Atom efficient preparation of zinc selenates for the synthesis of selenol esters under “On Water” conditions

Article abstract of DOI:10.3390/molecules22060953

We describe here an atom efficient procedure to prepare selenol esters in good to excellent yields by reacting [(PhSe)₂Zn] or [(PhSe)₂Zn]TMEDA with acyl chlorides under “on water” conditions. The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence of other functionalities in the starting material.

Full text of DOI:10.3390/molecules22060953

molecules
Article
Atom Efficient Preparation of Zinc Selenates for the
Synthesis of Selenol Esters under “On Water”
Conditions
Luca Sancineto 1, Jaqueline Pinto Vargas 2, Bonifacio Monti 1, Massimiliano Arca 3,
Vito Lippolis 3, Gelson Perin 4, Eder Joao Lenardao 4,* and Claudio Santi 1,
*
1
Catalysis and Organic Green Chemistry Group, Department of Pharmaceutical Sciences,
University of Perugia, Via del Liceo 1, 06100 Perugia, Italy; sancineto.luca@gmail.com (L.S.);
bonifaciomonti@gmail.com (B.M.)
2
3
4
Universidade Federal do Pampa—Unipampa, Av. Pedro Anunciação, 111,
Caçapava do Sul-RS 96570-000, Brazil; jaquelinevargas@unipampa.edu.br
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, S.S. 554 bivio per Sestu,
09042 Monserrato, Cagliari, Italy; marca@unica.it (M.A.); lippolis@unica.it (V.L.)
Laboratório de Síntese Orgânica Limpa-LASOL-CCQFA, Universidade Federal de Pelotas-UFPel,
P.O. Box 354, Pelotas-RS 96010-900, Brazil; gelson_perin@ufpel.edu.br
*
Correspondence: lenardao@ufpel.edu.br (E.J.L.); claudio.santi@unipg.it (C.S.);
Tel.: +55-53-3275-7533 (E.J.L.); +39-075-585-5112 (C.S.)
Academic Editor: Derek J. McPhee
Received: 11 May 2017; Accepted: 3 June 2017; Published: 8 June 2017
Abstract: We describe here an atom efficient procedure to prepare selenol esters in good to excellent
yields by reacting [(PhSe)2Zn] or [(PhSe)2Zn]TMEDA with acyl chlorides under “on water” conditions.
The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence
of other functionalities in the starting material.
Keywords: selenium; selenol esters; zinc; TMEDA; water
1. Introduction
Selenol esters are versatile tools in organic synthesis, once they can be easily converted to
a sort of more complex molecules, acting as acyl-transfers, and in other important functional groups
modifications [
mesophase range [
the attention to their pharmacological potential; the thiazolidine-4-carboselenoate II is a potent
antioxidant [ ], while the polyfunctionalized selenol esters III and IV presented high cytotoxic and
1]. Aromatic selenol esters, such as
I, are stable liquid crystals with a large nematic
2–4]. In contrast to their sulfur analogues, selenol esters only recently have attracted
5
antiproliferative activities against MCF-7 human cancer cells [6,7] (Figure 1).
The synthetic usefulness of selenol esters goes far beyond the transfer of acyl group [
8], or its use
as a protecting group for selenium compounds [9]. Selenol esters were explored in the total synthesis
of several complex molecules [10 14], such as the marine alkaloid amphimedime [10], apparicine [11],
–
(+)-geissoschizine [12], ciguatoxin CTX3C7d [13] and the peach moth (Carposia niponensis)
pheromone [14]. More recently, selenol esters have gained even more importance, after the discovery
that they can be used in native chemical ligation (NCL) reactions where the traditional thioester ligation
chemistry is prohibitive [15,16].
Molecules 2017, 22, 953; doi:10.3390/molecules22060953
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Figure 1. Examples of molecules bearing the selenol ester moiety.
