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. 2018 Jul 18;3(7):8003–8008. doi: 10.1021/acsomega.8b01155

Rationally Designed Circularly Arranged Sextuple Molecule with Dimethoxyphenolic Tentacles for Ample Hunting of Cyanide

Palwinder Singh 1,*, Harpreet Kaur 1, Harpreet Singh 1
PMCID: PMC6644536  PMID: 31458938

Abstract

graphic file with name ao-2018-011555_0011.jpg

Herein, we report the design, synthesis, and cyanide-scavenging behavior of circularly arranged sextuple molecule 4. The six syringaldehyde units carrying equal number of dimethoxyphenolic moieties projecting at the periphery make the molecule highly efficient for cleaning up cyanide from the aqueous solution. The stoichiometric data 1:6 showed that six units of cyanide interact with one unit of compound 4. The association constant of the compound for cyanide was 2.5 × 104 M–1, and its detection limit for cyanide was 10 nM. The compound was also found to remove cyanide bound to cytochrome c oxidase.

1. Introduction

The affinity of CN– for Fe2+ of cytochrome c (Cyt c) makes it one of the highly toxic anions1−6 because Cyt c–CcOX (cytochrome c oxidase) complex is the last enzyme in the respiratory electron transport chain and the blockage of this pathway limits the oxygen supply that ultimately proves lethal.7,8 In addition to the available reports on cyanide sensing9−18 and sequestering compounds such as hydroxocobalamin,19−24 dicyanocobalt(III) porphyrins,25−28 vitamin B12 analogues,29,30 and hexahydrated dichlorides of cobalt(II),31−34 it was found recently that compounds 1–3 (Chart 1) were capable of removing cyanide from the aqueous medium and human blood serum35,36 through the more prevalent keto-form of their phenolic moiety and disposing it off in the form of COOH. Hence, it was logically hypothesized that the presence of more such phenolic groups in the molecule may increase its cyanide-sensing capacity and that the capturing of cyanide per molecule of the receptor becomes more effective. Therefore, it was planned to introduce six 3-(4-hydroxy-3,5-dimethoxybenzylidene)indolin-2-one units on the benzene core, and consequently, compound 4 (Chart 2) was designed.

Chart 1. Cyanide Scavengers.

Chart 1

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Chart 2. Compound 4 and Its Energy-Minimized Geometry.

Chart 2

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2. Results and Discussion

2.1. Chemistry

Compound 5 was obtained by the methylation of syringaldehyde, and it was made to react with oxindole by heating at 145 °C to obtain compound 6 (Scheme 1). Compound 6 was procured as inseparable E- and Z-isomers in the ratio 4:1. For the synthesis of compound 8, first mesitylene was treated with formaldehyde and HBr–AcOH to get compound 7 and then compound 7 was refluxed with Br2 in 1,2-dibromoethane wherein compound 8 was obtained. Further reaction of compounds 6 and 8 in acetonitrile (ACN) in the presence of K2CO3 resulted into the replacement of all the six Br of compound 8 with compound 6, and consequently, compound 9 was procured. Selective demethylation of compound 9 was achieved by using AlCl3 in dichloromethane (DCM) providing desired compound 4 (Scheme 1). The energy-minimized geometry of compound 4 indicates circular shape of the molecule with the six 3-(4-hydroxy-3,5-dimethoxybenzylidene)indolin-2-one units projecting alternatively upward and downward of the benzene plane. All the six phenolic units are directed outward from the central hydrophobic core (Chart 2).

Scheme 1. Synthesis of Compound 4.

Scheme 1

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2.2. Cyanide-Scavenging Studies

Addition of compound 4 [1 μM, dimethyl sulfoxide (DMSO)–H2O (1:9) v/v] to the aqueous solutions of different anions changed the color of the solution containing cyanide (Figure 1). The UV–vis spectrum of compound 4 [1 μM, DMSO–H2O (1:9), pH 7.0] showed an absorption maximum at 373 nm. Incremental addition (1 μL at each step) of cyanide (1 μM in H2O) to the solution of compound 4 resulted in the decrease in intensity of the absorption band at 373 nm with concomitant emergence of a new band at 535 nm (Figure 2). The spectral changes were observed until the addition of 16 equiv of cyanide (very small changes after the addition of 10 equiv CN–). The band at 373 nm was diminished, and the other one at 535 nm was highly intense. At this stage, the compound–cyanide solution was dark orange in color. Apparently, the compound interacted with CN– and consequently resulted in the change of the UV–vis spectrum as well as the color of the solution of compound 4. The selective and competitive binding of the compound with cyanide was ascertained with the help of appropriate experiments, and the results are depicted in Figure 3. The stoichiometry of compound–cyanide, found through Job’s plot of continuous variation, was 1:6 (Figure 4), and the association constant (Ka) was 2.5 × 104 M–1 (Supporting Information). The detection limit of compound 4 for cyanide was 10 nM (Supporting Information). It was observed that in comparison to compounds 1–3, compound 4 was more effective in the detection of cyanide even at lower concentration than that of compounds 1–3 (Table S1).

