Letter pubs.acs.org/OrgLett
8‑Propyldithieno[3,2‑b:2′,3′‑e]pyridine-3,5-diamine (DITIPIRAM) Derivatives as Neutral Receptors Tailored for Binding of Carboxylates Agnieszka Cholewiak,† Agnieszka Tycz,†,‡ and Janusz Jurczak*,† †
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
‡
S Supporting Information *
ABSTRACT: The DITIPIRAM (8-propyldithieno[3,2b:2′,3′-e]pyridine-3,5-diamine)-based receptors 11 and 12 were readily synthesized, and their anion-binding properties were studied both in solution and in the solid-state. 1H NMR titrations revealed that receptor 12 equipped with two phenylurea groups preferentially binds carboxylates, even in the highly competitive DMSO-d6/CD3OH solvent mixture. X-ray analysis showed that receptor 12 exhibited great complementarity for benzoate, which is cooperatively bound by the means of four highly directional hydrogen bonds from the two urea groups. Comparison with the most effective acyclic receptors based on a structurally related rigid carbazole platform demonstrates that the DITIPIRAM motif provides a better suited geometry in the binding pocket, and consequently stronger anion binding.
T
he supramolecular chemistry of anions remains an area of intense research, owing to the important role anions play in biological systems, organic synthesis,1,2 and catalysis.3−6 One of the challenges in this field is the efficient preparation of anion receptors with high affinity and selectivity toward specifically targeted anionic guests.7 Neutral anion receptors are potentially superior to charged ones in terms of selectivity, but their affinities are remarkably lower. Much effort is being made to increase the binding strength while retaining the significant selectivity. The binding abilities of neutral hosts toward anions arise from a proper combination of many weak interactions, such as π-stacking, the hydrophobic effect, and hydrogen bonding, among which the latter is most crucial. However, a single hydrogen bond is too weak, and strong binding can only be achieved by multiple such interactions. Therefore, achieving perfect complementarity of a neutral receptor with a target guest requires that the hydrogen-bond donors be arranged in a precise manner within the host structure. Over the past few decades there has been immense progress in the field of anion complexation,8 resulting in the development of many efficient and selective anion receptors incorporating various hydrogen-bond donors,9−13 from which these incorporating syn-directed multiple donors were particularly effective (Figure 1). Ligands 114,15 and 216−19 possess two types of hydrogen-bond donor, originating from the pyrrole ring and from the amide groups, whereas receptors 320,21 and 422,23 have four donors from the urea moieties, and 524,25 incorporates similar urea donors supported by those from the pyrrole ring. Moreover, the presented ligands have relatively rigid central units, and a directly proportional correlation can be observed © 2017 American Chemical Society
Figure 1. Examples of anion receptors based on rigid aromatic core.
between the rigidity of the platform and the association constants. These acyclic ligands have been often found to be selective anion receptors, and additionally they can be prepared by a relatively simple route.26,27 Nevertheless, one of the most important aspects of designing effective anion receptors is understanding the relationship between a ligand’s structure and its affinity toward anions. The correct geometry of the binding site is extremely important, because of the need for complementarity to the anionic guest in the process of selective complexation.28 Therefore, in order to examine the impact of structural aspects on anion binding, and also keeping in mind the role of the rigidity of the receptor’s central part, we turned our attention to 8-propyldithieno[3,2-b:2′,3′-e]pyridine-3,5diamine (DITIPIRAM) (Figure 2). Received: April 25, 2017 Published: May 24, 2017 3001
DOI: 10.1021/acs.orglett.7b01235 Org. Lett. 2017, 19, 3001−3004
Letter
Organic Letters
In all conducted 1H NMR titrations the presence of anions caused a significant downfield shift of the urea group signals. This indicated the formation of hydrogen bonds between the receptors and the anions. Calculations of the stability constants by nonlinear curve fitting were done based on chemical shift changes as a function of anion concentration. Initial experiments in a DMSO-d6 + 0.5% H2O (v/v) mixture revealed the high affinity of 11 and 12 for all tested anions (Table 1).
Figure 2. Structure of key intermediate 8-propyldithieno[3,2-b:2′,3′e]pyridine-3,5-diamine (DITIPIRAM).
Table 1. Stability Constants Ka (M−1) for 1:1 Complexes of Receptors 11 and 12 with Various Anions at 298 Ka
DITIPIRAM (6) was obtained, for the first time nearly 20 years ago, by Paulmier and co-workers29 and since that time, to the best of our knowledge, was never reported. Our choice of DITIPIRAM as a potential platform for anion receptors was prompted by several important factors. First, the presence of the pyridine ring located between two thiophene rings should arrange the syn−syn conformation of urea groups, as is observed for dipicolinic acid derived anion receptors.30,31 Second, the synthesis of DITIPIRAM derivatives is relatively simple, and finally, these compounds can be readily transformed into the desired receptors in one step, as shown in Scheme 1. Herein we present an application of derivatives 11 and 12 as acyclic anion receptors.
entry
anion
11
12
1 2 3
DMSO-d6 + 0.5% H2O
solvent
Cl− MeCO2− PhCO2−
−b >10 000c 4450
3350 >10 000c >10 000c
4 5 6
DMSO-d6 + 5% CD3OH
Cl− MeCO2− PhCO2−
−b 1940 1700
1540 >10 000c 3750
7 8
DMSO-d6 + 10% CD3OH
MeCO2− PhCO2−
−d −d
4200 1560
a
Determined using 1H titration at 298 K; anions added as TBA salts; estimated errors
