Assessing parameter suitability for the strength evaluation of intramolecular resonance assisted hydrogen bonding in O-carbonyl hydroquinones

Article abstract of DOI:10.3390/molecules24020280

Intramolecular hydrogen bond (IMHB) interactions have attracted considerable attention due to their central role in molecular structure, chemical reactivity, and interactions of biologically active molecules. Precise correlations of the strength of IMHB’s with experimental parameters are a key goal in order to model compounds for drug discovery. In this work, we carry out an experimental (NMR) and theoretical (DFT) study of the IMHB in a series of structurally similar o-carbonyl hydroquinones. Geometrical parameters, as well as Natural Bond Orbital (NBO) and Quantum Theory of Atoms in Molecules (QTAIM) parameters for IMHB were compared with experimental NMR data. Three DFT functionals were employed to calculated theoretical parameters: B3LYP, M06-2X, and ωB97XD. O . . . H distance is the most suitable geometrical parameter to distinguish among similar IMHBs. Second order stabilization energies ?E_ij⁽²⁾ from NBO analysis and hydrogen bond energy (E_HB) obtained from QTAIM analysis also properly distinguishes the order in strength of the studied IMHB. ?E_ij⁽²⁾ from NBO give values for the IMHB below 30 kcal/mol, while E_HB from QTAIM analysis give values above 30 kcal/mol. In all cases, the calculated parameters using ωB97XD give the best correlations with experimental¹H-NMR chemical shifts for the IMHB, with R² values around 0.89. Although the results show that these parameters correctly reflect the strength of the IMHB, when the weakest one is removed from the analysis, arguing experimental considerations, correlations improve significantly to values around 0.95 for R²

Full text of DOI:10.3390/molecules24020280

molecules
Article
Assessing Parameter Suitability for the Strength
Evaluation of Intramolecular Resonance Assisted
Hydrogen Bonding in o-Carbonyl Hydroquinones
Maximiliano Martínez-Cifuentes 1,
*
, Matías Monroy-Cárdenas 2, Juan Pablo Millas-Vargas 2,
Boris E. Weiss-López 3 and Ramiro Araya-Maturana 2,4,
*
1
Programa Institucional de Fomento a la Investigación, Desarrollo e Innovación, Universidad Tecnológica
Metropolitana, Ignacio Valdivieso 2409, Casilla 9845, Santiago 8940577, Chile
Instituto de Química de Recursos Naturales, Universidad de Talca, Av. Lircay s/n, Casilla 747, Talca 3460000,
Chile; maty.monroy@gmail.com (M.M.-C.); jpmillas@utalca.cl (J.P.M.-V.)
Departamento de Química, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653,
Santiago 7800003, Chile; bweiss@uchile.cl
2
3
4
Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Universidad de Talca, Talca 3460000,
Chile
*
Correspondence: mmartinez@utem.cl (M.M.-C.); raraya@utalca.cl (R.A.-M.);
Tel.: +56-2-27877905 (M.M.-C.); +56-71-2200285 (R.A.-M.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Goar Sánchez
Received: 22 November 2018; Accepted: 8 January 2019; Published: 14 January 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Intramolecular hydrogen bond (IMHB) interactions have attracted considerable attention
due to their central role in molecular structure, chemical reactivity, and interactions of biologically
active molecules. Precise correlations of the strength of IMHB’s with experimental parameters are a
key goal in order to model compounds for drug discovery. In this work, we carry out an experimental
(NMR) and theoretical (DFT) study of the IMHB in a series of structurally similar o-carbonyl
hydroquinones. Geometrical parameters, as well as Natural Bond Orbital (NBO) and Quantum
Theory of Atoms in Molecules (QTAIM) parameters for IMHB were compared with experimental
NMR data. Three DFT functionals were employed to calculated theoretical parameters: B3LYP,
M06-2X, and
ω
B97XD. O . . . H distance is the most suitable geometrical parameter to distinguish
(2)
among similar IMHBs. Second order stabilization energies
∆
Eij from NBO analysis and hydrogen
bond energy (EHB) obtained from QTAIM analysis also properly distinguishes the order in strength
(2)
of the studied IMHB.
