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ADVANCES IN
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VOLUME 37
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ADVANCES IN CHEMISTRY RESEARCH
ADVANCES IN
CHEMISTRY RESEARCH
VOLUME 37
JAMES C. TAYLOR
EDITOR
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Preface vii
Chapter 1 The Electrochemical Determination of the
Synthetic Antioxidants Used as Stabilizers in
Mineral Oils and Biofuel 1
Jaromíra Chýlková, Markéta Tomášková,
Vladimír Jehlička, Ivan Švancara and
Renáta Šelešovská
Chapter 2 Cholinesterase-Inhibitory Activity of Essential Oils 15
Franko Burčul, Mila Radan, Olivera Politeo and
Ivica Blažević
Chapter 3 Phytochemical Functionalized Metal Nanocatalyst
(Ag, Au, Fe, Zn and Pd) for Remediation of
Organic Dyes 87
Brajesh Kumar, Kumari Smita and Brajendra Kumar
Chapter 4 Ionic Liquid-Promoted Synthesis of Phosphinates
and Bisphosphonic Acid Derivatives 121
Nóra Zsuzsa Kiss, Dávid Illés Nagy
and György Keglevich
Chapter 5 Low Molecular Mass Reactive Acrylamide
Copolymers as Carriers of Biologically
Active Compounds 141
M. V. Solovskiy, M. Yu. Smirnova, E. B. Tarabukina,
A. I. Amirova and N. V. Zakharova
destroyed with the emergence of new sub ensembles both in the expanded and
the collapsed forms. It was tried to find is there any correlation between the
principles of periodic structures in the amorphous molecular matter and those
in the universe.
Chapter 7 - Furans have, fundamentally, biological and chemical uses. For
several years, the authors have been working with substituted furans as
eletrophilic dienophiles joint to different nucleophilic dienes in Polar Diels-
Alder Reactions (P-DA). The principal objective of this analysis was the
preparation of benzofurans and dibenzofurans. To develop these reactions, the
authors used conventional thermal conditions and microwave irradiation. The
solvents employed were organic ones and protic ionic liquids (PILs). Also, the
authors worked in free solvent conditions. The authors demonstrated that
substituted furans result good electrophiles in cycloaddition processes. The
best experimental condition was the combination of microwave irradiation in
presence of PILs like ethylamonium nitrate (NEA) and N-methylimidazolium
tetrafluoroborate ([HMIM][BF4]). When the nitro group is used as substituent
in the electrophile, the process is irreversible due to the loss of nitrous acid.
Then this substituent is convenient for this transformation. Moreover, a
computational theoretical study of furan reactivity as dienophile in Polar
Diels-Alder reactions (P-DA) was performed. For this purpose, the Density
Functional Theory (DFT) method was employed. The principal aim of this
theoretical study was to analyze the reactivity, regioselectivity, solvent effect
(organics and ionic liquids) and reaction mechanisms of these reactions.
Gaussian 09 is the software used to develop the theoretical calculations. The
functional applied was B3LYP and the basis set 6-31G(d). The structures of
reactants, products and transition states were optimized and validated through
the calculation of the vibrational frequencies. For the analysis of reactivity and
regioselectivity, the nucleophilic and electrophilic global and local indexes
were used, respectively. The solvent effect was considered employing two
different solvatation models: the Polarizable Continuum Model (PCM) and the
Supermolecular Approach. For the mechanistic analysis, the stationary points
were located in the Potential Energy Surface (PES) and then optimized and
validated. The activation energy values and reactions paths were analyzed for
each reaction.
Chapter 8 - Petroleum asphaltenes are interesting molecules that have
been studied extensively due to various problems caused by the petroleum
industry. The high tendency of self association of asphaltene behavior is the
main strength of this complex behavior of crude oil. The phenomenon of
aggregation is the association of asphaltene molecules in particles of different
shape and size. This chapter of book discusses the use of surfactants in oil
chemical treatment to remedy the problems caused by asphaltenes during
production of crude oil. In this particular and specific case it will be presented
of Furrial area in eastern Venezuela, which is one of the most important
operational areas of the oil industry at Venezuela. Different changes in
pressure, temperature, and secondary recovery methods may induce
aggregation asphaltenes. These changes affect their interfacial properties
because they can alter the physicochemical properties in the medium (crude oil
or solvent) where they are present. The adsorption process of asphaltenes in
liquid-liquid aggregates interfaces, it is slower than the adsorption of
asphaltene molecules. The aggregation state of asphaltene also depend on the
nature of crude oil. Furrial crude oil has always been characterized by the high
tendency to precipitation of asphaltenes.
Asphaltenes aggregation significantly affects the stability of emulsions, oil
viscosity and asphaltene precipitation. Recently, Acevedo showed the colloidal
nature of asphaltenes focused on the point of view of its fractions A1 and A2,
the first insoluble in toluene. The A1 fraction is responsible for the
aggregation behavior due to its solubility behavior. This model can explain in
detail their aggregation in crude oil and other organic solvents. Surfactants are
commonly used in the solution to the problem of asphaltenes in crude oil
production, and stability of water in oil and asphaltene precipitation.
Surfactants are the main asset of the formulation components (a chemical
cocktail) used in the chemical treatment. Also the other formulation
components and additives such as polar solvents, play a key role. A good
formulation should increase surfactant´s properties such as, surface tension,
adsorption, interfacial activity, solubility, etc. The appropriate combination
between surfactants in solvent is important to achieve high dispersion thereof.
Besides the proper structure and conformation they are key in the work of
chemical treatment. For this reason the addition of molecules that help
disperse the surfactant is very important. There are still many things that
explain the action of surfactants in the chemical treatment. However, this
chapter aims to provide an efficient contribution to this important issue related
to the oil industry.
Chapter 1
ABSTRACT
In this chapter, the latest achievements on the electrochemical
determination of synthetic antioxidants are summarized concerning
mainly the substances based on phenolic compounds and used to stabilize
the mineral oils or to prevent undesirable oxidation processes in
Corresponding Author Address: Jaromíra Chýlková, University of Pardubice, Studentská 573,
532 10 Pardubice, Czech Republic. Email: Jaromira.Chylkova@upce.cz.
INTRODUCTION
The main reason for degradation of the mineral oils applied for lubricating
of metallic parts is their oxidation caused by air oxygen. This spontaneous
process is more pronounced at higher temperatures and in the presence of the
so-called wear metals that act as specific catalysts. The oxidation products are
various oxygen-containing compounds, such as aldehydes, ketones, ethers, or
carboxylic acids and their esters that subsequently undergo condensation and
polymerisation reactions, giving rise to a higher acidity and enhanced viscosity
of lubricating oils [1].
It is obvious that the oils after such a degradation are inevitably losing
their useful properties, which - if not being revealed in the right time - may
measured; the experiment being stopped when having achieved a value of 200
µS.cm-1.
Besides these rather common procedures, there are some less-known
possibilities and one is represented by a voltammetric method that enables to
define the content of antioxidants with the aid of their electrochemical
oxidation and whose details can be found in the ASTM D6971-09 standard,
when also a special RULER® apparatus is operated via such principles. When
going into some details, this voltammetric analysis requires a set of coloured
solutions with unspecified composition that have to be purchased as
commercially available formulations. Afterwards, the oily phase is isolated
with the aid of a sand-like material and the content of antioxidants indicated
with a carbonaceous electrode. The proper evaluation is then based on direct
comparison of two different media and of the respective responses – the first
one belonging to the used oil and the second to the new one.
In the framework of our long-time research, we have been developing and
testing various voltammetric procedures with a goal to obtain a simple but
reliable tool for determining some selected - but frequently used - antioxidants
in lubricating oils and biofuel. Usually, our effort has also been focused on
feasibility to discriminate among the individual substances. The working
electrodes have been chosen in accordance of a demand for the widest possible
applicability and without a necessity to mechanically (pre)treat the electrode
surface as a time-consuming and often not easy-to-perform operation that may
principally affect the electrochemical reactions taking place at the electrode or
in its vicinity and, subsequently, the corresponding current-flow response(s).
Figure 2. The current-potential dependence at the working solid electrode used in the
LSV mode.
In oil analyses, the antioxidants have to be first isolated from the matrix
by extracting with ethanol; best, when assisted by a short (ultra)sonication.
Then, the upper ethanolic layer - that will serve for later voltammetric analysis
- is purified from the oily residua by adding solid Na2SO4 with subsequent
filtrating through a dry filter paper.
For the BHA antioxidant, the current response is not linear with
concentration, which has been confirmed repeatedly. Due to this, the
quantification of this substance can be made with the aid of a special
programme called “Nonlinear” that has been proposed for this purpose by our
group [10]. The phenomenon of the peak overlay with respect to the function
of this programme can be described as follows. If one analyses the mixture of
BHA and BHT antioxidants, their signals appears quite close to each other
being partially overlapped (the peak maximum for the first one is +895 mV
and +1075 mV for the second; both versus Ag/AgCl. As found out, this
proximity affects mainly the peak shape of the follow-up substance, i.e., BHT.
The proper evaluation to obtain the correct peak height (or area, respectively)
then relies on a procedure depicted in Figure 3. Here, the part of the
voltammogram - namely, the curve between the maximum for BHA and the
following minimum - is linearized by approximating it with tangent in the
respective inflection point. Afterwards, a perpendicular from the maximum for
BHT (point “T”) is constructed, ending in point “P”; in other words, as an
intersection with the previously set tangent. The actual peak height for BHT is
then represented by the distance between points “P” and “T”.
For comfort use, the Nonlinear programme offers an algorithm comprising
all the steps for performing the above-described evaluation [11]. The user just
inputs the respective experimental data that characterise the I-E curve in the
range of interest and which have been read-out prior and automatically by the
analyser (software). Finally, the quantification of BHT is accomplished by the
standard addition method with linear I-vs-c relation.
In practical samples of crude-oil products, mixtures of TBHQ and BHT
antioxidants are often being the case; usually, at comparable concentrations.
The determination of both substances in the supporting electrolyte of choice is
normally feasible, due to the fact that the corresponding signals are sufficiently
separated and therefore fine evaluable. In this constellation, the maximum for
TBHQ can be found at a potential of +755 mV and at +1070 mV for BHT
(again, both versus Ag/AgCl). However, if an ethanolic extract with real oil
matrix is to be analysed, there is a particular effect evident in noticeable shift
of both peaks towards more positive potentials. If this occurs, the response for
BHT oxidation is already superposed upon the high background indicating the
decomposition of the supporting electrolyte and so deformed peaks are
difficult to compute.
Then it is possible to use again a mathematic evaluation via special
algorithm that is also integrated in the software. Its function is based on
subtraction of the base-line followed by derivation of the increasing part of the
respective voltammogram(s); the respective procedure being sketched in
Figure 4. Within, the part “A” illustrates the original voltammograms obtained
in the model sample spiked with a mixture of BHT and TBHQ antioxidants.
The part “B” represents the already processed curves serving for quantitative
evaluation of the content of TBHQ from the peak height, whereas BHT is
quantified by evaluating shown by the set “C”.
Figure 4. Typical linear scan voltammograms obtained by oxidising the TBHQ a BHT
mixture. A) Original recordings, B) and C) curves after processing by mathematic
transformation. Legend: 1 - base-line (supporting electrolyte) for comparison, 2 -
sample, 3 and 4 – standard additions of BHT, 5,6 - standard additions of TBHQ.
VOLTAMMETRIC DETERMINATION OF
PHENOLIC AND AMINIC ANTIOXIDANTS
In order to enhance the antioxidation effect, some oils are enriched by
selectively chosen mixtures made of phenols and aromatic amines and the
respective analyses should be able of distinguishing the individual items. And
voltammetry is one of the approaches that may do so this under certain
circumstances.
CONCLUSION
In this text, it has been shown that electrochemical measurements, namely,
linear scan voltammetry in combination with some solid electrodes are finely
applicable to determine a number of antioxidants used for stabilising mineral
oils and fuels against the undesirable oxidation. Moreover, in some cases, such
antioxidants can also be identified and quantified simultaneously. Typical
conditions for these analyses involve the use of acidic solutions based 0.10-
0.18 M H2SO4 and usually the presence of an organic solvent enabling to
dissolve properly the analytes and/or some matrix constituents. As shown and
discussed for the individual examples (mostly based on the authors’ own
results), one can analyse the new as well as the already used oils. Whenever
needed, the respective procedures may also incorporate a pre-extraction step in
combination with sonication.
It can be stated that this concise overview that summarises mainly some
original methods from our research [9-12, 15] demonstrates well the
possibilities of electrochemical measurements for rather atypical employment
like the analysis of oily and fuel materials. The use of voltammetric
procedures discussed herein can be recommended to control the degree of
oxidative degradation of selected oils and fuels.
Compared to the standard methods and instrumentation used for these
purposes, electrochemical experiments presented above offer an interesting
alternative with inexpensive equipment and relatively rapid and simple
procedures. Regarding the electroanalysis itself, the methodology surveyed
herein can be considered as another contribution into the database of already
existing practical applications with a similar focus, such as (i) electroanalysis
in non-aqueous media (see e.g., [16, 17]) and references therein, (ii)
electroanalytical tensammetry of oils and fuels [16, 17], or (iii) determination
of some trace metals in crude oil homogenised with a mixture of 65% HNO3 +
30% H2O2 by sonication and subsequently decomposed in a microwave
mineralisation unit [20].
REFERENCES
[1] Černý, J., (2001). Principles of low-temperature and high-temperature
oxidation of hydrocarbon mixtures. In: Černý, J. (ed) Reotrieb, 7th
conference. Velké Losiny, CZ, p. 45.
[2] “ASTM D2272-14a”, (2014). Standard Test Method for Oxidation
Stability of Steam Turbine Oils by Rotating Pressure Vessel. Prague, CZ:
Czech Office for Standards, Technology and Testing.
[3] Mužíková, Z., Černý, J., (2011). Possibilities and limitations of the
determination of oxidation stability of gasoline fuels. In: Černý, J. (ed)
Reotrieb, 17th conference. Velké Losiny, CZ, p. 43.
[4] Ladyka, N., Černý, J., (2012). Laboratorní testování oxidační stability
turbínových olejů/Laboratory testing of the oxidation stability of turbine
oils. Paliva 4, 61-65.
[5] Waynick, J. A., (2005). Characterization of biodiesel oxidation and
oxidation products. New York, USA: CRC Project NO.AVFL-2b.
[6] “ASTM D6186”, (2013). Standard Test Method for Oxidation Induction
Time of Lubricating Oils by Pressure Differential Scanning Calorimetry
(PDSC). Prague, CZ: Czech Office for Standards, Technology and
Testing.
[7] Tomašíková, S., Pospíšil, M., Mužíková, Z., Černý, J., (2013) Stanovení
oxidační stability metylesterů mastných kyselin pomocí tlakové
diferenciální skenovací kalorimetrie/Determination of oxidation stability
of the fattry acid methylesters with the aid of differential scanning
calorimetry. Paliva 5, 87-90.
[8] “EN 14112”, (2012). Fat and oil derivatives. Fatty acid methyl esters
(FAME). Determination of oxidation stability (accelerated oxidation
test). Prague, CZ: Czech Office for Standards, Technology and Testing.
[9] Chýlková, J., Tomášková, M., Mikysek, T., Šelešovská, R., Jehlička, J.,
(2012). Voltammetric Determination of BHT Antioxidant at Gold
Electrode in Biodiesel. Electroanalysis 24, 1374-1379.
[10] Tomášková, M., Chýlková, J., Jehlička, V., Navrátil, T., Šelešovská, R.,
(2013). Voltammetric determination of butylated hydroxyanisol in
biodiesel, mineral and synthetic oils using gold electrode. Sci. Pap.
Univ. Pardubice, Ser. A 19, 155-172.
[11] Tomášková, M., Chýlková, J., Jehlička, V., Navrátil, T., Švancara, I.,
Šelešovská, R., (2014). Simultaneous determination of BHT and BHA in
mineral and synthetic oils using linear scan voltammetry with a gold disc
electrode. Fuel 123, 107-112.
[12] Tomášková, M., Chýlková, J., Navrátil, T., Šelešovská, R., (2014).
Voltammetric determination of antioxidant TBHQ individually and
mixed with BHT in petroleum products using gold disc electrode.
Energy fuels 28, 4731-4736.
[13] Chýlková, J., Tomášková, M., Janíková, L., Šelešovská, R., Navrátil, T.,
Chudobová, P., (2016). Sensitive voltammetric method for the fast
analysis of the antioxidant pyrogallol using a boron-doped diamond
electrode in biofuels. Chem. Pap. (in press) DOI: 10.1007/s11696-016-
0025-3.
[14] Tomášková, M., Chýlková, J., Šelešovská, R., Janíková, L., (2016).
Voltammetric method for rapid determination of propyl gallate and its
application for monitoring of biofuels quality. Monatfh. Chem. (in
press). DOI: 10.1007/s00706-016-1860-1.
[15] Tomášková, M., Chýlková, J., Machalický, O., Šelešovská, R., Navrátil,
T., (2013). Voltammetric determination of different antioxidants in
petroleum products by working gold electrode. Int. J. Electrochem. Sci.
8, 1664-1677.
[16] Dahmen, E.A.M.F., (1986). Electroanalysis: Theory and applications in
aqueous and non-aqueous media and in automated chemical control (1st
ed.). Amsterdam, NL: Elsevier.
[17] Izutsu, K., (2009). Electrochemistry in non-aqueous solutions (2nd ed.).
New York, USA: Wiley.
[18] Kalvoda, R., Novotný, L., (1986). Polarographic behavior of petroleum
components in aqueous solutions: A study usig DPP and convective
adsorption accumulation. Collect. Czechoslov. Chem. Commun. 51,
1587-1594.
[19] Thomas, F. G., Henze, G., (2001). Introduction to voltammetric
analysis: Theory and practice. Collingwood VIC, Australia: CSIRO
Publishing; 51-52.
[20] Švancara, I., Fairouz, M., Ismail, Kh., Šrámková, J., Metelka, R., Vytřas,
K., (2004). Applicability of electrochemical stripping analysis at
mercury- and bismuth film plated carbon paste electrodes to crude oil
digests. Sci. Pap. Univ. Pardubice, Ser. A 10, 5-20.
Chapter 2
CHOLINESTERASE-INHIBITORY ACTIVITY
OF ESSENTIAL OILS
ABSTRACT
Essential oils (EOs) are a complex mixtures containing volatile
secondary metabolites with various structures (terpenes, terpenoids,
phenylpropanoids, and others). Their roles in plants vary from attracting
pollinators to a defense against insects, food storage, and adaptations to
harsh climate. Since ancient times, EOs are recognized for their medicinal
value, representing a valuable source of biologically active compounds.
EOs possess various activities including: antimicrobial, antiviral,
antioxidant, antitumor, etc. They have also been used as perfumes, flavors
for foods and beverages, remedies for the body and mind, and continue to
be of paramount importance to date.
Having a small molecular weight and lipid solubility, EO
constituents possess the ability to pass the blood-brain barrier. Given the
complexity of their chemical composition and ability to enter the brain,
*
Corresponding author address: University of Split, Faculty of Chemistry and Technology,
Division of Chemistry, Ruđera Boškovića 35, 21000, Split, Croatia, Europe. E-mail:
blazevic@ktf-split.hr.
EOs and their constituents offer a promising strategy for the treatment of
various neurological disorders. Alzheimer’s disease has been responsible
for more than 50% of neurological diseases among persons over the age
of 65 years. EOs are found to be potential acetylcholinesterase and
butyrylcholinesterase inhibitors, two enzymes which still represent the
only pharmacoterapeutic targets against Alzheimer’s disease. The
purpose of this chapter is to provide an overview of the current
knowledge about the activity of the EOs with defined chemical
composition, tested against cholinesterases and to identify the ones that
could be potentially used in Alzheimer’s treatment.
1. INTRODUCTION
Essential oils (EOs) are a mixture of volatile lipophilic constituents
produced in 17500 aromatic species of higher plants belonging mostly to
Asteraceae, Lamiaceae, Lauraceae, and Myrtaceae families [1]. EOs are
isolated from different plant organs, e.g., flowers (bergamot orange, Citrus
bergamia), leaves (lemon grass, Citronella spp.; eucalyptus, Eucalyptus spp.),
fruits (anise, Pimpinella anisum), seeds (nutmeg, Myristica fragrans), wood
(sandalwood, Santalum spp.), roots (vetiver grass, Chrysopogon zizanioides),
rhizomes (ginger, Zingiber officinale); turmeric (curcuma, Curcuma longa).
They are obtained by distillation process or cold pressing (from the citrus
peels). EOs possess various activities including: antimicrobial, antiviral,
antioxidant, antitumor, etc. During the last fifteen years, EOs have also been
recognized as cholinesterases inhibitors that represent the main target in
treatment of Alzheimer’s disease. Table 1 includes all the EOs reported with
their constituents (over 4%) that were tested against acetylcholinesterase
and/or butyrylcholinesterase.
Constituents of EOs belong mainly to terpenes (monoterpenes and
sesquiterpenes), terpenoids (monoterpenoids and sesquiterpenoids) of low
molecular weight and, to a lesser extent phenylpropanoids and others.
According to their functional groups they include saturated and unsaturated
hydrocarbons, alcohols, aldehydes, ketones, esters, ethers, oxides, phenols etc.
Structures of some common constituents found in EOs are given in Figure 1.
Terpenes
1 2 3 4 5 6
E
E
E E
H
H H
7 8 9 10
Terpeneoids
OH OH
OH OH O
OH
11 12 13 14 15 16
O Ac
O
O HO Ac O
17 18 19 20 21 22
Figure 1. (Continued)
O HO H
H
H OH
H H
23 24 25
Phenylpropanoids
OCH 3 OH O O
O O
O O
O
O
E E
O
26 27 28 29 30 31
Others
32 33
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
ACORACEAE
Acorus calamus L. (AC) India/Rhizome β-Asarone (79.5%), α-asarone (8.5%) 10.7 - [8]
ALTINGIACEAE
Liquidambar orientalis purchased from AYUS trans-Cinnamyl alcohol (45.1%), hydrocinnamyl <10% at 1000 µg/mL - [9]
GmbH (Weinstrasse, alcohol (41.1%)
Bühl/Baden, Germany)
ANACARDIACEAE
Pistacia lentiscus L. Tunisia/Leaf α-Pinene (14.4%), germacrene D (12.1%), terpinen-4- 55.3 - [11]
(14 population) ol (9.6%), δ–cadinene (8.1%), limonene (6.3%), β-
caryophyllene (4.9%), β-pinene (4.5%), γ-terpinene
(4.5%), sabinene (4.4%)
Tunisia/Leaf β-Caryophyllene (12.1%), α-pinene (10.4%), δ– 129.2 - [11]
cadinene (9.9%), germacrene D (8.2%), terpinen-4-ol
(7.2%), sabinene, (6.3%), limonene (6.0%)
Tunisia/Leaf Germacrene D (15.9%), δ–cadinene (10.2%), 148.3 - [11]
limonene (7.6%), α-pinene (7.2%), β-caryophyllene
(5.7%), sabinene, (4.8%), α-phellandrene (4.4%), β-
pinene (4.1%), δ–cadinol (4.0%)
Tunisia/Leaf α-Pinene (14.0%), germacrene D (8.2%), limonene 181.7 - [11]
(8.0%), δ–cadinene (7.4%), β-caryophyllene (7.0%),
terpinen-4-ol (4.6%), β-myrcene (4.5%), α-cadinol
(4.0%)
Tunisia/Leaf Germacrene D (13.1%), β-caryophyllene (11.7%), δ– 199.0 - [11]
cadinene (9.1%), limonene (6.8%), α-pinene (5.1%),
terpinen-4-ol (4.5%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Tunisia/Leaf Germacrene D (18.6%), δ–cadinene (15.2%), β- 226.7 - [11]
caryophyllene (12.3%), δ–cadinol (5.6%), α-cadinol
(5.0%), γ-muurolene (4.2%), α-humulene (4.0%)
Tunisia/Leaf Germacrene D (18.6%), δ–cadinene (11.3%), 233.7 - [11]
limonene (10.6%), α-pinene (9.4%), β-caryophyllene
(6.5%), sabinene (4.1%)
Tunisia/Leaf α-Pinene (11.0%), germacrene D (10.4%), limonene 238.7 - [11]
(9.5%), β-myrcene (7.8%), β-caryophyllene (7.4%), δ–
cadinene (7.0%), terpinen-4-ol (5.0%)
Tunisia/Leaf Germacrene D (11.7%), limonene (10.2%), δ– 310.3 - [11]
cadinene (9.2%), β-caryophyllene (8.7%), α-pinene
(6.5%), terpinen-4-ol (5.2%), β-pinene (4.6%), β-
myrcene (4.6%)
Tunisia/Leaf Germacrene D (13.2%), β-caryophyllene (11.4%), δ– 318.3 - [11]
cadinene (8.6%), limonene (7.8%), α-pinene (6.6%),
β-myrcene (6.3%), terpinen-4-ol (5.6%)
Tunisia/Leaf Limonene (20.7%), α-pinene (13.0%), germacrene D 383.3 - [11]
(8.4%), β-caryophyllene (7.1%), α-phellandrene
(6.7%), sabinene (6.1%), δ–cadinene (4.0%)
Pistacia lentiscus L. Tunisia/Leaf α-Pinene (11.6%), limonene (10.5%), germacrene D 400.3 - [11]
(14 population) (10.1%), β-caryophyllene (8.2%), δ–cadinene (7.2%),
β–myrcene (6.0%), terpinen-4-ol (4.3%)
Tunisia/Leaf α-Pinene (16.2%), germacrene D (11.2%), δ–cadinene 470.0 - [11]
(7.1%), β-pinene (5.9%), limonene (5.5%), sabinene
(5.1%), β-caryophyllene (4.8%), β–myrcene (4.7%),
terpinen-4-ol (4.5%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Ferula communis L. Tunisia/Flower Camphor (18.3%), α-pinene (15.3%), β-eudesmol - 64.6% at 10000 [84]
(9.3%), caryophyllene oxide (8.0%), myrcene (5.0%), μg/mL
γ-eudesmol (4.6%), β-pinene (4.4%)
Tunisia/Stem β-Eudesmol (28.1%), γ-eudesmol (11.1%), α- - 54.7% at 20000 [84]
eudesmol (9.6%) μg/mL
Tunisia/Leaf α-Eudesmol (25.2%), β-eudesmol (20.7%), γ- - 55.7% at 20000 [84]
eudesmol (10.1%), caryophyllene oxide (7.2%) μg/mL
Ferula lutea L. Tunisia/Root δ-3-Carene (72.6%), α-pinene (5.8%), myrcene 28.6 - [85]
(5.1%), α-phellandrene (4.0%)
Tunisia/Flower δ-3-Carene (31.2%), α-pinene (25.8%), 2,3,6- 70.3 - [86]
trimethylbenzaldehyde (10.9%), limonene (6.3%),
myrcene (5.1%), α-phellandrene (4.0%)
Ferulago carduchorum Iran/Aerial part (Z)-β-Ocimene (43.3%), α-pinene (18.2%), bornyl 23.6 µL/mL - [87]
Boiss and Hausskn acetate (4.0%)
Foeniculum vulgare Portugal/Aerial part α-Pinene (25.8%), limonene (16.6%), trans-Anethole 215.0 - [16]
Mill. (11.8%), p-cymene (11.5%), α-phellandrene (6.9%), β-
pinene (6.8%), fenchone (6.3%), β-myrcene (5.4%)
Portugal/Aerial part (E)-Anethole (70.2%), (Z)-anethole (18.6%), α- 252.0 - [88]
thujone (6.0%)
provided by Zaraphyt trans-Anethole (75.0%) 1187.7 - [32]
(Rabat, Morocco)/Aerial
part
ASTERACEAE
Artemisia absinthium Algeria/Aerial part Chamazulene (31.3%), camphor (16.5%), 4-terpineol 18.0% at 100 µg/mL 12.8% at 100 [20]
(4.3%) µg/mL
Artemisia annua L. China/Flower - β-Myrcene (37.7%), 1,8-cineole (16.1%), camphor 1250.0 - [19]
preflowering stage (15.0%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Centaurea lycopifolia Turkey/Whole plant Caryophyllene oxide (9.7%), spathulenol (7.3%), 63.5% at 200 µg/mL 65.8% at 200 [25]
Boiss. et Kotschy arachidic acid (5.0%), widdrol (4.3%), α-pinene µg/mL
(4.0%)
Centaurea balsamita Turkey/Whole plant α-Selinene (8.5%), hexatriacontane (8.3%), 2,5-di-tert 44.9% at 200 µg/mL 51.6% at 200 [25]
Lam. octyl-p-benzoquinone (7.4%), tetracosane (6.0%), 1,3- µg/mL
di-tertbutyl benzene (4.3%), (Z)-8-octadecen-1-ol
acetate (4.1%), arachidic acid (4.0%)
Centaurea iberica Trev. Turkey/Whole plant Arachidic acid (25.3%), hexadecanoic acid (5.9%), 49.6% at 200 µg/mL 59.0% at 200 [25]
ex Sprengel choleic acid (5.5%), isononane (5.0%), nonacosane µg/mL
(4.6%)
Crassocephalum Nigeria/Leaf β-Cubebene (13.8%), α-humulene (10.3%) 11.0 - [13]
crepidioides (Benth S. Nigeria/Stem Thymol (43.9%), 4-cyclohexabutyramide (20.9%) 12.2 - [13]
More)
Dittrichia viscosa Portugal/Aerial part trans-Nerolidol (8.4%), β-oplopenone (7.2%), δ- 916.9 - [16]
cadinene (5.7%), 1,8-cineole (5.6%), τ-cadinol (5.5%),
α-cadinol (5.3%), 10-epi-γ-eudesmol (4.2%)
Gynura bicolor DC Japan/Leaf (E)-β-Caryophyllene (31.4%), α-pinene (17.1%), α- 85.0 - [18]
humulene (9.7%), bicyclo-germacrene (8.1%),
phenylacetaldehyde (5.5%)
Japan/Stem α-Pinene (61.4%), β-pinene (14.4%), myrcene (5.1%) 92.0 - [18]
Inula graveolens L. purchased (origin: Bornyl acetate (54.0%), borneol (20.0%), camphene 270.0 - [21]
France) (4.9%)
Pluchea lanceolata India/Aerial part Linalool (32.2%), β-caryophyllene (8.5%), α-terpineol 2.5 - [22]
(DC.) Oliv. and Hiern (8.0%) spathulenol (7.4%), linalyl acetate (5.6%), 1,6-
dimethyl-4-(1-methylethyl)naphthalene (4.3%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Cordia gilletii Congo/Leaf Phytol (20.4%), hexadecanoic acid (15.2%), (E)-2- 105.6 369.3 [27]
hexenal (9.6%), nonacosane (9.2%), nonanal (5.8%),
eicosane (4.7%), heptacosane (4.5%)
BUDDLEJACEAE
Buddleja asiatica Lour. Pakistan/Leaf 1,8-Cineole (38.1%), β-sinensal (11.8%), 1,10-seco-1- 5.2 μM 27.9 μM [29]
hydroxy-calamenen-10-one (10.2%), α-phellandrene
(5.8%), α-pinene (4.9%)
BURSERACEAE
Boswellia ameero Balf. Yemen, Soqotra Island/ (3E,5E)-2,6-dimethyl-1,3,5,7-octatetraene (34.9%), 1- 41.6% at 200 µg/mL - [30]
f, Oleogum resins (2,4-dimethylphenyl)ethanol (20.3%), 3,4-
dimethylstyrene (17.3%), α-campholenal (13.4%), α-
terpineol (12.4%)
Boswellia elongata Balf. Yemen, Soqotra Island/ Verticiol (52.4%), caryophellene (39.1%), 29.6% at 200 µg/mL - [30]
f Oleogum resins methylcycloundecane-carboxylate (7.9%)
Boswellia socotrana Yemen, Soqotra Island/ (E)-2,3-Epoxycarene (51.8%), 5-isopropyl-2- 59.3% at 200 µg/mL - [30]
Balf. f, Oleogum resins methylbicyclo[3.1.0]hex-3-en-2-ol (31.3%), α-cymene
(7.1%)
CISTACEAE
Cistus creticus Italy/Leaf Vitispirane I (17.4%), manoyloxide (14.0%), 12.9% at 1000 μg/mL 29.1 [31]
hexahydrofarnesylacetone (6.8%), viridiflorol (5.2%),
(E)-phytol (5.1%)
Cistus libanotis Tunisia/Leaf Camphene (25.2%), α-pinene (21.6%), β-pinene 71.2 23.7 [31]
(10.8%), bornyl acetate (9.8%)
Cistus monspeliensis Tunisia/Leaf 13-epi-Manoyl oxide (17.7%), manoyloxide (11.1%), Nd at 1000 μg/mL 180.4 [31]
carvacrol (8.5%), borneol (6.3%)
Cistus salvifolius Italy/Leaf Germacrene D (9.1%), elemicin (8.7%), caryophyllene 58.1 34.2 [31]
oxide (6.7%), viridiflorol (4.6%), manoyloxide (4.5%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
FABACEAE
Bauhinia ungulata L. Brazil/Leaf β-Caryophyllene (15.9%), caryophyllene oxide 96.0% at 1000 - [35]
(9.2%), α-humulene (8.1%), epi-γ-eudesmol (7.5%), α- µg/mL
bisabolol (4.7%)
Peltophorum dasyrachis Thailand/Bark (+)-(S)-ar-turmerone (22.3%), octanoic acid (16.5%), 83.2 - [36]
Kurz ex Bakar hexadecanoic acid (6.6%), (+)-camphor (6.0%),
hexanoic acid (4.7%)
ILLICIACEAE
Illicium verum Hook. f. India/Fruit Anethole (major compound) 39.9 75.4 [37]
LAMIACEAE
Clinopodium México/Leaf Menthone (35.3%), piperitone oxide (31.2%), linalool 320.0 - [96]
macrostemum var. (5.2%)
laevigatum (Standl.) B.
