Metal-Organic Self-Assembled Trefoil Knots for C-Br Bond Activation

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Metal-Organic Self-Assembled Trefoil Knots for C-Br Bond Activation Thirumurugan Prakasam, Anthonisamy Devaraj, Rupak Saha, Matteo Lusi, Jérémy Brandel, David Esteban-Gómez, Carlos Platas-Iglesias, Mark A. Olson, Partha Sarathi Mukherjee, and Ali Trabolsi ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04650 • Publication Date (Web): 15 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019

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Metal-Organic Self-Assembled Trefoil Knots for C-Br Bond Activation Thirumurugan Prakasam1‡, Anthonisamy Devaraj2‡, Rupak Saha2, Matteo Lusi3, Jeremy Brandel4,5, David Esteban-Gómez6, Carlos Platas-Iglesias6, Mark Anthony Olson7, Partha Sarathi Mukherjee2* and Ali Trabolsi1* 1

New York University Abu Dhabi (NYUAD), Experimental Research Building, Building C1,

Saadiyat Island, Abu Dhabi, UAE. E-mail: [email protected] 2

Inorganic and Physical Chemistry Department, Indian Institute of Science, Bangalore-560012,

India. E-mail: [email protected] 3

Department of Chemical and Environmental Science, University of Limerick, Limerick,

Republic of Ireland. 4

Université de Strasbourg, IPHC, 25 rue Becquerel 67087 Strasbourg, France

5

CNRS, UMR7178, 67087 Strasbourg, France

6

Departamento de Química, Universidade da Coruña, Campus da Zapateira-Rúa da Fraga 10,

15008 A Coruña, Spain 7

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, PR China

‡

-Authors contributed equally

ABSTRACT: Synthesizing molecular knots that mimic the catalytic functionality of stereospecific or stereo-selective enzymes is an intriguing task in chemistry. Synthetic anion receptors even with moderate halide binding affinities may catalyze chemical reactions involving carbon-

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halogen bond cleavage. Herein we report isostructural self-assembled trefoil molecular knots (Cu-TK, Cd-TK, Zn-TK) based on Cu(II), Cd(II) and Zn(II) that are capable of binding and stabilizing bromide within their central cavity and are capable of catalyzing C-Br bond cleavage. We also describe the role of non-covalent interactions between the knots and bromide as well as the size and shape of the knots on their catalytic efficiency. Among the studied three knots, CuTK was found to be more effective than Zn-TK and Cd-TK in catalyzing C-Br bond cleavage. The catalytic efficiency of the knots towards C-Br bond cleavage was found to be related to a balance between their attractive electrostatic interactions with bromide as well as cavity size and shape of the knots. KEYWORDS: Anion receptors, C-Br bond cleavage, catalysis, trefoil Knot, [C-Hanion] interactions.

INTRODUCTION Trefoil knots are the most frequently observed knotted topology in proteins.1-4 It is speculated that knotted topologies play important roles in protein function by enhancing their catalytic activity, ligand-binding affinity, and increasing their macromolecular thermodynamic, kinetic, and mechanical stability.2,5-9 Coordination driven self-assembly10 has been established as a nice protocol towards the synthesis of complex architectures including molecular knots.11-16 However, reports on the practical application and utility of such molecular knots remain very limited. 17-22 An important contribution in this field was recently reported, whereby a synthetic metal-organic pentafoil knot was successfully employed to allosterically induce and/or regulate Lewis acidcatalyzed reactions such as the Michael addition and Diels-Alder cycloaddition by knot-


