Terminal Carboxylate Effects on the Thermodynamics and Kinetics of

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Terminal Carboxylate Effects on the Thermodynamics and Kinetics of Cucurbit[7]uril Binding to Guests Containing a Central Bis(Pyridinium)-Xylylene Site Iago Neira, Marcos D. García, Carlos Peinador, and Angel E. Kaifer J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02993 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019

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The Journal of Organic Chemistry

Terminal Carboxylate Effects on the Thermodynamics and Kinetics of Cucurbit[7]uril Binding to Guests Containing a Central Bis(Pyridinium)Xylylene Site Iago Neira,a,b Marcos D. García,b Carlos Peinadorb and Angel E. Kaifera,*

aDepartment bDepartamento

of Chemistry, University of Miami, Coral Gables, FL 33124, U.S.A.

de Química and Centro de Investigaciones Científicas Avanzadas (CICA).

Facultad de Ciencias, Universidade da Coruña, 15071, A Coruña, Spain. [email protected]

ABSTRACT A series of bis(pyridinium)-xylylene derivatives bearing carboxylate terminal groups were investigated as guests for the cucurbit[7]uril host in aqueous solution. While the presence of the terminal carboxylates has a modest effect on the thermodynamic stability of the complexes, the kinetics of complex association/dissociation is strongly affected. The relative position (meta, para) of the carboxylate group in relation to the pyridinium nitrogen also exerts a considerable effect on the binding kinetics.

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The cucurbit[n]uril1-4 (n = 5-8, 10, 13-15) hosts are a family of macrocycles formed by n glycoluril units connected by 2n methylene bridges. They exhibit a barrel-shaped structure with an equatorial plane of symmetry and an internal cavity, which can be accessed through two identical portals, lined by carbonyl oxygens. In aqueous solution the cucurbit[n]urils can reach extremely high binding affinities5,6 with guests containing hydrophobic moieties that fit well inside the cavity and positive charges suitably located to generate favorable ion-dipole interactions with the rims of carbonyl oxygens on the portals. Since the portals are rich in electronic density, they tend to hinder the binding of negatively charged guests. For instance, a good number of ferrocene derivatives are known to be excellent guests for cucurbit[7]uril (CB7, see structure in Figure 1), with binding affinities in the nanomolar to picomolar regime.7-9 In drastic contrast, ferrocenecarboxylate7 is not bound at all by CB7, arguably because of the strong electrostatic repulsions between the carboxylate on the guest and the carbonyl oxygens on one of the host portals that would result if the ferrocene moiety were included by the host cavity. We have investigated guests containing a 4,4’-bipyridinium (viologen) nucleus connected to aliphatic chains terminated in carboxylic acid groups.10 When the terminal -COOH groups are protonated the predominant binding site for CB7 is one of the two aliphatic side arms. However, upon deprotonation, the -COO- terminal groups repel the CB7 and confine it to the central viologen nucleus. Therefore, proton transfer reactions exert control on the average structure of these pseudo-rotaxane complexes. We also measured the kinetics of formation and dissociation of these complexes and noted that deprotonation of the terminal carboxylates leads to substantially slower binding kinetics compared to the same guests in the protonated state.11


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This kinetic slowdown is consistent with the anticipated difficulties expected to get a -COOgroup through the CB7 cavity.

Figure 1. Structures of the CB7 host and the guests surveyed here.

In this work, we decided to investigate a different class of CB7 guests, composed of a central bis(pyridinium)-xylylene binding site and terminal carboxylate groups. The structure of the relevant compounds is shown in Figure 1. Guest 12+ simply contains the central binding site without any terminal carboxylic acid groups. It is included here as the parent compound and was already partially investigated by our group.12 Guests 22+ and 32+ have a terminal carboxylic acid on each side arm, differing on their position relative to the pyridinium nitrogens. Finally, guest 42+ has two carboxylic acids on each side arm. Since we were interested on the effects that the negatively charged carboxylates may exert on the thermodynamics and kinetics of binding, we primarily carried out our experiments in neutral media to drive complete deprotonation of the carboxylates. Therefore, under neutral pH conditions guests 2 and 3 become zwitterionic and guest 42- is a dianion.



