Viable route and DFT study for the synthesis of optically active limonaketone: A barely available natural feedstock in Cedrus atlantica

Article abstract of DOI:10.1016/j.molstruc.2021.130221

Herein, we report a novel, easy and efficient synthesis pathway of optically active limonaketone, a high added value monoterpene, starting from limonene, natural and low-cost feedstock. The strategy was developed in an excellent three-step total synthesis of limonaketone, potentially important intermediate in limonene ozonolysis and barely available in Cedrus atlantica essential oil (0.1% yield). The first step was the epoxidation of limonene which proceed in 91% yield. The ozonolysis of the prepared limonene oxide leads to the formation of the characteristic ketone function of limonaketone in 92% yield. The last step was performed by a deoxygenation in the presence of Zn and gave limonaketone in quantitative yield. The optically pure limonaketone has been efficiently synthesized from limonene and the overall yield was 84%. A molecular electron density theory (MEDT) analysis was carried out by using density functional theory (DFT) calculations at the M06–2X/6–311G(d,p) (LANL2DZ for Zn) level to understand the observed chemoselectivity in the Zn-deoxygenation reaction as well as its corresponding mechanistic pathway.

Full text of DOI:10.1016/j.molstruc.2021.130221

Journal of Molecular Structure 1235 (2021) 130221
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Viable route and DFT study for the synthesis of optically active
limonaketone: A barely available natural feedstock in Cedrus atlantica
a,b,∗
c
c
Ayoub Abdelkader Mekkaoui
, Hicham Ben El Ayouchia , Hafid Anane ,
d
b
a,∗
Rachid Chahboun , Larbi El Firdoussi , Soufiane El Houssame
a
Laboratoire de Chimie, Modélisation et Sciences de l’environnement, Université Sultan Moulay Slimane, Faculté Polydisciplinaire de Khouribga, B.P 145,
5000 Khouribga, Morocco
2
b
Laboratoire de Chimie de Coordination et de Catalyse, Département de Chimie, Faculté des Sciences Semlalia, BP 2390, 40001 Marrakech, Morocco
c
Laboratoire de Chimie Analytique et Moléculaire, LCAM, Faculté Polydisciplinaire de Safi, Université Cadi Ayyad, Safi 46030, Morocco
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we report a novel, easy and efficient synthesis pathway of optically active limonaketone, a high
added value monoterpene, starting from limonene, natural and low-cost feedstock. The strategy was de-
veloped in an excellent three-step total synthesis of limonaketone, potentially important intermediate in
limonene ozonolysis and barely available in Cedrus atlantica essential oil (0.1% yield). The first step was
the epoxidation of limonene which proceed in 91% yield. The ozonolysis of the prepared limonene ox-
ide leads to the formation of the characteristic ketone function of limonaketone in 92% yield. The last
step was performed by a deoxygenation in the presence of Zn and gave limonaketone in quantitative
yield. The optically pure limonaketone has been efficiently synthesized from limonene and the overall
yield was 84%. A molecular electron density theory (MEDT) analysis was carried out by using density
functional theory (DFT) calculations at the M06–2X/6–311G(d,p) (LANL2DZ for Zn) level to understand
the observed chemoselectivity in the Zn-deoxygenation reaction as well as its corresponding mechanistic
pathway.
Received 14 January 2021
Revised 18 February 2021
Accepted 28 February 2021
Available online 8 March 2021
Keywords:
Cedrus atlantica
Limonaketone
Limonene
Deoxygenation
MEDT study
©
2021 Elsevier B.V. All rights reserved.
1
. Introduction
exocyclic one. It has been reported that limonaketone is produced
from the minor exocyclic double bond ozonolysis and is the most
volatile unsaturated product [11,12]. However, limonaketone and
limononaldehyde were the main products in d-limonene–OH and
d-limonene–O3 reactions [13,14].
