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Cite this: Chem. Commun., 2014, 50, 6281 Received 31st March 2014, Accepted 30th April 2014
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Activation of a carbonyl compound by halogen bonding† Stefan H. Jungbauer,ab Sebastian M. Walter,a Severin Schindler,ab Laxmidhar Rout,a Florian Kniepa and Stefan M. Huber*ab
DOI: 10.1039/c4cc03124e www.rsc.org/chemcomm
Using a prototypical Diels–Alder reaction as benchmark, we show that dicationic halogen-bond donors are capable of activating a neutral organic substrate. By various comparison experiments, the action of traces of acid or of other structural features of the halogen-bond donor not related to halogen bonding are excluded with high certainty.
Halogen bonds, the noncovalent interactions between electrophilic halogen substituents and Lewis bases,1 had received very little attention in previous decades2 but have re-emerged since the 1990s as a reliable motif for crystal engineering.3 Applications in solution, however, have only started to appear in the last few years.4 One research area in which hydrogen bonds play an important role is non-covalent organocatalysis.5 Halogen bonds, in contrast, have so far found very limited use in organic synthesis.6 This is somewhat surprising, given that halogen bonds can be similar in strength to hydrogen bonds7 but offer some potential advantageous features. These features include a very high directionality,8 interacting atoms that are bigger in size and more polarizable (‘‘softer’’)9 than hydrogen, and the fact that halogen-bond donors are typically based on different backbone groups than hydrogen-bond donors (e.g. perfluorinated groups), leading to different solubility profiles. Prior to 2011, there were two reports in which halogen-bond donors were used as organocatalysts: the reduction of quinoline derivatives, catalyzed by iodoperfluoroalkanes,6a and the ringopening polymerization of L-lactide, catalyzed by iodine trichloride.6b Although spectroscopic evidence for halogen bonding was obtained in both cases, it remains unclear whether or to which extend the mode of action is indeed based on halogen bonds, especially since only a limited number of comparison experiments were performed and acid traces were not excluded.
In the last years, we reported that dicationic imidazolium,6c pyridinium,6d and triazolium-based6e halogen-bond donors may serve as stoichiometric activators in reactions involving a carbon– halogen bond cleavage. Recently, we could also show that neutral halogen-bond donors can be used as organocatalysts in these reactions.6f However, in all these investigations it is not clear whether the halogen-bond donors bind to the neutral substrate, or to a halide anion that is liberated in equilibrium from the substrate. So, all in all, convincing evidence for the activation of a neutral compound by halogen bonding is still lacking. Herein, we show that halogen-bond donors act as organocatalysts in a prototypical Diels–Alder reaction (Scheme 1) and that the mode of activation is very likely based on halogen bonding (excluding, inter alia, hidden acid catalysis). We chose to use a Diels–Alder reaction because it represents a well established benchmark for Lewis acids, most notably also including hydrogenbonding thiourea derivatives.10 In addition, the feasibility of twofold halogen bonding to a carbonyl group has already been demon¨llhorn et al. in a solid state structure involving strated by Scho Michlers ketone, in which the carbonyl oxygen forms halogen bonds to two molecules of 1,4-diiodotetrafluorobenzene.11 In our previous investigations, we had used dicationic as well as neutral (polyfluorinated) halogen-bond donors. As a direct comparison between these two types of halogen-based Lewis acids had shown that cationic backbones generate much stronger halogenbond donors than neutral variants,12 we decided to employ dicationic imidazolium-based catalyst candidates like 2/OTf (Scheme 2) in this study. In a series of test reactions (including the Diels–Alder reaction of Scheme 1), this compound showed no activity, however. Reasoning that the weakly-coordinating triflate counterion might outcompete the neutral substrates for the electrophilic iodine centers, the anion
a
¨t Mu ¨nchen, Lichtenbergstraße 4, Department Chemie, Technische Universita D-85747 Garching, Germany b ¨r Chemie und Biochemie, Ruhr-Universita¨t Bochum, Fakulta¨t fu ¨tsstraße 150, D-44801 Bochum, Germany. Universita E-mail: [email protected]; Tel: +49 234 32-21584 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc03124e
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Scheme 1
Diels–Alder benchmark reaction.
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ChemComm Table 1 Diels–Alder reaction (Scheme 1) in the presence of various Lewis acids: yield of 1 after sixa hours (CD2Cl2, r.t.)
