Efficient synthesis of symmetrical bisamides from aldehydes and amides catalyzed by silica-bonded S-sulfonic acid nanoparticles

Article abstract of DOI:10.1080/00397911.2012.709573

Silica-bonded S-sulfonic acid nanoparticles (SBSSANPs) were easily synthesized from silica nanoparticles and showed to be an efficient catalyst in the synthesis the symmetrical N,N′-alkylidene bisamides. Reaction of aldehydes and amides in the presence of the catalyst afforded the corresponding bisamides in good to excellent yields. The extensive range of substrates suggests general applicability of the method. Reusability of the catalyst, simple workup procedure, and short reaction times are other advantages of this protocol. Copyright

Full text of DOI:10.1080/00397911.2012.709573

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An Efficient Synthesis of Symmetrical Bisamides From
Aldehydes and Amides Catalyzed by Silica-Bonded S-
Sulfonic Acid Nanoparticles
Mahmood Tajbakhsh a , Rahman Hosseinzadeh a , Heshmatollah Alinezhad a & Parizad Rezaee
a
a Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran,
Babolsar, Iran
Accepted author version posted online: 20 Mar 2013.
To cite this article: Mahmood Tajbakhsh , Rahman Hosseinzadeh , Heshmatollah Alinezhad & Parizad Rezaee (2013):
An Efficient Synthesis of Symmetrical Bisamides From Aldehydes and Amides Catalyzed by Silica-Bonded S-Sulfonic Acid
Nanoparticles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.709573
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ACCEPTED MANUSCRIPT
An efficient synthesis of symmetrical bisamides from aldehydes and amides
catalyzed by silica-bonded S-sulfonic acid nanoparticles
Mahmood Tajbakhsh1,, Rahman Hosseinzadeh1, Heshmatollah Alinezhad1, Parizad
Rezaee1
1Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran,
Babolsar, Iran
Corresponding Author , Tel. & Fax: +98-1125342302 E-mail: tajbaksh@umz.ac.ir
Abstract
Silica-bonded S-sulfonic acid nanoparticles (SBSSANPs) was easily synthesized from
silica nanoparticles and showed to be an efficient catalyst in the synthesis the
symmetrical N,N′-alkylidene bisamides. Reaction of aldehydes and amides in the
presence of the catalyst afforded the corresponding bisamides in good to excellent yields.
The extensive range of substrates suggests general applicability of the method.
Reusability of the catalyst, simple work- up procedure and short reaction times are other
advantages of this protocol.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: Bisamides, Silica-bonded S-sulfonic acid nanoparticles, Aldehydes,
Amides, Supported catalyst
INTRODUCTION
Bisamides are an important class of organic compounds because the amide moiety is
present in many biologically significant substances.[1] Symmetrical and unsymmetrical
N,N′-alkylidene bisamides and their derivatives are found as key structural sub-units for
the construction of peptidomimetic frameworks.[2–4]
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The preparation of symmetrical N,N′-alkylidene bisamides is an important organic
transformation and several methods reported for their synthesis. In most cases the
reaction between amides and aldehydes proceed in the presence of strong acid catalysts,
e.g. triflic acid [5], sulfuric acid,[6] hydrochloric acid[7] or acetic acid[8] which, among
them triflic acid is a more efficient catalyst in the formation of symmetrical bisamides.
These catalysts are corrosive, toxic and may destroy the acid sensitive functional groups
together with other side reactions. Zhu et al. have reported the synthesis of fluorine-
containing N,N′-alkylidene bisamides in the presence of fluoroalkanesulfonic acids.[9]
Perumal et al. reported an alternative approach to synthesis symmetrical N,N′-alkylidene
bisamides by reacting of aldehydes with nitriles in the presence of sulfamic acid with
moderate yields.[10] However, this reaction was limited to electron-withdrawing aromatic
aldehydes and did not work for electron-rich aromatic and aliphatic aldehydes. The
reaction of aldehydes with alkyl nitriles promoted by chlorosulfonic acid afforded
symmetrical bisamides and applied only for electron-deficient aldehydes.[11] Recently,
Harichandran et al. have reported the synthesis of symmetrical N,N’-alkylidene bisamides
by the reaction of aldehydes with amides, using phosphotungstic and boric acids as
catalyst.[12] Their method limited to the reaction of aromatic aldehydes with benzamide,
the reaction time was long with moderate yield. To address the above mentioned facts,
investigation to find an efficient and general method for the synthesis of symmetrical
bisamides still is an important research topic.
