Investigation of Chemical Stability of Dihalogenated Organotelluranes in Organic-Aqueous Media: The Protagonism of Water

Article abstract of DOI:10.1021/acs.joc.7b02971

The biological activity of tellurium compounds is closely related to the tellurium oxidation state or some of their structural features. Hypervalent dihalogenated organotelluranes 1-[butyl(dichloro)-λ⁴-tellanyl]-2-(methoxymethyl)benzene (1a) an

Full text of DOI:10.1021/acs.joc.7b02971

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Article
Investigation of chemical stability of dihalogenated organotelluranes
in organic-aqueous media: the protagonism of water
Mariana Lopes Teixeira, Leociley Rocha Alencar Menezes, Andersson
Barison, Alfredo Ricardo Marques de Oliveira, and Leandro Piovan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02971 • Publication Date (Web): 26 Jan 2018
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Investigation of chemical stability of dihalogenated organotelluranes in organicꢀ
aqueous media: the protagonism of water
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Mariana L. Teixeira, Leociley R. A. Menezes, Andersson Barison, Alfredo R. M. de
Oliveira, Leandro Piovan*
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Department of Chemistry, Universidade Federal do Paraná, Avenida Coronel Francisco
Heráclito dos Santos, 100 ꢀ Jardim das Américas, Curitiba – Paraná – Brazil
Tel: +55 041 3361ꢀ3178
*Eꢀmail: lpiovan@quimica.ufpr.br
Table of Contents/ Graphical Abstract:
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Abstract: The biological activity of tellurium compounds is closely related to the
tellurium oxidation state or some of their structural features. Hypervalent dihalogenated
organotelluranes 1ꢀ[butyl(dichloro)ꢀλ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1a) and 1ꢀ
[butyl(dibromide)ꢀλ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1b) have been described as
inhibitors of proteases (cysteine and threonine) and tyrosine phosphatases. However,
poor attention has been given to their physicochemical properties. Here, a detailed
investigation of the stability in water of these organotelluranes is reported, using 125Te
NMR analysis. Dihalogenated organotelluranes 1a and 1b were both stable in DMSOꢀd6
(from 25 to 75 ºC), demonstrating their thermal stability. However, the addition of a
phosphate buffer solution (pH 2ꢀ8) to 1a or 1b resulted in an immediate conversion to a
new Teꢀspecies, assumed to be the corresponding telluroxide. Similar behavior was
observed in pure water, demonstrating the low chemical stability of these dihalogenated
species in the presence of water. These results allow concluding that previous biological
activity reported for dihalogenated organotelluranes 1a and 1b could be attributed to the
corresponding derivatives from the reaction with water. In the same way as supposed to
ASꢀ101, we demonstrated that organotelluranes 1a and 1b are not stable in aqueous
solution. It suggests a proactive role of these organotelluranes in previously reported
biological activity.
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Introduction
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Tellurium is an important element from group 16 of the periodic table and its
chemical properties allow broad applications in both organic and inorganic chemistry1,
such as materials2,3 and pharmacological science4 and medicinal chemistry5. An intrinsic
characteristic of this element is its wide range of oxidation states (ꢀ2 to +6), which
allows the expansion of the Lewis octet rule6,7, giving the possibility of hypervalent
species8ꢀ10. These compounds have potential applications in enzymatic inhibition11ꢀ17
and some therapeutic applications18.
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Albeck et al. described for the first time the behavior of inorganic hypervalent
Te(IV) compounds as inhibitors of cysteine proteases (papain and cathepsin B), in
contrast to the complete absence of activity for Te(VI) pertelluranes12. From inorganic
telluranes (Te(IV) compounds), ASꢀ101 was identified as the most powerful inhibitor of
those proteases. Since then, ASꢀ101 has been described as an immunomodulator against
certain microorganisms18ꢀ21, and as having anticancer22ꢀ24, antimicrobial25, antiꢀ
inflammatory26, bactericidal27 and antiviral28,29 activity, as well as being a preventive
agent against Typeꢀ2 diabetes30.
Cunha et al. demonstrated that organotelluranes were more potent than ASꢀ101 in
the inhibition of cysteine proteases13,14. Piovan et al. reported a structureꢀactivity
relationship of dihalogenated organochalcogenanes in inhibition of cathepsins V and S
and that organotelluranes were superior to organoselenuranes15. The same behavior was
observed for inhibition of thiolꢀdependent protein tyrosine phosphatases (PTP1B and
the YopH)16 and 20S proteasome, in this case a threonine protease17. Recently, several
species of tellurium have been described, not only as inhibitors, but also as having other
important applications such as antimicrobial25, antiꢀinflammatory26 or anticancer
activity31,32
.
