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Imidazole Functionalyzed Pillar[5]arenes: Highly Reactive and Selective Supramolecular Artificial Enzymes Eduardo H. Wanderlind, Daiane G. Liz, Adriana P. Gerola, Ricardo Ferreira Affeldt, Vanessa Nascimento, Lizandra C. Bretanha, Rodrigo Montecinos, Luis García-Río, Haidi D Fiedler, and Faruk Nome ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00901 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 13, 2018
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ACS Catalysis
Imidazole Functionalyzed Pillar[5]arenes: Highly Reactive and Selective Supramolecular Artificial Enzymes Eduardo H. Wanderlind,a Daiane G. Liz,a Adriana P. Gerola,a Ricardo F. Affeldt,a Vanessa Nascimento,a Lizandra C. Bretanha,a Rodrigo Montecinos,b Luis Garcia-Rioc*, Haidi D. Fiedlera and Faruk Nomea* a
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900 Brazil.
b
Facultad de Química, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4860, Santiago, Chile.
c
Centro de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Departamento de Química Física, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Supporting Information Placeholder ABSTRACT: Phosphate diester hydrolysis is strongly accelerated, by a factor of 104, in the presence of artificial enzymes especially designed in the light of spatiotemporal concepts, anchoring imidazoles in a pillar[5]arene matrix. Host:guest complexes cleave the aryl phosphodiesters via nucleophilic attack of the properly placed imidazole moieties with release of 2,4-dinitrophenolate and formation of unstable phosphoroamidates which regenerate the catalyst and 2,4dinitrophenyl phosphate. Comparison of the reactivity of P5IMD with that of imidazole shows an increase of 270-fold. Asymmetrical diesters allow the formation of two different docking structures of the host:guest complex, with just one being reactive and, allowing selectivity increases of 102–fold, compared with the reaction in bulk water of the same asymmetrical diesters. KEYWORDS: Pillararene, Phosphodiester, Phosphate Hydrolysis, Supramolecular Catalysis, Imidazole Catalysis, Host:Guest Complex. INTRODUCTION Mimicking enzyme catalysis[1-4] in the design of nanoreactors is a source of inspiration for supramolecular catalysis.[5-7] The most important challenges in this field are increasing reaction rates and selectivities by proper selection of host receptor and functionality. Phosphoryl group transfer is one of the commonest biological reactions and is catalyzed by a large number of enzymes.[8] Because the negatively charged phosphate anions are targets for binding interactions with cations, the active sites of enzymes catalyzing phosphate transfer are mostly positively charged. In enzymes of the phospholidase D superfamily, nucleophilic attack, at the unreactive phosphorus center, is carried out by an active site amino-acid side-chain: a histidine imidazole.[9-11] Recognition properties of pillararenes allow selective binding of cationic, neutral and anionic molecules depending on the macrocycle functionalization.[12-17] Thus, inspired by active sites of the phospholidase D enzymes, we design a pillar[5]arene motif including imidazole groups (P5IMD in Chart 1) to achieve simultaneously a cationic and nucleophilic receptor. Supramolecular catalyst efficiency was examined on phosphate diesters because its reactivity should depend significantly on the nucleophile as well as on the docking of the phosphate diester [8]. In this letter we report a pillar[5]arene-based
supramolecular artificial enzyme showing a 104 catalytic effect for the hydrolysis of phosphate diesters, with an impressive 102-fold increase in selectivity. Chart 1. Structure of host and guests.
RESULTS AND DISCUSSION P5IMD was synthesized and characterized as described in SI section (Figures S1 to S10) and behaves as a pHdependent highly charged or neutral receptor, Figure 1. The titration profile was fitted to five independent pKa since protonation, in the highly symmetrical upper and lower rims of P5IMD, are independent and equivalent.
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Values of pKa of 3.41±0.03; 4.19±0.03; 4.40±0.03; 4.65±0.03 and 5.91±0.02 were obtained. Remarkably, the apparent imidazole acidity increases when incorporated in the structure of the pillararene, probably due to electrostatic repulsions promoted by the high number of positive charges. These acidity constants agree with imidazole chemical shift being strongly pH-dependent in the pD=37 region (insert in Figure 1 and Figures S8 to S10). The P5IMD pillararene ability to complex BDNPP was tested by NMR spectroscopy: a small induced downfield effect was obtained for imidazole NCHN signal at pD=5.5 in 35% v/v CD3OD/D2O (Figures S11 and S12). Additionally, NMR signals for BDNPP show a complexation induced upfield effect indicative that its encapsulation proceeds with inclusion of one aromatic ring in the P5IMD cavity with the other aryl group positioned outside the cavity (Figure 2).
