Substrate-selective catalysis.

DOI: 10.1002/chem.201402548

Review

& Selective Selectivity

Substrate-Selective Catalysis Emil Lindbck, Sami Dawaigher, and Kenneth Wrnmark*[a]

Chem. Eur. J. 2014, 20, 13432 – 13481

13432

2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Review Abstract: Substrate selectivity is an important output function for the validation of different enzyme models, catalytic cavity compounds, and reaction mechanisms as demonstrated in this review. In contrast to stereo-, regio-, and chemoselective catalysis, the field of substrate-selective catalysis is under-researched and has to date generated only a few, but important, industrial applications. This review points out the broad spectrum of different reaction types that have been

Introduction

*

In contrast to the tremendous development of homogeneous catalysis[1] in the fields of regio-,[2] chemo- and enantioselective reactions,[3] the corresponding development in the field of substrate-selective catalysis has not been observed. One reason for this might be that for the application of enzyme- or manmade catalysts in chemical synthesis, a high substrate selectivity is a problem, because it is desirable for the generality of the catalytic reaction that the enzyme- or artificial catalyst has as broad a scope as possible. Thus, research in the field of catalysis is going in the direction away from substrate selectivity. Nevertheless, substrate selectivity is widely studied in homogeneous catalysis as an output function to evaluate the validity of artificial enzyme models, since substrate specificity is one characteristic property of an enzyme.[4] In the field of heterogeneous catalysis[5] the efficiency of cavities as catalysts, such as those found in zeolites and nanoparticles, has often been evaluated in terms of substrate selectivity. In the process of compiling this review, we have discovered that in many publications the catalyst is substrate selective, but that aspect has not been the main issue of the studies or has not even been mentioned as a property of the catalyst. As a matter of fact, this is in particular the case for mechanistic investigations, for which competitive reactions have been employed to elucidate the reactions mechanism of a certain catalyzed reaction. These are frequently carried out by using the values of the relative reaction constant obtained to construct a Hammett plot and from that extract the reaction constant as the key parameter for the elucidation of the reaction mechanism.[6] However, at the same time, indirectly, the substrate selectivity of the catalyst has been evaluated. This natural lack of focus on the substrate selectivity of the catalyst in these types of publications and in others as well has resulted in difficulties to find hits using search terms in data bases related to substrate-selective catalysis. This forced us to rely a lot on manual search in compiling this review. We apologize in advance for examples that we have not found. An important issue is in how the observed substrate selectivity has been measured: [a] E. Lindbck, S. Dawaigher, K. Wrnmark Centre for Analysis and Synthesis, Department of Chemistry Lund University P.O. Box 124, S-221 00 Lund (Sweden) E-mail: [email protected] Chem. Eur. J. 2014, 20, 13432 – 13481

investigated in substrate-selective catalysis. The present review is the first one covering substrate-selective catalysis and deals with reactions in which the substrates involved have the same reacting functionality and the catalysts is used in catalytic or in stoichiometric amounts. The review covers real substrate-selective catalysis, thus only including cases in which substrate-selective catalysis has been observed in competition between substrates.

www.chemeurj.org

* *

As the conversion of substrate or as the formation of product? As yield or as rate constant? In separate single experiments of one substrate at a time or in substrate-competing experiments?

Hence, the different ways that substrate selectivity has been evaluated make comparisons between different catalytic systems very inconsistent. We have in this review tried to point out which type of method that has been used to establish substrate selectivity to make it possible for the reader to compare between different catalysts. When “product selectivity” is used as a measure of substrate selectivity in this review, it is understood that it is defined as the ratio of the rate/amount of formed main product of one substrate versus the other, if not stated otherwise. This corresponds to true substrate selectivity only if each substrate is converted to one product or if the formation of all products from each substrate is taken into account. We have only included catalysts that have proven to be substrate selective in competitive experiments. The reason for this is the following: in real cases of substrate-selective catalysis, such as enzyme catalysis or cracking of oil using a heterogeneous catalyst (vide infra), the catalysts are operating in the presence of many potential substrates. Thus, recording the substrate selectivity of a catalyst using a competitive experimental set-up is closer to the real situation. In contrast, using the reactivity of a catalyst towards single-substrate reactions to assess substrate selectivity is not the best way to represent substrate selectivity. The examples, given in for example Scheme 4 and Scheme 19, strongly supports this view, in which the substrate selectivity of the catalysts that is assessed from separate single-substrate reactions is reversed upon running the reaction in competition between substrates. The reason for the reversal of the substrate selectivity could be that when running a reaction in competition between substrates, one of the substrates could bind preferentially to the receptor part of the catalyst, and thereby blocking the access to the active site of the catalyst for the other substrate, thus, hampering the reaction of the other substrate and at the same time it is still possible for the coordinated first substrate to be reacted due to its proximity to the catalytic site. This means that many or all examples of substrate-selective catalysis in certain fields, for which a lot of design has been invested in creating substrateselective catalysts, such as supramolecular catalysis using cy-

13433


Review clodextrins,[4a] hydrogenation catalysts,[7] and molecular imprinted polymers,[8] but for which the evaluation has been based on individual single-substrate experiments, are not included in the present review. However, readers may find useful information about those systems by looking at the references listed above. This review does not either include kinetic resolution of racemic mixtures although formally containing two different substrates (enantiomers). That field has been reviewed elsewhere.[9] In this review we have arranged the catalysts according to what reaction type that they have been demonstrated to be substrate selective for. In doing this we have often felt it necessary to also present basic ideas about the mechanism for the different catalysts and interactions between the catalyst and the substrate to properly understand how the substrate selectivity has been achieved. This has led to that the review also provides an overview of catalysis today. It is also worth mentioning that this review covers substrate selectivity in which the substrates involved contain the same reacting functionality. In addition, although the title of the review is “Substrate-Selective Catalysis”, it also covers situations in which the “catalyst” is used in stoichiometric amounts and we have carefully pointed out each such situation. To the best of our knowledge, this is the first time that substrate-selective catalysis has been reviewed as such.

rin catalyst 3 (Figure 1).[11] The epoxidation of alkenes (500 equiv) by the catalysts 1 and 2 (1 mmol, 1 equiv) was carried out in the presence of iodosylbenzene (PhIO, 10 equiv) as the terminal oxidant in dichloromethane. In order to investigate the substrate selectivity, competitive experiments were performed on samples containing unspecified equimolar concentrations of alkenes: the samples were loaded with cyclooctene (4) in pair-wise competition with one equivalent of 5, 6, 7, 8, or 9 (Scheme 1) or they were loaded with 8 in competition with one of 10 or 11 (Scheme 1).[10, 12] In most experiments, the dendrimer–MnIII–porphyrin catalysts 1 and 2 showed two to three times higher selectivity for the less sterically hindered alkene than that of the parent catalyst 3. Additionally, the substrate selectivities in the epoxidations were found to slightly increase from substrate 5 to 6 to 7 over the competing sub-

Sami Dawaigher: Sami Dawaigher graduated from Lund University (Sweden) with a master of science in chemistry in 2003. After a few years working in fields unrelated to chemistry, he joined the group of Professor Wrnmark as an intern in 2009. Following the internship he took up Ph.D. studies in the same group in 2012. His work is focused towards the field of supramolecular chemistry ranging from studies of solvent-guest-host interactions, synthesis and functionalization of Trçger’s base derivatives and synthesis of porphyrins.

Emil Lindbck: Emil Lindbck was born in 1982 in Svngsta (Sweden). He studied chemistry at Lund University (Sweden), from where he obtained his B.Sc. degree in 2008. He then continued with Ph.D. studies at the University of Copenhagen (Denmark). As a part of his Ph.D. studies, he spent six months as a visiting scholar at the University of Seville (Spain), under the supervision of Dr. scar Lpez. He earned his Ph.D. degree in 2012, working with glycosidase inhibitors and artificial enzymes based on cyclodextrins. He is currently a postdoctoral researcher in the research group of Professor Kenneth Wrnmark at Lund University, working with supramolecular and asymmetric catalysis.

Figure 1. The MnIII–porphyrins 1 and 2 were investigated as shape-selective catalyst for the epoxidation of alkenes and compared with the parent MnIII– porphyrin 3.

1. Oxidations 1.1 Epoxidations Suslick and co-workers reported the design and the synthesis of MnIII–porphyrins 1 and 2 (Figure 1) as shape-selective catalysts for the homogeneous epoxidation of alkenes.[10] These MnIII–porphyrins contained bulky cascade dendrimers in order to investigate the influence of the steric bulk on the substrate selectivity compared to the parent unsubstituted MnIII–porphyChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Kenneth Wrnmark: Kenneth Wrnmark obtained his Ph.D. at the Royal Institute of Technology in Stockholm (Sweden) under the supervision of Prof. Christina Moberg, working with macrocyclic ligands. He then continued with post-doc studies at Universit de Strasbourg (France; 1994–1996) with Prof. JeanMarie Lehn, working on ruthenium-N-heterocyclic complexes. He started his independent career at Lund University (Sweden) as assistant professor in 1996 and he was promoted to senior lecturer in 2000. He became associate professor in 2003 and since 2010 he has been full professor of organic chemistry at Lund University. His research interests include supramolecular catalysis, self-assembly, molecular tubes, molecular receptors, Fe–carbene photochemistry and Trçger’s base chemistry.

13434


Review

Scheme 1. The pair-wise competitive epoxidations of alkenes 4–11 containing an internal or external double-bond in the presence of MnIII–porphyrins 1, 2, and 3 using PhIO as terminal oxidant.

Scheme 2. The pair-wise competitive epoxidation of alkenes 14 versus 16, 18 versus 19 and 24 versus 25 performed with catalysts 12, 13, and 20–23 using PhIO as the terminal oxidant.

140 equiv) and trans-stilbene (15, 140 equiv) by 12 (35 mmol, 1 equiv) in the presence of PhIO (6 equiv) as the terminal oxidant in dichloromethane and in single-substrate experiments furnished the corresponding cis- and trans-stilbene oxides 16 and 17, respectively (see Scheme 2a for structures). A quite different reactivity of 13 compared to 12 was observed, as compound 13 catalyzed the epoxidation of 14 (cis) to the corresponding cis-alkene oxide 16, whereas the opposite geometrical isomer 15 (trans) was inert under identical conditions. In line with these results a pair-wise competitive experiment (Scheme 2a) of a sample containing unspecified amounts of both isomers gave cis-stilbene oxide (16) in 82 % yield and unreacted trans-stilbene (15) in the presence of catalyst 12 (2 mol %), the substrate selectivity was thus determined as product selectivity. A similar observation was made in a pairwise competitive experiment between 18 (1.2 mL) and 19 (1.5 mL, Scheme 2b) in the presence of 13 (0.028 mmol), for which the epoxidation of the cis-isomer 18 proceeded six times faster. By the use of space-filling models, the side-on approach of cis- (14) and trans-stilbene (15) to the metal center of 13 (see Figure 2) indicated a large phenyl–phenyl repulsion between the trans-isomer 15 and catalyst 13, whereas the corresponding interaction between the catalyst and the cis-isomer 14 was less prominent. The observed cis-selectivity of 13 prompted the same research group to develop a series of similar FeIII–porphyrins 20–23 (Figure 2) carrying different aromatic substituents and thereby exhibiting modified steric environments around the porphyrin.[14] The pair-wise competitive epoxidation of cis- (24, 18 equiv, Scheme 2c) versus trans-cyclodecene (25, 43 equiv, Scheme 2c) by FeIII–porphyrins 20–23 (0.05 mmol, 1 equiv) using PhIO (18 equiv) as the terminal oxidant demonstrated, with the exception of 22, that the selectivity (corrected for amount of 24 and 25 present in the reaction mixture) in preference of the cis-isomer 24 increased by increased steric bulk of the catalyst. The highest cis-selectivity (8.9:1, III Figure 2. All the Fe –porphyrins above with the exception of 12 were found to preferen24/25) was observed for 23 containing eight orthotially epoxidize cis- over trans-olefins. Structure left top: The side-on approach of the methyl groups, which induced a shallow-shaped olefin toward the Fe = O group to illustrate the preferential epoxidation of cis-olefins.

strate 4. For these substrates, the selectivity increased from catalyst 1 to 2, which was in line with expectations, since 2 contained bulkier dendrimers than 1, and thus the periphery of the catalyst was more efficiently blocked in the former case.[10] A higher substrate selectivity of 7 over 4 than of 8 over 4 was also observed for catalysts 1 and 2 compared to the parent catalyst 3, indicating that the terminal alkene 7 is more accessible than the internal alkene 8 for the more sterically hindered catalysts.[12] Furthermore, in pair-wise competitive studies of the epoxidation of mixtures of alkenes by using PhIO as a stoichiometric oxidant, each containing 9/4, 10/8 and 11/8 (500 mmol each), respectively, demonstrated that catalysts 1 and 2 exhibited higher substrate selectivity than 3 (2 mol % each). In addition, the turnover numbers for 1 and 2 were essentially the same (2–4 s1) as those of 3 (3–4 s1).[10] In 1979, Groves and co-workers reported a study in which the FeIII–porphyrins 12 and 13 (Figure 2) were used as catalysts for the epoxidation of alkenes with PhIO as the stoichiometric oxidant.[13] They demonstrated that the epoxidation of cis- (14,

Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

13435


Review pocket surrounding the catalyst. It was speculated that these ortho-substituents implemented repulsive interactions in the approach of the trans-isomer of the substrate to the Fe–oxo group (26, Figure 2). These steric interactions would be less prominent in the side-on approach of the cis-isomer (27, Figure 2). The cis-selectivity was proposed to arise from a sideon approach, in which the p-orbital of the alkene approaches the catalyst from the side and in parallel to the plane of the porphyrin (Figure 2). In such an approach, one of the substituents on the double bond of a trans-alkene would encounter sterically hindrance from the substituents on the porphyrin ring. In contrast to trans-alkenes, this approach would furnish much less non-bonding interactions between the substituents on a cis-alkene and the substituents on the porphyrin ring. Collman and co-workers exploited a system constituting meso-tetraphenylporphyrin manganese(III) chloride (3, 70 mmol, 1 equiv, Figure 1) as a catalyst for the epoxidation of alkenes (29–86 equiv) in the presence of a substituted imidazole ligand (9 equiv), employing lithium hypochlorite (LiOCl, 9 equiv) in dichloromethane as the terminal oxidant.[15] The investigations revealed that the rate of the epoxidation was independent of the alkene concentration. However, different alkene substrates were epoxidized with different rates. This last observation led to the assumption that the alkene must be involved in the rate-limiting step. Hence, a mechanism consisting of two steps was suggested (Scheme 3): 1) reversible formation of an oxo–

dation of 4 occurred faster than 11, in the presence of [Bn2Me2N] + Cl (0.1 mmol), 4’-(imidazole-yl)-acetophenone (NAcPhIm, 0.62 mmol) as the ligand, and 3 (0.007 mmol) as catalyst in dichloromethane with LiOCl as the terminal oxidant (6.2 mmol, Scheme 4). It was shown that the binding of 4 to the active catalyst took place faster than for 11 and thus hampered the binding of the latter substrate. In another experiment, the presence of comparatively electron-rich terminal alkenes in the reaction mixture had a negligible effect on the rate of the epoxidation of 4, compared with 4 alone. All these observations led to the conclusion that electron-rich alkenes possessing cis-geometry had the highest binding ability to the metal–oxo complex I (Scheme 3) and that they were also the most reactive substrates in the competitive experiments. In order to address the shape selectivity in the epoxidations of alkenes by bulky MnIII–porphyrins, using LiOCl as the oxidant and a substituted imidazole ligand as promoter, namely 4’-(imidazol-1-yl)acetophenone, the reactivity of Mn–oxo–porphyrins 28–33 with alkenes (Figure 3) was separated into two separate components: 1) the binding energy for the formation

Figure 3. The MnIII–porphyrin complexes of 28–33 were investigated as substrate-selective catalysts in competitive epoxidations of alkenes.

Scheme 3. The proposed mechanism for the epoxidation of alkenes by MnIII–porphyrins.

metallocycle intermediate II from substrate–catalyze MnV precomplex I—the latter was experimentally supported—and 2) the decomposition of this intermediate to furnish a MnIII complex III and an epoxide IV. The last step was considered to be the rate-limiting step. From a set of two separate single-substrate experiments, it was concluded that the epoxidation of trans-b-methylstyrene (11) took place faster than cyclooctene (4) (Scheme 4). In contrast, in a pair-wise competitive experiment containing both alkenes (2–6 mmol of each), the epoxi-

Scheme 4. The epoxidation of trans-b-methyl styrene (11) and cyclooctene (4) in separate single-substrate and competitive experiments, using Mn–porphyrin 3 as catalyst, 4’-(imidazol-1-yl)acetophenone (NAcPhIM) as ligand and LiOCl as the terminal oxidant. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

of the intermediate II (Scheme 3) and 2) the rate constant for the breakdown of intermediate II.[16] In those investigations, the shape-selective epoxidation of alkenes was found to take place by sterically encumbered MnIII–porphyrins. The selectivities were governed by the relatively large differences in binding energies for the formation of an oxo–alkene intermediate between a Mn–oxo–porphyrin complex and an alkene. In addition, the difference in binding energies, and thus the substrate selectivity, arose from steric interactions between the substrates and catalyst rather than from differences in electronic density of the double bonds. Collman and co-workers also used the MnIII complexes of porphyrins 28–33[17] (4 mmol, 1 equiv, Figure 3) in the presence of PhIO (50 equiv) as the terminal oxidant and a bulky anionic ligand (3,5-di-tert-butylphenolate) in acetonitrile in the shapeselective epoxidation of alkenes (63 equiv).[18] Two important features were pointed out for these systems: 1) the porphyrins contained rigid molecular “picnic baskets” that constituted rigid cavities of variable dimensions on one face of the porphyrins and 2) the opening at the opposite side of the porphyrins was blocked by the bulky anionic ligand. The selectivity originated from the size-match of the cavity and the substrate. The selectivity was quantified by pair-wise competitive

13436


Review experiments (1:1) using the same conditions (exact conditions not specified) as above using trans-b-methylstyrene (11), cyclooctene (4) or 2-methyl-2-pentene (12) versus cis-2-octene (8), and 4 versus 1-octene (7, Scheme 1). In all experiments, the MnIII complexes of 28 and 29 gave rise to very slow reactions, since the cavities were too small to host the substrates. The MnIII complexes of 30–33 epoxidized 8 between 8.8 to 70 times faster than 11. The same catalysts also catalyzed the corresponding reaction of 8 by 1.6 to 1000 times faster than 4, with the exception of MnIII complex of 32, which showed a reversed selectivity, as it catalyzed the epoxidation of 4 five times faster. In most cases, terminal alkenes were less reactive with the MnIII–porphyrins as catalysts; however, the MnIII complexes of 30 and 33 epoxidized 7 faster than 4 by 1.7 and 7 times, respectively. In addition, the MnIII complexes of 30 and 33 epoxidized 8 more than 1000 times faster than 12. Recently, Badjic´ and co-workers reported the design and the synthesis of the MnIII–porphyrin complex 34 (Figure 4) as a catalyst for the size-selective epoxidation of alkenes.[19] Catalyst 34 is a gated basket of about 570 3 consisting of a porphyrin floor surrounded by four phthalimide sidewalls. One benzyl group is located on the top of each of the four sidewalls, behaving as four gates at the entrance/exit of the basket. In order to avoid non-selective epoxidation on the outside of the substrate-selective cavity of 34, it was important to block the MnIII species from reacting with the oxidant on its exterior, thus avoiding the formation of the active Mn=O species on the outside of 34. For this purpose the Lewis acid/Lewis base interaction between model catalyst, ZnII–porphyrin complex 38, and a small set of ligands of various sizes 35–37 (Figure 4) was investigated by UV/Vis spectroscopy. The study showed that the smallest ligand 35 bound to the interior of the basket, while the medium-sized ligand 36 displayed equal binding to

Figure 4. The MnIII–porphyrin 34 was investigated as a size-selective catalyst for the epoxidation of alkenes 8 and 4 (Scheme 5) in the presence of ligand 35, 36 and 37. The MnIII–porphyrin 39 was included in the study as the reference catalyst. Porphyrin 38 was a model catalyst. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

either side. The measurements also showed that the largest ligand 37 was bound to the exterior of 38. The ability of the MnIII–porphyrin complex 34 (0.05 mm) to perform size-selective catalysis was investigated by pair-wise competitive experiments in which a mixture of two variously sized alkenes cis-2-octene (8, 187 3, 0.15 m) and cis-cyclooctene (4, 142 3, 0.15 m) were epoxidized in the presence of 2(tert-butylsulfonyl)iodosylbenzene (tBuSO2PhIO, 5.0 mm) as the terminal oxidant in dichloromethane (Scheme 5). The competi-

Scheme 5. The pair-wise competitive epoxidation of alkenes 4 and 8 catalyzed by 39 and 34 (Figure 4), respectively, in the presence of promoter ligands 35 and 37 respectively, using tBuSO2PhIO as the terminal oxidant.

tive experiments were performed in dichloromethane in the presence of respective promoter ligands 35 and 37 (25 mm), assigned to bind to the interior and exterior side, respectively, of the gated basket of 34 (vide supra). The pair-wise competitive experiments were also performed using the conditions described above for the competitive epoxidation above with porphyrin 39 as a reference catalyst. In the presence of ligand 35, it was found that catalyst 34 displayed a slight preferential reactivity towards 8 over 4, since epoxides 40 and 41 were obtained in a 1.2:1 ratio in the preference of 40. Likewise, in the presence of ligand 37, catalyst 34 preferentially reacted with the linear alkene 8, though to a slightly larger extent than in the presence of 35, as a product ratio of 2.0:1 was achieved. The reference catalyst 39 displayed, as expected, the same substrate selectivity (determined as the product selectivity 40/ 41 = 1.27:1), regardless of the presence of ligand 35 or 37. This observation, together with the fact that catalyst 34 displayed different magnitudes of substrate selectivities (determined as the selectivities of the formation the corresponding main product) depending on whether ligand 35 or 37 was added to the reaction medium, led to the conclusion that the reactions took place on the inside of the gated basket of 34 in the presence of ligand 37 and on the outside in the presence of 35. Collman and co-workers found evidence for multiple oxygenating species in the pair-wise competitive epoxidations of cyclooctene (4, 1000 equiv) and styrene (42, 1000 equiv) in dichloromethane catalyzed by 2 mmol (1 equiv) of FeIII–porphyrin 43 (Figure 5) in the presence of three different terminal oxidants (250 equiv), namely PhIO, C6F5IO, or MesIO, one at a time.[20] At 25 8C it was demonstrated that the substrate selectivity of the epoxidations was moderately governed by the nature of the terminal oxidant employed, since the selectivities varied from (1.65 0.05):1 up to (2.30 0.05):1; determined as the product ratio of cyclooctene oxide/styrene oxide, when the different oxidants were employed. In contrast, repeating the experiments at 0 8C gave a slightly larger variation in the product selectivities; from (1.55 0.05):1 up to (2.35 0.05):1.

13437


Review

Figure 5. The structure of the substrate-selective catalysts 43 and 44 used in the competitive epoxidation of cyclooctene (4) versus styrene (42) carried out in the presence of various terminal oxidants.

The observed small but still significant difference in selectivity was pointed out to indicate that the three iodosylarenes gave rise to different active intermediates; in Scheme 6. The epoxidation of addition to an Fe–oxo intermediIII alkenes by (Fe –Por) 43 in the ate, a complex between 43 and presence of iodosylarenes as a terminal iodosylarene was also terminal oxidants was demonstrated to take place in two proposed to constitute a second parallel reaction pathways. active oxidant. Hence Collman and co-workers suggested that the epoxidation was catalyzed by means of two parallel reaction pathways (Scheme 6). Contrary to the case for 43, the epoxidations catalyzed by MnIII–porphyrin 44 (Figure 5) were found to proceed by essentially the same selectivity, regardless of the nature of the iodosylarene at each temperature investigated. Thus, it was suggested that a MnV–oxo– porphyrin served as the sole active intermediate.[20] In two consecutive publications on substrate-selective epoxidations of alkenes, Breslow and co-workers also used metalloporphyrins as catFigure 6. Breslow and coalysts.[21] An important difference workers exploited bridging between the two studies was in CuII ions between the Fe–porthe substrate-recognition units. In phyrin catalyst 48 and subthe first case, there were bridging strate both carrying metalbinding groups. metal ions between the catalyst

Figure 7. In the presence of CuII ions with PhIO as the terminal oxidant, catalyst 45 exhibited a preferential reactivity with substrate 46 over 47 and 48 as demonstrated in competitive experiments. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Figure 8. The MnIII complexes of 52–54 were investigated as substrate-selective catalysts for substrates 49–51.

and the alkene substrates; both pairs bearing metal-coordinating groups (Figures 6 and 7). In the second case, b-cyclodextrin moieties were installed in the periphery of the porphyrins as recognition units for alkene substrates carrying two lipophilic ends (Figure 8). In order to investigate the substrate selectivity of FeIII–porphyrin catalyst 45 (1.25 mmol, 1 equiv, Figure 7), bearing two cation recognition sites, pair-wise competitive experiments of substrate 46 (10 equiv), containing two cation-binding functionalities, or, of substrate 47 (10 equiv), containing one cation-binding functionality, versus non-coordinating substrate 48 (10 equiv) were performed in the absence and presence of CuII (40 equiv) using PhIO (6 equiv) as the terminal oxidant in acetonitrile.[21a] In the absence of CuII, the results showed that the epoxidation of 48 took place two times faster than 46. In contrast, in the presence of CuII the selectivity was reversed, as the epoxidation of 46 occurred 20 times faster. It was also found that in the presence of CuII, catalyst 45 exhibited no discrimination between 47 and 48. Thus, it was speculated that the binding of substrate 46 to catalyst 45 using the two interactions stretched the substrate over the active catalytic center (Figure 6) and thus this binding was more productive than the binding of substrate 47, which had only one binding functionality. The work reported in the second publication[21b] was initiated by the study of the binding abilities of substrates 49–51 to porphyrins 52–54 (Figure 8) in water by titration calorimetry. It

13438


Review was found that each substrate 49–51 formed a 1:1 complex with 52. Furthermore, due to the fact that 49 contains two para-nitrophenyl groups, substrate 49 bound 18 times stronger to porphyrin 52 than substrate 51, the latter lacking the more lipophilic para-nitrophenyl groups. The substrate selectivity of the MnIII complexes of 52–54 (0.09–0.15 mm) using PhIO (0.15–1.5 mm) as the terminal oxidant was investigated in pair-wise competitive epoxidation experiments of 49 or 50 versus 51 (1:1, 0.3–0.5 mm each) in an aqueous buffer at pH 8.0 and 25 8C. The addition of adamantanecarboxylate to the reaction mixture had a great impact on the selectivity, since the discrimination of 49 over 51 by the MnIII complexes of 52 and 53 increased by three times upon its addition. It was proposed that when the substrate bound to one face of the complexes, the oxo group of the active catalyst was attached to the opposite face, due to its bulkiness, and thus the catalyst performed non-selective epoxidation. It was suggested that adamantanecarboxylate coordinated to the external face of the catalyst and thereby impeded non-selective catalysis. The MnIII complex of 54, in which the b-cyclodextrin moieties were in a cis-position, furnished only poor selectivity, indicating that a productive binding geometry was reached only when the substrate was spanning over the entire plane of the MnIII–porphyrin as in the previous example. Hupp and co-workers applied a supramolecular approach to construct a catalytic system for the substrate-selective epoxidation of alkenes.[22] The catalytic system 55 + 56 (Scheme 7) was obtained by encapsulating the catalytic unit 55,[23] carrying two free metal-binding sites (pyridyl groups), to form a supramolecular cavity structure with Re–porphyrin square 56,[24] the latter equipped with Lewis acidic receptor sites containing ZnII. In the presence of equal or higher concentration of 56 compared to 55 in dichloromethane, an optimal complexation occurred by the directed assembly in such a way that one unit of 55 bound to two opposite walls of 56 with an association constant of approximately 106 m1, and thus bisecting the cavity. Two important features were pointed out for the catalytic system 55 + 56: 1) it increased the lifetime of the catalytic unit

Scheme 7. Encapsulation of the catalytic unit 55 to the cavity structure 55 + 56. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

55, compared to 55 alone by preventing the formation of an oxo-bridged dimer (Mn-O-Mn), and 2) it increased the substrate selectivity on the basis of the relative size of the substrates as will be demonstrated below. The epoxidation of styrene (42) by 55 + 56 yielded a tenfold improvement in the turnover number compared to 55 alone. It is worth noting that the presence of 56 also increased the lifetime of 55 from ten minutes to more than three hours. The substrate selectivity of the catalytic system 55 (3 mmol, 1 equiv) + 56 (3 mmol, 1 equiv) was investigated by the pairwise competitive epoxidation of alkenes using PhIO (100 equiv) as the oxidant in dichloromethane. The competitive epoxidation of cis-stilbene (14, 100 equiv) versus cis-3,3’5,5’-tetra-tert-butylstilbene (57, 100 equiv, Scheme 8) resulted

Scheme 8. The pair-wise competitive epoxidation of stilbene 14 versus 57 using 55 + 56, 55, or 59, as catalysts and 2-(tert-butylsulfonyl)-iodosylbenzene as the terminal oxidant. Product selectivity based on relative product concentration at the end of the reaction as determined by GC.

in that the latter more sterically encumbered substrate was 3.5 times less reactive (based on the relative concentrations of 16 and 58) with 55 + 56 as the catalyst than with 55 alone. In addition, the cavity size of 55 + 56 could be further modified upon inclusion of two equivalents of an additional cavitytuning ligand, 3,5-dinicotinic acid dineomenthyl, containing metal-coordinating pyridine moieties. In the presence of this fine-tuning ligand, the epoxidation of 14 took place seven times faster than 57 using 55 + 56, compared with 55 alone based on product formation as above. Later, modeling studies showed that the cavity-tuning ligand 3,5-dinicotinic acid dineomenthyl bound on the outside rather on the inside of the cavity of 55 + 56 and thus in fact limited the selectivity by not connecting the compounds of the size-selective assembly.[25] Nguyen, Hupp, and co-workers pursued the design and the synthesis of the supramolecular box 59 (Figure 9),[26] consisting of eighteen porphyrins; one MnIII–porphyrin dimer 60 a, two SnIV–porphyrin dimers 60 b, and four ZnII–porphyrin trimers 60. The box 59 was obtained in a step-wise manner, in which 60 b and 61 were mixed together to generate a sixteen-porphyrin box, consisting of two units of 60 b and four units of 61. As 60 b contained two bulky carboxylate ligands, 60 b was forced to selectively bind to the two peripheral Zn moieties of 61. Upon addition of 60 a to the sixteen-porphyrin box, it bound to the remaining free Zn moieties of 61 to furnish 59. However, structure 59 could also be obtained in a one-pot procedure by mixing 60 a (0.5 mmol, 1 equiv), 61 (4 equiv), and 60 b

13439


Review

Scheme 9. The pair-wise competitive epoxidation between quinolones 63 and 64 by 62 using 2,6-dichloropyridine-N-oxide as terminal oxidant.

