NMR chiral discrimination of chalcogen containing secondary alcohols

Article abstract of DOI:10.1002/chir.23030

Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatiz

Full text of DOI:10.1002/chir.23030

Received: 26 June 2018
DOI: 10.1002/chir.23030
Revised: 3 September 2018
Accepted: 8 October 2018
R E G U L A R A R T I C L E
NMR chiral discrimination of chalcogen containing
secondary alcohols
Naiade B.G. Marques2 | Raquel G. Jacob1 | Gelson Perin1 | Eder J. Lenardão1
Diego Alves1 | Márcio S. Silva1,2
|
1 Laboratório de Síntese Orgânica Limpa
Abstract
(LASOL), Centro de Ciências Químicas,
Here, we report the general strategies by which NMR spectroscopy can be used
to determine the enantiopurity and absolute configuration of chalcogen con-
taining secondary alcohols, including the evaluation of the use of chiral solvat-
ing and chiral derivatizing agents. The BINOL/DMAP ternary complex
demonstrated a simple and fast protocol for determining enantiopurity. The
drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral
derivatizing agent (CDA) for NMR chiral discrimination of chalcogen contain-
ing secondary alcohols. The chiral recognition by CDA and chiral solvating
Farmacêuticas e de Alimentos (CCQFA),
Universidade Federal de Pelotas (UFPel),
Capão do Leão, Brazil
2 Laboratório de Ressonância Magnética
Nuclear, Centro de Ciências Naturais e
Humanas (CCNH), Universidade Federal
do ABC, Santo André, Brazil
Correspondence
Márcio Santos Silva, Laboratório de
Síntese Orgânica Limpa (LASOL), Centro
de Ciências Químicas, Farmacêuticas e de
Alimentos (CCQFA), Universidade
Federal de Pelotas (UFPel), Capão do
Leão, RS, Brazil.
agent (CSA) was assessed using H, 77Se‐{1H}, and 125Te‐{1H} NMR spectros-
1
copy. A simple model for the assignment of the absolute configuration from
NMR data is presented.
Email: silva.ms@ufpel.edu.br
KEYWORDS
chalcogen compounds, chiral derivatizing agent, chiral solvating agent, NMR discrimination,
secondary alcohols
Funding information
Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES);
Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq);
Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP); Fundação
de Ámparo à Pesquisa do Estado do Rio
Grande do Sul (FAPERGS)
1 | INTRODUCTION
low reactivity,6 possible racemization,7 being highly hygro-
scopic, and very small ΔδRS values.8 Consequently, the
Nuclear magnetic resonance (NMR) spectroscopy is a
consolidated analysis used to evaluate the enantiopurity
and the assignment of absolute configuration of organic
compounds.1-4 The procedure relies on the use of an
enantiomerically pure reagent that causes an anisotropic
effect, which is predictable in the NMR spectrum. The
NMR recognition of secondary alcohols is commonly done
by derivatization with methoxytrifluoromethylphenylacetic
acid (MTPA), methoxyphenylacetic acid (MPA), or 9‐
anthrylmethoxyacetic acid (9‐AMA) chiral auxiliaries.5
However, these reagents have some problems, including
choice of chiral auxiliary is an important strategy for
NMR chiral recognition of secondary alcohols.
Among the different chiral reagents, Naproxen is a
stable, nonhygroscopic, and readily available chiral
carboxylic acid. Satisfactory results for NMR chiral
discrimination are presented in the literature, such as
phosphine oxides by Naproxen as a chiral solvating agent
(CSA)9 and aminophosphonates by Naproxen chloride as
a chiral derivatizing agent (CDA).10
NMR analysis using CSAs can often involve a trial‐and‐
error approach, and huge differences can occur because of
Chirality. 2018;1–11.
wileyonlinelibrary.com/journal/chir
© 2018 Wiley Periodicals, Inc.
1