CB7 was synthesized according to a literature method13 and its effective molecular weight determined as reported by our group.14 The guests were all prepared by reaction of dixylylene bromide with excess of the corresponding pyridine derivative in acetonitrile (see Experimental Section). Guests 12+ and 22+ had been previously reported, 12,15 while 32+ and 42+ are new. We also tried to prepare the derivative with a single ortho-carboxylate on each sidearm, but reaction of dixylylene bromide with picolinic acid led to decarboxylation and isolation of compound 12+. The binding interactions were initially assessed using 1H NMR spectroscopy. Figure 2 shows the changes observed in the NMR spectra of guest 22+ upon addition of CB7 in D2O solution. In the presence of 0.5 equivalents of CB7, we observed resonances corresponding to the bound and the free guests. In other words, the host exchange process is slow in the NMR time scale. Upon addition of 1.0 equivalent of CB7, the signal corresponding to the central aromatic protons (‘d’) on the guest is shifted upfield by ca. 1 ppm. This is a clear indication for the inclusion of the central aromatic inside the host cavity. While CB7 complexation shifts the resonances for protons ‘c’ and ‘b’ slightly upfield, the signal for proton ‘a’ shifts downfield. Overall, these complexation-induced shifts are consistent with the formation of a symmetric pseudo-rotaxane complex in which the CB7 host occupies the central bis(pyridinium)-xylylene site. Similar NMR spectroscopic data patterns were obtained with guests 12+ and 32+ (see data in S.I.), revealing the formation of similar symmetric pseudo-rotaxanes in these cases as well. In contrast to this, addition of CB7 to a D2O solution containing compound 42+ leads only to peak broadening of the guest’s central proton signal, suggesting external and rather weak interactions with the CB7 host. We also verified the formation of 1:1 complexes between CB7 and guests 22+ and 32+ using


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ESI mass spectrometric experiments in which we detected intense peaks corresponding to CB722+ and CB732+ (see data in S.I.) The pKa values for the simplified model cations 4- and 3-carboxy-1-methylpyridin-1-ium were estimated as 3.03 and 2.78, respectively (see details in Experimental Section), suggesting that the terminal carboxylic acid groups on compound 22+ and 32+ are relatively acidic. Since the reported pKa for CB7 is 2.2,16 it becomes impossible to investigate the binding affinity of the acidic forms of these two compounds, as CB7 would be protonated and the large concentration of protons would interfere with the binding properties of the hosts.

Figure 2. Partial 1H NMR spectra (D2O, pD=7.6, 400 MHz) of 1 mM 22+ (i) in the absence of CB7, and in the presence of (ii) 0.5 equiv of CB7, and (iii) 1.0 equiv of CB7.

The UV-Vis spectra of guest 2 in aqueous solution (pH 7.3) shows a band with maximum absorption at 262 nm (Figure 3). Upon addition of increasing concentrations of CB7 this band experiences a bathochromic shift and depressed absorbance. These features can be used to determine the equilibrium association constant (K) between CB7 and 2 by fitting the absorbance



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titration data to a 1:1 binding isotherm. Similar results were obtained with 3 at the same pH and the resulting values are given in Table 1.

Figure 3. Partial UV-Vis spectra and titration (top right insert) of guest 22+ (90 M) in aqueous solution (pH 7.3) in the presence of increasing concentrations of CB7. The concentration of CB7 increases from 0 to more than 3 equivalents in the direction of the arrow.

In order to investigate the kinetics of dissociation of these complexes, particularly in neutral pH solutions, we exposed each of the zwitterionic complexes (CB72 or CB73) in neutral aqueous solution

to

an

excellent

guest

for

the

CB7

host.