Despite the advances in the discovery of potential therapeutic properties of
tellurium compounds, research and development of new drugs (R&D) is a complex,
long and costly process33. In recent years, physicochemical, metabolic and
pharmacokinetic properties have emerged as important factors in the success of the drug
discovery and development process. Hence, the coupling of physicochemical properties
and the structure of the bioactive molecules, or structureꢀproperties relationship (SPR),
increases the chances of success in the development of biologically active compounds34.
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In the case of bioactive telluranes, only a few reports about their physicochemical
properties are available17,35ꢀ37. Silva and Andrade reported that organotelluranes 1a and
1b (Figure 1) were not thermally stable and suggested the formation of a telluroxide
derivative based exclusively on the 125Te NMR chemical shifts36. However, the identity
of Teꢀderivative in water remains inconclusive, since this telluroxide had never been
isolated. Another interesting point about organotelluranes’ reactivity is the
stoichiometry of reactions: in reaction with cysteine, the substitution of a single chlorine
atom is proposed36. On the other hand, two halogen atoms are substituted when
organotelluranes are exposed to water, explaining the telluroxide formation as proposed
in the literature36. Silberman et al. demonstrated that ASꢀ101 (Figure 1) is not stable in
aqueous or alcoholic solutions, indicating that this tellurane is sensitive to ligandꢀ
substitution reactions35. In the case of ASꢀ101, those authors also proposed telluroxide
formation, but here by ethylene glycol moiety substitution and maintenance of
halogens35. However, prior works by the same authors described that ASꢀ101 reacts
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with 4 equivalents of cysteine to originate Te(Cys)4 instead of 1 equivalent as
previously observed for organotelluranes.
Figure 1. Chemical structures of organotelluranes 1a and 1b and inorganic tellurane ASꢀ101.
In order to supply more data for this discussion, here we report an extensive study
of the chemical stability of bioactive dihalogenated organotelluranes (1ꢀ
[butyl(dichloro)ꢀλ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1a) and 1ꢀ[butyl(dibromide)ꢀ
λ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1b). Organotelluranes 1a and 1b have been
described as inhibitors of cysteine proteases15, protein tyrosine phosphatases16 and 20S
proteasome17. In our design, we assumed possible oral administration for them. The oral
route is most commonly used. Besides being safe and economical, it is comfortable and
painless in patients who are not prone to nausea, vomiting or difficulties to swallow
pills38. There is a precedent in clinical studies using ASꢀ101 where it was administered
in aqueous physiological solutions (usually as phosphateꢀbuffered saline (PBS) or as
propylene glycol/water mixtures)35. The investigation of 1a and 1b stabilities was
carried out by 125Te NMR analysis using different solvent mixes (organic and aqueous
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solutions), pH screening (2.5 to 8.0) and temperature variation (25 to 75 ºC). Also, 81Br,
1H and 13C NMR analyses were used to obtain complementary data.
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Results and Discussion
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Organotelluranes 1ꢀ[butyl(dichloride)ꢀλ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1a)
and 1ꢀ[butyl(dibromide)ꢀλ4ꢀtellanyl]ꢀ2ꢀ(methoxymethyl)benzene (1b) were both
prepared according to the procedures described in the literature16 (Scheme 1).
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Scheme 1. Reagents and conditions: (i) a: NaH, THF (0 °C, 30 min.); b: MeI (r.t., 3 h); (ii) a: tꢀBuLi,
THF (−78 °C, 30 min.); b: (nꢀBuTe)2, THF (r.t., 3 h); (iii) SO2Cl2, THF, (0 °C, 20 min.); (iv) Br2, THF, (0
°C, 20 min.).
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Organotelluranes 1a and 1b were first evaluated in pure DMSOꢀd6 and then in a
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mixture of DMSOꢀd6/phosphate buffered solution (pH 2ꢀ8) at 25 C. All assays were
monitored by 125TeꢀNMR. As can be seen in Figure 2, when pure DMSOꢀd6 was used as
solvent, the typical chemical shifts36 were observed for organotelluranes 1a (
and 1b (
= 887) in the 125Te NMR spectrum. However, addition of phosphate buffered
δ = 937)
δ
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solution (PBS) at pH = 7.5 (in the same tube containing DMSOꢀd6) caused the complete
disappearance of the prior signals for 1a and 1b, and the appearance of one signal
around
δ = 1255, from both compounds, indicating the formation of a new and common
tellurium species. To enhance the knowledge about their stability at different pH levels,
experiments employing PBS with pH = 2.0, 6.5 and 8.0 were performed and the same
behavior was observed. Acidic (pH = 2.0) or basic (pH = 8) solutions presented similar
results and a single signal at δDMSO PBS
=1260 was observed in the 125Te NMR spectra
/
for both 1a and 1b, demonstrating that a new Teꢀspecies was formed independent of the
pH value.