On the other hand synthetic methodologies based on green chemistry processes are of
increasing interest in organic chemistry. Although polymer-supported catalysts which
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have been widely used in research and in process chemistry due to its easy recovery, but
their use is also restricted because of easy damage of the organic backbone (thermal or
chemical).[13] One way to prevail over this problem of the traditional polymer-supported
catalysts is to change the expensive organic polymer chain to silica having a covalently
anchored organic spacer to create organic-inorganic hybrid (interphase) catalysts.[14] In
this type of solids, the reactive centers are highly mobile similar to homogeneous
catalysts and at the same time it has the advantage of recyclability of the heterogeneous
catalysts.
Herein we report a convenient and efficient method to prepare symmetrical bisamides by
condensing different alkyl and aryl aldehydes with variety of alkyl and aryl amides using
SBSSANPs as an efficient catalyst. The catalyst was prepared according to the known
literature procedure,[15] but, in the current work, the organic functional group covalently
anchored onto nanosilica (with 12.6 nm average particle size), and obtained the silica-
bonded S-sulfonic acid nanoparticles as depicted in scheme 1.
The catalyst was characterized by thermogravimetric (TG), scanning electron microscopy
(SEM), IR spectra and ion-exchange pH analysis (see the Supplementary Material,
Figures 1-3, available online).
RESULTS AND DISCUSSION
Initially the reaction of 4-chloro benzaldehyde 1 (1 mmol) with benzamide 2 (2 mmol)
with different amounts of catalysts were carried out in toluene at reflux temperature.
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After completion of the reaction, monitored by TLC, followed by standard work-up and
purification, N,N′- alkylidene bisamide 3 was obtained and the results are listed in Table
1.
As it is clear from this table, reaction in the absence of any catalyst gave very low yield
of the product after 6 hrs (Table 1, entry 1). Similar results were obtained when, silica gel
(SiO2), silica nanoparticles (SiO2 NPs) and silica sulfuric acid were applied in this
reaction ( Table 1, entries 2-4). Silica- bonded S-sulfonic acid (SBSSA)[15] gave higher
yield of the product under the same reaction conditions. Different amounts of the SBSSA
catalyst were examined, but did not improve the yield significantly ( Table 1, entries 5-9
). When silica-bonded S-sulfonic acid nanoparticles (SBSSANPs) was used as catalyst,
much higher yield of the product was obtained (Table 1, entries 10-13). The highest yield
(97%) was achieved with 0.08 g catalyst loading (Table 1, entry 12) and higher amount
of the catalyst decreased the reaction yield (Table 1, entry 13).
These observations clearly showed that the synthesized SBSSANPs is an efficient
catalyst in this reaction which might be due to the higher surface area and loading in
comparison with the conventional SBSSA.
This reaction was also tested in various solvents (Table 2). The results indicated that
different solvents affected the efficiency of the reaction. Acetone and CH2Cl2 afforded
moderate yields (Table 2, entries 1and 2). No product was observed in CH3CN and THF
(Table 2, entries 3 and 4), whereas when toluene was used as solvent, excellent yield of
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the product was formed (Table 2, entry 5). In addition, when the reaction was carried out
under solvent-free conditions, a low yield of the product was obtained (Table 2, entry 6).
The reaction did not proceed when low boiling solvents were used (Table 2, entries 1-4).
This might indicate the significant effect of temperature on the reaction. However,
highest yield was achieved when the reaction was carried out under reflux in toluene.
