Synthesis and anion binding studies of a new crown ether containing 2,2′-biimidazole

Tetrahedron Letters xxx (2014) xxx–xxx

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Synthesis and anion binding studies of a new crown ether containing 2,20 -biimidazole Maria C. Llinàs a, Joan Farran c, Mario V. Capparelli d, Gonzalo Anguera a, David Sánchez-García a,⇑, Jordi Teixidó a, Salvador Borrós b a

Grup d’Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, Barcelona 08017, Spain Grup d’Enginyeria dels Materials, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, Barcelona 08017, Spain Enantia, S.L., C/Baldiri Reixac, 10, Barcelona 08028, Spain d Unitat de Cristal.lografia, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain b c

a r t i c l e

i n f o

Article history: Received 1 June 2014 Revised 13 June 2014 Accepted 17 June 2014 Available online xxxx Keywords: 2,20 -Biimidazole Anion binding Crown ether Channels Crystal structure

a b s t r a c t A novel crown ether which incorporates the 2,20 -biimidazole moiety was prepared by cyclization of 1,10 dibenzyl-1H,10 H-[2,20 ]biimidazolyl-4,40 -dicarboxylic acid and 4,7,10-trioxa-1,13-tridecanediamine followed by removal of the benzyl groups. The diacid has been obtained by hydrolysis of the diester previously prepared by alcoholysis of the corresponding dicyano biimidazole. The cyano group is introduced by a palladium-catalyzed procedure starting from the corresponding dibromo biimidazole. The macrocyclic structure of the N-dibenzylated derivative of the receptor has been studied by X-ray diffraction. Binding constants for 1:1 biimidazole–anion complexation (Kassoc) are on the order of 105 M1  for H2PO 4 and Cl . Ó 2014 Elsevier Ltd. All rights reserved.

The structure of 2,20 -biimidazole1 is characterized by the presence of a double ethylenediamine moiety. This feature makes the biheterocycle amenable to produce metallic complexes2–4 and supramolecular ensembles.5 The rich chemistry of 2,20 -biimidazoles has been used in the design of polymeric sensors6,7 and receptors.8,9 However, the high insolubility of the unsubstituted heterocycles has hampered the application of biimidazoles in the preparation of complex systems. Ironically, this insolubility is largely due to the presence of the double ethylenediamine moiety which is responsible for the formation of long planar supramolecular bands of biimidazoles bound together by pairs of N–H  N hydrogen bonds.10 Over the last years, the development of synthetic methods to prepare substituted soluble 2,20 -biimidazoles has allowed several groups to study and expand the application of these compounds, for instance, as building blocks in the synthesis of conjugated macrocycles11–13 or in supramolecular chemistry.10 In this context the group of Allen14 reported the synthesis of 2,20 -biimidazoles soluble in organic solvents bearing secondary amides which display  moderate affinities for H2PO 4 and Cl . In the same report, it was suggested to constrain the biimidazoles to adopt only the syn

⇑ Corresponding author. Tel.: +34 93 267 21 22; fax: +34 93 205 62 66. E-mail address: [email protected] (D. Sánchez-García).

HN H N O

R

N N H

N NH A1-anti

R

O O

R

N

N

N H

N H

NH

O HN

A-

R

1-syn

Figure 1. anti and syn conformers of biimidazole–anion complexes.

geometry in order to improve the anion affinities and selectivities since this conformation requires minimal reorganization of the receptor (Fig. 1). Thus, as a part of our on-going research in the area of biimidazole and macrocyclic chemistry, we decided to synthesize a macrocycle containing a 2,20 -biimidazole diamide in order to assess its anion binding capabilities and compare the results with the reported values for the acyclic diamides. Synthesis of the macrocycle is outlined in Figure 2. The starting material is 1,10 -dibenzyl-4,40 -dibromo-2,20 -biimidazole (2) which was prepared via a simple three-step procedure as previously described by our group.15 This molecule has been carefully chosen taking into account two important structural features. First, the

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Please cite this article in press as: Llinàs, M. C.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.072

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M. C. Llinàs et al. / Tetrahedron Letters xxx (2014) xxx–xxx Br

N

N

N Bn

NC

Br

N

N

N

Pd2(dba)3 / dppf

N

N

78 ºC, N 2 atm., 1h

Bn

73%

Bn

Bn

78%

HCl(g) / EtOH

3

2

EtO2 C

CN

CuCN / Et4NCN

CO2Et

N

N

N

N

Bn

Bn

HO2C NaOH(aq) 2M

100 ºC, N 2 atm., 0.5h

N

N

N

N

Bn

96%

CO2H

Bn 5

4

O

O

O

NH

HN N

N

N

N

G

G

O

O

6 G = Bn 7 G=H

1. 4,7,10-Trioxa1,13-tridecanediamine / Et3N 2. DPPA, 23 ºC, DMF 28%

Na / NH 3 , 48%

Figure 2. Synthesis of macrocycle 7.

