One-pot synthesis of N-containing heterocycles from bioethanol via dehydrogenative dual-cross-condensation
0 Abstract
Green synthesis of N-containing heterocycles has drawn increasing attention due to their significant applications in pharmaceuticals, dyes, and materials, while remains a great challenge. Herein, we propose a one-pot synthesis of N-containing heterocycles from bioethanol and amino alcohols via dehydrogenative dual-cross-condensation and secondary-cross-condensation by cascade catalysis. Isolated yields of 93% to pyrrole in reaction of bioethanol with 2-aminoethanol, 95% to N-ethyl-1,2,3,4-tetrahydroquinoline in reaction of bioethanol with 2-aminobenzyl alcohol, and 94% to N-ethyl piperidine in reaction of bioethanol with 3-aminopropanol have been achieved using a Ni catalyst supported Zr-containing layered double oxides without any additives. This work provides not only a green and sustainable method for production of the N-containing heterocycles but also a promising way for the sustainable use of bioethanol and even biomass industry.
Keywords
INTRODUCTION
Given the ongoing energy demand, depletion of fossil-based resources, and environmental concerns, it is increasingly imperative to develop sustainable energy sources. Biomass, as the only renewable carbon resource in nature, has been considered a promising feedstock for the production of value-added fuels and chemicals, serving as a renewable alternative to fossil feedstocks[1-4]. Bioethanol, one of the initial building blocks produced industrially through biomass fermentation with a global production exceeding 100 billion tons per year[5-7], has been regarded as one of the most important and representative biomass-derived platform molecules. Converting of bioethanol to value-added chemicals is of great significance for the sustainable development of biomass industry and has drawn rising attention. Recently, ethanol has been applied as a raw material in the synthesis of valued-added hydrocarbons[8-10], such as butadiene, oxygen-containing chemicals[9-11], such as higher alcohols (C4-C12 alcohols) and aromatic alcohols/aldehydes, and N-containing chemicals[12,13], such as amines.
N-containing chemicals are pivotal bulk and fine chemicals with extensive application in the manufacture of pharmaceuticals, dyes, polymer materials, and agrochemicals[14-19]. More than 80% of the top 200 pharmaceuticals are N-containing chemicals and the annual global market of N-containing chemicals is more than $50 billion[15]. Specifically, nearly 75% of unique small-molecule pharmaceuticals contain a N-containing heterocycle[16], such as pyrrole, 1,2,3,4-tetrahydroquinoline (THQ), and piperidine. Piperidine and its derivatives have been applied in anticancer (Niraparib[20]) and antipsychotic (Preclamol[21]) pharmaceuticals. THQ and its derivatives have been widely applied to synthesize biologically active natural products[22,23], such as angustureine[22] and aspernigerin[23], and synthetic pharmacologically relevant agents[24-26], including antitumor agents[27], HIV-1 RT inhibitor[24], nNOS inhibitors[25], renin inhibitors[26]. N-ethyl-THQ (NETHQ) and its derivatives have also been recognized as effective human H3 receptors[8] and second near-infrared imaging agents[28]. In addition, THQ and its derivatives are also widely applied as starting materials to synthesize fine chemicals[17,29-37]. The conductive polypyrrole derived from polymerization of pyrrole has been widely applied in energy storage and conversion[38-40], sensors[40,41], actuators[38,40], and even water pollution control[40,42]. Industrially, pyrroles were formed by the reaction of ammonia or primary amine with a 1,4-dicarbonyl compound [Scheme 1A][43,44], and THQ and its derivatives were produced via hydrogenation of quinolines[45] that was prepared via reaction of aniline with α,β-unsaturated aldehyde [Scheme 1B][46]. The N-alkyl-THQ compounds are synthesized [Scheme 1B] via the N-alkylation of THQs with alkyl halides[47] or amidation of THQs with acyl chloride followed by a hydrogenation step[48], which requires excess amounts of halides and produces a large amount of halogen-containing wastewater. Development of methods for production of N-containing heterocycles in an atom-economical, green, and sustainable fashion is highly desired and has drawn great interest.
