Selenoxide elimination triggers enamine hydrolysis to primary and secondary amines: A combined experimental and theoretical investigation

Article abstract of DOI:10.3390/molecules26092770

We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under oxidative conditions, we observed and characterized the formation of primary and secondary amines as elimination products of such compounds, paving the way for a novel strategy to selectively release bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry and density functional theory (DFT).

Full text of DOI:10.3390/molecules26092770

molecules
Article
Selenoxide Elimination Triggers Enamine Hydrolysis to
Primary and Secondary Amines: A Combined Experimental and
Theoretical Investigation
Giovanni Ribaudo 1 , Marco Bortoli 2,3 , Erika Oselladore 1, Alberto Ongaro 1 , Alessandra Gianoncelli 1
,
Giuseppe Zagotto 4 and Laura Orian 2,
*
1
Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11,
25123 Brescia, Italy; giovanni.ribaudo@unibs.it (G.R.); e.oselladore@unibs.it (E.O.);
a.ongaro005@unibs.it (A.O.); alessandra.gianoncelli@unibs.it (A.G.)
Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, 35131 Padova, Italy;
marco.bortoli@unipd.it
Departament de Química, Institut de Química Computacional i Catàlisi, Universitat de Girona, C/M.A.
Capmany 69, 17003 Girona, Spain
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131 Padova, Italy;
giuseppe.zagotto@unipd.it
2
3
4
*
Correspondence: laura.orian@unipd.it; Tel.: +39-049-8275140
Abstract: We discuss a novel selenium-based reaction mechanism consisting in a selenoxide elimination-
triggered enamine hydrolysis. This one-pot model reaction was studied for a set of substrates. Under
oxidative conditions, we observed and characterized the formation of primary and secondary amines
as elimination products of such compounds, paving the way for a novel strategy to selectively release
bioactive molecules. The underlying mechanism was investigated using NMR, mass spectrometry
and density functional theory (DFT).
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Ribaudo, G.; Bortoli, M.;
Oselladore, E.; Ongaro, A.;
Gianoncelli, A.; Zagotto, G.; Orian, L.
Selenoxide Elimination Triggers
Enamine Hydrolysis to Primary and
Secondary Amines: A Combined
Experimental and Theoretical
Investigation. Molecules 2021, 26, 2770.
https://doi.org/10.3390/molecules
26092770
Keywords: selenoxide elimination; one-pot; imine-enamine; reaction mechanism; DFT calcula-
tions; selenium
1. Introduction
Academic Editor: Israel Fernández
In the past few decades, the selenoxide elimination reaction has been used to obtain
alkenes and has been largely applied in the synthesis of small molecules such as natural
products and bioactive compounds [1–4]. Generally, the organoselenides required for such
a reaction can be straightforwardly synthesized from electrophilic phenylselenyl chloride
or using diphenyl diselenides as precursors for the nucleophilic selenate. In the presence
of oxidants, such as peroxides or other reactive oxygen species (ROS), organoselenium
Received: 15 April 2021
Accepted: 5 May 2021
Published: 8 May 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
compounds are readily oxidized to selenoxides [5–7]. Then, an intramolecular syn elim-
ination occurs in opportune substrates, involving the hydrogen atom in vicinal position
with respect to the selenium nucleus. This leads to the formation of the corresponding
trans-olefine [8–10].
In the context of our studies on selenium-based derivatives of compounds of phar-
maceutical interest, we observed a peculiar behavior of amino organoselenides [10]. In
particular, under oxidative conditions, we previously detected the formation of primary
and secondary amines from mono- or disubstituted 2-phenyl-2-(phenylselanyl)ethan-1-
amines (Scheme 1).
Among the functional groups of biological relevance, the amino moiety is one of the
most frequently occurring. Nevertheless, drugs containing primary or secondary amines,
despite being very common, are endowed with some pharmacokinetic limitations such as
poor diffusion through membranes or blood–brain barrier under particular physiologic con-
ditions. Moreover, instability affects such compounds, as amines physiologically undergo
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 2770. https://doi.org/10.3390/molecules26092770
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Molecules 2021, 26, 2770
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metabolic phase 1 transformations such as oxidations or dealkylations or conjugations in
phase 2. These limitations can be partially overcome by derivatization to generate prodrugs
that can be “unmasked” under certain conditions that can be pH-, redox- or enzyme-
dependent [11]. Recent reports showed that selenoxide elimination can be employed by
drug-like derivatives responsive to reactive oxygen species (ROS) in innovative targeted
therapeutic strategies [12]. Moreover, we previously showed that compounds endowed
with bioactivity can be generated after release from such substrates. Molecules selectively
providing elimination products in response to oxidative stress represent attractive tools, in
particular in the context of central nervous system (CNS) drugs [10].
Scheme 1. Proposed mechanism for selenoxide elimination-triggered enamine hydrolysis.
Taking the step from these considerations, we investigated and characterized a one-pot
model reaction consisting in a selenoxide elimination-triggered enamine hydrolysis that
allows the formation of primary and secondary amines under oxidative conditions.
Additionally, this combined process is endowed with synthetic value, as it represents
an innovative approach for obtaining primary and secondary amines as elimination prod-
ucts under these specific conditions. Although selenium-catalyzed organic reactions, and
particularly selenoxide elimination, have been extensively studied [13–15], no examples of
selenium-based mechanisms for obtaining such amines were previously reported in the
literature.
2. Results and Discussion
From the point of view of the molecular mechanism, the considered oxidation-
triggered elimination is distinctive of organoselenium compounds having protons in the
position with respect to the chalcogen atom. This process occurs through a syn mechanism
and promotes the formation of olefins with high trans selectivity [ ]. The reaction is initi-
β-
8
ated by the oxidation of the selenium atom to the corresponding selenoxide, a step which
can be induced by different agents such as hydrogen peroxide, meta-chloroperoxybenzoic
acid (mCPBA) and ozone [7,16,17]. Then, an intramolecular syn elimination takes place:
the Se-C bond breaks producing the trans-olefin and selenenic acid, that is readily oxidized
to seleninic acid [10]. Interestingly, in the case of the studied compounds (Scheme 2), an
enamine is produced after the oxidation–elimination step. This can be protonated on both
the nitrogen atom and the β-carbon atom in acidic conditions. The latter event is favored
and the molecule, rearranging to an iminium ion and undergoing hydrolysis, subsequently
produces the corresponding amine (Scheme 1) [18,19].
In the field of synthetic organic chemistry, the preparation of primary aliphatic amines
can be achieved by Gabriel synthesis [20], by azidation–reduction [21], by Leuckart reac-
tion [22] or its variation involving the use of benzylamine and hydrogenolysis [23]. In
analogy, secondary aliphatic amines can be obtained through different processes: direct
alkylation [24], reductive amination [25] and the Fukuyama amine synthesis [26]. In the cur-
rent study, we aimed at investigating the formation of primary and secondary amines based
on the combination of known selenoxide elimination and enamine hydrolysis reactions. In

