A new imidazoline-containing Bunte salt: synthesis, molecular and electronic structure

Franciszek Sączewski 1 , Maria Gdaniec 2 ,  and Krzysztof Data 3
  • 1 Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
  • 2 Faculty of Chemistry, A. Mickiewicz Universit, Poznań, Poland
  • 3 Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
Franciszek Sączewski
  • Corresponding author
  • Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
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, Maria Gdaniec and Krzysztof Data
  • Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, Gdańsk, Poland
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Abstract

S-[(4,5-dihydro-1H-imidazol-2-yl)methyl]sulfothioate, a new imidazoline-containing Bunte salt 4 was prepared by reacting 2-chloromethylimidazoline 3 with sodium thiosulfate in aqueous solution at room temperature. The mechanism of the concerted SN2 reaction pathway was studied by means of quantum chemical calculations at the B3LYP/6-31G** level of theory. The molecular structure of compound 4 incorporating a formal amidine moiety was confirmed by single crystal X-ray diffraction analysis, while its electronic structure was studied using quantum chemical calculations at the MP2/6-311++G** level of theory.

Salts of S-alkylthiosulfuric acid (S-substituted thiosulfates, Bunte salts) have long been known as valuable reagents in synthetic organic chemistry [1] and in the industry [2]. Perspectives in the application of these sulfurating reagents have recently been defined in a versatile review article [3]. Thus, S-alkylsulfothioates are easily transformed into the corresponding sulfhydrides and sulfides [1], [4], [5], disulfides [6], [7], trisulfides [8], [9], as well as isothiocyanates and mercaptals [10]. They also serve as thiol precursors in the synthesis of 3-thioindoles [11] and in conjugated polymer self-assemblies on gold and silver surfaces [12]. Of special interest are alkylthiolation reactions, in which S-nucleophiles generated in situ from Bunte salts undergo a reaction with carbocations of isobenzofuranone and isoindolone [13], as well as the use of Bunte salts as the odorless thiol surrogates for the synthesis of α-sulfido carbonyl compounds via the thia-Michael addition [14]. Worth noting are also the biological activities of Bunte salts that include antimicrobial [15], antiradiation [16] and schistosomicidal [17] properties.

The most common methods developed for the preparation of S-alkyl thiosulfates include reactions of sodium or thalium thiosulfate with alkyl halides, alkenes or oxiranes [1], while some pharmacologically relevant, amino-containing analogs can be obtained by reacting aminothiols with chlorosulfonic acid [18]. Our continuous interest in the preparation of synthetically useful imidazolines containing the sulfate group of type A [19], [20], [21] prompted us to investigate the reactions of sodium thiosulfate with 2-chloro-4,5-dihydroimidazole and 2-chloromethyl-4,5-dihydroimidazole that were expected to provide new thiosulfates of type B and C, respectively (Figure 1).

Figure 1
Figure 1

Imidazoline derivatives containing a sulfate or thiosulfate group. Imidazolines containing the sulfate group A and reactions of sodium thiosulfate with 2-chloro 4,5-dihydroimidazole and 2-chloromethyl-4,5-dihydroimidazole to provide thiosulfates B and C.

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

First, 2-chloro-4,5-dihydroimidazole hemisulfate (1) [22] was subjected to a reaction with a 2-fold excess of sodium thiosulfate in aqueous solution at room temperature. An exothermic nucleophilic substitution reaction [23], [24], [25], [26] took place with vigorous evolution of sulfur trioxide. As shown in Scheme 1, the initially formed internal Bunte salt D proved to be unstable and decomposed with the formation of imidazolidine-2-thione (2) in quantitative yields. The identity of product 2 was confirmed by comparison of its IR spectrum and melting point with data of the commercially available imidazolidine-2-thione (Experimental section). The facile dehalogenation of 1 bears resemblance to the previously described reaction of sodium thiosulfate with 2-chloro-1-methylquinolinium tetraborate (CQMT) that can be used as a tool in medical diagnostics for the determination of thiosulfate ion in human urine [27], [28].

Scheme 1
Scheme 1

Reaction of 2-chloro-4,5-dihydroimidazole (1) with sodium thiosulfate.

