Shape-persistent aromatic oligoamides are a class of molecules defined by their uncollapsable structural framework by the aid of intramolecular hydrogen bonds ^{[1, 2, 3, 4, 5, 6]}. Among them,those constructed by coupling aromatic amines and acids with electrondonating groups at the ortho-position of the carbonyl group are especially appealing due to the crescent molecular structures containing introverted carbonyl groups in the cavity ^[7]. The importance of intramolecular hydrogen bonding interactions present in these compounds has been showcased by the efficient formation of the corresponding aromatic oligoamide macrocycles ^{[8, 9, 10, 11, 12]}. These aromatic oligoamides have displayed many interesting properties. For example,we recently reported the efficient extraction of some transition metal ions with acyclic species ^[13]. In addition,they have been demonstrated to serve as a new class of diverse mesogens of liquid crystals ^[14]. It was known that the introduction of soft donor atoms such as phosphorus or sulphur atoms into receptor substituents improved their complexing ability towards transition and heavy metal ions ^[15]. It is reasoned that the replacement of the amide carbonyl oxygen atoms by sulfur atoms may endow them with improved complexation properties.

Selective recognition of transition metal ions has attracted an increasing interest in recent years because of the need for the selective and efficient detection of biologically and chemically important cations ^{[16, 17]} (e.g.,Cu²⁺,Fe³⁺,Cr³⁺,Pb²⁺,Hg²⁺, etc.). Finding selective receptors for the soft transition metal copper ion is one of the research focuses. Many synthetic receptors have been reported for recognizing and sensing copper ions ^{[18, 19, 20]}. However,shape-persistent aromatic oligothioamides containing hydrophilic lumen have never been synthesized for this purpose. So far,modifications of crescent or folding aromatic oligoamides are still a difficult task. Herein,we report the synthesis of aromatic oligothioamide 1 with a crescent conformation and its selective recognition of copper(II) ion. To the best of our knowledge,this represents the first example of a crescent aromatic oligoamide with carbonyl oxygen atoms being replaced by sulfur atoms for metal ion recognition.

Chemical grade reagents were used without further purification for synthesis unless stated otherwise. Compounds 3 and 4 were prepared following our previous method in the literature ^{[8, 11]}. Column chromatography was carried out using silica gel (300- 400 mesh). Thin layer chromatography (TLC) was performed on glass-backed plates coated with silica gel 60 with F₂₅₄ indicator. NMR spectra were recorded at room temperature on a Bruker Avance-400 NMR spectrometer. High resolution mass data were collected by Waters Q-TOF Premier. The UV-vis spectra were measured using a Shimadzu UV-2350 spectrometer. Stock solutions of each ligand were prepared (c 1000 μmol/L) in acetonitrile.All stock solutions of metal ions were prepared from analytical grade nitrate salts which were dissolved (c 1000 μmol/L) in acetonitrile. Eleven metal nitrates including Li⁺,Na⁺,K⁺,Ca²⁺,Sr²⁺,Cd²⁺,Ni²⁺,Co²⁺,Cu²⁺,Zn²⁺,and Pb²⁺ salts were employed in the UV-vis experiment.

Compound 4 (1.57 g,3.36 mmol) was dissolved in dry CH₂Cl₂ (20 mL) and the mixture was added dropwise into a CH₂Cl₂ solution (30 mL) containing 3b (0.28 g,1.68 mmol) and Et₃N (0.42 g,2.52 mmol). After refluxing for 2 h,the reaction mixture was washed with diluted hydrochloric acid and water,dried over anhydrous MgSO₄ and filtered. Removal of CH₂Cl₂ and further purification by column chromatography (CHCl₂/CH₃OH = 20/1) provided the product 2 (1.48 g,86%) as a white solid (Scheme 1). ¹H NMR (400 MHz,CDCl₃):δ 9.45 (s,2H,NH),9.07 (s,1H,Ar),(s,2H, Ar),7.53 (t,2H,J= 5.0 Hz,NH),6.53 (s,2H,Ar),6.50 (s,1H,Ar),4.08 (m,8H,OCH2),3.86 (s,6H,OCH₃),3.50 (m,4H,CH₂),1.94 (m,2H, CH),1.81 (m,2H,CH),1.47 (m,16H,CH₂),1.35 (m,16H,CH₂),1.22 (t,6H,J= 7.2 Hz,NHCH₂CH₃),0.94 (m,24H,CH₃).¹³C NMR (100 MHz,CDCl₃):δ 164.4,162.1,160.3,160.0,146.8,137.3,120.3, 118.2,115.6,115.1,96.4,94.8,72.4,71.6,55.8,39.6,38.9,34.5, 30.8,30.2,29.7,29.1,29.0,24.1,23.6,23.0,23.9,14.9,14.0,11.2, 10.8. ESI-HRMS (m/z): Calcd. for C₆₀H₉₄N₄O₁₀ ([M+H]⁺): 1031.7048; Found 1031.7031.