∆
Eij from NBO give values for the IMHB below 30 kcal/mol, while EHB
from QTAIM analysis give values above 30 kcal/mol. In all cases, the calculated parameters using
B97XD give the best correlations with experimental 1H-NMR chemical shifts for the IMHB, with R2
ω
values around 0.89. Although the results show that these parameters correctly reflect the strength of
the IMHB, when the weakest one is removed from the analysis, arguing experimental considerations,
correlations improve significantly to values around 0.95 for R2.
Keywords: hydroquinone; polyphenol; hydrogen bond; DFT; NBO; QTAIM
1. Introduction
Hydrogen bonding (HB) is generally described as a stabilizing electrostatic interaction with a
partly covalent character. Some of the most direct experimental evidence of the HB formation is
the deshielding of the hydrogen atom involved in the interaction, which is easily observed by NMR
spectroscopy [
1,2]. It is well known that intramolecular hydrogen bonding (IMBH) has a key role in
determining the structure and properties of biologically-active molecules, and their study in model
Molecules 2019, 24, 280; doi:10.3390/molecules24020280
www.mdpi.com/journal/molecules

Molecules 2019, 24, 280
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compounds is relevant in drug design [
3–
5]. For example, IMBH formation is determinant for passive
membrane permeability of cyclic peptides [6] and in lipophilicity [7].
Any intramolecular hydrogen bonding IMHB is governed by the equilibrium between closed
(IMHB) and open (no IMHB) forms. Consequently, the implementation of IMHB considerations in drug
discovery programs requires experimental methodologies to assess the position of these equilibria,
which are dependent on the strength of each IMBH [8
]. The 1H-NMR spectroscopy is the most common
tool to measure the propensity of compounds to form IMHBs, nevertheless, up to now the throughput
of NMR, and other traditional methods, is limited in obtaining structure–activity relationships (SAR)
and driving rapid cycles of compound optimization [
allows one to assess, theoretically, the strength of IMBH through parameters such as the distance
hydrogen-acceptor, the distance donor-acceptor, and the hydrogen bond angle [ ]. Among the
theoretical estimated parameters for the HB interaction, those from Natural Bond Orbital (NBO)
and Quantum Theory of Atoms in Molecules (QTAIM) analysis [ 13] are the most popular. In this
8]. However, current computational chemistry
9
9–
field, DFT methodologies have proven to be valuable tools to calculate molecular properties with an
appreciably low computational time demand compared with ab initio methodologies.
Previously we have studied the properties of some ortho-carbonyl hydroquinones with capability
to cross membranes and to reach the inner mitochondrial membrane. These compounds act either as
oxidative phosphorylation (OXPHOS) uncouplers, complex I inhibitors, or exert both activities; as a
consequence they exhibit antitumor [14–16] or antiplatelet effects [17], or both. Interestingly, small
structural changes on the hydroquinone scaffold determine their biological activities [15]. All these
molecules exhibit strong resonance assisted intramolecular hydrogen bonding, assessed by 1H-NMR
spectrometry [18]. These compounds act either as weak acids into the mitochondrial membrane, or by
losing a hydrogen atom (or alternatively losing an electron followed by deprotonation) to afford the
corresponding semiquinone radical, which can interfere in cell signaling. The formation of IMHB
plays a key role [19,20] on both properties. IMHBs have shown appreciable effects on the antioxidant
and electrochemical properties of hydroquinones and related phenols [21,22].
On the other hand, the o-carbonyl hydroquinone motif is present on natural products with
different biological activities, such as the anticancer drugs doxorubicin and daunorubicin [23],
acylnaphtohydroquinones [24], shikonin [25], and in peyssonol A [26].
The precise assessment of the strength of the IMBH interaction has many difficulties.
