Synthesis of isobenzofuran derivatives from renewable 2-carene over halloysite nanotubes

Article abstract of DOI:10.1016/j.mcat.2020.110974

Condensation of a terpene 2-carene with 4-methoxybenzaldehyde over a range of acid aluminosilicates including halloysite nanotubes (HNT) was studied for as a model for preparation of isobenzofuran derivatives with a pharmaceutical potential. The catalysts were characterized by FTIR with pyridine, UV by adsorption of 2-phenylethylamine from the aqueous phase, SEM, TEM and N₂ physisorption. The largest selectivity to the desired product (ca. 70%) over halloysite nanotubes is associated with weak acidity of these catalysts (45 μmol/g), allowing avoiding side isomerization and condensation reactions. Moreover, the highest yield on air-dry HNT clearly indicates that weak Br?nsted sites favored the reaction. On the contrary, over strong Br?nsted and Lewis acids (Amberlyst-15, scandium triflate), the yield of isobenzofurans did not exceed 16% with formation of mainly 2-carene isomerization products. DFT calculations showed that interactions of the aldehyde with cyclopropane moiety of 2-carene giving isobenzofurans are more beneficial than an alternative direct attack of a proton, leading to side reactions. A possibility to reuse of HNT catalyst was confirmed. Overall, halloysite is a highly effective catalyst for production of isobenzofuran compounds based on 2-carene.

Full text of DOI:10.1016/j.mcat.2020.110974

MolecularCatalysis490(2020)110974
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Synthesis of isobenzofuran derivatives from renewable 2-carene over
halloysite nanotubes
A.Yu. Sidorenkoa,b,*, A.V. Kravtsovaa, P. Mäki-Arvelab, A. Ahob, T. Sandbergb, I.V. Il'inac,
N.S. Li-Zhulanovc,d, D.V. Korchaginac, K.P. Volchoc,d, N.F. Salakhutdinovc,d, D.Yu. Murzinb,**,
V.E. Agabekova
a Institute of Chemistry of New Materials of National Academy of Sciences of Belarus, 220141, Skaryna str, 36, Minsk, Belarus
b Åbo Akademi University, Biskopsgatan 8, 20500 Turku/Åbo, Finland
c Novosibirsk Institute of Organic Chemistry, Lavrentjev av. 9, 630090, Novosibirsk, Russian Federation
d Novosibirsk State University, Pirogova st. 1, 630090, Novosibirsk, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Keywords:
Terpene
Condensation of a terpene 2-carene with 4-methoxybenzaldehyde over a range of acid aluminosilicates including
halloysite nanotubes (HNT) was studied for as a model for preparation of isobenzofuran derivatives with a
pharmaceutical potential. The catalysts were characterized by FTIR with pyridine, UV by adsorption of 2-phe-
nylethylamine from the aqueous phase, SEM, TEM and N2 physisorption. The largest selectivity to the desired
product (ca. 70%) over halloysite nanotubes is associated with weak acidity of these catalysts (45 μmol/g),
allowing avoiding side isomerization and condensation reactions. Moreover, the highest yield on air-dry HNT
clearly indicates that weak Brønsted sites favored the reaction. On the contrary, over strong Brønsted and Lewis
acids (Amberlyst-15, scandium triflate), the yield of isobenzofurans did not exceed 16% with formation of
mainly 2-carene isomerization products. DFT calculations showed that interactions of the aldehyde with cy-
clopropane moiety of 2-carene giving isobenzofurans are more beneficial than an alternative direct attack of a
proton, leading to side reactions. A possibility to reuse of HNT catalyst was confirmed. Overall, halloysite is a
highly effective catalyst for production of isobenzofuran compounds based on 2-carene.
carenes
Isobenzofuran
halloysite
reaction mechanism
acidity
DFT
1. Introduction
by catalytic isomerization of 3-carene i.e. one of the major components
of turpentine [15–17].
