Letter pubs.acs.org/OrgLett
Probing Interactions between Hydrocarbons and Auxiliary Guests inside Cucurbit[8]uril Ramin Rabbani and Eric Masson* Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, United States S Supporting Information *
ABSTRACT: The affinities of 20 hydrocarbons for the cavity formed by the inner wall of cucurbit[8]uril and a tolyl unit linked to an auxiliary guest were measured in aqueous solution. Cucurbit[8]uril and the auxiliary guest, a substituted ruthenium tris(2,2′-bipyridyl) complex bearing a trifluoromethyl 19F NMR probe, displayed perfect selectivity toward cyclic hydrocarbons, and cis- and trans-decalin, in particular. Unlike π−π interactions, CH−π interactions, as well as differences in hydrocarbon solvation, contribute significantly to the recognition process.
C
ucurbit[n]urils (CB[n])1 form extremely tight complexes with a large number of guests in aqueous medium, with binding affinities higher by several orders of magnitude compared to cyclodextrins and other macrocycles.1a While positive substituents attached to the guest certainly enhance binding affinities upon interaction with the partially negative carbonylated portal of the macrocycles, the latter can also encapsulate neutral guests and even hydrocarbons.2 For example, Nau and co-workers measured a binding affinity of 1.3 × 106 M−1 for cyclopentane encapsulation into CB[6],2 and Isaacs and Lu measured a binding constant of 1.5 × 107 M−1 for diamantane into CB[8].3 The driving force of the binding event is the ejection of “high-energy” water from the cavity of CB[n]s, a process that is both enthalpically and entropically favorable.4 The impact of dispersive interactions between the guest and the inner wall of CB[n] is unclear, however: CB[n]s are notoriously nonpolar and nonpolarizable,4b thereby limiting such interactions; but a tight fit between the guest and the host, with interatomic distances falling within approximately 3 Å, necessarily generates such forces.5 While hydrocarbons have been encapsulated into CB[n]s (n = 6−8)2,3 and into acyclic congeners3 as sole guests, the ability of CB[8] to encapsulate two guests in its cavity6 has never been exploited toward hydrocarbon recognition. One can indeed suspect that small hydrocarbons could insert into the cavity formed between the outer surface of an auxiliary guest and the inner wall of CB[8], with some degree of selectivity. The objective of this study is to test this hypothesis. Our hydrocarbon capture assay consists of (1) forming a ternary complex between two auxiliary guests and CB[8] in the presence of an excess amount of the free macrocycle in aqueous conditions and (2) quantifying by nuclear magnetic resonance spectroscopy (NMR) the formation of the heteroternary complex formed by CB[8], the auxiliary guest, and the hydrocarbon (labeled H below) upon addition of an excess amount of the latter as a pure liquid. The excess amount of CB[8] is expected to favor the formation of the heteroternary complex © XXXX American Chemical Society
by preventing the formation of free auxiliary guest during the competition. The auxiliary guest must abide by a series of stringent requirements: (1) its binding affinity toward CB[8] should be high enough to form homoternary complexes but low enough to allow competitive binding by hydrocarbons; (2) its structure should generate readily decipherable 1H NMR spectra or contain NMR active isotopes that can be monitored instead; (3) it should exchange slowly on the NMR time scale as to readily quantify homo- and heterocomplexes by integration of their relevant signals; and (4) its structure should allow a systematic variation of its CB[8]-binding unit in subsequent studies. With these conditions in mind, we prepared auxiliary guest 1, a ruthenium(II) tris(2,2′-bipyridyl) complex, with one of the