr (772 mg, 7.5 mmol) and 96 mM 4pentenoic acid (2, 5.0 mL of a 0.10 M stock solution in pH 7.2 buffer, 0.5 mmol) was prepared by the addition of 4.8 M H2O2 (156 μL, 0.75 mmol, 0.14 M final concentration). Ditelluride 1a (50 μL of a 10 mM stock in 1,4-dioxane, 0.5 μmol, 0.10 mol % relative to 2, 96 μM final concentration) was added at once to produce a homogeneous solution. The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K.

Kinetic Experiment Employing Catalytic 5a in pH 7.2 Buffer. Tellurinic anhydride 6a (12.9 mg, 0.025 mmol) was dissolved in 0.1 M NaOH in D2O (2.5 mL, 0.25 mmol of NaOH) and the mixture stirred at room temperature until the solid was completely dissolved (∼15 min). An aliquot of this solution (50 μL, 1.0 μmol of 5a, 0.20 mol % relative to 2, 192 μM final concentration) was added dropwise to a solution of NaBr (772 mg, 7.5 mmol, 1.44 M final concentration) in a 0.10 M stock solution of 2 (5.0 mL, 0.5 mmol of 2, 96 mM final concentration) in pH 7.2 buffer. To this solution was added 4.8 M H2O2 (156 μL, 0.75 mmol, 0.14 M final concentration) to produce a homogeneous solution. The reaction vessel was immediately capped, stirred magnetically, and kept in a thermostated oil bath at 298 ± 1 K. General Procedure for Bromination Of Organic Substrates. The substrates 2,2-diphenyl-4-pentenoic acid (12),20 4-methyl-4pentenoic acid (16),21 ethyl 4-dimethylaminobenzoate (24),22 and ethyl 3-dimethylaminobenzoate (26)23 were prepared by literature procedures, and 1H and 13C NMR spectra are compiled in the Supporting Information. The substrates 4-pentenoic acid (2), 2methyl-4-pentenoic acid (14), 5-hexenoic acid (18), 1,3,5-trimethoxybenzene (9), N-phenylmorpholine (20), and anisole (28) are commercially available compounds and were used as received. In an open flask, 10 mL of 1.5 M NaBr in pH 6.2 phosphate buffer (0.23 M in PO4) or pH 4.2 phosphate buffer (5% NaH2PO4) was added to a solution of 1 mmol of substrate dissolved in 9.75 mL of distilled 1,4dioxane. To this mixture was added a freshly made solution of diphenyl ditelluride (1e, 0.25 mL of a 10 mM stock in 1,4-dioxane, 2.5 μmol, 0.25 mol % relative to substrate) followed by the addition of 8.8 M H2O2 according to Table 3. The reaction mixture was stirred at room temperature for the appropriate amount of time and was then diluted with 10 mL of water. The resulting solution was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with 0.5 M NaHSO3 (5 mL) and brine (10 mL), dried over MgSO4, and concentrated. Yields reported below are the mean of duplicate runs. 5-(Bromomethyl)dihydrofuran-2(3H)-one (3): 24 product obtained as a colorless oil (150 ± 1 mg, 84% yield); 1H NMR (CDCl3, 500 MHz) δ 4.79−4.74 (m, 1H), 3.60−3.54 (m, 2 H), 2.70−2.54 (m, 2H), 2.49−2.42 (m, 1H), 2.17−2.09 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 76.1, 77.6, 34.3, 28.0, 25.6. 5-(Bromomethyl)-3,3-diphenyldihydrofuran-2(3H)-one (13): 25 crude product recrystallized from EtOH to give 13 as a white solid (258 ± 7 mg, 78% yield); mp 88−89 °C (lit.20 mp 88−90 °C); 1H NMR (CDCl3, 500 MHz) δ 7.37−7.35 (m, 4H), 7.34−7.31 (m, 5H), 7.30−7.25 (m, 1H), 4.57−4.54 (m, 1H), 3.61 (dd, 1H, J = 5, 11 Hz), 3.52 (dd, 1H,1 = 6, 11 Hz), 3.17 (dd, 1H, J = 5, 13 Hz), 2.83 (dd, 1H, J = 9.5, 13 Hz); 13C NMR (CDCl3, 75 MHz) δ 176.1, 141.3, 139.1, 128.8, 128.3, 127.7, 127.4, 127.2, 127.0, 74.8, 58.0, 41.7, 32.7. 5-(Bromomethyl)-3-methyldihydrofuran-2(3H)-one (15): 24 product obtained as a colorless oil (169 ± 6 mg, 88% yield) as a 1.0/1.7 mixture of diasteroisomers; major diasteroisomer 1H NMR (CDCl3, 500 MHz) δ 4.60−4.54 (m, 1H), 3.55−3.47 (m, 2H), 2.76−2.70 (m, 1H), 2.66−2.61 (m, 1H), 1.75−1.68 (m, 1H), 1.31 (d, 3H, J = 7.0 Hz) and 13C NMR (CDCl3, 75 MHz) δ 178.3, 75.6, 35.3, 35.0, 33.5, 14.7; minor diasteroisomer 1H NMR (CDCl3, 500 MHz) δ 4.77−4.72 (m, 1H), 3.59 (dd, 2H, J = 4, 11 Hz), 2.87−2.77 (m, 1H), 2.44−2.38 (m, 1H), 2.12−2.06 (m, 1H), 1.31 (d, 3H, J = 7.0 Hz) and 13C NMR (CDCl3, 75 MHz) δ 179.0, 75.7, 34.1, 33.6, 33.4, 15.8. 5-(Bromomethyl)-5-methyldihydrofuran-2(3H)-one (17)25 and 4,5-Dibromo-4-methylpentanoic Acid (17′). A 7.3/1.0 mixture of 17 and 17′ (assessed by the examination of the 1H NMR spectrum) was obtained as a colorless oil (167 ± 2 mg, 82% yield). These compounds were separated by dissolving the crude mixture in 20 mL of Et2O and washing with saturated NaHCO3 solution (3 × 5 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The pH of the aqueous layer was adjusted to pH 4 by addition of 1 M HCl, and the products were then extracted with Et2O (3 × 15 mL). These organic extracts were separately combined, dried over MgSO4, filtered, and concentrated to give pure 17 (basic extraction) and 17′ (acidic extraction). I