Determination of the H-bond energy is possible only for the intermolecular hydrogen bond: the
energy of the intermolecular interaction is usually equal to the energy required to separate the two
interacting molecules [1]. However, there is no clear definition of the hydrogen bond energy for the
IMHB because the interacting entities cannot be fully separated [27].
Moreover, it is relatively easy to roughly calculate the relative strength of a series of IMBHs
when they take place in molecules with large structural differences; however, to assess the relative
strength of IMBHs in very similar molecules, establish correlations with experimental parameters,
and use these data to make correlations with biological activities, requires an adequate choice of
theoretical methodologies.
The aim of this work is to study the IMHBs experimentally and theoretically in a series of
structurally similar o-carbonyl hydroquinones. Calculated NBO and QTAIM parameters of the
IMHBs obtained by different DFT functionals (B3LYP, M06-2X, and
with experimental values obtained by NMR.
ωB97XD) will be correlated
2. Results
The studied compounds were synthesized according to Scheme 1 [28
hydroquinone ( ) or 2,3-dimethylhydroquinone ( ), the corresponding acylhydroquinones (
obtained by Fries rearrangement [30]. These compounds were oxidized with silver (I) oxide to
obtain the corresponding quinones ( ), which were not isolated. These quinones yield benzofurans
12 17) by reaction with the enamines ( 11). The last step involves an acid rearrangement of these
,29]. Starting from
1
2
3–5
) were
6–8
(
–
9–

Molecules 2019, 24, 280
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benzofurans, yielding the corresponding bicyclic hydroquinones (18
,
20
,
22
–24). Monomethyl ethers
of hydroquinone 19 and 21 were obtained by methylation of hydroquinones 18 and 20, respectively;
they were synthesized to assess the effect of blocking the hydroxyl group not involved in IMHB.
Hydroquinone
R1
R2
R3
R4
18 [31]
19 a [31]
20
H
H
Me
Me
H
H
H
H
H
Me
H
Me
Me
Me
Me
H
Me
H
Me
H
21 b
22 [32]
23 [32]
24 [15,33]
a
Me
-CH2-(CH2)-CH2-
Et
H
H
H
H
H
Note: Obtained by methylation of 18, b obtained by methylation of 20.
Scheme 1. Synthesis of the bicyclic hydroquinones studied in this work.
Three hybrid functional were employed in this work: B3LYP, composed of Becke three parameters
hybrid functional B3 and the non-local correlation functional of Lee, Yang, and Parr (LYP) [34–36].
The second corresponds to a hybrid meta-generalized gradient-approximation (hybrid meta-GGAs)
functional, M06-2x, which have been described as one the of the best Truhlar group functionals for
non-covalent interactions [37]. The last functional corresponds to the long-range corrected functional
ω
B97XD, which is designed to avoid rapid die-off of the non-coulomb part of the exchange functionals,
which affects the modelling of long distance processes [38].
In this first part, we study main geometrical parameters from the IMHBs and their correlation
with 1H-NMR chemical shifts. The results are presented in Table 1. Calculations were carried out at
DFT level using the B3LYP, M06-2X, and
ωB97XD functionals with the 6-311++g(d,p) basis set. Among
the geometrical parameters, only the O15 . . . H16 distances displayed enough differentiation to be used
as comparison parameters for correlation with the chemical shifts of chelated protons. Compound 21
displayed the largest chemical shift and a more de-shielded proton, indicating the strongest IMHB,
followed in strength by 20. The later indicates that methyl substituents on C1 and C2 increase the
IMHB strength. Additionally, the methylation at O12 and also a methyl group at C9 increase the
strength of the IHB in 21 and 22, respectively. The three functionals give the shortest O15 . . . H16
distance for 21, indicating the strongest IHB, which is in agreement with the largest downfield chemical
shift. The smallest chemical shift for 18 indicates the weakest IHB in the series. Nevertheless none of
the three functional gives the largest O15 . . . H16 distance for 18. These discrepancies can reflect the
presence of intermolecular interactions competing with the IMHB, contributing in a non-negligible
degree to the 1H-NMR spectra at the probe temperature, especially between pairs of molecules where

Molecules 2019, 24, 280
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one phenolic hydroxyl is replaced by a methoxy group. The same considerations can be applied to
correlations with the next parameters. Global correlation among the chemical shift and O15 . . . H16
distance for all molecules were carried out (Figure 1). Results indicate that the
ωB97XD functional
gives the best correlation with an R2 = 0.89, followed by M06-2X with a R2 = 0.85 and B3LYP, and the
worst correlation with R2 = 0.80.
