Conformational analysis for infrared spectroscopy and theoretical calculations of some 2-bromo-2-propyl 2-aryl-acetates, ibuprofen and naproxen analogs

Article abstract of DOI:10.1016/j.molstruc.2021.130027

Conformational analysis of new para–substituted 2-bromo-2-propyl 2-aryl-acetates (Y = H, OMe, Cl, and NO₂) (R1), ibuprofen (R2), and naproxen (R3) analogs using infrared (IR) spectroscopy and theoretical calculations was performed to determine

Full text of DOI:10.1016/j.molstruc.2021.130027

Journal of Molecular Structure 1233 (2021) 130027
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Conformational analysis for infrared spectroscopy and theoretical
calculations of some 2-bromo-2-propyl 2-aryl-acetates, ibuprofen and
naproxen analogs
Ana Carolina Abbud Hanna Roque, Daniel de Carvalho Santos, Marcelo Mota Reginato,
Adriana Karla Cardoso Amorim Reis∗
Department of Chemistry, Institute of Environmental, Chemical and Pharmaceutical Sciences–Federal University of São Paulo, Rua Professor Arthur
Riedel, 275, CEP: 09972-270, Diadema Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Conformational analysis of new para–substituted 2-bromo-2-propyl 2-aryl-acetates (Y = H, OMe, Cl, and
NO2) (R1), ibuprofen (R2), and naproxen (R3) analogs using infrared (IR) spectroscopy and theoretical
calculations was performed to determine the preferential conformers of these compounds in solvents
with increasing polarity (CCl4, CH3Cl, and CH3CN). The aryl-bromo-esters were synthesized via the cou-
pling reactions of 2-bromo-2-methylpropan-1-ol and the corresponding carboxylic acids, with good yields
(∼36–70%). The IR spectra showed that these compounds presented only one conformation, and the ex-
perimental data were supported by the theoretical results obtained by density functional theory (DFT)
calculations using the 6311+G (2df, 2p) basis set. The calculations revealed that all the studied com-
pounds presented two stable geometric conformations, which agrees with the data obtained experimen-
tally in CCl4. Theses conformers are stabilized by intramolecular hydrogen bonds. However, the orbital
interaction calculations using the natural bond orbital (NBO) method showed that the ηO → σ∗C-C, ηO
Received 15 September 2020
Revised 9 January 2021
Accepted 26 January 2021
Available online 1 February 2021
Keywords:
2-Bromo-2-propyl 2-aryl-acetate
Conformational analysis
Infrared spectroscopy
Theoretical calculations
Natural bond orbital
→ σ∗C-O, ηO → σ∗
and ηO → π∗
hyper-conjugations are the main interactions that stabilize the
C-O
C-O
conformations. The compounds preferentially adopt the anti-conformation because the steric effect be-
tween the gauche bromo and oxygen atoms overrides the hyper-conjugative interactions, in addition to
the stabilizing σC-H→ σ∗
interactions in the conformers.
C-Br
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
been directed towards the development of reversible derivatives,
such as prodrugs and mutual prodrugs, via chemical modifica-
tions. Chemical modification or derivatization temporarily masks
the acidic group of NSAIDs and appears to be a promising and
fruitful method for reducing or preventing the GIT toxicity via the
local insult mechanism. [6–9]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most
widely prescribed and used for reducing pain, fever, and inflamma-
tion. [1] The pharmacological effects of NSAIDs arise from the inhi-
bition of a membrane enzyme called cyclooxygenase (COX), which
is involved in prostaglandin biosynthesis. [2] These NSAIDs com-
petitively inhibit cyclooxygenase enzymes, which are primarily re-
sponsible for the conversion of arachidonic acid into prostaglandins
in inflammatory processes. [3]
Most prodrugs from NSAIDs have been synthesized by deriva-
tization of the free carboxylic group (-COOH) of the NSAID. [8,9]
Among the various types of prodrugs, esters and amides are the
most common. Many researchers have reported that the conver-
sion of the carboxylic group of NSAIDs to amide functional groups
increases their selectivity towards COX-2 and helps in decreasing
the GI toxicity of the parent drug. [10]
The discovery of two isoforms COX-1 and COX-2 in 1990 helped
scientists understand the side-effects of NSAIDs. [4] The major
drawback of long-term use of NSAIDs is their gastrointestinal (GI)
toxicity, which arises from the inhibition of COX-1 activity and
includes upper GI irritation, ulceration, dyspepsia, bleeding, and
in some cases, death. [2,4,5] Recently, considerable attention has
For the ester derivatives, the authors proposed that hydrolysis
of the synthesized prodrugs probably occurs via cleavage of the
ester bond by esterase in the intestine, but not in the stomach
where it was hypothesized to remain as an intact molecule. Thus,
the gastric side-effects produced by NSAIDs are prevented by the
ester derivatives. [10,11]
∗
Corresponding author at: 275, CEP: 09972-270, Diadema, São Paulo, Brazil.
E-mail address: adriana.amorim@unifesp.br (A.C.A.H. Roque).
https://doi.org/10.1016/j.molstruc.2021.130027
0022-2860/© 2021 Elsevier B.V. All rights reserved.