ligands bearing (1) a tolyl group at position 4′ as CB[8]-binding unit, (2) a carboxylate substituent at position 6′ to hamper CB[8] binding, and (3) a trifluoromethyl group at position 4 to allow easy monitoring of the binding event by 19F NMR spectroscopy. Opting for a metal−ligand complex was motivated by an earlier observation7 that Fe(II) and Ir(III) bis-terpyridine complexes with CB[7]- and CB[8]-binding units at position 4′ exchange slowly with the macrocycles on the NMR time scale. We also initially considered the possibility for fluorescence emission alterations upon hydrocarbon binding, but complex 1 was found to be nonemissive. Auxiliary guest 1 was prepared in five steps from 4trifluoromethylpyridine (see Figure 1).8 Selective acetylation of the later at position 2 followed by α-iodination and substitution with pyridine afforded intermediate 2 in a 55% yield.9 Condensation with intermediate 3 (formed by the aldol condensation of sodium 2-oxopropanoate and 4-tolualdehyde and subsequent elimination) afforded ligand 4.10 Heating the latter with a stoichiometric amount of Ru(II) bis(2,2′-bipyridyl) dichloride in an ethanol/water mixture afforded auxiliary guest 1 (60%) as a racemic mixture of Λ and Δ isomers.11 Received: June 27, 2017
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DOI: 10.1021/acs.orglett.7b01966 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
A series of 20 hydrocarbons, all liquid at room temperature, were then added to homoternary complex 12·CB[8]. The set contained six unbranched aliphatic members (C5−C10), seven cycloalkanes (C5−C8 and C10, as well as cis- and trans-decalin), six cycloalkenes (cyclopentene, cyclohexene, 1,3- and 1,4cyclohexadiene, cycloheptene, cyclooctatetraene), as well as benzene. Formation of heteroternary complex 1·H·CB[8] upon addition of an excess amount of hydrocarbon and sonication resulted in a new 19F NMR signal, upfield by 0.09−0.84 ppm from the one pertaining to homocomplex 12·CB[8] (see Figure 2
Figure 2. 19F NMR spectra of homoternary complex 12·CB[8] and heteroternary complex 1·H·CB[8] formed upon addition of an excess amount (10 μL) of (a) cyclopentane, (b) cyclohexane, (c) cycloheptane, and (d) trans-decalin to a 2.0 mM solution of complex 12·CB[8] (0.50 mL) in deuterium oxide.
and Table 1). All cyclic hydrocarbons except cyclodecane underwent encapsulation, while aliphatic members of the series did not show any affinity toward the auxiliary guest 1/CB[8] pair. While all 19F NMR signals pertaining to heteroternary complexes 1·H·CB[8] are located upfield from the 12·CB[8] pair of singlets, the magnitude of the shift varies greatly, with larger hydrocarbons generally generating larger shifts (cyclopentane and cyclopentene do not follow this trend). One can conclude that the distortion of the assembly caused by encapsulation is hydrocarbon-specific. The remarkably high shift observed with cyclooctane, cis- and trans-decalin compared to all other hydrocarbons (0.79−0.84 ppm vs 0.09−0.37 ppm; see Figure 2) suggests a profound change in overall geometry upon encapsulation of those large guests. The assay allowed us to quantify binding affinities of hydrocarbons relative to a reference hydrocarbon; benzene was chosen as reference as it is the sole aromatic member of the set. H Equilibrium (1) was first considered, and its constant Kaq→CB readily obtained from corresponding eq 2. SH and SCB[8] are the concentrations of free hydrocarbon H and free CB[8] at saturation in the medium, i.e., within a good approximation, their solubility in water.12 1 1 (12 ·CB[8]) + H + CB[8] ⇄ 1·H · CB[8] (1) 2 2
Figure 1. Preparation of auxiliary guest 1. 1H NMR spectra of (a) auxiliary guest 1 and (b) homoternary complex 12·CB[8]. 19F NMR spectra of (c) auxiliary guest 1 and (d) homoternary complex 12·CB[8] in deuterium oxide.
