Highly Recoverable Pd(II) Catalysts for the MizorokiâHeck Reaction

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

Highly Recoverable Pd(II) Catalysts for the Mizoroki−Heck Reaction Based on N‑Heterocyclic Carbenes and Poly(benzyl ether) Dendrons ́ ez-Sal, Juan C. Flores,* and Ernesto de Jesús* Alba Ortiz, Pilar Gom Departamento de Química Orgánica y de Química Inorgánica, Instituto de Investigación Química “Andrés M. del Río”, Universidad de Alcalá, Alcalá de Henares, Madrid 28871, Spain

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S Supporting Information *

ABSTRACT: Two series of bis(imidazolylidene)palladium complexes of general formula [PdBr2(NHC)2] have been prepared. The molecular weight of the complexes was enlarged by bonding poly(benzyl ether) dendrons of increasing size (G0 to G3) at the nitrogen atom of the NHC ligands. Complexes 1−4 contain monodentate NHC ligands coordinated in a trans mode, whereas complexes 9−12 contain a chelating ethylenebridged bis(NHC) ligand. The complexes were recovered from the product stream of a Mizoroki−Heck reaction by nanofiltration through thermally and chemically stable ceramic membranes. The recoverability is better for larger complexes and chelate ligands. In particular, chelate G3 complex 12 maintained a constant activity during the 13 recovery cycles performed, affording an accumulated turnover number (TON) of 13 000. On average, around 99.5% of the metal is recovered in each recovery cycle, and contamination by palladium is only 3 mg per kg of product. Several models to explain the efficiency of the recovery are discussed.

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INTRODUCTION The Mizoroki−Heck (MH) reaction1 is one of the most powerful and versatile palladium-catalyzed reactions for the formation of C−C bonds, with widespread applications in academic laboratories2 or on an industrial scale.3 An illustrative example of the consolidated position of Pd-catalyzed couplings in the pharma industry is that they represented 20% of the reactions employed by GlaxoSmithKline in 2010 to discover clinical candidates for respiratory diseases.4 Together with the cost of palladium, the need to meet strict specifications concerning the metal content of products, particularly drugs,5 is one of the main drawbacks of C−C couplings. An increase in catalyst productivity to reduce Pd loadings from the typical mol % level to the ppm or ppb level would therefore remove these price and contamination concerns.6 In this regard, numerous efforts are being directed to add recyclability to the highly active homogeneous catalysts developed for C−C coupling reactions.7 Strategies used for catalyst recovery most often confine catalyst and substrates/products in different phases, thereby reducing the advantages of the homogeneous process (activity, selectivity) or introducing operational difficulties.8 In this regard, organic solvent nanofiltration (OSN) is an attractive approach for the recycling of soluble organometallic catalysts given the availability of membranes resistant to solvents.9 As no phase transition or biphasic operation is required, OSN reduces energy usage, is operationally simple and easy to scaleup, and can be operated under continuous flow conditions.10 However, efficient separation needs a large enough size © XXXX American Chemical Society

difference between the catalyst to be retained and the molecules permeating the membrane (substrates and products). As such, the viability of separation may require molecular weight enlargement of the catalyst (MWE catalyst)11 using linear or hyperbranched polymers, dendrons or dendrimers, or other large substituents.12 Retention mechanisms involve both size exclusion and physicochemical interactions of the solute with the membrane.13 As such, the separation efficiency can be affected by the chemical composition of the membrane and solution (solvent, additives, salts, and other byproducts formed in the reaction, etc.) and has to be evaluated under actual operating conditions. The correct choice of membrane material is also critical for successful separation. In this regard, the thermal, mechanical, and chemical stability and long-term durability of ceramic membranes gives them an initial advantage for OSN applications compared to polymeric membranes (although the latter are currently cheaper to produce).14 Ceramic membranes tend to be somewhat less efficient in apolar solvents due to their hydrophilic nature but can be operated at the high temperatures often required for continuous operation and, in contrast to polymeric membranes, do not undergo swelling in contact with organic solvents. OSN technologies have demonstrated their suitability for the removal of Pd residues after a single MH reaction,15 thus Special Issue: In Honor of the Career of Ernesto Carmona Received: May 7, 2018

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DOI: 10.1021/acs.organomet.8b00295 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

Scheme 1. Synthesis of Bis(carbene) Pd(II) Complexesa

allowing the isolation of products with a purity that meets the specifications of the ICH guidelines.16,5 Their suitability for catalyst recycling has also been proven by examples in which the Pd catalyst has been reutilized after OSN separation in batch12b,17 or continuous mode.18 Nevertheless, the highest productivity achieved in OSN recyclings (around 30−40 μmol of metal per mol of product, excluding the metal remaining in the reactor at the end of the experiment)18b is not optimal compared with other alternatives. The catalysts tested in these experiments were mostly conventional Pd complexes of relatively small size which, in practice, were insufficiently retained by the membrane. Even when molecular weight enlarged catalysts are used, metal leaching from the MWE ligand, which reduces recoverability, and decomposition, which prevents reusability, still tend to limit their recyclability.19 When Herrmann and co-workers described the use of bis(NHC)−Pd(II) complexes (NHC = N-heterocyclic carbene ligand) as catalysts for the MH reaction for the first time,20 they observed that these catalysts did not undergo degradation by Pd(0) metal deposition, in contrast to the usual behavior of most catalysts in C−C coupling reactions. Further studies showed that cis-chelating bis-NHC ligands were particularly suitable as stable MH catalysts.21,22 The strength of the ligand coordination to the metal center is one of the keys to the success of NHC complexes in catalysis.23 For this reason, there is an increasing interest in immobilizing transition metal compounds to solid supports using N-heterocyclic carbene ligands.24 Consequently, the development of NHC Pd complexes for OSN recovery seems a natural, although relatively unexplored, alternative.17b,25 Herein we describe the synthesis of monodentate and chelate bis(NHC)−Pd(II) complexes, the molecular weight of which has been enlarged by bonding dendritic poly(benzyl ether) substituents26 of increasing size at the nitrogen atoms of the NHC ligand. In a previous paper, we showed that the palladium site of related bis(NHC) complexes was not significantly congested by dendritic poly(benzyl ether) substituents up to the third generation.27 The semirigid and three-dimensional structure of these dendrons should facilitate retention of the catalyst by the membrane. In addition, for one of these catalysts, we report quantitative conversions and Pd losses of less than 5 μmol per mol of product in the MH reaction used as model after 13 recovery cycles using ceramic membranes. Although the stability of the bis(NHC)−Pd(II) complexes and the good retention of the largest complexes form the basis for these findings, we also discuss several scenarios that might explain the results observed.

a (a) Synthesis of monoligated bis(NHC) complexes 1−4. (b) Synthesis of imidazolium bromides 5−8. (c) Synthesis of chelate bis(NHC) complexes 9−12.