As a consequence of the increasing demand for selenol esters, the number of methods to
prepare this class of compounds has been increased along the years [ 17 43] Among the strategies
to prepare selenol esters there are the reactions of nucleophilic selenium reagents with an acyl
group source, such as N-acyl benzotriazoles [17 18] activated carboxylic acids (using DCC [
or PBu3 [ 19 20]), enol esters [21], anhydrides [22 24], esters [25], carbon monoxide [26 27],
aldehydes [28 29] or acyl chlorides [ 30 43]. Other approaches to selenol esters involve the
alkylation of selenocarboxylate anions with alkyl halides [ 44 46] or the acidic hydration of
selenoalkynes [47 48]. The acyl substitution of acyl chlorides is by far the most explored method
1, –
,
3]
4,
5,
,
–
,
,
2,7, –
6, –
,
to access selenol esters, mainly because of its versatility, since the diversity of acyl chlorides that
can be prepared is practically endless. The pivotal step in this reaction is the generation of the
nucleophilic selenium species and a range of reagents have been used for this purpose, including
Se◦/ArMgBr [
2
], (NH2)2C=Se/Et3N [30], Se◦/NaBH4 [
6
], InI/(PhSe)2 [31
,39, ,37],
40], Se◦/LiAlH4 [32
(RSe)2/Zn/AlCl3 [33], Ph(NH2)C=Se [34], (Bu3Sn)2/(PhSe)2/hv [35
,
36], Se◦/R2C=CZrCp2Cl [38],
(RSe)2/Zn◦/[bmim]PF6 [41], (PhSe)2/Hg◦/dioxane [42] and (PhSe)2/SnCl2/CuBr2/[bmim]BF4 [43].
Despite these reaction systems afforded a range of selenol esters, they suffer from one or more of the
following drawbacks: use of VOCs as solvent, strong bases, strong and moisture sensible reducing
agents, expensive reagents and low atom-economy.
Significant progress towards the greenness of the synthesis of selenol esters has been recently
described [49,50]. Braga and co-workers described the solvent-free, microwave accelerated reaction of
diorganyl diselenides with acyl chlorides; good yields of selenol esters were obtained after irradiation
◦
at 80 C for only 2 min [49]. In the same year, some of us described the use of the bench stable
nucleophilic species, PhSeZnX (X=Br, Cl), in the synthesis of a range of selenol esters in good yields at
room temperature and using water as medium [50]. It was observed that the reaction was accelerated
when it was performed under “on water” conditions and, in addition, the water was reused for
subsequent cycles of reactions.
Nine years ago, we introduced a simple method to prepare in situ nucleophilic sulfur and
selenium reagents by reducing dichalcogenides with elemental zinc in an acidic biphasic system [51].
This protocol has been more recently used by us and others to effect a series of selenylation reactions
involving nucleophilic substitutions, ring opening and hydrochalcogenations [51
adopted by Flemer in the synthesis of peptides [54,55].
–53] and it was
The actual reactive specie in this protocol was supposed to be a zinc bis-selenate [(PhSe)2Zn]
probably in equilibrium with the corresponding selenol. Considering that [(PhSe)2Zn] is characterized
by a higher atom economy respect to the PhSeZn-halides in the insertion of PhSe groups, the possibility
to obtain it in a bench stable form is desirable. It could improve the versatility of its synthetic
application (avoiding the strong acidic conditions of the biphasic system), controlling or preventing
undesired side reactions like those observed when it was prepared and used in situ in the presence of
THF [56].

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2. Results
To better understand and prevent the side reaction observed in the presence of THF [56], DFT
calculations were performed comparing [(PhCh)2Zn] (Ch=S, Se) with the previously reported PhChZnX
(Ch=S, Se; X=Cl, Br) [57].
DFT-optimized geometries of the (PhCh)2Zn species (Ch=S, Se) show a nearly linear coordination
at the Zn center. This geometry has been observed in the gas phase for ZnH2 and ZnCl2, [58] although
several examples are reported of structurally characterized zinc(II) compounds featuring discrete
linear E–Zn–E moieties with E=O [58–60], S [61,62], or Se [63]. On passing from Ch=S to Ch=Se,
the natural charge polarization of the Ch–Zn bond decreases (1.233 and 1.093 e for Ch=S and Se,
respectively), suggesting a higher reactivity of (PhS)2Zn in all conditions as compared to (PhSe)2Zn.