Guest 1 formed a well-defined homoternary complex in the presence of 0.50 equiv of CB[8] in deuterium oxide, as shown by both 1H and 19F NMR spectroscopy (see Figure 1). Large upfield shifts are observed for all hydrogens of the CB[8]-binding tolyl unit (0.89−1.42 ppm), and 19F NMR spectroscopy allows easy monitoring of the binding process, with the chemical shift of the fluorine nuclei shifting downfield by 0.88 ppm upon complexation. The split into two singlets separated by 0.010 ppm (see Figure 1) is caused by the formation of the two pairs of diastereomers ΔΔ/ΛΛ-1 and ΔΛ/ΛΔ-1. Addition of an excess amount of CB[8] (with most of it remaining in suspension) did not impact the formation of the ternary complex (i.e., binary complex 1·CB[8] was not formed concomitantly). We also note that the carboxylate unit remains deprotonated in pure deuterium oxide in the presence of CB[8].
H K aq → CB =
[1·H ·CB[8]] [12 ·CB[8]]1/2 ·SH·SCB[8]1/2
(2)
Equilibrium (3) and eq 4 are used to calculate the binding rel of a hydrocarbon toward the auxiliary guest 1/ affinity Kaq→CB CB[8] pair, relative to a reference hydrocarbon Href. 1·H ref ·CB[8] + H ⇄ 1·H · CB[8] + H ref B
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DOI: 10.1021/acs.orglett.7b01966 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Physical Properties of Hydrocarbons H and Their Binding Affinities toward the Auxiliary Guest 1/CB[8] Pair hydrocarbon H cyclopentane cyclopentene cyclohexane cyclohexene 1,3-cyclohexadiene 1,4-cyclohexadiene benzene cycloheptane cycloheptene cyclooctane cyclooctatetraene cis-decalin trans-decalin
Va 96 92 112 108 104 104 100 130 126 148 131 173 173
SHb
Pvap,Hd −3
2.4 × 10 1.1 × 10−2 7.2 × 10−4 3.0 × 10−3 1.3 × 10−2 c 1.2 × 10−2 2.3 × 10−2 2.4 × 10−4 6.7 × 10−4 7.1 × 10−5 3.2 × 10−3 c 7.2 × 10−6 7.2 × 10−6
−1
4.2 × 10 5.1 × 10−1 1.3 × 10−1 1.2 × 10−1 1.3 × 10−1 9.0 × 10−2 1.3 × 10−1 2.9 × 10−2 3.3 × 10−2 1.7 × 10−2 c 1.0 × 10−2 1.0 × 10−3 1.6 × 10−3
Δδe
f Krel aq→CB
g ΔGrel aq→CB
h ΔGrel H→CB
i ΔGrel gas→CB
0.103 0.112 0.090 0.097 0.172 0.102 0.274 0.257 0.157 0.790 0.368 0.841 0.839
14 5.6 160 14 2.2 4.2 1.0 65 140 130 5.6 8700 7500
−1.57 −1.02 −3.00 −1.56 −0.48 −0.85 0.00 −2.47 −2.94 −2.86 −1.02 −5.38 −5.28
−0.26 −0.56 −1.07 −0.43 −0.16 −0.51 0.00 0.05 −1.00 0.32 0.00 −0.93 −0.85
0.47 0.26 −0.94 −0.40 −0.11 −0.68 0.00 −0.65 −1.65 −0.63 −1.34 −3.47 −3.10
a
Hydrocarbon volume (in Å3) (CPK model, see the Supporting Information for details). bHydrocarbon H solubility in water (in M).12 cCalculated; see the SI for details. dVapor pressure of hydrocarbon H (in bar).13 eChemical shift of the trifluoromethyl unit in complex 1·H·CB[8] relative to complex 12·CB[8]. fRelative binding affinity of the hydrocarbon toward the auxiliary guest 1/CB[8] pair in deuterium oxide. gRelative free binding energy of the hydrocarbon to the auxiliary guest 1/CB[8] pair (in kcal/mol). hRelative free energy of transfer of the hydrocarbon from its liquid phase to the cavity formed by CB[8] and auxiliary guest 1 (in kcal/mol). iRelative free energy of transfer of the hydrocarbon as an ideal gas to the cavity formed by CB[8] and auxiliary guest 1 (in kcal/mol). The reference hydrocarbon is benzene in all cases. rel K aq → CB =
[1·H ·CB[8]]·SH ref [1·H ref ·CB[8]]·SH
except in the C7 subset. Cyclopentane binds 2.6 times better than cyclopentene, and the affinity of cyclohexane is 11, 71, 38, and 160 times higher than cyclohexene, 1,3-cyclohexadiene, 1,4cyclohexadiene, and benzene, respectively. Cyclooctane also binds 22 times tighter than cyclooctatetraene. Among the 13 hydrocarbons that do bind to the auxiliary guest 1/CB[8] pair, benzene displays the lowest affinity. Before attempting to justify these trends, one should remember that forces at play in the recognition process are not only the interaction between the hydrocarbon, the auxiliary unit and the inner wall of CB[8], but also the desolvation energy of the hydrocarbon upon binding. To separate this effect, we H propose to calculate free energies ΔGH→CB , which correspond to the transfer of the hydrocarbon from its liquid phase (and not from the aqueous solution) to the cavity of CB[8] (see eqs 7 and 8; c(H)liq is the concentration of hydrocarbon in its liquid phase).
