Synthesis of benzamides through direct condensation of carboxylic acids and amines in the presence of diatomite earth@IL/ZrCl4 under ultrasonic irradiation

Article abstract of DOI:10.1007/s11164-018-3592-9

A green, rapid, mild and highly efficient pathway for the preparation of benzamide derivatives is reported. The reaction was performed through direct condensation of benzoic acids and amines under ultrasonic irradiation in the presence of Lewis acidic ionic liquid immobilized on diatomite earth (diatomite earth@IL/ZrCl₄). A new, highly efficient and green solid acid catalyst was easily prepared via a two-step procedure and used as an effective reusable catalyst. The prepared catalyst provides active sites for the synthesis of benzamides. The advantages of this method are the use of a superior and recoverable catalyst, low reaction times, simple procedure, high-yielding and eco-friendly process and use of ultrasonic irradiation as a green and powerful technology. Since benzamides are used widely in the pharmaceutical, paper and plastic industries, and also as an intermediate product in the synthesis of therapeutic agents, the presented new synthetic methods for this type of compounds can be of considerable importance.

Full text of DOI:10.1007/s11164-018-3592-9

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Synthesis of benzamides through direct condensation
of carboxylic acids and amines in the presence of diatomite
earth@IL/ZrCl4 under ultrasonic irradiation
Masoumeh Ahmadi1 Leila Moradi1 Masoud Sadeghzadeh2
•
•
Received: 30 May 2018 / Accepted: 10 September 2018
Ó Springer Nature B.V. 2018
Abstract
A green, rapid, mild and highly efficient pathway for the preparation of benzamide
derivatives is reported. The reaction was performed through direct condensation of
benzoic acids and amines under ultrasonic irradiation in the presence of Lewis
acidic ionic liquid immobilized on diatomite earth (diatomite earth@IL/ZrCl4). A
new, highly efficient and green solid acid catalyst was easily prepared via a two-step
procedure and used as an effective reusable catalyst. The prepared catalyst provides
active sites for the synthesis of benzamides. The advantages of this method are the
use of a superior and recoverable catalyst, low reaction times, simple procedure,
high-yielding and eco-friendly process and use of ultrasonic irradiation as a green
and powerful technology. Since benzamides are used widely in the pharmaceutical,
paper and plastic industries, and also as an intermediate product in the synthesis of
therapeutic agents, the presented new synthetic methods for this type of compounds
can be of considerable importance.
Keywords Benzamides Á Diatomite earth Á Solid acid catalyst Á Ultrasound
irradiation Á Diatomite earth@IL/ZrCl4
Introduction
The American Chemical Society’s Green Chemistry Institute Pharmaceutical Round
Table recently identified that amide formation avoiding poor atom economy
reagents is a priority area of research in the pharmaceutical industry [1–3]. As many
&
Leila Moradi
L_moradi@kashanu.ac.ir
1
2
Department of Organic Chemistry, Faculty of Chemisry, University of Kashan,
P.O. Box 8731753153, Kashan, Islamic Republic of Iran
Radiation Application Research School, NSTRI, P.O. Box 11365-3486, Tehran,
Islamic Republic of Iran
123

