Synthesis, spectroscopic characterization and structural study of 2-isopropenyl-3-methylphenol, carquejiphenol, a carquejol derivative with potential medicinal use

Article abstract of DOI:10.1016/j.molstruc.2018.04.001

In this work, 2-isopropenyl-3-methylphenol, hereafter referred to as carquejiphenol (CARP), a minor component of “carqueja” essential oil, was synthesized starting from carquejol and characterized by using Fourier Transform infrared (FT-IR) and Raman (FT-Raman) spectroscopies, Ultraviolet–Visible (UV–Visible) spectroscopy, Electron Impact Mass spectrometry (EI-MS), Hydrogen and Carbon Nuclear Magnetic Resonance (¹H- and ¹³C-NMR) and 2D ¹H–¹H gCOSY, ¹H–¹³C gHSQC, ¹H–¹³C gHMBC experiments. A very good correlation between the predicted FTIR, FTRaman, UV–visible and ¹H–¹³C-NMR spectra for monomer and dimer of CARP by using theoretical B3LYP/6-31G* and 6-311++G** calculations with the corresponding experimental ones was observed. The solvation energies for CARP were predicted by using both levels of calculations and considering the solvent effects with the polarised continuum and solvation models. The increase in volume in solution supports the H bonds formation due to the presence in its structure of an OH group, as revealed by atoms in molecules (AIM) analysis. A high stability for CARP was found by using natural bond orbital (NBO) and AIM studies, while the investigation of the frontier orbitals reveals that CARP is more reactive than carquejol and N-(3,4-dimethoxybenzyl)-hexadecanamide but less reactive than the sesquiterpene lactone cnicin. The proximity of both the electrophilicy and nucleophilicity index of CARP with those obtained respectively for carquejol and for N-(3,4-dimethoxybenzyl)-hexadecanamide, suggests that CARP could probably present pharmacological properties. The scaled quantum mechanical force field (SQMFF) methodology was used to compute the harmonic force fields and to perform the complete vibrational analysis. In this way, 63 normal modes of vibration were assigned and compared with other terpene substances.

Full text of DOI:10.1016/j.molstruc.2018.04.001

Accepted Manuscript
Synthesis, spectroscopic characterization and structural study of 2-isopropenyl-3-
methylphenol, carquejiphenol, a carquejol derivative with potential medicinal use
Manuel Minteguiaga, Eduardo Dellacassa, Maximiliano A. Iramain, Cesar A.N.
Catalán, Silvia A. Brandán
PII:
S0022-2860(18)30432-0
10.1016/j.molstruc.2018.04.001
MOLSTR 25074
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 30 October 2017
Revised Date: 29 March 2018
Accepted Date: 2 April 2018
Please cite this article as: M. Minteguiaga, E. Dellacassa, M.A. Iramain, C.A.N. Catalán, S.A. Brandán,
Synthesis, spectroscopic characterization and structural study of 2-isopropenyl-3-methylphenol,
carquejiphenol, a carquejol derivative with potential medicinal use, Journal of Molecular Structure
(2018), doi: 10.1016/j.molstruc.2018.04.001.
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ACCEPTED MANUSCRIPT
Synthesis, spectroscopic characterization and structural study of 2-
isopropenyl-3-methylphenol, carquejiphenol, a carquejol derivative
with potential medicinal use
a,b
b
c
Manuel Minteguiaga, Eduardo Dellacassa, Maximiliano A. Iramain, César A. N.
a
c,*
Catalán , Silvia A. Brandán
a
INQUINOA-CONICET, Instituto de Química Orgánica, Facultad de Bioquímica,
Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, T4000INI San
Miguel de Tucumán, Argentina.
b
Laboratorio de Biotecnología de Aromas. Departamento de Química Orgánica.
Facultad de Química, Universidad de la República. General Flores 2124, Montevideo,
1
1800, Uruguay.
c
Cátedra de Química General. Instituto de Química Inorgánica. Facultad de
Bioquímica, Química y Farmacia. Universidad Nacional de Tucumán. Ayacucho 471.
4
000. San Miguel de Tucumán. Tucumán. R. Argentina.
Abstract
In this work, 2-isopropenyl-3-methylphenol, hereafter referred to as carquejiphenol
(
CARP), a minor component of “carqueja” essential oil, was synthesized starting from
carquejol and characterized by using Fourier Transform infrared (FT-IR) and Raman
FT-Raman) spectroscopies, Ultraviolet-Visible (UV-Visible) spectroscopy, Electron
Impact Mass spectrometry (EI-MS), Hydrogen and Carbon Nuclear Magnetic
(
1
13
1
1
1
13
1
13
Resonance ( H- and C-NMR) and 2D H- H gCOSY, H- C gHSQC, H- C gHMBC
experiments. A very good correlation between the predicted FTIR, FTRaman, UV-
1
13
visible and H- C-NMR spectra for monomer and dimer of CARP by using theoretical
B3LYP/6-31G* and 6-311++G** calculations with the corresponding experimental
ones was observed. The solvation energies for CARP were predicted by using both
levels of calculations and considering the solvent effects with the polarised continuum
and solvation models. The increase in volume in solution supports the H bonds
formation due to the presence in its structure of an OH group, as revealed by atoms in
molecules (AIM) analysis. A high stability for CARP was found by using natural bond
orbital (NBO) and AIM studies, while the investigation of the frontier orbitals reveals
that CARP is more reactive than carquejol and N-(3,4-dimethoxybenzyl)-
hexadecanamide but less reactive than the sesquiterpene lactone cnicin. The proximity
of both the electrophilicy and nucleophilicity index of CARP with those obtained
respectively for carquejol and for N-(3,4-dimethoxybenzyl)-hexadecanamide, suggests
that CARP could probably present pharmacological properties. The scaled quantum
mechanical force field (SQMFF) methodology was used to compute the harmonic force
fields and to perform the complete vibrational analysis. In this way, 63 normal modes of
vibration were assigned and compared with other terpene substances.
Keywords: Carquejiphenol, vibrational spectra, molecular structure, force field, DFT
calculations.
*
Corresponding author. Tel.: +54-381-4247752; fax: +54-381-4248169;
E- mail: sbrandan@fbqf.unt.edu.ar (S.A. Brandán)

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1
. Introduction
In the present work we have synthesized 2-isopropenyl-3-methylphenol, one of the
products formed by air oxidation of carquejol [1] that, by simplicity, we have called
carquejiphenol (CARP). Carquejol, carquejyl acetate and eventually carquejiphenol are
distinctive components of the essential oil of Baccharis trimera (Less.) DC (syn. B.
genistelloides Pers. and B. triptera Mart.; vernacular name “carqueja”) (Asteraceae), a
medicinal and aromatic plant native to the Southern Cone of South America [1,2]. In
particular, these derivatives are interesting from the pharmacological and medicinal
point of view because they have curative properties [2-12] such as anti-inflammatory,
analgesic, antifungal, antiviral, antimicrobial [2-6] and cytotoxic [7,10]. Recently, we
have isolated carquejol from Baccharis trimera which was characterized by FT-IR, FT-
1
13
Raman, UV-Visible, electronic circular dichroism (ECD), Mass, H- and C-NMR and
1
1
1
13
1
13
2
D H- H gCOSY, H- C gHSQC, H- C gHMBC spectroscopies [13]. Its structural,
electronic, topological and vibrational properties were also studied combining the
experimental data with density functional theory (DFT) calculations [14,15]. Because
carquejol is a monoterpene alcohol with two chiral centres, its four possible
stereostructures were considered but vibrational circular dichroism (VCD) studies [16]
showed that the natural alcohol is constituted only by the (4S,5R) stereoisomer. The
absolute configuration (4S,5R) was theoretically confirmed by the experimental ECD
spectrum [13] whilst chiral analysis using a chiral selector capillary column CycloSil B
(Agilent Technologies) confirmed that both carquejol and carquejyl acetate from B.
trimera were enantiomerically pure [13]. The biological properties observed for
carquejol could be attributed to the proximity of its nucleophilic index with those
reported for other bioactive terpenes [17-22]. The predicted geometrical parameters,
harmonic force fields and the complete vibrational assignments for the most stable
conformations of carquejol were also reported [13]. On the other hand, molecular
electrostatic potential (MEP) surfaces revealed that the nucleophilic and electrophilic
sites of higher reactivity are principally centred on the OH group. At present, there is
almost no data on CARP in the literature so it is interesting to study its structure and
properties to compare them with those obtained for carquejol. At this point, we also
expected that the presence of the CH , H C=C-CH and OH groups on the benzene ring
3
2
3
of CARP could give interesting results considering that, structurally, carquejol has
similar groups. A remarkable difference between both compounds is that CARP do not
present chiral C atoms and, for this reason, it is interesting to know all its conformers