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

Next, we attempted an analogous reaction of sodium thiosulfate with 2-chloromethyl-4,5-dihydroimidazole (3). As shown in Scheme 2, the reaction carried out in aqueous solution at ambient temperature led to the formation of the expected Bunte salt that precipitated from the reaction mixture in the form of the stable zwitterion 4. The presence of the S-SO3 group in 4 was confirmed by a strong absorption at 1031 cm−1, characteristic of Bunte salts, found in the IR spectrum. A protonated 2-methyleneimidazoline moiety was identified by the presence of two singlets in the 1H NMR spectrum, corresponding to four protons of the imidazoline ring and two protons of the exocyclic CH2 group at 3.78 and 3.89 ppm, respectively, as well as three signals in the 13C NMR spectrum at 28.8 ppm (S-CH2), 45.2 ppm (CH2-CH2 grouping) and 170.2 ppm (quaternary C2 atom of imidazoline ring).

Scheme 2
Scheme 2

Reaction of 2-chloromethyl-4,5-dihydroimidazole (3) with sodium thiosulfate.

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

The constitution of the thiosulfate 4 was further investigated by single crystal X-ray diffraction analysis. The crystal unit of 4 consists of zwitterionic molecules with a proton transferred from the sulfate group to the 4,5-dihydro-1H-imidazole fragment. The molecular structure features the typical characteristics of the thiosulfate group [29], with the S-S bond length of 2.1097(6) Å (Figure 2). The crystal packing is dominated by intermolecular hydrogen bonding N-H···O interactions, with the molecules arranged in a ‘head-to-tail’ manner within the hydrogen-bonded chain propagating along the z axis (Figure 3A). There are also numerous C-H···O interactions formed predominantly between the molecules forming (-102) layers (Figure 3B).

Figure 2
Figure 2

Molecular structure of 4. Displacement ellipsoids are shown at the 50% probability level.

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

Figure 3
Figure 3

N-H···O and C-H···O interactions. (A) Hydrogen-bonded chain in 4. (B) C-H···O interactions between the molecules in (-102) layers. Hydrogen bonds are shown with dashed lines.

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

To gain a mechanistic insight into the reaction depicted in Scheme 2, we carried out DFT calculations (the B3LYP/6-31G** level of theory) on the concerted SN2 reaction pathway. As shown in Figure 4, the displacement of the chloride ion with thiosulfate occurs in the plane perpendicular to the imidazoline ring, in a nearly linear manner (S2-C1-Cl angle=170.32°), and is exothermic (ΔG=26.7 kcal/mol). The transition state TS has sufficiently low activation energy (Ea=3.5 kcal/mol) to undergo a substitution reaction under mild reaction conditions (Figure 5). The geometry of the transition state shows a single imaginary frequency pertaining to the S-C bond formation and C-Cl bond breakage at 409 cm−1.

Figure 4
Figure 4

Structure of the transition state TS: N1-S2, C1-Cl and C1-C2 atom distances (Å), S2-C1-Cl bond angle (°), electrostatic potential mapped on the isodensity surface (0.002 e/au3) and localization of frontier orbitals HOMO and LUMO (isovalue=0.032 e/au3).

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

Figure 5
Figure 5

Energy profile computed at the B3LYP/6-31G** level for the transformation 34 (SN2 reaction).

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

To identify reactive sites at compound 4, the electronic structure of this compound was studied using quantum chemical calculations at the MP2/6-311++G** level of theory. Bunte salts are defined as a class of sulfurating reagents bearing an SO3 ‘mask’ on the sulfur atom, which serves as a steric bulky group to prevent homocoupling and as a conjugated group to tune the electron effect on sulfur [3]. Shielding of the S(II) sulfur atom is assured by a negative electrostatic potential that surrounds the SO3 mask (Figure 6). As shown in Figure 4, the HOMO orbital is mainly localized at the S(II) sulfur atom of the thiosulfate moiety, which should be involved in the orbital-controlled reactions with electrophiles. On the other hand, scrutiny of the calculated charges in 4 suggests that electrostatically controlled reactions with electrophilic reagents should proceed preferentially at the C1 carbon atom. Studies of possible applications of 4 in the synthesis of new imidazoline-containing compounds are in progress.