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promoted cleavage of carbon-halogen bonds.23 A subsequent report described the use of a lanthanide-based trefoil knot of single handedness as an asymmetric catalyst in Mukaiyama aldol reactions.24 To the best of our knowledge these reports are the only examples on the use of molecular knots as reaction catalysts. Here we report the synthesis and characterization of a new copper-based trefoil knot (Cu-TK), which is isostructural to analogous Zn-TK and Cd-TK.25,26 The Cu-TK was obtained as the major product by reacting equimolar ratio of copper acetate with a simple pair of organic linkers, namely 2,6-diformyl pyridine (DFP) and diamino bipyridine (DAB), in isopropanol at 70 °C (Scheme 1). Taking advantage of the ability of these knots to form complexes with anions within their central cavity27 and inspired by the potential of synthetic molecular knots to catalyze the cleavage of carbon-halogen bonds,23 we have screened our three metal-organic non-trivial topological entities, Zn-TK, Cd-TK and Cu-TK for the ability to catalyze the hydrolysis of bromo-derivatives of Baylis-Hillman (B-H) adducts. Our studies have indicated that the Cubased trefoil knot is the most efficient catalyst among these three knots. Armed with the preliminary screening data we then demonstrated the breadth of the capabilities of this new CuTK catalyst on a library of both phenyl- and naphthalenyl-substituted bromo-derivatives of Baylis-Hilman (B-H) adducts. RESULTS AND DISCUSSION In our recent report on the template-directed synthesis of both Zn- and Cd-based metal-organic trefoil knots, Zn-TK and Cd-TK we discovered that the knotted structures offered a positively charged cavity, rich with polarized C-H bonds, capable of binding up to two bromide anions by means of electrostatic and C-H‧‧‧Br― interactions. The strength of the 2:1 complexes of both


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2Br―M-TK●4TFA (M = Zn or Cd) was determined using 1H NMR spectroscopy in aqueous solution with a global association constant27 of log  = 6.0 and 6.1, respectively (See SI for CdTK NMR anion binding experiment, Figures-S7 and S8). In order to gain insight into the effect that the identity of the metal has on the catalytic activity of the knots, we also prepared a third trefoil knot using the Cu(II) ion as a template. The copper trefoil knot, Cu-TK, was synthesized using a slightly modified synthetic procedure derived from our previously reported protocol. 25-26 Cu-TK was obtained as a major product in 76 % yield upon mixing stoichiometric amounts of the sub-components 2,6-diformyl pyridine (DFP), diamino bipyridine (DAB) and copper acetate monohydrate in isopropanol at 70 °C for 5 h (See SI, Scheme S1 for experimental details). 6+

DFP +

Cu(OAc)2 iPrOH, 70 ºC 76 %

4TFA

6TFA―

DAB-4H 4TFA

Cu-TK 6TFA

Scheme-1. Synthesis of the self-assembled copper trefoil knot (Cu-TK) using a metal-templated reaction employing trifluoroacetate salt (TFA) of diaminobipyridine (DAB-4H•4TFA), 2,6 diformyl pyridine (DFP) and copper (II) acetate in isopropanol at 70 °C. The coordination sphere of each copper metal ion is completed by a TFA anion, however for the sake of clarity, TFA anions are represented outside the coordination pocket. Electrospray ionization high-resolution mass spectroscopic (ESI-HRMS) analysis revealed three major peaks with mass-to-charge (m/z) ratios of 1108.1891 (calculated: 1108.1903),


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701.1311 (calculated: 701.1316) and 497.6027 (calculated: 497.6023), which correspond to [CuTK●4TFA]2+, [Cu-TK●3TFA]3+ and [Cu-TK●2TFA]4+, respectively (See SI, Figure S1 for full details). The isotopic distribution patterns of the assigned sets of peaks were in full agreement with the patterns predicted for the corresponding fragments. All attempts to crystallize the pure Cu-TK (without anions in the central cavity of trefoil knot) were unsuccessful. Single crystals of Cu-TK were eventually obtained by slow vapour diffusion of diethyl ether into a methanolic solution of Cu-TK in the presence of 2.5 equivalents of tetrabutyl ammonium bromide. Single crystal X-ray diffraction analysis confirmed the nontrivial knotted topology of Cu-TK. Structure refinement reveals that the copper atoms in Cu-TK are coordinated in a distorted octahedral geometry. Five nitrogen atoms  two from the 2,2’bipyridine and three from the 2,5-diiminopyridine  and one carboxylate, from a trifluoroacetate anion, constitute the coordination sphere of each copper(II) ion (Figure 1).

a)

d)

b)

c)

e)