A)
B)
pH 8.0
pH 7.5
pH 6.5
pH 8.0
pH 7.5
pH 6.5
pH 2.0
pH 2.0
DMSOꢀd6
1a
1b
DMSOꢀd6
Figure 2. 125Te NMR spectra (126.2 MHz) of A) organotellurane 1a and B) organotellurane 1b in pure
DMSOꢀd6 and DMSOꢀd6/~phosphate buffered solutions (pH 2ꢀ8) at 25 ºC.
Organotelluranes 1a and 1b have already been described as stable compounds in
DMSOꢀd6/Trisꢀbuffered solution17,36 and this prior observation clearly conflicts with our
results employing DMSOꢀd6/phosphateꢀbuffered solution. Since the experimental
differences involved the nature of buffer solution, we decided to carry out an assay in
pure D2O to compare the results under the same conditions. To our pleasure, only one
signal was observed in δD2O = 1271 (Figure 3), so now our results converged to that
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reported by Silva and Andrade (Figure S2 of Support information of reference 36).
Other mixtures of solvents were also evaluated (DMSOꢀd6/distilled water, DMSOꢀ
d6/D2O) and same result was obtained as from the previous assays, with the
disappearance of the signals for organotelluranes and the appearance of one signal at
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δDMSO/H2O dist.
= δDMSO/D2O 1254 (Figure 3). These results allow the conclusion that a new
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species of tellurium is derived from the reaction with water, with the pH parameter
(values or buffer nature) being irrelevant.
D2O
DMSOꢀd6/D2O
DMSOꢀd6/H2Odist
Figure 3. 125Te NMR spectra (126.2 MHz, 25oC) of organotellurane 1b in D2O, DMSOꢀd6/D2O and
DMSOꢀd6/distilled water.
After that, organotelluranes 1a and 1b were mixed and solubilized together in
DMSOꢀd6. The corresponding signals were observed (932 ppm for 1a and 887 ppm for
1b in DMSOꢀd6) in the 125Te NMR spectra. Besides these two signals, a third one at 914
ppm was observed, but although its identity was not explored (Figure 4), it is possibly a
compound with one chloride/one bromide bonded to the tellurium atom, showing the
lability of these ligands. When PBS or deuterated water was added to the tube, only one
signal in the 125TeꢀNMR spectrum at 1251 ppm was observed (Figure 4).
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DMSOꢀd6/D2O
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DMSOꢀd6/PBS (pH = 7,5)
DMSOꢀd6
Figure 4. 125Te NMR spectra (126.2 MHz, 25 C) of the mixture of organotelluranes 1a + 1b in DMSOꢀ
o
d6/D2O, DMSOꢀd6/PBS (pH 7.5) and DMSOꢀd6 (25 ºC).
It is important to highlight that the new Teꢀspecies must originate from a
displacement of halogens in 1a and 1b. To confirm the halogen release, a 81Br NMR
spectrum was recorded using organotellurane 1b solubilized in D2O. After recording
81Br NMR of KBr spectra in D2O (δKBr = 0.00 ppm), the spectrum of 1b was recorded,
and only a signal at
δ = 0 was observed, indicating the presence of bromide ions in
solution (Figure 5). Thus, it can be concluded that in the presence of water, bromide
ions were released from tellurane 1b, leading to the formation of a new product with
chemical shift in
δ
D2O = 1274 in the 125TeꢀNMR spectrum (Figure 5).
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125Te NMR
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1b/D2O
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81Br NMR
1b/D2O
KBr/D2O
Figure 5. 125Te NMR spectrum (126.2 MHz, 25 oC) of organotellurane 1b in D2O and 81Br NMR spectra
(108.06 MHz, 25 oC) of 1b and KBr in D2O.
Finally, the thermal stability of organotellurane 1b in anhydrous DMSOꢀd6 was
evaluated. The intention of this experiment was to analyze the behavior of dibromide
tellurane in DMSOꢀd6 at 35, 45, 55, 65 and 75 ºC, in the absence of water at high
temperatures for 15 min in each (Figure 6).
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75 ºC
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65 ºC
55 ºC
45 ºC
35 ºC
1b
Figure 6. 125Te NMR spectra (126.2 MHz) of organotellurane 1b in DMSOꢀd6 at different temperatures.
