A greatly improved procedure for the synthesis of an antibiotic-drug candidate 2,4-diacetylphloroglucinol over silica sulphuric acid catalyst: multivariate optimisation and environmental assessment protocol comparison by metrics

Article abstract of DOI:10.1039/d0ra05424k

Efforts toward the development of a straightforward greener Gram-scale synthesis of the antibiotic compound 2,4-diacetylphloroglucinol (DAPG) have been developed. This beneficial procedure was accomplished through the Friedel-Crafts acylation of phloroglucinol over inexpensive heterogeneous silica sulphuric acid (SSA) catalystviaultrasound-assisted (US) synthesis under solvent-free condition. The influences of various parameters such as temperature, catalyst loading, and reaction time on the reaction performance were analysed using a multivariate statistical modelling response surface methodology (RSM). A high yield ofDAPG(95%) was achieved at 60 °C after 15-20 min reaction with the presence of 10% (w/w)SSAas the catalyst. Column chromatography-free and a Gram scale-up reaction also exhibited the practical applicability of this newly developed protocol. TheSSAcatalyst was recovered and recycled up to 10 consecutive runs with no appreciable loss of activity. A plausible mechanism for the Friedel-Crafts acylation of phloroglucinol is proposed. Moreover, an environmental assessment has been carried out over this present method and compared with several established literature using the EATOS software and the Andraos algorithm to assess the consumption of the substrates, solvents, catalysts, and the production of coupled products or by-products. In addition, their energy consumptions were also determined. The data collected showed that the present method is the most promising one, characterised by the highest environmental impact profile against all the other reported methods. The physicochemical properties of the synthesisedDAPGwere assessed and exhibited reasonable oral bioavailability drug property as determined by Lipinski's rules.

Full text of DOI:10.1039/d0ra05424k

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A greatly improved procedure for the synthesis of
an antibiotic-drug candidate 2,4-
Cite this: RSC Adv., 2020, 10, 31824
diacetylphloroglucinol over silica sulphuric acid
catalyst: multivariate optimisation and
environmental assessment protocol comparison by
metrics†
*
Triana Kusumaningsih,
Wahyu Eko Prasetyo
and Maulidan Firdaus
Efforts toward the development of a straightforward greener Gram-scale synthesis of the antibiotic
compound 2,4-diacetylphloroglucinol (DAPG) have been developed. This beneficial procedure was
accomplished through the Friedel–Crafts acylation of phloroglucinol over inexpensive heterogeneous
silica sulphuric acid (SSA) catalyst via ultrasound-assisted (US) synthesis under solvent-free condition.
The influences of various parameters such as temperature, catalyst loading, and reaction time on the
reaction performance were analysed using
a multivariate statistical modelling response surface
methodology (RSM). A high yield of DAPG (95%) was achieved at 60 ꢀC after 15–20 min reaction with
the presence of 10% (w/w) SSA as the catalyst. Column chromatography-free and a Gram scale-up
reaction also exhibited the practical applicability of this newly developed protocol. The SSA catalyst was
recovered and recycled up to 10 consecutive runs with no appreciable loss of activity. A plausible
mechanism for the Friedel–Crafts acylation of phloroglucinol is proposed. Moreover, an environmental
assessment has been carried out over this present method and compared with several established
literature using the EATOS software and the Andraos algorithm to assess the consumption of the
substrates, solvents, catalysts, and the production of coupled products or by-products. In addition, their
energy consumptions were also determined. The data collected showed that the present method is the
most promising one, characterised by the highest environmental impact profile against all the other
reported methods. The physicochemical properties of the synthesised DAPG were assessed and
exhibited reasonable oral bioavailability drug property as determined by Lipinski's rules.
Received 21st June 2020
Accepted 10th August 2020
DOI: 10.1039/d0ra05424k
rsc.li/rsc-advances
compound was also documented to have benecial effects on
plant growth and it has been shown as a molecular signalling
compound.14 Owing to of its extensive applications, the
synthetic research of this privileged compound appears to draw
the continuing interest of scholars who are expected to be able
to afford a conceptual platform for the discovery of novel drugs.
Recently, various procedures for producing DAPG using either
the biosynthesis or synthetic pathway have been extensively
Introduction
DAPG, an antibiotic produced by Pseudomonas uorescence
2P24., is one of the most intriguing phenolic secondary
metabolite compounds.1–3 Originally, its antimicrobial1,4–7 and
fungicide or antifungal2,8,9 agents against various plant patho-
gens were paid attention to. By virtue of the unique structure of
DAPG (Scheme 1), the amphipathic molecules that consist of
the acyl group, alkyl group, and hydroxyl group can enable it to
interact with various receptors in organisms. Within this
context, earlier studies have addressed the antiviral,10 anti-
cancer, antiproliferative, anti-inammatory, and antimetastatic
potential11–13 of the non-nitrogenous polyketide DAPG. This
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Sebelas Maret
University, Jl. Ir. Sutami No. 36A, Surakarta, 57126, Indonesia. E-mail:
triana_kusumaningsih@staff.uns.ac.id
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra05424k
Scheme 1 Molecular structure of DAPG and its potential applications.
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studied.2–4,15,16 The common route to DAPG involves the Friedel– compound, we present herein various synthetic procedures to
Cras acylation of either phloroglucinol (PhL)2,16–21 or mono- develop a more sustainable route in order to convert phlor-
acetylphloroglucinol (MAPG)16 in the presence of Lewis or oglucinol and acetic anhydride into DAPG over SSA as a novel,
Brønsted acids, using an acylating agent (acyl halides, acid efficient, and reusable heterogeneous catalyst in an
anhydrides, and/or carboxylic acids).
environment-friendly US method. Furthermore, in order to
To date, a plethora of procedures have been reported for the meet the suitable operation conditions for the synthesis of
synthesis of DAPG and acylated phloroglucinol that utilize DAPG as well as to explain the effects of the factors on the
AlCl3,17,20 BF3–etherate,5,20,22 and ZnCl2 (ref. 22) as the catalyst. selected response, the design of experiment (DoE) using
Nevertheless, the foremost drawbacks that were encountered response surface methodology (RSM) was performed.35–37
with these last previous routes include variability in the yield, Hence, the three variables, namely, the temperature, catalyst
the use of harmful organic solvents, long reaction times, and loading, and reaction time, were selected. In addition, the
tedious workup protocols. Hence, as a result of increasing the developed procedure for DAPG has been compared with previ-
awareness of environmentally benign chemistry, a solvent-free ously established literature (Scheme 2) using the EATOS so-
method has been demonstrated for the synthesis of DAPG ware and the Andraos' algorithm, along with energy calculation
using various catalysts such as MSA,2 HCl, TFA, H2SO4, CH3- metric, in order to assess any process, information, and versa-
COOH, HBr/alumina, and MSA/CH3COOH.16 Meanwhile, tile outputs related to the “greenness” of the chemical reac-
despite the enormous advantages that are offered by a solvent- tion.38–41 Further, in order to provide the potential oral
free reaction, in pursuit of selecting an appropriate catalyst bioavailability of DAPG, a drug-likeness evaluation based on
system, we realized that each of these reported procedures have Lipinski's rule was also demonstrated.
several undesirable aspects, considering the environmental
consciousness. Typically, homogeneous catalysts oen
encounter recovery and reusability problems aer the reaction,
Experimental
which leads to high E-factor and results in unacceptably high
manufacturing costs. Therefore, it is still desirable to develop
various green techniques for the synthesis of DAPG that use
highly efficient and reusable catalysts.
