Carbodiimide-induced formation of transient polyether cages
The use of "fuel" compounds to drive chemical systems out of equilibrium is currently of interest because of the potential for temporally controlled, responsive behavior. We have recently shown that transiently formed crown ethers exhibit counterintuitive templation effects when generated in the presence of alkali metal cations: "matched" cations, such as K + with an 18-crown-6 analogue, suppress the formation of the macrocycles (negative templation). Here we describe two macrocyclic diacids that, on treatment with carbodiimides, give transient macrobicyclic cages analogous to polyether cages first reported by Parsons. Cage formation was followed by NMR spectroscopy.Similar negative templation effects are observed for the smaller cage when generated in the presence of K + and Na + , but with a weak, but reproducible, positive templation effect in the presence of Li + . The larger cage behaves similarly in the presence of Li + , 1 K + , Rb + , and Cs + , but differently with Na + , which appears to bind to both the cage and the initial macrocycle. IntroductionTaking inspiration from the use of chemical "fuels" (e.g., ATP) in biology, coupled reactions are currently being used to drive a wide variety of nonequilibrium processes, such as the transient formation of active gels 1 and supramolecular assemblies 2 and the operation of molecular machines. 3 Effecting transient changes in host-guest binding is an interesting challenge in this area. Notably, Nitschke 4 and Baldini and Di Stefano 5 have reported examples where the release and reuptake of molecular guests can be triggered through the disassembly or distortion of macrocycles.Key to many chemically driven nonequilibrium systems is the formation of a transient covalent bond, a simple technology that nevertheless can be adapted to complex function. 6 A handful of chemical reactions are currently being used to generate transient bonds in nonequilibrium systems, 7 including acid-base chemistry, 8,9 alkylation, 10 and redox reactions. [11][12][13][14] Among the most versatile fuel reactions is the formation of anhydrides or activated esters by the hydration of carbodiimides. 15,16 This chemistry has been applied, for example, to the generation of transient gels, 15,17,18 other assemblies, 19,20 and macrocycles, 16,21 and to the modulation of materials properties 22,23 and driving of intramolecular motion. 24,25 In previous work, 16 we showed that anhydride-based crown ethers could be generated by the action of a carbodiimides. An example is shown in Scheme 1a: when an aqueous solution of diacid TEG-Ac is treated with the carbodiimide N -(3-dimethylaminopropyl)-N ′ -ethylcarbodiimide hydrochloride (EDC), the macrocycle TEG-An is formed along with acyclic oligomers (not shown). The carbodiimide is converted to its corresponding urea, EDU, as a waste product. The anhydrides decompose over the course of minutes under these conditions. The behavior of the system is strongly dependent on the presence of added salts,
<!>Results and discussion<!>Conclusions
<p>but in a counterintuitive way. Like the analogous 18-crown-6, macrocycle TEG-An might be expected to bind, and thus be stabilized by, K + . Curiously, substantially less TEG-An is generated in the presence of K + relative to Li + , Na + , or Cs + . Kinetic modeling, and the observation that (acyclic) oligomeric anhydrides are also inhibited by K + , suggests that the cations inhibit the formation of the macrocycles, rather than binding to them once they have already formed. This negative templation effect thus derives from the kinetically controlled nature of the system.</p><p>While unusual temporal behavior of the system was observed, actual binding to cations by the macrocycles was unclear. Following well-established principles of supramolecular chemistry, we became interested in macrobicyclic cage systems that would have the potential to bind more-strongly to suitable cations once formed. These systems could also provide a platform to gain new insights into templation effects in transient host-guest systems.</p><p>Since cryptand-based systems do not bind cations effectively at the pH's best suited to carbodiimide-mediated anhydride formation, 26 we turned our attention to the bicyclic crown ethers C1 and C2 in Scheme 1b, which were first reported by Parsons. [27][28][29] Accordingly, we designed diacids C1-Ac and C2-Ac, which are expected to give cages C1-An and C2-An on treatment with EDC as in Scheme 1c.</p><!><p>The synthesis of the diacids, from a key cis macrocyclic diol reported by Parsons, 27   of the mixtures (Figures S2 and S3). HSQC and HMBC NMR analyses showed that the newly formed singlets above 4.5 ppm in Figure 2 indeed correspond to H α . DOSY NMR then showed that the singlets furthest downfield (4.73 ppm for C1-An, 4.46 ppm for C2-An) correspond to the cyclic anhydrides; that is, the species associated with these signals have diffusion coefficients slightly higher than the starting diacids. The other signals all have lower diffusion coefficients and thus must correspond to larger, oligomeric anhydrides. The deshielding of H α in cyclic relative to linear anhydrides was also found for TEG-An, 16 which was attributed to H α being held syn to the carbonyl groups in small macrocycles.</p><p>Having identified signals for C1-An and C2-An that could be easily monitored, we studied their generation in the presence of alkali metal cations. Results for the C1-An are shown in Figure 3. In the presence of Li + , there appears to be a small increase in the production of C1-An compared to the system without added salt. While this effect is small, it is reproducible (see Supporting Information). Conversely, with both Na + and K + , the formation of C1-An is suppressed, whereas Rb + and Cs + give similar behavior to the system without any added salts. Thus, we observe (possibly) weak positive templation of C1-An in the presence of Li + , negative templation with Na + and K + , and little effect from Rb   An, although the original experiments on the monocyclic system were run under very different conditions (D 2 O alone, 1 M salt concentrations). 