Modulating Basicity in Mg–Al Oxides for Selective N‑Alkylation of BIT with Improved Catalytic Performance

Abstract

Heterogeneous catalytic N-alkylation has increasingly been recognized as a sustainable approach for the formation of C–N bonds, particularly in the synthesis of high-value nitrogen compounds. Based on the characteristic that calcined hydrotalcites exhibit basic sites of varying strengths depending on their Mg/Al molar ratios, this study employed Mg–Al layered double hydroxides (LDHs) as precursors to synthesize a series of layered double oxides (LDOs) with different Mg/Al ratios via high-temperature topotactic transformation. These LDOs were then used as solid base catalysts to investigate the mechanistic influence of basic site strength on the N-alkylation of 1,2-benzisothiazolin-3-one (BIT) for the selective synthesis of N-butyl-1,2-benzisothiazolin-3-one (BBIT). Notably, Mg₄Al₁O-600 showcased superior catalytic activity, achieving a BIT conversion rate of 61.66% and a BBIT yield of 42.81% within 20 h. A structure–property correlation analysis suggests that the abundant medium-strength basic sites function as active centers for selective N-alkylation, thereby significantly improving selectivity toward BBIT. The predominant catalytic mechanism is identified as an S_N2 nucleophilic substitution. Additionally, kinetic analysis indicates that the reaction is largely influenced by the coupled mass transfer and reaction behavior of BIT.

1. Introduction

N-Alkylation, a crucial organic reaction for C–N bond formation, typically introduces specific alkyl groups into nitrogen-containing compounds. This process generates products with enhanced biological activity, pharmaceutical value, and industrial applications. , N-alkylation products are currently extensively used in pharmaceuticals, agrochemicals, dyes, and polymer materials. The synthesis of N-butyl-1,2-benzisothiazolin-3-one (BBIT), a derivative of 1,2-benzisothiazolin-3-one (BIT), via a catalytic N-alkylation reaction, exemplifies the production of industrial biocidal agents through selective functionalization. BBIT demonstrates superior antimicrobial activity and environmentally friendly properties. The N-butyl substituent enhances BBIT’s solubility and stability in nonaqueous systems compared to BIT, making it a preferred biocide in industries such as coatings, plastics, and leather. However, the N-alkylation reaction used to synthesize BBIT from BIT often employs homogeneous base catalysts (such as NaOH and KOH), leading to challenges including difficult catalyst recovery, environmental pollution, and high byproduct formation. , The competing O-alkylation side reaction also significantly reduces the selectivity toward BBIT, highlighting the need for the development of highly efficient and green catalytic systems.

Due to their superior catalytic efficiency and environmentally friendly properties, solid base catalysts are increasingly viewed as potential replacements for homogeneous catalysts. They represent a significant avenue in the advancement of next-generation catalytic materials. − The benefits of solid base catalysts are derived from their capacity to alleviate environmental concerns associated with homogeneous base catalysts. Moreover, their acid–base strength, surface active sites, and porous structures can be effectively modified through compositional alteration, surface functionalization, or thermal treatment. This adaptability allows them to meet the requirements of a broad spectrum of catalytic reactions. The existence of well-developed porosity and a high specific surface area also promotes robust substrate-catalyst interactions, thereby enhancing reaction efficiency. − For instance, Gawande et al. utilized an Al₂O₃–K₂O catalyst for the selective N-alkylation of aniline with benzyl bromide and allyl bromide. This approach yielded 72% N,N-dibenzylaniline in 7 h and 85% N,N-diallylaniline in just 1 h. Conversely, traditional homogeneous base catalytic systems often grapple with extended reaction times and diminished yields when secondary amines and alkyl halides are involved. , Hence, the Al₂O₃–K₂O catalyst vividly showcases the superiority of solid base catalysts in enhancing reaction efficiency. In a separate investigation, Su et al. employed an Al₂O₃-mordenite catalyst for the N-methylation of aniline, achieving a noteworthy 64% conversion in an exceptionally brief reaction time, underscoring a marked boost in catalytic efficiency. At present, N-alkylation reactions catalyzed by solid bases predominantly depend on surface basic sites, such as OH^–, O^2–, or other anionic species. These sites facilitate the reaction by boosting the reactivity of the substrate. In the conventional mechanism, the catalyst initially activates the nucleophilic reagent by amplifying its electron density and nucleophilicity, while concurrently polarizing the C-X bond of the alkyl halide, thereby augmenting its electrophilicity. The activated nitrogen nucleophile subsequently assaults the electrophilic carbon center of the alkyl halide, forming a C–N bond and producing the N-alkylated product. Ultimately, the product desorbs from the catalyst surface, regenerating the active site and completing the catalytic cycle. In certain reactions, substrates may feature multiple nucleophilic sites, often coexisting with strongly nucleophilic elements like oxygen. Addressing the issue of poor N–C bond selectivity in N-alkylation reactions, Chen et al. developed a robust Ni­(II)­(σ-aryl) complex, [Ni]-1, stabilized by an N-heterocyclic carbene ligand (L-1), demonstrating remarkable air and moisture stability. This catalyst was successfully employed in the N-alkylation of aniline with aryl chlorides, achieving high N–C bond selectivity. In their study on the reaction between ketoximes and symmetrically activated allyl dienes, Heaney et al. suggested that the topology of transition states leading to N/O-alkylation influences the chemoselectivity of the reaction. There is also an effective synthesis of N-alkylated amines using diazo compounds and trifluoromethanesulfonate esters as alkylating agents under basic conditions. , However, these studies often entail complex catalyst preparation and harsh reaction conditions, limiting their practical applications. In conclusion, while solid base catalysts offer advantages such as environmental compatibility and recyclability in N-alkylation reactions, challenges remain due to relatively slow reaction rates and limited selectivity. Furthermore, most existing methods depend on severe reaction conditions or intricate catalyst synthesis procedures. Therefore, the development of an efficient solid base catalytic system with high selectivity, mild reaction conditions, and easy preparation remains a significant area of research interest.

