Exploration of catalytic performance of nano-La2O3 as an efficient catalyst for dihydropyrimidinone/thione synthesis and gas sensing

In the present work, we report an proficient, elegant, and rapid one-pot synthesis of variety of 3,4-dihydropyrimidine-2(1H)-one/thione derivatives from β-dicarbonyl compounds, urea/thiourea, and various aromatic aldehydes using nano-La2O3 catalyst under ultrasonic irradiation. This novel synthetic strategy benefits with excellent yields, short reaction time, benign reaction conditions, clean transformation, and purification of products by non-chromatographic strategies. In addition, the synthesized nano-material was also explored as an effective gas sensor for NO2, LPG, methyl alcohol, and ammonia. The gas-sensing properties such as selectivity and sensitivity of selected gases along with response and recovery for nano-La2O3 sensor are reported in this paper. In this way, conferring nano-La2O3 is a multifunctional catalyst not only for organic synthesis but also for gas sensing. The synthesized La2O3 nano-material was characterized by Fourier transform IR, powder X-ray diffraction, field-emission scanning electron microscopy, high-resolution transmission electron microscopy, energy-dispersive spectroscopy, and Brunauer–Emmett–Teller isotherm. The formation of Biginelli adducts was confirmed by Fourier transform IR, 1HNMR, 13CNMR, DEPT-135 (distortionless enhancement by polarization transfer spectra), and mass spectral techniques.


Introduction
The most vital field of catalysis which has developed and pulled in researchers in the on-going years is derived from metal oxide nanoparticles. Metal oxide nanoparticles can catalyze large group of organic transformations on their dynamic surface and interstitial cavities [1]. An adjustment in their structures by acquainting different metal ions leads to catalysts that are exceptionally viable in higher selectivity and yield. Nowadays, the invention on metal oxide catalysts based on the principle of nano-chemistry has been notably utilized in variety of applications [2][3][4]. The two most crucial fields in which metal oxide nanoparticles play key role are organic synthesis and gas sensing [5,6]. These two fields are gaining attention in terms of environment safety for both mankind and animals. Several critical issues are emerging while carrying out organic reactions using classical methods. Similarly, it is the demanding need to monitor leakage and presence of gases in environment which are lethal to living things. By keeping this view in mind, we have focussed on development of multifunctional catalyst for green organic synthesis and real-time monitoring of gases. In the present investigation, we report nano-La 2 O 3 as a benign reaction catalyst for the synthesis of dihydropyrimidinones and effective chemi-sensor.
Organic reactions that take place using metal oxide nanoparticles take place smoothly due to high surface area and presence of active adsorption sites. Variety of nano-catalysis has been employed for the synthesis of organic compounds [7][8][9]. At the same time, ultrasonic irradiation has been comprehensively employed in organic conversions in recent years [10]. Biginelli adducts have been found to exert promising biological properties such as calcium channel blockers [11], anti-HIV [12], antioxidant [13], anticancer [14,15], antimicrobial [16], anti-tuberculosis [17], and anti-inflammatory activity [18]. This noteworthy medicinal profile of dihydropyrimidinones ( Fig. 1) has incited the advancement of modified methodologies for Biginelli reaction. The classical version of this reaction involves the acid-catalyzed, onepot reaction between benzaldehyde, ethyl acetoacetate, and urea in ethanol at reflux condition prompting the formation of Biginelli adduct. In the past few years, Lewis acid catalysis, solid-phase synthesis, room temperature ionic liquids microwave-assisted synthesis technique, ultrasonic-assisted organic conversion, solvent-free techniques, and some other related methods are reported [19][20][21][22][23]. Despite this, several reported methods have disadvantages such as use of harsh reaction conditions, elevated temperature, unsatisfactory yields, toxic catalysts and reagents, and long reaction time which are not adequate in terms of green chemistry principles ( Fig. 1).
Today, the most widely recognized gas sensors are metal oxide semiconductor materials which are produced at low cost and in vast quantities. There are two fundamental types of semiconducting metal oxide sensors inclusive of n-type, whose majority carrier is electron, and p-type, whose majority carrier is hole. La 2 O 3 is an excellent material with p-type semiconduction being applied in diverse applications [24][25][26][27][28][29]. Various types of pure and fabricated semiconducting materials have been found to exhibit goodto-excellent sensing responses to different hazardous and greenhouse gases [30][31][32][33][34]. The main object to sense these gases by various materials is to investigate the better sensing material at desired temperature. The gas sensors are particularly applicable in pollution control, to prevent industrial dangers, gas leakage protection and to make environment free from hazardous and toxic gases. In the present research, an attempt is made to sense the gases such as NH 3 , NO 2 , LPG, and methyl alcohol. LPG gas leakage can cause serious accidents [35]. Methanol (CH 3 OH) is a central nervous system depressant and it is converted into formic acid and then formate, disturbing metabolic acidosis [36]. Inhalation of ammonia (NH 3 ) causes immediate burning of the nose, throat, and respiratory tract. This can lead to bronchiolar and alveolar edema causing severe respiratory problems [37]. Nitrogen dioxide (NO 2 ) inflames the lining of the lungs, thereby diminishing immunity to lung disorders [38]. Therefore, it becomes very essential to monitor the presence of these gases in atmosphere to avoid any hazard to humans as well as animals.
During current years, the chemistry of lanthanum compounds and their applications in organic synthesis has grown rapidly. First and foremost, because of moderate price and low toxicity makes them appealing to be used in organic transformations and other important applications. The use of lanthanide (III) compounds as catalysts in organic synthesis has pulled in incredible attention from numerous researchers. La 2 O 3 is a cost effective basic materials which make them suitable for many organic reactions. Recently, lanthanum oxide has been found to be used as a recyclable catalyst for Michael addition and Hantzsch reaction. The advantages offered by synthetic ease of the catalysts and recyclability are prime significances to the advancement of heterogeneous catalytic materials. In this unique circumstance, herein, we wish to report the diverse applications of nano-La 2 O 3 Fig. 1 Some biologically active Biginelli products catalyst in the synthesis of Biginelli adducts and gas sensing of some flammable and hazardous gases. To the best of our insight, this is the first report on application of nano-La 2 O 3 in organic synthesis under ultrasonic irradiation and gas sensing of reported gases. The advantages of the present benign protocol for the synthesis of Biginelli adducts over most of the reported strategies are short reaction time, energy efficiency, clean reaction conversion, and excellent yields. Furthermore, nano-La 2 O 3 is investigated as gas sensor for the sensing of gases such as ammonia, methyl alcohol, nitrogen dioxide, and LPG. In this regard, nano-La 2 O 3 is not only a proficient catalyst for Biginelli reaction under ultrasonic irradiation but also an effective gas sensor.

