Interactions beyond H-bonding: unveiling the role of unorthodox noncovalent interactions in charged thiourea and its catalytic efficiency

Abstract

The development of a catalyst with a rapid turnover rate under ambient reaction conditions is highly desirable. Inspired by biocatalytic systems, the field of charge-driven catalysis provides useful guidelines for designing efficient catalysts. The strategic integration of different non-covalent interactions into a single catalytic system is an interesting phenomenon that could be engaged effectively for diverse chemical reactions. On this front, here, we report charged thioureas with a simple design perspective that offers a significant advantage in terms of catalytic activity by leveraging the unusual combination of a σ-hole and H-bond. The incorporation of charge over the thione functionality alters the conformation of H-bonds (E,Z; whereas it mostly exists as Z,Z in thiourea systems), and additionally offers σ-hole interactions for the activation of substrates. The catalyst demonstrated potential activity towards three different classes of organic reactions, resulting in good to excellent conversions at room temperature with the advantage of scalability. The charged catalyst exhibited multifold rate acceleration (5–40 min reaction time) compared to its neutral counterparts (>1 day). Kinetic studies, control experiments, computational analysis and mechanistic investigations support this remarkable catalytic activity.

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Introduction

Natural biocatalysts offer remarkable rate acceleration and selectivity by precisely positioning multiple functional groups and coordinating their interactions within an active site.^1–3 The catalytic perfection and the genesis of rate enhancements demonstrated by biocatalysts remain a source of inspiration for developing next-generation non-biological catalysts that could display similar properties and also favour mechanistic analysis.^4,5 In this line, more than two decades of research progress have aided in understanding the role of several non-covalent interactions,^6,7 such as hydrogen/halogen/chalcogen/pnictogen bonding^8–10 and electrostatic/dipole interactions^11,12 that lower the activation free energies of several chemical transformations, resulting in a rapid turnover.^13–15 These interactions play a pivotal role in diverse efficient catalytic systems,^16–23 including ureas and thioureas.^24,25 However, the self-association phenomenon of these systems has hampered their practical use.^26,27 Despite this complexity, H-bonds of urea/thiourea could be accessed and strengthened for substrate activation by employing a few strategic modes (Fig. 1). Early perceptions held the catalytic efficiency of urea/thiourea to be achieved by the innate ability to activate the substrate via Z,Z-conformations of strong dual H-bonds.^28,29 In the forefront, a seminal contribution by Schreiner and colleagues toward enhancing the acidity of thiourea by incorporating strong electron-withdrawing groups, received a great deal of attention, as it stabilizes the active Z,Z-conformer through internal rigidifying interactions (C–H⋯S).³⁰ Subsequently, other intramolecular modes of thiourea activation incorporating tethered urea³¹ and borates^32,33 have been explored (Fig. 1a) and demonstrated significant enhancements in rate, yield and selectivity for diverse chemical transformations. Additionally, studies by Jacobsen,³⁴ Herrera³⁵ and others revealed the assistance of external Lewis/Brønsted acids in the rate/yield enhancement of thiourea catalysts (Fig. 1b).

Fig. 1 (a–c) Different activation strategies of a thiourea system. (d) This work: SHATS as catalyst.

Building upon this domain, recently the concept of charge-enhanced acidity has shown a unique mode of thiourea activation, via electrostatic non-covalent interactions (Fig. 1c). Kass et al. reported electrostatically enhanced thiourea by incorporating pyridinium ion(s), and investigated their catalytic efficiency for the Friedel–Crafts alkylation of indole. Interestingly, a thiourea with two pyridinium centers displayed a profound rate enhancement 410 times higher than that of Schreiner's thiourea system with four electron-withdrawing (–CF₃) groups.³⁶ Later, Dudding et al. reported a thiourea-appended N-cyclopropenium moiety as a Brønsted acid catalyst (pK_a = 5.42, in DMSO) for pyranylation reactions.³⁷ Kim et al. studied the catalytic activity of various S-benzyl isothiouronium halides for the reductive amination of aldehydes^38,39 and transfer hydrogenation of N-heterocycles and achieved good conversions.^40,41 Overall, contemporary trends in the catalytic efficiency of thiourea derivatives are mostly explained by the innate dual H-bonds,²⁸ fine-tuned by the electronic character of N-substitutions using internal/external chemical stimuli. However, these strategies require either a multistep synthetic procedure or the stoichiometric use of additive/metal source/costly reagents. In contrast, the contribution of thione (–C=S of thiourea), particularly its σ-hole character upon S-alkylation and its influence on catalytic activity, has been largely overlooked.