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
The stable conformations of the NSAID aryl acetic amfenac (2-
amino-3-benzoylphenylacetic acid) and its 19 substituted deriva-
tives were studied to correlate their biological activities with struc-
tural parameters. The geometries of amfenac in the neutral and an-
ionic forms were totally optimized, based on standard geometries
and crystallographic data, using semiempirical AM1 and MNDO
quantum-mechanical methods. The conformational analysis shows
the existence of a rigid structure for rotations of the acetic acid
chain and the central carbonyl group around the bonds with the
phenylamine ring, whereas the carboxyl group and phenyl ring of
the benzoyl group can rotate almost freely. [12]
ibuprofen with thiosemicarbazide in the presence of POCl3. The
compound crystallizes in the triclinic system with space group
P-1 as discrete cations and chloride anions with two enan-
tiomers in the asymmetric unit. Full vibrational analysis of the
Fourier-transform infrared (FT-IR) and Fourier-transform Raman
(FT-Raman) spectra has been performed in conjunction with quan-
tum chemical calculations. The experimental data are consistent
with the presence of the thiadiazole NH protonated form in the
solid phase. The observation of the ν(N-N) and δ(C-N-N) normal
modes as strong signals in the IR and Raman spectra at 1189 (1180
cm−1) and 774 cm−1, respectively, suggests an N-N bond with
partial double-bond character in the thiadiazole moiety, consis-
tent with the computed results at the B3LYP/6-311++G(d,p) level
of approximation. The NBO analysis showed that the sulfur lone
pair and the exocyclic amine nitrogen lone pair orbitals both con-
NSAIDs
block
proteinoid
biosynthesis
by
inhibiting
prostaglandin H2 synthase (EC 1.14.99.1) in either rapidly re-
versible competitive or slow tight-binding mode. These different
modes of inhibition correlate with clinically important differences
in the isoform selectivity. Hypotheses have been advanced to ex-
plain the different inhibition kinetics, but no structural data have
been available to test them. The crystal structures of prostaglandin
H2 synthase-1 show that the enzyme forms complexes with
the inhibitors ibuprofen, methyl flurbiprofen, flurbiprofen, and
tributed to strong resonance interactions with the adjacent π∗
antibonding orbital of the protonated thiadiazole group. [16]
(N=C)
Previously,
esters, para–substituted
methyl-2-(sulfanyl)propyl
a conformational study of new S-nitrosothiol
S-nitrosothiol
derivatives,
ibuprofen deriva-
derivative of
2-
phenylacetates,
˚
alclofenac with distances of 2.6–2.75 A. These structures allow
tives, 2-(4-isobutylphenyl)propanoato, and
a
direct comparison of the enzyme complexes with reversible com-
petitive inhibitors (ibuprofen and methyl flurbiprofen) and slow
tight-binding inhibitors (alclofenac and flurbiprofen). The four
inhibitors bind to the same site and adopt similar conforma-
tions. In all the four complexes, the enzyme structure remains
essentially unchanged, exhibiting only minimal differences in the
inhibitor binding site. These results strongly oppose the hypothe-
ses explaining the difference between slow tight-binding and fast
reversible competitive inhibition by invoking global conformational
differences or different inhibitor binding sites. [13]
naproxen 2-(4-isobutylphenyl)-propanoate with 2-methyl-l-2-
(nitrososulfanyl)propyl was performed using IR spectroscopy
in solvents with increasing polarity, combined with theoretical
calculations, to determine the preferential conformers and the
potential of these compounds for nitric oxide (NO) release. The IR
spectra showed that these compounds present only one anticlinal
(ac) geometric conformation, and the experimental data were
supported by the theoretical results obtained by density functional
theory (DFT) calculations using the 6311+G (2df, 2p) basis set.
The calculation of the orbital interactions using the NBO method
Modeling studies suggest that while both the R-(R)- and R-(S)-
stereoisomers of the indomethacin ethanol-amide derivative can be
well accommodated in the binding site, the R-(R)-isomers must
adopt an energetically strained conformation compared to the R-
(S)-isomers to form a comparable set of hydrogen bonds and van
der Waals interactions with the enzyme. [14]
showed that the nO(NO) → σ(SN)
∗
hyperconjugative interaction
increased the S–N bond length, and strong nS → π(NO)∗ interaction
and electronic delocalization induced partial π character into
the S–N bond, which increased the capacity for NO release from
SNO-ESTERS. [17]
In this study, we synthesize the S-nitrosothiols 2-methyl-
The structural and conformational investigations were per-
formed experimentally in solution via NMR analysis of common
flexible salicylate and 2-aryl propionic acid NSAIDs by using a com-
bination of RDCs in PBLG-based weakly ordering liquid-crystalline
solvents, along with the AP-DPD theoretical approach. By apply-
ing this methodology, conformational descriptions have been ob-
tained for all the studied drugs from the simplest cases of diflu-
nisal and phenyl salicylic acid (which is characterized by a sin-
gle internal rotation), to the more complex cases with more inter-
nal torsions, i.e., naproxen, flurbiprofen, ibuprofen, and ketoprofen.
The AP-DPD theoretical model is a solid approach for treating the
2-(nitroso-sulfanyl)
propyl-phenylacetate-para-substituted
R1,
2-methyl-2-(nitrosothio)-propyl-2-(4-isobutylphenyl)-propanoate
R2, and 2-methyl-2-(nitrosothio)propyl-2-(6-methoxynaphthalen-
2-yl)propanoate R3 (derivatives of ibuprofen and naproxen,
respectively). A conformational study of the compounds is per-
formed using IR spectroscopy and theoretical calculations. This
combination of experimental and theoretical approaches en-
ables us to determine the most stable conformation that these
molecules can assume in relation to the carbonyl group. These
compounds are used as precursors of a series of novel substi-
tuted N-benzylamide NSAID conjugates that are synthesized via
unimolecular nucleophilic substitution reactions.
2. Materials and methods
experimental data for highly oriented molecules with no more
than two rotations and weakly oriented drug molecules charac-
terized by more complex conformational flexibilities. An interest-
ing aspect of the AP-DPD strategy is that for a given molecule, it
is possible to treat noncoupled rotations of the various molecular
fragments and combine the results to describe the entire molecule.
[15]
2.1. Synthesis of aryl-bromo-esters
The aryl-bromo-esters (R1–R3) were prepared from the cou-
pling reaction of intermediate 2, which was obtained from the
reaction of compound 1 with LiAlH4, which led to the reduction
of the ester group to the alcohol (2) with the corresponding car-
boxylic acids [18]. The aryl-bromo-esters R1–R3 were obtained in
moderate-to-good yields (36–70%) using the method in Scheme 1.
The ibuprofen derivative 5-(1-(4-isobutylphenyl)ethyl)-1,3,4-
thiadiazol-2-amine hydrochloride is prepared by cyclization of
2

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Scheme 1. Synthesis of Aryl-bromo-esters (R1-R3).
Table 1
Frequencies (ν, cm−1) and intensity ratios of carbonyl stretching bands (P, %) in the infrared
spectrum for the compounds 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted
R1(Y = H, OMe, Cl and NO2), 2-bromo-2-methylpropyl 2-(4-isobutyl-phenyl)propanoate
(derivative of Ibuprofen) R2 and 2-bromo-2-methylpropyl 2-(6-methoxynaphthalen-2-
yl)propanoate (derivative of Naproxen) R3, in solvents of increasing polarity.
Comp.
Y
P
CCl4
P
CHCl3
P
CH3CN
P
νCO
2νCO
νCO
νCO
R1
OMe
H
1743
1759
1743
1754
1747
-
90
10
70
30
100
-
3469
3492
3471
3493
3474
-
84
16
77
23
100
-
1725
1738
1729
1741
1729
1741
1734
1744
1724
1736
1720
1734
18
72
41
59
36
64
44
56
33
67
18
82
1738
1748
1738
1748
1737
1746
1742
1757
1725
1738
1728
1738
76
24
73
27
55
45
92
8
Cl
NO2
1748
1761
1731
1743
1734
1744
84
16
10
90
21
79
3474
3489
3450
3470
3451
3468
69
31
22
78
17
83
R2
R3
87
13
18
82
Each compound was purified by column chromatography on sil-
ica gel using hexane/ethyl acetate as the eluent. The structures of
all the compounds were determined by 1H NMR, 13C NMR, GC-MS
(ESI), elemental analysis, and IR (Supporting Information).
2.3. Computational methods
Calculations were performed using the Gaussian 09 program
[20] in Linux environment with 64-bits Ubuntu with three servers,
two of which contained 16 processors in two Intel® Xeon eight-
core E5-26770 sockets of 2.6 GHz, 128 GB RAM, and a 9-TB disk,
while the other contained two Intel® Xeon® six-core 5560 sockets,
12 processors with 96 GB of RAM, and a 3-TB disk.
2.2. Infrared spectroscopy
Representations of the molecular structures were plotted in the
Gaussview [21] and ChemCraft [22] visualization programs.
Density functional theory (DFT) was applied to investigate the
conformational changes with the functional hybrid B3LYP [23–
25] and standard 6-311+G (2df,2p) basis set. The orbital interac-
tions were calculated in NBO 3.1 [26].
Infrared spectra for the solutions were obtained on a FT-IR
Michelson BomemTM MB100 spectrometer with 1.0 cm–1 resolu-
tion, in the 4000–600 cm–1 range. The solutions were properly
prepared at a concentration of 0.02 mol•L–1 in CCl4, CH3Cl, and
CH3CN. For measurement of the carbonyl stretching band, we used
a NaCl cell with a 0.5-mm optical path. The determinations in the
first harmonic region were obtained in a quartz cell with a 1.0-cm
optical path, in CCl4. The GRAMS/4.04 program was used to ana-
lyze the bands [19]. The population of conformers was estimated
from the maximum of each component of the resolved carbonyl
doublet, and was expressed as a percentage of the absorbance,
assuming equimolar absorptivity coefficients for the referred con-
formers.
3. Results and discussion
3.1. Infrared spectroscopy analysis
Table 1 shows the frequency and intensity of the carbonyl
stretching bands of compounds R1–R3, which were analytically
3