The solvated species (PhCh)2Zn 2solv (solv=THF, H2O) were also successfully optimized. For both
·
solvents, solvated species show a distortion of the Ch–Zn–Ch moiety towards the usually encountered
tetrahedral coordination of the Zn center. A Second Order Perturbation Theory Analysis of Fock
Matrix in NBO Basis allows evaluating the interaction energies between the Zn center and each solvent
−1
molecule by about 50, 58, 48, and 55 kcal
and (PhSe)2Zn
·
mol for (PhS)2Zn
·
2THF, (PhS)2Zn
·
2H2O, (PhSe)2Zn 2THF,
·
·
2H2O, respectively. Such interactions arise from the electron density donation from the
oxygen LP of the solvent units to the antibonding empty Zn atomic orbitals (Figure 2) and, to a minor
extent, to the Zn-Ch antibonding NBOs, and result in an overall electron transfer of 0.095, 0.105, 0.133,
and 0.104 e for (PhS)2Zn
·
2THF, (PhS)2Zn
·
2H2O, (PhSe)2Zn
·
2THF, and (PhSe)2Zn 2H2O, respectively.
·
Notably, the interactions between (PhCh)2Zn species and the solvent units are remarkably stronger
than those calculated between PhChZnX (Ch=S, Se; X=Cl, Br and I) and the same solvents, which were
calculated in about 18 kcal·mol−1 at the same level of theory.
Figure 2. Drawings of the NBOs involved in the second order interaction between (PhSe)2Zn and the
THF fragments in the compound (PhSe)2Zn·2THF at the DFT-optimized geometry (energy difference
0.7465 a.u.; interaction energy 25.77 kcal
mol−1). Left: filled NBO LP localized on the oxygen donor
·
atom of one THF solvent fragment (NBO #127, 34.45% s and 65.54% p character). Right: virtual NBO
LP* localized on the Zn center (NBO #124, 9.51% s and 90.35% p character). Cutoff value: 0.1 |e|.
Hydrogen atoms have been omitted for clarity. (Grey = Carbon; Red = Oxygen; Yellow = Selenium;
Violet = Zinc).
All (PhCh)2Zn species and the corresponding solvated forms show their HOMOs largely
localized on the negatively charged Ch atoms (QS =
(PhCh)2Zn 2THF, and (PhCh)2Zn 2H2O; QSe 0.236,
(PhCh)2Zn·2THF, and (PhCh)2Zn·2H2O, respectively).
The LUMOs of (PhCh)2Zn species are antibonding MOs displaying a remarkable contribution
from the zinc atomic orbitals. About solvated species, it is worth noting that both (PhS)2Zn 2THF
and (PhSe)2Zn 2H2O feature empty molecular orbitals with large contributions from the virtual
−
0.315,
−
0.377, and
−
0.367 |e| for (PhSe)2Zn,
0.274 |e| for (PhSe)2Zn,
·
·
=
−
−
0.305, and
−
·
·
molecular orbitals of the solvent molecules, which are therefore sensibly stabilized. In particular, the
LUMO+4 MO calculated for THF shows an antibonding character with respect to the C–O bonds
Kohn-Sham (KS) eigenvalue
ε = +0.1389 Hartree). This orbital contributes to the LUMO+14 and

Molecules 2017, 22, 953
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LUMO+15 of (PhS)2Zn
·
2THF and (PhSe)2Zn
·
2THF, respectively, which are stabilized in energy by
0.887 eV (ε = +0.1063 Hartree for both virtual MOs). The strength of the interaction between THF
and (PhCh)2Zn accompanied by a low-lying MO with remarkable C–O antibonding character partly
localized on the coordinated THF units may account for the ring opening reactions of coordinated
solvents observed experimentally [56].
Therefore, we investigated the possibility to prepare an isolable zinc bis-selenate to be used in
the synthesis of chalcogenol esters avoiding the presence of THF during the reaction with the acyl
chlorides. Different conditions for the oxidative insertion of the zinc in the Se-Se bond starting from
the commercially available diphenyl diselenide were explored (Table 1). The reduction of diselenides
in organic solvents can be unequivocally evidenced by the discoloration of the originally yellow
solution and it was observed that both the presence of catalytic amount of TFA (10 mol %) and the
THF (or a 1:1 THF/water mixture) are mandatory for the reduction at reflux (Table 1, entries 4 and
5 respectively). Interestingly, the insertion did not occur in refluxing THF for 2 h (Table 1, entry 2)
neither in water suspension at the same temperature (Table 1, entry 1), as well as in the presence of
TFA (10 mol %) (Table 1, entry 3).
Table 1. Synthesis of compound 1.