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phoroamidate intermediates decompose relatively fast allowing catalyst regeneration. BDNPP monoanion hydrolysis (pKa ≈ -1.5) was examined as a function of [P5IMD], between pH 4.3 and 8.8[1921] , in aqueous and supramolecular environments (Figure 2 and Figures S17 to S20). Rate constant vs. [P5IMD] show that the rate constants increase up to a plateau, which is almost 104-fold larger than the spontaneous reaction in bulk water. The snapshot of the 1:1 host-guest complex in Figure 2 (see SI for calculation details) shows that binding of the phosphate diester to the host facilitates its reaction with imidazole.
Figure 2. Influence of P5IMD concentration on the first order rate constants for hydrolysis of BDNPP in H2O:MeOH 65:35 (v/v), at 25 ºC (●) pH=8.8 and (●) pH=4.3.
Figure 1. (A) Acid dissociation equilibria of P5IMD, exemplified with one of the rims of the host. (B) Potentiometric titration of P5IMD in H2O:MeOH 65:35 (v/v), at 25 ºC; insert: 1 H NMR chemical shifts of the imidazole NCHN, marked in blue in (A), as a function of pD. Experimental details on the SI.
Kinetic studies on the hydrolysis of BDNPP in the presence of P5IMD show two consecutive processes assigned to the release of both 2,4-dinitrophenolate leaving groups (Figure S13). These consecutive processes take place in well-separated timescales allowing their independent study. The fast initial absorbance increase corresponds to release of 2,4-dinitrophenolate promoted by nucleophilic attack of the imidazole moiety of the host on BDNPP, as confirmed by 31P NMR (Figure S14 to S16 and Table S1[18]). The second kinetic process corresponds to the P5IMD catalyzed hydrolysis of the 2,4-dinitrophenyl phosphate monoester formed in the first reaction and will be the subject of future reports. The current communication focuses on the analysis of the first reaction, i.e. the imidazole catalyzed hydrolysis of BDNPP, where the phos-
Analysis of the kinetic behavior using a one site binding model (kobs= (ko+ kP Kass [P5IMD]) /(1+ Kass [P5IMD])) allows estimation of the rate constants in the host guest complex (kP) and the equilibrium association constants (Kass). The results in Table 1 show that both binding ability and catalytic efficiency of P5IMD depend on pH and different P5IMD concentrations are needed to incorporate BDNPP at pH=4.3 and 8.8. The binding constant increases with acidity because the charge of the P5IMD host increases at lower pH. Binding constant at pH=4.3 is about 100-fold larger than at pH 8.8 and matches that of the dinitrophenyl phosphate binding to a cationic pillar[5]arene.[22] Conversely, the rate constant decreases approximately 25-fold due to loss of nucleophilic sites upon protonation of imidazole groups (Table 1). Table 1. Rate and equilibria constants obtained in the hydrolysis of the phosphate diesters by P5IMD. Ester BDNPP BDNPP
pH
ko / s-1
kPKass / M-1s-1
Kass / M-1
kP / s-1
8.8
1.9x10
-7
0.164 ± 0.005
86 ± 7
1.91x10-3
1.9x10
-7
0.169 ± 0.006
94 ± 8
1.80x10-3
-7
0.131 ± 0.002
7.4
BDNPP
6.9
1.9x10
BDNPP
5.6
1.9x10-7
0.13 ± 0.01
BDNPP
4.3
1.9x10-7
0.558 ± 0.001
PDNPP EtDNPP
8.8 8.8
-8
3.58x10 3.1x10
-8
7170 ± 26
7.78x10-5
-1
35 ± 7
4.77x10-5
-3
56 ± 21
4.82x10-6
(167 ± 7)x10 (27 ± 3)x10
The first order rate constant for the reaction of 5 mM P5IMD with BDNPP at the plateau is 1.9x10-3 s-1, a value 2
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ACS Catalysis 270-fold greater than the rate constant of 7.1x10-6 s-1 calculated for the reaction of the substrate with 5 mM of free neutral imidazole, using the reported second order rate constant of 1.42x10-3 M-1 s-1.[18] The observed increase is substantially larger than any statistical correction due to the number of imidazole rings surrounding the substrate in one of the P5IMD rims. Clearly, a large increase in reactivity arises from the persistent interaction between imidazole and phosphorus at appropriates distance and geometry. Figure 3 shows that kobs increases with pH in the reaction of BDNPP with P5IMD, reaching a plateau at pH ~7, consistently indicating that reactivity increases with deprotonation of the imidazolium rings. In fact, the solid line in Figure 3 represents the fit of kinetic data considering the P5IMD species distribution as a polyprotic acid and using its five pKa values determined by the potentiometric titration. The rate constant of the fully dissociated P5IMD being 2.5-fold, 7,3-fold, 9,4 fold and 50-fold faster than the P5IMD species with 4, 3, 2 and 1 neutral imidazoles, respectively (see SI).