dx.doi.org/10.1021/om500883f | Organometallics XXXX, XXX, XXX−XXX

Organometallics Data for 17: 1H NMR (CDCl3, 500 MHz) δ 3.54 (d, 1H, J = 11 Hz), 3.48 (d, 1H, J = 11 Hz), 2.74−2.61 (m, 2H), 2.42−2.36 (m, 1H), 2.13−2.06 (m, 1H), 1.58 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 175.7, 84.0, 39.4, 31.5, 29.1, 25.3. Data for 17′: 1H NMR (CDCl3, 500 MHz) δ 3.84 (s, 2H), 2.64 (t, 1H, J = 8 Hz), 2.34−2.21 (m, 2H), 1.87 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 178.7, 65.6, 41.8, 36.7, 30.7, 30.3; IR (NaCl) 2927, 1710, 1432, 1295 cm−1; HRMS (CI, positive mode, HRDFMagSec) m/z 272.9107 (calcd for C6H1079Br2O2 + H+ 272.9120). 6-(Bromomethyl)tetrahydro-2H-pyran-2-one (19)26 and 5,6Dibromohexanoic Acid (19′).3f The product was isolated as a 3.4/ 1.0 mixture of 19 and 19′ (assessed by the examination of the 1H NMR spectrum) as a colorless oil (200 ± 5 mg, 78% yield). These compounds were separated by dissolving the crude mixture in 20 mL of Et2O and washing with saturated NaHCO3 solution (3 × 5 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The pH of the aqueous layer was adjusted to pH 4 by addition of 1 M HCl, and the products were then extracted with Et2O (3 × 15 mL). These organic extracts were separately combined, dried over MgSO4, filtered, and concentrated to give pure 19 (basic extraction) and 19′ (acidic extraction). Data for 19:26 1H NMR (CDCl3, 500 MHz) δ 4.54−4.49 (m, 1H), 3.54 (dd, 1H, J = 4.5, 11 Hz), 3.49 (dd, 1H, J = 6.5, 10.5 Hz), 2.65− 2.60 (m, 1H), 2.52−2.45 (m, 1H), 2.16−2.11 (m, 1H), 2.03−1.96 (m, 1H), 1.93−1.84 (m, 1H), 1.76−1.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 170.3, 78.6, 33.7, 28.4, 26.3, 18.1. Data for 19′:3f 1H NMR (CDCl3, 500 MHz) δ 10.54 (bs, 1H), 4.19−4.14 (m, 1H), 3.86 (dd, 1H, J = 4, 10 Hz), 3.63 (t, 1H, J = 10 Hz), 2.48−2.40 (m, 2H), 2.26−2.19 (m, 1H), 1.99−1.92 (m, 1H), 1.89−1.74 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 179.3, 51.9, 35.9, 35.2, 33.1, 22.0. 2-Bromo-1,3,5-trimethoxybenzene (10): 27 product isolated as a white solid (229 ± 3 mg, 93% yield); mp 94−95 °C (lit.27 mp 95−97 °C); 1H NMR (CDCl3, 500 MHz) δ 6.17 (s, 2H), 3.88 (s, 6H), 3.82 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 160.4, 157.4, 91.5, 91.6, 56.3, 55.5. N-(4-Bromophenyl)morpholine (21): 28 product isolated as a tan solid (224 ± 1 mg, 93% yield); mp 111−113 °C (lit.28 mp 111−112 °C); 1H NMR (CDCl3, 500 MHz) δ 7.35 (AA′XX′ d, 2H, J = 7.5 Hz), 6.77 (AA′XX′ d, 2H, J = 7.5 Hz), 3.85 (d, 4H, J = 5.0 Hz), 3.11 (d, 4H, J = 5.