It is well-known that compounds bearing a tetrahydrofuran moiety
exhibit diverse biological activity [1,2]. Thus, many derivatives of
isobenzofuran (IBF) have anticancer, antiviral, thrombolytic, anti-
depressant, and other effects, being active ingredients of several drugs
[3–9]. In addition, substances with an isobenzofuran structure can be
used as part of perfume compositions [10].
Condensation of 2-carene 1 with aldehydes 2 on K-10 clay leads to
formation of hexahydroisobenzofurans 3 (as two diastereomers) and
compounds with 3-oxabicyclo[3.3.1]nonane structure 4 (Fig. 1a).
However, the IBF yield was just below 33% at 75–78% 2-carene con-
version [14]. In addition, under acid catalysis conditions carenes can be
isomerized (Fig. 1b) with the formation of terpene hydrocarbons 5 with
a p-menthane structure [14–16].
The green chemistry principles involve production of chemicals
using renewable feedstock [11]. In the context of green chemistry,
synthesis of some IBF derivatives was carried out using terpenoids as
starting compounds [5,10,12–14]. For example, analogues of the nat-
ural compound Sclerophytin A with anticancer activity were obtained
from (+)-carvone [5]. Reaction of 4-hydroxymethyl-2-carene with
anisaldehyde led to formation of substituted isobenzofurans [12]. In
fact, 2-carene per se, which is present in small amounts in various es-
sential oils, can be used for synthesis of IBF, is itself it can be obtained
A study of the biological activity of isobenzofurans synthesized
based on 2-carene showed that the product of condensation with va-
nillin (yield of 33%) demonstrated a pronounced neuroprotective ac-
tivity in the Parkinson's disease model in vivo [18]. Considering the
pharmaceutical potential of IBF, development of effective catalytic
methods for their synthesis from renewable terpenoids is an important
task. Note that a method was recently proposed for isobenzofurans
preparation based on a mixture of vanillin and 2-carene, where the
⁎ Corresponding author at: Institute of Chemistry of New Materials of National Academy of Sciences of Belarus, 220141, Skaryna str, 36, Minsk, Belarus.
⁎⁎ Corresponding author at: Åbo Akademi University, Biskopsgatan 8, 20500, Turku/Åbo, Finland.
E-mail addresses: Sidorenko@ichnm.basnet.by (A.Y. Sidorenko), dmurzin@abo.fi (D.Y. Murzin).
https://doi.org/10.1016/j.mcat.2020.110974
Received 21 March 2020; Received in revised form 17 April 2020; Accepted 19 April 2020
2468-8231/©2020ElsevierB.V.Allrightsreserved.

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
at 105 °C to a constant weight, grinded to a fine powder and held for at
least 72 h to obtain an air-dry state of the catalyst. Illite was activated
similarly using 10% HCl. For all studies, a catalyst fraction of less than
100 μm was used.
Halloysite nanotubes modified by hydrochloric acid with different
concentrations were previously characterized by XRD, XRF, MAS NMR,
SEM, TEM, SAED, FTIR with pyridine and N2 physisorption methods
[27,28]. In the current work, the following methods were applied to
analyze the studied materials.
A JEOL JEM-2100 transmission electron microscope was used to
obtain images of halloysite. The samples were prepared by applying an
aqueous dispersion to a copper plate, followed by drying. Photographs
of scanning electron microscopy (SEM) were obtained on a Zeiss Leo
1530 microscope after preliminary ultrasonic treatment with HNT.
The porous structure of aluminosilicates was studied with N2 phy-
sisorption using ASAP 2020 M P (Micromeritics) analyzer. The samples
(ca. 50 mg) were evacuated (residual pressure 0.013 Pa) for 1 h at
200 °C. The specific surface area was calculated by the Brunauer-
Emmett-Teller method. The volume and average pore diameter were
determined by the desorption branch of the isotherm using the Barrett-
Joyner-Halenda method [29].
Fig. 1. Scheme of 2-carene condensation with aldehydes (a) and isomerization
(b) in the presence of acid catalysts.