amine groups are blocked, improving the solubility of the biheterocycle in organic solvents. Second, its particular 4,40 substitution pattern allows the macrocyclization. The benzyl (Bn) group has been selected due to its stability in an extensive range of conditions.16 In the first step, the 4,40 -dibromo-biimidazole 2 was treated with CuCN17 in the presence of tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and 1,10 -bis(diphenylphosphino)ferrocene (dppf) as ligand in 1,4-dioxane at reflux for 12 h to provide the dicyano substituted biimidazole 3. In order to synthesize the corresponding dicarboxylic acid a convenient two-step procedure was used. Thus, while the acidic hydrolysis of 3 took place only with low yields; its basic hydrolysis renders mainly the corresponding amide as a very insoluble precipitate. Therefore, to avoid this drawback, the cyano derivative was heated with HCl in ethanol which yields diester 4. The saponification of 4 in basic media afforded the diacid 5 in excellent yield. The macrocyclic lactam was prepared following the protocol described by Quian et al. which uses diphenylphosphoryl azide (DPPA) as the activating reagent of the carboxylic acid.18 This methodology allows the direct macrocyclization of a diamine and a dicarboxylic acid without the need of high-dilution techniques. The chosen diamine, 4,7,10-trioxa-1,13-tridecanediamine, contains a diethylene glycol moiety. The aim of this selection is to allow additional interactions with the anions and improve the solubility. Thus, the cyclization of dicarboxylic acid 5 and 4,7,10-trioxa-1,13tridecanediamine provides macrocycle 6 in 28% yield. Finally, benzyl protecting groups were removed smoothly by treatment of 6 with sodium in liquid ammonia (Fig. 2). In order to confirm the macrocyclic structure of 7 by X-ray crystallography, many attempts to grow crystals were made. Unfortunately all the efforts were unsuccessful. However, crystals of 6, suitable for X-ray diffraction, were obtained by slow evaporation of a solution of the diamide in a mixture of methanol/dichloromethane. The relevant geometric parameters are given in the Supporting Information (SI) section. The molecular structure is shown in Figure 3. The structure was solved and refined by standard methods. Cbonded H atoms were placed in calculated positions [SHELX AFIX, C-H 0.93 Å for C(sp2) and 0.97 Å for C(sp3)]. N-bonded H atoms were located in Fourier difference maps and refined. All H atoms

Figure 3. Molecular structure of compound 6 showing the atomic numbering (for disordered C and O atoms (cf. SI) only the most populated positions are shown, for clarity). The displacement parameters are drawn at 50% probability.

were given Uiso = 1.2 Ueq (parent atom). Several atoms in the macrocycle were found to be disordered; each one was placed in two alternative positions with complementary occupancies [final values: 0.729(9) for C6, O7, and C8; 0.93(2) for O10; 0.87(1) for O13 and C14]. An isolated electron density peak, located within the channel running along c, was assigned to a water molecule of solvation and given occupancy 0.50; the corresponding H atoms could not be located. The final difference Fourier synthesis was featureless. All bond lengths and bond angles are within expected values.19 The shape of the macrocycle is approximately ellipsoidal; with average maximum/minimum dimensions of ca. 11.07 and 3.78 Å. However, the ring is far from planar; a side-on view shows that it is J-shaped, with the C3N2 rings at the top (flat) of the stem, and the C7, C9, C11, C13 (and H93, H111) atoms at the tip of the hook. The 5- and 6-membered rings are quite planar, and make dihedral angles of 40.01(11)° (C3N2/C3N2) and 84.67(12)° (C6/C6). Interestingly, the crystal structure displays cylindrical channels along c (Fig. 4a). Their walls are made of C atoms from phenyl rings, with distances to the center in the range 4.63–5.15 Å (3.78 Å for H351) (see SI, Table 1). Within the channels there are disordered water molecules of solvation, hydrogen bonded to symmetry-related neighboring waters and to O1 atoms (Fig. 4b). The origin of the water molecules is not certain, however it can be ascribed to residual water present in the solvent used in the crystallization (methanol). The anion recognition properties of macrocycle 7 with a wide    variety of anions (H2PO 4 , Cl , Br , NO2 in the form of their tetrabutylammonium salts) were investigated by means of UV–vis titrations. The set of spectra shows the appearance of an isosbestic point at 280 nm. This result in conjunction with the corresponding Job plot (cf. SI) confirms a 1:1 binding which is expected from such macrocyclic receptor (Fig. 5). Table 1 summarizes the 1:1 biimidazole–anion binding    constants (Kassoc) for H2PO 4 , Cl , Br , and NO2 that were derived from UV–vis titrations. The Kassoc obtained for all the anions are higher than the values reported previously for acyclic biimidazole diamides.14 For instance, the highest affinities for the acyclic diamides were found in the range of 6.8  104 and 1.4  105 for dihydrogenphosphate and chloride, respectively, whereas the same anions show binding constants of 3.9  105 and 2.2  105 with

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Figure 6. ESI mass spectrum of 7 in the presence of Bu4N+Cl. The main peak corresponds to the 1:1 adduct [7Cl]. Other peaks: [7-H] = 405, [7+35Cl] = 441.2, [7+37Cl] = 443.2.

