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

Authors: Anjaneyulu Bendi; Shalu Atri; G. B. Dharma Rao; Mohd Jamshaiya Raza; Nutan Sharma
Journal: Journal of Chemistry
 (2021)

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## Abstract

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. The 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 2-oxazoline derivatives have been carried out at the DFT/B3LYP/6-311 + G (d, p) level of theory to predict the optimized geometry. The 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.


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## Body

## 1. Introduction

2-Oxazoline is an attractive five-membered heterocyclic scaffold which is present in many bioactive natural products [1] and pharmaceuticals [2–5]. This nucleus is part of many drug-like compounds exhibiting antifungal, neuroprotective, cytotoxic, and antibiotic activities [6]. In addition, synthetic applications of 2-oxazolines include their use as unsurpassed catalytic ligands in asymmetric syntheses [7–10], protecting groups for carboxylic acids [11], monomers for thermoresponsive polymers [12], and linear polyethylene imines [13]. Due to the immense applications, these pharmaceutically important scaffolds attract the interest of synthetic organic chemists and tremendous research efforts from the past years are focused on the development of efficient routes for the preparation of 2-oxazoline derivatives. In this direction, multiple synthetic strategies which involve different substrates like imidate hydrochlorides [14], orthoesters [15], aldehydes [16–19], carboxylic acids [20–24], or their derivatives like ester [25–28], nitriles [29–33], and thioamides [34] have been developed to prepare the oxazolines. Despite the potential applications of these reported procedures, they suffer from several limitations, such as hazardous reaction conditions, expensive catalysts, longer reaction times, tedious work-up procedures, and a deficit of general applicability. Thus, the development of mild and efficient strategies is undeniably needed.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. These 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 [37–39]. 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 [42–45].Nowadays, calcium ferrite (CaFe2O4) nanoparticles have attracted significant attention among other metal ferrite nanoparticles. They 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, CaFe2O4 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 CaFe2O4 nanoparticles as a heterogeneous catalyst (Scheme 1).Scheme 1
Previous synthetic approach and our designed approach.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. The 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 [46–49].


## 2. Results and Discussion

CaFe2O4 nanoparticles were synthesised by a simple coprecipitation method using NaOH as a precipitating agent. The synthesised CaFe2O4 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 N2 adsorption-desorption isotherm analysis (BET analysis) (University of Delhi, New Delhi). Figure 1 presents the powder X-ray diffraction pattern of an as-prepared 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 γ = 90°. Crystallite size of the CaFe2O4 sample was calculated using Debye–Scherrer analysis and found to be 41.54 nm. Thereby, 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 CaFe2O4 nanoparticles as the catalyst in the synthesis of 2-Oxazoline derivatives.Figure 1
(a) Powder XRD pattern of as CaFe2O4. (b) CaFe2O4 crystallizes in orthorhombic symmetry.
(a)(b)TEM analysis was used to analyse the morphology of synthesised CaFe2O4 nanoparticles. A fully agglomerated spherical morphology was observed for the CaFe2O4 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).Figure 2
TEM image of CaFe2O4 nanoparticles.BET analysis was used to determine the surface area of CaFe2O4 nanoparticles. BET analysis indicates the surface area of CaFe2O4 nanoparticles observed to be 18.065 m2/g [50]. This increase in the surface area might be due to the smaller crystallite size of CaFe2O4 nanoparticles (Figure 3).Figure 3
N2 adsorption-desorption isotherm.To explore the viability of the designed synthetic strategy, a model reaction was performed by using thioamide1d and amino alcohol 2 at 50°C, varying the amounts of CaFe2O4 nanoparticles using the ultrasound irradiation approach (Table 1). From Table 1, it is clear that using 10 mol% of CaFe2O4 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. This may be anticipated due to the larger surface area provided by CaFe2O4 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.Table 1
Optimization of reaction conditionsa.
EntryCaFe2O4 mol%Time (min.)Yield (%)b1—406521406833407445408051040896204089aReaction conditions: 1d (1.0 mmol), 2 (1.2 mmol), CaFe2O4 (1–20) mol%, 50°C, and UI (40 min.) bIsolated yield.With the optimized conditions in hand (Table1, 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.Table 2
Substrate scope of the synthesis of various 2-oxazoline derivativesa under ultrasound and conventional stirring.
EntryCompounds 1a–jCompounds 3a–jUltrasound irradiation (UI)ConventionalTime (min.)Yield (%)bTime (h)Yield (%)b145889–10852208558133070660440897-88754530180625906-787745859-1083845861681920764701025504-535aReaction conditions: 1a–g (1 mmol), 2 (1.1 mmol), CaFe2O4 (10 mol%), H2O, 50°C, and UI. bIsolated yield.Thiobenzamides tolerated different functional groups such as methoxy, hydroxy, and halogen under the applied reaction conditions (Table2, entries 2, 3, and 4). Synthesis of 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 CaFe2O4 were studied using the reaction of 1b and 2 in the presence of CaFe2O4 (10 mol%) at 50°C for 20 min under ultrasonic irradiation (Table 3).Table 3
Recycling of CaFe2O4.
Runs123Yield (%)858482CaFe2O4 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 CaFe2O4 was observed from cycle to cycle due to mechanical loss. The recycled CaFe2O4 nanoparticles have been characterized by XRD; the absence of extra reflections in the PXRD pattern confirms the stability of CaFe2O4 after catalysis (Figure 4).Figure 4
XRD pattern of recycled CaFe2O4 nanoparticles.A plausible mechanism for the 2-oxazoline ring formation is depicted in Scheme2.Scheme 2
Plausible mechanism.