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Fig. 1. IR analytically resolved carbonyl stretching bands of 2-bromo-2-methylpropyl 2-(4-isobutylphenyl)propanoate R2, ibuprofen derivative, in carbon tetrachloride [(A)first
overtone and (C)fundamental)], chloroform (C) and acetonitrile (D).
solved for the νC=O fundamental transition, in solvents with in-
creasing polarity (CCl4, ε = 2.22; CHCl3, ε = 4.7; CH3CN, ε = 35.68)
and in the first harmonic region recorded in CCl4.
For compounds R1–R3, analysis shows that these bands exhibit
the same behavior in both the fundamental state and the first har-
monic region in CCl4, (Fig. 1, for R2). Two bands were observed
in the carbonyl stretching region (νC=O) and the first harmonic re-
gion, corresponding to twice the frequency observed in the funda-
mental region minus an anharmonicity value. All the compounds
except R1 (Y = Cl), which has one single carbonyl stretching band,
exhibited identical behavior.
The lowest frequency band for compound R1 in CCl4 (ε = 2.22)
Fig. 2. Selected dihedral angles in conformational search, SC1=C1-C2-C3-O4 and
corresponds to the highest population. In contrast, for compounds
SC2=C3-O5-C6-C7 in relation to carbonyl group, for the R1–R3 compounds.
R2 and R3, the highest frequency band corresponded to the high-
est population. The opposite behavior was observed in CHCl3
(ε = 4.7) for all the investigated compounds except R3, for which
we performed a relaxed double scan, considering two dihedral an-
the band population followed the same trend as observed in CCl4.
The same behavior was observed in the most polar solvent
(CH3CN (ε = 35.68)) as well as in the least polar solvent (CCl4)
for compounds R1 and R3 (naproxen derivatives). However, com-
pound R2 (an ibuprofen derivative) exhibited the opposite behav-
ior, where the lowest frequency conformer displayed the highest
population.
gles to have the greatest influence on the conformations of this se-
ries of compounds in relation to the carbonyl group. The Gaussian
09 [18] program was used to construct the surface graphs, which
display the conformer energy as a function of the rotational move-
ment applied to the two dihedral angles (Fig. 2).
The selected angles were rotated at intervals from 10 to 360°
(dihedral angles SC1 = C1-C2-C3-O4 and SC2 = C3-O5-C6-C7) using
density functional theory (DFT) with the B3LYP hybrid functional
[19–22]. The description of the atomic centers (H, C, O, N, and Br)
utilized the standard 6-31G(d,p) data set (Fig. 3).
Another important observation from Table 1 is that increasing
the solvent polarity modified the behavior of compounds R1–R3
and caused a decrease in the carbonyl stretching frequency for all
bands. These results are consistent with the fact that the C=O bond
order decreases in more polar solvents, which causes a decrease in
the νC=O value.
3.3. Theoretical calculations: conformational equilibrium
After identifying the minimum on the potential surface graphs,
the corresponding conformations were optimized at the DFT-
B3LYP/6-311+G(2df,2p) and DFT-M062X/6-311+G(2df,2p) levels of
theory to identify all the significant differences between the two
methods. The dihedral angles were assigned in relation to the α
dihedral angle (Fig. 4).
3.2. Conformational search using theoretical calculations
A conformational search was performed for compounds R1-R3
to determine the main (most stable) conformation. To ensure that
no degrees of freedom in the studied molecules were neglected,
4

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Fig. 3. Energy surface graphics as a function of the rotation of SC1=C1-C2-C3-O4 and SC2=C3-O5-C6-C7 dihedral angles, optimized at AM1 semi-empirical level, for the
R1–R3 compounds.
conformation with 0.60 kcal.mol–1 energy and low polarity (2.56
D). The νC=O values for the two conformers differ by 8 cm–1
(Fig. 5).
A search using two density functionals is necessary to deter-
mine the method with the best correlation to the experimental
data. The DFT-BYLYP level provided a more precise approximation
of the populations of the conformers than the DFT-M062X level,
where the latter showed the conversion of one of the local min-
Fig. 4. The α=C1-C2-C3-O4 dihedral angle.
ima into a global minimum in the identified conformations.
The DFT-B3LYP/6-311+G(2df,2p) calculations of the global min-
imum in relation to α = C1-C2-C3-O4 indicated the stability of the
A search using two density functionals is necessary to deter-
following conformations: the gauche conformation (g) was pref-
erential for compound R1 (Y = NO2) and was preferred for com-
pounds R1 (Y = H, OMe, and Cl) when there was a small variation
in the dihedral angle; R2 and R3 preferentially adopted an anti-
clinal (ac) and quasi-gauche (q-g) geometry, respectively (Table 2).
The local minima (highest energy conformers) for R1 (Y = H, OMe,
Cl, and NO2) were calculated and the a and b dihedral angles in
the global minimum (lowest energy conformers) were significantly
different from those in higher energy conformers. However, com-
pounds R2 and R3 did not display any significant variation be-
tween the lowest and highest energy conformations, where both
adopted an anti-clinal (ac) conformation.
mine the method with the best correlation to the experimental
data. The DFT-BYLYP level was more precise for determining the
populations compared to the DFT-M062X level, where the latter
showed the conversion of one of the local minima into a global
minimum in the identified conformations.
The results obtained using the DFT-B3LYP/6-311+G(2df,2p) cal-
culations for the global minimum in relation to α = C1-C2-C3-
O4 indicated the stability of the following conformations: com-
pound R1 (Y = NO2) preferentially adopts a gauche conformation
(g); when there is a small variation in the dihedral angle for com-
pounds R1 (Y = H, OMe, and Cl) and R2–R3, an anti-clinal (ac) and
quasi-gauche (q-g) geometry is preferentially formed (Table 2). The
local minima (highest energy conformers) for R1 (Y = H, OMe, Cl,
and NO2) were calculated, and the a and b dihedral angles were
found to differ significantly for higher energy conformers in rela-
tion to the global minimum (lowest energy conformers).
Compound R1 (Y = OMe) presents two stable conformations: a
low-energy anti-clinal (ac1) conformation with 73% population, 0
kcal.mol–1 energy, and high polarity (4.51 D), and a gauche (g2)
conformation with 0.60 kcal.mol–1 energy and low polarity (2.56
D). The νC=O values for the two conformers differ by 8 cm–1
(Fig. 5).
However, for compounds R2 and R3, the lowest and highest
energy conformations were not significantly different, where both
adopted an anti-clinal (ac) conformation.
Compound R1 (Y = H) preferentially adopts two conformations:
a low-energy anti-clinal (ac1) conformation with 75% population,
0 kcal.mol–1 energy, and high polarity (3.30 D) and a less stable
gauche (g2) conformation with 0.65 kcal.mol–1 energy and low po-
Compound R1 (Y = OMe) presents two stable conformations: a
low-energy anti-clinal (ac1) conformation with 73% population, 0
kcal.mol–1 energy, and high polarity (4.51 D), and a gauche (g2)
5