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Scheme 2 Anion exchange reaction; (i) 2.2 equiv. tetramethylammonium (TMA) BArF4, CH2Cl2/MeOH 3 : 1; yield: 68%.
was exchanged with the non-coordinating B[3,5-(CF3)2C6H3]4 (‘‘BArF4 ’’)13 anion by metathesis with NaBArF4. In further orientating experiments, the halogen-bond donor resulting from this anion exchange (2/BArF4) proved to be active in the activation of neutral compounds. However, although compound 2/BArF4 was obtained in high purity, it subsequently turned out to be very difficult to rigorously rule out that traces of NaBArF4 were the actual active component. Hence, we modified our synthetic approach and used the tetramethylammonium (TMA) salt instead of the sodium salt of this non-coordinating ion for the anion exchange reaction, yielding the product in 68% yield (Scheme 2). This batch of 2/BArF4 displayed similar activity as the one resulting from NaBArF4. To evaluate the catalytic activity of the halogen-bond donor, the Diels–Alder reaction shown in Scheme 1 was performed in CD2Cl2 and monitored by 1H-NMR spectroscopy in the presence of various catalyst candidates (see also Fig. 1). Without any catalyst, the background reactivity is comparably slow, with a yield of product 1 of 24% after roughly six hours (Table 1, entry 1 as well as Fig. 2), and an endo/exo ratio of approximately 5. As already indicated above, addition of 20 mol% of 2/OTf did not accelerate the reaction, likely because the counterions are too nucleophilic compared to the substrate (entry 2). In stark contrast, 20 mol% of halogen-bond donor 2/BArF4 considerably increase the rate of product formation, resulting in a yield of product 1 of 63% after approximately six hours (entry 3). Compared to the blank reaction, the product distribution is shifted more towards the endo product (endo/exo = 10). Using the initial inclination of the product formation over time graph as a rough orientation, it can be estimated that 2/BArF4 causes a relative rate acceleration krel of about a factor of 9 (relative to the blank reaction). These experiments clearly demonstrate the strong counterion effect since 2/OTf and the active variant 2/BArF4 differ only by the anion. To exclude that impurities remaining from the anion exchange step constitute the actual active reagent, we performed further comparison experiments, in which 20 mol% of TMA BArF4 or 2 mol% of methanol were added to the Diels–
Fig. 1
Further catalyst candidates applied.
6282 | Chem. Commun., 2014, 50, 6281--6284
Entry
Lewis acid
Equiv.b
Yielda [%]
1 2 3 4 5 6 7 8 9
— 2/OTf 2/BArF4 TMA BArF4 MeOH 2/BArF4 + 2.5 NBu4OTf 5 3/BArF4 4/BArF4
— 0.2 0.2 0.2 0.02 0.2 0.2 0.2 0.2
24 24 63 24 24 24 38 28 24
a Yield of 1 determined by 1H-NMR spectroscopy, extrapolated to six hours of reaction time (cf. Fig. S2 in the ESI). b Equivalents of Lewis acid.
Fig. 2 Yield versus time profile of the Diels–Alder reaction in the presence of various Lewis acids (cf. Table 1); y-axis: yield of 1 in %, x-axis: time in min.
Alder reaction (entries 4 and 5). No acceleration was observed in either case.14 Further evidence that the activity of 2/BArF4 is not caused by impurities from the anion exchange is the fact that its activity in the benchmark reaction can be completely quenched by addition of 2.5 equivalents of tetrabutylammonium triflate (entry 6). Taken together, this is a strong indication that the iodine centers, as the most electrophilic position of the cation,15 are essential for the activation, which is thus very likely based on halogen bonding. As our long-term goal is to establish halogen-bond donors as organocatalysts, we also compared the performance of 2/BArF4 with a prototypical hydrogen-bonding-based organocatalyst, namely thiourea 5.10 Using identical reaction conditions, 20 mol% of 5 lead to a noticeable rate acceleration of the Diels–Alder reaction, and 38% of product were obtained after six hours (entry 7; endo/exo = 7). In a rough estimation, the relative rate krel corresponds to a factor of 2. This comparison with a hydrogen-bond donor which has been the basis of numerous effective organocatalysts5 indicates that halogenbond based variants may in the future find comparable use. The reactivity difference found here is also in agreement with previous findings that thiourea 5 binds less strong to halides than 2/OTf,16 and that the organocatalytic activity of 5 in a halide abstraction reaction is lower than that of neutral polyfluorinated bidentate halogen-bond donors.6f
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Fig. 3 Cutouts of the 13C-NMR spectra of 2/BArF4 (bottom) and 2/BArF4 with approx. 8 equivalents of cyclohexanone (top). Imidazolium carbon atoms of 2/BArF4 marked (x-axis: ppm).
