Ultrasound-assisted green synthesis of dialkyl peroxides under phase-transfer catalysis conditions

Article abstract of DOI:10.3390/molecules25010118

The dialkyl peroxides, which contain a thermally unstable oxygen-oxygen bond, are an important source of radical initiators and cross-linking agents. New efficient and green methods for their synthesis are still being sought. Herein, ultrasound-assisted s

Full text of DOI:10.3390/molecules25010118

molecules
Article
Ultrasound-Assisted Green Synthesis of Dialkyl
Peroxides under Phase-Transfer Catalysis Conditions
Daniel Kopec´, Stefan Baj and Agnieszka Siewniak *
Department of Chemical Organic Technology and Petrochemistry, Silesian University of Technology,
Krzywoustego 4, 44-100 Gliwice, Poland; kopciu89@interia.pl (D.K.); stefan.baj@gmail.com (S.B.)
* Correspondence: agnieszka.siewniak@polsl.pl
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 26 November 2019; Accepted: 25 December 2019; Published: 28 December 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The dialkyl peroxides, which contain a thermally unstable oxygen–oxygen bond, are an
important source of radical initiators and cross-linking agents. New efficient and green methods
for their synthesis are still being sought. Herein, ultrasound-assisted synthesis of dialkyl peroxides
from alkyl hydroperoxides and alkyl bromides in the presence of an aqueous solution of an inorganic
base was systematically studied under phase-transfer catalysis (PTC) conditions. The process run in
a tri-liquid system in which polyethylene glycol as a phase-transfer catalyst formed a third liquid
phase between the organic and inorganic phases. The use of ultrasound provided high yields of
organic peroxides (70–99%) in significantly shorter reaction times (1.5 h) in comparison to reaction
with magnetic stirring (5.0 h). In turn, conducting the reaction in the tri-liquid PTC system allowed
easy separation of the catalyst and its multiple use without significant loss of activity.
Keywords: dialkyl peroxide; ultrasound irradiation; phase-transfer catalysis; tri-liquid PTC system;
third-liquid phase
1. Introduction
The phase-transfer catalysis (PTC) is a well-established technique in the synthesis of compounds
with important practical applications in pharmaceuticals, agrochemicals, fragrances, dyes, monomers,
and others [1]. It is a special type of heterogeneous catalysis in which the reaction occurs between
reagents that are located in two phases in the presence of a phase-transfer catalyst. The role of the
catalyst is to transport one of the reagents in the active state from a usually inorganic phase to an
organic phase, where the reaction with the organic reagent takes place [2]. PTC catalysts are often
quaternary ammonium salts, crown ethers, or polyethylene glycols. The benefits of using PTC are
minimization or elimination of organic solvents, the use of easily accessible, cheap and often safer
reagents (e.g., NaOH, KOH, K2CO3, etc. instead of NaH, t-BuOK, etc.), high yield and high purity of
products obtained, and simple synthesis procedure, to name a few.
The dialkyl peroxides are readily used as radical polymerization initiators, e.g., in the
polymerization of olefins and as crosslinking agents, e.g., for ethylene–propylene copolymers, silicone
rubbers, and others [3,4].
A convenient way to obtain unsymmetrical dialkyl peroxides is the reaction between alkyl
hydroperoxides and alkyl halides in the presence of inorganic bases, e.g., KOH and NaOH. This reaction
proceeds in a two-phase system. Maillard et al. carried out the reaction with a solid potassium hydroxide,
using polyethylene glycol [5] or benzyltriethylammonium chloride [6] as the phase-transfer catalyst.
These methods allowed them to obtain peroxide yields ranging from 18% to 80% after reaction times
from 0.5 to 72 h. The problem that occurs with the use of soluble PTC catalysts concerns the difficulties
of separating the catalyst from the reaction mixture. It may affect product purity and process costs.
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In previous work, we described the efficient method of the dialkyl peroxides synthesis from
alkyl hydroperoxides and alkyl bromides by using the immobilized PTC catalysts [ ]. This enabled
7
easy separation and reuse of the catalyst. However, to avoid the additional costs associated with the
immobilization of the catalyst on a solid support, we applied a tri-liquid PTC technique to obtain
dialkyl peroxides [8,9]. In this technique the liquid PTC catalyst is predominately located in a third
liquid phase and can be easily separated from the reaction mixture [10–12].
