Jesse V.
Gavette
a,
Christopher J.
Evoniuk
a,
Lev N.
Zakharov
b,
Matthew E.
Carnes
a,
Michael M.
Haley
*a and
Darren W.
Johnson
*a
aDepartment of Chemistry & Biochemistry and Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, USA. E-mail: dwj@uoregon.edu; haley@uoregon.edu; Fax: +1-541-346-0487; Tel: +1-541-346-1695
bCAMCOR—Center for Advanced Materials Characterization in Oregon, University of Oregon, Eugene, OR 97403, USA
First published on 24th April 2014
Anion binding studies of 1,10-phenanthroline- and 2-pyridyl-substituted urea-based receptors reveal that guest-dependent conformations exist in structural variants related to a previously investigated bipyridyl-based receptor. Dynamic conformational switching persists in a monofunctional pyridyl-urea receptor, and the preorganization provided by a phenanthroline-based analogue promotes convergence of anion coordinating groups to a single guest. Despite this predisposition for anion coordination, the conformational flexibility of the bipyridyl-based receptor provides the most selective motif for H2PO4− coordination. Furthermore, the two new phenanthrolyl- and pyridyl-receptors serve as models of the bipyridyl-based receptor, elucidating accurate stepwise association constants for 1:2 host/guest binding by this receptor, and suggest that oxoanions prefer the embrace of a “U” conformation in 1:1 complexes.
Recently, we have shown that a bipyridyl bisurea-based anion receptor (1, Fig. 1) is capable of adopting differing anion-dependent binding conformations due to limited rotation about the bipyridine bridging bond and unrestricted rotation of the arene–alkyne bonds.3 The conformational freedom in this system allows anionic guests the opportunity to experience a variety of different hydrogen bonding environments including those from bipyridyl nitrogens, ureas and even aryl C–Hs. Aryl C–H hydrogen bond donors have recently been shown to contribute significantly to anion binding in similar systems.4 As a result of the many available interactions with a potential guest, the bipyridine-based receptor demonstrated spectroscopically distinct conformational binding tendencies toward halides and oxoanions. The different anion-dependent, bound-states were shown to be reversible upon changing the anionic guest in excess from Cl− to HSO4− and back.
The conformational promiscuity and potential of receptor 1 to bind ditopically to two guests inspired further exploration into the nature of the conformational switching of this system. Herein we present the binding studies of structural analogues 2 and 3 (Fig. 1) and compare their effectiveness as anion receptors to 1. We hypothesized that the 1,10-phenanthroline receptor 2 (more conformationally restricted with the bipyridyl unit locked into planarity) and 2-pyridyl receptor 3 (“uncoupled” half of receptor 1) could offer insight into the nature of the guest-dependent binding conformations and possibly deconvolute the previously observed higher-ordered anion binding stoichiometry of 1. Receptor 2 is anticipated to interact with anions via either a U or W conformation (Fig. 2) where the U conformation is nearly identical to an anion-bound conformation observed for 1, and the W invokes coordination via an aryl C–H hydrogen bond, similar to the Z conformation proposed for 1.3 An S-type conformation is not possible for 2 due to the rigidity of the phenanthroline core. The U conformation is anticipated to be the dominant conformation observed for 2 given the preorganization of the receptor that directs the heteroaromatic phenanthroline nitrogens in a syn orientation, and places the urea groups on the same side of the heteroaromatic core promoting their simultaneous interaction with anionic guests.
Fig. 2 Representation of possible 1:1 host/guest binding conformations for receptors 1–3. Blue hexagons represent aromatic rings and the red wedges represent nitrogen atoms in the heteroarenes. |
Pyridine-based receptor 3 presents a single urea binding unit capable of coordinating anions in two different L-shaped conformations, denoted L-N (pyridine N directed at the guest) or L-CH (pyridine CH directed at guest) differentiated by rotating freely around the pyridine-alkyne single bond (Fig. 2). This receptor permits analysis of anion binding restricted to a single urea moiety while also investigating the effect of aryl C–H hydrogen bonding (observed previously in the binding of 1 with halides) versus interaction with the basic pyridine nitrogen (favoured for protic oxoanions). Additionally, this mono-urea fragment of receptors 1 and 2 will help model the conformational and thermodynamic properties of the bisurea-based systems and help determine how important preorganization of the urea groups is to binding within the pocket of the receptor.