General information
All chemicals were reagent grade, which were purchased from
Sigma-Aldrich (Singapore) and were used without further puri-
cation. Distilled water was obtained from a Sebelas Maret
University (UNS) water purication system. Infrared spectra
were recorded using a Fourier transform infrared (FT-IR)
Prestige-21 Spectrometer, Shimadzu with in the 4000–
400 cmꢁ1 region (samples were dispersed into potassium
bromide (KBr) pellet at room temperature). X-ray diffraction
(XRD) was performed using a Shimadzu Lab-X 6000 diffrac-
Over the past decade, heterogeneous catalysts have drawn
increasing attention from several industries due to their
number of benets such as easy recovery and reactivation by
a simple treatment, which play an essential green chemistry and
sustainability role.18,23–25 In addition, by combining the practice
of heterogeneous catalyst and an alternative sustainable
synthetic strategy, such as ultrasound-assisted synthesis (US),
much attention has been received due to their unique capabil-
ities of providing chemical transformation under milder
conditions.26–29 Specically, along with the utilization of the
heterogeneous catalytic system, US irradiation offers several
potential effects, such as the promotion of cavitation bubble
formation, increase in the active catalyst surface area, and
removal of impurities deposited on the catalyst.30,31 Besides,
heterogeneous catalysis in the solvent-free condition is
considered as a green and sustainable approach since the
elimination of solvents and reduces the environmental factor
(E-factor). To this endeavour, we developed a novel catalyst
system for the synthesis of DAPG, namely, silica sulphuric acid
or H2SO4–SiO2 (SSA), which was invented by Zolgol,32 obtained
from silica gel (SG) and supported by sulphuric acid,33 which
was used for the rst time in promoting the synthesis of
disulphide and thionitrites under mild conditions. This catalyst
system provided various benets, including increase in the
surface area, improved thermal and mechanical stabilities, as
well as simplicity of handling and reusability.32,34 Thus, we
would, in the future, be investigating these soon in the study for
promoting other chemical reactions.
˚
tometer with Cu Ka radiation (1.5418 A). Field Emission Scan-
ning Electron Microscopy (FE-SEM) images were obtained using
In this work, attracted by the potential Brønsted acid active
sites of SSA and as a part of our on-going endeavours in
designing a green synthetic route for a biologically promising Scheme 2 Various selected literature for the synthesis of DAPG.2,16,18,20
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a JEOL JSM-7900F instrument. The 1H and 13C NMR spectra product was subjected to further characterization in detail
were recorded using an Agilent DD2 NMR Spectrometer using using 1H NMR and 13C NMR. The collected spectra are shown in
CD3Cl3 as the solvent, operated at 25 ꢀC, 500 MHz for 1H and at the ESI.†
1
125 MHz for 13C. The collected chemical shis were reported in
1,10-(2,4,6-Trihydroxy-1,3-phenylene)bis(ethan-1-one) (3). H
parts per million (ppm) relative to that of tetramethylsilane NMR (CD3Cl3, 500 MHz) d ppm: 6.19 (s, 1H, ArH), 2.64 (s, 6H, 2ꢂ
(TMS) as the external reference. Coupling constants (J) are re- CH3).13C NMR (CD3Cl3, 125 MHz) d ppm: 205.56, 173.56, 170.65,
ported in hertz (Hz). Hydrogen coupling patterns were identi- 104.83, 98.63, 33.23.
ed as singlet (s), doublet (d), triplet (t), and multiplet (m).
1,10-(2,4,6-Trihydroxy-1,3-phenylene)bis(2-methylpropan-1-
Sonication was performed by using an Ultrasonic, Branson one) (5a). 1H NMR (CD3Cl3, 500 MHz) d ppm: 6.19 (s, 1H, ArH),
B1510R-DTH Ultrasonic Cleaner (frequency 20 kHz and 130 W). 3.52 (p, J ¼ 5.4 Hz, 2H, 2ꢂ –CH(CH3)2), 1.15 (d, J ¼ 5.4 Hz, 12H,
The progress of the reactions was observed by thin layer chro- 4ꢂ CH3).13C NMR (CD3Cl3, 125) d ppm: 212.07, 170, 168, 104.21,
matography (TLC), which was performed on gel 60 F254 (Merck) 98.97, 39.59, 19.21.
plates and visualised by using UV light (l ¼ 254 and 365 nm).
1,10-(2,4,6-Trihydroxy-1,3-phenylene)bis(3-methylbutan-1-
one) (5b). 1H NMR (CD3Cl3, 500 MHz) d ppm: 6.20 (s, 1H, ArH),
2.9 (d, J ¼ 5.6 Hz, 4H, 2ꢂ –CH2–CH(CH3)2), 2.26 (dh, J ¼ 11.0,
5.5 Hz, 2H, 2ꢂ CH2–CH(CH3)2), 0.97 (d, J ¼ 5.4 Hz, 12H, 4ꢂ
CH3). 13C NMR (CD3Cl3, 125 MHz) d ppm: 205.98, 167.07,
103.73, 99.19, 53.09, 24.94, 22.81.
Preparation and characterisation of the SSA catalyst
The SSA catalyst was prepared from silica gel (SG) (pore size 0.7–
0.85 cm3 gꢁ1 pore volume, particle size 230–400 mesh, and
surface area $ 480 m2 gꢁ1) and concentrated sulphuric acid by
following the reported procedure with slight modications.42,43
SG (12.375 g) was soaked in diethyl ether (50 mL) until a slurry
silica gel was formed, followed by the addition of concentrated
H2SO4 (6.25 mmol). The obtained mixture was mechanically
stirred for 15 min under a nitrogen atmosphere and dried at
60 ꢀC for 18 h to remove the solvent. The obtained residue was
1-(2,4,6-Trihydroxyphenyl)ethan-1-one (6a). 1H NMR
(CD3Cl3, 500 MHz) d ppm: 6.01 (s, 1H, 2ꢂ ArH), 2.70 (s, 3H,
CH3). 13C NMR (CD3Cl3, 125 MHz) d ppm: 203.58, 165.32,
107.01, 95.81, 32.21.
2-Methyl-1-(2,4,6-trihydroxyphenyl)propan-1-one (6b). 1H
NMR (CD3Cl3, 500 MHz) d ppm: 5.84 (s, 2H, 2ꢂ ArH), 3.84 (p, J ¼
5.4 Hz, 1H, –CH(CH3)2), 1.15 (d, J ¼ 5.5 Hz, 6H, 2ꢂ CH3).13C
NMR (CD3Cl3, 125 MHz) d ppm: 211.02, 172.70, 170.29, 105.74,
96.12, 39.58, 19.53.
ꢀ
heated at 120 C for 6 h in order to obtain the SSA catalyst as
a free-owing powder. The resultant SSA catalyst was gently
stored in a desiccator before further use. Aerwards, the
prepared catalyst was further characterized in detail using XRD,
FTIR, SEM-EDS, and acid–base titration. The acidity of the SSA
catalyst was measured by the acid–base titration method as
reported in a previous study.44 The SSA catalyst (100 mg) was
stirred in NaOH solution (20 mL of 0.1 M) for 6 h and then
titrated with HCl solution (0.1 M) to determine the acidity of the
sample. In addition, as a comparison, several protic acids
(acetic acid, methanesulfonic acid, and perchloric acid) were
also immobilised on silica gel using the same method. The
resultant catalysts were then tested on the same typical reaction
and conditions as that for the SSA catalyst.