Layered double hydroxides (LDHs) have the capacity to morph into topologically structured layered double oxides (LDOs) through a process of calcination. , The wide-ranging employment of LDOs as catalysts or supports in various chemical reactions can be attributed to their flexible microstructure, tunable composition, and robust hydrothermal stability. , Upon calcination, LDHs often display expansive surface areas, elemental synergy, and a shape memory effect. − The geometric structure and electronic properties of alkaline centers are also the main factors determining the catalytic activity of LDH. In this study, we investigate whether the topological transformation of LDHs and the concomitant evolution of basic sites can augment the rate and selectivity of BIT N-alkylation. We prepared LDOs by calcining Mg _x Al₁-LDHs with varying Mg/Al ratios at distinct temperatures. The structural progression from LDHs to LDOs was meticulously analyzed, and the influence of basic sites of disparate strengths on directing N/O-alkylation pathways was examined. Notably, the Mg₄Al₁O-600 variant demonstrated superior performance (achieving 61.66% conversion and 42.81% yield), a phenomenon attributed to its profusion of medium-strength basic sites and an optimally suited surface area. We optimized the catalytic conditions, appraised the stability, and revealed a mass-transfer and reaction-coupled process through kinetic analysis.

2. Experimental Section

2.1. Materials

1,2-Benzisothiazolin-3-one (BIT, 98%), Bromo-n-butane (BrBu, 98%), N-Butyl-1,2-benzisothiazolin-3-one (BBIT, 98%), N,N-Dimethylformamide (DMF, 98%), MgO and γ-Al₂O₃-both purchased from Macklin Reagents; Magnesium nitrate hexahydrate [Mg­(NO₃)₂·6H₂O, 99%], Aluminum nitrate nonahydrate [Al­(NO₃)₃·9H₂O, 99%], Ammonia solution, Methanol (CH₃OH, 99.9%), Anhydrous ethanol, Isopropanol and Urea [CO­(NH₂)₂, 99%]-purchased from Sinopharm Chemical Reagent Co. Ltd.

2.2. Catalyst Preparation

Layered double hydroxides (LDHs) of magnesium and aluminum, with varying Mg/Al molar ratios of 2:1, 3:1, 4:1, 5:1, and 6:1, were synthesized utilizing a urea hydrolysis approach. For this process, a specific quantity of Mg­(NO₃)₂·6H₂O and Al­(NO₃)₃·9H₂O was dissolved in 100 mL of deionized water, formulating solution A. Concurrently, a suitable quantity of urea (CO­(NH₂)₂) was dissolved in 150 mL of deionized water to prepare solution B; the molar ratio of urea to nitrate ions was maintained at n­[CO­(NH₂)₂]/n­[NO₃ ^–] = 4. These solutions, A and B, were subsequently amalgamated and subjected to vigorous stirring at 105 °C for a duration of 10 h to guarantee thorough decomposition of the urea. The resultant mixture was then aged statically at an equivalent temperature for an additional 18 h. The precipitate thus formed was rinsed exhaustively with deionized water and filtered until the filtrate achieved a neutral pH. The recovered filter cake was ultimately dried at 100 °C for 18 h, yielding the solid precursor, herein referred to as Mg _x Al₁-LDH.

The synthesized LDH precursors underwent calcination in a muffle furnace at temperatures of 300 °C, 400 °C, 500 °C, 600 °C, and 700 °C for 6 h, employing a heating rate of 10 °C/min. Subsequent to calcination, the solid residues were allowed to cool naturally to ambient temperature, yielding the final catalysts, labeled as Mg _x Al₁O-T. Here, ’x’ denotes the Mg/Al molar ratio in the precursor, while ’T’ signifies the calcination temperature.

2.3. Catalyst Characterization

X-ray diffraction (XRD) patterns for all powder samples were obtained utilizing a Rigaku SmartLab advanced diffractometer with Cu Kα radiation. The diffraction data were captured across a 2θ range of 5–80°, employing a scanning rate of 20°/min. The Brunauer–Emmett–Teller (BET) data were gathered using a Micromeritics ASAP 2460 automatic adsorption analyzer. Prior to measurement, samples underwent degassing under high vacuum (<2.66 Pa) at 150 °C for a duration of 10 h. Nitrogen physisorption measurements ensued, conducted at −196 °C. Fourier transform infrared (FT-IR) spectra were recorded utilizing a Vertex 70v FT-IR spectrometer across a wavenumber range of 400–4000 cm^–1. Thermogravimetric analysis (TGA) was executed to explore the thermal decomposition temperature and weight loss characteristics of the samples, with experiments conducted utilizing a STA449F5 Jupiter thermogravimetric analyzer under an Ar atmosphere, spanning a temperature range of 30–700 °C at a heating rate of 10 °C/min. The morphology of the catalysts, both pre- and postcalcination, was observed via an S-4800 cold field emission scanning electron microscope (SEM). The basic sites of the catalysts were identified through temperature-programmed desorption of CO₂ (CO₂-TPD) using an AutoChem II 2920 instrument. Initially, the samples were heated to 300 °C at a rate of 5 °C/min under an N₂ flow and maintained for 30 min. Following cooling to room temperature, CO₂ was adsorbed for 1 h, after which He purging occurred for 30 min to eliminate physically adsorbed CO₂. Subsequently, the temperature was escalated to 900 °C at a rate of 10 °C/min, and desorption signals were documented utilizing a thermal conductivity detector (TCD).

