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Reaction Mechanism of Iodine-Catalyzed Michael Additions Daniel von der Heiden,† Seyma Bozkus,† Martin Klussmann,‡ and Martin Breugst*,† †
Universität zu Köln, Department für Chemie, Greinstraße 4, 50939 Köln, Germany Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
‡
S Supporting Information *
ABSTRACT: Molecular iodine, an easy to handle solid, has been successfully employed as a catalyst in different organic transformations for more than 100 years. Despite being active even in very small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogen bond mechanism as well as hidden Brønsted acid catalysis are frequently discussed as possible explanations. Our kinetic analyses reveal a reaction order of 1 in iodine, indicating that higher iodine species are not involved in the rate-limiting transition state. Our experimental investigations rule out hidden Brønsted acid catalysis by partial decomposition of I2 to HI and suggest a halogen bond activation instead. Finally, molecular iodine turned out to be a similar if not superior catalyst for Michael additions compared with typical Lewis acids.
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INTRODUCTION For more than 100 years, molecular iodine (I2) has been known to effectively catalyze various transformations.1 Hibbert reported as one of the first findings in 1915 that tiny amounts of I2 (0.01 mol %) catalyze the conversion of diacetone alcohol (1) into mesityl oxide (2).2 Over the next decades, many reactions have been published in which molecular iodine acts as the sole catalyst (Scheme 1).1
Scheme 2. Proposed Pathways for HI Generation from Iodine5 and Proposed Modes of Activation for Iodine Catalysis
Scheme 1. Examples of Iodine-Catalyzed Reactions2,3
formation of HI and CO from methanol and iodine in the gas phase.5a In aqueous, alkaline solution, iodine readily disproportionates to yield iodide and different HIOn species. 5c Comparable reactions are also proposed for reactions of iodine with alcohols, and the intermediate organic hypoiodites are oxidized to the corresponding aldehydes.5d−f Accordingly, two modes of activation are often proposed for iodine-catalyzed reactions: Halogen-bond activation and a hidden Brønsted acid catalysis6 (Scheme 2, bottom). So far, only a few mechanistic studies have been performed, and Jereb and co-workers summarized those previous investigations on different classes of iodine-catalyzed reactions: “There is an open debate about the nature of the actual catalyst in I2-catalyzed reactions, particularly when conducted in protic
Iodine-catalyzed reactions have gained more importance in recent years due to the success of halogen bond donors in organic catalysis.4 However, the analysis of the origin of iodine catalysis is further complicated by a potential side reaction of molecular iodine. In the presence of protic solvents, iodine is known to slowly decompose to yield Brønsted acids like HI (Scheme 2, top).5 Cruickshank and Benson reported the © 2017 American Chemical Society
Received: February 24, 2017 Published: March 28, 2017 4037
DOI: 10.1021/acs.joc.7b00445 J. Org. Chem. 2017, 82, 4037−4043
The Journal of Organic Chemistry
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complexes.12 This effect could also explain the low yields observed for protic (and Lewis basic) solvents MeOH and iPrOH. Another plausible explanation is the decomposition of I2 (Scheme 2). However, in this case, the decomposition product has to be a less active catalyst compared to molecular iodine. Kinetic Analysis. To gain a better understanding of the role of iodine in these reactions, we monitored the kinetics of two iodine-catalyzed Michael additions in various solvents by IR spectroscopy and reaction calorimetry (Figure 1). trans-
solvents. There are a plethora of papers, but very little mechanistic explanation is given.”1d Most experimental studies relied on a simple comparison of yields, indicating that iodine is more reactive than its decomposition products.3a,7 In one of the very few detailed mechanistic studies, Katsuko and Takeshi identified charge-transfer complexes between I2 and alcohols in iodine-catalyzed alkoxy−alkoxy exchange reactions of alkylalkoxysilanes8 and suggested heterolytic cleavage of iodine in the transition state. As a consequence, the reaction mechanism and, therefore, the mode of activation of iodinecatalyzed reactions remained unclear.1b,d,f A recent computational investigation revealed that halogen bonding is strong enough to be catalytically relevant, lowering the activation energies for a subsequent nucleophilic attack by up to 30 kJ mol−1 (e.g., for the reaction of 3 and 4, Scheme 1),9 which prompted us to investigate these reactions in more detail experimentally. We now report on a thorough experimental study on iodine-catalyzed Michael additions to distinguish between halogen bond activation and Brønsted acid catalysis. The experimental data presented below clearly support the picture of halogen bond catalysis and rule out a significant contribution from Brønsted acids in these reactions.
