On the potential intermediacy of PhIBr2 as a brominating agent
PhIBr2, first purported 100 years ago, has been subject of few reports due to its low stability. However, a recent publication proposes a reaction of PIFA (PhI(OC(O)-CF3)2) with TMSBr to form PhIBr2 in-situ and demonstrated its efficacy in aryl brominations. Our report investigates this synthesis by replicating bromination reactions claiming to use in-situ PhIBr2 as described. The spectroscopical and computational results indicate formation of PhI and Br2 where Br2 is responsible for bromination and no supporting evidence for invoking PhIBr2 as an intermediate is found.
<!>Scheme 2. Comparison of observed bromination results using PIFA/2 TMS-Br and Br2 as brominating agent.<!>SUPPORTING INFORMATION
<p>I(III) compounds are widely used as safe and convenient oxidizing agents for a variety of chemical transformations. [1][2][3] The first and quintessential example, PhICl2, is an easily handled solid that acts as a replacement for Cl2 in chlorination reactions. 4 PhICl2 can be synthesized from PhI and Cl2 or other oxidative chlorinating conditions (e.g. PhI and H2O2/HCl). 5,6 On standing in solution or at room temperature, it degrades back into PhI and Cl2, which in solution occurs in a matter of hours. PhIF2 and related derivatives (most often with tolyl as the aryl group) are used as a fluorinating agents. [7][8][9] PhIF2 derivatives are somewhat less convenient to synthesize than PhICl2 and reactive with borosilicate glass; however, they are less prone to spontaneous degradation due to the high energy nature of F2. While the F and Cl analogues are common, the bromine analogue, PhIBr2, has scarcely been mentioned in the literature. This is presumably due to the instability of PhIBr2; the dissociation equilibrium lies on the side of PhI and relatively stable Br2, while the bond strength of the I-Br bond is quite weak in I(III) complexes. 10 Nonetheless, there have been several claims as to its existence and use. The first mention of PhIBr2 was over 100 years ago in 1905, which arose from mixing PhI and Br2 in petroleum ethers that resulted in the isolation of an oily precipitate that solidifies at lower temperatures. 11 Three papers regarding steroid chemistry from 1971, 2001, and 2002 claim the use of PhIBr2 as a brominating agent. [12][13][14] The 2001 and 2002 papers cite conditions from 1971, which in turn cites the 1905 paper, indicating that PhIBr2 can be generated in hexane from PhI and Br2 at -5 °C and is a solid that can be observed. A 1985 paper claims the use of PhIBr2 as a bromide transfer reagent towards alkyl iodides, 15 but cites an Organic Syntheses preparation method that only describes PhICl2. 16 Mixed PhI(OAc)(Br) intermediates have also been proposed as a brominating agent, generated from PhI(OAc)2 (PIDA) and either one equivalent of TMS-Br or alkali metal bromide salts or HBr. [17][18][19][20] However, in 1997 Evans conclusively demonstrated from UV-Vis experiments that these solutions result in the generation of molecular bromine and PhI with no evidence of PhIBr2 formation, and that Br2 is equally effective in the bromination reactions under the conditions purported to generate PhI(OAc)(Br). 21,22 The anti-addition of bromine across an alkene observed by Lupton and co-workers from PhI(OAc)2/excess PyrHBr (who did not invoke PhIBr2) is also consistent with Br2 being the active species since PhICl2 is known to result in syn addition with alkenes. 23,24 Evans reported the mixed PhI(OAc)(Cl) species was an observable compound by 1 H NMR spectroscopy, 22 and PhI(OAc)(Cl) has been determined to have desirable properties over PhICl2 in some applications. 18 Very recently, in 2020, a report published in The Journal of Organic Chemistry, Cossio and Vallribera (C&V) described the use of PhIBr2 generated in situ from PhI(OTFA)2 (PIFA) and 2 TMS-Br in dry CH2Cl2 as an effective brominating agent for a variety of arenes, within some cases PIFA and 2 TMS-Br exhibited differing reactivity to Br2 (Scheme 1). 25 For most arene substrates, the bromination reaction completed overnight, while only 4 hours were required with anisole. Furthermore, the anisole reaction with PhIBr2 as the bromination agent resulted in monobromination at the para position, whereas the use of Br2 gave a dibrominated product at the para and ortho positions. C&V also employed DFT calculations to propose a mechanism for the bromination of anisole starting from PhIBr2 as the reference energy point.</p><p>Scheme 1. Reported in situ generation of PhIBr2 and bromination of anisole. 25 We have recently published reports debunking claimed I(III) species where the spectroscopy or computational data was not consistent with the proposed species (e.g. PhI(OTf)2). 26 The scarcity of PhIBr2 literature, despite appearing to be a very interesting molecule and the ease with which it is apparently accessed, led us to question the 2020 C&V report invoking it as an intermediate in reactions taking place over the course of hours. Here we have investigated claims for the synthesis of PhIBr2 and its involvement in bromination, including the bromination reactions reported by C&V.