We

selected

the

ferrocenylmethyltrimethylammonium (Fc+) cation, which is known to form a highly stable complex with CB7 in aqueous solution,8 with a K value ca. six orders of magnitude higher than


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those of the CB7 complexes investigated here. The large difference in the K value insures a strong thermodynamic driving force pulling the CB7 out from the CB72 (or CB73) complex to form the much more stable CB7Fc+ complex. The dissociation process can be readily followed by NMR spectroscopy, as the signal for the free ‘d’ protons on guest 2 increases in intensity with time at the expense of the signal corresponding to the same protons in the complexed guest. The dissociation process is extremely slow, to the point that even after 15 days of exposure to the Fc+ cation, about 20% of the initial CB72 still remains in the solution. In contrast to this, the dissociation is much faster in acidic medium (pH 2.7), for the partially protonated guest 22+, as the dissociation is almost complete after exposure to the Fc+ cation for about 1h (Figure 4). Similar results were observed with guest 32+, but the dissociation processes seem to be generally faster in this case. The kinetic constants for dissociation (kOFF) extracted from these NMR experiments are given in Table 1, which also contains kinetic constants for association (kON) calculated from the simple expression, kON = K × (kOFF). Table 1. Thermodynamic (K) and kinetic (kON and kOFF) constant values for the binding interactions at 25 oC between guests 22+ and 32+ and the CB7 host at two different solution pH values. pH

Complex

K (M-1)

kON (M-1 s-1)

kOFF (s-1)

7.3

CB72

6.5 × 105

0.62

9.6 × 10-7

7.3

CB73

5.6 × 105

3.37

6.0 × 10-6

2.7

CB722+

ND

--

4.8 × 10-4

2.7

CB732+

ND

--

4.3 × 10-3

(ND) Not determined due to incomplete protonation of the terminal carboxylates and the partial protonation of CB7 at pH 2.7.



Figure 4. Partial 1H NMR (D2O, 400 MHz) spectra showing the dissociation of the CB722+ complex (1.0 mM) in the presence of 1.0 mM Fc+ as the competing guest. The red rectangle frames the xylylene proton signals of CB722+, while the blue rectangle frames the xylylene protons of free 22+. (i) In the absence of Fc+, (ii) 2 min (iii) 7 min, (iv) 20 min, and (v) 72 min after addition of Fc+.

The data in Table 1 are consistent with our previously reported findings on the complex between CB7 and guest 12+, as we estimated a minimum K value of 106 M-1 for this complex.12 We did not determine the K values at pH 2.7 because the calculated pKa values for relevant model compounds suggest the presence of both protonated and deprotonated termini at this pH value. At higher pH, where the carboxylates are fully deprotonated, both new guests, 2 and 3, form highly stable CB7 complexes, with binding affinities close to the micromolar regime under neutral pH conditions, probably reflecting weak electrostatic repulsions between the terminal carboxylate groups on the guest and the two ends (cavity portals) on the centrally located CB7 host. We must note here that Shi and co-workers have reported a much lower value (85 10 M1)

for the binding constant between the bis(ethyl ester) form of guest 22+ and CB7 in D2O

solution.15 Since the binding site for CB7 is the same in both cases, we believe that this value was erroneously determined because these authors failed to measure the effective molecular weight of their CB7 sample, leading to an overestimation of the CB7 concentrations in their