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solvents such as acetone, dimethylformamide (dmf), or tetrahydrofuran, and insoluble in alkanes. Their solubility in aromatic solvents increases with generation number. The trans arrangement of the NHC ligands is supported by the single 1H resonance observed for the N-bonded methylene protons (the two protons of each group are expected to be diastereotopic in cis isomers).28 The chemical shifts of around 170−171 ppm for the carbenic carbon are also consistent with a trans configuration since these resonances appear at lower frequencies for cis arrangements (157−165 ppm).28a−c,29 The molecular structures of G0 and G1 complexes 1 and 2, which were determined by X-ray diffraction methods (Figure 1), show that the NHC rings are tilted between 68 and 72° relative to the square-planar metal coordination plane. The Pd−C (2.036(8) Å for 1 and 2.01(2) Å for 2) and Pd−Br distances (2.394(1) and 2.458(3) Å) are within the ranges reported for other trans-[PdBr2(NHC)2] complexes in the

RESULTS AND DISCUSSION Synthesis of Complexes. We first prepared the series of bis(carbene) complexes 1−4 containing benzylic substituents of increasing molecular weight at the monodentate NHC ligand (Fréchet dendrons G0 to G3). Synthesis involved reaction of (η2:η2-1,5-cyclooctadiene)dibromidopalladium(II) with the appropriate silver(I) NHC complex27b in dichloromethane at room temperature following the procedure reported previously by us for related [PdBr2(NHC)2] dendrimers (Scheme 1a).27a The bis(NHC) palladium complexes were isolated in high yields (in general >85%) as analytically pure white or pale-yellow solids. They were characterized by NMR and IR spectroscopy and ESI mass spectrometry (see Experimental Section for details). The complexes are air-stable, soluble in chlorinated and polar B


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lium bromides with palladium(II) acetate in dmso (Scheme 1c). The procedure was based on a well-known method reported by Herrmann and co-workers for the synthesis of [PdX2(NHC)2] chelates and requires adequate control of the temperature ramp to attain good yields.20c,31 These complexes were obtained as spectroscopically and analytically pure yellow solids in yields of around 90%, irrespective of the dendritic generation. Special care was taken to remove any trace of Pd colloids by filtration of the solutions through a column of kieselguhr. The expected monopositive ions [M − Br]+ were observed in the ESI(+)-TOF mass spectra. Full synthetic and characterization details are given in the Experimental Section. Due to the chelate-type coordination of the bidentate ligand, the endo and exo protons of the ethylene bridge are chemically nonequivalent (see a partial view of the 1H NMR spectrum of G1 complex 10 in Figure 2a). The two CH2 protons are also diastereotopic in the methylene groups of the Gn substituents.

Figure 1. Molecular structures of complexes 1 (G0, top) and 2 (G1, bottom). Selected bond lengths (Å) and angles (deg) for 1: Pd− Br(1), 2.3939(13); Pd−C(1), 2.032(8); C(1)−N(1), 1.369(11); C(1)−N(2), 1.369(11); C(1)−Pd−Br(1), 91.4(2); C(1)−Pd− Br(1′), 88.6(2); Br(1)−Pd−Br(1′), 180; C(1)−Pd−C(1′), 180; N(1)−C(1)−N(2), 103.8(7). Selected bond lengths (Å) and angles (deg) for 2 [distances and angles for the second independent unit present in the crystal structure are given in brackets]: Pd−Br(1), 2.4589(10) [2.4626(11)]; Pd−C(1), 2.018(9) [2.035(9)]; C(1)− N(1), 1.382(11) [1.324(11)]; C(1)−N(2), 1.361(10) [1.380(10)]; C(1)−Pd−Br(1), 89.2(3) [90.1(3)]; C(1)−Pd−Br(1′), 90.8(3) [89.9(3)]; Br(1)−Pd−Br(1′), 180; C(1)−Pd−C(1′), 180.

Cambridge Structural Database (CSD): Pd−NHC 1.99−2.05 Å (mean 2.02 Å), Pd−Br 2.38−2.50 Å (mean 2.44 Å), respectively. Preparation of the bis(imidazolium) salts 5−8 started with the synthesis of 1,2-di(1H-imidazol-1-yl)ethane by reaction between imidazol and 1,2-dichloroethane (Scheme 1b). Although the method previously described employed 1,2dibromoethane,30 we found that the use of 1,2-dichloroethane reduced formation of the 1-vinylimidazole byproduct and increased the yield of 1,2-di(1H-imidazol-1-yl)ethane to 65% on a 10 g preparative scale. Subsequent reaction of this compound with 2 equiv of the corresponding Gn−Br dendron in acetone at 60 °C afforded 5−8 in almost quantitative yields after a reaction time ranging from 0.5 to 3 h (larger dendrimers required longer reaction times). The volume of acetone employed as solvent in the reaction was critical for isolation of the pure products in high yields as precipitation of the bis(imidazolium) bromides favored completion of the reaction, thereby avoiding the need for further purification steps. Any trace of 1,2-di(1H-imidazol-1-yl)ethane contaminating the precipitate was removed by washing the solid with hexane. Salts 5−8 are highly hygroscopic, soluble in chlorinated solvents, and quite insoluble in most other solvents. Intense peaks corresponding to the expected mono- or dipositive ions ([M − Br]+ or [M − 2Br]2+) were observed by ESI(+)-TOF mass spectrometry. The series of chelate bis(carbene) complexes, 9−12, was synthesized by direct reaction of the corresponding imidazo-

Figure 2. (a) Partial view of the 1H NMR spectrum of G1 complex 10, showing the protons for the three types of methylene group. The red lines correspond to the spectrum simulated for the AA’XX’ system formed by the ethylene bridge protons (2JAA′ = 2JXX′ = 5.5 Hz, 3JAX′ = −15.5 Hz, 3JAX′ = 8 Hz). (b) Molecular structure of 10. Selected bond lengths (Å) and angles (deg): Pd−Br(1), 2.4960(6); Pd−Br(2), 2.4863(6); Pd−C(1A), 1.970(4); Pd−C(1B), 1.969(4); C(1A)−Pd− Br(1), 91.03(11); C(1B)−Pd−Br(2), 94.09(11); C(1A)−Pd−C(1B), 84.14(16); Br(1)−Pd−Br(2), 92.23(2); C(1A)−Pd−Br(2), 168.53(12); C(1B)−Pd−Br(1), 170.49(11). C


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Organometallics Despite this, the chemical shift differences between protons of the same CH2 become progressively smaller on going from the inner to the outer dendron layers. The chemical shifts of around 160 ppm for the carbenic carbon are within the usual range for a cis arrangement (157−165 ppm).28a−c,29 The molecular structure of G1 complex 10 (see Figure 2b) shows the boatlike conformation of the seven-membered palladacycle, with a C(1A)−Pd−C(1B) angle of 84.1(1)°. The Pd−C (1.97 Å) and Pd−Br distances (2.49 Å) almost match the mean distances found in chelate or monodentate cis-[PdBr2(NHC)2] complexes (1.98 and 2.48 Å, respectively; CSD database search). The internal aryl groups of the dendritic branches are arranged almost in parallel (angle between planes of 2.7°) with centroid−centroid and centroid−plane distances (3.875 and 3.431 Å, respectively) suggesting the existence of π interactions between these face-to-face oriented aromatic rings.32 Evaluation of the Dendronized Pd−NHC Complexes in the MH Reaction. The MH coupling between paraiodotoluene and methyl acrylate was selected as model reaction for this study (Scheme 2). All reactions were Scheme 2. Model MH Reaction Tested Using Complexes 1−4 and 9−12 as Catalystsa

a

Figure 3. Kinetic profiles for (a) monodentate complexes 1−4 and (b) chelate complexes 9−12 under the conditions specified in Scheme 2.

