Origin of the Catalytic Effects of Molecular Iodine: A Computational

Research Article pubs.acs.org/acscatalysis

Origin of the Catalytic Effects of Molecular Iodine: A Computational Analysis Martin Breugst,* Eric Detmar, and Daniel von der Heiden Universität zu Köln, Department für Chemie, Greinstraße 4, 50939 Köln, Germany

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S Supporting Information *

ABSTRACT: Molecular iodine is an excellent catalyst for many organic transformations, but the origin of its catalytic activity is still unknown. To answer this question, we have analyzed four iodine-catalyzed reactions by density functional theory. Our calculations reveal that molecular iodine significantly reduces the activation free energies (−7.6 < ΔG⧧ < −1.8 kcal mol−1) for reactions involving α,β-unsaturated carbonyls or nitrostyrenes. Closer analysis of the nature of the interaction between iodine and the corresponding Michael acceptors suggests that halogen bonding is the origin of the catalytic activity. The computational and experimental studies show that hidden Brønsted acid catalysis as a competing pathway due to the formation of hydrogen iodide via hypoiodites in aprotic solvents seems less likely for these reactions. KEYWORDS: reaction mechanisms, density functional theory, halogen bonding, iodine catalysis, Michael additions

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Scheme 1. Examples of Iodine-Catalyzed Reactions5,6,8,9

INTRODUCTION Molecular iodinean easy to handle solidis soluble in many organic solvents, a weak oxidant, and a weak electrophile as well. Therefore, it is not surprising that I2 is frequently employed both as a stoichiometric reagent and as a catalyst in many different organic reactions.1 Transformations such as iodolactonizations or iodocyclizations are well-known synthetic procedures,2 and iodine can also be used in reactions with acetyl groups under basic conditions (i.e., the Lieben iodoform reaction).3 However, iodine atoms are incorporated in the final products, requiring the use of stoichiometric amounts of iodine in these reactions. Similarly, stoichiometric amounts are needed in reactions building on the redox properties of I2.4 In contrast, a large variety of transformations are known that use iodine only in catalytic amounts. Frequently, I2 is combined with stoichiometric amounts of tert-butyl hydroperoxide (TBHP) as co-oxidant to achieve highly efficient transformations (e.g., the condensation in Scheme 1, eq 1).5 Radical pathways are often proposed for these reactions, and a co-oxidant is usually required for high yields. However, molecular iodine can also be very effective without any additives. One of the first iodine-catalyzed reactions (Scheme 1, eq 2) was reported 100 years ago when Hibbert observed that tiny amounts of I2 (0.01 mol %) efficiently catalyze the dehydration of diacetone alcohol (4) to mesityl oxide (5).6 A large variety of different transformations employing only catalytic amounts of molecular iodine have been published ever since.7 Generally, Michael reactions such as the addition of thiophenol (6) to cyclohexenone (7)8 (Scheme 1, eq 3) can be achieved with 1−10 mol % of I2, and similar amounts are also needed for the Paal−Knorr synthesis of pyrrole 10 (Scheme 1, eq 4).9 While molecular iodine is a highly active catalyst for these reactions even in the absence of any additives, the underlying mode of activation and the origin of the catalytic effects are only poorly understood. © 2016 American Chemical Society

During the last years, iodine-catalyzed reactions gained more interest in light of recent developments of highly active halogenbond-based systems.10 In addition to applications in the fields of crystal engineering11 and anion recognition,12 halogen-bondbased catalysts have successfully been introduced into organic synthesis.13 In these cases, the catalytic effect was attributed to an attractive halogen bond between the iodine atoms of the catalysts and the substrates (e.g., halide atoms). The origin of this Received: February 13, 2016 Revised: April 6, 2016 Published: April 8, 2016 3203

DOI: 10.1021/acscatal.6b00447 ACS Catal. 2016, 6, 3203−3212

Research Article

ACS Catalysis interaction is likely to result from a positive polarization of the iodine atoms (the σ hole) due to an anisotropic electron distribution.10,14 Similarly to these catalysts, it could be proposed that molecular iodine also interacts with substrates as a halogenbond donor and activates those accordingly. Support for this hypothesis comes from the calculated electrostatic potential of I2 (Figure 1), which also reveals a significant positive polarization on the iodine atoms: i.e., a σ hole.