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MARQUES ET AL.
the molecular structure and/or functional group.11 How-
ever, the practicality, and low time‐consuming, to employ
a CSA, usually emerges as a desired alternative.
(Py‐d5), deuterated chloroform (CDCl3), N,N′‐diisopropyl-
carbodiimide (DIC), and N,N′‐dicyclohexylcarbodiimide
(DCC) were purchased from Sigma‐Aldrich, Brazil.
On the other hand, organic chalcogen (Se and Te)
compounds are versatile synthetic intermediates for the syn-
thesis of complex molecules.12,13 Furthermore, compounds
containing chalcogen atoms have demonstrated a wide
scope of pharmacological activities.14-16 Thus, the use of chi-
ral organochalcogen compounds represents a great opportu-
nity for increasing the range of synthetic intermediates17
and bioactive compounds.18 Among the methods used to
obtain chiral chalcogen containing secondary alcohols,
biocatalytic methods have exhibited a high effectivity.19
Considering the importance of organochalcogen com-
pounds and secondary alcohol derivatives, and due to the
possibility of exploring 77Se and 125Te NMR spectroscopy
to study chirality, we report a method for NMR chiral dis-
crimination and NMR assignment of the absolute config-
uration of chalcogen containing secondary alcohols. Our
strategy involves the use of the 1,1′‐bi‐2‐naphthol and
4‐(dimethylamino) pyridine (BINOL/DMAP) ternary
complex as a CSA and Naproxen as a CDA.
2.3 | General procedure for the synthesis
of racemic chalcogen containing secondary
alcohols
The racemic chalcogen (Se and Te) containing secondary
alcohols 1 were synthesized and characterized as recently
described.20 To a 5‐mL vial equipped with a magnetic stir-
rer and rubber septum under nitrogen, dialkyl or diaryl
dichalcogenide (0.5 mmol) and the epoxy (1.5 mmol)
were added, followed by the catalyst system (NaBH4/
Al2O3, 1.0 mmol/50 mg). The mixture was then stirred
for 120 minutes at 50 °C. The reaction progress was mon-
itored by thin layer chromatography (TLC) and gas chro-
matography (GC). After 20 minutes at room temperature,
the reaction medium was diluted with AcOEt (20 mL)
and washed with a saturated aqueous solution of NH4Cl
(15 mL). The phases were separated, and the aqueous
phase was extracted with AcOEt (2 × 20 mL). The organic
phase was dried over MgSO4, and the solvents were evap-
orated under reduced pressure. The product was purified
by flash column chromatography, eluting first with
hexane to remove the dialkyl or diaryl dichalcogenides
by‐products and then with hexane/AcOEt (8:2) to remove
the secondary chalcogen alcohol.
2 | MATERIALS AND METHODS
2.1 | Nuclear magnetic resonance
1H, 77Se‐{1H}, and 125Te‐{1H} spectra of Naproxen esters
derivatives were recorded using an NMR spectrometer with
300 or 500 MHz (Bruker, Avance III model). The probe was
a 5‐mm direct broadband observe (BBO) z‐gradient from
300 MHz and 5‐mm indirect TXI z‐gradient from
500 MHz. Spectra were recorded in deuterated chloroform,
deuterated pyridine, and deuterated benzene (5‐mm tubes)
at 298 K. The data reported includes chemical shift (δ), mul-
tiplicity, coupling constant (J) in hertz, and integrated inten-
sity. The 77Se NMR chemical shifts are reported in ppm
relative to the internal standard C6H5SeSeC6H5 (δ
463 ppm). The 125Te NMR chemical shifts are reported in
ppm relative to the internal standard C6H5TeTeC6H5 (δ
422 ppm). The parameters of 77Se‐{1H} and 125Te‐{1H}
NMR spectroscopy were 0.34 second of acquisition time,
1.0 second of relaxation time, 12.0 microseconds of pulse
width, 2048 sans, and 3.0 of line broadening, and the base-
line correction was carried out manually. The NMR pulse
sequence employed for 77Se‐{1H} and 125Te‐{1H} experi-
ments was gated decoupling.
2.4 | General procedure for NMR chiral
discrimination of racemic and chiral
chalcogen containing secondary alcohols
CSA
Samples for NMR spectroscopy were prepared by
weighing and dissolving the appropriate amount of
chalcogen alcohol 1, chiral auxiliary, and base in the
respective deuterated solvent to prepare a 20 mM
solution. The solutions were shaken for 2 minutes for
equilibration time.
CDA
Samples for NMR spectroscopy were prepared weighing
and dissolving 0.05 mmol of chalcogen alcohol 1,
0.05 mmol of Naproxen, and 0.05 mmol of DCC in
600 μL of CDCl3. The solutions were shaken for
10 minutes. A white solid is obtained. After 30 minutes,
the white solid is decanted, and the NMR spectra were
recorded. The solutions were prepared in a vial or directly
2.2 | Chemicals
Chiral auxiliaries (MTPA, BINOL, MPA, mandelic acid,
Naproxen), deuterated benzene (C6D6), deuterated pyridine