Figure 9. The supramolecular catalytic box 59 was exploited as a substrateselective catalyst for the epoxidation of alkenes. The catalytic box 59 was assembled by combining the porphyrin dimers 60 a and 60 b with the porphyrin trimer 61 in a one-pot procedure.

(2 equiv) in toluene, as the bulky ligands of 60 b implemented a self-sorting behavior between 60 a and 60 b. Due to the size-limited access of larger alkenes to the catalytic unit 60 a within the supramolecular box 59, it was assumed that smaller alkenes would be preferentially epoxidized using tBuSO2PhIO (100 equiv) as a terminal oxidant.[27] Thus, cis-stilbene (14, 100 equiv) and cis-3,3’,5,5’-tetra(tert-butyl)stilbene (57, 100 equiv) were epoxidized in the presence of 59 in a pair-wise competitive experiment (Scheme 8). Indeed, the sterically less encumbered 14 was epoxidized 5.5 times faster than 57 (defined as the relative concentration between products 16 and 58). The size-limited access to 60 a within 59 was supported by a similar competitive experiment in which 59 was replaced by 60 a alone; this did not furnish any discrimination between 14 and 57. Bach and co-workers synthesized the RuII–porphyrin complex 62 and explored it as a catalyst for the enantioselective epoxidation of quinolones including an 1-alkenyl substituent in the 3-position (see Scheme 9 for structures).[28] Catalyst 62 included a chiral tricyclic g-lactam scaffold, which established Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

a two-point hydrogen-bonding interaction[4b, 29] with quinolone substrates carrying a free NH group. In the presence of 2,6-dichloropyridine-N-oxide as the terminal oxidant in benzene, 62 furnished an 85–98 % ee in the epoxidation of quinolones carrying a 1-alkenyl substituent in the 3-position and no substituents on the nitrogen atom. The significance of a two-point hydrogen-bonding interaction between the substrate and the catalyst was established in a pair-wise competitive experiment in which a mixture of 63 and the N-methylated counterpart 64 (58.4 mmol of each) was epoxidized by 62 (11.7 mmol) in the presence of 2,6-dichloropyridine-N-oxide (64.2 mmol) in benzene (Scheme 9). After a reaction time of four hours, the product ratio between 65 and 66 was 91:9 and a high product ratio (84:16) was still maintained after 24 h. At this time, the conversion of 63 was virtually complete and 65 had been formed in 94 % ee, whereas 66 had only been obtained in 5 % ee. The result demonstrated that a two-point hydrogenbonding interaction was essential both to obtain high reactivity and high ee, since 64 can only make a one-point hydrogenbonding interaction with 62. The dinuclear complex 68 (Figure 10) was employed as a substrate-selective epoxidation-catalyst.[30] This complex con-

Figure 10. The substrate selectivity of catalyst 68 carrying an amidopyridine receptor unit was investigated and compared with catalysts 70 and 71.

sisted of both a catalytic center (MnIII) and an amidopyridine receptor unit. Isothermal titration calorimetry showed that the amidopyridine group in 68 was able to form a complex with para-vinylbenzoic acid (69), whereas the same acid did not exhibit any measurable binding to 70 (Figure 10), the latter lacking the amidopyridine group. In order to investigate the substrate selectivity in the epoxidations of alkenes, a pair-wise competitive epoxidation (1:1) of para-vinylbenzoic acid (69, 10 equiv) versus styrene (42,

13440


Review

Scheme 10. The pair-wise competitive epoxidation of 69 versus 42 (catalyst = 68, 70 or 71; Figure 10) using PhIO as terminal oxidant.

10 equiv) by catalyst 68 (1.3 mmol, 1 equiv) using PhIO (20 equiv) as the terminal oxidant in dichloromethane was performed (Scheme 10). Catalyst 68 showed a preferential reactivity for the former substrate. The addition of para-ethylbenzoic acid (10–98 equiv) to the reaction mixture diminished the selectivity. Thus, it was proposed that the selectivity for para-vinylbenzoic acid (69) was governed by the hydrogen-bonding interaction between the amidopyridine group of 68 and the carboxylic acid group of the substrate. This assumption was further supported by the observation that both catalysts 70 and 71, lacking the hydrogen-bonding unit, in fact epoxidized styrene (42) faster than para-vinylbenzoic (69) acid. In an attempt to achieve a kinetically labile catalytic system for substrate-selective epoxidations of alkenes, our research group reported the design and the synthesis of a MnIII-salen complex 72 as the catalyst part and a ZnII–porphyrin complex 73 as the receptor part of a supramolecular catalyst (Figure 11).[31] One of the ideas behind the labile system was to

Figure 11. A non-rigid supramolecular catalytic system; the catalytic cyclic heterodimer 74 is assembled by hydrogen bonding between catalytic part 72 and receptor 73.

circumvent the problem that supramolecular catalysts in general are too rigid to be effective.[32] The ligand framework of 72 was equipped with 2-quinolone units, whereas peripheral 2pyridone units were attached to 73. The hydrogen-bonding moieties of the two units 72 and 73 were designed to be arranged in such a way that the association of the two units would favor the formation of the catalytically active cyclic Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Figure 12. A schematic presentation of the self-assembly of a substrate-selective catalytic cavity from an equilibrium mixture containing a catalytic and a receptor part. Case a: the catalyst part does not include a strap, allowing the catalyst part to anticipate both a cisoid and transoid conformation. Case b: the catalyst part includes a strap that restricts it into a cisoid conformation.

heterodimer 74 (Figure 11) in dichloromethane, which would constitute a substrate-selective catalytic cavity (schematically depicted in Figure 12, case a). The complementary 2-pyridone2-quinolone framework in 74 was developed to furnish a weak association between 72 and 73, and thus allowing for the system to be dynamic in its operation, thereby among other things preventing product inhibition. Indeed, cavity 74 was formed; however, a complete analysis of the equilibria[31a, 33] revealed the formation of homo- and hetero-oligomers of catalyst 72 and receptor 73 and a cyclic trimer of 73, in addition to 74. It is worth noting that the analysis also demonstrated the formation of linear hetero-oligomers containing 72 and 73 as next-neighbors. In addition to 74, these oligomers were proposed to furnish moderate substrate selectivity in the epoxidations of alkenes. Later on, the analysis of the equilibria prompted our research group to increase the concentration of the catalytic cyclic heterodimer compared to other species by strapping the catalyst part in a cisoid conformation (schematically depicted in Figure 12, case b)[34] in an attempt to obtain higher substrate selectivity. We also envisaged that such a strapping would partially prevent unselective catalysis from taking place on the outside of the catalyst part. Thus, we designed and synthesized the strapped catalyst unit 75 (Figure 13 a), which corresponds to the cartoon catalyst in Figure 12 (case b). In order to achieve an even more efficient blockage of the outside of the catalytic system, we also designed and synthesized the catalyst unit 76 (Figure 13 b), which carries a centrally located pyridine N-oxide moiety in the strap, assumed to coordinate to the Mn-moiety. All the three catalytic systems 72 + 73, 75 + 73, and 76 + 73 were investigated as substrate-selective epoxidation catalysts

13441


Review

Scheme 11. The pair-wise competitive epoxidations of alkenes by supramolecular catalyst system 72 + 73, system 75 + 73 or system 76 + 73 in CH2Cl2 using PhIO as the terminal oxidant.

Figure 13. The catalytic cyclic heterodimers 81 and 82 containing two different strapped catalyst parts, 75 and 76, respectively.

in pair-wise competitive epoxidations of equimolar amounts of two alkene substrates in dichloromethane.[31, 33, 34] Hence, the pair-wise competitive epoxidation of pyridyl-appended styrene 77 (10 equiv) versus the phenyl-appended counterpart 78 (10 equiv) by the catalytic system 72 (1 equiv) + 73 (3 mmol, 1 equiv) using PhIO (4 equiv) as the terminal oxidant in dichloromethane (0.60 mL, Scheme 11) furnished a normalized substrate selectivity of 1.5:1 based on the relative ratio of 77 and 78 after 20 % of conversion, in preference for the former substrate.[31b] In a subsequent experiment, it was shown that 4-ethylpyridine (90 equiv) was a competitive inhibitor of 72 + 73, as the substrate selectivity decreased in the presence of this species, strongly suggesting that the ZnII moiety of 73 indeed exercised substrate recognition in the catalytic system 72 + 73.[31b] In order to investigate the effect of the strapping of the catalytic part on the substrate selectivity, systems 73 + 75 and 73 + 76 were compared with the unstrapped system 72 + 73. The competitive epoxidation of the (Z)styrene pair 77/78 and the (E)-styrene pair 79/80 was performed in the presence of each of the catalytic systems.[34] For both styrene pairs, a preferential epoxidation was observed for the pyridyl-appended styrene substrate and the normalized Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

substrate selectivity of the catalyst increased in the order 72 + 73 < 75 + 73 < 76 + 73. These results demonstrated two things: 1) the forced cisoid conformation of the catalytic part obtained by the strapping of the catalytic unit furnished higher normalized substrate selectivity and 2) insertion of a pyridine N-oxide in the strap led to a higher normalized substrate selectivity than having an unsubstituted alkane strap. The obtained results also led us to the conclusion that the concentration of the catalytic cyclic heterodimer in the equilibrium increases in the order [74] < [81] < [82].[34] In order to extend the substrate scope of our catalytic systems, pair-wise competitive epoxidations were also performed on the stilbene substrate pairs 83/14, 84/15, and 85/15 (30 mmol each), with PhIO (24 mmol) as terminal oxidant, 73 (3 or 9 mmol) as receptor, and 75 or 76 (3 or 9 mmol) as catalyst (Scheme 11). In line with the styrene substrates, the highest normalized substrate selectivities in preference for the pyridylappended ones were obtained in the presence of the strapped catalysts parts 75 or 76 together with receptor 73. Noteworthy, mono-pyridyl-stilbene (Z)-substrate 83 together with di-pyridyl-stilbene (E)-substrate 85 gave the highest normalized substrate selectivity (3.4:1) (85/15) of all the substrates employed in the study. The result for the latter substrate was pointed out to be not surprising, since it possessed two recognition elements and thus having two times higher probability to bind to the receptor. Very recently, a series of chiral tetradentate nitrogen-containing ligands, such as 86 (Figure 14), were exploited in the Mncatalyzed asymmetric epoxidation of alkenes.[35] The tetradentate ligands contained a conjugated p-system and two amino moieties, the latter displayed a strong s-donation to the metal. Additionally, the two amino moieties had a synergetic effect with regard to enantioselectivity and activity in the epoxidation of alkenes using hydrogen peroxide as the terminal oxidant. Moreover, the chiral oxazoline moieties tuned the enantioselective induction ability and the steric hindrance of the catalytic systems.

13442


Review

Figure 14. The chiral tetradentate based nitrogen ligand 86 gave rise to excellent yields in addition to up to 99 % ee in the Mn-catalyzed epoxidation of alkenes.

The asymmetric epoxidation of alkenes (0.42 m, 1 equiv) such as 2H-chromene derivatives, trans-stilbene, 1,2-dihydronaphthalene and indene with Mn(OTf)2/86 (0.2 mol %) in the presence of hydrogen peroxide (2 equiv) as the terminal oxidant and acetic acid (5 equiv) in acetonitrile furnished the corresponding epoxides in excellent yields and with up to > 99 % ee. In order to achieve an insight into the nature of the active oxidant, a pair-wise competitive experiment between the electron-rich substrate 87 (0.42 m) and the electron-deficient substrate 88 (0.42 m) was performed in the presence of 86 (0.2 mol %) and Mn(OTf)2 (0.2 mol %) with 50 % H2O2 (1.0 equiv) as terminal oxidant (Scheme 12). The result showed that the electron-rich substrate 87 was transformed to the corresponding epoxide 89 in 14.4 and 1.8 times higher yield and ee, respectively, than was achieved in the conversion of electronpoor 88 to 90. The obtained results indicated that the active oxidant is an electrophilic species. However, it was stated that more extensive work is required to determine the mechanistic aspects.

tained from each experiment was used to construct a Hammett plot (log(kX/kH) versus s + ), which displayed a negative reaction constant (1 = 1.10). The result showed that benzyl alcohols containing an electron-donating substituent in the para-position were the most reactive. Moreover, it also demonstrated that partial positive charge in the benzylic position in the ratedetermining step was born in the transition state of the reaction due to hydride abstraction. This conclusion was further supported by the observation of a PKIE (kH/kD = 1.41), using benzyl alcohol deuterated in the a-position. White and co-workers reported the design and the synthesis of a heterogeneous catalyst (RuO2-FAU) made by incorporating RuO2 nanoparticles ((1.3 0.2) nm) into the supercages of Faujasite (FAU) zeolite.[37] The catalyst RuO2-FAU displayed both high activity and chemoselectivity in the oxidation of allylic, benzylic, and saturated alcohols to their corresponding aldehydes and ketones in toluene at 80 8C under aerobic conditions. More interestingly, however, with regard to this review, a pair-wise competitive oxidation experiment of 1-heptanol (91, 0.5 mmol) versus cyclohexanol (92, 0.5 mmol) by RuO2FAU (0.1 g) using air (1 atm) as the terminal oxidant revealed a threefold higher reactivity of the former substrate, based on the relative conversion (Scheme 13 a). The substrate selectivity of RuO2-FAU was further investigated by performing a pairwise competitive experiment of benzyl alcohol (93) versus 9hydroxyfluorene (94) using the same conditions as above (Scheme 13 b). After 1.5 h, gas chromatography (GC)-analysis revealed the complete conversion of 93 to the corresponding aldehyde, whereas no oxidation products of 94 were detected. It is worth noting that changing the catalyst to pure hydrous RuO2 in a single-substrate experiment furnished efficient oxidation of 94 to the corresponding ketone. The observed size selectivity provided strong evidence that the RuO2 nanoclusters were located inside the supercages of the FAU zeolite. Thus, the rigidness and bulkiness of 94 prevented its hydroxyl group from getting close enough for the reaction with the reactive RuO2 nanoclusters inside the size limited supercages of the FAU zeolite.

Scheme 12. The pair-wise competitive Mn-catalyzed epoxidation of 87 versus 88 in the presence of the enantiopure ligand 86 using hydrogen peroxide as terminal oxidant.

1.2 Oxidation of alcohols The mechanism of the gold-catalyzed aerobic oxidation of benzyl alcohols was investigated using the primary kinetic isotope effect (PKIE) and competition experiments.[36] Thus, using Au/TiO2 (0.078 mmol) as the catalyst and 1 atm of O2 as the terminal oxidant, benzyl alcohol (0.39 mmol) was subjected to a pair-wise competitive oxidation with equimolar amounts of three different benzyl alcohols (0.39 mmol each) carrying various substituents in the para-position. The relative reactivity obChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 13. The pair-wise competitive oxidations of aliphatic (91 and 92) and benzylic alcohols (93 and 94) by RuO2-FOU using air (1 atm) as the terminal oxidant.

13443


Review Recently, with the aim to obtain size-selective catalysts for the aerobic oxidation of alcohols, Wang and co-workers reported a novel strategy for the synthesis of a series of catalysts.[38] These catalysts included a Pd-containing silica core. The core was covered by an outer silica shell consisting of pores of adjustable size. Interestingly, silylation with organosilanes of various sizes could further tune the pore sizes. The catalyst without the tuning organosilanes was termed Pd/SiO2@nSiO2. For this catalyst, N2-sorption experiments (Hurkins–Jura method) revealed a pore size of 1.5 nm. Silylation of Pd/SiO2@nSiO2 with n-propyltrimethoxysilane gave the pore-size-tuned catalyst Pd/ SiO2@nSiO2-C3, which exhibited a pore size of 1.1 nm. The catalyst Pd/SiO2@nSiO2-C8 obtained by treatment of Pd/ SiO2@nSiO2 with n-octyltrimethoxysilane displayed almost the same pore volume as that of nonporous silica nanospheres, indicating that dinitrogen had difficulties to penetrate the outer silica shell under the investigated conditions. The performance of the catalysts (0.25 mol % Pd) was investigated in the oxidation of benzyl alcohol (93, 1.0 mmol) and 3,5-di-tert-butylbenzyl alcohol (95, 1.0 mmol) to the corresponding aldehydes 96 and 97, respectively, in the presence of potassium carbonate (1.5 mmol) under oxygen atmosphere (1 atm) as the terminal oxidant in separate single-substrate experiments (see Scheme 14 for structures). The catalyst Pd/

for the oxidation of hydrophobic 95 than for 93. This result clearly indicated that the pore size was not large enough for 95 to reach the active sites of Pd. The fact that Pd/SiO2@nSiO2C8, despite its more hydrophobic inner surface, gave rise to an even lower conversion of 95 further supported this conclusion. To further support the size selectivity of the pore-size-tuned catalyst, 95 (0.05 mmol) was oxidized directly in pair-wise competition with 93 (0.05 mmol) in the presence of O2 (1 atm) as the terminal oxidant and K2CO3 (0.075 mmol) by Pd (2 mol %)/ SiO2@nSiO2-C3 or Pd (2 mol %)/SiO2@nSiO2-C8 in toluene (0.8 mL, Scheme 14). In the both cases, negligible oxidation of 95 was observed, whereas 93 was completely oxidized to the corresponding aldehyde 96.

1.3 Oxidation of aldehydes With the objective to obtain a size-selective catalyst for the oxidation of benzaldehydes to the corresponding esters, the design and a bottom-up synthetic approach was reported to produce silicate-1 crystals that were embedded with 1–2 nm sized gold nanoparticles (Au/silicalite-1).[39] Studies of Au/silicalite-1 with three-dimensional tomography showed that the gold nanoparticles were predominantly located within the zeolite crystals. Moreover, calcination experiments both ex situ and in situ revealed that the gold nanoparticles encapsulated within the crystals displayed high thermal stability. In order to investigate the aerobic catalytic performance of the gold nanoparticles located inside the crystals of Au/silicalite-1 (0.2 mol % Au), a pair-wise competitive experiment was executed where a mixture of benzaldehyde (96, 0.5 mmol) and 3,5-tert-butylbenzaldehyde (97, 0.5 mmol) was oxidized to their corresponding methyl esters 98 and 99, respectively, in methanol (60 mmol) in the presence of NaOMe (0.2 mmol) using air (pressure unspecified) as the terminal oxidant (Scheme 15).[39]

Scheme 14. The pair-wise competitive oxidation of 93 versus 95 by Pd/ SiO2@nSiO2-C3 and Pd/SiO2@nSiO2-C8 (catalyst = Pd/SiO2@nSiO2-C3 and Pd/ SiO2@nSiO2-C8) using oxygen as the terminal oxidant.

SiO2@nSiO2 gave rise to 62 % conversion in the oxidation of 93, indicating that the substrate is accessible for active sites of Pd located on the boundary between the outer shell and the core. Oxidation of the same alcohol with Pd/SiO2@nSiO2-C3 yielded a slightly higher conversion (65 %), showing that even after the tuning of the size of the nanopores on the outer shell, the active sites of Pd were still accessible for the substrate. It was proposed that the alkyl groups increased the hydrophobicity of the inner surface and thus provided a stronger driving force for the substrate to react with the catalytically active site, resulting in a higher conversion. Changing the catalyst to the even more hydrophobic catalyst Pd/SiO2@nSiO2-C8 furnished the highest conversion (68 %) observed for 93 in this study. Catalyst Pd/SiO2@nSiO2 gave rise to a slightly lower conversion (57 %) for the oxidation of 95 than it did for 93. Remarkably, Pd/SiO2@nSiO2-C3 provided a 3.5 times lower conversion Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 15. The pair-wise competitive oxidation of aldehydes 96 versus 97 to the corresponding esters 98 and 99, respectively, by Au/TiO2 and Au/silicalite-1 (catalyst = Au/TiO2 or Au/silicalite-1), respectively, using air as terminal oxidant.

The results were compared with those obtained with the reference catalyst Au/TiO2. The reference catalyst displayed essentially the same catalytic activity on both substrates. Conversely, Au/silicalite-1 behaved essentially only as a catalyst on benzaldehyde (96) as a substrate. The difference in catalytic activity of Au/silicalite-1 on 96 and 97 arose from their relative sizes.

13444


Review Since substrate 97 is much bulkier than 96 it cannot reach the catalytically active gold nanoparticles within the crystals, leading to a higher selectivity for the oxidation of 96 compared to 97.

1.4 Oxidation of CH bonds In 2013, the first use of a CuII–hemicryptophane complex 100 (Figure 15) was reported for the oxidation of cyclohexane to

clooctane. The competitive experiments between cyclohexane and adamantane led two conclusions: 1) the total yield of products obtained by 100 as catalyst is three times higher than that for 101 and 2) the cyclohexane/adamantane conversion ratio was shown to be 5:1 and 1.7:1 for 100 and 101, respectively. The obtained experimental data demonstrated the ability of the cage structure 100 to discriminate between these two substrates. Recently, the use of ruthenium(II) catalysts using bis(acetoxy)iodobenzene (BAIB, 0.5 mmol) as a terminal oxidant furnished site selective C(sp2)H hydroxylation of aromatic ketones[42] and aromatic Weinreb amides.[43] The catalyst and the conditions demonstrated also excellent functional group tolerance and chemoselectivity. More interestingly, with regard to this review was that the pair-wise competitive experiments (Scheme 16) between two aromatic ketones (102 (1.0 mmol)

Figure 15. The substrate selectivity of catalyst 100 was investigated by pairwise competitive oxidation of cyclohexane versus cyclooctane or adamantane and compared with the control catalyst 101.

cyclohexanol and cyclohexanone.[40] The complex catalyzed the oxidation of alkenes in the presence of hydrogen peroxide as the terminal oxidant. In particular one important feature was pointed out for 100; the cavity accommodated a CuII active site in which a substrate molecule could be included. The role of the cage structure was experimentally investigated: catalyst 100 provided a twofold higher yield for the oxidation of cyclohexane than the control catalyst 101[41] (Figure 15), lacking a cavity. It was experimentally supported that the higher yield did not arise from higher activity of catalyst 100, but rather from the protective effect of the cage structure on the active site, which hampered the deactivation of 100. In order to address the influence of the cavity on the substrate selectivity, pair-wise competitive CH oxidations of cyclohexane (50 equiv) versus cyclooctane (50 equiv) or adamantane (50 equiv) to their corresponding alcohols and ketones were performed by 100 (0.3 mmol, 1 equiv) or the control catalyst 101 (Figure 15) using hydrogen peroxide (1000 equiv) as the terminal oxidant in acetonitrile. The oxidation of cyclohexane versus cyclooctane by 101 was demonstrated to provide essentially the same conversions and yields for both substrates. Changing to catalyst 100 furnished a 1.3 times higher conversion of cyclooctane, whereas cyclohexane provided a 1.2 times higher yield than cyclooctane. Since cyclooctanol and cyclooctanone are more hydrophobic than the oxidized cyclohexanone counterparts, the oxidized cyclooctane species were suggested to have a longer residence time within the cavity, leading to over-oxidation and thus a lower yield. Similarly, the higher reactivity of cyclooctane was thought to originate from its higher hydrophobicity, which would furnish a stronger interaction between cyclooctane and the cavity. In contrast to when 101 was employed as the catalyst, these results showed a discrimination ability of catalyst 100 for cyclohexane and cyChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 16. The substrate selectivity (measured as product selectivity) of catalysts [Ru(O2CMes)2(p-cymene)] and [{Ru(p-cymene)Cl2}2] were investigated by pair-wise competitive C-H hydroxylation of aromatic ketones 102, 104 and 106 (a and b) and aromatic Weinreb amides 108 and 110(c), respectively, using BAIB as the terminal oxidant.

versus 104 (1.0 mmol) or 106 (1.0 mmol), Scheme 16a and b, respectively) or Weinreb amides (108 (1.0 mmol) versus 110 (1.0 mmol), Scheme 16c) using [Ru(O2CMes)2(p-cymene)] (2.5 mol %) as the pre-catalyst and using BAIB as the terminal oxidant showed the preferential hydroxylation of electron-rich substrates over electron-deficient ones (based on measured product selectivities).