2.4. Catalytic N-Alkylation Reaction

The N-alkylation of BIT with BrBu was typically conducted in a three-necked round-bottom flask, equipped with a reflux condenser. The reaction temperature was maintained between 70 and 110 °C. Both BIT and BrBu were introduced to the flask at predetermined molar ratios, after which a specific quantity of catalyst was added. The reaction proceeded in DMF as the solvent, under magnetic stirring at 240 rpm, over several hours at the chosen temperature. The resulting products were analyzed using an Agilent Ultimate 3000 HPLC system, featuring an Athena C18 column (150 × 4.6 mm, 5 μm). Calibration curves were established using reference compounds for both reactants and products, sourced from Macklin Biochemical Co., Ltd.

The conversion of BIT, the selectivity of BBIT, and the yield of BBIT were quantitatively assessed utilizing the external standard method and Gas Chromatography–Mass Spectrometry (GC-MS) analysis. The estimations were executed using the respective equations below (BBIT and OBIT are the main products):

$$\begin{array}{ll}\mathrm{BIT\; Conversion}(\%):& \mathit{C}=\frac{{\mathit{n}}_{\mathrm{BBIT}}+{\mathit{n}}_{\mathrm{OBIT}}}{n_{BIT}}\times 100\%\\ \mathrm{BBIT\; Selectivity}(\%):& \mathit{S}=\frac{{\mathrm{n}}_{\mathrm{BBIT}}}{{\mathit{n}}_{\mathrm{BBIT}}+{\mathit{n}}_{\mathrm{OBIT}}}\times 100\%\\ \mathrm{BBIT\; Yield}(\%):& \mathit{Y}=\frac{{\mathit{n}}_{\mathrm{BBIT}}}{{\mathit{n}}_{\mathrm{BIT}}}\times 100\%\end{array}$$

where n _BIT represents the initial moles of BIT added to the reaction; n _BBIT and n _OBIT represent the moles of the desired product BBIT and the byproduct OBIT, respectively.

3. Results and Discussion

3.1. Characterization of the Materials

The crystalline structure of the analyzed samples was meticulously characterized using powder X-ray diffraction (XRD). Figure a, in conjunction with Figure S1, delineates the XRD patterns of precursor LDH at varying Mg/Al ratios, both pre- and postcalcination. Within Figure a, it is observable that all Mg _x Al₁-LDH precursors (x = 2, 3, 4, 5 and 6) display characteristic diffraction peaks, which are indicative of hydrotalcite (JCPDS 00–089–0460). Notably, three pronounced peaks are discernible at approximately 11.5°, 23.3°, and 34.5°, which are attributed to the (003), (006), and (012) planes of a typical LDH, respectively. This observation underscores that despite the disparities in the Mg/Al ratio, all synthesized samples conspicuously retain the layered structure inherent to hydrotalcite. The diffraction peaks corresponding to the (110) and (113) planes are observed at angles of 60.4° and 61.6°, respectively. These findings suggest that the metal cations are uniformly dispersed within the layers resembling brucite structure. Notably, as the magnesium content escalates, there is a noticeable diminishment in the characteristic diffraction peaks of LDH in samples where Mg:Al ≥ 4. This trend is indicative of the formation of Mg₅(CO₃)₄(OH)₂·4H₂O (JCPDS 00-025-0513), albeit in minimal quantities when Mg:Al = 4. Conversely, a reduction in aluminum content might result in an inadequate positive charge density within the layered structure, thereby mitigating the stabilizing influence of interlayer anions. Such a phenomenon would consequently attenuate interlayer interactions, leading to a loss of structural order and diminished crystallinity. In samples with a heightened magnesium content, such as Mg:Al = 2, the presence of Mg­(OH)₂ (JCPDS 00-082-2454) and Al₅(OH)₁₃·(CO₃)·5H₂O (JCPDS 00-012-0627) is observed. This can potentially be ascribed to a surge in the positive charge density within the metal layers, leading to a nonuniform distribution of interlayer anions and subsequent structural distortions in the layered matrix. Figure S1 illustrates that all samples calcined at 500 °C present characteristic diffraction peaks associated with MgO (JCPDS 00–087–0651). Furthermore, as the Mg/Al ratio augments, the intensity of the MgO crystalline phase peaks intensifies. The absence of a detectable crystalline Al₂O₃ phase implies that Al₂O₃ is predominantly dispersed in an amorphous state within the MgO phase. To elucidate the influence of calcination temperature on the structure of the LDH precursor, XRD patterns of Mg₄Al₁-LDH precursors calcined at varying temperatures are depicted in Figure b. It is evident from Figure b that as the calcination temperature escalates from 300 to 700 °C, the distinctive diffraction peaks attributed to the LDH precursor progressively diminish, concomitant with the emergence and intensification of diffraction peaks corresponding to MgO. Notably, the MgO phase achieves significant stabilization at 600 °C, a finding that aligns with the subsequent TG-DTG analysis. At a lower calcination temperature of 300 °C, the observed formation of Al₂O₃ and MgCO₃·3H₂O phases can potentially be ascribed to the incomplete decomposition of the layered structure. In this context, Mg²⁺ predominantly associates with interlayer carbonate, whereas Al³⁺ precipitates as an Al₂O₃ phase. These observations substantiate the assertion that calcination at elevated temperatures disrupts the LDH structure, culminating in the generation of metal oxides.

1.

(a) XRD patterns of Mg _x Al₁-LDH (x = 2, 3, 4, 5 and 6) precursors. (b) XRD patterns of Mg₄Al₁O-T at different calcination temperatures. (c) FT-IR spectra of Mg₄Al₁O-T (T = 300, 400, 500, 600, and 700). (d) TG-DTG thermal analysis curves of the Mg₄Al₁-LDH precursor. (e) N₂ adsorption–desorption images of Mg₄Al₁O-T sample. (f) CO₂-TPD spectra of Mg₄Al₁O-T (T = 500, 600, 700).