L. Turner
Cyclotrichium niveum Turkey/Aerial plant Isomenthone (56.2%), pulegone (19.8%) Nd for 2000 µg/mL - [97]
Lavandula dentata L. Saudi Arabia/Leaf and Camphor (61.4%), fenchone (24.3%) 9.7 µL/mL - [50]
flower
Lavandula officinalis purchased (origin: Linalyl acetate (36.0%), linalool (34.0%) β- 820.0 - [21]
Chaix France) caryophyllene (4.5%)
Lavandula pedunculata Portugal/Aerial part Camphor (40.6%), fenchone (38.0%) 57.2% at 2500 48.2% at 2500 [98]
ssp. lusitanica (Chaytor) µg/mL µg/mL
Franco
Lavandula viridis Portugal/Aerial part Camphor (31.6%), 1,8-cineole (21.3%) 411.3 748.7 [99]
L’Hér
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Data not available (-)-Methyl acetate (19.0%), (+)-pulegone (18.0%), (-)- 56.0 - [2]
menthol (15.0%), (+)-piperitone (14.0%), (-)-
menthone (12.0%), piperitenone (7.0%)
Data not available (-)-Menthol (69.0%), (-)-menthone (18.0%) 88.0 - [2]
Data not available (-)-Menthone (36.0%), (+)-pulegone (35.0%), (+)- 30.0 - [2]
neomenthol (11.0%)
Data not available (-)-Menthol (96.0%) 54.0 - [2]
Data not available (-)-Menthone (32.0%), (-)-menthol (16.0%), (+)- 36.0 - [2]
piperitone (14.0%), (+)-pulegone (11.0%), menthyl
acetate (10.0%), piperitenone (4.0%)
Data not available (+)-Pulegone (84.0%), Piperitenone (4.0%) 52.0 - [2]
Data not available (-)-Carvone (73.0%), (-)-limonene (16.0%) 58.0 - [2]
Data not available (+)-Pulegone (81.0%), (-)-borneol (6.0%) 42.0 - [2]
Data not available (-)-Menthol (65.0%), (-)-menthone (14.0%), 154.0 - [2]
isomenthone (6.0%)
Data not available (-)-Menthone (30.0%), (+)-neomenthol (22.0%), (+)- 40.0 - [2]
pulegone (13.0%), (+)-neomenthyl acetate (13.0%),
borneol (5.0%)
Mentha japonica Data not available (-)-Menthone (57.0%), (+)-pulegone (29.0%), 120.0 - [2]
limonene (4.0%)
Mentha longifolia L. Brasil/Leaf Piperitenone oxide (60.8%), limonene (13.8%), 0.7 cm at 20 µg EO - [38]
carvone D (5.2%), germacrene D (5.2%), trans-β-
caryophyllene (4.7%)
Saudi Arabia/Leaf Pulegone (75.0%), 1,8-cineole (7.4%), l-menthone 1.0 µL/mL - [50]
(6.6%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Data not available (+)-Piperitenone oxide (57.0%), 1,8-cineole (13.0%), 37.0 - [2]
β-myrcene (7.0%)
Data not available (+)-Linalool (98.0%) 130.0 - [2]
Nepeta menthoides Iran/Aerial part 4a-α,7β,7a-α-Nepetalactone (18.4%), 4a-α,7α,7a-α- 64.9 - [100]
Boiss and Buhse Nepetalactone (17.6%), 1,8-cineol (16.7%), geranyl
acetate (7.0%), α–terpineol (5.3%), β-pinene (4.1%)
Ocimum basilicum L. Burkina Faso/Leaf Linalool (48.7%), eugenol (27.5%), trans-α- 32.4% at 100 µL/mL - [45]
bergamotene (5.4%)
Ocimum canum Sims Burkina Faso/Leaf 1,8-Cineole (59.9%), camphor (8.1%), β-pinene 36.2 - [45]
(5.8%), α-terpineol (4.6%), α-pinene (4.5%)
Ocimum gratissimum Nigeria/Leaf -Terpinene (52.9%), (Z)-tert-butyl-4-hydroxy anisol 6.5 - [13]
(Linn) (13.9%), caryophyllene (10.4%)
Nigeria/Seed α–Pinene (48.2%), caryophyllene (10.7%) 6.7 - [13]
Ocimum sanctum L. purchased (origin: India) Eugenol (59.0%), β–caryophyllene (33.0%) 1600.0 - [21]
Origanum ehrenbergii Lebanon/Aerial part Thymol (19.6%), p-cymene (16.1%), 2-isopropyl-1- 0.3 0.3 [46]
Boiss methoxy-4-methylbenzene (14.9%), -terpinene
(11.8%), carvacrol (6.7%)
Origanum majorana L. Tunisia/Aerial part Terpinen-4-ol (23.2%), cis-sabinene hydrate (17.5%), 150.3 - [101]
γ-terpinene (10.5%), p-cymene (9.0%), sabinene
(7.5%), α–terpinene (5.6%), α–terpineol (5.6%), α-
terpineol (4.7%), trans-sabinene hydrate (4.0%)
Egypt/Leaf 4-Terpineol (30.0%), γ-terpinene (15.4%), trans- 36.4 - [102]
sabinene hydrate (10.9%), α-terpinene (6.9%), (S)-
methanal,a,a4-trimethyl-3-cycolohexene-1-1 (6.5%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Phlomis nissolii L. Turkey/Aerial part Germacrene D (15.1%), β-caryophyllene (12.7%), 1.09 mg 3.03 mg galanthamine [105]
hexahydrofarnesyl acetone (11.9%), linalool (11.3%), galanthamine equivalent/g oil
caryophyllene oxide (7.1%), allo-aromadendrene equivalent/g oil
(6.9%), spathulenol (4.0%)
Phlomis pungens Turkey/Aerial part n-Hexadecanoic acid (68.1%), germacrene D (7.2%), 1.23 mg 2.52 mg galanthamine [105]
Willd. var. pungens hexahydrofarnesyl acetone (4.0%) galanthamine equivalent/g oil
Willd. equivalent/g oil
Rosmarinus Egypt/Aerial part 1,8-Cineole (19.6%), camphor (17.0%), α-pinene 20.8 - [23]
officinalis L. (15.1%), verbenon (9.6%), endoborneol (8.2%),
linalool (5.2%)
Portugal/Aerial part Verbenone (35.4%), α-terpineol (7.2%), camphor 69.8 - [88]
(5.5%)
Tunisia/Aerial part 1,8-Cineole (52.6%), camphor (7.8%), α-pinene 498.9 924.2 [48]
(7.1%), borneol (4.1%), trans-caryophyllene (4.1%)
1,8-Cineole (44.9%), α-pinene (9.5%), camphor 98.2 346.7 [48]
(8.0%), trans-caryophyllene (7.7%), borneol (6.2%)
1,8-Cineole (51.4%), α-pinene (8.3%), camphor 200.5 697.8 [48]
(7.2%), borneol (5.9%)
1,8-Cineole (39.1%), camphor (12.0%), borneol 122.8 29.5 [48]
(10.0%), α-pinene (8.0%), trans-caryophyllene (4.1%)
1,8-Cineole (50.3%), camphor (10.5%), α-pinene 478.0 918.2 [48]
(9.1%), borneol (5.9%), trans-caryophyllene (4.3%)
1,8-Cineole (23.2%), camphor (27.5%), camphene 108.8 122.7 [48]
(11.1%), α-pinene (10.4%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil AChE assay BuChE assay Ref
(percentages) IC50 (µg/mL)* IC50 (µg/mL)*
Turkey/Aerial part 1,8-Cineole (58.9%), α-pinene (5.6%), β- 53.7% at 25 μg/mL 51.2% at 100 μg/mL [111]
pinene (5.2%), β-myrcene (5.2%), camphor
(4.5%), β-caryophyllene (4.2%)
Cyprus/Leaf Camphor (49.2%), 1,8-cineole (17.6%), 50.0 if incubated 5 min; 150.0 if incubated 5 [6]
caryophyllene (11.9%), borneol (4.6%) 60.0 if incubated 30 min; min;
50.0 if incubated 60 min; 60.0 if incubated 30
60.0 if incubated 90 min. min;
40.0 if incubated 60
min;
35.0 if incubated 90
min
Cyprus/Leaf Camphor (49.3%), 1,8-cineole (21.5%), 40.0 if incubated 5 min; 10.0% at 300 µg/mL if [6]
caryophyllene (6.6%), camphene (5.0%) 55.0 if incubated 30 min; incubated 5 min;
60.0 if incubated 60 min; 14.0% at 300 µg/mL if
60.0 if incubated 90 min incubated 30 min;
17.0% at 300 µg/mL if
incubated 60 min;
21.0% at 300 µg/mL if
incubated 90 min
Salvia fruticosa Mill. Italy/Aerial part β-Pinene (13.7%), 1,8-cineole (10.6%), 37.0% at 1000 μg/mL Nd at 1000 µg/mL [112]
ssp. thomasii viridiflorol (9.7%), camphor (8.5%), α-pinene
(7.6%), β-caryophyllene (7.3%), α-humulene
(6.5%), myrcene (5.3%)
1,8-Cineole (25.7%), β-pinene (12.5%), 39.2% at 1000 μg/mL Nd at 1000 µg/mL [112]
viridiflorol (9.7%), β-caryophyllene (8.8%),
camphor (7.7%), α-pinene (6.8%), α-
humulene (6.1%), myrcene (5.3%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Salvia nydeggeri Turkey/Aerial part α-Pinene (15.8%), β-pinene (9.2%), cubebol (6.2%), 49.4% at 80 6.6% at 80 µg/mL [106]
caryophyllene oxide (5.6%), 1,8-cineole (4.8%) µg/mL
Salvia officinalis L. Romania/Leaf 1,8-Cineole (13.9%), thujone and camphor (12.2%), α- 0.48 μL/mL - [41]
and β-pinene (4.6%)
Portugal/Aerial part 1,8-Cineole (59.1%), α-pinene (8.4%), camphor 50.8 - [16]
(5.7%)
UK/Leaf α-Humulene (23.2%), camphor (11.0%), borneol 70.0 if incubated 330.0 if incubated 5 [6]
(8.7%), thujone isomers (6.2%), 1,8-cineole (5.4%), 5 min; min;
1H-cycloprop(e)-azulene,deca-hydro 50.0 if incubated 240.0 if incubated 30
1H-cycloprop(e)-azulene,deca-hydro 1,1,7-trimethyl- 30 min; min;
4-methylene-, (1a,a) (5.3%) 65.0 if incubated 210.0 if incubated 60
60 min; min;
80.0 if incubated 230.0 if incubated 90
90 min min
Salvia officinalis L. UK/Leaf α-Humulene (32.5%), ledol isomers (9.4%), thujone 100.0 if 35.0% at 300 µg/mL if [6]
purpurea isomers (8.4%), camphor (4.8%) incubated 5 min; incubated 5 min;
140.0 if 220.0 if incubated 30
incubated 30 min;
min; 240.0 if incubated 60
180.0 if min;
incubated 60 200.0 if incubated 90
min; min
240.0 if
incubated 90 min
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Thymbra capitata (L.) Spain/Aerial part Carvacrol (69.4%), γ-terpinene (7.7%), p-cymene 75.1 µL EO/L - [103]
Cav. (7.1%), (E)-β-caryophyllene (4.0%)
Spain/Aerial part Carvacrol (75.5%), γ-terpinene (5.5%), p-cymene 62.2 µL EO/L - [103]
(6.6%)
Spain/Aerial part Carvacrol (70.4%), p-cymene (7.3%), γ-terpinene 67.6 µL EO/L - [103]
(7.0%), (E)-β-caryophyllene (4.1%)
Portugal/Aerial part Carvacrol (68.1%), p-cymene (12.7%), γ-terpinene 51.9 - [16]
(6.1%)
Thymus caespititius Portugal/Aerial part α-Terpineol (40.3%), p-cymene (13.8%), γ-terpinene 5898.0 - [44]
Brot. (5.4%), τ-cadinol (5.2%)
Portugal/Aerial part α-Terpineol (35.2%), p-cymene (17.3%), γ-terpinene 4647.2 - [44]
(9.1%), τ-cadinol (6.2%)
Portugal/Aerial part α-Terpineol (23.5%), p-cymene (15.9%), γ-terpinene 1766.5 - [44]
(11.7%), τ-cadinol (6.9%)
Portugal/Aerial part α-Terpineol (51.5%), p-cymene (14.5%), γ-terpinene 12448.0 - [44]
(6.5%), τ-cadinol (6.2%)
Portugal/Aerial part α-Terpineol (40.5%), p-cymene (13.7%), γ-terpinene 3000.6 - [44]
(8.7%)
Portugal, Azores/Aerial Carvacrol (50.7%), carvacryl acetate (18.7%), p- 567.4 - [44]
part cymene (5.7%)
Portugal, Azores/Aerial Carvacrol (32.2%), thymol (23.0%), carvacryl acetate 181.4 - [44]
part (7.0%), p-cymene (5.9%)
Portugal, Azores/Aerial Carvacrol (61.9%), carvacryl acetate (11.5%) 158.9 - [44]
part
Portugal, Azores/Aerial Thymol (24.9%), α-terpineol (19.1%), p-cymene 3601.6 - [44]
part (11.5%), γ-terpinene (9.6%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Thymus zygis Loefl. ex Portugal/Aerial part Carvacrol (31.8%), p-cymene (23.5%), 980.3 - [44]
L. ssp. Sylvestris γ -terpinene (7.7%), borneol (6.4%)
(Hoffm. and Link) Portugal/Aerial part p-Cymene (35.9%), thymol (24.2%), γ-terpinene 1352.5 - [44]
Brot. Ex Couthino (7.1%), borneol (6.4%)
Portugal/Aerial part Carvacrol (34.6%), p-cymene (24.6%), 1479.3 - [44]
borneol (9.7%), camphene (5.3%)
Portugal/Aerial part p-Cymene (39.4%), thymol (21.6%), γ-terpinene 1766.6 - [44]
(10.7%), linalool (4.3%)
Thymus zygis Loefl. ex Portugal/Aerial part Carvacrol (43.6%), p-cymene (24.1%), 1.1 - [44]
L. ssp. zygis γ-terpinene (15.8%)
Zataria multiflora Iran/Aerial part Thymol (37.6%), carvacrol (33.7%), p-cymene (7.7%) 0.97 - [51]
Boiss.
LAURACEAE
Aniba canelilla Brasil/Trunk wood 1-Nitro-2-phenylethane (70.2%), methyl-eugenol Detection limit - [120]
(H.B.K.) Mez (25.8%) 0.01 ng/spot
Beilschmiedia glabra Leaf β-Eudesmol (15.4%), β-selinene (12.2%), 48.1% at 1000 - [121]
caryophyllene oxide (8.1%), γ-gurjunene (5.2%) µg/mL
Bark β-Eudesmol (19.3%), β-selinene (16.9%), δ-cadinene 45.2% at 1000 - [121]
(15.8%), germacrene D (9.8%), β-caryophyllene µg/mL
(5.5%)
Beilschmiedia Malaysia/Leaf β-Caryophyllene (12.1%), germacrene B (11.2%), α- 42.8% at 95 - [54]
kunstleri cadinol (10.4%), τ-muurolol (7.2%), caryophyllene µg/mL
oxide (7.0%), δ-cadinene (5.9%), ledol (4.9%)
Malaysia/Bark δ-Cadinene (13.4%), β-caryophyllene (10.6%), α- 50.3% at 95 - [54]
cadinol (9.0%), germacrene B (8.5%), caryophyllene µg/mL
oxide (5.4%), dehyroaromadendrene (4.4%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Beilschmiedia madang Malaysia/Leaf δ-Cadinene (17.0%), β-caryophyllene (10.3%), α- 55.2% at 95 60.4% at 95 µg/mL [55]
Blume cubebene (11.3%), bicyclogermacrene (6.7%), α- µg/mL
cadinol (5.8%), (E)-nerolidol (5.0%), germacrene D
(4.7%), α-humulene (4.3%)
Malaysia/Bark δ-Cadinene (20.5%), β-caryophyllene (6.7%), α- 48.2% at 95 50.2% at 95 µg/mL [55]
cubebene (15.6%), α-cadinol (10.6%) µg/mL
Beilschmiedia Malaysia/Leaf β-Eudesmol (24.1%), caryophyllene oxide (11.0%), β- 66.6% at 95 - [54]
maingayi panasinsene (10.2%), α-ylangene (4.3%) µg/mL
Malaysia/Bark β-Eudesmol (17.5%), caryophyllene oxide (12.8%), α- 53.3% at 95 - [54]
eudesmol (12.2%), β-panasinsene (11.6%) µg/mL
Beilschmiedia Malaysia/Leaf δ-Cadinene (28.7%), germacrene D (20.7%), β- 51.8% at 95 - [54]
penangiana caryophyllene (10.4%), α-copaene (7.7%), germacrene µg/mL
B (5.9%)
Malaysia/Bark δ-Cadinene (17.5%), germacrene D (14.6%), β- 47.1% at 95 - [54]
caryophyllene (12.6%), germacrene B (10.7%), µg/mL
viridiflorol (8.0%), τ-muurolol (7.5%), α-guaiene
(4.4%)
Beilschmiedia Malaysia/Leaf and stem Eugenol (45.3%), eugenol acetate (5.6%) 56.5% at 95 48.2% at 95 µg/mL [53]
pulverulenta Kosterm bark µg/mL
Cinnamomum purchased from Thai- 1,8-Cineole (39.9%), limonene (23.7%), o-cymene 60.6% at 120 - [47]
camphora (L.) J.Presl China Flavour and (9.1%), α-terpineol (5.0%), α-pinene (4.9%) µg/mL
Fragrances Industry Co.,
Ltd. and Perfumes world,
(Bangkok, Thailand)/
Leaves
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Eugenia pruniformis Brazil/Leaf β-Caryophyllene (46.9%), bicyclogermacrene 1798.0 - [60]
Cambess. (14.9%), globulol (8.9%), α–copaene (5.5%), α–
humulene (4.4%)
Eugenia riedeliana O. Brazil/Leaf Valerianol (28.1%), 10-epi-γ-eudesmol 67.3 - [62]
Berg (12.6%), β-caryophyllene (10.9%), α-
selinene (6.1%), δ-cadinene (5.6%), β-selinene (5.2%)
Eugenia sulcata Spring Brazil/Leaf β–Caryophyllene (24.6%), α–pinene (17.2%), β- 4.7 - [123]
ex Mart. pinene (10.9%), 1,8-cineole (5.6%), α–humulene
(5.1%), trans-calamenene (4.4%), γ-cadinene (4.3%)
Marlierea racemosa Brazil/Leaf Spathulenol (25.0%), muurola-4,10(14)-dien-1β-ol 35.0% at 600 - [63]
(13.2%), 14-hydroxi-9-epi-(E)-caryophyllene (5.5%) μg/mL
Brazil/Leaf Spathulenol (31.9%), p-mentha-1,5-dien-8-ol (6.6%), 65.2 - [63]
α-pinene (4.6%)
Melaleuca alternifolia Yamamoto Perfumery Terpinene-4-ol (35.6%), γ-terpinene (19.5%), α- 51.2 - [57]
Cheel Co. Ltd (Osaka, Japan) terpinene (8.3%), p-cymene (7.2%), 1,8-cineole
(4.4%)
supplied by Pranarom Terpinene-4-ol (46.9%), γ-terpinene (22.5%), α- 3.5 𝜇L/mL - [56]
terpinene (10.3%), p-cymene (5.9%)
Melaleuca cajuputi purchased from Thai- 1,8-Cineole (70.2%), α-terpineol (10.1%), limonene 0.63 - [47]
Powell China Flavour and (5.5%)
Fragrances Industry Co.,
Ltd. and Perfumes world,
(Bangkok,
Thailand)/Leaves
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
PINACEAE
Pinus brutia Ten. Turkey/Needle β-Pinene (47.5%), α-pinene (17.0%), germacrene D 28% at 200 25% at 200 𝜇g/mL [66]
(7.5%), β-caryophyllene (4.6%), α-terpineol (4.4%) 𝜇g/mL
Turkey/Twig β-Pinene (19.2%), α-pinene (14.5%), δ-3-carene 3% at 200 1% at 200 𝜇g/mL [66]
(14.2%), myrcene (11.0%), β-caryophyllene (9.7%), 𝜇g/mL
germacrene D (5.5%)
Pinus halepensis Mill. Turkey/Needle β-Pinene (46.8%), α-pinene (18.4%), β-caryophyllene 58% at 200 52% at 200 𝜇g/mL [66]
(9.2%), germacrene D (8.8%) 𝜇g/mL
Turkey/Twig β-Pinene (18.7%), limonene (18.7%), α-pinene 83.9% at 200 80.6% at 200 𝜇g/mL [66]
(16.4%), -3-carene (16.3%), β-caryophyllene (9.5%) 𝜇g/mL
Pinus heldreichii Italy/Needle α-Pinene (24.2%), β-pinene (8.4%), limonene (7.8%), 51.1 80.6 [68]
Christ ssp. α-cubebene (7.6%), terpinolene (5.9%), trans-
leucodermis. (Antoine) caryophyllene (4.5%)
E. Murray
Pinus nigraArnold Turkey/Needle α-Pinene (44.2%), β-pinene (21.3%), germacrene D 41% at 200 22% at 200 𝜇g/mL [66]
(16.7%), β-caryophyllene (4.9%) 𝜇g/mL
Turkey/Twig α-Pinene (69.5%), β-pinene (8.5%) 22% at 200 36% at 200 𝜇g/mL [66]
𝜇g/mL
Pinus nigra Arnold Italy/Needle α-Pinene (24.6%), β-pinene (10.9%), γ-cadinene 101.5 128.0 [68]
var. calabrica C. K. (9.9%), β-phellandrene (6.3%), manoyl oxide (6.2%),
Scheid trans-caryophyllene (4.2%), (Z)-β-ocimene (4.0%)
Pinus nigra Arnold Croatia/Needle α-Pinene (24.4%), β-pinene (16.0%), germacrene D 42.7 - [67]
ssp. dalmatica (Vis.) (14.6%), β-caryophyllene (9.6%)
Franco
Pinus nigra Arnold Italy/Needle α-Pinene (25.3%), limonene (22.6%), sabinene 94.4 162.5 [68]
ssp. nigra (12.8%), α-terpineol (8.3%), β-pinene (4.8%),
terpinolene (4.5%)
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
Tunisia/fresh leaf Limonene (24.6%), β-phellandrene (16.0%), α-terpineol 610.0 - [71]
(11.7%), -terpinene (8.4%), -cadinene (4.5%)
Tunisia/dried leaf Limonene (24.6%), β-phellandrene (15.7%), α-terpineol 520.0 - [71]
(9.6%), -terpinene (8.9%), α-eudesmol (5.1%), α-
cadinene (4.2%), α-selinene (4.1%)
Tunisia/dried leaf Limonene (23.5%), β-phellandrene (14.1%), -terpinene 440.0 - [71]
(11.3%), α-terpineol (10.1%), α-cadinene (5.5%), β-
eusdemol (5.3%)
Tunisia/dried leaf Limonene (22.1%), β-phellandrene (16.3%), α-terpineol 280.0 - [71]
(11.0%), -terpinene (7.4%), -cadinene (5.4%), β-
eusdemol (5.1%)
Tunisia/dried root Limonene (26.0%), β-phellandrene (15.9%), -terpinene 320.0 - [71]
(9.7%), α-terpineol (9.4%), -cadinene (4.9%), elemol
(4.3%), α-eusdemol (4.3%), valencene (4.1%)
Tunisia/dried root β-Eusdemol (14.2%), limonene (10.5%), β-phellandrene 270.0 - [71]
(8.2%), junipercamphor (8.2%), valencene (7.2%), α-
terpineol (6.8%), -cadinene (6.1%), elemol (4.6%),
germacrene B (4.5%), -terpinene (4.3%)
POLYGONACEAE
Polygonum hydropiper Pakistan/Leaf Decahydronaphthalene (38.3%), 1,2,3,6- 120.0 130.0 [73]
L. tetramethylbicyclo[2.2.2]oct-2-ene (36.3%), β-elemene
(6.8%)
Pakistan/Flower Caryophylene oxide (41.4%), β- caryophyllene epoxide 220.0 225.0 [73]
(18.2%), humulene oxide (16.1%), β-elemene (4.8%)
Polygonum minus Malaysia/Leaf; Stem; Dodecanal (24.5-59.5%), β-caryophyllene (8.9-19.6%), For all Nd at - [74]
Root decanal (10.3-11.6%) 10000 μg/mL
FAMILY/SPECIES Origin/Part used Major constituents of essential oil (percentages) AChE assay BuChE assay Ref
IC50 (µg/mL)* IC50 (µg/mL)*
provided by Zaraphyt Limonene (99.0%) 849.9 - [32]
(Rabat, Morocco)/
Peel
Nigeria/Peel Limonene (53.1%), β-pinene (9.5%), borneol (5.6%), 0.2 μL/mL 0.2 μL/mL [77]
neral (4.7%), sabinene (4.2%)
Citrus medica L. cv. Italy/Peel Limonene (15.2%), citropten (12.6%), γ-terpinene 621.0 - [127]
Diamante (10.3%), 9,17-octadecadienal (9.3%), hexadecanoic acid
(5.2%), nerol (4.7%), geraniol (4.6%)
Italy/Peel Limonene, (35.4%), γ-terpinene (24.5%), geranial (5.5%), 171.3 154.6 [128]
neral (4.4%)
Italy/Peel Limonene (44.5%), γ-terpinene (26.2%) 298.8 Nd at 102 μL/mL [128]
Citrus sinensis (L.) Nigeria/Peel Limonene (92.1%) 2.6 2.6 [76]
Osbeck Nigeria/Seed Limonene (13.7%), tetradecanoic acid (11.9%), 3.5 3.5 [76]
hexadecanoic acid (10.6%), borneol (5.4%), 6-
hydroxyeicosane (5.3%), α-terpineol (4.6%), β-
caryophyllene (4.3%), 1,8-cineole (4.2%), 3-dihydroxy-2-
octadecene (4.0%)
Haplophyllum Saudi Arabia/Aerial trans-p-Menth-2-en-1-ol (19.2%), cis-p-menth-2-en-1-ol 26.7% at 80 μg/mL Nd at 80 μg/mL [129]
tuberculatum Juss. part (13.2%), myrcene (10.1%), δ-3-carene (8.8%), β-
phellandrene (6.9%), limonene (6.6%), cis-piperitol
(6.4%), piperitone (4.1%), trans-piperitol (4.0%)
VALERIANACEAE
Valeriana wallichii AYUS GmbH β-Asarone (88.8%) <10% at 1000 µg/mL - [9]
(Weinstrasse,
Bühl/Baden,
Germany)
Acoraceae
Altingiaceae
Anacardiaceae
Annonaceae
Apiaceae
compound (over 70%) reported controversial IC50 with values of 252.0 and
1187.7 µg/mL.