2. Reductions 2.1 Hydrogenation of alkenes Urabe and co-workers reported a substrate-selective approach in the hydrogenation of substituted alkenes using Wilkinson’s catalyst [RhCl(PPh3)3] in the presence of a lithium salt of Keggin-type heteropoly acid (SiW12O404, HPA).[44] In their study, competitive experiments were conducted on different 1:1 mixtures of alkenes (0.4 m) in benzene/ethanol (1:1) using catalytic amounts of [RhCl(PPh3)3] (4 mm) in the presence of various lithium salts of oxoacids (20 mm) under hydrogen atmosphere (1 atm). The best substrate selectivity (6.4:1 in relative rate) was observed when Li4SiW12O40 was used as an additive and

13445


Review the alkene mixture consisted of styrene (42) and trans-b-methylstyrene (11). The authors argued that the SiW12O404 anion possessing a large polyhedron structure which is located near the coordination sphere of the cationic Rh complex, sterically hindered the approach of in particular sterically encumbered 1,1- and 1,2-disubstituted alkenes. Hence, the hydrogenation of 11 was slower than of 42. Nolte and co-workers reported the application of the rhodium(I) complexes 112 and 113[45] (Figure 16), as substrate-selec-

Figure 16. The cage catalyst 112 was used for the hydrogenation of substrates 114–116 to furnish the hydrogenated products 121–123 along with the isomerized products. 124–126. The cage catalyst 113 was found to catalyze double-bond migration in substrates 114–116. Association constants were determined between receptor 119 and each of substrates 115 and 116. Association constants were also determined between receptor 120 and each of substrates 117 and 118.

tive catalysts.[46] The complexes consisted of a basket-shaped host unit based on glycoluril, to which a catalytically active RhI center was attached. The complexes were investigated in the hydrogenation and migration of the double bond of the allylsubstituted arene substrates 114–116 (Figure 16). The investigations suggested that the binding of resorcinol (117) and catechol (118) substrates to the host involved hydrogen bonding to the carbonyl groups of the glycoluril and p–p stacking interactions with the phenylene unit of the host and guest, respectively.[47] A lower affinity for the host was expected for the catechol-based substrates due to the presence of competing intramolecular hydrogen bonds. To verify this hypothesis, 1H NMR titrations were performed in order to estimate the association constant between the model compound Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

receptor 119 and the substrates 114, 115, and 116 (Figure 16). The titrations showed that each of 115 and 116 formed a 1:1 complex with 119 with an association constant of (90 20) m1 and (2200 202) m1, respectively, in chloroform. Substrate 114, on the other hand, lacking hydroxyl groups, did not exhibit any measurable binding to 119.[46] The binding ability to the rhodium–acetoacetonate cage compound 120[45] was also investigated;[46] however, 115 and 116 reacted with the rhodium center of 120, instead of binding. Fortunately, model substrates 117 and 118 (Figure 16) could be used in the binding studies. The 1H NMR titrations revealed that 117 bound to 120 with an association constant of (3100 300) m1 in chloroform. Due to overlapping proton resonances in the 1H NMR spectrum, the association constant between 118 and receptor 120 could not be measured. However, the association constants between 118 and receptor 119 and between 112 and receptor 119 have previously been estimated to (2600 400) m1 [47b] and (2900 300) m1,[47a] respectively. Based on these results the association constant between receptor 118 to 120 was estimated to be in the same order. It was discovered that the rhodium–phosphine cage compound 113 catalyzed the migration of the allylic double bond of substrate 116 under an argon atmosphere.[45] Changing the atmospheric composition to H2/CO to achieve hydroformylation of 116 by 113 led to a complicated product mixture. Therefore, the authors decided to change the direction of their research program and instead investigating the catalytic performance of the ruthenium–hydride–phosphine cage compound 112 in the hydrogenation of substrates 114–116. The activation of substrates 114–116 exercised by catalyst 112 or the control catalyst [HRh{P(OPh)3}4], lacking a receptor unit, was studied in chloroform under a hydrogen atmosphere and furnished the corresponding hydrogenation products 121–123 along with the double-bond-migrated products 124– 126. Kinetic investigations of substrate 115 by the cage catalyst 112 revealed that the hydrogenation reaction pathway followed saturation kinetics, whereas the double-bond migration reaction pathway followed a different kind of kinetics, since both the reaction rate and the order in substrate of the rate equation, increased with increasing initial substrate concentration in the latter case. Separate single-substrate experiments using the control catalyst [HRh{P(OPh)3}4] showed that the hydrogenation rates of the substrates increased in the order 116 < 115 < 114. This demonstrated that the hydroxyl groups of 115 and 116 suppressed the hydrogenation reaction pathway and stimulated the double-bond migration reaction, since the ratio of hydrogenated versus isomerized products decreased in the order 114 > 115 > 116. The origin of this behavior was not clearly elucidated. Hydrogenation using the cage catalyst 112 revealed that the receptor moiety had a great impact on the hydrogenation rate. The rate of the hydrogenation of the allyl-substituted dihydroxyarene substrates 115 and 116 bound to the receptor part of the catalyst was 2.2 and 4.7 times higher, respectively, compared to the control catalyst [HRh{P(OPh)3}4], whereas the hydrogenation rate of the unbound substrate 114 by 112 was

13446


Review slower by a factor 12.1 compared to [HRh{P(OPh)3}4] as was found in separate single-substrate experiments. It is worth noting the fact that 112 displayed catalytic activity on substrate 114 indicated that the metal center of 112 partly reacted also with substrates 115 and 116 present in the reaction medium as unbound species to the receptor in addition to those bound to the receptor. It was also discovered that the ratio of hydrogenated versus double-bond-migrated products increased for substrates 115 and 116 by going from catalyst [HRh{P(OPh)3}4] to 112. Conversely, for substrate 114, [HRh{P(OPh)3}4] exhibited a higher hydrogenation versus double-bond migration ratio than that of catalyst 112. In order to investigate the substrate selectivity (determined as product selectivity) of the supramolecular catalyst 112 (10 mol %) in the hydrogenation of substrates 114–116 (3 equiv of each substrate) by hydrogen (0.4 atm), a competitive experiment was performed in chloroform (Scheme 17).

Scheme 17. The competitive hydrogenation of a reaction mixture consisting of equimolar amounts of 114, 115, and 116 by the rhodium-hydride phosphine cage compound 112, leading to hydrogenated products (121–123) and double-bond-migrated products (124–126).

This yielded the hydrogenated products 121, 122, and 123 in 40, 80, and 60 % yield, respectively, along with the doublebond-migrated products 124, 125, and 126 in 20, 20, and 40 % yield, respectively. It is worth noting that after 22 min, the conversion of substrate 114 had still not started, whereas 50 % of substrate 115 and 75 % of substrate 116 had been consumed. On the basis of these observations, the authors regarded the cage catalyst 112 as a substrate-selective catalyst. Reetz and co-workers reported the design and the synthesis of the b-cyclodextrin diphosphanes 127–131 (Figure 17) as ligands for the substrate-selective rhodium-catalyzed hydrogenation of alkenes.[48] As a control ligand, the b-cyclodextrin-free ligand PhN(CH2PPh2)2 was also included in the study. The substrate selectivity (determined as product selectivity) of the catalytic system ligand/[Rh(cod)]BF4 (0.5 mol %) was investigated in pair-wise competitive experiments of a substrate mixture containing unspecified equimolar amounts of 4phenyl-1-butene (132) and 1-decene (133) both in DMF and in water with added DMF (30 % v/v) under hydrogen atmosphere (1 atm, Scheme 18).

Figure 17. Cyclodextrins 127–131 were investigated as ligands in the rhodium-catalyzed substrate-selective hydrogenations of alkenes. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 18. The pair-wise competitive hydrogenation of 132 versus 133 by catalyst system ligand/[Rh(cod)]BF4 (Ligand = 127–131 or PhN(CH2PPh2)2).

In DMF, the control experiment with the catalytic system PhN(CH2PPh2)2/[Rh(cod)]BF4 furnished equal amounts of the hydrogenated products 134 and 135. An impact on the substrate selectivity was observed when PhN(CH2PPh2)2 was replaced by ligands 127–131, containing a b-cyclodextrin moiety (for structures see Figure 17). The substrate selectivities (determined as product selectivities) varied from 66:34 up to 74:26 in the preference of 134 over 135. It was postulated that substrate-selective binding occurred prior to the hydrogenation and that the phenyl group of 132 preferentially bound to the cavity of the b-cyclodextrin moiety. The reaction mixtures of the competitive hydrogenation experiments above performed in aqueous DMF consisted of two layers: a substrate-pair organic layer and an aqueous layer. The [Rh(cod)]BF4 complexes of ligands 127, 128, and 131 gave substrate selectivities (determined as product selectivities) from 81:19 up to 87:13 in preference of 134 over 135. The substrate selectivity was attributed to the interplay between molecular recognition, phase-transfer catalysis, and rhodium catalysis. The product selectivity decreased by performing the competitive hydrogenation experiments in the presence of paraxylene, which competed with the substrates for the binding interactions to the cavity of the b-cyclodextrin moiety of the catalyst. Westwall and Williams reported the competitive catalytic hydrogenations of allylic/homoallylic ethers using the cationic iridium complex [Ir(cod)(P(cC6H11)3)(Py)]PF6 as the pre-catalyst,[49] in their efforts to investigate whether an allyl ether bearing an auxiliary capable of chelating to the catalyst with a nitrogen donor atom would react faster than an allyl ether with an auxiliary incapable of chelation. It was anticipated that substrates capable to chelate to the catalyst would react more rapidly than substrates without such ability. A set of substrates, consisting of allylic ether moieties connected to either a 2-pyridyl or phenyl auxiliary had their rates of catalytic hydrogenation determined individually. Hence, in the individual experiments, allyl phenyl ether (136) reacted much faster (81 % conversion after 15 min) than 2(allyloxy)pyridine (137) (14 % conversion after 17 h, see Scheme 19 for structures). Allyl benzyl ether (138) reacted at about the same rate as allyl picolyl ether (139) (26 % conversion after 17 h for both). “Eneoate esters” were also investigated in an identical manner. Hence, phenyl acrylate and benzyl acrylate (140) exhibited high rates of hydrogenation (78 % con-

13447


Review gardless of catalyst, increasing the bulk of the substituent had a retarding effect on the rates of the hydrogenation.[50] In order to obtain a substrate-selective catalyst for the hydrogenation of alkenes, Kaneda and co-workers used Pd0 particles encapsulated within triethoxybenzamide (TEBA)-terminated poly(propylene imine) (PPI) dendrimers as nanoreactors.[51] The catalysts were termed Pd0/G3-TEBA, Pd0/G4-TEBA, and Pd0/ G5-TEBA (G = generation, Figure 18) and they were obtained

Scheme 19. The pair-wise competitive and separate single-substrate hydrogenations, respectively, of allylic ethers, using [Ir(cod)(P(cC6H11)3)(Py)]PF6 as pre-catalyst (2.5 mol %) in methanol between substrates 136 versus 137, 138 versus 139, and 140 versus 141.

version after 15 min and 90 % conversion after 17 h), whereas picolyl acrylate (141) exhibited much lower reactivity (38 % conversion after 17 h). In order to investigate the relative reactivities of the various phenyl- and pyridyl-appended substrates, a set of pair-wise competitive experiments was conducted. In a typical experiment an equimolar mixture of substrates (0.2 mmol) in methanol was added to the [Ir(cod)(P(cC6H11)3)(Py)]PF6 pre-catalyst (0.005 mmol) at room temperature. The solution was subjected to hydrogenolysis (1, 2.0 or 4.4 atm of H2) for 17 h (Scheme 19). In the pair-wise competitive hydrogenation of 136 versus 137, a reversal in the relative reaction rates was observed compared to that in the separate single-substrate experiments, with 137 exhibiting a 10 times faster rate of conversion than 136. The authors attributed this behavior to that the nitrogen atom in substrate 137 chelated to the catalyst and thereby inhibited the hydrogenation of 136. In the competitive reaction between 138 and 139, there was once again a preferential hydrogenation of the pyridyl-appended substrate 139 over the phenyl-appended one, 138. With the corresponding ester substrates 140 versus 141, there was also a reversal in the rate of hydrogenation of the substrates with a considerable decrease in the rate of hydrogenation of 140 (25 % conversion compared to 90 % in the individual experiment), while the rate of hydrogenation of 141 was only slightly retarded (33 % conversion in the competitive experiment compared to 38 % in the individual). Kacˇer et al. reported on the selectivities observed during the competitive hydrogenation of unsaturated hydrocarbons (amethylstyrene, cyclohexene, 1-methylcyclohex-1-ene, 1-tert-butylcyclohex-1-ene and 3-tert-butylcyclohex-1-ene) using each of the heterogeneous catalysts 3 % Pd/C, 5 % Pt/C and 5 % Rh/C. In their efforts to understand the effects of bulky substituents in close vicinity of a double bond on the reaction rates, competitive experiments were performed in which the substrates (1 mmol of each) in methanol and in the presence of the catalyst (0.1–0.01 g) were subjected to hydrogen atmosphere (1 atm) at 20 8C. From their studies it was concluded that reChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Figure 18. Presentation of Pd0/G5-TEBA with unbound Pd0.

from the third-, fourth-, and fifth-generations of PPI as ligand, respectively. The third to fifth generations of PPI were used to synthesize the catalysts for two reasons: 1) they possess a compact molecular size and 2) they include a high density of amino groups, which can form hydrogen bonds with suitable substrates in the catalytically active environment of the dendrimers. The separate single-substrate hydrogenations of various monoalkenes and dialkenes (1.00 mmol) by Pd0/G3-TEBA, Pd0/ G4-TEBA, and Pd0/G5-TEBA (5 mmol of Pd0) in toluene under hydrogen atmosphere (1.0 atm) showed that the rate of hydrogenation decreased by increased generation (G3 to G5) of dendrimers. The hydrogenation of cyclic substrates by Pd0/G5-TEBA revealed that the ring size of the substrates had a great impact on the rate of the hydrogenation. It was concluded that the crowded surface of the dendrimers, in particular in the case of Pd0/G5-TEBA, suppressed the accessibility of the substrates to the catalytic Pd0 nanoparticles encapsulated within the dendrimers. The pair-wise competitive hydrogenation of a mixture of cyclohex-3-en-ylmethanol (142, 0.5 mmol) and cyclohexene (9, 0.5 mmol) by Pd0/G5-TEBA (5 mmol of Pd) in toluene under 1 atm of hydrogen furnished cyclohexylmethanol (143) in quantitative yield, without any formation of cyclohexane (144) (Scheme 20 a). The substrate selectivity (determined as product selectivity) was, however, affected when Pd0/G5-TEBA was substituted for Pd0/G3-TEBA. This resulted in that 143 was formed in 100 % yield along with a 7 % yield of 144 (Scheme 20 a). The substrate selectivity (determined as product selectivity) was further lowered when the control catalyst Pd/C was employed, giving 143 and 144 (Scheme 20 a) in 60 and 10 % yield, respectively. The pair-wise competitive hydrogenation of equimolar amounts of N-methyl-3-cyclohexene-1-carboxamide (145) versus 9 by Pd0/G5-TEBA furnished cyclohexanecarboxamide (146) in 100 % yield together with trace amounts of 144 (Scheme 20 b). As a comparison, the control catalyst, Pd/C, fur-

13448


Review catalysts hydrogenated internal alkynes to the corresponding alkenes with high chemo- and Z-selectivity. More interestingly, however, with regard to this review was the finding that in a pair-wise competitive hydrogenation experiment, an unspecified amount of 3-phenyl-2-propyn-1-ol (148) versus an unspecified amount of 1-phenyl-1-propyne (149) by G2 Py-C6/Pd0 (amount not specified) under 1 atm of hydrogen (Scheme 21) revealed that the initial hydrogenation

Scheme 20. a) The pair-wise competitive hydrogenation of 142 versus 9 in the presence of catalysts Pd/C, Pd0/G3-TEBA and Pd0/G5-TEBA. b) The competitive hydrogenation of 145 versus 14 in the presence of catalysts Pd/C and Pd0/G5-TEBA.

Scheme 21. The pair-wise competitive hydrogenation of 148 versus 149 by the G2 Py-C6/Pd0 dendron.

nished 146 and 144 in 70 and 6 % yield respectively (Scheme 20 b). 1 H NMR and FT-IR experiments demonstrated that the formation of a hydrogen-bond between substrate 142 and the amino groups of the dendrimers took place on the inside of the dendrimers. Hydrogen bonding was significant for the comparable favorable penetration of polar substrates into the dendrimers. In a more recent work, the Kaneda group reported the design and the synthesis of the first to third generation of poly(amidoamino) (PAMAM) dendrons (a second-generation PAMAM dendron G2 Py-C6 147 is shown in Figure 19).[52] The

Figure 19. The structure of the second generation PAMAM dendron G2 Py-C6 (147).

PAMAM dendrons consist of a pyridine core and alkyl end groups. The dendrons self-assembled into spherical micelle-like structures in dichloromethane, which was confirmed by dynamic light scattering (DLS) experiments. These PAMAM dendrons were complexed with PdII which were subsequently reduced to furnish dendritic Pd0 nanocomposites, such as G2 PyC6/Pd0. The so-obtained dendritic Pd0 nanocomposites (Pd: 5 mmol; dendron: 82 mmol) were investigated as catalysts in separate single-substrate hydrogenations of conjugated cyclodienes (1.0 mmol) and internal alkynes (1.0 mmol) in dichloromethane under 1 atm of hydrogen. The results revealed that the conjugated cyclodienes were hydrogenated to the corresponding monoenes in high chemoselectivity. Furthermore, some of the Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

rate of the more polar substrate 148 was 28 times faster than for 149. Notably, performing the hydrogenation of both substrates in two separate single-substrate experiments demonstrated that the initial hydrogenation of 148 took place only 2.1 times faster than for 149. The preferential hydrogenation of 148 was attributed to hydrogen-bond formation between the hydroxyl group of the substrate and the amide groups within the dendron. Fonseca et al. reported the use of several competitive hydrogenation reactions between toluene and other alkyl arenes with various transition-metal nanoparticle catalysts in their efforts to understand the influence of the alkyl substituents on the rate of the reactions.[53] Seven different catalytic systems were tested in competitive hydrogenations. In a typical experiment, isolated nanoparticles of a given transition metal (0.026 mmol) were placed together with 3.25 mmol of each substrate in a reactor that was heated to 75 8C under 4 atm of hydrogen. From these experiments the authors could conclude that the selectivities observed were dependent on the sterics of the alkyl group, and that bulky alkyl groups lowered the rate of hydrogenation. Waldvogel and co-workers investigated the rhodium(I) complex 150 (see structure in Scheme 22) containing a NH,NR-stabilized N-heterocyclic carbene ligand, as a substrate-selective catalyst for the hydrogenation of alkenes.[54] Indeed, the pairwise competitive hydrogenation of a mixture of 1-dodecene (151) versus pentyl 3-butenoate (152) by 150 (unspecified amount) in THF under hydrogen atmosphere (1 atm) furnished

Scheme 22. The pair-wise competitive hydrogenation of 151 versus 152 by the RhI complex 150.

13449


Review a 40 % conversion of the former substrate and two times higher conversion of the latter substrate (Scheme 22). The observed substrate selectivity was explained as that 152 had a two-point interaction with the rhodium(I) complex 150 (Scheme 23), whereas the competing substrate 151 had only an one-point interaction site with 150.

ture under argon atmosphere (Scheme 24). The nonporous catalyst AlEtx@Aerosil 380 did not exhibit any discrimination between the substrates, indicating no preferential adsorption of any of the substrates on the surface of the catalyst. Changing to the porous aluminum-grafted catalyst AlEtx@SBA-1 furnished a 4–6 times higher reactivity of 96 compared to 153. The reduction by the hybrid catalyst AlEtx@SiMe2C8H17@SBA-1 proceeded at a lower rate compared to AlEtx@SBA-1; however, the relative reaction rate increased to 17:1 in the preference of 96 over 153 (Scheme 24). It was also shown that the activity of the catalysts decreased by increased length of the alkyl chains of the catalysts, since AlEtx@SiMe2C18H37@SBA-1 exhibited lower activity than AlEtx@SiMe2C8H17@SBA-1. However, the catalyst with the longer alkyl chains increased the size selecScheme 23. The selectivity of 152 over 151 executed by catalyst 150 in the Rh-catalyzed hydrogenation originating from a two-point interaction between 152 and 150. tivity, as the relative reaction rate increased to 20:1 in 2.2 Reductions of aldehydes and ketones To obtain size-selective catalysts for the Meerwein–Ponndorf– Verley reduction[55] of variously sized aldehydes to the corresponding alcohols, Anwander and co-workers reported the design and synthesis of the catalysts AlEtx@SBA-1, AlEtx@SiMe2C8H17@SBA-1 and AlEtx@SiMe2C18H37@SBA-1 (SBA = Santa Barbara Amorphous).[56] The aluminum-grafted catalyst AlEtx@SBA-1 was obtained by treating the mesoporous silica material SBA-1 with triethylaluminum. This process generated stable Al-O-Si linkages. The installed metal-centers contained unsaturated coordination sites, which implemented Lewis acidity and catalytic activity to AlEtx@SBA-1. A subsequent dinitrogen-sorption experiment showed that the pore diameter decreased from 2.2 nm for SBA-1 to 1.6 nm for AlEtx@SBA-1. In order to create compounds displaying even more profound size-selective catalysis than AlEtx@SBA-1, the authors rationalized that this would be achieved by creating smaller pore diameters than those in AlEtx@SBA-1. Thus, a two-step grafting sequence of SBA-1 was developed which included: 1) silylation and 2) metalation. The silylation step was performed by treating SBA-1 with dimethyl(dimethylamido)octylsilane and dimethyl(dimethylamido)octadecylsilane to obtain SiMe2C8H17@SBA1 and SiMe2C18H37@SBA-1, respectively. Investigation of the pore diameters by dinitrogen-sorption experiments revealed a diameter of 1.5 nm for SiMe2C8H17@SBA-1, resulting in a complete blockage of the entrance of SiMe2C18H37@SBA-1. In the following grafting step, aluminum centers were installed on the silica surface of SiMe2C8H17@SBA-1 and SiMe2C18H37@SBA1 upon treatment with triethylaluminum to furnish AlEtx@SiMe2C8H17@SBA-1 and AlEtx@SiMe2C18H37@SBA-1, respectively. The size selectivity of the above-mentioned catalysts (66 mmol with regard to the aluminum content) and the nonporous catalyst AlEtx@Aerosil 380 was investigated in the pairwise competitive Meerwein–Ponndorf–Verley reduction of benzaldehyde (96, 0.625 mmol) versus 1-pyrenecarboxaldehyde (153, 0.625 mmol) in isopropanol/toluene (4:1.3), in which isopropanol is the terminal reducing agent at ambient temperaChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 24. The pair-wise competitive Meerwein–Ponndorf–Verley reduction of 96 versus 153 by catalysts AlEtx@Aerosil 380, AlEtx@SBA-1, AlEtx@SiMe2C8H17@SBA-1 and AlEtx@SiMe2C18H37@SBA-1, using isopropanol as the terminal reducing agent.

the preference for 96 over 153 (Scheme 24). The obtained results showed that the size selectivity was dependent on the properties of the support material of the catalyst, since the catalysts derived from the mesoporous material SBA-1 furnished significantly larger size-selectivities than the nonporous catalyst AlEtx@Aerosil 380. Additionally, the pore size of the catalysts had an evident impact on the size selectivity, derived from the fact that the size selectivity increased from catalyst AlEtx@SBA-1 (largest pore diameter) to AlEtx@SiMe2C18H37@SBA1 (smallest pore diameter) over AlEtx@SiMe2C8H17@SBA-1. Chianese et al. reported the synthesis of bowl-shaped N-heterocyclic carbene (NHC) ligands 154–156 (Figure 20) that induced substrate selectivity in the iridium-catalyzed hydrosilylation of aryl methyl ketones.[57] The iridium complexes 157–159 of ligands 154–156 were synthesized (Scheme 25) and the activity of these complexes in the iridium-catalyzed hydrosilylation of acetophenone (160) was evaluated, in which the silyl ether 161 was the major product in all cases. To investigate whether the molecular bowls had any effect on the substrate selectivity, 157–159 (1.1 mmol) were investigated as catalysts in the pair-wise competitive hydrosilylation of 160 (37.2 mmol) versus aryl ketones 162, 163 or 164 (32.7 mmol of each) in benzene using diphenylsilane (0.372 mmol, Scheme 26). When “bowl” 159 was used as catalyst, the highest conversion ratio was recorded: the conversion of 160 was roughly 3.7 times higher than that of aryl ketone

13450


Review

Figure 21. The structure of the bowl-shaped phosphane ligands 165–167.

Figure 20. N-Heterocyclic carbenes 154–156 were used as ligands in the iridium-catalyzed hydrosilylation of aryl methyl ketones.

Scheme 27. The copper-catalyzed hydrosilylation of bulky ketones (ligand = 165, 166 and 167).

conducted between different ketones with a varying degree of bulkiness (for conditions see Scheme 28a–f). From these experiments it became clear that there was a high degree of substrate selectivity (determined as product selectivity) in favor of comparable bulkier ketones when the copper(I) complex of ligand 167 was used. The copper(I) complex of the smaller ligand 166 also proved effective at inducing substrate selectivity (determined as product selectivity) (Scheme 28 b). This is the opposite of what is observed when the less bulky PPh3 is used Scheme 25. The preparation of the iridium/N-heterocyclic carbene complexes 157–159 and the catalytic hydrosilylation of acetophenone 160 with iridium complexes 157–159. See Figure 20 for detailed ligand structures.

Scheme 26. The pair-wise competitive hydrosilylation of ketones 160, 162– 164 using bowl-shaped NHC–Ir complexes 157–159.

164. The authors provided no explanation for the observed substrate selectivity. Tsuiji and co-workers also reported the use of bowl-shaped ligands in the hydrosilylation of ketones and aldehydes. Hence, the bowl-shaped phosphane (bsp) ligands 165–167 (Figure 21) were synthesized and their effect on the copper-catalyzed hydrosilylation of a series bulky ketones was investigated (Scheme 27).[58] The copper(I) complex of ligand 167 provided excellent yields in most cases. The copper(I) complexes of ligands 165 and 166 also proved effective; however, they were not as effective as the complex of ligand 167. Following this line, a series of pair-wise competitive hydrosilylation reactions were Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 28. Copper(I)-catalyzed pair-wise competitive hydrosilylation experiments between ketones (or aldehydes) and ligands of variable bulkiness. Reported yields are after acidic work-up as in Scheme 27.

13451


Review

Scheme 30. The suggested catalytic cycle for the hydrosilylation of ketones and aldehydes using the copper(I) bowl-shaped ligand complexes 165–167.

and alkoxide B. In this catalytic cycle, alkoxide B undergoes transmetalation/s-bond metathesis with the silane, regenerating hydride A (step b). To explain the observed selectivity, the authors mentioned that the copper complexes have a preference to aggregate to form cubic clusters. With the bulky ketones, the aggregation process of the copper complex was retarded. This implies that alkoxide B, formed from the ketone, would be more likely to undergo step b with a bulky ketone, since its bulkiness is more likely to hamper aggregation compared to a less sterically encumbered hydride A. Conversely, if an aldehyde or less bulky ketone was used, alkoxide B would be more likely to aggregate; hence the reactivity of these substrates in step b would be lower.

3. Hydroformylations

Scheme 29. Copper(I)-catalyzed pair-wise competitive hydrosilylation experiments between ketones and aldehydes. Reported yields are after acidic work-up as in Scheme 27.

as a ligand (Scheme 28 d), for which the comparable less bulky ketones are more readily reduced. Pair-wise competitive experiments were also conducted between bulky ketones and aldehydes (for conditions see Scheme 29a–k), somewhat surprisingly, in the presence of the more bulky ligand 167 the bulkier ketones were more readily hydrosilylated than the aldehydes (see Scheme 29 a, f–k) based on the respective product formation. In contrast to other ligands tested, this was not the case with PPh3 ; the aldehyde was preferably hydrosilylated (Scheme 29 b) based on the product formation. By using ICy (N,N’-bis(cyclohexyl)imidazol-2ylidene), IMes (N,N’-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) or IPr (N,N’-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), respectively, as ligands, a virtual 1:1 mixture of products was obtained (Scheme 29c–e). Likewise, when a pair-wise competitive reaction between two aldehydes was conducted in the presence of 167, the bulkier aldehyde was more readily reduced (Scheme 28 g- h) based on the respective product formation. The proposed catalytic cycle is depicted in Scheme 30, with the key intermediates being the bsp-bearing copper hydride A Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Ichikawa and co-workers reported the design and the synthesis of phosphinite ligand 168 (see structures in Scheme 31) containing a b-cyclodextrin moiety, for the rhodium-catalyzed hydroformylation of alkenes.[59] The pre-catalytic system, [Rh(cod)Cl]2/168 (cod = 1,5-cyclooctadiene), was generated in situ upon treatment of [Rh(cod)Cl]2 with the free phosphinite ligand 168. The activity of the catalytic system was investigated on four different terminal alkene substrates and furnished turnover numbers varying from 19.1 up to 31.4 h1. Moreover, in all the cases except one, it was found that the catalytic system preferentially yielded the branched aldehyde regioisomers over the linear ones. The substrate selectivity (determined as product selectivity) was also investigated by pair-

Scheme 31. The pair-wise competitive hydroformylation of alkenes 132 vs 133 and 42 vs 7, respectively, by the catalytic system [Rh(cod)Cl2]/168.