M. Ahmadi et al.
as 65% of drug molecules prepared by pharmaceutical companies are attached to an
amide group. Amides are in the structures of potential drug compounds such as
loperamide (Imodium AD, antidiarrheal) acetaminophen (analgesic), lidocaine
(Xylocaine, local anesthetic), [4, 5] atorvastatin (cholesterol-lowering) [6], lisinopril
(inhibitor of angiotensin converting enzyme) [7], valsartan (blockade of
angiotensin-II receptors) [8], sorafenib [9] and diltiazem (calcium channel blockers
used in the treatment of angina and hypertension) [10], and lipitor [11–13] and
vyvanse [14], which have been widely used for the treatment of cancer,
hypercholesterolemia, and juvenile hyperactivity, respectively [15]. Amide com-
pounds are also widely used in industries such as paper, plastic and rubber and in
agricultural areas [16]. They are also used as an intermediate product in the
synthesis of therapeutic agents. Amide derivatives also show antiplatelet activity
[17, 18]. These compounds are usually produced from the reaction between
carboxylic acids and amines at high temperature ([ 180 °C) ,but this is incompat-
ible with most functionalized molecules [19]. Also, activation of carboxylic acids in
acid chloride form, anhydrides or esters requires a separate step, and this protocol
suffers from low atom economy [20, 21]. On the other hand, various coupling agents
have been used for the activation of carboxylic acids such as bis[bis(trimethylsi-
lyl)amino] tin(II) [22], titanium tetrachloride [23], trimethylaluminium [24],
tetrazoles [25], Lawesson’s reagent [26], benzoxazoles [27], oxalates [28],
phosphonium reagents, carbodiimides and uronium reagents [29] in amidation
reaction. The limitations of these reagents are stability, hazardous nature, toxicity,
cost and the requirement for the removal of byproducts that complicate the isolation
of the desired amides.
Recently, a number of researchers have developed efficient boron-based catalysts
for this transformation, but there are some drawbacks. Preparation of these catalysts
is not trivial, and separation of the products, as well as the homogeneous catalysts,
from the reaction mixture can be difficult [30–35]. Also, different catalysts such as
Glutaryl-7-ACA acylase [36], Ti, Zr and Al-supported mesoporous silica [37],
Montmorillonite K10 [38] and mesoporous silica SBA-15 [39] have been applied
for preparation of amides through direct amidation of acids.
Among the recent developments in catalysis, the use of ionic liquids has become
an active area of research. Ionic liquids show many advantages including
infinitesimally low vapor pressure, high thermal stability, low toxicity, and ease
of handling. All of these properties make them alternative ‘‘green’’ reaction media
for replacing volatile solvents in various catalytic processes [40–43].
Sonochemistry is increasingly valuable tool in organic chemistry, since it offers a
versatile and facile pathway for a large variety of syntheses. Without doubt,
compared with conventional thermal heating, the benefits of the sonochemical
processing method are substantial decreases of reaction time, enhanced organic
reaction rates, environmentally friendly reactions (using small amounts of solvents
and generating fewer side products) and in many cases, improved yields and purity
of the compounds and selectivity, in addition to lower cost and simplicity in
handling and processing.
Ultrasound is a sound wave with a frequency above 20 kHz. Acoustic cavitation
and acoustic streaming are the two basic phenomena associated with any ultrasonic
123

Synthesis of benzamides through direct condensation of…
process. Ultrasonic waves consist of compression and expansion cycles. When an
ultrasonic wave is passed through a liquid, a positive pressure is exerted on the
liquid during the compression cycle and a negative pressure is exerted during the
expansion cycle. During the negative pressure, molecules are pulled away from each
other, resulting in the formation of cavities in the liquid. Over many cycles, these
cavities grow and enlarge. Finally, collapse of the bubbles leads to very high
temperatures of more than 5000 K and high pressures of 2000 atmospheres [44–51].
Here, we reported a green and highly efficient synthesis of benzamide derivatives
by one-pot condensation of benzoic acids and amines in the presence of a green
reusable and highly efficient catalyst (diatomite earth@IL/ZrCl4) under ultrasound
irradiation (Scheme 1).
Experimental
Materials and apparatus
All the materials were purchased commercially from Sigma-Aldrich and Merck and
were used without further purification. A multiwave ultrasonic generator (Sonicator
3200; Bandelin, MS 73, Germany), equipped with a converter/transducer and
titanium oscillator (horn), 12.5 mm in diameter, operating at 20 kHz with a
maximum power output of 200 W, was used for the ultrasonic irradiation. The
ultrasonic generator automatically adjusted the power level. FT-IR spectra were
recorded with KBr disc using a Magna-IR spectrometer 550 Nicolet. NMR spectra
were recorded on a Bruker 400 MHz spectrometer with CDCl3 as a solvent and
TMS as an internal standard. Elemental analysis (CHN) was carried out on a Carlo
ERBA Model EA 1108 analyzer. The thermogravimetric analysis (TGA) curves
were carried out using a V5.1A DUPONT 2000. To investigate the morphology of
the functionalized diatomite, FE-SEM images and EDS spectrum of the products
were visualized by a Sigma ZEISS, Oxford Instruments, Field Emission Scanning
Electron Microscope.
Preparation of diatomite earth@IL/ZrCl4
In the first step, ionic liquid was prepared according to the procedure reported by
Sasaki et al. [52]. N-Methylimidazole (1 mmol) and 3-trimethoxysilylpropyl
chloride (1 mmol) were mixed in a dry 50-ml flask under nitrogen flow. The
system was evacuated and refilled with nitrogen, and this procedure was repeated
O
O
R2
Catalyst (10 mg)
OH
N
H
R2 NH2
+
dry toluene, r.t
ultrasound
R1
R1
(a-v)
Scheme 1 Synthesis of benzamide derivatives using diatomite earth@IL/ZrCl4
123