Table 1. Experimental chemical shifts (
geometric calculated parameters. Distances in angström, (Å), and angles in degree ( ).
δ
) in ppm of protons involved in hydrogen bonding, and main
◦
. . .
. . .
Distance (O15
H16
)
Distance (O11-H16
)
Angle (O15
H16-O11
)
δ ppm
Molecule
B3LYP
M062x ωB97XD B3LYP
M062x ωB97XD B3LYP
M062x ωB97XD
18
19
20
21
22
23
24
12.540
12.690
13.200
13.440
12.930
12.740
12.800
1.657
1.657
1.639
1.620
1.660
1.661
1.654
1.694
1.695
1.662
1.658
1.691
1.701
1.69
1.674
1.675
1.645
1.640
1.666
1.68
0.99
0.99
0.992
0.994
0.99
0.98
0.98
0.983
0.984
0.98
0.982
0.981
0.984
0.985
0.982
0.982
0.982
148
148
149
149
148
148
148
146
146
147
148
146
146
146
147
147
148
149
147
147
147
0.99
0.99
0.98
0.981
1.672
Figure 1. Correlations between H16 . . . O15 distance and 1H-NMR chemical shifts (
δ) for the
hydrogen bond.
In order to estimate the energy of IMHB, the open-close method was employed, which defines
the H-bond energy as the difference between the open and close conformers [39 40]. Calculations were
carried out with the functional B97XD, which presents the best correlation between experimental
,
ω
chemical shift and O16 . . . H15 distance. Table 2 shows that energy for IMHB in the studied
hydroquinones are around 15 kcal/mol. Hydroquinone 20 presents the highest value, 16.37 kcal/mol,
while 19 presents the lowest IMHB energy, 14.22 kcal/mol. These energy differences are large enough
to discard the contribution of the open form to the experimental NMR shieldings. Figure 2 shows the
correlation between Hydrogen bond energy (EHB) and 1H-NMR chemical shifts (
δ
), which presents a
R2 = 0.71, a value lower than the correlation with the O15 H16 distance (R2 = 0.89), calculated with
. . .
the same functional.

Molecules 2019, 24, 280
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Table 2. Hydrogen bond energy (EHB), calculated as the difference between open and close conformers.
Energies in kcal/mol.
Molecule
EHB
18
19
20
21
22
23
24
14.34
14.22
16.37
15.71
14.44
14.36
14.52
Figure 2. Correlation between Hydrogen bond energy (EHB) and 1H-NMR chemical shifts (δ).
(2)
The results from NBO analysis are presented in Table 3. Second order stabilization energies ∆Eij
between donor (ϕi) and acceptor orbital (ϕj) allow one to study orbital interactions responsible for the
IMHB. For all studied compounds, the HB donor atom is always an oxygen (two lone-pairs) and the
acceptor is the antibonding sigma orbital of an O-H groups (σ*OH). As we found in the geometrical
(2)
analysis, strong IMHB presence in 21 (the largest chemical shift) is in agreement with the largest
∆
Eij
(2)
obtained from the calculations with the three functionals. Nevertheless,
∆
Eij did not predict well
the weakest IMHB, corresponding to 18, and the lowest stabilization energy was not predicted by any
of the three calculations using the studied functionals. Global correlation among the chemical shift
and
indicate that the best correlation is obtained with the
∆
Eij(2) for all HQs were carried out (Figure 3). As in the geometrical analysis, correlation results
ω
B97XD functional, with R2 = 0.89. However,
in this case it was followed by B3LYP with R2 = 0.87 and then M06-2X, the one that gave the worst
correlation with R2 = 0.85.