Carbonyl compounds play an important role in photochemical
reactions and they have a substantial portion amongst the total
volatile organic compounds in the atmosphere [1]. Intense inter-
est was given to derived carbonyls from monoterpenes, a class of
naturally occurring compounds in plants which possess a range
of pharmacological properties [2,3]. In addition, carbonyls are pre-
sented as important intermediate in the ozonolysis of various ter-
penoids [4,5]. Among the quantified compounds in the limonene
ozonolysis reaction, limonaketone was found as the minor carbonyl
product [6]. Moreover, the reaction of ozone with limonene could
take place via addition to either the endocyclic or exocyclic dou-
ble bonds resulting in a multiple generations of oxidation prod-
ucts with different range of functional groups including carboxylic
acids, carbonyls, peroxides, and alcohols [7–10]. The calculated rate
constants suggest that endocyclic O3 addition is favoured than the
It is noteworthy to mention that only few studies on limon-
aketone isolation, synthesis (Scheme 1) and reactivity are reported
in the literature [12,15–19]. In 1902, Grimal has reported for the
first time an isolated ketone C H14 O from the essential oil of Atlas
9
cedar (Cedrus atlantica) [16]. In our previous study, limonaketone
(C H14 O) was extracted from Cedrus atlantica oil by distillation un-
9
der reduced pressure (0.1% of yield) and used as a precursor for
the synthesis of newly derived monoarylidenes [15]. Recently, we
have carried out limonaketone transformation in catalytic allylic
chlorination and catalytic deshydroaromatization [18,19]. On the
other hand, Veselovsky et al. have reported for the first time the
synthesis of limonaketone using Diels-Alder reaction of isoprene
and methyl vinyl ketone on dry silica gel [17]. In contrast, Don-
ahue et al. confirmed the presence of limonaketone with its meta-
substituted isomer 4-acetyl-2-methylcyclohexene as minor prod-
uct in the Diels-Alder reaction [12]. Moreover, Baucherel et al.
∗
Corresponding authors.
E-mail addresses: mekk.ayoub@gmail.com (A.A. Mekkaoui),
hous_soufiane@hotmail.com (S. El Houssame).
https://doi.org/10.1016/j.molstruc.2021.130221
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

A.A. Mekkaoui, H. Ben El Ayouchia, H. Anane et al.
Journal of Molecular Structure 1235 (2021) 130221
Scheme 3. Synthesis of limonene oxide 2.
Scheme 1. Different pathways to limonaketone.
have reported a double exocyclic bond cleavage of limonene into
the corresponding carbonyl derivative in 73% isolated yield [20].
Amongst the synthesized constituents of Cedrus atlantica essential
oil, limonaketone exhibited the most potent odor-active [21]. Con-
sequently, limonaketone has been qualified as a fragrance with ol-
factory description such as: typically Cedarwood; orange peel, but-
tery; orange; powdery, sweet, dill; cacao, floral, fruity [20,21].
To the best of our knowledge, limonaketone synthesis in a pure
isomeric state has never been studied. Herein an efficient proce-
dure to prepare optically active limonaketone from limonene has
been developed. Furthermore, a DFT calculations has been carried
out to predict the mechanistic aspect of each reagent or additive
in the reaction pathway of Zn-catalyzed deoxygenation step lead-
ing to the preparation of limonaketone.
Scheme 4. Ozonolysis of limonene oxide 2.
2. Results and discussion
2
.1. Limonaketone synthesis
Limonene, a natural and low-cost feedstock, was chosen as
Scheme 5. Synthesis of optically active limonaketone 4 from the epoxide 3.
a starting material due to its strong similarity with our tar-
get molecule limonaketone (Scheme 2). The first step involves
the epoxidation of the endocyclic double bond which afford the
limonene oxide. Ozonolysis of the exocyclic double bond produce
the ketone functionality. At the end, a deoxygenation reaction was
achieved to form our target limonaketone.
structure of 3 (cis/trans) was confirmed by NMR and GC–MS anal-
ysis (Supplementary Material, Figures S1-S7).
2
.4. Preparation of limonaketone (4)
The preparation of limonaketone
4 from the epoxide 3
2
.2. Synthesis of limonene oxide (2)
(
Scheme 5) was carried out according to the described procedure
by Cornforth et al. [24]. The synthetized optically active limonake-
tone 4 was confirmed by NMR and GC–MS analysis and compared
to the natural distilled limonaketone (Supplementary Material, Fig-
ures S8-S12).
The epoxidation reaction of R-limonene 1 was carried out ac-
cording to Fdil et al. procedure (Scheme 3) [22]. The limonene ox-
ide 2 was prepared in a 91% yield with a (trans/cis) ratio of (56/44).
Systematic investigations were undertaken to define the best
reaction conditions and the results are summarized in Table 1.
The examination of sodium iodide effect indicated the formation of
iodohydrin intermediate after the opening of epoxide (Entries 1–6).
The best result was obtained with 10 equivalences of NaI (Entry 6).