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and properties. With this perspective, the purposes of this work are first, to synthesize
1
CARP and later to characterize it by using FT-IR, FT-Raman, UV-Visible, EI-MS, H-
1
3
1
1
1
13
1
13
and C-NMR and 2D H- H gCOSY, H- C gHSQC, H- C gHMBC spectroscopies.
At the same time, we aimed to combine these experimental data with those from
theoretical DFT calculations using the hybrid B3LYP method together with the 6-31G*
and 6-311++G** basis sets [23,24], and so to study the structural, electronic,
topological and vibrational properties. Additionally, in order to identify CARP by using
vibrational spectroscopy, it is very useful the determination of the harmonic force fields
through the normal internal coordinates and the Scaled Quantum Mechanical Force
Field (SQMFF) methodology [25] by using those two levels of theory. A dimeric
species is also proposed for CARP, in agreement with other structures that contain a
phenol group, because this group is considered a strong hydrogen-bond acceptor and
donor [26]. Hence, experimental bands not justified by the monomeric species were
attributed to that dimeric structure. A complete assignments of all bands observed in the
vibrational spectra of CARP is presented. Finally, the frontier orbitals and a series of
descriptors were also calculated in order to predict reactivity and behaviour by using
both levels of theory [27-29]. These results were compared with those obtained for
carquejol [13] and those calculated for other terpenic substances [27-29]. Some
Lipisnki's and Veber's criteria were also applied for carquejiphenol in order to evaluate
its pharmacological properties [30,31].
2
. Experimental
Scheme for the synthesis of carquejiphenol (2-isopropenyl-3-methylphenol) from
carquejol:
Squeme 1. Synthesis of carquejiphenol

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2
.1. Obtention of carquejol
Carquejol was obtained from the essential oil of Baccharis trimera (Less.) DC as
described in [13]. This oil was composed of 71.4% carquejyl acetate, 0.5% carquejol
and 0.1% CARP according to the analysis by gas chromatography-mass spectrometry
(GC-MS). Chiral analysis using the GC-MS equippment with a chiral selector capillary
column CycloSil B, showed that both carquejol and carquejyl acetate from B. trimera
were enantiomerically pure [13].
2
.2. Oxidation of carquejol to carquejone with chromic acid in acetone.
The oxidant reagent was prepared by dissolving 0.67 g of chromium trioxide (CrO ) in
3
0
.60 mL of concentrated sulfuric acid and then diluted up to 5.0 mL with distilled water.
The oxidant reagent (2.0 mL) was then added dropwise (5 min) to carquejol (0.601 mg;
mmol) dissolved in freshly distilled acetone (8.0 mL) at 0º C under continuous
4
magnetic stirring. The progress of the reaction was monitored by thin layer
chromatography (TLC) [13]. If necessary, additional 0.10 mL increments of oxidant
reagent were added till complete disappearance of carquejol spot on TLC. The oxidant
excess was destroyed by adding a few drops of methanol and the organic layer was
decanted, diluted with hexane (10 mL), washed with brine (2 x 2 mL), dried (anhydrous
Na SO ) and the solvent evaporated to give 0.481 g of a yellowish oil (81% yield). The
2
4
oil analyzed by GC-MS was composed of carquejone (93.6 %), CARP (6.2 %) and
carquejol (0.2%). The oxidation step should be performed as quickly as possible to
shorten the time that carquejona was in acidic conditions which catalyzes its
isomerization to CARP. UV (ethanol) λmax (log ε) 220 nm (4.00). EI-MS (70 eV); m/z
+
(
(
(
%) [M] 148 (11), 133 (40), 120 (20), 105 (100), 92 (28), 91 (45), 79 (71), 77 (39), 68
1
21), 65 (13), 53 (10), 51 (15), 41 (9), 40 (9). H-NMR (200 MHz, CDCl ) δ 6.97 ddd
3
1H; 10, 4.8, 3; H-5); δ 6.11 ddd br (1H; 10, 3, 1.7; H-4); δ 5.00 br s (1H; H-7a); δ 4.96
m (fine splitting) (2H; H-7b + H-9a); δ 4.73 m (fine splitting) (1H; H-9b); δ 3.64 br s
1H; H-2); δ 3.18 dquint (1H; 20.4, ca. 2.5; H-6a); δ 3.00 dddd (1H; 20.4, 4.8, 1.7, 0.8;
(
1
3
H-6b); δ 1.76 br s (3H; fine splitting, 0.7 Hz; H-10) (see Figure S11a); C-NMR (50
MHz, CDCl ) δ 199.0 (C-3), 148.0 (C-5), 141.6 (C-1), 141.1 (C-8), 129.0 (C-4), 113.9
3
(C-7), 112.8 (C-9), 63.3 (C-2), 32.3 (C-6), 21.5 (C-10) (see Figure S11b).
Carquejone is unstable and readily isomerizes to 3-methyl-2-isopropenylphenol by both
alkalis and acids.