The acidity of the studied solids was determined by FTIR spectro-
scopy using pyridine as a probe molecule [30]. The samples were
preliminarily calcined at 350 °C for 1 h, then cooled to 100 °C and
pyridine was saturated at this temperature for 30 min. Identification of
Brønsted and Lewis acid sites (a.s) was carried out by absorption bands
at 1545 cm-1 and 1450 cm-1 respectively [31]. The concentration of
weak, medium, and strong a.s. was determined by the peak areas at
150 °C, medium and strong at 250 °C, while strong sites correspond to
desorption at 350 °C [32].
latter was obtained by 3-carene isomerization [19]. However, con-
densation of 2-carene per se with aldehydes over various catalysts has
not been systematically studied.
Halloysite is a natural aluminosilicate (clay mineral), the elemen-
tary layer of which is a combination of tetrahedral Si–O and octahedral
Al–O sheets [20–21]. Morphologically, this mineral is a nanoscale
multilayer tubes (Fig. S1, Supplementary Information). Halloysite na-
notubes (HNT) can be used as containers for controlled release of var-
ious agents, as adsorbents for industrial pollutants, as a part of bio-
composites, etc. [21–23]. Much less common is application of HNT as
acid catalysts [24–26].
In addition, acidity HNT, K-10, K-30, and IL materials were de-
termined by adsorption of 2-phenylethylamine from aqueous solutions
[33]. For such measurements 3.0 ml of an amine aqueous solution
(0.03 M) was added to ca. 50 mg of the catalyst dried at 110 °C and
stirred at room temperature for 2 h. After the catalyst separation, the
amine content in the filtrate was analyzed by UV spectroscopy (Shi-
madzu UV-2550) at a wavelength of 252 nm. The concentration of a.s.
corresponded to the amount of adsorbed 2-phenylethylamine.
Recently, it was shown that acid-modified halloysite is an active,
selective, and stable catalyst for the synthesis of physiologically active
chromene compounds based on terpenoid (-)-isopulegol [27,28]. Ac-
cordingly, halloysite can have a significant potential as a catalyst for
preparation of isobenzofurans based on 2-carene.
In the present work, condensation of 2-carene 1 with anisaldehyde
(4-methoxybenzaldehyde) 2 was used as a model reaction for pre-
paration of isobenzofuran derivatives preparation. The choice of the
reactant 4-methoxybenzaldehyde was based on its higher reactivity
compared to vanillin whereas a parent aryladehyde (i.e. benzaldehyde)
does not react with 2-carene [14]. 2-Carene containing mixture ob-
tained by 3-carene isomerization was also tested as starting material.
2.2. Reaction and analysis of products
All reagents were purchased from Sigma-Aldrich and had a purity of
at least 97%. The reaction of 2-carene 1 with 4-methoxybenzaldehyde 2
was carried out according to the following procedure. Substrate 1
(0.1 g), an equivalent amount of aldehyde, 0.1 g of tridecane (99.9%,
internal standard) and dried cyclohexane as a solvent were added to a
three-necked round bottom flask. The total volume of the mixture was
5.0 ml. After heating to 50 °C, 1.0 g of catalyst was added to the flask
and stirred at this temperature using a mechanical stirrer (600 rpm). An
excess of the catalyst was needed to have feasible reactivity. Samples of
the reaction mixture periodically taken from the reactor after addition
of ethyl acetate, vigorous shaking, and catalyst separation were ana-
lyzed by GC. The reaction in the presence of scandium triflate (30 mol.
%) as a homogeneous catalyst was carried out at 40 °C using methylene
chloride (5 ml) as a solvent.
2. Experimental
2.1. Preparation and characterization of the catalysts
The starting material for the catalyst preparation was halloysite
from the Dragon Mine (USA). Commercial montmorillonite clays K-10,
K-30 (Germany), illite clay (Russia), as well as strong Brønsted
(Amberlyst-15) and Lewis (scandium triflate) acids were used for
comparison. All commercially available materials including halloysite
were purchased from Sigma-Aldrich. The reference illite sample was
kindly provided by the Belarusian Scientific Research Geological
Exploration Institute. Its physicochemical characteristics were carefully
studied in [27].