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experiments. This is a common problem encountered with many cucurbit[n]uril samples when using their nominal molecular weights.14 In any instance, a K value of 85 M-1 is substantially lower than any other values determined for CB7 complexes with similar xylylene-based dicationic guests.17 Full deprotonation of the terminal carboxylates on guests 22+ and 32+ leads to zwitterionic guests (2 and 3) in which the dissociation kinetic processes are much slower than in their partially protonated counterparts (Table 1). The values obtained for the CB7 dissociation from either complex (CB72 or CB73) are similar to those previously reported by our group for the dissociation of a complex formed by CB7 and an axle-type guest containing a central viologen nucleus and two terminal carboxylate groups.11 An interesting aspect of our results revolves around the finding that the relative position of the carboxylic acid group versus the pyridinium nitrogen on the terminal phenyl rings affects the kinetics of the association and dissociation steps. Clearly placing the carboxylate groups on the para ring positions is more effective at slowing down the kinetics than placing them on the meta ring positions. The effect is substantial and results in differences of about one order of magnitude in the kOFF and kON values, regardless of the state of protonation of the carboxylic acid groups. The reasons behind this para versus meta effect are not entirely clear at this time. It can be argued that positioning of the carboxylate on the para position affords a more symmetric guest approach, in which the negative charge on the carboxylate affects equally all the carbonyl oxygens on the CB7 portal. In contrast, meta positioning may give rise to attractive forces from the positive charge on the pyridinium nitrogen to the rim of carbonyl oxygens on the portal, which will facilitate cavity insertion of the carboxylate. This situation is schematically represented in Figure 5.



Figure 5. Differences on the approach of guests 2 (top) and 3 (bottom) to the cavity of CB7.

Compound 42+ is not an effective guest for CB7 binding. Clearly, the presence of two carboxylates on each pyridinium ring creates a strong steric and electrostatic barrier for threading of the guest through the host cavity. Therefore, only weak external host-guest interactions take place in this case, as suggested by the broadening observed on the NMR resonance of the guest’s central aromatic protons upon addition of CB7. In conclusion, this work provides clear new evidence that terminal carboxylates on axle-type guests result in strong kinetic barriers for the formation and dissociation of pseudo-rotaxane complexes with the CB7 host. We have also observed a clear effect on the kinetic rate constants resulting from the relative location (para or meta versus the pyridinium nitrogen) of the carboxylate ring. On the other hand, the terminal carboxylate effects on the thermodynamic stability of the complexes are considerably less pronounced. EXPERIMENTAL SECTION


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Materials. Guest compounds 12+ and 22+ were prepared according to literature procedures.12,15 CB7 was prepared following Day and coworkers13 and its purity assessed as previously reported by our group.14 All other solvents and chemicals were commercially available and used as received. Synthesis

of

bis(3-carboxypyridinium)-p-xylylene

(32+).

A

mixture

of

1,4-

bis(bromomethyl)benzene (500 mg, 1.89 mmol) and nicotinic acid (466 mg, 3.78 mmol) in 45 mL of CH3CN was refluxed 18 hours. The white precipitate formed was filtered and washed with hot CH3CN and dried under vacuum to afford the final product (842 mg, 87%). 1H NMR (400 MHz, D2O): δ 9.19 (s, 2H), 8.87 (d, J = 6.3 Hz, 2H), 8.82 (d, J = 8.2 Hz, 2H), 8.07 – 7.99 (m, 2H), 7.48 (s, 4H), 5.83 (s, 4H) ppm. 13C{1H} NMR (100 MHz, D2O): δ 165.4, 146.6, 146.1, 145.6, 134.1, 133.8, 130.1, 128.5, 64.2 ppm. HRMS (ESI-TOF) m/z: Calcd for [M - 2Br]2+ C20H18N2O42+ 175.0628; Found 175.0641. Synthesis

of

bis(3,5-dicarboxypyridinium)-p-xylylene

(42+).

A

mixture

of

1,4-

bis(bromomethyl)benzene (250 mg, 0.97 mmol) and pyridine-3,5-dicarboxylic acid (316mg, 3.78 mmol) in 40 mL of CH3CN and 10 mL of DMF was refluxed 18 hours. The white precipitate formed was filtered and washed with hot CH3CN and dried under vacuum to afford the final product (172 mg, 30%). 1H NMR (400 MHz, D2O): δ 9.18 (d, J = 1.6 Hz, 4H), 9.06 (t, J = 1.6 Hz, 2H), 7.49 (s, 4H), 5.85 (s, 4H). ppm. 13C{1H} NMR (100 MHz, D2O): δ 167.2, 145.9, 144.9, 137.3, 134.1, 130.0, 64.2. ppm. HRMS (ESI-TOF) m/z: Calcd for [M - 2Br]2+ C22H18N2O82+ 219.0526; Found 219.0507. Methods. UV-Vis titrations were carried out by measuring the electronic absorption spectra of solutions containing a constant concentration of guest and variable concentrations of host. To determine the equilibrium association constants, absorbance values at a fixed wavelength (261