Molecules 2021, 26, 2770
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particular, this reaction was studied in aqueous solution and under oxidative conditions.
Thus, mono- and disubstituted symmetric, asymmetric and cyclic derivatives reported in
Scheme 2 were synthesized and reacted with hydrogen peroxide in the presence of water.
The overall reaction was studied in detail by NMR spectroscopy, mass spectrometry and
DFT calculations.
Scheme 2. Chemical structures of the studied compounds. The portion of the molecules providing the resulting amine is
highlighted in blue.
Compound
8 was synthesized by styrene azido-phenylselenenylation with the hyper-
valent iodine reagent (diacetoxyiodo)benzene, sodium azide and diphenyl diselenide in
dichloromethane (Scheme 3). The reaction involves the formation of an azido radical that,
after the addition to the double bond of the styrene, generates a carbon radical which is
then trapped by diphenyldiselenide to provide the product [27]. Racemic compound
9
was
obtained by reduction of the azido group of compound
in THF (Scheme 3).
8 with lithium aluminum hydride
Scheme 3. (a) (diacetoxyiodo)benzene/diphenyl diselenide/NaN3/DCM; (b) LiAlH4/THF.
Then,
hydrochlorides (Scheme 2; see Figures S1–S27 in Supplementary Materials for NMR and
mass spectra). In particular, compounds were obtained through direct alkylation using
the opportune halide, such as iodoethane, benzyl bromide, bis(2-bromoethyl) ether and
α0-dibromo-o-xylene. Compounds
and were obtained by reductive amination of com-
pound with benzaldehyde and p-nitrobenzaldehyde, respectively. By reacting compound
5 with iodoethane, the corresponding tertiary amine (compound 7) was prepared.
First, the combined reaction was studied in detail for compound in aqueous solu-
9 was subjected to different alkylation reactions to obtain compounds 1–7 as
1–4
α
,
5
6
9
3
tion by 1H-NMR. This substrate was chosen as a model also because the corresponding
elimination product, morpholine, represents an outstanding example of pharmacologi-
cally relevant moiety. Interestingly, it can be found in drugs acting on CNS (e.g., in the
antidepressants reboxetine and viloxazine and in the withdrawn stimulant phenmetrazine),
and which are used to treat pathologies where oxidative stress has been demonstrated
to play a role on disease onset and progression [28,29]. More in detail, compound 3 was
dissolved in deuterated water and reacted with 1.2 equivalents of hydrogen peroxide at
room temperature.

Molecules 2021, 26, 2770
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The analysis of this reaction showed the progressive disappearance of the
α
-hydrogen
signal, paralleled by the appearance of the signals corresponding to the two selenoxide
diastereoisomers (Figure S28 in Supplementary Materials). Calculations at COSMO-ZORA-
OLYP/TZ2P level of th−e1ory [30
,31] showed that in water, this reaction displays an energy
barrier of 14.5 kcal mol which separates the reactants from the selenoxide form (Iox, see
Figure 1a) lying at
−
39.5 kcal mol−1. As the reaction further proceeded, the signals of
such intermediates disappeared and the subsequent formation of the two particular signals
corresponding to morpholine hydrochloride (3.25 and 3.90 ppm) was observed. After
70 min, 72% relative abundance of secondary amine was observed in the NMR spectrum.
At the same time point, the relative abundance of the starting material was < 10% (Figure 2)
.
The mechanism for the last part of the reaction was computationally modelled in three
elementary steps. First, starting from the selenoxide, an intramolecular elimination reaction
requiring 7.6 kcal mol−1 takes place (TSelim, Figure 1a) that results in the cleavage of one
C-Se bond and the formation of selenenic acid (the further oxidation of selenenic acid to
seleninic acid detected experimentally was not computationally investigated) [
9] and the
corresponding enamine (SeOH En, Figure 1a) with a G of
+
∆
−
76.7 kcal mol−1 relative
to the starting reactants. Finally, the process that was involved in the cleavage of the
C-N bond to give the final morpholine molecule consist in two steps. The first requires
the addition of an H3O+ ion to the enamine with an activation energy of 51.8 kcal mol−1
(
(
TS1
Figure 1b). The final reaction of the C-N bond cleavage leads to the formation of
, Figure 1b) which are found to be 6.4 kcal mol−1
,
Figure 1b) and leads to an intermediate which is destabilized by 25.5 kcal mol−1
I,
morpholine and phenylacetaldehyde (
P
more stable than the starting enamine. The reaction involves a proton transfer from the
OH moiety of I to the N atom. This step requires a somewhat extended network of explicit
water molecules to be successfully modelled [32]. The inclusion of explicit water molecules
in mechanisms that involve proton transfers usually helps to recover more favorable
energetics [32–35]. Nevertheless, mechanistic features are not modified by this inclusion
and conformational studies on the model hydrogen bond network to obtain the most stable
configuration are quite tricky. As the detailed mechanistic analysis of this reaction is out
of the scope of this work, the effect of explicit water molecules was not addressed in this
context. All the solvation contributions were incorporated in the polarizing effect of the
dielectric continuum employed in the calculations. On the same basis, the reaction was
investigated by 1H-NMR spectroscopy for compounds
1–7 (see Figures S31, S33 and S36
in Supplementary Materials for representative NMR and mass spectra), demonstrating
the disappearance of starting material and the formation of the corresponding products
(43–93% relative abundance). Electrospray mass spectrometry (ESI-MS) studies, which
were performed in parallel, confirmed the identity of involved intermediates, including
enamines, and products. More in detail, primary and secondary amines generated after
the oxidation of compound 1–7 were characterized using positive ionization ESI-MS on
the same samples, while negative ionization ESI-MS analysis confirmed the presence
of seleninic acid and benzoic acid as final oxidation products. The latter very likely
generates from phenylacetaldehyde oxidation (see Figures S29, S30, S32, S34, S35 and S37
in Supplementary Materials for mass spectra) [36].

Molecules 2021, 26, 2770
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Figure 1. Gibbs free energies of the relevant intermediates and transition states characterized in water for the oxidation
and subsequent elimination of compound : ( ) corresponds to the top reaction of Scheme 1 whereas ( ) to the bottom
3
a
b
one. Water and hydrogen peroxide molecules are not shown in the minimum energy structures for clarity. Level of theory:
COSMO- ZORA-OLYP/TZ2P.
Following this NMR-scale mechanistic investigation and to gain further insight on
the underlying processes, the reactions involving compounds 1–7 were scaled up and
performed on the same substrates, in order to isolate the elimination products, verify the
identity and calculate the yield. Compounds were subjected to an overnight oxidation
using H2O2 and the corresponding amines were isolated with an average yield of 68%,
with a best isolated yield of 90%. 1H-NMR, 13C-NMR and ESI-MS analysis confirmed
the identity of the products, thus demonstrating the formation of primary and secondary
amines in the laboratory scale (see Supplementary Materials for experimental procedures,
yields, computational details and Figures S38–S58 for spectra).
(a)
1.0
0.8
0.6
0.4
0.2
0.0
0
10
20
30
40
50
60
70
Figure 2. Cont.