in water.[18] The reaction proceeds with formation of a phosphoroamidate intermediate, P5IMD-1 (see 31P NMR, Figure S16). Intermediate P5IMD-1 can either: i) react with water forming a complex of the catalyst and 2,4dinitrophenyl phosphate (P5IMD-M in Scheme 1); or ii) react with other imidazole group in an intramolecular reaction forming the phosphorodiamidate P5IMD-2 with additional release of 2,4-dinitrophenolate (a reaction important only at high pH). Subsequently, the fast hydrolysis of P5IMD-2 and P5IMD-3 results in the release of HPO42- regenerating the P5IMD catalyst. 10-3 10-4
kobs / s -1
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10-5 10-6 10-7
0
0,002
0,004
0,006
0,008
0,01
[P5IMD] / M Figure 4. Influence of P5IMD concentration on the first order rate constants for hydrolysis of (■ ) BDNPP, (●) PDNPP and (▲) EtDNPP in H2O:MeOH 65:35 (v/v), at 25 ºC and pH=8.8.
Scheme 1. Catalytic cycle for supramolecular phosphate diester hydrolysis.
Figure 3. Influence of pH on the first order rate constant for BDNPP hydrolysis in H2O:MeOH 65:35 (v/v), at 25 ºC. (■) [P5IMD]=5 mM; (---) in the absence of pillararene.
Figure 4 shows the effect of P5IMD on the hydrolysis of BDNPP compared with the effects upon hydrolysis of phenyl 2,4-dinitrophenyl phosphate (PDNPP) and ethyl 2,4-dinitrophenylphosphate (EtDNPP). The rate and equilibrium constants consistent with the fit are in Table 1. Although the leaving group is the same, changes in substrate structure promote large differences in reactivity, with an increase of rate constants of 1 : 7 : 520 for EtDNPP : PDNPP : BDNPP, respectively (Table 1). Thus, P5IMD reacts 520-fold with BDNPP than with EtDNPP, compared with a 5-fold effect observed in bulk water, acting as a selective supramolecular artificial enzyme.[18] Similarly, BDNPP reacts only 7-fold faster than EtDNPP with free imidazole.[18] The observed selectivity is related to differences in structure of the host:guest complexes with the asymmetric phosphate diesters (see below). Scheme 1 is consistent with the experimental data and previous results for the reaction of BDNPP with imidazole 3
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The inclusion complex, P5IMD-M, is responsible for the second slow kinetic process which corresponds to the P5IMD catalyzed hydrolysis of the 2,4-dinitrophenyl phosphate monoester and will be the subject of future reports. The slow reaction proceeds with general base catalysis by imidazole, since nucleophilic attack of imidazole on DNPP is not observed,[18] and decomposition of dinitrophenylphosphate in a non-functionalized cationic pillar[5]arene is 10-fold slower than observed in this work.[22] Phosphate transfer involving diesters are typically slow reactions involving concerted SN2(P) processes, with no additional intermediates of significant lifetime. In the trigonal bipyramidal transition state, nucleophile and leaving group are usually in the axial position. The two (equatorial) P−O− share more than a single negative charge and the third group in the equatorial plane is the nonleaving group of unsymmetrical diesters.[23-25] P5IMD complexation of asymmetric diesters was examined by molecular dynamic calculations, and 1H NMR spectroscopy. A PDNPP complexation induced downfield effect is observed for hydrogen atoms in position NCHN of imidazole (δ≈8.4ppm) substituted pillararene. Additionally, complexation induced upfield effect is observed for aromatic hydrogen atoms of the pillararene (δ≈6.4ppm). Remarkably, the aromatic hydrogen atoms of P5IMD do not show change in chemical shift upon BDNPP complexation, reflecting different complexation modes between PDNPP and BDNPP. In fact, PDNPP shows complexation induced upfield effect (Figure S21) both for hydrogens in the dinitrophenyl and in the phenyl rings, indicating that complexation takes place competitively by both sides of the phosphate diester. As shown in Scheme 2, P5IMD active site includes the P5IMD cavity and imidazole moieties circularly distributed at 72° angles. The nucleophilic N of the imidazole points towards the bulk solvent, and selectivity is a consequence of the molecular architecture, which prevents nucleophilic attack in axial position in relation to the microencapsulated leaving group (blue arrow in Scheme 2). The reactive pathway promotes the cleavage of the leaving group outside the cavity (green arrow in Scheme 2). Scheme 2. Nucleophilic attack pathways.