Scheme 1

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Scheme 1. Synthetic route of aromatic oligothioamide 1.

To a solution of 2 (0.80 g,0.78 mmol) in dry toluene (20 mL) was added the Lawesson’s reagent (0.75 g,1.86 mmol). The mixture was heated for 3 h at 70℃. Solvent was removedin vacuo,and the residue was extracted with CH₂Cl₂. The combined CH₂Cl₂ extracts were washed with diluted hydrochloric acid and water,dried over MgSO₄ and filtered. Removal of CH₂Cl₂ and further purification by column chromatography (CHCl₂/ CH₃OH = 50/1) provided product 1 (0.72 g,86%) as a pale yellow solid (Scheme 1).1H NMR (400 MHz,CDCl₃):δ 10.17 (s,2H,NH), 9.43 (S,2H,ArH),9.27 (s,1H,ArH),8.87 (t,2H,J= 2.4 Hz,NH),6.57 (s,1H,ArH),6.44 (S,2H,ArH),4.08-4.03 (m,8H,CH₂),3.88-3.80 (m,10H,CH₂CH₃),1.84-1.76 (m,4H,CH),1.43-1.33 (m,32H, CH2),0.98 (t,12H,J= 7.6 Hz,CH₃),0.90-0.89 (m,6H,NHCH₂CH₃), 0.86 (t,12H,J= 6.4 Hz,CH₃).¹³C NMR (100 MHz,CDCl₃):δ 193.9, 192.2,157.7,157.5,150.6,141.8,122.7,121.2,121.0,120.5,96.1, 95.2,72.4,72.0,56.1,41.7,39.5,39.0,30.6,30.2,29.1,29.0,24.0, 23.7,23.0,14.1,13.3,11.1,11.0. ESI-HRMS (m/z): Calcd. for C₆₀H₉₄N₄O₆S₄([M+H]⁺): 1095.6134; Found 1095.6128.

As shown in Scheme 1,the aromatic oligothioamide 1 was synthesized by simple thionation of the corresponding oligoamide 2 with the aid of the Lawesson’s reagent ^[20] in 86% yield. Compound 2 was prepared using a coupling reaction of a reduced product 3b from 3a by hydrogenation and acyl chloride 4 bearing alkoxy groups. The key precursor 4 was obtained following the literature procedure ^[9]. All compounds were characterized byv¹H NMR,¹³C NMR and HRMS (Figs. S1-S8 in Supporting information).

The patterns and chemical shifts for each amide proton of compound 2 are the same or similar to those of the previously reported compounds ^[9]. The high resolution ESI mass spectra of the oligothioamide 1 and oligoamide 2 showed highly intense peaks at m/z 1117.5958 [M+Na]⁺ (calcd. 1117.5954 [M+Na]⁺) and 1053.6865 [M+Na]⁺(calcd. 1053.6868 [M+Na]⁺),respectively, which are in full agreement with the desired structures (Figs. S7 and S8 in Supporting information). Interestingly,the ¹H NMR spectrum of 1 recorded in CDCl₃ revealed that the three-centre Hbonded amide protons and terminal amide protons all exhibited noticeable downfield shifts compared to those of compound 2. For example,a shift of 1.0 ppm (from 9.5 ppm to 10.5 ppm) was observed for NH protons in 1relative to those in 2 (Fig. S3 in Supporting information). We attribute the downfield shift to the difference of oligothioamide and oligoamide in delocalizing the lone pair electrons on the nitrogen to the double bond system.

The metal ion binding properties including selectivity of oligothioamide 1 and oligoamide 2 (each 20μmol/L) were examined in CH₃CN using the nitrate salts of Li⁺,Na⁺,K⁺,Ca²⁺,Sr²⁺,Zn²⁺,Cd²⁺,Ni²⁺,Co²⁺,Pb²⁺,and Cu²⁺ ions by UV-vis spectrometry. Among the metal ions tested,compound 1 only showed selective recognition of Cu²⁺. As shown in Fig. 1(a),upon addition of 25 equiv. of Cu²⁺ to the solution of 1,the maximum absorption band at 261 nm disappeared completely along with a concomitant change of two shoulder bands at 292 nm and 340 nm, while a new absorption band centred at 234 nm with high intensity appeared. A large blue shift of 27 nm and the absence of changes for other metal ions strongly suggest the occurrence of metal complexation and selectivity towards Cu²⁺ . As a control,compound 2 was also investigated for its selectivity towards these metal ions under the same conditions. Compound 2 displayed an absorption band centred around 229 nm as shown in Fig. 1(b). This band remains almost unchanged upon addition of 25 equivalents of Li^+,Na⁺,K⁺,Sr²⁺,Zn²⁺,Cd²⁺,or Pb²⁺ ions. Upon addition of 25 equivalentsof Ca²⁺,Ni²⁺,Co²⁺,or Cu²⁺,the absorption maximum was slightly red-shifted to various extents. Particularly,only a small red shift of ca.6 nm was observed for Cu²⁺ . The significant change of compound 1 compared to compound 2 in its absorption maxima and intensity upon addition of Cu²⁺ should be ascribed to the efficient interactionof Cu²⁺ with the lone pair electron of the S atoms in the thiocarbonyl group. Thus,a high Cu²⁺ selectivity was achieved in 1 only when the oxygen atoms in oligoamide 2 were replaced by the sulfur atoms, indicating the importance of the softer sulfur atoms in the oligothioamides for selective recognition of copper(II) ion.