Scheme 2. Iodine-Catalyzed Reactions for Computational Analysis19

Figure 1. Calculated electrostatic potential of molecular iodine on the 0.001 au isodensity surface (M06-2X-D3/aug-cc-pVTZ-PP).

Interactions between molecular iodine and Lewis bases were proposed more than 200 years ago.15 Further support for interactions between halides and Lewis bases comes from several crystal structures of halogen-containing complexes.16 The distances between the halogen atom and the acceptor atom of the Lewis base (usually oxygen or nitrogen) are much shorter than the sum of the van der Waals radii, indicating an attractive interaction. Similarly, the color of iodine in different solvents is usually rationalized by iodine−solvent complexes.17 In 2011, experimentally determined equilibrium constants for complexation reactions of molecular iodine with various Lewis bases were summarized in a comprehensive Lewis basicity scale (pKBI2 values).18 Interactions between I2 and ketones, aldehydes, or esters, i.e., typical electrophiles in organic transformations, are usually rather weak (ΔG < 1.5 kcal mol−1) but could be sufficient for catalytic purposes. In order to test the hypothesis that halogen bonding is also the origin of catalytic effects in iodine-catalyzed transformations, we have carefully analyzed the four model iodine-catalyzed reactions of Scheme 2 by density functional theory. These literatureknown reactions19 were chosen as no additional additives other than molecular iodine were employed, no or only aprotic solvents were used, and the background reactions were slow or nonexistent. We now report on the calculated free energy profiles for these reactions, and we discuss whether electrophile activation by halogen bonding to molecular iodine is feasible. In addition, we will analyze the possibility of hidden Brønsted acid catalysis for these transformations.

experimental values. Complexation energies for CH2Cl2 solution were calculated to be slightly higher in energy (ΔΔG = +0.4 kcal mol−1). However, this comparison shows that we underestimate the influence of molecular iodine in this computational analysis rather than overestimate its effect in catalysis. Intramolecular Aza-Michael Reaction. We chose the intramolecular cyclization of the aminochalcone 11 (Scheme 2)19a as our first reaction for three reasons. First, if catalytic effects can be observed, they should be much greater for this intramolecular reaction, as the entropic penalty is much smaller than that for intermolecular reactions. Second, no background reaction could be observed experimentally, but a high yield could be obtained for the iodine-catalyzed reaction.19a Third, only a few conformers had to be considered for this reaction, which allows a comparison of different computational methods. As the experimental conditions (molten state under solventfree conditions) cannot be adequately modeled with Gaussian09, we started to analyze different computational methods previously reported to be suitable for halogen bonding.21 Initially, optimizations were performed in the gas phase with M06-2X-D3,22 M06-L-D3,23 or ωB97X-D24 followed by singlepoint calculations with B2PLYP-D3.25 Subsequently, we tested a potential stabilization of charged intermediates in the liquid phase by employing a solvent with a small dielectric constant (e.g., dichloromethane) to mimic the experimental conditions. Regardless of the computational method employed, very similar results were obtained in all cases (see the Supporting Information for details). For the sake of clarity, we will only discuss values obtained with the B2PLYP-D3/aug-cc-pVTZ/ IEFPCM//M06-2X-D3/6-311+G(d,p)/IEFPCM level of theory in the following, which also allows the comparison of the different reactions of Scheme 2. The calculated Gibbs free energy profile for the intramolecular Michael addition of the aminochalcone 11 is summarized in Figure 2, and selected structures are depicted in Figure 3. The background reaction in the absence of any catalyst starts with a nucleophilic attack of the aniline moiety on the Michael system. This step proceeds through transition state TS1, yielding the zwitterionic intermediate 22. The high endergonicity of this