3-Methyl-1-(2,4,6-trihydroxyphenyl)butan-1-one (6c). 1H
NMR (CD3Cl3, 500 MHz) d ppm: 5.84 (s, 2H, 2ꢂ ArH), 2.83 (d,
2H, –CH2–CH<), 2.25 (dt, J ¼ 11.0, 5.5 Hz, 1H, CH2–CH(CH3)2),
0.96 (d, J ¼ 5.4 Hz, 12H, 4ꢂ CH3).13C NMR (CD3Cl3, 125 MHz)
d ppm: 206.16, 164.5, 165.7, 105.78, 96.11, 52.89, 25.53, 22.77.
1-(3-Acetyl-2,4,6-trihydroxyphenyl)-2-methylpropan-1-one
(7a). 1H NMR (CD3Cl3, 500 MHz) d ppm: 6.21(s, 1H, ArH), 3.57–
3.47 (m, 1H, –CH(CH3)2), 2.64 (s, 3H, CH3), 1.15 (d, J ¼ 5.4 Hz,
6H, 2ꢂ CH3). 13C NMR (CD3Cl3, 125 MHz) d ppm: 212.20,
205.45, 167.51, 166.80, 104.89, 99.18, 39.65, 33.23, 19.26.
1-(3-Acetyl-2,4,6-trihydroxyphenyl)-3-methylbutan-1-one
(7b). 1H NMR (CD3Cl3, 500 MHz) d ppm: 6.2 (s, 1H, ArH), 2.87 (d,
J ¼ 5.6 Hz, –CH2–CH(CH3)2), 2.64(s, 3H, CH3), 2.25 (dt, J ¼ 11.0,
5.5 Hz, 1H, CH2–CH(CH3)2), 0.96 (d, J ¼ 5.5 Hz, 6H, 2ꢂ CH3). 13
C
General synthesis of DAPG
A mixture of phloroglucinol 1 (1 mmol), acetic anhydride 2 (2 NMR (CD3Cl3, 125 MHz) d ppm: 206.66, 205.44, 166.73, 166.11,
mmol), and SSA was stirred in a round bottom ask at room 104.52, 103.13, 98.80, 53.05, 33.23, 25.50, 22.78.
temperature for 15 min and heated at 80 ꢀC for 1–2 h. For the US
method, the mixture was mechanically stirred for 5 min, fol-
lowed by sonication for 15–20 min at 60 C under the ambient
Reusability and heterogeneity of the SSA catalyst
ꢀ
atmosphere. TLC analysis was used to monitor the progress of The recovered SSA catalyst was soaked in ethyl acetate (10 mL)
the reaction. Aer the reaction was completed, the obtained under magnetic stirring for 30 min. It was ltered, followed by
mixture was cooled at the ambient temperature, then diluted washing with ethyl acetate (3ꢂ 5 mL), and was soaked again
with EtOAc (15 mL), ltered from the used catalyst, and water with acetone (3ꢂ 5 mL) and stirred for 15 min. Aer washing,
(25 mL) was added. The crude solution was extracted with the catalyst was ltered, dried in a rotary evaporator until the
EtOAc (3ꢂ 15 mL) and the combined organic layer was dried solvent was removed, and was then weighed. The amount of
over anhydrous Na2SO4. The solvent was evaporated under catalyst loss was recompensed by adding fresh SSA. Aerwards,
ꢀ
vacuum and the crude product was subjected to recrystallisa- the catalyst was reactivated at 120 C for 3 h. The reaction was
tion using benzene/petroleum ether 2 : 1 (v/v) following the repeated following the above procedure.
previous literature4 and used without column chromatography
To investigate the possible leaching of the active sites from
treatment (for compound 3, 5a and 5b). Aerwards, the isolated the catalyst surface of SSA into the reaction medium, a hot
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Table 1 Box–Behnken Design parameters obtained for various runs for the synthesis of DAPG
Responses
Experimental factors
Coded variables
Run
T (ꢀC)
Catalyst loading (%w/w)
t (min)
X1
X2
X3
The yield of DAPG (%)
1
2
3
4
5
6
37
8
9
10
11
12
13
14
15
16
17
18
19
20
25
25
25
80
25
25
80
60
80
60
25
60
25
60
80
80
60
80
60
60
10
20
5
20
10
20
5
20
20
10
10
10
10
10
5
20
60
60
60
30
20
30
30
20
60
30
20
30
60
30
20
20
20
30
20
ꢁ1
ꢁ1
ꢁ1
1
ꢁ1
ꢁ1
1
0
1
0
0
ꢁ1
1
1
1
0
10
8
6
1
ꢁ1
1
0
1
68
16
10
52
74
79
80
12
95
14
82
54
46
83
84
80
68
ꢁ1
ꢁ1
0
1
0
1
0
0
0
0
0
ꢁ1
ꢁ1
1
ꢁ1
1
ꢁ1
0
0
ꢁ1
ꢁ1
0
1
1
0
1
0
0
0
1
0
ꢁ1
ꢁ1
ꢁ1
0
5
20
10
20
5
0
1
ꢁ1
ꢁ1
ltration method was performed.25,44,45 Under the optimised a downloadable Java-archive le, which permits the evaluation of
conditions, the Friedel–Cras acylation of phloroglucinol was all of the chemicals used in the synthesis of DAPG and its work-
carried out. Aer 5 min of the reaction, all the catalyst particles up procedures. The data required for the EATOS analysis were
were separated by hot ltration and centrifuged. The reaction attained from the Material Safety Data Sheets (MSDSs) of Sigma-
was continued for 30 min in the absence of the catalyst and was Aldrich combined with the ChemSpider Database to validate
frequently monitored by TLC.
their consistency. In particular, the required data deals with risk,
human toxicity, chronic toxicity, eco-toxicology, accumulation,
and prices. The required data associated with their stoichio-
metric or amounts of material were obtained from the recent
literature.28,31,38,39 In addition, in an attempt to determine the
energy consumption of the current reaction, the previous energy
calculation metric method was followed.41
Response surface methodology (RSM)
The reaction optimisation was carried out using multivariate
statistical modelling RSM method (operated using Design-
Expert Version 11.0.5.0) in order to nd out the selected
parameters for the synthesis of DAPG using phloroglucinol,
acetic anhydride, and SSA as the catalyst. The reaction
temperature, catalyst loading, and reaction time were chosen as
independent variables based on the previous literature and the
results of the preliminary studies. The three independent vari-
ables were coded at ꢁ1, 0, and +1, which represent low value,
centre value, and high value, respectively, as presented in Table
1. According to the model, 20 sets of experiments were carried
out to build the desired model.
In silico evaluation of drug-likeness
Drug-likeness study was established based on Lipinski's rule using
online Molinspiration soware (https://www.molinspiration.com/
docu/miscreen/druglikeness.html), combined with SwissADME
soware (http://www.swissadme.ch/).