(4)
Substituting terms [1·H·CB[8]] and [1·Href·CB[8]] using eq rel 2 affords a simple expression for Kaq→CB and the corresponding relative free energy term (eqs 5 and 6). rel K aq → CB =
H K aq → CB H ref K aq → CB
rel rel ΔGaq → CB = − RT ln K aq → CB
(5)
(6)
The concentrations of assemblies 12·CB[8] and 1·H·CB[8] can be readily measured by integration of their relevant 19F NMR signal after calibration with an external standard present at a known concentration (2,2,2-trifluoroethylammonium chloride). As long as the solubility of free CB[8] does not depend on the nature of the added hydrocarbon (a reasonable approximation), knowing its exact solubility in this specific medium is not needed, as this term cancels out in the determination of the relative equilibrium constant Krel aq→CB. We note that while hydrocarbons do exhibit some affinity for CB[8] as standalone guests,3 the formation and concentration of complexes Hn·CB[8] (n ≥ 1) is irrelevant to equilibria 1 and 3 and to all associated equilibrium constants and free energy terms. A series of trends can be extracted from the relative binding constants (see Table 1): (1) guest volume plays a major role, with linear alkanes being too small (or thin) to undergo encapsulation, and cyclodecane being too large, most likely due to transannular repulsion. Cyclohexane also displays a stronger interaction for the auxiliary guest 1/CB[8] pair than cyclopentane and cycloheptane, by 11- and 2.5-fold, respectively. In the cycloalkene series, which are slightly smaller than their cycloalkane counterparts, cycloheptene binds better than cyclopentene and cyclohexene by 26- and 10-fold, respectively. cis- and trans-Decalin display remarkably strong binding affinities, up to 8.7 × 103 times higher than benzene, and at least 105 times higher than parent cyclodecane. (2) Adding degrees of unsaturation to the cyclic hydrocarbons decreases their binding affinities toward the auxiliary guest 1/CB[8] pair,
1 1 (12 ·CB[8]) + Hliq + CB[8] ⇄ 1·H · CB[8] 2 2
KHH→ CB =
[1·H ·CB[8]] [12 ·CB[8]]1/2 ·c(H)liq ·SCB[8]1/2
(7)
(8)
In addition to separating aqueous solvation from the recognition process, this free energy term has the advantage of being independent of the hydrocarbon solubility in water, an important source of experimental error in relation 2. Free energies ΔGrel H→CB use benzene as reference again. We note that, rel relative to benzene, the ΔGH→CB term is also the sum of the binding affinity of hydrocarbon H to the guest 1/CB[8] pair in aqueous solution ΔGrel aq→CB and of the relative solvation Gibbs energy ΔGrel H→aq of the hydrocarbon from its liquid phase to the aqueous solution. Ben-Naim14 showed that using a molarity scale to characterize the transfer of one solute molecule between phases (liquid hydrocarbon and aqueous solution in our case) at constant pressure and temperature affords a bona fide measure of the relative interaction between the solute molecule and its surroundings in both phases and this at any solute concentration; furthermore, the solvation term is independent of any standard state.14 C