In contrast, potassium iodide was less reactive than NaI (Entry 7).
Furthermore, the decreasing of Zn amount (Entries 8–9) confirms
that 3 equivalents represent the optimum with 100% of yield (En-
try 6). The use of acetic acid is explained due to its ability to open
the epoxide cycle (Entry 10). On the other hand, in the absence of
sodium acetate, the reaction exhibited a slight decrease in both of
conversion and yield (Entry 11).
2
.3. Ozonolysis of limonene oxide (2)
The epoxide 3 was prepared according to the procedure of De-
lay and Ohloff [23], via ozonolysis of the prepared limonene oxide
2
(Scheme 4) in a 92% yield with a (trans/cis) ratio of (57/43). The
The nature of Zn based catalysts seems to have effect on the
synthesis of limonaketone (Table 2). Among the used catalysts, ZnO
was the less reactive one and a total conversion and yield of limon-
aketone were obtained in the presence of metallic Zn species. A
Scheme 2. Synthesis method of optically active limonaketone.
2

A.A. Mekkaoui, H. Ben El Ayouchia, H. Anane et al.
Journal of Molecular Structure 1235 (2021) 130221
Table 1
Optimization of the synthesis reaction of limonaketonea.
Entry
Zn (eq)
NaI (eq)
Conversion (%)
Yield (%)
1
2
3
4
5
6
7b
8
9
3
3
3
3
3
3
3
2
1
3
3
1
33
47
49
69
92
100
9
27
36
45
67
80
100
8
2
4
6
8
10
10 (KI)
10
100
100
0
92
84
0
10
1
1
0c
1d
10
10
90
83
Fig. 1. Three-dimensional (3D) representation of the Mulliken ASD of radical
a
Reaction conditions: The epoxide 3 is added to the mixture of Zn, NaI,
−
cations, together with the nucleophilic Pk Parr functions of epoxide 3.
NaOAc (3.24 mmol) and AcOH (0.7 mL) in CH2Cl2 and the reaction is stirred
for 3 h at RT.
b
KI was used instead of NaI with the same conditions as entry 6.
that along a polar process, the GEDT [26] flux from epoxide 3, to-
c
Without AcOH.
wards ZnCl , in great agreement with the GEDT calculated at the
2
d
Without NaOAc.
TSs (see the section 2.2. Zn-catalyzed stepwise mechanism).
The electrophilicity and nucleophilicity indices of epoxide 3 are
ω = 0.78 eV and N = 2.28 eV, respectively. Allow its classification
Table 2
limonaketone synthesis with various Zn catalystsa.
¯
as a marginal electrophile and a moderate nucleophile within the
Catalyst
Conversion (%)
Yield (%)
electrophilicity [28] and nucleophilicity scales. On the other hand,
Zn
100
92
100
49
the ZnCl2 is a strong electrophile (ω = 2.33 eV) and a marginal
ZnCl2
ZnBr2
Zn(OTf)2
ZnO
¯
nucleophile (N = 0.46 eV).
97
59
+
Recently, Domingo et al. proposed the electrophilic P and nu-
96
34
k
−
44
15
cleophilic Pk Parr functions [29] as powerful tools in the study of
a
the local reactivity in polar processes. In order to predict the most
Reaction conditions: The epoxide 3 is added to the mixture of Catalyst (3
Eq.), NaI (10 eq.), NaOAc (3.24 mmol) and AcOH (0.7 mL) in CH2Cl2 and the
reaction is stirred for 3 h at RT.
favourable initial electrophile/nucleophile two-center interaction in
−
these deoxygenation reactions, the nucleophilic Pk Parr functions
of epoxide 3 was analysed. The maps of the atomic spin density
(
ASD) of the radical cation of epoxide 3 including the values of
moderate yields of limonaketone were obtained in the presence of
nucleophilic Parr functions, is given in Fig. 1.
2
ZnBr , ZnCl2 and Zn(OTf)2.
−
Analysis of the nucleophilic Pk Parr functions of epoxide 3 indi-
cates that the oxygen atoms O1 and O4 are the most nucleophilic
3. MEDT study
−
center of this specie, with a Pk value of 0.29 and 0.49, respectively.