Molecules 2021, 26, 2770
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(b)
80
t = 70 min
t = 50 min
60
40
t = 30 min
t = 15 min
20
t = 0 min
0
4.5
4.0
3.5
3.0
ppm
Figure 2. Reaction profiles for compound
ered for relative quantification are depicted as in the following:
secondary amine. Integrals were measured using acetonitrile as internal standard (
3
, intermediate and reaction products. The signals consid-
starting material, intermediate,
). Detailed views
•
•
•
a
of representative NMR spectra showing the considered signals (b).
3. Materials and Methods
3.1. Chemistry
Commercially available chemicals were purchased from Sigma-Aldrich and used
without any further purification if not specified elsewhere. NMR experiments were per-
formed on an Avance III 400 (Bruker, Billerica, MA, USA) spectrometer (frequencies: 400.13,
1
100.62 MHz for H and 13C nuclei, respectively) equipped with a multinuclear inverse
z-field gradient probe head (5 mm). For data processing, TopSpin 4.0.8 software was used,
and the spectra were calibrated using solvent signal (1H-NMR, δH = 7.26 ppm for CDCl3,
δH = 3.31 ppm for CD3OD, δH = 2.50 ppm for DMSO-d6; 13C-NMR, δC = 77.16 ppm for
CDCl3, 39.52 ppm for DMSO-d6, δC = 49.00 for CD3OD). Multiplicities are reported as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad; dd, doublet
of doublets. Mass spectra were recorded by direct infusion ESI on a LCQ Fleet ion trap
(Thermo Fisher Scientific, Waltham, MA, USA) mass spectrometer. For data processing,
Qual Browser Thermo Xcalibur 4.0.27.13 software was used. ESI parameters for samples
acquired in positive ionization mode: spray voltage 3.2 kV, capillary temperature 160 ◦C,
capillary voltage 43 V. ESI parameters for samples acquired in negative ionization mode:
spray voltage 5.0 kV, capillary temperature 160 ◦C, capillary voltage −8 V.
3.2. Synthesis of Compound 1
Compound
9 (100 mg, 0.36 mmol) was dissolved in iodoethane (2 mL) and DIPEA
(190
µ
L, 1.08 mmol) was added to the solution that was then deaerated, purged with
◦
nitrogen and refluxed under stirring at 90 C for 2 h. After TLC showed the disappearance
of the starting material (DCM/MeOH/NH3, 97.5/2.0/0.5), the mixture was cooled to r.t.
and the solvent was evaporated under reduced pressure. DCM (30 mL) was added, and
the solution was washed with 1 M KOH (3
×
10 mL), dried over magnesium sulphate and
evaporated at reduced pressure obtaining a viscous brownish liquid which was purified by
chromatographic column (silica gel, DCM/MeOH/NH3, 97.5/2.0/0.5). The hydrochloride
salt was then prepared, dissolving the product in anhydrous diethyl ether and adding a
2 M solution of HCl in diethyl ether dropwise.
1
White solid, 119 mg, 0.32 mmol, 89%. H-NMR (CD3OD, 400 MHz): 7.63–7.61 (m,
2H), 7.46–7.34 (m, 8H), 4.82 (dd, J = 10.7, 4.5 Hz, 1H), 4.06 (dd, J = 14.0, 10.7 Hz, 1H), 3.52
(dd, J = 14.0, 4.5 Hz, 1H), 3.20–3.06 (m, 4H), 1.19–1.10 (m, 6H); 13C{1H} NMR (CD3OD,
101 MHz): 138.8, 137.2, 130.6, 130.4, 130.3, 129.7, 129.2, 129.0, 56.3, 41.8, 9.0, 8.5; (ESI+) m/z
calcd for C18H24NSe+ [M + H]+: 334.11, found: 333.95.

Molecules 2021, 26, 2770
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3.3. Synthesis of Compound 2
Compound (100 mg, 0.36 mmol) was dissolved in EtOH (5 mL). Benzyl bromide
L, 124 mg, 0.73 mmol) and DIPEA (190
9
(87
µ
µ
L, 1.08 mmol) were added to the solution that
◦
was deaerated, purged with nitrogen and refluxed under stirring at 90 C for 2 h. After TLC
showed the disappearance of the starting material (hexane/diethyl ether, 6/1), the mixture
was cooled to r.t. and the solvent was evaporated under reduced pressure. DCM (30 mL)
was added, and the obtained solution was washed with 1 M KOH (3
×
10 mL), dried over
magnesium sulphate and evaporated under reduced pressure. The crude product was
purified by column chromatography (silica gel, hexane/DCM, 9/1) obtaining a viscous
liquid. The hydrochloride salt was then prepared dissolving the product in anhydrous
diethyl ether and adding a 2 M solution of HCl in diethyl ether dropwise.
1
White solid, 93 mg, 0.19, 52%. H-NMR (CD3OD, 400 MHz): δH (ppm) 7.57–7.20 (m,
18H), 6.80–6.78 (m, 2H), 4.56–4.43 (m, 3H), 4.31 (d, J = 12.7 Hz, 1H), 4.17 (d, J = 12.6 Hz,
1H), 3.87 (dd, J = 13.9, 10.9 Hz, 1H), 3.61 (dd, J = 13.9, 5.0 Hz, 1H); 13C{1H} NMR (CD3OD,
101 MHz): 138.0, 137.8, 132.9, 132.6, 131.6, 130.7, 130.5, 130.5, 130.3, 129.6, 128.7, 127.9, 60.4,
55.5, 41.6; (ESI+) m/z calcd for C28H28NSe+ [M + H]+: 458.14, found: 458.05.
3.4. Synthesis of Compound 3
Compound 9 (100 mg, 0.36 mmol) was dissolved in EtOH (5 mL). Bis(2-bromoethyl)
ether (84 mg, 0.36 mmol) and DIPEA (190 µL, 1.08 mmol) were added to the solution that
◦
was deaerated, purged with nitrogen and refluxed under stirring at 90 C for 2 h. After TLC
showed disappearance of starting material (DCM/MeOH/TEA, 95/4.5/0.5), the mixture
was cooled to r.t. and the solvent was evaporated under reduced pressure, DCM (30 mL)
was added and the so obtained solution was washed with 1 M KOH (3
×
10 mL), dried
over magnesium sulphate and evaporated at reduced pressure. The crude product was
purified by column chromatography (silica gel, DCM/MeOH/TEA, 95/4.5/0.5), obtaining
a viscous liquid. The hydrochloride salt was then prepared, dissolving the product in
anhydrous diethyl ether and adding a 2 M solution of HCl in diethyl ether dropwise.
White solid, 70 mg, 0.18 mmol, 50%. 1H-NMR (CD3OD, 400 MHz): 7.52–7.50 (m,
2H), 7.38–7.28 (m, 8H), 4.92 (dd, J = 10.4, 4.7 Hz, 1H), 4.13–4.07 (m, 1H), 4.00–3.69 (m,
4H), 3.64 (dd, J = 13.6, 4.7 Hz, 1H), 3.24–3.20 (m, 4H); 13C{1H} NMR (CD3OD, 101 MHz):
139.2, 136.9, 130.5, 130.2, 130.0, 129.5, 129.1, 129.1, 64.6, 62.1, 53.7, 41.4; (ESI+) m/z calcd for
C18H22NOSe+ [M + H]+: 347.95, found: 347.98.
3.5. Synthesis of Compound 4
Compound
9 (150 mg, 0.54 mmol) was dissolved in EtOH (6 mL). α,α
0-dibromo-o-
xylene (154 mg, 0.54 mmol) and K2CO3 (225 mg, 1.62 mmol) were added to the solution that
◦
was deareated, purged with nitrogen and refluxed under stirring at 90 C for 3 h. After TLC
showed the disappearance of the starting material (hexane/diethyl ether, 6/1), the mixture
was cooled to r.t. and the solvent was evaporated under reduced pressure, DCM (30 mL)
was added and the obtained solution was washed with 1 M KOH (3
×
10 mL), dried
over magnesium sulphate and evaporated under reduced pressure. The crude product
was purified by column chromatography (silica gel, hexane/diethyl ether, 89.75/9.75/0.5)
obtaining a viscous liquid. The hydrochloride salt was then prepared dissolving the product
in anhydrous diethyl ether and adding a 2 M solution of HCl in diethyl ether dropwise.
1
Green solid, 45 mg, 0.11 mmol, 20 %. H NMR (CD3OD, 400 MHz): 7.53–7.51 (m, 2H),
7.40–7.30 (m,12H), 4.82–4.79 (m, 1H), 4.67–4.58 (m, 4H), 4.29 (dd, J = 13.2, 10.2 Hz, 1H) 3.96
(dd, J = 13.2, 5.7 Hz, 2H); 13C{1H} NMR (CD3OD, 101 MHz): 138.9, 137.1, 134.8, 130.5, 130.2,
130.1, 130.1, 129.6, 129.1, 128.7, 123.8, 60.4, 60.0, 43.2; (ESI+) m/z calcd for C22H21NSe+ [M +
H]+: 379.08, found: 380.00.
3.6. Synthesis of Compound 5
Compound
9 (100 mg, 0.36 mmol) was dissolved in dry MeOH (5 mL). Benzaldehyde
(37
µL, 0.36 mmol) was added to the solution that was deaerated, purged with nitrogen and