MARQUES ET AL.
3
in an NMR tube. Usually, the vials were the best option
due the absence of the white solid in the NMR tube, and
by the possibility to use a centrifuge equipment for
faster decantation.
NMR experiment recorded did not show anisotropy of
the tellurium atom.
Regarding the strong influence of physical parameters
on the CSA interaction, the solvent and the substrate
were modified to evaluate the performance of the NMR
chiral discrimination by the (+)‐BINOL/DMAP ternary
complex. To verify the influence of the substrate, different
chalcogen alcohols 1 were tested (Table 1). The 77Se‐{1H}
NMR experiments recorded did not show an anisotropic
effect, and the 1H NMR experiments gave the same
results (Table 1, entries 3, 4, and 5). As can be seen in
Table 1, the presence of deuterated benzene improved
the anisotropic effect (Table 1, entries 2, 4, 5, and 6). An
excess of DMAP (2.0 and 3.0 equiv.) did not demonstrate
improvements.
3 | RESULTS AND DISCUSSION
3.1 | Chiral solvating agent
The study began with the synthesis of racemic chalco-
gen containing secondary alcohol 1. The synthesis was
carried out using a simple and nonconventional method
based on the solid support NaBH4/Al2O3 (Scheme 1).20
This atom‐economic strategy involves the ring‐opening
reaction of epoxides by nucleophilic species of chalco-
genides. Moreover, this simple procedure does not
involve harsh reaction conditions and is not time‐
consuming. The yields were moderate to satisfactory
(Scheme 1).
The protocol demonstrates a good baseline resolution
and faster chiral discrimination procedure. In an attempt
to improve the ΔδRS values of the CSAs obtained and to
access the absolute configuration, the CDA methodology
was evaluated.
After the synthesis of secondary chalcogen contain-
ing secondary alcohol 1, chalcogen alcohol 1a was cho-
sen as a substrate model for optimization of the NMR
chiral discrimination. Initially, different CSAs were eval-
uated due to the readiness of the method. By combining
1.0 equivalent of (+)‐MTPA, (+)‐MPA, (+)‐mandelic
acid, (+)‐BINOL, or (+)‐Naproxen with chalcogen alco-
hol 1a in CDCl3, the desired anisotropic effect was not
3.2 | Chiral derivatizing agent
After the CSA results, the chiral carboxylic acids ((+)‐
MTPA, (+)‐MPA, and (+)‐Naproxen) were evaluated as
CDAs for NMR chiral discrimination. Initially, the reac-
tion was performed using 0.25 mmol of chalcogen alcohol
1a, 0.25 mmol of DIC, and 0.25 mmol of the chiral car-
boxylic acid, using 2 mL of CH2Cl2 as the solvent at
30 °C under magnetic stirring (Table 2). The desired
product was obtained in 78% yield after 30 minutes with
(+)‐Naproxen chiral auxiliary. The reaction with (+)‐
MTPA did not work after 24 hours of reaction time. The
reaction with (+)‐MPA afforded a lower yield after
24 hours. Thus, the split signal of the enantiomers was
1
observed in the H and 125Te‐{1H} NMR spectra. Based
on the formation of a ternary complex21 and to improve
the intermolecular interactions, 1.0 equivalent of
4‐(dimethylamino) pyridine (DMAP) base was added to
the medium with the CSA. In this protocol, the split sig-
1
nals in the H NMR spectrum was observed only with
(+)‐BINOL/DMAP ternary complex. The 125Te‐{1H}
obtained only with (+)‐Naproxen, and the H and 125Te‐
1
{1H} NMR experiments showed substantial ΔδRS values
(Table 2, entries 5 and 6). To improve this result, DCC
was employed instead of the DIC coupling reagent. When
the reaction was performed with chalcogen alcohol 1a,
DCC, and (+)‐Naproxen, the yield increased to 87%. The
reaction of chalcogen alcohol 1a with DCC and (+)‐
MPA or (+)‐MTPA did not work after 24 hours of reac-
tion time.
After DCC was defined as the best coupling reagent
for the reaction between carboxylic acids and chalcogen
containing secondary alcohols to obtain diastereomeric
esters, the deuterated solvent was evaluated. By using
deuterated benzene, there was an improvement in the
ΔδRS value of the 125Te‐{1H} NMR (Table 3, entry 1).
However, the ΔδRS value of the 1H NMR spectrum
decreased significantly (Table 3, entry 2). Inversely, the
SCHEME 1 Synthesis of racemic chalcogen containing secondary
alcohol 1