Scheme 1. (A) Production methodology for pyrrole and (B) 1,2,3,4-tetrahydroquinoline and N-alkyl-1,2,3,4-tetrahydroquinolines; (C) The proposed reaction pathways for one-pot green and sustainable production of N-containing heterocycles from bioethanol.
During the past decade, combination of acceptorless dehydrogenation of alcohols with cross-condensation has become a powerful tool for the benign construction of pyrroles[49-51], pyridines[52-54], benzimidazole[55], and quinolines[56-58] from conversion of secondary alcohols with 1,2-amino alcohols, 1,3-amino alcohols or 2-aminobenzyl alcohols on homogeneous Ru, Ir, or Mn complexes. Despite the significant progress achieved, the applicability of the alcohols is limited to the secondary alcohols with excessive indispensable base additives. Undoubtedly, transforming bioethanol to value-added N-containing heterocycles is a preferred protocol due to the following benefits: (1) bioethanol is a nontoxic and easy-to-access feedstock with a production of more than 100 billion tons per year; (2) the production of N-containing heterocycles from bioethanol is a zero-carbon and even negative-carbon way with the sole by-product of water; (3) the production of N-containing heterocycles from bioethanol broadens the downstream chains of bioethanol industry, which is of great significance for the sustainable development of bioethanol and even the biomass industry. However, highly efficient formation of N-containing heterocycles from ethanol presents great challenges: (1) the uphill for ethanol direct dehydrogenation to acetaldehyde (ΔG298 K = 13.1 kcal·mol-1 at
Here we propose the one-pot green and sustainable production of N-containing heterocycles from bioethanol and amino-alcohols [Scheme 1C]. In our previous work[60], our group has claimed the first synthesis of THQ and its derivatives from 2-aminobenzyl alcohols and ethanol on a heterogeneous Ni catalyst: the Ni0-Niδ+ synergistic catalysis is responsible for alcohol dehydrogenation and hydrogen transfer while the acidic/basic sites for the dual-cross-condensation for the formation of C=C/C=N bond. By engineering the Ni0-Niδ+ synergistic catalysis via Ni particle size and post-treatment, isolated yields of 95% to THQ have been achieved. However, the reaction stopped at THQ without achieving the NETHQ. In this work, the influence of acidic/basic sites on the dual-cross-condensation and even secondary-cross-condensation was investigated in detail and the competition between dual-cross-condensation and even secondary-cross-condensation with self-condensation was modulated for the targeted production of the N-containing heterocycles. The ability for both dual-cross-condensation and secondary-cross condensation increases with the acidic sites of the catalyst, resulting in isolated yields of 93% to pyrrole from reaction of bioethanol with 2-aminoethanol, 95% to NETHQ from reaction of bioethanol with 2-aminobenzyl alcohol, and 94% to N-ethyl piperidine from reaction of bioethanol with 3-aminopropanol on Zr containing layered double oxides supported Ni (Ni-Zr-LDO) via in-situ topological transformation of Ni and Zr-containing layered double hydroxides (Ni-Zr-LDHs) without any addition of additives. After simple recovery by centrifugation, the catalyst could be directly reused and no decrease in either activity or selectivity is detected, showing great potential for industrialization. This work undoubtedly provides a green and sustainable method for production of value-added N-containing heterocycles.
EXPERIMENTAL
Chemicals
Ni(NO3)2·6H2O, Al(NO3)3·9H2O, Mg(NO3)2·6H2O, Zn(NO3)2·6H2O, ZrO(NO3)2·xH2O, NaOH, and Na2CO3 were purchased from Sinopharm Chemical Reagents Ltd. Anhydrous ethanol, 2-aminobenzyl alcohol, substituted 2-aminobenzyl alcohols, 2-aminobenzaldehyde, acetaldehyde, 2-aminoethanol, and 3-aminopropanol were purchased from Aladdin Reagents Co., Ltd. All chemicals were used directly without subsequent purification.