In the continuation of our research interests in the development of green synthesis of dialkyl
peroxide, we used ultrasound to accelerate the process of their synthesis in the tri-liquid PTC system
using nontoxic, cheap, and biodegradable polyethylene glycols as the PTC catalysts. In the literature,
there are many examples which prove that the combination of PTC and ultrasound contributes to the
intensification of the process [13–19].
2. Results and Discussion
Research on the influence of ultrasound on the course of the synthesis of dialkyl peroxides
was carried out on the example of the reaction between 1-bromobutane and cumyl hydroperoxide
(CHP) (Scheme 1). Polyethylene glycols and their derivatives were used as phase-transfer catalysts.
The reaction was carried out in such a way that the catalyst formed a third liquid phase. The other two
liquid phases were CHP dissolved in cyclohexane and a concentrated inorganic base solution.
P E G
+ KBr + H2O
OOR
OOH + RBr + KOH
ultrasound
Scheme 1. A model reaction.
2.1. Effect of Ultrasound
We started our research by comparing the influence of two techniques on the course of the model
reaction: an ultrasound irradiation and a magnetic stirring. In the case of the first technique, the
process was carried out in a thermostated ultrasound bath (45 kHz, 350 W), while, in the second one,
it was carried out with a magnetic stirrer (500 rpm). We chose the speed of 500 rpm based on our
previous research, which showed that above 400 rpm the rate of the model reaction in the tri-liquid
system was independent of the stirring speed. The other reaction conditions were the same (50 ◦C; 50%
KOH; PEG MM 2000—polyethylene glycol monomethyl ether CH3O(CH2CH2O)44CH3; cyclohexane
as an organic solvent).
The results presented in Table 1 clearly show that the use of ultrasound significantly caused a
decrease in the required reaction time. A similar peroxide yield was achieved after 1.5 h instead of 5.0 h,
as it was in the case of using magnetic stirring. This result confirmed that cavitation had a positive
effect on the intensification of the process of obtaining dialkyl peroxides in a tri-liquid system where
all reagents and catalyst remained in the separate phases.
Table 1. The effect of magnetic stirring or ultrasound irradiation. Reaction conditions: 1-bromobutane
0.21 g, 1.50 mmol; CHP 0.23 g, 1.50 mmol; PEG MM 2000 0.30 g, 0.15 mmol; 50% KOH 1.68 g, 30.00 mmol;
cyclohexane 3 cm3; temperature 50 ◦C; selectivity 100%.
Technique
Time (h)
Peroxide Yield (%)
Magnetic stirring, 500 rpm
Ultrasound irradiation
5.0
1.5
97
99
2.2. Effect of Catalyst Structure
PEGs with different chain lengths and different end groups –OH or –CH3 were used for the tests.
In Table 2 PEG means polyethylene glycol with the formula HO(CH2CH2O)nH, PEG MM means

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polyethylene glycol monomethyl ether HO(CH2CH2O)nCH3, and in turn PEG DM is polyethylene
glycol dimethyl ether CH3O(CH2CH2O)nCH3, whereas the number after the catalyst abbreviation
represents the average molecular weight of PEG.
Based on the results in Table 2, it might be observed that the reaction yield increased with increasing
length of the polyethylene oxide chain. The role of the catalyst is a complexation of potassium cation
(Scheme 2). Polyethylene glycols with low “n” values are too short to form complex with potassium
cation. Catalysts with higher “n” values, e.g., PEG MM 2000, are long enough to easily complex even
two cations at once, which results in their increasing activity and in higher peroxide yield [20].
Table 2. The effect of end groups and chain length of polyethylene glycols. Reaction conditions:
1-bromobutane 0.21 g, 1.50 mmol; CHP 0.23 g, 1.50 mmol; catalyst 0.15 mmol; 50% KOH 1.68 g,
30.00 mmol; cyclohexane 3 cm3; temperature 50 ◦C; reaction time 90 min; ultrasonic bath 45 kHz, 350 W;
selectivity 100%.