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2
.3. Alkaline isomerization of carquejone to carquejiphenol (3-methyl-2-
isopropenylphenol)
A 5% aqueous solution of sodium hydroxide (2 mL) was added dropwise to 297 mg
(2.0 mmol) of carquejone with magnetic stirring at room temperature. After 10 minutes,
the mixture was acidified with 5% HCl and extracted with methylene chloride (3 x 5
mL). The organic extracts were reunited, dried (anhydrous Na SO ), filtered and
2
4
evaporated to give 251 mg of an oily residue which was column chromatographed (Si
gel 230-400 mesh) using a mixture of hexane-methylene chloride as eluting solvent
yielding 155 mg (52% yield) of CARP. Needles, mp 41-43º C (99.7% pure by GC-MS).
+
UV (hexane) λmax (log ε) 210 nm (3.04), 279 nm (1.30). EI-MS (70 eV); m/z (%) [M]
1
48 (75), 133 (61), 115 (19), 105 (100), 103 (17), 91 (20), 79 (14), 77 (27), 65 (7.5), 63
1
(
9.5), 51 (10), 41 (2) (see Figure 1). H-NMR (200 MHz, CDCl ) δ 7.07 dd (1H; 8 and
3
7
.5 Hz; H-7), 6.78 br d (1H; 8 Hz; H-21), 6.76 br d (1H; 7.5 Hz; H-8), 5.52 dq (1H; 2
and 1.5 Hz; H-11), 5.38 br s (1H; disappears by exchange with D O; H-23), 5.06 dq (2
2
and 1 Hz; H-12), 2.25 br s (3H; H-18, H-19 and H-20); 2.03 dd (3H; 1.5 and 1 Hz; H-
1
3
1
4, H-15 and H-16) (see Figure S10a); C-NMR (50 MHz, CDCl ) δ 151.5 (C-6), 141.5
3
(
C-9), 135.8 (C-4), 129.4 (C-5), 127.8 (C-2), 121.8 (C-3), 118.2 (C-10), 112.3 (C-1),
3.4 (C-13), 19.3 (C-17) (see Figure S10b). IR and Raman spectra are shown in Fig. 5
and 6.
2
2
.4. Acid isomerization of carquejone to carquejiphenol
To carquejone (31 mg) dissolved in benzene (0.8 mL), 85% formic acid (0.2 mL) was
added and the mixture incubated 60 min at 70 ° C with magnetic stirring. Then the
reaction mixture was allowed to reach room temperature, diluted with dichloromethane
(
DCM) (20 mL), washed with 5% NaHCO (3 x 5 mL), brine (2 x 3 mL) and dried
3
(
anhydrous Na SO ). After filtering and solvent evaporation, the residue (20 mg,
2
4
6
2
4.5%) showed to be 98% CARP and 2% carquejone by GC-MS analysis.
.5. General experimental procedures
1
The NMR experiments were conducted in a Bruker instrument at 200 MHz ( H) and 50
1
3
MHz ( C). All the spectra were recorded in chloroform-D1 (deuterium degree min.
1
1
9
9.8%, Sigma-Aldrich) with 0.03% TMS as internal reference. 2D NMR spectra ( H– H
1
13
1
13
gCOSY, H– C gHSQC, H– C gHMBC) were acquired using standard Bruker

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programs. All the GC-MS (EI-MS), UV, FT-Raman and FT-IR analysis were performed
in the experimental conditions detailed previously [13].
3
. Computational details
GaussView program [32] was used to model the initial CARP structure, while their
optimizations were performed with the Gaussian 09 program [33] by using the hybrid
B3LYP/6-31G* and B3LYP/6-311++G** methods [23,24]. For both structures, the
potential energy surfaces (PES) described by the dihedral C6-C5-C9-C10 angles were
studied with both levels of theory. Figure S1 shows two stable conformers for CARP
by using the B3LYP/6-31G* level of theory, named C1 and C2 where both structures
have the same energies (-463.4930 a.u. in gas phase and -463.4997 a.u. in aqueous
solution by using the B3LYP/6-31G* level of theory) and, as a consequence, the same
properties are expected for both conformers in both media. The two most stable
conformers of CARP are shown in Figure 2. It is very interesting to study two charge’s
types in order to observe their differences, thus, the natural populations atomic (NPA)
[
34] charges and the Merz-Kollman (MK) [35] charges were used to calculate the
molecular electrostatic potentials with the NBO program [34]. Bond orders and the
donor-acceptor interactions were also calculated. The topological properties were also
evaluated at the two levels of theory by using the AIM2000 program [36]. On the other
hand, the normal internal coordinates built as other similar species with six member’s
rings [17-20,27-29] were employed together with the SQMFF methodology [25] and the
Molvib program [37] in order to compute the force fields at the two levels of theory. To
perform the complete vibrational assignments, a dimeric species of CARP was proposed
as phenol groups are considered strong hydrogen-bond acceptors and donors according
to Jelsch and Bisseyou [26]. Figure 3 shows the theoretical structure proposed for the
dimeric species. Here, the energy for the dimeric species is of -926.9976 a.u. by using
the B3LYP/6-31G* level of theory and their value decreases when it is corrected by
basis set superposition error (BSSE) [38]. Hence, experimental bands not justified by
the monomeric species can be easily attributed to that dimeric structure. Furthermore,
the complete assignments of all bands observed in the vibrational spectra of CARP were
performed considering both IR and Raman spectra and using for the monomer the
potential energy distribution (PED) contribution ≥ 10%. For the dimeric species, the
GaussView program [32] was used as an aid to perform the vibrational assignments. On
the other hand, the Gauge-Independent Atomic Orbital (GIAO) method [39] was
1
13
employed to predict the H and C chemical shifts with both methods, using

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Tetramethylsilane (TMS) as reference. In the same way, the predicted ultraviolet-visible
spectrum for CARP in water was computed by using Time-dependent DFT calculations
(TD-DFT) with both levels of theory and the Gaussian 09 program [33]. Due to the
presence of an isopropenyl group in the CARP structure in similar form than carquejol,
it was necessary to predict their reactivity and behaviour. Hence, the frontier orbitals
and the chemical potential (ꢀ), electronegativity (χ), global hardness (η), global softness
(S), global electrophilicity index (ω) and nucleophilicity indexes (Ε) descriptors were
computed [13,17-21,27,29] by using both methods and data later compared with those
from other terpenic substances [17-21]. In addition, the pharmacological properties of
carquejiphenol were also evaluated by using some Lipisnki's and Veber's criteria
[
30,31].
4
4
. Results and discussion
.1. Structural study in gas phase and in aqueous solution
Total and relative energies, dipolar moments and volume variations for the most stable
structure of CARP in gas and aqueous solution phases are summarized in Table 1
together with the solvation energy values by using both basis sets. The volume values
were calculated with the Moldraw program [40], while the corrected solvation energies
were computed taking into account the non-electrostatic terms with the polarised
continuum and solvation PCM/SMD models [41-43] and the Gaussian program [33].
The uncorrected solvation energy values were calculated for both basis sets from the
difference between the total energy values in solution and the values in gas phase. All
energy values presented in Table 1 were corrected by the zero point vibrational energy
(ZPVE) which is a correction to the electronic energy because the effects of molecular
vibrations persist even at 0 K. Note that the uncorrected and corrected solvation
energies slight increase their values by using the 6-31G* basis set but both decrease
with the greater basis set. First, we observed that the dipole moment values with both
basis sets increase in solution in accordance with their volumes and, that their variations
also increase with the basis set. Thus, Figure S2 shows the corresponding magnitudes
and orientations of the dipole moment vectors for CARP in gas phase when increase the
size of basis set at 6-311++G** basis set. Hence, higher total and solvation energies
3
values were observed when increase the volume from 0.5 to 1.2 Å .
So far, the CARP structure was not experimentally determined, for this reason, the
calculated geometrical parameters presented in Table 2 were compared with those
theoretical corresponding to carquejol [13] and to diterpenic substances as cembrane