Figure S2 presents the FT-IR spectra of the analyzed samples. It is evident that all samples display similar characteristic peaks of infrared absorption. The observed infrared absorption bands at approximately 3440 cm^–1 and 1638 cm^–1 are attributed to the stretching vibration υ­(O–H) of interlayer and adsorbed water, and the bending vibration δ­(O–H), respectively. These findings suggest the existence of H₂O and OH^– in the LDH precursors. The peaks observed around 1360–1380 cm^–1 are characteristic of the symmetric or asymmetric stretching vibrations of interlayer carbonate ions (CO₃ ^2–). The bands at lower wavenumbers (below 665 cm^–1) can be attributed to diverse lattice vibrations linked with metal hydroxides. As depicted in Figure c, with an increase in calcination temperature, the absorption intensity of hydroxyl groups initially escalates before it descends, peaking at Mg₄Al₁O-500. This could be attributed to the emergence of new surface hydroxyl groups during the transition into amorphous Mg–Al mixed oxides. A further rise in calcination temperature results in the elimination of these surface hydroxyl groups. Concurrently, the distinct absorption peaks associated with carbonate progressively diminish until they vanish, while the peaks indicative of metal oxides become increasingly prominent.

To investigate the thermal stability of Mg _x Al₁-LDH precursors and ascertain the optimal calcination temperature, we focused on Mg₄Al₁-LDH precursors. Their thermogravimetric analysis (TGA) was performed accordingly (Figure d). The TGA results reveal three distinct stages of weight loss within the range of 30–600 °C. The initial weight loss, observed between 30 and 230 °C, represents 13.27% of the total mass loss and is associated with the removal of surface-adsorbed water. The subsequent stage, from 250 to 340 °C, is attributed to the elimination of interlayer bound water or partial surface hydroxyl groups, contributing to 11.08% of the total mass loss. The third stage, occurring between 350 and 600 °C, constitutes 19.82% of the total weight loss and corresponds to the decomposition of interlayer carbonate, subsequently leading to the formation of mixed metal oxides. Beyond 600 °C, no further significant weight loss is observed, suggesting a phase stabilization to MgO and Al₂O₃ (Figure b).

3.

(a) Comparison of the catalytic activity of Mg _x Al₁O-500 in N-alkylation reactions. (b) Comparison of the catalytic activity of Mg₄Al₁-LDH precursor calcined at different temperatures in N-alkylation reactions.

SEM images (Figure ) depict the morphological transformation of Mg₄Al₁-LDH and Mg₄Al₁O-T as the calcination temperature increases. The precursor displays a typical layered structure. , At 300 °C, the layers are still intact but exhibit slight curling and surface roughening due to the loss of interlayer water. Between 400 and 600 °C, the structure gradually collapses, forming porous particles with rough surfaces, high dispersion, and surface area-this correlates with TGA results and optimal catalytic activity. At 700 °C, sintering occurs, resulting in larger, smoother particles, which reduces the surface area and active sites.

2.

SEM images of (a) Mg₄Al₁-LDH and (b–f) Mg₄Al₁O-T with different calcination temperatures: (b) Mg₄Al₁O-300, (c) Mg₄Al₁O-400, (d) Mg₄Al₁O-500, (e) Mg₄Al₁O-600, and (f) Mg₄Al₁O-700.

The N₂ adsorption–desorption method was employed to determine the surface area and pore structure of catalysts calcined at various temperatures, with the BET data summarized in Table S1. All five curves exhibit characteristics of a type IV adsorption isotherm (Figure e), suggesting that these materials predominantly possess a mesoporous structure. A marked increase in adsorption quantity for each curve at high relative pressures (p/p₀ > 0.8) signifies the existence of mesopores with large diameters or material agglomerates. , The average pore size, as determined by the BJH method, consistently exceeds 2 nm, further emphasizing the predominantly mesoporous nature of the sample’s pore sizes (Table S1). The Mg₄Al₁O-300 sample exhibited a low surface area (36.04 m²/g) but larger pores (8.31 nm), which can be attributed to insufficient layer collapse at low temperature and is consistent with the TG data. As the calcination temperature increased, the surface area initially increased to 224.51 m²/g (400 °C) but then decreased to 197.06 m²/g (600 °C), reflecting pore stabilization. Further heating to 700 °C resulted in sintering, which reduced the surface area to 176.08 m²/g and enlarged the pores, consistent with SEM observations.

To further substantiate the impact of calcination temperature on the surface basicity of Mg–Al mixed metal oxides, an analysis was conducted on the CO₂-TPD spectra of Mg₄Al₁O-T. As illustrated in Figure (f), the basic sites that form postcalcination of hydrotalcite can be categorized into three distinct groups: weak basic sites (comprising OH^– and surface-adsorbed water, with a temperature range of 150–250 °C), moderate basic sites (consisting of M-O and bridging hydroxyl groups, within a temperature range of 250–500 °C), and strong basic sites (characterized by unsaturated O^2–, existing between 500 and 800 °C). , The partial degradation of the layered structure results in a change in the proportion of basic sites possessing varying strengths. This is evident in Table , which shows a decrease in the number of moderate and strong basic sites as the calcination temperature increases. For instance, the Mg₄Al₁O-600 sample, treated at a temperature of 600 °C, displays a CO₂ adsorption capacity of approximately 54.47 μmol/g and also has a weak CO₂ desorption peak in the low-temperature region, but its overall basicity is still dominated by medium-strength sites (whose contribution to the catalytic performance is more significant). However, when the calcination temperature is elevated to 700 °C, the count of moderate basic sites diminishes to 34.45 μmol/g. This decline can be ascribed to a severe framework collapse, leading to a reduction in both the BET surface area and the coverage of basic sites. , It should be noted that the Mg₄Al₁O-600 sample exhibited only a negligible amount of CO₂ desorption in the low-temperature region, indicating that 600 °C represents the typical temperature for complete topological transformation of the LDH precursor. At this stage, the interlayer water and surface hydroxyl groups are almost completely removed, and the surface basic species are primarily composed of M-O or exposed O^2– sites, leading to a significant reduction in weak basic sites. In contrast, calcination at 700 °C may induce crystal sintering and partial structural reconstruction, generating more surface defects that facilitate the regeneration of weakly basic OH^– species, thus resulting in increased CO₂ desorption at low temperatures. Interestingly, there is a near-positive correlation between the density of moderate basic sites and the yield of BBIT. This can be attributed to the unique reactivity of various basic sites. For instance, strong basic sites, such as free O^2–, have high nucleophilicity and tend to interact preferentially with the carbonyl oxygen (C = O) in BIT molecules. This interaction forms strong hydrogen bonds or induces resonance-enhanced negative charge localization, thereby increasing the nucleophilicity of the carbonyl oxygen and facilitating O-alkylation of BIT. On the other hand, moderate basic sites (Mg²⁺-O^2–) can gently deprotonate the N–H bond in BIT, producing a nitrogen anion and enhancing its nucleophilicity. Given that the acidity of the N–H bond surpasses that of the C = O carbonyl oxygen, N-alkylation of BIT is more likely to occur at these sites. Conversely, weak basic sites (OH^–, Mg–OH) lack sufficient basicity to effectively deprotonate the N–H bond in BIT, leading to a lower reaction rate for N-alkylation. Moreover, these sites have limited activation ability toward the carbonyl oxygen, indicating that the O-alkylation side reaction of BIT is not significantly promoted.