The synthesis of 2 and 3 (Scheme 1) is loosely based on strategies utilized for related aryl-acetylene receptor systems.5–10 Sonogashira cross-coupling of 2-ethynyl-4-t-butylaniline11 to either 2,9-diiodo-1,10-phenanthroline12 or 2-bromopyridine generates aniline precursors 4 and 5 in 74% and 89% yield, respectively. Subsequent reaction with 4-nitrophenylisocyanate produces receptors 2 and 3 in 40% and 72% yield, respectively. Full synthetic details are provided in the ESI.†
Anion | 1 | 2 | 3 |
---|---|---|---|
a Value previously reported. b Association constant obtained from UV/Vis titrations. c Evidence exists for binding, but reliable association constants could not be determined. d Represents an apparent association constant obtained from fitting to a 1:1 model; however, a 1:2 model gave considerably better fits, although high errors and negative Ka values prevented report of this binding data and indicates that neither model appropriately reflects the solution stoichiometry. Association constants represent an average of at least three titrations with various anions added as the tetrabutylammonium salts in 10% DMSO–CHCl3 (or the perdeutero-equivalent for NMR titrations) at 298 K, and were determined using HypNMR 2006 or Hyperquad 2006. Table 3 contains revised values for Ka's with receptor 1 based on the refitting previous data using receptors 2 and 3 as model systems. | |||
Cl− | — | (2.60 ± 0.45) × 102 | (4.0 ± 0.2) × 101 |
Br− | — | (6.0 ± 0.1) × 101 | (5.0 ± 0.6) × 101 |
I− | — | —c | (6.0 ± 0.4) × 101 |
H2PO4− | (7.80 ± 2.0) × 104a | (4.60 ± 0.0045) × 104b | (3.10 ± 0.32) × 103 |
HSO4− | — | (3.30 ± 0.50) × 102 | (1.00 ± 0.09) × 102 |
OAc− | — | (2.60 ± 0.23) × 103d | (2.30 ± 0.34) × 103 |
Overall the phenanthroline-based receptor 2 has a greater affinity for the tested anions compared to receptor 3 which is unsurprising given that 2 contains two ureas with the propensity to converge on the guest molecules. Several interesting trends become apparent upon a more in-depth comparison of binding trends for 2 and 3. For instance, there are stark differences in the relative affinity toward halides for the two receptors. Receptor 2 has the greatest affinity for Cl− and binding drops off considerably for Br−. Weak binding was observed for I−, but accurate association constants could not be determined for 2. Receptor 3 shows little discrimination between the halides, though there may be a slight preference for I− over Cl−.
Receptors 2 and 3 both show a preference for oxoanions over halides, and H2PO4− yields the highest association constants though the preference exhibited by 3 is minimal. Dihydrogen phosphate induces significant downfield shifting of the urea resonances in 2, but broadening of the resonances (also observed previously with 1·H2PO4−) necessitated UV/Vis titrations for determination of accurate association constants. The results of these studies indicate that receptor 2 binds H2PO4− over an order of magnitude better than the more basic OAc− which is comparable to other flexible hydrogen bonding receptors.1g,h Given the comparable magnitude of binding and selectivity for H2PO4− by the similarly structured receptors 1 and 2, it is likely they coordinate via similar conformations. The similar binding conformation observed in these receptors is a testament to the multiple complementary hydrogen bond donors and acceptors afforded by the U conformation. Despite the similarities, 2 still has 1.7-fold lower association constant for H2PO4− than the previously reported 1·H2PO4− complex. The preorganization of 2 was anticipated to provide a greater preference for H2PO4−, but these studies suggest that conformational flexibility is more beneficial than preorganization in these systems. The extreme preference for H2PO4− over OAc− is not shared by simplified receptor 3, and both anions are bound similarly. Curiously, the association constants of 2 and 3 for OAc− are within error of one another. A possible explanation is the presence of more complicated and higher order stoichiometry binding of 2 and OAc−, but fitting of the binding data to an alternate model (e.g. 1:2 host/guest model) produced unsatisfactory association constants with either negative values or larger errors than the 1:1 model preventing confirmation of this theory.
