CHEMICAL REACTION KINETICS OF 1,5-BIS (3'-ETHOXY-4'-HYDROXYPHENYL)-1,4–PENTADIENT-3–ONE SYNTHESIS WITH FOOD GRADE RAW MATERIAL

Abstract

Objective: This research aims to develop the 1,5-bis (3'-ethoxy-4'-hydroxyphenyl)-1,4-pentadient-3-one (EHP) synthesis method from ethyl vanilin with food-grade quality and determines the order reaction and formation reaction rate constant of EHP. Methods: Synthesis of the EHP was carried out by reflux the starting material, ethyl vanillin (food grade) of various weights, acetone and hydrochloric acid as catalysts. The reflux results are then condensed for two days at cold temperatures. Determination of the reaction order and reaction rate constants are carried out by the graph method based on the reduction in the concentration of ethyl vanilin, which reacts with acetone each time unit. Results: The results showed the formation of EHP, which was synthesized by starting material of ethyl vanilin food grade 4 and 8 grams following pseudo-first-order reaction kinetics with reaction rate constants respectively 0,0116/minute and 0,005/minute. The formation of EHP, which was synthesized by starting material ethyl vanilin food grade 16 and 18 grams following zero-order reaction kinetics with reaction rate constants respectively 0,1451 mg/ml minute and 0,248 mg/ml minute. Conclusion: The synthesis of EHP from ethyl vanilin with food-grade quality has been success develop. The order reaction kinetics are different in the different mass of ethyl vanillin used.

Full text

Mulatsari et al.
Int J App Pharm, Vol 13, Special Issue 2, 2021, 67-70
The 3rd Postgraduate Seminar on Pharmaceutical Sciences 2020 | 67
CHEMICAL REACTION KINETICS OF 1,5-BIS (3'-ETHOXY-4'-HYDROXYPHENYL)-1,4–
PENTADIENT-3–ONE SYNTHESIS WITH FOOD GRADE RAW MATERIAL
Original Article
ESTI MUMPUNI1, ESTI MULATSARI1*, AGUS PUWANGGANA1, SOLA FIDE VICY1
1Faculty of Pharmacy, Universitas Pancasila, Jakarta, Indonesia
*Email: esti.mulatsari@univpancasila.ac.id
Received: 09 Sep 2020, Revised and Accepted: 09 Oct 2020
ABSTRACT
Objective: This research aims to develop the 1,5-bis (3'-ethoxy-4'-hydroxyphenyl)-1,4-pentadient-3-one (EHP) synthesis method from ethyl vanilin
with food-grade quality and determines the order reaction and formation reaction rate constant of EHP.
Methods: Synthesis of the EHP was carried out by reflux the starting material, ethyl vanillin (food grade) of various weights, acetone and
hydrochloric acid as catalysts. The reflux results are then condensed for two days at cold temperatures. Determination of the reaction order and
reaction rate constants are carried out by the graph method based on the reduction in the concentration of ethyl vanilin, which reacts with acetone
each time unit.
Results: The results showed the formation of EHP, which was synthesized by starting material of ethyl vanilin food grade 4 and 8 grams following
pseudo-first-order reaction kinetics with reaction rate constants respectively 0,0116/minute and 0,005/minute. The formation of EHP, which was
synthesized by starting material ethyl vanilin food grade 16 and 18 grams following zero-order reaction kinetics with reaction rate constants
respectively 0,1451 mg/ml minute and 0,248 mg/ml minute.
Conclusion: The synthesis of EHP from ethyl vanilin with food-grade quality has been success develop. The order reaction kinetics are different in
the different mass of ethyl vanillin used.
Keywords: EHP, Chemical reaction kinetics, Food grade ethyl vanillin
© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2021.v13s2.13 Journal homepage: https://innovareacademics.in/journals/index.php/ijap
INTRODUCTION
Indonesia is rich in biodiversity, which is considered as a medicinal
ingredient. One of the natural ingredient that has been developed and
researched is Curcumin. Curcumin is a yellow phenolic compound
contained in Curcuma longa (turmeric) and several other Curcuma
species, which has antioxidant activity, hepatoprotector, inhibitor of
several enzymes, anticancer, anti-inflammatory, immunomodulatory
