Diindolylquinoxalines

Abstract

The synthesis of a new series of 2,3—diindol—3’yl quinoxalines (DIQ), as well as a comparison of their anion recognition properties to those of our previously reported pyrrole based sensors, 2,3—dipyrrol—2’yl quinoxalines (DPQ) is reported. To the best of our knowledge, this new DIQ system represents the first example of a free-standing indole-based small molecule receptor for which evidence of anion binding is available both in solution and in the solid-state. It also provides one of the few structurally characterized neutral receptor-dihydrogen phosphate complexes. This work thus serves to demonstrate the utility of indoles as an anion recognition motif.

Anions are ubiquitous in biological milieus. Among the most important physiologically relevant anions is inorganic phosphate. Not only does it play a critical role in energy storage and signal transduction,¹ it recognized as essential structural element in teeth and bones.² On the other hand, elevated serum phosphate levels can result in calcification of tissues³ and is a recognized problem in patients suffering from chronic kidney failure. Phosphate is also a key pollutant whose role in the eutrophication of waterways is well recognized.⁴ This diversity of function has stimulated considerable current interest devoted to the recognition and sensing of phosphate anions.⁵ Increasingly, efforts in this area have focused on the use of acyclic small molecule receptors,⁴ including those based on amide, sulfonamide, urea, and pyrrole recognition units. While each of these motifs presents certain advantages, there is incentive to explore additional putative binding subunits that could be used to generate new receptor systems. One such motif is indole, a potential hydrogen bond donor that has yet to be exploited extensively in the area of anion sensor development. Indeed, currently only indolocarbazoles 1⁶ and bis(indolyl)methane, 2⁷ are known to the best of our knowledge, and, in the case of the latter system, quantitative binding studies were not fully carried out. Thus, there remains a need to explore the fundamental anion binding properties (e.g., selectivity, affinity) of indole-based receptors. Towards this end, we report here the synthesis of a new series of 2,3—diindol—3’yl quinoxalines (DIQ, 6 and 7), as well as a comparison of their anion recognition properties to those of our previously reported pyrrole based sensors, 2,3—dipyrrol—2’yl quinoxalines (DPQ, 3).⁸ To the best of our knowledge, this new DIQ system, which relies on β-connectivity, represents the first example of an indole-based small molecule receptor for which evidence of anion binding is available both in solution and in the solid-state. It also provides one of the few structurally characterized neutral receptor-dihydrogen phosphate complexes.⁹

Receptors 6 and 7 require very short syntheses. Although the synthesis of receptor 6 was not clearly described in the literature, the syntheses of 2,3—diindol—3’yl diketone 5¹⁰ and receptor 6¹¹ have been published. In the event, we have found that intermediate 5 is easily prepared by the reaction of indole Grignard reagent with indolyl oxaacethyl chloride 4. Subsequent reaction between the resulting diketone 5 and either o-phenyldiamine or its mono nitro analogue gave the final receptors 6 and 7 in unoptimized yields of 48, and, 30 respectively.

The association constants (K_a) of receptors 6 and 7 were determined from standard UV-vis absorption titrations carried out in dichloromethane. Fig 1 presents the observed changes in the UV-vis spectrum of receptor 7 recorded in dichloromethane upon the addition of tetrabutylammonium hydrogen phosphate (TBA—H₂PO₄). In the absence of the anion, an absorption maximum is seen at 434 nm. Upon addition of H₂PO₄^-, a large bathochromic shift was observed (Δλ_max = 40 nm). The resulting titration revealed several isosbestic points as expected for a 1:1 binding stoichiometry. Similar isosbestic points were also observed during the course of titrations carried out with F^-, Cl^-, HSO₄^- and BzO^- anions as well (all as TBA salts). This binding stoichiometry was confirmed in solution by Job plots and, in the case of receptor 7 and dihydrogen phosphate anion, by a single crystal X-ray analysis carried out in the solid state (cf. Fig. 3 and discussion below).

Figure 1.

Evolution of the UV-vis spectrum of receptor 7 (3.99 × 10^-5 M in dichloromethane) seen during upon titration with tetrabutylammonium hydrogen phosphate (TBA·H₂PO₄) (0 to 10 equiv.). (Inset) Job plot for the interaction between receptor 7 and TBA·H₂PO₄.

Figure 3.