 Figure 7. DFT optimized structures of [7H2PO 4 ] and [7Cl ].

Figure 4. (a) View of the unit cell contents down the c axis. (b) Detailed view of a channel down the c axis. Dashed lines indicate possible hydrogen bonds.

Table 1 Summary of the 1:1 biimidazole–anion binding constants (Kassoc)a for the different anions studied (25 °C) Anion

Kassoc (M1)

H2PO 4 

3.9  105 2.2  105 4.5  104 3.1  104

Cl Br NO 3 a

Errors are smaller than ±10%.

Figure 5. Representative UV–vis spectra of 7 (2.9  106 M) in CH2Cl2 during titration with Bu4N+Cl (25 °C).

macrocycle 7. Therefore, these results would confirm the hypothesis that the syn conformation induced by the macrocycle increases the complexing capacity of the receptor. Complementary studies regarding the stoichiometry of binding have been carried out by means of ESI-MS (ElectroSpray Ionization-Mass Spectrometry).20–22 Typically, the spectrum of a mixture of the receptor and the host displays peaks attributable to the formation of complexes (Fig. 6). Thus, a solution of 7 with Cl and H2PO 4 (1:1 in chloroform) is injected in the spectrometer and the spectrum is registered in the negative mode by a broad mass sweeping. The spectra show peaks with values of m/q 441 and 503 respectively corresponding to the complexes [7Cl] and [7H2PO4]. These results are compatible with the 1:1 stoichiometry proposed by the Job plot. Receptor 7 is quite selective toward dihydrogenphosphate and chloride. This result is in agreement with the findings by Allen14 with non macrocyclic biimidazole diamides. It is noteworthy that the value of the binding constant of dihydrogenphosphate (3.9  105) is slightly higher than Kassoc for chloride (2.2  105). In order to gain insight into this selectivity, DFT calculations have been carried out. It is hypothesized that this selectivity could be ascribed to the binding of dihydrogenphosphate not only with the heterocyclic moiety but with one oxygen atom from the polyethylene glycolic chain. On the other hand chloride would just interact with the amide groups and the imidazole protons. The geometry of receptor 7 was initially optimized with DFT using the common hybrid functional of Becke, 3-parameter, Lee– Yang–Parr functional along with the 6-311+G(d,p) basis set. The solvation effect of dichloromethane was considered using the PCM (polarizable continuum model). Next, dihydrogenphosphate and chloride anions were placed close to the macrocycle and the structures were finally optimized. Results show that the structure of complex [7H2PO 4 ] allows the formation of an extra H-bond which implies the OHphosphate  Oether interaction (Fig. 7). The presence of this additional interaction is consistent with the observed selectivity of the receptor for dihydrogenphosphate over chloride.

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M. C. Llinàs et al. / Tetrahedron Letters xxx (2014) xxx–xxx

Conclusions

References and notes

A crown ether incorporating 2,20 -biimidazole has been synthetized for the first time. The synthesis comprises five steps starting from a protected dibrominated 2,20 -biimidazole. The macrocyclic structure of the N-dibenzylated derivative of the receptor has been studied by X-ray diffraction. The crystal structure presents supramolecular channels. On the other hand, the ability to act as an anion receptor has been tested. This new macrocyclic receptor forms 1:1 complexes with anions. Binding constants for 1:1 biimidazole–anion complexation (Kassoc) are on the order of  105 M1 for H2PO 4 and Cl . These results would confirm the hypothesis that the syn conformation induced by the macrocycle improves the complexing capacity of the receptor when compared with the acyclic diamides.

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Acknowledgment A fellowship by the IQS (D.S.-G.) is gratefully acknowledged. Supplementary data Supplementary crystallographic data have been deposited with the Cambridge Crystallographic Data Centre under the number CCDC 968269, and can be obtained, free of charge, from www.ccdc.cam.ac.uk/data_request/cif. Supplementary data (experimental, spectroscopic titrations and spectral data of all new compounds, optimized coordinates of the DFT calculations) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.072.

Please cite this article in press as: Llinàs, M. C.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.072