</p><p>The reaction of PIFA and 2 equivalents of TMS-Br was carried out in both dry CD2Cl2 (the solvent from the C&V paper) and CDCl3, which gave identical results. In both cases, the reaction mixture turned red/orange immediately, consistent with the color of molecular Br2. This was confirmed from UV-Vis spectra of the reaction mixture, which gave an absorbance at 414 nm, consistent with a separately measured sample of Br2. A 1 H NMR spectrum of the reaction mixture taken 1 minute after mixing of the reagents gave resonances in the aromatic region indicative of only PhI being present. Combined, these data suggest that the conditions purported to give PhIBr2 result in PhI and Br2. It is stated in the C&V paper that there is an equilibrium for the PhIBr2 system that lies on the side of PhI and Br2, which we agree with. To investigate the potential observation of a small amount of some species consistent with PhIBr2 in solution, concentrated solutions of PhI and Br2 in both CDCl3 and CD2Cl2 were examined by proton NMR (1 hour, 500 scans) on a 500 MHz instrument. No evidence for any aromatic containing species other than PhI and minor impurities present in PhI before Br2 addition could be observed in this experiment. We attempted to replicate the 1905 report of PhIBr2 formation in which petroleum ether or hexane was used at -5 °C. 11 However, a mixture of PhI and Br2 in proteo-hexane at room temperature only gave 1 H NMR signals that correspond to the aromatic environment in PhI, and upon cooling the sample to -5 °C in the NMR probe, no change in the PhI resonances were observed, and no solid precipitate was formed as originally reported. 11 Given that we only observe PhI and Br2 from a mixture of PIFA and 2 TMS-Br in contrast to C&V who suggested it produces PhIBr2 in situ, we attempted to replicate the observations of C&V whereby they obtained only para brominated anisole in the reaction with PIFA and 2 TMS-Br, but a para-ortho dibrominated product in the reaction with Br2. C&V included NMR spectra of most reactions in the supporting information, unfortunately no spectra were included of the reactions with anisole that give the claimed divergent results for the two sets of conditions. Upon performing these reactions between anisole and either Br2 or PIFA and 2 TMS-Br in our laboratory, we found both reactions yielded identical outcomes, with exclusively a para monobrominated product formed in both cases (Scheme 2). We further investigated other substrates in the C&V paper that were on hand in our laboratory and they also gave identical bromination results by using either one equivalent of Br2 or PIFA/2 TMS-Br (Scheme 2). The only exception was for mesitylene, where use of PIFA/2TMS-Br resulted in some bromination of a methyl group, which is not observed when Br2 is used. However, no reactions yielded a dibrominated product.</p><!><p>Following our experimental studies suggesting that PhIBr2 is not the brominating agent, we conducted theoretical calculations to examine the PhIBr2-anisole system. We were able to reproduce the energetics of the relevant systems included in the SI by C&V (although it is apparent that the results in Figure 3 from C&V do not utilize a 6-31+G(d) basis set for Br as reported but potentially use a LANL2DZ basis and ECP). We note a disagreement between some geometry parameters shown in C&V Figure 1 and the optimized geometries, especially for bonds to Br and I. In the coordinates given for the optimized geometries, these bonds are up to 1 Å longer than shown in Figure 1, illustrated in Figure S59.</p><p>In the mechanism proposed by C&V, PhIBr2 is used as the reference point to examine the potential energy surface for the bromination of anisole, while it is also proposed that PhIBr2 is in equilibrium with PhI and Br2. It is therefore important to consider where PhI + Br2 lies on the potential energy surface relative to PhIBr2. Although C&V did not report results for this reaction, we have applied their computational approach to obtain a DG of -58.2 kJ/mol for the reaction PhIBr2 à PhI + Br2, which indicates that dissociation of PhIBr2 to PhI and Br2 is thermodynamically favourable. We investigated the reaction energetics with numerous computational approaches (Table S1), for which DG is exergonic with all methods. At the highest level of theory considered, DLPNO-CCSD(T)/def2-TZVPP(CPCM,CH2Cl2), the calculated DG is -47.8 kJ/mol.</p><p>The calculation results are consistent with our experimental results, where we have established that equilibrium lies on the side of PhI and Br2 at least to the limit of NMR detection. From both computational and experimental results, it is expected that PhI + Br2 are the dominant species in the reaction mixture generated either from PIFA and 2 TMS-Br, or from concentrated solutions of PhI and Br2.