[Et3NH][HSO4]-mediated functionalization of hippuric acid: an unprecedented approach to 4-arylidene-2-phenyl-5(4H)-oxazolones

Article abstract of DOI:10.1039/c5ra09290f

A facile, green and stereoselective approach for the synthesis of azlactones/oxazolones 3(a-q) has been developed. The protocol involves reaction of hippuric acid and substituted heterocyclic/aromatic aldehydes in ionic liquid [Et₃NH][HSO₄] to yield the desired 4-arylidene-2-phenyl-5(4H)-oxazolones in excellent yields (94-97%) with a high degree of purity. The remarkable feature of this pathway is that the ionic liquid eliminates the use of toxic and expensive acetic anhydride and is endowed with catalytic and medium engineering ability. This eco-friendly approach improved synthetic efficiency (94-97% yield), minimizing the production of chemical waste without using highly toxic reagents for the synthesis and more notably, it promoted the selectivity for Z-azlactones/oxazolones. Density functional theory (DFT) calculations revealed that the Z-isomer of compound 3a is stabilised by 2.32 kcal mol^-1 more than the E-isomer. This synthetic scheme possesses diverse applicability and is compatible to a range of functional groups (electron donating/electron withdrawing).

Full text of DOI:10.1039/c5ra09290f

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[Et3NH][HSO4]-mediated functionalization of hippuric acid: an unprecedentedView Article Online
DOI: 10.1039/C5RA09290F
approach to 4-arylidene-2-phenyl-5(4H)-oxazolones
Mehtab Parveen,*a Faheem Ahmad,a Ali Mohammed Malla,a Shaista Azaz,a Manuela Ramos
Silvab and P. S. Pereira Silvab
aDivision of Organic Synthesis, Aligarh Muslim University, Aligarh, 202002, India
bCEMDRX Physics Department, University of Coimbra, 3004-516 Coimbra, Portugal
Abstract
A facile, green and stereoselective approach for the synthesis of azlactones/oxazolone 3(a-q)
has been developed. The protocol involves reaction of hippuric acid and substituted
heterocyclic/aromatic aldehydes in ionic liquid [Et3NH][HSO4] to yield desired 4-arylidene-
2-phenyl-5(4H)-oxazolones in excellent yields (94-97%) with high degree of purity. The
remarkable feature of this pathway is that the ionic liquid eliminates the use of toxic and
expensive acetic anhydride and is endowed with catalytic and medium engineering ability.
This eco-friendly approach improved synthetic efficiency (94-97% yield), minimizing the
production of chemical wastes without using highly toxic reagents for the synthesis and more
notably, it promoted the selectivity for Z-azlactones/oxazolones. Density functional theory
(DFT) calculations revealed that the Z-isomer of compound 3a is stabilised by 2.32 kcal mol-1
more than the E-isomer. This synthetic scheme possesses diverse applicability and is
compatible to a range of functional groups (electron donating/ electron withdrawing).
Keywords: Eco-friendly, Solvent-free, Azlactones/oxazolones, [Et3NH][HSO4], DFT studies,
X-ray analysis, Stereoslectivity
*Corresponding author: Mehtab Parveen
E-mail: mehtab.organic2009@gmail.com; Tel: +91-9897179498

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DOI: 10.1039/C5RA09290F
Introduction
The first synthesis of Erlenmeyer azlactones, 4-Arylidene-2-phenyl-5(4H)-oxazolones has
been reported by Friedrich Gustav Carl Emil Erlenmeyer way back in 1893,1 representing an
important class of five-membered heterocyclic motifs possessing nitrogen and oxygen as
hetero atoms in their structural framework. The literatures revealed that C-2 and C-4
positions of the azlactones are significant for their various biological activities.2 Azlactones
have been found to be promising intermediates for the synthesis of variety of organic motifs,
including N-substituted pyrroles,3 amino acids,4 α-acylaminoalcohols ,5 thiamine,6 amides,7
peptides8 and other heterocyclic precursors.9 They have been also used as synthons for the
construction of various alkaloid skeletons,10 immunomodulators11 and biosensors coupling
and/or photosensitive composition devices for proteins.12 Recently, Zimmermann et al.13
have reported the application of azlactones for the synthesis of methacrylamidopeptide
macromonomers, employed in the synthesis of hydrogel supports for in-vivo cell growth.
Moreover, a plethora of medicinally important compounds bearing azlactones in their
structural framework have been reported possessing
antimicrobial,14 antitumor,15
antioxidant,16 anti-inflammatory,17 anti-HIV,18 anticonvulsant,19 antihypertensive20 and
tyrosinase inhibitors21 useful for the treatment of skin diseases associated with melanin
hyperpigmentation (Fig. 1). They have also been used in active site titrations of enzymes.22
Such immense synthetic utility and inherent pharmacological applications of azlactones have
inspired the organic chemists to develop various efficient and elegant protocols for their
synthesis.

