Mechanistic Insight into the Oxidation of Organic Phenylselenides by H2O2

Article abstract of DOI:10.1002/chem.201604915

The oxidation of organic phenylselenides by H₂O₂is investigated in model compounds, namely, n-butyl phenyl selenide (PhSe(nBu)), bis(phenylselanyl)methane (PhSeMeSePh), diphenyl diselenide (PhSeSePh), and 1,2-bis(phenylselanyl)ethane

Full text of DOI:10.1002/chem.201604915

A Journal of
Accepted Article
Title: Mechanistic Insight on the Oxidation of Organic Phenylselenides
by H₂O₂
Authors: Giovanni Ribaudo, Massimo Bellanda, Ileana Menegazzo,
Lando Peter Wolters, Marco Bortoli, Gerardo Ferrer-Sueta,
Giuseppe Zagotto, and Laura Orian
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10.1002/chem.201604915
Chemistry - A European Journal
Mechanistic Insight on the Oxidation of Organic
Phenylselenides by H2O2
Giovanni Ribaudo,[a] Massimo Bellanda,*[b] Ileana Menegazzo,[b] Lando P. Wolters,[b]
Marco Bortoli,[b] Gerardo Ferrer-Sueta,[c] Giuseppe Zagotto,[a] and Laura Orian*[a]
a Dipartimento di Scienze del Farmaco Università degli Studi di Padova, Via Marzolo 5, 35131 Padova, Italy.
bDipartimento di Scienze Chimiche Università degli Studi di Padova, Via Marzolo 1, 35131 Padova, Italy.
c
Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la
Repúbica, Igua 4225, Montevideo, Uruguay.
laura.orian@unipd.it, massimo.bellanda@unipd.it
Abstract:
The oxidation of organic phenylselenides by H2O2 is investigated in model compounds, i.e. n-butyl
phenyl selenide (PhSe(n-Bu)), bis(phenylselanyl)methane (PhSeMeSePh), diphenyl diselenide
(PhSeSePh) and 1,2-bis(phenylselanyl)ethane (PhSeEtSePh). Through a combined experimental
(1H and 77Se NMR) and computational approach, we characterize the direct oxidation of
monoselenide to selenoxide, the stepwise double oxidation of PhSeMeSePh leading to different
diastereomeric diselenoxides, the complete oxidation of the diphenyldiselenide leading to selenium-
selenium bond cleavage and subsequent formation of the phenylseleninic product. Oxidation of
PhSeEtSePh also results in the formation of phenylseleninic acid along with 1-
(vinylseleninyl)benzene which is derived from a side elimination reaction. The evidence of a direct
mechanism, in addition to an autocatalytic mechanism, which emerges from kinetic curves, is
discussed. By deliberation of observations of diselenides whose chalcogens are separated by alkyl
1
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spacers of different length, a rationale for the advantage of diselenide versus monoselenide catalysts
is presented.
Introduction
The reactivity of organoselenium compounds towards peroxides is characteristic of their chemistry,
keeping up the pressure on the researchers for this class of compounds for applications in catalysis
and biomedicine. [1] H2O2 is an environmentally-friendly, commercially inexpensive, easy to handle
and oxygen-rich reagent. Despite being thermodynamically favored, the oxidation of organic
substrates by H2O2 is kinetically unfavorable. [2]
In the late 1970s it was discovered that organoselenium compounds could be efficiently used
instead of metals to activate H2O2, affording high reactivity and selectivity in numerous organic
reactions. Organoselenides are employed as green catalysts in many synthetic transformations,
including Baeyer-Villiger oxidations of ketones/aldehydes, the conversion of alkenes to epoxides
and the oxidations of alcohols and nitrogen containing compounds. For an exhaustive overview of
this class of catalysts the reader is referred to valuable contributions and book chapters written by
Braga, Wirth, Santi and Back and co-workers. [1a,2,3]
Upon reaction with H2O2, organic monoselenides are oxidized to selenoxides and
diselenides are oxidized to seleninic acids via selenoseleninate; the latter inevitably implies
cleavage of the selenium-selenium bond. After oxidation, the selenoxide or seleninic acid acts as a
peroxide activator, i.e. reacts with H2O2 in situ to generate hydroxy perhydroxy selenane or
peroxyseleninic acid, respectively. These oxygen transfer agents are then able to oxidize organic
substrates (Scheme 1).
2
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OH
Se
OOH
Se
O
H2O
H2O2
H2O2
-H2O
Se
Se
R
R1
R
R1
R
R1
R
R1
-H2O
OH
OH
CATALYZED
ORGANIC
REACTIONS
O
O
O
O
3 H2O2
-2 H2O
2 H2O2
-2 H2O
Se
R1
Se
+
Se
Se
R
Se
+
R
Se
R
OOH
R1
OOH
OH
R1
OH
Scheme 1. Oxidation of mono- and diselenides by H2O2; R and R1 are alkyl/aryl groups.
The interest in organoselenides has also animated the biomedical community. The biological
role of selenium was assessed in 1973, where it was proven that glutathione peroxidase (GPx) is a
[4]
selenoprotein, i.e. containing selenium in the form of a selenocysteine (Sec) residue. GPx are a
class of enzymes which are ubiquitous in nature, protecting cells from oxidative stress by
converting hydrogen peroxide and harmful organic hydroperoxides to water/alcohols. To elucidate
the mechanism of the process, a three-step catalytic mechanism has been proposed (i) oxidation of
the selenol form of Sec (E-SeH) to a selenenic intermediate (E-SeOH), with simultaneous reduction
of one equivalent of hydroperoxide to produce water/alcohol; (ii) reduction of E-SeOH upon
reaction with one equivalent of glutathione (GSH), producing water and a selenenyl sulfide
intermediate (E-SeSG) and (iii) reduction of E-SeSG by reaction with a second equivalent of GSH
to produce the oxidized glutathione (GSSG), resulting in the regeneration of the initial configuration
of the enzyme (Scheme 2a).[5] Accidentally, as stressed by Flohé,[6] the first three selenium-enzymes
discovered were all peroxidases, which largely influenced the erroneous concept that selenium is
only a biological anti-oxidant. In contrast, it is important to remember that its presence in 25 human
proteins, possessing diversified functions, reveals that selenium also plays other biological roles,
which are currently under vigorous investigation. [7]
3
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(a)
E-SeH
+GSH
-GSSG
+ROOH
-ROH
+GSH
-H2O
E-Se-OH
E-SeSG
(b)
O
O
+RSH
-H2O
2
4
NHPh
SeOH
NHPh
+RSH
-RSSR
+RSH
-RSSR
SeSR
-H2O
+RSH
O
O
O
O
6
3
7
+RSH
NHPh
+RSH
-H2O
NHPh
SeH
N Ph
SeH
OH
N Ph
Se
SR
Se
-H2O
-RSSR
1
O
+ROOH
-ROH
-H2O
+RSH
+RSH
+ROOH
-ROH
O
O
+RSH
-H2O
NHPh
SeOH
N Ph
Se
O
5
4
O
+H2O
NHPh
SeOH
O
8
4
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H+
N
(c)
+H2O2
-H2O
Se-
+RSH
10
N
N
Se
Se
N
+RSH
-RSSR
Se
OH
12
9
+RSH
-H2O
+RSH
N
+H2O2
-H2O
Se
SR
11
N
O
Se
Se
N
13
Scheme 2. Catalytic mechanisms of GPx (a) (E represents the enzyme, GSH is glutathione), ebselen
(1) (b) and N,N-dimethylbenzylamine diselenide (9) (c).