## 3. 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 [46–49].The 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].The 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. The minimum energy of all the compounds is listed in the Table4.Table 4
Details of minimum energy,EHOMO, ELUMO, energy gap, dipole moment, and polarizability (α) of 2-oxazoline derivatives.
S. no.EntryStructureEnergy (hartree)EHOMO (ev)ELUMO (ev)Energy gap (ev)13a−478.47−0.2437−0.04970.194023b−593.03−0.2253−0.03900.186333c−553.72−0.2301−0.04130.188943d−3052.01−0.2456−0.05990.185753e−517.79−0.2530−0.02180.231263f−494.51−0.2537−0.06130.192473g−799.23−0.2371−0.05620.180983h−482.10−0.2505−0.00960.240993i−404.66−0.2523−0.00280.2495103j−286.69−0.2543−0.00270.2516The optimized geometry, bond lengths, bond orders, and Mullikan charges of compound3a are shown in Figure 5, and for the remaining compounds, the same has been provided in the supporting information.Figure 5
2-Phenyl oxazoline (3a).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. The 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. The frontier molecular orbitals are also useful to predict whether the studied molecular system belongs to a chemically soft or hard group [55–57]. The 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. The HOMO and LUMO pictorial representations of all other molecules are provided in the supporting information.Figure 6
Illustration of computed frontier molecular orbitals of compound3a.