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Figure 1 Biologically active molecules bearing oxazolone moiety in their structural
framework
The most well-known method for synthesis of azlactone is Erlenmeyer method, which
involves the direct condensation of aryl aldehydes with hippuric acid in the presence of acetic
anhydride as dehydrating agent and anhydrous sodium acetate as a homogeneous basic
catalyst.23 The catalyst promoted synthesis has become one of the hot areas in organic
synthesis in the last few decades. At present, a wide range of methods for synthesizing
azlactones in the presence of catalyst are available viz. POCl3,24 carbodiimides,25
polyphosphoric acid,26 perchloric acid27 and SO3 in DMF.28 In a spam of last nineteen years

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i.e. 1994-2013 several syntetic routes have been developed for the synthesis of azlactVoienweAsrticle Online
DOI: 10.1039/C5RA09290F
using different catalysts such as Al2O3,29 Bi(OAc)3,30 Bi(OTf)3,31 silica-supported
heteropolyacids,32 Yb(OTf)3,33 Ca(OAc)2,34 supported KF,35 anhydrous ZnCl2,36 Fe2O3,37
ZnO38 and Al2O3-H3BO3.39 Although, all of these reported protocols have certain merits, still
numbers of them have suffered from several shortcomings including use of expensive and
hazardous reagents, application of high boiling solvents, prolonged reaction times, tedious
workup procedures, high temperature, toxic waste generation, difficulty in separation and
recovery of the catalyst. Hence, it is of great practical importance to develop more versatile,
simple and environmentally benign methodologies, which will avoids or minimize all of
these complications.
In recent years, new safety and environmental requirements have motivated a great
deal of interest for organic chemists towards the design of new reaction systems satisfying the
green chemistry principles. Classical methods are being rectified to replace the profusely
used toxic volatile organic solvents (VOS) by suitable alternate solvent systems for easy
chemical transformations with the minimum generation of hazardous chemical wastes and
environmental pollution.40 Among the different strategies for accomplishing this goal, ionic
liquids (ILs) have attracted significant research interest due to their unique physicochemical
properties and environment friendly nature.41 From the past few decades ionic liquids due to
their exceptional features such as an almost undetectable vapour pressure, high thermal and
chemical stability, non-explosive properties, controlled miscibility, potentially recyclable
properties and strong solvent power for a wide range of organic, inorganic, and polymeric
molecules have attracted considerable attention as environmentally benign reaction media in
the green organic synthesis.42-48 Moreover, ionic liquids are called ‗‗designer solvents‘‘ and
have been proved to be very excellent catalysts as well as solvents for various organic
transformations.49-51

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Till now, only few ionic liquids such as [bmim][BF4]52 and [bmim][OH]53 have VbieeweAnrticle Online
DOI: 10.1039/C5RA09290F
reported for the synthesis of azlactones (Scheme 1). Since the utility of imidazolium ionic
liquids in the organic synthesis has been proven as the better alternative reaction media and
catalyst but the difficulty in preparation, their expensive cost and high toxicity confine their
applicability in synthetic transformations.54 This led the organic chemist to explore
alternative greener, milder, cheaper and efficient ILs in organic synthesis. In this regard
ammonium ionic liquid offers promising substitute due to their fascinating features such as
low cost, eco-friendly nature, facile synthesis, ease in separation, reusability and stability
towards water and air.55
Scheme 1 Synthetic route for azlactone synthesis employing IL

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Motivated by these findings, and in continuation of our on-going interest endowed
DOI: 10.1039/C5RA09290F
with the finding of novel synthetic protocols56 under the principles of green chemistry,
herein, we report a convenient and expeditious protocol for the synthesis of Erlenmeyer
azlactones from hippuric acid and aldehydes in the presence of Bronsted acid ionic liquid
[Et3NH][HSO4] as a green, efficient, cheap and recyclable catalyst as well as solvent. To the
best of our knowledge, [Et3NH][HSO4] has yet not been explored so far for the synthesis of
azlactones. The ionic liquid [Et3NH][HSO4] has been prepared by employing standard
procedures depicted in the literature (Scheme 2).57 It has emerged as a promising catalyst in
many organic transformations58 and possesses environmentally benign properties such as
nontoxicity, biocompatibility, recyclability, inexpensiveness and thermal stability. The
proficiency of this ionic liquid as both catalyst and medium made this protocol more practical
than the already reported procedures as it eliminates the use of toxic and expensive acetic
anhydride. Besides this, our present approach also displays some specific advantages as it
gives excellent yield (%) within a minimum reaction time and can tolerate a wide range of
functional groups. The structure of the model compound 3a has been authenticated on the
basis of single-crystal X-ray analysis and density functional theory (DFT) calculations.
Scheme 2 Pathway for the synthesis of ionic liquid
Results and Discussion
In the present study a library of 4-arylidene-2-phenyl-5(4H)-oxazolones (Erlenmeyer
azlactones) derivatives 3 (a-q) have been synthesized by using environmentally benign ionic