BuChE inhibitory activity of C. maritimum EO from Cyprus showed good
activity (59.8% at 121 µg/mL) with γ-terpinene and β-phellandrene as major
constituents (over 60%), while EO from Croatia showed weak activity (>25%
at 45.5 µg/mL) with monoterpene hydrocarbon limonene as the major
compound (57-74%). F. communis EO showed good inhibition but at very
high concentrations (>10000 µg/mL).
Asteraceae
Boraginaceae
relatively good inhibitory activity on both AChE (48.5% at 200 μg/mL) and
BuChE (43.7% at 200 μg/mL) [26].
EO from Cordia gilletii with high-molecular semivolatile constituents
such as phytol, hexadecanoic acid, (E)-2-hexenal and nonacosane (20.4%,
15.2%, 9.6% and 9.2%, respectively) as main compounds showed good
inhibitory activity on both AChE with IC50 of 105.6 μg/mL and BuChE with
IC50 of 369.3 μg/mL [27].
Buddlejaceae
Burseraceae
Cistaceae
Cupressaceae
Euphorbiaceae
rubber tree, Hevea brasiliensis) while other have been used as violent
purgative (Croton tiglium) and liquid bandage (Croton lechleri) and other have
very well-known ornamental usage (Poinsettia or Christmas star, Euphorbia
pulcherrima).
EOs from three chemotypes of Croton zehntneri having (E)-anethole
(33.7, 70.5, 89.1%), eugenol (49.1, 84.2%), (Z)-methyl isoeugenol (53.4,
81.5%), stragole (90.2%) and (E)-methyl isoeugenol (91.5%) as major
compounds were tested on AChE inhibitory activity via TLC-autobiography
test at 2000 μg/mL. All EOs showed inhibition of AChE with exception of
EOs having stragole (90.2%) and eugenol (89.1%) as major constituents [33].
Fabaceae
Illiciaceae
Lamiaceae
Lauraceae
Myrtaceae
Nelumbonaceae
Pinaceae
Piperaceae
small trees, shrubs or herbs and the best know species is Piper nigrum L.
which yields the most peppercorns and is used as a spice.
P. nigrum monoterpene (δ-3-carene, limonene, β-pinene, α-pinene, over
70%) EO type showed excellent activity on AChE with IC50 of 5.97 µg/mL
[69]. Three other Piper spp. (P. aleyreanum, P. anonifolium, P. hispidum) EOs
highly represented by sesquiterpenes i.e., selin-11-en-4-α-ol, β-elemene, β-
selinene, α-selinene, bicyclogermacrene, β-caryophyllene, α-humulene, and δ-
elemene) were tested for AChE activity via TLC autobiography method where
P. anonifolium and P. hispidum showed 100 times better activity than
phystostigmine which was used as control sample [70].
Poaceae
The Poaceae family (also known as grasses) comprises of 707 genera with
11337 species growing worldwide [7]. The Poaceae family includes the cereal
grasses, bamboos and the grasses of natural grassland and cultivated lawns as
well as pastures.
EO from only one species was reported i.e., Cymbopogon schoenanthus L.
Spreng. ssp. laniger (Hook) Maire et Weill to have inhibitory activity on
AChE with IC50 ranging from 260 to 670 µg/mL [71].
Polygonaceae
Rosaceae
The family Rosaceae (also called rose family) comprises of 90 genera with
2520 species growing worldwide, but especially in Northern hemisphere, often
not deserts or tropical rainforest [7]. The family includes herbs, shrubs, and
trees as well as some economically important products such are edible fruits:
apples, pears, quinces, apricots, plums, cherries, peaches, raspberries, loquats,
and strawberries, almonds, and ornamental trees and shrubs such as: roses,
meadowsweets, photinias, firethorns, rowans, and hawthorns.
Rosa damascena EO is the only one that was tested for both ChEs and
showed weak activity on both enzymes, having monoterpene alcohols as major
compounds (representing over 70% of EO, i.e., citronellol, geraniol, nerol)
[75].
Rutaceae
The family Rutaceae (also known as rue and citrus family) comprises of
161 genera with 2070 species growing largely in tropical areas [7]. Species in
this family generally contain herbs, shrubs and trees with flowers having
strong scent. The most economically known genus is Citrus which includes:
orange, lemon, grapefruit, lime, mandarin, and kumquat.
Seven species were reported of which six belong to Citrus and one to
Haplophyllum genus and all of them were tested on both ChEs. EO from C.
paradisi is one of the earliest reports of ChE inhibition by EO constituents,
namely nootkatone and auraptene showing 17-24% AChE inhibition at
concentration of 1.62 μg/mL [3]. Citrus EOs generally have limonene as the
major constituent ranging from 13.7% to 99.0% along with other
monoterpenes such as: β-pinene, γ-terpinene and others having excellent
activity reported for both ChEs in general [15, 23, 76, 77].
EOs from C. aurantifolia and C. limon having limonene over 40% as the
major constituent were tested on two different AChEs isolated from T.
castaneum and S. oryzae showed difference in activity with IC50 of 105.8 and
29.4 µg/mL, which was significant, and 35.3 and 20.2 µg/mL, respectively.
These results suggest the similar conclusion for selectivity for different AChE
active sites as in the cases of Artemisia monosperma (Asteraceae), Origanum
vulgare (Lamiaceae), Callistemon viminals (Myrtaceae) EOs mentioned
previously [15, 23].
Valerianaceae
Verbenaceae
Zingiberaceae
CONCLUSION
The essential oils with their main constituents represent adjuvant in the
treatment of neurological diseases such as Alzheimer’s due to the fact that they
show inhibition potential on ChEs which are target in treatment of such
diseases.
Most investigations on ChE inhibition were conducted on EOs obtained
from Lamiaceae (72 species), Asteraceae (25 species), Myrtaceae (14 species),
and Lauraceae (11 species) families. EOs which exhibited excellent inhibitory
activity on ChEs derive from: Lamiaceae (Lavandula dentata, Mentha
aquatica, M. arvensis, M. citrata, M. gentilis, M. spicata, Ocimum canum, O.
gratissimum, Origanum ehrenbergii, O. majorana, O. syracum, O. vulgare,
Rosmarinus officinalis, Salvia hydrangea, S. lavandulaefolia, S. leriifolia, S.
officinalis, S. pseudeuphratica, S. tomentosa, Thymus mastichina, T. zygis,
Zataria multiflora), following Asteraceae (Artemisia judaica, A.
macrocephala, A. maderaspatana, Asteriscus maritimus, Crassocephalum
crepidioides, Pluchea lanceolata), then Myrtaceae (Calistemon viminals,
Eucalyptus camaldulensis, E. globulus, E. sulcata, Melaleuca alternifolia, M.
cajuputi, Syzygium aromaticum), and Rutaceae (Citrus aurantifolia, C.
aurantum, C. limon, C. sinensis). Some other representatives of different
families that showed notable activity were: Acorus calamus (Acoraceae),
Xylopia aethiopica (Annonaceae), Buddleja asiatica (Buddlejaceae),
Cinnamomum zeylanicum (Lauraceae), Piper nigrum (Piperaceae).
Considering all the reports given in Table 1, it is clear that some EOs with
similar composition have different inhibitory effects against tested ChEs.
These investigations suggest that some constituents may have synergistic
effect on other components either in positive or negative manner. However
only few reports considered these effects which are quite reasonable in
complex mixtures such are EOs. In order to draw proper conclusions future
investigations should involve testing of those EOs that showed excellent
inhibitory activity using different combinations and ratios of the main
constituents. Such investigations of constituents should include monoterpenes
(i.e., 1,8-cineole, limonene, α-pinene, β-pinene, terpinene-4-ol, linalool, etc.),
sesquiterpenes (i.e., β-caryophyllene, α-humulene, caryophyllene oxide etc.),
phenylpropanoids (eugenol, β-asarone, etc.) and others.
Differences observed in the inhibitory activity between two studies
investigating the same EOs were, in some cases, very significant, (A.
macrocarpa, C. viminals, O. vulgare, C. limon, C. aurantifolia) towards two
AChEs isolated from different insects (S. oryzae, T. castaneum) which
ACKNOWLEDGMENT
This work has been supported by Croatian Science Foundation grant
number IP-2014-09-6897.
REFERENCES
[1] Regnault-Roger, C., Vincent, C., and Arnason, J. T., (2012). Essential
Oils in Insect Control: Low-Risk Products in a High-Stakes World.
Annu Rev Entomol 57, 405-424.
[2] Miyazawa, M., Watanabe, H., Umemoto, K., and Kameoka, H., (1998).
Inhibition of Acetylcholinesterase Activity by Essential Oils of Mentha
Species. J Agr Food Chem 46, 3431-3434.
[3] Miyazawa, M., Hideyuki, T., and Ishihara, M., (2001). Inhibition of
Acetylcholinesterase Activity by Essential Oil from Citrus paradisi. Nat
Prod Res 15, 205-210.
[4] Perry, N. S. L., Houghton, P. J., Theobald, A., Jenner, P., and Perry,
E. K., (2000). In-vitro Inhibition of Human Erythrocyte
Acetylcholinesterase by Salvia lavandulaefolia Essential Oil and
Constituent Terpenes. J Pharm Pharmacol 52, 895-902.
[5] Savelev, S., Okello, E., Perry, N., Wilkins, R., and Perry, E., (2003).
Synergistic and antagonistic interactions of anticholinesterase terpenoids
in Salvia lavandulaefolia essential oil. Pharmacol Biochem Behav 75,
661-668.
[6] Savelev, S. U., Okello, E. J., and Perry, E. K., (2004). Butyryl- and
acetyl-cholinesterase inhibitory activities in essential oils of Salvia
species and their constituents. Phytother Res 18, 315-324.
[7] Stevens, P. F., (2001 (onwards)). Angiosperm phylogeny website,
version 13, September 2013.
[8] Mukherjee, P. K., Kumar, V., Mal, M., and Houghton, P. J., (2007). In
vitro acetylcholinesterase inhibitory activity of the essential oil from
Acorus calamus and its main constituents. Planta Med 73, 283-285.
[9] Park, I.-K., (2014). Fumigant Toxicity of Oriental Sweetgum
(Liquidambar orientalis) and Valerian (Valeriana wallichii) Essential
Oils and Their Components, Including Their Acetylcholinesterase
Inhibitory Activity, against Japanese Termites (Reticulitermes speratus).
Molecules 19, 12547-12558.
[10] Murray, A. P., Gurovic, M. S. V., Rodriguez, S. A., Murray, M. G., and
Ferrero, A. A., (2009). Acetylcholinesterase Inhibition and Antioxidant
Activity of Essential Oils from Schinus areira L. and Schinus longifolia
(Lindl.) Speg Nat Prod Commun 4, 873-876.
[11] Aissi, O., Boussaid, M., and Messaoud, C., (2016). Essential oil
composition in natural populations of Pistacia lentiscus L. from
Tunisia: Effect of ecological factors and incidence on antioxidant and
antiacetylcholinesterase activities. Ind Crop Prod 91, 56-65.
[12] Adefeghaa, S. A., Oboh, G., Odubanjoa, T., and Ogunsuyia, O. B.,
(2015). A comparative study on the antioxidative activities,
anticholinesterase properties and essential oil composition of Clove
(Syzygium aromaticum) bud and ethiopian pepper (Xylopia aethiopica).
Riv Ital Sost Grasse XCII, 257-268.
[13] Owokotomo, I. A., Ekundayo, O., Abayomi, T. G., and Chukwuka, A.
V., (2015). In-vitro anti-cholinesterase activity of essential oil from four
tropical medicinal plants. Toxicol Rep 2, 850-857.
[14] Dempewolf, H., Rieseberg, L. H., and Cronk, Q. C., (2008). Crop
domestication in the Compositae: a family-wide trait assessment. Gen
Res Crop Evol 55, 1141-1157.
[15] Abdelgaleil, S. A. M., Mohamed, M. I. E., Shawir, M. S., and Abou-
Taleb, H. K., (2016). Chemical composition, insecticidal and
biochemical effects of essential oils of different plant species from
Northern Egypt on the rice weevil, Sitophilus oryzae L. J Pest Sci 89,
219-229.
[16] Albano, S. M., Lima, A. S., Miguel, M. G., Pedro, L. G., Barroso, J. G.,
and Figueiredo, A. C., (2012). Antioxidant, Anti-5-lipoxygenase and
Antiacetylcholinesterase Activities of Essential Oils and Decoction
Waters of Some Aromatic Plants. Rec Nat Prod 6, 35-48.
[17] Younsi, F., Trimech, R., Boulila, A., Ezzine, O., Dhahri, S., Boussaid,
M., and Messaoud, C., (2016). Essential Oil and Phenolic Compounds
of Artemisia herba-alba (Asso.): Composition, Antioxidant,
Antiacetylcholinesterase, and Antibacterial Activities. Int J Food Prop
19, 1425-1438.
[18] Miyazawa, M., Nakahashi, H., Usami, A., and Matsuda, N., (2016).
Chemical composition, aroma evaluation, and inhibitory activity
towards acetylcholinesterase of essential oils from Gynura bicolor DC.
J Nat Med-Tokyo 70, 282-289.
[19] Yu, Z., Wang, B., Yang, F., Sun, Q., Yang, Z., and Zhu, L., (2011).
Chemical Composition and Anti-acetylcholinesterase Activity of Flower
Essential Oils of Artemisia annua at Different Flowering Stage. Iran J
Pharm Res 10, 265-271.
[20] Orhan, I. E., Belhattab, R., Şenol, F. S., Gülpinar, A. R., Hoşbaş, S., and
Kartal, M., (2010). Profiling of cholinesterase inhibitory and antioxidant
activities of Artemisia absinthium, A. herba-alba, A. fragrans,
Marrubium vulgare, M. astranicum, Origanum vulgare subsp.
glandulossum and essential oil analysis of two Artemisia species. Ind
Crop Prod 32, 566-571.
[21] Dohi, S., Terasaki, M., and Makino, M., (2009). Acetylcholinesterase
Inhibitory Activity and Chemical Composition of Commercial Essential
Oils. J Agr Food Chem 57, 4313-4318.
[22] Srivastava, P., Jyotshna, Chanda, D., and Shanker, K., (2015). Chemical
Characterization and Acetylcholinesterase Inhibition Potential of
Volatile Components of Aerial Parts of Pluchea lanceolata (DC.) Oliv.
and Hiern. Rec Nat Prod 9, 586-591.
[32] Aazza, S., Lyoussi, B., and Miguel, M. G., (2011). Antioxidant and
Antiacetylcholinesterase Activities of Some Commercial Essential Oils
and Their Major Compounds. Molecules 16, 7672-7690.
[33] Santos, H. S., Furtado, E. F., Bertini, L. M., Bandeira, P. N.,
Albuquerque, M. R. J. R., Menezes, J. E. S. A., Trevisan, M. T. S., and
Lemos, T. L. G., (2010). Chemical composition and cholinesterase
inhibition of essential oils of three chemotypes from Croton zehntneri.
Rev Lat Am Quim 38, 45-51.
[34] Christenhusz, M. J. M. and Byng, J. W., (2016). The number of known
plants species in the world and its annual increase. Phytotaxa 261, 201-
217.
[35] Medeiros, S. R. N. A., Filho, A. A. d. M., Costa, H. N. R. d., Silva, F. d.
S., Santos, R. C. d., A.Takahashi, J., Ferraz, V. P., Melo, A. C. G. R. d.,
Ribeiro, P. R. E., Laranjeira, A. G. d. A., Kamezaki, A. K., Martins, R.
M. G., and Paulino, F. d. S., (2016). Chemical profile, antimicrobial
activity, toxicity on Artemia salina and anti-acetylcholinesterase
enzyme essential oil from Bauhinia ungulata L. (Fabaceae) leaves J
Med Plants Res 10, 442-449.
[36] Fujiwara, M., Yagi, N., and Miyazawa, M., (2010). Acetylcholinesterase
Inhibitory Activity of Volatile Oil from Peltophorum dasyrachis Kurz
ex Bakar (Yellow Batai) and Bisabolane-Type Sesquiterpenoids. J Agr
Food Chem 58, 2824-2829.
[37] Bhadra, S., Mukherjee, P. K., Kumar, N. S., and Bandyopadhyay, A.,
(2011). Anticholinesterase activity of standardized extract of Illicium
verum Hook. f. fruits. Fitoterapia 82, 342-346.
[38] de Sousa Barros, A., de Morais, S. M., Ferreira, P. A. T., Vieira, Í. G.
P., Craveiro, A. A., dos Santos Fontenelle, R. O., de Menezes, J. E. S.
A., da Silva, F. W. F., and de Sousa, H. A., (2015). Chemical
composition and functional properties of essential oils from Mentha
species. Ind Crop Prod 76, 557-564.
[39] Kennedy, D. O., Dodd, F. L., Robertson, B. C., Okello, E. J., Reay, J.
L., Scholey, A. B., and Haskell, C. F., (2011). Monoterpenoid extract of
sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties
improves cognitive performance and mood in healthy adults. J
Psychopharmacol 25, 1088-1100.
[40] Loizzo, M. R., Menichini, F., Tundis, R., Bonesi, M., Conforti, F.,
Nadjafi, F., Statti, G. A., Frega, N. G., and Menichini, F., (2009). In
vitro Biological Activity of Salvia leriifolia Benth Essential Oil
Relevant to the Treatment of Alzheimer’s Disease. J Oleo Sci 58, 443-
446.
[41] Cioanca, O., Mircea, C., Hritcu, L., Trifan, A., Mihasan, M.,
Aprotosoaie, A. C., Robu, S., Gille, E., and Hancianu, M., (2015). In
vitro – in vivo correlation of the antioxidant capacity of Salviae
aetheroleum essential oil. Farmacia 63, 34-39.
[42] Marchev, A., Ivanov, I., Denev, P., Nikolova, M., Gochev, V.,
Stoyanova, A., Pavlov, A., and Georgiev, V., (2015).
Acetylcholinesterase inhibitory, antioxidant, and antimicrobial activities
of Salvia tomentosa Mill. essential oil. J BioSci Biotechnol 4, 219-229.
[43] Şenol, F. S., Orhan, I., Celep, F., Kahraman, A., Doğan, M., Yilmaz, G.,
and Şener, B., (2010). Survey of 55 Turkish Salvia taxa for their
acetylcholinesterase inhibitory and antioxidant activities. Food Chem
120, 34-43.
[44] Dandlen, S. A., Miguel, M. G., Duarte, J., Faleiro, M. L., Sousa, M. J.,
Lima, A. S., Figueiredo, A. C., Barroso, J. G., and Pedro, L. G., (2011).
Acetylcholinesterase Inhibition Activity of Portuguese Thymus Species
Essential Oils. J Essent Oil Bear Pl 14, 140-150.
[45] Kiendrebeogo, M., Coulibaly, A. Y., Nebie, R. C. H., Zeba, B., Lamien,
C. E., Lamien-Meda, A., and Nacoulma, O. G., (2011).
Antiacetylcholinesterase and antioxidant activity of essential oils from
six medicinal plants from Burkina Faso. Rev Bras Farmacogn 21, 63-
69.
[46] Loizzo, M. R., Menichini, F., Conforti, F., Tundis, R., Bonesi, M., Saab,
A. M., Statti, G. A., Cindio, B. d., Houghton, P. J., Menichini, F., and
Frega, N. G., (2009). Chemical analysis, antioxidant, antiinflammatory
and anticholinesterase activities of Origanum ehrenbergii Boiss and
Origanum syriacum L. essential oils. Food Chem 117, 174-180.
[47] Phrompittayarat, W., Hongratanaworakit, T., Tadtong, S., Sareedenchai,
V., and Ingkaninan, K., (2014). Survey of acetylcholinesterase
inhibitory activity in essential oil derived from aromatic plants. Int J
Med Arom Plants 4, 1-5.
[48] Ben Jemia, M., Tundis, R., Pugliese, A., Menichini, F., Senatore, F.,
Bruno, M., Kchouk, M. E., and Loizzo, M. R., (2015). Effect of
bioclimatic area on the composition and bioactivity of Tunisian
Rosmarinus officinalis essential oils. Nat Prod Res 29, 213-222.
[49] Orhan, I., Aslan, S., Kartal, M., Şener, B., and Hüsnü Can Başer, K.,
(2008). Inhibitory effect of Turkish Rosmarinus officinalis L. on
acetylcholinesterase and butyrylcholinesterase enzymes. Food Chem
108, 663-668.
[50] Alsarar, A. S., Hussein, H. I., Abobakr, Y., Bayoumi, A. E., and
Alotaibi, M. T., (2014). Fumigant toxicity and antiacetylcholinesterase
activity of Saudi Mentha longifolia and Lavandula dentata species
against Callosobruchus maculatus (F.) (Coleoptera: Bruchidae). Turk J
Entomol 38, 11-18.
[51] Fariba Sharififar, M. M., Mohammad Jaber Azampour, and Zamani
Ehsan, (2012). Essential Oil and Methanolic Extract of Zataria
multiflora Boiss with Anticholinesterase Effect. Pakistan J Biol Sci 15,
49-53.
[52] Salleh, W. M. N. H. W., Ahmad, F., and Yen, K. H., (2015).
Antioxidant and Anticholinesterase Activities of Essential Oils of
Cinnamomum griffithii and C. macrocarpum. Nat Prod Commun 10,
1465-1468.
[53] Salleh, W. M. N. H. W., Ahmad, F., Yen, K. H., and Zulkifli, R. M.,
(2016). Chemical composition and biological activities of essential oil
of Beilschmiedia pulverulenta. Pharm Biol 54, 322-330.
[54] Salleh, W. M. N. H. W., Ahmad, F., Khong Heng, Y., and Mohamed
Zulkifli, R., (2016). Comparative study of the essential oils of three
Beilschmiedia species and their biological activities. Int J Food Sci Tech
51, 240-249.
[55] Salleh, W. M. N. H. W., Ahmad, F., and Yen, K. H., (2015). Chemical
compositions and biological activities of the essential oils of
Beilschmiedia madang Blume (Lauraceae). Arch Pharm Res 38, 485-
493.
[56] Gómez-Rincón, C., Langa, E., Murillo, P., Valero, M. S., Berzosa, C.,
and López, V., (2014). Activity of Tea Tree (Melaleuca alternifolia)
Essential Oil against L3 Larvae of Anisakis simplex. BioMed Res Int
2014, 1-6.
[57] Miyazawa, M. and Yamafuji, C., (2006). Inhibition of
acetylcholinesterase activity by tea tree oil and constituent terpenoids.
Flavour Frag J 21, 198-201.
[58] Zatelli, G. A., Zimath, P., Tenfen, A., Mendes de Cordova, C. M.,
Scharf, D. R., Simionatto, E. L., Alberton, M. D., and Falkenberg, M.,
(2016). Antimycoplasmic activity and seasonal variation of essential oil
of Eugenia hiemalis Cambess. (Myrtaceae). Nat Prod Res 30, 1961-
1964.
[59] Amaral, R. R., Fernandes, C. P., Botas, G. d. S., Cruz, R. A. S., Santos,
M. G., and Rocha, L., (2014). Anticholinesterase Activity of Essential
oil from Leaves of Neomitranthes obscura (DC.) N. Silveira. Lat Am J
Pharm 33, 860-863.
[60] Albuquerque, R. D. D. G., Tietbohl, L. A. C., Fernandes, C. P.,
Couteiro, P. P., Eiriz, D. N., Santos, M. G., Silva-Filho, M. V., Alves,
G. G., Bachinski, R., and Rocha, L., (2012). Chemical and Biological
Study of Essential Oils from Eugenia pruniformis Cambess., an
Endemic Species from Brazilian Atlantic Forest. Lat Am J Pharm 31,
830-834.
[61] Tietbohl, L. A. C., Lima, B. G., Fernandes, C. P., Santos, M. G., Silva,
F. E. B., Denardin, E. L. G., Bachinski, R., Alves, G. G., Silva-Filho, M.
V., and Rocha, L., (2012). Comparative Study and Anticholinesterasic
Evaluation of Essential Oils from Leaves, Stems and Flowers of
Myrciaria floribunda (H.West ex Willd.) O. Berg. Lat Am J Pharm 31,
637-641.
[62] de Souza, A., Lopes, E. M. C., da Silva, M. C., Cordeiro, I., Young, M.
C. M., Sobral, M. E. G., and Moreno, P. R. H., (2010). Chemical
composition and acetylcholinesterase inhibitory activity of essential oils
of Myrceugenia myrcioides (Cambess.) O. Berg and Eugenia riedeliana
O. Berg, Myrtaceae. Rev Bras Farmacogn 20, 175-179.
[63] de Souza, A., da Silva, M. C., Cardoso-Lopes, E. M., Cordeiro, I.,
Sobral, M. E. G., Young, M. C. M., and Moreno, P. R. H., (2009).
Differential Acetylcholinesterase Inhibition by Volatile Oils from two
Specimens of Marlierea racemosa (Myrtaceae) Collected from
Different Areas of the Atlantic Rain Forest. Nat Prod Commun 4, 1143-
1146.
[64] Dalai, M. K., Bhadra, S., Chaudhary, S. K., Bandyopadhyay, A., and
Mukherjee, P. K., (2014). Anticholinesterase activity of the standardized
extract of Syzygium aromaticum L. Phcog Mag 10, 272-282.
[65] Khan, S., Khan, H., Ali, F., Ali, N., Khan, F. U., and Khan, S. U.,
(2016). Antioxidant, cholinesterase inhibition activities and essential oil
analysis of Nelumbo nucifera seeds. Nat Prod Res 30, 1335-1338.
[66] Ustun, O., Senol, F. S., Kurkcuoglu, M., Orhan, I. E., Kartal, M., and
Baser, K. H. C., (2012). Investigation on chemical composition,
anticholinesterase and antioxidant activities of extracts and essential oils
of Turkish Pinus species and pycnogenol. Ind Crop Prod 38, 115-123.
[67] Politeo, O., Botica, I., Bilusic, T., Jukic, M., Carev, I., Burcul, F., and
Milos, M., (2011). Chemical composition and evaluation of
acetylcholinesterase inhibition and antioxidant activity of essential oil
from Dalmatian endemic species Pinus nigra Arnold ssp. dalmatica
(Vis.) Franco. J Med Plants Res 5, 6590-6596.
[68] Bonesi, M., Menichini, F., Tundis, R., Loizzo, M. R., Conforti, F.,
Passalacqua, N. G., Statti, G. A., and Menichini, F., (2010).
Acetylcholinesterase and butyrylcholinesterase inhibitory activity of
Pinus species essential oils and their constituents. J Enz Inhib Med
Chem 25, 622-628.
[69] Lomarat, P., Sripha, K., Phanthong, P., Kitphati, W., Thirapanmethee,
K., and Bunyapraphatsara, N., (2015). In vitro biological activities of
black pepper essential oil and its major components relevant to the
prevention of Alzheimer’s disease. Thai J Pharm Sci 39, 94-101.
[70] da Silva, J. K. R., Pinto, L. C., Burbano, R. M. R., Montenegro, R. C.,
Guimarães, E. F., Andrade, E. H. A., and Maia, J. G. S., (2014).
Essential oils of Amazon Piper species and their cytotoxic, antifungal,
antioxidant and anti-cholinesterase activities. Ind Crop Prod 58, 55-60.
[71] Khadri, A., Serralheiro, M. L. M., Nogueira, J. M. F., Neffati, M., Smiti,
S., and Araújo, M. E. M., (2008). Antioxidant and
antiacetylcholinesterase activities of essential oils from Cymbopogon
schoenanthus L. Spreng. Determination of chemical composition by
GC–mass spectrometry and 13C NMR. Food Chem 109, 630-637.