4
MARQUES ET AL.
TABLE 1 1H (500 MHz) NMR chiral discrimination of chalcogen containing secondary alcohol 1 by the (+)‐BINOL/DMAP ternary chiral
complexa,b
Entry
Chalcogen Alcohol
Solvent
Δδ, ppm
Δδ, Hz
1
2
3
4
5
6
7
1a
1a
1b
1b
1c
1d
1d
CDCl3
C6D6
0.0064
0.0069
0.0046
0.0071
0.0064
0.0045
‐‐‐c
3.2
3.5
2.3
3.6
3.2
2.3
‐‐‐c
CDCl3
C6D6
C6D6
C6D6
CDCl3
a1.0 equiv. of alcohol 1 with 1.0 equiv. of (+)‐BINOL and 1.0 equiv. of DMAP in the deuterated solvent (20 mM).
bExcess of DMAP (2.0 or 3.0 equiv.) did not demonstrate improvements.
cThere was no ΔδRS value.
TABLE 2 1H and 125Te‐{1H} NMR chiral discrimination of tellurium containing secondary alcohol 1a by CDAsa,b
Entry
CDA
NMR Exp.
Δδ, ppm
Δδ, Hz
1
2
3
4
5
6
(+)‐Mand. acid
(+)‐Mand. acid
(+)‐MTPA
125Te‐{1H}
1H
‐‐‐
‐‐‐
‐‐‐
‐‐‐
125Te‐{1H}
1H
‐‐‐
‐‐‐
(+)‐MTPA
‐‐‐
‐‐‐
(+)‐Naproxen
(+)‐Naproxen
125Te‐{1H}
1H
1.10
0.54
104.0
164.6
a1.0 equiv. of alcohol 1a with 1.0 equiv. CDA and 1.0 equiv. of DCC in 2 mL of CH2Cl2 solvent at 30 °C.
bThe (+)‐Naproxen ester was purified by column chromatography and analysed by 1H (300 MHz) and 125Te‐{1H} (94.7 MHz) NMR.
1
TABLE 3 Evaluation of the deuterated solvent in the H and 125Te‐{1H} NMR chiral discrimination of tellurium containing secondary
alcohol 1a by Naproxen drug as a CDAa,b
Entry
Solvent
C6D6
C6D6
NMR Exp.
Δδ, ppm
Δδ, Hz
1
2
125Te‐{1H}
1H
1.63
154.0
10.4
0.035
(Continues)

MARQUES ET AL.
5
TABLE 3 (Continued)
Entry
Solvent
Py‐d5
NMR Exp.
125Te‐{1H}
1H
Δδ, ppm
0.89
Δδ, Hz
84.2
3
4
Py‐d5
‐‐‐c
‐‐‐c
aThe samples were prepared by weighing and dissolving the appropriate amount of Naproxen ester derived from alcohol 1a to obtain a 20 mM solution.
bThe (+)‐Naproxen ester was purified by column chromatography and analysed by 1H (300 MHz) and 125Te‐{1H} (94.7 MHz) NMR.
cThere was no ΔδRS value.
FIGURE 1 125Te‐{1H} (94.7 MHz) NMR spectrum of Naproxen ester derived from tellurium containing secondary alcohol 1h in CDCl3 at
298 K
TABLE 4 77Se‐{1H} and 125Te‐{1H} NMR chiral discrimination of chalcogen containing secondary alcohol 1 by Naproxen as a CDAa,b
Entry
Chalcogen Alcohol 1
NMR Exp.
Δδ, ppm
Δδ, Hz
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
125Te‐{1H}
77Se‐{1H}
77Se‐{1H}
125Te‐{1H}
77Se‐{1H}
125Te‐{1H}
1.10
1.37
‐‐‐c
104.0
78.4
‐‐‐c
‐‐‐c
‐‐‐c
1.47
0.60
84.1
56.8
(Continues)