M. Ahmadi et al.
five times, and refluxed for 48 h. Secondly, diatomite earth (2.0 g) was dispersed in
dry toluene (50 mL) and ultrasonicated for 30 min. Then, 0.6 mmol of 1-(3
trimethoxysilylpropyl)-3-methyl-imidazolium chloride (IL) was added slowly with
continuous stirring during 1 h. After 18 h, 0.18 g of ZrCl4 was added and refluxed
overnight under dry N2 atmosphere. Finally, the resultant mixture was cooled and
separated by centrifugation and washed with acetone and methanol four times and
dried in a vacuum oven at 80 °C for 8 h (Scheme 2).
General procedure for the preparation of benzamides
Benzoic acid derivatives (1 mmol) and heterogeneous catalyst (10 mg) were mixed
for 5 min in 1 mL of anhydrous toluene. Then, the amine (1.2 mmol) was added and
the mixture was reacted under ultrasound for about 15–60 min at room temperature.
After completion of the reaction (monitored by TLC), the catalyst was separated
through filtration and the solvent was removed in vacuo. The obtained residue was
dissolved in chloroform (10 ml) and washed with 10% NaHCO3 (10 ml) and HCl
(1 M, 10 ml). The organic layer was extracted and dried over Na2SO4 and
concentrated under reduced pressure to afford the amide, which was purified by
recrystallization or column chromatography.
Representative spectral data
N-Methyl benzamide (a) White solid; mp: 76–78 °C [53]; IR (KBr) (mmax/cm-1):
1
3276 (NH), 1645 (CO), 1480–1583 (C=C); H NMR (400 MHz, CDCl3): d (ppm)
8:00 (d, J = 7.0 Hz, 2H; Ar), 7.50 (m, J = 7.0 Hz, 1H; Ar–H), 7.40 (d, J = 7.0 Hz,
2H; Ar–H), 7:00 (s, NH), 2.91 (d, J = 5.6 Hz, 3H).
N-Butylbenzamide (b) Oil; IR (KBr) (mmax/cm-1): 3413 (NH), 1666 cm-l (C=O);
1H NMR (400 MHz, CDCl3): d (ppm) 8:00 (d, J = 7.0 Hz, 2H; Ar–H), 7.64 (br s,
1H; NH), 7.5 (m, J = 7.0 Hz, 1H; Ar–H),) 7.4 (d, J = 7.0 Hz, 2H; Ar–H), 2.92 (t,
J = 6.4 Hz, 2H), 1.26 (d, J = 9.6, 4H), 0.89 (t, J = 6.4 Hz, 3H).
N
N
Reflux
N
N
(EtO)3Si
+
(EtO)3Si
Cl
Cl
N
N
N
N
ZrCl5
O
ZrCl5
Si
O
EtO Si
O O OHO
N
N
1.(EtO)3Si
OHOHOHOHOHOH
Cl
2. ZrCl4, Toluene, Reflux
Scheme 2 Synthesis of diatomite earth@IL/ZrCl4
123