General
Chemical reagents in high purity were purchased from SD fine chemicals and Avra synthesis and used without any further purification. 1 H NMR, 13 C NMR, and DEPT spectra were recorded with a Bruker using CDCl 3 and DMSO-d 6 as solvents, FT-IR spectra were obtained with potassium bromide pellets, and HRMS were recorded on Brucker with ESI as a source. The typical XRD spectrum was recorded using Bruker AXS D8 Advance, and the field-emission scanning electron microscopy (FE-SEM) spectrum was recorded using model: Nova nano-SEM 450 equipped with software xT microscope control. High-resolution transmission electron microscopy spectrum (HR-TEM) was recorded using Jeol/JEM 2100. EDS was recorded on Bruker Model: XFlash 6I30 (software: Espirit). BET was measured using instrument Autosorb iQ Station 1. Melting points were determined in open capillaries and uncorrected.

Synthesis of La 2 O 3 nanoparticles
3 M solution of sodium hydroxide (NaOH) was gradually added to a solution of 1 M lanthanum (III) nitrate hexahydrate (La(NO 3 ) 3 ·6H 2 O) taken in a beaker. The solution is continuously stirred on magnetic stirrer during the addition of sodium hydroxide. The pH of the solution was constantly examined until it reached 12. Then, 2-3 drops of oleic acid (as a surfactant) were mixed with the solution. The resulting solution is stirred at 80 °C for a period of 4 h, and then, solution is exposed to ultrasound irradiation for 1 h. After this, solution is cooled naturally and washed several times using distilled water and ethanol to get white color precipitate. The white color precipitate was dried in oven at 110 °C and then grinded into a fine powder using mortar pestle. The fine powder obtained is then calcined for 3 h at 850 °C to obtain fine lanthanum oxide nanoparticles.