Entry
Catalyst
Amount of Catalyst (% mol)
n~:1 Peroxide Yield (%)
1
2
3
4
5
6
7
8
9
PEG 200
PEG 600
PEG 1000
10
10
10
10
10
10
10
5
4
18
70
81
71
74
85
99
78
77
57
92
13
22
7
12
24
44
44
44
10
21
PEG MM 350
PEG MM 550
PEG MM 1100
PEG MM 2000
PEG MM 2000
PEG MM 2000
PEG DM 500
PEG DM 1000
1
10
10
10
11
1
n—number of ethoxylate group in PEGs and their derivatives X(CH2CH2O)nY, where X is –OH or –OCH3, and Y
is –H or –CH3.
When catalysts with similar molecular weights and chain lengths were compared (entries 2, 5, and
10 in Table 2), it appeared that the catalyst end groups also affected the dialkyl peroxide yield. The most
active catalyst in the reaction was that which had both –CH3 and –OH as end groups. In further
studies, PEG MM 2000 was used as a catalyst. The use of less than 10% of the catalyst relative to CHP
resulted in a significant drop in the peroxide yield (entries 7, 8, and 9).
2.3. Effect of a Kind, Concentration, and Amount of Inorganic Base and a Kind of Organic Solvent
The comparison of 50% solutions of two bases KOH and NaOH (entries 1 and 2 in Table 3), showed
that better peroxide yield was obtained by using a solution of potassium hydroxide. Most likely, this is
due to the fact that KOH is a stronger base than NaOH. In addition, PEGs more easily form complexes
with potassium cations than sodium ones [1]. Moreover, in the case of using a 50% NaOH solution,
the reaction mixture became turbid and viscous, which might hinder mixing of the reaction mixture.
In the case of KOH solutions of varying concentrations, it can be seen that, as the concentration
increased, the reaction yield also increased. With a 50% KOH solution the peroxide yield was close
to 100%.
The effect of 50% aqueous solution of KOH on the course of the model reaction was examined
for molar ratio KOH to CHP of 20:1, 10:1, and 5:1 (entries 2, 5, and 6 in Table 3). The other reaction
conditions remained unchanged. The peroxide yield increased with increasing molar ratio of KOH to
CHP. It should be emphasized that, in each case, the formation of a three-phase system was observed.

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Table 3. The effect of end groups and chain length of polyethylene glycols. Reaction conditions:
1-bromobutane 0.21 g, 1.50 mmol; CHP 0.23 g, 1.50 mmol; PEG MM 2000 0.30 g, 0.15 mmol; cyclohexane
3 cm3; temperature 50 ◦C; reaction time 90 min; ultrasonic bath 45 kHz, 350 W; selectivity 100%.
Entry
Base
Concentration of Base Solution
Molar Ratio KOH:CHP
Peroxide Yield (%)
1
2
3
4
5
6
NaOH
KOH
KOH
KOH
KOH
KOH
50
50
40
30
50
50
20
20
20
20
10
5
67
99
71
60
83
81
The selection of a suitable solvent is also crucial for the course of the model reaction, as well as
for the catalyst to remain in the third liquid phase immiscible with the others. For the tests, solvents
of various polarity were used, such as cyclohexane, toluene, and chlorobenzene. Only in the case of
cyclohexane, the three-phase system was stable even after the completion of the reaction. If toluene
was used, the tri-liquid system disappeared after the reaction and the peroxide yield was low (Table 4).
For chlorobenzene, only the two-phase system was observed.
Table 4. The effect of a kind of organic solvent. Reaction conditions: 1-bromobutane 0.21 g, 1.50 mmol;
CHP 0.23 g, 1.50 mmol; PEG MM 2000 0.30 g, 0.15 mmol; 50% KOH 1.68 g; organic solvent 3 cm3;
temperature 50 ◦C; reaction time 90 min; ultrasonic bath 45 kHz, 350 W; selectivity 100%.