Synthesis of benzamides through direct condensation of…
N-Phenylbenzamide (c) White solid; mp: 160–162 °C [54]; IR (KBr) (mmax/cm-1):
3303 (NH), 1635 (C=O); 1H NMR (400 MHz, CDCl3): d (ppm) d 8.80 (s, NH), 7.70
(d, J = 6 Hz, 2 H), 7.51 (t, J = 6.8 Hz, 1 H), 7.42 (t, J = 6.4 Hz, 2H), 7.33 (t,
J = 6.8 Hz, 2H), 7.27 (t, J = 8 Hz, 3H).
N-(4-Methoxyphenyl)benzamide (d) White solid; mp: 164–165 °C [54]; IR (KBr)
(mmax/cm-1): 3421 (NH), 1637 cm-l (C=O); 1H NMR (400 MHz, CDCl3): d (ppm)
8.12 (d, J = 7.2 Hz, 2H, Ar–H), 7.62 (d, J = 7.2 Hz, 1H, Ar–H), 7.48 (m,
J = 7.6 Hz, 3H, Ar–H), 6.77 (d, J = 8.8 Hz, 2H, Ar–H), 6.72 (d, J = 8.8 Hz, 2H,
Ar–H), 6.4 (s, 1H, NH), 3.75 (s, 3H, CH3).
N-(4-Chlorophenyl)benzamide (e) Colorless crystals; mp: 192–193 °C [37]; IR
(KBr) (mmax/cm-1): 3377 (NH), 1640 (C=O); 1H NMR (400 MHz, CDCl3): d (ppm)
7.86 (d, J = 7.2 Hz, 2H), 7.48–7.59 (m, 6H), 6.67 (s, NH).
N-(4-Bromophenyl)benzamide (f) Colorless crystals; mp: 198–200 °C [54]; IR
1
(KBr) (mmax/cm-1): 3421 (NH), 1646 cm-l (C=O); H NMR (400 MHz, CDCl3): d
(ppm): 7.86 (d, J = 7.2 Hz, 2H), 7.79 (s, NH), 7.49–7.58 (m, 6H).
N-(2-Bromoethyl)benzamide (g) White solid; mp: 105–106 °C [55]; IR (KBr)
1
(mmax/cm-1): 3303 (NH), 1635 (C=O), 1487–1577 (C=C); H NMR (400 MHz,
CDCl3): d (ppm): 7.79 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (t,
J = 7.6 Hz, 2H), 6.64 (s, NH), 3.9 (q, J = 6 Hz, 2H), 3.6 (t, J = 6 Hz, 2H).
N-(3-Bromopropyl)benzamide (h) White solid; mp: 53–55 °C [56]; IR (KBr) (mmax
/
cm-1): 3458 (NH), 1661 (C=O), 1488–1521 (C=C); 1H NMR (400 MHz, CDCl3): d
(ppm): 7.78 (d, J = 7.2 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H),
6.48 (bs, 1H), 3.62 (q, J = 6.4 Hz, 2H), 3.49 (t, J = 6.4 Hz, 2H), 2.20 (quin,
J = 6.4 Hz, 2H).
N-(2-Bromoethyl)-2,6-dimethoxybenzamide (i) White solid; mp: 147–150 °C; IR
1
(KBr) (mmax/cm-1): 3322 (NH), 1648 cm-l (C=O); H NMR (400 MHz, CDCl3): d
(ppm) 7.31(t, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 6.2 (br, NH), 3.88 (dt,
J = 17.6 Hz, 6 Hz, 2H), 3.83 (s, 6H), 3.61 (t, J = 6 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d (ppm): 167.6, 159.8, 134.2, 106.7, 105.2, 55.5, 47.4, 31.
N-(3-Bromopropyl)-2,6-dimethoxybenzamide (j) White solid; mp: 112–114 °C. IR
(KBr) (mmax/cm-1): 3262 (NH), 1661 (C=O); 1H NMR (400 MHz, CDCl3): d (ppm):
2.19 (q, J = 6.4 Hz, 2H), 3.56(t, J = 6.4 Hz, 4H), 3.81 (s, 6H), 5.9 (br, NH), 6.55(d,
J = 8.4 Hz, 2H), 7.26 (t, J = 8.4 Hz, 1H), 13C NMR (125 MHz, CDCl3) d (ppm):
167.7, 158.9, 134.1, 105.9, 105.7, 56, 39.3, 32.8, 30.8.
(S)-N-((Ethyl-2-pyrrolidiny1)methyl)-2,6-dimethoxybenzamide (k) White solid; mp:
102–103 °C [57]; IR (KBr) (mmax/cm-1): 3262 (NH), 166 l (C=O), 1H NMR
(500 MHz, CDCl3) d (ppm): 7.29 (t, J = 8.5 Hz, 2H), 6.6 (d, J = 8.5 Hz, 1H), 6.30
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M. Ahmadi et al.
(br, NH), 3.86 (s, 6H), 3.28 (m, 1H), 3.14 (m, 1H), 2.95 (m, 1H), 2.65 (q, J = 7 Hz,
1H), 2.2 (m, J = 8.5 Hz, 2H), 1.92 (m, 1H), 1.82 (m, 1H), 1.74 (m, 2H), 1.11 (t,
J = 7 Hz, 3H).
N-((S)-1-Hydroxy-3-phenylpropan-2-yl)benzamide (l) White solid; mp: 174–176 °C
1
[58]; IR (KBr) (mmax/cm-1): 3309 (NH), 1635 (C=O), 1485–1544 (C=C), H NMR
(400 MHz, CDCl3): d (ppm) 7.7 (d, J = 6 Hz, 2H), 7.5 (t, J = 6.8 Hz, 1H), 7.4 (t,
J = 6.4 Hz, 2H), 7.33 (t, J = 6.8 Hz, 2H), 7.27 (t, J = 8 Hz, 3H), 6.45 (br, s, NH),
4.39 (s, 1 H, CH), 3.79 (t, CH2), 3.01 (s, 2H, CH2).
N-((S)-1-Hydroxy-3-phenylpropan-2-yl)2,6-dimethoxybenzamide (m) White solid;
mp: 220–222 °C; IR (KBr) (mmax/cm-1): 3412 (NH), 1660 (C=O), 1474–1596
(C=C); 1H NMR (400 MHz, CDCl3): d (ppm) 7.2–7.3 (m, 6H), 6.56 (d, J = 8.4 Hz
2H), 6.28 (s, NH), 4.63 (m, 1H), 4.36 (t, J = 8 Hz, 1H), 4.14 (t, J = 8 Hz 1H), 3.82
(s, 6H, OCH), 3.28 (dd, J = 14, 5.2 Hz, 1H), 2.8 (dd, J = 14, 9.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d (ppm): 42, 56.27, 66.27, 71.83, 103.88, 107.66, 126.54, 128.7,
129.51, 131.65, 138.41, 159, 160.73, mass spectrum, m/z (relative intensity, %):
315.38 (0, M?); 206.2 (100), 178.2 (57), 165.1 (20), 91.1 (28), 83 (32), 42.1 (12),
77.1 (8).
N-((S)-1-Hydroxy-3-phenylpropan-2-yl)-6-chloropyridine-3-carboxamide (n) White
solid; IR (KBr) (mmax/cm-1): 3253 (NH), 1659 (C=O), 1452–1590 (C=C); 1H
NMR (400 MHz, CDCl3): d (ppm) 8.61 (s, 2H), 8.02 (d, J = 8 Hz, 2H), 7.26–7.42
(m, 5H), 6.52 (d, J = 4.8 Hz, NH), 4.45 (m, 1H), 3.82 (m, 2H), 3.04 (d, J = 7.2 Hz,
2H), 1.82 (s, OH).
N-Benzylbenzamide (o) White solid; mp: 104–106 °C [39]; IR (KBr) (mmax/cm-1):
3295 (NH), 1640 (C=O), 1490–1547 (C=C); 1H NMR (400 MHz, CDCl3): d (ppm)
7.80 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H),
7.31–7.52 (m, 4H), 6.61 (s, 1H), 4.63 (d, J = 5.2 Hz, 2H).
N-Benzyl-4-bromobenzamide (p) White solid; mp: 155–159 °C [59]; IR (KBr)
1
(mmax/cm-1): 3314 (NH), 1640 (C=O), 1482–1590 (C=C); H NMR (400 MHz,
CDCl3): d (ppm) 7.66 (d, J = 8 Hz 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.26–7.36 (m,
5H), 6.49 (s, NH), 4.62 (t, J = 5.6 Hz, 2H).
N-Benzyl-3-bromobenzamide (q) White solid; mp: 112–116 °C [59]; IR (KBr)
1
(mmax/cm-1): 3310 (NH), 1640 (C=O), 1466–1548 (C=C); H NMR (400 MHz,
CDCl3): d (ppm) 7.8 (s, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.26–7.35 (m, 6H), 6.40 (s,
NH), 4.64 (t, J = 5.6 Hz, 2H).
N-Benzyl-4-methoxybenzamide (r) White solid; mp: 124–125 °C [60]; IR (KBr)
1
(mmax/cm-1): 3265 (NH), 1632 (C=O), 1506–1607 (C=C); H NMR (400 MHz,
CDCl3): d (ppm) 7.76 (d, J = 8.4 Hz, 2H), 7.26–7.36 (m, 5H), 6.92 (d, J = 8.8 Hz,
2H), 6.48 (s, NH), 4.65 (d, J = 5.2 Hz, 2H), 3.85 (s, 3H, OCH3).
123