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RESULTS AND DISCUSSION Validation of the Computational Method. To get an idea of how well our computational analysis describes the strengths of interactions between carbonyl compounds and molecular iodine, we computed the interaction energies for different representative combinations that have previously been determined experimentally.20 Although benchmarking studies have shown the suitability of our computational method for the description of halogen bonding,21 Table 1 reveals that the computed values in CCl4 are 0.9−2.0 kcal mol−1 more endergonic than the 3204

DOI: 10.1021/acscatal.6b00447 ACS Catal. 2016, 6, 3203−3212

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ACS Catalysis

Table 1. Comparison of Experimentally Determined Equilibrium Constants20 and Free Energies with Computed Free Energies for the Reactions of Different Carbonyl Compounds with Molecular Iodine in CCl4 and CH2Cl2 Solutiona

a

In units of kcal mol−1; B2PLYP-D3/aug-cc-pVTZ/IEFPCM//M06-2X-D3/6-311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine. bIn CS2 solution.

Figure 2. Calculated free-energy profile for the uncatalyzed and iodine-catalyzed intramolecular cyclization of the aminochalcone 11 (in kcal mol−1, B2PLYP-D3/aug-cc-pVTZ/IEFPCM//M06-2X-D3/6-311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine).

step (ΔG = +29.2 kcal mol−1) is also reflected in a rather short

afford the Michael product 12 in an overall exergonic reaction (ΔG = −8.3 kcal mol−1). In the presence of molecular iodine, the complex 11-I2 is formed from the aminochalcone 11 and I2. The formation of this complex is exothermic but slightly endergonic (ΔH = −8.2 kcal mol−1; ΔG = +1.3 kcal mol−1), which is qualitatively in line with

C−N bond length (1.87 Å, Figure 3) within TS1. The calculated high activation free energy of +32.3 kcal mol−1 also explains why this reaction does not proceed in the absence of any catalyst.19a Proton transfer (→23) and subsequent keto−enol tautomerism 3205

DOI: 10.1021/acscatal.6b00447 ACS Catal. 2016, 6, 3203−3212

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ACS Catalysis

effect is also paralleled in the decreasing C−I distance from 11-I2, via TS1-I2, to 22-I2 (Figure 3) which can be rationalized by the development of a negative (partial) charge on the former carbonyl oxygen in the course of the reaction. Furthermore, the coordination to iodine also reduces the activation free energy to a level that is in good qualitative agreement with the required high temperatures in the experiments.19a Intermolecular Aza-Michael Reaction. As our computations indicated that electrophiles can be activated by molecular iodine in intramolecular reactions, we were wondering whether similar results can be obtained for bimolecular transformations. For a substantial lowering of the activation barrier, the interaction between I2 and the Michael acceptor must additionally compensate the unfavorable entropy of the intermolecular process. Therefore, we additionally analyzed the intermolecular reaction (Scheme 2) between methyl acrylate (13) and pyrrolidine (14) by density functional theory.19b Experimentally, the reaction between 13 and diethylamine proceeds slowly in dichloromethane (60% after 5 h) and is substantially accelerated by 5 mol % of I2 (93% after 15 min; 89% for the computationally analyzed 14).19b The calculated Gibbs free energy profile for this reaction is summarized in Figure 4, and selected structures are depicted in Figure 5. The uncatalyzed Michael reaction between 13 and 14 proceeds through transition state TS2 and affords the zwitterionic intermediate 24. Similarly to the intermolecular reaction discussed above, the transition state adopts a productlike geometry due to the endergonicity of this step with a rather short C−N bond. The much lower activation free energy calculated for the uncatalyzed reaction between 13 and 14 in comparison to the intramolecular process is reflected in the slow background reaction that is experimentally observed.19b After

Figure 3. Calculated transition states, iodine adducts, and selected bond lengths for the uncatalyzed and iodine-catalyzed intramolecular Michael reaction of the aminochalcone 11 (in Å, M06-2X-D3/6-311+G(d,p)/ IEFPCM, aug-cc-pVTZ-PP for iodine).