Entry
Solvent
Peroxide Yield (%)
1
2
cyclohexane
toluene
99
35
2.4. Synthesis of Dialkyl Peroxides and Recycling of Catalyst
We examined the effect of the alkyl chain length of the alkyl bromide on the peroxide yield under
the most favorable reaction conditions obtained on the basis of the present study (50% KOH, KOH to
CHP of 20:1, PEG MM 2000, and cyclohexane). It can be observed that the peroxide yield decreased
with the lengthening of the alkyl chain (Table 5). However, all peroxides were obtained with high
yields (70–99%).
Table 5. The effect of a kind of organic solvent. 1 alkyl bromide, 1.50 mmol; CHP 0.23 g, 1.50 mmol;
PEG MM 2000 0.30 g, 0.15 mmol; 50% KOH 1.68 g; cyclohexane 3 cm3; temperature 50 ◦C; reaction time
90 min; ultrasonic bath 45 kHz, 350 W; selectivity 100%.
Alkyl Bromide
Peroxide Yield (%)
n-bromopropane
96 (fresh catalyst)
93 (1th cycle)
89 (2nd cycle)
87 (3rd cycle)
75
99 (fresh catalyst)
95 (1th cycle)
91 (2nd cycle)
89 (3rd cycle)
70
2-bromopropane
n-bromobutane
2-bromobutane
n-bromopentane
n-bromohexane
88
85
To demonstrate the practical potential of the presented method, the recycling studies of the
catalysts were also investigated. In the case of the tri-liquid system, separation of the reaction mixture

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was easy, using just a simple phase separation. The separated catalyst was used for the next process.
Only a slight decrease in peroxide yield was observed.
2.5. Proposed Scheme of the Model Reaction Course
It is assumed that the reactions carried out in the tri-liquid PTC system occur mainly in the catalyst
phase. This requires that all reagents diffuse into the middle phase. In such a system, the model
reaction involves several steps: (1) formation of potassium hydroperoxide salt at the interface between
the organic and inorganic phases and then the formation of a complex with polyethylene glycol
PEG-K+PhC(CH3)2OO- (variant 1), or PEG forms a complex with KOH and then reacts with cumyl
hydroperoxide to form a complex PEG-K+PhC(CH3)2OO- (variant 2); (2) diffusion of alkyl bromide to
the catalyst phase; (3) reaction between alkyl bromide and PEG-K+PhC(CH3)2OO– (4) diffusion of the
product to the organic phase.
Ph
OOR
OOR
RBr
Ph
Ph
OOH
OOH
organic phase
OH-
-OO
+ K+
K+
+
Ph RBr
Ph
+
+
variant 2
+
KBr
H2O
variant 1
Ph
+
+
-
+
+
H2O
+
OOH KOH Ph
OO K
third-liquid catalyst phase
aqueous phase
where:
KOH
KBr
H2OH2O
- polyethylene glycol
Scheme 2. Proposed scheme of the model reaction course.
3. Materials and Methods
3.1. Chemicals
All applied organic reagents and solvents were of reagent grade purity and were used without
further purification, unless stated otherwise. The 1-Methyl-1-phenylethyl hydroperoxide (cumyl
hydroperoxide, CHP) was purified by the method described elsewhere [21].
The 1-Bromobutane (>98%) and cyclohexane were distilled prior to being used for synthesis. PEG
(polyethylene glycol) 200, PEG 600, and PEG 1000 were purchased from Alfa Aesar GmbH & Co KG
(Karlsruhe, Germany). PEG MM (polyethylene glycol monomethyl ether) 350, PEG MM 550, PEG
MM 1100, PEG MM 2000, PEG DM polyethylene glycol dimethyl ether) 500, and PEG DM 1000 were
purchased from Fluka Chemie GmbH (Steinheim, Germany).
3.2. Apparatus
UPLC was performed on Acquity Waters chromatography equipped with an Acquity Waters PDA
detector and an Acquity UPLC BEH C18 column (100 mm
USA). Reactions were performed in an ultrasonic bath EMAG Emmi 60 (Mörfelden-Walldorf, Germany).