Synthesis of benzamides through direct condensation of…
N-Benzyl-3,5-dinitrobenzamide (s) White solid; mp: 202–203 °C [61]; IR (KBr)
1
(mmax/cm-1): 3315 (NH), 1638 (C=O), 1454–1542 (C=C); H NMR (400 MHz,
CDCl3): d (ppm) 9.12 (s, 1H), 8.93 (s, 2H), 7.24–7.41 (m, 5H), 6.28 (s, NH), 4.7 (d,
J = 5.2 Hz, 2H).
N-Benzylpropionamide (t) White solid; mp: 51.2–52.3 °C [62]; IR (KBr) (mmax
/
cm-1): 3421 (NH), 1637 (C=O), 1488–1548 (C=C); 1H NMR (400 MHz, CDCl3): d
(ppm) 7.28–7.36 (m, 5H), 6.31 (s, NH), 4.64 (d, J = 5.2 Hz, 2H), 2.12 (q,
J = 7.2 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H).
N-(4-Methoxyphenyl)propionamide (u) White solid; mp: 78–85 °C [63]; IR (KBr)
1
(mmax/cm-1): 3421 (NH), 1637 (C=O), 1488–1548 (C=C); H NMR (400 MHz,
CDCl3): d (ppm) 7.43 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.16 (s, NH),
3.73 (s, OCH3, 3H), 2.36 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H).
N-Benzylacetamide (v) White solid; mp: 61 °C [64]; IR (KBr) (mmax/cm-1): 3414
(NH), 1639 (C=O), 1483–1571 (C=C); 1H NMR (400 MHz, CDCl3): d (ppm)
7.19–7.27 (m, 5H), 6.96 (s, NH), 4.32 (d, J = 5 Hz, 2H), 1.92 (s, 3H).
Results and discussion
Structural analysis of diatomite earth@IL/ZrCl4
The FT-IR spectrum of the prepared catalyst was evaluated in order to characterize
the surface functionlization. As can be seen in Fig. 1, the broad peaks at about 1089,
794 and 477 cm-1 in all the spectra contributed to asymmetric stretching,
symmetric stretching and bending vibrations in siloxane (Si–O–Si and Si–OH)
respectively. The broad peak at 3421 cm-1 was related to the stretching vibration in
the structural hydroxyl groups. In FTIR of the catalyst, the presence of a peak
around 2900 cm-1 (C–H in propyl chain) indicates that the chloropropyl chain is
covalently bound on the surface of the diatomite earth. Absorption at 1600 cm-1 is
related to C=N in the imidazole ring and suggests that ionic liquid (1-methylim-
idazolium chloride) was successfully loaded on the diatomite earth surfaces.
Symmetric stretching and bending vibrations in zirconium tetrachloride (Zr–Cl)
cannot be seen in the FT-IR spectrum, because it appears at around 990 cm-1 and
overlaps with the Si–OH peak.
Figure 2 shows SEM images of natural diatomite earth and the functionalized
sample. As can be seen, there has been small changes in the morphology of modified
diatomite surfaces showing that functionalization with IL/ZrCl4 has occurred.
EDX as a powerful technique was used for the evaluation of the catalyst content
elements. The result confirmed the presence of Si, O, C, N, Cl, and Zr in the catalyst
structure (Fig. 3). According to the weight percentage of the catalyst composition, it
is clear that about 2.5 wt% of ionic liquid and ZrCl4 were attached on the diatomite
earth surfaces.
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M. Ahmadi et al.
Fig. 1 FT-IR spectra of a diatomite earth (a) and diatomite earth@IL/ZrCl4 (b)
The thermal stability of the diatomite earth and catalyst (diatomite earth@IL/
ZrCl4) was evaluated by TGA (Fig. 4). The tGA curves show the mass loss of the
catalyst due to decomposition of attached organic groups with an increase in
heating. The first mass loss at 100–200 °C contributes to the evaporation of
physically adsorbed water. The weight loss at 200–600 °C is related to the thermal
decomposition of the ionic liquid and organic spacer covalently bonded to the
diatomite earth surfaces.
After the preparation and characterizations of the atalyst, we studied the
optimization of different reaction parameters using a model reaction under
ultrasonic irradiation. In this way, benzoic acid was reacted with butylamine in
dry toluene under ultrasound irradiation for just 15 min in the presence of a series of
potential catalysts. The reaction was performed in different solvents. As illustrated
in Table 1, the prepared solid acid catalyst showed best activity in toluene compared
to other organic solvents. According to the obtained results, 10 mg of catalyst was
the best amount with the higher yield. Furthermore, when the amount of the catalyst
was increased to 15 mg, the yield was not improved, while the uncatalyzed reaction
produced only 10% yield of the product.
When the direct reaction between the acid and the amine was carried out under
reflux conditions, a high temperature and long time were required, while ultrasonic
conditions led to an excellent yield of products in short reaction times. The probable
explanation for the positive association of irradiation is that the ultrasonic
irradiation could increase the number of active cavitation bubbles and the size of
123