X-ray diffraction (XRD) study
The XRD spectrum of La 2 O 3 nanoparticles was recorded at room temperature is depicted in Fig. 2. In the XRD spectrum, it can be clearly seen that the highly narrow sharp lines for the formation of La 2 O 3 nanoparticles. The Braggs reflection pattern can be assigned for the formation of lanthanum oxide with cubic phase. The intense diffraction peaks obtained from XRD data include the 2θ values 15 (Fig. 2) is detected at a diffraction angle of 30, which is assigned to (101) plane of La 2 O 3 . The other peaks are assigned to (002), (102), and (110) lattice planes belonging to cubic crystalline phase of La 2 O 3 (JCPDS card no. . This outcome implies that the pure La 2 O 3 crystals are successfully prepared by this method. The average particle size was calculated using Debye-Scherer's formula. [D = Kλ/β Cos θ], where D is average particle size, K is constant (0.9-1), β is full-width and half-maxima (FWHM) of diffracted peak, and θ is the angle of diffraction. The average particle size for lanthanum oxide nanoparticles was found to be 21.78 nm.

Field-emission scanning electron microscopy (FE-SEM)
The surface and structural morphology of prepared La 2 O 3 nanoparticles was characterized by field-emission scanning electron microscopy instrument, The FE-SEM micrographs of prepared lanthanum oxide nanoparticles are depicted in Fig. 3a, b. The FE-SEM images imply agglomerated nature of lanthanum oxide nanoparticles. These nanoparticles are found to be very effective to the surface area contribution.
The nitrogen adsorption-desorption curves (Fig. 6) also in agreement with the surface morphology found in FE-SEM images.

High-resolution transmission electron microscopy (TEM)
HR-TEM images of prepared lanthanum oxide are depicted in Fig. 4a, b. These images show the cubic crystal structure type and nanosized particles of La 2 O 3 nanoparticles. The material is calcined at 850 °C; at this temperature, the La 2 O 3 nanoparticles are converted to cubic crystal structure which are in agreement with the XRD results. The lanthanum oxide crystal formation is a temperature-dependent phenomenon. At lower temperature region (around 550 °C), its crystal formation is confined with the hexagonal lattice, while at the crossover range of high temperature, the cubic crystal formation is reported. From HR-TEM and FE-SEM evaluation, it has been found that the La 2 O 3 nanoparticles are not correct in crystal association on account of extreme agglomeration. However, the particle size is appropriately below nanometer range to conclude that the obtained La 2 O 3 is a perfect nano-material.

Energy-dispersive spectroscopy (EDS) study
The energy-dispersive spectra (EDS) was analysed for lanthanum oxide nanoparticles to confirm the elemental composition of prepared La 2 O 3 nanoparticles. The EDS spectrum of La 2 O 3 is illustrated in Fig. 5 clearly indicating the presence of elemental lanthanum and oxygen at 4.3 keV and 0.3 keV, respectively, which is in good agreement with the reported status of lanthanum oxide nanoparticles. The average elemental composition, atomic weight percentage of prepared La 2 O 3 nanoparticles is highlighted in Table 1.
In the molecular formula of lanthanum oxide, the stoichiometric atomic weight percentage for lanthanum to oxygen is 1:3, and in the present synthesis, the stoichiometric atomic weight percentage exactly matches with the ideal composition of La 2 O 3 material.

Brunauer-Emmett-Teller (BET) isotherm study
Surface area is an important aspect for the important applications such as surface adsorption and gas-sensing phenomenon. The nano-La 2 O 3 catalyst was investigated by nitrogen adsorption/desorption isotherm for the determining the quantitative aspects such as surface area, pore volume, and pore size determination. The typical adsorption isotherm of the La 2 O 3 catalyst is shown in Figs. 6, 7. The N 2 adsorption-desorption isotherm gives the detailed idea regarding surface area (BET), pore volume, and size distribution (Table 2). By plotting the isotherm, it is found that the isotherm belongs to type IV isotherm profile with reference to the BDDT system which is a typical characteristic of porous materials.

FT-IR spectrum
In the FT-IR spectrum (Fig. 7) of lanthanum oxide nanoparticles, very weak absorption bands at 3604.96 cm −1 are assigned to O-H symmetric stretching vibration of water molecules which is obtained due to hygroscopic nature of lanthanum oxide. The strong absorption band at 630.72 cm −1 is due to La-O stretching. Hence, the existence of abovementioned bands identifies the presence of La 2 O 3 .