In principle, halogen-bond donor 2/BArF4 might also act through the acidic backbone protons of the imidazolium moieties. Unfortunately, the corresponding non-iodinated analogue to 2/BArF4 could not be obtained, as the anion exchange remained incomplete. Instead, we chose to compare the monodentate variants 3/BArF4 and 4/BArF4 (Fig. 1) in the test reaction. When added in 20 mol%, the former accelerated the reaction markedly lower than 2/BArF4, but still outside of experimental errors. In contrast, the non-iodinated analogue 4/BArF4 did not increase product formation. As both compounds differ only at the C2-position of the imidazolium core, this renders a mode of action based on the imidazolium protons very unlikely. Further evidence that the iodine centers (but not the backbone protons) are causally related to the activation of the substrate stems from 13C-NMR titrations. When 8 equivalents of cyclohexanone as test substrate are added to halogen-bond donor 2/BArF4, the peak of the iodine-carrying carbon atom shifts by about 2.0 ppm, while the hydrogen-carrying carbon atoms of the imidazolium moieties shift by only 0.2 ppm (Fig. 3). This 13C-NMR shift could also be employed to determine the binding constant of 2/BArF4 to cyclohexanone (see ESI†). Fitting of the titration curve to a 1 : 1 stoichiometry yielded a value of K E 4 M 1. As the binding constant was obtained by observing the halogen-bond donor, the influence of other electrophiles on the binding constant can safely be disregarded. Finally, one of the most difficult issues in proof-of-principle studies involving halogen-bond donors is to rule out that traces of acid, either present as impurities or formed during the reaction, are the actual catalytically active species. This is especially true for the current test reaction, which is also strongly accelerated by trace amounts of acid. Using a non-nucleophilic base to directly exclude this failed, however, as some bases were inefficient to quench acid traces (Na2CO3, K2CO3), some lead to decomposition of 2/BArF4 (Cs2CO3, DBU), and one (2,6-bis(tert-butyl)pyridine) coordinated to 2/BArF4 according to 13C-NMR. Due to this absence of a suitable non-nucleophilic base, we next turned our attention towards indirect evidence to show that the halogen-bond donors are not contaminated with (and do not liberate) traces of acid. Once again, 13C-NMR shift investigations proved helpful in this regard, this time by focusing on the 13C-NMR shift of the carbonyl group of cyclohexanone upon the addition of either acid (triflic acid)17 or halogen-bond donor. These comparison experiments revealed that 2/BArF4 would
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need to be contaminated with at least 4% of acid to generate the same shift of the cyclohexanone carbonyl signal as was observed for 2/BArF4 – if the shift induced at cyclohexanone was entirely due to acid traces (see ESI† for details).18 Importantly, while the activity of 2/BArF4 in the test reaction can be quenched by 2.5 equivalents of NBu4OTf (Table 1, entry 6), even 1.2% – far less than 4% – of acid remain active in the Diels–Alder reaction in the presence of 2.5 equivalents of NBu4OTf, leading to full conversion to the product (1) (see ESI†). Thus, if the activity of 2/BArF4 would be due to acid traces, it should not be quenchable as just described, in contrast to the experimental results. While this evidence is certainly indirect, we feel that it excludes the action of acid impurities with high certainty, once again indicating that halogen bonding is at the heart of the observed reactivity. Finally, orientating DFT calculations were performed to demonstrate the feasibility of the halogen-bond based activation of neutral organic substrates. To this end, the M06-2X density functional19 was employed with the Gaussian09 suite of programs,20 in combination with a triple-zeta TZVPP21 basis set and the corresponding pseudopotential for iodine.22 Free energies were obtained by single-point calculations on the minimum or transition state structures with additional D3 dispersion corrections by Grimme23 and the SMD intrinsic solvation model24 using parameters for dichloromethane. Methyl vinyl ketone was found to form a stable complex with halogen-bond donor 225 featuring bidentate halogen-bonding with identical O–I distances of 2.86 Å, far below the sum of the van-der-Waals radii (3.50 Å; C–I–O angles: 1651; see ESI†).26 The binding to the halogen-bond donor leads to a slight elongation of the CQO bond of the ketone (1.23 Å vs. 1.21 Å), as would be expected for a Lewis acid adduct. More importantly, the barrier of activation of the Diels–Alder reaction shown in Scheme 1 was also found to be lowered by bidentate coordination of the ketone by halogen-bond donor 225 (cf. Fig. 4): while the uncatalyzed reaction has a reaction barrier of 29.5 kcal mol 1, coordination of the halogen-based Lewis acid reduces the barrier of activation to 26.5 kcal mol 1.