performed at 130 °C in dmf, with catalyst loadings of 0.1 mol %, and afforded exclusively methyl (E)-4-methylcinnamate. Naphthalene was used as internal standard when monitoring the reaction by gas chromatography (GC). Several precautions were taken to avoid misleading results. Thus, experiments were performed in duplicate, reaction vessels cleaned with aqua regia to remove any Pd residue,6b and blank tests routinely run to discard contamination of substrates, bases, or solvents with traces of Pd.33 As the real performance of the catalysts might be affected by contamination with traces of simple Pd(II) salts, which can be very active in MH reactions,34 several experiments were performed in which the catalyst solutions were pretreated with a Pd(II) scavenger, namely, poly(4-vinylpyridine) (PVPy), and filtered before use.35 The kinetic profiles obtained using these pretreated catalysts were identical to those obtained without treatment (Figure S3). A common feature of all the reactions tested here is that Pd deposits or colloids were never detected by visual or TEM analysis of the solutions, either during the reaction or after completion of the process. This apparent absence of degradation for bis-NHC catalysts was already noted by Herrmann and co-workers in their seminal studies.20a,b Notable differences were, however, observed between the kinetic profiles of monodentate and chelate complexes. The conversion versus time plots for monodentate complexes 1−4 are relatively complex, with several differentiated phases, namely, an initial period of around 2 h of elevated catalytic activity, a second period in which the reaction is apparently almost stopped, and a third period of slow evolution (Figure 3a). This behavior is indicative of the probable involvement of different catalytic species over the course of the reaction. The

time employed to complete the reactions was highly dependent on the catalyst concerned (ranging from 4.5 h for G2 complex 11 to 36 h for G3 complex 12), thus reflecting the irregular trend of the reaction rates in the initial period as regards the dendrimer generation (G0 < G1 < G2 > G3). Similar irregularities in the reaction kinetics of a series of dendritic catalysts are frequent and can be explained by the opposite effect of increasing dendron size on the protection of the active sites and their accessibility.36 Reactions with chelate complexes 9−12 were completed in around 8−10 h, except for the largest G3 complex. Conversion versus time plots show a typical sigmoid shape, with an induction period of around 4 h for G0 catalyst 9 and somewhat shorter for the larger catalysts (Figure 3b). Such induction periods are associated with formation of the Pd(0) active species from the Pd(II) precursor1d,37 in a process in which the triethylamine and olefin are potential reductants.1d,38 In accordance with this, we observed a drastic reduction in the induction period when the catalyst was incubated in the presence of methyl acrylate and triethylamine at 130 °C for 3.5 h prior to the catalytic reaction (Figure 4). Preincubation with only the olefin also reduced the induction period, although the reaction rate was slower in this case, whereas preincubation with only triethylamine had no apparent effect on the induction period (Figure S4). The turnover frequencies (TOF) determined at initial reaction times under preincubation conditions (Figure 4) show an effect of dendritic generation on the catalytic activity (G0 < G1 < G2 > G3) that follows a trend similar to that discussed above for the monodentate complexes. The evolution of 9 in dmf-d7 in the presence of methyl acrylate and triethylamine (2 equiv of each) was monitored by 1 H NMR spectroscopy in an attempt to gain information on the precatalyst incubation process. Complex 9 remained largely

Conditions: para-iodotoluene (0.50 mmol), methyl acrylate (0.60 mmol), triethylamine (0.6 mmol), Pd complex (0.5 μmol), naphthalene (internal standard, 0.50 mmol), and DMF (5 mL).

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Figure S6 for the analogous plots of 10−12). The profiles obtained in the successive reloading cycles of a given catalyst coincide, thus indicating the marked stability of the catalytic system. Moreover, the induction periods are shorter in the reloading cycles, as can be clearly observed for 9 in Figure 5. As previously observed for similar catalysts,40 the addition of an ammonium halide produces a comparable effect on the induction periods and the reloading cycles are initiated in the presence of the [NEt3H]I formed during the initial cycle of the MH reaction. After the induction period, the catalytic rates are slightly dependent on the type of cycle and tend to increase in the following order: initial cycle performed without catalyst preincubation < reloading cycles < initial cycle with preincubation. The catalytic system also seems quite stable in the case of nonchelate bis(NHC) complexes 1−4, for which similar conversions are measured at 2 and 24 h in the initial and successive reloading cycles (Table S2). As will be highlighted at the end of this section, the results disclosed in the preceding paragraphs can be interpreted in several ways. However, the absence of formation of palladium deposits, which contrasts with the behavior frequently observed for other Pd precursors, and the sustained activity over the various reloading cycles suggest that the above NHC complexes form homogeneous catalytic systems that might be suitable for recovery by nanofiltration techniques. Recycling Experiments. Recycling experiments were performed using the nanofiltration setup described in Figure S7. For operational simplicity, a cell for dead-end filtration was selected to demonstrate the proof of principle as cross-flow membrane devices require a more sophisticated setup that is not mandatory at this testing level. The filtration unit was equipped with commercially available ceramic membranes comprising a zirconia/titania selective layer. These membranes resisted the complete set of recovery runs performed with each catalyst without apparent degradation. In contrast, several commercially available “organic solvent resistant” polymeric membranes used in preliminary tests had to be replaced after every recovery cycle due to evident damage. A practical limitation of the dead-end cell is that it uses disk (flat) membranes. Ceramic membranes with a disk geometry are commercially available with only relatively high-molecularweight cutoffs (MWCO ≥ 1000 Da), while the ceramic membranes with tubular geometries used industrially are available starting from MWCOs of a few hundred daltons.14,41 The MWCO is defined as the minimum molecular weight of a solute that is 90% retained by a given membrane.42 Reactions were performed in batch mode in a conventional glass pressure tube and transferred to the nanofiltration cell at the end of every catalytic cycle. The cell was pressurized to obtain a flow through the membrane of approximately 10 mL/min. Around 90% of the reaction mixture was filtered, and the remaining 10% was returned to the glass reactor and combined with solvent and reactants to restore the initial conditions. Recycling experiments were performed with complexes 10− 12, all of which have molecular weights above the nominal MWCO of the membrane. Reactions were continued for exactly the same time in all successive cycles for a given catalyst, except for the initial cycle, which lasted longer (see the Experimental Section for details). The dendritic generation of the precatalyst had a clear effect on the evolution of the catalytic conversions over the successive recovery cycles (Figure 6a). Thus, while conversions abruptly fell to 50% in the second cycle for 10, they remained above 80% for seven

Figure 4. Comparison of the kinetic profiles for the chelate complexes 9−12 after preincubation of the catalysts with methyl acrylate and triethylamine. Lines represent the data fitting to a sigmoidal curve and are given as a guide to the eyes. The insert gives TOF values calculated at 40% conversion.

unaltered when this mixture was heated for 3 h at 130 °C (see Figures S5a,b). The presence of two new minor resonances (doublet at 6.85 ppm and singlet at 5.02 ppm), which correspond to an NHC Pd complex that diffuses at a rate comparable to that of 9 (evidenced by a DOSY experiment) should, however, be noted. The formation of this complex is probably a key step in the activation of 9, although all efforts to identify it have failed thus far. Subsequent addition of aryl iodide (1 equiv) did not produce any apparent change in the mixture, except for formation of the biaryl coupling product (Figure S5c). These results are consistent with initial observations that highlighted the recovery of important amounts of the bis(NHC) precursors in MH reactions performed at high temperature under conditions similar to those used here.39 The important point here is that these results point to the activation of only a small fraction of the bis(NHC) precursors under these conditions. Since the MH reactions occurred without apparent degradation of the catalysts, the reusability of complexes 9− 12 was subsequently analyzed performing several reloading experiments. After completing the initial reaction cycle, the concentration of para-iodotoluene, methyl acrylate, and triethylamine was restored by adding fresh reagents, and the reaction was restarted without intermediate separation of the products. The kinetic profiles for the initial cycle and four reloading cycles of G0 catalyst 9 are compared in Figure 5 (see

Figure 5. Kinetic profiles for G0 chelate complex 9 during the initial cycle, four consecutive reloading cycles, and the initial cycle after preincubation of the catalyst. Conversions were measured by GC and are referenced to the amount of aryl iodide added in each reaction cycle. E


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is a poor approach for assessing the recoverability of a catalyst.19 Consequently, in addition to Pd content analysis, we also evaluated the recoverability of 12 by determining the kinetic profiles for several of the recovery cycles (Figure 7). These experiments showed that the catalytic activity is almost constant over the recovery cycles.

Figure 7. Kinetic profiles obtained by CG for the G3 chelate complex 13 at the initial cycle and four recovery cycles (2, 3, 10, and 13) in the nanofiltration experiments.