and antimicrobial [1]. Due to these various activities, various
modifications have been made to the structure of curcumin to increase
its stability, potency, selectivity and bioavailability [1]. By modifying
the chemical structure of curcumin, Sardjiman et. al has succeeded in
obtaining and synthesizing three curcumin derivatives, named
pentagamavunon, hexagamavunon, and gamavuton.
Gamavuton is one of the curcumin analogue that is synthesized at
cold temperatures using aromatic aldehyde and acetone as well as
hydrochloric acid catalyst without using solvents [2]. The chemical
structure of Gamavuton can be modified by changing the methoxy
group to ethoxy to produce a new compound named 1,5-bis (3'-
ethoxy-4'-hydroxyphenyl)-1,4-pentadien-3-one (EHP). EHP has
better biological activity than curcumin, pentagamavuton,
hexagamavuton, and gamavuton [1].
EHP has antioxidant and antibacterial activity. EHP is stronger in
warding off free radicals so that the antioxidant activity of EHP is
better than curcumin and gamavuton [3]. The antibacterial activity
test showed that antibacterial potential of EHP is better than
amoxicillin and cefadroxyl in killing gram-positive bacteria
(Staphylococcus aureus, Staphylococcus epidermidis) and gram-
negative bacteria (Eschericia coli, Salmonella thypi) [4]. EHP was
known has anti-inflammatory activity [5].
EHP has a lot of benefits making this compound a great potential to
be produced on an industrial scale. This is reinforced by the
cheapness of food-grade ethyl vanillin as starting materials. So that
it is hoped that new domestic-produced drugs will be available
which is effective, safe, affordable to the public and able to compete
in the market. To develop the synthesis EHP into an industrial scale,
it is necessary to develop the optimum conditions for the synthesis
EHP using food-grade ethyl vanillin as starting materials that are
effective and efficient; and studying the chemical reaction kinetics
about formation reaction of EHP by determining the reaction order
and reaction rate constants.
Chemical kinetics is a branch of chemistry that studies the velocity of
chemical reactions [6]. Reaction kinetics can be studied by varying
one of the factors that affect the rate of the reaction (for example,
the concentration of reactants) and controlling for other factors (for
example, temperature and catalyst concentration) [7]. Information
on the reaction rate constants and the reaction order of reagents can
be used to design factory equipment and reactors in the production
process [8].
The data needed to synthesize EHP in an industrial scale include
reaction order and reaction rate constants. Reaction order cannot be
determined by looking at the equation of a reaction but must go
through an experiment [9]. One of them is by varying the weight of
one of the reactants, like food-grade ethyl vanillin and controlling
other factors such as temperature and catalyst concentration. This is
because the chemical reaction mechanism consists of several steps
and the reaction rate is often determined by the speed of the
reaction steps [10].
Reflux is a method in chemistry to synthesize a compound, both
organic and inorganic [11]. Generally used to synthesize compounds
whose initial ingredients are volatile. In this condition, when heating
is usually the initial material is volatile before the reaction runs to
completion. The principle of the reflux method is that volatile
materials will evaporate at high temperatures, but will be cooled by
a condenser so that the material that was in the form of vapor will
condense on the condenser and fall back into the reaction vessel so
that the solvent or reactants will remain during the reaction [12].
MATERIALS AND METHODS
Materials
The materials that were used in determine the reaction order and
formation reaction rate constant of EHP were food-grade ethyl
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ISSN- 0975-7058 Vol 13, Special Issue 2, 2021