Figure 1.

Figure 1

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Color change of compound 4 (1 μM, DMSO–water, 1:9 v/v) in the presence of anions (10 equiv): CN–, F–, Cl–, Br–, I–, AcO–, SCN–, HSO4–, H2PO4–, HCO3–, and CO32–.

Figure 2.

Figure 2

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UV–vis titration of compound 4 (1 μM in DMSO–H2O, 1:9) against CN– (1 μM in H2O).

Figure 3.

Figure 3

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Monitoring of UV–vis absorbance of compound 4 at 535 nm. Graph showing the selectivity of compound 4 for CN– and competitive binding of the compound with CN– in the presence of other anions.

Figure 4.

Figure 4

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Job’s plot for compound 4 with CN– monitored at 535 nm.

Assisted removal of compound 4 of cyanide from an aqueous solution was demonstrated with a physical experiment. Addition of 10 μL of 1 μM cyanide to 1 mL of 10 nM solution of compound 4 in acetone–water (1:9) turned the color of the solution to orange, indicating that 10 nM CN– is detected by the compound (Figure 5A). The aqueous part of this solution left after repeated (4–5 times) extraction with ethyl acetate did not respond to the addition of compound 4 (Figure 5A), indicating that all the cyanide was bound to the compound and extracted with ethyl acetate. The observations were confirmed by performing a control experiment (Figure 5B) in which the aqueous solution of cyanide was extracted 4–5 times with ethyl acetate, but still the aqueous part responded to compound 4, indicating that cyanide was not removed with ethyl acetate. Similar experiments with compounds 1 and 3 required, respectively, 10 μM and 200 nM compound for the removal of 10 μM and 10 nM cyanide from the respective aqueous solution (Table S1).

Figure 5.

Figure 5

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Schematic representation of the experiment showing extraction of cyanide from the aqueous solution with the help of compound 4.

Therefore, in consistent with the design of the molecule, compound 4 was capable of selective and competitive detection of CN–. The mass spectrum of the solution of compound 4 with cyanide (solution obtained after the last addition of cyanide in the UV–vis experiment) showed peaks at m/z 2081 and 2230 supporting the addition of cyanide to the compound and subsequent hydrolysis of the CN group to COOH (Figure 6, Supporting Information).

Figure 6.

Figure 6

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Mass spectrum of the solution of compound 4 and cyanide showing the reaction of cyanide with compound (m/z 2081 calcd m/z 2081 [M + H]+) and subsequent hydrolysis of CN to COOH (m/z 2230 calcd m/z 2230 [M + Na]+).

The compatibility of compound 4 with the CcOX pathway as well as the removal of Cyt c–CcOX bound cyanide was screened through enzyme immunoassay. Complementing the enzymatic activity of CcOX, Cyt c–Fe2+ was oxidized to Fe3+ in the presence of CcOX, and hence, the absorbance intensity at 550 nm gets decreased (Figure 7A). Incremental addition of cyanide to CcOX was made, and the resulting solution was added to the solution of Cyt c. A stepwise increase in the absorbance intensity at 550 nm (Figure 7B) was observed, which indicated the blockage of CcOX with CN–. Further addition of compound 4 to the above solution of Cyt c–CcOX–CN– decreased the absorbance intensity at 550 nm (Figure 7C). Apparently, the compound removed cyanide from CcOX, and the latter oxidized Cyt c–Fe2+ to Fe3+, resulting in the decrease of intensity at 550 nm. The binding of cyanide to compound 4, in preference to CcOX, was checked by adding cyanide solution to the solution of Cyt c–CcOX–compound 4: the absorbance intensity at 550 nm remains minimum up to the addition of 160 μM cyanide. However, addition of more cyanide to the above solution led to the increase in the absorbance intensity at 550 nm (Figure 7D). All these observations indicated that (i) 160 μM cyanide was accommodated by compound 4 and (ii) the cyanide preferred compound 4 over CcOX for interaction. Therefore, the compound under present investigation may act as an effective antidote of cyanide poisoning.

Figure 7.

