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

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

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.

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

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

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

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

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

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

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.

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 S_N2 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 (E_a=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

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).

Figure 5

Energy profile computed at the B3LYP/6-31G** level for the transformation 3→4 (S_N2 reaction).

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

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).