From an operational point of view, it is also important to note that the ceramic membrane did not retain the ammonium iodide formed in the reaction (Figure S8). Poor permeation of salts through polymeric membranes often means that these salts accumulate, thus resulting in their precipitation in the reactor and introducing operational complications.17a,18b A final recovery experiment was performed with monodentate G2 complex 3. However, although the molecular weight of this complex (3309.80 Da) is close to that of chelate G3 complex 12 (3580.08), the conversions obtained with 3 decreased below 80% after only four recovery cycles (Figure S11). The recoverability of this monodentate bis-carbene complex is even superseded by that of G2 chelate complex 11 despite the much smaller size of the latter. This result highlights the potential influence of the design on the recoverability of a catalyst. Interpretation of the Recycling Experiments. We have shown above that Pd complexes with bidentate NHC ligands of enlarged molecular weight are homogeneous catalysts for the MH reaction that can be efficiently recovered using nanofiltration techniques. In particular, the initial activity of complex 12 was maintained after 13 recovery cycles, affording an accumulated turnover number (TON) of 13 000 at an average turnover frequency (TOF) of 80 h−1 (Figure S10). Moreover, the initial Pd loading is just 0.1 mol %, and 99.5% of the metal is recovered, on average, in each recovery cycle (except for the first). As such, Pd wastage is as low as 5 μmol per mol of product, and a theoretical TON of 200 000 could potentially be attained using 12 in a continuous reactor. The concentration of palladium in the product (5 μmol per mol of product or, in other words, 3 mg per kg of product) is, for instance, within the safe concentration limit recommended by ICH for orally administered drugs.5 Despite the high recoverability demonstrated by complex 12, the nature of the retained species, the nature of the activated species, and the nature of the dormant species remain to be clarified. The starting point is the nature of the real catalyst. The MH coupling of activated substrates can be promoted by very small (homeopathic) amounts of ligand-free Pd catalysts (single atoms or small clusters).1d,43 In addition,

Figure 6. (a) Conversions obtained in the recovery experiments after reaction for 7 h (for 10 and 11) and 12 h (for 12) [reaction times in the initial cycle were 12 and 16 h, respectively]. (b) Dashed lines represent the evolution of Pd content over the successive recovery cycles for 11 (●) and 12 (△) determined from the amount of Pd found in the corresponding permeate. The solid line represents the calculated evolution of Pd content for complex 12 determined from the membrane rejection constant determined for the complex in pure dimethylformamide (99.8%, see the Supporting Information). Pd content is given as μmol of Pd per mol of para-iodotoluene added in each cycle. The palladium content was quantified by ICP-MS analysis, as described in the Supporting Information.

cycles in the case of 11. For the largest precatalyst 12, almost complete conversions were observed for the 13 cycles performed before we decided to stop the experiment (Figure 6a). The evolution of the Pd content over the successive recovery cycles (dashed lines in Figure 6b; quantified by ICPMS analysis) shows that the better performance obtained with the largest precatalyst is a reflection of the lower permeation of the membrane to the Pd species present in the reaction mixture in this case. One observation that we are currently unable to explain is the marked Pd leaching observed in the first recovery cycle. Possible contamination of the starting precatalyst with low molecular weight Pd species is unlikely considering the accurate elemental analyses and the precautions taken in the experimental procedure (as described above). The solid line in the upper part of Figure 6b represents the expected evolution of the Pd content in a solution of G3 complex 12 in pure dimethylformamide submitted to several cycles of nanofiltration recovery (the trace was determined from the membrane rejection value of 99.8% measured for the complex in a single experiment in the same solvent; see the Supporting Information for details). The close similarity between the slopes of the experimental and calculated curves of Pd content for complex 12 from the second recovery cycle means that permeation of the Pd species present in the catalytic mixture is similar to what would be expected for complexes that essentially retain the structure of complex 12. As noted by Gladysz, the widespread use of product yield, conversion or turnover numbers (TON) as a function of cycle F


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eliminate the NHC ligand by reductive coupling with the organyl or hydride ligands.49 The lack of detection of Pd nanoparticles during or at the end of the reaction should be remembered here. For instance, analysis of the bulk solution for samples of 9 taken at 40 and 100% conversion by dynamic light scattering (DLS) demonstrated the absence of aggregates above the detection limit of 0.6 nm. In addition, none of the aggregates localized by TEM microscopy contained palladium (energy-dispersive X-ray spectroscopy analysis, EDS). The most conclusive evidence against this scenario is nevertheless the clear correlation observed between recoverability and size of the catalytic precursor. Scenario B. Activation of the catalytic precursor occurs basically after decoordination of the NHC ligand, with the unaltered precursor being recovered in this scenario. The rejection of (small) ligand-free Pd species by the membrane seems unlikely (and aggregation to give larger particles has not been observed). To explain the elevated recoverability of the G3 catalyst, it has to be assumed that the fraction of precursor activated in each catalytic cycle is very small (maximum 0.5% of the initially added complex). This quantity of ligand-free Pd species might, however, be sufficient to justify the activity observed in the MH reaction. In this scenario, the reaction kinetics should be dependent on the rate of metal leaching from the precursor. In the recovery experiments, the naked Pd species are removed, and the stability of the reaction kinetics in different catalytic cycles for G3 catalyst 12 (Figure 7) can be easily understood. The main weakness of scenario B is that naked Pd species should accumulate in the successive reloading experiments. Consequently, either the reaction rate should increase or the formation of Pd deposits should be observed. This contradiction can be solved by making the (undemonstrated) assumption that NHC decoordination can be reversed at the end of the catalytic reaction. Scenario C. The NHC ligand remains coordinated in the active species formed during the catalytic cycle and in the dormant species formed between recovery cycles. This is the simplest scenario and explains most of the observations discussed in this report. As pointed out by Gladysz,50 the induction period in the recovery cycles suggests that the catalyst is not being recycled in its active form.

complexes catalyzing MH reactions at high temperature are often merely reservoirs that decompose under catalytic conditions to deliver ligand-free Pd atoms to the reaction medium.35c,37a,44 Aggregation of Pd to produce metal nanoparticles and eventually Pd black deposits is a normal evolution of the ligand-free Pd(0) species involved in the catalytic cycle. However, there is some agreement with the hypothesis that the MH reaction is homogeneously catalyzed in solution irrespective of the Pd metal precatalyst45 and that Pd aggregates may also be involved in the catalysis as metal reservoirs.46 In this respect, we ran two classic tests intended to distinguish between homogeneous and heterogeneous catalysis.33e,47 Of these, the mercury test was inconclusive. Thus, a drop of mercury was added to the reaction mixture at 20% conversion, but the reaction continued to a conversion of around 70% and then stopped (Figure S12). In addition, the reliability of the mercury test has been questioned with homogeneous Pd−catalyzed reactions because Pd(0) intermediates can react with Hg, thereby poisoning the homogeneous catalyst.47b,c,48 The Collman test is based on the difficulty of large aggregates to diffuse into the polymeric matrix of a substrate anchored to a polymer (for this test, 4iodobenzoate groups were attached to a Wang resin). The observation of reactivity under similar conditions to those employed for soluble substrates, as was the case for the two catalysts tested here (9 and 12; see the Supporting Information for details), is considered a symptom of homogeneous catalysis. It should also be noted at this point that the high reproducibility of the kinetic profiles observed in the above reactions is more typical of homogeneous catalysis. Evidence for or against several possible scenarios involving NHC-ligated complexes, ligand-free species, and metal aggregates (Scheme 3), in which the possibility of MH catalysis by Pd nanoparticles has not been considered for the reasons indicated above, is analyzed below. Scheme 3. Several Simplified Scenarios for Interpretation of the Recovery Experiments