Molecules 2021, 26, 2770
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stirred at r.t. for 2 h. After TLC showed disappearance of starting materials (hexane/diethyl
ether 6/1), the mixture was cooled in an ice bath and NaBH4 (16 mg, 0.43 mmol) was added
in portions. The ice bath was removed, and the mixture was stirred at r.t. for other 2 h.
After TLC showed the disappearance of the starting material (hexane/diethyl ether 6/1),
the solution was cooled in an ice bath and first acidified to pH = 2 by the addition of 1 M
HCl and the basified to pH = 14 by the addition of 8 M KOH. The solvent was evaporated
under reduced pressure. DCM (30 mL) was added, and the solution was washed with 1 M
KOH (3
×
10 mL), dried over magnesium sulphate and evaporated under reduced pressure,
obtaining a viscous liquid. The crude product was purified by column chromatography
(silica gel hexane/EtOAc, 9/1 with 0.5% TEA). The hydrochloride salt was then prepared,
dissolving the product in anhydrous diethyl ether and adding a 2 M solution of HCl in
diethyl ether dropwise.
1
White solid, 125 mg, 0.31 mmol, 86%. H-NMR (CDCl3, 400 MHz): 7.42–7.19 (m, 15H),
4.49 (dd, J = 7.9, 7.0 Hz, 1H), 3.0 (d, J = 3.4 Hz, 2H), 3.26 (dd, J = 12.6, 8.2 Hz, 1H), 3.16 (dd,
J = 12.6, 7.0 Hz, 1H); 13C{1H} NMR (CDCl3, 101 MHz): 140.7, 140.0, 135.4, 128.8, 128.6, 128.5,
128.4, 128.1, 127.9, 127.8, 127.2, 127.0, 53.4, 53.3, 48.2; (ESI+) m/z calcd for C21H22NSe+
[M + H]+: 368.08, found: 367.93.
3.7. Synthesis of Compound 6
Compound
dehyde (82 mg
9
(150 mg, 0.36 mmol) was dissolved in dry MeOH (6 mL). p-Nitrobenzal
µ
L, 0.36 mmol) was added to the solution that was deareated, purged with
nitrogen and stirred overnight at r.t. After TLC showed the disappearance of the starting
material (6/1 hexane/diethyl ether), the mixture was cooled in an ice bath and NaBH4
(16 mg, 0.43 mmol) was added portion wise. The ice bath was removed, and the mixture
was stirred at r.t. for other 2 h. After TLC showed the disappearance of the starting material
(6/1 hexane/diethyl ether), the solution was cooled in an ice bath and first acidified to
pH = 2 by the addition of 1 M HCl and the basified to pH = 14 by the addition of 8 M KOH.
The solvent was evaporated under reduced pressure. DCM (30 mL) was added, and the
solution was washed with 1 M KOH (3
×
10 mL), dried over magnesium sulphate and
evaporated under reduced pressure, obtaining a viscous liquid. The crude product was
purified by column chromatography (silica gel hexane/EtOAc, 9/1 with 0.5% TEA). The
hydrochloride salt was then prepared, dissolving the product in anhydrous diethyl ether
and adding a 2 M solution of HCl in diethyl ether dropwise.
1
White solid, 135 mg, 0.31 mmol, 87%. H-NMR (DMSO-d6, 400 MHz): δH (ppm) 9.56
(br, 1H), 9.25 (br, 1H), 8.24 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.44–7.42 (m, 2H),
7.36–7.25 (m, 8H), 4.88 (dd, J = 9.7, 5.6 Hz, 1H), 4.26 (s, 2H), 3.74–3.72 (m, 2H); 13C{1H} NMR
(DMSO-d6, 101 MHz): 148.2, 139.5, 138.2, 134.8, 134.0, 131.9, 129.8, 129.2, 128.7, 128.5, 128.4,
124.0, 50.5, 49.8, 42.2; (ESI+) m/z calcd for C21H21N2O2Se+ [M + H]+: 413.08, found: 412.89.
3.8. Synthesis of Compound 7
Compound 5 (100 mg, 0.27 mmol) was dissolved in iodoethane (5 mL). The solution
was deaerated, purged with nitrogen and refluxed under stirring at 90 ◦C for 2 h. After
TLC showed the disappearance of the starting material (hexane/diethyl ether, 6/1), the
mixture was cooled to r.t. and the solvent was evaporated under reduced pressure. DCM
(30 mL) was added, and the solution was washed with 1 M KOH (3
×
10 mL), dried
over magnesium sulphate and evaporated under reduced pressure obtaining a viscous
colorless liquid. The crude product was purified by column chromatography (silica gel,
hexane/EtOAc/TEA, 97/2.5/0.5) obtaining a viscous liquid. The hydrochloride salt was
then prepared dissolving the product in anhydrous diethyl ether and adding a 2 M solution
of HCl in diethyl ether dropwise.
1
White solid, 69 mg, 0.15 mmol, 57 %. H-NMR (CD3OD, 400 MHz): 7.51–7.06 (m, 15H),
4.77 (dd, J = 10.8, 4.7 Hz, 0.5H), 4.60 (dd, J = 10.5, 4.6 Hz, 0.5H), 4.39–4.22 (m, 2H), 4.06 (dd,
J = 13.9, 10.6 Hz, 0.5H), 3.88 (dd, J = 13.9, 10.7 Hz, 0.5H), 3.63–3.48 (m, 1H), 3.30–3.13 (m,
2H), 1.27–1.22 (m, 3H); 13C{1H} NMR (CD3OD, 101 MHz): 138.8, 138.3, 137.4, 137.3, 132.3,