GPx’s inherent biological activity has inspired the synthesis of organoselenium compounds
which could mimic the detoxifying anti-oxidant ability of the enzyme and thus be employed in
medicine. [1b,8] The oldest and most popular GPx mimic is ebselen (2-phenyl-1,2-benzisoselenazol-
[9]
3(2H)-one),
but so far the mechanistic details of its catalytic activity have not been fully
unravelled. Ebselen is a cyclic selenenyl amide (Scheme 2b, 1) and ring opening is required for the
formation of the active selenol species as discerned in the GPx cycle. This can occur via successive
reactions with two equivalents of thiol, first forming a selenenyl sulfide (2) and then the selenol
species (3), which subsequently may reduce the peroxide.[10,11] As with GPx, this mechanism is
based upon the hypothesis that the selenol is the active reducing agent wherein its oxidation leads to
selenenic acid (4), an elusive species that has been isolated only in a clathrate.[12] Alternatively, the
first step has been proposed to be the reduction of the hydroperoxide forming a seleninyl amide (5)
whose successive reaction with a thiol may lead to an equilibrium of selenurane (6) and seleninyl
5
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sulfide (7) as the products, where the latter is monocyclic;[10,11] the conversion of 5 to 7 may also
occur stepwise via 8, where ring opening occurs by hydration. The seleninyl sulfide 7 is then
reduced by a second equivalent of thiol to selenenic acid (4), which connects it again to the GPx-
like cycle described above (Scheme 2b). This mechanism is based on the hypothesis that the
reducing agent is a selenenyl amide, the oxidation of which leads to the corresponding seleninyl
amide. It has also been suggested that after reduction by thiol with loss of water, the selenurane (6)
can be converted back to ebselen (1) (Scheme 2b). [10,11]
Ebselen is considered as the parent compound of a family of selenenyl amides which have
been specifically designed and synthesized to gain an enhanced level of peroxidase activity. [13] Two
other classes of GPx mimics, both possessing lesser degree of structural complexity, are intensively
studied, i.e. aryl and alkyl monoselenides and aryl diselenides. Compounds of the monoselenide
class react with peroxides to form selenoxides. A more complex general mechanism for aryl
[14]
diselenides has been proposed by Iwaoka and Tomoda.
It involves cleavage of the Se-Se bond
by reaction with a thiolate, resulting in the formation of a selenenyl sulfide (11) and a selenol (10),
triggering the formerly discussed GPx-like mechanism (Scheme 2c). Alternatively, the diselenide
(9) has been proposed to react with the peroxide, forming a selenoseleninate (13) and water as
products (Scheme 2c). The latter step was investigated in silico using N,N-dimethylbenzylamine
diselenide and it led to a severely distorted structure with an excessively elongated Se-Se bond, thus
it was excluded as a possibility.[15] One important advantage of using mono- and diselenides is that
they are easier to synthesize than selenenyl amides. In addition to this, the presence of two selenium
nuclei undoubtedly enhances the catalytic activity of diselenides, which have received a great deal
of attention in the recent years. [16]
On the basis of this excursus the significance of the elementary reaction of an organic mono-
/diselenide with H2O2 (extendable to generic organic hydroperoxides) emerges. To the best of our
knowledge, the mechanistic details of the oxidation of organoselenides by H2O2 have not been
rigorously analyzed and reported yet. Nevertheless, it is worth to mention the contributions of Trout
6
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et al. in their ab initio study of the oxidation of organic sulfides by H2O2 in aqueous solution,
highlighting the role of explicit water molecules in the mechanism of the process. [17]
Contained in this paper is a presentation of the results from combined experimental and
theoretical mechanistic investigations concerning the oxidation by H2O2 of four organoselenides: n-
butyl phenyl selenide (PhSe(n-Bu)), diphenyl diselenide (PhSeSePh), bis(phenylselanyl)methane
(PhSeMeSePh) and bis(phenylselanyl)ethane (PhSeEtSePh) (Figure 1).
Figure 1. From left to right, molecular geometries of n-butyl phenyl selenide (PhSe(n-Bu)), 1,2-
bis(phenylselanyl)ethane (PhSeEtSePh), bis(phenylselanyl)methane (PhSeMeSePh) and the global
minimum conformation of diphenyl diselenide (PhSeSePh); level of theory scalar-ZORA-
OLYP/TZ2P-sc.
These compounds were chosen as model organoselenides to allow the comparison of a
monoselenide and a diselenide (PhSe(n-Bu) and PhSeSePh), and to investigate the effect which a
spacer of increasing length has upon the reactivity of a diselenide (PhSeMeSePh and
PhSeEtSePh). It is worth to note that PhSeSePh itself is a molecule of paramount importance,
being widely used as green catalyst as well as a drug, with twice the efficiency of ebselen.[18] For
clarity, these four compounds will be referred to in the text using the above described short names;
all derivatives will be labelled with progressive numbers as indicated in the schemes.
Materials and Methods
Synthesis. Commercially available chemicals were purchased from Aldrich and used as received,
1
13
unless otherwise stated. H and C{1H} NMR spectra were recorded on a Bruker Avance III 400
MHz spectrometer and on a Bruker AMX 300 MHz spectrometer. All spectra were recorded at
room temperature, the solvent for each spectrum is given in parentheses. Chemical shifts are
7
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reported in ppm and are relative to the residual solvent peak. Datasets were edited with Bruker
TopSpin suite and iNMR. The multiplicity of signals are reported as singlet (s), doublet (d), triplet
(t), quartet (q), multiplet (m), broad (br) or a combination of any of these. High resolution mass
spectra (HRMS) were recorded on a ESI-TOF Mariner from Perseptive Biosystem and on a Xevo
G2 from Waters, using electrospray (ES) ionization. The purity profile of the compounds was
assayed by HPLC using a Varian Pro-Star system equipped with a Biorad 1706 UV-VIS detector
and an Agilent C-18 column (5μm, 4.6 x 150 mm). An appropriate ratio of water (A) and
acetonitrile (B) was used as mobile phase with an overall flow rate of 1 mL min-1; the general
method for the analyses is reported here: 0 minutes (90% A-10% B), 15 minutes (10% A-90% B),
20 minutes (10% A-90% B), 21 minutes (90% A-10% B), 25 minutes (90% A-10% B). The purity
of all compounds was ≥ 97%, unless otherwise stated.