Synthesis of benzamides through direct condensation of…
Fig. 2 SEM images of diatomite earth (a, b) and diatomite earth@IL/ZrCl4 (c, d)
the individual bubbles, both of which are expected to result in higher maximum
collapse temperatures and accelerated respective reactions. In continuation of our
investigation, the role of ultrasonic irradiation on the yield and time of the reactions
was investigated. A model reaction was employed under various powers of
ultrasound irradiation. It was found that the reaction gave satisfactory yields in the
presence of 10 mg of diatomite earth@IL/ZrCl4 under ultrasonic irradiation with a
power of 60 W (Table 2).
After evaluation of the optimized reaction conditions, the condensation of
benzoic acid derivatives and different amines in the presence of solid acid catalysts
was studied. As shown in Table 3, reactions proceeded with good yields of
products. The system was applicable to aliphatic and aromatic amines with various
groups, such as Cl, Br, OCH3 and OH. Anilines with electron-donating groups on
the phenyl ring and aromatic acids with electron-withdrawing groups, showed
higher yields of products. Also, aliphatic amines (and aliphatic acids) are more
active than aromatic types. On the other hand, the hydroxyl group on amine moiety
does not need to be protected (entries 12 and 13) and no side reaction was observed
with substrates having an unprotected hydroxyl group.
For estimation of catalyst efficiency, a model reaction was considered and
repeated with a recycled catalyst. When the reaction was complete, the catalyst was
separated and washed with acetone and methanol four times and dried in a vacuum
123