It is worth mentioning here that the application of σ-hole based non-covalent interactions is being widely investigated in the field of supramolecular and crystal engineering chemistries.^42–44 Conversely, harnessing σ-holes as a tool in catalysis has received attention recently, but this is often engaged with selective halogen (I), chalcogen (Se, Te) and pnictogen (Sb) bonding.^45–48 Ironically, the σ-hole character of sulfur remains largely untapped for catalytic application,⁴⁹ possibly due to its weak nature. However, with our ongoing interest in electrostatically tuned active site catalysis,^50–53 we sought to bridge the chemical spaces of thiourea (i.e., H-bond and thione) with synthetic modulation, where the intramolecular functionalities act in a concerted manner to partly replicate the biocatalytic mode of operation. Realizing such a catalytic pocket within a simple molecular scaffold is a challenging yet interesting task; however, clues can be drawn from recent research advances in electrostatic catalysis.^12,54,55 To accomplish this hypothesis, we envisioned that the alkylation of thione with a non-coordinating anion, would likely enhance the H-bond strength or its Brønsted acidity and also provide additional stabilizing interactions through its σ-hole. We believe this synergistic effect could transcend the barrier of substrate–catalyst interaction and thereby facilitate the chemical reaction with rapid turnover. With this understanding, herein, we unveil a sigma-hole-assisted thiouronium salt (SHATS), featuring enhanced hydrogen bonding (pK_a: 0.49/3.1) and an alkylated thione σ-hole (molecular electrostatic potential (MESP): 35.1 kcal mol⁻¹). Its practical utility is demonstrated in the challenging catalytic isomerization of α-pinene oxide, transfer hydrogenation of N-heterocycles, and cycloaddition reactions. We observed that SHATS harmonizes catalytic efficiency with remarkable kinetics under mild reaction conditions.

Results and discussion

Preparation and structural features of SHATS

At the outset, the thiourea was accessed by the commonly employed preparation procedure. Aniline and phenyl thiocyanate are simply allowed to react in the presence of dichloromethane as a solvent at room temperature for 24 h. The thione of the prepared thiourea was alkylated using trimethyloxonium tetrafluoroborate (SHATS-1)/methyl trifluoromethanesulfonate (SHATS-2) in acetonitrile (Fig. 2a) with high isolated yield (88%/90%; see SI). The synthetic ease and bench-stable nature of SHATS-1 encouraged us to scale up its preparation to 20 mmol (Fig. 2). The alkylation of thiourea was confirmed by the appearance of a singlet methyl proton at 2.69 ppm (¹H NMR) and the corresponding carbon at 14.73 ppm (¹³C NMR) using NMR spectroscopic analysis (Fig. S26 and S27, SI). Furthermore, it is noteworthy that the peak at ∼168 ppm in ¹³C NMR clearly confirms the thione functionality in SHATS and rules out the other possible resonance structure. FT-IR analysis of SHATS confirms the presence of –C=S⁺– (1050 cm⁻¹) and, interestingly, we observed a significant variation in the peak nature of amide –NH (3243 cm⁻¹ and 3301 cm⁻¹) compared to the source molecule diphenyl thiourea (DPTU), which confirms its unsymmetrical nature (Fig. S8 and S10, SI). This observation motivated us to crystallize the compound to elucidate its exact position by single-crystal X-ray diffraction (SCXRD). Nevertheless, the conformation of the two hydrogens of thiourea is crucial, as it has a significant impact on their catalytic activity. Closer analysis of SHATS-1 revealed that it is crystallized in the P2₁2₁2₁ orthorhombic space group with four molecules in the asymmetric unit. Among them, two molecules correspond to the cationic part of SHATS (methylated thiourea), and the other two molecules are BF₄⁻ anions (Fig. 2b). These molecules are mainly connected via strong intermolecular N–H⋯F bonds (Fig. 2c). Surprisingly, the two hydrogens of SHATS-1 are observed to be located in the E,Z conformation, and the two phenyl rings are not coplanar φ1 (°) = C5–N1–C4–C13 = 76.16 and φ2 (°) = C5–N2–C6–C11 = 120.07; φ3 (°) = C19–N3–C18–C17 and φ4 (°) = C19–N4–C20–C25 with respect to thiourea. Conversely, SHATS-2 is crystallized in the Pbca orthorhombic space group with both methylated thiourea (cation) and triflate (anion) in the asymmetric unit (Fig. 2e). In SHATS-2, the molecules are connected via infinite N–H⋯O²⁴ hydrogen bonds, and crystal packing is further supported by weak C12–H12⋯O2 hydrogen bonds (Fig. 2f). As observed in SHATS-1, the two hydrogens are here in anti-orientation, and the phenyl rings are not coplanar with respect to thiourea φ1 (°) = C7–N1–C1–C2 = 70.94 and φ2 (°) = C7–N2–C8–C9 = 50.82.