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Figure 1. Single crystal structure of Cu-TK with bromide anions (brown spheres), the copper ions are depicted in green. Structural representations of the Cu-TK: front views showed in stick model (a), space-filling (b), and side view (c). Crystal packing of Cu-TK (d, e). The metal-organic coordination motif of Cu-TK resembles closely to those of Zn-TK and CdTK (Figure 2). Unlike Zn-TK and Cd-TK, which possess C3 symmetry, the Cu-based derivative adopts an asymmetrical knotted structure (point group C1). In Cu-TK, one of the three carboxylate ligands is oriented in an opposite direction to the other two (Figure 2). Much like what is observed for both Zn-TK and Cd-TK, the bipyridine moieties of the DAB ligand strands of Cu-TK are sandwiched between two phenoxy substituents. The distance between the centroids of four of the six phenoxy rings and the closest bipyridyl ring is about 3.4 Å, i.e. typical of π-π stacking distance. The remaining two phenoxy moieties are about 3.55 and 3.75 Å apart from the closest bipyridine suggesting a weaker interaction. In addition, two of the phenoxy oxygen atoms point towards the cavity of the knot while the other four face outward. The difference in the solid-state structure adopted by Cu-TK compared to Zn-TK and Cd-TK (Figure 2) is likely due to the more distorted coordination environment on account of the JahnTeller effect.28-30 Indeed, as observed for Zn-TK, all five Zn-N bond distances fall within a rather narrow range (2.10-2.30 Å), while for Cu-TK, two of the Cu-N bond distances differ significantly (2.21 and 2.45 Å for all three copper ions) and are longer than that of the remaining three Cu-N bond distances (2.00-2.08 Å for all three copper metal ions). The unit cell of Cu-TK consists of two molecular knots of opposite direction on top of each other along the axis of a centrosymmetric P1̅ space group. The knots are alternated by a bromide ion that balances one of the positive charges. The missing counter ions (presumably disordered


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bromide or acetate anions) could not be identified and located on the experimental electron density map.


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Figure 2. Crystal structures of the self-assembled metal-organic trefoil knots Cu-TK (a), Zn-TK (b) and Cd-TK (c). Hydrogen atoms, solvent molecules and counter ions are omitted for clarity.

ESI-HRMS analysis of a methanolic solution of Cu-TK provided further evidence for the bromophilic nature of Cu-TK and the presence of bound bromide ions in its structure. The existence of a 1:2 complex in the gas phase between Cu-TK and bromide ions was confirmed by ESI-HRMS, which exhibited two peaks with m/z values of 1074.1223 and 678.4201 corresponding to [Cu-TK●2TFA●2Br]2+ and [Cu-TK●TFA●2Br]3+, respectively (Figure S2). In addition, the experimental isotopic distributions for both [Cu-TK●2TFA●2Br]2+ and [CuTK●TFA●2Br]3+ matched well with the calculated patterns for the corresponding formulas. Building on X-ray crystallographic evidence and ESI-HRMS analysis, it can be inferred that the Cu-based trefoil knot is capable of binding two bromide anions whereby the two TFA anions located outside of the Cu-TK cavity are exchanged with two bromide anions which, in Zn-TK


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and Cd-TK, go on to reside within the knot’s central cavity. This exchange process is facilitated by the electrostatic attraction between the positively charged host cavity and the negatively charged bromides.

Folded or knotted enzymes like dehalogenases catalyze carbon-halogen bond cleavage using their three-dimensional halide stabilizing binding pocket in aqueous solution.31-32 In particular, haloalkane dehalogenase is a microbial enzyme that catalyzes the hydrolysis of primary haloalkanes into their corresponding alcohols and halides via SN2 mechanism.33 The halide stabilizing site is a hydrophobic binding pocket surrounded by amino-acid residues with a cavity volume of around 40 Å3.34 Similarly, our knots feature a hydrophobic 3D cavity with an inner volume ranging from 65 to 80 Å3 and capable of stabilizing halides through electrostatic interactions and H-bonds with a relatively high binding constant. In fact, it has been shown that even species with moderate binding affinities towards halides can enhance reactions involving carbon-halogen bond cleavage.35-39 On account of their relatively high binding constants, we speculated that our knots can efficiently catalyze reactions that involve the cleavage of carbonhalogen bonds by stabilizing the bromide leaving group through C─HBr─ interactions and long range MBr─ electrostatic interactions (Scheme 2). Therefore, we employed our metal-organic knots as catalysts in the hydrolysis of stereo-defined bromo olefin-based derivatives of BaylisHilman adducts,40-44 the products of which are widely used in the preparation of various natural and bioactive compounds.45-49