Preparations
NiMgAl-LDHs, NiZnAl-LDHs, NiAl-LDHs, and NiAlZr-LDHs
The NiAl-LDHs with Ni/Al molar ratio 2/1, NiAlZr-LDHs with Ni/Al/Zr molar ratio 2/0.9/0.1, NiMgAl-LDHs with Ni/Mg/Al molar ratio 0.81/3.0/1, and NiZnAl-LDHs with Ni/Zn/Al molar ratio 0.7/1.5/1,
Ni-NiAl-LDO, Ni-NiAlZr-LDO, Ni-ZnAl-LDO, and Ni-MgAl-LDO
Ni-NiAl-LDO or Ni-NiAlZr-LDO was prepared by calcination of NiAl-LDHs or NiAlZr-LDHs at 400 °C for 1 h under H2 flow in a tube furnace. Ni-ZnxAl-LDO was prepared by calcination of NiZnxAl-LDHs at 500 °C for 1 h under H2 flow. Ni-MgAl-LDO was prepared by calcination of NiMgAl-LDHs at 700 °C for
Characterizations
The textural structures were recorded on a Brooker V80 diffractometer using Cu Kα radiator (λ =
NH3- and CO2-temperature-programmed desorption (TPD) profiles were obtained using a Micrometric ChemiSorb 2920 chemisorption instrument with a thermal conductivity detector (TCD). Typically, the Ni-LDO samples (100 mg) were pretreated at 400 °C under H2/He flow for 0.5 h and then cooled to 50 °C to adsorb NH3 or CO2. The TPD profiles were recorded from 50 to 400 °C at a heating rate of 10 °C·min-1. In-situ Fourier transform infrared (FT-IR) spectra of pyridine adsorption were recorded on an iS50 FT-IR (NICOLET) spectrometer as the procedures reported in our previous report[60] (for details see the Supplementary Materials).
For FT-IR spectra of ethanol adsorption, 15 mg of sample was firstly pressed into a self-supporting wafer and then loaded into the in-situ IR cell. After treatment under H2 (20 mL·min-1) at 350 °C for 1 h, the system was cooled in Ar to 120 °C and the spectrum for background was recorded. Then the ethanol was bubbled into the system until equilibrium was reached, and then the system was purged by Ar until the spectra showed no change. The inlet and outlet valves were turn off and the in-situ FT-IR spectra were recorded until the spectra showed no change. Then the system was further purged by Ar and the spectra were recorded. For piperidine adsorption/desorption, the system was first evacuated and the spectrum for background was recorded at 50 °C. The piperidine was bubbled into the system and the spectra were recorded until the spectra showed no change. Then the adsorbed piperidine was purged by Ar at 50, 100, 150, 200, and 250 °C for 5 min and the spectrum was recorded respectively.
Catalytic test
First, 30 mg of catalyst was dispersed in 3 mL of ethanol solution containing 0.5 mmol of 2-aminobenzyl alcohol and sealed in a 25 mL pressure-resistant glass reactor. Then the reactor was heated in oil bath of
The spent catalyst was recovered by centrifugation and then thoroughly washed with ethanol. Subsequently, the recovered catalyst was directly applied as catalyst in the reaction of 2-aminoethanol with ethanol.
