Proceedings of the 2nd International Conference on Modern Medicine and Global Health

DOI: 10.54254/2753-8818/45/20240519

Modification of ibuprofen synthesis through the mechanism

analysis

Xinzhi Hu1,5, Yulai Song2,6, Jincheng Li3,7, Yueying Huang4,8,*

1
Department of chemistry, Hanyang University, Seoul, 04763, Republic of Korea
2
Collège beausoleil, Villars-sur-Ollon, 1884, Switzerland
3
Vanke Meisha Academy, Shenzhen, 519082, China
4
Department of chemistry, University of Oxford, Oxford, OX1 3TA, United Kingdom

5
h20000720@hanyang.ac.kr
6
songyulai489@gmail.com
7
18145820005@163.com
8
yueying.huang@chem.ox.ac.uk
*corresponding author’s e-mail: yueying.huang@chem.ox.ac.uk

Abstract. Ibuprofen is a common anti-inflammatory drug (NSAID) that was first invented and
patented by Boots UK back in the 1960s. Even though ibuprofen is made in huge amounts
worldwide nowadays, researchers are still trying to improve how it's synthesized to make the
process more efficient, sustainable, and less harmful to the environment. This paper looks at how
ibuprofen synthesis methods have evolved over history, from Boots' original approach to more
recent stuff like the BHC process, using electrochemistry, and continuous flow systems. It
examines the mechanism, green chemistry measures, and the pros and cons of each technique.
While it gave the first usable manufacturing method, Boots' synthesis wasn't so great with its
atom economy. The BHC synthesis boosted yield and atom economy a lot by streamlining the
process. Newer ways aim to make it even more selective and sustainable by using novel
chemistries and tighter process control. Basically, ibuprofen synthesis has steadily progressed
over time thanks to step-by-step innovation and a better understanding of the mechanisms. The
paper suggests ways forward to produce this important drug in safer, more efficient, eco-friendly
ways using modern green chemistry practices. Any pharmaceutical synthesis impacts people and
the environment, so we gotta keep improving processes.

Keywords: ibuprofen, synthesis, mechanism.

1. Introduction
Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has become a ubiquitous presence in
worldwide healthcare due to its widespread use for alleviating pain, reducing inflammation, and
lowering fever. This widespread usage can be attributed to its over-the-counter availability, potent
therapeutic benefits, and comparatively minimal side effects. Despite its pervasive presence, the
synthesis of ibuprofen is still a subject of ongoing research, with continuous efforts to refine and improve
its production process. The main focus of such research involves optimizing the synthetic procedure to
maximize yield, reduce reaction time, and minimize the use of hazardous reagents or catalysts. As the

© 2024 The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0
(https://creativecommons.org/licenses/by/4.0/).

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production of ibuprofen continues to grow in response to worldwide demand, it becomes increasingly