DOI: 10.1021/acs.orglett.7b01966 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1 shows that most trends are lost using this new energy term. The reduction of its overall magnitude compared to rel ΔGaq→CB is striking, however (−1.1 to +0.3 kcal/mol range compared to −5.4 to +0.0 kcal/mol; see Table 1). One can thus conclude that (1) the desolvation of hydrocarbons upon encapsulation into CB[8] has a major impact on binding affinities measured in aqueous solution and (2) the cohesive forces between the hydrocarbons in the liquid state are responsible for the narrower range of relative free energies ΔGrel H→CB. In order to isolate the intermolecular interactions between the hydrocarbons, auxiliary guest 1 and the inner wall of CB[8] with barely any influence from solvation, one has to consider an equilibrium in which the hydrocarbon behaves as an ideal gas. We H thus considered equilibrium 9; its equilibrium constant Kgas→CB can be derived from eq 10, with Pvap,H being the vapor pressure of the hydrocarbon at room temperature, which is proportional to the molar gas concentration by a factor of RT.15 The new relative free energy term ΔGrel gas→CB (see Table 1) is calculated similarly to rel ΔGaq→CB (see relations 3−6 with vapor pressures replacing molar solubilities). 1 1 (12 ·CB[8]) + Hgas + CB[8] ⇄ 1·H ·CB[8] 2 2 H K gas → CB =
[1·H ·CB[8]]·RT [12 ·CB[8]]1/2 ·Pvap,H·SCB[8]1/2
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Eric Masson: 0000-0001-9387-4783 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the National Science Foundation (Grant No. CHE-1507321) and the American Chemical Society American Petroleum Fund (grant 56375-ND4) for their financial support.
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REFERENCES
(1) (a) Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.; Lu, X. RSC Adv. 2012, 2, 1213. (b) Barrow, S. J.; Kasera, S.; Rowland, M. J.; del Barrio, J.; Scherman, O. A. Chem. Rev. 2015, 115, 12320. (c) Cao, L.; Sekutor, M.; Zavalij, P. Y.; Mlinaric-Majerski, K.; Glaser, R.; Isaacs, L. Angew. Chem., Int. Ed. 2014, 53, 988. (d) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew. Chem., Int. Ed. 2005, 44, 4844. (2) Florea, M.; Nau, W. M. Angew. Chem., Int. Ed. 2011, 50, 9338. (3) Lu, X.; Isaacs, L. Angew. Chem., Int. Ed. 2016, 55, 8076. (4) (a) Biedermann, F.; Uzunova, V. D.; Scherman, O. A.; Nau, W. M.; De Simone, A. J. Am. Chem. Soc. 2012, 134, 15318. (b) Nau, W. M.; Florea, M.; Assaf, K. I. Isr. J. Chem. 2011, 51, 559. (5) (a) Grimme, S. Chem. - Eur. J. 2012, 18, 9955. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput. Chem. 2011, 32, 1456. (6) (a) Kim, J.; Jung, I.-S.; Kim, S.-Y.; Lee, E.; Kang, J.-K.; Sakamoto, S.; Yamaguchi, K.; Kim, K. J. Am. Chem. Soc. 2000, 122, 540. (b) Smith, L. C.; Leach, D. G.; Blaylock, B. E.; Ali, O. A.; Urbach, A. R. J. Am. Chem. Soc. 2015, 137, 3663. (7) Joseph, R.; Nkrumah, A.; Clark, R. J.; Masson, E. J. Am. Chem. Soc. 2014, 136, 6602. (8) Zabarska, N.; Sorsche, D.; Heinemann, F. W.; Glump, S.; Rau, S. Eur. J. Inorg. Chem. 2015, 2015, 4869. (9) Thapa, P.; Karki, R.; Yun, M.; Kadayat, T. M.; Lee, E.; Kwon, H. B.; Na, Y.; Cho, W.-J.; Kim, N. D.; Jeong, B.-S.; Kwon, Y.; Lee, E.-S. Eur. J. Med. Chem. 2012, 52, 123. (10) (a) Berg, K. E.; Tran, A.; Raymond, M. K.; Abrahamsson, M.; Wolny, J.; Redon, S.; Andersson, M.; Sun, L.; Styring, S.; Hammarstrom, L.; Toftlund, H.; Akermark, B. Eur. J. Inorg. Chem. 2001, 2001, 1019. (b) Elmes, R. B. P.; Erby, M.; Bright, S. A.; Williams, D. C.; Gunnlaugsson, T. Chem. Commun. 