RESULTS AND DISCUSSION
For topological transformation, NiMgAl-LDHs, NiZnxAl-LDHs (where x represents Zn/Al molar ratio), NiAl-LDHs, and NiAlZr-LDHs were first prepared [Supplementary Figure 1] via a nucleation/crystallization separation method[61]. The (003), (006), (012), (015), (018), (110), and (113) reflections typical of LDH structure are clearly observed [Supplementary Figure 1]. Calcination of NiMgAl-LDHs at 700 °C for 1 h under H2 atmosphere [Supplementary Figure 2a] produced both of MgAl-LDO phase with characteristic reflections around 36.6°, 43.5°, and 63.1° (JCPDS: 45-0946) and metallic Ni phase with reflections at 44.5°, 51.9°, and 76.4° (JCPDS: 04-0850). Similarly, after calcination of NiZnAl-LDHs at 500 °C for 1 h under H2 atmosphere [Supplementary Figure 2b-d], besides the diffractions of metallic Ni phase at 44.5°, 51.9° and 76.4°, the (100), (002), (101), (110), and (103) reflections characteristic of ZnAl-LDO are also clearly observed around 31.7°, 34.4°, 36.2°, 56.5°, and 62.8° (JCPDS: 76-0704). The (111), (200), and (220) reflections characteristic of NiAl-LDO (JCPDS: 71-1179) are clearly observed around 37.2°, 43.3°, and 62.9° in Ni-NiAl-LDO [Supplementary Figure 2e] and Ni-NiAlZr-LDO [Supplementary Figure 2f]. No diffractions of ZrO2 or Al2O3 are detected in each case. In the TEM image for Ni-NiAlZr-LDO [Figure 1A], Ni particles are observed to be well dispersed in a narrow distribution with the maximum particle size at
Figure 1. (A) TEM and (B) HRTEM image of Ni-NiAlZr-LDO. Insertion in (A) is the histogram of Ni particle distribution; (C) The basic and acidic properties of the Ni-LDO; (D) NH3-TPD profiles of Ni-NiAlZr-LDO and Ni-NiAl-LDO. TEM: Transmission electron microscopy; HRTEM: high-resolution TEM; LDO: layered double oxides; TPD: temperature-programmed desorption.
In our previous report[60], Ni0-Niδ+ synergy plays a vital role in ethanol dehydrogenation, thereby promoting dual-cross-condensation. In this work, to exclude the effect of electronic properties of Ni on the reaction, the electronic properties of Ni in each case were also detected via quasi in-situ XPS. In the Ni 2p3/2 XPS spectra, binding energies at 855.70 eV assigned to NiO[62-64], at 852.97 eV to Niδ+ sites[62-64], and 852.02 eV to Ni0 sites[62-64] are observed on Ni-Zn1.5Al-LDO [Supplementary Figure 4a]. The Niδ+ sites result from the interaction between Ni particles with the support. The binding energies to Ni0 sites and Niδ+ sites slightly shift to 852.31 and 853.74 eV on Ni-NiAl-LDO [Supplementary Figure 4b] and 852.49 and 853.76 eV on Ni-NiAlZr-LDO [Supplementary Figure 4c]. According to the deconvoluted area, the Niδ+/Ni0 ratio has been quantified and summarized in Supplementary Table 1. The Niδ+/Ni0 ratio has been determined to be 0.76-0.78 in each Ni-LDO [Supplementary Table 1], implying that the great differences in the following catalytic performance do not contribute to the electronic properties of Ni.
The CO2-TPD was then conducted to determine the basic properties of the prepared Ni-LDO. For each sample, a broad CO2 desorption is observed between 100 and 400 °C [Supplementary Figure 5], which can be deconvoluted into three contributions at the region with a maximal temperature < 170 °C, 190-270 °C, and > 270 °C. The contributions have been identified[60] as the adsorption of CO2 on weak, medium-strong, and strong basic sites. The amount of the basic sites is quantified and summarized in Figure 1C. The total amount of basic sites has been determined to be 0.808, 0.205, 0.288, 0.316, 0.524, and 0.535 mmol·g-1 on Ni-MgAl-LDO, Ni-Zn1.5Al-LDO, Ni-Zn2.0Al-LDO, Ni-Zn2.5Al-LDO, Ni-NiAl-LDO, and Ni-NiAlZr-LDO [Figure 1C], respectively.