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liquid [Et3NH][HSO4] possessing both catalytic as well as medium engineering capabViileiwtyAr.ticle Online
DOI: 10.1039/C5RA09290F
This protocol offers several advantages over other existing synthetic methodologies in terms
of yield (94-97 %), purity of products, reaction times, operational procedure, catalyst stability
and recyclability. This synthetic scheme possesses diverse applicability and is compatible to a
range of functional groups (electron donating/ electron withdrawing).
Characterization of [Et3NH][HSO4] ionic liquid
The synthetic route for the preparation of the catalyst (IL) employed in the present protocol
has been shown in Scheme 2. The ionic liquid [Et3NH][HSO4] obtained has been
1
1
characterized on the basis of H NMR and 13C NMR spectral analysis. In the H NMR
spectrum, a triplet resonating at around δ 1.32 integrating for nine protons signifies the
presence of three methyl (3 × CH3) group. Similarly, a multiplet resonating at δ 3.25 has been
attributed to six protons of methylene (3 × CH2) group. A sharp singlet at δ 9.08 for one
proton has been assigned to -NH (D2O-exchangeable) proton (Fig. S1†). In 13C NMR spectral
study, a pair of strong absorption band resonating at around δ 16.27 and 59.35 has been
assigned to methyl (CH3) and methylene (CH2) carbons, respectively (Fig. S2†). The spectral
data was found to be in good agreement, thus confirmed the formation of desired ionic liquid
[Et3NH][HSO4].
Chemistry
The synthetic pathway for the preparation of series of azlactones/oxazolone 3 (a-q) has been
depicted in Scheme 3. Herein, a series of compounds were typically accessed via a solvent
free, efficient and environmentally benevolent cyclodehydration-condensation reaction
process, involving various heterocyclic/aromatic aldehydes with hippuric acid in the presence
of IL [Et3NH][HSO4] to yield target 4-arylidene-2-phenyl-5(4H)-oxazolones in excellent

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yields (94-97 %) with high degree of purity. The structural elucidation of all theDsOyIn: 1t0h.1e0s39iz/Ce5dRA09290F
compounds 3 (a-q) has been established on the basis of elemental analysis, IR, 1H NMR, 13C
NMR and mass spectral studies. The analytical results for C, H and N were found to be
within ± 0.3% of the theoretical values. The spectral analysis has been in good corroboration
with the expected structural framework of the synthesized compounds. IR spectrum of all the
synthesized compounds displayed characteristic signals for (-C=N), lactone carbonyl (C=O)
and (CO-O) resonating at around 1638-1656, 1745-1764 and 1192-1215 cm-1, respectively.
The exocyclic double bond attached to the oxazolone ring displayed the absorption band
resonating around 1594-1624 cm-1. Characteristic peaks for the different substituted
functional moieties such as nitro, methoxy and C=Oγ-pyrone etc., have been discussed in the
1
experimental section. In H NMR spectral analysis, each synthesized compound exhibited a
characteristic sharp down field singlet resonating at around δ 7.32-7.44, attributed to the
olefinic (=C-H) proton which is in agreement with the Z-configuration as reported in the
literature.59 The aromatic protons of the phenyl ring attached at the position 2 of azlactones
13
ring were exhibited a multiplet resonating in the range of δ 7.50-8.10. In C NMR spectral
study, the absorption band resonating at around δ 170.0-175.3 has been assigned to the
carbonyl group of the azlactone ring. Similarly, the signals at δ 132.5-135.5, 136.4-143.2 and
159.7-163.8 has been attributed to vinylic, C-4 and C-2 carbon of the products, respectively.
The detailed spectral assignment of the compound 3 (a-q) has been discussed in experimental
section. The mass spectral analysis of all the synthesized azlactone derivatives has been
found to be in good conformity with the proposed structures. The molecular structure of
compound 3a was further supported by single crystal X-ray crystallographic analysis.

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DOI: 10.1039/C5RA09290F
Scheme 3 Synthetic scheme for the synthesis of azlactone derivatives 3 (a-q)

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DOI: 10.1039/C5RA09290F
Optimization of reaction condition
Initially, we focused our study to probe the optimized reaction conditions for the present
protocol including amount of catalyst, reaction temperature and investigating efficiency of
various catalyst on a selected model reaction using p-(N,N-dimethylamino)benzaldehyde 1a
and hippuric acid 2 to establish the best possible reaction conditions for the synthesis of
azlactone 3a. In order to optimize the reaction conditions we first probed the effect of the
catalyst loading by carrying out the model reaction with different concentration of the
o
catalyst viz. 3, 5, 10, 15, 20 and 25 mol% at 100 C under solvent free condition and the
results were noted in terms of reaction time and yield (Table 1). The results revealed that with
every subsequent increase in concentration of catalyst from 3 mol% to 20 mol%, there has
been a remarkable improvement in the yield from 55-97 %, with prominent drop in reaction
time from 140-15 mins (entries 1-5, Table 1). However, further increase in the concentration
of the catalyst (>20 mol%) did not have any significant effect on the reaction. It can be
inferred from the above results (entry 5, Table 1 ) that 20 mol% of the catalyst is satisfactory
o
to gain the optimum yield in the shortest reaction time under neat conditions at 100 C,
therefore 20 mol% of the catalyst was selected for further studies.