M. Ahmadi et al.
Fig. 3 EDX of diatomite earth@IL/ZrCl4
Fig. 4 TGA graphs of a diatomite earth (a) and diatomite earth@IL/ZrCl4 (b)
oven at 80 °C for 8 h. The separated catalyst was reused five times. As shown in
Fig. 5, the product yields reduced to a small extent on each cycle (run 1, 87%; run 2,
85%; run 3, 82%; run 4, 78% and run 5, 74%).
In addition, the reversibility of the benzamides was studied. The appropriate
secondary amide, N-butyl benzamide (0.15 mmol), and water (2 mL) were added to
a tube. Toluene (2 mL) and, diatomite earth@IL/ZrCl4 (10 mg) were added and the
tube was sealed and heated under ultrasonic irradiation for 1 h (Scheme 3). Then,
the solvent was removed on a rotary evaporator and the products were analyzed.
The results showed only 3% hydrolysis into benzoic acid and butylamine occurred.
123

Synthesis of benzamides through direct condensation of…
Table 1 Optimization
of
catalysts
and
O
O
C4H9
N
OH
Catalyst
solvents
+
C4H9NH2
H
Solvent
Ultrasound, r.t
Entry
Solvent
Catalyst
Yielda (%)
1
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH3CN
THF
No catalyst
10
27
80
70
65
58
65
25
20
75
80
80
74
78
87
85
2
CuO (10 mol%)
CoFe2O4 (10 mol%)
ZrCl4 (10 mol%)
ZrCl4 (10 mol%)
ZrCl4 (10 mol%)
ZrCl4 (10 mol%)
ZrO2 (10 mol%)
ZnCl2 (10 mol%)
Fe3O4 (10 mol%)
3
4
5
6
7
8
Toluene
Toluene
Toluene
CH2Cl2
THF
9
10
11
12
13
14
15
16
Diatomite earth@IL/ZrCl4 (10 mg)
Diatomite earth@IL/ZrCl4 (10 mg)
Diatomite earth@IL/ZrCl4 (10 mg)
Diatomite earth@IL/ZrCl4 (10 mg)
Diatomite earth@IL/ZrCl4 (10 mg)
Diatomite earth@IL/ZrCl4 (15 mg)
CH3CN
Toluene
Toluene
Toluene
Benzoic acid (1 mmol), butylamine (1.2 mmol), dry toluene (1 ml), catalyst and ultrasound with power of
60 W, 15 min
aIsolated yield
Table 2 The effect of ultrasonic
irradiation on the formation of
benzamides
Entry
Power (W)
Yield (%)a
1
2
3
4
5
30
40
50
60
70
48
56
68
87
85
Benzoic acid (1 mmol), butylamine (1.2 mmol), dry toluene (1 ml),
catalyst (10 mg), ultrasound, 15 min
aIsolated yields
To measure the extent of Zr leaching, the hot filtration test was employed. For
this, the reaction between benzoic acid and butylamine under optimized conditions
was performed. The reaction mixture was filtered after 7.5 min to remove the
catalyst. Continuation of the reaction under the same conditions showed 54%
123