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diterpene [44] and 7-methyl-16-oxo-4,10-bis-(prop-1-en-2-yl)-17,18-dioxa-14,15-diaza-
6
,9 1,12
tetra-cyclo-[9.4.2.1 .0 ]octa-deca-6,8,14-trien-5-yl acetate] (KAP) [45]. The
structures of these compounds are given in Figure S3. The root-mean-square deviation
(RMSD) values were used to see the correlations in the bond lengths and angles
between experimental and calculated values. Here, the better bond lengths correlations
are observed for the isopropenyl group in relation to those corresponding to the ring
(0.101-0.099 Å), as can be seen in Table 2. Figure 4 shows clearly the differences
between the bond lengths of carquejol with those corresponding to carquejiphenol.
Hence, in CARP the ring is planar and as a consequence the distances from C1-C2 to
C6-C1 are lower in CARP than carquejol with the exception of the C2-C3 distance that
is surprisingly minor in carquejol than CARP because it is the only double bond
observed in the carquejol ring. On the other hand, the C5-C9, C9=C10 and C9-C13
distances corresponding to the isopropenyl groups in carquejol and CARP are
practically the same while the C4-O22 distance in CARP is lower, as expected because
3
2
the C4 atom in carquejol has sp hybridization while that atom in CARP has sp
hybridization. For the bond angles, we also observed the better correlations for the
isopropenyl group while not very good correlations are observed when the dihedral
angles of CARP are compared with the corresponding to carquejol. In particular, the
dihedral C10=C9-C5-C4 angle related to the isopropenyl group in CARP (-106.5º, by
using 6-311++G** basis set) is very similar to that experimental value of -92.5º
observed in the crystalline kallolide A acetate pyrazoline structure [45]. In the dimeric
CARP structure are expected inter-molecular H bonds because of the presence of OH
groups which are strong hydrogen-bond acceptors and donors [26], as are indicated in
Figure 3 by means of dashed lines. Here, the interaction energy for the dimeric species,
calculated taking into account the BSSE energy by using 6-31G* basis set, is 10.23
kJ/mol which results from the difference between the uncorrected energy of -926.9976
and the corrected energy by BSSE of -926.9937 a.u.
4
.2. NPA and MK Charges, MEP and bond orders
The investigations on the hydrophobic and hydrophilic sites and the atomic charges
involved in all bonds are of interest in CARP because this species could have potential
pharmacological properties as was reported for carquejol [13]. Hence, for CARP by
using both basis sets were studied the atomic natural population (NPA) and Merz-
Kollman (MK) charges together with the molecular electrostatic potential (MEP) values
[
35]. The bond orders expressed as Wiberg indexes were also calculated in order to

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investigate the characteristics of all their bonds by using the two levels of theory. Thus,
in Table S1 are summarized the calculated MK and NPA charges, the molecular
electrostatic potential and the bond order values. The behaviours of both MK and NPA
charges on the C atoms by using both levels of theory are easily observed in Figure S4.
Both basis sets show practically the same behaviours of both MK and NPA charges on
all C atoms but, in particular, the NPA charge on the C3 atom is slightly higher than the
corresponding MK by using the 6-311++G** basis set while the MK charges on the C3
and C17 atoms are higher by using the 6-31G+ basis set. On the other side, we observed
that the MK charges on the C4, C6 and C9 are higher than the other ones.
In relation to the molecular electrostatic potential (MEP) values, the values observed in
Table S1 were calculated for all atoms from the atomic Merz-Kollman (MK) charges
[
35] with the Gaussian 09 program [33] while the MEP mapped surfaces were built with
the GaussView program [32]. When the MEP values are represented in a graphic (see
Figure S5) in order to examine their variations, we observed practically the same
behaviours with both basis sets and, the higher values are observed on the C4 atom, as
expected because this is linked to the O atom of the OH group. Besides, the MEP values
on all atoms are more negative by using the 6-311++G** basis set. When, the mapped
MEP surface, presented in Figure S6, was analyzed, we observed the same red and blue
colorations on the OH group, as was also observed in carquejol. Hence, the nucleophilic
and electrophilic sites, identified by the red and blue colours respectively, are located on
the OH groups. Here, obviously the H23 atom linked to the O24 atom presents the less
negative values with both basis sets because they are the most labile. Probably, this
similarity in the MEP surface of CARP could be related to a potential pharmacological
property, as compared with carquejol.
Table S1 shows the bond order (BO) expressed as Wiberg indexes for CARP by using
both levels of theory. Analyzing the behaviours of all BO values of the C atoms,
represented in Figure S7, similar variations are observed with both basis sets but the
C5, C6 and C9 atoms present the higher values. These atoms are respectively linked to
the isopropenyl, methyl and H C13–C9=C10 groups, as observed in Figure 2. Figure S7
3
also shows that the 6-311++G** basis set predicted higher BO values for practically all
atoms, in particular the C13 and C17 atoms.
4
.3. Stability studies
NBO [34] and AIM [36] calculations were used to investigate the stability of CARP in
gas phase by using the hybrid B3LYP method and the two 6-31G* and 6-311++G**

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levels of theory. In Table S2 are summarized the most important donor-acceptor energy
interactions while in Table S3 are presented their topological properties. Regarding first
the donor-acceptor energy interactions, we clearly observed that by using the higher size
of the basis set enhance the number of contributions to the stability increasing
significantly the total energy from 1352.85 to 6048.63 kJ/mol. Thus, the new
ETLP→ σ* and ETLP→ π* delocalizations only appear when the 6-311++G** basis set is
used. Evidently, the donor-acceptor energy interactions are strongly dependent of the
∆ETσ→ σ*
∆
∆
size of the basis set, as was also observed in carquejol [13]. Here, the
interactions are observed with both basis sets.
∆ETπ→ π*
The atoms in molecules theory (AIM) [46] is interesting to study the different
interactions types expected in a molecule. The AIM2000 program [36] was employed to
compute the topological properties, as recommended by Bader’s theory [46]. Thus, the
2
electron density distribution,
critical points were calculated together with the eigenvalues (
matrix and the 1/ 3 ratio. Table S3 shows those parameters calculated for both basis
sets. Here, the properties computed in the bond critical points (BCPs) and ring critical
ρ
(r) (BCPs) and the Laplacian values, ∇
ρ(r) in the bond
λ
1, 2,
λ
λ3) of the Hessian
λ
λ
points (RCPs) with both levels of theory show closed-shell interaction where λ1/λ3 < 1
2
and ∇
ρ(r) > 0. Thus, we observed the clear intra-molecular H bond formation with
both basis sets, which is the O22---H14 interaction. The exhaustive inspection of the
values showed that the properties are slightly higher by using the 6-31G* basis set.
Here, the RCP belong to the ring while RCPN is the new RCP formed by the H bond
interaction. The details of the molecular model for CARP in gas phase by using 6-31G*
basis set can be seen in Figure S8. Evidently, these two NBO and AIM studies support
the high stability of CARP due to the donor-acceptor energies and to the intra-molecular
interactions.
4
.4. Frontier orbitals and descriptors
It is well known that the reactivities of different species can be predicted by using the
frontier orbitals, as reported by Parr and Pearson [47]. Also, the behaviours of diverse
systems can be predicted by means of the calculations of parameters identified as
descriptors, which are broadly reported in the literature [17-20,29]. Here, Table S4
shows the calculated HOMO and LUMO orbitals, energy band gap, chemical potential,
electronegativity (χ), global hardness (η), global softness (S), global electrophilicity
index (ω) and global nucleophilicity index (Ε) for CARP by using the hybrid B3LYP