Results and discussion
Primarily, we began our study by preparing the Brønsted acid
SSA catalyst following the reaction pathway (Scheme 3).43 It was
further characterised by several techniques including FT-IR,
Environmental assessment
For the environmental assessment of the present method, an
overview of several relevant methods of synthesis of DAPG are
summarised in Scheme 1. The environmental assessment was
performed by employing the freeware package Environmental
Assessment Tool for Organic Syntheses (EATOS) soware devel-
oped by Eissen and Metzger40 and the algorithm by Andraos,46
which considers the consumption of substrates, solvents, cata-
lysts, coupled products, and by-products. However, in this
assessment, we did not take into account the workup and puri-
Scheme 3 The preparation of SSA involving the addition of sulphuric
cation phases due to the lack of literature details. An EATOS is acid to SG.
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XRD, SEM, EDS analysis, and acid–base titration. The measured The traditional homogenous catalysts including both the
XRD patterns for SG and SSA (ESI, Fig. S2†) consist of similar Brønsted and Lewis acids such as HCl, H2SO4, CH3COOH, MSA,
patterns, with a broad peak in the range of 22.6ꢀ, which and MSA/CH3COOH showed varying catalytic activities under
corroborated the non-crystalline nature of SG.47 The decrease in the oil-bath method. According to Table 2, the reactions carried
this peak's intensity compared to that of SSA implies that sul- out using HCl, H2SO4, and CH3COOH were found to give low
phonation was successfully achieved.48
catalytic activities. Even aer these reactions were carried out
Aerwards, FT-IR analysis was employed in order to conrm under reux with vigorous stirring for 12 h, they still gave
the successive functionalisation of SG to form SSA. Upon sul- incomplete reactions (only less than 20% yields of 3). In addi-
phonation treatment, the FTIR spectrum of SSA was identical to tion, several unexpected products (phenylacetate) were also
that of SG with the presence of a few additional S–O vibrational observed (as conrmed by TLC and NMR analysis). On the
frequencies, as exhibited in Fig. 1. The band at about 2600 cmꢁ1 contrary, when MSA and MSA/CH3COOH were introduced as
was linked to the O–H vibration of the sulphonate group. Other the catalyst, moderate yields of 40–70 and 80% were observed,
peaks at 1252, 1080, 1024, and 709 cmꢁ1 were attributed to the respectively. The same typical reaction was then screened
asymmetric O]S]O, symmetric O]S]O, S]O stretch, and carefully under the US method, which proceeded smoothly. In
S–O stretch, respectively.43,49 As a note, aer the sulphonation of contrast, there was no observed product for the use of HCl,
silica gel by sulphuric acid, some hydroxyl groups of silica gel (the H2SO4, and CH3COOH as the catalyst, whereas the presence of
isolated hydroxyl group) may still remain, which was proved from MSA and MSA/CH3COOH could improve the yield to 82 and
the FTIR analysis, which showed the presence of the silanol 88%, respectively.
group band within the range of 3447–3500 cmꢁ1
.
Aerwards, 20% (w/w) SSA was tested as the catalyst in
43,50,51
The morphology of SG and SSA was studied via SEM, as a similar typical reaction via the conventional method (oil-bath)
shown in ESI, Fig. S3A and C.† The sulphonation of SG also and US method, which resulted in DAPG yield of 85% and
reveals a similar morphology to that of neat SG, which is rein- 90%, respectively. As an important aspect, we found that the
forced by the XRD and FTIR results. Thus, it might be inferred reaction proceeded faster to give a higher yield of DAPG under
that the sulphonation of SG does not affect it in terms of the size the US method compared to the previously employed homoge-
and the shape. According to the EDS analysis (ESI, Fig. S3B and nous catalysts used under oil-bath method. Aerwards, an
D†), the existence of the SO3H group on neat SG was also increase in the catalyst loading to 30% (w/w) resulted in a lower
observed, which was indicated by the presence of a strong signal yield of DAPG, accompanied by the formation of triacetylphlor-
in the region for O and S. In general, these results show that the oglucinol as a by-product. Fortunately, as the catalyst loading
introduction of the SO3H group does not alter the silica gel decreases to 10% (w/w), the yield of the product increased to be
framework.43 Also, to investigate the acidity of the SSA catalyst, 95% and no by-product of phenylacetate was observed. Interest-
the acid–base titration method was employed. The acidity was ingly, it was noticed that the presence of only liquid sulphuric
found to be 3.8 mmol H+ per g SiO2, which suggests a strong acid or silica gel could lead to rather low yields, followed by the
acidic nature.49
formation of side products. Nevertheless, the high activity of the
SSA catalyst may be attributed to its high acidity value caused by
the intense dispersion of the SO3H group on the surface of
silica.43 In addition, we envisaged that the synergistic effects
between the active site of the SSA catalyst and silica gel also could
enhance the catalytic activity. It is worth mentioning that silica
gel itself has been used as a catalyst in various types of organic
reactions through the silanol group as an active site.52,53 Thereby,
the presence of two different active sites could possibly improve
the collision frequency between the substrates and the catalytic
sites of the SSA catalyst.
Catalyst screening
In this study, in an endeavour to meet the green chemistry
goals,23 we decided to use green and halogen-free acetic anhy-
dride (2) instead of acyl chloride as an acylating agent to
synthesize DAPG. Initially, room temperature reaction with and
without the presence of the catalyst was carried out under
solvent-free condition. Unfortunately, there was no desired
product reaction observed for both of these typical reactions.
In an attempt to improve the yield, the addition of a small
amount of acetic acid (ꢃ1 mmol) could increase the yield of
DAPG, albeit it was an insignicant improvement. It has been
reported that Friedel–Cras acylation may be enhanced with the
presence of hydrogen bonding (H-bond) from a certain solvent
and/or catalyst. Acetic acid could provide H-bond donor solvent
molecules for Friedel–Cras acylation.54 Aerwards, when the
reaction was extended (overnight condition), it prompted the
formation of several by-products (controlled by TLC), which were
possibly obtained by decomposition of the product or its inter-
mediates due to rough irradiation. In terms of the reaction time,
this fruitful result revealed a signicant improvement in the
Friedel–Cras acylation of phloroglucinol to DAPG. The possible
interpretation for the positive association of this method is that
Fig. 1 FTIR spectra of SG and SSA.