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CONCLUSIONS

Herein we have reported the recovery of Pd catalysts in a model MH reaction by means of organic solvent nanofiltration techniques (OSN). A strategy was designed on the basis of the strong coordination of monodentate or chelate NHC ligands to the Pd center, the size of which was enlarged by the attachment of poly(benzyl ether) dendrons. We have found that the recoverability is better for larger complexes and chelate ligands. In particular, chelate G3 complex 12 maintained a constant activity during the 13 recovery cycles performed, at the end of which the reactor conserved almost 90% of the initial Pd content. As a consequence, contamination of the coupling product with palladium was very low (3 mg per kg of product, below international specifications for orally administered drugs). In addition, catalyst separation was performed using ceramic membranes, which are very stable to organic solvents and under astringent reaction conditions (a feature highly desirable for continuous flow operation). These results are encouraging and permit us to anticipate the viability of implementing the process under continuous flow operation,

Scenario A. Marked decomposition of the NHC precursor results in the liberation of naked Pd species, which are the real active species. In the presence of an excess of olefin and amine, Pd(0) species are prevalent in solution at the end of the reaction, and their aggregation might produce metal nanoparticles that would be easily recovered due to their high molecular weight. Detachment of palladium from the NHC complexes can be favored under MH conditions because (NHC)xPd(II) aryl, alkenyl, or hydride intermediates can G


Article

Organometallics

OCH2Ph), 5.48 (s, 8H, NCH2Ar), 6.39 (t, 4JH,H = 2.3 Hz, 4H, pArG0), 6,46 (d, 4JH,H = 2.3 Hz, 8H, o-ArG0), 6.55−6.58 (m, 28H, pArG1, o-ArG1, and Imz), 7.22−7.36 (m, 80H, Ph). 13C{1H} NMR (CDCl3): δ 54.2 (CH2), 69.8 (OCH2Ar), 69.9 (OCH2Ph), 101.46 (pArG1), 102.1 (p-ArG0), 106.3 (o-ArG1), 107.1 (o-ArG0), 121.2 (Imz− C4,5), 127,5 and 128,5 (o- and m-Ph), 127.0 (p-Ph), 136.8 (ipso-Ph), 138.6 (ipso-ArG0), 139.3 (ipso-ArG1), 159.9 (m-ArG1), 160.0 (m-ArG0), 169.7 (Imz−C2). IR (KBr): ν 1595 and 1451 (s, C−Carom), 1497 (s, CNC), 1294 (m, C−O−Cas), 1154 and 1053 cm−1 (s, C−O−Cs). MS (ESI+-TOF in CH2Cl2/MeOH/NH4HCOO 5 mM): m/z 3148.18 [M − 2Br + H]+ (calcd 3148.18). Bis(1,3-bis{3,5-bis[ω-octahydro-dendroG3-(oxymethylenebenzene-1,3,5-triyl)-α-yl]benzyl}imidazol-2-ylidene)dibromidopalladium(II) (4). [PdBr2(cod)] (0.016 g, 0.043 mmol) and [AgBr(1,3-bis(G3)imidazol-2-ylidene)] (0.290 g, 0.0851 mmol). Yield: 199 mg (70%). Anal. Calcd (%) for C426H368N4O56Br2Pd (6705.70): C, 76.30; H, 5.53; N, 0.84. Found: C, 76.10; H, 5.41; N, 0.95. 1H NMR (CDCl3): δ 4.66 (s, 16H, OCH2ArG1) 4.72 (s, 32H, OCH2ArG2), 4.81 (s, 64H, OCH2Ph), 5.42 (s, 8H, NCH2Ar), 6.35 (broad d, 8H, o-ArG0), 6.39 (broad t, 8H, p-ArG1), 6.43 (broad t, 20H, p-ArG0,G2), 6.53 (broad d, 52H, o-ArG1,G2 and Imz), 7.15−7.26 (m, 160H, Ph). 13 C{1 H} NMR (CDCl 3 ): δ 54.4 (CH 2 ), 69.7 (OCH2ArG2), 69.9 (OCH2ArG1 and OCH2Ph), 101.5 (p-ArG0,G1,G2), 106.4 (o-ArG1,G2), 106.9 (o-ArG0), 121.4 (Imz−C4,5), 127.5 and 128.5 (o- and m-Ph), 127.8 (p-Ph), 136.7 (ipso-Ph), 138.7 (ipso-ArG0), 139.2 (ipso-ArG1), 139.3 (ipso-ArG2), 159.8 (m-ArG1), 159.9 (m-ArG2), 159.7 (m-ArG0), 169.8 (Imz−C2). IR (KBr): ν 1595 and 1451 (s, C− Carom), 1497 (s, CNC), 1294 (m, C−O−Cas), 1151 and 1052 cm−1 (s, C−O−Cs). MS (ESI+-TOF in CH2Cl2/MeOH/NH4HCOO 5 mM): m/z 6541.52 [M − 2Br + H]+ (calcd 6541.52). Synthesis of Bis(imidazolium) Bromides (5−8). A solution of 1,2-di(1H-imidazol-1-yl)ethane and benzyl bromide in acetone was stirred at 60 °C for the time specified for each compound. Once this reaction time passed, the white precipitate was separated by filtration and dried under vacuum. Any trace of 1,2-di(1H-imidazol-1-yl)ethane remaining in the final product was removed by successive washings with hexane. 1,1′-Bis(benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibromide (5). 1,2-Di(1H-imidazol-1-yl)ethane (0.500 g, 3.08 mmol), benzyl bromide (0.73 mL, 6.16 mmol), and acetone (15 mL). Reaction time: 30 min. Yield: 1.55 g (100%). Anal. Calcd (%) for C22H24N4Br2 (504.27): C 52.40; H 4.80; N 11.11%. Found: C 52.15; H 4.58; N 11.24%. 1H NMR (dmso-d6): δ 4.71 (s, 4H, CH2CH2), 5.41 (s, 4H, CH2), 7.34−7.40 (m, 10H, Ph), 7.68 (s, 2H, Imz−H4or5), 7.81 (s, 2H, Imz−H4or5), 9.26 (s, 2H, Imz−H2). 13C{1H} NMR (dmso-d6): δ 47.9 (CH2CH2), 51.5 (CH2), 122.4 (Imz−C4,5), 127.7 (m-Ph), 128.3 (pPh), 128.4 (o-Ph), 133.9 (ipso-Ph), 136.2 (Imz−C2). IR (KBr): ν 1557 and 1454 (s, CC), 1497 cm−1 (m, CNC). MS (ESI+-TOF, dmso): m/z 423.12 [M − Br]+ (calcd 423.12). 1,1′-Bis(3,5-bis[ω-dihydro-dendro G1-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibromide (6). 1,2-Di(1H-imidazol-1-yl)ethane (1.02 g, 6.30 mmol), G1− Br (4.82 g, 12.6 mmol), and acetone (50 mL). Reaction time: 2.5 h. Yield: 5.84 g (100%). Anal. Calcd (%) for C50H48N4O4Br2 (928.75): C 64.66; H 5.21; N 6.03%. Found: C 64.61; H 4.82; N 5.89%. 1H NMR (dmso-d6): δ 4.66 (s, 4H, CH2CH2), 5.03 (s, 8H, OCH2Ph), 5.25 (s, 4H, NCH2Ar), 6.61 (broad s, 6H, o-Ar and p-Ar), 7.30−7.35 (m, 20H, Ph), 7.65 (s, 2H, Imz−H4or5), 7.73 (s, 2H, Imz−H4or5), 9.33 (s, 2H, Imz−H2). 13C{1H} NMR (dmso-d6): δ 47.9 (CH2CH2), 51.5 (NCH2Ar), 68.9 (OCH2Ph), 100.9 (p-Ar), 104.1 (o-Ar), 122.3 (Imz− C4,5), 127.7 (m-Ph), 127.4 (p-Ph), 127.9 (o-Ph), 136.0 (ipso- Ar), 136.1 (ipso-Ph), 136.2 (Imz−C2), 159.3(m-Ar). IR (KBr): ν 1598 and 1444 (s, CC), 1497 (m, CNC), 1302 (m, C−O−Cas), 1164 and 1058 cm−1 (s, C−O−Cs). MS (ESI+-TOF, dmso): m/z 847.29 [M − Br]+ (calcd 847.29). 1,1′-Bis(3,5-bis[ω-tetrahydro-dendroG2-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibromide (7). 1,2-Di(1H-imidazol-1-yl)ethane (250 mg, 1.54 mmol), G2−Br (2.49 g, 3.08 mmol), and acetone (30 mL). Reaction time: 7.0 h. Yield: 2.66 g (97%). Anal. Calcd (%) for C106H96N4O12Br2