Figure 7

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Working of the compound with cytochrome c oxidase: (A) UV–visible absorbance of 5.5 μM cyt c in assay buffer was monitored at a wavelength of 550 nm on incremental (10 μL) addition of CcOX (diluted in enzyme buffer). Decrease in absorbance was due to the oxidation of Fe2+ to Fe3+ of Cyt c by CcOX. (B) Change in absorbance at 550 nm of Cyt c on addition of CcOX solution along with 0–3 μM CN–, showing decrease in the enzymatic activity of CcOX in the presence of cyanide. (C) Absorbance intensity of solution obtained at step “B” was decreased on addition of 2 μM compound 4, indicating removal of cyanide from CcOX by the compound. (D) (a) No absorbance at 550 nm in the presence of compound 4 (10 μM) and 160 μM CN– and (b) addition of more CN– increased the absorbance intensity at 550 nm.

3. Conclusions

In conclusion, the rational modification of compounds 1–3 to compound 4 has significantly improved its cyanide-scavenging capacity. Supporting the design of the molecule, in comparison to compounds 2 and 3, the present compound was capable of removing cyanide from the aqueous solution and CcOX at much lower concentration than that of compounds 2 and 3. Detailed studies with the compound using animal models will be reported in the near future.

4. Experimental Section

1H and 13C NMR spectra were recorded on JEOL 400 MHz and Bruker 500 MHz NMR spectrometers, respectively, using CDCl3 as the solvent. Chemical shifts are given in parts per million with tetramethylsilane as the internal reference. Both 1H and 13C NMR spectra of compounds 9 and 4 were recorded by keeping the relaxation time 5–7 s. It seems that the CH2 and central benzene signals are buried inside the molecule and hence difficult to pick up though the integration in 1H NMR spectrum and number of carbons are correct. Mass spectra were recorded on a Bruker micrOTOF-Q II mass spectrometer. Reactions were monitored by thin-layer chromatography (TLC) on glass plates coated with silica gel GF-254. Column chromatography was performed with 60–120 mesh silica. Infrared (IR) and UV–vis spectral data were recorded on FTIR Agilent CARY 630 and BIOTEK Synergy H1 Hybrid Reader instruments, respectively.

4.1. Synthesis of 3,4,5-Trimethoxybenzaldehyde (5)37

To the stirred solution of syringaldehyde (4 g, 21.9 mmol) in dimethylformamide (50 mL), K2CO3 (4.54 g, 32.92 mmol), CH3I (3.73 g, 26.34 mmol), and KI (catalytic amount) were added. The reaction was allowed to stir overnight at room temperature. After the completion of reaction, it was quenched by adding water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to procure pure product 5, creamish white solid (90%), mp 75–76 °C, δH (400 MHz; CDCl3): 3.94 (s, 9H, OCH3), 7.13 (s, 2H, ArH), 9.87 (s, 1H, CHO); δC (normal/DEPT-135; CDCl3): 56.4 (OCH3), 61.0 (OCH3), 127.1 (C), 139.0 (C), 149.0 (C), 191.1 (C=O). HRMS (ESI) m/z: for C10H12O4 [M + H]+ calcd, 197.0808; found, 197.0727.

4.2. Synthesis of Compound 6

3,4,5-Trimethoxybenzaldehyde (2 g, 10.20 mmol) and oxindole (1.35 g, 13.58 mmol) were heated at 145 °C for 1 h. The reaction mass was purified by column chromatography to obtain compound 6, yellow solid (80%), mp 156 °C. δH (500 MHz, CDCl3): 3.90 (s, 6H, OCH3(major)), 3.96 (s, 3H, OCH3(major)), 3.96 (s, 3H, OCH3(minor)), 3.99 (s, 6H, OCH3(minor)), 6.89–6.90 (d, J = 7.37 Hz, 1H, ArH(minor)), 6.91–6.92 (d, J = 3.15 Hz, 1H, ArH(major)), 6.93–6.94 (d, J = 3.09 Hz, 1H, ArH(major)), 6.95 (s, 2H, ArH(major)), 7.05–7.08 (t, J = 7.90 Hz, 1H, ArH(minor)), 7.23–7.26 (t, J = 7.38 Hz, 2H, ArH(major,minor)), 7.50 (s, 1H, bridged H(minor)), 7.54–7.55 (d, J = 7.60 Hz, 1H, ArH(minor)), 7.78 (s, 1H, bridged H(major)), 7.78–7.82 (d, J = 7.97 Hz, 1H, CH(major)), 7.84 (s, 2H, CH(minor)), 8.13 (br, 1H, NH(minor)), 8.26 (br, 1H, NH(major)). δC (normal/DEPT-135; CDCl3): 56.2 (OCH3), 61.0 (OCH3), 109.8 (CH), 110.1 (CH), 121.7 (CH), 121.8 (CH), 123.1 (CH), 126.7 (C), 128.7 (C), 129.8 (CH), 130.5 (C), 137.6 (CH), 141.5 (C), 153.3 (C), 169.5 (C=O). HRMS (ESI) m/z: for C18H17O4N [M + H]+ calcd, 312.1230; found, 312.1182.