important to develop more efficient, sustainable, and safe manufacturing processes.
Dr. Stewart Adams, a pharmacologist from the United Kingdom, and his research team at the Boots
Pure Drug Company in Nottingham created ibuprofen. Their research was initiated in the late 1950s,
with the aim of developing a drug that could effectively relieve pain and inflammation without causing
significant side effects. The Boots team applied for an ibuprofen patent in 1962, and it was approved in
1966. [1,2] Then clinical trials began to evaluate ibuprofen's safety and effectiveness in treating a variety
of illnesses, including pain and inflammation. Ibuprofen was licensed for medicinal use in the United
Kingdom in 1969 after successful laboratory testing and clinical trails. [3] In the 1970s, structural
research on ibuprofen showed its particular binding interactions with COX enzymes, shedding light on
its anti-inflammatory properties.[4] In the 1980s, research concentrated on ibuprofen
absorption,distribution, metabolism, and excretion (pharmacokinetics). The research led to a better
understanding of its bioavailability, half-life, and interactions with various tissues. Researchers
investigated the stereochemistry of ibuprofen, which relates to the spatial arrangement of its atoms, in
the 1990s. The pharmacological characteristics of ibuprofen stereoisomers were examined.[5]Further
research was conducted in the 2000s to better understand the potential negative effects of ibuprofen,
notably on the gastrointestinal system and cardiovascular health. Studies looked into the trade-off
between its therapeutic effects and potential dangers.[6] In the 2010s, scientists researched
nanotechnology-based ibuprofen formulations to improve solubility and bioavailability, potentially
boosting efficacy and minimizing side effects.[7] In the 2020s, modern analytical techniques such as
computer modeling and sophisticated spectroscopy were used to acquire a better knowledge of
ibuprofen's molecular interactions. Ibuprofen has become one of the most widely used medications
globally as its aboudant beneficial. For instance, pain relief, anti-inflammatory properties, over-the-
Counter availablity, lower incidence of gastrointestinal irritation. Ibuprofen can be acquired over-the-
counter, therefore it is thought that its medical benefits have greatly enhanced patients' lives. As a human
anti-inflammatory medication. Ibuprofen has weak but distinct anti-inflammatory properties,
comparable to aspirin milligram for milligram, with far less negative effects on the stomach. The
medication's analgesic properties are most likely a result of its anti-inflammatory effects. Since it stops
the production of prostaglandins and has no effect on the adrenopituitary axis, it is a nonsteroidal agent.
Ibuprofen has been shown to be helpful in cases of rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, gout, and Bartter's syndrome.[8]
Over the years, various methods have been developed for the synthesis of ibuprofen, each has its
own advantages and limitations. These pre-existing methods have contributed significantly to the
availability and accessibility of ibuprofen, but they also face certain challenges. These limitations
include low yield, lengthy reaction times, iterative use of mentallic reagents or catalysts and hazardous
reagents or catalysts.
To overcome these limitations, researchers have focused on developing modifications to the
synthesis techniques to improve yield and efficiency for many years. These modifications involve
optimizing reaction conditions, exploring alternative catalysts, and utilizing greener and safer reagents.
By solving and lessening these limitations, it is expected that the modified synthesis methods can
enhance the overall production of ibuprofen and reduce its environmental impact.
In that case, this thesis aims to contribute to this ongoing research by exploring modifications in
ibuprofen synthesis through mechanism learning. This thesis aim to dissect the history and evolution of
ibuprofen synthesis, critique previous methods, and outline aims and objectives for future studies, with
the ultimate goal of enhancing the production process of this essential therapeutic drug.Modifying and
breaking the limitations of existing technologies through research on synthesis mechanism,the resulting
synthetic effort is both a creative and inventive achievement(higher atom economy and greener) in
synthetic strategy.

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2. Discussion

2.1. Boot's synthesis:

The Boots pure drug company developed for manufacture of ibuprofen in the 1961.[9] And this method
was also named as Boot's synthesis of ibuprofen.In order to synthesize ibuprofen by this method,(see
Figure 1) on the first step after the reaction of isobutylbenzene and acetic anhydride under the catalysis
of AlCl3, The reaction of isobutylbenzene with acetic anhydride initiates the synthesis, producing 1-(4-
isobutylphenyl)ethan-1-one.In the later phases of production, the para-acetyl group of this molecule is
converted into the propionic acid substituent of ibuprofen. First, a Darzens reaction occurs between ethyl
chloroacetate and the acetyl group to form an,α,β-epoxy ester ethyl 3-(4-isobutylphenyl)-3-
methyloxirane-2-carboxylate. The aldehyde is then produced by hydrolysis and decarboxylation 2-(4-
isobutylphenyl)propanal. Aldoxime (E)-2-(4-isobutylphenyl)propanal oxime is produced by
condensation with hydroxylamine and is then dehydrated with acetic anhydride to yield nitrile 2-(4-
isobutylphenyl)propanenitrile. Ibuprofen is created by hydrolyzing nitrile to a carboxylic acid while
being affected by an acid.[10]

Figure 1. Synthesis route of Boot's synthesis of ibuprofen.

Mechanism:
①Figure 2 shows Ethyl chloroacetate is first deprotonated at its halogenated site, resulting in a
carbanion that is stabilized by resonance with its enolate form. This nucleophile makes an attack on
carbonyl carbon in compound 1-(4-isobutylphenyl)ethan-1-one. Following the expulsion of the chloride
leaving group, the oxygen anion of the resultant tetrahedral intermediate takes part in an intramolecular
SN2 reaction to create the,α,β-epoxy ester ethyl 3-(4-isobutylphenyl)-3-methyloxirane-2-carboxylate.

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Figure 2. Mechanism in Boot's synthesis of ibuprofen.