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Molecular dynamics calculations allow the snapshot of 1:1 host-guest complexes formed by insertion of PDNPP and EtDNPP into P5IMD cavity by both sides of diester (Figure 5). The reactive complexes are those where the nonleaving group is included in the cavity (B and D in Figure 5). Structures A and C (Figure 5) are unreactive, with the poorest leaving groups phenoxy and ethoxy, respectively, in the reactive position outside the cavity. Values of ∆G for host:guest complexes as a function of the interaction distance between the diesters and P5IMD were calculated (SI section) and the Average Force Potential calculated under conditions where 60% of the imidazole groups were protonated. For the asymmetric diesters, ∆G values showed that inclusion of the dinitrophenyl group of PDNPP (nonreactive complex) is preferential and consistent with the selectivity promoted by P5IMD. Conversely, inclusion of EtDNPP takes place mostly by the ethoxy group.
Figure 5. Snapshot of 1:1 host-guest complex of phosphate diesters and P5IMD. A and B show insertion of PDNPP by dinitrophenol and phenol moieties respectively. C and D show insertion of EtDNPP by dinitrophenol and ethoxy groups respectively.
Detailed analysis of the complex reveals important consequences of the docking mode. Inclusion of the phenoxy group of PDNPP decreases the average distance between the phosphorus atom and the center of the cavity by less than 1Å relative to the position obtained by its inclusion by the dinitrophenyl moiety. This effect increases in the complex formed by EtDNPP where the distance from phosphorus atom to the center of the cavity decreases more than 2Å on going from inclusion of dinitrophenoxy to ethoxy groups. Deeper inclusion of phosphorus atom in the cavity of the host:guest complex separates the reactive center from the nucleophilic imidazole group decreasing its reactivity. In conclusion, P5IMD is a very efficient and selective supramolecular catalyst for phosphate diester hydrolysis 4
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ACS Catalysis showing a 104 rate enhancement at neutral pH in comparison with bulk water. The phosphate diester hydrolysis proceeds via nucleophilic attack on the host:guest complex with expulsion of the leaving group placed outside the pillararene cavity. Geometrical restrictions preclude nucleophilic attack with expulsion of the leaving group docked inside the cavity. These spatiotemporal arrangements promote an increase in selectivity, which reaches 102-fold higher than in bulk water. Formation of nonproductive host:guest supramolecular complexes, with the best leaving group being docked into the cavity, allows to consider P5IMD as an example of highly efficient and selective artificial enzyme.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedure, NMR characterization of the host:guest complexes and reaction monitoring, as well as molecular dynamic calculations (pdf).
AUTHOR INFORMATION Corresponding Authors * Email:
[email protected] * Email:
[email protected] ORCID Eduardo H. Wanderlind: 0000-0002-0534-5898 Rodrigo Montecinos: 0000-0003-0080-1839 Luis Garcia-Rio: 0000-0003-2802-8921 Faruk Nome: 0000-0001-8864-6807
Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT The authors thank Brazilian funding from CNPq, CAPES and FAPESC, and CEBIME (UFSC) for HRMS analysis; and financial support from Ministerio de Economia y Competitividad of Spain (projects CTQ2014-55208-P and CTQ2017-84354-P), Xunta de Galicia (GR 2007/085; IN607C 2016/03 and Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09) and the European Union (European Regional Development Fund-ERDF).
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lecular General Base Catalysis in the Hydrolysis of a Phosphate Diester. Calculational Guidance to a Choice of Mechanism. J. Org. Chem. 2013, 78, 1343-1353.
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