Figure 6
Figure 6

Electronic structure of thiosulfate 4: localization of HOMO (top left), LUMO (top right) (isovalue=0.032 e/au3) and electrostatic potential (bottom) (isovalue=−83.68 kJ/mol).

Citation: Heterocyclic Communications 23, 5; 10.1515/hc-2017-0177

Experimental

Melting points were determined on a Boetius apparatus and are uncorrected. FT-IR spectra were measured on a Nicolet 380 spectrometer. 1H NMR and 13C NMR spectra were recorded in dimethyl sulfoxide-d6 on a Varian Gemini instrument operating at 200 MHz and 50 MHz, respectively. Sodium thiosulfate (Na2S2O3×5H2O) and imidazolidine-2-thione (2) were acquired from a commercial source and used as provided. 2-Chloro-4,5-dihydro-1H-imidazole (1) and 2-chloromethyl-4,5-dihydro-1H-imidazole (3) were prepared according to the literature procedures in [22] and in [30], respectively. The diffraction data for single crystals of 4 were collected with an Oxford Diffraction SuperNova diffractometer using Cu Kα radiation. The intensity data were collected and processed using the CrysAlisPro software [31]. The structure was solved by direct methods with the program SIR-2004 [32] and refined by a full-matrix least-squares method on F2 with SHELXL-2016/6 [33]. Quantum chemical calculations were performed with the program Spartan v.8.0 (Wavefunction, Inc., Irvine, CA, USA).

Reaction of sodium thiosulfate with 2-chloro-4, 5-dihydroimidazole

To a solution of 1 (5 g, 25 mmol) in water (10 mL) was added Na2S2O3×5H2O (12.4 mg, 50 mmol) with stirring. After an exothermic reaction had subsided, the mixture was kept at room temperature for 1 h, and then cooled to 5°C. The precipitated pure imidazolidine-2-thione (2) was collected by filtration, washed with cold water and dried; yield 2.1 g (82%), mp 197–200°C. Spectroscopic and physicochemical properties of product 2 were virtually identical to those of commercially available imidazolidine-2-thione.

Reaction of sodium thiosulfate with 2-chloromethyl-4, 5-dihydroimidazole

To a solution of 3 (2 g, 13 mol) in water (5 mL) was added Na2S2O3×5H2O (6.45 g, 26 mol). The mixture was stirred for 10 min and then kept at ambient temperature for 12 h. The precipitated Bunte salt 4 was separated by suction, washed with cold water and dried; yield 1.6 g (64%); mp 147–149°C (dec.); FT-IR (KBr): ν 3376, 3282, 2970, 2928, 1604, 1596, 1254, 1220, 1196, 1031, 619 cm−1; 1H NMR: δ 3.78 (s, 4H, CH2-CH2), 3.89 (s, 2H, CH2), 9.85 (s, 2H, 2×NH); 13C NMR: δ 28.8 (S-CH2), 45.2 (C4- and C5-imidazoline), 170.2 (C2-imidazoline).

Crystal data for Bunte salt 4

(C4H8N2O3S2; M=196.24 g/mol): monoclinic, space group P21/c (no. 14), a=8.22560(12) Å, b=9.45112(13) Å, c=9.75528(15) Å, β=99.6136(14)°, V=747.736(19) Å3, Z=4, T=130.15 K, μ(CuKα)=6.186 mm−1, Dcalc=1.743 g/cm3, 8294 reflections measured (13.134°≤2Θ≤148.946°), 1526 unique (Rint=0.0824, Rsigma=0.0353), which were used in all calculations. The final R1 was 0.0404 [I>2σ(I)] and wR2 was 0.1065 (all data). Illustrations were prepared with the OLEX2 software [34].

CDC 1550367 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).

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  • [1]

    Distler, H. The chemistry of Bunte salts. Angew. Chem. Int. Eng. Ed. 1967, 6, 544–553.