The acidic properties of the Ni-LDO were characterized via in-situ FT-IR spectra of pyridine adsorption. In the in-situ FT-IR spectra of pyridine adsorption [Supplementary Figure 6], a band at 1,457 cm-1 is clearly observed while no band is present at 1,540 cm-1, indicating that only Lewis (L) acidic sites are detected in each sample. The amount of acidic sites determined on Ni-MgAl-LDO, Ni-Zn1.5Al-LDO, Ni-Zn2.0Al-LDO, Ni-Zn2.5Al-LDO, Ni-NiAl-LDO, and Ni-NiAlZr-LDO are 0.012, 0.030, 0.037, 0.051, 0.080, and
To correlate the selectivity to dual-cross-condensation with the acidic-basic sites [Supplementary Table 2], the Ni-LDO was then applied as catalyst in the reaction of 2-aminobenzaldehyde and acetaldehyde, as given by:
.
A selectivity of 67% to quinoline, the dual-cross-condensation product, is obtained on Ni-Zn1.5Al-LDO in
Figure 2. (A) Correlation of the selectivity to dual-cross-condensation with L acidic sites in reaction of 2-aminobenzaldehyde and acetaldehyde; (B) Time course in the reaction between 2-aminoethanol with acetaldehyde on Ni-NiAlZr-LDO at 120 °C under ambient atmosphere; (C) In-situ FT-IR of piperidine adsorption on Ni-NiAlZr-LDO at 50 °C; (D) Time course based on piperidine conversion in the reaction between piperidine with ethanol on Ni-NiAlZr-LDO at 120 °C under ambient atmosphere. LDO: Layered double oxides; FT-IR: Fourier transform infrared.
The Ni-LDO was also applied as catalyst in the reaction of 2-aminoethanol with acetaldehyde. As seen by monitoring the product composition in the reaction, the fraction of 2-aminoethanol decreases and pyrrole, the dual-cross-condensation product between acetaldehyde and 2-amino acetaldehyde increases over time [Figure 2B], as given in:
.
Only trace of pyrazine - the self-condensation product between 2-amino acetaldehyde - is detected, demonstrating the excellent dual-cross-condensation ability on Ni-NiAlZr-LDO, as expressed in:
.
However, on Ni-NiAl-LDO [Supplementary Figure 7] the pyrazine domains in the products further confirm that the introduction of Zr promotes the dual-cross-condensation. It is noted that no 2-amino acetaldehyde is detected on either Ni-NiAlZr-LDO or Ni-NiAl-LDO, demonstrating the rapid condensation between 2-amino acetaldehyde with acetaldehyde or itself.
In-situ FT-IR spectra using piperidine as the probe molecule were recorded to determine the role of strong L acidic sites on the secondary-cross-condensation. On Ni-NiAlZr-LDO [Figure 2C], the bands at 2,945, 2,917, and 2,848 cm-1 to the stretching mode of C–H bond[65,66] while no band at 3,235 cm-1 to the stretching mode of N–H bond[67] are observed under low piperidine coverage (1 min of adsorption), indicative of the dissociation of N–H bond under low piperidine coverage. Increasing adsorption time, new bands at 2,932 and 2,860 cm-1 to C–H bond[65,66] and at 3,235 cm-1 to N–H bond are detected [Figure 2C], demonstrating the non-dissociative adsorption of N–H bond under high piperidine coverage. For comparison, only bands at 2,932, 2,860, and 3,235 cm-1 to the non-dissociative adsorption of N–H bond are observed on Ni-NiAl-LDO [Supplementary Figure 8], demonstrating that the strong L acidic sites derived from Zr species facilitate the adsorption of piperidine via the interaction between the strong L acidic sites and the lone-pair electrons in N, which facilitates the deprotonation by the basic sites, forming dissociative adsorption of N–H bond. Then, the FT-IR spectra of piperidine desorption were recorded at varied temperatures. Increasing desorption temperature, the bands for non-dissociative adsorption of N–H bond rapidly decrease on Ni-NiAlZr-LDO [Supplementary Figure 9], clearly indicative of the weak adsorption of non-dissociative adsorption of N–H bond. The band at 2,945 cm-1 blue shifts to 2,951 cm-1 and then slowly declines
.