with the practical advantage that OSN technologies are easily adaptable to both micro- or large-scale syntheses. Although several scenarios have been analyzed to explain these results, further studies are needed to disclose the basis of the high recyclability of the bis(NHC) complexes. Preformed complexes enlarged with (expensive) dendrons are surely not the ideal approach to obtain catalysts for practical applications. However, these well-defined molecular catalysts working under homogeneous conditions can be studied using the powerful techniques available to the molecular chemist. Recovery mechanisms are often poorly understood due to the difficulties associated with poorly defined catalytic systems working in a heterogeneous catalytic medium.

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EXPERIMENTAL SECTION

General Procedures and Materials. Gn−Br dendrimers,26 [PdBr2(cod)],51 and (1,3-bis(Gn)imidazol-2-ylidene)bromidosilver(I)27b were prepared as described in the literature. Other general procedures and materials, and the modified procedure for the synthesis of 1,2-di(1H-imidazol-1-yl)ethane, are described in the Supporting Information. The following abbreviations/notations are used: Imz refers to the imidazole ring, Ph refers to terminal, and Ar refers to internal aromatic rings in poly(benzyl ether) dendrons, and ipso refers to the first ring-position on going from the azole ligand. Preparation of Complexes trans-[PdBr2(NHC)2] (1−4). [PdBr2(cod)] was added to a Schlenk tube containing a solution of the appropriate [AgBr(NHC)] complex in dichloromethane (25 mL). The reaction mixture was then stirred at room temperature for 1 h (1), 3 h (2 and 3), or 6 h (4). The suspension was subsequently filtered, the solution evaporated to dryness under vacuum, and the residue washed with hexane (3 × 15 mL) and dried under vacuum. Complexes 1−4 were isolated as white or pale-yellow solids. Complex 4 was purified by chromatography over silica gel using dichloromethane/ethyl acetate (1:1) as the eluent. Bis(1,3-bis(benzyl)imidazol-2-ylidene)dibromidopalladium(II) (1). [PdBr2(cod)] (0.376 g, 1.00 mmol) and [AgBr(1,3-bis(G0)imidazol-2-ylidene)] (0.877 g, 2.01 mmol). Yield: 689 mg (90%). Anal. Calcd (%) for C34H32Br2N4Pd (762.87): C, 53.53; H, 4.23; N, 7.34. Found: C, 52.95; H, 4.25; N, 7.16. 1H NMR (CDCl3): δ 5.70 (s, 8H, CH2), 6.62 (s, 4H, Imz), 7.26−7.28 (m, 12H, Ph), 7.41−7.43 (m, 8H, Ph). 13C{1H} NMR (CD2Cl2): δ 55.1 (CH2), 121.7 (Imz−C4,5), 128.7 and 129.3 (o- and m-Ph), 129.1 (p-Ph), 136.9 (ipso-Ph), 170.7 (Imz−C2). IR (KBr pellet): ν 1603 and 1454 (s, C−Carom), 1495 cm−1 (s, CNC). MS (ESI+-TOF in CH2Cl2/MeOH/NH4HCOO 5 mM): m/z 681.08 [M − Br]+ (calcd 681.08). Bis(1,3-bis{3,5-bis[ω-dihydro-dendroG1-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl}imidazol-2-ylidene)dibromidopalladium(II) (2). [PdBr2(cod)] (0.043 g, 0.11 mmol) and [AgBr(1,3-bis(G1)imidazol-2-ylidene)] (0.200 g, 0.232 mmol). Yield: 160 mg (90%). Anal. Calcd (%) for C90H80N4O8Br2Pd (1611.85): C, 67.06; H, 5.00; N, 3.48. Found: C, 66.64; H, 5.00; N, 3.58. 1H NMR (CDCl3): δ 4.88 (s, 16H, OCH2Ph), 5.60 (s, 8H, NCH2Ar), 6.45 (t, 4JH,H = 2.2 Hz, 4H, p-Ar), 6.62 (s, 4H, Imz−H4,5), 6.71 (t, 4JH,H = 2.2 Hz, 8H, o-Ar), 7.25−7.30 (m, 40H, Ph). 13C{1H} NMR (CDCl3): δ 54.6 (CH2), 70.1 (OCH2Ph), 102.1 (p-Ar), 107.4 (o-Ar), 121.3 (Imz−C4,5), 127.6 and 128,4 (o- and m-Ph), 127.8 (p-Ph), 136.7 (ipso-Ph), 138.4 (ipsoAr), 160.1 (m-Ar), 169.7 (Imz−C2). IR (KBr): ν 1595 and 1452 (s, C−Carom), 1497 (s, CNC), 1294 (m, C−O−Cas), 1152 and 1058 cm−1 (s, C−O−Cs). MS (ESI+-TOF in CH2Cl2/MeOH/NH4HCOO 5 mM): m/z 1626.37 [M + NH4]+, 1451.52 [M − 2Br + H]+ (calcd 1451.51). Bis(1,3-bis{3,5-bis[ω-tetrahydro-dendroG2-(oxymethylenebenzene-1,3,5-triyl)-α-yl]benzyl}imidazol-2-ylidene)dibromidopalladium(II) (3). [PdBr2(cod)] (0.022 g, 0.059 mmol) and [AgBr(1,3-bis(G2)imidazol-2-ylidene)] (0.200 g, 0.117 mmol). Yield: 164 mg (85%). Anal. Calcd (%) for C202H176Br2N4O24Pd (3309.80): C, 73.30; H, 5.36; N, 1.69; Found: C, 72.22; H, 5.44; N, 1.83. 1H NMR (CDCl3): δ 4.76 (s, 16H, OCH2ArG1), 4.89 (s, 32H, H