2012, 48, 2588. (11) Hammarstroem, L.; Alsins, J.; Boerje, A.; Norrby, T.; Zhang, L.; Akermark, B. J. Photochem. Photobiol., A 1997, 102, 139. (12) (a) Maczynski, A.; Shaw, D. G.; Goral, M.; WisniewskaGoclowska, B.; Skrzecz, A.; Maczynska, Z.; Owczarek, I.; Blazej, K.; Haulait-Pirson, M.-C.; Kapuku, F.; Hefter, G. T.; Szafranski, A. J. Phys. Chem. Ref. Data 2005, 34, 441−476 477−552, 657−708, 1399−1487. (b) Shaw, D. G.; Maczynski, A.; Goral, M.; Wisniewska-Goclowska, B.; Skrzecz, A.; Owczarek, I.; Blazej, K.; Haulait-Pirson, M.-C.; Hefter, G. T.; Huyskens, P. L.; Kapuku, F.; Maczynska, Z.; Szafranski, A. J. Phys. Chem. Ref. Data 2006, 35, 93. (13) In CRC Handbook of Chemistry and Physics, 97th ed.; CRC Press/ Taylor & Francis: Boca Raton, FL, 2017. (14) Ben-Naim, A. J. Solution Chem. 2001, 30, 475. (15) Winget, P.; Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2000, 104, 4726. (16) Grimme, S. Angew. Chem., Int. Ed. 2008, 47, 3430.
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This new series of relative free energies shows a preference of the auxiliary guest 1/CB[8] pair for larger guests such as 7- and 8membered rings with relative binding energies greater than 6membered rings (−1.07 vs −0.43 kcal/mol on average). The small volumes of cyclopentane and cyclopentene remain rel penalizing, however (ΔGgas→CB = +0.47 and +0.26 kcal/mol). The decrease in binding affinity with increasing degrees of unsaturation in the 6-membered ring series generally persists. Slip-stacked π−π interactions between benzene and auxiliary guest 1, if present at all, do not play a significant role in the recognition process: on average, other hydrocarbons show a stronger affinity for the auxiliary guest 1/CB[8] pair than benzene (ΔGrel gas→CB = −0.57 kcal/mol even after exclusion of decalin). This observation is fully consistent with Grimme’s conclusion that the geometrical arrangement of the assembly formed by two small interacting units (less than 10 atoms each), aromatic or not, determines the magnitude of the interaction and not any specific interaction between π orbitals.16 Like in aqueous solution, the strongest affinities are measured with cis- and transdecalin (−3.5 and −3.1 kcal/mol), whose rigid and elongated shapes seem optimal for encapsulation. While we cannot comment on cyclooctatetraene at this stage, four hydrocarbons, cyclohexane, cycloheptene, as well as trans- and cis-decalin, stand out for their strong affinity compared to analogues bearing the same number of carbon atoms. A geometrical feature common and exclusive to the first three is their parallel axial C−H bonds, which point directly toward the aromatic probe. This suggests that unlike insignificant π−π stacking, CH−π interactions are a major driving force of the recognition process.
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Preparation and characterization of guest 1 and precursors; assay description and results; computational details (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01966. D
DOI: 10.1021/acs.orglett.7b01966 Org. Lett. XXXX, XXX, XXX−XXX