Consequently, the most favourable initial nucleophile/electrophile
interaction along the deoxygenation reactions of epoxide 3 with
ZnCl2 will occur between the most nucleophilic center of epoxide
Recently, the molecular electron density theory (MEDT) was
proved to be a powerful tool for the theoretical understanding
the reactivity of organic reactions [25]. In order to highlight the
deoxygenation step leading to the preparation of limonaketone
3
, the O1 and O4 oxygen of epoxide 3 and carbonyl, respectively,
and the most electrophilic center of ZnCl2 complex, the Zn atom,
forming the complex 1 and complex 2. To explain the chemo selec-
tivity experimentally observed, the Gibbs free energy of two com-
plexes 1 and 2 were calculated (Scheme 6). The Gibbs free energy
calculation shows that complex 1 is more stable thermodynami-
cally than complex 2 by 2.23 kcal/mol, which is in good agreement
with the experimental outcomes. This is effectively a starting point
for the stepwise mechanism represented in Figs. 2 and 3.
(
Scheme 5), the catalyst ZnCl2 was chosen for the computational
study. This MEDT study represents a key tool to predict and un-
derstand the role, the effect and the mechanistic aspect of each
reagent or additive in the reaction pathway.
3
.1. Global and local electrophilicity/nucleophilicity index analysis
Numerous studies devoted to polar organic reactions have
proven that the analysis of the reactivity indices defined within
the conceptual DFT (CDFT) [26,27] is an effective tool to predict
and understand the reactivity of the reagents involved in polar re-
action. In order to predict the reactivity of epoxide 3 and ZnCl2 in
the corresponding deoxygenation reaction, the global CDFT indices,
namely, the electronic chemical potential, μ, chemical hardness, η,
electrophilicity, ω, and nucleophilicity, N at the ground state of the
reagents, were computed and analysed (Table 3).
The electronic chemical potential of ZnCl , μ= −6.21 eV is lower
2
than that of epoxide 3, μ= −3.84 eV. Consequently, it is expected
Table 3
Electronic chemical potential (μ, in ev), chemical hardness (η, in ev), global
electrophilicity (ω, in eV) and global nucleophilicity N of epoxide 3 and ZnCl2.
μ
H
ꢀ
N
Epoxide 3
ZnCl2
−3.84
−6.21
9.38
8.26
0.78
2.33
2.28
0.46
Scheme 6. Competitive reaction paths associated with the complexation reaction
of epoxide 3 with ZnCl2.
3

A.A. Mekkaoui, H. Ben El Ayouchia, H. Anane et al.
Journal of Molecular Structure 1235 (2021) 130221
4
3
0
0
2
8.69
5
.45
0
0
-
-
10
20
-
19.51
-
160
-
161.02
Reaction coordinate
Fig. 2. Gibbs free energy profile (in kcal/mol) of the most favorable reaction paths associated with the deoxygenation of complex 1 and NaI.
4
3
2
1
0
0
0
0
0
2
5.16
1
1.32
8
.66
0
-
10
-
140
-
141.49
Reaction coordinate
Fig. 3. Gibbs free energy profiles (in kcal/mol) of the reaction of iodohydrin with HI.
3
.2. Zn-catalyzed stepwise mechanism
of the O1-H single bond via TS2 is 28.69 kcal/mol, this value is
higher than TS1 by 23.24 kcal/mol. The formation of iodohydrin is
endothermic by 161.02 kcal/mol. The subsequent O1–H single bond
formation is considered as the rate-limiting step for deoxygenation
reaction of epoxide 3 catalyzed by zinc.
Analysis of the stationary points involved in the deoxygenation
reactions of the epoxide 3 with ZnCl2 indicates that these reactions
take place through stepwise mechanisms. The free energy profiles
of the reaction associated with the deoxygenation reactions of the
epoxide 3 with ZnCl2 are represented in Figs. 2 and 3.