Fig. 4 Stacked partial 1H NMR spectra and proposed binding conformations for (a) 2·Cl− and (b) 3·Cl−. Equiv. of guest at left of spectra. |
The 1H NMR titration spectra for 2 and 3 with HSO4− confirm this assertion (Fig. 5), showing little to no downfield shifting of Hc′ and Hd′′, respectively. The lack of shifting of the aryl C–H resonances indicates they are not involved in hydrogen bonding to HSO4− in either case. Since the aryl C–H hydrogen bonding is not observed in any of the receptor oxoanion systems it is believed that the conformational preference exhibited by these receptors is a result of the ureas being directed toward the heteroaryl nitrogens, which allows for an additional advantageous hydrogen bond between the protic anions and the free base pyridyl lone pair in the U and L-N conformation for 2 and 3, respectively. The overall results of these analyses demonstrate that anion-dependent binding conformations are a trait represented by these receptors as a class even when the system is as simple as a single pyridine and urea unit (3). Additionally, preorganization of the receptor system (2) can influence the anion driven conformational outputs.
Fig. 5 Stacked partial 1H NMR spectra and proposed binding conformations for (a) 2·HSO4− and (b) 3·HSO4−. Equiv. of guest at left of spectra. |
Receptor | Conformation | Anion | |||
---|---|---|---|---|---|
Cl− | H2PO4− | HSO4− | OAc− | ||
a ΔE = E(complex) − E(receptor) − E(anion). | |||||
2 | W | −13.9 | −25.6 | −18.7 | −32.7 |
U | −20.1 | −56.2 | −40.3 | −48.3 | |
3 | L-CH | −13.7 | −27.1 | −20.5 | −31.1 |
L-N | −12.5 | −35.0 | −29.1 | −32.5 |
The binding energies for all of the anionic complexes with 2 indicate that guest coordination is preferred in a U conformation where both urea groups can simultaneously bind guests (Fig. 6a and b), and the anion stability trend in this conformation is H2PO4− > OAc− > HSO4− > Cl− which is consistent with 1H NMR data. The calculated structures of 3 demonstrate that the protic anions also prefer interaction with the free base pyridyl nitrogen (L-N conformation) versus the aryl C–H (L-CH conformation) (Fig. 6d). Chloride binding is stabilized most by the L-CH conformation, which avoids a repulsive interaction with the pyridyl lone pair and allows for formation of an opportunistic C–H aryl hydrogen bond. Again, the binding energies of the most stable conformer of 3 are identical to those from the solution binding studies. Overall, the computational studies mirror the findings from NMR experiments: the heteroaryl nitrogen directs oxoanions toward the binding pocket while diverting halides to settle with the weak C–H hydrogen bond.
Fig. 6 Calculated structures (ωB97X-D/6-31G(d,p)) of preferred binding conformations for (a) 2·Cl−, (b) 2·HSO4−, (c) 3·Cl− and (d) 3·HSO4−. |
The microscopic association constant (Km) represents the binding of a guest with a single binding site. Since 3 showed a similar differential coordination motif for halides versus oxoanions compared to 1 this allows the binding constants for complexes of 3 to be representative of Km in systems of 1 believed to form 1:2 host/guest complexes (e.g. Cl−, Br−, HSO4− and OAc−).19 If it is assumed that there is no cooperativity between the two structurally equivalent binding sites of 1 (e.g. α = 1), the overall association constant (K12) and stepwise constant K11(Z/S) of binding in either a Z or S conformation can be calculated (Table 3). Using this calculated K12 value as a constant, a more realistic approximation of the K11 value was determined by re-fitting the binding data for 1 (Table 3). One thing that stands out is that the values from the re-fitting process (K11) are noticeably larger than the K11(Z/S) values calculated from the statistical relationship (2Km). In the case of HSO4− and OAc− the larger K11 values could be explained by the formation of a weak intramolecular chelate complex with the receptor which would be anticipated for binding these anions in a more U-like conformation for 1:1 complexes. Assuming that the energetic differences between 1 and 2 in adopting the U conformation are negligible, association constants for 2 may serve as reasonable estimates for the formation of 1:1 complexes of 1·anion in the U conformation (K11(2), Scheme 2). Comparison of K11 for HSO4− with the Ka for 2·HSO4− (a representative of binding in the U conformation) produces very similar values which suggests the 1·HSO4− complex is more U-like in its binding conformation.
