Guest-induced organization of an optimal receptor from a dynamic receptor library: Spectroscopic screening

Abstract

Complexation of a cis-protected palladium ion and a family of exo-bidentate and -tridentate ligands results in the formation of an equilibrium mixture of numerous metal-linked receptors that are referred to as a dynamic receptor library. We found that a guest induced the selective formation of the optimal receptor of its own. Screening of the library by using difference NMR facilitates the search for new receptors because in difference NMR only receptors interacting with the guest can be observed. An unpredictable heterotopic receptor was discovered by this screening method. Interestingly, the new receptor thus found was assembled quantitatively only in the presence of its optimal guest.

A multicomponent system composed of metal ions and several different bridging ligands generates an equilibrium mixture of numerous cyclic and cage-like complexes that is referred to as a dynamic receptor library (1, 2). Selection of optimal receptor(s) for a given guest from the library provides an efficient way to the discovery of new receptors that may be unpredictable by conventional approaches. The most intriguing processes that work in the dynamic system are the autoselection and autoformation of the optimal receptor. As shown in Scheme S1, a guest molecule is bound selectively by its optimal receptor (autoselection). Subsequently, the equilibrium shifts so that the portion of the selected receptor increases because of substantial stabilization by the host–guest interaction (autoformation). Several groups have been studying the dynamic receptor library to search for suitable receptors through the autoselection and autoformation processes (3–7). The simplest cases are our previous work on the guest-induced organization of its own receptors from an equilibrium mixture resulting from a metal and a few ligands (8–10).

Scheme 1.

To expand such a prototypical system into a more general and complex system, the development of efficient methods for the rapid and efficient screening of the library is desired. Here, we show that the spectroscopic screening using difference NMR technique provides a very efficient solution to this problem. We deal with a complex dynamic receptor library generated from several components and succeed in the discovery of an otherwise unpredictable receptor framework for a given guest, as discussed in the following sections.

Materials and Methods

Preparation and Physical Properties of 9⋅7.

(en)Pd(NO₃)₂ (1) (0.052 mmol, 15.0 mg), ligands 2 (0.026 mmol, 8.0 mg) and 3 (0.013 mmol, 2.0 mg) were suspended in D₂O (1.5 ml) and the mixture was stirred at 80°C for 1 h. Then Na⋅7 (0.0098 mmol, 1.8 mg) was added and the mixture was stirred at room temperature for 4 h. NMR showed the quantitative formation of 9⋅7 complex (not isolated). ¹H NMR (500 MHz, D₂O) δ = 10.20 (s, 4H), 9.14 (s, 2H), 8.97 (d, J = 5.6 Hz, 4H), 8.88 (d, J = 8.1 Hz, 4H), 8.82 (d, J = 5.6 Hz, 2H), 8.80 (d, J = 8.1 Hz, 2H), 8.35 (d, J = 6.3 Hz, 4H), 7.62–7.59 (m, 6H), 7.33 (d, J = 6.3 Hz, 4H), 2.81–2.70 (m, 8H), 2.64 (brs, 8H). ¹³C-NMR (125 MHz, D₂O) δ = 169.8 (Cq), 169.2 (Cq), 164.2 (Cq, guest), 154.9 (CH), 154.4 (CH), 152.0 (CH), 151.9 (CH × 2), 146.4 (Cq), 140.7 (CH), 140.6 (CH × 2), 134.2 (Cq), 134.1 (Cq), 127.3 (CH × 2), 123.9 (CH), 98.8 (Cq, guest), 47.0 (CH₂). The assignments were confirmed by ¹H-¹H-relay correlation spectroscopy (COSY), CH-COSY. Coldspray ionization (CSI)-MS (H₂O+DMF) m/z = 958.2 [9⋅7-(NO₃)₃]²⁺, 908.5 [9-(NO₃)₃]²⁺. Preparation and physical properties of 9⋅8, NMR spectra of 9⋅7 [13C, distortionless enhancement by polarization transfer (DEPT), H-H relay-COSY, and CH COSY] and 9⋅8 (H-H relay-COSY), CSI-MS (11) spectra of 9⋅7 and 9⋅8 are provided in Supporting Text, which is published as supporting information on the PNAS web site, www.pnas.org.

Results and Discussion

A dynamic library we test here is generated from (en)Pd(NO₃)₂ (1), which is a useful coordination unit for the self-assembly of metal-linked receptors (12–14), and several pyridyl-appended bridging ligands 2-6 (Scheme S2). Difference NMR is obtained from spectra before and after guest addition. We assume that only receptors that interact with the guest should be observed as positive peaks because of either the equilibrium shifts toward the interacted receptors or chemical shift change of the interacted receptors. Noninteracted receptors are mostly cancelled or should be observed as negative residue because of the equilibrium shift.