To study the scope of the reaction, a series of aldehydes and amides were reacted in the
presence of SBSSANPs in toluene at reflux temperature (Table 3). In all cases, aromatic
aldehydes substituted with either electron-donating or electron-withdrawing groups
underwent the reaction smoothly and gave the products in good to excellent yields. The
reaction is also compatible with aliphatic aldehydes, as propionaldehyde and
formaldehyde reacted with benzamide and acetamide, the related bisamides were
resulted in good yields (Table 3, entries 15, 16, 26). In some reported methods, the
reaction of benzaldehyde with acetamide did not occur and only starting material was
recovered in quantitative yield,13 but, in this method the reaction afforded the related
bisamide in 83% yield (Table 3, entry 17).
In order to examine the possibility to synthesize the unsymmetrical N,N′-alkylidene
bisamides, p- chlorobenzaldehyde (1 mmol) reacted with a mixture of benzamide (1
mmol) and acetamide (1 mmol) under same reaction conditions (Table 4). After 3 hr,
62.7% of N-[benzoylamino(4-chlorophenyl)methyl]-benzamide (4a), 20.7% of N-
[acetylamino(4-chlorophenyl)methyl]-acetamide (5a) and 16.6% of N-(acetamido(4-
chlorophenyl)methyl)benzamide (6a) was obtained (Table 4, entry 1). When, 4-
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methoxybenzaldehyde and p-nitrobenzaldehyde were applied in this reaction, 5b and 5c
was formed in 50.2% and 36.6% yield respectively and other products were obtained in
lower yields (Table 4, entries 2 and 3).
All the known compounds were characterized by their melting points and comparison of
their IR, 1H-NMR and 13C- NMR spectra with authentic samples. The structure of
unknown compounds (Table 3, entries 4, 5, 11, 12, 14, 15, 21, 22, 23, 27-31) were
deduced by elemental and spectral analysis.
The reusability of SBSSANPs was also investigated in this system. Under optimized
conditions after completion of the reaction, the reaction mixture was cooled and filtered
off, The residue was dissolved in boiling ethanol (40 ml) and filtered off to remove the
catalyst. The catalyst was washed with hot ethanol (20 ml), dried and reused directly for
three subsequent runs in the reaction of 4-chloro benzaldehyde with benzamide (Table 3,
entry 6). As shown in the Figure 1, the yield of product decreased slightly after four runs.
Finally, the crystallinity of the synthesized bisamides were assessed by XRD patterns
(see also Supplementary Material). The XRD patterns for four samples (Table 3, entries
6, 7, 19, 26) showed that these bisamides are crystalline in nature, which could be due to
the presence of the two amide groups and hard segment such as aryl rings as well as the
interchain hydrogen bonds. This is in agreement with other similar studies. [18]
EXPERIMENTAL
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General Information
All the starting materials were supplied commercially from Aldrich or Merck Chemical
Co. The SBSSA catalyst was made according to the literature procedure.[15] Nanosilica
with 12.6 nm average particle size was purchased from Nissan Chemical (Tokyo, Japan).
1H- and 13C-NMR spectra were recorded on a Bruker DRX-400 AVANCE (400 and 100
MHz respectively) in DMSO-d6 as solvent. Chemical shifts are on the δ scale, relative to
internal Me4Si. Thermo gravimetric analysis (TGA) were recorded on a Stanton Redcraft
STA-780 (London, UK). Scanning electron microscopic (SEM) images were observed
under CAMScan-MV2300 instrument (England). X-ray powder diffraction (XRD)
patterns of the PIs were recorded by an X-ray diffractometer (XRD, GBC MMA
Instrument) with Be-filtered Cu Kα radiation. Melting points were determined on a
thermo scientific IA9200 and are uncorrected. Mass spectra were obtained on an Agilent
technologies instrument and IR spectra were determined on a Shimadzu instrument.
Preparation Of 3-Mercaptopropylsilica 1 (MPS)
Silica nanoparticles was activated by refluxing in hydrochloric acid (4 M) for 24 h,
washed with distillated water and dried completely.[19] Refluxing the activated silica gel
(10 g) with 3-mercaptopropyltrimethoxysilane (MPTMS, 5 mmol) in dry toluene for 18
h. The solid materials were filtered off and washed with hot toluene for 12 h in a
continuous extraction apparatus (Soxhlet) and dried in oven at 110 ºC overnight to give
the surface-bounded thiol (MPS) group.