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 150.2, 131.9, 117.2, 112.1, 66.7, 49.1. 2-Bromo-4-((tert-butyldimethylsilyloxy)methyl)-N,N-dimethylaniline (23): product isolated as a pale yellow oil (316 ± 3 mg, 92% yield); 1H NMR (CDCl3, 500 MHz) δ 7.51 (d, 1H, J = 1.0 Hz), 7.21 (dd, 1H, J = 1.0, 8.5 Hz), 7.05 (d, 1H, J = 8.5 Hz), 4.65 (s, 2H), 2.78 (s, 6H), 0.94 (s, 9H), 0.10 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 150.6, 137.3, 131.6, 125.8, 120.2, 119.0, 63.9, 44.3, 25.9, 18.4, −5.3; HRMS (ESI, HRDFMagSec) m/z 344.1040 (calcd for C15H2679BrNOSi + H+ 344.1039). Ethyl 3-bromo-4-(dimethylamino)benzoate (25): product isolated as a pale yellow oil (258 ± 2 mg, 95% yield); 1H NMR (CDCl3, 500 MHz) δ 8.20 (d, 1H, J = 2.0 Hz), 7.92 (dd, 1H, J = 2.0, 8.5 Hz), 7.02 (d, 1H, J = 8.0 Hz), 4.35 (q, 2H, J = 7.0 Hz), 2.89 (s, 6 H), 1.38 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 165.3, 155.6, 135.5, 129.5, 124.8, 119.1, 116.7, 60.8, 43.6, 14.3; IR (NaCl) 1709,1246, 1115 cm−1; HRMS (ESI, HRDFMagSec) m/z 272.0278 (calcd for C11H1479BrNO2 + H+ 272.0281). Ethyl 2-bromo-5-(dimethylamino)benzoate (27): product isolated as a pale yellow oil (258 ± 6 mg, 95% yield); 1H NMR (CDCl3, 500 MHz) δ 7.41 (d, 1H, J = 9.0 Hz), 7.04 (d, 1H, J = 3.0 Hz), 6.64 (dd, 1H, J = 3, 9 Hz), 4.39 (q, 2H, J = 7.5 Hz), 2.95 (s, 6 H), 1.40 (t, 3 H, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 166.94, 149.1, 134.1, 132.6, 116.0, 114.2, 106.4, 61.2, 40.3, 14.1; IR (NaCl) 1726, 1254, 1123 cm−1; HRMS (ESI, HRDFMagSec) m/z 272.0281 (calcd for C11H1579BrNO2 + H+ 272.0281). 4-Bromoanisole (29): product isolated as a colorless liquid (43 ± 2 mg, 23% yield); 1H NMR (CDCl3, 500 MHz) δ 7.37 (AA′XX′ d, 2H, J = 8.5 Hz), 6.78 (AA′XX′ d, 2H, J = 9.0 Hz), 3.78 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 158.6, 132.2, 115.7, 112.8, 55.4.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

Article

S Supporting Information *

Text and figures giving general methods and NMR spectral data (1H, 13C, and 125Te NMR) for all noncommercial compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail for M.R.D.: mdetty@buffalo.edu. Author Contributions

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the U.S. Office of Naval Research for partial support of this research through award N0014-09-1-0217. Dr. Dinesh K. Sukumaran (SUNY-Buffalo) is acknowledged for the help with 125Te NMR experiments.

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REFERENCES

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