M. Ahmadi et al.
Table 3 Synthesis of benzamide derivatives using diatomite earth@IL/ZrCl4 (10 mg) under ultrasonic
irradiation (60 W)
O
O
R2
OH
Catalyst (10 mg)
N
H
R2 NH2
+
dry toluene, r.t
ultrasound
R1
R1
Time
(min)
Yielda
(%)
Entry
Amine
Acid
Product
O
O
O
O
O
O
O
NHCH3
OH
OH
OH
OH
OH
OH
CH3NH2
1
15
15
60
45
40
40
25
78
87
70
72
70
71
77
a
O
NHC4H9
C4H9NH2
2
3
4
5
6
7
b
O
NH2
N
H
c
O
OMe
NH2
N
H
MeO
Cl
d
e
O
Cl
NH2
N
H
O
Br
NH2
N
H
Br
Br
f
O
O
O
Br
NH2
N
H
OH
OH
OH
g
O
N
H
Br
8
9
25
32
32
77
70
73
Br
NH2
h
OMe O
OMe O
Br
N
H
NH2
Br
Br
OMe
i
OMe
OMe O
OMe O
Br
N
H
OH
10
NH2
OMe
OMe
j
OMe O
OMe O
C2H5
N
H
OH
N
11
20
80
NH2
N
OMe
OMe
C2H5
k
123

Synthesis of benzamides through direct condensation of…
Table 3 continued
Time
(min)
Yielda
(%)
Entry
Amine
Acid
Product
OH
O
O
OH
OH
OH
OH
12
35
82
N
H
NH2
l
OH
OMe O
OMe O
13
14
40
76
N
H
OMe
NH2
NH2
OMe
m
OH
O
O
OH
OH
42
78
N
H
Cl
N
Cl
N
n
O
O
NH2
OH
N
15
16
17
18
20
20
20
35
90
90
92
82
H
o
O
O
O
NH2
OH
N
H
Br
Br
Br
Br
p
q
r
O
NH2
NH2
OH
OH
N
H
O
O
N
H
MeO
O2N
MeO
O2N
O
O
OH
N
H
NH2
NH2
19
18
95
NO2
NO2
s
O
OH
OH
N
H
20
21
22
10
20
15
95
93
95
O
O
t
H
N
NH2
O
MeO
MeO
u
O
OH
NH2
N
H
O
v
aIsolated yield
123

M. Ahmadi et al.
Fig. 5 Reusability of diatomite earth@IL/ZrCl4 as the catalyst for the synthesis of 1b
O
O
C4H9
N
OH
diatomite earth@IL/ZrCl4
H
+
H2O
C4H9NH2
+
Dry toluene, r.t
ultrasound
Scheme 3 Reversibility study of N-butyl benzamide into benzoic acid and butyl amine
conversion after other 7.5 min. This result shows that the amount of leaching of the
catalyst into the reaction mixture should be very low and confirms that the catalyst
acts heterogeneously in the reaction.
The reaction mechanism
A proposed mechanism is illustrated in Scheme 4. The activation of the carboxylic
acid occurred through the interaction between Zr and the carbonyl group of
carboxylic acid followed by the nucleophilic addition of amine. Then, the amide
was formed after the removal of a water molecule. In this mechanism, the diatomite
earth@IL/ZrCl4 activates the C=O groups for better reactions with nucleophiles. In
fact, this green catalyst can be used for other significant organic reactions and
transformations.
123

Synthesis of benzamides through direct condensation of…
NH2tBu
OH
O
tBu
ZrCl5
N
N
NH2
OH
O
ZrCl5
N
N
NHtBu
OH2
O
N
N
ZrCl5
ZrCl5
N
N
H2O
NHtBu
N
N
O
ZrCl5
Scheme 4 Schematic mechanism for the synthesis of benzamides in the presence of diatomite earth@IL/
ZrCl4
Conclusions
In conclusion, we have presented an efficient method for the synthesis of
benzamides using diatomite earth@IL/ZrCl4 under ultrasonic irradiation. The Lewis
acidic ionic liquid immobilization was carried out through the reaction between
1-(3-triethoxysilyl)-propyl-3-methylimidazolium chloride molecules and the
hydroxy groups of diatomaceous earth surfaces, followed by the addition of
zirconium (IV) chloride. The prepared catalyst provides active sites for the synthesis
of benzamides. The advantages of this method are the use of a superior catalyst, the
recoverability of the catalyst, low reaction times, simple procedure, a high-yielding
and eco-friendly process, and the use of ultrasonic irradiation as a valuable, green
and powerful technology.
Acknowledgement The authors are grateful for financial support from the University of Kashan by Grant
No. 784946.
123

M. Ahmadi et al.
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