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132.2, 131.4, 130.6, 130.5, 130.5, 130.4, 130.3, 130.3, 130.1, 129.7, 129.6, 129.0, 128.9, 128.8,
128.6, 58.8, 56.3, 56.1, 50.9, 50.2, 42.1, 41.4, 28.0, 8.9, 8.5; (ESI+) m/z calcd for C23H26NSe+
[M + H]+: 396.12, found: 395.94.
3.9. Synthesis of Compound 8
Diphenyldiselenide (414 mg, 1.33 mmol), (diacetoxyiodo)benzene (1.000 g, 3.10 mmol)
and sodium azide (346 mg, 5.32 mmol) were added to a solution of styrene (231 mg,
2.22 mmol) in DCM (20 mL). The mixture was deaerated and purged with nitrogen. After
overnight stirring at r.t., a saturated solution of NaHCO3 (10 mL) was added, the organic
phase was separated, and the aqueous phase was extracted with DCM (2
×
20 mL).
The organic phases were reunited and evaporated at reduced pressure. The obtained
yellow liquid was purified by column chromatography (silica gel, pure hexane then 90:10
hexane/diethylether), obtaining a colorless liquid.
1
Colorless liquid, 257 mg, 0.85 mmol, 38%. H NMR (CDCl3, 400 MHz,): δH 7.54–7.51
(m, 2H), 7.37–7.27 (m, 8H), 4.44 (dd, J = 9.7, 5.7 Hz, 1H), 3.91 (dd, J = 12.5, 9.8 Hz, 1H),
3.75 (dd, J = 12.5, 5.8 Hz, 1H); 13C{1H} NMR (CDCl3, 101 MHz): 139.0, 135.7, 129.3, 128.9,
128.6, 128.5, 128.0, 127.9, 55.6, 46.5; (ESI+) m/z calcd for C14H14N3Se+ [M + H]+: 304.19,
found: 304.15.
3.10. Synthesis of Compound 9
Compound
8 (1.010 g, 3.33 mmol) was dissolved in anhydrous THF (20 mL) and
the solution was deaerated and purged with nitrogen. The system was equipped with
a reflux apparatus and a solution of 1 M LiAlH4 (5 mL, 5.01 mmol) was added portion
wise to the mixture; after the addition, the mixture was stirred for 2 h. After TLC showed
disappearance of starting material (DCM/MeOH/NH3, 97.5/2.0/0.5), wet diethyl ether
was slowly added to the solution and distilled water was then added. The resulting bi-
phasic mixture was filtered, and the aqueous phase was separated and extracted with
diethyl ether (2
×
20 mL). The organic phase was dried over magnesium sulphate and
evaporated at reduced pressure obtaining a viscous colorless liquid that was purified by
column chromatography (silica gel, DCM/MeOH/NH3, 97.5/2.0/0.5).
1
Colorless liquid, 503 mg, 1.82 mmol, 55%. H NMR (CDCl3, 400 MHz): 7.53–7.51 (m,
2H), 7.37–7.27 (m, 8H), 4.43 (dd, J = 9.6, 5.7 Hz, 1H), 3.91 (dd, J = 12.6, 9.6 Hz, 1H), 3.74 (dd,
J = 12.6, 5.7 Hz, 1H); 13C{1H} NMR (CDCl3, 101 MHz): 140.2, 135.1, 128.8, 128.7, 128.3, 127.8,
127.6, 127.0, 51.8, 46.8; (ESI+) m/z calcd for C14H16NSe+ [M + H]+: 278.04, found: 277.80.
3.11. Laboratory Scale Oxidation Procedures
3.11.1. Oxidation of Compound 3
Compound
round-bottom flask and H2O2 (530
3
(1.50 g, 3.92 mmol, 1 eq) was dissolved in 120 ml of distilled H2O in a
L, 4.70 mmol, 1.2 eq) was then added to the mixture.
µ
The solution was stirred overnight and checked by TLC. Further 1.2 eq of H2O2 were then
added in order to consume the remained reactant. After TLC showed the disappearance of
the starting material, the mixture was cooled in an ice bath, filtered and the filtrate was
evaporated under reduced pressure, adding ethanol to facilitate solvent removal. The
resulting yellowish precipitate was washed with small aliquots of acetone, obtaining the
desired product as a white solid.
Morpholine
HCl: white solid, 435 mg, 3.52 mmol, 90%; 1H-NMR (CD3OD, 400 MHz):
·
3.91–3.88 (m, 4H), 3.25–3.22 (m, 4H); 13C{1H} NMR (CD3OD, 101 MHz): 64.9, 44.6; (ESI+)
m/z calcd for C4H10NO+ [M + H]+: 88.08, found: 87.93.
3.11.2. Oxidation of Compound 1, 4, 5 and 7
The selenoamine (1 eq) was dissolved in a MeOH/H2O mixture (85/15) in a round-
bottom flask. 1.2 eq of H2O2 were then added to the mixture and the solution was stirred
overnight. The solution was stirred overnight and checked by TLC. Further 1.2 eq of
H2O2 were then added in order to consume the remained reactant. After TLC showed