[72] Ahmad, S., Ullah, F., Sadiq, A., Ayaz, M., Imran, M., Ali, I., Zeb, A.,
Ullah, F., and Shah, M. R., (2016). Chemical composition, antioxidant
and anticholinesterase potentials of essential oil of Rumex hastatus D.
Don collected from the North West of Pakistan. BMC Complement Alt
Med 16, 1-11.
[73] Ayaz, M., Junaid, M., Ullah, F., Sadiq, A., Khan, M. A., Ahmad, W.,
Shah, M. R., Imran, M., and Ahmad, S., (2015). Comparative chemical
profiling, cholinesterase inhibitions and anti-radicals properties of
essential oils from Polygonum hydropiper L: A Preliminary anti-
Alzheimer’s study. Lipids Health Dis 14, 1-12.
[74] Ahmad, R., Baharum, S., Bunawan, H., Lee, M., Mohd Noor, N.,
Rohani, E., Ilias, N., and Zin, N., (2014). Volatile Profiling of Aromatic
Traditional Medicinal Plant, Polygonum minus in Different Tissues and
Its Biological Activities. Molecules 19, 19220.
[75] Senol, F. S., Orhan, I. E., Kurkcuoglu, M., Khan, M. T. H., Altintas, A.,
Sener, B., and Baser, K. H. C., (2013). A mechanistic investigation on
anticholinesterase and antioxidant effects of rose (Rosa damascena
Mill.). Food Res Int 53, 502-509.
[76] Ademosun, A. O., Oboh, G., Olupona, A. J., Oyeleye, S. I., Adewuni, T.
M., and Nwanna, E. E., (2016). Comparative Study of Chemical
Composition, In Vitro Inhibition of Cholinergic and Monoaminergic
Enzymes, and Antioxidant Potentials of Essential Oil from Peels and
Seeds of Sweet Orange (Citrus sinensis [L] Osbeck) Fruits. J Food
Biochem 40, 53-60.
[77] Ganiyu Oboh, T. A. O. a. A. O. A., (2014). Essential Oil from Lemon
Peels Inhibit Key Enzymes Linked to Neurodegenerative Conditions
and Pro-oxidant Induced Lipid Peroxidation. J Oleo Sci 63, 373-381.
[78] The Angiosperm Phylogeny, G., (2009). An update of the Angiosperm
Phylogeny Group classification for the orders and families of flowering
plants: APG III. Bot J Linn Soc 161, 105-121.
[79] dos Santos, R. C., de Melo Filho, A. A., Chagas, E. A., Takahashi, J. A.,
Ferraz, V. P., Fernández, I. M., Ribeiro, P. R. E., de Melo, A. C. G. R.,
and Holanda, L. C., (2015). Chemical composition, antimicrobial and
anti-acetylcholinesterase activities of essential oil from Lantana camara
(Verbenaceae) flowers. J Med Plants Res 9, 922-928.
[80] Magda M Fathy, H. H. E., Marwa A Hussein, Hanaa H Ahmed, and and
Hussein, A. A., (2015). The role of Zingiber officinale in the treatment
of Alzheimer’s disease: In-vitro and in-vivo evidences. Res J Pharm
Biol Chem Sci 6, 735-749.
[81] Arruda, M., Viana, H., Rainha, N., Neng, N. R., Rosa, J. S., Nogueira, J.
M. F., and do Carmo Barreto, M., (2012). Anti-acetylcholinesterase and
Antioxidant Activity of Essential Oils from Hedychium gardnerianum
Sheppard ex Ker-Gawl. Molecules 17, 3082-3092.
[82] Polatoğlu, K., Karakoç, T. C., Yücel Yücel, Y., Gücel, S., Demirci, B.,
Başer, K. H. C., and Demirci, F., (2016). Insecticidal activity of edible
Crithmum maritimum L. essential oil against Coleopteran and
Lepidopteran insects. Ind Crop Prod 89, 383-389.
[83] Generalić Mekinić, I., Blažević, I., Mudnić, I., Burčul, F., Grga, M.,
Skroza, D., Jerčić, I., Ljubenkov, I., Boban, M., Miloš, M., and
Katalinić, V., (2016). Sea fennel (Crithmum maritimum L.):
phytochemical profile, antioxidative, cholinesterase inhibitory and
vasodilatory activity. J Food Sci Tech Mys, 1-9.
[84] Nguir, A., Mabrouk, H., Douki, W., Ben Ismail, M., Ben Jannet, H.,
Flamini, G., and Hamza, M. A., (2016). Chemical composition and
bioactivities of the essential oil from different organs of Ferula
communis L. growing in Tunisia. Med Chem Res 25, 515-525.
[85] Ben Salem, S., Znati, M., Jabrane, A., Casanova, J., and Ben
Jannet, H., (2016). Chemical Composition, Antimicrobial, Anti-
acetylcholinesterase and Cytotoxic Activities of the Root Essential oil
from the Tunisian Ferula lutea (Poir.) Maire (Apiaceae). J Essent Oil
Bear Pl 19, 897-906.
[86] Znati, M., Jabrane, A., Hajlaoui, H., Harzallah-Skhiri, F., Bouajila, J.,
Casanova, J., and Jannet, H. B., (2012). Chemical Composition and in
vitro Evaluation of Antimicrobial and Anti-acetylcholinesterase
Properties of the Flower Oil of Ferula lutea Nat Prod Commun 7, 947-
950.
[87] Golfakhrabadi, F., Khanavi, M., Ostad, S. N., Saeidnia, S., Vatandoost,
H., Abai, M. R., Hafizi, M., Yousefbeyk, F., Rad, Y. R.,
Baghenegadian, A., and Ardekani, M. R. S., (2014). Biological
Activities and Composition of Ferulago carduchorum Essential Oil. J
Arthropod Borne Dis 9, 104-115.
[88] Mata, A. T., Proença, C., Ferreira, A. R., Serralheiro, M. L. M.,
Nogueira, J. M. F., and Araújo, M. E. M., (2007). Antioxidant and
antiacetylcholinesterase activities of five plants used as Portuguese food
spices. Food Chem 103, 778-786.
[89] Jyotshna, Srivastava, N., Singh, B., Chanda, D., and Shanker, K.,
(2015). Chemical composition and acetylcholinesterase inhibitory
activity of Artemisia maderaspatana essential oil. Pharm Biol 53, 1677-
1683.
[90] Medimagh, S., Daami-Remadi, M., Jabnoun-Khiareddine, H., Naffati,
M., Ben Jannet, H., and Hamza, M. h. A., (2013). Chemical
Composition and In Vitro Evaluation of Antimicrobial and Anti-
acetylcholinesterase Activities of the Root Oil from Asteriscus
maritimus (L.) Less Growing in Tunisia. J Essent Oil Bear Pl 16, 443-
450.
[91] Lee, B. H., Nam, T. G., Park, W. J., Kang, H., Heo, H. J., Chung, D. K.,
Kim, G. H., and Kim, D.-O., (2015). Antioxidative and neuroprotective
effects of volatile components in essential oils from Chrysanthemum
indicum Linné flowers. Food Sci Biotechnol 24, 717-723.
[92] Chemsa, A. E., Erol, E., Öztürk, M., Zellagui, A., Özgür, C., Gherraf,
N., and Duru, M. E., (2015). Chemical constituents of essential oil of
endemic Rhanterium suaveolens Desf. growing in Algerian Sahara with
antibiofilm, antioxidant and anticholinesterase activities. Nat Prod Res,
1-5.
[93] Alza, N. P. and Murray, A. P., (2016). Chemical Constituents and
Acetylcholinesterase Inhibition of Senecio ventanensis Cabrera
(Asteraceae). Rec Nat Prod 10, 513-518.
[94] Polatoğlu, K., Karakoç, Ö. C., Yücel Yücel, Y., Demirci, B., Gören, N.,
and Başer, K. H. C., (2015). Composition, insecticidal activity and other
biological activities of Tanacetum abrotanifolium Druce. essential oil.
Ind Crop Prod 71, 7-14.
[95] Polatoğlu, K., Servı, H., Yücel, Y. Y., and Nalbantsoy, A., (2015).
Cytotoxicity and Acetylcholinesterase inhibitory and PRAP activities of
the essential oils of selected Tanacetum L. species. Nat Vol Essent Oils
2, 11-16.
[96] Villa-Ruano, N., Pacheco-Hernández, Y., Cruz-Durán, R., and Lozoya-
Gloria, E., (2015). Volatiles and seasonal variation of the essential oil
composition from the leaves of Clinopodium macrostemum var.
laevigatum and its biological activities. Ind Crop Prod 77, 741-747.
[97] Orhan, I., Şenol, F. S., Gülpinar, A. R., Kartal, M., Şekeroglu, N.,
Deveci, M., Kan, Y., and Şener, B., (2009). Acetylcholinesterase
inhibitory and antioxidant properties of Cyclotrichium niveum, Thymus
praecox subsp. caucasicus var. caucasicus, Echinacea purpurea and E.
pallida. Food Chem Toxicol 47, 1304-1310.
[98] Costa, P., Gonçalves, S., Valentão, P., Andrade, P. B., Almeida, C.,
Nogueira, J. M. F., and Romano, A., (2013). Metabolic profile and
biological activities of Lavandula pedunculata subsp. lusitanica
(Chaytor) Franco: Studies on the essential oil and polar extracts. Food
Chem 141, 2501-2506.
[99] Costa, P., Grosso, C., Gonçalves, S., Andrade, P. B., Valentão, P.,
Gabriela Bernardo-Gil, M., and Romano, A., (2012). Supercritical fluid
extraction and hydrodistillation for the recovery of bioactive compounds
from Lavandula viridis L’Hér. Food Chem 135, 112-121.
[109] Kunduhoglu, B., Kurkcuoglu, M., Duru, M. E., and Baser, K. H. C.,
(2011). Antimicrobial and anticholinesterase activities of the essential
oils isolated from Salvia dicroantha Stapf., Salvia verticillata L. subsp.
amasiaca (Freyn and Bornm.) Bornm. and Salvia wiedemannii Boiss. J
Med Plants Res 5, 6484-6490.
[110] Şenol, F. S., Orhan, I. E., Erdem, S. A., Kartal, M., Şener, B., Kan, Y.,
Celep, F., Kahraman, A., and Dogan, M., (2011). Evaluation of
Cholinesterase Inhibitory and Antioxidant Activities of Wild and
Cultivated Samples of Sage (Salvia fruticosa) by Activity-Guided
Fractionation. J Med Food 14, 1476-1483.
[111] Topçu, G., Öztürk, M., Kuşman, T., Demırkoz, A. A. B., Kolak, U., and
Ulubelen, A., (2013). Terpenoids, essential oil composition, fatty acid
profile, and biological activities of Anatolian Salvia fruticosa Mill. Turk
J Chem 37, 619-632.
[112] Tundis, R., Loizzo, M. R., Bonesi, M., Leporini, M., Menichini, F., and
Passalacqua, N. G., (2016). A study of Salvia fruticosa Mill subsp.
thomasii (Lacaita) Brullo, Guglielmo, Pavone and Terrasi, an endemic
Sage of Southern Italy. Plant Biosyst Int J Dealing All Asp Plant Biol,
1-12.
[113] Kivrak, İ., Duru, M. E., Öztürk, M., Mercan, N., Harmandar, M., and
Topçu, G., (2009). Antioxidant, anticholinesterase and antimicrobial
constituents from the essential oil and ethanol extract of Salvia
potentillifolia. Food Chem 116, 470-479.
[114] Öztürk, M., (2012). Anticholinesterase and antioxidant activities of
Savoury (Satureja thymbra L.) with identified major terpenes of the
essential oil. Food Chem 134, 48-54.
[115] Zengin, G., Sarıkürkçü, C., Aktümsek, A., and Ceylan, R., (2016).
Antioxidant Potential and Inhibition of Key Enzymes Linked to
Alzheimer’s Diseases and Diabetes Mellitus by Monoterpene-Rich
Essential Oil from Sideritis galatica Bornm. Endemic to Turkey Rec
Nat Prod 10, 195-206.
[116] Sevindik, H. G., Özek, T., Yerdelen, K. Ö., Önal, M., Özbek, H.,
Güvenalp, Z., and Demirezer, L. Ö., (2016). Chemical Composition,
Antioxidant Capacity, Acetyl- and Butyrylcholinesterase Inhibitory
Activities of the Essential Oil of Thymus haussknechtii Velen. Rec Nat
Prod 10, 503-507.
[117] Costa, P., Gonçalves, S., Grosso, C., Andrade, P. B., Valentão, P.,
Bernardo-Gil, M. G., and Romano, A., (2012). Chemical profiling and
biological screening of Thymus lotocephalus extracts obtained by
supercritical fluid extraction and hydrodistillation. Ind Crop Prod 36,
246-256.
[118] Ceylan, R., Zengin, G., Uysal, S., Ilhan, V., Aktumsek, A., Kandemir,
A., and Anwar, F., (2015). GC-MS analysis and in vitro antioxidant and
enzyme inhibitory activities of essential oil from aerial parts of endemic
Thymus spathulifolius Hausskn. et Velen. J Enz Inhib Med Chem, 1-8.
[119] Jukic, M., Politeo, O., Maksimovic, M., Milos, M., and Milos, M.,
(2007). In vitro acetylcholinesterase inhibitory properties of thymol,
carvacrol and their derivatives thymoquinone and thymohydroquinone.
Phytother Res 21, 259-261.
[120] Silva, N. N. S., Silva, J. R. A., Alves, C. N., Andrade, E. H. A., da
Silva, J. K. R., and Maia, J. G. S., (2014). Acetylcholinesterase
Inhibitory Activity and Molecular Docking Study of 1-Nitro-2-
Phenylethane, the Main Constituent of Aniba canelilla Essential Oil.
Chem Biol Drug Des 84, 192-198.
[121] Salleh, W. M. N. H. W., Ahmad, F., Yen, K. H., and Zulkifli, R. M.,
(2015). Chemical Compositions and Biological Activities of Essential
Oils of Beilschmiedia glabra. Nat Prod Commun 10, 1297-1300.
[122] Kiran, S., Kujur, A., and Prakash, B., (2016). Assessment of
preservative potential of Cinnamomum zeylanicum Blume essential oil
against food borne molds, aflatoxin B1 synthesis, its functional
properties and mode of action. Innov Food Sci Emerg Tech 37, Part A,
184-191.
[123] Lima, B. G., Tietbohl, L. A., Fernandes, C., Cruz, R. A. S., da Silva
Botas, G., Santos, M. G., Silva-Filho, M. V., and Rocha, L., (2012).
Chemical Composition of Essential Oils and Anticholinesterasic
Activity of Eugenia sulcata Spring ex Mart. Lat Am J Pharm 31, 152-
155.
[124] Tundis, R., Loizzo, M. R., Bonesi, M., Menichini, F., Mastellone, V.,
Colica, C., and Menichini, F., (2012). Comparative Study on the
Antioxidant Capacity and Cholinesterase Inhibitory Activity of Citrus
aurantifolia Swingle, C. aurantium L., and C. bergamia Risso and Poit.
Peel Essential Oils. J Food Sci 77, H40-H46.
[125] Chaiyana, W. and Okonogi, S., (2012). Inhibition of cholinesterase by
essential oil from food plant. Phytomedicine 19, 836-839.
[126] Zarrad, K., Hamouda, A. B., Chaieb, I., Laarif, A., and Jemâa, J. M.-B.,
(2015). Chemical composition, fumigant and anti-acetylcholinesterase
activity of the Tunisian Citrus aurantium L. essential oils. Ind Crop
Prod 76, 121-127.
[127] Conforti, F., Statti, G. A., Tundis, R., Loizzo, M. R., and Menichini, F.,
(2007). In vitro activities of Citrus medica L. cv. Diamante (Diamante
citron) relevant to treatment of diabetes and Alzheimer’s disease.
Phytother Res 21, 427-433.
[128] Menichini, F., Tundis, R., Bonesi, M., de Cindio, B., Loizzo, M. R.,
Conforti, F., Statti, G. A., Menabeni, R., Bettini, R., and Menichini, F.,
(2011). Chemical composition and bioactivity of Citrus medica L. cv.
Diamante essential oil obtained by hydrodistillation, cold-pressing and
supercritical carbon dioxide extraction. Nat Prod Res 25, 789-799.
[129] Al-Rehaily, A. J., Alqasoumi, S. I., Yusufoglu, H. S., Al-Yahya, M. A.,
Demirci, B., Tabanca, N., Wedge, D. E., Demirci, F., Bernier, U. R.,
Becnel, J. J., Temel, H. E., and Baser, K. H. C., (2014). Chemical
Composition and Biological Activity of Haplophyllum tuberculatum
Juss. Essential Oil. J Essent Oil Bear Pl 17, 452-459.
Chapter 3
ABSTRACT
In this chapter, we describe a simple, cost-effective and ecofriendly
approach for the fabrication of different metal nanoparticles (MNPs)
including silver, gold, iron, zinc and palladium by using different plant
phytochemicals as a potential reducer and stabilizers. It can be used as a
catalyst, photocatalyst, adsorbent or an alternative agent for removal of
different organic dyes. The kinetic enhancement of MNPs on
degradation/removal of dyes can possibly provide significant and
*
Corresponding author email: krmbraj@gmail.com; Tel: +91-6542243083; +91-8757618562.
1. INTRODUCTION
For the last few decades, wastewaters containing dyes and organic
pollutants from various industries, factories, and laboratories discharged into
water reservoirs without any treatment and it represents an increasing
worldwide environmental hazard (Safavi and Momeni, 2012). These dyes are
being used in large quantities in several industries for different applications
such as textiles, papers, leathers, foodstuffs, cosmetics, laser materials,
xerography, laser printing, gasoline, additives, etc. In most of the cases, the
resultant by-products contain dyes and heavy metal ions or both (Sharma et al.,
2012). It has been estimated that over 15% of the total world production of
dyes is lost in their synthesis and dyeing process (Safavi and Momeni, 2012).
Most of these anthropogenic dyes are carcinogenic, harmful and reduce the
light penetration in aqueous systems. As a consequence, it causes a negative
effect on photosynthesis, harmful to human health and contributes a big share
to the overall imbalance of the ecosystem (Singla et al., 2014).
In recent years, several processes have been studied to reach partial or
complete degradation of organic pollutant compounds such as adsorption,
coagulation, biodegradation and chemical or photochemical degradation
(Wang et al., 2008). Although physical and chemical methods usually show
high dye-removal efficiencies, high operating costs are the main drawback due
to the large-scale application of these methods (Prasannan and Imae, 2013).
Furthermore, due to the high chemical stability of synthetic dyes, conventional
biological treatment using bacteria cannot remove the dyes efficiently (Huo et
al., 2013). So, it is necessary to develop new technologies enabling to use non-
toxic and easily available materials for the complete removal of the pollutant
from wastewater and favors the concept of environmental remediation using
natural material and its modified form. Therefore, a critical need in the field of
nanotechnology is the development of reliable and eco-friendly processes for
the synthesis of metallic nanoparticles.
1
Figure 1. Scheme for the preparation and application of MNPs.
1
Figure 2. The structural formula of different organic dyes.
Overall at present, azo dyes represent the largest class of organic dyes
listed in the CI (65 – 70% of the total dyes) and their relative share among
reactive, acid and direct dyes is even higher, it can be expected that they make
up the vast majority of the dyes discharged by textile processing industries
(Gupta and Suhas, 2009; Christie 2007). Anthraquinone dyes are the second
largest class, followed by triarylmethanes and phthalocyanines of the entries in
the CI. Moreover, reactive dyes are known to form a covalent bond with the
fiber in the dyeing process. This leads to favorable properties such as wash-
fastness. However, the unfixed dye reacts with water to form hydrolyzed or
Oxo-dye intermediate that has lost its bonding capacity and thus cannot be
reused. Consequently, dye recovery is not an option with reactive dyes and the
treatment process must lead to final destruction or disposal of these organic
pollutants (Lam et al., 2012).
Degradation (%)
Plant Processing Catalytic
Plant/Chemicals MNPs Organic dyes or rate of Ref.
Materials and Size reagents/Sunlight
reaction (k)
Leaf Mimosa pudica AuNPs 16 nm rhodamine B (Rh B) NaBH4 k = 0.6319 Devi et al.,
min-1 2015
Pogestemon AuNPs 10–50 nm MB NaBH4 k = 0.1758 min-1 Paul et al.,
benghalensis 2015
Cinnamomum Au/TiO2 8-20 nm MO Sunlight k = 0.346 h-1 Nick et al.,
tamala 2013
Coccinia grandis AgNPs 20-30 nm Coomassie Brilliant Fluorescent UV - Arunachalam
Blue G-250 light et al., 2012
Morinda tinctoria AgNPs 79-96 nm MB Sunlight 95.3% at 72 h Vanaja et al.,
2014
Mussaenda AgNPs 82-88 nm MO NaBH4 >50%, 45 mins Thivaharan
erythrophylla et al., 2016
Green, Oolong and FeNPs 40-50 nm MG - 81.6%, 75.6% Huang et al.,
black teas and 67.1% 2014
Green tea FeNPs 130-270 nm MB NaBH4 k = 0.0404 min-1 Lin et al.,
2015
Andean Blackberry FeNPs 54.5 ± 24.6 MB, CR, MO Sunlight k = 0.0105475, Kumar et al.,
nm 0.0043240, and 2016a
0.0028930 min-1
Grape leaf FeNPs 18-30 nm Orange II High temperature >92% Luo et al.,
2015
Cassia fistula ZnO NPs 5-15 nm MB UV and Sunlight >96% Suresh et al.,
2015
Plectranthus ZnO NPs 88 nm MR UV light 92.45%, k = Fua and Fu,
amboinicus 0.01421 min-1 2015
Degradation (%)
Plant Processing Catalytic
Plant/Chemicals MNPs Organic dyes or rate of Ref.
Materials and Size reagents/Sunlight
reaction (k)
Coleus aromaticus PdNPs 2.8 nm MO, MR, NaBH4 k = 0.1137, Vilas et al.,
Eriochrome black T, 0.1552, 0.2772, 2016
MB, Rhodamine B 1.0060, 0.3056
min-1
Myristica fragrans PdNPs 2.9 nm MO, MR, NaBH4 k = 0.1576, Vilas et al.,
Eriochrome black T, 0.0994, 0.4046, 2016
MB, Rhodamine B 1.2442, 0.1109
min-1
Andean Blackberry PdNPs 55-60 NM MB Sunlight >72%, k = Kumar et al.,
0.0021614 min-1 2015b
Plumeria alba AuNPs 28 ± 5.6 MB, Eosin Y, MR, NaBH4 - Mata et al.,
CR, Ethidium 2016
bromide
Flower Lantana camara AgNPs 33 ± 5 nm MB Sunlight k = 3.407 x 10-3 Kumar et al.,
min-1 2016b
Lantana camara AuNPs 10.6 ± 2.9 nm MB Sunlight >62% Kumar et al.,
2016d
Punica granatum AgNPs, 36 and MB, MO, Eosin Y NaBH4 83, 99, 96% MeenaKumari
AuNPs 18 nm 95, 94, 91% and Philip,
2015
Seed & Sacha Inchi Oil AgNPs 60 nm MB Sunlight 2.776 x 10−3 Kumar et al.,
Fruit min−1 2014a
Sacha Inchi Oil AuNPs 5–15 nm MB Sunlight 3.263 × 10−3 Kumar et al.,
min−1 2016e
Capsicum baccatum AuNPs 23.9 ± 9.7 nm MB Sunlight >50%, k = 1.9585 Kumar et al.,
x 10−3 min−1 2015a
nanoparticles using Sacha inchi oil in the presence of sunlight and TEM
characterization revealed the nanostructure were highly dispersed, distorted
cubic in shape and 60 nm size. The stable and crystalline nanoparticles showed
photocatalytic activity in the decomposition of the MB (>65%) without using
any reducing agent and the calculated first-order rate constants were found to
be 2.776 x 10−3 min−1 (Kumar et al., 2014a). In another study, a new approach
for the synthesis of monodispersed silver nanoparticles was reported by using
cheaply available Sacha inchi shell biomass (SISB) and can be used as a
photocatalyst for the remediation of methyl orange (MO). The UV–vis
spectroscopy and Transmission electron microscopy (TEM) techniques
indicated the SPR at 420 nm (Figure 4a) corresponds to spherical shape with
7.2 nm sized silver nanoparticles. Further, the experimental evidence showed a
strong effect of the pH 2 for maximum removal of MO in the presence of
silver nanoparticles and sunlight (~60%, 5 h, 64 mg/L) from aquatic systems
the rate constant was found to be 0.0008898 min-1 (Kumar et al., 2014b).
Absorbance (a.u.)
4,0 (a) AgNPs
(b) AuNPs
3,5 (c) FeNPs
(d) ZnO-NPs
3,0 (e) PdNPs
2,5
2,0
1,5
1,0
0,5
0,0
Wavelength (nm)
Figure 4. UV-vis spectrum of different nanoparticles prepared using phytochemicals of
different sources.
Besides TiO2, ZnO NPs has photoadsorption to the visible light range and
exhibit photocatalytic activity and decolorization of basic dyes in the visible
light range owing to their lower band gap. Suresh et al., 2015 presented the
green synthesis of ZnO nanoparticles (Nps) using aqueous Cassia fistula plant
extract as fuel by solution combustion synthesis. The extract was found to
contain reducing components such as polyphenols (11%) and flavonoids
(12.5%). The Nps were found to have a hexagonal wurtzite structure. UV–
visible absorption of ZnONPs showed absorption band at 370 nm which can
be assigned to the intrinsic band-gap absorption of ZnO due to the electron
transitions from the valence band to the conduction band. TEM image
confirms the formation of nanoparticles and the average crystallite sizes were
found to be ~5–15 nm. The ZnO-NPs were evaluated for photodegradative,
antimicrobial and antioxidant activities. It showed efficient MB degradation
(>96%) under UV and Sun light illumination. Not only photocatalytic activity
but also ZnO NPs showed significant antioxidant activity against 1, 1-
Diphenyl-2-picrylhydrazyl (DPPH) free radicals and antibacterial activity
against Klebsiella aerogenes, Escherichia coli, Plasmodium desmolyticum and
Staphylococcus aureus. Kumar et al., 2014c demonstrated the application of
discarded agricultural waste for the fabrication of ZnO-NPs. They proved that
the aqueous peel extract of Citrus paradisi promotes the fabrication of the
ZnO-NPs with particle size ranging from 12 to 72 nm. The synthesized ZnO-
NPs exhibited strong UV absorption spectra with the absorption peak ranging
from 360 to 375 nm due to their excitonic transition (Figure 4d). The formed
ZnO-NPs are highly stable and exhibited more than 56% degradation of MB in
sunlight for 6.0 h. In addition, the current study has clearly demonstrated that
the ZnO-NPs are responsible for significant antioxidant activity (≥80% for 1.2
mM). Stan et al., 2015 successfully prepared the hexagonal wurtzite structure
of ZnO nanoparticles using aqueous extracts of Allium sativum (garlic), Allium
cepa (onion) and Petroselinum crispum (parsley). The biomolecules present in
the plant extract also influenced the particle size and obtained size varies
between 14 and 70 nm. The photodegradation studies conducted in the
presence of UV light irradiation indicated that ZnO nanoparticles prepared
using garlic extract exhibit the highest efficiency in the photodegradation of
MB dye.
Highly stable and spherical zinc oxide nanoparticles (25– 40 nm) are
produced by using zinc nitrate and Aloe barbadensis Miller leaf extract. As a
result, greater than 95% conversion to nanoparticles was achieved using aloe
leaf broth concentration greater than 25%. It was shown that the zinc oxide
nanoparticles were poly dispersed. The particle size could be controlled by
varying the concentrations of leaf broth solution (Sangeetha et al., 2011;
Kharissova et al., 2012). Fua and Fu, 2015 demonstrated the synthesis of ZnO
absorbance peak around 360 nm, and 500 – 700 nm (Figure 4e). The obtained
PdNPs were crystalline in nature with decahedron morphology and size around
55-60 nm. It further used as photocatalyst for the decomposition of MB using
sunlight and an enhanced photocatalytic activity (>72%, k = 0.0021614 min-1)
for PdNPs was observed due to electron relay effect.
Trung et al., 2015 reported the facile and green synthesis of activated
carbon-supported palladium (Pd/AC) containing homogeneously dispersed Pd
nanoparticles (Pd NPs) by using eco-friendly and naturally available
Cinchonidine as the capping agent. The Pd NPs in the synthesized Pd/AC
hybrid are uniform with sizes predominantly in the range 4 to 7 nm. The
synthesized Pd/AC was characterized with various methods, such as TEM,
XRD, and XPS, and the influence of the synthetic conditions on its properties
was investigated. The advantages of cinchonidine over conventional capping
agents include its easy depletion after the synthesis with a simple rinsing
process. Owing to the ultrafine, well-dispersed and purified Pd NPs, the
synthesized hybrid exhibits excellent catalytic activities in the reduction of 4-
nitrophenol and methylene blue. These findings further the development of
novel stabilizing agents from naturally available sources for the preparation of
heterogeneous catalysts with enhanced performance.