②The,α,β-epoxy ester ethyl 3-(4-isobutylphenyl)-3-methyloxirane-2-carboxylate is changed into an

aldehyde in the following process. The ester is first hydrolyzed by acid, producing the carboxylic acid.
This molecule spontaneously decarboxylates in acidic circumstances to produce the aldehyde 2-(4-
isobutylphenyl)propanal in balance with its enol tautomer.(see Figure 3)

Figure 3. Mechanism in Boot's synthesis of ibuprofen.

③As shown in Figufd 4 aldehyde 2-(4-isobutylphenyl)propanal and hydroxylamine are then

condensed to produce aldoxime (E)-2-(4-isobutylphenyl)propanal oxime. The hydroxylamine's
nucleophilic attack on the aldehyde carbonyl carbon is where the mechanism starts. Expulsion of a water
molecule leaves the aldoxime after a few proton exchanges.

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Figure 4. Mechanism in Boot's synthesis of ibuprofen.

④Following that, acetic anhydride is used to dehydrate the aldoxime (E)-2-(4-

isobutylphenyl)propanal oxime. The nitrile product 2-(4-isobutylphenyl)propanenitrile is produced by
acetylating compound (E)-2-(4-isobutylphenyl)propanal oxime, which results in an O-acetyl aldoxime
that easily removes acetic acid. The nitrile 2-(4-isobutylphenyl)propanenitrile is then hydrolyzed under
acid-catalyzed conditions. The carboxylic acid (ibuprofen) is produced by two nucleophilic additions of
water and the removal of ammonium.(see Figure 5)

Figure 5. Mechanism in Boot's synthesis of ibuprofen.

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Table 1. The Boots’ synthesis of ibuprofen atom economy [11].

Reagent Utilized in ibuprofen Unutilized in ibuprofen
Formula Mr Formula Mr Formula Mr
C10H14 134 C10H13 133 H 1
C4H6O3 102 C2H3 27 C2H3O3 75
C4H7ClO2 122.5 CH 13 C3H6ClO2 109.5
C2H5ONa 68 0 C2H5ONa 68
H3O 19 0 H3O 19
NH3O 33 0 NH3O 33
H4O2 36 HO2 33 H3 3
Total Ibuprofen Waste products
C20H42NO10ClNa 514.5 C13H18O2 206 C7H24NO8ClNa 308.5

Atom economy=206/514.5=40%
Analyse:
By using this method ibuprofen can be made of materials that are readily accessible.
Additionally,it can also lower the energy cost and equipment corrosion. Table 1 shows the atom
economy of Boot's synthesis is only 40%, in other words, the ingredients utilized in the synthesis were
wasted to a greater than 50% extent.For example, the UK market for ibuprofen is about 3 ×10 6 Kg per
year,and the waste will be 4.5 ×10 6 Kg.[11] Besides, the reactions are complex(6 steps)and the use of
Alcl3 can cause environmental pollution.

2.2. BHC synthesis:

The Boots-Hoechst-Celanese business created the BHC synthesis of ibuprofen in 1992[9], which was a
considerable advancement over the original Boots technique. Figure 6 shows in this reaction,
isobutylbenzene undergoes a Friedel-Crafts acylation to produce 1-(4-isobutylphenyl)ethan-1-one,
which is the first step in the BHC synthesis of ibuprofen. However, this pathway differs significantly in
how this intermediate is converted to ibuprofen. First, a catalytic hydrogenation reduces the aromatic
ketone of 1-(4-isobutylphenyl)ethan-1-one to an alcohol 1-(4-isobutylphenyl)ethan-1-ol. In the presence
of a palladium catalyst, carbon monoxide is carbonylated with 1-(4-isobutylphenyl)ethan-1-ol to
generate ibuprofen.[12]

Figure 6. BHC synthesis of ibuprofen.

Mechanism: The Friedel-Crafts acylation of isobutylbenzene to 1-(4-isobutylphenyl)ethan-1-one

proceeds in the same way mechanically as the Boots procedure, as was previously demonstrated.