Article

Organometallics

1595 and 1452 (s, CC), 1497 (m, CNC), 1319 (m, C−O−Cas), 1152 and 1058 cm−1 (s, C−O−Cs). MS (ESI+-TOF, CH2Cl2/ MeOH/HCOONH4 5 mM): m/z 951.17 [M − Br]+ (calcd 951.17). (1,1′-Bis(3,5-bis[ω-tetrahydro-dendroG2-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)dibromidopalladium(II) (11). Pd(OAc)2 (63 mg, 0.28 mmol), 7 (500 mg, 0.28 mmol), and dmso (3 mL). Yield: 474 mg (90%). Anal. Calcd (%) for C106H94N4O12PdBr2 (1882.13): C 67.64; H 5.03; N 2.98%. Found: C 67.37; H 4.90; N 3.21%. 1H NMR (CDCl3): δ 4.14 (m, 2H, CHHCHH), 4.80 (m, 8H, OCHHAr), 4.89 (m, 16H, OCHHPh), 4.97 (d, 2H, 2JH,H = 14.4, NCHHAr), 5.32 (overlapping resonances, 4H, CHHCHH and NCHHAr), 6.40 (t, 2H, p-ArG0), 6.42 (d, 4H, oArG0), 6.47 (t, 4H, 3JH,H = 2.0, p-ArG1), 6.55 (overlapping d; 8H, 3JH,H = 2.0, o-ArG1; 2H, Imz), 6.66 (d, 2H, 3JH,H = 1.9, Imz), 7.25−7.38 (m, 40H, Ph). 13C{1H} NMR (CDCl3): δ 47.9 (CH2CH2), 54.7 (NCH2Ar), 70.0 (OCH2ArG1 and OCH2Ph), 101.4 (p-ArG1), 103.3 (p-ArG0), 106.4 (o-ArG1), 107.5 (o-ArG0), 122.2 (Imz−C4,5), 127.6 (m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.7 (ipso-Ph), 139.0 (ipsoArG0), 139.9 (ipso-ArG1), 159.9 (m-ArG1), 160.05 (m-ArG0 and Imz− C2). IR (KBr): ν 1595 and 1451 (s, CC), 1497 (m, CNC), 1321 (m, C−O−Cas), 1153 and 1053 cm−1 (s, C−O−Cs). MS (ESI+-TOF, CH2Cl2/MeOH/HCOONH4 5 mM): m/z 1799.51 [M − Br]+ (calcd 1799.51). (1,1′-Bis(3,5-bis[ω-octahydro-dendroG3-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)dibromidopalladium(II) (12). Pd(OAc)2 (9 mg, 0.041 mmol), 8 (145 mg, 0.041 mmol), and dmso (1.5 mL). Yield: 133 g (89%). Anal. Calcd (%) for C218H190N4O28Br2Pd (3580.08): C 73.14; H 5.35; N 1.56%. Found: C 73.32; H 5.62; N 1.82%. 1H NMR (CDCl3): δ 3.84−4.00 (m, 2H, CHHCHH), 4.69−5.10 (m, 58H, NCHHAr, OCH2ArG1,G2, and OCH2Ph), 5.11−5.42 (m, 4H, NCHHAr and CHHCHH), 6.35 (broad s, 2H, p-ArG0), 6.39 (broad s, 4H, o-ArG0), 6.42 (broad s, 4H, p-ArG1), 6.48 (broad s, 8H, p-ArG2), 6.54 (broad s, 8H, o-ArG1), 6.58 (broad s, 18H, o-ArG2 and Imz−H), 6.61 (broad s, 2H, Imz), 7.23−7.34 (m, 80 H, Ph). 13C{1H} NMR (CDCl3): δ 47.9 (CH2CH2), 54.7 (NCH2Ar), 69.7 (OCH2ArG1,G2), 69.9 (OCH2Ph), 101.5 (p-ArG1,G2), 102.7 (p-ArG0), 106.3 (o-ArG1,G2), 107.5 (o-ArG0), 124.6 (Imz−C4,5), 127.5 (m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.7 (ipso-ArG2,G3), 139.1 (ipso-ArG0), 139.3 (ipso-ArG1), 159.9 (m-ArG2), 160.05 (m-ArG0,G1 and Imz−C2). IR (KBr): ν 1596 and 1451 (s, C C), 1497 (m, CNC), 1299 (m, C−O−Cas), 1158 and 1052 cm−1 (s, C−O−Cs). MS (ESI+-TOF, CH2Cl2/MeOH/HCOONH4 5 mM): m/z 3496.18 [M − Br]+ (calcd 3496.18). Catalytic and Recovery Studies. MH Reaction. Methyl acrylate (0.90 mL, 10 mmol), para-iodotoluene (1.83 g, 8.5 mmol), triethylamine (1.39 mL, 10 mmol), and naphthalene (1.08 g, 8.5 mmol) were dissolved in dmf (50.0 mL). An aliquot of this solution (3 mL) was then transferred to a glass ampule together with 1 mL of a freshly prepared solution of the corresponding catalyst (25 μmol) in dmf (50 mL). The overall reaction volume was completed with an additional amount of dmf (1 mL). The reaction time was started when the ampule was introduced into a silicone bath previously warmed to 130 °C. The reaction progress was monitored by gas chromatography, using the added naphthalene as an internal reference. At the end of the reaction, the volatiles were removed in vacuo, the residue extracted with dichloromethane (20 mL), and the organic phase washed with water (3 × 15 mL), dried over MgSO4, and evaporated to dryness. The methyl (2E)-3-(4-methyl)phenylprop-2-enoate product thus obtained was weighed and the yield compared with that measured by GC. Recovery Procedure. The MH reactions were performed as specified above in pressure ampules of 250 mL fitted with a J. Young valve. The ampules were filled with a dmf solution (100 mL) of methyl acrylate (1.083 mL, 12.0 mmol), para-iodotoluene (2.202 g, 10.0 mmol), triethylamine (1.674 mL, 12.0 mmol), and naphthalene (1.296 g, 10 mmol) as internal standard, and the corresponding catalyst (10 μmol) in dmf (50 mL). The solution was stirred at 130 °C for 12 h (for 3, 10, and 11) or 16 h (for 12) in the initial cycle, and for 7 h (for 3, 10, and 11) or 12 h (for 12) in successive cycles. The solution was then transferred into the nanofiltration cell under