Table 3. Second order stabilization energies (∆ σ* O11-H16
Eij(2)) between donor LP O15 and acceptor
orbitals involved in the IMHB. Energies in kcal/mol.
(2)
∆Eij LP O15 → σ* O11-H16
Molecule
B3LYP
M06-2X
ωB97XD
18
19
20
21
22
23
24
27.14
27.02
28.99
31.15
27.65
26.67
27.47
23.12
22.95
26.13
26.6
23.23
22.54
23.44
25.11
24.87
27.99
28.62
25.68
24.59
25.27

Molecules 2019, 24, 280
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Figure 3. Correlations between second order stabilization energies
1H-NMR chemical shifts (δ) for IMHB.
∆
Eij(2) LP O15 → σ* O11-H16 and
2
The QTAIM analysis is presented in Table 4. It shows negative values for ∇ ρ and H for all
studied compounds, indicating the covalent nature of their IHBs. |V|/G ratio is also a sensitive
parameter for evaluating the covalency [41,42]. V can be interpreted as the pressure exerted on the
electrons by the HB system, while G can be interpreted as the pressure exerted (as a reaction) by the
2
electrons on the HB system, at the critical point. For negative values of ∇ ρ, as occurred in all our
cases, values of |V|/G > 2 were indicative of covalent interaction [2]. Hydrogen bond energy (EHB)
was obtained from the potential energy density (V) [13]. All values were slightly above 30 kcal/mol,
while NBO analysis gave all energies slightly below 30 kcal/mol for the same interaction. These values
were approximately twice those calculated by the open-close method, which indicates that NBO and
AIM overestimate the interaction energy for the IMHB. EHB values calculated by different methods
have shown to be generally inconsistent [43]. As we found in both geometrical and NBO analysis, the
strongest IHB is obtained for compound 21 and is well represented by QTAIM analysis for the three
functionals, giving the highest EHB for 21. On the other hand, similarly to NBO analysis, here QTAIM
EHB also did not adequately reflect the weakest IMHB present in 18. Global correlations between
QTAIM EHB and chemical shifts are presented in Figure 4. A better performance is shown by
ωB97XD
and B3LYP with a R2 = 0.88. As in the above cases, M06-2X gave the worst correlation with R2 = 0.85.
The results shown in Figure 3 corroborates that correlations with the weakest IMHB of this series
are not well represented by the computational calculations employed. In order to test what is the
impact of the weakest IMHB on the correlations studied previously, compound 18 was eliminated
from the data and correlations were obtained again. The results showed a significant improvement,
without change in the relative position among different functionals and parameters studied.

Molecules 2019, 24, 280
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Table 4. Atoms-in-molecule parameters for IHB of 18–
24. Electron density at the critical point ρBCP
2
(a.u), its Laplacian ∇ ρ (a.u.), electron kinetic energy density G (a.u.), potential energy density V (a.u.),
total electron energy density H (a.u.), and hydrogen bond energy EHB (kcal/mol).