1. Basicity of Hydrotalcite (Mg₄Al₁O-T) Calcined at Different Temperatures.

			Desorbed CO2 (μmol/g)
Catalysts	S BET (m2/g)	BBIT Yield (%)	100–300 °C	300–500 °C	500–800 °C	M-Basicity(μmol/m2)
Mg4Al1O-500	209.04	40.06	63.01	56.29	83.37	26.93
Mg4Al1O-600	197.06	42.81		54.47	45.87	27.64
Mg4Al1O-700	176.08	30.73	59.24	34.45		19.56

^aDetemined by CO₂-TPD.

^bM-Basicity (basicity density of moderate-strength basic sites) = desorbed CO₂/S _BET.

3.2. Catalytic Performance

The catalytic performance of various catalysts on the N-alkylation reaction of BIT was investigated, and the results are shown in Table . The conversion of BIT was notably low (15.89%) in the blank control experiment executed without a catalyst. This is attributed to the fact that the reaction, absent a catalyst, is reliant primarily on the weak basicity of BIT itself or the polarity of the solvent, thereby lacking effective catalytic active sites and culminating in a languid reaction rate. Furthermore, individual metal oxides exhibited limited catalytic activity. For instance, Al₂O₃, which principally provides Lewis acidic sites unsuitable for base-catalyzed reactions, resulted in an exceptionally low BIT conversion. In contrast, when BIT conversion was compared with MgO, it increased to 26.97%, and the selectivity toward BBIT improved to 74.39%. This improvement can be attributed to the presence of moderate basic Mg–O sites and a limited number of exposed strongly basic O^2– sites on the MgO surface. The Mg–O basic sites offer moderate basicity, which aids in the nucleophilic attack of BIT on BrBu, thereby favoring the N-alkylation pathway. On the other hand, NaOH, as a strong homogeneous base, can effectively activate BIT molecules, making them more susceptible to nucleophilic substitution with BrBu, thus achieving the highest conversion rate. However, due to its homogeneous nature, both N/O-alkylation pathways may occur simultaneously during the reaction, resulting in only moderate selectivity. The existing literature has also tested the catalytic performance of various catalysts (Cs/Al₂O₃, Mg/LTA, K/LTA, 5%Cs/LTA, etc.). Although the 5%Cs/LTA catalyst achieved a BBIT yield of 49.45%, these catalysts are relatively complex to prepare and rely on precious metals. All mixed oxides (Mg _x Al₁O-T) derived from calcined LDH precursors exhibited significantly enhanced catalytic activity and improved selectivity toward BBIT. This improvement is primarily attributed to the higher specific surface area and the greater number of medium-strength basic sites of the layered double oxide (LDO) compared to the parent LDH, which favor the N-alkylation pathway of BIT.

2. Evaluation of Various Catalysts in the N-Alkylation Reaction of BIT to Prepare BBIT .

Entry	Catalysts	Conversion (%)	Selectivity (%)	Yield (%)	Standard deviation
1	None	15.89	59.96	9.53	0.65
2	Al2O3	3.97	35.27	1.40	2.03
3	MgO	26.97	74.39	20.06	1.06
4	NaOH	70.10	48.36	33.90	2.56
5	Cs/Al2O3	11.57	36.10	5.13	3.11
6	Mg/LTA	40.15	60.19	25.14	2.16
7	K/LTA	51.69	64.34	36.42	1.96
8	5%Cs/LTA	69..48	71.17	49.45	2.03
9	Mg4Al1-LDH	62.87	18.71	11.76	2.33
10	Mg4Al1O-600	61.66	69.42	42.81	1.89

^aReaction conditions: BIT 0.0033 mol, BrBu 0.0066 mol, air, 100 °C, 20 h.

As the Mg content increases (resulting in a higher Mg/Al ratio), there is a corresponding improvement in both BIT conversion and BBIT selectivity, with these reaching their peaks at a ratio of 4, where they are approximately 58.29% and 70.23% respectively. However, the continued addition of Mg leads to a substantial decline in performance, with the conversion rate falling to 56.31%. Upon analysis of the XRD, it is suggested that an excess of Mg diminishes crystallinity, thus reducing surface area. Furthermore, overpopulation of active sites on the surface may disrupt the balanced adsorption of reactants and impede product desorption (Figure a). As depicted in Figure b, there is an upward trend in BBIT selectivity and BIT conversion as the calcination temperature increases from 300 to 700 °C, peaking at 600 °C (61.66%). This is then followed by a decrease attributed to sintering and aggregation, as verified by SEM. In comparison to similar catalysts, the Mg₄Al₁O-600 catalyst demonstrates superior activity and selectivity.