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Table 1 Effect of catalyst loading on the model reaction
Entry
Catalyst (mol%)
Time (min)a
Yield (%)b
3
140
95
70
45
15
15
55
63
73
82
97
97
1
2
3
4
5
6
5
10
15
20
25
Reaction conditions: p-(N,N-dimethylamino)benzaldehyde (1a, 2 mmol), hippuric acid (2, 2
mmol), [Et3NH][HSO4] (3-25 mol%), 100 oC.
aReaction Progress monitored by TLC.
bIsolated yield of products.
In order to optimize the reaction temperature for the present study we have carried out
the model reaction at different temperatures (Table 2). It was noticed that the reaction was
strongly influenced by the temperature in terms of yield and reaction time. Initially the
reaction was allowed to stir at room temperature it takes almost 5 hrs to complete the reaction
o
with poor yield of the product 3a. With increase in temperature from 25 to 100 C, the yield
of the desired product 3a increased significantly from 35-97% within the minimum period of
reaction time (entries 1-5, Table 2). However, no further enhancement in the yield of product
o
3a was witnessed when the reaction temperature was raised from 100 to 110 C. Thus,
keeping in view the above optimized reaction conditions, 100 °C was chosen as the optimum
temperature for all the reactions.

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Table 2 Effect of temperature on the model reaction
Entry
Temp. (oC)
Time (min)a
Yield (%)b
Room Temp.
5
2
35
54
67
73
97
97
1
2
3
4
5
6
50
70
1.5
40
15
15
90
100
110
Reaction conditions: p-(N,N-dimethylamino)benzaldehyde (1a, 2 mmol), hippuric acid (2, 2
mmol), [Et3NH][HSO4] (20 mol%), 25-110 oC.
aReaction Progress monitored by TLC.
bIsolated yield of products.
In order to establish the superiority of our synthesized ionic liquid [Et3NH][HSO4] for
the present protocol we have screened different ionic liquids on the model reaction. Table 3
lists the effect of different ionic liquids on the model reaction without using any volatile
organic solvents. It was clear from (Table 3) that the catalytic activity was potentially
influenced by the anionic part of the ionic liquids. The higher yield of the product was
obtained when the strongly acidic [HSO4] anion was explored (Table 3). However, the
reaction was slow and less efficient when the ionic liquids with [H2PO4] and [CH3COO]
anions were probed, which may be due to the weaker acidity of the phosphate and acetate
anions as compared to [HSO4] anion. The above results demonstrated that the reaction was
strongly influenced by the acidity of the ionic liquids. This can be presumably attributed to
the pKa values (acid dissociation constant) of their respective anions (HSO4, H2PO4 and
CH3COO) which offer a quantitative measurement of the strength of an acid, smaller the pKa
value, stronger is the acid. The results obtained (Table 3) in terms of products yield and

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reaction time are in good agreement with acidity/pKa values of their respective anions which
DOI: 10.1039/C5RA09290F
follow the order as: HSO4 (pKa = -3) > H2PO4 (pKa = 2.15) > CH3COO (pKa = 4). In order
to probe the effect of cationic part of the ionic liquid on the azlacones synthesis, the reaction
was performed in quaternary ammonium cationic bisulfate ionic liquids with different alkyl
chain length. It was found that the cations with shorter alkyl chains gives better yield and the
efficiency of the ionic liquids decrease sequentially with the increase in the cation chain
length of the ionic liquid (entries 1-3, Table 3). The reason may be that the longer alkyl
groups of the ammonium cations lead to bigger aggregations.60 The cationic ILs with short
alkyl chains does not form definite aggregations but those with longer alkyl chains gradually
form well-defined aggregations.61 These aggregations may lead to non-uniform and co-
adjacent structure of ILs systems, which causes complication for the transfer of electrons and
protons in the molecular interior, thus hindering the reaction which leads to decrease in the
yield of the products with stretched reaction times. The similar results were obtained in the
case of [HPO4] and [CH3COO] that increasing the cationic chain length decreases the yield of
the product (entries 4-7, Table 3). These results suggested that the cation part of the ionic
liquid influenced the reactivity of ionic liquid to a greater extent. Thus, it is obvious that
tuning of triethylammonium cation by HSO4 anion in the present study provides excellent
yields (94-97 %) of the desired products 3a. These results imply that [Et3NH][HSO4] is the
best ionic liquid catalyst/promoter for the synthesis of present azlactone derivatives.