2
ρBCP
∇ ρ
Functional Molecule
G
V
|V|/G
H
EHB
18
19
20
0.0537
0.0537
0.0560
0.0587
0.0546
0.0533
0.0541
−
−
−
−
−
−
−
0.0377 0.0459
0.0378 0.0460
0.0383 0.0478
0.0392 0.0501
0.0383 0.0469
0.0374 0.0455
0.0378 0.0463
−
−
−
−
−
−
−
0.1013 2.2070
0.1015 2.2065
0.1051 2.1987
0.1100 2.1956
0.1033 2.2025
0.1003 2.2044
0.1020 2.2030
−
−
−
−
−
−
−
0.1472
0.1475
0.1529
0.1601
0.1502
0.1457
0.1483
31.91
31.96
33.12
34.65
32.54
31.59
32.14
21
B3LYP
22
23
24
18
19
20
0.0454
0.0454
0.0490
0.0495
0.0458
0.0446
0.0459
−
−
−
−
−
−
−
0.0408 0.0444
0.0409 0.0444
0.0427 0.0479
0.0428 0.0483
0.0412 0.0449
0.0402 0.0435
0.0410 0.0448
−
−
−
−
−
−
−
0.0990 2.2297
0.0990 2.2297
0.1066 2.2255
0.1074 2.2236
0.1001 2.2294
0.0970 2.2299
0.0999 2.2299
−
−
−
−
−
−
−
0.1434
0.1434
0.1545
0.1557
0.1450
0.1405
0.1448
31.19
31.19
33.57
33.83
31.53
30.57
31.48
21
M06-2X
22
23
24
18
19
20
0.0510
0.0508
0.0546
0.0553
0.0518
0.0502
0.0512
−
−
−
−
−
−
−
0.0380 0.0447
0.0381 0.0446
0.0394 0.0479
0.0396 0.0485
0.0386 0.0457
0.0376 0.0439
0.0381 0.0449
−
−
−
−
−
−
−
0.0989 2.2125
0.0987 2.2130
0.1057 2.2067
0.1069 2.2041
0.1010 2.2100
0.0973 2.2164
0.0993 2.2116
−
−
−
−
−
−
−
0.1435
0.1434
0.1536
0.1553
0.1466
0.1412
0.1442
31.14
31.10
33.30
33.66
31.81
30.64
31.29
21
ωB97XD
22
23
24
Figure 4. Correlations between hydrogen bond energy EHB (kcal/mol) and experimental chemical
shifts δ (ppm) of proton involved in IMHB.
Figure 5 shows correlations between 1H-NMR chemical shifts and O11-H16 . . . O15 distance for
the IHBs. R2 for B3LYP changed from 0.80 to 0.88, from 0.85 to 0.91 for M06-2x, and from 0.89 to 0.95
for ωB97XD.

Molecules 2019, 24, 280
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1
Figure 5. Correlations between O-H . . . O distance and H-NMR chemical shifts (
δ) for the IMHB,
excluding the weakest value.
1
Similarly, correlations between H-NMR chemical shifts and NBO energy for the IHBs are
presented in Figure 6. R2 changed from 0.88 to 0.95 for B3LYP, from 0.85 to 0.92 for M06-2X, and from
0.89 to 0.96 for ωB97XD.
Figure 6. Correlations between second order stabilization energies
experimental chemical shifts (δ) of protons involved in IMHB, excluding the weakest value.
∆
Eij(2) LP O15 → σ* O11-H16 and
Finally, correlations between 1H-NMR chemical shifts and QTAIM energy for the IHBs, presented
in Figure 7, showed a change in R2 from 0.88 to 0.94 for B3LYP, from 0.85 to 0.91 to M06-2X, and from
0.88 to 0.94 for ωB97XD.

Molecules 2019, 24, 280
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Figure 7. Correlations between hydrogen bond energy EHB (kcal/mol) and experimental chemical
shifts δ (ppm) of protons involved in IMHB, excluding the weakest value.
3. Materials and Methods
3.1. Synthetic Procedures
Melting points are uncorrected. All NMR spectra were acquired using a Bruker AVANCE DRX
300 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) operating at 300.13 MHz (1H) or