The composition of the reaction mixture was determined using a
Khromos GKh-1000 gas chromatograph with a flame ionization de-
tector, a Zebron ZB-5 capillary column (30 m x0.25 mm x0.25 μm), and
helium as a carrier gas. The evaporator and detector temperature was
250 °C and 280 °C respectively. The temperature increase was realized
from 50 to 280 °C at a ramping rate of 15 °C/min followed by an iso-
thermal mode at 280 °C. The total analysis time was 25 minutes. A ty-
pical chromatogram of the reaction mixture is shown in Fig. S2.
The reaction mixture was separated by preparative column chro-
matography. The structure of the reaction products was determined
using 1H and 13C NMR spectroscopy and a high resolution mass
The acid treatment of HNT was carried out using the following
procedure [27]. First 5-7 g of solid were added to a three-necked flask
(50 ml) equipped with a reflux condenser and a thermometer, and then
5% HCl solution was added at the rate of 5 ml of solution per 1 g of clay.
The mixture was heated to 90 °C and stirred (300 rpm) at this tem-
perature for 3 h. Thereafter, halloysite was washed by decantation until
there were no Cl- ions (control with AgNO3). The solid phase was dried
2

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
Fig. 2. Images of scanning (a) and transmission (b) electron microscopy of treated with 5% HCl halloysite nanotubes.
spectrometry. Detailed procedures for isolating and verification of the
compounds structure are presented in Supplementary Information.
catalysts applied in low-temperature reactions.
3.2. Catalytic activity of studied catalysts
3. Results and Discussion
3.2.1. Products selectivity and mechanistic discussion
3.1. Catalyst morphology and properties
In the presence of initial HNT, the condensation of 2-carene 1 with
4-methoxybenzaldehyde 2 practically did not proceed. Over acid-
treated halloysite, selectivity to isobenzofurans 3 (70.9%) was sig-
nificantly higher compared with montmorillonites K-10, K-30 and illite
IL (Table 1). The diastereomers ratio 3a/3b on HNT was lower than for
K-10 and K-30 catalysts. Formation of a small amount (0.8%) of com-
pounds with 3-oxabicyclo[3.3.1]nonane structure 4 was observed on
halloysite, whereas 2-carene isomerization products 5 were absent. The
largest initial 2-carene consumption rate (r0) was observed on K-10 and
K-30 (Table 1).
Images of scanning and transmission electron microscopy of the
acid-treated halloysite demonstrate characteristic multilayer nanoscale
tubes (Fig. 2). Destruction sites were observed at the ends of HNT
(Fig. 2b), which is associated with the rupture of Si –O– Al bonds be-
tween the tetra- and octahedral halloysite sheets as a result of acid
action and subsequent crosslinking of Si–OH fragments with the for-
mation of amorphous SiO2 [27,34]. Note that modification of HNT with
5% HCl led to a slight decrease in the Al2O3 content while their specific
surface area increased from 60 to 130 m2/g (Table S1). All the studied
aluminosilicates are mesoporous (Table S1). Adsorption-desorption
isotherms were shown in the previous work of the authors [27].
According to FTIR spectroscopy with pyridine, concentration of a.s.
in halloysite nanotubes increased from 34 to 45 μmol/g after their
treatment with 5% HCl. At the same time, weak acid sites prevail in
HNT (Table S2). Montmorillonites K-10 and K-30, as well as acid-acti-
vated illite IL were more acidic. It is important to note that acidity
according to FTIR correlates well with the values obtained by the ad-
sorption of 2-phenylethylamine from an aqueous solution (Fig. 3).
Although the concentration of a.s. measured using pyridine was
significantly lower probably due to the catalyst pretreatment at 350 °C,
a linear correlation between the values obtained by different methods
clearly demonstrates relevance of using FTIR for characterization of
On the other hand, over strong Brønsted (Amberlyst-15) and Lewis
(scandium triflate) acids 2-carene predominantly isomerized into ter-
pene hydrocarbons 5 (menthadienes, cymenes, menthenes), giving ac-
cordingly very low selectivity to IBF 3 (Table 1).