    • Crossref
    • Export Citation
  • [2]

    Watson, C. D. Bunte Salt Dyes. In The Chemistry of Synthetic Dyes; Venkataraman K., Ed. Academic Press: New York, 1974; Vol. 7, pp 35–68.

  • [3]

    Qiao, Z.; Jiang, X. Recent development in sulfur-carbon bond formation reaction involving thiosulfate. Org. Biomol. Chem. 2007, 15, 1942–1946.

  • [4]

    Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, C. A.; Senanayake, C. H. The reaction of Grignard reagents with Bunte salts: a thiol-free synthesis of sulfides. Org. Lett. 2014, 16, 1196–1199.

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Zhang, R.; Yan, Z.; Wang, D.; Wang, Y.; Lin, S. NaI-mediated acetamido sulfenylation of alkenes with Bunte salts as thiolating reagent leading to β-acetamido sulfides. Synlett 2017, 28, 1195–1200.

    • Crossref
    • Export Citation
  • [6]

    Milligan, B.; Swan, J. M. New synthesis of disulfides from Bunte salts. J. Chem. Soc. 1962, 2172–2177.

    • Crossref
    • Export Citation
  • [7]

    Xiao, X.; Feng, M.; Jiang, X. Transition-metal-free persulfuration to construct unsymmetrical disulfides and mechanistic study of sulfur redox process. Chem. Commun. 2015, 51, 4208–4211.

    • Crossref
    • Export Citation
  • [8]

    Milligan, B.; Saville, B.; Swan, J. M. Trisulfides and tetrasulfides from Bunte salts. J. Chem. Soc. 1963, 3608–3614.

    • Crossref
    • Export Citation
  • [9]

    Milligan, B.; Swan, J. M. Cyclic trisulphides from Bunte salts. J. Chem. Soc. 1965, 2901–2904.

    • Crossref
    • Export Citation
  • [10]

    Westlake, H. E.; Dougherty, J. R. G. The use of Bunte salts in synthesis III. The preparation of aliphatic disulfides. J. Am. Chem. Soc. 1942, 64, 149–150.

    • Crossref
    • Export Citation
  • [11]

    Qi, H.; Zhang, T.; Wan, K.; Luo, M. Catalytic synthesis of 3-thioindoles using Bunte salts as sulfur sources under metal-free conditions. J. Org. Chem. 2016, 81, 4262–4268.

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    Kraft, M.; Adamczyk, S.; Polywka, A.; Zilberberg, K.; Weijtens, Ch.; Meyer, J.; Gorrn, P.; Reidl, T.; Scherf, U. Polyanionic alkylthiosulfate-based thiol precursors for conjugated polymer self-assembly onto gold and silver. ACS Applied Mater. Interfaces 2014, 6, 11758–11765.

    • Crossref
    • Export Citation
  • [13]

    Ukhin, L. Y.; Akopova, A. R.; Bicherov, A. V.; Kuzmina, L. G.; Morkovnik, A. S.; Borodkin, G. S. Reaction of Bunte salts with carbocations of isobenzofuranone and isoindolone. Tetrahedron Lett. 2011, 52, 5444–5447.

    • Crossref
    • Export Citation
  • [14]

    Kin, Y. M.; Lu, G.-P.; Cai, Ch.; Yi, W.-B. An odorless thia-Michael addition using Bunte salts as thiol surrogates. RSC Adv. 2015, 5, 27107–27111.

    • Crossref
    • Export Citation
  • [15]

    Stefańska, J. Z.; Starościak, B. J.; Orzeszko, A.; Kazimierczuk, Z. Antimicrobal activity of organic thiosulfates (Bunte salts). Pharmazie 1998, 53, 190–192.

  • [16]

    Bauer, L.; Sandberg, K. R. α-Amidinium thiosulfates (Bunte Salts) as antiradiation drugs. J. Med. Chem. 1964, 7, 766–768.

    • Crossref
    • PubMed
    • Export Citation
  • [17]

    de Oliveira Penido, M. L.; Nelson, D. N.; Vieira, L. Q.; Marcos, P.; Coelho, Z. Schistosomicidal activity of alkylaminooctanethiosulfuric acids. Mem. Inst. Oswaldo Cruz Rio de Janeiro. 1994, 89, 595–602.