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Table 2 Preliminary Study Reactiona
Method
Conventional method (oil-
bath)
US
Run
Catalyst
t (min)
Yieldb (%)
t (min)
Yieldb (%)
1
2
3
4
5
3 mmol of MSA
3 mmol of CH3COOH
3 mmol of TFA
3 mmol of H2SO4
20 wt% silica gel
3 mmol of HCl
30–45
45
45
45
45
40–80
20
20
15–20
20
20
60–86
c
c
10
10
92–94
25
<10
12–17
c
c
6
45
20
7
8
9
10
20 wt% of SSA
10 wt% of SSA
10 wt% of SSA/1 mmol of CH3COOH
No catalyst
45
45
30–45
120
85
88
15–20
15–20
15–20
120
87–90
92–95
93
94–96
c
c
a
Reaction conditions: 1 mmol of phloroglucinol (1), 2 mmol of acetic anhydride (2) and the above-mentioned catalyst were operated under
conventional procedure at 80 ꢀC and US method at 60 ꢀC. b Isolated yield. c No reaction.
the ultrasonic waves can boost the number of active cavitation assume that the reasonable rst step of this reaction is that the
bubbles and the size of the individual bubbles, leading to the SSA catalyst activated acetic anhydride through protonation
improvement in the reaction efficiency with increased reaction over the Brønsted acid active sites of the catalyst to form an
rates and reduced reaction time.31,55
acylium ion (I). Aerwards, the resultant acylium ion takes part
Encouraged by this result, we considered several solvents for in the Friedel–Cras acylation, which leads to the competition
further investigation (Table 3). Briey, it is well known that the for phenylacetate (PA) through O-acetylation or hydrox-
solvent used is an important factor inuencing the chemical hyacetophenone (HAP) C-acetylation (II). Moreover, PA could
reactivity both in the reaction mechanism and the reaction rate.56 undergo Fries rearrangement reaction through the O-acylation
However, the result showed that the use of solvents caused the process, which is processed faster than the C-acylation one,
formation of several products including by-products. Accord- followed by the formation of MAPG and subsequently followed
ingly, the implementation of a solvent-free condition is indeed by the formation of DAPG (III). Notably, this Friedel–Cras
greatly preferable for the synthesis of DAPG promoted by the SSA acylation reaction is commonly processed faster than the ordi-
catalyst. This is evidenced in that the reaction rate observed in nary aromatic compound or phenol due to the presence of
the solvent-free condition leads to more favourable reaction
kinetics instead of the reactions demonstrated in the presence of
any solvent. The main reason why the solvent-free condition
Table 3 Solvent effecta
T (ꢀC) t (min) Yieldb (%) Solvent rankingd
could promote this reaction effectively is strongly attributed to
the fact that one of the reactants is in the liquid phase (acetic
anhydride) at the reaction temperature. Thereby, it must be
miscible with phloroglucinol, where the molecular movement
and the contact between the reactants with higher concentrations
is favoured and the yield of DAPG is improved.29,57,58 Hence,
Green Chemistry principle 5, which states that the “use of
solvents should be made unnecessary wherever possible and
innocuous when used”, is successfully implemented.23
Run Solvent
e
1
2
3
4
5
6
7
8
Solvent-free
Chloroform
DCM
Toluene
Benzene
Acetonitrile
60–80 20–30
Reux 20–60
Reux 20–60
Reux 20–120
Reux 20–120
92
65
Highly hazardous
Hazardous
68
c
Problematic
c
Highly hazardous
Reux 20–120 55
68
Problematic
e
Nitrobenzene Reux 20–60
Water Reux 20–120
c
Recommended
A plausible mechanism for the synthesis of DAPG using SSA
a
Reaction conditions: 1 mmol of phloroglucinol (1), 2 mmol of acetic
We herein also propose a possible mechanism reaction anhydride (2) and 20% of SSA catalyst were used under the US
b
c
d
method at 60 ꢀC. Isolated yield. No reaction. Ranking of solvents
(Scheme 4) for the ultrasound-promoted one-pot synthesis of
DAPG from phloroglucinol and acetic anhydride under solvent-
free condition with the presence of SSA as the catalyst. We
with respective to CHEM21 solvent guide of “classical” solvents.59
e
Not reported.
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strongly activating agents from the three phenol groups of between catalyst loading and the reaction temperature (BC)
phloroglucinol.60,61
showed a signicant negative effect on the DAPG yield.
According to Table 4, the p-value can be used as an indicator for
checking the signicance of each coefficient, where p-values
less than 0.05 imply that the model terms are signicant. The
linear term of A, B, and the quadratic term of A (A2) and B (B2) are
signicant. Fig. 2 shows good linear correlation between the
actual and predicted yield of DAPG. Accordingly, the developed
model can possibly predict the yield of the experimental reac-
tion. Considering all the above descriptions, it is strongly evi-
denced that the developed second-order quadratic model (as
presented in eqn (1)) could fruitfully predict the performance of
Friedel–Cras acylation of phloroglucinol by altering the
selected operating conditions. To validate the predictability of
the model, duplicate runs were performed under the above-
optimized conditions. In both the cases, the obtained yields
were achieved to be 93% and 91%, which are slightly lower than
the predicted ones. Nevertheless, these results still closely
match with the predicted result of 95%.
The relationship visualisation between the temperature and
catalyst loading as the designated variables, and yield as the
response is observed in the surface response graphs, which are
plotted in 3D surface response, as presented in Fig. 3. Fig. 3A
displays the response surface of DAPG yield calculated as
a function of the reaction temperature and catalyst loading at
the minimum reaction time (x1 ¼ ꢁ1). The yield of DAPG
increased rapidly to an optimum value with the increase in the
reaction temperature and catalyst loading. It was observed that
the reaction temperature plays a more dominant role in this
typical reaction than the catalyst loading. However, the yield of
DAPG slightly dropped aer the reaction was operated at 80 ꢀC
with the catalyst loading at 20% (w/w). Besides, increasing the
reaction temperature to more than 1 h also considerably
accelerates the formation of the by-products such as tri-
acetylphloroglucinol and several undetectable products, which
can reduce the yield and purity of DAPG. The formation of
undetectable compounds can be explained on the basis of the
collateral effects of the US wave on the thermally unstable
organic compounds, which are able to decompose underneath
longer reaction times and higher temperature.55 Furthermore, it
is evident that the typical reaction of Friedel–Cras acylation of
phenolic compounds only requires a small amount of catalyst
loading, which is also reported in several literatures.18,62 In
accordance with the green chemistry principles, any reaction
processed with a small amount of catalyst loading is desirable
to a reaction that requires an extra stoichiometric amount of the
catalyst.
Optimization of the reaction using RSM
In this work, an efficient statistical technique, namely, design of
experiment (DoE) approach, has been employed, which is
available for establishing the model and optimizing the reac-
tion condition. This optimization approach has been broadly
used in the elds of chemical engineering and analytical
chemistry. However, it has not been popularly used in organic
synthesis. Response surface methodology (RSM) is a part of
DoE, which can provide an efficient means of the effects and
interaction between multiple system input parameters either
separately or in combination through an accurate second-order
polynomial equation. In this work, the optimum reaction
conditions were studied by varying several signicant parame-
ters in this reaction, including the effect of temperature, catalyst
loading, and reaction time, according to the prior results and
the literature report.18 Eqn (1) shows the second-order quadratic
model relationship between the DAPG yield (Y) and the
preferred variables.
Y ¼ 84.03 + 29.70A + 6.75B ꢁ 1.63C + 3.83AB ꢁ 2.79AC ꢁ
2.88BC ꢁ 39.93A2 ꢁ 12.30B2 + 1.58C2
(1)
where Y is the DAPG yield, and A, B, and C stand for the coded
variables in the Friedel–Cras acylation of phloroglucinol. The
coefficient estimate denotes the probable change in the
response (Y) per unit change in the factor value aer all the
remaining factors are kept constant.