Selectivity to isobenzofuran 3 in the presence of halloysite decreases
with increasing 2-carene conversion (Fig. 4a,b). In this case, an increase
in the ratio 3a/3b was observed (Fig. 4c). These dependences may in-
dicate further transformations of isobenzofurans under reaction con-
ditions. Indeed, storage of a diastereomers 3a,b mixture on K-10 clay
led to a decrease in their amount, moreover the GC peak intensity of the
isomer 3b decreased to a larger extent (Fig. S3).
Based on the dependences of selectivity to isobenzofurans 3 on 2-
carene conversion (Fig. 4), as well as the results of their storage on K-10
(Fig. S3), it can be concluded that compounds 3 in the reaction con-
ditions undergo secondary transformations (apparently polymeriza-
tion), the isomer 3b being less stable. The largest concentration of
isobenzofurans 3 in the reaction mixture was observed at 60% 2-carene
Table 1
Selectivitya in 2-carene condensation with anisaldehyde over studied catalysts.
c
Catalystb
ro
,
Reaction
Selectivity, mol. %
μmol/
time, h
(g·min)
3
3a 3b
3a/3b
4
5
HNT
IL
8.6
2
4
3
3
2
3
70.9 49.7 21.2 2.3
50.3 32.8 17.5 1.9
51.4 40.7 10.7 3.8
0.8
1.9
2.7
2.2
0
4.2
1.3
3.8
5.1
K-30
K-10
14.3
14.4
52.3 43.8 8.5
5.2
4.0
3.0
Amberlyst-15 7.6
3.0
2.4
0.6
12.9 52.3
Scandium
-
16.3 12.2 4.1
6.4
77.0
triflated
a
b
c
At 60% 2-carene conversion.
Air-dry state.
Fig. 3. Dependence of acidity measured by FTIR with pyridine adsorption and
2-phenyl 2-phenylethylamine adsorption from the liquid phase.
Initial rate of 2-carene consumption.
At 20% conversion.
(●–Initial and ○ – acid-modified halloysite; X – IL; Δ – К-10; ◊ – К-30)
d
3

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
Fig. 4. Selectivity to isobenzofuran isomers (a), their sum (b) and 3a/3b ratio (c) as a function of 2-carene conversion over halloysite.
conversion (Fig. S4). Note that although the initial rate of 2-carene
consumption on K-10 is much higher than for HNT, 60% conversion
was observed only after 3 h (Table 1). The form of concentration de-
pendencies clearly indicates K-10 catalyst deactivation (Fig. S5),
probably due to formation of polymerization products.
strong Brønsted acidity caused ß-pinene isomerization [35]. Moreover,
heteropolyacids (HPW/SiO2) catalyzed the β-pinene condensation with
aldehydes to oxabicyclo[3.3.1]nonane compounds [36].
Thus, on aluminosilicates with a relatively low acidity, condensa-
tion of 2-carene 1 with 4-methoxybenzaldehyde 2 occurs with the in-
volvement of the cyclopropane ring, leading to formation of iso-
benzofuran 3 as two diastereomers depending on the chiral carbon
atom configuration in the intermediates (Fig. 6). In the presence of
strong Brønsted (Amberlyst-15) and Lewis (scandium triflate) acids, the
cyclopropane moiety in 2-carene is opened with formation of an in-
termediate 1’ with a p-menthane structure, which in a subsequent re-
action with the aldehyde gives 3-oxabicyclo[3.3.1]nonane compound 4
(Fig. 6). However, considering that terpene hydrocarbons 5 are the
main products on Amberlyst-15 and scandium triflate (Table 1), it can
be assumed that, in the presence of strong acids, ion 1’ is predominantly
deprotonated to form isomerization products.
When the reaction mixture obtained on HNT after complete con-
version of 2-carene was separated, isobenzofurans 3 (34%) and two
products with 3-oxabicyclo[3.3.1]nonane structure 4 (2 %) were iso-
lated, one of which had a diene moiety (Supplementary Information).
To understand the reasons of different selectivity over studied ma-
terials, an analysis of the isobenzofurans yield dependence on catalysts
acidity was carried out.