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Table 3 Effect of ionic liquids on the model reaction
Entry
Catalyst
Time (min)a
Yield (%)b
1
2
3
4
5
6
7
[Et3NH][HSO4]
[Pr3NH][HSO4]
15
30
45
40
55
48
60
97
90
84
86
68
78
60
[Bu3NH][HSO4]
[Et3NH][H2PO4]
[Bu3NH][H2PO4]
[Et3NH][CH3COO]
[Bu3NH][CH3COO]
Reaction conditions: p-(N,N-dimethylamino)benzaldehyde (1a, 2 mmol), hippuric acid (2, 2
mmol), different ionic liquids (20 mol%), 100 oC.
aReaction Progress monitored by TLC.
bIsolated yield of products.
After optimization of the reaction conditions, the substrate scope of [Et3NH][HSO4]
catalysed system was inspected under the optimized reaction conditions. As shown in Table
4, a wide variety of heterocyclic/aromatic aldehydes possessing electron-withdrawing and
electron-donating groups reacted with hippuric acid to afford the corresponding azlactones in
excellent yields (94-97%). In the present study a comparative study has also been carried out
for the present protocol with the previously reported conventional method by carrying out the
reaction of aldehydes with hippuric acid in the presence of acetic anhydride and
stoichiometric amounts of sodium acetate. It was observed that the reaction took prolonged
reaction time for completion with moderate yield (70-78%). The results revealed that
employing ionic liquids [Et3NH][HSO4] in the present protocol enhances selectivity and
product conversion, thus, proves beneficial over the Erlenmeyer methods for the synthesis of
azlactones in terms of yield and reaction times. An important feature of these reactions in

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ionic liquids is that there is no evidence for significant formation of a side reaction and the
DOI: 10.1039/C5RA09290F
efficient conversion was noticed in the sulfate acid ionic liquids.
Table 4 Synthesis of azlactone derivatives 3 (a-q)
Products
Structure
Acetic anhydridea
Ionic Liquidb
Time Yield
Time
(hrs)
Yield
(%)
(min)
(%)
2
78
72
15
97
3a
2.5
18
95
3b
2.5
2.0
75
70
22
20
94
96
3c
3d
2.8
3.0
74
72
23
18
95
96
3e
3f

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3.2
3.4
3.5
70
74
76
17
15
24
97
3g
3h
3i
96
95
3.0
2.8
75
73
25
22
96
94
3j
3k
3.0
3.2
74
76
18
20
95
97
3l
3m
3.0
3.4
71
75
23
19
95
94
3n
3o

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2.8
3.2
73
76
24
20
96
3p
3q
95
aReaction conditions: Differently substituted heterocyclic/aromatic aldehydes 1 (a-q) (2
mmol) with hippuric acid (2, 2 mmol) in presence of acetic anhydride and stoichiometric
amounts of sodium acetate at 140 oC.
bReaction conditions: Differently substituted heterocyclic/aromatic aldehydes 1 (a-q) (2
mmol) with hippuric acid (2, 2 mmol) in [Et3NH][HSO4] (20 mol%) at 100 oC.
Reaction mechanism
The probable mechanistic pathway for the IL [Et3NH][HSO4] catalyzed synthesis of
azlactone derivatives has been presented in Scheme 4. The reaction is initiated with the
protonation of carboxylic group of the hippuric acid by protic ionic liquid [Et3NH][HSO4]
catalyst which is believed to facilitate the cyclodehydration of the substrate to form
intermediate (I) which is resonance stabilised as intermediate (II). The further protonation of
the carbonyl group of the aldehydes by the catalyst generates active electrophilic site for the
attack of intermediate (II) which facilitates the formation of C-C bond to yield intermediate
(III). The subsequent elimination of water molecule from intermediate (III) promoted by the
ionic liquid eventually leads to the formation of target azlactone with the regeneration of the
catalyst [Et3NH][HSO4].

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Scheme 4 Plausible mechanistic catalytic cycle for the synthesis of target azlactone
derivatives 3(a-q)
The stereochemistry around C=C was authenticated by single crystal X-ray
crystallographic analysis of compound 3a, where C=C was found to have Z-geometry.
Among the two possible geometrical isomers (E/Z), Z-isomer has been obtained as the
exclusive products (Fig. 2), which has been well established further on the basis of density

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functional theory (DFT) calculations. This Z-selectivity can be interpreted as a way to
DOI: 10.1039/C5RA09290F
minimise steric interactions among various substituents. To compare the relative stability of
the E and Z-isomers of the compound 3a, we have performed the calculation of the vacuum
single-point energies of the optimized geometries to obtain the energy differences. It was
found that the Z-isomer is stabilised by 2.32 kcal mol-1 more than the E-isomer. This
difference in energy is the reason that during crystallization process, Z-isomer gets
exclusively crystallised out. Moreover, the intramolecular hydrogen bonding between H5 of
N,N-dimethyl phenyl ring and N2 of the azlactone ring enhances its stability which promotes
its selectivity than the corresponding E-isomer (Fig. 2). The rotations about single bonds
(intramolecular torsions) are worth 1-3 kcal mol-1 but can be as high as 10 kcal mol-1 due to
steric factors or restricted rotation,62 so this can easily explain the calculated energy
differences. The agreement between the experimental and calculated geometry has been
found to be good (Table 5) and our data suggest that the supramolecular aggregation has little
importance in the stabilization of the observed molecular geometry. On the basis of these
results, all the synthesized compounds were believed to possess Z-configuration across C=C.
Table 5 Comparison of selected geometrical parameters for compound 3a as determined by
X-ray diffraction and from DFT calculation
Torsion angle (o)
Form I
Form II (3a)
DFT
C6-C9-C10-N2
C7-C6-C9-C10
N1-C3-C8-C7
0.8(5)
176.1(3)
179.5(3)
178.7(3)
-1.5(5)
-0.2(4)
-175.1(2)
-178.9(2)
-178.3(2)
1.8(4)
-0.09
179.94
-179.52
179.97
-0.13
C12-O1-C11-O2
N2-C12-C13-C14
Note: In a chain of atoms A-B-C-D, a positive torsion angle correspond to a clockwise
rotation of the bond A-B in order that it may eclipse the bond C-D and a negative torsion
angle requires a rotation in the opposite sense. So, the absolute differences between the
torsion angles presented are relatively small.