The fraction of piperidine clearly decreases while that of N-ethyl piperidine increases on Ni-NiAlZr-LDO [Figure 2D], indicating that the piperidine converts to N-ethyl piperidine. However, no piperidine conversion is detected on Ni-NiAl-LDO [Supplementary Figure 11]. The FT-IR spectra of the piperidine adsorption/desorption combined with the reaction results clearly demonstrate the strong L acidic sites introduced by Zr species facilitate the dissociation of N–H bond in piperidine, which provides an opportunity for the further cross-condensation between aldehyde and Nδ- in the piperidine to afford N-ethyl piperidine.
The in-situ FT-IR spectra of ethanol adsorption/desorption were recorded to determine the role of the acid-base sites in ethanol dehydrogenation. On Ni-NiAlZr-LDO [Figure 3A], the ethanol adsorption at 120 °C gave absorption bands at 1,576, 1,446, 1,419, 1,378, 1,103, 1,072, and 1,056 cm-1. According to a previous report[60,68-70], the bands at 1,446 and 1,378 cm-1 can be assigned to the modes of CH2 and CH3 in adsorbed ethoxide; the band at 1,103 cm-1 can be assigned to the stretching mode of C–O bond in on-top ethoxy group; the band at 1,056 cm-1 can be assigned to the stretching mode of C–O bond in bridging ethoxide species; the band at 1,072 cm-1 can be assigned to the stretching mode of C–O bond in on-top ethoxy group on Niδ+ sites; the bands at 1,576 and 1,419 cm-1 can be assigned to the νs and νas modes of OCO in adsorbed acetate species. The adsorbed acetate species results from the cleavage of the α–C–H bond in the ethoxy group (generating acetaldehyde) and is followed by reacting with oxygen on the support surface, which creates oxygen vacancies on the support surface. With prolonging the reaction time, the intensity of the bands to acetate peak at 1,576 and 1,419 cm-1 increases, while that for the stretching mode of C–O bond in ethoxy species decreases [Figure 3A], demonstrating the process of dehydrogenation of ethoxide to acetaldehyde. Simultaneously, a new band at 1,042 cm-1, which is assigned to the bridging ethoxide on oxygen-defective NiAlZr-LDO, is observed with increasing time [Figure 3A], well accounting for the formation of acetate species. On Ni-ZnAl-LDO [Supplementary Figure 12], similar results are observed to that on Ni-NiAlZr-LDO, except the slower increases in the bands to acetate, slower decrease in the bands for stretching mode of C–O bond in ethoxy species, and the absence of the band at 1,042 cm-1, indicative of the weaker dehydrogenation on Ni-ZnAl-LDO than that on Ni-NiAlZr-LDO. On Ni-NiAl-LDO
Figure 3. (A) In-situ FT-IR spectra of ethanol adsorption on Ni-NiAlZr-LDO at 120 °C under ambient atmosphere; (B) Normalized intensity of the band at 1,576 cm-1 as a function of adsorption time ethanol adsorption on varied Ni-LDO at 120 °C; (C) Normalized intensity of the band at 1,576 cm-1 as a function of desorption time detected in ethanol desorption on varied Ni-LDO at 120 °C. FT-IR: Fourier transform infrared; LDO: layered double oxides.
Then, the Ni-LDO was applied as catalyst in the reaction of 2-aminobenzyl alcohol with bioethanol at
Figure 4. (A) Time course based on 2-aminobenzyl alcohol conversion in the reaction of 2-amino benzyl alcohol with ethanol on Ni-NiAlZr-LDO at 120 °C under ambient atmosphere; (B) Catalytic performance on Ni-LDO in reaction of 2-aminobenzyl alcohol and ethanol at 120 °C in 26 h; (C) Substrates screening for Ni-NiAlZr-LDO catalyzed synthesis of NETHQ derivatives. The data in parentheses are reproduced results. LDO: Layered double oxides; NETHQ: N-ethyl-THQ; THQ: 1,2,3,4-tetrahydroquinoline.