In pursuit of maximizing catalytic efficiency, a comprehensive examination of the impact of various parameters, including feed ratio, catalyst loading, reaction temperature, and duration, on BIT conversion and BBIT yield was conducted. As illustrated in Figure a, there was a consistent rise in BBIT yield as the molar ratio of BrBu to BIT increased from 1.4 to 2.0, peaking at an n_BrBu/n_BIT ratio of 2.0. Notably, a slight decrease in yield was documented when this ratio was augmented further to 2.2. This diminution could potentially be attributed to a heightened propensity of BrBu to engage in side reactions or alterations in the solvent environment, both of which detrimentally affected the selectivity for the desired product. While an escalation in catalyst dosage typically bolstered the conversion rate, a decline in BBIT yield was observed when the catalyst quantity surpassed 2.5 to 3 times the mass of BIT (Figure b). This phenomenon might be linked to catalyst agglomeration at elevated loadings, diminishing its effective interaction with the reactants. Moreover, an overabundance of catalyst might foster side reactions, thereby compromising the selectivity toward BBIT. Optimal BIT conversion and BBIT yield were realized when the catalyst loading was equivalent to twice the mass of BIT. The reaction temperature significantly influenced both the conversion and product yield (Figure c). As the temperature rose from 70 to 100 °C, the BBIT yield consistently increased, indicating that moderate heating enhances product desorption. However, a further temperature increase to 110 °C resulted in a decrease in BBIT yield. This decrease can be attributed to the acceleration of side reactions, such as the formation of brominated byproducts or thermal decomposition of BIT, or to the evaporation of BrBu surpassing its condensation rate (boiling point of BrBu: 104 °C). Consequently, 100 °C was determined to be the optimal reaction temperature. Figure d illustrates that the yield of BBIT peaked at 42.81% after 20 h. Extending the reaction time beyond this point resulted in a decline in selectivity, while the conversion of BIT remained relatively stable. This could be due to the accumulation of products inhibiting effective contact between reactants and the catalyst, or the system nearing equilibrium. Based on these results, under optimal conditions using Mg₄Al₁O-600 as the catalyst (100 °C, 20 h), the BBIT yield reached 42.81%, with a corresponding BIT conversion of 61.66%.

4.

Influences of (a) material ratio, (b) catalyst amount, (c) temperature, and (t) time.

3.3. Recyclability and Stability of Catalyst

Heterogeneous catalysts necessitate not only high catalytic activity but also long-term stability. As such, the recyclability of Mg₄Al₁O-600 was evaluated under optimized conditions. After each cycle, the catalyst was efficiently separated from the reaction mixture via vacuum filtration, then washed multiple times with DMF and methanol before being dried in a 100 °C oven for 10 h. The dried catalyst was separated into three parts for regeneration; the first part was calcined in air at 400 °C for 6 h and the second part at 600 °C for 6 h, with both being reused in subsequent reactions. The third part was prewashed with diluted ammonia solution twice before solvent washing, then dried and calcined at 400 °C for 6 h. Figure a shows the recycling performance of Mg-based catalysts using these three different reactivation strategies. Of the three strategies, alkaline washing proved to be the most effective for regenerating Mg₄Al₁O-600, as it demonstrated superior stability. For instance, after the third run, the catalyst maintained a high BIT conversion rate of 54.74%. However, its performance significantly declined in the fourth cycle (45.37% conversion), even though the average BBIT yield over the four cycles remained relatively high at 35.59%; notably better than those of the other two methods, which were 18.82% and 25.37%, respectively. To evaluate the structural integrity of Mg₄Al₁O-600 during recycling, fresh and four-times-used catalysts were characterized. As shown in Figure b, all three reactivation methods retained distinct MgO diffraction peaks after four cycles. Notably, the peak intensity was significantly higher for the catalyst regenerated by alkaline washing followed by calcination, suggesting that this treatment removed amorphous or poorly crystalline byproducts covering the MgO surface, thereby enhancing the exposure of active phases. Moreover, such amorphous deposits can weaken M-O vibrations, diminishing catalytic activity. FT-IR analysis further supports this: simple calcination did not significantly enhance M-O vibrations (400–600 cm^–1 for Mg–O/Al-O and 600–800 cm^–1 for Mg–Al–O), while alkaline washing followed by calcination led to clearer vibration bands (Figure c). This again indicates that amorphous deposits tend to accumulate on the catalyst surface during reaction. Multiple ammonia washing may cause the destruction of LDO structure or the loss of active species, while residual ammonium salts may block the alkali active sites, thereby leading to a sharp decline in catalytic performance. After reacting for 12 h, the catalyst was filtered and the subsequent reaction was observed, the results showed that the conversion of BIT did not increase, and this hot filtration experiment also proved that the catalytic reaction was heterogeneous catalysis (Figure d).

5.

(a) Cyclic stability of different activation modes. (b) XRD patterns of fresh catalysts and fourth catalysts with different activation modes. (c) FT-IR patterns of fresh catalysts and fourth catalysts with different activation modes. (d) Thermal filtration experiment.