Fig. 2 (a) General preparation procedure and highlights of SHATS. (b) Single-crystal structure of SHATS-1 (hydrogen atoms are not shown for clarity), and the molecules are shown in the asymmetric unit. (c) Their intermolecular interactions. (d) Pictorial representation of synthesized SHATS-1. (e) Single-crystal structure of SHATS-2 (hydrogen atoms are not shown for clarity) and molecules are shown in the asymmetric unit and (f) molecules are connected via infinite N–H⋯O hydrogen bonds. (g) Pictorial representation of synthesized SHATS-2.

H-bonding, pK_a and molecular electrostatic potential analysis (MESP) analysis

Intrigued by the structural features of SHATS, particularly the observation of the anti-orientation of their two hydrogens, encouraged us to investigate their H-bond capacity using ³¹P NMR spectroscopic analysis (Fig. 3a).⁵⁶ For this purpose, tributylphosphine oxide (TBPO) was chosen as a probe molecule, with its characteristic phosphorus resonance appearing at 43.71 ppm in CCl₄ using phosphoric acid in D₂O as an external NMR standard. Initially, we titrated the probe molecule with different equivalents of SHATS-1 and observed the maximum chemical shift upon employing 2 equivalents of SHATS-1 with TBPO (48.00 ppm, Δδ = 4.29 ppm), due to the resultant optimal H-bond interaction of –NH– with –P=O. Subsequently, we recorded the ³¹P NMR spectra with SHATS-2, STU and DPTU catalysts. SHATS-2 with a different counter anion, displayed a similar chemical shift (48.02 ppm, Δδ = 4.32 ppm) upon its interaction with the probe molecule. Conversely, upon examining the interaction of neutral thioureas, such as DPTU and STU, resulted in noticeable downfield shifts at 48.88 ppm (Δδ = 5.17 ppm) and 51.51 ppm (Δδ = 7.8 ppm), respectively. Notably, with the given chemical environments of SHATS-1 and 2, particularly with non-coordinating anions, the displayed chemical shifts are unexpectedly lower than those of DPTU and STU. This observation could be explained by the dual H-bonding interaction (in the cases of DPTU and STU) with the probe molecule, which might have caused the larger chemical shifts. Whereas, the two N–H protons of SHATS-1 and 2 spatially orient in the E,Z conformation (Fig. 2c and f), thereby possibly limiting their interaction with the –P=O of the probe molecule. This indicates the intervention of alkylated thione (–C=S⁺–) over the relative conformation of hydrogen bonds in SHATS.

In order to understand the influence further, we decided to study the acidity of the hydrogens. Subsequently, we computed the pK_a values (in DMSO) of DPTU, STU, SHATS-1 and SHATS-2. DPTU and STU showed pK_a values of 13.6 and 8.3, respectively, which are found to be similar to those in the literature.⁵⁷ However, considering the unsymmetrical nature of the two –NHs in SHATS-1, we calculated the acidities of both hydrogens. To our delight, the free hydrogen atom associated with N1 displayed a pK_a value of 0.49, and for that associated with N2 (i.e., interaction with the BF₄⁻ ion), resulted 3.1. The higher acidity of N1H̲ is ascribed to the neighbouring positively charged thione functionality. It is worth noting that the acidity is considerably higher than those for STU associated with four strong electron-withdrawing groups (pK_a = 8.3) and DPTU (pK_a = 13.6). In addition, our experimental analysis of pK_a in DMSO : H₂O (1 : 1) of SHATS-1 showed a value of 3.9 (Fig. S1, SI), which closely resembles the calculated value. Furthermore, to explain the aforementioned observations, we analysed the molecular electrostatic potential surfaces (MESP). Generally, MESP is an important tool for understanding the electrostatically driven non-covalent interactions.⁵⁸ The MESP mapping clearly reveals that a considerable amount of positive potential (values of 35.1 and 34.3 kcal mol⁻¹ for SHATS-1 and SHATS-2, respectively) resides around the alkylated thione moiety. In contrast, the sulfur atom in STU and DPTU displayed MESP values of −29.7 and −12.6 kcal mol⁻¹, respectively (Fig. 3b). This is further supported by the calculated natural bond orbital (NBO) charge, which was +0.65 for alkylated thione in SHATS. The corresponding sulfur in DPTU and STU displayed only +0.03 and +0.117, respectively (Fig. 3c). To our delight, these results unambiguously support our hypothesis that the alkylated thione (–C=S⁺–) with a non-coordinating anion could act as a powerful intramolecular handle (σ-hole, as a secondary interaction) for the facile activation of the hydrogen bond of thiourea.

Fig. 3 Structural features of SHATS, diphenyl thiourea (DPTU) and Schriener's thiourea (STU). (a) ³¹P NMR spectra representing titration experiments of TBPO and SHATS-1 (with varying concentrations, mol. eq.) in CCl₄ (left) and H-bonding interactions of different catalysts (right). (b) The molecular electrostatic potential surface of catalysts, wherein blue and red colors signify the positive and negative potential regions, respectively (isosurface value of 0.001 au). The σ-holes of the catalysts are shown as red-coloured dots, and the corresponding MESP values for the sulfur atom of SHATS-1, SHATS-2, DPTU and STU are 35.1, 34.3, −29.7, and −12.6 kcal mol⁻¹, respectively. (c) Computed NBO charges of select atoms at the B3LYP/6-31G+(d,p) level of theory in DCM.