Scheme 2.

A successful example follows. An intractable mixture was obtained when metal 1 was combined with ligands 2-6 (Fig. 1a). On addition of a small amount of sodium trichloroacetate (7⋅Na) as a guest, the spectrum was slightly changed (Fig. 1b), but the comparison of these two spectra hardly gave implications for the selected receptors. In the difference spectrum, however, several prominent peaks appeared (Fig. 1c), which are indicative for the presence of 3-pyridyl and 4-pyridyl groups. Thus the contribution of ligands 2 and 3 is elucidated, yet the ratio of 1:2:3 was ambiguous. Therefore we carried out the second screening using only ligands 2 and 3 (Figs. 1 d and e). The difference spectrum became much clearer showing the ratio 1:2:3 = 4:2:1 (Fig. 1f). Two inequivalent 3-pyridyl groups were observed, whose ratio was estimated to be 2:1. In the third experiment, by mixing these three components in a 4:2:1 ratio in the presence of excess sodium trichloroacetate, the selective formation of a single product was finally observed (Fig. 1g).

Figure 1.

¹H-NMR observation of the guest-induced organization of an optimal receptor. (a) A mixture from 1-6; before guest addition ([1]₀ = 29 mM, [2]₀ = 3.2 mM, [3]₀ = 4.9 mM, [4]₀ = 3.2 mM, [5]₀ = 4.9 mM, [6]₀ = 4.9 mM). (b) After guest addition ([7]₀ = 0.42 mM). (c) Difference NMR (spectrum b-a). (d) A mixture from 1-3; before guest addition ([1]₀ = 10 mM, [2]₀ = 3.2 mM, [3]₀ = 4.9 mM). (e) After guest addition ([7]₀ = 0.42 mM). (f) Difference NMR (spectrum f-e). (g) The spectrum of 9⋅7 assembled from 1, 2, 3, and 7 ([1]₀ = 6.5 mM, [2]₀ = 3.2 mM, [3]₀ = 1.6 mM, [7]₀ = 2.4 mM).

We assigned the structure of this product as D_2h symmetric complex 9 accommodating 7 in its bowl-shaped cavity (Scheme S3). This structure agrees with the component ratio and the desymmetrized framework of ligand 2. The structure of 9⋅7 was, in fact, strongly supported by CSI-MS measurement. The solution prepared from 1, 2, 3, and 7⋅Na in a 4:2:1:1 ratio showed clear peaks for m/z [9⋅7-(NO₃)₃]²⁺ (Fig. 2a). The observation of 9⋅7 species suggests that guest 7 is strongly bound by 9. Although neutral guest CBr₄ (8) also induced the formation of 9⋅8 (as discussed later), CSI-MS showed only peaks for [9-(NO₃)₂]²⁺, [9-(NO₃)₃⋅(DMF)n]³⁺ (n = 0–3) (Fig. 2b), indicating the dissociation of 9⋅8 complex under the MS conditions.

Scheme 3.

Figure 2.

CSI-MS spectra of 9⋅7 and 9⋅8 complexes. (Inset a) Expansion of [9⋅7-(NO₃)₃]²⁺ fragment. (Inset b) Expansion of [9-(NO₃)₃]²⁺ fragment in the analysis of 9⋅8.

It is particularly interesting that, in the absence of the guest, the complexation of 1, 2, and 3 (4:2:1 ratio) does not give a single product but a mixture of three compounds 9-11 (Scheme S4). Thus, host 9 assembles quantitatively only if four components (1-3 and 7) are combined in a proper ratio. Such a combination can be hardly found if each combination is examined individually but quite efficiently accessed by the spectroscopic screening the receptor library.

Scheme 4.

For the same receptor library, we examined the spectroscopic screening with other guests that are quite different from 9 in shape. The same host (9) was also selected when excess CBr₄ (8) was used as the guest. However, sodium adamantane-1-carboxylate interacted strongly with homotopic host 10.

Conclusions

The screening of a dynamic receptor made possible the facile discovery of the optimal receptor for a given guest. The library generated from metals and ligands includes, in principle, infinite number of metal-linked receptors, each of which may not exist without the guest but may form predominantly only in the presence of the guest. Most interestingly, the given guest induces the organization of its own receptor from the dynamic library. These aspects are successfully demonstrated by discovering heterotopic receptor 9, which does not exist as a stable form without the guest and thus is hardly predictable.

Abbreviation

CSI

coldspray ionization