3.4. Catalytic Mechanism

As described above, the catalytic performance of Mg _x Al₁O-T significantly surpasses that of its Mg _x Al₁O-LDH precursors and other metal oxide catalysts. This superiority is attributed to the generation of basic sites with varying strengths and abundances upon calcination of the hydrotalcite precursors. Based on these results and supported by previous literature, a plausible reaction mechanism for the selective N-alkylation of BIT over Mg₄Al₁O-600 is proposed (Scheme ). Initially, the BIT molecule is captured by the basic sites on the catalyst surface. The medium-strength basic sites, formed by M-O pairs, primarily interact with the proton in the secondary amine group (−NH), while the strong basic sites (O^2–) preferentially associate with the carbonyl oxygen. Simultaneously, n-butyl bromide (BrBu) adsorbs onto the LDO catalyst surface, where the bromide anion weakly coordinates with Mg²⁺ or Al³⁺ cations, thereby promoting polarization of the C–Br bond and facilitating its susceptibility to nucleophilic attack. This adsorption also brings BrBu into close proximity with the reactive site of BIT. Given that the reaction is conducted in a polar aprotic solvent (DMF), the transformation proceed via an S_N2-type nucleophilic substitution mechanism. The nitrogen atom, activated via deprotonation by the catalyst’s basic site, attacks the butyl carbon center, leading to C–N bond formation and displacement of the Br^– ion. The resulting BBIT product is formed, while the Br^– ion combines with the proton originally abstracted from -NH to yield HBr. Additionally, the strong basic sites interacting with the carbonyl oxygen increase its electron density, enhancing polarization of the C = O bond. This polarization renders the carbonyl oxygen more enolate-like (C–O^–), thereby increasing its nucleophilicity and propensity to attack the butyl carbon. Following C = O bond cleavage, the required proton for the carbon site may originate partly from the deprotonated -NH group or from the reversible acid–base behavior of hydroxide ions (OH^–) at weaker basic sites under the strongly basic environment. This observation is further supported by the postreaction FT-IR spectrum of the catalyst, where a noticeable attenuation of the O–H stretching vibrations in the 3400–3600 cm^–1 region indicates the consumption or interaction of surface hydroxyl groups (Figure c). Subsequently, the BBIT and OBIT products desorb from the catalyst surface, completing the catalytic cycle and allowing for catalyst regeneration.

1. Possible Mechanism for the Selective N-Alkylation of BIT Catalyzed by the Mg₄Al₁O-600 Catalyst.

3.5. Kinetic Study

When studying reaction kinetics, it is crucial to remove the impact of diffusion effects. This ensures that the reaction takes place within the kinetically controlled regime. , The impact of external diffusion under certain temperature, pressure, and reaction system conditions can be negated by fine-tuning the stirring speed and catalyst concentration. As illustrated in Figure a, the initial reaction rate stabilizes or fluctuates within a narrow range when the stirring speed exceeds a critical value of 240 rpm. This suggests that the reaction is no longer constrained by external mass transfer and is predominantly governed by intrinsic chemical kinetics. Furthermore, the impact of catalyst concentration on the reaction rate was assessed (Figure b). It was observed that when the catalyst concentration attains a threshold of approximately 0.07 g·ml^–1, the effects of external diffusion can be substantially mitigated. A linear regression analysis of the data yielded a correlation coefficient of R²=0.997, reinforcing this assertion. As depicted in Figure c, the effects of internal diffusion can be diminished by modulating the particle size of the catalyst. Catalysts with higher mesh numbers displayed a reduced initial reaction rate, which can be attributed to the increased propensity for smaller particles to aggregate within the reaction medium. Such aggregation likely curtails the effective exposure of surface active sites, thereby slowing the reaction rate. Conversely, catalysts with lower mesh numbers demonstrated diminished aggregation tendencies, leading to enhanced dispersion and structural stability of the layered catalyst. This, in turn, augments the exposure of basic active sites, resulting in a more rapid initial reaction rate. Based on comprehensive analysis and experimental validation, a stirring speed of 240 rpm and a catalyst particle size between 40 and 60 mesh were determined to effectively negate the influences of both external and internal diffusion during kinetic studies.

6.

Excursion of the mass transport effect of (a) stirring speed on the initial reaction rate of BIT, (b) catalyst concentration on the initial reaction rate of BIT, and (c) catalyst particle size on the initial reaction rate of BIT.

Previous studies have indicated that the cleavage of the C–Br bond in n-butyl bromide (BrBu) proceeds readily and does not constitute the rate-determining step in nucleophilic substitution reactions. Based on this understanding, and to simplify the kinetic modeling, it is assumed that both the adsorption of BrBu on the catalyst surface and its mass transfer from the bulk phase have negligible influence on the overall reaction rate. Therefore, the N-alkylation of BIT is considered to be primarily governed by the behavior of BIT itself. Specifically, the kinetically controlled stage is defined as the surface reaction involving BIT adsorption, deprotonation of the -NH group, and subsequent C–N bond formation via nucleophilic attack on the butyl carbon of BrBu. This surface process comprises two elementary steps: (1) the cleavage of the N–H bond to form a nucleophilic nitrogen species, and (2) the substitution reaction with the polarized C–Br bond of BrBu. The apparent reaction rate constant for this kinetically relevant stage is denoted as k. Based on the above assumptions, the kinetic model can be expressed as follows:

$$-{\mathit{r}}_{\mathrm{BIT}}=-{\mathrm{d}\mathit{C}}_{\mathrm{BIT}}/\mathrm{d}\mathit{t}={\mathit{k}}_{\mathrm{s},\mathrm{BIT}}·\theta ·{\alpha }_{\mathrm{m}}·({\mathit{C}}_{\mathrm{BIT}}-{\mathit{C}}_{\mathrm{BIT},\mathrm{s}})={\mathit{kC}}_{\mathrm{BIT},\mathrm{s}}\frac{m_{\mathrm{cat}}}{V}={\mathit{kC}}_{\mathrm{BIT},\mathrm{s}}$$ 1

Let k _mc,BIT = k _s,BIT·θ·α_m· $\frac{m_{\mathrm{cat}}}{V}$ then the equation can be simplified as

$${\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}·({\mathit{C}}_{\mathrm{BIT}}-{\mathit{C}}_{\mathrm{BIT},\mathrm{s}})={\mathit{kC}}_{\mathrm{BIT},\mathrm{s}}$$ 2