×
2.1 mm, 1.7 µm) (Waters Corp., Milford, MA,

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3.3. Experimental Procedure
Typical reaction was carried out in a two-neck round bottom flask (10 cm3) (Vitromin S.C.,
Kobyłka, Poland), equipped with a reflux condenser, which was immersed into an ultrasonic bath
(45 kHz, 350 W). An aqueous solution of inorganic base (30.00 mmol), a phase-transfer catalyst
(0.15 mmol), CHP (1.50 mmol), and 1-bromobutane (1.50 mmol) were added, in this order, to the flask.
The temperature was controlled and kept constant throughout the process (with a precision
After 1.5 h, the reaction mixture was cooled, and a sample was taken from the organic layer.
±
1 ◦C).
Analysis: Samples were analyzed by liquid chromatography UPLC (Waters Corp., Milford,
MA, USA). The mobile phase was a mixture of acetonitrile:water (80:20 v/v), and the flow rate was
0.25 cm3/min. All peroxide yields were determined on the basis of UPLC analysis and calculated from
the calibration curves of peroxide standards.
Catalyst recycling: Studies on the possibility of reusing the catalyst were carried out on a
twice-larger scale, according to the procedure described above. After completion of the reaction,
the mixture was cooled, and the catalyst phase was separated from the other two phases: organic and
inorganic. The separated catalyst was used in the next process.
Product isolation: The organic phase was concentrated on a rotary evaporator (Heidolph
Instruments GmbH & CO. KG, Schwabach, Germany). Purification of the product was carried out
1
by column chromatography. Toluene was used as a mobile phase. H, 13 C NMR chemical shifts of
dialkyl peroxides are available in the Supplementary Materials file.
4. Conclusions
The combination of tri-liquid PTC system and ultrasound allowed for the development of an
effective method of dialkyl peroxides synthesis. On the one hand, the formation of a third liquid phase
by the catalyst simplifies the procedure for its separation and allows its use several times in subsequent
processes. This, in turn, affects the reduction of investment and operating costs of the process. On the
other hand, the use of ultrasound offers the intensification of the process, significantly reduces the
reaction time, and allows peroxides to be obtained with high yields. In addition, PEGs used as catalysts
are cheap, readily available, nontoxic, and easily biodegradable compounds. All this proves that the
developed green approach has significantly practical appeal.
Supplementary Materials: The following are available online. 1H, 13 C NMR chemical shifts of dialkyl peroxides.
Author Contributions: Performance of experiments, D.K.; conceptualization S.B. and A.S.; supervision of the
project, S.B. and A.S.; HPLC analysis, A.S.; writing—original draft preparation, review, and editing, A.S. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
2.
3.
4.
5.
Starks, C.M.; Liotta, C.L.; Halpern, M. Phase-Transfer Catalysis: Fundamental, Applications and Industrial
Perspectives; Chapman&Hall: New York, NY, USA, 1994.
Makosza, M.; Fedorynski, M. Phase Transfer Catalysis—Basic Principles, Mechanism and Specific Features.
Curr. Catal. 2012, 1, 79–87. [CrossRef]
Snchez, J.; Myers, T.N. Peroxides, Organic. In Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed.;
Seidel, A., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2006; Volume 18, pp. 425–506.
Berkessel, A.; Vogl, N. Synthetic uses of peroxides. In The Chemistry of Peroxides, 1st ed.; Rappoport, Z., Ed.;
John Wiley & Sons, Ltd.: Chichester, UK, 2006; Volume 2, pp. 307–596.
Bourgeois, M.-J.; Montaudon, E.; Maillard, B. An Easy Access to Unsymmetrical Peroxides. Synthesis 1989
1989, 700–701. [CrossRef]
,

Molecules 2020, 25, 118
7 of 7
6.
Moulines, J.; Bougeois, M.-J.; Campagnole, M.; Lamidey, A.-M.; Maillard, B.; Montaudon, E. Phase-Transfer
Catalytic Alkylation of Hydroperoxides: A Convenient Route to Mixed Dialkyl Peroxides. Synth. Commun.
1990, 20, 349–353. [CrossRef]
7.
8.
9.