Selectivity towards isobenzofurans 3 decreases from 70.9 to 50.2%
with a increase in the a.s. concentration in the catalyst from 45 to
63 μmol/g and remains almost unchanged with a further increase in
acidity (Fig. 5a). At the same time the isomers 3a/3b ratio increases
(Fig. 5b). This dependence can be explained by a lower stability of
compound 3b under the reaction conditions compared with 3a. Thus,
3b over more acidic catalysts K-10 and K-30 undergoes secondary
transformations. It is also important to note that with an increase in the
ratio of weak (W) to the sum of medium (M) and strong (S) acid sites, a
significant increase in IBF selectivity was observed (Fig. 5c).
Based on the discussion above, the highest selectivity to iso-
benzofurans 3 in the presence of halloysite is due to low acidity of this
catalyst. Moreover, a decrease in IBF selectivity with an increase in the
a.s. concentration is due to secondary transformations (polymerization)
of the compound 3 under the reaction conditions, especially 3b. It is
important to note that the isomerization by-products 5 and compounds
with 3-oxabicyclo[3.3.1]nonane structure 4 on all studied aluminosi-
licate catalysts (halloysite, illite, montmorillonites) are formed in very
small quantities (Table 1).
3.2.2. Influence of halloysite thermal pretreatment
Taking into account that selectivity of the reactions of terpenoids
can strongly depend on the catalyst thermal treatment conditions
[27,32], the reaction of 2-carene with anisaldehyde was studied in the
presence of acid-modified halloysite, dried at temperatures from 50 to
105 °C for 2 h immediately before the reaction.
After HNT thermal pretreatment at 50 °C, selectivity to iso-
benzofurans 3 (73.7%) was slightly higher compared with an air-dry
one (70.9%), however, the initial rate of 2-carene consumption in-
creased (Table 2). A further increase in the catalyst drying temperature
led to a sharp decrease in IBF yield, whereas compounds with 3-ox-
abicyclo[3.3.1]nonane structure
4 and products of 2-carene iso-
merization 5 were dominant in the reaction mixture (Table 2).
Note that the time to reach 60% conversion on halloysite nanotubes
dried at 60 – 105 °C was longer than for air-dried HNT (Table 2). This
can be explained by a partial deactivation of the catalyst, which is in-
dicated by the characteristic kinetic curves (Fig. S6), as well as a change
Similar results were observed in the case of terpene β-pinene con-
densation with paraformaldehyde to nopol, where selective formation
of this product occurred on weak Lewis and Brønsted a.s, while the
Fig. 5. Selectivity to isobenzofuran (a)
and 3a/3b ratio (b) as a function of
catalyst acidity as well as a ratio of
weak to sum of medium and strong a.s.
(c) at 60% 2-carene conversion.
(○ – Acid-modified halloysite; X – IL; Δ
– K-10; ◊ – K-30).
4

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
Fig. 6. The mechanism of 2-carene condensation with aldehydes.
consistent with data on the effect of catalyst acidity on the yield of these
compounds (Fig. 5). An increase in the strength of a.s. due to dehy-
dration of halloysite (drying at 60–105 °C) leads to occurrence of the
side reactions of 2-carene isomerization as well as formation of com-
pounds with 3-oxabicyclo[3.3.1]nonane structure (Table 2).
Table 2
Selectivity of 2-carenea reaction with anisaldehyde depending on the HNT
drying temperature.
Temperature of ro,
Reaction
Selectivity, mol. %
HNT drying,°C
μmol/
time, h
(g·min)
3
3a 3b
3a/3b
4
5
Air-dry
50
8.6
26.1
7.2
7.9
8.4
2
70.9 49.7 21.2 2.3
73.7 54.4 19.3 2.8
0.8
0.9
-
3.2.3. DFT calculations
0.5
4
2.5
To further evaluate the proposed mechanism for 2-carene con-
densation with 4-methoxybenzaldehyde (Fig. 6), DFT calculations
performed with the Jaguar 9.9 program [38] using dispersion-corrected
hybrid density functional technique B3LYP-D3 implanted with a 6-
31G** basis set for structural geometry optimization.