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Figure 2 Asymmetric unit of compound 3a with the ellipsoids drawn at the 50% probability
level, with atomic labelling scheme. The intra-molecular interactions are drawn as dashed
lines
Recyclability of the catalyst (IL)
The recycling of catalyst is an important step, so as to satisfy the criteria of green chemistry
principles and also to manage the cost of the process. In order to explore the extent of
recyclability of our catalyst system, the model reaction has been conducted six consecutive
times on the same recycled catalyst. After first fresh run with 97% yield, water was added to
the reaction mixture and the product was isolated by filtration. The ionic liquid was recovered
from the filtrate by removing the water under reduced pressure. The recovered catalyst was
then reused for five more subsequent cycles and found to retain its catalytic activity and
showed minimal decreases in yield. The product was obtained in 94%, 91%, 88%, 85%, and
83% after successive cycles (Fig. 3) thus, proving the catalyst‘s reusability with high catalytic

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performances. The results demonstrate that our catalytic system is almost staDbOleI: 10to.10w39a/rCd5sRA09290F
moisture and could be recycled without a significant loss in yield.
Figure 3 Recyclability of the catalyst
X-ray Crystallographic Study of Compound 3a
In this study we crystalized a new polymorph, form II, of the model compound 3a (Fig. 2).
The unit cell is monoclinic with the non-centrosymmetric and chiral space group P21.
Comparing with the previously published polymorph, form I,63 our unit cell has similar a, b
and β parameters while c parameter with half the value of the reported structure. This led us
to suspect that there could be an error in any of the structures. For this reason, several tests
were performed to verify the validity of the two structures. The use of the ADSYMM routine
in PLATON64 with the largest tolerances allowed did not reveal any different symmetry for
both structures. The simulated powder patterns displayed appreciable differences in the
intensities of some peaks indicating that the two packings are indeed different. The molecules
are planar with geometry similar to that found in form I (Table 5). Like in form I, the
molecules are linked in infinite chains running parallel to the a-axis, via C-H…O hydrogen

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bonds (Fig. 4, Table 6). These chains have a periodicity of eleven atoms, graphD-OseI:t10s.1y0m39/bCo5RlA09290F
C(11) according to Etter‘s graph-set theory.65,66 In this polymorph there are also an
intramolecular C-H...N hydrogen bond, forming six-membered rings with graph-set symbol
S(6) and an intramolecular C-H...O hydrogen bond with graph-set symbol S(5) (Table 6).
Figure 4 Packing diagram of polymorph II (3a) in a view along the b axis, with the H-bonds
shown as dashed lines
Table 6 H-bond geometry (Å, º) of compound 3a
D-H
H...A
D...A
D-H...A
C2—H2C....O2i
C5—H5...N2 (intra)
C18—H18...O1 (intra)
0.96
0.93
0.93
2.53
2.47
2.48
3.480(3)
3.111(3)
2.800(3)
172
126
100
(Symmetry code i: -1+x, -1+y, z)

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The packing of the two polymorphs is remarkably similar viewed along the b-axis as
DOI: 10.1039/C5RA09290F
can be seen in a whole-lattice overlay of the structures of the two forms (Fig. 5). However, if
we look at the whole-lattice overlay along the a-axis (Fig. 6) we see clearly the different
orientation of some molecules in forms I and II. In these whole-lattice overlays there are
2×2×2 unit cells of form II and 2×2×1 of form I.
Figure 5 Whole-lattice overlays for structures of the form I (green) and form II (red) viewed
along the b-axis
Figure 6 Whole-lattice overlays for structures of the form I (green) and form II (red) viewed
along the a-axis

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DOI: 10.1039/C5RA09290F
Fingerprint Plots
Comparing the same molecule in different crystal environments, Hirshfeld surfaces and
fingerprint plots67-70 have been shown to be a powerful tool for elucidating and comparing
intermolecular interactions, especially in case of the study of polymorphism of molecular
materials. The intermolecular interactions of this new polymorph and of the previously
reported63 were analysed using the two-dimensional fingerprint plots69,70 derived from
Hirshfeld surfaces,67,68 using the software CrystalExplorer, version 3.1.71 2D-fingerprint plots
were generated by using the di and de pairs measured on each individual spot of the
calculated Hirshfeld surface. The 2D fingerprint plots of Form I and Form II are displayed in
Fig. 7. The fingerprint plots have the same basic features, with both showing the presence of
a pair of short sharp spikes, a characteristic of weak hydrogen bonding, in this case the C-
H…O hydrogen bonds. The differences are more evident in the fingerprint plots of the O…H
interactions (Fig. 8).
(a)
(b)
Figure 7 Two-dimensional fingerprint plots for the polymorphs I (a) and II (b)