Fig. 4 Transition state structure of the Diels–Alder reaction catalyzed by halogen-bond donor 2, as obtained by DFT calculations (M062X TZVPP). Distances in Ångstrom. Graphic representation by CYLview.27
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The fact that the transition state is more stabilized by the halogen-bond donor than the starting material (ketone) is also evident from the I–O distances, which are 2.70 and 2.75 Å in the transition state, markedly shorter than in the adduct with methyl vinyl ketone alone (C–I–O angles: 1651 for both). The transition state is also more asynchronous in the presence of the halogen-bond donor, as the b-carbon of the ketone features a longer C–C distance to the diene (2.59 vs. 2.28 Å), while the distance of the g-carbon to the target carbon atom of cyclopentadiene is noticeably shorter (1.99 vs. 2.12 Å). Despite the orientating nature of these calculations, they still provide further indication that the activation of neutral organic substrates by halogen-bond donors is feasible and thus support the experimental findings. Using a prototypical Diels–Alder reaction as benchmark, extensive evidence was presented to show that dicationic halogen-bond donors with non-coordinating counterions are capable of activating a carbonyl compound. By various comparison experiments, the action of traces of acid as well as of other structural features of the halogen-bond donor not related to halogen bonding were excluded with high certainty. This is thus the first case in which strong evidence for the activation of a neutral organic compound by halogen bonding is provided. We believe that the results presented herein represent an important further step towards the future utilization of halogen bonding in (enantioselective) organocatalysis. Our research was funded by the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft. L.R. thanks the Humboldt Foundation for a postdoctoral scholarship. We thank Prof. Dr. Thorsten Bach for his support at TU Munich. This work was also supported by the Cluster of Excellence RESOLV (EXC 1069) funded by the DFG.
Notes and references 1 Reviews: (a) P. Metrangolo, F. Meyer, T. Pilati, G. Resnati and G. Terraneo, Angew. Chem., Int. Ed., 2008, 47, 6114; (b) M. Fourmigue, Curr. Opin. Solid State Mater. Sci., 2009, 13, 36; (c) A. C. Legon, Phys. Chem. Chem. Phys., 2010, 12, 7736; (d) Y. Lu, Y. Wang and W. Zhu, Phys. Chem. Chem. Phys., 2010, 12, 4543; Selected publications: (e) N. L. Kilah, M. D. Wise, C. J. Serpell, A. L. Thompson, N. G. White, K. E. Christensen and P. D. Beer, J. Am. Chem. Soc., 2010, 132, 11893; ( f ) A. Vargas Jentzsch, D. Emery, J. Mareda, P. Metrangolo, G. Resnati and S. Matile, Angew. Chem., Int. Ed., 2011, 50, 11675; ( g) L. A. Hardegger, B. Kuhn, B. Spinnler, L. Anselm, R. Ecabert, M. Stihle, B. Gsell, R. Thoma, J. Diez, J. Benz, J.-M. Plancher, G. Hartmann, D. W. Banner, W. Haap and F. Diederich, Angew. Chem., Int. Ed., 2011, 50, 314; (h) A.-C. C. Carlsson, J. Grafenstein, A. Budnjo, J. L. Laurila, J. Bergquist, A. Karim, R. Kleinmaier, U. Brath and M. Erdelyi, J. Am. Chem. Soc., 2012, 134, 5706; (i) L. Meazza, J. A. Foster, K. Fucke, P. Metrangolo, G. Resnati and J. W. Steed, Nat. Chem., 2013, 5, 42.
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ChemComm 2 (a) O. Hassel and C. Roemming, Q. Rev., Chem. Soc., 1962, 16, 1; (b) H. A. Bent, Chem. Rev., 1968, 68, 587; (c) R. Weiss, G. E. Miess, A. Haller and W. Reinhardt, Angew. Chem., Int. Ed. Engl., 1986, 25, 103; (d) A. C. Legon, Angew. Chem., Int. Ed., 1999, 38, 2686. 3 Reviews: (a) L. Brammer, G. M. Espallargas and S. Libri, CrystEngComm, 2008, 10, 1712; (b) G. Cavallo, P. Metrangolo, T. Pilati, G. Resnati, M. Sansotera and G. Terraneo, Chem. Soc. Rev., 2010, 39, 3772. 4 (a) M. Erdelyi, Chem. Soc. Rev., 2012, 41, 3547; (b) T. M. Beale, M. G. Chudzinski, M. G. Sarwar and M. S. Taylor, Chem. Soc. Rev., 2013, 42, 1667. 5 (a) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38, 1187; (b) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713. 6 (a) A. Bruckmann, M. A. Pena and C. Bolm, Synlett, 2008, 900; (b) O. Coulembier, F. Meyer and P. Dubois, Polym. Chem., 2010, 1, 434; (c) S. M. Walter, F. Kniep, E. Herdtweck and S. M. Huber, Angew. Chem., Int. Ed., 2011, 50, 7187; (d) F. Kniep, S. M. Walter, E. Herdtweck and S. M. Huber, Chem. – Eur. J., 2012, 18, 1306; (e) F. Kniep, L. Rout, S. M. Walter, H. K. V. Bensch, S. H. Jungbauer, E. Herdtweck and S. M. Huber, Chem. Commun., 2012, 48, 9299; ( f ) F. Kniep, S. H. Jungbauer, Q. Zhang, S. M. Walter, S. Schindler, I. Schnapperelle, E. Herdtweck and S. M. Huber, Angew. Chem., Int. Ed., 2013, 52, 7028. 