Catalytic application 1: isomerization of biomass-derived α-pinene oxide to α-campholenic aldehyde

Motivated by the experimental and computational correlations with our hypothesis, next, we asked whether the developed SHATS would demonstrate beneficial catalytic activity with rapid turnover. Thus, we commenced our experimental investigation with the challenging isomerization of biomass-derived α-pinene oxide (APO) to α-campholenic aldehyde (CA). The choice of the reaction is due to the desired product CA, as it is a key precursor for sandalwood-like odorants and has potential industrial demand and market value (CAS number: 4501-58-0).^52,59 Furthermore, the dihydroxylated α-trans derivative of CA has demonstrated potent anti-Parkinson activity in preclinical animal models, highlighting its potential as a lead compound in neuropharmacological research.⁶⁰ However, in principle, controlling the selectivity of α-pinene oxide isomerization is not a trivial task, as it leads to more than a hundred different products, even at slightly elevated temperatures.⁶¹

Representative isomers are depicted in Fig. S2 (SI). Although it involves heightened complexity, we sought to study this isomerization reaction, as it transposes the epoxide to an aldehyde functionality, and any identified catalytic system that tends to achieve high selectivity under mild conditions may potentially be considered for commercial and late-stage functionalization applications. Conversely, most of the literature precedents report the use of metal-based and/or heterogeneous catalytic systems and often require high temperature.^62,63

Determination of the nature of catalysis. Intrigued by our activation modes in SHATS (H-bond and σ-hole), the ability of SHATS-1 (5 mol%) was first assessed for the isomerization of APO using dichloromethane (1 mL) as solvent at room temperature (Fig. 4). The reaction proceeded with faster kinetics, leading to nearly quantitative conversion of APO with high selectivity to CA (94%) within 5 min of reaction time. The encouraging initial results could be explained by the synergistic influence of the H-bond and σ-hole of alkylated thione with tetrafluoroborate as a non-coordinating anion. However, SHATS-2, the cationic analogue of SHATS-1, resulted in the desired CA with 64% selectivity under the same reaction conditions. This clearly discloses that BF₄⁻ is a better non-coordinating anion than triflate, which amplifies the positive charge over the alkylated thione functionality, and thereby the Lewis acidic nature of the σ-hole. To ascertain this, we carried out the reaction using DPTU and STU as standalone H-bonding catalysts and observed only trace conversion (2–4%). Attempts to extend the reaction time to 3 h also resulted in no significant change in the conversion. To gain additional insight into the enhanced activity demonstrated by SHATS-1, we synthesized SHATS-3 containing a single N–H (with N–Me on the other side) and examined it under identical reaction conditions. However, SHATS-3 afforded only 52% conversion while maintaining good selectivity (89%). Furthermore, we prepared SHATS-4, wherein the pristine thiourea was alkylated with benzyl chloride. Although it is not a direct structural analogue of SHATS-1, we intended to understand the impact of free –NH₂. Thus, SHATS-4 was tested, which resulted in significantly reduced activity, affording only 6% conversion of APO with 44% selectivity toward CA. At this end, the issue of the role of BF₄⁻ may arise, as SHATS-2 does not deliver superior activity. To address this, we tested the catalytic efficiency of the ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMTFB), but it showed only a trace conversion of APO. Subsequently, to ascertain the role of the H-bond in the isomerization reaction, SHATS-5 was developed with a piperidine-derived thiouronium skeleton (with no free hydrogen in the nitrogen) and employed it as a catalyst under the same reaction conditions, and obtained an APO conversion of 28%. Notably, in the absence of H-bonding interactions in SHATS-5, this level of conversion indicates the involvement of an additional contributing site to the observed activity (which we believe is due to the σ-hole interaction of the alkylated thione).

Fig. 4 Screening of catalysts for the isomerization of APO to CA.

Optimization studies. With the identified catalyst in hand, we sought to investigate reaction parameters, such as variation in solvent and catalyst loading for the SHATS-1-catalyzed isomerization of APO to CA (Fig. S3, SI). Amongst the tested series of solvents, dichloromethane outperforms both in terms of conversion and selectivity. Thus, we retained it as the choice of solvent and varied the catalyst loading from 2.5 to 10 mol%. Decreasing the loading to 2.5 mol% resulted in detrimental impacts, whilst increasing it to 7.5 and 10 mol% showed quantitative conversion with slightly less selectivity.