◦
Entry
Solvent
Additive
Time
T ( C)
Discoloration
1
2
3
4
5
H2O
THF
H2O
none
none
TFA 10 mol %
TFA 10 mol %
TFA 10 mol %
2 h
2 h
1 h
20 min
20 min
70
reflux
70
reflux
70
No
No
No
Yes
Yes
THF
H2O/THF
Using the conditions depicted in Table 1, entry 4, after the discoloration, the THF was
removed under-reduced pressure, giving a whitish amorphous and, unfortunately, relatively unstable
solid, which was used without further purification. The supposed formation of a polymeric
form of the reagent
77Se NMR. Similarly, starting from diphenyl disulfide, the zinc bis-thiolate
(Figure 3). In this case, the starting material is colorless and the reduction time was arbitrarily
chosen according to that of the reduction of diphenyl diselenide to afford A monomeric
1
was confirmed by the presence of a broad signal at
−
41 ppm in the
2
was formed in situ
1.
and more stable zinc selenate (3) can be prepared according to the literature using the bidentate
TMEDA(N,N,N1,N1-tetramethyl-ethylendiamine) for the stabilization of the complex
3, with TMEDA
in the place of THF [64].
Figure 3. Reagents investigated in the present work.
The reactivity of 1,3 and 2 with benzoyl chloride (4a) for the formation of the selenol ester 5a or
thiol ester 6a, was evaluated in “on water” conditions (Table 2, entries 10–12) and these results were
compared with some data recently reported using other zinc selenates, as well as different reaction
conditions (Table 2, entries 1–3, 5–9). The bis-phenylselenate (1) showed an interesting reactivity
affording, after 30 min, the formation of 5a in 83% yield (Table 2, entry 10). This result confirms

Molecules 2017, 22, 953
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that zinc selenates, as previously reported, are efficient selenenylating reagents for the on-water acyl
substitution. In addition, the use of water as medium for the reaction with the acyl chloride prevents
the undesired ring opening of THF [56], affording diphenyl diselenide and benzoic acid as side organic
products of residual decomposition, and TMEDA when
are removed during the workup due to their water solubility. We also observed that the reactivity
of in THF depends on the acid used as catalyst in the oxidative zinc insertion into the Se-Se bond
(Table 2, entries 3 and 4) and that the best results were obtained using TFA. When the reaction was
performed using the TMEDA-stabilized zinc selenate , we observed only a decrease of the reactivity,
obtaining a good conversion of 4a into 5a (71%) in 30 min (Table 2, entry 11). Interestingly, the
sulfur-containing reagent afforded only 50% of conversion (Table 2, entry 12) and this is consistent
3 was used. Reasonably the zinc derivatives
1
3
2
with DFT calculations, that evidenced a higher reactivity of the sulfur reagents. This aspect, probably,
represents a problem for the stability of the zinc thiolate during the solvent evaporation or in the
presence of water, leading to a faster decomposition of the reactant.
From the results reported in Table 2, it appears clear that zinc-bis-chalcogenates are considerably
more atom-efficient respect other similar reagents (compare entries 10,11 vs. 7,8; and 12 vs. 9) and this
is an important parameter to be evaluated in terms of “greenness” of a synthetic process.
Table 2. Zinc chalcogenates 1–3 in the preparation of chalcogenol esters.
ae (%) b
Entry
Reagent
Medium
Time (h) Yield (%) a
Reference
1
2
3
4
5
6
7
8
9
PhSeZnCl
PhSeZnBr
[PhSeZnSePh] 1
[PhSeZnSePh] 1
PhSZnBr
THF
THF
THF
THF
THF
24
24
3
3
24
4
3
3
3
25
30
66
60
79.6
79.6
54.6
–
66
60
54.6
79.6
77
[50]
[50]
[56]
–
[57]
[56]
[50]
[50]
[57]
–
32 c
40 d
86
[PhSeZnSePh/PhSeH]
PhSeZnCl
HClacq/Et2O
H2O
38
60
70
65
83
66
50
PhSeZnBr
PhSZnBr
[PhSeZnSePh] 1
[PhSeZnSePh]TMEDA 3
[PhSZnSPh] 2
H2O
H2O
H2O
H2O
10
11
12
0.5
0.5
0.5
–
–
H2O
76
a
b
c
Conversion estimated by NMR; Atom economy = m.w. of final product
×
100/
Σ
(m.w. reactants);
1 was
prepared in the presence of 10 mol % of TfOH. Compound 5a was formed together with 34% PhC(O)O(CH2)4SePh
and 28% PhC(O)O(CH2)4 O(CH2)4SePh; d
was prepared in the presence of 10 mol % of TFA. Compound 5a was
formed together with 27% PhC(O)O(CH2)4SePh and 5% PhC(O)O(CH2)4 Cl.