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level of theory and the 6-31G* and 6-311++G** basis sets. The equations used to
calculate these parameters can also be seen in Table S4. The values were compared with
those obtained for carquejol [13] and for terpene substances, as N-(3,4-
dimethoxybenzyl)-hexadecanamide (DMH) [29] and cnicin [19] because for these two
compounds it has been reported biological activities. Figure S9 shows the behaviors of
the Frontier orbitals and descriptors calculated for CARP in gas phase at the B3LYP/6-
3
1G* level of theory and for the previously mentioned compounds. From the gap values
with both basis sets, we observed that CARP is more reactive than carquejol and DMH,
but cnicin is the most reactive of all them, as observed in Figure S9. This fact is clearly
justified because cnicin is a terpenic compound with various OH, C=O, C=C groups in
their structure which confer to it interesting biological properties. Figure S9 shows the
behavior of all the descriptors where clearly it is observed that cnicin has a high
electrophilicity index. Note that the nucleophilicity index of carquejol is similar to that
observed for cnicin while this index in CARP is similar to that observed for DMH. On
the contrary, the electrophilicity index for CARP is similar to that observed for
carquejol by using the same basis set and, as a consequence CARP could present similar
properties than carquejol.
In this work, only three of the four Lipisnki's and Veber's criteria were applied for
carquejiphenol in order to evaluate its pharmacological properties [30,31]. Hence,
according to the rule of 5’ states, carquejiphenol could present absorption or permeation
due to that: (i) CARP has one donor OH group (< number than 5 H-bond donors), (ii)
the molecular weight (MWT) is <<< than 500 and, (iii) CARP has only an H-bond
acceptor O atom (< 10 H-bond acceptor). Consequently, pharmacological properties
could be expected for carquejiphenol.
4
.5. NMR study
1
13
Figures S10a and S10b show the experimental H and C NMR spectra of CARP in
1
1
1
13
1
13
CDCl , respectively while the 2D H– H gCOSY, H– C gHMBC and H– C gHSQC
3
spectra are given in Figures S10c, S10d and S10f, respectively. Here, these 2D spectra
were used for multiplicity determinations and were very important because they showed
the spin-spin coupling between the hydrogen atoms of the molecule (gCOSY
experiment), hydrogen atoms directly bonded to carbon (HSQC experiment) and long
distance (two and three bonds) correlation of C with H (HMBC experiment). On the
1
13
other hand, in Tables S5 and S6 are presented the predicted H and C NMR chemical

ACCEPTED MANUSCRIPT
shifts for carquejiphenol by using the GIAO method [39] calculated with both basis sets
and compared with the corresponding experimental ones by means of the RMSD values.
As observed in other compounds [13,17-20], the theoretical calculations overestimated
the values in relation to the experimental ones, hence, a better correlation is observed
1
13
for the H nucleus (0.4-0.3 ppm) while for the C nucleus (7.0-6.8 ppm) the values
slightly increase. Here, we observed that the increase in the size of the basis set from 6-
1
3
1G* to 6-311++G** improve notably the results especially for the H nucleus than the
C atoms. The H atom that belongs to the OH group was not considered in the RMSD
value because this chemical shift depends heavily on sample concentration and
temperature.
4
.6. Vibrational study
The experimental IR and Raman spectra of CARP in solid phase can be seen in Figures
and 6, respectively compared to the corresponding predicted for the monomer and
5
dimer species by using B3LYP/6-31G* frequencies and intensities Lorentzian band
shapes for a 1:1 population ratio of each species. Comparing first the IR spectra, a
-1
strong band at 1317 cm is observed in the spectrum predicted for the CARP monomer
but in the average spectrum considering the dimeric species the intensity of that band
decreases notably, as was experimentally observed. Hence, it is evident that the dimeric
species should be considered because this species also justify the wide IR band in the
-1
region 3500-3400 cm attributed to the H bonds formation, as revealed by the AIM
analysis. On the other hand, when the predicted Raman spectra for monomer and dimer
are transformed from scattering activities to intensities, by known equations [48,49],
better correlations are observed between the predicted and experimental Raman spectra,
as observed in Figure 6. Both B3LYP calculations optimize the CARP structures with
C symmetries. Therefore, for CARP, 63 normal modes of vibration are expected, all
1
active, in both spectra. In order to perform the complete vibrational analysis and
assignments of all bands observed in both IR and Raman spectra, the SQMFF procedure
[
25] and the Molvib program [37] were used. Here, the normal internal coordinates for
CARP were not presented because they are similar to other reported [13,17-20]. The
harmonic force fields were calculated for both levels of theory but, the B3LYP/6-31G*
method was employed in the assignments due to that the scale factors used here are
valid for that level of theory [25]. For the monomeric species we have considered the
potential energy distribution (PED) contributions ≥ 10% while the assignments for the

ACCEPTED MANUSCRIPT
dimeric species were carried out with the aid of the GaussView program [32]. The
observed and calculated wavenumbers together with the assignments for CARP using
the B3LYP/6-31G* method are presented in Table 3 while the PED contributions
corresponding to the normal vibration modes of the monomer in gas and in aqueous
solution phases can be seen in Tables S7 and S8, respectively. Brief discussions on the
assignments for some groups corresponding to monomer and dimer are presented
below.
4
.6.1. Band Assignments of Monomer
4
.6.1.1. OH modes. Generally, in compounds containing this group, the OH stretching
-1
modes are assigned in the 3752-3430 cm region [13,18-20,29,50,51], hence, in CARP
-1
these modes are easily assigned to the very strong IR band at 3514 cm because they
-1
-1
are predicted at 3597 cm in gas phase, at 3572 cm in aqueous solution and, in the
-1
dimer at 3624 cm . In this region, as observed in Figure 4, the bands are broads
probably due to the H bonds formation because the OH groups are strong hydrogen-
bond acceptors and donors [27], as reported for thymidine by Görbitz et al. [50] and, as
observed by the AIM study. The SQM calculations predicted the in-plane deformation
-1
or rocking modes for the CARP dimers at 1380 and 1358 cm while for the monomer in
-1
-1
gas phase at 1159 cm and in solution at 1173 cm .
4
.6.1.2. CH modes. In CARP, the SQM/B3LYP/6-31G* calculations predicted the three
-1
expected C-H stretching modes between 3079 and 3044 cm , this way, these modes for
-1
the monomer are clearly assigned to the IR band of medium intensity at 3077 cm . In
carquejol [13], the in-plane deformation or rocking modes are predicted between 1377
-1
-1
and 1157 cm , hence, these modes in CARP are predicted between 1498 and 1106 cm
2
because all C-H groups are linked to C with sp hybridization while in carquejol some
3
C-H groups present sp hybridization. Later, these modes are assigned to the IR and
-1
shoulder bands at 1483, 1464, 1455, 1256, 1185, 1160 and 1121 cm . The out-of-phase
modes in carquejol [13] are assigned in accordance with the calculations to the IR bands
-1
at 997, 985, 768, 726 and 700 cm , in CARP; these modes are assigned to the IR and
-1
shoulder bands at 972, 900, 781 and 746 cm
4
.6.1.3. CH modes. CARP has two CH groups and the expected six stretching modes
3
3
-1
are predicted as completely pure in the 3090-2914 cm region. Thus, the antisymmetric
and symmetric stretching modes are assigned to the IR bands at 3031, 2966, 2947 and
-1
2
919 cm , as can be seen in Table 3. Obviously, the Raman bands observed with
medium and strong intensities are evidently assigned to symmetrical modes. In