Control experiments. Recent studies in the field of σ-hole catalysis have shown that chloride ions (Cl⁻) can bind strongly to the σ-holes of chalcogen bond donors, effectively suppressing the catalytic activity that proceeds through σ-hole interactions.^50,64,65 To investigate this effect in the SHATS system, we conducted the optimized model reaction of APO in the presence of 5 equivalents of tetrabutylammonium chloride. Under these conditions, we observed a significant drop in both conversion (28%) of APO and selectivity (18%) to CA.

In addition, we examined well-established commercial Brønsted acids, such as trifluoromethanesulfonic acid (TfOH) and p-toluenesulfonic acid (PTSA), under the optimized reaction conditions. It is worth noting that, although TfOH resulted in 98% conversion of APO, the reaction led to the formation of multiple byproducts, affording just trace (2%) selectivity toward the desired product, CA. Conversely, PTSA provided 40% conversion of APO with 12% selectivity toward CA. Collectively, these results unequivocally reiterate that, beyond the H-bond/strong Brønsted acid interaction, the additional secondary interaction (σ-hole) in SHATS-1 also assists in suitably positioning the substrate in the active catalytic pocket and facilitates the smooth progress of isomerization selectively under ambient conditions.

Scale-up studies, recyclability and mechanistic investigations. Scalability of the catalytic transformation, without much variation from the optimized reaction conditions, is a critical step at which many identified systems fail before progressing to industrial application. To our delight, we successfully scaled up our optimized catalytic protocol on both 1 and 10 g scales. The reactions proceeded smoothly and resulted in the desired CA in just 5 minutes, maintaining high efficiency. The catalyst was recovered by rota evaporation of the reaction solvent (while retaining a few mL of solvent), and it was allowed to precipitate by using a combination of non-polar solvents.

The recovered catalyst retains the original crystallinity (Fig. 5a) and was successfully reused for five cycles, demonstrating the robustness and practical viability of the catalytic system. Furthermore, with the experimental evidence, we proposed a probable reaction mechanism for the isomerization of APO to CA. In this context, the epoxide ‘O’ of APO gets activated by the strong H-bond and secondary interactions from the σ-hole in SHATS-1, resulting in ring opening with carbocation formation. It is worth mentioning here that the requisite spatial orientation for the synergistic activity of the H-bond and σ-hole (in SHATS-1) could be attained through the simple bond rotation of the C–N bond, as the energy between the two conformers is relatively lower (ΔE = 1.4 kcal mol⁻¹). Furthermore, the other conformer could be stabilized through the π–π stacking interaction between the two phenyl rings. To gain more detailed insights into the catalyst–substrate activation mode, we optimized a computational model for their interaction (Fig. 5c). Although these values do not correspond to a short-range classical σ-hole interaction, they are not negligible, as literature reports σ-hole interactions involving sulfur at angles of around 80° and 140°.⁴⁴ Our optimized model indicates that the substrate is activated via a strong H-bond with additional secondary interaction from the σ-hole of the alkylated thione of SHATS-1. Subsequent methyl migration and carbon–carbon bond scission allow the formed carbocation to rearrange with simultaneous ring expansion, resulting in the desired product and regenerating the catalyst for further catalytic cycles (Fig. 5d). To the best of our knowledge, this is the first report of a simple organocatalytic protocol enabling the selective isomerization of biomass-derived α-pinene oxide to α-campholenic aldehyde with quantitative conversion at room temperature within a short reaction time (for a comparison with literature reports, please refer to Table S1 in SI).

Fig. 5 (a) Scale-up study using SHATS-1 as a catalyst. (b) Calculated energy difference between SHATS-1 conformers. (c) Optimized catalyst–substrate interaction model. (d) Proposed mechanism of SHATS-1-catalyzed isomerization of APO to CA.

Catalytic application 2: transfer hydrogenation and tandem alkylation of quinoline derivatives

The demonstrated catalytic ability of SHATS-1 toward a challenging isomerization reaction prompted us to investigate it further for the transfer hydrogenation of N-heterocycles using Hantzsch 1,4-dihydropyridine esters (HE) as a hydride source. We intend to study this reaction, based on our previous understanding that an acidic/H-bonding system with electrostatic enhancement could significantly change the reaction kinetics⁵⁰ and the wide applications of the product (Fig. S4, SI).⁶⁶ We now believe that SHATS-1 has a better design feature and could display its potential toward the selective and partial hydrogenation of quinoline derivatives. As this reaction involves a completely different mechanistic insight from that of the isomerization reaction, we screened all the above-studied catalysts (10 mol%) for a model reaction where quinoline (0.5 mmol) has been taken as a representative substrate, HE (2.2 equiv.) in the presence of the previously optimized solvent, i.e., dichloromethane at room temperature (28–30 °C). Again, SHATS-1 is found to be an efficient catalyst (Fig. S5, SI) as it resulted in the desired tetrahydroquinoline (THQ) product with quantitative conversion in 25 min. It is noteworthy that under these model reaction conditions, STU resulted in the product with trace conversion. Even after extending the reaction time to two days, STU and DPTU resulted in only 80% and 7% conversions, respectively. Investigation of other catalysts under the reaction conditions (Fig. S5, SI) confirms the importance of the synergistic catalytic pocket in SHATS-1. Furthermore, the systematic screening of reaction parameters, including solvents, catalyst, HE loadings, and time, revealed the necessity for dichloromethane (1 mL), 5 mol%, 2.2 equiv., and 45 min, respectively, for the efficient transfer hydrogenation of quinoline (Fig. S6, SI).