1
The best conditions optimized for
1
and
3
were applied to a series of acyl chlorides 4a
–h,
affording the corresponding selenol esters 5a
–
h; the conversion rate as well as the isolate yields
are reported in Table 3. All the final products were fully characterized by GC-MS, 1H- and 13C-NMR
after purification by flash chromatography (For 1H- and 13C-NMR of the purified compounds see
Supplementary Materials).
Results collected in Table 3 indicate that the reaction works well with various acyl chlorides
(4a–h), including aromatic and aliphatic ones, with the only exception of cinnamic derivative 4g,
that afforded only in traces of the corresponding selenol ester 5g (Table 3, entry 7). In contrast to
the previously described biphasic system [56], this approach tolerates functional groups sensitive
to reduction, allowing the preparation of selenol ester 4d (R=3,5(NO2)2C6H3) in excellent yields
(Table 3, entry 4). Noteworthily, it can be observed that acyl chlorides bearing electron-withdrawing

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groups gave better yields, probably because of the more pronounced electrophilic character of the
carboxylic carbon.
Table 3. Synthesis of selenol esters 5.
Conv, % of 4 in 5
(Yield, %) of 5 Using 1
Conv, % of 4
in 5 Using 3
Entry
Substrate 4
Product 5
1
84 (80)
81 (53)
71 (57)
66
80
40
5a
4a
2
3
4b
5b
4c
5c
4
92 (90)
80
4d
5d
5
6
83 (64)
80 (65)
62
35
4e
5e
4f
5f
7
8
8
76
80
4g
5g
75 (69)
4h
5h
In order to clarify the nature of the species that are involved in the reaction mechanism leading to
5a, the possible 1:1 initial intermediate model species formed by the interaction between (PhSe)2Zn
1
and PhCOCl 4a was optimized. The only optimized geometry of the adducts shows PhCOCl
interacting with the zinc atom of (PhSe)2Zn through its carbonyl group, thus distorting the Ch–Zn–Ch
group towards a roughly trigonal geometry. A natural population analysis shows that the interaction
results in a charge-transfer (CT) from PhCOCl to (PhSe)2Zn, whose LUMO is partly localized on the
positively charged metal ion (QZn = +0.857). The CT-interaction results in an increase in the positive
charge on the acyl carbon and the polarization of the C=O bond (|∆QCO| = 1.083, 1.177 for PhCOCl;

Molecules 2017, 22, 953
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and PhSeZnSePh
·
PhCOCl, respectively). Therefore, the activated carbonyl group in PhCOCl might
be more suitable to undergo a nucleophilic attack by the chalcogen donor of a second molecule of
(PhCh)2Zn.
The TMEDA-stabilized reagent
3 was investigated using the same set of acyl chlorides 4a–h and,
generally, it confirmed a slightly/moderate reduced reactivity with a superimposable trend respect to
the nature of the substrate. The only exception was observed for acyl chloride 4g, that using TMEDA
afforded selenol ester 5g in 80% yield (Table 3, entry 7).
Considering that the complex
3 is reported in literature as particularly stable and it is sufficiently
soluble in several organic solvents, we envisioned the possibility to perform a ”one-pot” synthesis
and chromatographic purification of the selenol ester 5a following the setup reported in Figure 4.
A pump fluxes petroleum ether through a Flash Pack Jones Chromatography apparatus silica gel
column packed with 5 g of silica flash (40–63
µm) and, at the head of the column, was poured the
reagent (0.25 mmol), mixed with 500 mg of the same silica. The column was conditioned with the
3
solvent and the substrate (0.5 mmol), dissolved in DCM, was injected. After the column, the eluent
was fractioned and the fractions were isolated and characterized by NMR. The selenol ester 5a was
obtained as pure compound (separated from both, diphenyl diselenide and benzoic acid) in a yield
comparable to that observed in the bench condition (60%). This protocol allowed to bypass the workup
of the reaction saving a considerable amount of organic solvents (15 mL of EtOAc), brine solution (20
mL) and Na2SO4, reducing the production of wastes.
Figure 4. One-pot synthesis and chromatographic purification of the selenol ester 5a.