7 E. Corradi, S. V. Meille, M. T. Messina, P. Metrangolo and G. Resnati, Angew. Chem., Int. Ed., 2000, 39, 1782. 8 S. M. Huber, J. D. Scanlon, E. Jimenez-Izal, J. M. Ugalde and I. Infante, Phys. Chem. Chem. Phys., 2013, 15, 10350 and cited ref. 9 R. G. Pearson, J. Am. Chem. Soc., 1963, 85, 3533. 10 A. Wittkopp and P. R. Schreiner, Chem. – Eur. J., 2003, 9, 407. ´, K. Boubekeur and B. Scho ¨llhorn, J. Mol. Struct., 11 J.-L. Syssa-Magale 2005, 737, 103. 12 S. M. Walter, S. H. Jungbauer, F. Kniep, S. Schindler, E. Herdtweck and S. M. Huber, J. Fluorine Chem., 2013, 150, 14. 13 N. A. Yakelis and R. G. Bergman, Organometallics, 2005, 24, 3579 and cited ref. 14 Water reduces the activity of 2/BArF4, and so in all experiments described herein, the water content of CD2Cl2 was kept o10 ppm. 15 In the crystal structure of 2/OTf (see ref. 6c), close contacts between oxygen atoms of the triflate with the iodine substituents were observed. 16 S. M. Walter, F. Kniep, L. Rout, F. P. Schmidtchen, E. Herdtweck and S. M. Huber, J. Am. Chem. Soc., 2012, 134, 8507. 17 HBArF4 is not experimentally accessible. 18 The 13C-NMR shift of the cyclohexanone carbonyl carbon atom in the presence of 2/BArF4 did not change over several hours (more than the reaction time used in the Diels–Alder study), which rules out a release of acid by slow decomposition of the halogen-bond donor. 19 Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215. 20 M. J. Frisch, et al., Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford CT, 2009 (see ESI†). 21 F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys., 2005, 7, 3297. 22 K. A. Peterson, D. Figgen, E. Goll, H. Stoll and M. Dolg, J. Chem. Phys., 2003, 119, 11113. 23 S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys., 2010, 132, 154104. 24 A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys. Chem. B, 2009, 113, 6378. 25 The non-coordinating BArF4 anions were omitted and the octyl side chains were replaced by methyl groups for reasons of computational costs. 26 A. Bondi, J. Phys. Chem., 1964, 68, 441. ´ de Sherbrooke, 2009, http:// 27 C. Y. Legault, CYLview, 1.0b, Universite www.cylview.org.
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Cite this: Chem. Commun., 2014, 50, 6281 Received 31st March 2014, Accepted 30th April 2014
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Activation of a carbonyl compound by halogen bonding† Stefan H. Jungbauer,ab Sebastian M. Walter,a Severin Schindler,ab Laxmidhar Rout,a Florian Kniepa and Stefan M. Huber*ab
DOI: 10.1039/c4cc03124e www.rsc.org/chemcomm
Using a prototypical Diels–Alder reaction as benchmark, we show that dicationic halogen-bond donors are capable of activating a neutral organic substrate. By various comparison experiments, the action of traces of acid or of other structural features of the halogen-bond donor not related to halogen bonding are excluded with high certainty.
Halogen bonds, the noncovalent interactions between electrophilic halogen substituents and Lewis bases,1 had received very little attention in previous decades2 but have re-emerged since the 1990s as a reliable motif for crystal engineering.3 Applications in solution, however, have only started to appear in the last few years.4 One research area in which hydrogen bonds play an important role is non-covalent organocatalysis.5 Halogen bonds, in contrast, have so far found very limited use in organic synthesis.6 This is somewhat surprising, given that halogen bonds can be similar in strength to hydrogen bonds7 but offer some potential advantageous features. These features include a very high directionality,8 interacting atoms that are bigger in size and more polarizable (‘‘softer’’)9 than hydrogen, and the fact that halogen-bond donors are typically based on different backbone groups than hydrogen-bond donors (e.g. perfluorinated groups), leading to different solubility profiles. Prior to 2011, there were two reports in which halogen-bond donors were used as organocatalysts: the reduction of quinoline derivatives, catalyzed by iodoperfluoroalkanes,6a and the ringopening polymerization of L-lactide, catalyzed by iodine trichloride.6b Although spectroscopic evidence for halogen bonding was obtained in both cases, it remains unclear whether or to which extend the mode of action is indeed based on halogen bonds, especially since only a limited number of comparison experiments were performed and acid traces were not excluded.