75.47 MHz (13C). Measurements were carried out at a probe temperature of 300 K.
3.1.1. 1-(5-Hydroxy-3,3,6,7-tetramethyl-2-morpholino-2,3-dihydrobenzofuran-4-yl)ethan-1-one (14)
To a solution of 1-(2,5-dihydroxy-3,4-dimethylphenyl)ethan-1-one (400 mg, 2.2 mmol) in 20 mL
of dichloromethane, Ag2O (1.28 g) was added and stirred with magnetic stirring for one hour. Then,
the filtered solution was added over a solution of 4-(2-methylprop-1-en-1-yl)morpholine (314 mg,
2.2 mmol), in CH2Cl2 (10 mL), yielding 637 mg of the furan (14) (2.0 mmol, 90% yield). 1H-NMR
δ
(CDCl3): 1.37 (s, 3H, 3-CH3); 1.45 (s, 3H, 3-CH3); 2.14 (s, 3H, Ar-CH3); 2.19 (s, 3H, Ar-CH3); 2.33–2.60
(m, 4H, 2 CH2-O); 2.61 (s, 3H, CH3CO); 3.70 (m, 4H, 2 CH2-N); 4.68 (s, 1H, O-CH-N); 7.09 (s, 1H,
5-OH). 13C-NMR
(CDCl3): 11.82; 12.51; 19.80; 31.17; 32.81; 45.07; 49.28; 66.75; 108.78; 120.94; 122.53;
123.74; 128.69; 147.01; 150.86; 205.43. M.P.: 140.1–142.2 ◦C. IR (KBr) /cm−1: 842.77; 1684.89; 2836.66;
×
×
δ
ν
2909.00; 2949.52; 2981.35; 3357.56. HRMS calculated: 319.1784; found: 319.1787.
3.1.2. 5,8-Dihydroxy-4,4,6,7-tetramethylnaphthalen-1(4H)-one (21)
A solution of furan 14 (451 mg, 1.4 mmol) in ethanol (15 mL) was refluxed for 2 h, then the
solution was poured in a mixture ice and water, and the solid precipitate was filtered and dried
1
yielding hydroquinone 21 (256 mg, 78% yield). H-NMR
δ
(CDCl3): 1.61 (s, 6H, 2
×
4-CH3); 2.23 (s, 3H,
Ar-CH3); 2.26 (s, 3H, Ar-CH3); 4.55 (s, 1H, 5-OH); 6.23 (d, 1H, J = 10 Hz, 2-H), 6.82 (d, 1H, J = 10 Hz,
3-H), 13.20 (s, 1H, 8-OH). 13C-NMR
δ(CDCl3): 11.56; 13.04; 25.17; 38.03; 112.68; 123.43; 124.04; 131.51;
131.64; 143.52; 155.12; 160.73; 191.11. P.F.: 200.5–201.6 ◦C. IR (KBr)
3406.75. HRMS calculated: 232.1099; found: 232.1113.
ν
/cm−1: 1658.84; 2963; 2998.71;
3.1.3. 8-Hydroxy-5-methoxy-4,4,6,7-tetramethylnaphthalen-1(4H)-one (22)
To a solution of hydroquinone 21 (100 mg, 0.43 mmol) in acetone (20 mL), powdered K2CO3
(85 mg, 0.6 mmol) and dimethyl sulfate (0.1 mL, 0.6 mmol) were added and stirred with magnetic

Molecules 2019, 24, 280
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stirring at reflux for 3 h. To the filtered mixture, a solution of KOH (5% in methanol) was added
and kept at room temperature overnight. Then, it was neutralized with HCl 10% and extracted with
CH2Cl2 5
×
20 mL. The organic phase was washed with water and dried with anhydrous sodium
sulfate, then was filtered and the solvent was eliminated at vacuum, by purification in flash column
chromatography with hexane/ethyl acetate (5:1) as eluent, the product 22 was obtained (79 mg, 74%
yield) 1H-NMR
δ
(CDCl3): 1.57 (s, 6H, 2
3H, 8-OCH3); 6.24 (d, 1H, J = 10 Hz, 2-H); 6.78 (d, 1H, J = 10 Hz, 3-H); 13.44 (s, 1H, 5-OH). 13C-NMR
(CDCl3): 11.39; 14.77; 27.09; 38.15; 61.49; 112.36; 124.13; 124.84; 137.88; 139.43; 149.29; 157.10; 160.76;
×
4-CH3); 2.20 (s, 3H, Ar-CH3); 2.31 (s, 3H, Ar-CH3); 3.72 (s,
δ
190.92. P.F.: 82.1–84.3 C. IR (KBr) ν
/cm−1: 1655.95; 2848.23; 2920.58; 2972.67; 3001.61; 3042.12; 3441.48.