3. Materials and Methods
Reactions were conducted in a round bottom flask and were stirred with Teflon-coated magnetic
stirring bars at 800 rpm. Solvents and reagents were used as received unless otherwise noted.
Analytical thin-layer chromatography (TLC) was performed on silica gel 60 F254 precoated aluminum
foil sheets and visualized by UV irradiation or by KMnO4 staining. Kieselgel 60 (70–230 mesh) silica
gel was used for column chromatography. NMR experiments were conducted at 25 ◦C with a DPX
200 spectrometer (Bruker, Faellanden, Switzerland).) operating at 200 MHz for 1H, 50.31 MHz for
13C experiments or with a Bruker DRX spectrometer (Bruker, Faellanden, Switzerland) operating at
400 MHz for 1H, 100.62 MHz for 13C and 76.31 MHz for 77Se. Chemical shifts (
per million (ppm), relative to TMS ( = 0.0 ppm) and the residual solvent peak of CDCl3 (
77.00 ppm in 1H- and 13C-NMR, respectively) and PhSeSePh = 464 ppm in 77Se. Data are reported
δ
) are reported in parts
= 7.26 and
δ
δ
δ
as chemical shift (multiplicity, coupling constants where applicable, number of hydrogen atoms, and
assignment where possible). Abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), quin

Molecules 2017, 22, 953
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(quintet), dd (doublet of doublet), dt (doublet of triplet), tt (triplet of triplet), m (multiplet), br. s
(broad signal). Coupling constants (J) are quoted in Hertz (Hz) to the nearest 0.1 Hz. GC-MS analyses
were carried out with an HP-6890 gas chromatography (dimethyl silicone column, 12.5 m) equipped
with an HP-5973 mass-selective detector (Hewlett-Packard, Waldbronn, Germany). Acyl chlorides
used for obtaining the selenol esters 5a
,
5e
, 5f and 5h are commercially available; acyl chlorides used
for obtaining the selenol esters 5b 5c
,
, 5d and 5g were synthesized according to the literature [65].
Density Functional Theory (DFT) calculations were performed with the commercial suite of software
Gaussian09 [66]. All calculations were carried out with the mPW1PW hybrid functional [67] and the
full-electron Ahlrichs double-
ζ basis sets with polarization functions (pVDZ) for all atomic species [67].
NBO populations [68 70] and Wiberg bond indices [71] were calculated at the optimized geometries,
–
which were verified by harmonic frequency calculations. The results of the calculations were examined
with GaussView 5 [72] and Molden 5.3 [73] programs.
General Procedure for the Synthesis of Selenol Esters 5a–h
To a water suspension of the zinc complexes
(1 mmol) was added at room temperature and under stirring. After 30 min, the reaction mixture was
extracted with ethyl acetate (3 10 mL), washed with brine (2 20 mL), dried with Na2SO4 and
1 or 3 (0.5 mmol, 6 mL of H2O), acyl chloride 4
×
×
concentrated under vacuum to obtain a residue that was purified by flash chromatography.
Se-Phenyl benzoselenoate (5a) [40] was purified eluting with 20% DCM in petroleum ether. Yellow solid.
m.p.: 39◦–40 ◦C (Lit.: [38] 37◦–38 ◦C). 1H-NMR (CDCl3, ppm)
δ: 7.96–7.92 (m, 2H, H-Ar), 7.63–7.42
(m, 8H, H-Ar) ppm. 13C-NMR (CDCl3, ppm)
δ: 193.5, 138.5, 136.4, 133.9, 129.4, 129.1, 128.9, 127.4,
125.8 ppm. CG-MS: m/z (%) = 262 (1) [M+], 157 (5), 105 (100), 77 (50), 51 (14).
Se-Phenyl 2-bromobenzoselenoate (5b) [74] was purified eluting with 5% EtOAc in petroleum ether.
1
Yellow oil. H-NMR (CDCl3, ppm)
δ
: 7.72–7.6 (m, 4H, H-Ar), 7.45–7.34 (m, 5H, H-Ar) ppm. 13C-NMR
(CDCl3, ppm) δ: 194.4, 140.6, 135.8, 134.3, 132.6, 129.5, 129.2, 128.8, 127.3, 126.6, 118.0 ppm.77Se-NMR
(CDCl3, ppm) δ: 662.1 ppm. CG-MS m/z (%) = 340 (1) [M+], 232 (3), 183 (100), 157 (54), 76 (16), 50 (9).