Baj, S.; Siewniak, A.; Socha, B. Synthesis of dialkyl peroxides in the presence of polymer-supported
phase-transfer catalysts. Appl. Catal. A Gen. 2006, 309, 85–90. [CrossRef]
Baj, S.; Siewniak, A. Synthesis of dialkyl peroxides in the presence of polyethylene glycol or its derivatives as
phase-transfer catalyst in liquid–liquid–liquid system. Appl. Catal. A Gen. 2007, 321, 175–179. [CrossRef]
Baj, S.; Siewniak, A. Tri-liquid system in the synthesis of dialkyl peroxides using tetraalkylammonium salts
as phase-transfer catalysts. Appl. Catal. A Gen. 2010, 385, 208–213. [CrossRef]
10. Yadav, G.D.; Sowbna, P. Process intensification and waste minimization in liquid–liquid–liquid phase transfer
catalyzed selective synthesis of mandelic acid. Chem. Eng. Res. Des. 2012, 90, 1281–1291. [CrossRef]
11. Zhao, Q.; Zhao, X.; Sun, J.; Yang, L.; Shen, Y. Catalytic Process for the Hydroxide-Initiated Reaction of the
“Weakly Acidic” Substrate in the Third-Liquid Phase-Transfer Catalytic System. Ind. Eng. Chem. Res. 2018
57, 13318–13326. [CrossRef]
,
12. Yadav, G.D.; Lande, S.V. Intensification of Rates and Selectivity Using Tri-liquid versus Bi-liquid Phase
Transfer Catalysis: Insight into Reduction of 4-Nitro-o-xylene with Sodium Sulfide. Ind. Eng. Chem. Res.
2007, 46, 2951–2961. [CrossRef]
13. Yang, H.-M.; Hung, Y.-H.; Tu, C.-Y. Synthesis of butyl salicylate by phase-transfer catalysis with dual-site
phase-transfer catalyst and ionic liquid in tri-liquid system. J. Taiwan Inst. Chem. Eng. 2014, 45, 1421–1427.
[CrossRef]
14. Yang, H.-M.; Chen, Y.-C. Ultrasound-assisted third-liquid phase-transfer catalyzed esterification of potassium
4-methoxyphenylacetate by dual-site phase-transfer catalyst. J. Taiwan Inst. Chem. Eng. 2012, 43, 897–903.
[CrossRef]
15. Yang, H.-M.; Chiu, C.-C. Ultrasound-assisted phase-transfer catalysis: Benzoylation of sodium
4-acetylphenoxide by dual-site phase-transfer catalyst in a tri-liquid system. Ultrason. Sonochem. 2011, 18,
363–369. [CrossRef] [PubMed]
16. Yang, H.-M.; Lin, D.-W. Third-liquid phase-transfer catalyzed esterification of sodium benzoate with novel
dual-site phase-transfer catalyst under ultrasonic irradiation. Catal. Commun. 2011, 14, 101–106. [CrossRef]
17. Yang, H.-M.; Peng, G.-Y. Ultrasound-assisted third-liquid phase-transfer catalyzed esterification of sodium
salicylate in a continuous two-phase-flow reactor. Ultrason. Sonochem. 2010, 17, 239–245. [CrossRef]
[PubMed]
18. Yang, H.-M.; Chen, C.-H. Catalytic esterification of sodium salicylate in third-liquid phase under
ultrasound-assisted tri-liquid phase-transfer catalysis. J. Mol. Catal. A Chem. 2009, 312, 107–113. [CrossRef]
19. Vivekanand, P.A.; Wang, M.-L.; Hsieh, Y.-M. Sonolytic and Silent Polymerization of Methacrlyic Acid
Butyl Ester Catalyzed by a New Onium Salt with bis-Active Sites in a Biphasic System—A Comparative
Investigation. Molecules 2013, 18, 2419–2437. [CrossRef] [PubMed]
20. Neumann, R.; Sasson, Y. Mechanism of base-catalyzed reactions in phase-transfer systems with poly(ethylene
glycols) as catalysts. The isomerization of allylanisole. J. Org. Chem. 1984, 49, 3448–3451. [CrossRef]
21. Kharasch, M.S.; Fono, A.; Nudenberg, W. The Chemistry of Hydroperoxides. VI. The thermal decomposition
of α-cumyl hydroperoxide. J. Org. Chem. 1951, 19, 113–127. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
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