In the last years, we reported that dicationic imidazolium,6c pyridinium,6d and triazolium-based6e halogen-bond donors may serve as stoichiometric activators in reactions involving a carbon– halogen bond cleavage. Recently, we could also show that neutral halogen-bond donors can be used as organocatalysts in these reactions.6f However, in all these investigations it is not clear whether the halogen-bond donors bind to the neutral substrate, or to a halide anion that is liberated in equilibrium from the substrate. So, all in all, convincing evidence for the activation of a neutral compound by halogen bonding is still lacking. Herein, we show that halogen-bond donors act as organocatalysts in a prototypical Diels–Alder reaction (Scheme 1) and that the mode of activation is very likely based on halogen bonding (excluding, inter alia, hidden acid catalysis). We chose to use a Diels–Alder reaction because it represents a well established benchmark for Lewis acids, most notably also including hydrogenbonding thiourea derivatives.10 In addition, the feasibility of twofold halogen bonding to a carbonyl group has already been demon¨llhorn et al. in a solid state structure involving strated by Scho Michlers ketone, in which the carbonyl oxygen forms halogen bonds to two molecules of 1,4-diiodotetrafluorobenzene.11 In our previous investigations, we had used dicationic as well as neutral (polyfluorinated) halogen-bond donors. As a direct comparison between these two types of halogen-based Lewis acids had shown that cationic backbones generate much stronger halogenbond donors than neutral variants,12 we decided to employ dicationic imidazolium-based catalyst candidates like 2/OTf (Scheme 2) in this study. In a series of test reactions (including the Diels–Alder reaction of Scheme 1), this compound showed no activity, however. Reasoning that the weakly-coordinating triflate counterion might outcompete the neutral substrates for the electrophilic iodine centers, the anion
a
¨t Mu ¨nchen, Lichtenbergstraße 4, Department Chemie, Technische Universita D-85747 Garching, Germany b ¨r Chemie und Biochemie, Ruhr-Universita¨t Bochum, Fakulta¨t fu ¨tsstraße 150, D-44801 Bochum, Germany. Universita E-mail: [email protected]; Tel: +49 234 32-21584 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc03124e
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Scheme 1
Diels–Alder benchmark reaction.
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ChemComm Table 1 Diels–Alder reaction (Scheme 1) in the presence of various Lewis acids: yield of 1 after sixa hours (CD2Cl2, r.t.)
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Scheme 2 Anion exchange reaction; (i) 2.2 equiv. tetramethylammonium (TMA) BArF4, CH2Cl2/MeOH 3 : 1; yield: 68%.
was exchanged with the non-coordinating B[3,5-(CF3)2C6H3]4 (‘‘BArF4 ’’)13 anion by metathesis with NaBArF4. In further orientating experiments, the halogen-bond donor resulting from this anion exchange (2/BArF4) proved to be active in the activation of neutral compounds. However, although compound 2/BArF4 was obtained in high purity, it subsequently turned out to be very difficult to rigorously rule out that traces of NaBArF4 were the actual active component. Hence, we modified our synthetic approach and used the tetramethylammonium (TMA) salt instead of the sodium salt of this non-coordinating ion for the anion exchange reaction, yielding the product in 68% yield (Scheme 2). This batch of 2/BArF4 displayed similar activity as the one resulting from NaBArF4. To evaluate the catalytic activity of the halogen-bond donor, the Diels–Alder reaction shown in Scheme 1 was performed in CD2Cl2 and monitored by 1H-NMR spectroscopy in the presence of various catalyst candidates (see also Fig. 1). Without any catalyst, the background reactivity is comparably slow, with a yield of product 1 of 24% after roughly six hours (Table 1, entry 1 as well as Fig. 2), and an endo/exo ratio of approximately 5. As already indicated above, addition of 20 mol% of 2/OTf did not accelerate the reaction, likely because the counterions are too nucleophilic compared to the substrate (entry 2). In stark contrast, 20 mol% of halogen-bond donor 2/BArF4 considerably increase the rate of product formation, resulting in a yield of product 1 of 63% after approximately six hours (entry 3). Compared to the blank reaction, the product distribution is shifted more towards the endo product (endo/exo = 10). Using the initial inclination of the product formation over time graph as a rough orientation, it can be estimated that 2/BArF4 causes a relative rate acceleration krel of about a factor of 9 (relative to the blank reaction). These experiments clearly demonstrate the strong counterion effect since 2/OTf and the active variant 2/BArF4 differ only by the anion. To exclude that impurities remaining from the anion exchange step constitute the actual active reagent, we performed further comparison experiments, in which 20 mol% of TMA BArF4 or 2 mol% of methanol were added to the Diels–
Fig. 1
Further catalyst candidates applied.