13452


Review wise competitive experiments. Hence, 4-phenyl-1-butene (132, 5 vol %) versus 1-decene (133, 5 vol %) under CO/H2 atmosphere (1:1, 20 kg cm2) using 168 (60 mmol) as ligand and [Rh(cod)Cl]2 (60 mmol) as catalyst furnished a selectivity of 61:39 (defined as the molar ratio of the hydroformylation products, Scheme 31a). A control experiment using the pre-catalytic system [Rh(cod)Cl]2/PPh3 was also conducted and led only to a modest selectivity. Thus, the selectivity obtained by the use of the phosphinite ligand 168 was proposed to arise from the preferential binding of 132 in the cavity of the b-cyclodextrin. A similar competitive experiment between styrene (42, 5 vol %) and 1-octene (7, 5 vol %) using 168 (60 mmol) as ligand, under 20 kg cm2 atmosphere of CO/H2 (1:1) and [Rh(cod)Cl]2 (60 mmol) as catalyst gave a substrate selectivity (determined as product selectivity) of 30:70 in the preference of 172 over 171 (Scheme 31b). This led to the conclusion that 7 formed a stronger inclusion complex with the cyclodextrin appended phosphinite ligand 168 than 42. Breit and co-workers reported the design and the synthesis of a library of monodentate phosphane ligands (such as 173 in Scheme 32), each equipped with a guanidine moiety for the

Scheme 32. The pair-wise competitive hydroformylation of a 1:1 mixture of two alkenes, one (174) capable of making hydrogen bonds to the catalyst containing a designed hydrogen-bonding motif. [a] Signifies the ratio between linear and branched regioisomers of 175 and 7, respectively.

recognition of carboxylic acids by hydrogen-bonding interactions.[60] Some of the ligands gave rise to significantly higher reaction rates compared to triphenylphosphine itself in addition to excellent regioselectivities in the rhodium-catalyzed hydroformylation of alkenes bearing a carboxylic acid functionality. In the presence of ligand 173 (10 equiv) and [Rh(acac)(CO)2] (1 mm, 1 equiv, acac = acetylacetonate) in THF under a 10 atm of CO/H2 (1:1) atmosphere, the hydroformylation of but-3enoic acid (174, 200 equiv) proceeded in a much higher regioselectivity (linear/branched, 23:1) and much faster than for the corresponding methyl ester 175 (200 equiv) as evaluated in single-substrate reactions (see Scheme 32 for structures). Additionally, acetic acid behaved as an inhibitor and lowered the regioselectivity in the hydroformylation of 174 by outcompeting the hydrogen-bonding interaction between the substrate and the catalyst. These observations demonstrated that the interaction between the carboxylic acid functionality and the guanidine moiety of ligand 173 was essential for the catalytic performance. This conclusion was further supported by the Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

pair-wise competitive epoxidations of 174 versus 175 and 174 versus 7 (0.13 m of each) in the presence of [Rh(acac)(CO)2] (0.5 mol %) and 173 (10.0 mol %) in THF (6 mL) under 4 atm of CO/H2 (1:1) atmosphere (Scheme 32). The results showed that the hydroformylation Figure 22. The bidentate of 174, carrying a carboxylic acid phosphorus ligand 176 confunctionality took place more than taining anionic binding sites was exploited as a receptor ten and six times faster than for for anionic substrates in the 175 and 7, respectively, both lack- rhodium-catalyzed hydroforing a carboxylic acid functionality. mylation of alkenes. The bisphosphine ligand 176[61] (Figure 22) was exploited as a neutral anion receptor[62] in the substrate-selective and regioselective rhodium-catalyzed hydroformylation of alkenes carrying a carboxylate functional group.[63] Under hydroformylation conditions (5 atm CO/H2 = 1:1), high-pressure (HP) NMR studies demonstrated that equimolar amounts of ligand 176 and [Rh(acac)(CO)2] exclusively formed a trigonal bipyramidal hydrido complex [HRh(176)(CO)2], constituting the active catalyst for the hydroformylation. Moreover, under the same gas composition in CD2Cl2, the binding constants of acetate and hydrogen phosphate anions to the substrate-binding site of 176 in [Rh(176)(CO)2H] were investigated by HP NMR titration studies. They showed that the binding constants were larger than 105 m1 and 103.7 m1 for acetate and hydrogen phosphate anions, respectively. In sharp contrast to these anionic substrates, acetic acid and trihydrogen phosphate did not display any measurable binding with 176. The substrate selectivity of the catalytic system [Rh(acac)(CO)2]/176 was investigated in pair-wise competition experiments at 20 atm atmosphere of CO/H2 (1:1) in dichloromethane (Scheme 33). Molecular modeling showed that the

Scheme 33. The pair-wise competitive hydroformylation of terminal alkenes having anionic (177, 179) and neutral (175, 178) functional groups, catalyzed by the designed catalyst [Rh(acac)(CO)2]/176 having an anionic binding functionality.

13453


Review anionic substrate 177 precisely spans the distance between the receptor and the catalytic metal centers of [Rh(acac)(CO)2]/ 176. Hence, the pair-wise competitive hydroformylation of 177 (200 mmol) versus its methyl ester analogue 178 (200 mmol) in the presence of [Rh(acac)(CO)2]/176 (2.0 mmol) as pre-catalyst and diisopropylamine (DIPEA, 3.0 mmol) in CH2Cl2 (Scheme 33a) showed an initial high conversion of the anionic substrate 177 and at the same time a significantly lower consumption of 178. The mechanism for the conversion of 177 into its hydroformylation product followed first-order kinetics. During the progress of the reaction, when a significant amount of 177 was consumed, the formed anionic hydroformylation product bound to the receptor of the catalyst, and thus competed for the binding interactions with remaining 177, leading to faster hydroformylation of the competing ester substrate 178. Until approximately 60 % of 177 was consumed, substrate 178 reacted with negative-order kinetics, and thereafter following the normal first-order kinetics for hydroformylations. This indicates that initially the preassociation of 177 with the pocket of 176 increases its “effective concentration” around the catalytic metal center, outcompeting substrate 178, but in the final phase of the reaction this effect is attenuated due to product inhibition. Molecular modeling showed that in contrast to substrate 177, the anionic substrate 179 is too short for being synchronously bound to the receptor and the metal center of the catalytic system [Rh(acac)(CO)2]/176. Thus, it was assumed that substrate 179 that was bound to the receptor of the catalyst had to dissociate before catalysis could take place. Indeed, the pair-wise competitive hydroformylation of 179 versus 175 (200 mmol each, same conditions as above, Scheme 33b) showed that the ester substrate 175 reacted slightly faster than the anionic substrate 179. Moreover, both substrates followed first-order kinetics and reacted independently of each other. A third pair-wise competitive hydroformylation experiment between the two anionic substrates 177 and 179 (200 mmol each) in the presence of [Rh(acac)(CO)2]/176 (2.0 mmol) as catalyst and triethylamine (3.0 mmol) in CH2Cl2 (Scheme 33c) showed that both substrates followed first-order kinetics. In line with molecular modeling, the longer substrate 177 reacted faster than the shorter substrate 179, since any 179 that was bound to the receptor of the catalyst had to dissociate prior to catalysis took place on the metal center.

4. Addition Reactions 4.1 1,4-Additions Mandolini and co-workers reported that the salophen–uranylbased complexes 180 and 181[64] (Figure 23) behaved as effective catalysts for the 1,4-addition of thiophenol to 2-cyclopenten-1-one (182) and its 4,4-, 5,5-, and 6,6-dimethyl derivatives 183–185 (Scheme 34) in the presence of triethylamine in chloroform.[65] The design of the catalysts was based on two well-known properties of salophen–uranyl complexes: 1) they are able to bind both ionic and neutral donor groups and 2) the uranyl center binds to carbonyl groups and thus activates Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Figure 23. The substrate selectivity of catalysts 180 and 181 in the 1,4-addition of thiophenol to substrates 182–185 was investigated.

Scheme 34. a) The pair-wise competitive 1,4-addition of thiophenol to 182 and 185 in the absence and presence of catalyst 181. b) The pair-wise competitive 1,4-addition of thiophenol to 184 and 185 in the absence and presence of catalyst 181.

them towards nucleophilic additions. First, the association constants between the catalysts and the substrates employed were determined by 1H NMR in CDCl3 and/or UV/Vis titrations in CHCl3.[65a] The binding studies showed that 181, containing a cleft, coordinated substrates much stronger than 180, lacking a cleft. The stronger substrate binding to 181 was proposed to arise from van der Waals interactions between the walls of the cleft and the substrate. It is worth noting that the binding ability to 181 was also found to depend on the location of the bulky but hydrophobic gem-dimethyl groups.[65a] The reactivity order of thiophenol with the 2-cyclopenten-1one substrates 182–185 (Figure 23) in 1,4-additions in the absence of catalyst was shown to decrease in the order 182 > 185 > 184 > 183, as determined in separate single-substrate experiments, indicating that the reactivity is dependent on the steric bulk of the gem-dimethyl groups, as well as their distance from the site of nucleophilic attack. In the presence of control catalyst 180, the order of reactivity of substrates 182– 185 was still maintained; however, their comparable reactivities spanned over a wider range. In the presence of the designed substrate-selective catalyst 181 on the other hand, the

13454


Review relative reactivity of substrates 182–185 was even more pronounced. Moreover, the reactivity order of the substrates was changed in the presence of catalyst 181 compared to in the presence of catalyst 180, since some of the substrates displayed a very low affinity toward the catalyst 181 in parallel with non-productive binding to the catalyst[65a] In order to assess the substrate selectivity (determined as product selectivity) of catalyst 181 (13 mmol), a pair-wise competitive experiment of 182 (1.01 mol) versus 185 (4.04 mol) was performed in the presence of thiophenol (1.00 mol) and triethylamine (50 mmol) in chloroform (Scheme 34a). The result was that the 1,4-addition product of 182 was formed as the sole product. Contrary, in the absence of catalyst 181, thiophenol was distributed evenly between the competing species (Scheme 34a). Thus, in the presence of 181, the substrate selectivity arose from favorable interactions between 182 and the cleft of 181. Similarly, a pair-wise competitive experiment of 184 (1.03 mol) versus 185 (1.02 mol) in the presence of thiophenol (1.00 mol) and triethylamine, but in the absence of 181 essentially proceeded without any substrate selectivity (determined as product selectivity) (Scheme 34b). By adding 181 (44 mmol) to the reaction mixture on the other hand, thiophenol reacted almost exclusively with 184. Since 184 and 185 are regioisomeric substrates, the selectivity was proposed to arise from the recognition of their different shapes by the catalyst.[65a] 4.2 [4+2] Cycloadditions Westwall and Williams reported the use of substrate selectivity in an effort to gain understanding of the grounds for chiral inductions in reactions employing catalytic chiral auxiliaries as means to enhance the stereochemical outcome of a reaction.[49] The authors suggested, that by attaching a chiral auxiliary to a prochiral substrate in a reversible manner (such as transesterification), one could influence the stereochemistry of the formed product. In theory, the attached auxiliary should enhance the reactivity of the substrate and at the same time favor the formation of a single stereoisomer. After the reaction, the auxiliary can be removed in a reversible manner to be attached to another molecule of the prochiral substrate. The transition-metal-catalyzed Diels–Alder reaction between cyclopentadiene (186) and “eneoate esters” was the first reaction to be studied by the authors with the purpose to test whether a chiral auxiliary containing a coordinating group (a pyridyl group) attached to the dieneophile was capable of chelating to a suitable transition-metal species and whether the resulting chelation would accelerate the reaction. To first gain information about whether there would be a rate acceleration, achiral models of the chiral auxiliaries were used. Following this line of research, pair-wise competitive experiments were set up in dichloromethane as solvent with mixtures of benzyl propenoate (140) and 2-picolinyl propenoate (141, 0.05 mmol of each) in the presence of various transitionmetal containing promoters (0.05 mmol) that were allowed to react with diene 186 (0.25 mmol) over a period of 16–18 h at 10 8C (Scheme 35). The promoters tested were Zn(OTf)2, HgI2, AgBF4, FeCl3, Ni(NO3)2·6 H2O, MgBr2·OEt2 and Cu(OTf)2. The highChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 35. The pair-wise competitive Diels–Alder reaction between 140 and 141 with cyclopentadiene (186) as diene component promoted by Cu(OTf)2.

est selectivities for 141 over 140 were seen when Cu(OTf)2 was used as a promoter (Scheme 35). Interestingly, in a control experiment where the competitive reactions were run without a promoter, both 140 and 141 reacted at the same rate, demonstrating that any changes in relative rates should be attributed to the action of the transitionmetal promoter. The effect of the solvent on the substrate selectivity was also investigated. This was investigated with Cu(OTf)2 as the promoter in a new set of competition experiments between 140 and 141. The experiments confirmed dichloromethane to be the solvent of choice, owing this to its non-coordinating character; with coordinating solvents the reaction was much less selective between 140 and 141. To test whether the observed rate enhancements using achiral auxiliaries could be implemented with chiral auxiliaries, atert-butylbenzyl propenoate (0.05 mmol, 187) and a-tert-butylpicolyl propenoate (0.05 mmol, 188) were prepared and tested in a pair-wise competitive reaction (Scheme 36) with 186 in

Scheme 36. The pair-wise competitive reaction between a-tert-butylbenzyl propenoate (187) and a-tert-butylpicolyl propenoate (188) with cyclopentadiene (186) as diene component promoted by Cu(OTf)2 (0.05 mmol).

the presence of Cu(OTf)2 (0.05 mmol) as promoter. The substrate with the 2-picolyl containing chiral auxiliary was converted the fastest. Unfortunately, the induced diastereoselectivity was low and actually highest in the product of 187 containing the benzylic auxiliary. Moreover, a pair-wise competitive experiment between 140 (0.05 mmol) and the chiral enoate ester 189 (0.05 mmol) in the presence of 186 (0.25 mmol) as diene component and promoter Cu(OTf)2 (0.05 mmol) gave the results depicted in Scheme 37. It could be concluded that substrate 189 with a sulfur-containing benzylic chiral auxiliary exhibited moderate rate enhancements over the one containing parent benzyl auxiliary (140). The rate enhancement was at the same level as the pi-

13455


Review

Scheme 40. The EtAlCl2-promoted competitive Diels–Alder reaction between the dienophiles 191 and 192 with cyclopentadiene (186) in CH2Cl2.

Scheme 37. Cu(OTf)2-promoted pair-wise competitive reaction between 140 and 189 with cyclopentadiene (186) as diene component.

colyl auxiliary (Scheme 36). However, a higher diastereoselectivity was obtained in the reaction with 189 than with 188. Clapham and Shipman[66] studied the selective complexation of 2-hydroxyethyl esters by Lewis acids and used pair-wise competitive experiments to find a Lewis acid that could enhance the selectivity for 2-hydroxyethyl acrylates (190) over ethyl acrylate (191) in the Diels–Alder reaction with 186 (Scheme 38).

ment between 191 and 2-methoxyethylacrylate (192) was conducted under the same conditions as between 190 and 191 using ethylaluminum dichloride as the Lewis acid (Scheme 40). It was observed that there was a clear preference for the formation of product 194 over 193 showing a 97:3 ratio. Strukul and co-workers reported a substrate-selective catalytic Diels–Alder reaction.[67] The rate of the cycloaddition of 186 to a series of linear trans-a,b-unsaturated aldehydes 195– 201 with Cr(salen)Cl catalyst (202, 2 mol %), in chloroform or in aqueous sodium dodecylsulfate (SDS), was studied (Scheme 41).

Scheme 38. The EtAlCl2-promoted pair-wise competitive Diels–Alder reaction between 190 and 191 with cyclopentadiene (186) as diene component.

It was hypothesized that the formation of an initial bond between the Lewis acid and the hydroxyl group of a 2-hydroxyethyl ester by ligand exchange would allow discrimination between 190 and 191 (Scheme 39). This action of the Lewis acid was in turn thought to activate the dienophile towards cycloaddition reactions.

Scheme 39. The proposed chelate formation between a 2-hydroxyethyl ester and a Lewis acid.

Several competition experiments were run using mixtures of 190, 191, and cyclopentadiene (186) in 1:1:1 molar ratios to screen the ideal Lewis acid. In a typical experiment 5.0 mmol each of 190 and 191 and the appropriate Lewis acid (5 mmol) were dissolved in dichloromethane at 0 8C; cyclopentadiene (186, 5 mmol) was then added and after 1 hour the reaction mixture was quenched and the reaction mixture was analyzed by GC. Ethyl aluminum dichloride was found to be the most selective Lewis acid with a product distribution ratio of 83:17 favoring the product of 191. To confirm that the substrate selectivity (product selectivity) was due to the formation of a chelate complex between the hydroxyl group of 191 and the Lewis acid, and not due to another effect of the b-oxygen, a pair-wise competitive experiChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 41. The Cr–salen-catalyzed competitive Diels–Alder reaction between cyclopentadiene (186) and linear trans-a,b-unsaturated aldehydes (195–201).

In the study, aldehydes 195–201 were tested all together competitively at the same molar concentration (0.09 m) in the presence of 2.1 equivalents of 186 per aldehyde added. Without a catalyst and in chloroform, the reactions proceeded at a much lower rate for all substrates employed; however, there was a pronounced difference in the activity for the aldehyde with the shortest chain (20 % yield compared to 11–7 % for the other aldehydes), indicating that 195 was intrinsically more reactive than the longer analogues 196–201. However, in the presence of catalyst 202 (2 mol %) in chloroform, a more pronounced activity was observed for all substrates with only a small decrease in reactivity with increasing chain length, suggesting that the length of alkyl-chain had a negligible influence on the CrIII-catalyzed reaction. In water, without SDS and 202, the cycloaddition proceeded faster than in chloroform and showed a decreasing trend in activity with increasing chain length of the aldehyde. When the reaction was run in water with added SDS (0.24 m) there was a clear increase in the rate of conversion of all of the aldehydes, indicating that the micelle-forming SDS also catalyzed the reaction. The au-

13456


Review thors explained the observed catalytic effect of the SDS by the local increased acidity present on the surface of the micelles, resulting in that the reaction displayed Brønsted acid catalysis.[68] The effect of the concentration of SDS in water on the reaction was investigated in the range 60–480 mm both with and without catalyst 202. It was evident that without 202, there was an increase in the formation of the products of 195, compared to the substrates with longer alkyl chains, a result of Brønsted catalysis as stated by the authors. With 202 present, the effect of the SDS concentration was surpassed by the catalytic action of 202. The reaction in water with SDS and 202 added showed comparable activities to that of the reaction in chloroform and 202; however, there was a slight anomaly in observed reactivity compared to earlier experiments in that 196 was reacting faster than 195. The results above indicated two different phenomena that contributed to the catalysis seen in the reaction when both SDS and 202 were present, namely the Brønsted acid catalysis by the micelle surfaces and the catalysis by 202 within the micelles. Moreover, the authors subtracted the contribution from the Brønsted acid catalysis (determined from the reaction in water/SDS in the absence of 202) from the overall observed catalysis in the presence of 202 in an attempt to estimate the net catalytic effect of 202 on the reaction. The so-obtained data demonstrated according to the authors that there was an increased reactivity with increased hydrophobicity of the substrates when only the net catalytic activity of 202 was considered. This result was manifested in that the most hydrophobic substrate, 201, reacted 3.5 times faster than 195 in water/SDS after correcting the data for the catalytic effect of 202. This was explained as that catalyst 202 was solvated inside the hydrophobic environment inside the micelle and thus being more readily reached by the more hydrophobic substrates. Chow et al. reported the synthesis, reactivity and substrate selectivity (determined as product selectivity) of a dendritic bis(oxazoline)copper(II) catalyst 203 (Figure 24).[69] The catalytic efficiency of 203 in the Diels–Alder reaction of 186 and crotonyl imide (204, Scheme 42 a) was examined. It was found that 203 was less effective as a catalyst than dendritic ligands of lower generations. The substrate selectivity (measured as product selectivity) of 203 (0.0018 m, 20 mol %) was evaluated in the pair-

Scheme 42. a) The Diels–Alder reaction between cyclopentadiene (186) and crotonyl imide (204) catalyzed by 203. b) The pair-wise competitive Diels– Alder reaction between 207 and 208 using 186 as diene and in the presence of 203 as catalyst.

wise competitive reaction between dieneophiles 205 and 206 (0.03 m each) and diene 186 (0.03 m each) (Scheme 42b). The catalyst demonstrated a minimal selectivity for the less bulky dieneophile 205 (1.18:1.0 ratio). The rate of formation of the product 207 ((0.67 0.01) ms1) was slightly higher than the rate of formation of the product 208 ((0.57 0.01) ms1) in the competitive experiment. The authors attributed this result to high steric crowding imposed by the dendritic sectors of the catalyst, thus favoring the less-sterically crowded substrate 205.

4.3 [3+2] Cycloadditions Greco et al. reported the Pd-catalyzed [3+2] cycloaddition of carbon dioxide and trimethylenemethane (TMM) under mild conditions.[70] In the reaction, 2-(acetoxymethyl)-3-(trimethylsilyl)propene (209) was used to generate TMM. In order to understand the kinetics of the reaction, a pair-wise competition experiment where CO2 and benzylideneacetone (210) reacted with 209 was conducted. Hence, an equimolar mixture of 209 and 210 (0.50 mmol of each) together with [Pd(PPh3)4] (0.040 mmol, 0.08 equiv), was reacted in THF (24 mL) in the presence of CO2 (1 atm) at 50 8C. The reaction was left overnight and the product ratio was analyzed using GC (Scheme 43). There was a clear favor for the formation of the product from [3+2] addition of CO2 to 209. Wender and Strand reported on the silver(I)-catalyzed cyclocarboamination of alkynes with aziridines.[71] Although formally a [3+2] cycloaddition reaction, it was speculated that the reaction involves a cationic intermediate. To demonstrate this, a competitive experiment (see conditions in Scheme 44) in which three different alkynes substituted with groups with different electronic properties (211 a–c) competing for aziridine 212 in the presence of AgSbF5 as catalyst was performed (Scheme 44) leading to substituted 2-pyrroline products 213 a–c. That the more electron-rich alkyne reacted in preference to less electron-rich alkynes was “consistent with the capture of cationic intermediates in the product forming step” as expressed by the authors.

Figure 24. Dendritic bis(oxazoline)copper(II) catalyst 203 for Diels–Alder reactions. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

13457


Review

Scheme 43. The pair-wise competitive [3+2] cycloaddition between the 2atom components CO2 and 210 with the 3-atom component precursor 209 using [Pd(PPh3)4] as pre-catalyst.

217 b, respectively. It was evident that the ee of 217 a was influenced by the presence of alkyne 215 b. The authors hypothesized that this was due to the coordination of a second alkyne to an octahedral rhodium(III) intermediate leading to a situation in which olefin insertion could occur via transition states that were affected by the sterics and electronics of the spectator alkyne and therefore affecting the enantiomeric outcome. According to the authors, the result obtained was consistent with their hypothesis. In the same study and in an effort to understand the underlying mechanism, a pair-wise competitive experiment was set up between the two different alkenyl isocyanates 214 (0.184 mmol) and 217 (0.184 mmol) in the cycloaddition reaction with 215 a (0.184 mmol) as alkyne and catalyzed by [Rh(C2H4)2Cl]2 (0.0055 mmol) and GUIPHOS (0.0110 mmol, Scheme 46). The ratio of products was found to be roughly 1:1

Scheme 44. The AgSbF6-catalyzed competitive [3+2] cycloaddition between alkynes 211 a-c as the two-atom component and with aziridine 212 as the three-atom component.

4.4 [2+2+2] Cycloadditions Rovis and co-workers encountered substrate-dependent enantioselectivity in their study of the rhodium-catalyzed asymmetric [2+2+2] cycloaddition of alkenyl isocyanate (214) with diarylacetylenes (tolanes) (215 a and 215 b, see Scheme 45 for

Scheme 46. The Rh-catalyzed pair-wise competitive reaction between isocyante alkenes 214 and 217 in the [2+2+2] cycloaddition reaction with alkyne 215 a.

after 16 h reflux in toluene. The observed lack of substrate selectivity (determined as product selectivity) suggested that the alkene substrate is not involved in the rate-limiting step.

5. Allylic Cleavage

Scheme 45. The pair-wise Rh-catalyzed competitive reaction between alkynes 215 a and 215 b in the [2+2+2] cycloaddition reaction with the alkene isocyante 214.

structures).[72] In the study, an initial screening of different tolanes revealed a large variation in enantioselectivity. It was suggested that the observed variation in enantioselectivity was due to the coordination of a second alkyne to the rhodium intermediate. To validate this hypothesis, a pair-wise competition experiment was set up between acetylenes 215 a and 215 b that lead to cycloaddition products with different ee’s (Scheme 45). In the experiment, 215 a (0.140 mmol) and 215 b (0.140 mmol) together with 214 (0.231 mmol) were dissolved in toluene in the presence of [Rh(C2H4)2Cl]2 (0.0069 mmol) and a BINOL–phosphoramidite ligand (GUIPHOS, 216, 0.0138 mmol). After 16 h, the product distribution was found to be 2:1 (217 a/217 b) and the ee’s 92 and 91 % for 217 a and Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

The removal of an allyloxycarbonyl group from water-insoluble carbonates[73] and N-substituted-O-allyl carbamates,[74] in a biphasic aqueous/organic solvent reaction medium, catalyzed by the water-soluble catalyst [Pd(OAc)2]/TPPTS (TPPTS = 3,3’,3’’phosphinidynetris(benzenesulfonic acid) trisodium salt) was investigated in the presence of randomly permethylated b-cyclodextrins (218, 10 mol %), as inverse phase-transfer catalyst[75] (see Scheme 47 for structures). This inverse phase-transfer catalyst transferred water-insoluble substrates from the organic layer to the aqueous layer, in which they reacted with the water-soluble catalyst. The presence of the inverse phase-transfer catalyst 218 in the reaction medium gave rise to an enhancement of the reaction rate of up to 300 times over the uncatalyzed reactions. Control experiments with methyl-a-glucoside and maltoheptaose, subunit analogues of the b-cyclodextrin, did not increase the rate of reaction. Thus, in the presence of the inverse phase-transfer catalyst 218, molecular recognition between the substrate and 218 gave rise to the increase in reaction rate. As expected, the allyloxycarbonyl groups of carbonates and carbamates carrying lipophilic groups that fitted into the cavity of the inverse phase-transfer catalyst 218 were removed much faster than from those counterparts having less lipophilic groups.

13458


Review moter 218 (0.31 mmol) and [Pd(OAc)2] (0.045 mmol)/TPPTS (0.40 mmol) as pre-catalyst, as 223 and 224 were obtained in a 32:1 ratio in the preference of 223 (Scheme 47d). Notably, replacing 218 with acetonitrile as the mass-transfer promoter in control experiments did not furnish any substrate selectivities (determined as product selectivity). Thus, the substrate selectivities (determined as product selectivity) in Scheme 47 do not arise from preferential reactivity of 219 and 223 with [Pd(OAc)2]/TPPTS, but it is more likely that they arise from beneficial molecular recognition processes of 219 and 223 with 218.

6. Condensation Reactions 6.1 Nitroaldol condensations In 2004, Lin and co-workers reported the synthesis of a series of bifunctional mesoporous silica nanospheres (MSN) materials that included two functional groups: one group that behaved as a catalytic group and a second that formed various non-covalent interactions with the substrates, and thus acted as a receptor unit (Figure 25).[76] All these materials were investigated

Scheme 47. The removal of allyloxycarbonyl group from carbonates (a and b) and carbamates (c and d) by [Pd(OAc)2]/TPPTS in the presence of the phase-transfer promoter 218. The experiments in a) and c) were run as two separate single-substrate reactions and the experiments in b) and d) were run as two pair-wise competitive reactions.