Fig. 1

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Fig. 1. (a) UV-vis absorption spectra of 1 (20μmol/L) upon addition of salts (25 equiv.) of Li+,Na+,K+,Ca2+,Sr2+,Zn2+,Cd2+,Ni2+,Co2+,Pb2+,and Cu2+ in CH3CN; (b) UV-vis absorption spectra of 2 (20μmol/L) upon addition of salts (25 equiv.) of Li+,Na+,K+,Ca2+,Sr2+,Zn2+,Cd2+,Ni2+,Co2+,Pb2+,and Cu2+ in CH3CN.

To elucidate the complexation between 1 and Cu²⁺ ,UV-vis absorption spectral variations of 1 (2.0×10^-5mol/L) in CH₃CN solution were studied by titrating with Cu²⁺ from 0 to 6.0×10^-5mol/L. As shown in Fig. 2(a),the maximum absorbance at 261 nm gradually decreased,while two new absorbances that centred at ca.210 nm and 225 nm appeared. The presence of an isosbestic point at 250 nm indicated the formation of a new complex between 1 and Cu²⁺. The data of Job’s plot from absorption spectra in Fig. 2(b) afforded a 1:1 stoichiometry for the complex of 1 and Cu²⁺. The binding constant of the complex between 1 and Cu²⁺ was thus estimated to be (4.3±0.9)×10⁴L/mol (R²= 0.991) by using the nonlinear fitting of the titration curve (Fig. S9 in Supporting information). In addition,the complexation of compound 1 and Cu²⁺ was also examined in CD₃CN by ¹H NMR technique. The signals from both amide protons (c,f) and interior aromatic protons (b,e) broadened upon the addition of Cu(NO₃)₂. The exterior aromatic protons (a,d) experienced the same change in signal broadening (Fig. S4 in Supporting information). This result indicated that the complexation of compound 1 with Cu²⁺ did occurviacoordination of its internal thiocarbonyl sulfurs with the cation,which explains the efficient recognition of Cu²⁺.

Fig. 2

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Fig. 2. (a) Titration curves of compound1in CH3CN (2.0×10-5mol/L) upon addition of Cu2+ at 0,0.4,0.8,1.2,1.6,2.0,2.2,2.4,2.8,3.2,3.6,4.0,4.4,4.8,5.2,5.6,and 6.0×10-5mol/L; (b) Job’s plot for the determination of stoichiometry of the complex formed by 1 and Cu2+.

Detection limit (DL) is usually evaluated according to the equation DL =K×Sb1/S,where K= 3,where Sb₁ is the standard deviation of the blank solution and S is the slope of the calibration curve ^[21] (see Fig. 3). The detection limit of compound 1 for Cu²⁺ was determined to be about 6.3×10^-7mol/L.

Fig. 3

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Fig. 3. Absorbance of compound 1 at 292 nm as a function of Cu2+ concentration.

In summary,the aromatic oligothioamide 1 with a crescent conformation was synthesized by one-pot thionation of the corresponding oligoamide with the Lawesson’s reagent. The study of the UV-vis spectra revealed that the compound 1 displayed high selectivity for Cu²⁺ due to the presence of highly electron-rich S atoms. In sharp contrast,the corresponding oligoamide 2 failed to show any Cu²⁺ recognition preference over other metal ions.

This work was supported by the National Natural Science Foundation (No. 21172158),NSAF (No. 11076018),Sichuan Province Science and Technology Support Programme (No. 2011FZ0048),the National Fund of China for Fostering Talents in Basic Science (No. J1210004) and Open Project of Key Laboratory for Radiation Physics and Technology of Ministry of Education (No. 2010-08). Analytical & Testing Center of Sichuan University is acknowledged for NMR analyses.

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2013.05.025.