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RESULTS AND DISCUSSION Solvent Effects. We started our analysis of iodine-catalyzed reactions by analyzing the influence of the solvent in these transformations. The reaction between trans-crotonophenone (3) and indole (4) using 5 mol % of I2 was deactivated after 3 min by filtration through a mixture of Na2S2O3 and Na2CO3 on silica, and the reaction progress was monitored by HPLC (Scheme 3; see the Supporting Information for more details). Scheme 3. Solvent Dependency of the HPLC Yields of the Iodine-Catalyzed Michael Addition between transCrotonophenone (3) and Indole (4)
We chose the reaction between 3 and 4 for this analysis as no product can be detected in the absence of any catalyst even after prolonged reaction times, and previous computational data indicated that this reaction is extremely susceptible to iodine catalysis.3a,9 Most aprotic solvents resulted in acceptable to high yields and only for DMSO and DMF no product formation was observed even after extended reaction times. As DMSO (and similarly DMF) can form strong halogenbonded complexes with molecular iodine itself,10 it is likely that this competing complexation reaction deactivates the catalyst for the Michael addition. This interpretation is supported by the comprehensive Lewis basicity scale based on reactions with molecular iodine:11 DMSO (ΔG = −8.9 kJ mol−1) and DMF (ΔG = −4.6 kJ mol−1) bind significantly stronger to iodine than other solvents (Et2O, +0.3; CH3CN, +0.4; benzene, +3.5 kJ mol−1). These findings are also in agreement with the previous analysis of solvent effects of different halogen-bonded
Figure 1. Determining the reaction order in iodine for the reaction between indole (4) and chalcone (9) in 1,4-dioxane (top, IR analysis, ([4] = [9] = 0.5 mol L−1; [xylene] = 90 mmol L−1 (internal standard) 23 °C), 5-methoxyindole (11) and chalcone (9) in acetonitrile (bottom, reaction calorimetry, [9] = 100 mmol L−1, [11] = 80 mmol L−1, [xylene] = 23 mmol L−1 (internal standard), 23 °C) plotting the initial rates versus the iodine concentration.
Chalcone (9) was employed as electrophile for the kinetic investigations [instead of trans-crotonophenone (3)] to ensure suitable extended reaction times for the kinetic measurements. While the reaction between the electrophile 9 and indole (4) was studied by IR spectroscopy, 5-methoxyindole (11) was chosen as nucleophile for the calorimetric experiments. The reaction is more exergonic in the case of 11, which leads to a better signal-to-noise ratio in the kinetic runs. All reactions proceed with high yields, and no side products could be 4038
DOI: 10.1021/acs.joc.7b00445 J. Org. Chem. 2017, 82, 4037−4043
The Journal of Organic Chemistry
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In all cases, significantly higher yields have been obtained for iodine compared to the Brønsted acid HI. Similar results have also been observed in the reactions of 5-methoxy- (11) and 5cyanoindole (12) with both Michael acceptors 3 and 9 (Table 2). The use of trifluoromethanesulfonic acid as another strong
detected under the reaction conditions. As shown in the Supporting Information, conversions determined by 1H NMR spectroscopy at different points of the reaction perfectly fit to those determined by reaction calorimetry, indicating that this method is suitable for reaction monitoring. In all cases, conversions were determined by 1H NMR spectroscopy at the end of the kinetic experiments with respect to an internal standard (xylene; see the Supporting Information for details). To determine the reaction order in iodine, a series of kinetic experiments with variable iodine concentrations under otherwise identical conditions were studied in different solvents. Plotting the initial rate13 versus the concentration of iodine (Figure 1) resulted in linear correlations, indicating a reaction order of 1 for iodine (see the Supporting Information for more details). Similar conclusions can also be obtained from doublelogarithmic plots or the reaction progress kinetic analysis method.14 The results exclude the participation of higher iodine species (e.g., I3+ or I3−) in