General procedure for the preparation of alkyl aryl selenides
Alkyl aryl selenides were prepared according to a procedure reported by Walker et al.[19] with minor
modifications. Briefly, diphenyl diselenide (0.321 mmol, 1 eq) was dissolved in 10 mL of ethanol.
NaBH4 (0.962 mmol, 3 eq) was added over a period of 15 minutes to the solution, which was being
stirred in an ice bath. After 30 minutes a solution of the opportune alkyl bromide (0.802 mmol, 2.5
eq) in 2 mL of ethanol was slowly added to the mixture. The resulting solution was allowed to stir
at room temperature for an additional 2 hours, after which the solvent was evaporated. The light
yellow residue obtained was suspended in diethyl ether (20 mL) and the mixture was washed with
water (3 x 10 mL). The organic layer was evaporated to provide the desired alkyl aryl selenide as
light yellow oil. Yields: 76-89 %.
n-butyl phenyl selenide (PhSe(n-Bu))
1
Rf=0.76 (hexane); m.p.<25°C; H NMR (400 MHz, CDCl3, 25°C): δ=7.46 (m, 2H; PhH), 7.27 (m,
3
3H; PhH), 2.94 (t, J(H,H)=7.4 Hz, 2H; CH2), 1.72 (m, 2H; CH2), 1.45 (m, 2H; CH2), 0.93 (t,
8
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3J(H,H)=7.4 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 25°C): δ=132.5, 130.9, 129.1, 126.5, 32.3,
27.7, 23.1, 13.7; ESI-MS: m/z 215.0339 [M+] [C10H15Se+]; elemental analysis calcd (%) for
C10H14Se: C 56.3, H 6.6; found: C 56.3, H 6.6.
n-heptyl phenyl selenide
1
Rf=0.74 (hexane); H NMR (400 MHz, CDCl3, 25°C): δ=7.51 (m, 2H; PhH), 7.27 (m, 3H; PhH),
3
2.94 (t, J(H,H)=7.3 Hz, 2H; CH2), 1.73 (m, 2H; CH2), 1.42 (m, 2H; CH2), 1.4-1.3 (m, 4H; CH2),
3
13
0.93 (t, J(H,H)=7.4 Hz, 3H; CH3); C NMR (100 MHz, CDCl3, 25°C): δ=132.4, 130.8, 129.0,
126.6, 31.7, 30.2, 29.8, 28.8, 28.0, 22.6, 14.1; MS: m/z 257.0803 [M+] [C13H21Se+]; elemental
analysis calcd (%) for C13H20Se: C 61.2, H 7.9; found: C 61.3, H 7.9.
n-nonyl phenyl selenide
1
Rf=0.72 (hexane); H NMR (400 MHz, CDCl3, 25°C): δ=7.51 (m, 2H; PhH), 7.26 (m, 3H; PhH),
3
2.94 (t, J(H,H)=7.3 Hz, 2H; CH2), 1.72 (m, 2H; CH2), 1.4-1.2 (m, 10H; CH2), 0.92 (t,
3J(H,H)=7.4 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 25°C): δ=132.4, 130.7, 128.9, 126.6, 31.9,
30.2, 29.8, 29.4, 29.2, 29.1, 27.4, 22.6, 14.1; MS: m/z 285.1119 [M+] [C15H25Se+]; elemental
analysis calcd (%) for C15H24Se: C 63.6, H 8.5; found: C 63.7, H 8.4.
Synthesis of bis(phenylselanyl)alkanes
Previous reports described the preparation of bis(phenylselanyl)alkanes from diphenyl diselenide
under a number of conditions, such as using sodium hydroxide and hydrazine hydrate in N,N-
dimethyl-formamide;[20] RhCl(PPh3)3, hydrogen and triethylamine in tetrahydrofuran;[21] sodium
hydroxide, formaldehyde and sodium hydrogen sulfite in ethanol and dichloromethane.[22] While
most of the reported procedures require handling of delicate reactants, long reflux times or multi-
step reactions,[23,24] we optimized the conditions for the reaction of diphenyl diselenide with sodium
borohydride in ethanol to generate a straightforward procedure to obtain the desired compounds in
9
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mild conditions, with a single step, producing good yields. The compounds were prepared
following the procedure for alkyl aryl selenides using 1.25 eq of alkyl halide (1,2-dibromo ethane or
diiodomethylene) and 5 eq of NaBH4.
bis(phenylselanyl)methane (PhSeMeSePh)
1
Yield: 46%. Rf=0.79 (hexane); m.p.<25°C; H NMR(400 MHz, CDCl3, 25°C): δ=7.58 (m, 4H;
PhH), 7.31 (m, 6H; PhH), 4.29 (s, 4H; CH2); 13C NMR (100 MHz, CDCl3, 25°C): δ=133.0, 130.8,
+
129.1, 127.6, 21.0; ESI-MS: m/z 328.9707 [M+] [C13H13Se2 ]; elemental analysis calcd (%) for
C13H12Se2: C 47.9, H 3.7; found: C 47.8, H 3.7.
1,2-bis(phenylselanyl)ethane (PhSeEtSePh)
1
Yield: 32 %. Rf=0.75 (hexane); m.p.<25°C; H NMR(400 MHz, CDCl3, 25°C): δ=7.46 (m, 4H;
PhH), 7.27 (m, 6H; PhH), 3.16 (s, 2H; CH2); 13C NMR (100 MHz, CDCl3, 25°C): δ= 133.1, 129.2,
+
127.7, 127.2, 27.2; ESI-MS: m/z 342.9501 [M+] [C14H15Se2 ]; elemental analysis calcd (%) for
C14H14Se2: C 49.4, H 4.1; found: C 49.4, H 4.2.
NMR analysis and kinetic studies. NMR experiments were performed at 25°C on a Bruker
1
Avance III 400 spectrometer (400.13 MHz H frequency, 100.62 MHz 13C frequency, and 76.37
77
MHz Se frequency) equipped with a 5 mm multinuclear inverse z-field gradient probe-head. For
1
data processing the Topspin 3.5 software was used. The H chemical shifts were reported in ppm
1
and referenced to the residual solvent signal. H and 77Se resonances assignments were obtained
1
using 2D H–77Se heteronuclear multiple-bond correlation (1H–77Se HMBC) experiment with
gradient coherence selection. [25] 77Se chemical shifts were referenced to diphenyl diselenide in
1
CDCl3 (463.0 ppm). The H–77Se HMBC spectra were acquired using a repetition delay of 1 s; a
total of 300 experiments of 16-40 scans were accumulated and processed with a magnitude
1
calculation; 33.3 ms evolution delay was used for H–77Se long-range coupling constants; the
10
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spectral width was 13 ppm in F2, 600-1200 ppm in F1. Zero-filling in both F1 and F2 dimensions,
multiplication with a Gaussian function (in F2) and a squared sine function (in F1) were performed
prior to 2D Fourier Transform. To follow reaction kinetics, compounds (10 mM) were dissolved in
0.5 mL of methanol-D4 before the addition of the opportune amount of H2O2 in D2O (1 or 3
1
equivalents [26]) several H one-dimensional NMR spectra were recorded with 8 transients, 12 ppm
spectral width, and 32k data points. Exponential multiplication with line broadening of 0.3 Hz was
applied prior to Fourier Transform.