MNPs + hν → e- + h+ (1)
5. TOXICITY OF DYES
Use of synthetic dyes has an adverse effect on all forms of life. Nearly
50% of organic dyes are non-biodegradable, insoluble, toxic and their
persistence in wastewater. More than 79105 metric tonnes of dye stuffs are
produced worldwide annually, with 10 to 50% of this amount being released
into wastewater (Russ et al., 2000; Julkapli et al., 2014). These high
concentrations of dyes in effluents interfere with the penetration of visible
light into the water, resulting in a hindrance to photosynthesis and a decrease
in gas solubility, since less than 1 mgL−1 of dye is highly visible. Furthermore,
colorants having aromatic and heterocyclic rings containing oxygen, nitrogen
or sulfur, are regarded as toxic, carcinogenic, and xenobiotic compounds (Jie
et al., 2013). They cause toxicity not only to aquatic life and may be
mutagenic and carcinogenic and can cause intense damage to human beings,
including the reproductive system and dysfunction of the kidneys, brain, liver,
and central nervous system (He et al., 2011; Julkapli et al., 2014). According
to the criteria of the European Union for the classification of dangerous
substances, the acute toxicity of azo dyes, is low and the values of LD50
(median letal dose) are 250-2000 mg Kg-1 body weight (Clarke and Anliker,
1980). Dyes have various effects on human health depending on the
application area. Skin irritation and contact dermatitis have been reported for
some synthetic dyes and the use of azo dyes made from carcinogenic amines
has been banned by legislation in many countries. Some azobasic, acid and
direct dyes are classified into very toxic or toxic to fishes, crustaceans, algae
and bacteria, while reactive azo dyes are toxic only at very high concentrations
(>100 mg L-1), therefore, excluded from considering toxic for aquatic
organisms (Novotný et al., 2006). Nohynek et al., 2004 investigated that the
hair dye ingredients (p-aminophenol, Lawsone) have moderate to low acute
toxicity and human poisoning accidents are rare only due to oral ingestion.
The use of food additives in food products including the food food or
beverages colorants can cause toxic and carcinogenic effects. Several azo dyes
can cause the genesis of malignant tumors due to DNA damage (Gürses et al.,
2016). As a consequence, some food scientists try to use natural colorants in
order to hinder the negative effects of synthetic colorants.
It is very important to know whether biodegradation of a dye leads to
detoxification of the dye or not. Kalyani et al., 2009 and Parshetti et al., 2006
reported that that the phytotoxicity of the metabolites produced after the
biodegradation of Reactive Red 2 and Malachite Green were less toxic
compared to the original dye. Similarly, Jadhav et al., 2008 studied
6. TOXICITY OF MNPS
With increasing the public knowledge about health care in the world,
people are increasingly concerned about the rise of possible subsequent
diseases caused by new technologies including nanotechnology and
application of nano-materials especially inhalation during manufacturing or
usage. Some evidence proved the safety of application of nano-structured
materials (Dastjerdi and Montazer, 2010). Living cells become more
permissive to chemical and physical compounds found in blood circulation,
including circulating nanoparticles depending of their material, size, charge,
surface engineering, and others characteristics (Leite et al., 2015). Toxicity are
caused by physical restraints or the release of toxic ions from metallic
nanoparticles or from the production of reactive oxygen species (ROS).
Further, the toxicity of some metallic nanoparticles has been found to be light-
dependent (e.g., TiO2), becoming more toxic under irradiation, 51, 110
whereas others (e.g., CeO2) have antioxidative effects (Quigg et al., 2013).
Silver is mentioned as an almost non-toxic to mammalian systems
(Dastjerdi and Montazer, 2010). Skin-innoxiousness of nano-silver colloidal
solution especially in the case of smaller nano-particles has been demonstrated
via the skin irritation test performed on the rabbits (Lee and Jeong, 2005). In
addition, rats orally exposed to AgNPs showed several synaptic structures
modifications and degeneration in hippocampus (Skalska et al., 2015). Toxic
effects of Ag-NP were also observed in cortical cell cultures inducing
oxidative stress and higher Ca2+ intracellular levels, triggering increased levels
of cell death. AgNPs are mostly internalized by astrocytes inducing
morphologic modifications, but in neuron cells these alterations require higher
concentrations of nanoparticles (Haase et al., 2012). Several studies have
emerged showing that AuNP can induce cellular damage by necrosis,
apoptosis, oxidative stress, inflammation, DNA damage, alterations in gene
expression, or through indirect mechanisms (Leite et al., 2015). Pan et al.,
2007 reported that the cytotoxicity of modified gold nanoparticles depended
primarily on their size and not on ligand chemistry. Particles 1–2 nm in size
were highly toxic and both smaller gold compounds (Tauredon) and larger 15-
nm.
Iron oxide nanoparticles are generally considered as safe, biocompatible
and non-toxic materials (Arami et al., 2015). LD-50 (the median lethal dose or
the dose required to kill half of the tested animals during a specified time) of
the uncoated iron oxide nanoparticles was reported to be 300–600 mg Fe kg-1
body weight. This value was increased to 2000–6000 mg Fe kg-1 when the
IONPs were coated with stabilizing and biocompatible dextran molecules
(Wada et al., 2001). Fe3O4 nanomaterials can induce microglial activation and
subsequent increased levels of pro-inflammatory cytokines release, resulting in
cytotoxicity effects in a broad range of neuronal cells (Xue et al., 2012). In
another study by Geppert et al., 2009 showed that the incubation of astrocyte
primary cultures with magnetic iron oxide nano-particles has also
demonstrated that the particles do not induce any acute damage to these brain
cells. Lower doses of the iron nanoparticles can cause mild side effects such as
nausea, vomiting or flatulence whereas acute doses can cause severe side
effects such as inhibition of acetylcholinestrase in red blood cells, inhibition of
Na+–K+, Mg2+, and Ca2+-ATPases activities in brain and activation of the
hepatotoxicity marker enzymes in serum and liver (Arami et al., 2015).
The toxic effect of ZnO nanoparticles is due to their solubility in the
extracellular region, which in turn increases the intracellular Zn2+ level. The
exposure of ZnO nanoparticles induces oxidative stress and cytotoxicity,
mitochondrial dysfunction in RKO colon carcinoma cells, increased oxidative
stress, increased intracellular Ca2+ level, decreased mitochondrial membrane
potential, and interleukin-8 productions in the BEAS-2B bronchial epithelial
cells and A549 alveolar adenocarcinoma cells (Pandurangan and Kim, 2015).
Owing to its biological inertness, metallic Pd(0), forming the Pd
nanostructures, shows a priori the safest toxicity profile among palladium
species. Nevertheless, it progressively accumulates in the environment,
especially in aquatic ecosystem. Chen et al., 2015 studied the dose-dependent
toxic effect of Pd on zebrafish development. It indicated that acute Pd
exposure significantly decreased both the survival rate (LC50: 292.6 μg/L, viz.
2.75 μM) and hatching rate (IC50: 181.5 μg/L, viz. 1.71 μM) of zebrafish
during embryonic development. The heartbeat rate of zebrafish embryos was
also decreased after Pd exposure. In other study, Peric et al., 2012 compared
the toxicity of inorganic and organic palladium compounds on cardiovascular
system of rat. It seems that palladium, when bound in an organic compound
(linked to TEA in Pd complex), does not contribute significantly to cardio-
toxicity. Besides this, it was also reported that the phytochemicals protect
metal nanoparticles from degradation and their functionalization with silver
and gold nanoparticles suppresses the toxicity against various cance cell lines
(Kumar et al., 2016f, g).
CONCLUSION
In conclusion, we have reviewed the current progress in the environmental
application of metal nanoparticles mediated remediation of organic dyes.
Phytochemical functionalized metal nanoparticles, and its beneficial effects,
offer the solar light harvesting potential for the degradation of organic dyes,
shorter reaction time, low-cost reagents, and possible environment friendly
alternative to chemical methods. The obtained results declared that the
phytochemical functionalized nanocatalysts (Ag, Au, Fe, Pd and Zn) showed
markedly high removal efficiency of the organic dye pollutants and promising
catalyst. The mechanism of catalysis in the presence of metal nanoparticles
can be described as an electron transfer process from donor NaBH4 to an
acceptor dye. The photocatalytic degradation effect of silver nanoparticles was
higher as compared to gold and iron oxide nanoparticles. The photocatalytic
effect of smaller and spherical nanoparticles was also higher as compared to
larger and triangular nanoparticles. Organic moiety and phytochemical
functionalization on the surface of metal nanoparticles not only reduces the
toxicity but also increase the stability of nanoparticles and lower the
manufacturing cost of catalyst. It supports the use of renewable energy for
environmental protection and this technology to be adequately attractive
compared to other techniques.
ACKNOWLEDGMENT
This scientific work has been funded by the TATA College, Kolhan
University, Chaibasa, Jharkhand, INDIA and Prometeo Project of the National
Secretariat of Higher Education, Science, Technology and Innovation
(SENESCYT), Ecuador.
REFERENCES
Ahmed, S., Rasul, M. G., Martens, W. N., Brown, R. and Hashib, M. A.
(2010). Heterogeneous photocatalytic degradation of phenols in
wastewater: a review on current status and developments. Desalination,
261(1), 3-18.
Alam, Md. N., Roy, N., Mandal, D. and Begum, N. A. (2013). Green
chemistry for nanochemistry: exploring medicinal plants for the biogenic
synthesis of metal NPs with fine-tuned properties. RSC Adv., 3, 11935-
11956
Arami, H., Khandhar, A., Liggitt, D. and Krishnan, K. M. (2015). In vivo
delivery, pharmacokinetics, biodistribution and toxicity of iron oxide
nanoparticles. Chem. Soc. Rev., 44, 8576-8607.
Arunachalam, R., Dhanasingh, S., Kalimuthu, B., Uthirappan, M., Rose, C.
and Mandal, A. B. (2012). Phytosynthesis of silver nanoparticles using
Coccinia grandis leaf extract and its application in the photocatalytic
degradation. Colloids and Surfaces B: Biointerfaces, 94, 226–230.
Bhattacharjee, A. and Ahmaruzzaman, M. (2015). A novel and green process
for the production of SnO2 quantum dots and its application as a
photocatalyst for the degradation of dyes from aqueous phase. Journal of
Colloid and Interface Science, 448, 130–139.
Chen, M., Chen, S., Du, M., Tang, S., Chen, M., Wang, W., Yang, H., Chen,
Q. and Chen, J. (2015). Toxic effect of palladium on embryonic
development of zebrafish, Aquatic Toxicology, 159, 208–216.
Christie, R. M. (2007). Environmental Aspects of Textile Dyeing, CRC Press,
Cambridge.
Clarke, E. A. and Anliker, R. Organic dyes and pigments, In: Hutzinger, O.,
Editor. The handbook of environmental chemistry, vol. 3, part. A.
Anthropogenic Compounds. United States: Sringer-Verlag, 1980, 1-215.
Dastjerdi, R. and Montazer, M. (2010). A review on the application of
inorganic nano-structured materials in the modification of textiles: Focus
on anti-microbial properties, Colloids and Surfaces B: Biointerfaces, 79,
5–18.
Devi, H. S., Singh, N. R., Singh, H. P. and Singh, T. D. (2015). Facile
synthesis of biogenic gold nanocatalyst for efficient degradation of
organic pollutants, Journal of Environmental Chemical Engineering, 3,
2042–2049.
Jie, R. H., Guo, G. B., Zhao, W. G. and An, S. L. (2013). Preparation and
photocatalytic degradation of methyl orange of nano-powder TiO2 by
hydrothermal method supported on activated carbon. Journal of Synthetic
Crystals, 42, 2144–2149.
Julkapli, N. M., Bagheri, S. and Hamid, S. B. A. (2014). recent advances in
heterogeneous photocatalytic decolorization of synthetic dyes. Scientific
World Journal, Volume 2014, Article ID 692307, pages 25.
Kalyani, D. C., Telke, A. A., Dhanve, R. S. and Jadhav, J. P. (2009).
Ecofriendly biodegradation and detoxification of Reactive Red 2 textile
dye by newly isolated Pseudomonas sp. SUK1. Journal of Hazardous
Materials, 163, 735–742.
Kamat, P. V. (1993). Photochemistry on nonreactive and reactive
(semiconductor) surfaces. Chem. Rev., 93, 267-300 Kharisov BI, Dias
HVR, Kharissova OV, Jiménez-Pérez VM, Pérez BO, Flores BM (2012)
Iron-containing nanomaterials: synthesis, properties, and environmental
applications. RSC Adv., 2, 9325–9358.
Kharissova, O. V., Dias, H. V. R., Kharisov, B. I., Perez, B. O. and Perez, V.
M. J. (2012), The greener synthesis of nanoparticles, RSC Adv., 2, 9325-
9358.
Kou, J. and Varma, R. S. (2012). Beet juice-induced green fabrication of
plasmonic AgCl/ Ag nanoparticles. ChemSusChem, 5(12), 2435–2441.
Kumar, B., Smita, K., Cumbal, L. and Debut, A. (2014a). Sacha inchi
(Plukenetia volubilis L.) oil for one pot synthesis of silver nanocatalyst:
An ecofriendly approach. Industrial Crops and Products, 58, 238–243.
Kumar, B., Smita, K., Cumbal, L. and Debut, A. (2014b). Sacha inchi
(Plukenetia volubilis L.) shell biomass for synthesis of silver nanocatalyst.
Journal of Saudi Chemical Society in press, http:// dx.doi.org/10.1016/
j.jscs.2014.03.005.
Kumar, B., Smita, K., Cumbal, L. and Debut, A. (2014c). Green Approach for
Fabrication and Applications of Zinc Oxide Nanoparticles. Bioinorganic
Chemistry and Applications, Volume 2014, Article ID 523869, 7 pages.
Kumar, B., Smita, K. and Cumbal, L. (2015a). Phytosynthesis of gold
nanoparticles using Andean Ajı′ (Capsicum baccatum L.). Cogent
Chemistry, 1, 1120982.
Kumar, B., Smita, K., Cumbal, L. and Debut, A. (2015b). Ultrasound agitated
phytofabrication of palladium nanoparticles using Andean blackberry leaf
and its photocatalytic activity. Journal of Saudi Chemical Society, 19,
574–580.
Kumar, B., Smita, K., Cumbal, L., Debut, A., Galeas, S. and Guerrero, V. H.
(2016a). Phytosynthesis and photocatalytic activity of magnetite (Fe3O4)
nanoparticles using the Andean blackberry leaf. Materials Chemistry and
Physics, 179C, 310-315.
Kumar, B., Smita, K. and Cumbal, L. (2016b). Biosynthesis of silver
nanoparticles using Lantana camara flower extract and its application. J
Sol-Gel Sci Technol, 78, 285–292.
Kumar, B., Smita, K., Angulo, Y. and Cumbal, L. (2016c). Valorization of
rambutan peel for the synthesis of silver-doped titanium dioxide
(Ag/TiO2) nanoparticles. Green Process Synth, 5(4), 371-377.
Kumar, B., Smita, K. and Cumbal, L. (2016d). Biofabrication of nanogold
from the flower extracts of Lantana camara. IET Nanobiotechnology, 10
(3), 154 – 157.
Kumar, B., Smita, K., Cumbal, L. and Debut, A. (2016e). One pot synthesis
and characterization of gold nanocatalyst using Sacha inchi (Plukenetia
volubilis) oil: Green approach. Journal of Photochemistry and
Photobiology, B: Biology, 158, 55–60.
Kumar, B., Smita, K., Seqqat, R., Benalcazar, K., Grijalva, M. and Cumbal, L.
(2016f). In vitro evaluation of silver nanoparticles cytotoxicity on Hepatic
cancer (Hep-G2) cell line and their antioxidant activity: Green approach
for fabrication and application. Journal of Photochemistry and
Photobiology, B: Biology, 159, 8–13.
Kumar, B., Smita, K., Cumbal, L., Camacho, J., Hernández-Gallegos, E.,
Chávez-López, M. G., Grijalva, M. and Andrade, K. (2016g). One pot
phytosynthesis of gold nanoparticles using Genipa americana fruit extract
and its biological applications, Materials Science and Engineering C, 62,
725–731.
Lam, S. M., Sin, J. C., Abdullah, A. Z. and Mohamed, A. R. (2012).
Degradation of wastewaters containing organic dyes photocatalysed by
zinc oxide: a review, Desalination and Water Treatment, 41, 131–169.
Lee, H. J. and Jeong, S. H. (2005). Bacteriostasis and skin innoxiousness of
nanosize silver colloids on textile fabrics, Textile Research Journal, 75
(7), 551–556.
Leite, P. E., Pereira, M. R., Santos, C. A., Campos, A. P., Esteves, T. M. and
Granjeiro, J. M. (2015). Gold nanoparticles do not induce myotube
cytotoxicity but increase the susceptibility to cell death. Toxicol. In Vitro,
29, 819–827.
Novotný, C., Dias, N., Kapanen, A., Malachová, K., Vándrovcová, M.,
Itävaara, M. and Lima, N. (2006). Comparative use of bacterial, algal and
protozoan tests to study toxicity of azo and anthraquinone dyes.
Chemosphere, 63, 1436-1442.
Pan, Y., Neuss, S., Leifert, A., Fischler, M., Wen, F., Simon, U., Schmid, G.,
Brandau, W. and Jahnen-Dechent, W. (2007). Size-Dependent
cytotoxicity of gold nanoparticles. Small, 3(11), 1941 – 1949.
Pandurangan, M. and Kim, D. H. (2015). In vitro toxicity of zinc oxide
nanoparticles: a review. J Nanopart Res, 17, 158.
Parshetti, G., Kalme, S., Saratale, G. and Govindwar, S. (2006).
Biodegradation of Malachite green by Kocuria rosea MTCC 1532. Acta
Chimica Slovenica, 53, 492–498.
Paul, B., Bhuyan, B., Purkayastha, D. D., Dey, M. and Dhar, S. S. (2015).
Green synthesis of gold nanoparticles using Pogestemon benghalensis (B)
O. Ktz. leaf extract and studies of their photocatalytic activity in
degradation of methylene blue. Materials Letters, 148, 37–40.
Peric, T., Jakovljevic Vladimir, L. j., Zivkovic, V., Krkeljic, J., Petrovic, Z. D.,
Simijonovic, D., Novokmet, S., Djuric, D. M. and Jankovic, S. M. (2012).
Toxic effects of palladium compounds on the isolated rat heart. Med
Chem., 8(1), 9-13.
Prasannan, A. and Imae, T. (2013). One-pot synthesis of fluorescent carbon
dots from orange waste peels. Industrial and Engineering Chemistry
Research, 52, 15673–15678.
Quigg, A., Chin, W. C., Chen, C. S., Zhang, S., Jiang, Y., Miao, A. J.,
Schwehr, K. A., Xu, C. and Santschi, P. H. (2013). Direct and indirect
toxic effects of engineered nanoparticles on algae: role of natural organic
matter. ACS Sustainable Chem. Eng., 1, 686−702.
Russ, R., Rau, J. and Stolz, A. (2000). The function of cytoplasmic flavin
reductases in the reduction of azo dyes by bacteria. Applied and
Environmental Microbiology, 66(4), 1429–1434.
Safavi, A. and Momeni, S. (2012). Highly efficient degradation of azo dyes by
palladium/hydroxyapatite/Fe3O4 nanocatalyst. Journal of Hazardous
Materials, 201–202, 125–131.
Sangeetha, G., Rajeshwari, S. and Venckatesh, R. (2011). Green synthesis of
zinc oxide nanoparticles by Aloe barbadensis miller leaf extract: structure
and optical properties. Mater. Res. Bull., 46, 2560–2566.
Singla, P., Sharma, M., Pandey, O. P. and Singh, K. (2014). Photocatalytic
degradation of azo dyes using Zn-doped and undoped TiO2 nanoparticles.
Applied Physics A, 116 (1), 371-378.
Vizuete, K. S., Kumar, B., Guzmán, K., Debut, A. and Cumbal, L. (2016a).
Shora (Capparis petiolaris) fruit mediated green synthesis and application
of silver nanoparticles. Green Process Synth, 5, 2016 (in press).
Vizuete, K. S., Kumar, B. and Cumbal, L. (2016b). Ecofriendly synthesis of
monodispersed silver nanoparticles using Andean Mortiño berry and its
photocatalytic activity. Journal of Molecular Liquids, under
communication.
Wang, H., Nui, J., Long, X. and He, Y. (2008). Sonophotocatalytic
degradation of methyl orange by nano-sized Ag/TiO2 particles in aqueous
solutions. Ultrason. Sonochem., 15, 386–392.
Wada, S., Yue, L., Tazawa, K., Furuta, I., Nagae, H., Takemori, S. and
Minamimura, T. (2001). New local hyperthermia using dextran magnetite
complex (DM) for oral cavity: experimental study in normal hamster
tongue. Oral Diseases, 7, 192–195.
Xue, Y., Wu, J. and Sun, J. (2012). Four types of inorganic nanoparticles
stimulate the inflammatory reaction in brain microglia and damage
neurons in vitro. Toxicol. Lett., 214, 91–98.
Zhu, X., Qiu, F., Li, X., Rong, X., Wang, J. and Yang, D. (2016). Silver
carbonate loaded on activated carbon composite photocatalyst with
enhanced photocatalytic activity under visible light irradiation. In press,
http:// dx.doi.org/ 10.1080/ 10667857.2015.1116219.
BIOGRAPHICAL SKETCH
Dr. Brajesh Kumar, PhD
Department of Chemistry, TATA College, Kolhan University,
Chaibasa, 833202, Jharkhand, India
Centro de Nanociencia y Nanotecnologia,
Universidad de las Fuerzas Armadas ESPE,
Sangolqui, Ecuador
Chapter 4
IONIC LIQUID-PROMOTED
SYNTHESIS OF PHOSPHINATES AND
BISPHOSPHONIC ACID DERIVATIVES
ABSTRACT
These days, the ionic liquids (ILs) are in the focus as green and
tunable solvents in organic syntheses. However, another application of
ILs has also emerged based on their potential as catalysts or additives in
different reactions. IL additives may enhance the rate of the reactions,
and promote complete conversions. Literature examples are shortly
overviewed in this paper. We found that the microwave (MW)-assisted
esterification of phosphinic acids may also be facilitated by the presence
of 10% of a suitable IL. The presence of e.g., [bmim][PF6] allowed a
lower temperature of ca. 160–180°C (instead of ca. 220°C), shorter
reaction times, and higher conversions/yields. Hence, a novel method was
developed for the syntheses of cyclic and acyclic phosphinates. In another
field, the synthesis of dronic acid derivatives, such as pamidronic acid
Corresponding author E-mail address: zsnkiss@mail.bme.hu.
†
Corresponding author E-mail address: gkeglevich@mail.bme.hu.
1. INTRODUCTION
Ionic liquids (ILs) became widely used reaction media due to advantages
meant by the fine tunability of their properties (e.g., polarity and lipophilicity)
and recirculability, not speaking about the fact that they are regarded green
solvents [1–6].
ILs are especially suitable for homogeneous catalytic reactions, such as
hydrogenations [7] and hydroformylations [8], as the transition metal catalyst
remains in the IL phase, and can be recycled [9, 10]. The work-up may
comprise a simple phase separation [11].
As a typical industrial application, the synthesis of dodecylbenzene by
Friedel–Crafts alkylation involves the use of imidazolium [AlCl4] ILs as a
solvent [12].
The second generation of ILs include task-specific species with side
chains promoting special reactions [13, 14]. Thus, the ILs may serve as
solvents, and also as catalysts in a number of cases giving rise to twin
advantages of non-volatility and unnecessity for an additional catalyst.
Examples among others, include Friedel–Crafts acylations [15], hydrolyses
[16], multicomponent reactions [17, 18], and syntheses of heterocycles
[19–21].
Recently, ILs have started finding applications as catalysts, or as
additives, meaning that they are used only in smaller amounts, and often
together with microwave (MW) irradiation. This protocol seems to be a green
approach
[3, 22, 23].
FeCl3-based ionic liquids (e.g., [bmim]Cl∙FeCl3) applied in a catalytic
amount can promote MW-assisted Friedel–Crafts acylations and alkylations
[24, 25].
The Fischer esterification of carboxylic acids was carried out in the
presence of 3 equivalents of an acidic IL ([bmim][HSO4]) under MW
irradiation, resulting in the corresponding esters in almost quantitative yields
[26]. Later on, other Brønsted acidic ILs with a [HSO4]– anion applied in
efficient, and the use of acid chlorides means cost. A “greener” approach could
start from phosphinic acids, however, these species do not undergo direct
esterification with alcohols [45]. Interestingly, we found that the direct
esterifications may take place under microwave (MW) conditions [48, 49].
Other possibilities for the synthesis of phosphinates, involve alkylating
esterification of the phosphinic acids by alkyl halides [50], or the use of
activating agents, such as the T3P® reagent [51]. The Arbuzov reaction
represents another approach to phosphinates [52]. Among these variations, the
most environmentally-friendly protocol is the direct esterification [53]. Under
MW irradiation, the direct esterification of phosphinic acids with alcohols
used in a 15-fold molar excess afforded the phosphinates in variable yields.
The esterifications were especially efficient using longer carbon atom chain
(n ≥ 4) alcohols at or above 200°C. Phenols were not found to be suitable
reaction partners in MW-assisted direct esterifications. The desired products
could be identified in the reaction mixtures, but their quantity remained below
3% [54, 55].
The energetics of the esterifications under discussion were explored by
quantum chemical calculations. The direct esterification was found to be
thermoneutral with a rather high (≥130 kJ mol–1) enthalpy of activation. Such
reactions may be promoted by MW irradiation via the beneficial effect of the
statistically occurring local overheatings [56, 57].
The obvious disadvantage of the MW-assisted esterification is the high
reaction temperature (200–235°C), the longer reaction times (up to 6 hours)
required, and the limitation in terms of the nucleophile partner: when alcohols
with low boiling point were used, the yields of the phosphinates remained low,
and the attempts to perform esterifications with phenol derivatives remained
unsuccessful.
As demonstrated in the Introduction, certain organic chemical
transformations became more efficient in the presence of ILs, especially under
MW irradiation. We wished to try this possibility utilizing ILs as additives for
the synthesis of cyclic phosphinates [58].
First, we wished to test different ILs as potential catalysts in the
esterification of 1-hydroxy-3-phospholene oxide 1 with n-pentanol at 180°C
(Scheme 1). The esterifications were carried out as described earlier [49], but
in the presence of a catalytic amount of the imidazolium salts. As can be seen
in Table 1, the blind probe experiment led to a conversion of 82% after a 2 h’s
irradiation time (Table 1/Entry 1). The use of 10% of [bmim][BF4] led to
phosphinate 2g in a conversion of 41% (Table 1/Entry 2), while the
[bmim][PF6] additive had a more remarkable effect, the conversion became
complete after 30 min (Table 1/Entry 3). Applying the same reaction
conditions, [emim][HSO4], [emim][MeSO4], [emim][EtSO4] and [emim][Cl]
additives were less efficient (Table 1/Entries 4–7). In the presence of these
additives, the conversions remained under 30%. The addition of [emim][Ac] to
the reaction mixture led to a similar outcome obtained with [bmim][BF4]
(Table 1/Entry 8). It is worth mentioning that in a few cases, the conversions
could be improved allowing longer irradiation times (Table 1/Entries 2 and 5–
7).
Scheme 1.
Scheme 2.
Scheme 3.
Encouraged by the above results, and realizing the potential in the use of
ILs as additives, we attempted to extend the MW-assisted and IL-promoted
direct esterification to the reaction of phenol derivatives as well. As was
mentioned above, previous attempts to obtain the aryl phosphinates via MW-
assisted direct esterification remained unsuccessful [55].
Along the lines of the above, we tested several ILs in the reaction of
hydroxy-3-phospholene oxide 1 with phenol (Scheme 4). To our surprise,
while there was practically no reaction in the absence of an IL, all IL tested
promoted the esterification to a smaller or greater extent (Figure 1). In
accordance with our previous experience, the application of [bmim][PF6] had
the most beneficial effect.
Thus, in the next stage of our work, we wished to synthesize new
aryloxyphospholene oxides (7) applying a catalytic amount of [bmim][PF6]
under MW irradiation (Scheme 5). The direct esterifications were carried out
in a closed vial, irradiating the reaction mixture under conditions given in
Table 4.
Scheme 4.
Scheme 5.
in the presence of IL has been less studied [64]. Pamidronic acid (12),
alendronic acid (13), risedronic acid (14) and zoledronic acid (15) were
prepared in tributylammonium chloride as the solvent, starting from the
appropriate acetic acid (8-11), and using 2 equivalents of phosphorus
trichloride, and 1 equivalent of phosphorous acid as the P-reagents (Scheme
6). Low yields of 12–31% were reported, and the purities were not provided
[65].
Scheme 6.
Scheme 7.
In the case of zoledronic acid (15), imidazol-1-yl-acetic acid (11) was the
starting material, and phosphorus trichloride and phosphorus acid were applied
in a quantity of 2.5 and 1.7 equivalents, respectively, in 1.6 equivalents of
various ILs. Again excessive yields of 90-92% were reported due to neglect of
the criterions of purity [68]. In one instance, sodium zoledronate (15-Na) was
prepared starting from crude zoledronic acid (15) obtained using 1.6
Scheme 8.
Scheme 9.
equivalent of the IL, the yields were almost identical with those of the solvent-
free variations, for pamidronic acid (12) 42% vs. 44% (Table 5/Entries 7 and
1), and for alendronate (13-Na) 5% vs. 0% (Table 5/Entries 6 and 1). It can be
concluded that it is enough to use ILs as an additive in a quantity of 0.3 or 0.6
equivalents [67, 69]. Hence, we demonstrated the catalytic effect of ILs in the
syntheses of hydroxy-bisphosphonic acid derivatives. The catalytic effect of
ILs has not yet been clarified. According to one explanation, they may
enhance the electrophilic character of the carbonyl group in the starting
carboxylic acid.