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However, HF takes the place of the Alcl3. The aromatic ketone 1-(4-isobutylphenyl)ethan-1-one is
hydrogenated to the alcohol 1-(4-isobutylphenyl)ethan-1-ol in the following synthesis process. By
activating H2 by surface adsorption, the palladium catalyst speeds up the process. Additionally, the
ketone adheres to the palladium surface [13]. By bringing it close to the activated H2, this encourages
hydrogenation.
Another palladium-catalyzed reaction, carbonylation of alcohol 1-(4-isobutylphenyl)ethan-1-ol with
carbon monoxide, is the last step. Following is a potential mechanism [14]. Alcohol 1-(4-
isobutylphenyl)ethan-1-ol is in equilibrium with its benzyl chloride analog in the presence of copious
hydrochloric acid. The benzyl chloride is added oxidatively to the palladium core to start the catalytic
cycle. The Pd-C sigma bond is subsequently completed by the addition of carbon monoxide. Finally,
the catalyst is revived and the ibuprofen is released by water's nucleophilic attack on the acyl
intermediate.(see Figure 7)

Figure 7. Mechanism in BHC synthesis of ibuprofen.

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Table 2. The BHC synthesis of ibuprofen [11].

Reagent Mr Utilized in ibuprofen Mr Unutilized in ibuprofen Mr
C10H14 134 C10H13 133 H 1
C4H6O3 102 C2H3O 43 C2H3O2 59
H2 2 H2 2 0
CO 28 CO 28 0
Total Ibuprofen Waste products
C15H22O4 266 C13H18O2 206 C2H4O2 60

Atom economy=206/266=77%
Analyse:
The BHC synthesis is ultimately a much "greener" method since it offers a number of advantages
over the Boots synthesis. The synthesis, obviously, requires fewer steps to complete than the latter.The
conversion of isobutylbenzene to ibuprofen takes place in three steps as opposed to six in the Boots
method.The technique also achieves twice the atom utilization (77%) of the original Boots process
(40%), demonstrating improved atom economy(As can be seen from the Table 2 that the BHC synthesis
has a higher atomic economy than Boot's synthesis).And BHC synthesis does not use aluminum chloride
that causes pollution to the environment.Last but not least, the procedure featured effective separation
and recovery of catalysts and reaction byproducts, which reduced the amount of waste generated.
The BHC synthesis stil use hazardous material(HF) .Besides,the atom economy is only 77%, and
using this method to produce ibuprofen in large quantities would result in significant waste.In the
future,a simpler, more effective, and stereo-specific method is still needed for ibuprofen's synthesis..

2.3. Electrochemical carboxylation for ibuprofen synthesis:

Any process induced or accompained by the passage of an electric current, including. The transfer of
electrons between two substances is referred to as an electrochemical reaction. An electrochemical cell
is represented by the two electrodes and the ionic conductor in between. The process that occurs in the
cell as a whole is a redox process in which one species is reduced while another is oxidized.[15]
Traditionally, 2-hydroxy-2-arylpropanoic acids can be synthesized using hydrogen cyanide from the
appropriate cyanohydrins. However, the requirement to use quite poisonous cyanides makes this
approach less appealing and somewhat challenging from the standpoint of industry. It is preferable to
construct a high yield system with an undivided cell, performing electrochemical carboxylations, in
order to establish a convenient and economically useful synthesis process of ibuprofen. Electrochemical
carboxylatiopn would refer to a method of introducing a carboxyl group into the ibuprofen molecule
using an electrochemical reaction. Ibuprofen's chemical structure comprises a propionic acid moiety,
which might be selectively changed to add a carboxyl group via electrochemical carboxylation.
[16]Early studies of electrocarboxylation of alkyl aryl ketones revealed a low yield of carbonxylated
products from acetophenones; nevertheless, it was later demonstrated that acetophenone may be
electrochemically carboxylated with significant yields in an undivided celi employing an oxalate
electrode. electronchemical reactions
Analyse:
Electochemical reactions can often be carried out under milder conditions compared to traditional
chemical reactions, which might reduce the formation of unwanted byproducts or the degradation of
senstive moleculesd. This method can be considered as an environmentally friendly approach since they
can eliminate the need for certain hazardous reagents or generate less waste. Electrochemical reactions
often exhibit high elctron transfer efficiency, making them efficient for the conversion of molecules.
Moreover, elctrochemical reactions can sometimes offer high selectivity, allowing people to target
specific functional groups for modification. This could potentially enable the introduction of a carbpxyl
group at a desired position in the molecule.