These results show that organotellurane 1b was thermally stable in DMSOꢀd6
reinforcing our observation about the role of water as pivotal for the transformation of
dihalogenated organotelluranes 1a and 1b.
Based on the 125Te NMR data, we assume that organotelluranes 1a and 1b were
transformed into corresponding telluroxide. However, telluroxide could occur in
equilibrium with corresponding dihydroxytelluride39, which could imply two types of
125Te NMR signals. In view of the proposed formation of a telluroxide or
dihydroxytelluride, from 1a and 1b, in aqueous media, we tried to synthesize these
compounds via oxidation of telluride 1 (Scheme 1) using hydrogen peroxide40, sodium
hydroxide41 or ꢀbromosuccinimide42. However, the syntheses were not successful, due
N
to the difficulty of isolating the formed species.
On the other hand, it is known that a noncovalent intramolecular interaction
involving nonꢀligand electrons in the oxygen and antibonding molecular orbital of the
Te=O bond in 3 can prevent the dihydroxytelluride 4 formation43. This nonꢀcovalent
interaction is responsible for increasing the stability of the telluroxide 343 (Scheme 2)
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and avoids the βꢀelimination reaction in telluroxides44. To confirm this hypothesis,
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tellurane 1b in D2O was analyzed via H and C NMR, and it was possible to observe
signals indicating the conversion of dibromide organotellurane into a new species
without butyl carbon chain changes (see supporting information).
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Scheme 2. Preventing the hydration reaction of telluroxide through the intramolecular TeꢀO interaction.
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In contrast, we succeeded in synthesizing oxatellurole 2a (Scheme 3), which
contains an intramolecular covalent TeꢀO bond that simulates the change of a Teꢀ
halogen bond (halogen release was previously confirmed – Figure 5) with a TeꢀO bond
like one from a water attack on 1a and 1b. To our pleasure, a signal at δDMSO = 1219
was observed, indicating that 2a is structurally similar to the product of 1a and 1b after
reaction with water (~ 1256 ppm). So, it can be suggested that a TeꢀO bond was formed
in place of at least one TeꢀCl or TeꢀBr bond in the organotelluranes exposed to water.
Finally, 125Te NMR analysis showed that 2a was stable to water exposure (
Figure 7). This observation indicates that organotelluroles are new waterꢀstable
hypervalent Teꢀcontaining compounds for biological applications.
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Scheme 3. Reagents and conditions: (i): Nꢀchlorosuccinimide, dichloromethane (0 °C, 20 min.)
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i
OH
Te
O
Te
Cl
2a
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2
DMSOꢀd6/D2O
DMSOꢀd6
Figure 7. 125Te NMR spectra (126.2 MHz, 25 oC) of oxatellurole 2a in DMSOꢀd6 and DMSOꢀd6/D2O.
Conclusion
Our observations allowed us to conclude that organotelluranes 1a and 1b, when
exposed to organicꢀaqueous or just aqueous solution are immediately converted into
new species. This transformation was observed in the presence of D2O, distillated water
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or buffered solution, independent of the pH (value or buffer nature). Analysis of Brꢀ
NMR of 1b in D2O demonstrated release of bromide ions, indicating the occurrence of a
displacement reaction in dibromide tellurane 1b. We also assumed the formed Teꢀ
species is a telluroxide, but in our opinion this claim needs more investigation. In the
same way as supposed to ASꢀ101, we demonstrated that organotelluranes 1a and 1b are
not stable in aqueous solution. It suggests a proactive role of these organotelluranes in
previously reported biological activity, being the named telluroxide the possible active
specie.
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Experimental Section
General Methods:
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Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III at
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9.4 Tesla (400 MHz for HꢀNMR, 100 MHz for 13CꢀNMR, 126.2 for 125TeꢀNMR and
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108.06 MHz for 81Br). The chemical shifts of 1H and 13C NMR were registered relative
to an internal standard (tetramethylsilane (δTMS = 0.00)) and 125Te NMR to an external
1
standard (diphenyl ditelluride (C6H5Te2 = 422.0)). HꢀNMR data were reported as
follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, qt = quintet, st = sextet and m = multiplet), coupling constant in Hz and relative
intensity (integral). 13CꢀNMR and 125TeꢀNMR data were reported as chemical shift in
ppm (δ).
Infrared spectra were recorded from KBr discs on a Bomem MB100 (Fourier Transform
Infrared – FTIR) spectrometer. Maximum absorption (νmax) is reported in wavenumber
(cmꢀ1).
1. Synthesis
2ꢀButyltellurobenzyl alcohol (2): 1ꢀBromoꢀ2ꢀ(methoxymethyl)benzene (0,372 g, 2
mmol), under argon atmosphere, was dissolved in anhydrous THF (15 mL) at ꢀ78 ºC.