Thus, in two separate single-substrate experiments, the removal of the allyloxycarbonyl group from [1,1’-biphenyl]-4-ylmethyl allyl carbonate (219) and [1,1’-biphenyl]-2-ylmethyl allyl carbonate (220) by [Pd(OAc)2]/TPPTS as pre-catalyst in the presence of the inverse phase-transfer promoter 218 (0.31 mmol) and and diethylamine as an allyl scavenger revealed that the reaction occurred four times faster with the former substrate (Scheme 47a). The high substrate selectivity (determined as product selectivity) was maintained in a pairwise competitive experiment of 219 versus 220 (0.56 mmol each), in the presence of promoter 218 (0.31 mmol) and [Pd(OAc)2] (0.045 mmol)/TPPTS (0.40 mmol) and product 221 was obtained in a 82:18 ratio over product 222 (Scheme 47b). Likewise, in two separate single-substrate experiments involving N-dodecyl-O-allyl carbamate (223) and N,N-dihexyl-O-allyl carbamate (224) revealed a higher rate for the consumption of the linear substrate 223, showing a factor 47 increase in the rate over substrate 224 (Scheme 47c). This selectivity was confirmed in a pair-wise competitive experiment of 223 versus 224 (0.56 mmol each) in the presence of phase-transfer proChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Figure 25. The schematic presentation of the bisfunctionalized MSN-catalysts carrying one catalytic unit and one receptor unit.

as substrate-selective catalysts in the nitroaldol condensation reaction between various benzaldehydes and nitromethane. The study involved three bifunctional MSN catalysts that all were equipped with 3-[2-(2-aminoethylamino)ethylamino]propyl (AEP) groups as the catalytic units and three different receptor units, namely, ureidopropyl (UDP), 3-mercaptopropyl (MP) and allyl (AL). The study also involved monofunctionalized MSN, as a reference catalyst, AEP-MSN, which only contained the catalytic unit AEP. Investigation of the average pore diameters of the MSN catalysts AEP-MSN and AEP/UDP-MSN, functionalized with hydrophilic groups by a dinitrogen-sorption experiment revealed a pore diameter of 2.6 and 2.29 nm, respectively. The catalysts AEP/MP-MSN and AEP/AL-MSN, carrying hydrophobic groups, displayed smaller average pore diameters of approximately 1.5 nm, as determined by transmission electron microscopy (TEM). In order to investigate the substrate selectivity (determined as product selectivity) of the MSN catalysts in the nitroaldol condensation, equimolar amounts of para-hydroxybenzaldehyde (5.0 mmol, 227) and one of para-methoxybenzaldehyde (5.0 mmol, 228), para-butoxybenzaldehyde (5.0 mmol, 229) or para-(octyloxy)benzaldehyde (5.0 mmol, 230) at each time

13459


Review

Scheme 48. The pair-wise competitive nitroaldol condensations between 227 and each of 228, 229 or 230 and nitromethane catalyzed by various bisfunctionalized MSN compounds.

were pair-wise competitively reacted with nitromethane (10.0 mL) in the presence of one of the MSN catalysts at each time (50 mg, Scheme 48). For all the three substrate combinations investigated, it was discovered that neither the monofunctionalized AEP-MSN nor the hydrophilic bifunctionalized AEP/UDP-MSN catalysts displayed any substrate selectivities (determined as product selectivity). Changing to the catalysts AEP/MP-MSN and AEP/AL-MSN, containing hydrophobic receptor units, revealed a preference for the more hydrophobic substrates 228, 229 and 230 over 227. The highest-substrate selectivity (determined as product selectivity) was observed for catalyst AEP/AL-MSN that furnished a product ratio (234/231) of 2.58:1, when 227 was reacted with nitromethane in competition with 230. The obtained results demonstrated that the hydrophobic receptor units AL and MP had a significant effect on the substrate selectivity, as they preferentially allowed the more hydrophobic substrates to enter the mesopores in which the nitroaldol condensation took place. With the aim to obtain substrate-selective catalysts for the nitroaldol condensation between various para-substituted benzaldehydes and nitromethane, two different functional groups were grafted into the pores of well-ordered mesoporous silica MCM-41 (MCM = mobile crystalline material).[77] 3-Aminopropyl (AP) groups constituted one of the grafted functional groups in all the catalysts and was designed to constitute a Brønsted base-containing catalytic site. The secondary functional groups included UDP, MP, or methyl (ME) as well as the residual silanol groups tuned the surface of the material to be hydrophobic or hydrophilic. The ME groups implemented the highest hydrophobicity into the pores. The MP groups furnished an intermediate dielectric environment of the pores, whereas the silanol and UDP groups resulted in the highest hydrophilicity of the pores. The catalysts APUDP1, APMP1, and APME1 were obtained by grafting equal number of moles of the corresponding organotrimethoxysilanes to the channel walls of MCM-41. Besides these catalysts, also APME2 and APME3, containing higher fractions of ME groups than APME1, were prepared by grafting 3:1 and 9:1 ratios of methyltrimethoxysilane/3-aminopropyltrimethoxysilane. A reference catalyst, API1, was obtained by grafting only 3-aminopropyltrimethoxysilane and no secondary functional groups to MCM-41. All the grafting was conducted in isopropanol because of the fact that previous work had demonstrated that grafting of 3-aminopropyltrimethoxysilane in this solvent led to optimum-site-located AP groups, which furnished efficient solid-catalyzed nitroaldol conChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

densations.[78] Dinitrogen-sorption experiments showed that the catalysts based on MCM-41 had pore widths from 2.7 to 3.2 nm. Thus, in order to investigate the impact of the pore size on the substrate selectivity, similar functionalized catalysts were synthesized from SBA-15 material, which has pore widths approximately two times larger than that of MCM-15. These catalysts were termed APUDP1-SBA, APMP1-SBA, APME1-SBA, and API-SBA and possessed pore widths in the range of 5.9– 6.2 nm. The catalytic experiments were initiated by studying the performance of API1, APUDP1, APMP1, and APME1 in the nitroaldol condensation between para-hydroxybenzaldehyde (227, Scheme 49) and para-methylbenzaldehyde (235, Scheme 49)

Scheme 49. The nitroaldol condensations of 227, 229 and 236 with nitromethane catalyzed by API1, APUDP1, APMP1, APME1, APME2, or APME3, performed as separate single-substrate experiments.

with nitromethane in separate single-substrate reactions.[77] For each catalytic system, the difference in reaction rate for the transformation of substrates 227 and 235 to the corresponding para-nitrostyrenes 231 and 236, respectively, (Scheme 49) was attributed to the different hydrophobicity of the substrates and not to steric effects, since the two substrates are of similar size. The different reactivity of the various catalysts (API1, APUDP1, APMP1, and APME1) arose either from the different hydrophobicity of the mesopores obtained by grafting different secondary functional groups or the relative diffusion rate of 227 and 236 into the mesopores of the catalysts. Indeed, the hydrophilic catalysts API1, lacking secondary functional groups, and APUDP1 (20 mg), carrying ureidopropyl groups, exhibited higher catalytic activity on the more hydrophilic substrate 227 (1 mmol) over 235 (1 mmol), in the presence of CH3NO2 (10 mL) with conversion ratios (235/227) of 6:10 and 8:10, respectively, in pair-wise competitive reactions. In sharp contrast to API1 and APUDP1, the hydrophobic catalysts APMP1 and APME1, containing the more hydrophobic secondary functional groups than APUDP1, provided a preferential reactivity on 235 over 227. The hydrophobic catalyst APMP1 gave a conversion ratio (235/227) of 12:10, whereas the more hydrophobic catalyst APME1 furnished a ratio of 13:10. Using the hydrophobic catalysts APMP1 (20 mg) and APME1 (20 mg) in the pair-wise competitive nitroaldol condensations of 235 versus 227 (1 mmol each) in nitromethane (10 mL) resulted in an initial conversion ratio (235/227) of 12:10. However, the ratios changed rapidly to 1:1 as the reaction progressed. It is worth noting that the pair-wise competitive nitroaldol condensation of 235 versus 227 (1 mmol each), using the same conditions as above, gave a higher preference for the consumption of 235, when the fraction of methyl groups was increased in the catalysts as in APME2 and APME3. Both catalysts furnished an initial conversion ratio (235/227) of

13460


Review 18:10. However, only APME3 achieved a conversion ratio > 1:1 after 75 % conversion of the both substrates. In order to investigate the effect of the steric bulk of the substrates on the substrate selectivity of the catalysts, 235 and para-butoxybenzaldehyde (229) were reacted with nitromethane in both separate single-substrate and pair-wise competitive experiments. The single-substrate experiments revealed that the hydrophobic catalysts APMP1 and APME1 furnished conversion ratios (235/229) of 21:10 and 22:10, respectively. Regarding the hydrophilic catalysts, the monofunctionalized catalyst API1 yielded a ratio of 15:10 (235/229), whereas a lowest ratio = 13:10 (235/229) was observed for APUDP1, carrying the comparable most hydrophilic secondary functional groups. The corresponding pair-wise competitive experiments of 235 versus 229 (1 mmol each, 10 mL CH3NO2, 20 mg catalyst), revealed higher substrate selectivities than those observed in the individual experiments. The hydrophobic methylgroup-grafted catalysts APME1, APME2, and APME3 furnished the highest conversion ratios (235/229) of 27:10, 32:10 and 42:10 respectively. However, the substrate selectivity decreased with the progress of the reaction. The catalysts were also investigated in the nitroaldol condensation of benzaldehydes 227 and 235 with nitromethane, both individually and in pair-wise competitive reactions of both benzaldehyde substrates (1 mmol of each substrate, 10 mL CH3NO2, 20 mg catalyst). All the catalysts API1, APUDP1, APMP1, and APME1 exhibited higher activity with substrate 227 than with 235. The separate single-substrate experiments’ conversion ratios (227/235) were in the range of 16:10 to 24:10. In an effort to increase the mass transport of the bulkier substrate 235 into the channels and thus to achieve selectivity of this substrate over 227, catalysts API1-SBA, APUDP1-SBA, APMP1-SBA, and APME1-SBA, based on more lipophilic SBA-15, were also investigated. These catalysts had essentially no impact on the substrate selectivity compared to the catalysts based on MCM-14. Hence, pair-wise competitive nitroaldol condensations of 227 versus 235 (1 mmol each) in the presence of CH3NO2 (10 mL) by one of the catalysts API1-SBA, APUDP1-SBA, APMP1-SBA, and APME1-SBA, respectively, 20 mg each, resulted in the conversion ratios (227/235) 21:10, 21:10, 20:10 and 17:10, respectively.

7. Substitution reactions 7.1 Electrophilic aromatic substitutions The groups of Olah and Brown made extensive mechanistic studies of the electrophilic aromatic substitution (EAS) reaction, where they used pair-wise competitive experiments to determine the relative rates of the consumption of different aromatic compounds in EAS under Lewis-acid promoted-conditions. It was observed that the trend in substrate selectivity results from the differences in the nucleophilic character of the arenes involved, regardless of the type of EAS and promoter. Thus, not surprisingly, the highest selectivities were observed when the difference in nucleophilicity between the competing arenes was high. Several reviews have been written dealing Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

with their findings.[79] In the present review we highlight the results regarding substrate selectivity and add more recent reports by other authors.

7.1.1 Friedel–Crafts alkylations In a quest to establish the mechanism of aromatic benzylations, isopropylations, and tert-butylations, Olah and co-workers reported the relative reactivities of benzene versus alkylbenzenes as substrates in pair-wise competitive EAS reactions (Scheme 50).[80] In these pair-wise competitive experiments

Scheme 50. The pair-wise competitive Friedel–Crafts alkylation between benzene vs toluene, xylene, or mesitylene with an alkylhalide and promoted by AlCl3.

conducted in nitromethane, a mixture of benzene (0.25 mol), alkylbenzene (0.25 mol), and the desired the alkylhalide (0.05 mol) was treated with a non-stoichiometric amount of AlCl3 (0.05 mol). From the results of the experiments it could be concluded that the relative reactivity of the alkylbenzenes was higher than that of benzene: Moreover, the size and number of alkyl substituents in the substrate affected the relative rates: toluene exhibited the highest relative rate among the monoalkylated arenes during benzylation reactions (ktoluene/ kbenzene ca. 3); xylene (all three isomers) exhibited a higher relative rate than toluene (kxylene/kbenzene ca. 4); and mesitylene exhibited the highest overall relative rate (kmesitylene/kbenzene ca. 5). This result was attributed to the fact that the alkylbenzenes formed more stable p-complexes with the Lewis acid than the parent benzene prior to forming a s-complex with the electrophile. This explanation was also consistent with the observed trend in relative rates of the different alkylbenzenes, for which the highest substrate selectivities were observed with the alkylbenzenes that had the more electron-donating alkyl groups. Changing the Lewis acid promoter from AlCl3 to AgBF4 or FeCl3/CH3NO2 in the competitive reactions did not change the selectivities, strengthening the idea that the substrate selectivity indeed arose from the inherent differences in the nucleophilicity of the competing arenes and not from the nature of the promoter. In contrast, in a competitive experiment Mayr and co-workers demonstrated that the relative electrophilicity of the alkylating agents could be controlled by the variation of the concentration of the Lewis acid. Hence, in the pair-wise competitive alkylation of p-methoxyphenyl-phenyl-methyl chloride 237

13461


Review (0.40 mmol) and p-methoxyphenyl-p-methylphenyl-methyl chloride 238 (0.80 mmol) with 2-methyl-1-pentene (239, 0.20 mmol) in the presence of an excess of BCl3 (6.0 mmol, 5 equiv), the relative rate constant, k237/k238, was determined to 7.2:1. Upon lowering the amount of BCl3 to 0.06 mmol (0.05 equiv), the value of k237/k238 was reduced to 0.18:1. This result was attributed to that the less reactive 238 was converted preferentially at low catalyst loading due to its higher concentration compared to 237 (Scheme 51).[81]

In two separate pair-wise competitive acylation studies of benzene versus toluene (0.05 mol of each) employing acetyl chloride (0.01 mol) as electrophile using AlCl3 (0.01 mol) as catalyst or employing acetyl fluoride (0.01 mol) as electrophile and using BF3 (0.01 mol) as catalyst, respectively, the relative rates ktoluene/kbenzene were found to be 131:1 and 140:1, respectively (Scheme 53). The authors attributed this high substrate

Scheme 53. The pair-wise competitive Friedel Crafts acylations between toluene and benzene using different acylation reagents and catalysts.

Scheme 51. The BCl3-promted pair-wise competitive alkylation of 237 versus 238 with 239 as nucleophile. With an excess of the Lewis acid promoter, BCl3, the more electron-rich substrate 237 is consumed more rapidly. With low concentrations of the promoter, the less reactive 238 is consumed more rapidly due to being present in higher concentration.

Mayr and co-workers conducted a study of the relative reactivities of alkyl chlorides under Friedel–Crafts conditions, in which pair-wise competitive experiments with variations in substrate ratios (ranging from 1:1 to 1:100) were conducted to establish the relative reactivities of 23 different alkyl chlorides in the ZnCl2-catalyzed (0.2 equiv) alkylation of allyltrimethylsilane (1.5 equiv, Scheme 52 a).[82] It was found that the relative

Scheme 52. a) The pair-wise competitive ZnCl2-catalyzed alkylation of 23 different alkyl chlorides with allyltrimethylsilane was studied. b) The relative rates spanned 11 orders of magnitude between the least reactive alkyl halide 240 and the most reactive 241.

rates (expressed as krel) spanned over eleven orders of magnitude between the least reactive 1-adamantyl chloride (240) and the most reactive bis(p-methoxyphenyl)methyl chloride (241) (Scheme 52 b). A correlation was found between the carbocation stability and the alkylating ability of the alkyl chlorides involved.

selectivity relative to Friedel–Crafts alkylations (131:1 for acylation compared to 3:1 for alkylation) to “the weakly electrophilic character of the acylium ion and the higher likelihood of the transition states to resemble s-complexes”.[83]

7.1.3 Halogenations In their study of the directing effects of different substituent groups in aromatic halogenations, Olah and co-workers conducted a series of pair-wise competitive experiments to establish the relative rate of the FeCl3-catalyzed halogenation of benzene versus alkylbenzenes, halobenzenes, and a,a,a-trifluoromethoxybenzene (Scheme 54). Generally, the substrate

Scheme 54. The FeCl3-catalyzed pair-wise competitive halogenations between benzene vs alkylbenzenes, halobenzenes and a,a,a-trifluoromethoxybenzene, respectively.

selectivities were, as expected, much lower than for alkylations, due to the strong electrophilic nature of the halogenating agents, being free halonium ions. Also as expected, the least nucleophilic and thus most deactivated arene (a,a,a-trifluoromethoxybenzene) reacted the slowest.[84] 7.1.4 Alkynylations

7.1.2 Friedel–Crafts acylations The substrate selectivities in Friedel–Crafts acylations of arenes were found to be much higher than those found in the corresponding alkylations. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Waser and co-workers reported the gold-catalyzed direct alkynylation of aromatic heterocycles using alkynyl hypervalent iodine reagents.[85] In their mechanistic study of the reaction, pair-wise competitive alkynylation experiments were run in an

13462


Review effort to obtain information about the kinetics of the reaction. Hence, an equimolar mixture (3 equiv each) of indole (242) and 5-cyanoindole (243), and an equimolar mixture (3 equiv each) of 243 and 5-methoxyindole (244), respectively, were subjected to alkynylation conditions in the presence of triisopropylsilylethynyl-1,2-benziodoxol-3(1 H)-one (TIPS-EBX, 1 equiv) and AuCl (5 mol %) as catalyst in diethyl ether (Scheme 55).

Scheme 55. The AuCl-catalyzed pair-wise competitive alkynylation experiments using hypervalent iodine reagent (TIPS-EBX) with indoles 242, 243, and 244. Note the preference for the formation of product of the more electron-rich indole.

As seen in Scheme 55, the more electron-rich indole in each pair was preferentially alkynylated (based on product distribution), indicating an electrophilic character of the reagent in the rate-determining step.

7.2 Allylic alkylations (Tsuji–Trost) Rebek and co-workers studied the substrate selectivity (determined as product selectivity) in the Tsuji–Trost allylic alkylation reactions[86] using a catalyst consisting of a Pd complex of the cavitand ligand 248.[87] This ligand features a geminal diphenyl-substituted oxazoline moiety attached to a resorcinarene cavitand. The PdII complex of the oxazoline moiety is a wellknown catalyst for the Tsuji–Trost allylic alkylations and the resorcinarene moiety is well-known for binding size- and shapecomplementary molecules (Figure 26). First, ligand 248 and [{Pd(C3H5)Cl}2], the latter as the Pd source, were evaluated for substrate selectivity in separate single-substrate experiments using substrates 249–253, one at a time, and employing dimethyl malonate as the nucleophile

Figure 26. The structure of ligand 248, consisting of a cavitand attached to diphenyl-substituted oxazoline and control ligand 254. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 56. The substrate selectivity (measured as product selectivity) of the Tsuji–Trost alkylation of substrates 249–253, using ligands 248 or 254 in the presence of [Pd(C3H5)Cl]2, CH2(CO2Me)2, and N,O-bis(trimethylsilyl)acetamide (BSA) as determined from separate single-substrate experiments. *Note that for product 255, not all substrate was converted with ligand 248.

(Scheme 56). The experiments were repeated with control ligand 254 (Scheme 56). In both cases, the linear products (255–259) were formed exclusively in favor of the more branched products. This result was attributed to the two geminal phenyl groups on the oxazoline moiety on ligands 248 and 254. These phenyl groups sterically hindered the nucleophilic addition of the malonate to the allylic carbon that will result in the more branched product. The observed reaction rates were faster for ligand 254 than for ligand 248 due to the increased bulk of 248 hindering the access of the substrates to the catalytic site of the metal as explained by the authors. For ligand 248, the rates varied significantly with the various substrates, while for ligand 254 the rates were more uniform. To establish the substrate selectivity (determined as product selectivity) of the system, a series of pair-wise competitive experiments (1:1, non-specified amount of moles) between the substrate pairs 249/250, 250/251, 250/252, 250/253 and 252/ 253 in the presence of dimethylmalonate (3 equiv), using each ligand 248 and 254 (3.2 mol %) and [{Pd(C3H5)Cl}2] (1.4 mol %) were performed. The results are summarized in Scheme 57. Interestingly, in the competitive allylic alkylation of 249 versus 250 with [{Pd(C3H5)Cl}2] as the pre-catalyst it was found that 249 was slowing down the catalytic cycle when ligand 248 was used. The authors attributed this to that substrate 249 quickly formed a h3-complex with the catalyst and that this new complex was virtually inert to nucleophilic substitution. This was further confirmed by the fact that when using the control ligand 254, there was a preference for substrate 249 without any observed retarding effects on the catalytic cycle. The product distribution showed that substrate 250 was more reactive towards the Pd0 species than substrate 251. Hence it was argued by the authors that the oxidative addition was faster for substrate 250. The above observations led the authors to the conclusion that the connectivity of the homoal-

13463


Review

Scheme 57. The substrate selectivity (measured as product selectivity) of the Tsuji–Trost palladium-catalyzed allylic alkylation determined in the pair-wise competitive reactions of substrates 249–253, using ligands 248 and 254. The product distribution was determined by 1H NMR after workup. Note that only the linear addition products (255–259) were formed (see structures in Scheme 56).

lylic carbon in the substrate influenced the rate of oxidative addition. It could be concluded that the rate of oxidative addition increased with the decreasing order of connectivity; quaternary (251) < tertiary (250) < secondary (249) as was experimentally observed. To further investigate this connectivity effect, substrates 250, 252, and 253, which all contain tertiary carbons in the homoallylic position, were run in pair-wise competitive reactions (1:1) with dimethyl malonate as nucleophile (3 equiv). No significant difference was observed in the pair-wise competitive reaction when ligand 254 (3.2 mol %) was used. In the pair-wise competitive experiments (1:1) of 250 versus 252 with ligand 248 (3.2 mol %) and dimethylmalonate (3 equiv), however, the reaction seemed to favor the product 258. For 250 versus 253, product 256 was the favored one. With 252 versus 253, there was significant substrate selectivity (determined as product selectivity) in preference for 252, leading to product 258. The authors argued that the catalyst containing Pd bound to ligand 248 had an ability to stabilize the transition-state of the oxidative addition step in an increasing order going from 1-ethyl-1pentyl 253 < isopropyl 250 < cyclohexyl 252. Hence, it was concluded that the observed substrate selectivity arose from the ability of the cavitand to stabilize the transition state of the oxidative addition of the substrate in the catalytic cycle in the Tsuji–Trost reaction.

8. Coupling Reactions

the reaction of aryl electrophiles with alkyl Grignard reagents[88] and the second reaction studied was between alkyl electrophiles and aryl Grignard reagents.[89] The research methodology used in the investigations was based on the use of competitive Hammett studies, reaction monitoring using GC and density functional theory (DFT) calculations. The first study indicated that FeI behaved as the catalytic species and that the oxidative addition of the aryl electrophile to the catalysts constituted the rate-limiting step. However, it was not clear whether the transmetalation step took place before or after the oxidative addition. In line with the first study, the second study showed an uncertainty in the relative order of the oxidative addition and transmetalation step. In order to obtain a mechanistic insight into the Fe-catalyzed cross-coupling reactions, competitive Hammett experiments (log(krel) versus s) were performed. Thus, pairwise crosscoupling reactions were performed using [Fe(acac)3] (25 mmol) as a pre-catalyst in a N-methyl-2-pyrrolidone (NMP)/THF (1:10) solvent system containing the electrophiles phenyl triflate

Scheme 58. The pair-wise competitive Fe-catalyzed coupling reactions of aryl triflate 260 versus each of 261–265 with octyl Grignard reagent (265) catalyzed by [Fe(acac)3].

(260, 0.5 mmol) and one of the electrophiles 261, 262, 263, or 264 (0.5 mmol) and the nucleophile octyl Grignard reagent (265, 0.9 mmol). The relative reaction rate (krel = kA/kB) between two substrates A and B was obtained from a plot ln([A]o/[A]) versus ln([B]o/[B]) ([A]o and [B]o are the initial concentrations of the two electrophiles) in which krel signified the slope of the graph. The competition studies showed a preferential reactivity of those para-substituted phenyl triflates carrying electronwithdrawing substituents (Scheme 58). The pair-wise competitive cross-coupling reactions of phenyl Grignard reagent 266 (1.2 mmol) versus each of 267, 268, 269, 270, 271 or 272 (1.2 mmol each), respectively, with cyclohexyl bromide (0.1 mmol, 273) as electrophile in the presence of [Fe(acac)3] (0.05 mmol) as pre-catalyst in diethyl ether gave a preferential reactivity of those Grignard reagents possessing electron-donating para-substituents. In contrast the electron-withdrawing substituents of substrates 270–272 impeded the reaction compared to PhMgBr (266) (Scheme 59).

8.1 Cross-coupling reactions 8.1.1 Fe-catalyzed cross-coupling reactions

8.1.2 Stille cross-coupling reactions

In two consecutive publications, Norrby and co-workers investigated the mechanisms of the aryl–alkyl cross-coupling reaction using FeIII as a pre-catalyst. The first reaction studied was

In a study performed in 1993, the effect of various ligands and added lithium chloride was explored for the Stille cross-coupling reaction between organic triflates and arylstannanes.[90]

Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

13464


Review

Scheme 59. The pair-wise competitive Fe-catalyzed cross-coupling reactions of aryl Grignard reagent 266 versus each of 267–272 with cyclohexyl bromide (293), catalyzed by [Fe(acac)3].

was developed in the aryl ring during the rate-limiting step, the transmetalation, and thus the carbon–Pd bond formation was initiated before the breaking of the carbon–tin bond. The Hammett plot did not result in any linear correlation when lithium chloride was added to the reaction mixture. The plot gave, however, the information that both electron-donating and electron-withdrawing substituents on the arylstannanes yielded higher reaction rates compared to 275 with the exception for 278. The authors attributed this behavior to the reaction proceeding along two parallel mechanisms, requiring opposite electronic environments.