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M-TK●6TFA Solvent 1

R = OMe

2

M2+ = Cd2+, Cu2+ &Zn2+

Scheme-2. Proposed scheme for knot-mediated hydrolysis reaction facilitated by anion-binding of a bromo derivative of Baylis-Hilman adduct (1), facilitated by the knot’s anion binding ability. This transformation is traditionally achieved through a two-step reaction.50a Attempts to achieve this reaction in one-step using the previously reported conditions for an aliphatic bromide derivative did not lead to any conversion.50b We first investigated the catalytic efficiency of the three metal-based trefoil knots, namely ZnTK, Cd-TK and Cu-TK for the hydrolysis of a model compound 1a (in Scheme 2, R = OMe, Table 1; see Scheme S2 for synthetic details). Blank reactions without knots were also carried out under identical conditions to compare catalytic performance (Table 1). In our attempts to find out the best conditions that allow us not only to achieve the highest yield but also to evaluate knot’s reusability, the hydrolysis of 1a was first tested under three different conditions. All three reactions were carried out in the presence of 20 mol% of Cu-TK at temperatures ranging between 25 and 40 °C. Two out of the three reactions were performed under homogenous catalytic conditions in an acetonitrile and water (2:1 v/v) mixed solvent employing Cu-TK catalyst in the absence and in the presence of K2CO3, respectively. Excess (4 equiv.) of K2CO3 was added to achieve anion exchange and remove the cavity bound bromide as solid KBr to complete the catalytic cycle. At room temperature over a period of 48 hours, the conversions of 1a to 2a were 51 % in the absence of K2CO3 and 54 % in the presence of K2CO3, respectively.


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When the reaction temperature was elevated to 35-40 C, the yield increased to 76 % in the absence of K2CO3 along with 21 % of isomeric byproduct in 16 h. When the similar reaction was carried out in the presence of K2CO3 at 35-40 C, the conversion was 78 % along with 15 % isomeric byproduct in just 2.5 h (See SI, Figures S13 and S14, Table S1). This indicates an important role of K2CO3 to make completion of the reaction faster, possibly by helping in removing the bromide ion from the cavity as KBr. Two control reactions were carried out: one reaction using neither Cu-TK nor K2CO3, and the 2nd control reaction in presence of 4 equivalents of K2CO3 (without Cu-TK) in the same mixed solvent at a temperature ranging between 35-40 °C. Such control experiments afforded just 11 % and 28 % of hydrolyzed product along with 2 % of isomeric byproduct 2a’ (Table S1, Figures S13 and S14). The above experimental results confirm the ability of our Cu-TK in catalyzing the cleavage of C-Br bonds through stabilization of the bromide ions within the central cavity. However, recovery of the catalyst after the completion of the reaction in homogeneous fashion was unsuccessful. Table 1. Optimization of the (Z)-methyl 2-(bromomethyl)-3-phenylacrylate (1a) hydrolysis reaction conditions using trefoil knots with three different central metal ions as catalysts in wet CH3CN (acetonitrile and water (25:1 v/v)) under heterogeneous catalytic reaction conditions. Formation of 2a was calculated using 1H-NMR spectroscopy Entry

M-TK

1 2 3 4 5 6 7 8

Cu-TK Cu-TK Cu-TK Cu-TK Cu-TK Zn-TK Cd-TK Cu-TK (IIcycle)

Loading (mol%)

Temp. (°C)