Mulatsari et al.
Int J App Pharm, Vol 13, Special Issue 2, 2021, 67-70
The 3rd Postgraduate Seminar on Pharmaceutical Sciences 2020 | 68
vanillin (Sigma Aldrick), acetone (Merck), and concentred
hydrochloric acid 37% (Merck).
Instrumentation
The apparatus that was used in determine the reaction order and
formation reaction rate constant of EHP were Beaker glass (Pyrex),
test tube (Pyrex), 100 ml measuring cylinder (Pyrex), rough scales
(Pyrex), boiling stone, three-neck gourds, thermometer, condensor,
heat mantle (SEOH), 1 and 2 ml volumetric pipette (Pyrex), 10 ml
volumetric flask (Pyrex), rubber bulb, spectrophotometer
ultraviolet-visible (Shimadzu UV 1900), and refrigerator.
Preparation of standard food-grade ethyl vanillin
Weighed carefully approximately 20 mg of food-grade ethyl vanillin,
then dissolved in 10.0 ml acetone. The solution was pipette 2.0 ml
then added acetone up to 10,0 ml and homogenized.
Monitoring the concentration of ethyl vanillin per unit time
The ethyl vanillin powder was weighed 4 grams, then added with 50
ml acetone and stirred until it was homogeneous in a three-neck
flask. Added concentred hydrochloric acid 1 ml, and boiling stone.
The thermometer is attached to the hole on one side of the three-
neck flask. The other hole on the other side is blocked with a rubber
stopper. The condenser is installed and set over the three-neck flask
and the heat mantle underneath the flask. The heat mantle is turned
on and it is ensured that water always flows through the condenser.
The temperature is maintained at 70 ° C. After the temperature
reaches 70 °C, pipette 1.0 ml of the reactant mixture then add
acetone to 10.0 ml. Pipette 1.0 ml of the solution again, then add
acetone to 10.0 ml. The ethyl vanillin in the solution was measured
for absorbance at a wavelength 333.5 nm. Measurement of ethyl
vanillin absorbance for reactants was also carried out at 10 to 90
min. After the reflux process is complete, the reflux compound is
transferred to the erlenmeyer, then closed its mouth and cooled for
2 d in a refrigerator. The same was done for the variation of ethyl
vanillin weights 8, 16, and 32 grams.
Statistical analysis
Statistical evaluation of variation concentration of ethyl vanillin per
unit time carried out using the SPSS with One-sample t-test. Data
were expressed as the significance value (Sig). Sig ≤ 0,05 was
considered the concentration of ethyl vanilin statistically significant
for [13].
RESULTS
Determination of the reaction order and formation reaction
rate constant of EHP
The reaction kinetics formation of 1,5-bis (3'-ethoxy-4'-
hydroxyphenyl)-1,4-pentadien-3-one (EHP) was determined based on
the reduction concentration of ethyl vanillin as a reactant each time
unit. The reduction concentration of ethyl vanillin was only caused by
the cross-aldol condensation reaction between ethyl vanillin and
enolate from acetone, which was accelerated by the acid catalyst to
produce a candidate compound for the EHP product [2]. Monitoring
the reduction of the concentration of ethyl vanillin for synthesis EHP
with variations in the weight of the starting material of ethyl vanillin
food grade 4, 8, 16, and 32 grams resulted in data the concentration of
ethyl vanillin which decreased each time unit. Determination of
concentration was carried out by directly comparing the ethyl vanillin
absorbance sampled each unit time with ethyl vanillin absorbance as a
standard whose concentration was known. Ethyl vanillin
concentration data per unit time are shown in table 1.
Table 1: Ethyl vanillin concentration data per unit time
Food grade ethyl vanillin raw material (grams) 4 8 16 32
Concentration of ethyl vanillin (mg/ml) per
unit time (minutes)
0
38.4635
40.5462
37.9874
42.5100
10
36.9000
37.8035
37.2733
41.5957
20
33.7840
36.7486
36.2455
38.1984
30
29.5860
34.2790
34.8010
36.1102
40
24.5171
32.9184
33.7137
34.1032
50
23.4838
32.1178
32.9563
30.3704
60
20.9304
30.2893
30.2514
28.8719
70
18.6042
28.1687
29.0018
25.6694
80
15.9750
27.6006
26.7459
23.9923
90
13.7084
25.2312
25.1987
20.5301
To determine whether there is a significant effect effect of the cross
aldol condensation reaction on the reduction in the concentration of
ethyl vanillin at each time unit. It was analyzed statistically. Ethyl
vanillin concentration data for each unit of time obtained were
analyzed by one-sample t-test. Statistical test with One-sample t-test
uses the 95% confidence level. Table 2 presents the calculated
significance value of One-sample t-test on each variable and the
results of hypothesis testing.
Table 2: The calculated significance value of one-sample t-test
Food grade ethyl vanillin (grams)
Calculated significance value
Result
4
0.001
Significantly different
8
0.000
Significantly different
16
0.002
Significantly different
32
0.001
Significantly different
Table 2 presents that the calculated significance value of the one-
sample t-test on each variable is less than 0.05. This suggests that
there is an effect between the cross aldol condensation reaction on
the reduction the concentration of ethyl vanillin per unit time. In
other words, the concentration of ethyl vanillin at each time unit was
significantly different with the concentration of ethyl vanillin at t = 0.
Determination of the reaction order is done by graphing the
relationship between time (minutes) vs changes in reactant
concentration. The reaction order is based on the most linear graph
which is indicated by the value of the correlation coefficient (R2),
which is the largest (close to 1) of the correlation curve between
concentration; ln concentration; and 1/concentration (y-axis) with
time (x-axis). In this study, acetone and hydrochloric acid were
made excess, so it can be analyzed that the reaction order is a
pseudo-order model [10], where it is possible to have a pseudo-first-
order or pseudo-second-order reaction kinetics. The following is the
analysis of the reaction kinetics of ethyl vanillin reduction which
reacts with acetone to form a candidate compound for EHP products
in each of the weight variations of food grade ethyl vanillin 4,8,16,32
grams.