Catalyst Preparation (2)
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To a magnetically stirred mixture of 3-mercaptopropylsilica (1, 5 g) in CHCl3 (20 mL),
chlorosulfonic acid (1.00 g, 9 mmol) was added dropwise at 0 °C during 2 h. The mixture
was stirred for 2 h until all HCl was removed from reaction vessel. The mixture was then
filtered, washed with methanol (30 mL) and dried at room temperature to give the silica
bonded functionalized sulfonic acid nanoparticles 2 (SBSSANPs) as a cream powder.
Analysis Of The Sbssanps
Scanning electron microscopy was used to study the structure of the catalyst. Comparing
the primary particle size and the size of finally nanoparticles, the SEM morphologies
show that the particles are approximately 30-40 nm in size, and they show some degree
of aggregation. The catalyst shows characteristic IR peaks at around 3100-3700, 2928,
2852, 1020-1250 and 650 cm−1 due to O-H of silanols, C–H stretching vibrations, Si–O–
Si stretching vibrations and –SO3H groups, respectively.[20] Quantitative determination of
the organic functional group covalently anchored onto the surface in compound 2 was
performed with thermogravimetric analysis (TGA). Typically a loading at ca. 1.20
mmol/g for surface bound –SO3H group was obtained. When sulfonated product 2 was
placed in an aqueous NaCl solution, the solution pH dropped instantaneously to pH≈1.62,
as ion exchange occurred between protons and sodium ions (proton exchange capacity:
1.19 mmol/g of sulfonic acid 2) which is in good agreement with the result obtained from
TGA and titration analysis.
A General Procedure For The Synthesis Of Symmetrical Bisamides 3
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A mixture of aldehyde (1 mmol), amide (2 mmol) and SBSSANPs (0.08 g) in toluene (7
mL) was heated under reflux. The completion of the reaction was followed by TLC
analysis. After vigorously stirring for the appropriate time a white viscous solid was
obtained. The mixture was cooled and filtered, the residue was boiled in ethanol (40 ml).
The catalyst was removed by simple filtration on a sintered glass funnel (Porosity Grades
5) and washed with hot ethanol. The combined ethanolic solution concentrated under
vacuum to afford the products, which were purified by recrystallisation in the suitable
solvent (ethanol or acetone). The reaction times, the yields and the melting points are
listed in Table 3. The analytical data for the new products are shown in the
Supplementary Material.
CONCLUSION
In conclusion, we have developed a highly efficient synthesis of symmetrical bisamides
from aldehydes and amides under simple reaction conditions. Mild heterogeneous
reaction conditions, using inexpensive range of substrate compatibility and simple work
up procedure are the main advantages of this protocol, for the synthesis of N,N′-
alkylidene bisamides from aldehydes and amides.
SUPPLEMENTARY DATA AVAILABLE
1H-NMR and 13C- NMR spectra; SEM morphologies; XRD patterns; FTIR spectra;
thermal gravimetrical and ion-exchange pH analyses of the materials are available online
in the Supplementary Material.
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ACKNOWLEDGMENTS
We are thankful to the Research Council of Mazandaran University for the partial support
of this work.
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Table 1. One-pot condensation reaction between 4-chlorobenzaldehyde and benzamide in
the presence of different catalysts
Entry
catalyst
Catalyst loading (g)
Time (h) Yield (%)a
1
2
3
4
5
6
7
8
9
10
No Catalyst
0.05
6
10
38
15
31
45
60
73
73
74
78
SiO2 NP b
SiO2
12
12
6
0.05
Silica Sulforic acid 0.1 ( 0.28 mmol)
SBSSA c
0.05 (0.017 mmol)
0.08 (0.030 mmol)
0.1 (0.034 mmol)
0.15 (0.051 mmol)
0.20 (0.068 mmol)
0.03 (0.036 mmol)
3
3
3
3
3
SBSSANPs
3
11
12
0.05 (0.060 mmol)
0.08 (0.096 mmol)
3
3
80
97
13
0.1 (0.120 mmol)
3
88
a Isolated yield.
b SiO2 with 12.6 nm average particle size.
c Non-nanoparticles silica-bonded S- sulfonic acid.