◦
HRMS Calculated: 246.1256; found: 246.1265.
3.2. Computational Calculations
The calculations were carried out using the Gaussian 09 [44] program package (Revision a.01;
Gaussian, Inc.: Wallingford, CT, USA). No symmetry constraints were imposed on the optimizations,
which were performed at the DFT B3LYP/6-311++G (d,p) level. No imaginary vibrational frequencies
were found at the optimized geometries, indicating that they are true minima of the potential energy
surface. NBO analysis was performed using the NBOPro 6.0 [45] program package (NBO 6.0; University
of Wisconsin: Madison, WI, USA). QTAIM analysis was performed using the AIM2000 [46] program
package (Büro für innovative software, Bielefeld, Germany).
4. Conclusions
In this work, we found that O . . . H distance is the most suitable geometrical parameter for
distinguishing among IMHBs of similar strengths. Second order stabilization energies ∆
Eij(2) from NBO
analysis and hydrogen bond energy (EHB) obtained from QTAIM analysis were also able to properly
(2)
distinguish among IMHBs in the studied molecule series. In all cases,
the IMHB lower than EHB obtained from QTAIM analysis.
EHB from QTAIM gave values somewhat above 30 kcal/mol, which are approximately twice of those
calculated by the open-close method. In all cases, parameters calculated using B97XD gave the best
∆
Eij from NBO give values for
∆
Eij(2) are slightly below 30 kcal/mol, while
ω
correlations with experimental 1H-NMR chemical shifts for the IMHBs, with values of R2 around 0.89.
Despite this, the results showed that the employed parameters correctly described the strength of the
IMHB, when the weakest one was removed from the analysis, correlations improved significantly to
values around 0.95 for R2. These results can help to select the most suitable parameters for modeling
molecules with IMHBs of similar strengths and achieving an adequate distinction between them
through computational calculations.
Author Contributions: Conceptualization, M.M.-C. (Maximiliano Martínez-Cifuentes) and R.A.-M.; methodology,
M.M.-C. (Maximiliano Martínez-Cifuentes) and R.A.-M.; software M.M.-C. (Maximiliano Martínez-Cifuentes)
and M.M.-C. (Matías Monroy-Cárdenas); validation, M.M.-C. (Maximiliano Martínez-Cifuentes), R.A.-M., and
B.E.W.-L.; formal analysis, M.M.-C. (Maximiliano Martínez-Cifuentes), R.A.-M., and B.E.W.-L.; investigation,
M.M.-C. (Matías Monroy-Cárdenas), J.P.M-V., and R.A.-M.; writing—original draft preparation, M.M.-C.
(Maximiliano Martínez-Cifuentes) and R.A.-M.; writing—review and editing, M.M.-C. (Maximiliano
Martínez-Cifuentes), R.A-M., and B.E.W.-L.; project administration, M.M.-C. (Maximiliano Martínez-Cifuentes)
and R.A.-M.; funding acquisition, M.M.-C. (Maximiliano Martínez-Cifuentes), R.A.-M., and B.E.W.-L.
Funding: This research was funded by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT),
grant number 11170142 (M.M.-C. (Maximiliano Martínez-Cifuentes)) and 1180069 (R.A.-M.).
Acknowledgments: Powered@NLHPC: this research was partially supported by the supercomputing
infrastructure of the NLHPC (ECM-02). R.A-M thanks Programa de Investigación Asociativa en Cáncer Gástrico
(PIA-CG), Universidad de Talca, Talca.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2019, 24, 280
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Sample Availability: Samples of the compounds are available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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