Molecules 2021, 26, 2770
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the disappearance of the starting material, the solvent was evaporated under reduced
pressure. Water was added to the reaction flask in order to dissolve the desired product and
eliminate most of the insoluble byproducts. The final compounds were isolated following
the procedure described above.
Diethylamine
HCl: white solid; 55 mg, 0.50 mmol, 82%; 1H-NMR (CD3OD, 400 MHz):
·
3.06 (q, J = 7.3 Hz, 4H), 1.32 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (CD3OD, 101 MHz): 43.5, 11.6;
(ESI+) m/z calcd for C4H12N+ [M + H]+: 74.10, found: 73.9.
Isoindoline
HCl: brown solid, 69 mg, 0.44 mmol, 69%; 1H NMR (DMSO-d6, 400 MHz):
·
10.21 (br, 2H), 7.52–7.36 (m, 4H), 4.48 (s, 4H); 13C{1H} NMR (DMSO-d6, 101 MHz): 134.4,
127.6, 122.4, 49.2; (ESI+) m/z calcd for C8H10N+ [M + H]+: 120.08, found: 119.98.
Benzylamine
HCl: white solid, 183 mg, 1.27 mmol, 85%; 1H NMR (CD3OD, 400 MHz):
·
7.49–7.40 (m, 5H), 4.12 (s, 2H); 13C{1H} NMR (CD3OD, 101 MHz): 134.4, 130.2, 130.0, 129.9,
44.4; (ESI+) m/z calcd for C7H10N+ [M + H]+: 108.08, found: 107.88.
1
N-ethylbenzylamine
·
HCl: white solid, 114 mg, 0.66 mmol, 75%; H-NMR (CD3OD,
400 MHz): 7.52–7.44 (m, 5H), 4.19 (s, 2H), 3.12 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (CD3OD, 101 MHz): 132.7, 130.9, 130.6, 130.3, 52.0, 43.8, 11.5; (ESI+) m/z
calcd for C9H14N+ [M + H]+: 136.11, found: 135.97.
3.11.3. Oxidation of Compound 2 and 6
The compounds were obtained following the procedure reported above. Although,
after the evaporation of the MeOH/H2O mixture and the addition of water, the mixture
was acidified with 0.2 M HCl to pH 2–3 and heated for a couple of hours at 40 ◦C in order
to facilitate the hydrolysis of the enamine.
Dibenzylamine
HCl: white solid, 47 mg, 0.22 mmol, 33%; 1H NMR (CD3OD, 400 MHz):
·
7.52–7.45 (m, 10H), 4.25 (s, 4H); 13C{1H} NMR (CD3OD, 101 MHz): 131.8, 130.1, 128.8, 128.5,
49.5; (ESI+) m/z calcd for C14H16N+ [M + H]+: 198.13, found: 198.06.
p-Nitrobenzylamine: white solid, 15 mg, 0.08 mmol, 45%; 1H NMR (DMSO-d6, 400 MHz):
8.78 (br, 3H), 8.26 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 4.17 (s, 2H); 13C{1H} NMR
+
(DMSO-d6, 101 MHz): 147.4, 141.7, 130.2, 123.5, 41.3; (ESI+) m/z calcd for C7H9N2O2
[M + H]+: 153.07, found: 152.93.
3.12. Computational Details
The oxidation–elimination–hydrolysis mechanism of compound
3 was modeled
with an in silico approach based on DFT. The oxidation and elimination initial reactions
(Scheme 1, top line) were modelled on the basis of a recent in-depth study on analogous
reactions by some of the authors of this work [10]. The only difference with Scheme 1 is
that the in the computational model, the direct product of the elimination process is the
selenenic acid analogue of the seleninic acid. The oxidation from selenenic to seleninic
acid was not investigated in silico. The oxidation reaction keeps the stereochemistry of
the C carbon bonded to Se fixed and can take two pathways, leading to diastereomeric
geometries of oxidized products (R–R and R–S). In light of the conclusions drawn in a
recent work [10], only the pathway leading to the R–R diastereomer was investigated due
to its more favorable reaction energies. The quantum chemistry calculations for the oxida-
tion mechanism were performed using the Amsterdam Density Functional (ADF) [37–39].
The energy profiles were obtained from geometries and energies computed by using the
OLYP functional [40,41], which is known to perform well for reactivity studies on or-
ganic compounds, and it has been recently benchmarked [30] and applied [31] to organic
dichalcogenides and amines [42]. OLYP was combined with the TZ2P basis set for all the
atoms [43]. The TZ2P basis set is of triple- quality and has been augmented with two sets
of polarization functions. Core shells of the atoms (1s for C, F, N and O and up to 3p for
Se) were treated by using the frozen-core approximation. Scalar relativistic effects were
accounted for using the Zeroth Order Regular Approximation (ZORA) [44
ical integration was performed by using the fuzzy-cell integration scheme developed by
Becke [47 48]. Energy minima and transition states have been verified through vibrational
–46]. The numer-
,

Molecules 2021, 26, 2770
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analysis. All minima were found to have zero imaginary frequencies and all transition
states have one that correspond to the mode of the reaction under consideration. For single
point calculations in water, the conductor-like screening model was employed (COSMO),
as implemented in ADF [49–51]. Water was parameterized using the default values in ADF,
i.e., a dielectric constant of 78.39 and a solvent radius of 1.93 Å. The empirical parameter in
the scaling function in the COSMO equation was set to 0.0. The radii of the atoms were
taken to be MM3 radii divided by 1.2, giving 1.350 Å for H, 1.700 Å for C, 1.608 for N,
1.517 for O and 1.908 for Se [49,52]. This level of theory is referred to as (COSMO)-ZORA-
OLYP/TZ2P. Geometry optimizations were conducted in the gas phase and frequency
calculations were employed to establish the nature of the stationary points found (all real
frequencies for minima and one imaginary frequency for transition states). Thereafter,
single point calculations in COSMO water were used to obtain the ∆G values reported in
the main text. Relative free Gibbs energies are shown for the gas phase calculations and for
the water single points in Table S1.
4. Conclusions
Amines are present in a vast portion of biologically active compounds, and their
relevance in medicinal chemistry is crucial. More specifically, such moieties are often
present in CNS-targeting molecules. In several drugs or drug-like compounds, variously
substituted amines represent a part of the pharmacophore or are employed to enhance
water solubility. We here reported the experimental and in silico characterization of an
innovative combined reaction consisting in a selenoxide elimination-triggered hydrolysis
for the preparation and/or selective release under oxidative conditions of several model
primary and secondary amines. This may allow an effective in situ release of high-value
pharmaceutical compounds that overcomes multiple limitations to which amines are often
subjected to in the organism. Moreover, the ability of this reaction to be triggered in
an oxidizing environment is very promising for the development of amino-containing
molecules that can be selectively activated only in case of excessive oxidative stress levels.
Supplementary Materials: The following are available online, Figures S1–S27: NMR and ESI-MS
characterization of compounds 1–9
; Figures S28–S37: representative 1H-NMR and ESI-MS spectra
of the oxidation study with H2O2; Figures S38–S58: 1H-NMR, 13C-NMR and ESI-MS spectra of
the isolated compounds obtained by oxidation with H2O2; Table S1: Gibbs free energies relative to
free reactants for the selenoxide-triggered amine formation; Table S2: geometries of the optimized
structures of the selenoxide-triggered amine formation reaction.
Author Contributions: Conceptualization, G.R., M.B.; data curation, G.R., M.B., E.O., A.O.; funding
acquisition, A.G., L.O.; investigation, G.R., M.B., E.O., A.O.; methodology, G.R., M.B., L.O.; project
administration, L.O.; supervision, G.Z., L.O.; validation, G.Z., L.O.; visualization, G.R., M.B.; writing
—original draft preparation, G.R., M.B.; writing—review and editing, G.R., M.B., A.G., G.Z., L.O. All
authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by Università degli Studi di Padova, thanks to the P-DiSC
(BIRD2018-UNIPD) project MAD3S (Modeling Antioxidant Drugs: Design and Development of
computer-aided molecular Systems), P.I. L.O., and by Università degli Studi di Brescia. Calculations
were carried out on the Bastion system of the CNAF institute (Bologna, Italy) thanks to the INCIpit
grant (Insights on Chalcogen Nitrogen Interaction, ISCRA C HP10C15ZCK).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in the supplementary materials.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Not available.