With the optimum reaction conditions in hand, the scope of SHATS was explored for differently substituted quinoline derivatives (Fig. 6a). We observed that the mono- and di-substitution of alkyl group(s) over various positions of quinoline resulted in partially hydrogenated THQs with good yields (65–76%). Remarkably, electron-withdrawing substituents, irrespective of their positions, showed nearly quantitative conversion (99%). Moreover, we observed no dehalogenation or over-hydrogenation in the case of reducible functionality (–NO₂), signifying the group tolerance of the substrate under the optimized reaction conditions. Additionally, SHATS-1 was able to catalyze the transfer hydrogenation reaction with faster kinetics (25 min) even at room temperature, whereas most literature reports generally required slightly elevated to higher temperatures or a long reaction time.^67,68 With the observed promising catalytic activity, the practical applicability of the SHATS-1-catalyzed transfer hydrogenation of quinoline was extended to a scaled-up reaction (Fig. 7 and Section 13, SI). The successful demonstration of 10 mmol scale (86% yield of desired THQ) with the advantage of simple product isolation that requires no column chromatographic separation, clearly emphasizes its potential for practical utility.

Fig. 6 (a) Substrate scope of transfer hydrogenation of N-arenes using SHATS-1 as catalyst. Reaction conditions: catalyst (5 mol%), quinolines (0.5 mmol), HE (2.2 equiv.), and DCM (1 mL) at RT (28–30 °C) for 25 min. (b) Tandem reductive alkylation using SHATS-1 as a catalyst and its substrate scope. Reaction conditions: catalyst (5 mol%), quinolines (0.5 mmol), aldehyde (0.6 mmol), HE (3.3 equiv.), and DCM (1 mL) at RT (28–30 °C) for 2 h. Conversion/selectivity was determined by GC analysis.

Fig. 7 (a) Scale-up reaction: catalyst (5 mol%), quinoline (10 mmol), HE (2.2 equiv.) and DCM (20 mL) at RT (28–30 °C) for 45 min. (b) Time vs. conversion plot of transfer hydrogenation of quinoline carried out in the presence of different catalysts at room temperature (28–30 °C).

The versatility of the SHATS-1 catalyst was also demonstrated by the successful tandem functionalization of quinoline derivatives, which leads to step-economic synthesis of N-alkylated tetrahydroquinolines (Fig. 6b). We observed that aromatic (including heterocyclic) and aliphatic aldehyde derivatives underwent the tandem reaction smoothly and resulted in the product with quantitative conversion and selectivity (76–99%).

Kinetics and NMR-spectroscopic investigations. Inspired by the short reaction time, we carried out a time-dependent conversion for the transfer hydrogenation of N-heterocycles using SHATS-1 and compared its activity with DPTU and STU. The plot revealed that SHATS-1 exhibited ∼150-fold rate enhancement against DPTU (k_rel = 1), whereas the neutral counterpart STU showed only 2-fold enhancement (Fig. 7b). The observed multifold rate enhancement with SHATS-1 encouraged us to elucidate their structural space, including the mode of interaction with the substrate. Thus, quinoline and the catalyst with a suitable 1 : 1 stoichiometric concentration in CDCl₃ were employed to study the ¹H-NMR spectroscopic analysis (Fig. 8). Interestingly, the hydrogen in the C-4 position of quinoline originally appeared at 8.11 ppm, and remained there or shifted to 8.11, 8.14, 8.39 ppm upon its interaction with DPTU, STU and SHATS-1, respectively (Fig. 8a). The higher chemical shift of the –C4H– of quinoline observed with SHATS-1 could be attributed to the strong synergistic interaction of the H-bond and σ-hole. This is further supported by the upfield shift of –CH₃ over thione (Fig. 8b) and downfield shift of N–H peaks (Fig. 8c). In this line, to probe the role of the σ-hole in substrate activation, we recorded a similar ¹H-NMR spectrum of quinoline with SHATS-5 (no H-bonds) and observed a downfield shift of –C4H– of quinoline to 8.27 ppm (Fig. S90, SI). This confirms that secondary interaction (σ-hole) is also responsible, along with the strong H-bond, for the activation of quinoline, and upholds our experimental observation. In order to gain more insight into the SHATS-1 reaction process, we performed a few control experiments. First, we carried out individual reactions using quinoxaline and isoquinoline as substrates under our optimized reaction conditions. In both cases, we observed the complete recovery of starting materials, disclosing that the catalytic reaction did not proceed via 1,2-hydride addition; rather, it adopts the 1,4-addition route.