## 4. Global Reactivity Descriptors

The global reactivity descriptors of synthesised 2-oxazoline derivatives are calculated within the framework of DFT [58, 59]. The 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]. The formulas for the global reactivity descriptors are listed in Table 5.Table 5
Formulas for global reactivity descriptors.
S. no.DescriptorFormula1Ionization potentialIE = −EHOMO2Electro affinityEA = −ELUMO3Chemical hardnessη=IE−EA/24Chemical potentialμ=−IE+EA/25Global softnessS=1/η6Electro negativityχ=IE+EA/27Electrophilicity indexω=μ2/2η8Maximum charge transferΔNmax=−μ/η9Energy changeΔEback−donation=−η/4All 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.Table 6
Calculated values of global reactivity descriptors.
EntryIEEAημSχωΔNmaxΔEback − donation3a0.24370.04970.0970−0.146710.30930.14670.11091.5124−0.02433b0.22530.03900.0932−0.132210.73540.13220.09371.4187−0.02333c0.23010.04130.0944−0.135710.59040.13570.09751.4369−0.02363d0.24560.05990.0929−0.152810.77010.15280.12561.6451−0.02323e0.25300.02180.1156−0.13748.65050.13740.08171.1886−0.02893f0.25370.06130.0962−0.157510.39500.15750.12891.6372−0.02413g0.23710.05620.0905−0.146711.05580.14670.11891.6213−0.02263h0.25050.00960.1205−0.13018.30220.13010.07021.0797−0.03013i0.25230.00280.1248−0.12768.01600.12760.06521.0224−0.03123j0.25430.00270.1258−0.12857.95010.12850.06571.0217−0.0314In the present finding, the molecule3j 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 ΔNmax have the maximum value for the molecule 3d. The 3d molecule transfers maximum charge in the direction of the electrophile. The parameter ΔEback − 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.


## 5. Molecular Electrostatic Potential Map

The behavior and reactivity of the molecules with other chemical species provides data about the shapes of the 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. The surfaces with blue and red colors represent the positive and negative values of the potentials, while the green color indicates zero potential. [64, 65]. The 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). The red-colored surfaces with negative MEP corresponds to high electron density, demonstrating the strong attraction between the proton and points on the molecular surface. The blue-colored surfaces with positive MEP correspond to areas of the lowest electron density. The MEP maps of the remaining compounds are provided in the supporting information.Figure 7
Illustration of MEP surface for compound3a.The 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.


## 6. 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]. The 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. The 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 [67–69]. The determined dipole moment, polarizability, and thermodynamic parameters of all the synthesised 2-oxazoline derivatives are also listed in Table 7.Table 7
Dipole moment, polarizability, and thermodynamic parameters of 2-oxazoline derivatives.
EntryThermodynamic parametersDipole moment (μ) (debye)Polarizability (α) (a.u.)EThermal (K cal/mol)CV (cal/mol-K)S (cal/mol-K)3a107.3533.4696.401.22115.043b129.1842.77108.930.43137.463c110.6238.260100.860.62122.173d101.8537.78108.322.81139.553e125.9738.26103.781.49122.383f99.8532.5695.883.64109.843g86.0431.4294.661.55110.613h151.7839.06102.361.38113.113i121.1934.79100.391.3693.403j72.1420.2978.001.3756.27


## 7. General Procedure

### 7.1. Synthesis of Calcium Ferrite Nanoparticles

0.5 M of Ca (NO3)2.4H2O and 1.0 M of Fe (NO3)3.9H2O 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. Then, the addition of NaOH was stopped and stirred for some more time. The mixture resulted in the formation of a precipitate. The 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.


### 7.2. Synthesis of 2-Oxazolines by the Ultrasonic Irradiation Method

To a mixture of thioamide1 (a-j) (1 mmol) and aminoethanol 2 (1.1 mmol), CaFe2O4 nanoparticles (10 mol%) were added with stirring and the reaction was stirred at 50°C under sonication for the time detailed in Table 2. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered and washed with ethyl acetate 2-3 times. CaFe2O4 nanoparticles were separated, and the filtrate was concentrated. To remove the excess 2-aminoethanol in some cases after solvent removal, crude was passed through a short plug of silica gel. Analytical data of all the synthesised compounds can be found in the literature [34].


## 7.1. Synthesis of Calcium Ferrite Nanoparticles

0.5 M of Ca (NO3)2.4H2O and 1.0 M of Fe (NO3)3.9H2O 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. Then, the addition of NaOH was stopped and stirred for some more time. The mixture resulted in the formation of a precipitate. The 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.