Figure 2. The effect of the solvent or/and additive in the preparation of alendronate
(13-Na).
SUMMARY
It was shown that both in the MW-assisted direct esterification of
phosphonic acids, and in the synthesis of certain dronic acid derivatives from
the corresponding carboxylic acids and phosphorus trichloride/phosphorous
acid, catalytic amounts of suitable imidazolium ILs promoted the reactions
regarding reaction time and yield. It may be a general trend that the use of less
IL is more advantageous, than its use as a solvent.
REFERENCES
[1] Ghandi, K. A review of ionic liquids, their limits and applications.
Green Sust. Chem., 2014, 4, 44-53.
[2] Hajipour, A. R.; Rafiee, F. Recent progress in ionic liquids and their
applications in organic synthesis. Org. Prep. Proced. Int., 2015, 47, 249-
308.
[3] Oliver-Bourbigou, H.; Magna, L.; Morvan, D. Ionic liquids and
catalysis: Recent progress from knowledge to applications. Appl. Catal.,
A, 2010, 373, 1-56.
[4] Keglevich, G.; Baán, Z.; Hermecz, I.; Novák, T.; Odinets, I. L. The
Phosphorus aspects of green chemistry: The use of quaternary
phosphonium salts and 1,3-dialkylimidazolium hexafluorophosphates in
organic synthesis. Curr. Org. Chem., 2007, 11, 107-126.
[5] Keglevich, G.; Grün, A.; Hermecz, I.; Novák, T.; Odinets, I. L.
Quaternary phosphonium salt and 1,3-dialkylimidazolium
hexafluorophosphate ionic liquids as green chemical tools in organic
syntheses. Curr. Org. Chem., 2011, 15, 3824-3848.
[6] Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Second Ed.;
Wiley-VCH, 2008.
[7] Dyson, P. J. Review: Synthesis of organometallics and catalytic
hydrogenations in ionic liquids. Appl. Org. Chem., 2002, 16, 495-500.
[8] Haumann, M.; Riisager, A. Hydroformylation in room temperature ionic
liquids (RTILs): Catalyst and process developments. Chem. Rev., 2008,
108, 1474-1497.
[9] Lee, J. W.; Shin, J. Y.; Chun, Y. S.; Jang, H. B.; Song C. E.; Lee, S.
Toward understanding the origin of positive effects of ionic liquids on
catalysis: Formation of more reactive catalysts and stabilization of
reactive intermediates and transition states in ionic liquids. Acc. Chem.
Res., 2010, 43, 985-994.
[10] Olivier-Bourbigou, H.; Magna, L.; Morvan, D. Ionic liquids and
catalysis: Recent progress from knowledge to applications. Appl. Catal.,
A, 2010, 373, 1-56.
[11] Olivier, H. Recent developments in the use of non-aqueous ionic liquids
for two-phase catalysis. J. Mol. Catal. A: Chem., 1999, 146, 285-289.
[12] He, Y.; Wan, C.; Zhang, Q.; Zhan, X.; Cheng, D.; Chen, F. Durability
enhanced ionic liquid catalyst for Friedel–Crafts reaction between
benzene and 1-dodecene: insight into catalyst deactivation. RSC Adv.,
2015, 5, 62241-62247.
[13] Amarasekara, A. S. Acidic ionic liquids. Chem. Rev., 2016, 116, 6133-
6183.
[14] Giernoth, R. Task-specific ionic liquids. Angewandte Chem., 2010, 49,
2834-2839.
[15] Earle, M. J.; Hakala, U.; Hardacre, C.; Kärkkäinen, J.; McAuley, B. J.;
Rooney, D. W.; Seddon, K. R.; Thompson, J. M.; Wähälä, K.
Chloroindate(III) ionic liquids: Recyclable media for Friedel-Crafts
acylation reactions. Chem. Comm., 2005, 7, 903-905.
[16] Weng, J.; Wang, C.; Li, H.; Wang, Y. Novel quaternary ammonium
ionic liquids and their use as dual solvent-catalysts in the hydrolytic
reaction. Green Chem., 2006, 8, 96-99.
[17] Dake, S. A.; Raut, D. S.; Kharat, K. R.; Mhaske, R. S.; Deshmukh, S.
U.; Pawar, R. P. Ionic liquid promoted synthesis, antibacterial and in
vitro antiproliferative activity of novel α-aminophosphonate derivatives.
Bioorg. Med. Chem. Lett., 2011, 21, 2527-2532.
[18] Kumar, P. S. V.; Suresh, L.; Bhargavi, G.; Basavoju, S.; Chandramoul,i
G. V. P. Ionic liquid-promoted green protocol for the synthesis of novel
naphthalimide-based acridine-1,8-dione derivatives via a
multicomponent approach. ACS Sust. Chem. Eng., 2015, 3, 2944-2950.
[19] Jarikote, D. V.; Siddiqui, S. A., Rajagopal, R.; Daniel, T.; Lahoti, R. J.,
Srinivasan, K. V. Room temperature ionic liquid promoted synthesis of
1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron
Lett., 2003, 44, 835-1838.
[20] Shaabani, A.; Rahmati, A.; Rad, J. M. Ionic liquid promoted synthesis of
3-(2′-benzothiazolo)-2,3-dihydroquinazolin-4(1H)-ones. Compt. Rend.
Chim., 2008, 11, 759-764.
[21] Ghorbani, M.; Noura, S.; Oftadeh, M., Gholami, E.; Zolfigol, M. A.
Novel ionic liquid [2-Eim] HSO4 as a dual catalyticsolvent system for
preparation of hexahydroquinolines under green conditions. RSC Adv.,
2015, 5, 55303-55312.
[22] Martínez-Palou, R. Ionic liquid and microwave-assisted organic
synthesis: A “green” and synergic couple. J. Mex. Chem. Soc., 2007, 51,
252-264.
[23] Zhang, Q.; Zhang, S.; Deng, Y. Recent advances in ionic liquid catalysis
Green Chem. 2011, 13, 2619-2637.
[24] Alexander, M. V., Khandekar, A. C., Samant, S. D. Sulfonylation
reactions of aromatics using FeCl3-based ionic liquids. J. Mol. Catal. A:
Chem., 2004, 223, 75-83.
[25] Chen, Y.; Zu, Y.; Fu, Y.; Zhang, X.; Yu, P.; Sun, G.; Efferth, T.
Efficient Lewis acid ionic liquid-catalyzed synthesis of the key
intermediate of coenzyme Q10 under microwave irradiation. Molecules,
2010, 15, 9486-9495.
[26] Arfan, A.; Bazureau, J. P. Efficient combination of recyclable task
specific ionic liquid and microwave dielectric heating for the synthesis
of lipophilic esters. Org. Process. Res. Dev., 2005, 9, 743-748.
[27] Tao, D. J.; Lu, X. M.; Lu, J. F.; Huang, K.; Zhou, Z.; Wu, Y. T.
Noncorrosive ionic liquids composed of [HSO4] as esterification
catalysts. Chem. Eng. J. 2011, 171, 1333–1339.
[28] Zhang, P.; Liu, H.; Fan, M.; Liu, Y.; Huang, J. A review on biodiesel
production by transesterification catalyzed by ionic liquid catalysts.
Curr. Org. Chem., 2016, 20, 752-760.
[29] Kotadia, D. A.; Soni, S. S. Sulfonic acid functionalized solid acid: an
alternative eco-friendly approach for transesterification of non-edible
oils with high free fatty acids. Monatsh Chem., 2013, 144, 1735-1741.
[30] Leadbeater, N. E.; Torenius, H. M.; Tye, H. Microwave-assisted
Mannich-type three-component reactions. Mol. Diversity, 2003, 7, 135-
144.
[31] Estager, J.; Lévéque, J. M.; Turgis, R.; Draye, M. Solventless and swift
benzoin condensation catalyzed by 1-alkyl-3-methylimidazolium ionic
liquids under microwave irradiation. J. Mol. Catal. A: Chem., 2006, 256,
261-264.
[32] Arfan, A.; Paquin, L.; Bazureau, J. P. Acidic task-specific ionic liquid as
catalyst of microwave-assisted solvent-free Biginelli reaction. Russ. J.
Org. Chem., 2007, 43, 1058-1064.
[33] Peng, J; Deng, Y. Ionic liquids catalyzed Biginelli reaction under
solvent-free conditions. Tetrahedron Lett., 2001, 42, 5917-5919.
[34] Sing, V.; Kaur, S.; Sapehiyia, V.; Sigh, J.; Kad, G. L. Microwave
accelerated preparation of [bmim][HSO4] ionic liquid: an acid catalyst
for improved synthesis of coumarins. Catal. Commun., 2005, 6, 57-60.
[35] Yang, X.; Yang, L.; Wu, L. [Hmim][HSO4]: An efficient and reusable
catalyst for the synthesis of spiro[dibenzo[a,i]-xanthene-14,3'-indoline]-
2,’8,13-triones and spironaphthopyran[2,3-d]pyrimidine-5,3'-indolines.
Bull. Korean Chem. Soc., 2012, 714-716.
[36] Ren, R. X.; Wu, J. X. Mild conversion of alcohols to alkyl halides using
halide-based ionic liquids at room temperature. Org. Lett., 2001, 3,
3727-3728.
[37] Nguyen, H.-P.; Matondo, H.; Baboulene, M. Ionic liquids as catalytic
“green” reactants and solvents for nucleophilic conversion of fatty
alcohols to alkyl halides. Green Chem., 2003, 5, 303-305.
[38] Nguyen, H. P.; Kirilov, P.; Matondo, H.; Baboulene, M. The reusable
couple “PTSA/1-alkyl-3-methylimidazolium ionic liquids”: Excellent
reagents-catalyst for halogenations of fatty diols. J. Mol. Catal. A:
Chem., 2004, 218, 41-45.
[39] Ranu, B.; Jana, R. Catalysis by ionic liquid. A green protocol for the
stereoselective debromination of vicinal-dibromides by [pmIm]BF4
under microwave irradiation. J. Org. Chem., 2005, 70, 8621-8624.
[40] Kim, Y. J.; Varma, R. S. Microwave-assisted preparation of
imidazolium-based tetrachloroindate(III) and their application in the
tetrahydropyranylation of alcohols. Tetrahedron Lett., 2005, 46, 1467-
1469.
[41] Sing, J.; Gupta, N.; Kad, G. L. Efficient role of ionic liquid (bmim)HSO4
as novel catalyst for monotetrahydropyranylation of diols and
tetrahydropyranylation of alcohols. Synth. Commun., 2006, 36, 2893-
2900.
[42] Leadbeater, N. E.; Torenius, H. M. A study of ionic liquid mediated
microwave heating of organic solvents. J. Org. Chem., 2002, 67, 3145-
3148.
[43] Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New
Domain; Mathey, F., Ed.; Pergamon: Amsterdam, 2001.
[44] Keglevich, G. Phosphinine derivatives and their use as versatile
intermediates in P-heterocyclic chemistry. In: Topics in Heterocyclic
Chemistry; Gupta, R. R., Ed.; Bansal, R. K., Vol. Ed.; Springer:
Dordrecht, 2009; Vol. 20, pp 65–98.
[45] Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New
York, 2000.
[46] Kiss, N. Z.; Keglevich, G. An Overview of the synthesis of phosphinates
and phosphinic amides. Curr. Org. Chem. 2014, 18, 2673-2690.
[47] Keglevich, G., Kiss, N. Z., Mucsi, Z. Synthesis of phosphinic acid
derivatives; traditional versus up-to-date synthetic procedures. Chem.
Sci. J., 2014, 5, 1000088.
[48] Kiss, N. Z.; Ludányi, K.; Drahos, L.; Keglevich, G. Novel synthesis of
phosphinates by the microwave-assisted esterification of phosphinic
acids. Synth. Commun., 2009, 39, 2392-2404.
[49] Kiss, N. Z.; Böttger, É.; Drahos, L.; Keglevich, G. Microwave-Assisted
Direct Esterification of Cyclic Phosphinic Acids. Heteroatom Chem.
2013, 24, 283-288.
[50] Bálint, E.; Jablonkai, E.; Bálint, M.; Keglevich, G. Alkylating
esterification of 1-hydroxy-3-phopsholene oxides under solventless MW
conditions. Heteroatom Chem., 2010, 21, 211-214.
[63] Rogers, M. J.; Gordon, S.; Benford, H. L.; Coxon, F. P.; Luckman, S. P.;
Monkkonen, J.; Frith, J. C. Cellular and molecular mechanisms of action
of bisphosphonates. Cancer, 2000, 88, 2961-2978.
[64] Nagy, D. I.; Grün, A.; Garadnay, S.; Greiner, I.; Keglevich, G. Synthesis
of hydroxymethylenebisphosphonic acid derivatives in different
solvents. Molecules, 2016, 21, 1046-1064.
[65] De Ferra, L.; Turchetta, S.; Massardo, P.; Casellato, P. Preparation of
bisphosphonic acids and salts thereof. WO2003/093282, 2003.
[66] Hao, E.; Jiang, X.; Liu, Y.; Zhang, Q.; Wang, D.; Xie, M.; Wang, H.;
Guo, H.; Li, G. A method for preparing alendronate sodium.
CN104558028, 2015.
[67] Nagy, D. I.; Grün, A.; Garadnay, S.; Greiner, I.; Keglevich, G.
Investigation of the effect of medium in the preparation of alendronate;
Till now the best synthesis in the presence of an ionic liquid additive.
Heteroatom Chem., submitted for publication.
[68] Hao, E.; Jiang, X.; Liu, Y.; Zhang, Q.; Wang, D.; Xie, M.; Wang, H.;
Guo, H.; Li, G. Method for preparing sodium zoledronate.
CN104610357, 2015.
[69] Grün, A.; Nagy, D. I.; Garadnay, S.; Greiner, I.; Keglevich, G. Efficient
synthesis of pamidronic acid using an ionic liquid additive. Lett. Drug.
Des. Discov., 2016, 13, 475-478.
Chapter 5
ABSTRACT
Low molecular mass linear statistic copolymers of acrylamide (AA)
are promising as carriers for drugs and biologically active compounds
(BAC). Minor toxicity of polyacrylamide (PAA) for warm-blooded
animals makes it possible to use AA copolymers with reactive
comonomers for the purpose of drug delivery. Since they are not
biodegradable, their molecular mass should be restricted to (2–5) × 104
for their complete removal from the organism.
The aim of the current work was to synthesize low molar mass ionic
AA copolymers for drug delivery and to study their behavior in water
solutions.
*
Corresponding Author Email: smirnova_mariann@list.ru.
1. INTRODUCTION
An important problem of modern polymer chemistry is the use of
macromolecular compounds for controlled modification of properties of
biologically active compounds (BAC), i.e., drugs, haptens and biocydes [1, 2].
Currently, it is possible to obtain composites between low molecular weight
BAC and polymers and, thus, to achieve increased solubility in water,
prolonged action, increase in biological activity, to avoid side effects, and
provide controlled delivery of a BAC into target cell. Among other methods of
biologically active polymer synthesis is formation of ionic or covalent bonds
between BAC and water-soluble non-toxic polymers (carriers). Ready
medicinal preparations can be used as BAC, and thus the main problem is a
development of suitable polymer carriers. Synthetic carbon-chain copolymers
of N-vinylpyrrolydone [3] and N-(2-hydroxypropyl)methacrylamide [4] have
proven effectiveness as carriers for BAC.
Non-toxic hydrophilic acrylamide (AA) copolymers are also promising as
BAC carriers [3]. However, they are still not thoroughly studied in this
respect; only the use of acrylamide/acrylic acid copolymers for immobilizing
protein BAC has been reported [5, 6]. There are no data published on
modification of low molecular weight BAC with AA copolymers. Carbon-
chain polymers, including acrylamide copolymers, do not undergo noticeable
metabolism and are removed intact from the organism via kidney filtration (if
their molecular mass (MM) does not exceed 40000). Therefore, in the present
work we focused on developing methods for synthesizing low molecular mass
(ММ = (20-40)·103) ionogenic AA copolymers (both anionic and cationic).
The goal of the present work was synthesizing reactive ionogenic AA
copolymers, determining their composition and molecular mass and using
these products as BAC carriers.
CH 2 CH CH 2 CH
m2
C O COOH
NH2
CH 2 CH CH 2 CH
m2
C O C O
NH2 NH
H3C C CH3
CH 2
SO3H
I (R = H); II (R = CH3-) III
Taking into account the high reactivity of AA and its tendency towards
formation of crosslinked structures, copolymerization of AA with AAc,
MAAc and AAMPSAc was carried out at rather low temperature (50°C). The
results of copolymerization experiments are summarized in Table 1. It can be
seen that MM of anionic AA copolymers can be controlled by varying
comonomer concentration in the initial mixture (Experiments 2-3, 11-12, 13-
14), varying initiator concentration (Experiments 1-2) and introducing 2-
propanol, which is used as a chain transfer agent in production of
poly(acrylamide) (Experiments 3-5, 7-8). The values of viscometric average
molecular masses (Мη) of copolymers I-III (with m2 = 18.2-22.8 mol.%) were
equal to (10 – 39)·103 (Table 1). In the case of copolymers I-7, I-8, MM
determined by sedimentation and diffusion analysis (MSD) turned out to be
41·103 and 50·103, respectively.
Table 2 shows that with increasing MSD, translational diffusion
coefficients D0 decrease, and, correspondingly, the values of efficient
hydrodynamic radii of macromolecules RhD (calculated from the D0 values)
increase. The values of hydrodynamic invariant A0 are close to the average
№ The initial reaction mixture АА-АAc (I), АА-MAAc (II) and AA-
AAMPSAc (III) copolymers
[М2], [М1+М2], Solvent Yield,% m2, [η], cm3/g Мη·10-3,
mol. % wt. % mol. % (MSD)·10-3
Copolymerization of АА with АAc (I)
1 20 20 2-propanol 99.5 20.4 17 10
2 20 20 2-propanol 98.8 20.1 25 19
3 20 30 2-propanol 99.5 19.8 31 27
4 20 30 2-propanol + 99.8 20.1 40 39
ethanol
5 32 30 2-propanol + 99.7 31.1 20 (41)
ethanol
6 35 30 ethanol 96.9 34.7 32 (50)
Copolymerization of АА with MAAc(II)
7 20 30 2-propanol 99.9 19.0 25 19
8 20 30 2-propanol + 99.8 19.2 29 25
ethanol
9 20 30 ethanol 99.6 19.0 33 29
Copolymerization of АА with AAMPSAc (III)
10 25 25 ethanol 99.2 22.8 32 28
11 20 15 ethanol 99.6 19.3 21 16
12 20 40 ethanol 99.8 18.5 38 36
13 20 40 2-propanol 99.8 19.1 25 19
14 20 50 2-propanol 98.8 18.2 28 23
Note: AIBN concentration is 3 wt. %; in Experiments 1, 7, 8, 12, 13, 14 it is 4.5 wt. %
(1)
IV V
(2)
I
Polymer m2, mol. % [η]·102, cm3·g-1 So, Do·107, cm2/s MSD·10-3 RhD, nm
Sv
PAA 0 0.40 1.7 3.3 50 6.3
I-7 32.3 0.21 1.8 4.5 36 4.6
I-3 50.7 0.19 1.6 5.6 23 3.7
H2C NH2
H O H
H
OH H
CH3
HO
OH O H
H NH2 H
OH H
O
H3C
H HN CH3 OH
H
2
H R NH
H H2N 1
OH R CH2
O
H2N O
H
H
O
H2C NH2 H
HO NH2 O
H O CH2 O
H
H H H H OH
HO O H2N NH2
H NH2 NH2
NB GB
H2C OH
H O H H2 C OH
H O
NH2 H
H
HO NH2
H OH HO
OH
OH
OH OH
КB АB
radius RhD calculated from these parameters. Table 4 shows that with
increasing content of AAc units in the copolymer, its molecular mass drops
from MSD = 5.0·104 (for the initial PAA) to MSD = 2.3·104 (for the copolymer
with carboxyl group content equal to 50.7 mol. %); i.e., molecular mass of
PAA decreases by more than a factor of 2. These data indicate that in the
selected conditions, alkaline hydrolysis of PAA is accompanied by destruction
of polymer backbone, and decrease in macromolecule size is mainly related to
the decrease in MM of hydrolyzed PAA (AA-AAc copolymer) as compared to
that of the initial PAA. It should be noted that PAA hydrolysis in the selected
conditions and the accompanying thermodestruction of low molecular weight
AA-AAc copolymer result in simultaneous changes in MM and m2. The higher
degree of hydrolysis, the lower the molecular mass of the hydrolyzed PAA.
The relationship between the MM of AA-AAc copolymer and the degree of
hydrolysis in the studied interval of copolymer compositions can be described
by the following equation: M/M1 = 1-1.17·10-2·m2, where M and M1 are the
molecular masses (MSD) of the initial and hydrolyzed PAA, respectively. This
relationship can be used for predicting the corresponding characteristics in the
synthesis of low molecular weight AA-AAc copolymers by alkaline
hydrolysis.
Table 5 shows that the MSD and MW for AA-MAAc copolymer are
virtually similar, and in the case of polymeric complex, these parameters are
higher by a factor of 1.2-1.3. The hydrodynamic radius of the macromolecules
in the complex (RhD) obtained from the values of diffusion coefficient (which
were determined by isothermal translational diffusion) is significantly higher
than that of AA-MAAc copolymer (by a factor of 1.6). Increase in the values
of the MSD, MW and RhD parameters after interaction between the copolymer
and the antibiotic confirms formation of a complex.
In Vitro toxicity of all studied polymeric complexes (in cell cultures) was
lower by a factor of 4-4.5 than that of non-modified antibiotics [11, 12].
Polymeric complexes retain high antimicrobial activity inherent in the non-
modified antibiotic, despite rather low content of the drug in complexes (15-20
wt. %). The stable complex AA-MAAc +amikacin demonstrates the lowest
antibacterial activity and, at the same time, the lowest in vitro toxicity. Direct
relationship between biospecific activity and toxicity of polymer-BAC
complex and the stability of this complex allows controlling antibacterial
activity of polymeric complexes of cationic antimicrobial drugs and their
toxicity via the changing content of COOH groups in the macromolecule
and their distribution along the copolymer backbone.
In addition to complexation with aminoglycoside antibiotics, copolymers
III were used for modification of antiviral preparation Arbidol (VI).
CH3
H2C N
CH3
HO O
C * HCl * H2O
OC2H5
Br N CH 2 S
CH3
VI
CH 2 CH CH 2 CH CH 2 CH
m1 m2 m3
C O C O C O
HN HN
NH2
H3C C CH3 H3C C CH3
CH 2 CH 2 R
- +
SO3H SO3 N XVI
H R
VII
VIII IX
OH O OH O NH2
OH
O
* HCl
OH
H OH
CH3 OH N
H3C CH3
X
H3C CH3
N OH CH3
OH H
HO
O
OH
NH2 O OH N OH
(CH 2)2
NH2 O
C O C O
CH 2 CH CH 2 C
m1 m2
CH3
XI
The LD50 value found for polymeric ketimine of doxycycline was equal to
1200 mg/kg, which is approximately 2 times higher than that for pure
antibiotic; thus, the derivative is not toxic (Table 8). In case of intraperitoneal
introduction with an antigen (ram erythrocytes), polymeric ketimine of
doxycycline exerts an influence on antibody response and demonstrates
immunosuppressive properties (depending on the administered dose); these
properties are more pronounced than in the case of pure antibiotic, particularly
when the dose is equal to 10 mg/kg.
3. EXPERIMENTAL
3.1. Monomers and Reagents
CONCLUSION
Some methods were proposed for the synthesis of novel polymer carriers
of BAC based on low molecular weight acrylamide copolymers which contain
–COOH, -SO3H and –NH2 groups. The composition, molecular masses and
other parameters, as well as in vitro toxicity of the polymers, were studied.
Complexation between acrylamide anionic copolymers and aminoglycoside
antibiotics in water and water-salt solutions was studied by physico-chemical
methods. The factors which affect the stability of the formed polymer
complexes were revealed. It was established that toxicity and antimicrobial
activity of the polymer complexes depend on their stability. Copolymers of
acrylamide with 2-acrylamido-2-methylpropanesulfonic acid were used to
obtain water-soluble non-toxic complexes of Arbidol; these complexes possess
broad-spectrum antiviral activity.
It was demonstrated that the obtained low molecular weight anionic and
cationic copolymers of acrylamide are promising carriers for various drugs.
REFERENCES
[1] Plate, N. A., &Vasil’ev A. E. (1986). Physiologically Active Polymers.
Moscow: Chemistry.
[2] Thatte, S., Datar, K. and Ottenbrite R. M. (2005). Perspectives on:
polymeric drugs and drug delivery systems. J. Bioact. Compat. Polym.,
20: 585-601.
[3] Panarin E. F., Lavrov N. A., Solovskiy M. V., Schal’nova L. I. (2014).
Polymers – Carriers of Biologically Active Substantives. Saint-
Petersburg: Profession.
[4] Kopecek J. &Kopeckova P. (2010). HPMA copolymers: origins, early
developments, present and future.Adv. Drug Deliv. Rev., 62: 122-149.
[5] Torchilin, V. P., Reyzez, I. L., Tischenko, E. F. et al. (1976).
Immobilization of enzymes on biocompatible carriers. IV. Modification
α-chymotrypsin of water-soluble copolymers of vinyl series. Evaluation
of accessibility in various ways immobilized α-chymotrypsin for protein
inhibitor. Bioorg. Chem., 2 (12): 1687-1694.
[6] Martensson, K. &Mosbach, K. (1972). Covalent coupling of pullulanase
to an acrylic copolymer using a water-soluble carbodiimide. Biotechnol.
Bioeng. 14: 715-724.
[7] Solovskiy, M. V., Gavrilova, I. I., Smirnova, M. Yu., Schul’tseva, E. L.
(2008). Synthesis of low molecular weight water soluble anionic
copolymers of acrylamide.IzvestijaVUZov. Series Chem. and Chem.
Technol., 51: 72-74.
[8] Tsvetkov, V. N. (1989). Rigid-chain polymers. New-York: Plenum.
[9] Solovskiy, M. V., Eropkin, M. Yu., Eropkina, E. M. et al. (2007).
Synthesis and properties of low-molecular-weight copolymers of
acrylamide with 2-acrylamido-2-methylpropanesulfonic acid, as
potential drug carriers. Russ. J. Appl. Chem., 80 (10): 1703-1707.
[10] Afinogenov, G. E. and Panarin, E. F. (1993). Antimicrobial polymers.
Saint-Petersburg: Hyppocrat.
Chapter 6
THE PHENOMENON OF
MASS CONCENTRATION PERIODICITY
IN AMORPHOUS MATTER:
A NEW KIND OF PERIODICITY IN NATURE
ABSTRACT
Periodic structures in some amorphous substances (water, starch,
heart biomatrix, styrene-maleic anhydride copolymer (1:1) esterified by
bis-tri-n-butyltinoxide and gelatin) were investigated by the gravitational
mass spectroscopy method (GMS). There are periodic sub ensembles
(PSE) of masses in the interval from 30 mio. to 4 billion Daltons. PSE
were characterized to have 5 mass peaks, at log m = 7.62; 8.57; 9.02; 9.31
and 9.54 (m in Daltons), they were represented as sub micelle and micelle
structures in the expanded form. In white gravitational noises, PSE were
observed to be stable, in colored gravitational noises, however, these
periodic structures were destroyed with the emergence of new sub
ensembles both in the expanded and the collapsed forms. It was tried to
find is there any correlation between the principles of periodic structures
in the amorphous molecular matter and those in the universe.
Corresponding author Email: aist@zubow.de.
1. INTRODUCTION
It is known that molecular mass concentrations (clusters, domains) are
formed under the influence of gravitational noises (GN) [1]. GN themselves
are generated by a huge number of galaxies, stars, nebulae, planets and black
holes. GN in the universe cause clusters of galaxies (https://en.wikipedia.
org/wiki/Millennium_Run) and giant voids (https://en.wikipedia.org/wiki/
Void_(astronomy)) resembling on molecular level some porous materials [2],
Figure 1.
Figure 1. Heterogeneity of baryonic mass distribution in the universe (A, 1500 Mpc/h,
http://bigclosetr.us/topshelf/blog/13640/universal-brain-neuron-network) and
molecular matter (B, C, ~ 10- 6m) (bone: http://www.umich.edu/~bme332/ch9bone/
bme332bone.htm).
2. EXPERIMENTAL
As objects of the long-range order (LRO) investigation served distilled
water, starch, proteins (biomatrix of duck heart muscle and gelatin, Dr. Oetker,
FRG), and an organotin polymer [4]. LRO was analyzed using the GMS
method [1].
Figure 2. GMS spectra of potato starch powders: A – in white noises [1], B - heated at
523 K for 30 s (color noise [1]). The signal of the ring oscillation (α-D-glycopyranose)
was indicated by arrow.
Figure 3. GMS spectra of two water samples: A - storage for 2 years under quasi-white
noise conditions (iron, grounded, heat and sound isolated box, 295 ± 3 K), B -
exposition to colored noises (mixing and UV radiation). The water cluster models were
kindly provided by the professors Lenz [5] and Chaplin [6]. Amorphous structure of
water at 225K was given the right (http://phys.org/news/2011-11-supercool-doesnt-
.html).