Then, tercꢀBuLi (2,5 mL, 4 mmol, 1,7 mol Lꢀ1 in pentane) was carefully added
dropwise, thereby resulting a yellow or green clear mixture was stirred at 0 ºC for 30
min. After that, the mixture was cooled to 0 oC and dibutyl ditelluride (0,740 g, 2 mmol)
was added and the mixture was stirred for 3h at room temperature. The reaction was
quenched with ammonium chloride (15 mL) and brine (15 mL), the organic phase was
diluted with diethyl ether (50 mL) and washed with brine (2x20 mL). The organic phase
was separated, dried over anhydrous magnesium sulphate and filtered. The solvent was
removed under reduced pressure and the residue was purified by flash chromatography
using a mixture of hexane and ethyl acetate (80:1) as eluent to afford the purified orange
1
dark oil of the product in 51% yield. H NMR (CDCl3, 400 MHz, TMS) δ 7.71 (m,
3
1H), 7.24 (m, 2H), 7.10 (m, 1H), 4.69 (s, 2H), 4.63 (s, 2H), 2.85 (t, J = 7.61, 2H), 1.75
3
3
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(qt, 3J = 7.59, 2H), 1.39 (st, J = 7.24, 2H), 0.89 (t, J = 7.39 Hz, 3H); C (100 MHz,
CDCl3) δ 144.6, 140.9, 138.1, 132.5, 128.9, 128.8, 128.5, 128.4, 127.9, 127.8, 127.6,
126.9, 114.9, 68.7, 65.2, 33.7, 25.1, 13.4, 8.3; 125Te (126.24 MHz, CDCl3) δ 354.
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1ꢀButylꢀ1ꢀchloroꢀ2,1λ4ꢀbenzoxaꢀtellurole (2a): Hydroxytelluride 2 (100 mg, 0,34
mol) was dissolved in DCM (2 mL) at 0 ºC. Then, Nꢀchlorosuccinimide (NCS) (50 mg,
0,34 mol) with excess of 10% was added, thereby resulting a clear mixture was stirred
at r.t. for 30 min. After this, the flask was kept in a freezer for 24h, filtered on cotton
and the remained NCS was extracted with distilled water (3x10 mL). The organic
portions were combined and preꢀdried with brine (2x10mL), and dried with anhydrous
MgSO4, then the solvent was removed under vacuum without heating. The solid crude
was crystallized from distilled water/DMSO (5:1) to afford purified colorless crystals of
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the product in 40 % yield. H NMR (DMSOꢀd6, 400 MHz, TMS) δ 8.22 (m, 1H), 7,59
2
(m, 1H), 7.52 (m, 1H), 7.45 (m, 1H), 5.61 (d, J = 14.7 Hz, 1H), 5.30 (d, 2J = 14.7 Hz,
1H), 2.91 (m, 2H), 1.52 (m, 2H), 1.25 (st, 3J = 7.24 Hz, 2H), 0.77 (t, 3J = 7.35 Hz, 3H);
13C (100 MHz, DMSOꢀd6) δ 148.6, 132.5, 130.8, 128.5, 128.1, 123.4, 73.7, 43.2, 26.7,
23.5, 13.2; 125Te (126.24 MHz, DMSOꢀd6) δ 1218.
2. Stability Assays
1
The chemical stability studies were performed using the 125Te, 81Br, H and 13C nuclear
magnetic resonance (NMR) technique. In all analyses of 125Te NMR a capillary tube
was used, containing the diphenyl ditelluride (C6H5Te2), as external standard with
chemical shift calibrated to 422 ppm. It is worth mentioning that, in the spectra of 125Te,
the spectral window was read from 0 to 3000 ppm, as in though, in the absence of
signals above 2000 ppm, the spectral window will be shown between 200 and 2000 ppm
(see Supporting Information for details).
Acknowledgments.
L. P. and A. R. M. O. thank the Brazilian National Council for Scientific and
Technological Development (CNPq, Conselho Nacional de Desenvolvimento Científico
e Tecnológico) for financial support (Proc. 456834/2014). M. L. T. thanks the
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for a MSc.
fellowship. We thank for experimental support for this research from the Centro de
Ressonância Magnética Nuclear at the Universidade Federal do Paraná (UFPR). We are
grateful to MSc. Amanda Maciel for help with buffer solutions.
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Supporting Information Available:
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The Supporting Information is available free of charge on the ACS Publications
website at DOI:
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General experimental methods and conditions for stability assays, spectral data of
1H, 13C, 125Te and 81Br – NMR and infrared (FTIR).
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