From the above equation, the concentration of BIT adsorbed on the catalyst surface can be expressed as

$${\mathit{C}}_{\mathrm{BIT},\mathrm{s}}=\frac{{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}}{{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}+k}·{\mathit{C}}_{\mathrm{BIT}}$$ 3

The kinetic equation is then modified as

$$-{\mathit{r}}_{\mathrm{BIT}}=-{\mathrm{d}\mathit{C}}_{\mathrm{BIT}}/\mathrm{d}\mathit{t}=\frac{\mathit{k}·{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}}{{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}+\mathit{k}}·{\mathit{C}}_{\mathrm{BIT}}$$ 4

Let k _app = $\frac{\mathit{k}·{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}}{{\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}+\mathit{k}}$ then the equation can be simplified as

$$-{\mathrm{d}\mathit{C}}_{\mathrm{BIT}}/\mathrm{d}\mathit{t}={\mathit{k}}_{\mathrm{app}}·{\mathit{C}}_{\mathrm{BIT}}$$ 5

As can be seen from the above equation, in the initial stage of the reaction k _app= k _mc,BIT, Therefore, the reaction equation can be expressed as

$$-{\mathrm{d}\mathit{C}}_{\mathrm{BIT}}/\mathrm{d}\mathit{t}={\mathit{k}}_{\mathrm{mc},\mathrm{BIT}}·{\mathit{C}}_{\mathrm{BIT}}$$ 6

As the alkylation reaction progresses, the influence of the mass transfer process weakens. When k _app = k, the reaction enters the reaction-controlled stage. Therefore, the reaction equation can be expressed as

$$-{\mathrm{d}\mathit{C}}_{\mathrm{BIT}}/\mathrm{d}\mathit{t}=\mathit{k}·{\mathit{C}}_{\mathrm{BIT}}$$ 7

The relationship between molar concentration and conversion during the reaction is given by

$${\mathit{C}}_{\mathrm{BIT}}={\mathit{C}}_{\mathrm{BIT},0}(1-{\mathit{x}}_{\mathrm{BIT}})$$ 8

By combining the kinetic equations, the relationship between time and conversion can be expressed as

$$-\ln (1-{\mathit{x}}_{\mathrm{BIT}})={\mathit{k}}_{\mathrm{app}}\mathit{t}+\mathit{c}$$ 9

The activation energy can be calculated using the modified Arrhenius equation as

$$\ln k=(-{\mathit{E}}_{\mathrm{a}}/\mathit{R})(1/\mathit{T})+\ln \mathit{A}$$ 10

Where, k _s,BIT is the mass transfer rate constant, θ is the percentage of active sites, α_m is the number of active sites (m²/g), C _BIT is the BIT concentration in the liquid phase (mol/L), C _BIT,s is the concentration of BIT adsorbed on the catalyst surface (mol/L), m _cat is the mass of the catalyst (g), V is the solution volume (ml) and k is the rate constant.

The conversion of BIT was observed at varying reaction temperatures (343.15, 353.15, 363.15, and 373.15 K) over time. The results of the plots of -ln­(1-x_BIT)-t against time are depicted in Figure a. After analyzing the data, it was determined that the reaction process is characterized by two distinct phases: an initial stage controlled by mass transfer, succeeded by a chemically controlled reaction stage. The rate constants at different temperatures are compiled in Table . All fitted lines demonstrated high linear correlation coefficients (R² > 0.95), suggesting that the overall kinetics closely align with a first-order reaction model. Furthermore, the rate constants in the chemically controlled stage were significantly higher than those in the mass transfer-controlled stage. Consequently, the kinetic model primarily focuses on the mass transfer–reaction coupling behavior of BIT, while the mass transfer and adsorption of BrBu can be simplified, as they do not significantly contribute to the rate-determining step. The activation energy for the reaction-controlled stage, as calculated based on the slope of the Arrhenius plot (Figure b), was found to be 29.67 kJ/mol.

7.

(a) Linear fitting at different temperatures and (b) Arrhenius curve.

3. Rate Constants at Different Reaction Temperature.

Temperature (K)	k mc,BIT	R 2	k	R 2
343.15	0.0093	0.9998	0.0426	0.9883
353.15	0.0135	0.9915	0.0559	0.9831
363.15	0.0183	0.9842	0.0801	0.9851
373.15	0.0227	0.9699	0.0936	0.9929

4. Conclusion

In conclusion, we prepared a series of highly dispersed and stable nanocatalysts (Mg _x Al₁O-T) through the calcination of Mg _x Al₁-LDH and applied them to the selective N-alkylation of BIT. Under optimal conditions, the Mg₄Al₁O-600 outperformed all reference catalysts, achieving a BIT conversion of 61.66% and a BBIT yield of 42.81%, which was superior to all comparative catalysts. Phase characterization demonstrated the presence of well-dispersed active species, a substantial surface area, and moderate basicity. The S_N2-based alkylation mechanism is facilitated by medium-strength basic sites (M-O sites) that promote -NH deprotonation, and strong sites (exposed O^2–) that enhance carbonyl nucleophilicity. Remarkably, the catalyst maintained high stability across four cycles. Kinetic analysis suggested a mechanism coupling mass transfer and reaction. These findings underscore the potential of Mg–Al mixed oxides for selective N-alkylation. In the future, strategies such as heteroatom doping, surface functionalization, and hierarchical structure design can be further explored to improve catalytic activity and stability. In addition, this catalytic system is expected to be extended to the N-alkylation reactions of other heterocyclic compounds and amide substrates, showing broad application prospects in fine chemicals and pharmaceutical synthesis.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.5c00083.

• XRD patterns of Mg _x Al₁O-500, FT-IR spectra of Mg _x Al₁-LDH (x = 2, 3, 4, 5, and 6) precursors, and BET data graph of the Mg₄Al₁O-T catalyst (PDF)

The authors declare no competing financial interest.