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Table 2
Relative free energy (kcal mol−1), relative population (%), calculated stretching band (νC=O, cm−1), dipole moment (μ/D) and selected dihedral angles (deg) for the different
conformers of 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted R1 (X = H, OMe, Cl and NO2), 2-bromo-2-methylpropyl-2-(4-isobutylphenyl)propanoate (derivative of
Ibuprofen) R2 and-2-bromo-2-methylpropyl 2-(6-methoxynaphthalen-2-yl)propanoate (derivative of Naproxen) R3, at the DFT/6-311+G (2df.2p) level of theory.
Dihedral angles /o c
Comp.
Y
Conf.
aE
bP (%)
dνC=O
μ/D
α
β
γ
δ
ε
φ
ω
ϕ
α’
β’
R1
OMe
ac(1)
g(1)
0
73
27
75
25
100
66
34
11
89
10
90
1790
1798
1790
1799
1788
1790
1800
1782
1788
1783
1787
4.51
2.56
3.30
2.89
3.06
6.97
6.61
3.90
3.56
3.73
4.90
96.67
-35.57
-95.26
-37.05
3.06
-82.29
146.50
83.73
145.01
94.01
90.06
15.01
73.32
-84.94
81.99
-85.54
178.50
175.37
-178.70
175.13
177.47
176.02
179.22
-178.59
177.63
-178.12
-174.76
-112.65
114.72
112.52
116.42
-175.61
178.03
-144.0
-0.47
-2.57
0.29
61.07
-66.60
61.18
61.59
-63.45
54.0
67.32
61.87
-67.25
-66.89
64.88
179.41
61.39
63.46
-60.91
-64.35
-61.20
-176.64
177.56
177.82
177.25
-179.25
-64.61
-
-
0.60
0
-
-
H
ac(1)
g(1)
-
-
0.65
0
-2.82
-1.27
2.74
-
-
Cl
ac(1)
g(1)
-
-
NO2
0
-88.09
-23.42
-107.62
-94.0
-
-
c(1)
0.38
1.23
0
0.64
57.0
177.11
179.23
-176.64
179.21
-176.86
-
-
R2
R3
ac(2)
ac(1)
ac(2)
ac(1)
175.05
-116.04
-175.90
-116.04
1.09
-64.96
67.41
64.18
67.28
124.02
-30.72
134.54
-31.24
-56.25
150.32
-46.14
-144.68
-1.32
1.20
1.29
0
-97.32
93.52
-0.54
a
The relative free Gibbs energy (relative electronic energy plus ZPE correction).
b
The relative population is reported as a percentage. eα=C(1)-C(2)-C(3)-O(4); β=C(1)-C(2)-C(3)-O(5); γ =C(2)-C(3)-O(5)-C(6); δ=C(3)-O(5)-C(6)-C(7); ε=O(4)-C(3)-O(5)-
C(6);φ=O(5)-C(6)-C(7)-C(8); ω=O(5)-C(6)-C(7)-C(9); ϕ=O(5)-C(6)-C(7)-Br(10); α’=C(13)-C(2)-C(3)-O(4); β’=C(13)-C(2)-C(3)-O(5).
larity (2.89 D). The difference in the calculated νCO values for the
two equilibrium geometries was 9 cm–1. A single stable anti-clinal
(ac1) conformation was found for compound R1 (Y = Cl), with a
dipole moment of 3.06 D and a carbonyl stretching frequency of
1788 cm–1. Two stable conformations were identified for com-
pound R1 (Y = NO2): a low-energy gauche (g1) conformation with
66% population, 0 kcal.mol–1 energy, and high polarity (6.97 D),
and a less stable conformation cis (c2) with 0.38 kcal.mol–1 energy
and low polarity (6.61 D). The difference in the calculated νC=O
values for the two conformations was 10 cm–1
.
Compound R2 (ibuprofen derivative) displayed two stable con-
formations: a low-energy gauche (ac1) conformation with 89%
population, 0 kcal.mol–1 energy, and low polarity (3.56 D) and a
less stable anti-clinal (ac2) conformation with 1.23 kcal.mol–1 en-
ergy and high polarity (3.90 D). The difference in the calculated
νC=O values for the two conformations was 6 cm–1. Two stable
conformations were also observed for compound R3 (a naproxen
derivative): a low-energy anti-clinal (ac1) conformation with 90%
population, 0 kcal.mol–1 energy, and low polarity (3.73 D) and a
less stable anti-clinal (ac2) conformer with 1.29 kcal.mol–1 energy
and high polarity (4.90 D). The corresponding νC=O values for the
two structures differ by 5 cm–1
.
No significant changes were found in the other dihedral an-
gles in all stable conformers of compounds R1–R3. The calculated
carbonyl stretching frequencies for all the studied compounds and
the relative populations of the conformers were consistent with
the experimentally obtained values from the IR spectra recorded
in CCl4. Thus, it is inferred that the two bands found in the
IR spectra must correspond to the two computationally found
conformations.
3.4. Calculations with solvent effects
Theoretical calculations conducted for the gas phase indicate
that compounds R1–R3 adopt the ac conformation, except for R1
with Y = Cl for which the minimum energy corresponds to the g
conformation.
Fig. 5. Structural representations calculated at the DFT / B3LYP / 6-311 + G (2df,
2p) level of theory for the lowest energy (A) and highest energy (B) conformers of
2-bromo-2-methylpropyl 2-(4’-methoxyphenylacetate) [R1 (Y= OMe)].
6