Fig. 8 ¹H NMR spectra for the interaction study of DPTU, STU, SHATS-1 and 2 with quinoline. (a) ¹H NMR spectra region represents the chemical shifts of C2H and C4H of quinoline, and upon its interaction with different catalysts. (b) ¹H NMR spectra region represents the chemical shift of the S-CH₃ peak of SHATS-1 and upon its interaction with quinoline. (c) ¹H NMR spectra region represents the chemical shift of the N–H peak of SHATS-1 and upon its interaction with quinoline.

Based on the control experiments, we propose the catalytic cycle depicted in Fig. 9. First, the SHATS-1 catalyst synergistically activates and protonates the quinoline nitrogen. This further favours hydride transfer from HE via a 1,4-addition pathway, leading to enamine I, and subsequently tautomerized to imine Ia. The in situ-generated imine undergoes the same process to yield the desired THQ product and regenerate the catalyst for further cycles.

Fig. 9 Plausible mechanism of transfer hydrogenation of quinoline using SHATS-1 as a catalyst.

Catalytic application 3: synthesis of dihydroquinazolinones via cyclocondensation reaction

After demonstrating that SHATS-1 could act as a potential catalyst for transfer hydrogenation reactions, we turned our attention to the activation of anthranilamides for their cycloaddition with carbonyl compounds, as this reaction also involves the formation of an important N-heterocyclic compound, dihydroquinazolinone (DHQ). On this front, anthranilamide (0.5 mmol) and benzaldehyde (0.6 mmol) were selected as substrates for the model reaction in the presence of SHATS-1 (5 mol%) at room temperature. Next, we optimized the reaction parameters, including solvent, catalyst amount and reaction temperature (Fig. S7, SI).

Generally, the solvent plays a critical role in a cycloaddition reaction and contributes significantly to achieving selectivity toward the desired product. Unlike isomerization and transfer hydrogenation reactions, this cycloaddition reaction worked well in the presence of polar protic solvents like methanol and yielded the product with excellent conversion of 99% in 10 min. Consequently, variation of catalyst loading revealed that decreasing the catalytic loading from 5 mol% has a significant impact on reaction yield. Notably, even lower catalyst loading (1 mol%) resulted in complete conversion with an additional reaction time of 40 min. However, increasing the loading has no drastic effect on conversion or reaction time.

With the optimal conditions, the generality and diversity of our catalytic protocol were evaluated for the reaction of anthranilamide with a handful of aldehydes, and the results are presented in Fig. 10. The reaction proceeded smoothly with various aromatic/aliphatic aldehydes and dialdehydes, resulting in the corresponding products with good isolated yields (86–99%) within 10 min. Aromatic aldehydes bearing strong electron-withdrawing groups (–NO₂) offered slightly better yields than those of aldehydes with electron-donating groups (–OH, –OMe) or halogen-substitutions (–Br, –Cl). The biomass-derived heterocyclic aldehyde, furfural, also afforded the corresponding product in good yield. To our surprise, a challenging substrate like ketone (9s–9v) also resulted in quantitative conversion with a slightly extended reaction time. These findings led us to investigate the reaction progress using ¹H NMR spectroscopic studies. An initial control experiment in the absence of a catalyst resulted in low/trace conversion after 24 h. This confirms the role of the catalyst in the preparation of DHQs. We next probed the role of the catalyst (5 mol%) using anthranilamide (1 equiv.) and benzaldehyde (1.2 equiv.) as model substrates using CD₃OD as solvent. The catalytic activity demonstrated by SHATS-1 for the cycloaddition reaction is again relatively higher than for STU, consistent with the results obtained in α-pinene oxide isomerization and transfer hydrogenation reactions.

Fig. 10 Substrate scope of cycloaddition reaction of anthraniliamide with carbonyl compounds. Reaction conditions: anthralinamide (0.5 mmol), benzaldehyde (0.6 mmol), catalyst (5 mol%), MeOH (1 mL), time (10 min). Isolated yield.

Although STU resulted in the desired product under the same reaction conditions, it required 8 h to achieve complete conversion. This could be visualized in the NMR studies, with the relatively long-lasting presence of starting materials and imine (intermediate) peaks (Fig. 11a). In contrast, the quick disappearance of the above-mentioned peaks in the case of the SHATS-1 catalyst not only reveals its rapid turnover but also its efficiency toward clean product formation (in the crude reaction mixture). Surprisingly, there is no imine peak even at the very initial (1–2 minutes) reaction time (in the NMR sample tube), and the reaction get complete within 5–10 minutes (Fig. 11b). With this understanding, the plausible reaction mechanism for SHATS-1-catalyzed DHQ formation is shown in Fig. 12. Initially, the synergistic catalytic pocket in SHATS-1 activates the electrophilic carbonyl center and facilitates its reaction with anthranilamide to form the corresponding imine (I′). Subsequently, the intramolecular attack of amide nitrogen on the imine C results in cyclization and sets the desired product free from the catalytic cycle.