60
13.3 10.0 3.2
3.1
2.7
6.8
23.2 23.7
36.9 22.3
27.2 33.3
70
4
11.6 8.5
7.3 6.4
3.2
0.9
105
5
a
At 60% conversion.
The calculated energies for intermediates 3a’and 3b’ generated
during interactions of the aldehyde with the cyclopropane ring of 2-
carene were significantly lower than in the alternative path, where 2-
carene was converted into p-menthenyl cation 1’ (Fig. 7). The energy
for the intermediate 3a’ was 6.0 kJ/mol lower than for 3b’, and the
resulting diastereomer 3a was 6.8 kJ/mol more stable compared to 3b.
Note that the DFT optimization of the intermediates 3a’,b’ structure
showed that their isopropyl fragment with a charge on carbon is not
planar (Fig. 7), which obviously facilitates further cyclization into
isobenzofurans 3a,b. The optimized structures of substrate 1, as well as
the reaction products 3a,b and 4 are shown in Fig. S8
in the color of the reaction mixture (Fig. S7) due to formation of sec-
ondary products.
A sharp decrease in the isobenzofurans yield with an increase in the
halloysite drying temperature can be explained by a change in the
nature and strength of active sites on the catalyst surface. Thus, acidity
of layered silicates (including halloysite) is associated with exchange
and coordinatively unsaturated metal ions, hydroxyl groups, water
molecules bound to cations [37]. Water molecules due to interactions
with the metal cations (Lewis a.s.) are polarized and act as Brønsted
z
acids according to the scheme [L(H2O)x]z+=[L(OH)(H2O)x-1
]
+-1+H+. It is known that with increasing hydration of the aluminosi-
licate surface, the strength of such acid sites is decreasing [37].
Drying of halloysite led to its dehydration (Table S3) and a sharp
decrease in the yield of isobenzofurans 3, i.e. these compounds are
selectively formed when weak Brønsted acidity prevails. This is
Thus, DFT calculations show that formation of isobenzofurans with
the participation of the cyclopropane fragment of 2-carene is thermo-
dynamically more favorable than formation of p-menthenyl ion leading
to the 3-oxabicyclo[3.3.1]nonane compound. The predominant pro-
duction of diastereomer 3a is energetically more favorable compared
5

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
Fig. 7. DFT calculated energy diagram and the optimized structure of the intermediates.
with 3b. The calculation results are completely consistent with the
experimental results of the reaction in the presence of halloysite with
weak acidity. Apparently, a somewhat higher energy of the isomer 3b
compared with 3a is the reason for its instability under the reaction
conditions. It is also obvious that a direct proton attack on 2-carene
with subsequent p-menthenyl ion formation requires strong acids,
which is observed on Amberlyst-15 and scandium triflate (Table 1).
Table 3
Selectivity to isobenzofuransa on halloysite depending on the starting reagents
Reagents
ro,
Reaction
Selectivity, mol. %
μmol/
(g·min)
time, h
3
3a 3b
3a/3b
2-carene containing
mixtureb
2.1
7.0
71.4 37.0 34.7 1.1
2-carene b and 3-carene 7.8
1.5
1.5
71.5 44.9 26.6 1.7
74.7 51.3 23.4 2.2
b
2-carene per se
3-carene per se
8.6
3.2.4. Using of 2-carene containing mixture for isobenzofuran synthesis
Considering that 2-carene is an expensive compound, a possibility of
halloysite utilization as a catalyst for isobenzofurans preparation was
studied using a 2-carene containing mixture of terpene hydrocarbons
obtained by isomerization of readily available 3-carene on montmor-
illonite K-30 at 140 °C [19]. The reaction products were 2-сarene
(13.2%), mentadienes (21.4%), menthenes (3.0) and cymenes (3.8).
The chromatogram of the resulting mixture are shown in Fig. S9. Note
that 3-carene isomerization catalyzed by clays was studied in detail in
[15,16].
No reaction
a
b
At 50% conversion.
2-Carene content was 0.1 g.
further 3b transformations.