Mulatsari et al.
Int J App Pharm, Vol 13, Special Issue 2, 2021, 67-70
The 3rd Postgraduate Seminar on Pharmaceutical Sciences 2020 | 69
Fig. 1: Chemical reaction kinetics analysis curve of EHP synthesis weight variation of food grade ethyl vanillin: (A) 4 grams; (B) 8 grams;
(C) 16 grams; (D) 32 grams
Table 3: Details of the rate constant the formation of EHP
Food grade ethyl vanilin (grams)
Correlation coefficient (R
2
)
Gradient or reaction rate constants
4
0.9886
k’ = 0.0116/minute
8
0.9903
k’ = 0.0050/minute
16
0.9783
k = 0.1451 mg/ml minute
32
0.9944
k = 0.2480 mg/ml minute
DISCUSSION
In the synthesis of EHP with food-grade ethyl vanillin 4 grams as
raw material, the R2 value for the zero-order kinetics graph model
was 0.9841; whereas for the first and second-order kinetics graph
model, respectively 0.9886; and 0.9505. Based on these data, the
formation of EHP with food-grade ethyl vanillin 4 grams follows the
pseudo-first-order reaction kinetics. In the synthesis of EHP with
food-grade ethyl vanillin 8 grams as raw material, the R2 value for
the zero kinetics graph model was 0.9899; whereas for the first and
second-order kinetics graph model, respectively 0.9903; and 0.9805.
Based on these data, the formation of EHP with food-grade ethyl
vanillin 8 grams follows the pseudo-first-order reaction kinetics. In
the synthesis of EHP with food-grade ethyl vanillin 16 grams as raw
material, the R2 value for the zero kinetics graph model 0.9783;
whereas first and second-order kinetics graph model respectively
0.9620; and 0.9403. Based on these data, the formation of EHP with
food-grade ethyl vanillin 16 grams follows the zero-order reaction
kinetics. In the synthesis of EHP with food-grade ethyl vanillin 32
grams as raw material, the R2value for the zero kinetics graph model
was 0.9944; whereas the first and second-order kinetics graph
model respectively 0.9793; and 0.9427. Based on these data, the
formation of EHP with food-grade ethyl vanillin 32 gram follows the
zero-order reaction kinetics. The reaction kinetics following the zero
order means that increase the concentration of ethyl vanillin the
reaction has no effect on the reaction rate of EHP formation. If the
reaction kinetics of reduction the concentration of ethyl vanillin
follows the first order, it means that increase the ethyl vanillin
concentration in the system will increase the reaction rate 2 times.
Meanwhile, if the reaction kinetics of ethyl vanillin reduction follows
second order, increasing the concentration of ethyl vanillin in the
system will increase the reaction rate 4 times. The reaction order for
the formation of EHP synthesized with food grade ethyl vanillin with
weight variations of 4 and 8 grams follows the first-order reaction
kinetics. This indicates that the reaction of EHP formation with food
grade ethyl vanillin as starting materials with weight variations of 4
and 8 grams is faster than the reaction of EHP formation with food
grade ethyl vanillin as starting material weight variations of 16 and
32 grams, which follow the zero-order reaction kinetics. The
decrease in reaction rate in the formation of EHP with the starting
material of ethyl vanillin food-grade variations of weight 16 and 32
grams indicates that an increase the amount of ethyl vanillin as the
reactant, does not always provide an increase the rate of reduction
in the ethyl vanillin concentration to forming EHP. That is due to an
increasing amount of ethyl vanillin may causes the probability of
collision between ethyl vanillin and acetone to decrease and the
probability of collisions between ethyl vanillin molecules increases
[14]. As a result, there is a decrease in the rate of reduction of ethyl
vanillin to forming EHP. Determination of the reaction rate
constants based on the gradient value (value b) on the graph of the
reaction kinetics model, which is the most linear [10] or the value of
the correlation coefficient (R2) is the largest (close to 1). Table 3
details the gradient values on a linear graph of the relationship
between time and changes in concentration.
CONCLUSION
The formation of 1,5-bis (3'-ethoxy-4'-hydroxyphenyl)-1,4-
pentadien-3-on (EHP) which was synthesized based on variations
in the weight of the raw material of food grade 4 and 8 gram ethyl
vanillin following pseudo-first-order reaction kinetics with rate
constants respectively 0.0116/minute and 0.005/minute.
Meanwhile the weight variation of the raw material of food-grade
ethyl vanillin 16 and 32 gram following zero-order reaction
kinetics with reaction rate constants respectively 0.1451 mg/ml
minute and 0.248 mg/ml minute. The synthesis of EHP from ethyl
vanilin with food grade quality has been success develop. The
order reaction kinetics are different in the different mass of ethyl
vanillin used. The synthesis is very potential to develop EHP as
chemical drug material.

Mulatsari et al.
Int J App Pharm, Vol 13, Special Issue 2, 2021, 67-70
The 3rd Postgraduate Seminar on Pharmaceutical Sciences 2020 | 70
ACKNOWLEDGMENT
The authors are grateful for a research grant from Ministry of
Research, Technology and Higher Education of the Republic of
Indonesia for funding the research.
FUNDING
Funding from the Ministry of Research, Technology and Higher
Education of the Republic of Indonesia.
AUTHORS CONTRIBUTIONS
All the authors have contributed equally.
CONFLICT OF INTERESTS
There are no conflicts of interest.
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