Fig. 11 In situ monitoring of (a) STU and (b) SHATS-1 catalyzed formation of dihydroquinazolinones using ¹H NMR spectroscopic analysis.

Fig. 12 Plausible mechanism of SHATS-1-catalysed synthesis of dihydroquinazolinones via cyclocondendsation reaction.

SHATS-1 catalyzed in situ product crystallization. Conceptual advances in the field of catalysis have led to diverse limitations associated with scalability and practicability to be surmounted. In the forefront, recently, the concept of in situ product crystallization (ISPC) has simplified downstream processing, which is mostly being practised in biocatalytic reactions.⁶⁹ As the name of the process indicates, it integrates in parallel the reaction progress and selective crystallization of the targeted product, ensuring the robust performance of the catalytic system. Inspired by this concept and as the reaction between anthranilamide and benzaldehyde is completed in a few minutes in the presence of SHATS-1, we then sought to perform the reaction without stirring. Thus, we mixed the starting materials anthranilamide (0.5 mmol) and benzaldehyde (0.6 mmol) in the presence of SHATS-1 (10 mol%) using methanol as solvent (1 mL), and left it undisturbed and monitored the reaction progress. Gratifyingly, we could observe the growth of the DHQ crystal over time, and in 15–30 minutes overall, the non-stirred reaction achieved quantitative conversion (Fig. 13). Subsequently, the crystalline product was filtered off and dried. The isolated yield of DHQ is 96%. It is noteworthy that the 20-fold scaled-up reaction mixture also yields the crystalline product under identical non-stirred conditions, which clearly signifies the efficiency of SHATS-1 (Fig. 13). Notably, parallel experiments carried out in a similar way using DPTU and STU as a catalyst exhibited no noticeable change even after the time was extended to 24 h. We believe that this experiment not only reveals the great potential of the synergistic catalytic pocket in SHATS-1 but also demonstrates a key objective of organic and catalytic chemistry: facilitating transformation under energy efficient conditions with spontaneous crystallization of the product.

Fig. 13 Snapshots of reaction progress under non-stirred reaction conditions in the presence of different catalysts over the period of the reaction at regular intervals. Reaction conditions: anthralinamide (0.5 mmol), benzaldehyde (0.6 mmol), catalyst (DPTU/STU/SHATS-1)-10 mol%, MeOH (1 mL), 28–30 °C. Reaction conditions for scale-up: anthralinamide (10 mmol), benzaldehyde (12 mmol), catalyst (SHATS-1)-10 mol%, MeOH (20 mL), 28–30 °C.

Conclusions

In summary, we disclosed herein the production of an active catalytic pocket out of a classic scaffold with an electrostatic intervention. This intramolecular mode of activation distinguishes itself from the previous literature reports on a thiourea-based catalytic system and its activation procedure. The molecular structure of SHATS-1 with E,Z conformation of H-bonds was confirmed by crystallographic analysis, and its acidic strength was evaluated both experimentally and computationally. The scope of the SHATS-1 catalyst is broad, and it demonstrated its efficiency toward challenging organic transformations, resulting in desired products, such as α-campholenic aldehyde, tetrahydroquinolines and dihydroquinazolinones, with excellent conversion over a span of minutes at room temperature. The experimental studies reveal that the σ-hole interaction, along with the acidic strength of the H-bond were instrumental in achieving the observed high turnover rate. Additionally, SHATS-1 also helps the in situ product crystallization of dihydroquinazolinones. We strongly believe that this concept of thiourea activation may not only assist the catalytic field, but is also likely diversify its application toward protein interaction studies, sensing applications, charge-incorporated perovskite materials, organic molecular materials, controlled crystallization and so on.

Author contributions

P. M. synthesized and characterized the catalysts, carried out catalytic experiments and wrote the original draft. P. R. and B. P. carried out a few optimization studies and substrate variations. S. T. carried out single crystal analysis. D. D. and B. G. carried out computational studies. S. S. conceived the project and wrote the original draft of the manuscript with contributions from all authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

All the experimental procedures and characterization details supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01735a.

CCDC 2481672–2481674 contain the supplementary crystallographic data for this paper.^70a–c

Acknowledgements

The authors thank SERB (grant no. CRG/2023/007197), CSIR (project no. MLP-0077), and UGC (SRF fellowship) for financial support. Analytical facilities by MEMED&CIF of CSIR-CSMCRI are gratefully acknowledged (CSIR-CSMCRI Communication no. 72/2025).

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