6
MARQUES ET AL.
TABLE 4 (Continued)
Entry
Chalcogen Alcohol 1
NMR Exp.
125Te‐{1H}
125Te‐{1H}
77Se‐{1H}
Δδ, ppm
0.76
Δδ, Hz
72.3
7
1g
1h
1i
8
2.52
239.5
15.4
9
0.27
10
11
1j
125Te‐{1H}
77Se‐{1H}
0.04
3.3
1 k
1.73
99.3
a1.0 equiv. of alcohol 1 with 1.0 equiv. Naproxen and 1.0 equiv. of DCC in 2 mL of CH2Cl2 solvent at 30 °C.
bThe (+)‐Naproxen esters were purified by column chromatography and analysed by 77Se‐{1H} (57.4 MHz) and 125Te‐{1H} (94.7 MHz) NMR.
cThere was no ΔδRS value.
FIGURE 2 Enantiomer ratio evaluation
of tellurium containing secondary alcohol
1a by chiral chromatographic gas analysis
ΔδRS value of the CH3 group in deuterated benzene of the
1H NMR increased. This type of result is difficult to pre-
dict and is caused by the anisotropic effect of the
solvent.21 When deuterated pyridine was employed, the
split signal decreased for the 125Te‐{1H} NMR spectrum
1
and vanished for the H NMR spectrum (Table 3, entries
3 and 4).
These results exalt the advantages of multinuclear
NMR spectroscopy because of the substantial ΔδRS values
and no overlapping of the signals. 77Se and 125Te NMR
have great potential due to the characteristics of selenium
and tellurium nuclei, such as a wide spectral window,
SCHEME 2 Synthesis of enantiopure Naproxen esters derived
from (S)‐Naproxen and (R)‐chalcogen containing secondary
alcohols 1a and 1b

MARQUES ET AL.
7
FIGURE 3 77Se‐{1H} (54.7 MHz), and
125Te‐{1H} (94.7 MHz) NMR spectra of
Naproxen esters derived from (S)‐
Naproxen and the racemic or (R)‐
enantiomer chalcogen containing
secondary alcohols 1a and 1b. 77Se‐{1H}
and 125Te‐{1H} NMR spectra were
recorded in CDCl3 at 298 K

8
MARQUES ET AL.
FIGURE 5 Calculated conformational structures of Naproxen
esters derived from chalcogen containing secondary alcohols 1a
and 1b using PM6 semiempirical method
method was tested. For this purpose, chalcogen alcohol
1a (0.05 mmol), Naproxen (0.05 mmol), and DCC
(0.05 mmol) were added in a 5‐mm NMR tube with
600 μL of CDCl3. Shaking was carried out for 2 minutes.
After this time, the NMR tube showed the presence of a
white solid in suspension. After 30 minutes, the white
solid was decanted. Then, the 125Te‐{1H} NMR experi-
ment was possible. By using the DIC as a coupling
reagent, there was no white solid and the 125Te‐{1H}
NMR experiment was recorded immediately. Chalcogen
alcohol 1a and the intermediate of the coupling reaction
FIGURE 4 1H (300 MHz) NMR spectra of (S)‐Naproxen esters
derived from the racemic (bottom spectrum) and (R) (up spectrum)
enantiomer of tellurium containing secondary alcohol 1a in CDCl3
at 298 K
1
were observed by H NMR spectra in the mix and shake
I = ½, reasonably high natural abundance, and no signif-
icant nuclear Overhauser effect (nOe).22 These great fea-
tures can be witnessed by observing the 125Te‐{1H} NMR
spectra of Naproxen ester formed from chalcogen contain-
ing secondary alcohol 1h (Figure 1).
protocol using the DIC coupling reagent.
Finally, with the best conditions established, we
expanded the mix and shake methodology ((S)‐
Naproxen/DCC) for other secondary chalcogen alcohol
1. As can be seen in Table 4, the ΔδRS values of 77Se‐
{1H} and 125Te‐{1H} NMR spectra were superior than the
1H NMR experiments, and there was no overlapping of
signals. In most cases, selenium and tellurium nuclei
demonstrated the same profile of anisotropy diamagnetic
and, consequently, a similar ΔδRS values. For chalcogen
alcohol 1h, the ΔδRS value was higher than other chalco-
gen alcohols (Table 4, entry 6). There was no splitting of
the signals in chalcogen alcohols 1c and 1d. The presence
of the butyl group in the chalcogen atom disturbed the
Furthermore, multinuclear NMR spectroscopy is an
1
efficient alternative to overcome H NMR limitations,23
such as overlap of signals, combined with broad and fea-
tureless spectra. Therefore, the 1H NMR spectra of
Naproxen ester derived from chalcogen containing sec-
ondary alcohol 1a is severely hampered due to the
numerous scalar couplings.
With the possibility of performing the reaction inside
the NMR tube without purification, the mix and shake
SCHEME 3 Effect of the shielding cone
by carbonyl on the Cα‐H organic groups in
the esters derived from (S)‐Naproxen and
(R)‐chalcogen containing secondary
alcohols 1a and 1b