General procedure for the synthesis of 3,4-dihydropyrimidine-2(1H)-ones/thiones
The synthesized nano-material has been proficiently used as a heterogeneous catalyst for the synthesis of dihydropyrimidine-2(1H)-one/thione derivatives (4a-4n) under ultrasonic irradiation (Scheme 1). A mixture of aromatic aldehyde (10 mmol), urea/thiourea (10 mmol), ethyl acetoacetate/ acetyl acetone (10 mmol), and nano-La 2 O 3 (8 mol%) was mixed in a 50 ml conical flask containing ethyl alcohol as a solvent. This mixture was exposed ultrasonic irradiation at 50 °C for an appropriate time ( Table 3). The mixture is then cooled to room temperature after completion of reaction (monitored by TLC). Finally, ethyl acetate was added slowly and filtered off to get extract containing crude products leaving behind nano-La 2 O 3 catalyst. The extract was dried over sodium sulphate and solvent was evaporated using rotary evaporator. Pure products were obtained by further purification using ethanol. The recovered catalyst was washed with ethanol and used for five successive runs to check its reusability. The structure of all synthesized products was confirmed using spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, DEPT-135, and Mass spectral data.
All the experiments were performed at the optimized concentration of catalyst. For catalyst study, standard reaction between of benzaldehyde, urea, and ethyl acetoacetate was investigated (entry 4 m in Table 3). The catalyst loading was varied from 2 to 12 mol% (Table 4). By varying catalyst concentration from 2 to 12% mol%, the best outcome was obtained using concentration of 8 mol% catalyst under ultrasonic irradiation at 50 °C. Catalyst loading and selection of solvent were the important tasks during the present study. The increase in catalyst loading was found to exert substantial effect on product yield. There was not much difference in the yield and reaction time when catalyst loading was changed from 8 to 10 and 12 mol%. However, in terms of catalytic efficiency, 8 mol% was found to be the better choice, and therefore, the remaining experiments were performed at the concentration of 8 mol%. From the literature survey, we found that ethanol was the most common solvent used for the dihydropyrimidinone synthesis under variety of reaction conditions, and therefore, ethanol was selected as a solvent with prime choice. During the solvent effect study, when we switched our attention to other solvents (Table 5), there was marked effect on the yield of the product. With water as a solvent, very less amount of product was obtained and with other solvents, the yield was significantly less compared to ethanol as a solvent. In case of water as a solvent, the unsatisfactory yield might be due to hygroscopic property of lanthanum oxide. The scope and generality of this protocol were studied by performing the experiments with broad range of aromatic aldehydes. Importantly, we found that benzaldehydes with variety of substitution pattern did not show large difference in the yield of 3,4-dihydropyrimidine-2(1H)-ones/thiones in this novel route. The substituents such as OH, Cl, OCH 3, and N(Me) 2 have survived which is another benefit associated with this protocol. The ultrasound irradiation disperses the agglomerated nanoparticles, thereby increasing their surface area, and also provides sufficient activation energy to reactant molecules. Henceforth, duel effect of ultrasound irradiation is observed during the course of reaction.
When we switched our attention to some previously reported catalysts to compare our findings, most of the reported methods afforded less yields with longer reaction run (Table 6). This suggests that nano-La 2 O 3 catalyst under ultrasonic irradiation is more superior than most of the reported method. The probable reaction mechanism is depicted in Scheme 2 which suggests that reaction proceeds in two important stages, first aldol reaction between β-dicarbonyl compound and aromatic aldehyde and second cyclization between aldol dehydration product and urea/ thiourea to furnish desired products. Importantly, the catalyst was reused for five successive runs and vitally no significant loss in its catalytic activity was found ( Fig. 8 and Table 7).

Preparation of La 2 O 3 sensor by screen-printing method
The nano-La 2 O 3 paste used in screen printing was prepared by maintaining the inorganic-to-organic materials ratio at 7:3. The inorganic part consists of a functional material nano-La 2 O 3 . The organic part consists of 8% ethyl cellulose (EC) and 92% butyl carbitol acetate (BCA). The nano-La 2 O 3 powder (0.7 g) along with ethyl cellulose (EC) was mixed thoroughly in an acetone medium with mortar and pestle. A solution of BCA which was added dropwise until proper thixotropic properties of the paste were achieved. Nano-La 2 O 3 thick films were prepared on glass substrate using standard screen-printing technique. The films were dried under IR radiation for 45 min to remove the organic vehicle and then fired at temperature 400 °C for 5 h in muffle furnace.

