Ultrasound-Accelerated, Concise, and Highly Efficient Synthesis of 2-Oxazoline Derivatives Using Heterogenous Calcium Ferrite Nanoparticles and Their DFT Studies

A rapid and operationally simple approach for synthesising biologically relevant 2-oxazoline derivatives has been developed through highly efficient ultrasound-promoted coupling reactions of thioamides and amino alcohols using calcium ferrite nanoparticles as heterogeneous catalysts. *e major advantage of using ultrasound irradiation lies in the drastic reduction of reaction time as compared with conventional stirring. Furthermore, quantum chemical investigations for the synthesised 2oxazoline derivatives have been carried out at the DFT/B3LYP/6-311 +G (d, p) level of theory to predict the optimized geometry. *e molecular properties such as bond lengths, bond orders, Milliken charges, frontier molecular orbitals, global reactivity descriptors, molecular electrostatic potential map, and thermodynamic parameters of all the compounds have also been reported at the same level of theory.

In the past few decades, ultrasound has emerged as a potent tool for a variety of organic reactions [35,36]. Ultrasound-promoted reactions result in shorter reaction time, reduced undesired reactions, pure products with high yields using simple open systems, and milder reaction conditions as compared to conventional heating methods. ese advantages rightly put this technique under green, clean, and ecofriendly methodology. However, this technology has not been much exploited in the synthesis of heterocyclic ring systems [37][38][39]. Considering this lacuna as an opportunity and our interest in ultrasound-promoted heterocyclic synthesis [40,41], we have developed an efficient and rapid methodology for the synthesis of 2-oxazolines. On the other hand, magnetic nanoparticles have attracted significant attention as heterogeneous catalysts in the last few years as they enhance reusability and prevent catalytic loss because of their simple separation technique which is an attractive alternative to filtration. Catalysts that are of low cost and are readily available greatly enhance the economic viability of the chemical process. Magnetically recoverable and recyclable nanocatalysts are being used for various reduction, oxidation, and condensation reactions, and their greener generation methods and ecofriendly applications are an ideal merge for the development of sustainable pathways in organic synthesis [42][43][44][45].
Nowadays, calcium ferrite (CaFe 2 O 4 ) nanoparticles have attracted significant attention among other metal ferrite nanoparticles.
ey have significant properties like easy workup, multicycle, and cleaner reaction profiles, besides minimization of organic waste generation in comparison to conventional catalytic systems. Moreover, to the best of our knowledge, CaFe 2 O 4 nanoparticles have not been exploited till now in the synthesis of 2-oxazolines. Keeping this in mind, herein we have developed a mild and efficient ultrasound-assisted methodology for the synthesis of 2-oxazoline derivatives using CaFe 2 O 4 nanoparticles as a heterogeneous catalyst (Scheme 1).
Moreover, the theoretical quantum chemical calculations for all the synthesised 2-oxazoline derivatives were performed with the density functional theory (DFT) using Gaussian 09 and Gauss View 06 software. e optimized molecular geometry of the series of compounds has been computed using the DFT (B3LYP) method with a 6-311 + G(d, p) basis set. In general, the DFT/B3LYP method is used to study the geometrical, spectral, and different molecular properties of chemical compounds because this method offers an excellent tradeoff between chemical accuracy and computational cost [46][47][48][49].