6282 | Chem. Commun., 2014, 50, 6281--6284
Entry
Lewis acid
Equiv.b
Yielda [%]
1 2 3 4 5 6 7 8 9
— 2/OTf 2/BArF4 TMA BArF4 MeOH 2/BArF4 + 2.5 NBu4OTf 5 3/BArF4 4/BArF4
— 0.2 0.2 0.2 0.02 0.2 0.2 0.2 0.2
24 24 63 24 24 24 38 28 24
a Yield of 1 determined by 1H-NMR spectroscopy, extrapolated to six hours of reaction time (cf. Fig. S2 in the ESI). b Equivalents of Lewis acid.
Fig. 2 Yield versus time profile of the Diels–Alder reaction in the presence of various Lewis acids (cf. Table 1); y-axis: yield of 1 in %, x-axis: time in min.
Alder reaction (entries 4 and 5). No acceleration was observed in either case.14 Further evidence that the activity of 2/BArF4 is not caused by impurities from the anion exchange is the fact that its activity in the benchmark reaction can be completely quenched by addition of 2.5 equivalents of tetrabutylammonium triflate (entry 6). Taken together, this is a strong indication that the iodine centers, as the most electrophilic position of the cation,15 are essential for the activation, which is thus very likely based on halogen bonding. As our long-term goal is to establish halogen-bond donors as organocatalysts, we also compared the performance of 2/BArF4 with a prototypical hydrogen-bonding-based organocatalyst, namely thiourea 5.10 Using identical reaction conditions, 20 mol% of 5 lead to a noticeable rate acceleration of the Diels–Alder reaction, and 38% of product were obtained after six hours (entry 7; endo/exo = 7). In a rough estimation, the relative rate krel corresponds to a factor of 2. This comparison with a hydrogen-bond donor which has been the basis of numerous effective organocatalysts5 indicates that halogenbond based variants may in the future find comparable use. The reactivity difference found here is also in agreement with previous findings that thiourea 5 binds less strong to halides than 2/OTf,16 and that the organocatalytic activity of 5 in a halide abstraction reaction is lower than that of neutral polyfluorinated bidentate halogen-bond donors.6f
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Fig. 3 Cutouts of the 13C-NMR spectra of 2/BArF4 (bottom) and 2/BArF4 with approx. 8 equivalents of cyclohexanone (top). Imidazolium carbon atoms of 2/BArF4 marked (x-axis: ppm).
In principle, halogen-bond donor 2/BArF4 might also act through the acidic backbone protons of the imidazolium moieties. Unfortunately, the corresponding non-iodinated analogue to 2/BArF4 could not be obtained, as the anion exchange remained incomplete. Instead, we chose to compare the monodentate variants 3/BArF4 and 4/BArF4 (Fig. 1) in the test reaction. When added in 20 mol%, the former accelerated the reaction markedly lower than 2/BArF4, but still outside of experimental errors. In contrast, the non-iodinated analogue 4/BArF4 did not increase product formation. As both compounds differ only at the C2-position of the imidazolium core, this renders a mode of action based on the imidazolium protons very unlikely. Further evidence that the iodine centers (but not the backbone protons) are causally related to the activation of the substrate stems from 13C-NMR titrations. When 8 equivalents of cyclohexanone as test substrate are added to halogen-bond donor 2/BArF4, the peak of the iodine-carrying carbon atom shifts by about 2.0 ppm, while the hydrogen-carrying carbon atoms of the imidazolium moieties shift by only 0.2 ppm (Fig. 3). This 13C-NMR shift could also be employed to determine the binding constant of 2/BArF4 to cyclohexanone (see ESI†). Fitting of the titration curve to a 1 : 1 stoichiometry yielded a value of K E 4 M 1. As the binding constant was obtained by observing the halogen-bond donor, the influence of other electrophiles on the binding constant can safely be disregarded. Finally, one of the most difficult issues in proof-of-principle studies involving halogen-bond donors is to rule out that traces of acid, either present as impurities or formed during the reaction, are the actual catalytically active species. This is especially true for the current test reaction, which is also strongly accelerated by trace amounts of acid. Using a non-nucleophilic base to directly exclude this failed, however, as some bases were inefficient to quench acid traces (Na2CO3, K2CO3), some lead to decomposition of 2/BArF4 (Cs2CO3, DBU), and one (2,6-bis(tert-butyl)pyridine) coordinated to 2/BArF4 according to 13C-NMR. Due to this absence of a suitable non-nucleophilic base, we next turned our attention towards indirect evidence to show that the halogen-bond donors are not contaminated with (and do not liberate) traces of acid. Once again, 13C-NMR shift investigations proved helpful in this regard, this time by focusing on the 13C-NMR shift of the carbonyl group of cyclohexanone upon the addition of either acid (triflic acid)17 or halogen-bond donor. These comparison experiments revealed that 2/BArF4 would