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References
1.
Jones, D.N.; Mundy, D.; Whitehouse, R.D. Steroidal Selenoxides Diastereoisomeric at Selenium; Syn-Elimination, Absolute
Configuration, and Optical Rotatory Dispersion Characteristics. J. Chem. Soc. D Chem. Commun. 1970, 2, 86–87. [CrossRef]
Sharpless, K.B.; Lauer, R.F.; Teranishi, A.Y. Electrophilic and Nucleophilic Organoselenium Reagents. New Routes to Alpha,
Beta-Unsaturated Carbonyl Compounds. J. Am. Chem. Soc. 1973, 95, 6137–6139. [CrossRef]
2.
3.
4.
Heffner, R.J.; Jiang, J.; Joullie, M.M. Total synthesis of (−)-nummularine F. J. Am. Chem. Soc. 1992, 114, 10181–10189. [CrossRef]
Nicolaou, K.C.; Reddy, K.R.; Skokotas, G.; Sato, F.; Xiao, X.Y.; Hwang, C.K. Total Synthesis of Hemibrevetoxin B and (7aα)-Epi-
hemibrevetoxin B. J. Am. Chem. Soc. 1993, 115, 3558–3575. [CrossRef]
5.
Vargas, D.; Fronczek, F.R.; Fischer, N.H.; Hostettmann, K. The Chemistry of Confertiflorin and the Molecular Structure of
Confertiflorin and Allodesacetylconfertiflorin, Two Molluscicidal Sesquiterpene Lactones. J. Nat. Prod. 1986, 49, 133–138.
[CrossRef]
6.
7.
8.
9.
Callant, P.; Ongena, R.; Vandewalle, M. Iridoids: Novel Total Synthesis of (
Tetrahedron 1981, 37, 2085–2089. [CrossRef]
Waring, A.J.; Zaidi, J.H. Synthesis of a 4-acylcyclohexa-2,5-dienone: 3,4-dihydro-3,3,8a-trimethyl-naphthalene-1,6(2H,8aH)-dione.
J. Chem. Soc. Perkin. Trans. 1985, 1, 631–639. [CrossRef]
Sharpless, K.B.; Young, M.W.; Lauer, R.F. Reactions of Selenoxides: Thermal Syn-elimination and H218O Exchange. Tetrahedron
Lett. 1973, 14, 1979–1982. [CrossRef]
±
)- Isoiridomyrmecin and of ( )-Verbenalol.
±
Ribaudo, G.; Bellanda, M.; Menegazzo, I.; Wolters, L.P.; Bortoli, M.; Ferrer-Sueta, G.; Zagotto, G.; Orian, L. Mechanistic Insight
into the Oxidation of Organic Phenylselenides by H2O2. Chem. Eur. J. 2017, 23, 2405–2422. [CrossRef] [PubMed]
10. Ribaudo, G.; Bortoli, M.; Ongaro, A.; Oselladore, E.; Gianoncelli, A.; Zagotto, G.; Orian, L. Fluoxetine Scaffold to Design Tandem
Molecular Antioxidants and Green Catalysts. RSC Adv. 2020, 10, 18583–18593. [CrossRef]
11. Simplício, A.L.; Clancy, J.M.; Gilmer, J.F. Prodrugs for Amines. Molecules 2008, 13, 519–547. [CrossRef]
12. Sun, C.; Wang, L.; Xianyu, B.; Li, T.; Gao, S.; Xu, H. Selenoxide Elimination Manipulate the Oxidative Stress to Improve the
Antitumor Efficacy. Biomaterials 2019, 225, 119514. [CrossRef]
13. Guo, R.; Huang, J.; Huang, H.; Zhao, X. Organoselenium-Catalyzed Synthesis of Oxygen- and Nitrogen-Containing Heterocycles.
Org. Lett. 2016, 18, 504–507. [CrossRef]
14. Santi, C.; Bagnoli, L. Celebrating Two Centuries of Research in Selenium Chemistry: State of the Art and New Prospective.
Molecules 2017, 22, 2124. [CrossRef] [PubMed]
15. Shao, L.; Li, Y.; Lu, J.; Jiang, X. Recent Progress in Selenium-Catalyzed Organic Reactions. Org. Chem. Front. 2019, 6, 2999–3041.
[CrossRef]
16. Krief, A.; Dumont, W.; De Mahieu, A.F. Novel Synthesis of Selenones: Application to the Synthesis of Alkyl Cyclopropanecar-
boxylates. Tetrahedron Lett. 1988, 29, 3269–3272. [CrossRef]
17. Sevrin, M.; Dumont, W.; Krief, A. Synthetic Route to Vinyl Selenides and Vinyl Selenoxides. Tetrahedron Lett. 1977, 18, 3835–3838.
[CrossRef]
18. Stamhuis, E.J.; Maas, W. Mechanism of Enamine Reactions. II. 1 The Hydrolysis of Tertiary Enamines. J. Org. Chem. 1965, 30,
2156–2160. [CrossRef]
19. Capon, B.; Wu, Z.P. Comparison of the Tautomerization and Hydrolysis of Some Secondary and Tertiary Enamines. J. Org. Chem.
1990, 55, 2317–2324. [CrossRef]
20. Gabriel, S. Über eine Darstellungsweise primärer Amine aus den entsprechenden Halogenverbindungen. Ber. Dtsch. Chem. Ges.
1887, 20, 2224–2236. [CrossRef]
21. Corey, E.J.; Link, J.O. A General, Catalytic, and Enantioselective Synthesis of Alpha.-Amino Acids. J. Am. Chem. Soc. 1992, 114,
1906–1908. [CrossRef]
22. Leuckart, R. Über eine neue Bildungsweise von Tribenzylamin. Ber. Dtsch. Chem. Ges. 1885, 18, 2341–2344. [CrossRef]
23. Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. Chiral Ligand-Controlled Asymmetric Conjugate Addition of Lithium
Amides to Enoates. J. Am. Chem. Soc. 2003, 125, 2886–2887. [CrossRef]
24. Von Hofmann, A.W.V. Researches Regarding the Molecular Constitution of the Volatile Organic Bases. Philos. Trans. R. Soc. 1850
140, 93–131. [CrossRef]
,
25. Russell Bowman, W.; Coghlan, D.R. A Facile Method for the N-alkylation of
[CrossRef]
α-Amino Esters. Tetrahedron 1997, 53, 15787–15798.
26. Fukuyama, T.; Jow, C.-K.; Cheung, M. 2- and 4-Nitrobenzenesulfonamides: Exceptionally Versatile Means for Preparation of
Secondary Amines and Protection of Amines. Tetrahedron Lett. 1995, 36, 6373–6374. [CrossRef]
27. Tingoli, M.; Tiecco, M.; Chianelli, D.; Balducci, R.; Temperini, A. Novel Azido-phenylselenenylation of Double Bonds. Evidence for
a Free-radical Process. J. Org. Chem. 1991, 56, 6809–6813. [CrossRef]
28. Bortoli, M.; Dalla Tiezza, M.; Muraro, C.; Pavan, C.; Ribaudo, G.; Rodighiero, A.; Tubaro, C.; Zagotto, G.; Orian, L. Psychiatric
Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico. Comput. Struct. Biotechnol. J. 2019
,
17, 311–318. [CrossRef]
29. Ribaudo, G.; Bortoli, M.; Pavan, C.; Zagotto, G.; Orian, L. Antioxidant Potential of Psychotropic Drugs: From Clinical Evidence to
In Vitro and In Vivo Assessment and toward a New Challenge for In Silico Molecular Design. Antioxidants 2020, 9, 714. [CrossRef]