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Table 2. Solvent effect on the reaction between 4-chlorobenzaldehyde (1 mmol) and
benzamide (2 mmol) catalyzed by SBSSANPs (0.08 g)
Entry Solvent a Time (h) Yield (%)b
1
2
3
4
5
6
Acetone 18
CH2Cl2 16
CH3CN 24
36
42
0
THF
24
3
0
Toluene
Neat c
97
4
8
a The reaction was carried out in 7 mL of solvent at reflux.
b Isolated yield.
c
The reaction was carried out at 100 ° C.
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Table 3. Synthesis of symmetrical bisamides using SBSSANPs under optimized
conditions
Entrya R1
R2
Time
(h)
4
Yield
(%) b
93
Found mp(°C) Reported
[Lit]
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
236-
238
237-238 [5]
242-243 [5]
4-CH3C6H4
4-CN C6H4
3-Br C6H4
4-Br C6H4
4-Cl C6H4
6
3
3
3
3
3
3
8
91
98
93
89
97
97
97
77
230-
234
240-
243
230-234
[12b]
215-
217
-
-
259-
260
257-
261
230-232
[12b]
3-O2N C6H4
4-O2NC6H4
4-MeO C6H4
227-
230
190-192
[16]
265-
267
265-267 [5]
221-222 [5]
224-
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226
10
11
12
13
14
15
16
17
18
19
20
Furfuryl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
5
8
8
3
3
8
4
6
6
3
3
94
87
83
97
93
87
96
83
90
93
98
201-
205
206-208
[12a]
PhCO
294
-
-
dec.
159-
161
4-Acetamido
C6H4
4-FC6H4
252-
255
226-228
[12b]
2-Cl-5- O2N
255-
258
-
C6H3
Et
165-
168
-
H
225-
227
216-218 [6]
239-240 [5]
269-270 [5]
258-259 [5]
270-272 [5]
Ph
228-
231
4-CH3C6H4
4-Cl C6H4
4-O2N C6H4
CH3
258-
262
CH3
256-
258
CH3
267-
269
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21
22
23
24
25
26
27
28
29
30
31
4-FC6H4
CH3
CH3
CH3
CH3
CH3
CH3
3
8
6
8
6
3
5
4
4
4
4
96
89
87
79
92
93
82
91
93
92
91
268-
271
259-261
[17]
4-Pyridyl
2-Naphthyl
4-MeO C6H4
Ph CH=CH-
H
261-
264
-
220-
223
-
216-
218
221-222 [5]
193-
195
195-197
[16]
191-
193
196-198 [5]
Ph
4-CH3
C6H4
4-CH3
C6H4
4-CH3
C6H4
3-Cl
210-
214
-
-
-
-
-
4-Cl C6H4
4-O2N C6H4
4-O2N C6H4
4-CN C6H4
170-
172
220-
223
242-
244
C6H4
3-Cl
228-
230
C6H4
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aOptimized conditions: aldehyde (1 mmol), amide (2 mmol), SBSSANPs (0.08 g),
Toluene at reflux temperature.
b Isolated yield.
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Table 4. Synthesise of unsymmetrical N,N′-alkylidene
bisamides
Entrya R1
Product Time (h) Yield (%) b
1
2
3
4-Cl C6H4
4a
3
3
3
62.7
20.7
16.6
30.7
50.2
19.1
18.6
63.6
17.8
5a
6a
4-MeO C6H4 4b
5b
6b
4-O2N C6H4 4c
5c
6c
aReaction conditions: aldehyde (1 mmol), acetamide (1 mmol), benzmide (1 mmol),
SBSSANPs (0.08 g), Toluene, reflux.
bRatio determined by 1H-NMR analysis.
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Scheme 1. Preparation of silica-bonded S-sulfonic acid nanoparticles (SBSSANPs).
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21

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Figure 1. Reusability of SBSSANPs
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