Anions | Macroscopic association constants | ||
---|---|---|---|
K 11 (M−1)a | K 11( Z / S ) (M−1)b,d | K 12 (M−1)c,d | |
a Values determined from re-fitting of titration data to a stepwise 1:2 host/guest model with the K12 value held constant. b Values calculated from expected statistically corrected equilibrium relationship (K(Z/S) = 2Km). c Values calculated from expected statistically corrected equilibrium relationship (K12 = αKm2) and assumed α = 1. d Values for Km were assumed to be equal to the determined association constant for 3 with the corresponding anion. | |||
Cl− | (2.30 ± 0.06) × 102 | 8.0 × 101 | 1.59 × 103 |
Br− | (1.50 ± 0.06) × 102 | 1.00 × 102 | 1.59 × 103 |
HSO4− | (3.70 ± 0.06) × 102 | 2.00 × 102 | 1.00 × 104 |
OAc− | (2.11 ± 0.002) × 104 | 4.60 × 103 | 5.25 × 106 |
The K11 for 1 toward OAc− is much higher than 2·OAc− (Table 1), but these differences might be a result of the unreliable stoichiometry for 2·OAc−. These assertions cannot be definitively confirmed without the determination of the EM value which is not presently viable. The calculated and re-fit 1:1 values, K11 and K11(Z/S) respectively, for Br− on the other hand are quite similar, and seem to confirm that binding in the Z conformation is the most dominant form. Gratifyingly, this was previously indicated by 1H NMR shifting of the aryl C–H resonance. The re-fit K11 value for Cl− is significantly higher than the anticipated binding constant for chloride binding strictly in the Z conformation (K11(Z/S)), and is similar to the value for 2·Cl−. The different shifting profiles of 2·Cl− and 1·Cl− (Fig. S38†) would indicate that 2·Cl− is in a U conformation and 1·Cl− is in a Z conformation. The previously reported 1H NMR spectra for the titration of 1 with Cl− indicated similar involvement of the urea and aryl C–H hydrogens in the coordination of Cl− throughout the titration. These observations make it difficult to imagine an intramolecular chelate complex forming that involves the aryl C–H hydrogen bond. The larger K11 value may instead indicate some form of intermolecular complex though no direct evidence yet exists for this in solution. While using binding data from 2 and 3 have yielded more acceptable binding values for 1 and a reasonable assessment of the 1·HSO4− binding conformation, discrepancies with other complexes indicate that either more complicated equilibria are present or that cooperativity cannot be neglected in these systems.
Additionally, in comparison of the binding studies of 2 and 3 to 1, more reliable binding data for the stepwise formation of 1:2 host/guest complexes of 1 for several anions were able to be determined. These comparisons also suggest that oxoanions, particularly HSO4−, seem to prefer a 1:1 host/guest complex in a U conformation en route to higher ordered complexes. This comparison unfortunately does not clarify the binding conformation of 1·Cl−, and in fact contradicts previously acquired solid state and solution phase binding data. Ultimately, these studies have shed light on the anion-induced conformational preferences of an interesting class of receptors, and the insights gained from these systems can be extended toward the improved design of anion affected supramolecular switches and foldamer systems.
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 970878 and 970877. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc00950a |
‡ Crystallographic data for: 2·(MeOH)2: (C50H50N8O6)·2(CH3OH)·0.69(CH2Cl2), M = 972.99, 0.16 × 0.11 × 0.03 mm, T = 100(2) K, CuKα radiation λ = 1.54178 Å, triclinic, space group P, a = 13.5061(5) Å, b = 13.6726(5) Å, c = 15.5153(5) Å, α = 112.007(2)°, β = 103.362(2)°, γ = 102.907(2)°, V = 2427.06(15) Å3, Z = 2, Dc = 1.331 Mg m−3, μ = 1.409 mm−1, F(000) = 1021, 2θmax = 135.82°, 23032 reflections, 8453 independent reflections [Rint = 0.0381], R1 = 0.0589, wR2 = 0.1677 and GOF = 1.048 for 8453 reflections (849 parameters) with I > 2σ(I), R1 = 0.0751, wR2 = 0.1833 and GOF = 1.048 for all reflections, max/min residual electron density +1.252/−0.481 eÅ3. 3·H2O: C24H24N4O4, M = 432.47, 0.38 × 0.21 × 0.10 mm, T = 193(2) K, MoKα radiation λ = 0.71073 Å, monoclinic, space group P21/n, a = 12.6483(16) Å, b = 6.9763(9) Å, c = 25.125(3) Å, α = γ = 90, β = 101.115(2)°, V = 2175.4(5) Å3, Z = 4, Dc = 1.320 Mg m−3, μ = 0.092 mm−1, F(000) = 912, 2θmax = 54.00°, 23515 reflections, 4739 independent reflections [Rint = 0.0282], R1 = 0.0487, wR2 = 0.1339 and GOF = 1.011 for 4739 reflections (385 parameters) with I > 2σ(I), R1 = 0.0635, wR2 = 0.1503 and GOF = 1.011 for all reflections, max/min residual electron density +0.383/−0.170 eÅ3. |
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