Computational methodology. All calculations were carried out using the Amsterdam Density
[27]
Functional (ADF) program developed by Baerends and co-workers
and the Quantum-regions
[28]
Interconnected by Local Descriptions (QUILD) program.
The numerical integration was
performed using the fuzzy cells integration scheme developed by Becke. [29] The molecular orbitals
(MOs) were expanded in a large uncontracted set of Slater type orbitals (STOs, no Gaussian
functions are involved). All geometries and energies are obtained using the TZ2P basis set. [30] The
TZ2P basis set is of triple- quality for all atoms and has been augmented with two sets of
polarization functions. Core shells of the atoms (1s for C and O; up to 3p for Se) were treated by the
frozen-core approximation, here denoted ‘-sc’. NMR chemical shielding constants have been
[30]
calculated using the all-electron quadruple- quality QZ4P basis set.
All calculations include
scalar relativistic effects, accounted for using the zeroth-order regular approximation (ZORA). [31]
[32]
For the computation of NMR chemical shifts,
the geometries and NMR shielding tensors
were calculated with the OPBE functional. [33] The scalar-ZORA-OPBE/TZ2P-sc approach has been
found to give reliable geometries for the class of compounds in this study. [34]
The shielding constant was in two cases broken down as the sum of a diamagnetic and
paramagnetic contribution (=d+p); the spin-orbit term must also be added, but only when
explicitly considered in the calculations, which is not our case. [32,35] The diamagnetic term is almost
constant for a given nucleus in different compounds because it depends mainly on the core-shell
electrons and cancels out in the chemical shift calculation. The paramagnetic term can be further
decomposed as the sum of two terms (p=pocc-occ+pocc-vir): the former is a sum over all pairs of
occupied orbitals; the latter is a sum over all pairs of orbitals consisting of an occupied orbital and
virtual orbital; each term is weighted by the inverse of the energy gap and is proportional to the
11
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occ-vir
magnetic coupling between the involved orbitals. p
is the largest contribution to p and is
mostly responsible for the variation in chemical shift. [35]
The energy profiles were obtained from geometries and energies computed using the OLYP
[33b,36]
functional,
which was chosen because it is known to perform well for reactivity studies on
[37]
[34]
[38]
organic compounds,
and it has been recently benchmarked
and applied
to organic
dichalcogenides. Energy minima and transition states have been verified through vibrational
[39]
analysis.
All minima were found to have zero imaginary frequencies and all transition states
have one, corresponding to the mode of the reaction under consideration.
Results and discussion
This section is organized as follows: firstly, the reactivity of the monoselenide is described and
discussed; following this, the results pertaining the diselenides in which the chalcogens are
separated by methylene and ethylene groups are presented; in the latter case there is a limitation due
to the side elimination reaction, which leads to Se-Se bond cleavage and alkene formation; finally,
diphenyl diselenide is considered, stressing the mechanistic implications related to the presence of a
direct Se-Se bond.
Oxidation of PhSe(n-Bu)
It is well known that arylselenides react with peroxides by undergoing direct oxidation to provide
the corresponding selenoxides (Scheme 3a).
12
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(a)
O
OH
Se
OOH
HO
HO
Se
Se
Se
H2O
H2O2
-H2O
H2O2
-H2O
-H2O
17
16
PheSe(n-Bu)
(14)
15
H2O2
(b)
O
OOH
Se
HO
Se
Se
+
2 x
+ H2O
17
15
PheSe(n-Bu)
(14)
Scheme 3. Mechanism of oxidation of PhSe(n-Bu) by H2O2. The direct oxidation step is shown in
blue.
1
77
The reaction of PhSe(n-Bu) (14) with H2O2 in methanol was characterized by H and Se
NMR. A few minutes after addition of H2O2 a new set of peaks began to appear, shifted down-field
with respect to the original signals, which may be attributed to the selenoxide 15. Upon oxidation,
all methylene multiplets of the butyl chain become more complex due to the fact that the two
protons of each CH2 are no longer equivalent, but diastereotopic. This effect is particularly evident
for the methylene groups in  and  position with respect to the Se nucleus, for which two well
distinguished signals for each proton can be observed (Figure 2 (d)). The reactants and final
products were also characterized by 1H-77Se-HMBC experiments. In general, one expects to observe
correlations between the Se nucleus and protons separated by 2 or 3 covalent bonds for these
experiments. Indeed, the 1H–77Se HMBC spectrum of PhSe(n-Bu) shows three peaks (77Se  = 290
ppm) corresponding to the correlations with the aromatic protons in ortho and with the methylene
protons in  and  positions (Figure 2 (a)) The same pattern of signals was observed for oxidation
77
product 15 at the end of the reaction time, which possessed a much higher Se chemical shift (856
ppm) (Figure 2 (b)).; the identity of this species was also confirmed by HRMS analysis on the
reaction product (m/z 231.02, Figure S1).
13
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Since 77Se NMR is a very practical tool in the assessment of the oxidation states of Se
nuclei, [40] we have systematically measured and calculated the 77Se chemical shifts (Table 1). With
the established protocol, i.e. scalar-ZORA-OPBE/QZ4P//scalar-ZORA-OPBE/TZ2P-sc, we found
77
adequate agreement between measured and calculated Se  values, holding true when considering
the . Firstly, the calculations do not predict any change in 77Se chemical shift with increasing
length of the alkyl chain, in agreement with the experiment. The deviation of approximately 40 ppm
from the measured value obtained for 14, which is within the error typically reported for DFT
calculations on Se compounds,[41] may be due to neglecting conformational effects; the error
becomes smaller in the oxidized species, which are characterized by possessing a more rigid
structure.
It was possible to follow the reaction kinetics of PhSe(n-Bu) reacting with H2O2 with NMR,
due to the fact that the NMR signals of reactants and products do not overlap. In particular, the
integrated area of the multiplets corresponding to the aromatic protons and to the CH2 protons,
which are always well isolated during the reaction, were used to monitor the kinetics (Figure 2 (c)
and (d)). During the reaction the disappearance of 14 was closely accompanied by the emergence of
15 (Figure 2 (e)); no other signals were detected in the NMR spectrum, indicating the absence of an
intermediate species.