Se-Phenyl 4-butylbenzoselenoate (5c) [50] was purified eluting with 20% DCM in petroleum ether. Yellow
1
oil. H-NMR (CDCl3, ppm)
δ: 7.85 (d, J = 8.1 Hz, 2H, H-Ar), 7.61–7.57 (m, 2H, H-Ar), 7.44–7.41 (m, 3H,
H-Ar), 7.31–7.26 (m, 2H, H-Ar), 2.67 (t, J = 7,8 Hz, 2H, CH2), 1.61 (quin, J = 8.15 Hz, 2H, CH2), 1.36
(sex, J = 7.6 Hz, 2H, CH2), 0.95 (t, J = 7.2 Hz, 3H, CH3) ppm. 13C-NMR (CDCl3, ppm)
δ
: 192.7, 149.8,
136.4, 136.2, 129.3, 129.0, 127.5, 126.0, 35.8, 33.1, 22.3, 13.9 ppm. 77Se-NMR (CDCl3, ppm)
δ
: 661.0 ppm.
CG-MS m/z (%) = 318 [M+], 161 (100), 91 (30).
Se-Phenyl-3,5-dinitrobenzoselenoate (5d) [50] ◦was purified eluting with 5% EtOAc in petroleum ether.
◦
◦
1
Yellow solid. m.p.: 148–150 C (Lit.: [48] 148 –150 ). H-NMR (CDCl3, ppm) δ: 9.28 (t, J = 2.05 Hz, 1H,
H-Ar), 9.04 (d, J = 2.06 Hz, 2H, H-Ar), 7.7–7.4 (m, 5H, H-Ar) ppm. 13C-NMR (CDCl3, ppm)
δ: 190.4,
148.9, 141.5, 136.1, 130.07, 129.9, 126,7, 124.1, 122.6 ppm. 77Se-NMR (CDCl3, ppm) δ: 662.3 ppm.
Se-Phenyl 2-phenylethaneselenoate (5e) [75] was purified eluting with 20% DCM in petroleum ether.
Yellow solid. m.p.: 41–43 ◦C (Lit.: [59] 41◦–43 ◦C). 1H-NMR (CDCl3, ppm)
7.34–7.26 (m, 8H, H-Ar), 3.88 (s, 2H, CH2) ppm. 13C-NMR (CDCl3, ppm)
δ
: 7.45–7.35 (m, 2H, H-Ar),
δ
: 198.9, 135.8, 132.6, 130.1,
129.3, 128.9, 128.8, 127.8, 126.6, 53.6 ppm. CG-MS m/z (%) = 276 [M+], 157 (22), 119 (26), 91 (100),
65 (26).
Se-Phenyl thiophene-2-carboselenoate (5f) [22] was purified eluting with 5% EtOAc in petroleum ether.
1
Yellow oil. H-NMR (CDCl3, ppm)
δ: 7.88 (dd, J = 1.2, 3.9 Hz, 1H, H-Ar), 7.71 (dd, J = 1.2, 4.96, Hz, 1H,
H-Ar), 7.63–7.58 (m, 2H, H-Ar), 7.44–7.41 (m, 3H, H-Ar), 7.17 (dd, J = 3.9, 4.96 Hz, 1H, H-Ar) ppm.
13C-NMR (CDCl3, ppm)
: 183.6, 143.1, 136.3, 133.7, 132.0, 129.4, 129.2, 128.0, 125.5 ppm. CG-MS m/z
(%) = 268 (1) [M+], 157 (16), 111 (100), 83 (20).
δ

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(E)-Se-Phenyl 3-phenylprop-2-eneselenoate (5g) [65] was purified eluting with 5% EtOAc in petroleum
ether. Yellow solid. m.p.: 79–80 ◦C (Lit.: [57] 81◦–82 ◦C).1H-NMR (CDCl3, ppm)
: 7.58–7.54 (m, 5H,
δ
H-Ar), 7.43–7.40 (m, 6H, H-Ar), 6.78 (d, J = 15.0 Hz, 1H, CH) ppm. 13C-NMR (CDCl3, ppm)
δ:
190.8, 141.1, 135.9, 133.9, 130.9, 129.4, 129.1, 129.0, 128.6, 128.1, 126.3 ppm. 77Se-NMR (CDCl3, ppm)
δ: 663.6 ppm. CG-MS m/z (%) = 288 (1) [M+], 157 (14), 131 (100), 103 (55), 77 (36).