</p><p>For the reaction of PhIBr2 and anisole, C&V calculated an activation energy of 93 kJ/mol (DG) for the ratedetermining step (TS for initial engagement of PhIBr2 with anisole to form the Wheland intermediate), in apparent agreement with the reported 4-hour reaction time at room temperature for which they estimate a t1/2 = 0.88 h. However, other DFT methods (Table S3) yield a significantly higher barrier; B3LYP-D3(BJ)/def2-SVP (PCM,CH2Cl2) gives a 142 kJ/mol barrier (t1/2 = 3 x 10 8 h) while M06-2X/def2-SVP (PCM,SMD,CH2Cl2) gives 188 kJ/mol (t1/2 = 4 x 10 16 h). Moreover, single-point energy calculations at the geometries reported by C&V (combined with Gcorr corrections from C&V to give DG) give barriers of 193 kJ/mol (M06-2X/def2-SVP (PCM,SMD,CH2Cl2)) and 199 kJ/mol (wB97XD/def2-TZVP (PCM,SMD,CH2Cl2). More extensive MP2 and DLPNO-CCSD(T) calculations yield an even larger barrier of 202-236 kJ/mol (DG, Table S3). Such a high barrier cannot be overcome at the reported experimental conditions. Moreover, the reaction energetics are relative to PhIBr2, for which it is necessary to consider the calculated DG for the formation of PhIBr2 from PhI and Br2 that would increase the total barrier even further. The calculated barriers indicate that the proposed mechanism is not energetically feasible.</p><p>The proposed TS was explored further with intrinsic reaction coordinate (IRC) calculations. While TS1 is confirmed to connect to the vdW reactant complex (RC1, PhIBr2 + anisole), in the other direction, the reaction coordinate leads to mono-bromination at the para position of the anisole but with a structure that is inconsistent with the intermediate structures reported by C&V (Int1-syn and Int1-anti). A new intermediate (Int1) was optimized (Figure S61) consistent with the IRC results that lie ca. 5 kJ/mol higher in free energy than the C&V intermediates. Int1 has the non-bonded Br atom in the same plane as the anisole ring, 3.69 Å from the O atom and 4.9 Å from the neighbouring Cring atom (not above/below the ring as in the C&V intermediates), for which a second bromination does not appear to be feasible following this reaction pathway. However, although the calculated mechanism does lead to para-bromination, the calculated barriers remain impossibly high.</p><p>The C&V paper reports that bromination also occurs using PIFA and one equivalent of TMS-Br, albeit with a reduced yield. Previously, one equivalent of TMS-Br in conjunction with PhI(OAc)2 (PIDA) has also been used to effect brominations, although as discussed by Evans, it has been determined that these conditions result in the generation of molecular bromine. 22 In our hands, one equivalent of TMS-Br with PIDA or PIFA in dry CDCl3 and CD2Cl2 resulted in the generation of PhI, Br2, TMS-OAc or TMS-OTFA depending on the reagent used, and one equivalent of the PIDA or PIFA remaining. The reduced yield for these reactions compared to 2 equivalents of TMS-Br can be explained by the formation of insufficient amounts of Br2 to complete the reaction.</p><p>Finally, we calculated DG (M06-2X/def2-SVP (PCM,DCM,CH2Cl2) for the addition of one and two equivalents of TMS-Br to PIFA. The addition of one equivalent of TMS-Br to generate PhI(OTFA)Br is -66 kJ/mol, while the addition of a second equivalent is also favourable at -72 kJ/mol, giving a total DG of -138 kJ/mol to generate PhIBr2 from PIFA and 2 TMS-Br. We cannot exclude that PhIBr2 may be transiently formed from PIFA and two equivalents of TMS-Br. However, our experimental observations together with our calculated results suggest that if PhIBr2 is formed, it immediately decomposes into PhI and Br2. We have not, however, been able to locate a transition state for this decomposition (or the corresponding oxidative addition) to evaluate the barrier to the forward and reverse reaction, but experiments suggest the formation of Br2 is instantaneous at room temperature from visual observation while NMR experiments show it is complete in the time (~ 1 minute) to introduce the sample to the spectrometer and obtain a single scan.</p><p>We have demonstrated that a mixture of PIFA and 2 TMS-Br gives a solution containing Br2 with no evidence of any observable concentration of PhIBr2. Calculations indicate PhIBr2 lies 18-70 kJ/mol higher in free energy than PhI and Br2, and experimental observations show that Br2 is generated immediately in the reaction. The calculated free energy surface and observed reaction rates suggest that PhIBr2 is not involved in the aryl brominations under consideration. It is demonstrated that Br2 gives the same reactivity as that proposed for PIFA and 2 TMS-Br.</p><p>Based on present results, PhIBr2 should not be invoked as an intermediate for these reactions under the previously reported conditions. However, the mixture of PIFA or PIDA and 2 TMS-Br could be used as a convenient source of Br2 in environments such as a glovebox where in situ generation of Br2 rather than handling the bulk liquid is desirable.</p><!><p>The supporting Information is available free of charge on the pubs.acs.org. NMR spectra, UV-Vis plots, and the details of computational data (.pdf)</p>