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However, Electrochemical reactions can be complex, necessitationg meticulous tuning of reaction

variables such as electode materials, electrolytes, current density, and reaction duration. Because of this
complexity, developing and replicating the process can be difficult. Modifying the chemical structure
of ibuprofen can significantly impact its biological activity, pharmacokinetics, and safety profile. Any
modifications should be carefully evaluated to ensure that the resulting compund retains its intend
therapeutic effects. While small-scale electrochemical reactions in a laboratory setting may be feasible,
scaling up the process for industrial production may provide hurdles in terms of maintaing consistent
and efficient reactions.[17] Electrochemical processes may not always exhibit the necessary selectivity,
and the possibility of side reactions or the generation of undesirable byproducts should be concerned.

2.4. Continuous-flow synthesis of ibuprofen

In recent years,the manufacture of ibuprofen using continuous flow is gaining popularity.Firstly,
propionic acid is added to isobutylbenzene and heated to 150 °C under the condition of triflic acid
catalysis for 5 minutes The mixture is then continued to react in a solution dominated by PhI(OAc)2
HC(OMe)3, with MeOH as the catalyst, at a temperature of 50 °C for 2 minutes.At this point, a
manganese-containing compound is formed. The compound was transferred to KOH solution and
continued to react with MeOH as catalyst at 65 °C for 3 minutes. (see Figure 8)

Figure 8. Cntinuous-flow synthesis of ibuprofen.

Analyse
Continuous-flow synthesis allows for greater control over reaction conditions, potentially resulting
in improved yields and purities. The technique is easily scaled up without requiring significant changes,
making it suited for large-scale production. When compared to batch procedures, flow chemistry
frequently entails handling smaller volumes of hazardous compounds at any given time, lowering the
risk of accidents and exposure. Continuous-flow systems provide for exact control of reaction
parameters like temperature, pressure, and reaction time. This can increase selectivity and limit the
generation of undesirable byproducts. When compared to traditional batch synthesis, the effective use
of reagents, reduced waste generation, and enhanced energy efficiency in flow processes can result in a
smaller environmental imprint. Complex multistep syntheses can be incorporated easily into a single
continuous-flow system, eliminating the need for intermediate isolations and purifications.
Nonetheless, setting up a continuous-flow system necessitates the use of specialized equipment such
as pumps, reactors, and control systems. The initial investment might be substantial, especially for small-
scale companies. Continuous-flow systems can become clogged or blocked, particularly when working
with solid reactants or precipitates. This can cause the process to be disrupted and require cleaning and
maintenance. While flow chemistry allows for faster optimization, it can also make identifying optimal

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conditions more challenging due to the dynamic nature of the reactions and the intricate interplay of
variables.

3. Conclusion
In conclusion, this essay has examined how ibuprofen synthesis techniques have evolved over the past
many decades. Even though the original Boots synthesis had limitations including low atom economy
and the use of potentially dangerous chemicals, it developed the first feasible approach for the
manufacturing of ibuprofen. With fewer stages, less waste, and greater atom economy than the Boots
technique, the BHC synthesis greatly outperformed it. To further improve sustainability, efficiency, and
selectivity, more contemporary methods including electrochemical carboxylation and continuous flow
systems have been developed.
The specific methods continue to advance even as the fundamental goals—maximizing productivity
and purity while reducing cost, waste, and environmental impact—remain consistent. Every new
technique expands on what has come before and fixes flaws in older techniques. This incremental
breakthrough has greatly improved the way this vital analgesic medication is produced. There is still a
lot of room for the ibuprofen synthesis process to be made even more efficient, secure, and eco-friendly
with the use of contemporary green chemistry concepts and cutting-edge technology.
To help with the construction of synthetic routes, research should concentrate on completely
clarifying reaction processes going forward. Spectroscopic investigation as well as computer modeling
can offer insightful molecular-level information. Processes should be evaluated using thorough lifecycle
and sustainability criteria that cover everything from the procurement of raw materials to the disposal
of trash. Emerging ibuprofen manufacturing techniques can strive for optimal synthesis—efficient,
selective, scalable, safe, and producing minimal waste—by adopting a holistic approach. The objective
of developing completely green, next-generation procedures for this essential medication may be
achieved with persistent research and innovation.

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