20 5 10 20 25 20 20 20

25 35-40 35-40 35-40 35-40 35-40 35-40 35-40

Time (h) 7 5 5 5 5 5 5 5

% Conversion with M-TK** 41 17 26 69 71 12 30 8

% Conversion with M-TK and K2CO3** 46 23 32 74 74 15 34 70

% Conversion without M-TK/K2CO3** 1 1 2 1 1 2 1 -

% Conversion with only K2CO3** 2 2 2 2 2 2 1 -

1

**% conversion based on crude H-NMR spectroscopic measurements using TMS as internal standard.


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To explore the reusability of the catalyst, the hydrolysis reaction of 1a was carried out in heterogeneous fashion using 20 mol% of Cu-TK both in the absence and in the presence of 4 equivalents of K2CO3 in wet acetonitrile (commercial grade) in the temperature range between 35-40 °C. Within only 5 hours, the obtained yields and conversion of 2a were calculated to be 69 % and 74 % respectively, without the detection of any isomeric byproduct (See SI, Figure S9). These yields in addition to the ones obtained under homogenous conditions reflect the enhancement of conversion in the presence of K2CO3. This could be due to the fact that K2CO3 may help in removing the bromide ions, through anion exchange, and precipitate them as KBr from the cavity of the knot and increases its catalytic activity. When the reaction was performed using neither Cu-TK nor K2CO3, only trace (1-2 %) amount of conversion was observed. A similar result (~2 % conversion) was also observed when only K2CO3 was used without the knot. The reaction mixture was centrifuged to isolate the catalyst as solid for further re-use. TGA analysis (Figure S16) of the isolated catalyst showed similar thermal stability to that of fresh CuTK up to 200 C. The recovered knot was also subjected to HR-MS which revealed the absence of any bromide within the knot and confirmed that bromide ions were successfully removed using K2CO3 (Figures S17-18). Since, Zn-TK is isostructural with Cu-TK, the counter anion exchange of Zn-TK was probed by 1H-NMR spectroscopy. The spectral changes observed by 1

H-NMR spectroscopy upon the addition of bromide anions and later K2CO3 to Zn-TK in

methanol is shown in Figure S19. Therefore, our heterogeneous catalysis approach offers advantages over the homogenous strategy in terms of reusability and short reaction time. These initial results demonstrated the catalytic activity of Cu-TK towards the hydrolysis of 2(bromomethyl)-3-arylacrylates. In order to further optimize the reaction conditions and determine the minimal amount of Cu-TK that can generate the highest yield of conversion, the


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amount of Cu-TK in the reaction was systematically varied between 5 and 10 mol%. Lower catalyst loadings (10 mol% and 5 mol%) in the presence of 4 equivalents of K2CO3 led to lower conversions of 32 % and 23 %, respectively (Table 1, entries 2 & 3). Increasing the catalyst loading to 25 mol% of Cu-TK had no appreciable effect on the conversion (Table 1, entry 5). Thus, the optimum reaction conditions for the hydrolysis of (Z)alkyl 2-(bromomethyl)-3-arylacrylate can be achieved with 20 mol% catalytic loading of Cu-TK in presence of 4 equivalents of K2CO3 in a temperature range of 35-40 °C for 5 h (Table 1, entry 4).The optimized conditions were then adopted to screen the catalytic activity of all three trefoil knots (Figure 3) namely Cu-TK, Zn-TK, and Cd-TK separately. 20 mol% catalyst loading of Zn-TK and Cd-TK in the presence of 4 equivalents of K2CO3 showed 15 % and 34 % conversions, respectively (Table 1, entries 6 & 7 and Figure S10). These results demonstrated that the nature of the metal ion in the knot plays a role in affecting the catalytic activity of the trefoil knot with Cu-TK being more effective over Zn-TK and Cd-TK. To gain further insight into the superior performance of Cu-based knot over that of Zn and Cd, the knots were modeled using density functional theory (DFT) calculations. Electrostatic potential surface mapping of the three metal-organic trefoil knots (Figure 3) revealed their structures to be electrostatically positive, with the most positive values localizing in their inner cavities. The electrostatic potential distribution of Cu-TK and Cd-TK are similar, while the electrostatic potential of the inner cavity of Zn-TK is distinctively less positive. Another interesting observation that is worth noting is that both Cd-TK and Zn-TK have similar circularly-shaped channels of similar volume (80 Å3), with Cd-TK having larger openings and a narrower neck than Zn-TK. On the other hand, the asymmetric conformation of Cu-TK gives rise to a slightly more flattened cavity having a smaller volume (65 Å3). The discordantly


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shaped cavity of the asymmetrical trefoil knot (Cu-TK) is likely to be responsible for its

enhanced catalytic activity as compared to both the Zn- and Cd-based knots. Figure 3. Computed molecular electrostatic potential maps of Cu-TK, Zn-TK, and Cd-TK (hartree) on the molecular surfaces defined by 0.001 electronsbohr3 contour of the electron density. Isothermal titration calorimetry (ITC) studies were carried out to determine the affinity of the three trefoil knots for bromide in water. The titrations (Figures S3 and S4) suggested the successive formation of Br─M-TK and 2Br─M-TK complexes (M = Cu and Zn) with an overall stronger binding of Br─ by Zn-TK (log β = 7.4(2)) than by Cu-TK (log β = 6.6(3)) and favorable enthalpic and entropic contributions for both systems (Figure S6). In the case of CuTK, the higher enthalpic contribution suggests that the binding of bromide is dominated by attractive forces, while for Zn-TK, the entropic contribution prevails. The higher enthalpic