14
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(e)
Figure 2. Experimental characterization by NMR of PhSe(n-Bu) (10mM) oxidation by 3
equivalents of H2O2: 77Se-HMBC of reduced (a) and oxidized (b) PhSe(n-Bu); representative
1
changes in the H-NMR for aromatic protons (c) and for the methylene group directly attached to
selenium (d), after 4 (blue), 55 (green) and 310 minutes (red) from the addition of H2O2. The
normalized area of the NMR signals shown in panels (c) and (d), averaged for each compound, have
been used to derive the kinetic profile represented in (e); the kinetic curves are labeled with the
compound numbers used in the text.
15
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Table 1. Experimental[a] and computed[b] 77Se NMR chemical shifts, in ppm, relative to (CH3)2Se.
Compound
Alkyl
Methyl
Ethyl
Propyl
Butyl (14)
Pentyl
Heptyl
Nonyl
Butyl (15)
–
Exp.
202,203[c]
325,326,327[c]*
288[c]
Comp.
193.4
n-Alkyl phenyl selenide
264.1
253.1
290[d]
292[c]
291[d]
291[d]
856[e]
339[d]
252.9
253.0
252.7
252.9
n-Alkyl phenyl selenoxide
PhSeEtSePh (23)
857.0
360.3
PhSeMeSePh (18)
–
345[d]
255 / 867[e]
858[e]
391.4
PhSe(O)MeSePh (19)
PhSe(O)MeSe(O)Ph (20)
–
242.2, 874.2
855.6
R.R
R.S
859.9, 868.2
388.1 / 593.9[f]
Diphenyl diselenide (33)
–
463[d]
456[e]
[a] Measured at 25°C as described in materials and methods. [b] Computed at scalar-ZORA-OPBE/QZ4P//scalar-ZORA-
[c]
[d]
[e]
[f]
OPBE/TZ2P-sc.
Data from Ref. [42]
Solvent: CDCl3
Solvent: MeOD-d4.
77Se chemical shifts for two
different stable conformations, see text.
As the product of the reaction between PhSe(n-Bu) and H2O2 was straightforwardly
characterized as 15, relatively few reaction mechanisms are considered plausible. In primis, we
explored the direct oxidation, which, based on purely electronic energies, occurs via a reaction
barrier of +16.2 kcal mol–1, leading to the selenoxide product 15 at –36.8 kcal mol–1.
[2,43]
According to a mechanistic hypothesis (Scheme 1),
15 can subsequently react with
H2O, to form a dihydroxy product (16). This reaction involves a transition state (TS) at +22.8 kcal
mol–1, after which the product is obtained at +13.1 kcal mol–1 (among the conformers we considered
the most stable product, which has two hydroxy groups at roughly a 180º angle). From 16, the
hydroxy perhydroxy selenane 17 can be formed upon reaction with H2O2, which lies at +3.3 kcal
mol-1; for this step a barrier of +15.6 kcal mol–1 has been computed (Scheme 3a). The possibility of
a direct conversion of 15 into 17 was explored, which is suggested to form, after addition of a
second equivalent of H2O2, via a transition state at +15.0 kcal mol–1 (relative to 14 and H2O2,
Scheme 3a). Several conformations were also located for this product. Presumably, the hydroxy
16
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perhydroxy selenane will initially form in a conformation which has the hydroxy- and perhydroxy-
substituents approximately orthogonal to each other, at a relative energy of +13.9 kcal mol–1.
However, the species with these substituents at a 180º angle (in plane with the phenyl ring) was
found to be the minimum energy structure, being more than 10 kcal mol–1 lower in energy, at +3.3
kcal mol–1. On the basis of the energetics, we therefore assume that the transition from the
selenoxide 15 to 17 is more likely to occur in one step, i.e., addition of H2O2. 17 is considered to be
the active oxidant species in numerous Se-catalyzed organic reactions. In addition, the hydroxy
perhydroxy selenane itself might act as an oxidant towards 14, reacting with one equivalent of the
starting compound (Scheme 3b). In this reaction, an oxygen atom from the perhydroxy group is
transferred to 14, forming the selenoxide product 15, and the remaining hydroxy group leaves
together with the hydrogen from the perhydroxy group to form water, thereby generating a second
equivalent of 15. The computed energy barrier for this reaction is +23.6 kcal mol–1, with the
products having a relative energy of –40.1 kcal mol–1. On the basis of the energetics, and largely
due to the lack of evidence for an autocatalytic mechanism in the kinetic profile (Figure 2 (b)), this
oxidation mechanism for 14 was ruled out.
Oxidation of PhSeMeSePh and oxidation of PhSeEtSePh
O
O
O
Se Se
H2O2
-H2O
Se
Se
H2O2
-H2O
Se Se
PhSeMeSePh
(18)
19
20
H2O2
H2O2
OOH O
OOH
Se
HO
HO
Se Se
Se
22
21
Scheme 4 Mechanism of oxidation of PhSeMeSePh by H2O2. The direct oxidation step is shown in
blue.
17
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As with PhSe(n-Bu), the combination of 1H and 77Se NMR proved to be a useful tool in the
1
characterization of the reaction between PhSeMeSePh (18) and H2O2. The H–77Se HMBC
spectrum of 18 shows a single group of signals (77Se =343 ppm), as expected for a fully reduced
symmetric dinuclear selenide. When the oxidation was carried out using one equivalent of H2O2,
two distinct sets of peaks were observed in the selenium dimension, at 255 ppm and at 867 ppm,
compatible with the presence of a reduced and an oxidized Se nucleus, respectively (Figure 3 (a)).
Interestingly, only very weak signals were detected at the Se frequency for the initial unoxidized.
The new signal at 255 ppm was assigned to the reduced selenium atom of 19, which despite being
close to a seleninyl group, appears to be strongly shielded; this up-field shift is also supported by
DFT calculations (vide infra). As the two groups of signals at 255 and 867 ppm have approximately
the same intensity, we can ascertain that only the mono-oxidized product 19 was formed. The
identity of 19 was confirmed also by HRMS analysis on the reacted sample (m/z 342.93, Figure
S2).
18
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Figure 3. Experimental characterization by NMR of PhSeMeSePh(10mM) oxidation by H2O2:
77Se-HMBC of PhSeMeSePh oxidized by 1 equivalent of H2O2 (a) and by 3 equivalents of H2O2
(b); the weak signal at 343 ppm, indicated by the arrow derive from a small amount of unreacted
1
starting reagent. For the reaction using 3 equivalents of H2O2, representative changes in the H-
NMR for aromatic protons (c) and for the methylene bridge (d), after 4 (blue), 295 (green), and 845
minutes (red) are shown. The two sidebands around the peak at 4.34 ppm derive from the scalar
coupling with natural abundance of 77Se. The normalized areas of selected NMR signals have been
used to derive the kinetic profile represented in (e); the reaction was monitored regularly up to 617
minutes and a single spectrum at 845 minutes was recorded to verify that the reaction had reached
completion (not included in the kinetic profile); the kinetic curves are labeled with the compound
numbers used in the text.