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DOI: 10.1039/C5RA09290F
(a)
(b)
Figure 8 Two-dimensional fingerprint plots of the O…H interactions for the polymorphs I
(a) and II (b)
XPac Analysis
The XPac program72 allows the comparison of complete crystal structures and the
quantification of their degree of similarity, based on the positions and geometric
conformations of the molecules in the lattice. With this method it is possible to identify
similar ―supramolecular constructs‖ (sub-components of complete crystal structures) of 0-, 1-
or 2-dimensionality in different crystal structures of specific molecules (polymorphs) or
crystal structures of similar molecules (families) and of 3-dimensionality in isostructural
assemblies.73 In the XPac method, each crystal structure is represented by a cluster of
molecules, with a central, core molecule and a shell of contacting molecules (usually 14). The
two clusters are then compared by computing the mean differences δa(º) and δp(º) between all
possible combinations of sets of angles and interplanar angles, respectively, between a chosen
group of atoms in the core molecule and the corresponding atoms in one shell molecule.
The crystal structures of polymorphs I and II were compared with each other using the
program XPac,72 with geometric parameters generated from a set of 22 non-H atomic
positions for each molecule. Each crystal structure was represented by a cluster consisting of

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a central molecule and its 14 closest neighbours. Comparing the clusters of 14 neighVbieowuArrticle Online
DOI: 10.1039/C5RA09290F
molecules, 10 molecules were matched in the overlay, which corresponds to matching planes
(similarity of 2D supramolecular constructs). In Fig. 9 it is presented a plot of δp against δa
where we can see the high degree of similarity exhibited by the two structures. The vertical
(blue) and horizontal (red) lines indicate the average values of δa and δp, 0.8º and 1.3º
respectively. Each pair of values (δa,i, δp,i) provides information about how much the
geometry of an assembly of two neighbour molecules deviates from the geometry of a second
such assembly. The dissimilarity index x74,75 is a measure of how far two structures deviate
from perfect geometrical similarity and it is obtained from all M data points (δa,i, δp,i) that can
be generated for the cluster under study.
∑ ∑( )
In the present study the dissimilarity index is 1.5. A value of zero corresponds to
perfect geometric similarity. In conclusion, the XPac analysis demonstrates that crystal
structures of forms I and II are very similar but not isostructural.
Figure 9 XPac plot of δp against δa (º). Upper right corner: dissimilarity index x (º)

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DOI: 10.1039/C5RA09290F
Nonlinear optical properties
The crystal obtained in this study has some features that make it a potentially efficient
nonlinear optical material: (i) absence of an inversion centre in the crystal structure; (ii) the
molecule may have an appreciable hyperpolarizability since it has a strong electron donor
(the dimethylamino group) connected by a conjugated π-bridge to the oxazolone group which
acts as an electron acceptor in this case. To determine the NLO response of this new
polymorph we measured the Second-Harmonic Generation (SHG) efficiency of the molecular
crystal with the Kurtz-Perry method76 using a polycrystalline sample. A good SHG efficiency
of 1.4 times the urea standard was observed.
Experimental
Materials and general methods
All the reagents were purchased from Merck and Sigma-Aldrich (India) as ‗synthesis grade‘
and used without further purification. Melting points of all synthesized compounds were
determined on a Kofler apparatus and are uncorrected. Fourier transform-infrared (FT-IR)
spectra were recorded in the 400-4000 cm-1 wave-number range using a Perkin-Elmer (2000
FTIR) Spectrometer by the KBr pellet method. 1H NMR and 13C NMR spectra were recorded
on a Bruker Avance-II 400 MHz instrument in CDCl3 solvent. The chemical shifts (δ) are
reported in ppm relative to the TMS as an internal standard and J values are reported in
Hertz. Mass spectra were recorded on a JEOL D-300 mass spectrometer. Elemental analysis
(C, H and N) was conducted using a Thermo Scientific (FLASH 2000) CHN Elemental
Analyser. Thin layer chromatography (TLC) glass plates coated with silica gel G254 (E-
Merck) were used to check the purity of the reagent as well as the progress of the reaction.