4.3. Synthesis of 1,3,5-Tris(bromomethyl)-2,4,6-trimethylbenzene (7)38

To the mixture of mesitylene (2.4 g, 20 mmol), paraformaldehyde (2 g, 70 mmol), and glacial acetic acid (10 mL), 14 mL of 31% HBr–acetic acid solution was added rapidly. The reaction mixture was kept for 12 h at 95–110 °C and then poured into 100 mL of water. The solid was filtered, washed with water, and dried in vacuum to obtain a white solid 7 (91%), mp 187 °C, δH (400 MHz; CDCl3): 4.57 (s, 6H, CH2Br), 2.46 (s, 9H, CH3); δC (normal/DEPT-135; CDCl3): 15.5 (CH3), 30.0 (CH2), 133.3 (C), 138.0 (C).

4.4. Synthesis of Compound 8(39)

Br2 (1.24 mL) was added dropwise over a period of 2 h to a stirred and boiling solution of 7 (2 g) in 1,2-dibromoethane (14 mL). Stirring and boiling were continued for another 22 h, the mixture was cooled down, and the deposited crystals were filtered and washed with 1,2-dibromoethane. Yield: 3 g (95%), yellow colored shining crystals, mp 307–308 °C. δH (400 MHz; CDCl3): 4.68 (s, 12H).

4.5. Synthesis of Compound 9

Solution of compound 6 (587 mg, 1.88 mmol) and K2CO3 (433.96 mg, 3.149 mmol) in dry ACN was stirred for 10 min. Then, compound 8 (200 mg, 0.314 mmol) was added. The reaction mixture was stirred and refluxed for 5 h (TLC). After the completion of reaction, it was quenched with water. The crude product was purified through column chromatography to get compound 9 as yellow solid, 50%, mp 185 °C. δH (500 MHz, CDCl3): 3.33–3.63 (m, 12H, OCH3), 3.72–3.99 (s, 44H, OCH3), 4.72–5.64 (b, 12H, CH2), 6.45–6.64 (m, 6H, ArH), 6.82–6.91 (m, 14H, ArH), 6.99–7.09 (m, 8H, ArH), 7.50–7.96 (m, 14H, ArH). δC (normal/DEPT-135; CDCl3): 43.0 (CH2), 56.2 (OCH3), 60.7 (OCH3), 104.7 (CH), 105.1 (CH), 106.9 (CH), 108.7 (CH), 110.0 (CH), 111.5 (CH), 118.1 (CH), 119.1 (CH), 120.3 (CH), 121.0 (CH), 122.3 (CH), 126.4 (C), 128.3 (CH), 129.6 (CH), 130.2 (C), 136.8 (+ve, CH), 137.1 (CH), 138.0 (CH), 139.2 (C), 139.7 (C), 140.5 (C), 152.5 (C), 152.2 (C), 165.9 (C=O), 168.3 (C=O), 168.4 (C=O). ν̅ (cm–1): 1688 (C=O). HRMS m/z: for C120H108N6O24 [M + Na]+ calcd, 2040.7340; found, 2040.7329.

4.6. Synthesis of Compound 4

The reaction mixture obtained by the slow addition of anhydrous AlCl3 (198.40 mg, 1.48 mmol) to the solution of compound 9 (200 mg, 0.099 mmol) in dry DCM was stirred for 12 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and evaporated under vacuum. Crude solid was washed with diethyl ether to get pure product 47%, mp 240 °C. δH (500 MHz, CDCl3): 3.83–3.95 (OCH3), 4.77–5.26 (CH2), 5.82–6.27 (OH), 6.83–7.06 (ArH), 7.07–7.93 (ArH). δC (normal/DEPT-135; CDCl3): 40.1 (CH2), 41.1 (CH2), 46.0 (CH2), 56.1 (OCH3), 56.2 (OCH3), 56.2 (OCH3), 60.9 (OCH3), 61.0 (OCH3), 106.4 (CH), 106.7 (CH), 106.8 (CH), 106.9 (CH), 108.8 (CH), 109.3 (CH), 110.0 (CH), 119.1 (CH), 121.3 (CH), 121.4 (CH), 121.8 (CH), 122.8 (C), 123.0 (CH), 126.0 (C), 128.6 (CH), 129.4 (CH), 129.9 (CH), 130.2 (C), 137.3 (CH), 137.7 (CH), 137.9 (CH), 138.3 (CH), 139.1 (C), 139.4 (C), 143.1 (C), 152.7 (C), 153.1 (C), 153.2 (C), 153.4 (C). ν̅ (cm–1): 3358 (OH), 1692 (C=O). HRMS: m/z for C114H96N6O24 [M + K + Na – H]+ calcd, 1993.2610; found, 1993.2596.