ACCEPTED MANUSCRIPT
-1
carquejol [13], the CH deformation modes are assigned between 1587 and 1436 cm
3
while the rocking and twisting modes are predicted between 1084/1026 and 220/171
-1
cm , here, these modes are predicted respectively in the 1461/1361, 1074/1010 and
-1
2
10/108 cm regions. Therefore, the IR and Raman bands observed in these regions
were assigned to those vibration modes, as shown in Table 3.
2
4
.6.1.4. CH modes. Carquejol has two CH groups with sp hybridization and one CH
2
2
2
3
group with sp hybridization while in CARP only a =CH group is observed [13]. Thus,
2
in carquejol the symmetrical =CH groups modes are assigned to the very strong Raman
2
-1
-1
band at 3032 cm . Here, the antisymmetrical modes are predicted at 3102/3100 cm
-1
whiles the corresponding symmetrical modes at 3026/3024 cm . Thus, the CH
2
deformation, rocking, waging and twisting modes are predicted respectively in the
-
1
1
400/1388, 1010/914, 919/918 and 671/666 cm regions. Hence, they are assigned as
can be seen in Table 3.
.6.1.5. Skeletal modes. In carquejol [13], the C-O stretching modes are predicted
4
-1
-1
between 1063 and 1020 cm and assigned to 1065 cm . Here, the very strong IR band
-1
at 1278 cm is easily assigned to that mode corresponding to the monomer. In
compounds containing C=C bonds, the corresponding stretching modes are assigned in
-1
the 1680-1659 cm region [16-18]; therefore, in CARP those modes are assigned to the
-1
IR and Raman bands at 1638 and 1643 cm . Note that the other expected C-C
stretching modes corresponding to the ring are assigned to the bands in the 1610-1483
-1
cm region, as predicted by the SQM calculations. On the other side, the strong IR
-1
-1
bands at 1074 and 914 cm and the IR band of medium intensity at 947 cm are
associated to C-C stretching modes, as detailed in Table 3.
4
.6.2. Band Assignments of Dimer
4
.6.2.1. OH modes. Here, possibly the H bond formation in solution due to dimeric
species shifts the OH stretching modes toward higher wavenumbers. Hence, the very
-1
strong IR bands at 3514 cm is clearly assigned to those vibration modes. The in-plane
-1
deformation modes are predicted at 1380 and 1358 cm and, for this reason, they are
-1
assigned to the Raman band and shoulder at 1395 and 1361 cm , as indicted in Table 3.
The out-of-plane deformation modes are predicted in the CARP dimer at 622 and 346
-1
-1
-1
cm . Hence, the IR band at 638 and 406 cm and the Raman band at 332 cm are
assigned to those vibration modes, as observed in Table 3.

ACCEPTED MANUSCRIPT
4
.6.2.2. CH modes. In the dimer of CARP, the C-H stretching modes are predicted
-1
between 3163 and 3079 cm , then, these modes are clearly assigned to the IR band of
-1
medium intensity at 3077 cm . The in-plane deformation or rocking modes in the dimer
-1
are predicted between 1498 and 1106 cm . Later, these modes are assigned to the IR
and Raman bands observed in that region. According to the calculations, the out-of-
phase modes are assigned to the IR bands at 951 and 558 cm-1.
4
.6.2.3. CH modes. In the dimeric species, the two stretching modes are predicted as
3
-1
practically pure in the 3090-3037 cm region. Thus, both antisymmetric and symmetric
stretching modes are assigned in that region, as can be seen in Table 3. In the dimer, the
-1
CH deformation modes are predicted between 1447 and 1449 cm while the rocking
3
-1
and twisting modes are predicted between 1074/1039 and 210/97 cm , hence, they are
assigned as predicted by calculations.
-1
4
.6.2.4. CH modes. In the dimer the symmetric modes are predicted at 3053 cm and,
2
for these reasons, these modes are assigned to the Raman band of medium intensity at
-1
3
044 cm while the CH deformation, rocking, waging and twisting modes are
2
predicted at higher wavenumbers than the corresponding to the monomer. Thus, for the
dimer, these modes are predicted, respectively, in the 1464, 1074/1039, 943/927 and
-1
7
64/730 cm regions. Hence, they are assigned accordingly.
-1
4
.6.2.5. Skeletal modes. The IR band of medium intensity at 1333 cm is associated to
C-O stretching modes of the dimer while in this species, the C=C bonds are predicted in
-1
the 1726-1636 cm region [17-20]; therefore, those modes are assigned to the Raman
-1
bands at 1643 and 1584 cm . The C-C stretching modes are predicted between 1498
-1
and 1295 cm , as predicted by the calculations. The deformation and torsion ring modes
-1
are predicted for both monomer and dimer between 1119/499 and 737/97 cm , as in
similar compounds [17-20,29,50,51] and, as a consequence they were assigned in those
regions.
5
. Force Field
The calculations of the frontier orbitals have evidenced that CARP is more reactive than
carquejol [13] and DMH [28] but, cnicin is the most reactive of all them. For these
observations, it is very important to predict force constants in order to analyze the
harmonic force of the different bonds in CARP. Thus, their force constants were
calculated from the force fields in gas phase at the 6-31G* and 6-311++G** levels of
theory and, later, they were compared in Table 4 with those reported for carquejol and

ACCEPTED MANUSCRIPT
other terpenic compounds, such as cnicin [19], 13-epi-sclareol [20] and onopordopicrin
[
[
18]. As it was explained in the section of computational details, the SQMFF approach
25] and the Molvib program [37] were used to obtain the scaled force fields at both
levels of theory. First, we compared the force constants for CARP by using both levels
of theory. Here, we observed a slightly increase in the f( O-H) force constant when the
size of the basis set increase from 6-31G* at 6-311++G** basis set but, a diminishing in
the values for the f( C-H), f( =CH ) and f( C-C) force constants are observed while
there are not observed changes in the values of the f( =CH ) and f( C-OH) force
constants. When the values are compared with those calculated for carquejol by using 6-
1G* basis set, the f( O-H) force constant do not change but the f( C-H) and f( C-C)
force constants decrease their values. The planarity of the ring in CARP justifies the
ν
ν
ν
ν
2
δ
δ
2
3
ν
ν
ν
difference in the f(
ν
C-C) force constants while the existence in carquejol of a C-H bond
3
where the C atom present a sp hybridization probably could explain the diminishing in
2
the f(
hybridization.
. Ultraviolet-visible spectrum
νC-H) force constants because in CARP all C atoms of the ring have sp
6
The UV-visible spectrum for CARP in aqueous solution was predicted by using TD-
DFT calculations with the B3LYP/6-31G* method and the Gaussian program [33] while
the experimental one was recorded in n-hexane solution. Both spectra are compared in
Figure 7. In the experimental spectrum two bands were observed, one intense at 210
nm and other of lower intensity at 279 nm together with a shoulder at approximately
1
90 nm, while the theoretical calculations predicted for CARP in aqueous solution a
shoulder at 164 nm and two bands, one intense at 184.4 nm and other of lower intensity
at 248 nm. There was very good concordance between the spectra but, evidently, the
predicted spectrum is shifted toward lower wavelengths in relation to the experimental
one. In phenol, two bands of approximately the same intensities at 200 and 269 nm are
also observed as reported in Ref [52]. These bands can be easily assigned to the π→π*
transitions due to the C=C double bonds, as predicted the NBO analysis and in
agreement with literature data [53,54].
8
. Conclusions
Carquejiphenol, a minor component of the Baccharis trimera essential oil, was
synthesized and later characterized by using FT-IR, FT-Raman, UV-Visible, EI-MS,
1
13
1
1
1
13
1
13
H- and C-NMR and 2D H- H gCOSY, H- C gHSQC, H- C gHMBC