Molecules 2021, 26, 2770
13 of 13
30. Bortoli, M.; Zaccaria, F.; Dalla Tiezza, M.; Bruschi, M.; Fonseca Guerra, C.; Bickelhaupt, F.M.; Orian, L. Oxidation of organic
diselenides and ditellurides by H2O2 for bioinspired catalyst design. Phys. Chem. Chem. Phys. 2018, 20, 20874–20885. [CrossRef]
31. Bortoli, M.; Bruschi, M.; Swart, M.; Orian, L. Sequential oxidations of phenylchalcogenides by H2O2: Insights into the redox
behavior of selenium via DFT analysis. New J. Chem. 2020, 44, 6724–6731. [CrossRef]
32. Yildiz, I. A DFT Approach to the Mechanistic Study of Hydrozone Hydrolysis. J. Phys. Chem. A 2016, 120, 3683–3692. [CrossRef]
33. Bayse, C.A. DFT Study Of The Glutathione Peroxidase-Like Activity of Phenylselenol Incorporating Solvent-Assisted Proton
Exchange. J. Phys. Chem. A 2007, 111, 9070–9075. [CrossRef]
34. Bayse, C.A. Transition States for Cysteine Redox Processes Modeled by DFT and Solvent-Assisted Proton Exchange. Org. Biomol.
Chem. 2011, 9, 4748–4751. [CrossRef] [PubMed]
35. Antony, S.; Bayse, C.A. Modeling the Mechanism of the Glutathione Peroxidase Mimic Ebselen. Inorg. Chem. 2011, 50, 12075–12084.
[CrossRef] [PubMed]
36. Chen, H.; Wang, W.; Yang, Y.; Jiang, P.; Gao, W.; Cong, R.; Yang, T. Solvent Effect on the Formation of Active Free Radicals From
H2O2 Catalyzed by Cr-Substituted PKU-1 Aluminoborate: Spectroscopic Investigation and Reaction Mechanism. Appl. Catal. A
Gen. 2019, 588, 117283. [CrossRef]
37. te Velde, G.; Bickelhaupt, F.M.; Baerends, E.J.; Fonseca Guerra, C.; van Gisbergen, S.J.A.; Snijders, J.G.; Ziegler, T. Chemistry with
ADF. J. Comput. Chem. 2001, 22, 931–967. [CrossRef]
38. Fonseca Guerra, C.; Snijders, J.G.; te Velde, G.; Baerends, E.J. Towards an Order- N DFT Method. Theor. Chem. Acc. 1998, 99,
391–403. [CrossRef]
39. Baerends, E.J.; Ziegler, T.; Atkins, A.J.; Autschbach, J.; Bashford, D.; Baseggio, O.; Bérces, A.; Bickelhaupt, F.M.; Bo, C.; Boerritger,
P.M.; et al. ADF2018; SCM, Theoretical Chemistry; Vrije Universiteit: Amsterdam, The Netherlands, 2018.
40. Handy, N.C.; Cohen, A.J. Left-right Correlation Energy. Mol. Phys. 2001, 99, 403–412. [CrossRef]
41. Handy, N.C.; Cohen, A.J. A Dynamical Correlation Functional. J. Chem. Phys. 2002, 116, 5411–5418. [CrossRef]
42. Savoo, N.; Laloo, J.Z.A.; Rhyman, L.; Ramasami, P.; Bickelhaupt, F.M.; Poater, J. Activation Strain Analyses of Counterion and
Solvent Effects on the Ion-Pair SN2 Reaction of and CH3Cl. J. Comput. Chem. 2020, 41, 317–327. [CrossRef] [PubMed]
43. Van Lenthe, E.; Baerends, E.J. Optimized Slater-Type Basis Sets For the Elements 1-118. J. Comput. Chem. 2003, 24, 1142–1156.
[CrossRef]
44. van Lenthe, E.; Baerends, E.J.; Snijders, J.G. Relativistic Regular Two-Component Hamiltonians. J. Chem. Phys. 1993, 99, 4597–4610.
[CrossRef]
45. van Lenthe, E.; Baerends, E.J.; Snijders, J.G. Relativistic Total Energy Using Regular Approximations. J. Chem. Phys. 1994, 101,
9783–9792. [CrossRef]
46. van Lenthe, E.; Snijders, J.G.; Baerends, E.J. The Zero-Order Regular Approximation for Relativistic Effects: The Effect of
Spin–Orbit Coupling in Closed Shell Molecules. J. Chem. Phys. 1996, 105, 6505–6516. [CrossRef]
47. Becke, A.D. A Multicenter Numerical Integration Scheme for Polyatomic Molecules. J. Chem. Phys. 1988, 88, 2547–2553. [CrossRef]
48. Franchini, M.; Philipsen, P.H.T.; Visscher, L. The Becke Fuzzy Cells Integration Scheme in the Amsterdam Density Functional
Program Suite. J. Comput. Chem. 2013, 34, 1819–1827. [CrossRef] [PubMed]
49. Pye, C.C.; Ziegler, T. An Implementation of the Conductor-Like Screening Model of Solvation within the {Amsterdam} Density
Functional Package. Theor. Chem. Acc. 1999, 101, 396–408. [CrossRef]
50. Klamt, A.; Schüürmann, G. COSMO: A New Approach to Dielectric Screening in Solvents with Explicit Expressions for the
Screening Energy and its Gradient. J. Chem. Soc. Perkin Trans. 1993, 2, 799–805. [CrossRef]
51. Klamt, A.; Jonas, V. Treatment of the Outlying Charge in Continuum Solvation Models. J. Chem. Phys. 1996, 105, 9972–9981.
[CrossRef]
52. Allinger, N.L.; Zhou, X.; Bergsma, J. Molecular Mechanics Parameters. J. Mol. Struct. THEOCHEM 1994, 312, 69–83. [CrossRef]