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Table 3
Relative free energy (kcal mol−1), relative population (%), calculated stretching band (νC=O/cm−1), dipole moment (μ/D), and selected dihedral angles (deg) for the different
conformers of 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted R1 (X = H, OMe, Cl and NO2), 2-bromo-2-methylpropyl 2-(4-isobutylphenyl)propanoate (derivative of
Ibuprofen) R2 and 2-bromo-2-methylpropyl 2-(6-methoxynaphthalen-2-yl)propanoate (derivative of Naproxen) R3, at the DFT-M062X/6-311+G(2df,2p) level of theory and
IEF PCM method (polarizable continuum model).
c
Dihedral angles /o
Comp
Y
Conf.
aE
bP (%)
dνC=O
μ/D
α
β
γ
δ
ε
φ
ω
ϕ
α’
β’
R1
OMe
H
ac(1)
ac(1)
g(1)
0
100
98
2
1855
1856
1857
1857
1860
1862
1849
1852
1852
1853
4.35
2.81
2.81
2.99
6.62
5.87
3.64
3.92
3.84
4.52
96.80
79.63
78.53
141.76
-74.20
76.66
164.69
63.76
-81.27
63.69
-81.00
-168.89
169.29
177.05
174.75
-172.32
177.86
-177.43
168.47
-177.30
168.98
-100.71
100.30
100.94
-173.23
172.73
-100.88
165.45
-102.01
171.53
-99.41
7.57
7.38
1.33
-3.51
5.61
-0.56
2.70
-8.20
2.59
-7.78
63.45
62.41
61.63
63.21
55.84
63.52
61.20
64.85
61.99
66.45
62.95
-179.50
178.97
178.00
179.90
-62.66
-
-
0
-98.13
-39.86
103.66
-101.23
-16.90
-116.34
95.38
-64.30
-65.15
-63.37
-179.26
-63.18
-65.07
-61.35
-64.45
-59.93
2.43
0
Cl
ac(1)
g(1)
100
75
24
1
NO2
0
c(1)
0.67
2.55
0
-179.83
178.01
-178.08
178.78
-178.56
R2
R3
ac(1)
ac(2)
ac(2)
ac(1)
117.33
154.77
177.42
154.73
-62.52
-28.62
-62.67
-28.52
99
2
2.48
0
-116.21
95.74
92
a
The relative free Gibbs energy (relative electronic energy plus ZPE correction).
b
The relative population is reported as
a
percentage.c α=C(1)-C(2)-C(3)-O(4);β=C(1)-C(2)-C(3)-O(5);γ =C(2)-C(3)-O(5)-C(6);δ=C(3)-O(5)-C(6)-C(7);ε=O(4)-C(3)-O(5)-
C(6);φ=O(5)-C(6)-C(7)-C(8);ω=O(5)-C(6)-C(7)-C(9);ϕ=O(5)-C(6)-C(7)-S(10); ꢀ= C(7)-S(10)-N(13)-O(14); α’=C(15)-C(2)-C(3)-O(4); β’=C(15)-C(2)-C(3)-O(5).
The solvent effects were incorporated using the IEF PCM
method (polarizable continuum model) [27]. The starting geome-
tries were obtained from the gas-state calculations and optimized;
the carbonyl stretching frequencies and relative conformer popula-
tions are shown in Table 3. Overall, the solvent exerted a consider-
able effect on the calculated conformations.
trend was not pronounced for R2 and R3, which is attributed to
the presence of the methyl group in the α-position, which reduces
the possibility of forming intramolecular hydrogen bonds with the
carbonyl group and makes solvation difficult. Solvation calcula-
tions using IEF PCM failed to accurately describe the experimen-
tal data, but the trends were very similar to the experimental re-
sults. We believe that the use of other solvation calculation meth-
ods such as PCM-SMD or even IEF PCM, which specifies the solvent
molecule in the starting geometry, may lead to more satisfactory
results.
IEF PCM did not exactly reproduce the experimentally observed
behavior, but indicated a clear trend in polar solvents, where there
was a population inversion for compound R1 compared to the ex-
perimental data. In the ac conformers, solvation of the carbonyl re-
gion is less hindered, which may justify the observed results. This
Fig. 6. Molecular graphs for the ac conformers of the compounds R1(Y= H, OMe, Cl and NO2) showing electrostatic and charge transfer (intramolecular hydrogen bonds)
interactions between the negative oxygen atoms in the carbonyl and the ester groups and the adjacent hydrogen atoms.
7