Se-Phenyl dodecaneselenoate (5h) [76] was purified eluting with 20% DCM in petroleum ether. Yellow oil.
1H-NMR (CDCl3, ppm)
δ: 7.55–7.53 (m, 2H, H-Ar), 7.42–7.39 (m, 3H, H-Ar), 2.73 (t, J = 7.5 Hz, 2H,
CH2C(O)), 1.73 (quin, J = 7.4 Hz; 2H, CH2), 1.4–1.3 (m, 16H, CH2), 0.94–0.90 (t, J = 6.5 Hz, 3H, CH3) ppm.
13C-NMR (CDCl3, ppm)
δ: 200.3, 135.7, 129.2, 128.7, 126.5, 47.5, 31.8, 29.5, 29.3, 29.26, 29.17, 28.8, 25.3,
22.6, 14.0 ppm. CG-MS m/z (%) = 340 (2) [M+], 183 (100), 157 (34), 109 (20), 85 (27), 71 (30), 57 (43).
4. Conclusions
In conclusion, we report here that the side reactivity of zinc bis-selenates with the solvent (THF)
during the reaction with acyl chlorides can be rationalized by DFT calculations demonstrating that
the interactions between (PhSe)2Zn species and the solvent units are remarkably stronger than those
calculated between PhSeZnCl and PhSeZnBr and THF. Even if water seems to be equally able to
coordinate the Zn, it was not possible to perform the oxidative zinc insertion directly in “on water
conditions”. Nevertheless, after the removal of THF, the solid product obtained by the reduction of
PhSeSePh with Zn in the presence of a catalytic amount of TFA (formally [(PhSe)2Zn]) can be efficiently
used for the synthesis of selenol esters starting from the corresponding acyl chlorides and using water
as reaction medium. Furthermore, the complex [(PhSe)2Zn]-TMEDA, prepared according to literature,
showed a similar reactivity in water having the additional advantage to be bench stable. To the best of
our knowledge, this is the first example that report the use of [(PhSe)2Zn]-TMEDA as nucleophilic
reagent and the possibility to use it in a one pot reaction-purification process is an intriguing aspect
that is currently under deep investigation by some of us. It is important to underline that the reagents
reported in the present work (1, 2, and 3) are more atom-efficient not only relative to the previously
reported zinc-halo-selenates, but also among most of the alternative known methods for the synthesis
of selenol esters. During the preparation of this manuscript a further synthesis of these compounds
appeared starting from anhydrides, evidencing the current interest in this class of derivatives [24].
Nevertheless, in our opinion, both in terms of atom economy and general applicability, it can be
claimed that the use of acyl chloride results largely preferable if compared to the anhydrides.
Supplementary Materials: Copies of the 1H and 13C-NMR spectra are available online. Optimized geometries
in orthogonal Cartesian format, Mulliken and Natural charges, and thermochemical data for all investigated
compounds are available from M.A. upon request.
Acknowledgments: Financial support from the Dipartimento di Scienze Farmaceutiche, Università degli Studi
di Perugia “Fondo per il sostegno della Ricerca di Base 2014—Composti Organici ed Ibridi Inorgano-Organici del
Selenio nella Sintesi Eco-Compatibile di Molecole Bioattive”. L.S. was fellow with a Regione Umbria, project “POR
Umbria 2007–2013,”. Eder Joao Lenardao was Bolsista CAPES—Processo no. BEX 6391/14-1 and Mrs. Vargas was
in CAPES Sandwich program with a Doctorate scholarship (PDSE process 99999.001342/2014-02). This research
was undertaken as part of the scientific activity of the international multidisciplinary “SeS Redox and Catalysis”
network. M.A. and V.L. thank the Università degli Studi di Cagliari for financial support.
Author Contributions: C.S. and G.P. conceived and designed the experiments; J.P.V. and B.M. performed the
experiments; C.S., L.S. and E.J.L. analyzed the data; V.L. and M.A. designed and executed DFT calculations; C.S.,
L.S., E.J.L., and V.L. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest and the founding sponsors had no role in the
design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in
the decision to publish the results.
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Sample Availability: Original samples (due to their instability) are not available but can be provided upon request.
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