The deduction that the addition of 1equivalent of H2O2 leads only to the formation of the
mono-oxidized species 19 is also inferred by the results obtained by the oxidation of 18 by 3
equivalents of H2O2 (Figure 3 (b)). Using these conditions in conjunction with the 1H–77Se HMBC
experiment, a new set of signals appeared at 858 ppm, a value seen to be shifted only slightly up-
field with respect to the spectrum of 19. However, the peaks at 77Se = 858 ppm cannot be assigned
to a single molecular form. Specifically, there was an observation of two peaks in the aromatic
region (correlation with protons in ortho to Se nucleus) and three peaks in the aliphatic region
19
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(correlations with methylene protons) (Figure 3 (b)). Despite this observation in the NMR spectrum,
HRMS confirmed the exclusive presence of the diselenoxide form (m/z 360.93, Figure S2). In order
to fully comprehend this behavior, the reaction product obtained from the oxidation of 18 by 3 eq.
of H2O2 was analyzed by HPLC-DAD, revealing the formation of two diasteroisomers, namely
(R,R)-20 (or (S,S)-) and (R,S)-20. Also in support of this argument, is the identification of two
species exhibiting superimposed UV spectra in the chromatogram. Furthermore, the relative
abundance of the two diasteroisomers was estimated to be approximately 6:5, fully consistent with
1
the observations by H NMR, discussed below (Figures S5, S6 and S7). Notably, similar spectral
behavior has previously been reported for optically active disulfoxides. [44]
Considering the use of 3 equivalents of H2O2, the kinetics for the complete oxidation of 18
to the di-oxidized species 20 was fully characterized by 1D 1H NMR. This was possible because all
involved species (Scheme 4) possess at least one signal well separated from those of the others
(Figure 3 (c) and (d)). The disappearance of 18 was followed by monitoring the singlet at 4.34 ppm,
which corresponds to the two equivalent protons of the methylene bridge. The protons become
dissimilar after one Se nucleus is oxidized to form 19, causing the NMR signal to be split into a
second order doublet of doublets centred at 4.46 ppm. The intensity of this signal increases
throughout the duration of the reaction in parallel with those of the multiplets at 7.48 and 7.79 ppm,
1
which were unambiguously assigned with the H–77Se HMBC experiments as aromatic protons in
ortho position to the reduced and oxidized Se nuclei of 19.
Upon treatment with approximately 1 equivalent of H2O2, the conversion of the initial
product to 19 reached about 90% and then very slowly it started to decrease accompanied by the
appearance of new signals which may be attributed to 20, and 19 remained as the predominant
species (>80%, not shown). The kinetic profile obtained using 3 equivalents of H2O2 shows that 19
reached a maximum conversion of approximately 55% and then was further oxidized to 20, which
remained as the major product at the end of the reaction (Figure 3 (e)). The NMR experiments
clearly show that two different products were obtained at completion of the reaction. As mentioned
20
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above, three different signals are present in the spectral region between 4.4 and 4.8 ppm: two
doublets characterized by the same splitting of 11.2 Hz and centered at 4.39 ppm (Figure 3 (d)) and
4.82 ppm and a triplet at 4.65 ppm (not shown). The two doublets are assigned to the methylene
protons of the (R,S)/(S,R) diasteromeric forms, which are predicted, at scalar-ZORA-
OPBE/QZ4P//scalar-ZORA-OPBE/TZ2P-sc, to have very different chemical shift values
(=1.1ppm), while the triplet is assigned to a second order spin system for the methylene in which
the two protons resonate at a very similar frequency, in accordance with the computations which
reveal two symmetry-equivalent methylene protons both in the (R,R), and the (S,S) form.
Unfortunately, the two signals at lower field overlap with the strong, broad solvent signal,
meaning the relative quantities of the two diasteroisomers could not be discerned from them.
However, it was possible to estimate this integration of the multiplets in the aromatic region at the
end of the reaction (Figure 3 (c)). The relative areas of the three groups of signals centered at 7.93,
7.67 and 7.58 ppm are 4.0, 10.9 and 7.5, respectively, and they can be rationalized only assuming a
ratio of 6:5 between the diasteroisomers, whose signals partially overlap (4.0:6+(4x1.2):6x1.2).
Computed 77Se chemical shifts for compounds 18-20 are in agreement with experimental
77
values (Table 1); in particular, upon mono-oxidation the Se NMR  of the oxidized chalcogen is
shifted down field by almost 500 ppm, while the 77Se NMR  of the unoxidized nucleus
unexpectedly decreases by approximately 150 ppm: the initial values change from 391.4 ppm to
77
874.2 and 242.2 ppm, respectively. In 20, the two Se NMR chemical shifts are almost identical
and have the characteristic value measured for a selenoxide, i.e. 855.6 ppm for (R,R)-20 and slightly
different shifts of 859.9 and 868.2 ppm for the Se nuclei in (R,S)-20, which are not symmetry-
77
equivalent. The decrease in the Se chemical shift for the non-oxidized Se nucleus in 19, detected
also experimentally, can be qualitatively rationalized by investigating the transitions between
occupied and virtual MOs that contribute most to pocc-vir, which in turn constitutes the more
important part of the paramagnetic part (p) of the shielding constants. The idea behind this
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approach is that the field-induced magnetic moment in a molecule increases if, after applying the
̂
magnetic field operator 퐵 on an occupied orbital, the resulting function overlaps well with an
occ-vir
unoccupied orbital in the molecule. Each contributing term to p
is proportional to this
magnetic coupling between occupied and unoccupied MOs and inversely proportional to their
energy difference. Taking 18 as reference, it is evident that the up-field shift of the reduced Se
nucleus in 19 derives entirely from p, as d is essentially the same for 18 and 19 (it is also worth
noting that less negative p values imply larger  values, i.e. smaller chemical shift values); the data
is summarized in Table 2.
Table 2 Decomposition of the shielding constant  into diamagnetic (d) and paramagnetic (p)
components, as well as selected contributions from occupied-virtual orbital transitions to the
paramagnetic part of the shielding constant and related orbital energy differences for the reduced Se
nuclei in 18 and 19; all  values are in ppm and only contributions above 70 ppm are shown. MOs
of 18 and 19 involved in the listed transitions are shown in Scheme S4.