3.2.5. Catalyst recycling
In order to study the possibility of halloysite reusing, the catalyst
was separated from the reaction mixture, washed with ethyl acetate
(3 × 7 ml ×5 min), distilled water, dried for 2 h at 105 °C, and kept in
air for at least 24 h before reuse. Immediately before the reaction,
halloysite was dried for 2 h at 50 °C. The activity and selectivity of HNT
after the second reaction cycle remained almost unchanged (Table 4).
It should be noted that after reuse of the catalyst, a slight decrease in
When using 0.76 g of the mixture of terpene hydrocarbons con-
taining 0.1 g of 2-carene in condensation with 0.1 g of anisaldehyde
over 1.0 g of air-dried halloysite, selectivity to isobenzofurans was ca.
71%, which is similar to that in the case of individual 2-carene
(Table 3). The chromatogram of the reaction products with 2-carene
containing mixture as a reagent is shown in Fig. S10. For a specifically
prepared mixture of 2-carene and 3-carene (0.1 g + 0.15 g), the yield of
isobenzofurans remained almost unchanged (Table 3). 3-Carene per se
over halloysite did not undergo any transformation.
Table 4
Selectivity of 2-carenea reaction with anialdehyde depending on the reaction
cycle
Note that in the case of an individual 2-carene compound 3a was
predominantly formed, whereas in the case of a 2-carene containing
mixture, the amount of isomers 3a and 3b formed was almost the same
(1.1:1). Simultaneously the initial reaction rate was significantly lower
(Table 3). It is possible that the products of 3-carene isomerization
present in the starting mixture (menthadienes, menthenes, cymenes)
can act as condensation inhibitors due to interactions with active sites
on the halloysite surface, also affecting the 3a/3b value by preventing
Halloysiteb utilization
Reaction time,
Selectivity, mol. %
cycle
h
3
3a 3b
3a/3b
4
5
1
2
0.5
0.5
75.6 56.4 19.2 2.9
73.4 51.2 22.2 2.3
0.8 2.6
0.9 2.5
a
b
At 60% conversion.
Dried at 50 °C before the reaction.
6

A.Y. Sidorenko, et al.
MolecularCatalysis490(2020)110974
Table 5
isobenzofuran compounds with a pharmaceutical potential based on
terpne 2-carene. Further research should be directed to the catalytic
synthesis of other isobenzofuran derivatives and elucidation their
physiological activity.
Physico-chemical properties of halloysite nanotubes after utilization in the re-
action
Halloysite
Porous structure
Acid site concentration,
μmol/g
SBET,
Vpore
,
Dpore
,
CRediT authorship contribution statement
m2/g
cm3/g
nm
A.Yu. Sidorenko: Conceptualization, Investigation, Writing - ori-
ginal draft. A.V. Kravtsova: Investigation, Methodology. P. Mäki-
Arvela: Methodology, Investigation. A. Aho: Investigation. T.
Sandberg: Formal analysis. I.V. Il'ina: Investigation. N.S. Li-
Zhulanov: Formal analysis. D.V. Korchagina: Investigation. K.P.
Volcho: Writing - review & editing. N.F. Salakhutdinov: Writing -
Fresh
129
114
0.34
0.36
11.3
13.9
45.0
43.0
After reaction cycle
review
& editing. D.Yu. Murzin: Writing - review & editing,
Supervising. V.E. Agabekov: Writing - review & editing, Project ad-
ministration.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
This work was funded by the BRFFR (grant Kh18MS-029) and RFBR
(grant 19-53-04005). The research visit of A.S. to ÅAU to study physico-
chemical properties of the catalysts was financially supported by
Research Mobility Program of Åbo Akademi University. The authors are
grateful to Dr. T.F. Kuznetsova (IGICh of NAS of Belarus) for performing
N2 physisorption and to Dr. H. Pazniak for recording TEM images.
Fig. 8. SEM image of halloysite nanotubes after utilization in the reaction.
the specific surface area was observed, while the concentration of acid
sites remained practically unchanged (Table 5). According to scanning
electron microscopy, the morphology of halloysite particles after the
reaction did not change either (Fig. 8).
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2020.110974.
4. Conclusions
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