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contribution to the free energy of binding of bromide for Cu-TK than for Zn-TK is in accordance with DFT calculations which reveal a more positive electrostatic potential for the cavity of Cu-TK than for Zn-TK. These results suggest that the better catalytic activity of CuTK might be due to the stronger attractive electrostatic interactions between the inner binding cavity of TK and the bromide ions, rather than the overall stability of the final complexes. Similar ITC studies carried out on Cd-TK (Figure S5) suggested the precipitation/aggregation of bromide complexes above two equivalents of bromide, what prevented us from determining the stability constants and thermodynamic parameters of the complexation. As Cd-TK and Cu-TK exhibit similar electrostatic potential distributions, this behavior confirms the influence of the cavity size in the complexation mechanism, as suggested by the DFT studies. The combined results suggest that the catalytic efficiency results from a balance of attractive electrostatic interactions between host and guest as well as the knot cavity size and shape. Taking into consideration that Cu-TK/K2CO3 heterogeneous system was found to be the best performing catalyst under our optimized reaction conditions for the conversion of cinnamyl bromide to cinnamyl alcohol, a library of bromo-olefin derivatives containing ester moieties and bearing electron withdrawing or donating groups were screened (1b – 1h, Table 2). In the presence of 20 mol% of Cu-TK with 4 equivalents of K2CO3, compounds 1b – 1h were converted into their corresponding cinnamyl alcohols with conversion yields ranging from 64 % to 86 % (Table 2). Interestingly, when napthalenyl acrylate-based Baylis-Hillman adduct (1h) was subjected to hydrolysis under homogeneous reaction conditions (20 mol% of Cu-TK), the expected alcohol (2h) was obtained in addition to an isomeric compound 2i (Figure S11). The appearance of two isomeric products can be attributed to the bulkiness of the naphthalenyl group in the starting


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material which potentially hinders the nucleophilic attack of H2O molecules allowing the reaction to proceed through both concerted SN2 and SN2' mechanisms, respectively. In contrast, using the heterogeneous protocol, the same reaction afforded exclusively 2h in 64 % conversion (Table 2, entry 8, Figure S12) without any isomeric byproduct. Table 2. Hydrolysis of Z-bromo olefins using copper trefoil knot as catalyst in wet acetonitrile.

a

% conversion is based on crude 1H NMR with 20 mol% loading of Cu-TK in presence of 4

equivalents of K2CO3. All reactions were performed in wet CH3CN medium. In order to prove


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the validity of these yields, compound 2a was isolated as a pure compound (See SI, section S5c) using silica gel chromatography and the obtained yield (69 %) compare well to the yield (74 %) determined by 1H NMR. The heterogeneous reaction proceeded via a concerted SN2 mechanism that provides good selectivity for the naphthyl substrate. In the heterogeneous reaction, only trace amount of water was used as the nucleophile (wet acetonitrile) which facilitates C-Br bond cleavage via SN2 mechanism leading to the formation of 2h without any side products. However, in case of the homogeneous reaction, a large excess of water was used as the nucleophile which enables the hydrolysis reaction via both SN2 and SN2' pathways that led to the formation of the hydrolyzed product 2h along with the byproduct 2i.