As shown in eqn (1), A (temperature) has a major effect on
the DAPG yield (Y). Similarly, the catalyst loading (B), and the
interaction between the temperature and catalyst loading (AB)
also showed a positive impact on the DAPG yield. In different
circumstances, the effects on the model parameters revealed
that the reaction temperature (C), the interaction between the
temperature and the reaction time (AC), and the interaction
Fig. 3B reports the response surface of the DAPG yield
calculated as a function of temperature and reaction time at the
catalyst loading (x2 ¼ 0), whereas Fig. 3C shows the dependence
of DAPG yield on the catalyst loading and reaction time calcu-
lated for the intermediate reaction temperature (x3 ¼ ꢁ1). Both
these graphs highlight that no noteworthy effects were observed
on the DAPG yield by varying the reaction time within the pre-
determined range. Finally, several runs were carried out in
order to conrm the validity of the optimum condition, which
was predicted by the statistical model. Therefore, the real
Scheme 4 Proposed mechanism for the ultrasound-assisted Friedel–
Crafts acylation between phloroglucinol (1) and acetic anhydride (2)
promoted by SSA catalyst.
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Table 4 Coefficients of the quadratic model and ANOVA
Source
Sum of squares
df
Mean square
F-Value
p-Value
Model
A-temperature
B-catalyst loading
C-reaction time
AB
AC
19711.72
8454.79
429.10
26.85
85.70
52.66
51.51
6787.07
586.87
9.96
9
1
1
1
1
1
1
1
2190.19
8454.79
429.10
26.85
85.70
52.66
85.14
328.68
16.68
1.04
3.33
2.05
<0.0001
<0.0001
0.0022
0.3310
0.0979
0.1830
0.1874
<0.0001
0.0007
0.5477
Signicant
BC
51.51
2.00
A2
6787.07
586.87
9.96
263.85
22.81
0.3872
B2
1
1
C2
Residual
Lack of t
Pure error
Cor total
257.23
227.23
30.00
10
5
5
25.72
45.45
6.00
7.57
0.0222
Signicant
19968.95
19
be effective for predicting the DAPG yield precisely due to the
less percentage of error (less than 6%).18
With the optimized conditions in hand, we further explored
the scope of this reaction using several selected acylating agents
(Scheme 5). Besides acetic anhydride, several acyl sources were
selected for the synthesis of DAPG derivatives bearing different
alkyl moieties. Generally, it was observed that this reaction took
a slightly longer time to produce the expected products when
the acetyl group was replaced with longer alkyl chains. The
different reactivity due to electronic and steric reasons might be
inuenced by the selectivity of this reaction. However, these
results are still tolerable within the above-mentioned optimized
conditions. Furthermore, we also investigated the selectivity of
the SSA catalyst for the synthesis of monoacylphloroglucinol
derivatives (an analogue of the commercial antispasmodic
agent, Flopropione63,64) by reacting 1 mmol equivalent of the
acylating agent. For this reaction, a high yield of mono-
acylphloroglucinol was observed in less than 10 min without the
formation of the by-product. This clearly proved that the SSA
catalyst can play an important role as a selective catalyst for this
typical reaction.
Fig. 2 Linear correlation between the actual and predicted yield of
DAPG.
experiment was performed in the presence of 10% SSA and
operated at 60 ꢀC for 20 min with three repetitions. The ob-
tained yield was found to be 94%, which is relatively close to the
predicted result of 95%. Accordingly, this model was found to
Fig. 3 Dependence of DAPG yield (3D surface interaction plots) on (A)
the reaction temperature and catalyst loading calculated for the Scheme
5 The scope studied under the optimised conditions.
minimum temperature (x1 ¼ ꢁ1); (B) the reaction temperature and Reagents and conditions: (a) Ac2O (2 mmol), SSA (10%), 60 ꢀC, US, 15–
reaction time calculated for the intermediate catalyst loading (x2 ¼ 0); 20 min, (b) RCOCl (2 mmol), SSA (10%), 60 ꢀC, US, 20–25 min, (c) Ac2O
(C) catalyst loading and reaction time calculated for the intermediate (1.2 mmol), SSA (10%), 60 ꢀC, US, 10–15 min, (d) RCOCl (1.1 mmol), SSA
reaction temperature (x3 ¼ ꢁ1).
(10%), 60 ꢀC, US, 20–25 min.
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In addition, in order to assess the feasibility of this method
on a preparative scale, Gram-scale synthesis was then examined
under the optimal reaction conditions. For the small scale
Friedel–Cras acylation reaction, 1 mmol equivalent of phlor-
oglucinol (1) and 2 mmol equivalents of acetic anhydride (2) was
required with the yield of 95%. Fortunately, when the reaction
was scaled-up ten times to the previous stoichiometric ratio,
DAPG was also afforded in a reproducible yield of about 93%
(Scheme 6).
Hence, DAPG, which is a privileged building block and
versatile synthetic intermediate, could be simply synthesised by
the present method. In addition, to our great delight, when the
same type of reaction was carried out under an inert atmo-
sphere, there were no signicant differences. This indicates that
this typical reaction is relatively constant under ambient
atmosphere conditions. In the best cases, especially for prod-
ucts 3, 5a, and 5b, they can be puried only using recrystalli-
sation technique or without additional chromatographic
treatment.
Fig. 4
S
ꢁ1 and EIin values for the synthetic routes of A, B, C, D, and E
investigated with the EATOS software.
indexes, namely, the mass index (Sꢁ1), environmental factor (E-
factor), environmental index input (EIin), and environmental
index output (EIout). Sꢁ1 and EIin of all the investigated strate-
gies are presented in Fig. 4. Sꢁ1 refers to the quantity of
chemical used, whereas EIin calculates the price of the starting
materials used and their detailed risk information (collected
from MSDS). The highest Sꢁ1 value of 108 resulted for the
synthesis of B, which is mainly ascribed to a large amount of
solvent (dioxane) and substrates used. This synthetic method
was also exemplied by the highest EIin (419.86 PEI per kg). The
synthesis of A, C, D, and E, which differ from method B due to
the use of solvent-free condition, are characterised by a lower
Sꢁ1 equal to 3.44, 12.14, 1.76, and 1.61, respectively and lower
EIin equal to 13.71, 22.87, 5.60, and 5.25, respectively.
Remarkably, the present method (synthesis of E) is charac-
terised by the lowest Sꢁ1 and Eiin due to a relatively low number
of input materials and low-risk value of the substrates used.
Fig. 5 depicts the E-factor and the EIout of the ve studied
synthetic pathways. These calculations represent the amount of
waste produced and take into account its nature during the
chemical process. The synthesis of B is the most mass-intensive
compared to the other methods due to the large amount of
waste produced (107 kg gꢁ1 product), which is mainly ascribed
to the amount of solvent (dioxane) and substrates used.
According to green chemistry principles, the remediation of
waste is not preferable but the prevention of waste from the
source is mostly preferable.23,68 Therefore, solvent reduction or
Reaction schemes of the ve synthetic pathways leading to
DAPG assessed by the EATOS tool, Andraos algorithm, and
energy requirement
The subject of metrics in chemical transformations is increas-
ingly becoming important for measuring the greenness of
a reaction. In this study, our main scope encompasses
a comparative environmental assessment of the ve synthetic
pathways leading to DAPG (Scheme 1): (1) synthesis of A: reac-
tion of phloroglucinol with acetic anhydride in the presence of
MSA and acetic acid under solvent-free microwave-assisted
(MW) (88% yield);16 (2) synthesis of B: phloroglucinol with
acetic anhydride in the presence of BF3-etherate as the catalyst
and dioxane as the organic solvent under conventional heating
(30% yield);20 (3) synthesis of C: the reaction between phlor-
oglucinol and acetic anhydride in the presence of MSA as the
catalyst under solvent-free conventional heating (30–80%
yield);2 (4) synthesis of D: the reaction of phloroglucinol with
acetic anhydride in the presence of natural activated zeolite
mordenite (nHZMOR) as the heterogeneous catalyst under
solvent-free conventional heating (95% yield);18 and (5)
synthesis of E (present work): reaction of phloroglucinol with
acetic anhydride in the presence of SSA as the heterogeneous
catalyst under solvent-free ultrasound-assisted (95% yield).