MARQUES ET AL.
9
anisotropic effect. The results reveal that the group
bonded to the chalcogen atom is important for the
effectivity of 77Se‐{1H} and 125Te‐{1H} NMR chiral
discrimination. The presence of an aryl ring can afford
significant shielding and upfield shifts of the resonances
of the alcohol hydrogen and chalcogen atoms that are
positioned closer to the ring.
In some chalcogen alcohol 1, the derivatization with
Naproxen drug was followed by overlapping of the signals
in the 1H NMR experiments. Otherwise, there were
exceptions, as chalcogen alcohol 1j had a ΔδRS value of
Naproxen ester that was 0.11 ppm (33.7 Hz). There was
also splitting of the methoxyl signals from the Naproxen
group (Figure S41, ΔδRS = 0.012 ppm). Moreover, the
125Te‐{1H} NMR chiral discrimination of chalcogen alco-
hol 1j was less efficient (Table 4, entry 10). This outcome
established a connection between the efficacy of proton
and chalcogen nuclei in the NMR chiral discrimination,
possibly due to the conformational structures involved
in the anisotropic effect.
alcohols 1a and 1b were performed using the protocol
DCC/(S)‐(+)‐Naproxen in CH2Cl2 (Scheme 2).
With the Naproxen esters containing the chalcogen
atoms in hand, 1H, 77Se‐{1H}, and 125Te‐{1H} NMR
experiments were recorded. As can be seen in Figure 3,
77Se‐{1H} and 125Te‐{1H} chemical shifts do not have the
same pattern. In the 77Se‐{1H} NMR of the Naproxen ester
of (S)‐Naproxen and (R)‐selenide alcohol 1b, the chemical
shift was downfield, and for the 125Te‐{1H} NMR of the
Naproxen ester of the (S)‐Naproxen and (R)‐telluride
alcohol 1a, the chemical shift was upfield. According to
the 1H NMR spectra, the proton chemical shifts of
enantiopure Naproxen esters of chalcogen alcohols 1a
and 1b demonstrated the same profile. These results con-
1
firm the major precision of H NMR spectroscopy in the
assignment of absolute configuration.
To understand the conformation of the chiral struc-
tures, the 1H NMR spectra were analysed. As can be seen
in Figure 4, the CH3 and CH groups of the alcohol sub-
strate are shielded. The opposite was observed for CH2.
The CH3 group of the Naproxen substrate was shielded
A significant difference in the signal integration of the
77Se‐{1H} and 125Te‐{1H} NMR spectra of the Naproxen
ester derivatives formed from chalcogen containing sec-
ondary alcohols 1a, 1b, and 1k was detected (Figure
S42, 62:38 ratio, instead of 50:50 ratio). These results were
a consequence of the kinetic resolution of the enantio-
mers during the Naproxen coupling reaction and were
confirmed by chiral chromatographic gas analysis
(Figure 2). The 1H NMR chiral discrimination of the
respective chalcogen containing secondary alcohols
using the ternary chiral complex ((+)‐BINOL/DMAP)
methodology combined with the deconvolution proce-
dure did not show kinetic resolution of the enantiomers
(Figure S55). Thus, for the enantiomeric excess (ee) mea-
surement, the ternary complex system can be used
1
in the H NMR spectra. Based on the Mosher model,
the shielding effect of both CH3 groups is due to the spa-
tial orientation of the Naproxen ester of (S)‐Naproxen
and (R)‐chalcogen alcohol, which are the CH3 groups suf-
fering the anisotropic effect of the aromatic rings
(Scheme 3). Shielding of the CH group can be visualized
by the conformational preference of the Naproxen ester.
The CH group is shielded by the cone of the carbonyl
group (Scheme 3). These results are in agreement with
the assignment of the absolute configuration of
aminophosphonates by Naproxen.10
An estimate of chalcogen chemical shifts for chiral
Naproxen ester derivatives 1a and 1b may be provided
by semiempirical method. Thus, the molecular geometry
of the compounds was optimized using the PM6 and
PM7 methodologies.24,25 To understand the 77Se‐{1H}
and 125Te‐{1H} chemical shifts and provide additional
insight into chalcogen organic compounds, the molecular
structure of both chiral compounds is presented
(Figure 5). Firstly, the shielding of the CH group can be
confirmed by the torsion angle with the carbonyl group
(11° for 1b and 13° for 1a). This geometry shows the prox-
imity between the chalcogen elements with the oxygen
atom from carbonyl group (Se‐O is 3.496 Å and Te‐O is
2.181 Å). These distances could be explained by electro-
static sigma‐hole interactions.26 Chalcogen bonding
(ChB) plays as a conformational lock to stabilize the
interaction between nearby heteroatoms (O and N) with
low‐valent heavy chalcogen by charge transfer to the anti-
bonding orbital. Based on the molecular geometries
(Figure 5), the shortest distance of tellurium element rep-
resents a greater sigma‐hole interaction. The 125Te‐{1H}
1
employing H NMR spectroscopy in a simple and rapid
method. Although, in some chalcogen containing second-
ary alcohol 1 evaluated (chalcogen containing alcohols
1e, 1f, 1g, 1h, 1i, and 1j), Naproxen/DCC was an
effective protocol without the enantiomer kinetic resolu-
tion (Support Information).
3.3 | Assignment of the absolute
configuration
Another evaluation to carry out was the assignment of the
absolute configuration of the chalcogen containing second-
ary alcohol 1. To obtain the enantiopure chalcogen con-
taining secondary alcohols 1a and 1b, the ring‐opening
reaction between (R)‐(+)‐propylene oxide and the anion
phenylchalcogenolate was performed. After, the derivati-
zation of enantiopure chalcogen containing secondary