Figure 3 showed the GMS spectra of two water samples, the first sample
was stored for a long time in white noises and the second one shortly in
colored noises [1]. In the range of sub micelle and micelle structures, there
were periodic mass accumulations at log m = 7.62; 8.57; 9.02; 9.31 and 9.54
Daltons, which were also present in some synthetic polymers, for example, in
polyethylene, polystyrene, polypropylene etc. The form of the mass
distribution curves in the sub ensembles was almost the same, i.e., there is a
certain analogy in the periodicity of recurring events. On the other hand, the
spectrum showed any periodic voids between the sub ensembles of masses.
These voids in the spectra were not an indication for a balance between the
signals from collapsed and expanded micelle forms that mutually extinguish
each other.
In these mass/frequency ranges [1], the formation of micelles is simply
forbidden by the gravitational white noises, voids therefore periodically arise.
Similar effects can be observed when sound is directed on powders
(https://en.wikipedia.org/wiki/Cymatics).
External energy influences on water caused by colored noises destroyed
the LRO organization in the range of sub micelle and micelle structures while
in the area of small clusters the equilibrium expanded-collapsed clusters was
shifted toward collapsed structures (-f).
Similar regularities we observed in solutions of salts, acids, organic
liquids, plants’ biomatrices, animal proteins and synthetic polymers, too.
Figure 4 showed photographs of some supra molecular structures in
amorphous polymers and colloidal systems. One can notice some kind of a
diffuse periodicity in the voids of the nano material further, stationary waves
in the solid mineral agate. However, observe a periodicity in the mass
distribution on the nano level in amorphous matter using the electron
microscopy is impossible.
Figure 6. GMS spectrum of fresh heart duck biomatrix (10 min. After slaughter). Weak
shock waves.
Figure 7. GMS spectrum of dried duck heart biomatrix (Figure 6). A – signals from
myosin heads, B – signals from actin heads, C - range of sub ensembles (sub micelles
and micelles). Weak shock waves.
Figure 8. GMS spectrum of TOP. Weak shock waves, Zubow constant 9.4E-15 N/m. C
- range of large periodic mass concentrations (sub ensembles). The first cluster signal
belongs to -SnBu3, the second one to the domain consisting of 3 repeating polymer
units.
Figure 9. GMS spectra of fish collagen (bladder, FB) and gelatin (film, G). RASC -
domain consisting of: Gly 22 –Pro % 13% - Hyp 10% - Glu 9.8% - Ala 8% - Arg 7.6%
(weight %). NC1-hexamer model (168,931 Da) is taken from [9]. Weak shock waves.
Figure 9 showed the GMS spectra of collagen (fish bubble) and gelatin.
We remember that gelatin is a protein, which was extracted from various
animal organs at a hard impact of color noises from chemical technologies.
Both spectra were very different especially in the interval C. The exposure to
colored noises (boiling, extraction, filtration, drying and pressing a film) led
not only to an easier spectrum of the sub ensembles, but also to an increased
number of periodic structures from 4 to 7, at the same time in the gelatin
appeared some voids. Moreover, it was visible that the harmony of small- and
medium-sized domains in the expanded form was disturbed, in gelatin, besides
the expanded forms collapsed domains appeared. So, the RASC signal (base
domain of 11 average units [8]) strongly pronounced in the native collagen
disappeared in gelatin. From this it follows that the investigation of high
structures of biopolymers (tertiary, quaternary and higher structures) should be
carried out under conditions being adequate to their existence in the body (in
vivo).
The analogy between the structure of the molecular amorphous matter and
the visible structure in the universe suggested that there should also be applied
the periodicity of mass and void distribution in the latter. In the universe, such
periodic mass concentrations (sub ensembles) are known, for example, the
galaxy clusters [10] with a period of 500 ... 650 million l.y. however, no data
yet on the periodicity of clusters in the dark matter (https://en.wikipedia.
org/wiki/Dark_matter#/media/File:COSMOS_3D_dark_matter_map.png),
such as of neutrino clouds [11]. If it will be found so it should be caused by a
certain generator of super-gravitational noises being outside the baryonic
universe.
To find this generator could be possible using a gravitational compass [1].
On the other hand, if the analogy exists, so the properties of the universe being
similar to those of colloidal systems, can be described applying the well-
known rules of the colloidal chemistry. Remember the process of coalescence
in colloidal chemistry is the basis for the gravitation [12].
In Figure 10, the GMS spectrum of water under microgravity conditions
(free fall, first 0.4 s, state maximally approximated to the real white noises,
[1]) was given.
Figure 10. GMS spectrum of water under microgravity conditions. Weak shock waves.
From the spectrum it was evident that the microgravity weakly influenced
the periodicity of the mass concentrations in the range C (Figure 3), that means
the periodicity of sub ensembles and voids was preserved, generally. However,
all water clusters were transformed into the collapsed forms, the number of
sub ensembles in the range C slightly increased and the signal from the base
water cluster (H2O)12 completely disappeared. The transition of water clusters
into the collapsed form is due to reduced lengths of the hydrogen bonds -
H...O-. This is possible when the influence of external gravitational fields on
the balance between protons and neutrinos becomes smaller (see Figure 11).
The balance really determines the bond length [12] and is characterized by
canonical structures (below in Figure 11). The weakening of the external
gravitational field increased the potential energy of the canonical structures
with strengthening the hydrogen bonds and the densifying all water clusters.
Figure 11. Modeled proton oscillations between physical vacuum (PV) and baryonic
state, and proton (p) interaction with neutrinos (ν) in a chemical bond (1-2). The
number of canonical structures characterizing the chemical bonds was given below
[12].
It should be mentioned that the time of the free fall (state of acceleration,
first 0.4 s) could not have been sufficient for the formation of a new
thermodynamic state of the entire water cluster ensemble under microgravity.
Here the signal of the rare cluster (H2O)178 appeared it emerged under strong
color noise influences (boiling, stirring, etc.), normally.
The new type of periodicity in amorphous matter can be illustrated as a
family of pendulums each with its own mass/frequency (see first Zubow
equation in [1].), Figure 12, but with one oscillation vector for the whole
pendula family agreeing with the direction of the gravitational compass [1]. In
turn this vector of all pendula, oscillating as protons’ ensembles [13], is
directed to large mass-analogues in our universe. Here each oscillator type is
characterized by its own mass concentration (domains, domains’ associates or
Figure 12. Model of a new type of periodic mass concentration in amorphous matter.
For understanding, three different mass ensembles and their hypothetical GMS
spectrum were given, only. The arrow showed the direction of the dominant mass in
the universe.
CONCLUSION
The amorphous molecular matter is characterized by periodic structures of
mass sub ensembles appearing mostly when external energy influences (white
noises) are excluded, and they are less pronounced in the colored noises.
Periodic structures in the amorphous matter occur in the mass range from
30 million to 4 billion Dalton.
REFERENCES
[1] Zubow K., Zubow A. V., Zubow V. A. The Way to the ETIs. Applied
gravitational mass spectroscopy. Nova Sci. Publ. NY, 2014.
https://www.novapublishers.com/catalog/product_info.php?products_id
=42668&osCsid=5bd85d42dc273360fd48126de7be9daf.
[2] https://arxiv.org/pdf/astro-ph/0504097v2.pdf.
[3] Efremov J. F. Periodic colloidal structures. - L.: Chemistry, 1971. - 192
p (in Russian). http://jes.ecsdl.org/content/120/6/185C.abstract.
[4] Zubow K., Zubow A. V., Zubow V. A. Long-Range Order in Organotin
Monomers and Polymers. Physical Chemistry-An Indian Journal. 2013,
v.8, no.5, pp.198-206. ID: Phy3482676.
[5] Annika Lenz, Lars Ojamäe. On the stability of dence versus cage-shaped
water clusters: Quantum-chemical investigations of zero-point energies,
free energies, basis-set effects and IR spectra of (H2O)12 and (H2O)20.
Chemical Physics Letters. 2006, v. 418, pp. 361-367.
[6] Chaplin M., SBU London, http://www.lsbu.ac.uk/water/index.html.
[7] Ke Zhang, Liwei Zhang, Yongming Chen. Robust Organic/Inorganic
Hybrid Porous Thin Films via Breath-Figure Method and Gelation
Process. Macromolecular Rapid Communications. 2007, vol. 28, pp.
2024-2028. DOI: 10.1002/marc.200700384.
[8] Zubow K., Zubow A., Zubow V. A. Phenomenal properties of the
domain ensembles in proteins. Biochemistry and Molecular Biology
Journal. Delaware. USA. 2016, vo. 2, no., 1, pp. 1-10.
http://biochem-molbio.imedpub.com/phenomenal-properties-of-the-
domain-ensembles-in-proteins.pdf.
[9] Manuel E. Than, Stefan Henrich, Robert Huber, Albert Ries. The 1.9- α
crystal structure of the noncollagenous (NC 1) domain of human
placenta collagen IV shows stabilization via a novel type of covalent
Met-Lys cross-link. Proc Natl Acad Sci U S A. 2002 May 14, vol. 99,
no.10, pp. 6607–6612. doi: 10.1073/pnas.062183499..
[10] http://www.wissenschaft.de/archiv/-/journal_content/56/12054/1542
367/Kosmischer-Schaum/.
[11] Zubow A., Zubow K., Zubow V. A. Radiation of Axions and Neutrinos
from the Center of the Milky Way: Structure of the Center. Horizons in
World Physics. Ed. Albert Reimer. 2015, v. 283, pp. 1-21. Nova Sci.
Publ. NY. ID_30510. https://www.novapublishers.com/catalog/pro
duct_info.php?products_id=54346.
[12] Zubow K., Zubow A., Zubow V.A. Revision of the Nature of
Gravitation and the Nature of the Chemical Bond, Ed. Advances in
Chemistry Research. Ed. J. C. Taylor. NY, NovaPublish. Inc. 2016, vol.
32, pp. 141-164.
[13] Zubow A., Zubow K., Zubow V. A. Nature of Energy. Phenomenon of
Electric Neutral Particles’ Emission in Chemical and Mechano-
Chemical Reactions. Horizons in World Physics. Nova Sci. Publish. NY,
2014, vol. 22, pp. 37-52. https://www.novapublishers.com/catalog/
product_info.php?products_id=50340&osCsid=994455a7afd05deb7075
94aaf444ed06.
Chapter 7
ABSTRACT
Furans have, fundamentally, biological and chemical uses. For
several years, we have been working with substituted furans as
Author Contributions: M. Cainelli realized joint to C. Ormachea the theoretical study. Authors
M. Kneeteman and P.M.E. Mancini wrote the protocol, and wrote the first draft of the
manuscript. All authors read and approved the final manuscript.
*
Corresponding author Email: pmancini@fiq.unl.edu.ar.
†
ABBREVIATIONS
[BMIM][BF4]: Tetrafluoroborate n-butylimidazolium
[BMIM][PF6]: Hexafluorophosphate n-butylimidazolium
CA: Cycloadduct
DA: Diels-Alder
DFT: Density Functional Theory
FMO: Frontier Molecular Orbitals
INTRODUCTION
Furan is an aromatic heterocyclic compound with, fundamentally,
biological and chemical uses. Two important derivatives are 2-furoic acid and
furfural. Nowadays, several synthesis processes are very well known. Among
them, it is convenient to cite the following ones: synthesis of Paal-Knorr,
synthesis of Feist-Berani, and those that use acyloins or alkyniloxiranes as
starting material. Industrially, the furan is obtained by decarbonylation of
furfural.
Although the principal reaction that the furan ring suffers is the
electrophilic aromatic Substitution (SEAr), it has been known that aromatic
heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder
reactions despite their aromaticity and hence its inertness expected. In view of
their electron-rich constitution and electron-donor properties, they have been
involved mostly as the diene component in the cycloaddition process. Thus,
furans have been used efficiently in this capacity since the early days of the
Diels-Alder reaction [1]. Also there are a limited number of examples of five-
membered aromatic heterocycles acting as dienophiles in Diels-Alder
reactions. A special driving force permits expression of such unusual
heterocycle behavior.
Theoretical Calculations
Electronic properties of reactions involving 2- and 3- nitrofuran and
different dienes were studied theoretically in order to explain the reactivity and
mechanism of these processes.
The dienophile has the highest value of electronic chemical potential (μ),
which indicates that the charge transference process derives from the dienes to
the first one. In these cases, the diene is going to act as nucleophile and the
dienophile as electrophile.
The diene that presents the highest difference of global electrophilicity
(Δω), respect to the dienophile, is the Danishefsky’s diene. Then, the polarity
of the reactions involving this diene would be higher and the results more
favorable than those in which 1-methoxy-1,3-butadiene and isoprene are
employed.
Dienophile ωk(eV)
C2 0.10
2-nitrofuran
C3 0.38
C2 0.43
3-nitrofuran
C3 0.06
Diene Nk(eV)
C1 1.20
Isoprene
C4 0.92
C1 0.74
1-metoxy-1,3-butadiene
C4 0.94
C1 0.56
Danishefsky’s diene
C4 1.46
Mechanism of Reaction
In cycloaddition reactions, such as DA with nitro-dienophiles, primary
adducts retaining the nitro group are not observed. Therefore, there is an
elimination stage of the substituent group as nitrous acid that needs to be
consider. This is a domino process that involves consecutive reactions. If
asymmetric dienes such as Danishefsky’s diene are used, an extra stage,
corresponding to the elimination of -OMe group and hydrolysis of –OSiMe3
group, is also present. Here, only the process until the formation of the primary
adducts is consider in the mechanism study. This is because it is the
determinant step of the reaction. It is necessary taken into account that the
irreversible character of these reactions is due to the elimination of the nitrous
acid and the subsequent aromatization of the products.
2-nitrofuran
3-nitrofuran
Figure 1. Transition states for para (left) and meta (right) cycloadducts.
30 TS
25
20
15
24 kcal/mol
10
ΔE (kcal/mol)
5
(a)
0
-5
-10
-15
-20
-25
-30
CA
25
TS
20
15
10
17.5 kcal/mol
5
ΔE (kcal/mol)
(b) 0
-5
-10
-15
-20
-25
-30 CA
Figure 2. Reaction path of 2-nitrofuran (a) and 3-nitrofuran (b) with isoprene.
The Δω of the reaction for this system is 1.76 eV and 1.60 eV for 2-
nitrofuran and 3-nitrofuran respectively. This reactions present one transition
state (TS, Figure 3) for each, ortho and meta products.
2-nitrofuran
3-nitrofuran
Figure 3. Transition states for ortho (left) and para (right) cycloadducts.
ΔEa=2.52 kcal/mol
30 TS
25
20
15
22.5 kcal/mol
ΔE (kcal/mol)
10
5
(a) 0
-5
-10
-15
-20
CA
35 TS
30 ΔEa=14.81 kcal/mol
25
20
15
ΔE (kcal/mol)
10
13.37 kcal/mol
5
(b) 0
-5
-10
-15
-20 CA
Figure 4. Reaction path of 2-nitrofuran (a) and 3-nitrofuran (b) with 1-methoxy-1,3-
butadiene.
The Δω of the reaction for this system is 1.83 eV for 2-nitrofuran and 1.67
eV for 3-nitrofuran. The only product is the para isomer, which derives from
the bond between the most electrophilic atom of the dienophile (C3 for 2-
nitrofuran and C2 for 3-nitrofuran) and the most nucleophilic atom of the diene
(C4). This reaction is highly asynchronous and presents two transition states
(TS1 and TS2, Figure 5). The TS1 is associated with the bonding formation
between these two reactive atoms and the TS2 corresponds to the second
bonding formation between the dienophile and the C1 of the diene. The
difference in the bonding distances are [(ΔrTS1=1,24 Å), (ΔrTS2=0,90 Å)] for 2-
nitrofuran and [(ΔrTS1=1,24 Å), (ΔrTS2=0,90 Å)] for 3-nitrofuran.
We are in presence of a two-step mechanism. This fact does not agree
with the pericyclic reaction concept. In a similar way, we detected, in a
theoretical study, that the reaction of 3-nitropyridine as electrophilic
dienophile with Danishefsky’s diene, presents a mechanism with two step and
a detectable intermediate state [25].
The primary cycloadduct is not observed in all of these cases because of
the relative stability of the nitrate adduct respect to the final product with
elimination of nitric acid. The irreversible step of the DA reaction (impulsive
force) is the extrusion of nitrous acid and the stability is related to the
aromaticity of the final product.
The energy barrier of the TS1 is 18.95 kcal/mol and the energy of the TS2
is 16.83 kcal/mol for 2-nitrofuran (Figure 6a). The energy barrier of the para
cycloadduct is higher than those in which 3-nitrofuran is employed as
dienophile (11.31 kcal/mol and 6.55 kcal/mol for TS1 and TS2 respectively,
Figure 6b). Moreover, the energy of the TS1 is the determinant step of the
reaction because it presents higher values of energy than the TS2.
2-nitrofuran
3-nitrofuran
For this analysis, the dienophile used was the 3-nitrofuran and the IL
employed for the solvent effect was tetrafluoroborate of 1-methyllimidazolium
-[HMIM][BF4]- (Figure 7). This selection is related to the possibility of
hydrogen bonding formation between this molecules.
If the classical interaction between the electrophile and the IL is
considered, which means that the IL cation interact via hydrogen bonding with
the nitro group of the electrophile, the global electrophilicity index is too high
(ca. tetrafluoroborate of 1-methyllimidazolium and ethyl ammonium nitrate).
These results are not compatible with the experimental data, probably because
the anion is not considered formally (although the rate of the reaction is higher
than those when a molecular solvent is used, the yields and the temperature of
the reactions do not change enough).
25
TS1
TS2
20
15
5
(a)
0
-5
-10
-15
-20 CA
15 TS1
10 TS2
5 11.31 kcal/mol
6.55 kcal/mol
ΔE (kcal/mol)
0
(b)
-5
-10
-15
CA
-20
Figure 6. Reaction path of 2-nitrofuran (a) and 3-nitrofuran (b) with Danishefsky’s
diene.
Figure 7. [HMIM][BF4].
For this reason, the supermolecular approach was explored. In this case
the anion is considered. When one par anion-cation of IL is taken into account,
the anion interacts only with the cation (electrostatic interactions) without
affecting the 3-nitrofuran, enabling a planar arrangement of hydrogen bond
between the cation and the dienophile (Figure 8).
Figure 8. One and two pairs anion-cation of IL interacting with the dienophile
Figure 9. Optimized geometries observed when the 3rd and 4th IL molecules are
added.
There is a second ω value that is related to the structure where a same
anion is interacting with both, the dienophile and the cation, which reduces the
effect of the hydrogen bonding interaction due to the rotation in the plane
(Figure 10).
Figure 10. Structures observed when a same anion is interacting with both, the
dienophile and the cation.
Computational Methods
The theoretical DFT calculations were carried out using the Gaussian 09
[18] program. The hybrid functional [19] employed was B3LYP [20], together
with the standard 6-31G(d) basis set [21].
Initially, the geometric structures of reactants and products were
optimized using the Berny analytical gradient optimization method [22]. The
mechanistic study was realized through the construction of the Potential
Energy Surface (PES) for every system. The structures of transition states
(TSs) were located, optimized and then verified through IRC (Intrinsic
Reaction Coordinates) calculations [23]. The frequency calculations were
realized in order to validate the optimized structures. Reactants and
cycloadduct (CA) structures were verified by the absence of negative
frequencies and the TSs by the presence of only one imaginary frequency.
The reactivity of the systems was studied using some indexes defined in
terms of the electronic chemical potential (μ) and the chemical hardness (η).
The chemical potential is the charge transfer capacity of the system in basal
state and the hardness is the resistance to change the chemical potential when
the number of electrons variates. Both quantities may be approached in terms
of the one electron energies of the frontier molecular orbital HOMO and
LUMO, εH and εL [24].
εH +εL
μ= 2
(1)
η = εL − εH (2)
μ2
ω = 2η (3)
Recently an empirical (relative) nucleophilicity index, N, has been
introduced based on the HOMO energies obtained within the Kohn-Sham
scheme.
∂ρ(r) ∂μ
f(r) = ( ∂n
) = (∂v(r)) (5)
v(r) n
2
fμα = |cμα | + cμα ∑v≠μ cvα Sμv (7)
fk+ and fk- are the Fukui functions for a nucleophilic and electrophilic attack,
respectively. Local electrophilicity and nucleophilicity indexes, ωk and Nk, can
be obtained using the following expressions.
ωk = ωfk+ (8)
𝑁k = 𝑁fk− (9)
CONCLUSION
In this work the use of furan derivatives acting as electrophilic dienophiles
in P-DA cycloaddition was demonstrated. These reactions are useful for the
preparation of benzofurans and dibenzofurans in one step. The discussion as
extended considering solvent effects influence, specially the employment of
PIL´s. In this conditions it could be demonstrated that the TS of the reactions
have charge separation and then, the solvent effect is important. Moreover, the
influence of different forms to develop the process was analyzed. In this sense,
the use of microwave irradiation gave the best results.
On the other hand, a computational theoretical study of the reactivity of
furans 2- and 3- nitro substituted as dienophiles in P-DA reactions involving
several nucleophilic dienes was realized. For this purpose, the Density
Functional Theory (DFT) method was employed. When isoprene and 1-
methoxy-1,3-butadiene are employed, only one TS is observed. However
when Danishefsky’s diene is employed, two TSs are noted corresponding with
each bonding formation. The similar activation energies of the reactions
employing isoprene as diene, explain that the obtention of both isomers is
equally possible. Moreover, when 1-metoxy-1,3-butadiene is employed, the
mechanism suggests a preference for the ortho cycloadduct. However, the final
product is the same and the experimental determination is not possible.
Finally, the reactions involving the Danishefsky’s diene are completely
regioselective and the product is the result of the bonding formation of the
most nucleophilic atom of the diene with the most electrophilic atom of the
dienophile. The TS1 is the determinant step of these reactions due to it is
higher value of activation energy.
The global electrophilicity of the dienophile increase when IL is employed
as a reaction media. The PCM is not adequate to explain this effect because it
does not consider the solute-solvent specific interactions. On the other hand,
the supermolecular approach considers the hydrogen bonding interaction and
is more consistent with the experimental results obtained when 2- and 3-
nitrofuran are used as electrophiles in DA reactions using ILs as solvents.
In general the experimental results were coincident with the theoretical
analysis.
ACKNOWLEDGMENT
This research was supported by the Agencia Nacional de Ciencia y
Tecnología (ANCyT) of Argentina -PICT 2014 No.1587-, and by CAI+D
2011 -No 66, 501 201101 00478 LI-at the Universidad Nacional del Litoral,
Santa Fe, Argentina. C. Ormachea thanks to the Consejo Nacional de
Investigaciones Científicas y Técnicas (CONICET) of Argentina for the
scholarship.
Funding Sources
REFERENCES
[1] (a) Diels O; Alder K; Naujoks E. Ber. Dtsch. Chem. Ges. 1929, 62, 554.
(b) Diels O; Alder K. Justus Liebigs Ann. Chem. 1931, 490, 243.
[19] (a) Parr RG; von Szentpaly L; Liu S. J. Am. Chem. Soc. 1999, 121,
1922. (b) Parr RG; Pearson RG. J. Am. Chem. Soc. 1983, 105, 7512. (c)
Parr RG; Yang W. Oxford University Press: New York, 1989.
[20] (a) Lee C; Yang W; Parr RG. Phys. Rev. B: Condens. Matter Mater.
Phys. 1988, 37, 785. (b) Becke AD. J. Chem. Phys. 1993, 98, 5648.
[21] Morales-Bayuelo A; Vivas-Reyes R. Journal of Quantum Chemistry,
2014, article ID 239845.
[22] Hehre WJ; Radom L; Schleyer PVR; Pople JA. Ab initio Molecular
Orbital Theory. Wiley, New York, 1986.
[23] Gonzáles C; Schlegel HB. J. Phys. Chem. 1990, 94, 5523.
[24] Kohn W; Sham LJ. Phys. Rev. 1965, 140, 1133.
[25] (a) Domingo LR; Chamorro E; Pérez P. J. Org. Chem. 2008, 73, 4615.
(b) Domingo LR; Pérez P. Org. Biomol. Chem. 2011, 9, 7168.
[26] Fukui K. J. Phys. Chem. 1970, 74, 4161.
[27] Domingo LR; Aurell MJ; Pérez P; Contreras R. Tetrahedron, 2002, 58,
4417.
[28] (a) Tomasi J; Persico M. Chem. Rev. 1994, 94, 2027. (b) Simkin BY;
Sheikhet I. Quantum chemical and statistical theory of solutions a
computational approach. Ellis Horwod, London, 1995.
Chapter 8
ABSTRACT
Petroleum asphaltenes are interesting molecules that have been
studied extensively due to various problems caused by the petroleum
industry. The high tendency of self association of asphaltene behavior is
the main strength of this complex behavior of crude oil. The phenomenon
of aggregation is the association of asphaltene molecules in particles of
different shape and size. This chapter of book discusses the use of
surfactants in oil chemical treatment to remedy the problems caused by
asphaltenes during production of crude oil. In this particular and specific
case it will be presented of Furrial area in eastern Venezuela, which is
one of the most important operational areas of the oil industry at
Venezuela. Different changes in pressure, temperature, and secondary
Polar Zone
Where MH is the mass of the hydrophilic area and M the molecular mass
of the whole molecule.
The HLB Davies method assigns a specific value to different groups
which are present in the surfactant and the contribution of each to the HLB is
determined by equation 2:
where HLB1 and are HLB2 HLB surfactants numbers 1 and 2, x1 and x2 their
weight fractions in the mixture and HLBMixture, the HLB of the surfactant
mixture. For example, suppose you want to determine the HLB of a mixture of
70% of TWEN 80 (HLB = 15) with 30% SPAN 80 (HLB = 4.3). The
calculation proceed as follows:
The heteroatom-containing polar group while the aliphatic tail, typically, have
less than 16 carbon atoms to prevent crystallization
When nonionic and anionic surfactants are mixed often exhibit strong
interactions that affect surface activity. These interactions give rise to
significant deviations from ideal mixing laws and adsorption behavior [16].
For example, AOT adsorption at the oil/water precoated consider Tween
80. Tween 80 layers adsorbs irreversibly after the interface is rinsed with
deionized water. The presence of Tween 80 at the oil water inhibits adsorption
of AOT [17].
May interface is acting to fractionate species in more persistent surfactant
commercially. However, the irreversible adsorption is consistent with recent
molecular simulations, due to interactions between poly (ethylene oxide) head
groups and the interface [18].
2. ASPHALTENES: INTRODUCTION
Asphaltenes are the fraction of petroleum compounds defined based on its
solubility, and insoluble in n-heptane and soluble in toluene. Here the
problems of asphaltenes begins in its very definition. Also are compounds of
higher polarity oil. Among its main features is that they are a complex mixture
of hydrocarbons. But undoubtedly are molecules with fascinating properties.
They have represented the scientific and technical challenge because of its
complex phase behavior in the oil industry. In exploration and production, the
adsorption of asphaltenes on mineral produces wettability changes and
blockage of pores in the reservoir rock. Adsorption at interfaces also raw water
produces very stable emulsions. Aggregation leads flocculation and
precipitation in different production facilities and even in the same reservoir
rock. During refining asphaltenes produce poisoning of catalysts and are
responsible for the formation of coke in the process of improvement. In most
of these cases are surfactants which can counteract the negative effect of
asphaltenes in oil. This chapter discusses this and some examples of
operational areas in Venezuela.
Asphaltenes are solid dark color, its chemical structure has been the
subject of many investigations [19, 20, 21] are pericondensaded polyaromatic,
with the presence of heteroatoms (N, S, O) trace metals (V, Ni, Fe) with and
naphthenic alkyl chains attached to the aromatic centers. In the oil it is in form
of colloid being in equilibrium pseudo which may rupture thermodynamic
changes as pressure and temperature, and this may cause precipitation
generating multiple disadvantages in the oil industry [22, 23] and operationally
defined as present in the fossil fuel as soluble and insoluble aromatic solvent
on a paraffin low molecular mass fraction.
The problems caused by this fraction during oil production, are connected
to the tendency of separation of the asphaltenes from the liquid phase,
increasing costs in the oil industry, flocculation can be induced by changes in
pressure, temperature, composition that generates a reduced stability of
colloids of asphaltenes in oil. Crude Oil is a complex mixture and describe
each fraction present in detail is impractical. The asphaltenes found in
petroleum bordered by the other fractions keeping in suspension, which can
use the Flory-Huggins theory, applied in polymers, which are mixtures of
large molecules with many small solvent, which is you can be used to
determine the solubility of asphaltenes in mixtures of thermodynamic manner.
The first model solubility for asphaltenes was proposed by Hirschberg [24],
which has been used in many applications and have made many adaptations.
Applying the theory Flory-Huggins of the Gibbs energy change by mixing
asphaltene with maltenes at constant pressure and can be evaluated by the
following equation:
(4)
Many studies [48-51] have shown that oil viscosity are greatly influenced
by the colloidal structure of the asphaltenes present in fossil fuels. The
presence of these associated macromolecules have a profound influence on the
viscosity. Lin et al. [52], showed that the particles are associated giving an
increased viscosity, they used the model Pal-Rhodes [53] and changing two
parameters described the relationship between viscosity asphalt and asphaltene
content. The Pal-Rhode model [54] was originally to describe the
viscosity/concentration emulsions given in the following equation relationship.