(1777.72): C 71.61; H 5.44; N 3.15%. Found: C 71.31; H 5.52; N 3.23%. 1H NMR (dmso-d6): δ 4.66 (s, 4H, CH2CH2), 4.98 (s, 8H, OCH2ArG1), 5.04 (s, 16H, OCH2Ph), 5.26 (s, 4H, NCH2Ar), 6.56− 6.68 (m, 18H, ArG0,G1), 7.27−7.40 (m, 40H, Ph), 7.65 (s, 2H, Imz− H4or5), 7.76 (s, 2H, Imz−H4or5), 9.20 (s, 2H, Imz−H2). 13C{1H} NMR (dmso-d 6): δ 47.9 (CH2CH2), 51.5 (NCH2Ar), 68.7 (OCH2ArG1,G2 and OCH2Ph), 100.4 (p-ArG0,G1,G2), 105.9 (oArG0,G1,G2), 122.5 (Imz−C4,5), 127.1 (m-Ph), 127.3 (p-Ph), 127.8 (o-Ph), 136.2 (ipso-ArG0,G1 and Imz−C2), 138.3 (ipso-ArG2), 138.6 (ipso-Ph), 158.9 (m-ArG0,G1,G2). IR (KBr): ν 1589 and 1453 (s, C C), 1497 (m, CNC), 1295 (m, C−O−Cas), 1110 and 1076 cm−1 (s, C−O−Cs). MS (ESI+-TOF, dmso): m/z 808.35 [M − 2Br]2+ (calcd 1616.70). 1,1′-Bis(3,5-bis[ω-octahydro-dendroG3-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-(ethane-1,2-diyl)diimidazolium Dibromide (8). 1,2-Di(1H-imidazol-1-yl)ethane (19.6 mg, 0.12 mmol), G3−Br (400 mg, 0.24 mmol), and acetone (10 mL). Reaction time: 17.0 h. The solid thus obtained was washed with hexane until any trace of 1,2-di(1H-imidazol-1-yl)ethane was removed (3 × 15 mL). Yield: 1.68 g (84%). Anal. Calcd (%) for C218H192N4O28Br2 (3475.68): C 75.33; H 5.57; N 1.61%. Found: C 74.43; H 5.23; N 2.05%. 1H NMR (dmso-d6): δ 4.64 (s, 4H, CH2CH2), 4.95 (s, 8H, OCH2ArG1), 5.00 (s, 48H, OCH2ArG2 and OCH2Ph), 5.24 (s, 4H, NCH2Ar), 6.56−6.64 (m, 42H, ArG0,G1,G2), 7.20−7.35 (m, 80H, Ph), 7.63 (s, 2H, Imz−H4or5), 7.74 (s, 2H, Imz−H4or5), 9.21 (s, 2H, Imz− H2). 13C{1H} NMR (dmso-d6): δ 47.9 (CH2CH2), 52.5 (NCH2Ar), 68.8 (OCH2ArG1, OCH2Ph), 100.4 (p-ArG1), 100.9 (p-ArG0), 106.0 (o-ArG1), 107.1 (o-ArG0), 122.3 (Imz−C4,5), 127.1 (m- and p-Ph), 127.8 (o-Ph), 136.30 (ipso-ArG0,G1 and Imz−C2), 138.4 (ipso-Ph), 159.0(m-ArG0,G1). IR (KBr): ν 1596 and 1451 (s, CC), 1497 (m, CNC), 1298 (m, C−O−Cas), 1158 and 1054 cm−1 (s, C−O−Cs). MS (ESI+-TOF, dmso): m/z 3392.29 [M − Br]+ (calcd 13392.29). Preparation of Complexes [PdBr2(NHC∧NHC)] (9−12). A mixture of Pd(OAc)2 and the corresponding bis(imidazolium) bromide was dissolved in dmso and heated at 50 °C for 2 h. The temperature was then increased to 110 °C at a rate of 0.5 °C/min and maintained at 110 °C for 1 h. The greenish solution was subsequently filtered through kieselguhr, and the column washed with dichloromethane (2 × 5 mL). The dmso and dichloromethane filtrates were combined and evaporated to dryness under vacuum. After dissolution of the residue in dichloromethane (10 mL) and addition of hexane (15 mL), the precipitate was separated by filtration and dried under vacuum to give corresponding complex 9−12 as a yellow solid. (1,1′-Bis(benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)dibromidopalladium(II) (9). Pd(OAc)2 (86 mg, 0.38 mmol), 5 (193 mg, 0.38 mmol), and dmso (1.2 mL). Yield: 215 mg (93%). Anal. Calcd (%) for C22H22N4PdBr2 (608.66): C 43.41; H 3.64; N 9.20%. Found: C 43.77; H 3.57; N 9.58%. 1H NMR (CDCl3): δ 4.60 (m, 2H, CHHCHH), 5.25 (d, 2H, 2JH,H = 14.8, NCHHAr), 5.59 (d, 2H, NCHHPh), 5.60 (m, 2H, CHHCHH), 6.76 (d, 2H, 3JH,H = 2.0, Imz), 7.12 (d, 2H, Imz), 7.23−7.37 (m, 10H, Ph). 13C{1H} NMR (CDCl3): δ 47.8 (CH2CH2), 54.7 (NCH2Ph), 122.2 (Imz−C4or5), 124.9 (Imz− C4or5), 128.4 (m-Ph), 128.6 (p-Ph), 128.9 (o-Ph), 135.4 (ipso-Ph), 159.4 (Imz−C2). IR (KBr): ν 1557 and 1454 (s, CC), 1497 cm−1 (m, CNC). MS (ESI+-TOF, CH2Cl2/MeOH/HCOONH4 5 mM): m/z 527.01 [M − Br]+ (calcd 527.01). (1,1′-Bis(3,5-bis[ω-dihydro-dendroG1-(oxymethylenebenzene1,3,5-triyl)-α-yl]benzyl)-3,3′-methylenediimidazol-2,2′-diyliden)dibromidopalladium(II) (10). Pd(OAc)2 (97 mg, 0.43 mmol), 6 (400 mg, 0.43 mmol), and dmso (2.3 mL). Yield: 408 mg (92%). Anal. Calcd (%) for C50H46N4O4Br2Pd (1033.15): C 58.13; H 4.49; N 5.42%. Found: C 57.78; H 4.69; N 5.60%. 1H NMR (CDCl3): δ 4.48 (m, 2H, CHHCHH), 4.89 (d, 4H, 2JH,H = 11.7, OCHHPh), 4.97 (d, 4H, OCHHPh), 5.17 (d, 2H, 2JH,H = 14.5, NCHHAr), 5.43 (d, 2H, NCHHAr), 5.48 (m, 2H, CHHCHH), 6.50 (broad s, 6H, o- and pAr), 6.62 (d, 2H, 3JH,H = 2.2, Imz), 6.89 (d, 2H, Imz), 7.27−7.31 (m, 20H, Ph). 13C{1H} NMR (CDCl3): δ 47.7 (CH2CH2), 54.6 (NCH2Ar), 70.1 (OCH2Ph), 101.7 (p-Ar), 107.8 (o-Ar), 122.2 (Imz−C4,5), 127.7 (m-Ph), 128.0 (p-Ph), 128.5 (o-Ph), 136.5 (ipsoPh), 137.7 (ipso-Ar), 159.2 (m-Ar) 160.2 (Imz−C2). IR (KBr): ν I


Article

Organometallics *E-mail: [email protected].

argon. Under continuous stirring, the cell was pressurized with argon at 1.5 bar to obtain a flow through the 90 cm diameter membrane of approximately 10 mL/min. The permeate was collected under argon in a Schlenk tube to a volume of 70 mL. Then, dmf (70 mL) was subsequently added to the retentate in the cell, and a further 70 mL of solution was filtered under continuous stirring. The result of this twostep filtration procedure is that around 90% of the initial reaction mixture was filtered. The two permeate fractions collected in each recovery cycle were combined and evaporated to dryness. The solid residue was weighed and a small fraction separated for analysis of the Pd content. The remaining solid was extracted with dichloromethane (50 mL), and the organic phase was washed with water (3 × 30 mL), dried over MgSO4, and evaporated to dryness. The methyl (2E)-3-(4methyl)phenylprop-2-enoate product thus obtained was weighed and analyzed by 1H NMR. The retentate was again transferred to a pressure ampule and a new load of substrates, triethylamine, internal standard, and solvent was added (to complete an overall volume of 100 mL). The procedure was then repeated. X-ray Crystallographic Studies. Suitable single crystals of 1, 2, and 10 were obtained by the following methods: slow evaporation of a dichloromethane solution of 1; slow diffusion of hexane into a dichloromethane solution of 2; slow diffusion of diethyl ether into a solution of 10 in dimethylformamide. A summary of crystal data, data collection, and refinement parameters for the structural analysis is given in Table S1. Crystals were glued to a glass fiber using an inert polyfluorinated oil and mounted in the low temperature N2 stream (200 K) of a Bruker-Nonius Kappa-CCD diffractometer equipped with an area detector and an Oxford Cryostream 700 unit. Intensities were collected using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Data were measured with exposure times of 10 s per frame for 1 (5 sets; 272 frames; phi/omega scans; 2.0° scan-width), 60 s per frame for 2 (3 sets; 150 frames; phi/omega scans; 2.0° scanwidth), 45 s per frame for 10 (4 sets; 825 frames; phi/omega scans; 0.5° scan-width). Raw data were corrected for Lorenz and polarization effects. The structures were solved by direct methods, completed by subsequent difference Fourier techniques, and refined by full-matrix least-squares on F2 (SHELXL-97).52 Anisotropic thermal parameters were used in the last cycles of refinement for the non-hydrogen atoms, except in the case of compound 2 where six atoms remain isotropic. Absorption correction procedures were carried out using the multiscan SORTAV (semiempirical from equivalent) program.53 Hydrogen atoms were included in the last cycle of refinement from geometrical calculations and refined using a riding model. All the calculations were made using the WINGX system.54

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ORCID

Pilar Gómez-Sal: 0000-0002-9279-210X Juan C. Flores: 0000-0001-6356-555X Ernesto de Jesús: 0000-0001-8101-1358 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Spanish Ministerio de Economia,́ Industria y Competitividad (projects CTQ201455005-P and CTQ2017-85203-P). A.M.O. is grateful to the Spanish Ministerio de Educación, Cultura y Deporte for an FPU Doctoral Fellowship. Dedicated to Professor Ernesto Carmona on the occasion of his 70th birthday.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00295. General procedures, synthesis of 1,2-di(1H-imidazol-1yl)ethane, crystallographic tables for 1, 2, and 10, catalytic conditions, full kinetic profiles, incubation experiments, nanofiltration details, Pd analyses, retention factors, and miscellaneous tests (PDF) Accession Codes

CCDC 1839922−1839924 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

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