Single crystal X-ray diffraction structure of receptor 7·TBA·H₂PO₄. Thermal ellipsoids are scaled to the 50% probability level. Most hydrogen atoms and the TBA cations have been omitted for clarity. (a) View illustrating the two types of phosphate bound receptor 7 complexes found in the solid state structure; (b) view of the (receptor 7·TBA·H₂PO₄)₈ complex seen in the unit cell.

Association constants determined from these titrations are summarized in Table 1. An inspection of this table reveals that in the case of receptor 6 the greatest affinity is displayed for dihydrogen phosphate anion, followed by F^- > BzO^- > Cl^- > HSO₄ ^-. This same table also confirms that, as proved true in the case of the corresponding DPQ systems, the nitro-bearing receptor 7 shows higher affinities across the board than does the unsubstituted system 6. This result is attributed to the electron withdrawing nitro group, which serves to increase the pyrrole NH acidity. Consistent with this postulate, receptor 7 shows biphasic behavior¹² when subject to titration with fluoride anion in dichloromethane. Under these conditions, the fluoride anion presumably acts as both a general base and as an anionic substrate (cf. Supporting Information).

Table 1.

Anion Binding Constants (K_a; M^-1)^a for Receptors 6 and 7 in Dichloromethane at 22°C

	38	6	7
F-	118000	2100	-b
Cl-	65	170	470
HSO4-	N.D.	80	250
BzO-	N.D.	600	2700
H2PO4-	80	6800	20000C

^aValues were determined by UV-vis spectroscopic titrations; errors are <±10%. All anions were used in the form of their respective tetrabutylammonium (TBA) salts.

^bA reliable binding constant could not be determined due to the observation of biphasic behavior.

^CThe association constant for the interaction of receptor 7 with H₂PO₄^- was also examined in acetone, acetonitrile, and DMSO: the K_a values are 5,600, 2,400 and 300 M^-1, respectively. N.D. — not determined.

Among the anionic substrates for which clean binding behavior is seen, receptor 7, like its congener 6, shows good selectivity for phosphate anion (K_a(H₂PO₄)/K_a(Cl) = 42, K_a(H₂PO₄)/K_a(BzO) = 7 and K_a(H₂PO₄)/K_a(HSO₄) = 80). Such a high inherent selectivity was not seen in either the corresponding DPQ systems (K_a(rept. 7)/K_a(rept. 3) = 250 for H₂PO₄ ^-)⁸ or in the indolecarbazole⁶ based receptors reported recently by Beer. We ascribe this selectivity to the presence of the β-connectivity linking the two indole motifs to the quinoxaline core; this provides a more open (and potentially less rigid) cavity that is expected to favor binding of this relatively larger anionic substrate.

Further support for the notion that compound 7 can act as a dihydrogen phosphate anion receptor comes from a single crystal X-ray diffraction analysis of the complex formed between 7 and TBA·H₂PO₄. This structure reveals the presence of two different phosphate-receptor interactions in the solid state. In one complex, a molecule of receptor 7 interacts with two phosphate anions that, in turn, interact with one another via a hydrogen bonds. In the other complex, receptor 7 binds three phosphates that again exist in a self-associated network (cf. Fig. 3). As the result of these and other hydrogen bonding interactions, a series of infinite phosphate channels and wires is observed in the solid state.¹³ Nonetheless, the overall anion-to-receptor binding stoichiometry is 1:1, as expected based on the solution phase Job plot analyses.

A further notable feature of receptor 7 is that color changes are seen upon the addition of F^- and H₂PO₄ ^- anions (Figure 2). Such color changes are considered a useful feature of anion receptors in that they allow analytes to be detected easily without recourse to spectrometers.¹⁴

Figure 2.

Color changes observed upon the addition of anions (10 equiv.) to otherwise identical solutions of receptor 7 (4.34 × 10^-5 M in dichloromethane). From left to right; F^- + 7, Cl^-+ 7, BzO^- + 7, HSO₄ ^- + 7, H₂PO₄ ^-+ 7, 7.

In summary, the new indole-based receptors 6 and 7 provide a new series of anion receptors that are particularly effective for dihydrogen phosphate anion. Receptor 7 allows for the visual detection of this anion via the production of a simple, anion-triggered color change (as well as fluoride for which less clean binding behavior is seen). The interaction between H₂PO₄ ^- and receptor 7 also gives rise to the formation of a unique extended structure in the solid state, leading to the suggestion that systems such as 7 could be used as the basis for new engineered crystalline materials. We are currently studying this possibility while working to produce more elaborate indole-based receptors.

Scheme 1.

Synthetic Scheme