To obtain the entire representation for the quantication of
all the substances involved in the synthetic process, the reaction
was evaluated by EATOS.40,65–67 It was feasible to measure four
Scheme 6 Preparative scale synthesis of DAPG under the above Fig. 5 E and EIout values for the synthetic routes of A, B, C, D, and E
optimised conditions.
investigated with the EATOS software.
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elimination in organic synthesis can considerably minimize the that the synthesis of D and E (present method) show better CI
environmental impact of a given chemical process by devel- because of the use of a highly efficient and low-cost catalyst and
oping cleaner processes.
the use of solvent-free condition with no excess reagents
On the other hand, performing the reaction under solvent- compared to the other studied methods.
free protocol (synthesis of A, C, D, and E) dramatically
In order to consider the quantity of material footprint,
reduces the amount of waste. The synthesis of A and C produced Andraos algorithm39,46,69 was employed to the ve syntheses for
2.43 and 11.14 kg waste per kg product, respectively. Mean- the production of DAPG (Table 5, Fig. 7). According to this
while, the lesser E-factor value in the synthesis of D and E (0.76 calculation, the synthesis of E (present work) is closer to the
and 0.61 kg waste per kg product) is due to no signicant excess ideal conditions compared to the other investigated methods.
of the solvent and/or reagents used and the higher yield isolated The synthesis of D is also closer to the ideal conditions but is
compared to the other methods. Besides, it is worthy to note characterised by lower Material Recovery Parameter (MRP) and
that not only can the solvent and/or reagents be saved according Reaction Mass Efficiency (RME) than the synthesis of E. The
to the present protocol but also the catalyst loading has been synthesis of A is characterised by lower value in all the param-
minimally employed. The heterogenous catalyst can be eters compared to the synthesis of D and E. Nevertheless, this
collected and reused several times without having a negative method presents better environmental prole than the
effect on the yield of DAPG.
synthesis of C and B. These methods are in accordance with
The value of EIout can be considered as the character of the green chemistry principles,23 which stress in solvent-free
waste produced. The EIout value of synthesis B clearly conrms conditions. The synthesis of B recorded the lowest value in all
that the use of dioxane as the solvent and BF3OEt2 as the cata- the parameters, which was mainly ascribed to a large amount of
lyst presents the lowest environmental impact than those of the solvent (dioxane) and substrates used. As an important aspect,
other synthesis methods, which are characterised by the highest we found that the reactions performed in solvent-free condi-
value of environmental impact (16.6 PEI per kg). The synthesis tions proved to have a better environmental prole in terms of
of A and C, which use MSA as the catalyst, present an EIout equal the mass ows, environmental impacts of the substances
to 5.72 and 16.6 PEI per kg, respectively. Meanwhile, the EIout involved, and waste produced.
obtained for the synthesis of D and E, which employed eco-
Despite the enormous benets offered by EATOS and
friendly heterogeneous catalyst systems, are considered to be Andraos algorithm, both these tools do not take into account
lower values of environmental impact (2.57 and 2.05, respec- the energy required in the process. The energy intake during the
tively) compared to all of the studied methods.
process can be calculated by a simple energy calculation metric
Furthermore, the production costs are reveal the environ- developed by Clark and co-workers.41 Table 6 shows the energy
mental and social costs in a reliable way.40 The EATOS tool can intake requirement obtained for the Friedel–Cras acylation
be used to establish the environmental impact of their reaction between phloroglucinol and acetic anhydride for the
production through the costs of the substrates involved. Fig. 6 methods studied. Because of the lack of detailed data regarding
shows the value of the cost index (CI) for the ve studied the heating power used in the synthesis A, B, and C, we assumed
methods, which represents the material costs during the that the conventional (oil-bath) method was employed with
chemical process. The comparison of the CI clearly shows that a similar heating power as that in synthesis D (our previous
synthesis B presents the highest CI equal to 78532.22-unit work).18
EATOS compared to the other reactions. On the contrary, the
The MW reaction or the synthesis of A has been stated to give
synthesis of A, C, D, and E is characterised by lower CI equal to 88% yield of DAPG, which could associate to the lowest energy
3395.44, 8755.13, 2395.08, and 2237.31-unit EATOS, respec- usage of about 13.26 kW molꢁ1. By taking all of the conven-
tively. However, the synthesis of C presents higher CI compared tional methods into account, the synthesis of B, C, and D
to the other solvent-free methods, which is attributed to the use signicantly corresponded to higher energy usage of 2400,
of excess catalyst. Also, in this case, it is important to underline 12 000, and 757.89 kW molꢁ1, respectively. The low yield in the
synthesis of B and the long-time reaction in the synthesis of C
cause the energy requirement per mol to be extremely high as
compared to the energy usage in the synthesis of C. The oil-bath
method is characterised by the requirement of prolonged time
Table 5 Comparison of raw material footprint for the synthesis of A–E
according to the Andraos algorithm
A
B
C
D
E
AE
Rxn yield
1/SF
MRP
RME
0.424
0.881
0.391
0.904
0.132
0.182
0.300
0.111
0.207
0.001
0.633
0.600
0.617
0.053
0.012
0.633
0.942
0.617
0.867
0.319
0.633
0.947
0.617
1.000
0.370
Fig. 6 CI values for the synthetic routes of A, B, C, D, and E investi-
gated with the EATOS software.
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SSA was compared with that of the heterogeneous catalyst
system employed in the previous study,16,18 it was found that the
present method demonstrated higher yield and faster reaction.
Recycling experiment of the SSA catalyst
To increase the environmental benets of the current developed
method, we investigated the reusability of the SSA catalyst in the
model reaction. The ease of recovery and recycling of the SSA
catalyst can be easily demonstrated. Aer the synthesis of DAPG
was completed, the SSA catalyst was recovered by extracting the
mixture with acetone and ethyl acetate (1 : 2) and was subjected
to subsequent cycles of the same typical reaction. It was found
to retain the catalytic activity for up to ten consecutive runs,
thus showing remarkably constant catalytic activity (Fig. 8).
The recycled catalyst was characterised by XRD, FTIR, and
SEM analyses. The XRD pattern of the recycled catalyst was
found to be the same as that of the fresh one, indicating that
there was no signicant structural change in the catalyst aer
the tenth run (ESI, Fig. S4†). According to the FTIR spectrum,
there was no appreciable change in the recycled SSA catalyst. All
the characteristic bands in the fresh SSA catalyst were retained
in the spectrum, corroborating that there was no loss in the
structure of the recovered catalyst (ESI, Fig. S5†). In addition,
SEM analysis conrmed that the surface morphology of the
recycled catalyst did not signicantly change aer the tenth run
(ESI, Fig. S6†).