the rate-limiting step of these transformations. In combination with the effective deactivation of iodine by iodide (see below), the experimentally observed first order in iodine also argues against mechanistic proposals involving a heterolytic cleavage of I2 (→ I+ and I−)15 as the latter should recombine with molecular iodine and form the triiodide anion. Halogen Bond vs Brønsted Acid Catalysis. Next, we had to distinguish between halogen bond activation or an activation by Brønsted acids formed under the reaction conditions (Scheme 2). As both pathways are in agreement with a reaction order of 1 in iodine, we started this analysis with a comparison of the reactivities of both species in different solvents for the reaction shown in Scheme 3. Both catalysts (I2 and HI) were used in 5 mol % loadings in acetonitrile, and the reactions were deactivated by addition of an aqueous alkaline Na2S2O3 solution. Commercially available, aqueous HI (57 wt %) was used for acetonitrile solutions which turned out to be unsuitable for the less polar solvents CH2Cl2 and toluene because it formed inhomogeneous mixtures. Therefore, anhydrous HI freshly prepared from KI and H4P2O7 was used for these solvents (see the Supporting Information for details).16 As the solubility of HI is limited in these solvents, slightly smaller catalyst loadings (3 and 2 mol %) were used for CH2Cl2 and toluene, and the results are summarized in Table 1.
Table 2. Yields for the I2- and HI-Catalyzed Reaction between Substituted Indoles and Several Michael Acceptors (CH3CN, 23 °C)
CH3CN CH2Cl2 toluene a
catalyst loading (mol %) 5 3 2
yield (iodine) (%) a
93 (73) 72 60
a
R2
product
time (min)
yield (iodine) (%)
yield (HI) (%)
H OMe CN H OMe CN
Me Me Me Ph Ph Ph
5 14 15 10 12 16
3 3 3 20 20 20
73 78 72 47 51 23
40 45 31 16 17 14
Brønsted acid gave essentially the same results in acetonitrile. These comparisons indicate that iodine seems to be the more active catalyst system compared to simple Brønsted acids. As the different yields in Table 1 and 2 indicate that different mechanisms might be responsible for I2 and HI catalysis, we set out to experimentally distinguish between these pathways (Table 3). Acetonitrile was used as the solvent for these Table 3. Yields for the I2- and HI-Catalyzed Reaction between trans-Crotonophenone (3) and Indole (4) in the Presence of Additives (CH3CN, 23 °C, 3 min) entry
catalytic system
yield (%)
entry
catalytic system
yield (%)
1 2 3 4 5
no catalyst I2 I2 + H2Oa I2 + KI I2 + MS
0 73 71 0 78
6 7 8 9
HI HI + KI HI + MS HI + MS + KI
40 40 19 0
a
The water content (28 mol %) is identical to those reactions that employ aqueous HI as catalyst.
Table 1. HPLC Yields (Yields in Parentheses) for the I2- and HI-Catalyzed Reaction between trans-Crotonophenone (3) and Indole (4) in Different Solvents (23 °C, 3 min) solvent
R1
experiments to ensure homogeneous reactions, and we employed aqueous HI (57 wt %) as Brønsted acid. In the absence of any catalyst, no product could be detected by HPLC (Table 3, entry 1). We initially analyzed the influence of traces of water in the reaction mixture on the catalytic activity of molecular iodine. Addition of 28 mol % water (the amount of water present in the experiments with HI) resulted in an almost identical yield (Table 3, entry 3), indicating that small amounts of water do not affect the reactivity of molecular iodine. The catalytic activity of molecular iodine can be completely suppressed by addition of KI (approximately 1 equiv), while the reactivity of the Brønsted acid remains unchanged upon addition of KI (Table 3, entries 4 and 7). This is most likely caused by the formation of triiodide ions (eq 1).18 This assumption is further supported by strong UV bands at 290 and 360 that were observed when KI was added to an iodine solution in CH3CN (see the Supporting Information for details).19 Furthermore, no product could be detected by
yield (HI) (%) 58a (40)a 34 17
Average of four experiments; standard deviation 3%.
A potential side reaction, the addition of HI to transcrotonophenone (3),17 was not observed under the reaction conditions. However, small amounts of the addition product (