4.7. UV–Vis Titration of Compound 4 with CN–

Stock solution of compound 4 (1 × 10–3 M) was diluted to 1 μM concentration by using DMSO–H2O, 1:9 v/v. Stock solution of NaCN (1 × 10–3 M, water) was prepared. The absorbance of the compound solution was noted, which shows absorption maxima at 373 nm. Incremental addition (1 μL) of cyanide solution to the compound solution was made. The absorption intensity at 373 nm gets decreased, and the intensity of new band at 535 nm goes up.

4.8. Selectivity of Compound 4 for CN–

Stock solutions of CN–, Br–, F–, AcO–, H2PO4–, HCO3–, SCN–, CO32–, Cl–, and I– (10–3 M in water) were prepared. Each anion (170 μL, 17 equiv) was added to the compound solution one by one, and UV–vis spectrum was recorded. Decrease in the absorption band at 373 nm and emergence of a new band were observed only in the case of cyanide solution.

4.9. Experiments Showing Removal of CN– from Water by Compound 4

Removal of CN– from its aqueous solution with the help of compound 4 was ensured. Cyanide (10 μL, 1 μM) and compound (10 μL, 1 μM) were taken in acetone–water (1:9, 1 mL). This orange colored solution was extracted with ethyl acetate (4 × 25 mL). Addition of compound 4 (10 μL, 1 μM) to the aqueous part (obtained after extraction with ethyl acetate) did not change the color of the solution, indicating absence of cyanide in the aqueous part. As a control experiment, cyanide (10 μL, 10 μM) was taken in acetone–water (1:9, 1 mL), and the solution was extracted was ethyl acetate (4 × 25 mL). Treatment of the aqueous part (left after extraction with ethyl acetate) with compound 4 (10 μL, 10 μM) turned the color of the solution orange, indicating the presence of cyanide in the aqueous part.

4.10. Working of Compound with Cytochrome c Oxidase

The preparation of assay buffer, enzyme buffer, and other reagents was as per the protocol available with the assay kit. The absorbance of cyt c (5.5 μM) at 550 nm was noted. To the solution of cyt c (5.5 μM having 25 μL cyt c and 975 μL assay buffer), 0.5 μL dithiothreitol (0.1 M) was added and kept for 15 min. Incremental addition (10–50 μL) of CcOX (5 μL CcOX diluted with 45 μL enzyme dilution buffer) was made, which led to a decrease in the absorbance intensity at 550 nm. Addition of cyanide (1–3 μM) to the solution of CcOX was followed by the transfer of each of this solution (CcOX–1 μM CN–, CcOX–2 μM CN–, CcOX–3 μM CN–) to the vial containing cyt c, and absorbance at 550 nm was noted. Last, compound 4 (10 μM) was added to the solution containing CcOX–3 μM CN– and cyt c.

Alternatively, 500 μL of solution containing cyt c (5.5 μM, 25 μL) and CcOX (5 μL CcOX diluted with 45 μL enzyme dilution buffer) in assay buffer was mixed with 500 μL acetone–water (1:9 v/v) solution containing compound 4 (10 μL, 10 μM in acetone) and CN– (62.5 μL, 160 μM in water). UV–vis spectrum of the above solution was recorded. More cyanide (up to 185 μM) was added to the above solution, and UV–vis spectra were recorded.

Acknowledgments

Financial assistance from SERB-DST, New Delhi, is gratefully acknowledged. H.K. and H.S. thank UGC and CSIR, respectively, for fellowship. UGC is acknowledged for grant to Guru Nanak Dev University under University with Potential for Excellence programme.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01155.

  • 1H and 13C NMR spectra, mass spectra, IR spectra, stoichiometry, and binding constant (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao8b01155_si_001.pdf (1MB, pdf)

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