The use of tamponic solution such as NaOAc/AcOH generates a
solution with pH = 4.64, which may lead to the formation of HI
from NaI, as shown in this equilibrium reaction:
The mechanism of deoxygenation reaction of epoxide 3, is ini-
tialized with a coordination of epoxide 3 by oxygen atom to ZnCl2
forming complex 1 as illustrated in Scheme 6. In the next step, a
nucleophilic attack of the lone pair on the iodine to the C2 site,
leading to the formation of an intermediate complex IC1. Hence,
cleavage of the C2–O1 bond can easily take place, with a free en-
ergy barrier of 5.45 kcal/mol and is thermodynamically exergonic
by 19.51 kcal/mol. After the formation of intermediate IC1, it would
be likely to undergo the protonation via proton-transfer from acetic
acid to the oxygen atom (O1) of IC1, leading to the release of
the iodohydrin product, in good agreement with the experimen-
NaI + AcOH ꢀ AcONa + HI
After its generation, the iodohydrin is protonated by hydro-
gen iodide, forming the intermediate reactional complex IC2. The
−1
calculated free energy barrier is 11.32 kcal mol . The last step
of this mechanism corresponds to an elimination of diiodide and
water molecule, leading to the release of limonaketone 4. The
formation of the intermediate complexes IC2 is endothermic by
8
.66 kcal/mol. From these intermediate, the value of the Gibbs
free energy barrier for this elimination is 25.16 kcal/mol. Fi-
nally, the formation of the limonaketone product is exothermic by
1
tal NMR H spectrum; meanwhile an active zinc species catalyst is
regenerated. The computed free energy barrier for the formation
141.490 kcal/mol.
4

A.A. Mekkaoui, H. Ben El Ayouchia, H. Anane et al.
Journal of Molecular Structure 1235 (2021) 130221
ane were purchased from commercial sources of chemical reagent
grade and used as received, unless otherwise indicated.
4
.2. Preparation of limonene oxide (2)
The limonene oxide (2) was obtained by an epoxidation reac-
tion of R-limonene (1) [22]. A certain amount of ruthenium com-
plex (S/C = 650, 0.012 mmol) in 5 ml of dichloromethane is in-
troduced into a 100 ml three-necked flask equipped with a ball
condenser surmounted by an oil bubbler. The mixture is stirred
at room temperature for 5 min under a stream of oxygen before
adding isobutyraldehyde (1.72 mg, 24 mmol). After 4 min of stir-
ring, limonene (7.8 mmol) is added, and the mixture is stirred for
1.5 h under a stream of oxygen. The obtained residue is filtered
through a column of basic alumina (5% Et O/hexane) affording the
2
limonene oxide (2) in a yield of 91%. The trans/cis ratio are deter-
mined by GC analysis.
4
.3. Ozonolysis of limonene oxide (2)
A solution of limonene oxide (2) (1 g, 6.58 mmol) mixture in
dry CH Cl2 (25 mL) was magnetically stirred at −78 °C and a
2
stream of ozone in oxygen was bubbled through it, and the course
of the reaction was monitored by TLC. When the starting material
was consumed (3 h), the solution was flushed out with an argon
stream for eliminating the ozone excess. Then triphenylphosphine
(
2 g, 7.63 mmol) was added at −78 °C. The solution was stirred
for 4 h, letting the temperature increase to room temperature.
Removal of the solvent under vacuum afforded a crude product
which was purified by column chromatography (5% Et O/hexane)
2
to afford the epoxide 3 (932 mg, 92%) as colourless oil. The mix-
ture was identified by NMR and GC–MS analysis (Supplementary
Material, Figures S1-S7) and was found to be the same as reported
by Delay et al. [23].
Fig. 4. Optimized geometries (in DCM) of the stationary points involved in the de-
oxygenation reactions of the epoxide 3 with ZnCl2. Distances are given in A˚ .
The polar nature of the deoxygenation reaction was analysed
evaluating the GEDT at the TSs. Along this reaction, the values of
the GEDT are 0.10, 0.09, 0.005 and 0.004 e at TS1, TS2, TS3 and
TS4, respectively. The calculated GEDT values indicate that TS1 and
TS2 have some polar character. While the GEDT at the TS3 and
TS4 is negligible, indicating the non-polar nature of the protona-
tion/elimination reaction of iodohydrin.
4
.4. Limonaketone (4) from (3)
The preparation of limonaketone (4) was performed by a mod-
ified procedure of Cornforth et al. [24]. A solution of epoxide
(0.1 g, 0.65 mmol), in CH Cl2 (2.5 mL) was added at 0 °C
3
2
over 5 min to a stirred mixture of a zinc precursor (0.127 g,
.95 mmol, 3 eq.), NaI (0.97 g, 6.49 mmol, 10 eq.), NaOAc (0.266 g,
.24 mmol,), and acetic acid (0.7 mL) in CH Cl . After being stirred
1
The geometries of the TSs and the intermediate involved in the
deoxygenation reactions of the epoxide 3 with ZnCl2 are given in
Fig. 4. At the complex 1 associated with the nucleophilic attack of
the epoxide 3 by oxygen atom O1 at the zinc atom of ZnCl2 com-
3
2
2
at room temperature for 3 h, the mixture was filtered and ex-
tracted with CH Cl . The separated organic layer was washed with
2
2
˚
water, saturated NaHCO3, and saturated NaCl. The organic layer
was dried over MgSO4, concentrated to give pure limonaketone (4)
(0.89 g) (Supplementary Material, Figures S8-S12).