Results and Discussion
CaFe 2 O 4 nanoparticles were synthesised by a simple coprecipitation method using NaOH as a precipitating agent. e synthesised CaFe 2 O 4 nanoparticles were characterized by X-ray diffraction (XRD) (JNU, New Delhi), transmission electron microscopy (TEM) (IARI, New Delhi), Fourier-transform infrared (FT-IR) spectroscopy, and N 2 adsorption-desorption isotherm analysis (BET analysis) (University of Delhi, New Delhi). Figure 1 presents the powder X-ray diffraction pattern of an asprepared sample, which crystallizes in orthorhombic symmetry with space group Pnma having lattice parameters a � 9.231 (5); b � 3.005 (2); c � 10.690 (6)Å; and α � 90, β � 90, and c � 90°. Crystallite size of the CaFe 2 O 4 sample was calculated using Debye-Scherrer analysis and found to be 41.54 nm. ereby, smaller crystallite size (lies in nanoregime) is mainly accountable for broadening of the diffracted peaks. Consequently, a smaller crystallite size provides a high surface area. And by taking advantage of this, we have used CaFe 2 O 4 nanoparticles as the catalyst in the synthesis of 2-Oxazoline derivatives.
TEM analysis was used to analyse the morphology of synthesised CaFe 2 O 4 nanoparticles. A fully agglomerated spherical morphology was observed for the CaFe 2 O 4 sample under TEM images, and crystallite size was found to be ∼13 nm. Generally, agglomeration might occur due to involving low-temperature synthetic conditions and the absence of a capping agent during the synthesis of nanoparticles ( Figure 2).
BET analysis was used to determine the surface area of CaFe 2 O 4 nanoparticles. BET analysis indicates the surface area of CaFe 2 O 4 nanoparticles observed to be 18.065 m 2 /g [50]. is increase in the surface area might be due to the smaller crystallite size of CaFe 2 O 4 nanoparticles ( Figure 3).
To explore the viability of the designed synthetic strategy, a model reaction was performed by using thioamide 1d and amino alcohol 2 at 50°C, varying the amounts of CaFe 2 O 4 nanoparticles using the ultrasound irradiation approach (Table 1). From Table 1, it is clear that using 10 mol% of CaFe 2 O 4 resulted in the formation of product 3d at a maximum yield of 89% (Table 1, entry 5). It should be noted here that 3f was obtained with a very less yield of 65% when the reaction was performed without a catalyst.
is may be anticipated due to the larger surface area provided by CaFe 2 O 4 nanoparticles in organic transformations. However, an increase in the amount of catalyst from 10 mol% to 20 mol% did not increase the yield of compound 3d.
With the optimized conditions in hand (Table 1, entry 5), we next turned our attention to the scope and robustness of the reaction by testing various thioamides 1a-j with amino alcohol 2, and the results are summarized in Table 2. 2-Oxazolines containing cyclohexyl, aryl, and heteroaryl ring as well as alkyl chain substituents were effectively synthesised in good yields.
iobenzamides tolerated different functional groups such as methoxy, hydroxy, and halogen under the applied reaction conditions ( 2-oxazolines was also well accomplished by using heterocyclic thioamides ( Table 2, entries 6 and 7). Analytical data of all the synthesised compounds were compared with those reported in the literature [34].
In order to justify sustainable chemistry concerns, reusability and recovery of CaFe 2 O 4 were studied using the reaction of 1b and 2 in the presence of CaFe 2 O 4 (10 mol%) at 50°C for 20 min under ultrasonic irradiation (Table 3).
CaFe 2 O 4 was used successfully in consecutive runs (the yield decreased from 85% to 82% after 3 runs, Table 3), although a weight loss of approximately 5% of CaFe 2 O 4 was observed from cycle to cycle due to mechanical loss. e recycled CaFe 2 O 4 nanoparticles have been characterized by XRD; the absence of extra reflections in the PXRD pattern confirms the stability of CaFe 2 O 4 after catalysis ( Figure 4).
A plausible mechanism for the 2-oxazoline ring formation is depicted in Scheme 2.

Computational Studies
In the present study, quantum chemical calculations were used initially to optimize the geometry of all the molecules using the density functional theory (DFT), (B3LYP) method, and a 6-311++G (d, p) basis set with the aid of Gaussian 09 program package and Gauss View 6.0 [46][47][48][49].
e obtained optimized geometries of all the synthesised 2-oxazoline molecules are used as inputs for vibrational frequencies calculations [51,52], and we also computed the variety of properties like bond lengths, bond angles, dihedral angles, dipole moments, molecular electrostatic potential surfaces (MEPS), thermodynamic properties, and global reactivity descriptors at the same level of theory and plotted them using Gauss View 6.0 [53]. e equilibrium geometry optimization of the synthesised 2-oxazoline derivatives has been carried out by energy minimization with the DFT/B3LYP level of theory at the 6-311++G (d, p) basis set. e minimum energy of all the compounds is listed in the Table 4. e optimized geometry, bond lengths, bond orders, and Mullikan charges of compound 3a are shown in Figure 5, and for the remaining compounds, the same has been provided in the supporting information.
As we know, frontier molecular orbitals provide important optical and electric properties as well as the kinetic      stability of chemical molecules [54]. Hence, in the present work, the frontier molecular orbitals are also computed using the DFT/B3LYP method with the 6-311++G (d, p) basis set. e HOMO and LUMO are useful in determining the molecular reactivity and provide the pathway to interact with other related molecules. Generally, the chemical reactivity and kinetic stability of the molecular systems are characterized by the bandgap (HOMO-LUMO), which plays a very important role in the field of theoretical quantum chemistry. e frontier molecular orbitals are also useful to predict whether the studied molecular system belongs to a chemically soft or hard group [55][56][57]. e pictorial representation of HOMO and LUMO of compound 3a is shown in Figure 6, and the calculated energies of HOMO and LUMO are listed in Table 4. e HOMO and LUMO pictorial representations of all other molecules are provided in the supporting information.