16 For comparison, we looked at the formation of TEG-An under similar conditions to those used for C1-An (Figure S13).</p><p>While these experiments were challenging and yield data with some uncertainty, similar negative templation behavior was observed.</p><p>As noted in the Introduction, negative templation in the crown ethers implies that the formation of the macrocycle TEG-An is suppressed; that is, the cation must be interacting with some precursor leading to the macrocycle and preventing anhydride formation, as opposed to interacting with the macrocycle itself once formed. A possible explanation is that the presence of cations promotes the direct hydrolysis of the acyl pyridinium intermediate leading to anhydride formation, TEG-I in Chart 1. This is consistent with the observation that the formation of acyclic anhydrides is also suppressed in the TEG-Ac system (the involvement of alternative intermediates, such as O-acylisoureas, is of course also possible). Regardless of the mechanistic origin, the binding affinities of cations to 18-crown-6, the direct analogue of TEG-An, predict the selectivity. That is, 18-crown-6 shows the strongest binding to K + and TEG-Ac shows the strongest negative templation with K + . Binding affinities of C1, the crown ether (non-anhydride) analogue of C1-An, are therefore of interest.</p><p>It is known to bind Na + and K + in methanol but exclude Rb + and Cs + (Li + has not been reported). 29 This behavior is consistent with the templation effects in Figure 3, matching the behavior of TEG-An. Negative templation could therefore arise from accelerated hydrolysis of intermediates leading to C1-An, such as C1-I in Chart 1, because of the proximity of the metal ion to the anhydride precursor.</p><p>The possible positive templation behavior in the presence of Li + is curious. The DFToptimized geometries of the complexes in Figure 4 show that while both Li + and Na + should fit well inside the cavity of C1-An, the smaller Li + should sit much deeper in the cavity and farther from the anhydride group. Presuming that similar behavior would occur for precursors such as C1-I, the Li + may have less of an effect on the formation of the anhydride and may indirectly promote cyclization through some other mechanism, such as preorganization of the acids for coupling.</p><p>The behavior of the C2-Ac/C2-An system is somewhat different. 1 H NMR spectra acquired over the course of the reaction are significantly more complex, reflecting a greater propensity to oligomerize because of its greater conformational flexibility. The signals assigned to H α are less well separated from those of the linear anhydrides but still distinguishable in most cases. While the complexity of the spectra, and low concentrations of C2-An, makes analysis challenging, there appears to again be a negative templation effect for C2-An in the presence of at least K + (Figure S14).</p><p>The behavior of the system in the presence of NaCl is quite distinct, however. 1 H NMR spectra taken approximately 3 min after the addition of EDC to C2-Ac in the presence of each salt are shown in Figure 5a. Whereas the spectra are quite similar in the presence of LiCl, KCl, RbCl, and CsCl, with clear peaks assigned to H α and H β for C2-An, the spectrum acquired in the presence of NaCl shows broadened peaks in the expected region for H α and a signal for H β that is shifted distinctly downfield.</p><p>We suspected that diacid C2-Ac itself may bind Na + under the conditions of the EDCfueling experiments. When it is titrated with NaCl in the absence of EDC, clear changes in the 1 H NMR spectra, shown in Figure 5b, are observed, suggesting binding. Curve fitting of the changes in chemical shifts gives binding constants on the order of 650 M −1 . While similar analysis is unfortunately challenging for C2-An under comparable conditions (because it is only transiently formed within a complex mixture), the significant change in chemical shift for H β compared to the other four salt systems suggests that binding also occurs for the cage.</p><p>Interestingly, when the anhydrides are isolated from acetonitrile in the presence of LiCl, only Na + complexes were observed in the mass spectra, suggesting an affinity for this cation. This is the first direct evidence for binding of cations in a transient crown-ether-based supramolecular host. The analogous cage from Parsons, C2 (Scheme 1b) does indeed bind Na + , 27 although curiously binding to K + and Rb + is stronger. This suggests that binding of the cations to C2-An may be kinetically controlled; that is, dictated in part by pre-binding to C2-Ac.</p><!><p>The results here demonstrate that carbodiimide chemistry can be used to generate crownether-based cages. The transient cages exhibit negative templation effects similar to analogous crown ether macrocycles. The smaller cage C1-An may show weak positive templation in the presence of Li + , which can be explained by the binding of the Li + cation farther from the incipient anhydride. These results suggest that negative templation, which suppresses the formation of macrocycles, may be avoided by locating the transient anhydride bond far from cation binding sites. The larger C2-Ac/C2-An system shows unique behavior in the presence of Na + , which appears to bind to both the diacid and macrocycle.</p>