8.1.2 Negishi cross-coupling reactions The study led to the recommendation that triphenylarsine should be used in preference to the other investigated ligands PPh3, TFP (tri(2-furyl)phosphine), (o-tol)3P, dppf (1,1’-bis(diphenylphosphanyl)ferrocene), [2,4,6-(MeO)3C6H2]3P and (p-MeOC6H4)3P together with the pre-catalyst [Pd2(dba)3]. It is worth noting, however, that it was also discovered that when hindered triflates served as the electrophile, the presence of triphenylarsine hampered the cross-coupling reactions and the reactions proceeded more efficiently under ligand-free conditions. The effect of lithium chloride as an additive was inconsistent, as it varied depending on the ligands and solvent used. To address the electronic influence of the arylstannanes during the transmetalation step, pair-wise competitive studies were performed (Scheme 60). The studies were conducted on

Scheme 60. The pair-wise competitive Stille cross-coupling reactions of arylstannanes 275 versus each of 276–279 with triflate 274 catalyzed by the system [Pd2(dba)3]/AsPh3.

mixtures in NMP containing the pre-catalyst [Pd2(dba)3] (0.0035 mm) and the ligand triphenylarsine (0.028 mm) together with the vinyl triflate 274 (0.35 mm) and the competing arylstannanes 275 and one of 276, 277, 278, or 279 (0.52 mm of each). The experiments were set up twice, in the presence of lithium chloride (1.05 mm) and in its absence. The substrate selectivity was derived from the relative transmetalation rate (kx/ kH) of two competing arylstannanes. In the absence of lithium chloride, the Hammett plot (log(kx/kH) versus s) furnished a fairly good linear correlation with a negative Hammett reaction constant (1 = 0.89). Hence, the insertion of electron-donating groups on the arylstannanes increased the rate of the reaction. The negative slope was interpreted as positive charge Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride also known as PEPPSI-IPr (see Scheme 61 for structure) was exploited as a catalyst in the Ne-

Scheme 61. The pair-wise competitive Negishi PEPPSI-IPr-catalyzed crosscoupling of aryl halide 281 versus 282 using butylzinc bromide (280) as coupling partner.

gishi cross-coupling reaction of polybromobenzenes and polybromobiphenyls with butylzinc bromide (280) to furnish the corresponding polybutylbenzenes and polybutylbiphenyls, respectively, in astonishing chemoselectivities (up to > 99:1) in addition to very good yields in most of the cases.[91] PEPPSI-IPr (20 mmol) was also explored in a pair-wise competitive crosscoupling reaction experiment (Scheme 61) of equimolar amounts of 1,4-dibromobenzene (281) versus para-bromotoluene (282, 0.5 mmol of each) with butylzinc bromide 280 (1 mmol) as the coupling partner. The reaction yielded 1,4-dibutylbenzene (283) and para-butyltoluene (284) in a combined yield of 91 % (based on 280) and in a 9:1 ratio in preference for 283 over 284. Based on the high selectivity in favor for 283, it was rationalized that at least two distinct Pd0 species participated in the conversion of 281 to 283. The reaction was initiated in such a way that the major Pd0 species in the bulk solution underwent oxidative addition with 281 under activation control as stated by the authors, whereas a second Pd0 species, liberated from the reductive elimination, participated in a second oxidative addition, under diffusion control. Mayr and co-workers used [Pd(PPh3)4] (20 mmol) as a pre-catalyst and lithium chloride as a promoter in the competitive studies of the Negishi cross-coupling reaction in order to evaluate the relative reaction rate of bromobenzenes carrying various substituents.[92] In the study, the pair-wise competitive Pdcatalyzed and lithium chloride promoted (2 mmol) cross-cou-

13465


Review

Scheme 62. The pair-wise competitive Negishi cross-coupling reaction of bromobenzene (285) versus substituted bromobenzenes (287–290) with arylzinc iodide 286 as coupling partner and using [Pd(PPh3)4] as pre-catalyst and LiCl as promoter.

iodides bearing electron-donating substituents. For example, 286, carrying a para-methyl group, reacted 4.1 times faster than 291, with an electron-withdrawing para-ethyl carboxyl group (Scheme 63).[92] However, as shown in Scheme 63a–c, the effect of the substituents (expressed as the relative reactivities kA/kB) was less pronounced when the two competing para-substituted phenylzinc iodides reacted with bromobenzenes containing less electron-withdrawing substituents as in 292 (chloro) compared to 288 and 289 (cyano) (compare Scheme 63c with Scheme 63a,b). The construction of a competitive Hammett plot for the reaction of 288 with the coupling partner system of para-substituted phenylzinc iodides/lithium chloride under Pd catalysis as above resulted in a linear correlation with a negative Hammett reaction constant (1 = 0.98). The negative Hammett reaction constant demonstrated an increasing reactivity for those parasubstituted phenylzinc iodides with electron-donating substituents.

pling reaction of substituted bromobenzenes (287– 290, 2 mmol) versus bromobenzene (285, 2 mmol) with para-tolylzinc iodide (286, 2 mmol) as the coupling partner was studied in THF (Scheme 62). Analyzing all the competitive experiments included in the study resulted in the conclusion that those bromobenzenes carrying electron-donating substituents reacted significantly slower than those carrying electron-withdrawing substituents. The reactivity range was as large as 103, ranging from para-methoxybromobenzene (287, Scheme 62a) to para-bromobenzonitrile (288, Scheme 62b). Moreover, the location of Scheme 63. The pair-wise competitive Negishi cross-coupling reactions between phenyl the strong electron-withdrawing substituent CN on zinc iodides 286 and 291 with various substituted bromobenzenes (288, 289, and 292) as electrophiles, using [Pd(PPh3)4] as pre-catalyst. the bromobenzenes had a great impact on their reactivity with the Pd complex: the reactivity decreased in the order para > meta, ortho (see Scheme 62b–d). 8.1.3 Suzuki cross-coupling reactions The comparable lower reactivity of ortho-substituted bromoIn two subsequently published works, Monteiro and co-workbenzene was attributed to steric effects. Furthermore, the ers investigated the effect on the reactivity of various substituHammett plot (log(kx/kH) versus s) for meta- and para-substients in the para-position of arylboronic acids in the Pd-catatuted bromobenzenes exhibited a good linear correlation, lyzed Suzuki cross-coupling reaction: first with vinyl bromide[93] yielding a positive Hammett reaction constant (1 = 2.5). It was 0 suggested that the oxidative addition to the reactive Pd speand later on with (E)-bromostilbene.[94] cies proceeded over a three-centered transition state, and In their first published work, two sets of competitive experibased on the positive Hammett reaction constant that negaments were set up. In the first experiment, a mixture of phetive charge was built up on the benzene ring on going from nylboronic acid (293), para-methylphenylboronic acid (294) reactant to transition state. and para-methoxyphenylboronic acid (295, 0.025 mmol of The pair-wise competitive Negishi cross-coupling reaction each) were coupled with vinyl bromide, generated in situ from between para-substituted phenylzinc iodides 286 and 291 1,2-dibromoethane (0.75 mmol), in the presence of [Pd(OAc)2] using para-bromobenzonitrile (288, 2.00 mmol) as coupling (3 mmol), PPh3 (6 mmol) and KOH (2.5 mmol, Scheme 64 a). The partner and [Pd(PPh3)4] (0.02 mmol, 1 mol %) as the pre-catalyst second competitive experiment was conducted in the same way apart from the replacement of 294 and 295 with paraand LiCl (2.00 mmol) as the promoter was performed. The chlorophenylboronic acid (296) and para-trifluoromethylpheeffect of having different substituents in the para-position of nylboronic acid (297, Scheme 64b). Comparison of the relative the phenylzinc reagent was investigated. The results showed reactivities (kX/kH) revealed that the arylboronic acids 294 and a preferential reactivity for those para-substituted phenylzinc Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

13466


Review

Scheme 64. The competitive Suzuki cross-coupling reactions of arylboronic acids (293–297) with vinyl bromide generated in situ from 1,2-dibromoethane.

295, bearing electron-donating substituents, displayed higher reactivity than 293, whereas 296 and 297, which have electron-withdrawing substituents, yielded lower reactivities than 293. A plot of log(kX/kH) versus s gave a linear correlation furnishing a negative Hammett reaction constant (1 = 1.26), showing that a small positive charge was built up in the transition state of the rate-determining step. It was stated that the obtained Hammett reaction constant might be explained in such a way that the electron-donating groups of the arylboronic acids increased the nucleophilicity of the aryl moiety, and thereby facilitated the rate-determining transmetalation. The competitive Suzuki cross-coupling reactions of various para-substituted arylboronic acids with (E)-bromostilbene led to the same conclusion, namely, that the arylboronic acids carrying electron-donating substituents displayed the highest reactivity. The cyclopalladated phosphine-free imine complex 298 (see structure in Scheme 65) was identified as an excellent catalyst for Suzuki cross-coupling reaction between aryl bromides and

playing a positive slope (1 ca. 1). The obtained Hammett reaction constant was considered to be too low to signify a ratelimiting nucleophilic substitution step. Sulfur-containing palladacyclic compounds were investigated as catalysts for the Suzuki cross-coupling reaction.[96] Some of these catalysts provided excellent yields for the reaction of not only electron-rich and -poor aryl bromides, but also of electron-poor aryl chlorides with phenylboronic acids as the coupling partner to furnish the corresponding biaryls. Competitive experiments revealed that electron-donating substituents on the arylboronic acids gave rise to higher reactivities than those counterparts bearing electron-withdrawing substituents. Aryl halides carrying electron-withdrawing substituents on the other hand turned out to be more prone to couple than those equipped with electron-donating substituents.

8.1.4 Hiyama–Denmark cross-coupling reactions Denmark and co-workers performed a qualitative study of the effects of various substituents on the silicon atom of alkenylsilanes in the Pd-catalyzed cross-coupling reaction with substituted iodobenzenes.[97] The effect of various alkyl- and phenyl groups along with alkoxy groups on the silicon was investigated by competitive reactions using two different activators, namely tetrabutylammonium fluoride (TBAF) and potassium trimethylsilanoate (TMSOK). Hence, pair-wise competitive crosscoupling reactions between (E)-dimethyl(1-pentenyl)silanol (301) and dialkyl/diaryl(1-heptenyl)silanols 302, 306, and 307 (0.5 mmol of each) with substituted iodobenzenes (0.5 mmol) as coupling partners in the presence of [Pd(dba)2] (25 mmol) as the Pd source and TBAF (2.0 mmol), revealed a weak, but still significant, steric effect on the relative reactivities of the silanols (Scheme 66 a,b). Additionally, the identity of the substitu-

Scheme 65. The competitive Suzuki cross-coupling reaction between substrates 282, 285, 287, 299, and 300 as electrophiles and phenylvoric acid (293) as coupling partner and catalyzed by Pd complex 298.

phenylboronic acid (293), resulting in more than 105 turnovers even for unactivated aryl bromides.[95] In order to investigate the reaction mechanism, 298 (25 mmol) was employed as a catalyst in a competitive cross-coupling experiment of a mixture of para-bromotoluene (282), bromobenzene (285), para-methoxybromobenzene (287), para-trifluorobenzene (299), and para-bromophenyl acetate (300, 5 mmol of each) with phenylboronic acid (293, 0.75 mmol) as the coupling partner in the presence of K2CO3 (1 mmol, Scheme 65). The outcome of the experiment revealed that the arylbromides bearing electronwithdrawing substituents were the most reactive. A plot of log(kX/kH) versus s gave a fairly good linear correlation disChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

Scheme 66. a) The pair-wise competitive cross-coupling reactions between silanols 301 versus each of 302, 306, and 307 with para-iodoanisole (303) as electrophile using [Pd(dba)2] as pre-catalyst and TBAF as promoter. b) The pair-wise competitive cross-coupling reactions between silanols 301 versus 306 with para-iodoanisole (303) as electrophile, using [Pd(dba)2] as pre-catalyst and TMSOK as promoter.

ents on the silicon atom of the silanols had virtually no impact on the relative reactivities of the silanols; silanol 301 containing two methyl groups reacted slightly faster than 302 carrying two ethyl groups with para-iodoanisole (303) to furnish 304

13467


Review and 305 in a 56.7:43.3 ratio (Scheme 66 a). The following experiment, 301 versus 306, the latter having two isopropyl groups, furnished essentially the same product ratio. In contrast, in the competitive cross-coupling reaction between 301 and 307, the latter containing two tert-butyl groups, demonstrated that the less sterically encumbered substrate 301 was much more reactive than 307, as 304 and 305 were formed in a 96.4:3.6 ratio. The results obtained when TMSOK was used as the activator were in sharp contrast to those obtained in the presence of TBAF. The pair-wise competitive cross-coupling reactions of dimethylsilanol 301 versus diisopropylsilanol 306 with various substituted iodobenzenes revealed significantly higher reactivity of the former substrate. For example, the competitive crosscoupling reaction of 301 (0.5 mmol) versus 306 (0.5 mmol), the latter containing two isopropyl groups, with 303 (0.5 mmol) as electrophile and [Pd(dba)2] (5 mol %) as pre-catalyst, furnished 304 and 305 in a 100:0 ratio (Scheme 66 b), revealing the influence of a strong steric effect on the reactants. In summary, in the presence of TBAF, the competitive studies demonstrated that the reactivity of the alkenylsilanes slightly decreased with increasing number of alkoxy substituents on the silicon atom compared to 301. By changing the activator to TMSOK, the competitive cross-coupling reactions of 301 versus ethoxy-substituted silanes displayed no evident substrate selectivity (determined as product selectivity). The observed relative reactivities in the presence of TBAF compared to TMSOK were explained by the involvement of different reaction mechanisms.

8.2 Heck reactions Milstein and co-workers reported the synthesis of the pincer PdII complexes 308–310 (Figure 27) and surveyed their abilities as catalysts in the Heck reaction.[98] Thanks to the stabilizing

Figure 27. The pincer PdII complexes 308–312 were investigated as catalysts in the Heck reaction.

pincer ligand system, the complexes displayed thermal robustness up to 180 8C in addition to stability towards oxygen and moisture. In the Heck reaction between iodobenzene and methyl acrylate, catalysts 308–310 yielded essentially complete conversion of the substrates along with very high yields of the product. It was also demonstrated that the turnover numbers (TONs) in some cases exceeded 5 105. More interestingly, however, the complexes also displayed high catalytic activity in the Heck reaction of unactivated aryl bromides. Catalyst 309 turned out to be more efficient than 308 and 310, since the metal center of 309 possessed higher electron density than Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

that of 308 due to the presence of two methyl groups on the aromatic ligand in the former case. The higher activity of 309 compared to 310 was explained as 309 was less sterically encumbered. Of more interest to this review is that catalyst 309 was employed in a competitive experiment (exact conditions unspecified) in which a mixture of para-bromoiodobenzene, iodobenzene, para-iodotoluene and para-iodoanisole was reacted with methyl acrylate as the coupling partner in a molar ratio of 5:5:5:5:1 to furnish a linear Hammett correlation with s, with a positive reaction constant, 1 = 1.39, showing that electron-withdrawing substituents accelerate the coupling reactions. It was argued that the value of the reaction constant was too low to justify a nucleophilic aromatic substitution mechanism as the rate-limiting oxidative addition step. It was instead stated that the insertion of the alkene to the metal center might constitute the rate-limiting step. Later on, Liang and co-workers reported the pincer PdII complexes 311 and 312 (Figure 27) that were electronically different compared to 308–310, since 311 and 312 contain an anionic amido diphosphine ligand.[99] As for complexes 308– 310, complexes 311 and 312 also displayed thermal stability. The Heck reaction between iodobenzene and styrene catalyzed by 311 or 312 gave extraordinary high TONs of up to 4.5 107. Complex 311 (0.92 mm) was employed in a pair-wise competitive experiment in which a mixture of an activated, unactivated, and deactivated aryl bromide (92 mm of each) was reacted with styrene (0.516 m) as the coupling partner at 160 8C in NMP. The experiment furnished a linear Hammett correlation with a reaction constant of 1 = 0.60. The so-obtained reaction constant demonstrated that aryl bromides carrying electronwithdrawing substituents were the most reactive. However, the reaction constant was considered to be too small for the oxidative addition to constitute the rate-limiting step. Herrmann and co-workers investigated the mechanism of the Heck vinylation of arylbromides catalyzed by the phosphapalladacycle 313 (Figure 28) and [Pd(P(oTol)3)2] as the reference catalyst.[100] The study led to the conclusion Figure 28. The phosphapallathat the Heck reaction catalyzed dacycle 313 was exploited as by 313 proceeded without any a catalyst in the Heck reaction. PdIV intermediates. However, it was proposed that 313 was converted to a highly active anionic Pd0 species. The study included pair-wise competitive reactions where styrene (42) and n-butyl acrylate (314, 5 equiv of each) were reacted with differently substituted bromobenzenes (1 equiv) as coupling partners in the presence of either 2 mol % of 313 or [Pd(P(o-Tol)3)2] (Scheme 67). The study showed that both catalysts preferred 314 over 42. The study also demonstrated that the substituents on the bromobenzenes affected the product distribution and thus the aryl moiety affected the catalyst’s discrimination of the alkenes. This indicated that the insertion of the aryl bromide into the catalyst took place prior to the association of the alkene to the catalyst. The authors also presented a Hammett plot (log(product ratios) versus s),

13468


Review

Scheme 67. The pair-wise competitive Heck alkenylation of styrene (42) versus n-butyl acrylate (314) with different bromobenzenes 300, 285, and 287 as electrophiles and with 313 or [Pd(P(o-Tol)3)2] as pre-catalysts.

which was obtained from the pair-wise competitive reaction between bromobenzene (5.0 mmol, 285) and a substituted bromobenzene (5.0 mmol) with 314 (1.0 mmol) as the coupling partner. Both reactions using [Pd(P(o-Tol)3)2] (2 mol %) or 313 (2 mol %) as the pre-catalyst furnished a positive reaction constant of 1.01 and 1.58, respectively. The positive reaction constants showed that electron-withdrawing substituents on the aryl bromides accelerated the reactions. Additionally, the fact that the reactions catalyzed by 313 displayed a 1.6 times larger reaction constant than the ones with [Pd(P(o-Tol)3)2] indicated that the active species discriminating among the aryl bromides were not the same for the two catalysts. The palladacycle 320 (see structure in Scheme 68) turned out to be one of the most efficient pre-catalysts for the Heck alkenylation of aryl halides when it was reported in 2003.[101]

plot displayed a Hammett correlation with a positive reaction constant (1 = 2.7), showing that aryl bromides carrying electron-withdrawing substituents were the most reactive. The authors claimed that the obtained reaction constant strongly indicated that the oxidative addition of the aryl bromide to a catalytically active Pd0 species constituted the rate-limiting step. Also Norrby and co-workers exploited a Hammett study to investigate the relative reactivity in the cationic version of the Heck reaction.[6] In this study, the pair-wise competitive reaction of styrene (48 mmol) versus para-substituted styrenes (displaying a range of s-values between 0.87 to 0.54, 48 mmol) with phenyl triflate (192 mmol) as the coupling partner, using [Pd2(dba)3] (48 mmol) as the pre-catalyst in the presence of 1,3bis(diphenylphosphino)propane (96 mmol) was conducted. The so-obtained Hammett plot displayed a linear correlation, from electron-donating substituents and to the weakly electronwithdrawing para-chloro substituent, yielding a negative reaction constant, 1 = 0.53, indicating that the aryl ring served as an electron-source for the reaction center in the selectivity-determining step. However, when substituents possessing higher s-values than the para-chloro substituent were included in the plot the linear correlation collapsed, indicating that the selectivity-determining step is dependent on whether the styrene coupling partner included an electron-donating or electronwithdrawing substituent in the para-position. Thus, to clarify the non-linearity, the original Hammett plot was separated into two plots: one leading to the branched coupling-products and the second leading to the linear coupling-products. The Hammett plot leading to the branched coupling-products furnished a linear correlation throughout the investigated s-spectrum with a reaction constant (1) of 0.74. The obtained reaction constant indicated that positive charge developed on the benzylic position. The Hammett plot leading to the linear coupling-products on the other hand did not furnish a linear correlation, indicating that this reaction pathway was insensitive to the electronic properties of the substituent in the paraposition. 8.3 CH Alkenylations

Scheme 68. The competitive Heck reaction between different arylbromides and n-butyl acrylate (314) using Pd-complex 320 as a pre-catalyst.

The efficient couplings of aryl iodides and activated aryl bromides with n-butyl acrylate (314) took place at ambient temperature. The palladacycle 320 (10 mmol) was investigated in a competitive experiment in which a mixture of bromobenzene, para-bromoanisole, para-bromotoluene, 1-bromo-4-chlorobenzene, para-bromobenzonitrile, 1-(4-bromophenyl)ethanone, and 1-bromo-4-nitrobenzene (0.14 mmol of each) was reacted with 314 (0.2 mmol) as the coupling partner to furnish their respective coupling products in dimethylacetamide (DMA) at 150 8C in the presence of sodium acetate and tetrabutylammonium bromide (TBAB) (Scheme 68). The concentrations of the coupling products were recorded by GC, although the values were not reported directly in the publication, but were used to construct a Hammett plot (log(krel) versus s). The Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

[Pd(CH3CN)2Cl2] was found to be an effective pre-catalyst in the regioselective C-2 alkenylation of indoles and pyrrols carrying a N-(2-pyridyl)sulfonyl directing group.[102] The active catalyst was effective with a large variety of alkenes as coupling partners, such as conjugated electron-deficient alkenes, 1,3-dienes, and conjugated 1,1- and 1,2-disubstituted alkenes. The directing group was conveniently removed by using reductive desulfonylation to furnish the corresponding free-NH indoles and pyrroles. To acquire insight into the mechanism of these alkenylation reactions, a mixture of the N-protected indole (321, 0.1 mmol) and the more electron-deficient N-protected indole 322 (0.1 mmol) was subjected to a pair-wise competitive reaction with methyl acrylate (323, 0.1 mmol) as the coupling partner, using [Pd(CH3CN)2Cl2] (10 mol %) as the pre-catalyst in the presence of Cu(OAc)2·H2O (0.2 mmol) as the reoxidant in DMA (Scheme 69 a). The experiment gave the result that 324 and 325 was formed in a 2.3:1 ratio with the preference of 324

13469


Review

Scheme 69. The Pd-catalyzed pair-wise competitive alkenylation of a) indoles 321 and 322 and b) pyrrols 326 and 327, with methyl acrylate (323) as the electrophile and Cu(OAc)2 as terminal oxidant.

over 325, showing that the more nucleophilic substrate 321 was the most reactive. The electronic effect was even more pronounced in the pair-wise competitive experiment of 326 versus 327 using the same conditions as above (Scheme 69 b), in which the substituents were directly attached to the reactive heterocyclic ring as demonstrated by the fact that alkenylation products 328 and 329 were obtained in a 14.3:1 ratio. The sodiscovered strong effect due to the different electronic properties of the heterocyclic substrate indicated the participation of an electrophilic palladation pathway in the formation of the palladacycles intermediate present in the mechanism of the CH alkenylation. In the presence of N-protected amino acids as ligands, studies of the initial reaction rates demonstrated a significant rate enhancements in the aerobic PdII-mediated alkenylation of phenylacetic acids compared to the case without these ligands.[103] The studies included a pair-wise competitive reaction in which a mixture of 2-(trifluoromethyl)phenylacetic acid (330) and 2-(methyl)phenylacetic acid (331, 0.25 mmol of each) was reacted with ethyl acrylate (332, 1.0 mmol) as a coupling partner and [Pd(OAc)2] (0.025 mmol) as the pre-catalyst, in the presence of 0.05 mmol of Boc-Val-OH or Ac-Ile-OH or without ligand, respectively, using O2 as the terminal oxidant, to furnish the alkenylation products 333 and 334, respectively (Scheme 70). In the absence of ligand the electron-rich substrate 331, reacted approximately five times faster (k330 :k331 = 0.22:1) than the electron-deficient substrate 330. The addition of Boc-Val-OH to the reaction mixture also furnished the pref-

erential reactivity of 331 over 330 (k330 :k331 = 0.58:1), though to a lesser extent than having no ligand present. Remarkably, the reactivity order was the opposite in the presence of Ac-Ile-OH, since substrate 330 reacted the fastest (k330 :k331 = 1.87:1). [{Ru(p-cymene)Cl2}2] was exploited as a pre-catalyst in the coupling reactions of benzamides with alkynes to furnish the corresponding ortho-alkenylated products in high regio- and stereoselectivity.[104] The same catalyst was employed in the coupling between phenylpyrazoles and alkynes to selectively furnish the corresponding dialkenylated products. Acetic acid was present in the reaction mixture as a promoter. The pairwise competitive coupling of the para-methyl substituted N,Ndimethylbenzamide 335 versus the para-chloro substituted counterpart 336 (each 0.125 mmol) with diphenylacetylene (215 a, 0.5 mmol) as the coupling partner, using [{Ru(p-cymene)Cl2}2] (0.0125 mmol) as the pre-catalyst in the presence of acetic acid (1 mmol) and AgSbF6 (0.05 mmol) displayed a tiny preference for substrate 335, based on measured product selectivities as 337 and 338 was obtained in a 54:46 ratio, respectively (Scheme 71 a). Based on the combination of kinetic

Scheme 71. The pair-wise competitive Ru-catalyzed alkenylation of a) N,N-dimethylbenzamides 335 and 336 and b) phenylpyrazoles 339 and 340, with diphenylacetylene (215 a) as coupling partner.

isotope effect studies and the very similar reactivities of the two substrates, it was proposed that the cleavage of the CH bond took place through an acetate-assisted deprotonation. Another competitive experiment between methylsubstituted phenylpyrazole 339 (0.125 mmol) and chloro-substituted phenylpyrazole 340 (0.125 mmol) with diphenylacetylene (215 a, 0.5 mmol) as the coupling partner, using [{Ru(p-cymene)Cl2}2] (0.0125 mmol) as the pre-catalyst in the presence of acetic acid (1 mmol) and AgSbF6 (0.05 mmol) was conducted. It resulted in a higher effect on the substrate selectivity due to the substituents compared to Scheme 70. The Pd/(amino acid)-catalyzed pair-wise competitive CH alkenylation reacthe benzamide case above (Scheme 71 b), based on tion of arene 330 versus 331 with 332 as coupling partner. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

13470


Review determined product selectivities; dialkenylated products 341 and 342 were obtained in a 64:36 ratio. According to the authors, this result indicated that the cleavage of the CH bond occurred by means of an electrophilic aromatic substitution (SEAr)-like mechanism. [{Ru(p-cymene)Cl2}2] was also exploited as a pre-catalyst in the oxidative C(sp2)H alkenylation of aryl carbamates[105] and aromatic esters[106] with alkenyl-substituted esters in the presence of Cu(OAc)2·H2O as the terminal oxidant and AgSbF6 as promoter. The so-formed active cationic catalyst displayed chemoselectivity and site selectivity in parallel with tolerance for a broad spectrum of substituents on the substrates. The two pair-wise competitive alkenylations of two different aromatic esters, 343 (1.50 mmol) versus 98 (1.50 mmol) or 344 (1.50 mmol) in dichloroethene (DCE) with ethyl acrylate as the electrophile (1.00 mmol) in the presence of Cu(OAc)2·H2O (1.00 mmol) as terminal oxidant, and [{Ru(p-cymene)Cl2}2] (5 mol %) as pre-catalysts in the presence of AgSbF6 (41 mol %) demonstrated a higher reactivity for the electron-rich substrates (Scheme 72 a,b) based on measured product selectivi-

Scheme 72. The pair-wise competitive oxidative CH alkenylation of aromatic esters 98, 343 and 344 (a and b) and aryl carbamates 345 and 346 (c), employing pre-catalyst [{Ru(p-cymene)Cl2}2], ethyl acrylate as the coupling partner and Cu(OAc)2 as the terminal oxidant.

ties. Using two aryl carbamates 345 (1.00 mmol) versus 346 (1.00 mmol) in dimethoxy ethane (DME) with ethyl acrylate (0.50 mmol) as the electrophile in the presence of Cu(OAc)2·H2O (1.00 mmol), AgSbF6 (10 mol %) and [{Ru(p-cymene)Cl2}2] (2.5 mol %) yielded essentially the same results as above (Scheme 72 c) based on measured product selectivities. [{Ru(p-cymene)Cl2}2] also acted as a pre-catalyst in the hydroxyl-assisted oxidative annelations of internal symmetrical and unsymmetrical alkynes by a-naphthols, 4-hydroxycoumarin and 4-hydroxy-1-methylquinolin-2(1 H)-one, respectively, in the presence of Cu(OAc)2·H2O as the terminal oxidant.[107] Interestingly, the annelation of unsymmetrical alkynes by a-naphthols occurred in excellent regioselectivities and high yields. Most essential, however, for this review, the pair-wise competitive experiments between alkenyls 215 a (1.00 mmol) and 352 (1.00 mmol) for the annelation of a-naphthol (0.50 mmol) in Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

the presence of Cu(OAc)2·H2O (1.00 mmol) as the terminal oxidant and [{Ru(p-cymene)Cl2}2] (2 mol %) as the pre-catalyst (Scheme 73), revealed that the catalyst exhibited the highest activity for the alkynes with a moderate electron-withdrawing aromatic rings attached next to the triple bond, alkyne 215 a, based on determined product selectivity.

Scheme 73. The pair-wise competitive hydroxyl-assisted oxidative annelation of internal alkynes 215 a versus 352 with naftol 353 as the coupling partner, with [{Ru(p-cymene)Cl2}2] as pre-catalyst and Cu(OAc)2 as the terminal oxidant.

8.4 CH Arylations Fagnou and co-workers described the Pd-catalyzed direct arylation reaction of electron-deficient perfluoroarenes with various aryl halides as the coupling partner using [Pd(OAc)2] as pre-catalyst in the presence of PtBu2MeHBF4 and K2CO3.[108] Computational studies demonstrated that the CH functionalization step took place through a concerted metalation–deprotonation (CMD) mechanism. The relative reactivity of the different perfluorobenzenes was investigated by pair-wise competitive experiments in which a 1:1-mixture of two perfluorobenzenes was treated with para-bromotoluene as the coupling partner under Pd catalysis. These experiments led to two conclusions: 1) the relative rate of arylation of two competing species parallels their relative acidities—hence, the presence of a fluorine substituent remote to the CH bond being transformed to a Caryl bond increased the reactivity—and 2) for substrates including two distinct CH bonds, direct arylation took place on the most acidic CH bond. A study performed on the Pd-catalyzed direct arylations of a wide range of (hetero)arenes led to the conclusion that the involvement of a CMD mechanism for the CH cleavage may be much more common than originally thought.[109] The study involved a pair-wise competitive experiment in which a mixture of benzothiophene (356) and 3-fluorobenzothiophene (357, 0.35 mmol of each) was subjected to the Pd-catalyzed arylation with ethyl para-bromobenzoate (358, 0.07 mmol) as the coupling partner using [Pd(OAc)2] (0.035 mmol) as the pre-catalyst in the presence of PCy3HBF4 (0.070 mmol) and pivalic acid (0.21 mmol) in DMA (Scheme 74). The relative reactivity was

Scheme 74. The Pd-catalyzed pair-wise competitive direct arylation of benzothiophenes 356 versus 357 with ethyl 4-bromobenzoate (358) as the coupling partner.