Table 4
Energy of orbital interactions calculated by the Natural Bond Orbital method (kcal.mol−1) for the 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted R1 (X = H. OMe. Cl and NO2).
R1 Y=OMe
R1 Y=H
R1 Y=Cl
R1 Y = NO2
Orbital Interaction
ac(1)
g(1)
Orbital Interaction
ac(1)
g(1)
Orbital Interaction
ac(1)
Orbital Interaction
g(1)
c(1)
σ
π
σ
σ
C(2)-C(3)→σ∗
3.55
1.09
1.17
3.25
18.09
2.68
3.91
3.97
-
3.24
-
πC(3)-C(4)→σ∗
1.92
3.32
0.99
-
2.28
-
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
C(3)-C(4)→σ∗
3.46
2.24
2.42
2.45
3.33
3.68
3.06
2.13
4.07
4.84
4.02
4.11
4.03
4.09
18.87
35.12
7.81
48.35
πC(2)-C(4)→σ∗
3.01
1.14
3.47
4.46
3.59
20.86
-
3.36
C(2)-C(3)→σ∗C(3)-C(4)
πC(3)-C(4)→σ∗C(12)-H(14)
C(3)-C(4)→σ∗C(2)-C(3)
C(1)-C(2)
πC(2)-C(4)→π∗C(11)-C(14)
-
C(14)-O(15)
C(12)-H(14)
C(11)-C(14)
C(3)-C(11)→σ∗
-
π
σ
σ
σ
π
π
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
C(3)-C(4)→π∗
-
C(3)-C(4)→σ∗C(5)-H(10)
σC(3)-C(11)→π∗
1.91
C(3)-C(11)→π∗C(14)-O(15)
C(2)-C(3)
4.27
17.69
4.09
-
C(3)-C(12)→σ∗
1.73
-
C(3)-C(11)→σ∗
σC(3)-C(11)→σ∗ C(14)-O(15)
-
C(15)-O(16)
C(14)-O(15)
C(14)-O(15)
πC(4)-C(5)→π∗
C(3)-C(12)→σ∗C(15)-O(17)
C(15)-O(16)
1.11
3.26
20.34
20.12
3.82
3.79
3.52
2.57
2.55
2.23
-
C(3)-C(11)→π∗C(4)-C(5)
σC(4)-H(9)→σ∗
-
C(14)-O(15)
σC(11)-H(12)→ σ∗
C(3)-C(12)→π∗C(15)-O(16)
-
C(5)-C(6)→σ∗
πC(5)-C(6)→π∗C(5)-C(6)
20.35
3.53
2.75
2.38
-
σC(11)-H(12)→ σ∗C(2)-C(3)
σC(11)-H(13)→ σ∗C(14)-O(16)
σC(11)-H(13)→ σ∗C(3)-C(4)
σC(11)-H(13)→ σ∗C(14)-O(15)
σC(11)-H(13)→ π∗C(14)-O(15)
σC(11)-C(14)→ π∗ C(14)-O(15)
σC(11)-C(13)→ σ∗ C(2)-C(3)
σC(17)-H(19)→ σ∗O(16)-C(17)
C(5)-C(6)→π∗
19.90
20.03
-
C(5)-C(6)→σ∗C(1)-C(6)
C(4)-H(9)
σC(11)-H(12)→σ∗
C(1)-C(2)
2.40
1.56
4.27
6.80
1.92
3.97
3.85
-
C(5)-C(6)→π∗C(1)-C(2)
C(5)-C(6)→σ∗C(4)-C(5)
σC(11)-H(12)→σ∗C(2)-C(3)
σC(11)-H(12)→σ∗C(14)-O(15)
σC(11)-H(12)→π∗C(3)-C(4)
σC(11)-H(12)→σ∗ C(3)-C(4)
σC(11)-H(12)→π∗C(14)-O(15)
σC(11)-H(13)→σ∗ C(14)-O(15)
σC(11)-H(13)→π∗C(2)-C(3)
σC(11)-H(13)→σ∗ C(14)-O(15)
σC(11)-C(14)→π∗ C(4)-O(16)
σC(11)-C(14)→σ∗ C(3)-C(4)
σC(11)-C(14)→σ∗C(3)-C(11)
σC(11)-C(14)→σ∗C(14)-O(15)
σO(16)-C(20)→σ∗O(16)-C(20)
σC(20)-H(21)→σ∗C(11)-C(14)
σC(20)-H(22)→σ∗C(23)-Br(32)
σC(23)-C(28)→σ∗ C(23)-C(24)
-
C(3)-C(4)
C(5)-H(10)→σ∗
C(11)-C(14)→σ∗
3.47
1.05
3.99
1.36
3.33
1.57
3.25
2.74
1.03
1.15
4.15
2.33
7.04
4.00
2.97
6.84
2.32
19.23
34.96
7.93
49.75
4.75
4.74
O(16)-C(18)
3.45
2.76
2.39
4.16
3.90
4.06
2.36
18.65
35.44
8.34
2.64
1.11
47.33
C(6)-H(11)→σ∗C(15)-O(16)
-
C(21)-Br(14)→σ∗
C(4)-C(5)
O(16)-C(18)
C(12)-H(13)→σ∗
4.28
1.46
2.39
2.52
6.67
-
C(22)-H(23)→σ∗
6.27
-
C(12)-H(13)→π∗C(15)-O(16)
C(12)-H(14)→σ∗ C(15)-O(16)
C(12)-H(14)→π∗C(15)-O(16)
C(12)-H(14)→σ∗ C(3)-O(4)
C(12)-H(14)→σ∗C(15)-O(16)
C(12)-C(15)→σ∗ C(15)-O(17)
C(22)-H(25)→σ∗C(18)-C(21)
C(22)-H(25)→σ∗C(21)-C(26)
C(21)-C(22)
-
C(26)-H(28)→σ∗C(21)-C(26)
-
σC(21)-H(22)→ σ∗C(20)-C(25)
η2 O(15)→σ∗
-
C(20)-C(25)
η1 O(15)→ σ∗
2.27
19.45
35.65
8.11
1.06
2.64
44.75
3.83
1.03
1.06
18.77
35.33
8.40
47.77
3.65
η2 O(15)→σ∗C(11)-C(14)
1.04
η2 O(15)→ σ∗C(11)-C(14)
η2 O(15)→ σ∗C(11)-C(14)
η1 O(16)→ σ∗C(14)-O(16)
η1 O(16)→ σ∗C(14)-O(15)
η1 O(16)→ σ∗C(17)-H(18)
-
η1 O(16)→σ∗C(11)-O(16)
C(14)-O(15)
C(12)-C(15)→σ∗C(3)-C(4)
-
η2 O(16)→σ∗C(14)-O(15)
C(3)-C(12)
η2 O(16)→ σ∗
19.56
35.58
8.13
44.58
3.43
4.01
2.20
2.60
3.83
-
η2 O(16)→ σ∗C(12)-C(15)
η1 O(16)→ σ∗C(15)-O(17)
η2 O(16)→ σ∗C(15)-O(17)
η2 O(16)→ π∗C(17)-H(19)
C(14)-O(15)
η12O(16)→ σ∗C(15)-O(16)
C(18)-c(21)
σC(28)-H(31)→σ∗O(16)-C(20)
5.02
7.05
20.40
35.18
8.40
46.63
3.18
3.46
C(23)-Br(32)
η1 O(15)→σ∗
η2 O(15)→σ∗C(11)-C(14)
η2 O(15)→σ∗C(11)-C(14)
η1 O(16)→σ∗C(14)-O(16)
η1 O(16)→π∗C(14)-O(15)
η2 O(16)→σ∗ C(14)-O(15)
η2 O(16)→σ∗C(20)-H(21)
C(20)-H(22)
ꢁ (kcal.mol−1
)
136.59
ꢁ (kcal.mol−1
)
113.93
158.08
ꢁ (kcal.mol−1
ꢁ (kcal.mol−1
)
)
197.71
210.48
172.54
186.55
.54