With the optimized reaction conditions, we then examined the generality of this Ni-NiAlZr-LDO catalyzed protocol for N-containing heterocycles. First, the reactions of 2-aminobenzyl alcohol with substituents in 4-position were examined on Ni-NiAlZr-LDO at 120 °C [Figure 4C]. The phenyl, methoxy, methyl formate, and trifluoromethyl substituents on the benzene ring of 2-aminobenzyl alcohol are well tolerated, furnishing isolated yields of 85%-91% to substituted NETHQ [Figure 4C]. Then, the substituents in 5-position were examined. The halide, methoxy, and 3-(1-piperidinyl) propoxy group are well tolerated, affording isolated yields of 84%-91% to substituted NETHQ. One of the products, the 6-[3-(1-piperidinyl) propoxy]-substituted NETHQ has been recognized as an effective H3 receptor antagonist[17,71]. It is noted that no clear effects of the position of the substituents on the yields to NETHQ are detected. Also, the isopropanol was applied as the substrate, affording 2-methyl THQ rather than the N-isopropyl-2-methyl THQ (isolated yield of 86%), as given in:
.
which implies the steric hindrance might suppress the N-alkylation of THQ.
Then the reaction is extended to the reaction of aliphatic 3-aminopropanol with ethanol. On Ni-NiAlZr-LDO [Figure 5A], the fraction of 3-aminopropanol decreases and that of 3-aminopropionaldehyde, pyridine, and piperidine increases firstly and then drops over time. Simultaneously, the fraction of N-ethyl piperidine increases over time [Figure 5A]. These results indicate that 3-aminopropanol first converts to 3-aminopropionaldehyde, which then undergoes cross-dual-condensation with acetaldehyde to form pyridine. Pyridine is hydrogenated to piperidine via hydrogen transfer, and finally, piperidine converts to N-ethyl piperidine through secondary cross-condensation [Supplementary Figure 23]. An isolated yield of 94% to N-ethyl piperidine has been afforded an on Ni-NiAlZr-LDO in 48 h at 170 °C. However, on Ni-NiAl-LDO without Zr species, the reaction stops at piperidine and only traceable N-ethyl piperidine is detected in reaction of 3-aminopropanol with ethanol [Figure 5B]. A selectivity of 83% to piperidine is achieved on Ni-NiAl-LDO in 48 h at 170 °C. These results confirm that the introduction of Zr species promotes not only the dual-cross-condensation but also the secondary-cross-condensation. Interestingly, pyridine rather than 2,3-dihydropyridine is determined as a key intermediate for production of piperidine and then N-ethyl piperidine [Figure 5A and B].
Figure 5. Time course based on 3-aminopropanol conversion in the reaction of 3-aminopropanol with ethanol at 170 °C under ambient atmosphere on Ni-NiAlZr-LDO (A) and Ni-NiAl-LDO (B); (C) Time course based on 2-aminoethanol conversion in the reaction of 2-aminoethanol with ethanol on Ni-NiAlZr-LDO at 120 °C under ambient atmosphere; (D) Correlation of the selectivity to dual-cross-condensation with L acidic sites in reaction of 2-aminoethanol with ethanol. LDO: Layered double oxides.
Then the Ni-LDO was applied as catalyst in reaction of 2-aminoethanol with ethanol, the fraction of 2-aminoethanol declines while that of pyrrole, the dual-cross-condensation product from 2-amino acetaldehyde and acetaldehyde, increases over time [Figure 5C]. A selectivity of 93% to pyrrole has been achieved in 24 h of reaction on Ni-NiAlZr-LDO. No 2-amino acetaldehyde is detected during reaction, indicative of the rapid condensation between 2-aminoacetaldehyde and acetaldehyde. Similar results are detected on Ni-NiAl-LDO [Supplementary Figure 24], except for the pyrazine, the self-condensation product from 2-amino acetaldehyde itself. Only a selectivity of 44% to pyrrole is obtained on Ni-NiAl-LDO [Supplementary Figure 24]. The selectivity to pyrrole almost linearly increases with increasing L acidic sites [Figure 5D], confirming that increasing the L acidic sites facilitates the dual-cross-condensation to form pyrrole. It is noted that the conjugation between the lone pair of electrons on N atom with C=C bond in pyrrole makes the hydrogenation of pyrrole proceed under 1 MPa of H2 and hydrogen transfer is difficult to proceed [Supplementary Figure 25]. The reaction stops in pyrrole rather than tetrapyrrole in reaction of 2-aminoethanol with ethanol [Figure 5C and Supplementary Figure 24]. Also, the secondary alcohols are well tolerated in the synthesis of pyrroles [Supplementary Table 3].