Eocc-vir
(eV)
Selected
d
p

contributions
occ-vir
to p
1306.7
2995.4
-1688.7
18
-207.0
-114.6
-199.9
-83.2
3.23
4.41
4.53
4.54
4.80
4.93
5.65
7.78
HOMO
HOMO
HOMO
HOMO

LUMO







LUMO+4
LUMO+5
LUMO+6
LUMO+7
LUMO+6
LUMO+11
LUMO+11
-92.8
HOMO
-71.6
HOMO-1
HOMO-1
HOMO-6
-77.5
-74.8
Sum: -921.4
1454.7
2995.2
-1540.5
19
-73.3
-73.7
3.33
4.62
4.75
5.21
7.19
7.98
HOMO
HOMO
HOMO
HOMO-1
HOMO-7
HOMO-7






LUMO
LUMO+5
LUMO+7
LUMO+7
LUMO+4
LUMO+10
-91.8
-107.0
-138.8
-98.0
Sum: -582.6
In both cases, the sum of the terms contributing to pocc-vir converges slowly, but more so in 19 than
in 18. For both compounds the dominant terms are found between MOs whose energy separation is
below 8.0 eV. An analysis of all the involved couples is beyond the scope of this work (isodensity
22
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plots are available in Scheme S4); however, it is illustrative to examine just the HOMO-LUMO
transition. This constitutes the largest contribution to the p of 18, but when compared to 19, its
HOMO-LUMO
value of p
is more than halved. As the energy gaps are similar (3.23 vs 3.33 eV), the
origin of this discrepancy can be found in the change of the value of the integral
̂
̂
⟨휑퐿푈푀푂|퐵|휑퐻푂푀푂⟩, where 퐵 is the magnetic field operator, which is proportional to the angular
̂
momentum operator; the effect of 퐵 upon an atomic p orbital (AO) typically results in a rotation of
90º.[35] In 18, coupling necessarily occurs through the common lobes located on the Se nuclei (the
HOMO has Se pz / Se px character, 41.5% and 42.4% on the two chalcogens, respectively), and
upon application of the field operator they gain the required symmetry to overlap with the Se px / Se
pz lobes of the LUMO (4.8% and 5.1% on the two chalcogens; the LUMO has also important
phenyl character). In 19 however, there is a significant change in the HOMO due to the presence of
oxygen; its composition is dominated by Se (oxidized) px /py / Se (reduced) px / O px /py (6.1%,
35.1% and 33.6%, respectively), while in the composition of the LUMO one finds Se (oxidized) px
/ Se (reduced) pz / O px (3.6%, 4.4% and 1.2%, respectively). Upon application of the field operator
to the HOMO, only the lobes found on the reduced Se nucleus gain the necessary symmetry to
overlap with the LUMO. This subsequently results in a net decrease of the magnetic coupling and,
in absolute terms, of the pHOMO-LUMO in 19.
Mechanistically, the first oxidation of PhSeMeSePh by H2O2 was computed to occur via a
reaction barrier of +17.2 kcal mol–1 and to have a reaction energy of –36.8 kcal mol–1. By reaction
with another equivalent of H2O2, 19 becomes the doubly oxidized product 20, existing either as
(R,R)-20 or (R,S)-20 (Figure 4). We do not consider the pathways involving (S,S)-20 since it is
energetically equivalent to the pathways involving (R,R)-20.
23
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Figure 4. Molecular geometries of (R,R)-20 (left) and (R,S)-20 (right), optimized at scalar-ZORA-
OLYP/TZ2P-sc.
From the calculations it was found that the formation of (R,S)-20 goes via a lower reaction
barrier (+17.5 kcal mol–1, vs. +18.5 kcal mol–1 for (R,R)-20), leading to only a slightly less stable
product: –34.2 kcal mol–1 vs. –34.4 kcal mol–1. These numbers were generated for the products in
their lowest-energy conformations. Other possible configurations, obtained by rotations around the
selenium-methylene bonds, are typically all very close in energy.
Also in this case we have explored an alternative route in the reaction between 19 and a
second equivalent of H2O2, wherein a hydroxy perhydroxy intermediate 21 is formed; for this path,
a TS at +14.6 kcal mol–1 and a reaction energy of +5.8 kcal mol–1 were found (Scheme 4). A
catalytically active hydroxy perhydroxy species 22 can be generated also from the fully oxidized
product 20 (E‡ = +16.5 kcal mol–1, E = +1.8 kcal mol–1, Scheme 4). The reactions involving
these species are shown and commented in the Supporting information (Scheme S1). On the basis
of the energetics, the direct oxidation is the favoured mechanism, in agreement with the
experimental kinetics, in which there is no evidence for the presence of autocatalytic mechanisms.
In PhSeEtSePh (23), the longer alkyl bridge imposes a larger distance between the Se
nuclei than in PhSeMeSePh. After initial oxidation and due to the presence of  protons, a fast
elimination reaction takes place leading to monoselenides and olefins as products.
24
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O
OOH
Se
HO
H2O2
-H2O
H2O2
Se
Se
Se
Se
Se
PhSeEtSePh
(23)
24
26
O
H2O2
-H2O
Se
Se
30
28
H2O2
OOH
O
H2O2
HO
Se
Se
Se
Se
O
O
O
H2O2
-H2O
O
Se
Se
Se
OH
OOH
OH
31
27
25
32
29
Scheme 5 Mechanism of oxidation of PhSeEtSePh by H2O2. The direct oxidation step is shown in
blue.
1
The first H–77Se HMBC spectrum (Figure 5 (a)), the acquisition of which started around
five hours after the addition of H2O2, was of lower quality with respect to those measured for
PhSe(n-Bu) and PhSeMeSePh in analogous conditions and showed the presence of several groups
of weak signals at different 77Se . Notably, if the spectrum was Fourier transformed during its
acquisition, changes in the relative populations of the different species were observed suggesting
77
that the reaction was still in slow progress. The peaks detected in the Se spectrum at frequencies
of 334, 320, 863, 868 and 850 ppm were assigned to PhSeEtSePh, the reduced and oxidized
selenium nuclei of 24, 25 and 30, respectively. No correlations between a reduced selenium and the
alkene protons were detected, indicating that the mono-oxidized product of the first step (24) did
1
not undergo -elimination to form 28. As expected, other H–77Se HMBC experiments acquired at
different times during the reaction showed a variation of the relative populations of the different
species; this finally lead to the appeareance of a peak at 1158 ppm corresponding to the seleninic
acid 31 (Figure 5 (b)), which was confirmed by subsequent HRMS analysis. Despite the relative
complexity of the reaction, its kinetic profile could be derived by proton NMR. The starting reagent
PhSeEtSePh could be monitored by following the changes in the area of the singlet at 3.14 ppm,
assigned to the four equivalent protons of the ethylene bridge (Figure 5 (e)). When the first
25
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selenium is oxidized to give 24, this singlet becomes a complex pattern of signals characterized by
three multiplets at 2.98, 3.23 and 3.40 ppm with relative areas of 1:2:1 (Figure 5 (e)). The multiplet
at 3.23 ppm was used to follow 24 during the reaction. The protons of the ethylene bridge of 25
result in two multiplets of comparable intensities, at 2.95 and 3.50 ppm; the latter signal remains
isolated during the reaction, making it possible to use it as a probe in monitoring 25. Finally, by
integration of the signals at 6.34 and 7.09 ppm, correspond to the alkene protons in  and 
positions with respect to Se, respectively, the formation of 30 could be followed.