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need to be contaminated with at least 4% of acid to generate the same shift of the cyclohexanone carbonyl signal as was observed for 2/BArF4 – if the shift induced at cyclohexanone was entirely due to acid traces (see ESI† for details).18 Importantly, while the activity of 2/BArF4 in the test reaction can be quenched by 2.5 equivalents of NBu4OTf (Table 1, entry 6), even 1.2% – far less than 4% – of acid remain active in the Diels–Alder reaction in the presence of 2.5 equivalents of NBu4OTf, leading to full conversion to the product (1) (see ESI†). Thus, if the activity of 2/BArF4 would be due to acid traces, it should not be quenchable as just described, in contrast to the experimental results. While this evidence is certainly indirect, we feel that it excludes the action of acid impurities with high certainty, once again indicating that halogen bonding is at the heart of the observed reactivity. Finally, orientating DFT calculations were performed to demonstrate the feasibility of the halogen-bond based activation of neutral organic substrates. To this end, the M06-2X density functional19 was employed with the Gaussian09 suite of programs,20 in combination with a triple-zeta TZVPP21 basis set and the corresponding pseudopotential for iodine.22 Free energies were obtained by single-point calculations on the minimum or transition state structures with additional D3 dispersion corrections by Grimme23 and the SMD intrinsic solvation model24 using parameters for dichloromethane. Methyl vinyl ketone was found to form a stable complex with halogen-bond donor 225 featuring bidentate halogen-bonding with identical O–I distances of 2.86 Å, far below the sum of the van-der-Waals radii (3.50 Å; C–I–O angles: 1651; see ESI†).26 The binding to the halogen-bond donor leads to a slight elongation of the CQO bond of the ketone (1.23 Å vs. 1.21 Å), as would be expected for a Lewis acid adduct. More importantly, the barrier of activation of the Diels–Alder reaction shown in Scheme 1 was also found to be lowered by bidentate coordination of the ketone by halogen-bond donor 225 (cf. Fig. 4): while the uncatalyzed reaction has a reaction barrier of 29.5 kcal mol 1, coordination of the halogen-based Lewis acid reduces the barrier of activation to 26.5 kcal mol 1.
Fig. 4 Transition state structure of the Diels–Alder reaction catalyzed by halogen-bond donor 2, as obtained by DFT calculations (M062X TZVPP). Distances in Ångstrom. Graphic representation by CYLview.27
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The fact that the transition state is more stabilized by the halogen-bond donor than the starting material (ketone) is also evident from the I–O distances, which are 2.70 and 2.75 Å in the transition state, markedly shorter than in the adduct with methyl vinyl ketone alone (C–I–O angles: 1651 for both). The transition state is also more asynchronous in the presence of the halogen-bond donor, as the b-carbon of the ketone features a longer C–C distance to the diene (2.59 vs. 2.28 Å), while the distance of the g-carbon to the target carbon atom of cyclopentadiene is noticeably shorter (1.99 vs. 2.12 Å). Despite the orientating nature of these calculations, they still provide further indication that the activation of neutral organic substrates by halogen-bond donors is feasible and thus support the experimental findings. Using a prototypical Diels–Alder reaction as benchmark, extensive evidence was presented to show that dicationic halogen-bond donors with non-coordinating counterions are capable of activating a carbonyl compound. By various comparison experiments, the action of traces of acid as well as of other structural features of the halogen-bond donor not related to halogen bonding were excluded with high certainty. This is thus the first case in which strong evidence for the activation of a neutral organic compound by halogen bonding is provided. We believe that the results presented herein represent an important further step towards the future utilization of halogen bonding in (enantioselective) organocatalysis. Our research was funded by the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft. L.R. thanks the Humboldt Foundation for a postdoctoral scholarship. We thank Prof. Dr. Thorsten Bach for his support at TU Munich. This work was also supported by the Cluster of Excellence RESOLV (EXC 1069) funded by the DFG.
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