After 2 h in reaction of 2-aminoethanol with ethanol, the spent Ni-NiAlZr-LDO was simply recovered by centrifugation, thoroughly washed with ethanol. Then, the recovered Ni-NiAlZr-LDO was directly reused in the reaction of 2-aminoethanol with ethanol. Almost no decreases in either 2-aminoethanol conversion or pyrrole selectivity are observed in 25th run [Figure 6], showing excellent reusability and great potential for further industrialization.
Figure 6. Reusability of Ni-NiAlZr-LDO in reaction of 2-aminoethanol and ethanol at 120 °C under ambient atmosphere. LDO: Layered double oxides.
Combined the above results with our previous reference, the catalytic cycle is illustrated [Figure 7]: (1) the ethanol and amnio alcohol first convert to acetaldehyde and amnio aldehyde via the dissociative adsorption of O–H bond on-Niδ+ and cleavage of α–C–H bond on Ni0 to generate acetaldehyde bonded with support O; (2) the generated acetaldehyde and amnio aldehyde dual-cross-condensate to form unsaturated N-containing heterocycles; (3) the hydrogenation of unsaturated N-containing heterocycles to saturated N-containing heterocycles rapidly occurs to form the saturated N-containing heterocycles by the active H species from the dehydrogenation step; (4) the strong L acidic sites facilitates the further activation of the saturated N-containing heterocycles to generate the N-ethyl N-containing heterocycles.
Figure 7. Proposed catalytic cycle for the synthesis of N-containing heterocycles from ethanol and amino alcohols on Ni-NiAlZr-LDO. LDO: Layered double oxides.
CONCLUSIONS
In conclusion, green and sustainable synthesis of N-containing heterocycles from bioethanol and amino alcohols has been achieved on Ni-LDO with tunable acidic sites via dehydrogenative dual-cross-condensation and even secondary-cross-condensation. Increasing acidic sites, especially strong L acidic sites, by Zr species not only promotes dual-cross-condensation but also provides strong adsorption sites of THQ/piperidine for the following secondary-cross-condensation of THQ to NETHQ and piperidine to N-ethyl piperidine. For the synthesis of five-membered N-containing heterocycles, the reaction stopped in pyrrole and the hydrogen transfer was suppressed. The mechanism for the modulation of hydrogen transfer for the synthesis of tetrapyrrole is also interesting and deserves to be investigated in detail.
DECLARATIONS
Authors’ contributions
Conceptualized and supervised the project: An, Z.; He, J.
Synthesized the catalysts and performed the catalytic tests: Zhang, J.; Liang, L.
Performed the in situ FT-IR: Zhang, J.
Performed sample characterizations and data analysis: Zhang, J.
Reviewed the paper: Zhu, Y.; Shu, X.; Song, H.
All the authors discussed the results and revised the manuscript.
Availability of data and materials
The raw data supporting the findings of this study are available within this Article and its Supplementary Materials. Further data is available from the corresponding authors upon reasonable request.
Financial support and sponsorship
This work was supported by the National Key R&D Program of China (2021YFB3801603) and National Natural Science Foundation of China (22138001 and 22288102).
Conflicts of interest
He, J. is Guest Editor of the Special Issue “She Energy-Catalysis for Sustainability: Advancements and Challenges” of the journal Chemical Synthesis. He, J. was not involved in any steps of editorial processing, notably including reviewer selection, manuscript handling, or decision-making. The other authors declare that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2025.
Supplementary Materials
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