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Table 5
Energy of electronic interactions calculated by the Natural Bond Orbital method (kcal.mol-1), for the
2-bromo-2-methylpropyl 2-(4-isobutylphenyl)propanoate (derivative of Ibuprofen) R2 and 2-bromo-
2-methylpropyl 2-(6-methoxynaphthalen-2-yl)propanoate (derivative of Naproxen) R3.
R2 Ibuprofen
R3 Naproxen
Orbital interaction
ac(2)
ac(1)
Orbital interaction
ac(2)
ac(1)
σ
C(1)-C(6)→σ∗
-
3.22
2.82
2.74
2.75
2.37
3.10
1.31
4.57
3.92
4.60
3.71
2.68
2.59
4.12
1.28
2.07
1.06
4.32
π
π
π
C(9)-C(14)→π∗
15.76
16.92
17.31
4.29
-
15.88
17.25
16.81
4.37
1.01
2.59
3.75
2.54
2.12
2.53
1.95
4.11
2.94
2.68
3.87
1.50
1.05
5.00
C(1)-C(2)
πC(2)-C(3)→σ∗
-
C(9)-C(14)→π∗C(3)-C(4)
C(9)-C(14)
πC(2)-C(3)→σ∗C(11)-C(13)
C(2)-H(8)
3.53
2.66
2.30
2.91
-
C(10)-C(13)→π∗
C(10)-C(13)
σC(3)-C(4)→σ∗ C(11)-C(16)
σC(14)-H(16)→σ∗
σC(3)-C(11)→σ∗
σC(17)-H(18)→σ∗C(3)-C(9)
σC(14)-H(16)→σ∗C(19)-H(21)
σC(17)-H(18)→σ∗C(19)-H(21)
σC(3)-C(11)→π∗C(4)-C(5)
C(16)-H(17)
2.85
3.90
1.70
-
σC(3)-C(11)→σ∗ C(13)-O(14)
σC(4)-H(9)→σ∗
4.43
-
σC(17)-H(18)→π∗C(23)-O(25)
σC(4)-H(9)→σ∗C(2)-C(3)
C(3)-C(4)
σC(17)-C(19)→σ∗
C(23)-O(25)
C(5)-C(6)
σC(4)-H(12)→σ∗
4.08
4.85
-
σC(17)-C(19)→σ∗C(10)-C(13)
σC(17)-C(23)→π∗C(23)-O(24)
σC(17)-C(23)→σ∗ C(10)-C(13)
σC(17)-H(22)→σ∗O(24)-C(31)
σO(24)-C(31)→σ∗C(17)-C(23)
σC(31)-H(33)→σ∗C(34)-Br(43)
σC(34)-C(39)→σ∗ C(34)-C(39)
4.62
2.36
2.30
3.18
2.95
3.98
4.70
-
σC(11)-H(12)→σ∗
σC(11)-H(12)→π∗C(13)-O(14)
σC(11)-H(12)→σ∗ C(13)-O(14)
σC(11)-H(13)→σ∗C(16)-H(18)
σC(11)-C(16)→σ∗ O(15)-C(33)
σC(11)-C(16)→σ∗C(2)-C(3)
πC(13)-O(14)→σ∗C(2)-C(3)
σC(20)-H(22)→σ∗ C(3)-C(11)
2.95
3.95
2.23
-
1.35
4.21
σC(34)-C(39)→σ∗C(31)-H(31)
C(39)-H(42)
σC(34)-Br(43)→σ∗
2.96
σC(33)-H(34)→σ∗C(5)-C(6)
C(24)-C(31)
C(13)-O(15)
1.66
1.09
σC(34)-Br(43)→σ∗
2.91
3.97
2.76
5.00
())
σC(33)-H(34)→σ∗
C(35)-H(37)
C(13)-O(15)
3.99
σC(34)-Br(43)→σ∗
C(39)-H(42)
σC(41)-H(32)→σ∗
C(36)-Br(45)
7.12
18.35
35.37
7.65
1.27
47.53
4.19
4.99
-
7.27
σC(39)-H(42)→σ∗
7.12
7.52
-
7.31
C(34)-Br(43)
η2 O(14)→σ∗
18.96
35.37
8.60
η1 O(24)→σ∗
8.61
η2 O(14)→σ∗C(11)-C(13)
η1 O(15)→σ∗C(13)-O(15)
η1 O(15)→σ∗C(13)-O(14)
η2 O(15)→π∗C(13)-H(35)
η2 O(15)→σ∗ C(13)-O(14)
η2 O(15)→σ∗C(33)-H(34)
η2 O(15)→σ∗C(33)-H(35)
η1 O(24)→σ∗C(23)-O(15)
η2 O(24)→π∗C(31)-H(32)
η2 O(24)→σ∗ C(23)-O(25)
η2 O(24)→σ∗C(31)-H(33)
η2 O(24)→σ∗C(31)-H(34)
η1 O(25)→σ∗C(34)-Br(43)
η2 O(25)→σ∗C(17)-C(23)
2.72
45.37
4.91
-
46.46
3.50
2.73
46.35
3.48
3.30
-
1.52
-
2.22
3.41
18.25
35.60
215.43
18.89
35.32
224.56
η2 O(15)→π∗C(13)-O(14)
-
1.54
η2 O(25)→σ∗C(17)-C(23)
C(36)-Br(45)
C(23)-O(24)
ꢁ (kcal.mol−1
)
169.21
183.69
ꢁ (kcal.mol−1
)
The review article by Tomasi et al. explains in a simplified and
instructive manner that the factors that lead to the continuous
IEF PCM are often unsuitable for certain systems [27]. The authors
suggest that this may be attributed to the model’s failure to con-
sider some surface areas at specific points in the molecule, which
leads to poor-precision simulation of molecular solvation. Other
continuous solvation models such as PCM-SMD (a continuous sol-
vation model based on the quantum mechanical charge density
of the solute) afford good results for molecular solvation calcula-
tions. We believe that this model may be an alternative to bet-
ter simulate the effects of solvation on the compounds evaluated
herein, and it will be the subject of future study by our research
group.
O16-C18) did not differ significantly based on the conformational
search.
The highest-energy orbital interactions found for compounds
R1–R3 involve the aromatic ring and were not listed because high
values are already expected for the orbital interactions in this re-
gion due to aromaticity.
The most significant electronic interactions are those with two
pairs of electrons from the carbonyl group oxygen atom (C=O) and
the adjacent oxygen in the ester group R-O-(CO). Therefore, the
main interactions that stabilize the conformation of compounds
R1–R3 are ηO→ σ∗C-C, ηO→ σ∗C-O, ηO→ σ∗C-O, and ηO→ π∗
C-O
(as highlighted in Tables 4 and 5).
The sum of the orbital contributions to the lowest energy (more
stable) conformation is greater than that determined from the ex-
perimental and theoretical data, which enabled us to identify two
conformations: the anti-clinal conformation is the preferred and
lowest energy conformer (global minimum) for para-substituted
2-methyl-2-(bromo)propyl-phenyl acetate R1 (Y = H, OMe, Cl, and
NO2), R2, and R3 based on the dihedral angle between the aro-
matic ring and the carbonyl group.
3.5. NBO calculations
In NBO analysis, a large E value indicates intensive interaction
between electron donors and electron-acceptors; the possible in-
tensive interactions are summarized in Tables 4 and 5. All elec-
tronic interactions with energy values >1 kcal.mol–1 were con-
sidered in the data analysis. The first important finding is that
for the different conformations, the electronic interactions in the
compounds surrounding the orbitals of the atoms that formed the
dihedral angles α and β (α = C3-C12-C15-O16 and β = C16-C15-
For compounds R2 and R3 (NSAID derivatives), the ηO→ σ∗
C-O
electronic interaction was not significant. Other orbital interactions
such as ηO→ π∗
were more significant than in the case of R1
C-O
(Y = OMe, H, and Cl), which indicates that these interactions con-
9