The kinetic profile is shown in (Figure 5 (f)). Directly after the addition of H2O2,
PhSeEtSePh started to disappear whilst 24 formed at a similar rate. At about 200 minutes 24
reached a maximum conversion of approximately 80%, where its concentration remained constant.
At this point 23 continued to decrease along with a relatively slow formation of both 25 and 30. At
380 min a sharp acceleration in the disappearance of 24 is observed; this was accompanied by a
proportionate increase in the concentration of 25. However, the relative concentration of 25 quickly
diminished due to a -elimination reaction, resulting in the rapid formation of the alkene 30, whose
concentration shares an inverse relationship with 24 and 25 after approximately 400 min, and the
seleninic acid 31, which may be further oxidized to form 32. HRMS analysis confirmed the identity
of the 24, 25 and 30 (m/z 358.94, 374.94 and 200.99, respectively; Figure S3). 30 was also
identified (m/z 200.99). Notably, there is evidence of autocatalysis in this mechanism, but only in
the second part of the process: the onset of the sigmoidal profile is rationalized through the
computational mechanistic investigation.
26
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Figure 5. Experimental characterization by NMR of PhSeEtSePh (10mM) oxidation by 3
equivalents of H2O2: 77Se-HMBC of PhSeEtSePh 5 hours after addition of H2O2 (a) and at the end
of the reaction (b) with H2O2; representative changes in the 1H-NMR in the aromatic (c) and alkene
regions (d) and in the ethylene bridge (e), after 5 (blue), 105 (red), 257 (green), 410 (purple), and
552 minutes (yellow) from the addition of H2O2. The two sidebands around the peak at 3.14 ppm
77
derive from the scalar coupling with natural abundance of Se. The normalized areas of selected
NMR signals have been used to derive the kinetic profile represented in (f); the kinetic curves are
labeled with the compound numbers used in the text.
In silico, the reaction of 23 with the first equivalent of H2O2 (Scheme 5) leads to the mono-
oxidized product 24. For this step, the incoming H2O2 may approach the Se nucleus from either
above or below (referring to the Se nucleus on the left hand side in Fig. 1). The transition states for
these two possibilities are very close in energy: the barrier for H2O2 approaching from the same side
as the ethylene bridge is pointing, is only 0.1 kcal mol–1 higher in energy, at +17.4 kcal mol–1.
However, the product from this higher-energy TS, with the doubly bonded oxygen and the ethylene
C–C bond in approximately eclipsed positions, is 1 kcal mol–1 more stable (–35.8 kcal mol–1 vs. –
34.8 kcal mol–1). In the second oxidation of the second Se center, we again discovered that the
lowest-energy pathway is obtained when the doubly-bonded oxygen already present is in a roughly
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eclipsed position with respect to the ethylene bridge. In the following discussion, we therefore only
consider the pathway for the first oxidation where the H2O2 approaches on the side in which the
ethylene bridge is pointing (E‡ = +17.4 kcal mol–1, E = –35.8 kcal mol–1).
From the acquired product 24, reaction with a second equivalent of H2O2 can generate the
doubly oxidized species 25. Again, the incoming H2O2 has a choice between two sides to approach
from, giving either (R,R)-25 or (R,S)-25 (we do not consider the pathway leading to (S,S)-25, as it is
energetically equivalent to that of (R,R)-25). The lowest-energy pathway is obtained when H2O2
comes from the side in which the ethylene bridge is pointing, i.e., from below in Figure 1 for the Se
nucleus on the right; this route involves a reaction barrier of +17.0 kcal mol–1 (relative to 24 and
H2O2), and leads to the formation of (R,S)-25 and water at a relative energy of –36.7 kcal mol–1.
Alternatively, with a slightly higher barrier of +18.0 kcal mol–1, H2O2 has the option of approach
from the opposite side, and this leads to the formation of (R,R)-25 at –35.0 kcal mol–1. The reactions
involving the hydroxyl perhydroxy species 26 and 27 are shown and commented in the Supporting
information (Scheme S2); by analogy with the monoselenide, we consider that overall oxidation by
H2O2 is energetically more favorable and relatively uncomplicated from a mechanistic viewpoint,
inferring that this route is more probable for the reaction.
An interesting observation was made for the doubly oxidized product 25, for which a -
elimination reaction is observed to take place. As shown in Scheme 5, this produces 1-
(vinylseleninyl)benzene (29) and benzeneseleninic acid (31). The reaction barrier for this step is
+19.5 kcal mol–1, leading to the products at +0.6 kcal mol–1. -elimination of the mono-oxidized
product 24, generating the alkenes 28 and 29, results in the calculation of a higher barrier of +21.2
kcal mol–1; this presumably prevents this reaction from occurring, despite possessing a favorable
reaction energy of –3.0 kcal mol–1. In addition, the latter reaction would subsequently be followed
by oxidation of 28 to 30 (E‡ = +19.3 kcal mol–1, and E = –33.1 kcal mol–1). For both -
elimination reactions, the resulting phenyl selenenic acid 29 undergoes a successive reaction with
28
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10.1002/chem.201604915
Chemistry - A European Journal
H2O2 to form the benzeneseleninic acid 31; this step is seen to have a relatively low reaction barrier
of +12.6 kcal mol–1 and a large negative reaction energy of –49.2 kcal mol–1. It’s important to
consider that benzeneseleninic acid 31 can itself be oxidized by H2O2 to form
benzeneperoxyseleninic acid 32. This species can thereupon oxidize 23 or 24, triggering an
autocatalytic mechanism in the second part of the whole process. The oxidation of 23 by 32 has an
activation energy of +8.1 kcal mol–1 and an overall reaction energy of –30.3 kcal mol–1, leading to
the formation of 24 and 31. In comparison with the oxidation of 23 by 26, this step is much more
favorable energetically (Scheme S2 I); this suggests that the autocatalytic behavior observed is due
to benzeneperoxyseleninic acid and can be established only once it is formed, that is in the later
stage of the whole process. This would explain why the kinetic profile suddenly becomes sigmoidal,
and also the sharp acceleration in the rate at which 24 diminishes (Figure 5 (f)).
Oxidation of PhSeSePh
O
O
H2O2
-H2O
H2O2
-H2O
Se
Se
Se
Se
O
Se
Se
PhSeSePh
(33)
35
34
H2O2
H2O2
OOH
OOH
HO
HO
Se
Se
Se
Se
O
36
37
Scheme 6 Mechanism of oxidation of PhSeSePh by H2O2. The direct oxidation step is shown in
blue.
An important feature of PhSeSePh is the presence of a direct Se-Se bond, which, being
substantially weaker than the Se-C bond, [34] may break upon oxidation. The 1H–77Se HMBC of 33
29
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