Electrical characterization and gas-sensing study of La 2 O 3 nano-catalyst
The gas-sensing properties of La 2 O 3 thick films was examined at different elevated temperatures from 350 °C to room temperature. The electrical resistance of the thick film sensor was measured in the absence of any other gases in the glass-domed chamber. The typical semiconducting nature of lanthanum oxide thick film is shown in Fig. 9, wherein continuous decrease in temperature, the change in resistance of the film was recorded. Resistance increases at the initial stage in low-temperature region, and with a progression of temperature, resistance decreases in a high-temperature region to document a semiconducting behaviour of the La 2 O 3 oxide. The gas-sensing performance was measured by static gas sensor assembly. The DC resistance of the thick films of La 2 O 3 thick film sensor was measured using traditional half bridge method, at the series of elevated temperatures. The film was fixed at the base of gas-sensing assembly, wherein Chromel-Alumel thermocouple was firmly fixed to sense the temperature of the thick film sensor. The temperature sensed by thermocouple was digitally recorded with the aid of temperature recorder (model number PEW-202/PEW-205). The gases selected for the sensing purpose were brought within the chamber with the help of inlet metallic pipe. The DC voltage was applied to the circuit, and simultaneously, resistance of the film was recorded by digital millimetre (model number CIE Classic 5175). Each cycle of the gas introduced inside the glass chamber was pulled back by lifting the glass chamber and settled temperature was provided to evacuate the gas build-up of the film. The oxygenated air was permitted through the chamber at every gas affectability cycle. The electrical resistance of the thick films in the presence of air (Ra), as well as in the presence of gas (Rg) was measured to calculate the gas response or sensitivity (S) which is given by Eq. 1: The sensing of gases NH 3 , LPG, NO 2, and CH 3 OH of 500 ppm concentrations has been examined at temperature of 50-350 °C. The electrical resistance, selectivity, sensitivity, and response-recovery time were measured for the thick film of lanthanum oxide sensor (Table 8).

Sensitivity and selectivity of lanthanum oxide sensor
The sensitivity of selected gases (500 ppm concentration) against temperature (50-350 °C) is shown in Fig. 10 and the compared selectivity of these gases is shown in Fig. 11. The sensitivity and selectivity can be calculated by applying the temperature to the particular sensor for the sensing of particular gas. The data obtained from methyl alcohol gas-sensing study indicate that the maximum response is 63% at 100 °C. Previously reported response for methanol gas using lanthanum oxide sensor was 60% at higher temperature reported by Yue Gao [50]. On the other hand, the response showed by La 2 O 3 sensor for LPG, NH 3 , and NO 2 was found to be 55%, 27%, and 53%, respectively, at the temperature 200 °C. The gas response reported in the present work is found to be more significant in comparison with the previous reported data. The selectivity data presented in Fig. 11 indicate that all the gases are found to show good-to-excellent selectivity for lanthanum oxide sensor. The response and recovery is depicted in Fig.12. For gases LPG, methyl alcohol, and NO 2, the selectivity is over 80% (Table 9). When we compared our methanol gas-sensing results with some the reported data (Table 10), it can be clearly seen that methanol gas sensing reported herein is not only fantastic, but also observed at little lower temperature. This gives idea about better sensing potential of lanthanum oxide nano-material reported herein. Thus, by keen observation, on the basis of sensing response and selectivity data, we can conclude that nano-La 2 O 3 can be effectively applied as gas sensor for these gases.

Conclusions
In summary, catalytic performance of the nano-La 2 O 3 was explored in Biginelli reaction for the one-pot synthesis of 3,4-dihydropyrimidine-2(1H)-one/thione derivatives under ultrasonic irradiation and it was found that the present method has brilliant efficiency in the synthesis of Biginelli adducts. Short reaction time, use of economical, non-toxic and green catalyst and clean reaction conversion with magnificent yields are the key highlights of the protocol revealed   in this and, therefore, renders this elegant protocol environmentally suitable synthetic methodology for the Biginelli reaction. In addition, nano-La 2 O 3 was also explored as gas sensor for four different gases showing better sensitivity and selectivity to flammable and toxic methyl alcohol. The response and recovery are found to be very effective for the toxic methanol gas as compared to the previous reports. In this context, nano-La 2 O 3 is not only an efficient catalyst for Biginelli reaction under ultrasonic irradiation, but also an effective gas sensor, thereby presenting its multifunctional character.