10
MARQUES ET AL.
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not affected by this shielding, and is in agreement with
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4 | CONCLUSION
In this work, general strategies were evaluated to explore
the NMR chiral discrimination of chalcogen (Se and Te)
containing secondary alcohols. The (+)‐BINOL/DMAP
ternary complex demonstrated a rapid and simple proce-
dure to evaluate the enantiopurity of the chalcogen alco-
hols. (S)‐Naproxen was an effective chiral derivatizing
agent. Moreover, (S)‐Naproxen is a stable, nonhygro-
scopic, and readily available compound. 77Se‐{1H} and
125Te‐{1H} NMR spectroscopy were useful to overcome
limitations such as smaller ΔδRS values and overcrowded
1H NMR spectra. The assignment of absolute configura-
tion was performed by 1H NMR spectroscopy. The confor-
mation of the (S)‐Naproxen esters were similar to the
literature, providing confidence for using this CDA for
other related structures.
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lence of diastereomeric esters of alpha‐substituted phenylacetic
acids for the determination of stereochemical purity. J Am Chem
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ACKNOWLEDGMENTS
11. Yang L, Wenzel T, Williamson RT, Christensen M, Schafer W,
Welch CJ. Expedited selection of NMR chiral solvating agents,
for determination of enantiopurity. ACS Cent. 2016;2(5):332‐340.
The authors are grateful to Fundação de Ámparo à
Pesquisa do Estado do Rio Grande do Sul (FAPERGS),
Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP), Conselho Nacional de Desenvolvimento Cien-
tífico e Tecnológico (CNPq), and Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
for financial support. The authors thank the professor
Patrick Teixeira Campos (IFSul‐RS/Brazil) to support
the conformational analysis.
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C‐Se, and C‐Te bond formation via cross‐coupling and atom‐
economic addition reactions. Chem Rev. 2011;111(3):1596‐1636.
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ORCID
Eder J. Lenardão http://orcid.org/0000-0001-7920-3289
Márcio S. Silva http://orcid.org/0000-0002-7606-564X
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chloroquinoline, a novel multitarget compound with anxiolytic
activity: contribution of the glutamatergic system. J Psych Res.
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