ACCEPTED MANUSCRIPT
spectroscopies. The molecular structure of the monomer and dimer were theoretically
determined in gas phase by using the hybrid B3LYP method and the 6-31G* and 6-
3
11++G** basis sets. Two structures with the same energies were found in the potential
1
13
energy surface. The predicted FTIR, Raman, H-NMR, C-NMR and UV-visible
spectra of both forms showed a very good correlation with the corresponding
experimental ones. The predicted corrected solvation energies for CARP were also
computed by using both levels of calculations and considering the solvent effects with
the polarised continuum and solvation models. The increase in the volume in solution
support the H bonds formation due to the presence of a OH group, as suggested in the
literature and as revealed by AIM analysis. High stability for CARP was found by using
NBO and AIM studies, while the investigation of the frontier orbitals reveal that CARP
is more reactive than carquejol and hexadecanamide but, the terpene cnicin is the most
reactive. The proximities in the electrophilicy index of CARP with that obtained for
carquejol and of the nucleophilicity index with that calculated for N-(3,4-
dimethoxybenzyl)-hexadecanamide suggest probably that carquejiphenol could present
pharmacological properties. The SQMFF methodology was used together with the
Molvib program to compute the force fields and to perform the complete vibrational
analysis. Hence, the 63 vibration normal modes were assigned and the force constants
are also reported and compared with other reported from the literature.
Acknowledgements. This work was supported with grants from CIUNT Project
2
6/D207 and 26/D510 (Consejo de Investigaciones, Universidad Nacional de
Tucumán) and CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas,
R. Argentina). MM thanks to ANII (Agencia Nacional de Investigación e Innovación,
Uruguay) for PhD scholarships (POS-2011-1-3332 and POS NAC 2013-1-11316) and
to Universidad Nacional de Tucumán (PEEP Program). The authors would like to thank
Prof. Tom Sundius for his permission to use MOLVIB.
Supporting Information Available: Tables S1-S8 and Figures S1-S14.

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[

ACCEPTED MANUSCRIPT
Caption Figures
Scheme 1. Synthesis of carquejiphenol
Figure 1. Mass spectrum of carquejiphenol obtained by using Electron Impact Mass
Spectrum and an ionization potential of 70 eV.
Figure 2. Theoretical molecular structures of the most stable C1 and C2 conformers of
carquejiphenol and atoms numbering (GaussView program).
Figure 3. Dimeric structure of the most stable C1 conformer of carquejiphenol and
atoms numbering. The intra-molecular H bond is identified in dashed lines (GaussView
program).
Figure 4. Variations of the C-C and C-O bond lengths of carquejiphenol with those
corresponding to carquejol in gas phase by using B3LYP/6-31G* level of theory. The
structures of both species are also presented.
Figure 5. Experimental infrared spectrum of carquejiphenol in the solid state compared
with the corresponding predicted for C1 and with the predicted for the two monomeric
and dimeric species by using B3LYP/6-31G* frequencies and intensities Lorentzian
band shapes for a population 1:1 ratio for each species.
Figure 6. Experimental Raman spectrum of carquejiphenol in the solid state compared
with the corresponding predicted for C1 and with the predicted for the two monomeric
and dimeric species by using B3LYP/6-31G* frequencies and intensities Lorentzian
band shapes for a population 1:1 ratio for each species.
Figure 7. Experimental UV-visible spectrum of carquejiphenol in n-hexane compared
with the corresponding predicted for the monomeric and dimeric species by using
B3LYP/6-31G* frequencies and intensities Lorentzian band shapes for a population 1:1
ratio for each species.

ACCEPTED MANUSCRIPT
Table 1. Calculated total energies (E), relative (∆E), dipole moments (µ), volume
variations (∆V) and solvation energies (∆G) for carquejiphenol in gas and aqueous
solution phases by using two level of theory.
B3LYP/6-31G*
3
Property
E (Hartrees)
µ(D)
Gas phase
-463.4930
1.27
PCM
-463.4997
1.77
∆E(kJ/mol)
∆V(Å )
-15.57
3
V(Å )
178.4
178.9
0.5
B3LYP/6-311++G**
3
Property
E (Hartrees)
µ(D)
Gas phase
PCM
-463.6340
1.69
∆E(kJ/mol)
∆V(Å )
-463.6263
1.13
-20.20
3
V(Å )
177.5
178.7
1.2
Solvation energy (kJ/mol)
#
Basis set
∆Gu
∆Gne
21.57
∆Gc
-37.14
6
-31G*
-15.57
6
6
-311++G**
Species
-20.20
Gas phase
22.78
PCM
Corrections Z.P.V.E
-42.98
∆E(kJ/mol)
E (Hartrees)
Gas phase
-463.6866
-463.8182
(kJ/mol)
Basis set
#
PCM
-463.6932
-463.8257
∆E=∆Gu
-17.31
-19.67
∆Gc
6
-31G*
-38.88
-42.45
-311++G**
#
∆
G , See text, Z.P.V.E, zero point vibrational energy
u

ACCEPTED MANUSCRIPT
Table 2. Comparison of calculated geometrical parameters for carquejiphenol with the
corresponding theoretical for carquejol and experimental ones for other terpenes
B3LYP method
a
b
c
d
Parameters
Carquejiphenol
Carquejol
Exp
Exp
6
-31G*
6-311++G**
Bond lengths (Å)
1.390
6-31G*
C1-C2
C2-C3
C3-C4
C4-C5
C5-C6
C6-C1
C5-C9
1.392
1.392
1.396
1.407
1.409
1.402
1.499
1.337
1.511
1.513
1.372
0.090
0.099
0.032
1.510
1.334
1.514
1.546
1.526
1.514
1.531
1.335
1.512
1.508
1.334
1.490
1.550
1.390
1.394
1.404
1.408
1.400
1.498
1.524
1.385
1.524
C9=C10
C9-C13
C6-C17
C4-O22
1.333
1.509
1.511
1.373
1.429
1.428
b
RMSD
0.091
c
RMSD
0.101
d
RMSD
0.035
Bond angles (º)
121.4
C3-C4-O22
C5-C4-O22
C4-C5-C9
121.5
117.0
119.3
122.0
122.2
121.1
116.5
119.2
121.1
6.6
112.4
109.2
117.3
110.4
121.1
125.1
113.6
107.8
112.6
117.1
119.3
C6-C5-C9
121.9
C10=C9-C13
C10=C9-C5
C13-C9-C5
C1-C6-C17
C5-C6-C17
122.5
122.2
119.3
118.3
121.1
116.3
119.2
121.2
b
RMSD
6.6
b
RMSD
10.2
10.1
c
RMSD
1.5
1.6
Dihedral angles (º)
74.7
C10=C9-C5-C6
C10=C9-C5-C4
C13-C9-C5-C4
H23-O22-C4-C3
O22-C4-C3-C2
72.7
-108.7
71.5
107.0
-16.0
-106.5
73.4
-92.5
-179.5
179.6
65.5
145.2
146.1
a
b
c
d
This work, From Ref [13]; From Ref [37] for; From Ref [38]