plex, the length of the Zn–O1 forming bond is 2.02 A and the C2–
˚
O1 bond length is 1.502 A. At the first TS of this stepwise mech-
˚
anism, the lengths of the I–C2 forming bond is 3.06 A, while the
Limonaketone (4): [α]D25= + 120.7 (C = 2,3; CHCl3); 1H NMR
˚
Zn–O1 and C2–O1 bonds length becomes 1.936 and 2.387 A re-
(
300 MHz, CDCl ): δ 5.34 (m, 1H; =CH), δ = 2.48 (m, 1H; -CH),
spectively. The Zn–O1 and I–C2 bonds length at the corresponding
3
˚
δ = 2.15 (m, 2H; -CH2), δ = 2.12 (s, 3H; -CH2), δ = 1.96 (m, 2H;
intermediate complex (IC1) are 1.923 and 2.228 A respectively. At
13
-
CH ), δ = 1.85 (m, 2H), 1.60 (d, 3H; -CH ). C NMR (75 MHz,
the second TS associated with the protonation of IC1 by acetic acid,
2
3
˚
CDCl3): δ: 211.57, 133.70, 119.24, 47.16, 29.45, 27.83, 27.01, 24.87,
the lengths of the O1–H forming bond is 1.370 A. At the TS3 asso-
2
3.31. MS (EI): m/z = 138 [M]+
.
ciated with the protonation of iodohydrin by hydrogen iodide, the
˚
lengths of the O1–H forming bond is 1.504 A. Finally, at TS4 the
˚
4.5. Computational details
lengths of the I–I forming bond is 3.11 A.
The quantum chemical calculations reported in this paper were
performed using M06–2X functional with the 6–311G(d, p) basis
set for C, N, O, and H nuclei and the LANL2DZ type basis set
for Zn included in the GAUSSIAN 09 package [30]. The stationary
points were characterised by frequency calculations at the same
computational level in order to ensure all reactants, intermedi-
ates and products have no imaginary frequency and that TSs have
one imaginary frequency. In order to confirm that TS is correctly
connect to two associated minima, the intrinsic coordinate (IRC)
4
. Experimental section
4
.1. Materials
(
R)-(+)-limonene (97%), triphenylphosphine (Pφ ), zinc powder
3
(
Zn), sodium iodide (NaI), sodium acetate (NaOAc), magnesium sul-
fate (MgSO ), Sodium bicarbonate (NaHCO ), acetic acid (AcOH),
4
3
dichloromethane (CH Cl ), diethyl ether, ethyl acetate and hex-
2
2
5

A.A. Mekkaoui, H. Ben El Ayouchia, H. Anane et al.
Journal of Molecular Structure 1235 (2021) 130221
paths [31] were done in both forward and backward directions
employing the second-order González–Schlegel integration method
Supplementary materials
[
32,33]. Solvent effects of dichloromethane (DCM) were taken into
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130221.
account by using the polarisable continuum model (PCM) devel-
oped by Tomasi’s group [34,35]. Natural atomic charges were cal-
culated via natural population analysis (NPA) [36,37], to evaluate
the value of the global electron density transfer (GEDT) [38,39] as
measure of the polar character of the studied reaction.
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The global electrophilicity index [40], ω, is given by the fol-
2
lowing expression, ω=(μ /2η), in terms of the electronic chem-
[
[
ical potential, μ, and the chemical hardness, η. Both quanti-
ties may be approached in terms of the one-electron energies of
the frontier molecular orbitals HOMO and LUMO, εH and ε , as
L
μ≈(ε +ε )/2 and η=(ε −ε ), respectively [41,42]. The empirical
H
L
L
H
(
relative) nucleophilicity index N [43,44], based on the HOMO en-
ergies obtained within the Kohn–Sham scheme [45], is defined as
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Rachid Chahboun: Methodology, Conceptualization, Supervision.
Larbi El Firdoussi: Conceptualization, NMR study, Supervision.
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Declaration of Competing Interest
(2017) 208–215, doi:10.1016/j.phytochem.2017.09.017.
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The authors declare that they have no known competing finan-
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influence the work reported in this paper.
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