nm) were fitted to a 1:1 binding isotherm using open source fitting software (available at http://supramolecular.org/). Time dependent NMR experiments were carried out in D2O solutions at controlled pD values. Dissociation constants were determined by fitting the time dependent concentrations, measured by integration of the proper resonances, to first-order kinetics.

The pKa values for model pyridinium acid compounds were estimated using

MarvinSketch software (version 6.2.2), calculation module, developed by ChemAxon (http://www.chemaxon.com/products/marvin/marvinsketch).

ASSOCIATED CONTENT Supporting Information NMR spectroscopic data, thermodynamic and kinetic studies on the host-guest binding interactions between CB7 and guests 2 and 3 under acidic and neutral conditions. The Supporting Information (PDF file) is available free of charge on the ACS Publications website. AUTHOR INFORMATION Corresponding Author *Angel E. Kaifer, Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA. Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT


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The authors are grateful to the U.S. National Science Foundation (to AEK, CHE-1412455) and Ministerio de Economía, Industria y Competitividad (to CP, MINECO FEDER CTQ2016-75629-P) for the generous support of this work. IN acknowledges the MECD (FPU program) for financial support.

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(10) Sindelar, V.; Silvi, S.; Kaifer, A. E. Switching a Molecular Shuttle On and Off: Simple, pHControlled PseudorotaxanesBased on Cucurbit[7]uril. Chem. Commun. 2006, 2185-2187. (11) Kaifer, A. E.; Li, W.; Silvi, S.; Sindelar, V. Pronounced pH Effects on the Kinetics of Cucurbit[7]uril-based Pseudorotaxane Formation and Dissociation. Chem. Commun. 2012, 48, 6693-6695. (12) Sindelar, V.; Moon, K.; Kaifer, A. E. Binding Selectivity of Cucurbit[7]uril: Bis(pyridinium)-1,4xylylene versus 4,4 '-Bipyridinium Guest Sites. Org. Lett. 2004, 6, 2665-2668. (13) Day, A.; Arnold, A. P.; Blanch, R. J.; Snushall, B. Controlling Factors in the Synthesis of Cucurbituril and its Homologues. J. Org. Chem. 2001, 66, 8094-8100. (14) Yi, S.; Kaifer, A. E. Determination of the Purity of Cucurbit[n]uril (n=7, 8) Host Samples. J. Org. Chem. 2011, 76, 10275-10278. (15) Mei, L.; Xie, Z. N.; Hu, K. q.; Yuan, L. Y.; Gao, Z. Q.; Chai, Z. F.; Shi, W. Q. Supramolecular Host– Guest Inclusion for Distinguishing Cucurbit[7]uril-Based Pseudorotaxanes from Small-Molecule Ligands in Coordination Assembly with a Uranyl Center. Chem. Eur. J. 2017, 23, 13995-14003. (16) Hwang, I.; Jeon, W. S.; Kim, H. J.; Kim, D.; Kim, H.; Selvapalam, N.; Fujita, N.; Shinkai, S.; Kim, K. Cucurbit[7]uril: A Simple Macrocyclic, pH-Triggered Hydrogelator Exhibiting Guest-induced Stimuli-responsive Behavior. Angew. Chem. Int. Ed. 2007, 46, 210-213. (17) Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.; Zavalij, P. Y.; Isaacs, L. The Cucurbit[n]uril Family: Prime Components for Self-Sorting Systems. J. Am. Chem. Soc. 2005, 127, 15959-15967.


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Terminal Carboxylate Effects on the Thermodynamics and Kinetics of

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