13471


Review evaluated as the relative product formation. After 2 h GC-MS revealed the formation of 359 and 360 in a 1: > 20 ratio in the preference of 360. The outcome of the experiment was not in line with the expectation for SEAr reactivity, since this reaction pathway would furnish a higher reactivity of the more electron-rich substrate. In fact, a pair-wise competitive Friedel– Crafts acylation of 356 versus 357 revealed a four times higher reactivity of 356 compared to 357. However, a CMD mechanism fitted the result, since the calculated free energy of activation for the CMD pathway to the CH was 15 % smaller for compound 357 compared to 356. In cases in which normally low reactivities are observed for the Pd-catalyzed direct arylation of heterocyclic compounds with various aryl halides, Ligault and co-workers demonstrated that the introduction of a carbon–chlorine bond in the heterocyclic compounds can implement enhanced reactivity.[110] This conclusion was based on the following pair-wise competitive reaction: a mixture of 2-methylthiophene (361) and 2chlorothiophene (362, 0.5 equiv of each) was subjected to the Pd-catalyzed direct arylation using [Pd(OAc)2] (2 mol %) as the pre-catalyst with ortho-bromotoluene (363, 0.2 equiv) as the coupling partner in the presence of pivalic acid (30 mol %) and PCy3HBF4 (4 mol %) and K2CO3 (1.5 equiv). The experiment demonstrated that the reaction preferentially took place on the more electron-deficient thiophene 362 based on product analysis, as 364 and 366 were obtained in a 1:11 ratio (Scheme 75 a). The effect of the chlorine-substituent was also

Scheme 75. The Pd-catalyzed pair-wise competitive direct arylations of a) thiophenes 361 and 362 and b) indoles 367 and 368 with aryl bromides 363 and 282, respectively, as coupling partner.

investigated for indoles. Thus, in a pair-wise competitive experiment a mixture of 1-methyl-1H-indole (0.5 mmol, 367) and 2-chloro-methyl-1H-indole (0.5 mmol, 368) was direct arylated with para-bromotoluene (282, 1 equiv) as the coupling partner using [Pd(OAc)2] (2 mol %) as the pre-catalyst in the presence of pivalic acid (30 mol %), PCy3HBF4 (4 mol %) and K2CO3 (1.5 equiv, Scheme 75 b). Remarkably, in spite of the site of arylation being switched from C2 to C3 for the chlorinated substrate 368, based on product analysis this substrate displayed only 1.6 times higher reactivity than the competing non-chlorinated substrate 367, which exclusively underwent arylation in the 2-position to furnish 369. Campeau and co-workers reported a detailed mechanistic investigation of the Pd-catalyzed direct arylation of pyridine NChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

oxides using an aryl bromide as the coupling partner.[111] The investigation included both experimental studies and DFT calculations. The two investigations led to the conclusion that the arylation of pyridine N-oxides followed an inner-sphere CMD pathway. The experimental study included also competitive experiments in which pyridine N-oxides 371–375 (1.22 mmol of each) underwent a pair-wise competitive Pd-catalyzed direct arylation using [Pd(OAc)2] (0.015 mmol) as the pre-catalyst and para-bromotoluene (282, 0.300 mmol) as the coupling partner in the presence of PtBu3HBF4 (0.018 mmol) and K2CO3 (0.39 mmol) to furnish the corresponding C-2 arylated products (Figure 29). Each separate single-substrate experiment demon-

Figure 29. The relative reactivities obtained computationally and experimentally for the pair-wise competitive Pd-catalyzed direct C2-arylation of pyridine-N-oxides possessing various electronic environments.

strated that para-bromotoluene coupled preferentially with the most electron-deficient heterocycle (the relative reactivities were based on the product ratios). The higher reactivity of 375 carrying a methoxy group in the 4-position compared to 374 having a methyl group in the corresponding position was due to the s-withdrawing effect of the methoxy group affecting the 2-position. Interestingly, the DFT calculations of the relative reactivities under an inner-sphere CMD mechanism was in agreement with those results obtained experimentally (Figure 29). Lapointe and co-workers showed that the site-selective direct arylation of heterocycles containing chemically distinct CH bonds could be achieved.[112] The relative preferential reactivity of the CH bonds within the investigated heterocycles could be tuned using different catalytic systems. More interestingly, however, with the focus on this review, was the establishment of a reactivity chart for the Pd-catalyzed direct arylation of electron-rich heterocycles. This chart was created by performing pair-wise competitive experiments in which a mixture of two heterocycles (356 and 376–382, 0.30 mmol of each) was directly arylated using 1-bromo-4-(trifluoromethyl)benzene (299, 0.075 mmol) as the coupling partner and [Pd(OAc)2] (0.030 mmol) as the pre-catalyst in the presence of pivalic acid (0.18 mmol), PCy3HBF4 (0.060 mmol), and K2CO3 (0.90 mmol) in DMA (Scheme 76). The relative reactivities of the heterocycles were based on the product distribution obtained from 19F NMR spectroscopy of the crude reaction mixture. Moreover, the experimental product ratios were compared with the theoretically ones obtained from DFT calculations of the difference in free energy of activation (DDG ¼6 ) for the CMD pathway of the two reactants going to products. Comparison of the theoretical and experimental results dem-

13472


Review

Scheme 76. The pair-wise competitive Pd-catalyzed direct arylation of heterocycles 356 and each of 376–382 using 1-bromo-4-(trifluoromethyl)benzene (299) as coupling partner.

onstrated that they were very similar and, for example, both the experimental and theoretical method identified imidazopyrimidine 376 and thiazole 377 as the most reactive substrates based on product distribution, and that benzothiophene (356), 2-propylthiophene (382) and 2-formylfuran (381) were the least reactive ones. Gevorgyan and co-workers exploited [PdCl2(PPh3)2] as the pre-catalyst in a protocol for the site-selective direct arylations of indolizines in the 3-position.[113] The reactions proceeded smoothly with various kinds of substituents in the 2-position of the indolizines. It was noted that the direct arylation reactions proceeded efficiently, even in those cases in which electron-rich aryl bromides were used as the coupling partner. Experimental and computational data strongly supported that the direct arylation took place via a SEAr-pathway. Hence, it was expected that an electron-withdrawing group in the 2-position of the indolizine would impede the reaction, whereas an electron-donating group would accelerate the reaction. This hypothesis was investigated in a competitive experiment in which a 1:1:1-mixure of indolizine (383), 2-methylindolizine (379), and 2-carboethoxyindolizine (384) was subjected to direct arylation with para-nitrobromobenzene (385) as the coupling partner in the presence of [PdCl2(PPh3)2] as the pre-catalyst together with potassium acetate and water in NMP (exact conditions unspecified, Scheme 77). The relative rates of aryla-

Scheme 77. The Pd-catalyzed competitive direct arylation of indolizines (379, 383, and 384) using para-bromonitrobenzene (385) as electrophile. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

tions of 383/379/384 were found to be 1.00:0.97:0.66. In line with expectations for a SEAr-pathway, substrate 384 carrying an electron-withdrawing substituent underwent the slowest direct arylation. However, substrate 379 reacted slightly slower than substrate 383. Thus, it was assumed that the methyl group of 379 exercised sterical hindrance and thus hampered the reaction compared to 383. The SEAr-pathway for the competitive Pd-catalyzed direct arylation of indolizines was supported by the competitive Friedel–Crafts acylation above of a mixture of 383, 379, and 384, since this experiment displayed the same reactivity trend as for the direct arylation reaction. Later on, Gevorgyan and co-workers also used [PdCl2(PPh3)2] as a highly efficient pre-catalyst for the direct arylation of 1,4disubstituted 1,2,3-triazoles in the 5-position. Moreover, the same catalyst was successfully employed for the direct arylation of N-monosubstituted 1,2,3-azoles in the 5-position.[114] The use of experimental investigations and DFT calculations gave strong support for that this direct arylation takes place through a SEAr-pathway. One of the experimental studies constituted two pair-wise competitive studies, in which triazole 386 was direct arylated in presence of triazoles 387 and 388 (0.1 mmol of each), respectively, using bromobenzene (285, 0.3 mmol) as the coupling partner and [PdCl2(PPh3)2] (0.010 mmol) as the pre-catalyst (Scheme 78). The observed

Scheme 78. The Pd-catalyzed pair-wise competitive direct C5-arylation of triazoles 386–388 using bromobenzene (285) as electrophile.

highest reactivity of the comparable most electron-rich triazole 387 constituted an evidence for a SEAr-pathway. DeBoef and co-workers reported a study in which the effects of oxidants, such as H4Mo11VO40 (HPMV), AgOAc, Cu(OAc)2, and organic acids, were studied in the Pd-catalyzed oxidative coupling between benzofuran and both substituted and unsubstituted benzenes.[115] The study demonstrated that the coupling between benzene and benzofuran (389) using AgOAc as the oxidant together with [Pd(OAc)2] as the pre-catalyst furnished a small preference of up to 1.8:1 for the coupling in the 2-position over the coupling in the 3-position of benzofuran. The ratios of the coupling products were, however, slightly dependent on the identity and concentration of the organic acid. Using HPMV as the oxidant under Pd catalysis furnished almost exclusively coupling in the 2-position of 389. Based on experi13473


Review mental studies, it was assumed that the reactions oxidized by AgOAc proceeded by a PdII/Pd0 pathway. For HPMV on the other hand, it was proposed that the reaction pathway included PdIV intermediates. One of the investigations included a series of pair-wise competitive experiments in which a mixture of para-xylene and para-methoxyanisole (390, 14.9 mmol of each) or benzene and pentafluorobenzene (391, 14.9 mmol of each) was reacted with benzofuran (389, 0.423 mmol) as coupling partner using [Pd(OAc)2] (0.042 mmol) as a pre-catalyst in the presence of either HPMV (0.085 mmol, Scheme 79 a) Scheme 80. The Pd-catalyzed pair-wise competitive coupling of phenyl siloxanes (397 and 398) with the organic carbonate (396) as electrophile.

1.42 mmol of each) was reacted with 396 (0.712 mmol) as the coupling partner and [Pd(dba)3] (0.0712 mmol) as the pre-catalyst in the presence of TBAF (2.85 mmol) (Scheme 80). The competitive experiments demonstrated that phenyl siloxanes carrying an electron-withdrawing para-substituent were the most reactive. Additionally, the reaction displayed a positive reaction constant (1 = 1.4), indicating that a negative charge was developed in the benzene ring in the transition state of the reaction. The fact that the Hammett plot did not display a nonzero slope demonstrated that either the transmetalation or reductive elimination steps constituted the rate-limiting step, but not the oxidative addition, since this step does not involve the arene containing the substituent marking for Hammett correlation. However, based on several circumstantial evidences the authors pointed out the transmetalation step to be the rate-limiting one.

Scheme 79. The Pd-catalyzed pair-wise competitive oxidative coupling between various benzenes using benzofuran (389) as the coupling partner in the presence of different oxidation reagents.

or AgOAc (1.27 mmol, Scheme 79 b). In the case of HPMV as the oxidant, the reactions were performed under 3 atm of O2 as a terminal oxidant. As outlined in Scheme 79 a and b, all the oxidation reagents gave a preferential reactivity of 390 over para-xylene, as determined from product selectivities. In the competitive coupling reaction between benzene and the significantly more electron-deficient substrate 391 under the same reaction conditions, the oxidation reagents yielded opposite discriminations; HPMV implemented a higher reactivity of benzene (Scheme 79 c), whereas AgOAc favored the coupling between 391 and 389 (Scheme 79 d), as determined from product selectivities. The obtained results using AgOAc were consistent with a CMD palladation mechanism. In contrast, the reversed selectivity in the presence of HPMV indicated a different reaction mechanism. 8.5 Allyl–aryl couplings DeSong and co-workers performed a Hammett analysis of the Pd-catalyzed coupling between ethyl 2-cyclohexenylcarbonate (396) and para-substituted phenyl siloxanes.[116] A linear Hammett correlation (log(krel) versus s) was obtained from a series of pair-wise competitive experiments in which a mixture of triethoxy(phenyl)silane (397) and 398 (R = OMe, Me, Cl, CO2Et, Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

8.6 Pd-catalyzed intramolecular cyclizations Kaneda and co-workers encountered substrate-selective catalysis in their work involving intramolecular cyclization of g-acetylenic acids using dendrimer-encapsulated Pd2 + catalysts.[117] In their work, a cooperative effect between Pd2 + species and the confined nanocavity of the poly(propylene imine) (PPI) dendrimers on the intramolecular cyclization of acetylenic acids was found. Investigating different generations of dendrimers encapsulating Pd2 + as catalyst in the cyclization reaction, fifthgeneration dendrimers (G5-Pd2 + 8, as denoted by the authors) were found to be the most efficient. From the point of interest of this review, an intermolecular competitive reaction between g-acetylenic acid (0.1 mmol, 399) and d-acetylenic acid (0.1 mmol, 400) by using G5-Pd2 + 8 (1 mmol) as catalyst resulted in the quantitative conversion of 399 based on the observed product selectivity; only 401 was formed and no 402 was formed. In a control experiment, in which a PdCl2/(PhCN)2/ triethylamine(TEA) system was used instead of G5-Pd2 + 8, a mixture of 401 and 402 was formed (Scheme 81). The authors explained that the observed substrate selectivity (determined as product selectivity) was due to the sterical constraints offered by the nanocavity of G5-Pd2 + 8.

13474


Review

Scheme 81. The palladium-catalyzed intermolecular competitive cyclization of g-acetylenic acid (399) and d-acetylenic acid (400) using either G5-Pd2 + 8 or a PdCl2(PhCN)2/triethylamine(TEA) system.

9. Transaminations Breslow and co-workers have in a succession of papers reported a series of artificial coenzymes that mimicked the enzymatic transamination reaction, in which amino acids are synthesized from a-ketoacids, through the simultaneous conversion of pyridoxamine phosphate (403) to pyridoxal phosphate (404) (Scheme 82).[118] Natural enzymes are both catalytic and sub-

Figure 30. Transaminase coenzyme mimics: 405 pyridoxamine attached to primary b-cyclodextrin rim, 406 pyridoxamine, 413 pyridoxamine attached to the secondary b-cyclodextrin rim, 414 pyridoxamine attached to synthetic macrocycle, substrates; 407 pyruvic acid, 408 phenylpyruvic acid, 409 indolylpyruvic acid.

Scheme 83. The pair-wise competitive transamination reactions involving substrates 407, 408 and 409 promoted by coenzyme mimics 406 and 405.

Scheme 82. The substrate-selective step in the catalytic transamination of aketoacids is promoted by the coemzyme pyridoxamine phosphate (403).

strate-selective. However, this does not necessarily imply that the regeneration of 403 from 404 and the substrate-selective reaction occur in the same catalytic cycle. In enzymatic transaminations, it is the pyridoxamine phosphate coenzyme 403 located within the catalytic cavity of the transaminase that generates the substrate selectivity by reacting with an a-ketoacid, producing pyridoxamine phosphate (Scheme 82). The pyridoxamine phosphate is then regenerated in another cycle, closing the catalytic cycle. Initially, in an effort to introduce substrate selectivity for aketoacids that could bind into models of enzyme cavities, pyridoxamine was attached to a cyclodextrin moiety. The first example of such a compound was produced by attaching pyridoxamine to the primary face of the native b-cyclodextrin through a thioether linkage, leading to compound 405 (Figure 30).[118a] To investigate whether 405 exhibited substrate seChem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

lectivity in a typical transamination reaction, the promoting activity of 405 was compared with the one of pyridoxamine itself (406, Figure 30) as well as the promoting activity of 406 together with one equivalent (0.05–5 mm) of b-cyclodextrin in the reductive amination of three a-ketoacids as substrates, pyruvic acid (407), phenylpyruvic acid (408), and 3-indolylpyruvic acid (409). The reactions were conducted at pH 8, in a phosphate-buffered (4.0 m) water–ethanol environment either in separate single-substrate reactions or in pair-wise competition (Scheme 83). In the separate single-substrate experiments, it was noted that in the presence of 406 as promoter all three substrates exhibited the same transamination rate. When b-cyclodextrin was present along with 406, the rate of transamination of 407 was unchanged, while the rate of transamination of the other two substrates was somewhat retarded compared with when 406 was used as promoter. In the presence of 405, there was a substantial increase in the rate of transamination of the aromatic substrates 408 and 409. In the pair-wise competitive experiments (exact conditions not specified) one could observe an increase in the relative transamination rate of the aromatic substrates 408 and 409 over aliphatic 407 in the presence of 405 with a factor of 200, agreeing well with the known preference of b-cyclodextrin for aromatic guests.[75a] It could be concluded that 405 both increased the rate of the re-

13475


Review action and exhibited selectivity towards the amination of 408 and 409 over 407 compared to 406. In addition, due to the enantiomerically pure b-cyclodextrin moiety, a non-negligible amount of chiral induction was observed during the amination of indolylpyruvic acid as a 2:1 ratio between the l- and denantiomer of tryptophan (412) was observed. Pyridoxamine was attached to the secondary rim of b-cyclodextrin to obtain 413 (Figure 30). The transaminating ability of 413 was investigated in the same manner as for 405,[118b] revealing similar substrate selectivities. Interestingly the observed chiral induction was the opposite of that observed for 405, with 409 as substrate when 413 was used as promoter. Compound 413 showed a 1.8:1 preference for the d-enantiomer of 412 compared with the 2:1 preference for the l-enantiomer observed with 405 as promoter. To investigate if the coenzyme mimics based on pyridoxamine would function with a more general binding group, pyridoxamine was attached to a synthetic macrocycle with a hydrophobic cavity (414, Figure 30).[118c] The enzyme model promoted similar substrate selectivities during the competitive transaminations as cyclodextrins 405 and 413; however, as 414 is achiral, no chiral induction was observed in the products. It was concluded from the experiments with 405, 413, and 414 as promoters of competitive transaminations that the initial non-covalent binding force between the modified pyridoxamine and the substrate was hydrophobic in nature. In later investigations, Breslow and co-workers improved the rate of the transamination reaction by binding covalently the pyridoxamine unit in the 5-position to flexible chains containing an amino group at the end (415) (Figure 31),[118d, 119] and in this

Figure 31. Pyridoxamine units with basic side-chains. The rate of transamination increased by mounting basic side chains on the pyridoxamine promoter.

way promoting the proton transfer required in the transamination reaction. When the basic amino group was enantiomerically pure as in promoter 416 (Figure 31), the optical activity of the product amino acid was improved compared to the cyclodextrin attached promoters 405 and 413. Further on, in a quest to construct macromolecular transaminase mimics, Breslow and co-workers experimented with polymeric and dendrimeric structures.[120] Hence, polymer 417 (Figure 32) was constructed by covalently attaching pyridoxamine to alkylated polyethyleneimine (PEI) to simulate the hydrophobic environment within an enzyme. Kinetic studies conducted with 417 as a promoter Figure 32. Pyridoxamine atin various buffered solutions totached to PEI. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

gether with substrate 407 showed an increase in reaction rate by factor 6700–8300 at pH 5, compared to 406. In contrast, at higher pH, the rate enhancement decreased, indicating that the basic groups of the polymer were involved in proton transfer of the transamination process itself instead of the various buffers used. The length of the alkyl group attached to the pyridoxamine–PEI polymer seemed to influence the rate enhancement, with the rates increasing with the increase in chain lengths. The increases in rate were attributed to both the ability of the chains to modify the pKa of the protonated amino groups in 417 and to their ability to create a cavity in which the transamination could occur in a less aqueous environment. Alkylation of the pyridoxamine–PEI polymer with dodecyl (417, R = C12H25) resulted in a catalytic system that exhibited a rate enhancement for substrates 407 (increased a factor 5) and 408 (increased a factor 7.5), compared to the unalkylated–PEI polymer, as determined by separate single-substrate experiments. Interestingly, substrate 408 showed a tenfold increase in reactivity over 407 based on the product analysis. The observed selectivity was thought to arise from the nonpolar interaction between the phenyl group of substrate 408 and the dodecyl groups of 417. Two pair-wise competitive experiments were run with 408/407/417, R = C12H25 (20:20:1) and 409/407/417, R = C12H25 (20:20:1) at 28 8C and pH 7.5 for 1 h (Scheme 84). The result for the substrate selectivity of 417 as

Scheme 84. The pair-wise competitive transamination reactions involving substrates 407, 408, and 409 promoted by the coenzyme and pyridoxamine mimic 413.

catalyst was based on the product ratio from each competitive reaction and was found to be 8.5:1 (411/410) and 20:1 (412/ 410), respectively. Hence it was argued that the dodecylated– PEI increased the reaction rate of the transamination for the less polar substrates 408 and 409 by a preferential hydrophobic interaction to the less polar substrate. Later, Breslow and co-workers experimented with the attachment of pyridoxamine to PEI in a non-covalent fashion in an attempt to mimic the binding of the pyridoxamine cofactor in real transaminases.[121] This non-covalent polymer–pyridoxamine system consisted of two components (Figure 33). One component, 418, was supposed to mimic the environment of the holoenzyme and was achieved by using a fully methylated PEI polymer that contained some lauryl groups. The other component, the pyridoxamine cofactor, was modified so that it carried a hydrophobic side chain as a binding group, making it possible to bind to 418 by hydrophobic interactions. This binding group was varied during the course of the study. The best

13476


Review

Figure 33. Non-covalent transamination mimics. Pyridoxamines 419 and 416 non-covalently bound to PEI. Scheme 86. The regeneration of pyridoxamine 419 from pyridoxaldehyde 421 using amino acid 422 as a sacrificial reagent.

rates for the transamination were recorded with two C10 side chains or an alkyl-tethered steroid side chain as the hydrophobic binding group attached to the pyridoxamine unit, compounds 419 and 420, respectively. Two pair-wise competitive experiments were executed using 408/407/419 (30:30:1) and 409/407/419 (30:30:1) at 20 8C, pH 7.5 in the presence of methylated PEI with 8.7 % laurylation (418, 25 mm). The ratios of the formed amino acids were found to be (14 2):1 (411/410) and (29 1):1 (412/410), respectively (Scheme 85), and were taken as a measure of substrate selectivity. These values were slightly higher than those reported using pyridoxamine covalently attached to PEI as promoters for the transaminations (vide supra).

(P4VIm, Scheme 87). In single-substrate experiments, P4VIm was used, along with a stoichiometric amount of 406 to promote the transamination of 407 to 410 in water at pH 7.5 and

Scheme 87. The preparation of P4VIm and partially dodecylated P4 VIm.

Scheme 85. The pair-wise competitive transamination reaction involving substrates 407, 408, and 409 promoted by PEI 418 and coenzyme and pyridoxamine mimic 419.

Until this point the mimics of transaminations had consumed the coenzyme pyridoxamine in the making of pyridoxal. In order to develop real transamination mimics, the transformation of pyridoxal back to pyridoxamine had to be solved. All the preceding studies had focused on the first step of the transamination, namely the substrate selective reaction of an a-ketoacid with pyridoxamine and thus one equivalent of the pyridoxamine was required to transaminate the a-ketoacid (Scheme 82). To address the catalytic artificial transamination, a method had to be devised to regenerate pyridoxamine. Breslow found a solution by treating aldehyde (421) formed during the transamination of 419 with 2-amino-2-phenylpropionic acid (422), resulting in an oxidative decarboxylation, yielding pyridoxamine, aldehyde, and carbon dioxide. This in turn regenerated 419 allowing for a full transamination to proceed (see Scheme 86) with multiple turnovers (TON = 81) using a catalytic amount of 419 and partially dodecylated PEI.[121, 122] In a more recent work, Breslow and colleagues attached pyridoxamine 406 and its alkylated derivative 419 to polyvinylimidazoles using hydrophobic interactions.[123] The polyvinylamidazoles were formed by the polymerization of 4-vinylimidazole Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

20 8C. The rate of the transamination showed a 100-fold increase compared to the reaction in which 406 was employed without promoter. Single-substrate experiment studies were also conducted using 419 as a stoichiometric cofactor in the presence of P4VIm, at pH 7.5 and 20 8C. The rate of the transamination of 407 showed a 121404-fold increase in rate compared to the reaction without promoter. Partially dodecylated P4VIm led to decreased rates in the transamination of 407 using 419 as promoter. In contrast, P4VIm was more effective as promoter in the transamination of phenyl pyruvic acid (408), whereby the reaction was too rapid to follow by the method used. To determine the true substrate selectivity of the system of alkylated pyridoxamine (419)/P4VIm in the transamination reactions, pair-wise competitive studies were performed using the substrate mixture 408/407/419 (30:30:1) at pH 7.5 and 20 8C in the presence of P4VIm (1.5 g L1) as promoter (Scheme 88 a). The substrate selectivity was determined as product selectivity; a product ratio of 3:1 (411/410) was observed. When instead a P4VIm polymer that was 4.5 % dodecylated was used in an analogous competitive selectivity study, this ratio was increased to (19 1):1 (Scheme 88 b). Using 409 instead of 408 as substrate and P4VIm polymer that was 4.5 % dodecylated, the observed ratio was even higher; however, the authors did not specify the exact ratio (Scheme 88 c). It was argued that in both cases, the more hydrophobic substrates 408 and 409 were reacting faster than 407 , as determined by product selectivities, due to the active site (the pyridoxamine moiety of 419) being present in a more hydrophobic environment offered by the P4 VIm polymer.

13477


Review

Scheme 88. The pair-wise competitive transamination reactions involving substrates 407, 408, and 409 promoted by P4VIm and coenzyme and pyridoxamine mimic 419.

10. Industrial applications of substrateselective catalysis There are only a few but important processes in the industry that utilize substrate-selective catalysis to obtain commercially interesting products. To the best of our knowledge industrial applications of substrate-selective catalysis have been limited to the use of zeolites. Zeolites are crystalline aluminosilicates with open channels of molecular dimensions that have cations trapped inside their framework.[124] These properties make the zeolites shape-selective catalysts. The shape of the channels found within the zeolites governs the outcome of the catalytic reaction. This does not necessarily imply that a shape-selective catalyst is substrate selective, although it does not exclude the possibility either. The single most important industrial process incorporating shape-selective catalysis in a substrate-selective manner is the steam cracking of hydrocarbons to produce short olefins. Here, shape-selective zeolite catalysts have been used for several decades after the pioneering work of Weisz in the 1960s and 1970s.[125] There are several reviews covering the subject of shape-selective catalysis by zeolites until 2011 and the more recent developments regarding zeolites have been concerned with increasing their overall efficiency as catalysts rather than improved substrate selectivity.[126] In oil cracking, long hydrocarbon chains are heated in presence of a catalyst to give shorter aliphatic chains. In shape-selective steam cracking of hydrocarbons, the intracrystalline space in the zeolites, where the cracking takes place, is of similar dimensions to linear hydrocarbons, working as a size-exclusion filter, keeping highly branched hydrocarbons away from the catalytic site (Figure 34). When the hydrocarbon chain is inside this intra-

Figure 34. A conceptual illustration of the substrate selectivity in the steam cracking of alkanes. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

crystalline space, the acidic properties of the zeolite catalyst enable the breaking of CC bonds. The limited space of the cavity hinders the formation of transition states leading to branched hydrocarbons. This results in the formation of only the linear fragments. Another application of shape-selective catalysis that has shown to be substrate selective is in hydrogenations. A platinum-enriched zeolite catalyst was developed that only acted on ethylene in a 1:1 mixture with propylene in the production of ethane. Here, the zeolite operates by restricting the formation of propane rather than hindering the access of propylene. The intracrystalline channels of the zeolite offer adequate space for the mobility of ethylene, propylene, hydrogen and ethane, but not for propane and hence propylene is not consumed in the reaction.[127] In the production of 1-butene (used as a copolymer), a calcium-containing zeolite has been used to selectively dehydrate n-butanol to 1-butene in mixtures with isobutanol without dehydrating the latter.[128] Here, the shape of the zeolite restricts the access of the isobutanol to the active site of calcium, where the dehydration occurs, resulting in the dehydration of the less branched n-butanol.