experimental association constants for the reactions of simple aldehydes and ketones with iodine.20,26 The C−N bond formation occurs through transition state TS1-I2 and yields the zwitterionic complex 22-I 2. The C−N bond length is significantly longer (2.01 Å) in comparison to that in the uncatalyzed reaction, and the energies of both the transition state TS1-I2 and the zwitterionic intermediate 22-I2 are significantly lowered. After dissociation of iodine, proton transfer, and tautomerization the same Michael adduct 12 is obtained. A direct comparison of the uncatalyzed and I2-catalyzed reactions reveals a significant stabilization of both TS1-I2 (ΔΔG⧧ = −5.7 kcal mol−1) and 22-I2 (ΔΔG = −10.9 kcal mol−1). This

Figure 4. Calculated free-energy profile for the uncatalyzed and iodine-catalyzed intermolecular Michael reaction of methyl acrylate (13) and pyrrolidine (14) (in kcal mol−1, B2PLYP-D3/aug-cc-pVTZ/IEFPCM//M06-2X-D3/6-311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine). 3206

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Figure 5. Calculated transition states, iodine adducts, and selected bond lengths for the uncatalyzed and iodine-catalyzed intermolecular Michael reaction of methyl acrylate (13) and pyrrolidine (14) (in Å, M06-2XD3/6-311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine).

proton transfer and tautomerization, the Michael product 15 is obtained in an exergonic reaction (ΔG = −7.0 kcal mol−1). The initial step for the iodine-catalyzed reaction is again the coordination of I2 to the Michael acceptor 13. The slightly more endergonic reaction with the acrylate 13 (ΔG = +2.6 kcal mol−1) in comparison to the chalcone 11 (ΔG = +1.3 kcal mol−1) can also be rationalized by the higher Lewis basicity of the latter.20 An alternate coordination to the C−C double bond can also be discussed for this process. However, according to our calculations, an interaction with the carbonyl group is preferred over an interaction with the double bond (ΔΔG = +1.1 kcal mol−1; not shown in Figure 4). From this π complex, addition of iodine through an intermediate iodonium cation and subsequent ring opening by iodide would result in the formation of methyl 2,3-diiodopropionate (not shown in Figure 4). Although this reaction is energetically feasible (ΔG = −2.1 kcal mol−1), the iodonium intermediate is too high in energy (ΔG = +45.7 kcal mol−1) for a competing side reaction. Similar to the intramolecular reaction discussed above, both the transition state TS2-I2 and the resulting zwitterionic intermediate 24-I2 are stabilized by molecular iodine. While the activation free energy of TS2-I2 is reduced by 2.4 kcal mol−1, the corresponding intermediate 24-I2 is lowered by 5.5 kcal mol−1 upon coordination to iodine. In comparison to the intramolecular reaction discussed above (Figures 2 and 3), the stabilization of all species by I2 is much smaller in the intermolecular reaction. This finding can be rationalized by the unfavorable entropy of bimolecular reactions and the higher Lewis basicity of ketones in comparison to esters. Friedel−Crafts Reaction. After establishing a significant transition state stabilization by molecular iodine in both intraand intermolecular aza-Michael reactions, we investigated whether similar effects are also observable for reactions of less reactive C-nucleophiles such as indoles (Scheme 2).19c The calculated Gibbs free energy profile for the Friedel−Crafts reaction of indole (17) and trans-crotonophenone (16) is summarized in Figure 6, and selected structures are depicted in Figure 7. The uncatalyzed reaction proceeds with a very high activation free energy (TS3, ΔG⧧ = +34.7 kcal mol−1) in line with no product formation in the absence of any catalyst. The

Figure 6. Calculated free-energy profile for the uncatalyzed and iodinecatalyzed reaction of indole (17) with an α,β-unsaturated Michael acceptor 16 (in kcal mol−1, B2PLYP-D3/aug-cc-pVTZ/IEFPCM// M06-2X-D3/6-311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine).

Figure 7. Calculated transition states, iodine adducts, and selected bond lengths for the uncatalyzed and iodine-catalyzed Friedel−Crafts reaction of indole (17) and trans-crotonophenone (16) (in Å, M06-2X-D3/6311+G(d,p)/IEFPCM, aug-cc-pVTZ-PP for iodine).

resulting Wheland intermediate 26 is very unstable, and a small energy difference (