In an attempt to check the catalyst leaching during reaction
time, hot ltration test was performed.25,44,45 Aer the SSA
catalyst was ltrated under hot condition, followed by the
continuation of the reaction for 30 min, no signicant
improvement in the yield of DAPG was observed. Thereby, it
obviously conrmed that no effective leaching of the active
species from the SSA catalyst took place into the reaction
medium. Furthermore, this observation also strengthens the
heterogeneity of the SSA catalyst.
Fig. 7 Comparison of the raw material footprint for the synthetic
routes A, B, C, D, and E to DAPG.
and inefficient strategy for transferring heat into the system. In
contrast, the present method (synthesis of E), which was
assisted by US, corresponded to a lower energy usage of 56.14
kW molꢁ1 compared to the oil-bath methods. It is interesting to
notice that the application of US for the synthesis of DAPG
could increase the rate of reaction and required a smallest
amount of energy throughout compared to the oil-bath
methods. Nevertheless, the present method required slightly
higher energy as compared with the MW method (synthesis of
A). Accordingly, the MW method could demonstrate a shorter
reaction time than the US method. Besides the lowest energy
required, the obtained yield of method A is lower than that of
our developed method. Finally, reecting on all the used green
parameters, it is obvious that the present method signicantly
improved the synthetic procedure for DAPG compared to the
conventional and MW techniques.
Comparison experiments of the SSA catalyst
As a further effort, we compared the activity of SSA catalyst with
a variety of protic acids (acetic acid, methanesulfonic acid, and
perchloric acid) immobilised on silica gel, following the same
typical reaction, as presented in Table 7. Moreover, we also
undertook the comparative study of their catalytic performance
with a reported heterogeneous catalyst such as zeolite.8 In the
comparison of the activity of SSA with the other protic acids
immobilised on silica gel, the highest yield of DAPG was ob-
tained by using SSA as the catalyst (Table 7). When the activity of
Drug-likeness screening
Drug-likeness is a qualitative method employed in drug design,
which is designated to optimize pharmacodynamics, pharma-
cokinetics, and pharmaceutical properties, such as the solu-
bility, bioavailability, chemical stability, and distribution prole
in the human body.70 The most common rule used to evaluate
the drug-likeness aspect is Lipinski's rule of ve.71 According to
the results (Table 8), all the synthesised compounds, either
diacylphloroglucinols or monoacylphloroglucinol, are in
accordance with the adequate criteria of Lipinski's rule of ve,
i.e., molecular weight (MW), hydrogen bond donor (HBD),
hydrogen bond acceptor (HBA), and log P; therefore, they can be
considered as oral drug candidates.
Table
6 Comparison of the energy consumed by oil-bath (D),
microwave (MW), and ultrasound (US) heating for the Friedel–Crafts
acylation between phloroglucinol and acetic anhydride
Method
Heating method
mmol
A
MW
1
B
C
D
E
US
1
Oil-bath
1
Oil-bath
2.5
Oil-bath
1
Yield (%)
P (kW)
t (h)
E (kW h)
E (kW h mol)
Ref
88
30
1.44
0.5
0.72
2400
20
60
1.44
2
2.88
12 000
2
95
1.44
0.5
0.72
757.89
18
95
Conclusions
0.7
0.02
0.01
13.26
16
0.16
0.33
0.05
56.14
Present
In summary, we have developed a sustainable and highly effi-
cient synthetic method of the highly valuable organic
compound DAPG from phloroglucinol over the eco-friendly
heterogeneous SSA catalyst under milder conditions. The
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Table 7 Comparison of the catalyst performance of SSA with a variety of protic acid (acetic acid, methanesulfonic acid, and perchloric acid)
immobilised silica gels and other heterogeneous catalyst systems
Runs
Catalyst
Cat. loading
T (ꢀC)
t (min)
Yield (%)
Ref
1
2
3
4
5
6
7
8
H2SO4–SiO2
HClO4–SiO2
HBr–SiO2
TFA–SiO2
20%
20%
20%
20%
60
60
60
60
80
80
80
80
15–20
40
95
64
54
70
10
0
Present work
Present work
Present work
Present work
Present work
16
60
120
120
30
30
30–45
Zeolite Y
20%
a
MSA/alumina
MSA/graphite
Activated natural zeolite mordenite
a
0
95
16
18
20%
a
Not reported.
environmental assessment prole, the sustainable reaction
conditions, viz., solvent-free condition and ultrasound assis-
tance for the synthesis of DAPG under the optimum conditions
were evaluated to be a convenient tool for meeting the green
chemistry principles23 of waste reduction and energy require-
ment reduction. However, as compared with the MW method
(synthesis of A), the newly developed method required slightly
higher energy. Nonetheless, the practicality and sustainability
signicantly improved the synthetic procedure for DAPG, as
established using the EATOS soware, Andraos algorithm, and
the energy requirement calculations. These results have evalu-
ated the most substantial contribution and improvements of
this method against the others reported in the literature con-
cerning the synthesis of DAPG. Furthermore, all DAPG deriva-
tives satisfy the Lipinski's rule of ve; thus, they would not
exhibit problems in the oral bioavailability.
Fig. 8 Recycling of the SSA catalyst on the DAPG yield under the
optimum conditions.
Table 8 Evaluation of drug-likeness of the synthesised compounds
with respect to Lipinski's rule of five
Lipinski's rule of ve
Conflicts of interest
MWa
<500
HBDb
<5
HBAc
<10
Log P
There are no conicts to declare.
Compound
<5
nVd
3
210.19
266.29
294.35
168.15
196.20
210.23
238.24
252.27
3
3
3
3
3
3
3
3
5
5
5
4
4
4
5
5
0.83
2.25
2.80
0.70
1.40
1.72
1.57
1.81
0
0
0
0
0
0
0
0
Acknowledgements
5a
5b
6a
6b
6c
7a
7c
The authors are thankful to the Ministry of Research, Tech-
nology and Higher Education, the Republic of Indonesia for
providing nancial support through Penelitian Dasar Unggulan
Perguruan Tinggi (PDUPT) 2019 grant (contract agreement
number: 719/UN27.21/PN/2019). The authors also wish to
gratefully acknowledge to the Institute of Research and
Community of Services Sebelas Maret University for partially
nance through Hibah Penelitian Unggulan (PU-UNS) 2020
(contract agreement number: 452/UN27.21/PN/2020), Hibah
Pascasarjana (PPS) 2019 grant (contract agreement number:
516/UN27.21/PP/2019) and Hibah Pascasarjana (PPS) 2020 grant
(contract agreement number: 452/UN27.21/PN/2020). We are
also grateful to Septin D Anggraini S. Si and Ita Apriana, S. Si for
being assistant during the preparation of catalyst.
a
b
c
MW: molecular weight.
HBD: hydrogen bond donor. HBA:
hydrogen bond acceptor. d nV: number of violations.
present method shows signicant advantages, both in terms of
sustainability and efficiencies. It uses no solvent and is a metal-
free catalyst, and uses US waves as an alternative green source of
energy. It also has rapid reaction times, an excellent yield,
a simple workup, and an inexpensive and recyclable catalyst.
RSM analysis and the conrming experiment of the Friedel–
Cras acylation reaction run inꢀdicated that the highest DAPG
yield (95%) was achieved at 60 C aer 20 min employing the
SSA catalyst at a concentration of 10% (w/w). According to the
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