    • Crossref
    • Export Citation
  • [18]

    Tanaka, T.; Nakamura, H.; Tamura, Z. A simple synthesis of amino-containing Bunte salts by the reaction of aminothiols with chlorosulfonic acid. Chem. Pharm. Bull. 1974, 21, 2725–2728.

  • [19]

    Sączewski, J.; Gdaniec, M. First tandem nucleophilic addition-electrophilic amination of Eschenmoser’s salts: synthesis of cyclic and spiro-fused hydrazonium salts. Tetrahedron Lett. 2007, 48, 7624–7627.

    • Crossref
    • Export Citation
  • [20]

    Sączewski, J.; Gdaniec, M. Synthesis of heterocycles by intramolecular nucleophilic substitution at an electron-deficient sp2 nitrogen atom. Eur. J. Org. Chem. 2010, 2387–2394.

  • [21]

    Sączewski, J.; Korcz, M. Synthesis and reactivity of heterocyclic hydroxylamine-O-sulfonates. Heterocycl. Commun. 2014, 20, 133–147.

  • [22]

    Trani, A.; Belasio, E. Synthesis of 2-chloroimidazoline and its re-activity with aromatic amines, phenols and thiophenols. J. Heterocycl. Chem. 1974, 11, 257–261.

    • Crossref
    • Export Citation
  • [23]

    Łączkowski, K. Z.; Jachowicz, K.; Misiura, K.; Biernasiuk, A.; Malm, A. Synthesis and biological evaluation of novel 2-(1H-imidazol-2-ylmethylidene)hydrazinyl-1,3-thiazoles as potential antimicrobial agents. Heterocycl. Commun. 2015, 21, 109–114.

  • [24]

    Krauze, A.; Grinberga, S.; Sokolova, E.; Domracheva, I.; Shestakova, I.; Duburs, G. Synthesis of polysubstituted pyridines as potential multidrug resistance modulators. Heterocycl. Commun. 2015, 21, 93–96.

  • [25]

    Vijay, T. A. J.; Sandhya, N. C.; Pavankumar, C. S.; Rangappa, K. S.; Kempegowda Mantelingu, K. Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen-4-ones. Heterocycl. Commun. 2015, 21, 159–163.

    • Crossref
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Journal + Issues

This peer-reviewed journal publishes preliminary communications, research articles and reviews on developments in all phases of heterocyclic chemistry, including inorganic ring systems. The scope includes development of novel synthetic methods, rational design and synthesis of new drugs targeting specific biological receptors and development of new substrates and catalysts in materials chemistry.

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    Imidazoline derivatives containing a sulfate or thiosulfate group. Imidazolines containing the sulfate group A and reactions of sodium thiosulfate with 2-chloro 4,5-dihydroimidazole and 2-chloromethyl-4,5-dihydroimidazole to provide thiosulfates B and C.

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    Reaction of 2-chloro-4,5-dihydroimidazole (1) with sodium thiosulfate.

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    Reaction of 2-chloromethyl-4,5-dihydroimidazole (3) with sodium thiosulfate.

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    Molecular structure of 4. Displacement ellipsoids are shown at the 50% probability level.

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    N-H···O and C-H···O interactions. (A) Hydrogen-bonded chain in 4. (B) C-H···O interactions between the molecules in (-102) layers. Hydrogen bonds are shown with dashed lines.

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    Structure of the transition state TS: N1-S2, C1-Cl and C1-C2 atom distances (Å), S2-C1-Cl bond angle (°), electrostatic potential mapped on the isodensity surface (0.002 e/au3) and localization of frontier orbitals HOMO and LUMO (isovalue=0.032 e/au3).

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    Energy profile computed at the B3LYP/6-31G** level for the transformation 34 (SN2 reaction).

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    Electronic structure of thiosulfate 4: localization of HOMO (top left), LUMO (top right) (isovalue=0.032 e/au3) and electrostatic potential (bottom) (isovalue=−83.68 kJ/mol).