Summary and Outlook Searching the chemical literature for articles related to substrate-selective catalysis has revealed a fair amount of ways a catalytic system becomes substrate selective. In the reactions discussed above, it is observed that the mode of discrimination between substrates varies considerably between different catalytic systems: we have found systems discriminating substrates based on size, shape, hydrogen bonding, electronic environment, and polarity. Likewise, the catalytic systems differ considerably in how they are selective: some catalysts are organometallic and rely on different ligands for introducing selectivity into the system, owing their substrate discrimination to the difference in their steric interactions with different substrates. Other catalysts rely on a separate substrate-binding moiety, a receptor unit, attached to the catalytic part of the system, forming a catalytic cavity. This last approach is a common feature of homogeneous artificial enzyme mimics. Another function of the attached receptor unit is to simply protect the catalyst from degrading.[129] These approaches are of course appealing from a designer’s point of view, whereas the heterogeneous case, in which the specific design of the cavity is more difficult, is in fact more successful in obtaining high substrate selectivities. Yet another mode of discrimination is found in, for example, organometallic coupling reactions in which the transition-metal catalyst is sensitive to the electronic effects of the substituents attached at both coupling partners, giving rise to different rates for different substituents of for instance the oxidative addition and transmetalation step, resulting in substrate selectivity. Impressively almost all the important reaction types of organic chemistry and organometallic chemistry are represented in substrate-selective catalysis; however, only the heterogeneous catalysts show very high substrate selectivities up to

13478


Review > 99:1, comparable to the very high selectivities obtained in asymmetric catalysis > 99:1 using homogeneous catalysts. In contrast, in homogeneous catalysis, the substrate selectivities are modest, in the best cases reaching 10:1, with only a few exceptions. This fact is interesting, since it is more difficult to design and synthesize a catalytic cavity of a heterogeneous catalyst compared to a cavity of a homogeneous catalyst. The reason for this discrepancy could be found in that the development of heterogeneous catalysts has been taking place in industry over a long time period with industrially important goals to solve, for instance to manufacturing useful fuels, leading to that a lot of resources have been allocated to this field, making it possible to screen and develop many potential catalysts. Surprisingly, taken the reasoning above into account, still only a few substrate-selective catalysts have reached industrial applications, and these have all been heterogeneous catalysts, a fact that would not have been changed if we had included substrate selectivity based on only separate single reactions as an assessment criterion in this review. In general, substrate-selective catalysis is important in cases in which there is more than one potential substrate that could react and the product of only one substrate is the desired one. A potential application in which substrate-selective catalysis may be important is as a second step in biotechnology processes, in which cell cultures have produced a plethora of organic molecules with similar functional groups of which one type of molecule is going to be used as substrate in a second transformation to the desired product.[34] There are three ways to proceed toward the desired product. 1) React the product mixture with a non-selective catalyst. Then separate the desired product from the product mixture at this later stage (Figure 35, A). 2) Separate the desired substrate from the initial reaction mixture and transform the so-isolated desired substrate to the desired product by an unselective catalyst (Figure 35, B). If the separation processes in A and B are difficult, then there is a good

case for a substrate-selective catalyst operating on the initial product mixture. 3) By employing a substrate-selective catalyst, the desired molecule in the initial product mixture is selectively reacted to the desired product (Figure 35, C). It is likely that the separation of the desired product from the unreacted feed stock originating from the initial transformation will be easier than the separations in A and B. This can be attributed to the fact that the desired compound has been chemically modified and has therefore rather different physical properties compared to the unreacted substrates. A similar substrate-selective approach could be applied to other processes generating a pool of reactants in a non-selective step, such as in oil cracking and waste refinements in order to solve industrially relevant problems. We have in the introduction argued that the substrate selectivity of a catalyst must be assessed in competition with other substrates. Another methodological issue is how to record substrate selectivity; as consumption of starting material or as formation of product. As the term substrate selective implies that it is the catalyst’s discrimination among the different substrates which should be recorded. Using the formation of products as a measure of the conversion of substrate is risky, since there might be products formed that are not detected in the reaction mixture. Moreover, if the substrate selectivity in competitive experiments is not recorded as the ratio of rate constants of the disappearance of starting materials obtained in, but, for instance, as the ratio of the amount consumed starting materials, it is highly desirable to state at what percentage of conversion the substrate selectivity has been measured. In summary, although this review demonstrates that there are many reaction types that are represented in substrate-selective catalysis, only a few catalysts have been designed for this purpose. The majority of examples of substrate-selective catalysis are found in competitive reactions that have been used in mechanistic investigations, an objective different from designing catalysts with the purpose of yielding high substrate selectivity. This is probably one of the explanations to the in general encountered low substrate selectivities in this review. Nevertheless, the examples constitute good examples of which reactions types can be targeted for substrate selectivity using approaches involving designed catalysts. The overall conclusion is that substrate-selective catalysis is an under-researched field of chemistry, waiting for new approaches and important applications. When taking on this challenge, we strongly encourage the researchers to use conversion of starting materials in competition with each other to evaluate the performance of the so-designed catalytic systems for substrate-selective catalysis.

Acknowledgements

Figure 35. A favorable case (C) for substrate-selective catalysis in comparison to traditional solutions (A and B). See main text for details. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

We thank the Swedish Research Council, The Royal Physiographic Society in Lund, the Crafoord Foundation, and the Swedish Foundation for Strategic Research for financial support.

13479


Review Keywords: competitive experiments · heterogeneous catalysis · homogeneous catalysis · receptors · substrate selectivity

[1] a) P. W. N. M. Van Leeuwen, Homogeneous Catalysis Understanding the Art, Kluwer Academic, London, 2004; b) P. W. N. M. Van Leeuwen, J. C. Chadwick, Homogeneous Catalysts, Wiley-VCH, Weinheim, 2011. [2] S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901 – 2915. [3] J. P. Collman, X. M. Zhang, V. J. Lee, E. S. Uffelman, J. I. Brauman, Science 1993, 261, 1404 – 1411. [4] a) R. Breslow, Artificial Enzymes, Wiley-VCH, Weinheim, 2005; b) J. W. Steed, J. L. Atwood, Supramolecular Chemistry, Wiley-VCH, Weinheim, 2009; c) P. Ballester, A. Vidal-Ferran, in Supramolecular Catalysis (Ed.: P. W. N. M van Leeuwen), Wiley-VCH, Weinheim, 2008. [5] a) P. B. Weisz, Annual Rev. Phys. Chem. 1970, 21, 175 – 196; b) N. Mizuno, M. Misono, Chem. Rev. 1998, 98, 199 – 217; c) I. Fechete, Y. Wang, J. C. Vedrine, Catal. Today 2012, 189, 2 – 27; d) Handbook of Heterogeneous Catalysis (Eds.: G. Ertl, H. Knçzinger, F. Schth, J. Weitkamp), Wiley-VCH, Weinheim, 2008. [6] P. Fristrup, S. Le Quement, D. Tanner, P. O. Norrby, Organometallics 2004, 23, 6160 – 6165. [7] P. S. Hallman, B. R. McGarvey, G. Wilkinson, J. Chem. Soc. A 1968, 3143 – 3150. [8] a) J. Matsui, I. A. Nicholls, I. Karube, K. Mosbach, J. Org. Chem. 1996, 61, 5414 – 5417; b) I. A. Nicholls, J. Matsui, M. Krook, K. Mosbach, J. Mol. Recognit. 1996, 9, 652 – 657. [9] a) E. Vedejs, M. Jure, Angew. Chem. 2005, 117, 4040 – 4069; Angew. Chem. Int. Ed. 2005, 44, 3974 – 4001; b) J. M. Keith, J. F. Larrow, E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5 – 26. [10] P. Bhyrappa, J. K. Young, J. S. Moore, K. S. Suslick, J. Am. Chem. Soc. 1996, 118, 5708 – 5711. [11] R. D. Jones, D. A. Summerville, F. Basolo, J. Am. Chem. Soc. 1978, 100, 4416 – 4424. [12] P. Bhyrappa, J. K. Young, J. S. Moore, K. S. Suslick, J. Mol. Catal. A 1996, 113, 109 – 116. [13] J. T. Groves, T. E. Nemo, R. S. Myers, J. Am. Chem. Soc. 1979, 101, 1032 – 1033. [14] J. T. Groves, T. E. Nemo, J. Am. Chem. Soc. 1983, 105, 5786 – 5791. [15] J. P. Collman, J. I. Brauman, B. Meunier, S. A. Raybuck, T. Kodadek, Proc. Acad. Sci. USA 1984, 81, 3245 – 3248. [16] J. P. Collman, J. I. Brauman, B. Meunier, T. Hayashi, T. Kodadek, S. A. Raybuck, J. Am. Chem. Soc. 1985, 107, 2000 – 2005. [17] J. P. Collman, J. I. Brauman, J. P. Fitzgerald, P. D. Hampton, Y. Naruta, T. Michida, Bull. Chem. Soc. Jpn. 1988, 61, 47 – 57. [18] J. P. Collman, X. M. Zhang, R. T. Hembre, J. I. Brauman, J. Am. Chem. Soc. 1990, 112, 5356 – 5357. [19] B. Y. Wang, T. Zˇujovic´, D. A. Turner, C. M. Hadad, J. D. Badjic´, J. Org. Chem. 2012, 77, 2675 – 2688. [20] J. P. Collman, L. Zeng, R. A. Decreau, Chem. Commun. 2003, 2974 – 2975. [21] a) R. Breslow, A. B. Brown, R. D. McCullough, P. W. White, J. Am. Chem. Soc. 1989, 111, 4517 – 4518; b) R. Breslow, X. J. Zhang, R. Xu, M. Maletic, R. Merger, J. Am. Chem. Soc. 1996, 118, 11678 – 11679. [22] M. L. Merlau, M. D. P. Mejia, S. T. Nguyen, J. T. Hupp, Angew. Chem. 2001, 113, 4369 – 4372; Angew. Chem. Int. Ed. 2001, 40, 4239 – 4242. [23] M. O. Senge, C. J. Medforth, T. P. Forsyth, D. A. Lee, M. M. Olmstead, W. Jentzen, R. K. Pandey, J. A. Shelnutt, K. M. Smith, Inorg. Chem. 1997, 36, 1149 – 1163. [24] R. V. Slone, J. T. Hupp, Inorg. Chem. 1997, 36, 5422 – 5423. [25] L. Miljacic, L. Sarkisov, D. E. Ellis, R. Q. Snurr, J. Chem. Phys. 2004, 121, 7228 – 7236. [26] S. J. Lee, K. L. Mulfort, X. Zuo, A. J. Goshe, P. J. Wesson, S. T. Nguyen, J. T. Hupp, D. M. Tiede, J. Am. Chem. Soc. 2008, 130, 836 – 838. [27] S. J. Lee, S.-H. Cho, K. L. Mulfort, D. M. Tiede, J. T. Hupp, S. T. Nguyen, J. Am. Chem. Soc. 2008, 130, 16828 – 16829. [28] a) P. Fackler, C. Berthold, F. Voss, T. Bach, J. Am. Chem. Soc 2010, 132, 15911 – 15913; b) P. Fackler, S. M. Huber, T. Bach, J. Am. Chem. Soc. 2012, 134, 12869 – 12878. Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

[29] a) C. L. Perrin, J. B. Nielson, Annual Rev. Phys. Chem. 1997, 48, 511 – 544; b) B. Kojic-Prodic, K. Molcanov, Acta Chim. Slov. 2008, 55, 692 – 708. [30] P. A. Ulmann, A. B. Braunschweig, O.-S. Lee, M. J. Wiester, G. C. Schatz, C. A. Mirkin, Chem. Commun. 2009, 5121 – 5123. [31] a) S. Jonsson, F. G. J. Odille, P. O. Norrby, K. Wrnmark, Org. Biomol. Chem. 2006, 4, 1927 – 1948; b) S. Jonsson, F. G. J. Odille, P. O. Norrby, K. Wrnmark, Chem. Commun. 2005, 549 – 551. [32] J. K. M. Sanders, Chem. Eur. J. 1998, 4, 1378 – 1383. [33] F. G. J. Odille, S. Jonsson, S. Stjernqvist, T. Rydn, K. Wrnmark, Chem. Eur. J. 2007, 13, 9617 – 9636. [34] E. Sheibani, K. Wrnmark, Org. Biomol. Chem. 2012, 10, 2059 – 2067. [35] W. Dai, J. Li, G. S. Li, H. Yang, L. Y. Wang, S. Gao, Org. Lett. 2013, 15, 4138 – 4141. [36] P. Fristrup, L. B. Johansen, C. H. Christensen, Catal. Lett. 2008, 120, 184 – 190. [37] B. Z. Zhan, M. A. White, T. K. Sham, J. A. Pincock, R. J. Doucet, K. V. R. Rao, K. N. Robertson, T. S. Cameron, J. Am. Chem. Soc. 2003, 125, 2195 – 2199. [38] H. Yang, Y. Chong, X. Li, H. Ge, W. Fan, J. Wang, J. Mater. Chem. 2012, 22, 9069 – 9076. [39] A. B. Laursen, K. T. Højholt, L. F. Lundegaard, S. B. Simonsen, S. Helveg, F. Schueth, M. Paul, J.-D. Grunwaldt, S. Kegnoes, C. H. Christensen, K. Egeblad, Angew. Chem. 2010, 122, 3582 – 3585; Angew. Chem. Int. Ed. 2010, 49, 3504 – 3507. [40] O. Perraud, A. B. Sorokin, J.-P. Dutasta, A. Martinez, Chem. Commun. 2013, 49, 1288 – 1290. [41] M. Ciampolini, N. Nardi, Inorg. Chem. 1966, 5, 41. [42] V. S. Thirunavukkarasu, L. Ackermann, Org. Lett. 2012, 14, 6206 – 6209. [43] F. Yang, L. Ackermann, Org. Lett. 2013, 15, 718 – 720. [44] K. Urabe, Y. Tanaka, Y. Izumi, Chem. Lett. 1985, 1595 – 1596. [45] H. Coolen, P. vanLeeuwen, R. J. M. Nolte, J. Org. Chem. 1996, 61, 4739 – 4747. [46] H. Coolen, J. A. M. Meeuwis, P. Vanleeuwen, R. J. M. Nolte, J. Am. Chem. Soc. 1995, 117, 11906 – 11913. [47] a) R. P. Sijbesma, R. J. M. Nolte, J. Org. Chem. 1991, 56, 3122 – 3124; b) R. P. Sijbesma, A. P. M. Kentgens, R. J. M. Nolte, J. Org. Chem. 1991, 56, 3199 – 3201. [48] M. T. Reetz, S. R. Waldvogel, Angew. Chem. 1997, 109, 870 – 873; Angew. Chem. Int. Ed. Engl. 1997, 36, 865 – 867. [49] A. D. Westwell, J. M. J. Williams, Tetrahedron 1997, 53, 13063 – 13078. [50] P. Kacˇer, L. Laate, L. Cˇerveny´, Collect. Czech. Chem. Commun. 1998, 63, 1915 – 1926. [51] M. Ooe, M. Murata, T. Mizugaki, K. Ebitani, K. Kaneda, Nano Lett. 2002, 2, 999 – 1002. [52] T. Mizugaki, M. Murata, S. Fukubayashi, T. Mitsudome, K. Jitsukawa, K. Kaneda, Chem. Commun. 2008, 241 – 243. [53] G. S. Fonseca, E. T. Silveira, M. A. Gelesky, J. Dupont, Adv. Synth. Catal. 2005, 347, 847 – 853. [54] N. Meier, F. E. Hahn, T. Pape, C. Siering, S. R. Waldvogel, Eur. J. Inorg. Chem. 2007, 1210 – 1214. [55] J. J. Li, Name Reactions, Third ed., Springer, 2006. [56] C. Zapilko, Y. Liang, W. Nerdal, R. Anwander, Chem. Eur. J. 2007, 13, 3169 – 3176. [57] A. R. Chianese, A. Mo, D. Datta, Organometallics 2009, 28, 465 – 472. [58] T. Fujihara, K. Semba, J. Terao, Y. Tsuji, Angew. Chem. 2010, 122, 1514 – 1518; Angew. Chem. Int. Ed. 2010, 49, 1472 – 1476. [59] R. M. Deshpande, A. Fukuoka, M. Ichikawa, Chem. Lett. 1999, 13 – 14. [60] a) T. Sˇmejkal, D. Gribkov, J. Geier, M. Keller, B. Breit, Chem. Eur. J. 2010, 16, 2470 – 2478; b) T. Sˇmejkal, B. Breit, Angew. Chem. 2008, 120, 317 – 321; Angew. Chem. Int. Ed. 2008, 47, 311 – 315. [61] P. Dydio, W. I. Dzik, M. Lutz, B. de Bruin, J. N. H. Reek, Angew. Chem. 2011, 123, 416 – 420; Angew. Chem. Int. Ed. 2011, 50, 396 – 400. [62] J. L. Sessler, P. Gale, W.-S. Cho, Anion Receptor Chemistry, RSC, Cambridge (UK), 2006. [63] P. Dydio, R. J. Detz, J. N. H. Reek, J. Am. Chem. Soc. 2013, 135, 10817 – 10828. [64] A. R. Vandoorn, M. Bos, S. Harkema, J. Vaneerden, W. Verboom, D. N. Reinhoudt, J. Org. Chem. 1991, 56, 2371 – 2380. [65] a) V. V. Castelli, A. Dalla Cort, L. Mandolini, D. N. Reinhoudt, L. Schiaffino, Chem. Eur. J. 2000, 6, 1193 – 1198; b) V. V. Castelli, A. Dalla Cort, L.

13480


Review

[66] [67] [68]

[69] [70] [71] [72] [73]

[74]

[75]

[76] [77] [78] [79] [80]

[81] [82] [83] [84]

[85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96]

[97]

Mandolini, D. N. Reinhoudt, J. Am. Chem. Soc. 1998, 120, 12688 – 12689. a) G. Clapham, M. Shipman, Tetrahedron Lett. 1999, 40, 5639 – 5642; b) G. Clapham, M. Shipman, Tetrahedron 2000, 56, 1127 – 1134. F. Trentin, A. Scarso, G. Strukul, Tetrahedron Lett. 2011, 52, 6978 – 6981. a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816 – 7817; b) R. Breslow, U. Maitra, D. Rideout, Tetrahedron Lett. 1983, 24, 1901 – 1904; c) P. A. Grieco, P. Garner, Z. He, Tetrahedron Lett. 1983, 24, 1897 – 1900. H. F. Chow, C. C. Mak, J. Org. Chem. 1997, 62, 5116 – 5127. G. E. Greco, B. L. Gleason, T. A. Lowery, M. J. Kier, L. B. Hollander, S. A. Gibbs, A. D. Worthy, Org. Lett. 2007, 9, 3817 – 3820. P. A. Wender, D. Strand, J. Am. Chem. Soc. 2009, 131, 7528 – 7529. M. E. Oinen, R. T. Yu, T. Rovis, Org. Lett. 2009, 11, 4934 – 4937. a) T. Lacroix, H. Bricout, S. Tilloy, E. Monflier, Eur. J. Org. Chem. 1999, 3127 – 3129; b) C. Torque, H. Bricout, F. Hapiot, E. Monflier, Tetrahedron 2004, 60, 6487 – 6493. a) J. Cabou, H. Bricout, F. Hapiot, E. Monflier, Catal. Commun. 2004, 5, 265 – 270; b) H. Bricout, L. Caron, D. Bormann, E. Monflier, Catal. Today 2001, 66, 355 – 361. a) L. J. Mathias, R. A. Vaidya, J Am Chem. Soc 1986, 108, 1093 – 1094; b) F. Hapiot, A. Ponchel, S. Tilloy, E. Monflier, C. R. Chim. 2011, 14, 149 – 166. S. Huh, H. T. Chen, J. W. Wiench, M. Pruski, V. S. Y. Lin, J. Am. Chem. Soc. 2004, 126, 1010 – 1011. A. Anan, K. K. Sharma, T. Asefa, J. Mol. Catal. A 2008, 288, 1 – 13. K. K. Sharma, T. Asefa, Angew. Chem. 2007, 119, 2937 – 2940; Angew. Chem. Int. Ed. 2007, 46, 2879 – 2882. a) G. A. Olah, Acc. Chem. Res. 1971, 4, 240; b) L. M. Stock, H. C. Brown, Adv. Phys. Org. Chem.1963, 1, 35 – 154. a) G. A. Olah, S. H. Flood, S. J. Kuhn, J. Am. Chem. Soc. 1962, 84, 1688 – 1695; b) G. A. Olah, Na Overchuc, S. J. Kuhn, S. H. Flood, M. E. Moffatt, J. Am. Chem. Soc. 1964, 86, 1046 – 1054; c) G. A. Olah, S. H. Flood, M. E. Moffatt, J. Am. Chem. Soc. 1964, 86, 1060 – 1064. H. Mayr, C. Schade, M. Rubow, R. Schneider, Angew. Chem. 1987, 99, 1059 – 1060; Angew. Chem. Int. Ed. Engl. 1987, 26, 1029 – 1030. J. P. Dau-Schmidt, H. Mayr, Chem. Berichte 1994, 127, 205 – 212. G. A. Olah, S. Kobayash, J. Am. Chem. Soc. 1971, 93, 6964 – 6967. a) G. A. Olah, S. J. Kuhn, B. A. Hardie, S. H. Flood, J. Am. Chem. Soc. 1964, 86, 1039 – 1044; b) G. A. Olah, B. A. Hardie, S. J. Kuhn, J. Am. Chem. Soc. 1964, 86, 1055 – 1060; c) G. A. Olah, S. J. Kuhn, B. A. Hardie, S. H. Flood, J. Am. Chem. Soc. 1964, 86, 1044 – 1046; d) G. A. Olah, T. Yamato, T. Hashimoto, J. G. Shih, N. Trivedi, B. P. Singh, M. Piteau, J. A. Olah, J. Am. Chem. Soc. 1987, 109, 3708 – 3713. J. P. Brand, C. Chevalley, R. Scopelliti, J. Waser, Chem. Eur. J. 2012, 18, 5655 – 5666. L. Krti, B. Czak, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Amsterdam, 2005. C. Gibson, J. Rebek, Org. Lett. 2002, 4, 1887 – 1890. J. Kleimark, A. Hedstrçm, P. F. Larsson, C. Johansson, P. O. Norrby, ChemCatChem 2009, 1, 152 – 161. A. Hedstrçm, U. Bollmann, J. Bravidor, P. O. Norrby, Chem. Eur. J. 2011, 17, 11991 – 11993. V. Farina, B. Krishnan, D. R. Marshall, G. P. Roth, J. Org. Chem. 1993, 58, 5434 – 5444. I. Larrosa, C. Somoza, A. Banquy, S. M. Goldup, Org. Lett. 2011, 13, 146 – 149. Z. B. Dong, G. Manolikakes, L. Shi, P. Knochel, H. Mayr, Chem. Eur. J. 2010, 16, 248 – 253. V. R. Lando, A. L. Monteiro, Org. Lett. 2003, 5, 2891 – 2894. C. M. Nunes, A. L. Monteiro, J. Braz. Chem. Soc. 2007, 18, 1443 – 1447. H. Weissman, D. Milstein, Chem. Commun. 1999, 1901 – 1902. a) D. Zim, A. S. Gruber, G. Ebeling, J. Dupont, A. L. Monteiro, Org. Lett. 2000, 2, 2881 – 2884; b) D. Zim, S. M. Nobre, A. L. Monteiro, J. Mol. Catal. A 2008, 287, 16 – 23. S. E. Denmark, L. Neuville, M. E. L. Christy, S. A. Tymonko, J. Org. Chem. 2006, 71, 8500 – 8509.

Chem. Eur. J. 2014, 20, 13432 – 13481

www.chemeurj.org

[98] M. Ohff, A. Ohff, M. E. vanderBoom, D. Milstein, J. Am. Chem. Soc. 1997, 119, 11687 – 11688. [99] M. H. Huang, L. C. Liang, Organometallics 2004, 23, 2813 – 2816. [100] V. P. W. Bçhm, W. A. Herrmann, Chem. Eur. J. 2001, 7, 4191 – 4197. [101] C. S. Consorti, M. L. Zanini, S. Leal, G. Ebeling, J. Dupont, Org. Lett. 2003, 5, 983 – 986. [102] A. Garc a-Rubia, B. Urones, R. G. Arrayas, J. C. Carretero, Chem. Eur. J. 2010, 16, 9676 – 9685. [103] K. M. Engle, D. H. Wang, J. Q. Yu, J. Am. Chem. Soc 2010, 132, 14137 – 14151. [104] Y. Hashimoto, K. Hirano, T. Satoh, F. Kakiuchi, M. Miura, J. Org. Chem. 2013, 78, 638 – 646. [105] J. Li, C. Kornhaass, L. Ackermann, Chem. Commun. 2012, 48, 11343 – 11345. [106] K. Graczyk, W. Ma, L. Ackermann, Org. Lett. 2012, 14, 4110 – 4113. [107] V. S. Thirunavukkarasu, M. Donati, L. Ackermann, Org. Lett. 2012, 14, 3416 – 3419. [108] M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 8754 – 8756. [109] S. I. Gorelsky, D. Lapointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848. [110] B. Ligault, I. Petrov, S. I. Gorelsky, K. Fagnou, J. Org. Chem. 2010, 75, 1047 – 1060. [111] H.-Y. Sun, S. I. Gorelsky, D. R. Stuart, L.-C. Campeau, K. Fagnou, J. Org. Chem. 2010, 75, 8180 – 8189. [112] D. Lapointe, T. Markiewicz, C. J. Whipp, A. Toderian, K. Fagnou, J. Org. Chem. 2011, 76, 749 – 759. [113] C. H. Park, V. Ryabova, I. V. Seregin, A. W. Sromek, V. Gevorgyan, Org. Lett. 2004, 6, 1159 – 1162. [114] S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan, Org. Lett. 2007, 9, 2333 – 2336. [115] K. C. Pereira, A. L. Porter, S. Potavathri, A. P. LeBris, B. DeBoef, Tetrahedron 2013, 69, 4429 – 4435. [116] K. H. Shukla, P. DeShong, J. Org. Chem. 2008, 73, 6283 – 6291. [117] Z. Maeno, T. Mitsudome, T. Mizugaki, K. Jitsukawa, K. Kaneda, Heterocycles 2012, 86, 947 – 954. [118] a) R. Breslow, M. Hammond, M. Lauer, J. Am. Chem. Soc. 1980, 102, 421 – 422; b) R. Breslow, A. W. Czarnik, J. Am. Chem. Soc. 1983, 105, 1390 – 1391; c) J. Winkler, E. Coutouliargyropoulou, R. Leppkes, R. Breslow, J. Am. Chem. Soc. 1983, 105, 7198 – 7199; d) R. Breslow, A. W. Czarnik, M. Lauer, R. Leppkes, J. Winkler, S. Zimmerman, J. Am. Chem. Soc. 1986, 108, 1969 – 1979. [119] a) S. C. Zimmerman, R. Breslow, J. Am. Chem. Soc. 1984, 106, 1490 – 1491; b) S. C. Zimmerman, A. W. Czarnik, R. Breslow, J. Am. Chem. Soc. 1983, 105, 1694 – 1695. [120] a) L. Liu, R. Breslow, J. Am. Chem. Soc. 2002, 124, 4978 – 4979; b) L. Liu, R. Breslow, J. Am. Chem. Soc. 2003, 125, 12110 – 12111; c) R. Breslow, L. Liu, M. Rozenman, J. Am. Chem. Soc. 2002, 124, 12660 – 12661; d) W. J. Zhou, L. Liu, R. Breslow, Helv. Chim. Acta 2003, 86, 3560 – 3567. [121] L. Liu, W. J. Zhou, J. Chruma, R. Breslow, J. Am. Chem. Soc. 2004, 126, 8136 – 8137. [122] J. J. Chruma, L. Liu, W. J. Zhou, R. Breslow, Bioorg. Med. Chem. 2005, 13, 5873 – 5883. [123] R. Skouta, S. Wei, R. Breslow, J. Am. Chem. Soc. 2009, 131, 15604 – 15605. [124] P. B. Venuto, P. S. Landis, Adv. Catal. 1968, 18, 259 – 267. [125] P. B. Weisz, Pure Appl. Chem. 1980, 52, 2091 – 2103. [126] a) F. G. Dwyer, T. F. Degnan, Stud. Surf. Sci. Catal. 1993, 76, 499 – 530; b) N. Rahimi, R. Karimzadeh, Appl. Catal. A 2011, 398, 1 – 17. [127] N. Y. Chen, P. B. Weisz, Chem. Eng. Prog. Symp. Ser. 1967, 63, 86 – 89. [128] P. B. Weisz, V. J. Frilette, R. W. Maatman, E. B. Mower, J. Catal. 1962, 1, 307 – 312. [129] J. Elemans, E. J. A. Bijsterveld, A. E. Rowan, R. J. M. Nolte, Chem. Commun. 2000, 2443 – 2444.

13481


CATALYSIS. A speedy marriage in supramolecular catalysis.

Understanding catalysis.

Processive catalysis.

Catalysis steps.

Gold catalysis.

Synergistic-cooperative combination of enamine catalysis with transition metal catalysis.

Bifunctional catalysis.

Tandem rhodium catalysis: exploiting sulfoxides for asymmetric transition-metal catalysis.

Molecular catalysis science: Perspective on unifying the fields of catalysis.

One-pot consecutive catalysis by integrating organometallic catalysis with organocatalysis.

Orthogonal tandem catalysis.

Nanoparticles for Catalysis.

Cofactor assisted enzymatic catalysis.

Psychrophily and catalysis.

Energetics of enzyme catalysis.

Catalysis seen in action.

Catalysis: The complexity of intimacy.

Additive Effects on Asymmetric Catalysis.

The imitation of enzymic catalysis.

On gold catalysis and beyond

Catalysis by yeast alcohol dehydrogenase.

Plant biomass fractionation meets catalysis.

Enzyme catalysis: Evolution made easy.

Organic chemistry: Catalysis marches on.