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DOI: 10.1039/C5RA09290F
Synthesis of ionic liquids
Triethylammonium sulfate [Et3NH][HSO4]. The [Et3NH][HSO4] ionic liquid was
synthesized by the standard procedure as reported earlier in the literature .57 1H NMR (400
13
MHz, DMSO-d6, δ, ppm): 1.32 (t, 9H), 3.25 (m, 6H), 9.08 (s, 1H, D2O exchangeable). C
NMR (100 MHz, DMSO-d6, δ, ppm): 16.27 (CH3), 59.35 (CH2).
The various other ionic liquids i.e. [Pr3NH][HSO4], [Bu3NH][HSO4],
[Et3NH][H2PO4], [Bu3NH][H2PO4], [Et3NH][CH3COO] and [Bu3NH][CH3COO] used for
the comparative study with respect to [Et3NH][HSO4] were synthesized with the similar
standard procedures as depicted in literature.57
1
n-Tributylammonium dihydrogen phosphate [Bu3NH][H2PO4]. H NMR (400
MHz, DMSO-d6, δ, ppm): 0.98 (t, 9H), 1.36 (m, 6H), 1.54 (m, 6H), 3.13 (m, 6H), 8.39 (s, 1H,
13
D2O exchangeable). C NMR (100 MHz, DMSO-d6, δ, ppm): 15.8 (C-4, CH3), 20.5 (C-3,
CH2), 28.6 (C-2, CH2), 57.9 (C-1, CH2).
1
n-Tributylammonium acetate [Bu3NH][CH3COO]. H NMR (400 MHz, DMSO-
d6, δ, ppm): 0.94 (t, 9H), 1.31 (m, 6H), 1.49 (m, 6H), 3.23 (m, 6H), 8.29 (s, 1H, D2O
13
exchangeable). C NMR (100 MHz, DMSO-d6, δ, ppm): 17.5 (C-4, CH3), 22.3 (C-3, CH2),
27.8 (C-2, CH2), 58.2 (C-1, CH2), 172.4 (C=O), 25.4 (CH3).
General procedure for the synthesis of azlactones under solvent free conditions
The solution of hippuric acid 2 (2 mmol) and 20 mol% of the ionic liquids [Et3NH][HSO4]
was allowed to stir at 80 oC for 5 min. After 5 min, aldehydes 1 (a-q) (2 mmol) was added to
the reaction mixture and was further heated at 100 oC with constant stirring. After completion
of the reaction as evident from thin layer chromatography (TLC), the reaction mixture was
allowed to cool at room temperature and the reaction mixture solidified spontaneously. Then
water was added to the reaction mixture and was further stirred for 5 min. The precipitate was

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isolated by simple filtration, washed with appropriate solvents. The water was removed from
DOI: 10.1039/C5RA09290F
filtrate under reduced pressure to recover the ionic liquid, which was then reused in
subsequent cycles. The crude product obtained was recrystallized with chloroform-methanol
to afford the pure product 3 (a-q).
Spectral Characterization
(Z)-4-(4-(dimethylamino)benzylidene)-2-phenyloxazol-5(4H)-one (3a)
Compound 3a crystallized from CHCl3-MeOH as red needle shaped crystal. Yield: 97%, m.p.
o
215 oC, reported 212-214 C; Anal. calc. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58; found:
cm-1: 1764 (C=O), 1642 (C=N), 1598 (C=C), 1192 (C-
KBr
max
C, 73.75; H, 5.69; N, 9.46. IR ν
O)lactone,. 1H NMR (400 MHz, CDCl3, δ, ppm): 2.98 (s, 6H, 2 × CH3), 7.18 (dd, 2H, H-3‘ and
13
H-5‘), 6.64 (dd, 2H, H-2‘ and H-6‘), 7.36 (s, 1H, =C-H), 7.60-8.10 (m, 5H, ArH). C NMR
(100 MHz, CDCl3, δ, ppm): 126.8 (C-1‖),128.1 (C-2‖ and C-6‖), 128.9 (C-3‖ and C-5‖),
131.2 (C-4‖), 163.8 (C-2), 141.6 (C-4), 175.3 (C-5), 129.8 (C-1‘), 132.4 (C-2‘ and C-6‘),
113.2 (C-3‘ and C-5‘), 151.7 (C-4‘), 134.8 (H-C=C), 44.1 (2 × CH3). MS (ESI) m/z: 292.12
[M+H] +•.
(Z)-4-(4-fluorobenzylidene)-2-phenyloxazol-5(4H)-one (3b)
Compound 3b crystallized from CHCl3-MeOH as yellow crystalline solid. Yield: 95%, m.p.
o
o
181 C, reported 183-185 C;29 Anal. calc. for C16H10FNO2: C, 71.91; H, 3.77; N, 5.24;
found: C, 71.88; H, 3.73; N, 5.27. IR ν cm-1: 1778 (C=O), 1656 (C=N), 1594 (C=C), 1195
KBr
max
(C-O)lactone. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (s, 1H, =C-H), 7.54 (dd, 2H, H-3‘ and
H-5‘), 7.98 (dd, 2H, H-2‘ and H-6‘), 7.56-8.05 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3, δ,
ppm): 127.3 (C-1‖), 128.1 (C-2‖ and C-6‖), 129.6 (C-3‖ and C-5‖), 132.8 (C-4‖), 162.7 (C-
2), 143.2 (C-4), 173.8 (C-5(C=O)), 135.3 (H-C=C), 130.3 (C-1‘), 133.8 (C-2‘ and C-6‘), 116.8
(C-3‘ and C-5‘), 163.4 (C-4‘). MS (ESI) m/z: 267.07 [M+H] +•.