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
Fig. 7. Molecular graphs for the ac conformers of the compounds R2 and R3 showing electrostatic and charge transfer (intramolecular hydrogen bonds) interactions between
the negative oxygen atoms in the carbonyl and the ester groups and the adjacent hydrogen atoms.
Table 6
Charge (Mulliken) (e) of selected atoms obtained at DFT-B3LYP/6-311+G (2df,2p) level for the 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted
R1 (Y = H, OMe, Cl and NO2), 2-bromo-2-methylpropyl 2-(4-isobutylphenyl)propanoate (derivative of Ibuprofen) R2 and 2-bromo-2-methylpropyl 2-(6-
methoxynaphthalen-2-yl)propanoate (derivative of Naproxen) R3 (the minus sign indicates excess of negative charge).
Comp
Y
Conf.a
C1
C2
C3
O4
O5
C6
C7
Br10
C11
R1
OMe
ac(1)
g(1)
0.648
0.756
0.828
0.785
0.512
0.755
0.747
0.454
0.540
0.513
0.643
-0.113
-0.123
-0.242
-0.125
-0.270
-0.136
0.088
0.583
0.203
0.595
0.481
0.137
-0.338
-0.363
-0.337
-0.364
-0.328
-0.342
-0.348
-0.328
-0.325
-0.333
-0.334
-0.077
-0.042
0.075
-0.178
-0.210
-0.166
-0.197
-0.154
-0.248
-0.197
-0.173
-0.091
-0.158
-0.099
0.555
0.546
0.521
0.522
0.345
0.484
0.512
0.573
0.391
-0.531
0.396
-0.171
-0.168
-0.170
-0.166
-0.177
-0.169
-0.157
-0.170
-0.176
-0.171
-0.179
-
-
-0.090
0.125
H
ac(1)
g(1)
-0.086
0.065
-0.045
-0.070
-0.044
-0.066
-0.058
-0.049
-0.062
-0.056
Cl
ac(1)
g(1)
-
NO2
0.073
-
c(1)
-0.158
-0.200
-0.014
-0.114
-0.108
-
R2
R3
ac(2)
ac(1)
ac(2)
ac(1)
-0.434
-0.484
-0.447
-0.447
tribute the most to stabilizing the compound. The sum of all or-
bital interactions between the more and less stable conformers
was 14.48 and 9.13 kcal.mol–1 for R2 and R3, respectively.
The increased electron density at the oxygen atoms leads to
elongation of the respective bond lengths and a lowering of the
corresponding stretching wave number. The electron density is
transferred from the n(O) to the anti-bonding π orbital of the
bonds. The hyper-conjugative interaction energy was deduced from
the second-order perturbation approach. The delocalization of the
electron density between occupied Lewis-type (bond or lone pair)
NBO orbitals and formally unoccupied (anti-bonding) non-Lewis
NBO orbitals corresponds to a stabilizing donor–acceptor interac-
tion. Hence, the title compound is stabilized by these orbital inter-
actions (Table 5).
Waals radius minus the distance between the two corresponding
atoms). Table 7 shows the atomic charge of each atom in the R1–
R3 conformers.
The data in Tables 6 and 7 show that for the lowest energy and
most stable R1 (Y = H, OMe, Cl, and NO2) conformers, there are
four electrostatic and charge-transfer interactions (intramolecular
hydrogen bonds) that contribute to the stability of the conformers;
for the higher-energy conformations, only three interactions were
observed (Fig. 6).
For compounds R2 (an ibuprofen derivative) and R3 (a
naproxen derivative), five interactions were observed for the high-
est energy anti-clinal (ac2) conformer and four interactions for the
lowest energy anti-clinal (ac1) conformer (Fig. 7). The low-energy
anti-clinal (ac1) conformers of compounds R2 and R3 exhibit a
strong interaction between O4•••H6, indicative of a strong charge-
transfer process, which may justify the lower number of interac-
tions observed for these compounds (Table 7).
Table 6 shows selected interatomic distances and the sum of
the corresponding van der Waals radii of the involved atoms (the
value is calculated as the sum of the difference in the van der
10

Table 7
˚
Selected Interatomic Distances (A) (intramolecular hydrogen bonds) at DFT/6-311+G (2df.2p) level of 2-bromo-2-methylpropyl-2-aryl-acetate-para-substituted R1(X = H, OMe, Cl and NO2), 2-bromo-2-methylpropyl 2-(4-isobutyl-
˚
phenyl)propanoate (derivative of Ibuprofen) R2 and 2-bromo-2-methylpropyl 2-(6-methoxynaphthalen-2-yl)propanoate (derivative of Naproxen) R3 (sum of van der Waals radii = 2.72 A).
A
A’
B
B’
C
C’
D
D’
E
E’
F
F’
G
G’
H
H’
Comp.
Y
Conf.
O4...H2
ꢂl
O4...H6
ꢂl
O4...H11
ꢂl
O4...H12
ꢂl
O5...H2
ꢂl
O5...H8
ꢂl
O5...H9
ꢂl
O4...H11
ꢂl
R1
OMe
ac(1)
g(1)
2.55
2.86
2.55
2.85
2.56
2.50
2.95
3.20
2.47
3.20
2.47
0.17
-0.14
0.17
-0.13
0.16
0.22
-0.23
-0.48
0.25
-0.48
0.25
2.27
0.45
-
-
3.19
2.88
3.11
2.82
3.02
3.32
2.92
2.81
3.52
2.81
3.74
-0.47
-0.16
-0.39
-0.1
2.48
2.39
2.48
2.38
2.48
2.45
2.42
2.40
3.25
2.40
3.23
0.24
0.33
0.24
0.34
0.24
0.27
0.3
2.65
2.66
2.65
2.66
2.64
2.57
2.66
2.73
2.63
2.73
2.65
0.07
0.06
0.07
0.06
0.08
0.15
0.06
-0.01
0.09
-0.01
0.07
2.74
2.73
2.74
2.74
2.63
-
-0.02
-0.01
-0.02
-0.02
0.09
-
-
-
2.26
0.46
-
-
-
-
H
ac(1)
g(1)
2.28
0.44
-
-
-
-
2.26
0.46
-
-
-
-
Cl
ac(1)
g(1)
2.59
0.13
-
-
-0.3
-
-
NO2
2.61/2.65
2.28
0.44/0.43
0.15
-
-
-0.6
-
-
c(1)
-
-
-0.2
2.74
2.64
2.64
2.65
2.65
-0.02
0.08
0.08
0.07
0.07
-
-
R2
R2
Ibuprofen
Naproxen
ac(1)
ac(2)
ac(1)
ac(2)
2.27
0.45
2.70
3.49
2.70
3.62
0.02
-0.77
0.02
-0.9
-0.09
-0.8
0.32
-0.53
0.32
-0.51
3.79
2.66
3.78
2.65
-1.07
0.06
-1.06
0.07
2.57
0.15
2.27
0.45
-0.09
-1.02
2.68
0.04

A.C.A.H. Roque, D. de Carvalho Santos, M.M. Reginato et al.
Journal of Molecular Structure 1233 (2021) 130027
The preference for the anti-conformation between the bromo
and ester-oxygen atom [ϕ = O(5)-C(6)-C(7)-Br(10)] (Table 2) is
consistent with the expectations from the stronger H-bonds,
O(5)•••H8 and O(5) ••H9 (Table 6), of the methyl groups. An-
other strong intermolecular hyper-conjugative interaction that sta-
Coordenação Nacional de Aperfeiçoamento do Ensino Superior
(CAPES - Brazil) for the research fellowships granted to D.C.S and
M.M.R. Professor Paulo Roberto Olivato is gratefully acknowledged
for providing laboratory facilities.
bilizes the gauche conformation σC(CH3)-H(CH3)→σ∗
is also
Supplementary materials
C-Br
operative.
The calculations indicate that these interactions are important
because they decrease the strength of the C–Br bond and justify
the high positive charge on the carbon atom and negative charge
on the Br atom, which weakens this bond. Thus, we can infer
that these compounds are excellent precursors for the synthesis
of derivatives via unimolecular nucleophilic SN1 reactions with the
formation of carbocations.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130027.
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All authors declare no conflict of interest.
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The authors thank Fundação de Amparo à Pesquisa do Es-
tado de São Paulo (FAPESP - Grant Numbers: 2010/51784-3 and
2013/16644-4) for financial support. The authors also thank
12