KBr

K2CO3

─

─


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Scheme-3. Heterogeneous catalytic cycle of the hydrolysis reactions of bromo derivatives of Baylis-Hilman adducts. Reactions conditions: 20 mol% of Cu-TK in presence of 4 equivalents of K2CO3 in wet acetonitrile at a temperature range of 35-40 °C. In order to evaluate the reusability of the knots (Scheme 3), Cu-TK was recovered by filtration after the first cycle and treated with the bromo compounds of 1a, 1d, and 1g in wet CH3CN along with the addition of 4 equivalent of K2CO3 for 5h at a temperature range of 35-40 °C. Such reactions afforded 70 %, 71 % and 74 % conversions of compounds 2a, 2d and 2g respectively, which are close in yield to that of first catalytic cycle (Scheme 3, Table 1, entry 8, Table 2, entry 4 & 7, and Figure S15). This clearly demonstrated the reusable nature of Cu-TK without much loss of catalytic efficiency. CONCLUSION In summary, we report here the synthesis and characterization of a new trefoil Cu(II) molecular knot (Cu-TK) using coordination self-assembly. This Cu-TK is capable of binding bromide ions in its intramolecular pocket. This ability to bind bromide has been exploited for the efficient catalysis of hydrolysis via C-Br bond cleavage of bromo derivatives of Baylis-Hillman adducts. The present study also revealed a better catalytic efficiency of the Cu-TK compared to analogous knots, Cd-TK and Zn-TK. Our results demonstrate that a firm binding of halides within metal-coordinated knotted receptors can be a useful strategy to promote carbon-halogen bond cleavage, thereby catalyzing chemical reactions that are traditionally promoted by metals or metal salts. For the last six decades, research on non-trivial structures have mainly focused on developing new synthetic approaches to access novel structural topologies. Research directed at developing practical applications of such structures however remains severely underexplored.


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Our results pave the way for the development of a new generation of anion-receptors with improved catalytic activity. Development of new knotted architectures with different topologies and chiral functional groups for stereo-/enantio-selective chemical transformation is under investigation. EXPERIMENTAL SECTION Materials and Methods: All reagents and starting materials were purchased from SigmaAldrich and used without further purification. The zinc trefoil knot, cadmium trefoil knot, diamino bipyridine (DAB) ligand and 2,6-diformyl pyridine were synthesized as previously reported.25,26 Synthesis of the Copper Trefoil Knot (Cu-TK): Pale pink solid of freshly boc-deprotected DAB●4TFA (0.21 g, 0.25 mmol) was stirred with copper acetate monohydrate (0.05 g, 0.25 mmol) and 2,6-diformyl pyridine (DFP) (0.03 g, 0.25 mmol) in 10 mL of isopropanol in a 50 mL round bottom flask at 70 °C for 5 hours. The warm solution was filtered and the light green precipitate was washed with isopropanol. The precipitate was dried under vacuum for 6 hours and was isolated in 76 % (0.15 g) yield. Trefoil

knot,

Cu-TK●6TFA:

Yield:

76

%;

MS

(ESI-HRMS):

m/z

Calcd

for

(C107H81Cu3F12N15O14)2+: 1108.1903 [Cu-TK●4TFA]2+, found: 1108.1891 [Cu-TK●4TFA]2+, m/z Calcd for (C105H81Cu3F9N15O12)3+: 703.1316 [Cu-TK●3TFA]3+, found: 701.1311 [CuTK●3TFA]3+, m/z Calcd for (C103H81Cu3F6N15O10)4+: 497.6023 [Cu-TK●2TFA]4+, found: 497.6027 [Cu-TK●2TFA]4+. ASSOCIATED CONTENT


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Supporting Information HR-MS data of Cu-TK and 2Br─Cu-TK4TFA, anion binding experiments of trefoil knots using ITC and 1H NMR spectroscopy. Synthesis of the starting materials 1a -1h and products 2a2h, characterization data of the products of catalytic reactions. Computational details. X-ray crystallographic data for Cu-TK (CIF). AUTHOR INFORMATION Corresponding Author *[email protected] and [email protected] Author Contributions All authors contributed to the writing of the manuscript and have given approval to its final version. ‡-Both authors contributed equally.

ACKNOWLEDGMENT The research described here was sponsored by New York University Abu Dhabi, in the UAE. T.P and A.T thank NYUAD for its generous support for the research program at NYUAD. We would like to acknowledge the Al Jalila Foundation (AJF201646) for funding this research work. The authors also thank the Core Technology Platforms at NYUAD. P.S.M. thanks the Science and Engineering Research Board (New Delhi) for a research grant [Grant No. EMR/2015/002353]. A.D is thankful to UGC-New Dehli for Dr. D. S. Kothari postdoctoral fellowship. The authors thank Dr. Rana Bilbeisi for performing the titration experiment of bromide with Cd-TK by 1H NMR and determining the binding constants.


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SYNOPSIS Metal-Organic Self-Assembled Trefoil Knots for C-Br Bond Activation

Cu

Br Cu

Cu


27

Metal-Organic Self-Assembled Trefoil Knots for C-Br Bond Activation

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