Global Reactivity Descriptors
e global reactivity descriptors of synthesised 2-oxazoline derivatives are calculated within the framework of DFT [58,59]. e ionization potential and electron affinity of the molecule are calculated as per the Janak theorem [60] and Perdew et al. [61]. On the basis of Koopman's theorem, global reactivity and site selectivity are also determined for the synthesised molecules [62,63]. e formulas for the global reactivity descriptors are listed in Table 5.
All the global reactivity descriptors of 2-oxazoline derivatives are calculated by using the DFT/B3LYP method with the 6-311++G [49,59] basis set, and the calculated values are listed in Table 6.
In the present finding, the molecule 3j has the highest value of η, 3i has the highest value of μ, 3g has the highest value of S, 3f has the highest value of ω, and χ and ΔN max have the maximum value for the molecule 3d. e 3d molecule transfers maximum charge in the direction of the electrophile. e parameter ΔE back − donation has a maximum value for the molecule 3g, which provides valuable information about the reactive behavior of the molecular systems via the electronic back-donation process.

Molecular Electrostatic Potential Map
e behavior and reactivity of the molecules with other chemical species provides data about the shapes of the     Journal of Chemistry chemical molecules with positive, negative, and neutral electrostatic potential regions represented by blue, red, and green colors. Generally, MEP maps are obtained by the mapping of electrostatic potential onto the total electron density with color code. e surfaces with blue and red colors represent the positive and negative values of the potentials, while the green color indicates zero potential. [64,65]. e MEP map for the synthesised 2-oxazoline derivatives is computed by using the DFT/B3LYP method with the 6-311++G [49,59] basis set with level of theory as shown in Figure 7 for the 3a with a color range from 4.254E − 2 (deepest red) to +4.254E − 2 (deepest blue). e red-colored surfaces with negative MEP corresponds to high electron density, demonstrating the strong attraction between the proton and points on the molecular surface. e blue-colored surfaces with positive MEP correspond to areas of the lowest electron density. e MEP maps of the remaining compounds are provided in the supporting information.

Journal of Chemistry
e positive regions of MEP are preferred sites for nucleophilic attacks, while the negative regions are preferred sites for electrophilic attacks. Knowledge about reactive sites in a molecule permits experts to investigate the possible interactions of complex drugs with proteins.

Other Molecular Properties
DFT can also be used to calculate various thermodynamic properties of molecular systems that can help in understanding chemical processes, including the design of viable industrial chemical processes [66]. e thermodynamic parameters are obtained at 298.15 K and 1.00 atm pressure by the vibrational frequency calculations at the DFT/B3LYP/ 6-311G(d, p) level of theory and are depicted in Table 7. e dipole moment and polarizability are also important molecular properties of the various molecular systems for providing information about the charge density, reactivity index, and distribution of charge within a molecule [67][68][69]. e determined dipole moment, polarizability, and thermodynamic parameters of all the synthesised 2-oxazoline derivatives are also listed in Table 7 3 .9H 2 O were dissolved separately in distilled water and mixed completely using a magnetic stirrer at 70°C. Subsequently, 6 M NaOH solution was added dropwise with the help of a burette until the pH of the solution reached 12. en, the addition of NaOH was stopped and stirred for some more time.
e mixture resulted in the formation of a precipitate. e resulting precipitate was stirred at 70°C for 2.5 h. After that, it was filtered and washed with ethanol followed by deionized water until pH 7 was reached and then dried at 60°C. To get a crystalline product, the resulting powder was calcined at 300°C for 2.5 h in a muffle furnace.

Conclusion
In conclusion, we have succeeded in developing an efficient and operationally simple ultrasound-accelerated strategy for the synthesis of 2-oxazoline derivatives. is has been developed through the use of calcium ferrite nanoparticles. Moreover, the avoidance of workup makes this protocol easy to execute for the synthesis of a wide variety of 2-oxazolines. is methodology follows the green chemistry principle as it is completely devoid of the use of any solvent and adorned with operational simplicity and economic viability in an ecofriendly time-and costeffective manner. e products were obtained in good yields with short reaction times, and the protocol accommodates a variety of functionalities. Furthermore, 2-oxazoline derivatives are used as intermediates in the synthesis of biologically active drug molecules and are also used to prepare efficient catalysts for organic transformations. In order to use the 2-oxazoline derivatives in the abovementioned processes, there is a need to know the properties of these derivatives. In this regard, we have studied the properties of these synthesised derivatives using DFT. erefore, we can use any one of the derivatives based on the requirements in our future research work.

Data Availability
Supporting information is provided with the manuscript.