Where ƞ0 are ƞ and the viscosity of the emulsion and solvent respectively,
ƞr represents the relative viscosity and ɸ is the volume fraction of particles. K
is the constant of solvation which is affected by the associations and the
exponent is the result of -2.5 assume associations spherically. Sheu et al. [55],
using equation viscosity raised by Pal-Rhodes describes the viscosity of
solutions of asphaltenes in function of the concentration of asphaltenes in
different aromatic solvents, various investigations have determined that the
concentration of asphaltenes is determinant in viscosity.
Pal [56], leads to a new viscosity for solutions of asphaltenes, taking into
account the cluster and nanoclusters asphaltenes, at low concentration
asphaltenes are as nanoclusters disc-shaped and are separated not interacting,
and high concentrations nanoclusters interact to form cluster, resulting in an
increase in the fraction of effective volume due to a continuous phase
immobilized by cluster, this indicates that the viscosity is dependent on the
interactions of the cluster creating a kind of network throughout the fossil fuel
that its viscosity increases, making it difficult to transport.
Aggregation processes asphaltenes affect their properties producing
negative consequences, since their separation from the liquid phase and an
increase in viscosity, which can indicate that the problem of scale when
aggregates change from nanometers to microns sizes.
(6)
(7)
CH3 CH3
CH3
+ +
NH3 NH3 +
NH3
- -
O O -
O
O O CH3 CH3
CH3
O O O O O O O
O O O
- -
O H N+ O OH- N+ +
OH OH OH OH OH OH
3 3H N
3
N N N
N N N
O O O
O O H3 C H3 C H C NH2 NH2NH
O 3 2
- -
O O O O- OO
HO OHO HOO O + + +
NH3 NHNH
3 3
H3C H3CH3C
The Furrial is almost the most important oil field in Venezuela, located
north of Monagas state with more than 120 active wells. This is a mature oil
field; accordingly program Lift Gas (LPG) was implemented at the end of
2012. Following the implementation of LPG, was detected in most wells with
this production method, the formation of W/O emulsions stable high viscosity
because the high shear generated in the gas inlet to the production line. Figure
5 shows the evidence for this effect.
The tests were performed by applying a chemical treatment (improved
flow) in these wells showed high emulsion viscosity and thus increase
productivity in the “Furrial” field.
Testing in the laboratory to control parameters set (API, water and
sediments (W&S), bottles of test, measurement threshold flocculation and
viscosity).
Once taken to the field for testing under dynamic conditions by online
reviews with multiphase flow meter AGAR, it was monitored in parallel other
parameters: API, A&S and viscosity. It was obtained by application of the
chemical, a decrease in viscosity with 96% and increase the production rate
tested in a range of 6% to 11% wells.
Applying a flow best, it allowed to observe an increase in the mobility of
well fluid collection system, optimizing production. In a gas lift system,
sufficient agitation to allow the water dispersed in oil in a form “W/O” high
viscosity emulsion, stabilized by different species of interfacial activity present
in crude occurs. This phenomenon directly affects the rheological
characteristics, and the fluid runs through the entire production system.
In this step, efficiency tests were performed with different asphaltene
dispersants intermediates and emulsion breakers for the selection of the most
favorable combination, to determine the proportions and the best concentration
of the final product. The analyses of control used in this phase were
asphaltenes flocculation threshold, bottle and viscosity tests. These activities
were carried out with samples of Well 1, which presented a significant
increase in viscosity with an approximate magnitude of 10,000 cP @ 210°F
when the change of method of production to gas lift occurs.
Laboratory tests allowed to determine that the viscosity increase is related
to emulsion present into the sample; dramatic reductions in viscosity levels
were obtained by applying increasing concentrations of product flow
improver, which contains an emulsion breaker. As can be seen in Figure 6.
In the last 20 years there has been a special interest in the study of the
phenomenon of asphaltene, which is due, on the one hand, their presence in
most field applications of injection of miscible gases, and other, and
exploitation of increasingly deep deposits containing crudes with unstable
asphaltenes.
The problems generated by these colloidal agents at the level of lines of
transfers and processing stations crude oil are diverse, and is problematic field
is not exempt under review, equipped with a crude oil asphalt nature and after
high production by at least 30, also wet.
The crude oil Furrial, has a high tendency to destabilization and
precipitation of asphaltenes and this component an emulsifying agent,
influenced by high water cuts accompanying the oil produced, generated
during the various stages of the production process, emulsions stable affecting
the viscosity and hence the fluid velocity.
Based on this a project that monitored the effects of unstable asphaltenes
from the crude stream that comes from Furrial field selecting a chemical
treatment that stabilizes the system dewatering constant output of crude
outside specifications began one water and sediment percentage well above the
established by the manufacturer dehydrators station.
The constant output of dehydration OOS (Outside Of Specification),
coinciding with the migration of certain wells in the form of gas lift, has
generated a call from acercs care possible destabilization of asphaltenes by this
method of artificial lift. This control measure applied through a chemical
dispersant treament of asphaltenes can lead to stabilization of the system and
maintain constant dehydration and low current oil specifications handled by
the main station Jusepín 2.
Asphaltenes do not have a definite melting point so they remain in solid
form, massing and pluging the dehydration equipment. Such is the case of
electrostatic dehydrators that make up the main station Jusepín 2 wherein these
colloidal agents generate severe problems being deposited on the walls and
electrodes of the apparatus, serving as natural insulation to prevent the passage
of alternating current, destabilizing and to system.
The knowledge of the system is to be applied where the treatment is key,
equipment and processes them covering dewatering plant crude oil Jusepín
main station 2 is described in detail.
corresponds to an installed to treat crude MBD 460 and handle 182 MBDP
water capacity.
Each team is 120 inches in diameter and 45 feet long; They are also
designed to operate at a maximum and 125 psia and 210°F operate with a
voltage in the primary circuit (power) of 480 volts, and convert it by a
transformer secondary voltage of 23000 volts. Typically, the voltage of the
secondary circuit can be selected between 16000, 19500 and 23000 volts. This
selection is made by the manufacturer and basically depends on the
conductivity of crude oil and water content. Flow distribution dehydrators is
done by control valve located in the discharge of dry crude oil. The maximum
level of interface on computers is 51 inches or 43% filling of the container to
prevent short circuits.
The LAG, a production method that uses compressed gas at high pressure
and external energy source, the gas is injected at a point in the column of fluid
in the tubing, it is intended to lighten or displacing the fluid column within the
production tubing, reducing its weight. Thus, the energy reservoir is sufficient
to carry the fluids from the bottom to the surface.
However, as reflected in Figure 10, the migration of new wells of Furrial
to be produced by this method of artificial lift generated instability asphaltenes
present in the crude stream handled by the process dewatering the EPJ-2.
The injection of gases rich in this survey method promotes asphaltene
precipitation in training and at the level of the well respectively. This effect is
because these injections cause changes in the composition of the reservoir
fluids and pH changes of the medium, which destabilizes the asphaltenes
present in crude, causing them to flocculate and precipitate, causing thus
changes wettability and well plugging level of training and subsequently
transfer lines and processing equipment.
Unstable
asphaltenes. Dewatering
System OOS (% WyS>
0.7)
It is noteworthy that this migration field wells The Furrial that produced
by natural flow, and presetaban the problem of unstable asphaltenes and in
relation to the above the gas lift, increased this instability generating stronger
emulsions, reaching system dehydration Jusepín main station 2, a crude oil
emulsions with many problems and asphaltene.
Clearly, (see Figure 10), it is evident as following the incorporation of
new wells (taken as example the well FN-23) asphaltenes are unstable as a
result of this injection of paraffins (gas injection) that causes that the
protective resin layer is broken, leading to asphaltene particles aglomerarce
including flocculating and possibly precipitating on the walls and electrodes of
the electrostatic dehydrator operating in the EPJ-2, destabilized dewatering
system.
As indicated before, the issue of asphaltenes in the oil field is fairly new,
so it can be said that experimental laboratory methods are extremely important
when drawing conclusions and recommendations to decide the real options to
correct or prevent problems associated with asphaltenes.
Before any field test first involved a complete diagnosis of the system
(wells that had already migrated to LAG, transfer lines and the main station
Jusepín 2) it was performed. In the particular case of this work it was taken as
reference the Well FN - 23 were established, then the variables that influence
the problem, knowing the experiences they have with other chemical
treatments in order to define the parameters to be evaluated (before during and
after the test), a dispersing chemical aromatic base was selected to repair the
electrodes affected by unstable asphaltenes and the evaluation program was
established, preparing formats for data collection and selection of systems and
equipment chemical injection.
It was shown that by performing laboratory tests such as threshold
determination flocculating asphaltenes to be unstable, they are deposited at the
interface in the dehydration process, stabilizing the emulsion present in the
stream of crude oil from Furrial Field.
This method, called threshold determination flocculation is based on
determining absorbance change oil by adding a nonsolvent continuously (n-
heptane). At the beginning of the titration, the addition of n-heptane produces
a dilution effect leading to a decrease in absorbance. Later, when the process
of asphaltene, the particles scatter radiation and an increase in absorbance is
observed. Curves like those shown in Figure 11. The curve minimum
corresponds to the lower volume of n-heptane required to begin to form
particles and asphaltenes called flocculation threshold are obtained.
REFERENCES
[1] Israelachvili J. Intermolecular and Surface Forces, Third Edition:
Revised Third Edition 3rd Edition, Amsterdam, The Netherlands, 2011.
[2] Czajka, A.; Hazell, G.; Eastoe, J. Langmuir. 2015. 31 (30), 8205–8217.
[3] Ito, T; Miranda, P.C.L.; Morgon, N.H.; Heerdt, G.; Dreiss, C.; Sabadini,
E. Langmuir. 2014. 30, 11535−11542.
[4] Griffin, W. C. J. Soc. Cosmet. Chem. 1949. 1, 311-326.
[5] ICI Americas Inc. 1980. El HLB systems a time-saving guide to
emulsifier selection.
[6] Griffin, W. C. J. Soc. Cosmet. Chem. 1954. 5, 249-256.
[7] Salager, J. L.; Forgiarini, A.; Bullon, J. J. Surfactants Deterg. 2013.16,
449−472.
[8] Shinoda, K; Saito, H. J. Colloids Inter. Sci. 1969. 30, 2, 258-263.
[9] Tadros, T. J. Cosmet. Sci. 2006. 57, 153-169.
[10] Michael J. Owen. Ind. Eng. Chem. Prod. Res. Dev. 1980. 19, 97-103.
[11] X. Li, R. M. Washenberger, L. E. Scriven, and H. T. Davis. Langmuir.
1999.15, 2278-2289.
[12] Alakhova, D. Kabanov, A.V. Mol. Pharmaceutics. 2014. 11,
2566−2578.
[13] Vaughn, T.; Suter, H. R.; Lundsted, L; Kramer, M. G. J. Amer. Oil
Chem. Soc. 1951. 28, 7, 294-299.
[14] Lima, A.; Mansur, C.; Lucas, E.; Gonzalez, G. Energy and Fuels. 2010.
24, 2369–2375.
[15] Goual L.; Sedghi, M.; Xiaoxiao X.; Zhu, Z. Langmuir. 2014. 30,
5394−5403.
[16] Hines, J.; Thomas, R. J. Phys. Chem. B., 1997. 101, 9215−9223.
[17] Kirby, S.; Anna, S.; Walker, L. Langmuir. 2015. 31 (14), 4063–4071
[18] Huston, K. J.; Larson, R. G. Langmuir. 2015. 31 (27), 7503–7511.
[19] Strausz P. Mojesky W. Lown E. Energy Fuels. 1999, 13, 228-247.
[20] Murgich J. Abanero J. Strausz O. Energy Fuels. 13, 278-286.
[21] Andersen S. Speight L. Div. Fuel. 1992, 37, 1335-1341.
[22] Acevedo S. Ranaudo M. Escobar G. Gutierrez L. Gutierrez X.
Asphaltene: Fundamentals and Applications; Sheu E. Mullins O.
Plenum Press: New York, 1995; Chapter 4, p 131.
[23] Ignasiak T. Kemp-Jones A. Strausz O. Org. Chem 1977, 42, 312-320.
[24] Hirschberg, A. de Jomg L. Schipper, B. Meijer. J. Soc. Pet. Eng. J.
1984(3), 24, 283-293.
[45] Eyssautier, J.; Espinat, D,; Gummel, J.; Levitz, P.; Becerra, M.; Shaw, J.
Energy Fuels 2012, 26, 2680-2687.
[46] Eyssautier, J.; Frot, D.; Barre, L. Langmuir 2012, 28, 11997-12004.
[47] Zuo, J. Y.; Mullins, O. C.; Freed, D.; Elshahawi, H.; Dong, C.; Seifert,
D. J. Energy and Fuels 2013 27 (4), 1722-1735.
[48] Ganeeva, Y.; Yusupova, T.; Romanov, G. Russ. Chem. Rev. 2011, 80,
993-1008.
[49] Sheu, E.; De Tar, M.; Storm, D. Fuel 1991, 70, 1151-1156.
[50] Storm, D.; Sheu E. Fuel 1993, 72, 233-237.
[51] Reerink H.; Lijzenga, Anal. Chem. 1975, 47 (13): 2160-2167.
[52] Rao B. Serrano J. Fuel Science and Tecnology International, 1986, 4,
483-500.
[53] Lin M. Lunsford K. Glover C. Davison R. Bullin J. In Asphaltene:
Fundamental and application. Ed. Sheu E. Mullins O., Plenum Press,
New York, 1995, 155-176.
[54] Pal R. Rhodes E. J. Rheology, 1989, 33, 1021-1045.
[55] Sheu E. Storm D. Tar M. Journal of Non-Crystal. Solid, 1991, 341, 131-
133.
[56] Pal. R. A New model for the viscosity of asphaltene solutions. The
Canadian Journal of Chemical Engineering, 2015, 93(4), 747-755.
[57] Acevedo S, 2012, Revista Ingeniería UC, 19, 2, 7 -15.
[58] Tayeb, K.; Delpoux, O.; Barbier, J.; Marques, J.; Verstraete J.; Vezin,
H.; Energy Fuels, 2015, 29 (7), 4608–4615.
[59] Pereira J, Sánchez O, Mendez B, Alvarez J, 2011, Revista Ciencia e
Ingeniería. Vol. 32, No. 1, pp. 39-44.
[60] Acevedo, S.; Escobar, O.; Echevarria, L.; Gutiérrez, L.; Méndez, B.
Energy Fuels, 2004, 18,305-311.
[61] Gutiérrez, L. B.; Ranaudo, M. A.; Méndez, B.; Acevedo, S. Energy
Fuels 2001, 15, 624-628.
[62] Rondón, M.; Pereira, J.; Bouriat, P.; Graciaa, A.; Lachaise, J.; Salager,
J. Energy Fuels, 2008, 22, 702-707.
[63] Pereira, J. C.; Delgado, J. G.; Scorzza, C.; Rodriguez, S.; Salager, J. L.
Energy Fuels 2011, 25, 1045−1050.
[64] Miñana-Perez, M.; Graciaa, A.; Lachaise, J.; Salager, J. L. Colloids
Surf. A 1995, 100, 217–224.
[65] Silva, I.; Borges, B.; Blanco, R.; Rondón, M.; Salager, J.; Pereira, J.
Energy Fuels 2014 28 (6), 3587-3593.
butadiene, 181, 182, 183, 185, 187, 188, catalytic properties, 105
189, 190, 191, 194, 195, 203 cell culture, 109, 113, 151
butyrylcholinesterase, viii, 16, 53, 54, 74, cell death, 109, 115
77, 79, 84 cell line, 111, 115
central nervous system, 108, 116
Ceramics, 116
C chain transfer, 144
chemical, vii, viii, xi, xii, 13, 15, 79, 88, 89,
Ca2+, 109, 110
90, 92, 109, 111, 124, 135, 139, 160,
cabbage, 71
170, 172, 174, 177, 179, 180, 187, 190,
caffeine, 103
201, 202, 206, 207, 208, 212, 215, 223,
calcium, 113, 130
224, 225, 226, 227, 230, 231
cancer, 115
chemical bonds, 172
capillene, 18, 23, 58
chemical reactions, 187
capillin, 18, 23, 58
chemical stability, 88
carbon, 13, 86, 117, 124, 127, 130, 143,
Chile, 101
180, 191, 214, 222
China, 22, 23, 33, 35, 44, 45, 46
carbon atoms, 214
chlorine, 153
carbon dioxide (CO2), 86, 107
chlorobenzene, 130
carbonyl groups, 147
cholinesterase, 53, 72, 73, 74, 75, 78, 79,
carboxyl, 147, 149, 150
81, 85
carboxylic acid, 2, 61, 122, 130, 132, 133,
chromatography, 103
134, 145
chymotrypsin, 161
carboxylic acids, 2, 61, 122, 134, 145
Cistaceae, 60
carboxylic groups, 222
classes, 90, 187
carcinoma, 110
classification, 74, 80, 108
cardiovascular system, 110
cleavage, 103
carotenoids, 89
cluster model, 166
carvacrol, 18, 21, 26, 32, 33, 39, 40, 41, 42,
clusters, 105, 164, 167, 171, 172, 173
43, 63, 64, 85
CMC, 213
carvone, 18, 29, 30, 31, 37, 62
coenzyme, 136
caryophyllene oxide, 18, 22, 23, 24, 25, 26,
cognitive performance, 75
28, 34, 35, 37, 38, 39, 42, 43, 44, 45, 49,
collagen, 170, 174
53, 58, 63, 70
combustion, 104, 105
case studies, 139
commercial, 66, 225
case study, 231
complexity, viii, 15
catalysis, 101, 106, 111, 123, 127, 134, 135,
composites, 143
136, 187
composition, vii, viii, x, 4, 15, 58, 62, 63,
catalyst, ix, 87, 100, 101, 107, 111, 122,
64, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80,
123, 135, 137, 138
81, 82, 83, 84, 86, 89, 103, 105, 142,
catalyst deactivation, 135
143, 150, 152, 153, 160, 211, 215, 219,
catalysts, ix, 2, 99, 102, 106, 107, 121, 122,
229
123, 124, 135, 136, 137, 214
compounds, viii, 2, 54, 55, 56, 58, 59, 61,
catalytic activity, 98, 99, 101, 113
62, 63, 64, 68, 82, 88, 91, 98, 108, 109,
catalytic effect, 100, 133
catalytic hydrogenation, 135
110, 117, 142, 149, 155, 180, 183, 186, Cyprus, 21, 36, 57
187, 214, 219 cytokines, 110
condensation, 2, 123, 137 cytotoxicity, 82, 83, 109, 110, 115, 117
conduction, 104, 107 Czech Republic, 1
conductivity, 3, 229
conference, 12, 120
configuration, 9, 226 D
constituents, viii, 11, 15, 16, 19, 20, 21, 22,
decomposition, 7, 97, 100, 106
24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35,
degradation, viii, ix, 2, 11, 87, 88, 89, 92,
36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
93, 96, 98, 99, 100, 101, 102, 103, 104,
47, 48, 49, 50, 52, 56, 57, 59, 61, 62, 67,
105, 107, 111, 112, 113, 114, 116, 117,
68, 69, 70, 71, 72, 79, 82, 84
118, 119, 187
construction, 201
degradation mechanism, 103
consumption, 55
degradation process, 89, 107
contact dermatitis, 108
degradation rate, 96, 102
contaminant, 92
dehydration, 227, 228, 230, 231
contradiction, 69
deposits, 227
controversial, 57, 58
derivatives, vii, ix, x, 12, 58, 85, 105, 121,
COOH, 90, 143, 151, 160
123, 124, 128, 129, 130, 132, 133, 134,
copolymerization, 143, 144, 145
136, 138, 140, 142, 155, 158, 160, 162,
copolymers, vii, ix, x, 141, 142, 143, 144,
179, 180, 181, 183, 184, 186, 188, 189,
145, 146, 147, 149, 150, 151, 152, 153,
203
154, 158, 160, 161, 162, 170, 212, 213
desorption, 220
correlation, xi, 76, 163, 216
destruction, 92, 149
cosmetics, 88, 91
detectable, 196
cost, vii, ix, 87, 89, 98, 100, 102, 103, 111,
detection, viii, 2, 3
113, 124, 189
detergents, 91
Costa Rica, 101
detoxification, 92, 108, 114
cotton, 91
DFT, xi, 178, 201, 203
coumarins, 137
diabetes, 84, 86
covalent bond, 91, 143, 158
dialysis, x, 142, 146, 150, 159
covering, 3, 227
dielectric constant, 201, 203
criticism, 217
dienes, xi, 178, 180, 181, 182, 183, 184,
Croatia, 15, 21, 42, 48, 57
186, 187, 188, 189, 190, 191, 203
crop, 96, 101
diet, 71, 101
crude oil, xi, xii, 11, 13, 207, 208, 213, 217,
differential scanning, 3, 12
219, 220, 221, 227, 228, 229, 230, 231
differential scanning calorimetry, 3, 12
crystal structure, 174
diffusion, 103, 144, 147, 148, 151, 153, 154,
crystalline, 97, 98, 99, 106, 118
160
crystallization, 132, 214
diseases, viii, 16, 70, 71, 76, 79, 80, 86, 109,
crystals, 130
130
CTAB, 210
distillation, 16, 113, 159
cultivation, 55
distilled water, 3, 165
Cupressaceae, 60
distribution, x, 142, 143, 151, 164, 167, 168,
cyclic and acyclic phosphinates, ix, 121
171, 229
fluorescence, 217
fluorophores, 217
H
food, viii, 15, 57, 60, 61, 81, 85, 108
halogenation, 123
food additive, 60, 108
hardness, 201
food products, 108
harvesting, 111
formaldehyde, 213
Hawaii, 101
formation, 98, 99, 101, 102, 104, 105, 143,
HBD, 179, 188
144, 147, 149, 151, 154, 156, 164, 167,
hemisphere, 60, 68, 69
169, 172, 187, 191, 196, 197, 203, 210,
hepatotoxicity, 110, 155
214, 216, 223
heptane, 214, 230, 231
France, 23, 24, 28
herpes virus, 145
free energy, 216
hexane, 83
free radicals, 104, 105
hippocampus, 109
friction, 225, 226
homogeneity, 130
fruits, 16, 55, 65, 68, 75
HRTEM, 213
FTIR, 3, 99, 102, 103, 105
Hungary, 23, 121
fuel, viii, 2, 3, 11, 12, 104, 215, 218, 232,
hybrid, 98, 106, 201
233, 234
hydrocarbons, 16, 55, 56, 58, 214
functionalization, 111
hydrogen, 105, 147, 150, 172, 187, 197,
furan, vii, xi, 178, 179, 181, 183, 185, 186,
199, 200, 201, 203, 204, 208, 213, 215,
187, 189, 203
216
hydrogen bonds, 147, 150, 172, 203, 213,
G 215
hydrolysis, 92, 130, 132, 146, 147, 148,
gene expression, 109 158, 159, 191
genus, 54, 59, 62, 66, 68 hydrophilicity, 220, 221
germacrene D, 18, 19, 20, 21, 23, 26, 29, hydrophobicity, 222
30, 31, 33, 34, 35, 37, 39, 43, 44, 48, 49, hydrothermal synthesis, 98
53, 58, 63 hydroxyapatite, 117, 130
Germany, 19, 52, 53, 113, 163 hydroxyl, 107
Gibbs energy, 215 hyperthermia, 119
glucosinolates, 89
gold compound, 110
gold nanoparticles, 100, 101, 109, 111, 114,
I
115, 116, 117
Illiciaceae, 62
gravitation, 171
illumination, 102, 104, 106
gravitational field, 172
immune response, 157
gravitational mass spectroscopy, x, 163,
immunostimulant, 151
164, 174
impulsive, 196
Greater Antilles, 62
in vitro, 72, 74, 76, 79, 81, 83, 85, 86, 115,
groundwater, 92
117, 119, 136, 151, 152, 160, 162
in vivo, 76, 112, 162, 171
India, 19, 23, 24, 28, 32, 45, 47, 87, 119,
120
PIT, 210
planets, 164
R
plants, viii, 15, 16, 55, 60, 72, 74, 75, 76,
radiation, 96, 175, 188, 230
80, 81, 89, 112, 113, 167
radical copolymerization, x, 142, 153
plastics, 91
radicals, 79, 107
platinum, 100
radius, 147, 149, 151, 154
PNA, 4, 10
rainforest, 68
Poaceae, 67
reactants, xi, 101, 130, 133, 137, 178, 201
polar, xii, 82, 123, 178, 181, 183, 186, 188,
reaction mechanism, xi, 178
201, 202, 208, 213, 216, 221
reaction rate, 188
polarity, 122, 190, 214, 228
reaction temperature, 124
polarization, 188
reaction time, ix, 111, 121, 124, 127, 134,
pollinators, viii, 15
188
pollutant, 88, 116
reactions, ix, xi, 2, 4, 101, 106, 121, 122,
pollutants, 88, 92, 105, 107, 111, 112, 116
123, 124, 127, 130, 132, 134, 135, 136,
polyacrylamide, ix, 141, 146, 162
137, 178, 179, 180, 181, 182, 183, 185,
polydispersity, 153
186, 187, 188, 189, 190, 191, 192, 194,
polyesters, 91
198, 203, 204
polygonaceae, 67
reactive oxygen, 109
polymer chain, 147
reactivity, xi, 103, 113, 127, 144, 178, 180,
polymer destruction, 147
181, 186, 189, 190, 201, 203
polymer synthesis, 143
reagents, 93, 94, 95, 111, 130, 137, 186
polymers, 143, 144, 145, 150, 160, 161,
recovery, xii, 82, 92, 208, 220
212, 215, 216
red blood cells, 110
polyphenols, 103, 104
regeneration, 5, 9
polypropylene, 167
regioselectivity, xi, 178, 182, 184, 185, 189,
polystyrene, 167, 170
190, 191, 192
population, 19, 20
remediation, 88, 89, 92, 97, 100, 102, 103,
porous materials, 164
111, 120
Portugal, 22, 24, 28, 31, 33, 34, 38, 40, 41,
renewable energy, 111
42, 43, 53
resins, 26, 59, 212
potato starch, 165
resistance, 201
proteins, 96, 165, 167, 174
retention volume, 156
protons, 172, 219, 223
rhizome, 54, 69
pulegone, 18, 28, 29, 30, 31, 33, 62, 64
rings, 90, 108, 180, 183, 217
pumps, 228
Romania, 38
purification, 120, 182
room temperature, 98, 99, 100, 101, 105,
pyrimidine, 123, 137
116, 135, 137
ROS, 109
Q Rosaceae, 68
roses, 68
quantification, 3, 6, 7 Russia, 141
quantum chemical calculations, 124 Rutaceae, 68, 70
quantum dots, 112
quaternary ammonium, 136
technologies, 88, 106, 109, 170 universe, xi, 163, 164, 171, 172, 173, 174
technology, 96, 111, 228 UV absorption spectra, 104
TEM, 97, 99, 102, 104, 105, 106 UV light, 93, 98, 104
temperature, ix, xii, 3, 12, 93, 96, 101, 103, UV radiation, 166
121, 127, 136, 144, 146, 182, 185, 187, UV spectrum, 156
198, 201, 207, 210, 212, 215, 216, 219,
220, 226, 231
terpenes, viii, 15, 16, 17, 72, 84 V
terpenoids, viii, 15, 16, 71, 72, 77, 84, 105
Valerianaceae, 69
terpinen-4-ol, 18, 19, 20, 21, 23, 27, 32, 41,
vanadium, 215
42, 60, 65
vegetables, 56, 67
testing, 3, 4, 12, 70, 182, 224
Venezuela, vi, vii, xii, 207, 214, 223
textiles, 88, 112
Verbenaceae, 69, 80
Thailand, 28, 33, 35, 44, 45, 46, 49, 51
viscosity, xii, 2, 147, 208, 210, 217, 218,
thermodestruction, 149
223, 224, 226, 227, 234
thermogravimetry, 219
vitamins, 98
thin films, 118
voltammetric, viii, 2, 4, 5, 6, 9, 11, 12, 13
thymol, 18, 24, 32, 33, 39, 40, 41, 42, 43,
voltammetry, 2, 5, 9, 11, 12
58, 63, 64, 85
voltammogram, 6, 7
titanium, 99, 115
toluene, xii, 130, 208, 213, 214, 219
toxic effect, 110, 117 W
toxic products, 92
toxic substances, 89 waste, 99, 100, 104, 116, 117
toxicity, ix, x, 72, 75, 77, 108, 109, 110, wastewater, 88, 92, 96, 101, 108, 112, 116
111, 112, 116, 117, 118, 141, 142, 149, water, ix, x, xii, 9, 88, 91, 92, 98, 102, 105,
151, 152, 155, 157, 160, 162 108, 141, 142, 143, 149, 150, 151, 159,
transesterification, 137 160, 161, 162, 163, 166, 167, 168, 170,
transformation, xi, 8, 124, 178, 180 171, 172, 174, 201, 208, 209, 210, 212,
transition metal, 122 214, 220, 221, 223, 224, 225, 226, 227,
transition state, xi, 135, 178, 192, 194, 196, 228, 229
197, 201 water clusters, 172, 174
transmission electron microscopy, 99, 213 water purification, 98
transport, 217, 218 wells, 223, 224, 226, 227, 229, 230
treatment, vii, viii, ix, xii, 10, 16, 70, 80, 86, West Africa, 61
88, 90, 92, 96, 122, 130, 207, 208, 213,
223, 227, 231
Turkey, 24, 25, 28, 33, 34, 35, 36, 37, 38, X
39, 42, 48, 49, 51, 84
XPS, 106
X-ray diffraction (XRD), XRD, 98, 99, 101,
U 102, 105, 106