## 7.2. Synthesis of 2-Oxazolines by the Ultrasonic Irradiation Method

To a mixture of thioamide1 (a-j) (1 mmol) and aminoethanol 2 (1.1 mmol), CaFe2O4 nanoparticles (10 mol%) were added with stirring and the reaction was stirred at 50°C under sonication for the time detailed in Table 2. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered and washed with ethyl acetate 2-3 times. CaFe2O4 nanoparticles were separated, and the filtrate was concentrated. To remove the excess 2-aminoethanol in some cases after solvent removal, crude was passed through a short plug of silica gel. Analytical data of all the synthesised compounds can be found in the literature [34].


## 8. Analytical Data of Some Representative Compounds

### 8.1. 2-Phenyl-4,5-dihydrooxazole (3a) [34]

Colorless oil; yield: 200 mg (88%).1H NMR (400 MHz, CDCl3): δ = 4.07 (t, J = 9.6 Hz, 2 H), 4.44 (t, J = 9.6 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 2 H), 7.46 (t, J = 4.2 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), (ESI-MS): m/z = 147 [M+].


### 8.2. 2-(4-Bromophenyl)-4,5-dihydrooxazole (3d) [34]

Light yellow solid; yield: 250 (89%); mp 94–96°C.1H NMR (400 MHz, CDCl3): δ = 4.05 (t, J = 9.6 Hz, 2 H), 4.44 (t, J = 9.6 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.8 Hz, 2 H), (ESI-MS): m/z = 225 [M+], 227 (M+2).


### 8.3. 2-(Pyridin-3-yl)-4,5-dihydrooxazole (3f) [34]

Light yellow solid; yield: 150 mg (88%); mp 65–67°C. 1 H NMR (400 MHz, CD3OD): δ = 3.87 (t, J= 12.0 Hz, 2 H), 3.94 (t, J = 11.6 Hz, 2 H), 7.46 (dd, J = 4.8, 4.8 Hz, 1 H), 8.17 (td, J = 2.0, 2.0 Hz, 1 H), 8.59 (dd, J = 1.4, 1.4 Hz, 1 H), 8.89 (d, J = 2.4 Hz, 1 H). MS (ESI-MS): m/z = 148 [M+].


## 8.1. 2-Phenyl-4,5-dihydrooxazole (3a) [34]

Colorless oil; yield: 200 mg (88%).1H NMR (400 MHz, CDCl3): δ = 4.07 (t, J = 9.6 Hz, 2 H), 4.44 (t, J = 9.6 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 2 H), 7.46 (t, J = 4.2 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), (ESI-MS): m/z = 147 [M+].


## 8.2. 2-(4-Bromophenyl)-4,5-dihydrooxazole (3d) [34]

Light yellow solid; yield: 250 (89%); mp 94–96°C.1H NMR (400 MHz, CDCl3): δ = 4.05 (t, J = 9.6 Hz, 2 H), 4.44 (t, J = 9.6 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.8 Hz, 2 H), (ESI-MS): m/z = 225 [M+], 227 (M+2).


## 8.3. 2-(Pyridin-3-yl)-4,5-dihydrooxazole (3f) [34]

Light yellow solid; yield: 150 mg (88%); mp 65–67°C. 1 H NMR (400 MHz, CD3OD): δ = 3.87 (t, J= 12.0 Hz, 2 H), 3.94 (t, J = 11.6 Hz, 2 H), 7.46 (dd, J = 4.8, 4.8 Hz, 1 H), 8.17 (td, J = 2.0, 2.0 Hz, 1 H), 8.59 (dd, J = 1.4, 1.4 Hz, 1 H), 8.89 (d, J = 2.4 Hz, 1 H). MS (ESI-MS): m/z = 148 [M+].


## 9. Conclusion

In conclusion, we have succeeded in developing an efficient and operationally simple ultrasound-accelerated strategy for the synthesis of 2-oxazoline derivatives. This 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. This 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 cost-effective manner. The 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. Therefore, we can use any one of the derivatives based on the requirements in our future research work.



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