ACCEPTED MANUSCRIPT
-1
Table 3. Observed and calculated wavenumbers (cm ) and assignments for
carquejiphenol in gas phase and in aqueous solution and their dimer
a
B3LYP/6-31G* Method
Experimental
Monomer
Dimer
GAS
GAS
Assignments
νO22-H23
CH
PCM
Assignments
νO22-H23
CH
b
b
c
IR
514vs
Raman
SQM
SQM
Calc Assignments
3624 νO-H
3
3218vw
3597
3102
3071
3053
3032
3026
2999
2998
2981
2971
2928
2914
3572
3100
3078
3062
3056
3024
3003
2998
2977
2967
2926
2916
3
163vw
ν
a
2
ν
a
2
3200 νC-H
3
077m
031w
3079m
νC2-H7
νC1-H21
νC3-H8
νC2-H7
νC1-H21
νC3-H8
3188 νC-H
3
063w
044m
3090
3053
3037
ν
ν
ν
a
CH
3
2
3
3
s
CH
3
3032sh
008w
992sh
981m
ν
ν
ν
ν
ν
ν
ν
s
CH
CH
2
ν
ν
ν
ν
ν
ν
ν
s
CH
CH
2
s
CH
3
a
a
a
a
3
3
3
3
(C17)
(C13)
(C17)
(C13)
(C17)
(C13)
a
a
a
a
3
3
3
3
(C17)
(C13)
(C17)
(C13)
(C17)
(C13)
2
CH
CH
CH
CH
CH
CH
2
2
966s
947s
919s
2977sh
2947w
2918s
2
s
CH
3
3
s
CH
3
3
2
s
CH
s
CH
2
1
1
865w
638m
610m
2871w
1643s
1659
1606
1585
1487
1465
1461
1449
1445
1440
νC9=C10
1653
1603
1576
1481
νC9=C10
1726 νC=C
1641 νC-C
1613m
1584m
1493w
1464w
νC3-C4νC1-C2νC4-C5
βC1-H21νC2-C3
νC5-C6
νC3-C4νC4-C5
νC2-C3
1
580s
1636 νC-C
1
483m
βC1-H21νC5-C6
1498 βC-HνC-C
1
1
1
464vs
455sh
455sh
βC2-H7βC1-H21
1464 δCH
2
δ
δ
δ
δ
a
a
a
a
CH
CH
CH
CH
3
3
3
3
(C13)
(C17)
(C17)
(C13)
1457
βC2-H7νC3-C4
1
446sh
1447
1436
1429
δ
δ
δ
s
s
s
CH
3
1
433s
433s
433s
1436
1434
1432
1426
1388
1370
1361
δ
δ
δ
δ
a
a
a
a
CH
CH
CH
CH
3
3
3
3
(C13)
(C17)
(C17)
(C13)
1
1435w
CH
3
1
1
422sh
CH
3
1
394w
372m
1395m
1378m
1400
1382
1368
δCH
2
δCH
2
1380 δO-H
1
δ
δ
s
CH
3
3
(C17)
(C13)
δ
δ
s
CH
3
3
(C17)
(C13)
1
361sh
1330vw
306sh
s
CH
s
CH
1358 δO-H
1330 νC-O
1304 νC-O
1295 νC-C
1
333m
1
1305
νC5-C6νC1-C6
1
1
1
1
1
290sh
278vs
278vs
278vs
185vs
1287sh
1275s
1305
1282
1272
1255
1167
1159
1122
1077
νC5-C6
νC4-O22
νC5-C9νC4-O22
βC1-H21
βC2-H7
1272
1257
1251
1173
1153
1119
1074
1052
1044
νC5-C9
1275s
βC1-H21
νC4-O22
δO-H
1258sh
1188vw
1165w
1121w
1076s
1251 βC-H
1199 βC-H
1154 βC-H
1106 βC-H
1
160s
δO-H
βC2-H7βC3-H8
1
121w
βC3-H8
βR
1
1
074s
1
βR νC1-C2
νC1-C2
1074 ρCH
1053 ρCH
1040 ρCH
1039 ρCH
3
3
3
3
ρCH
2
2
1
057
ρ'CH
3
(C13)
(C17)
ρ'CH
3
3
(C13)
(C17)
1
1
1
1
043w
043w
019w
005w
1044w
1044w
1022w
1004w
979vw
952vw
1047
ρ'CH
3
ρ'CH
ρCH
1022
1012
ρCH
3
(C17)
(C13)
1020
1010
ρCH
3
(C17)
ρCH
3
ρCH
3
(C13) ρCH
2
9
88w
72w
47m
975
951
943
927
βR
1
9
943
940
918
γC2-H7
958
931
919
γC2-H7
γC-H
9
νC6-C17
νC6-C17
wagCH
2
2
9
25sh
925w
wagCH
2
wagCH
2
wagCH

ACCEPTED MANUSCRIPT
9
14s
910w
874w
782w
782w
911
850
νC9-C13 ρCH
2
910
869
νC9-C13
9
7
7
00sh
81vs
81vs
γC3-H8γC1-H21
γC3-H8γC1-H21
868
785
780
764
752
730
651
647
622
590
579
558
530
528
507
506
456
442
394
389
358
346
290
277
210
194
183
166
120
97
γC-H
γC-H
γC-H
τwCH
γC-H
τwCH
777
768
βR
1
776
773
γC3-H8
7
61vw
746vw
712vw
γC4-O22
2
βR βR
1
2
2
7
46s
7
28sh
737
τR
1
737
τR
1
6
6
45vs
45vs
βR
βR
1
666
625
τwCH
2
671
626
τwCH
2
1
6
5
5
5
38w
82w
82w
65w
631sh
582w
582w
568w
νC5-C9
νC5-C9νC6-C17
τOH
βR
τR
γC-H
τR
βR
3
574
569
549
521
500
βC5-C9βR
3
577
568
552
521
499
βC5-C9τwCH
γC6-C17γC4-O22
τR τR
2
3
τR
τR
1
3
γC6-C17
τR
5
50w
2
3
2
2
5
4
18w
99w
522w
502w
βR
3
βR
3
3
βR
2
βR
2
δCCC
δCCC
γC-C
γC-C
τOH
4
71sh
483vw
468vw
446vw
392sh
388w
4
4
4
43w
36w
06w
440
βC4-O22γC9-C10
447
βC4-O22γC9-C10
3
99sh
383
357
γC6-C17
385
358
337
τR
3
γC6-C17
τR
3
3
3
3
45vw
32vw
13vw
βC6-C17 δC10C9C13
βC6-C17
τOH
δCCC
τOH
313
278
227
194
187
169
108
94
τOH
δCCC
δCCC
τwCH
γC-C
2
95w
δC10C9C13βC6-C17
275
230
198
189
168
153
97
δC10C9C13
2
37m
τR
γC5-C9
τwCH (C13)
βC5-C9
τwCH (C17)
τR βC9-C10
2
τR
2
3
1
96s
3
τwCH (C13)
1
1
82sh
53sh
3
γC5-C9
βC5-C9
βC-C
γC-C
1
07s
3sh
7sh
3
τwCH
3
(C17)
τwCH
τwCH
γC-C
3
9
3
3
τR βC9-C10
3
6
73
4
9
τwCCC
52
τwCCC
49
δOH---O
Abbreviations: ν, stretching; β, deformation in the plane; γ, deformation out of plane; wag, wagging;
τ , torsion; β , deformation ring τ , torsion ring; ρ, rocking; τw, twisting; δ, deformation; a,
R
R
a
b
c
antisymmetric; s, symmetric. This work, From scaled quantum mechanics force field; From B3LYP/6-
1G* calculation.
3

ACCEPTED MANUSCRIPT
Table 4. Comparison of main scaled internal force constants for carquejiphenol in gas
and aqueous solution phases compared with those calculated for carquejol.
B3LYP Method
a
Carquejiphenol
-31G*
6-31G*
Force
constant
b
c
d
e
6
6-311++G**
Carquejol
Cnicin
Epi
Onopor
f(ν
f(ν
f(ν
f(ν
f(ν
f(ν
f(δ
f(δ
f(δ
O-H)
C-H)
=CH2)
CH2)
C-O)c
C-C)
=CH2)
CH2)
7.20
5.10
5.16
7.40
5.07
5.05
7.20
4.80
5.19
4.67
4.80
4.87
0.40
0.80
0.70
6.99
6.92
7.16
4.96
5.22
4.79
5.44
5.20
4.74
4.47
4.90
4.80
6.47
0.40
6.27
0.40
0.44
0.76
0.43
0.76
0.45
0.77
0.74
C-OH)
0.70
0.70
-1
-2
Units are mdyn Å for stretching and mdyn Å rad for angle deformations
a
b
c
d
e
This work; From Ref [13]; From Ref [19] for; From Ref [120; From Ref [18]