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Exploring Catalytic Tellurium-Based Antioxidants: Synthesis and Evaluation
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

This thesis is concerned with the synthesis and evaluation of various tellurium-based chain-breaking antioxidants. The purpose is to find novel regenerable compounds with improved radical-trapping capacity.

In the first part of this work, we explore the possibilities to incorporate tellurium into tocopherols and aromatic amines. Overall, tocopherols carrying alkyltelluro groups are better radical-trapping agents than the corresponding sulfur- and selenium analogues. Among them, 7-octyltelluro δ-tocopherol showed a ca. 17-fold higher reactivity than recorded for α-tocopherol and much better regenerability. Even longer inhibition times were recorded for the corresponding bis(tocopheryl) tellurides. In the aromatic amine series, diphenyl amines carrying alkyltelluro groups were shown to function as efficient radical-quenchers capable of inhibiting peroxidation for 460 min in the presence of N-acetylcysteine. Thiol-consumption experiments suggested that the long inhibition times are due to efficient quenching of in-situ formed alkoxyl radicals in a solvent cage.

In the second part of the thesis, we study how the antioxidant properties are affected by variations in the electron density at tellurium and the number of alkyltelluro substituents in the molecule. Evaluation of a series of aryltelluro phenols carrying electron donating and electron withdrawing groups in the para-position of the aryl moiety suggested that a high electron density at the heteroatom prolonged the inhibition time. Among alkyltelluro phenols, alkyltelluro resorcinols and bis(alkyltelluro) phenols, phenols carrying alkyltelluro groups in both ortho positions were superior when it comes to radical-trapping activity and regenerability.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1423
Keyword [en]
antioxidant, tellurium, selenium, radical-trapping, chain-breaking, ROS, glutathione peroxidase, tocopherol, aromatic amine, oxidative stress
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-302475ISBN: 978-91-554-9684-5 (print)OAI: oai:DiVA.org:uu-302475DiVA: diva2:957745
Public defence
2016-10-27, B41, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2016-10-03 Created: 2016-09-04 Last updated: 2016-10-03
List of papers
1. Catalytic Antioxidants: Regenerable Tellurium Analogues of Vitamin E
Open this publication in new window or tab >>Catalytic Antioxidants: Regenerable Tellurium Analogues of Vitamin E
2013 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, no 24, 6274-6277 p.Article in journal (Refereed) Published
Abstract [en]

In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-213569 (URN)10.1021/ol403131t (DOI)000329077700042 ()
Available from: 2013-12-28 Created: 2013-12-28 Last updated: 2017-12-06Bibliographically approved
2. Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols
Open this publication in new window or tab >>Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 6, 2447-2457 p.Article in journal (Refereed) Published
Abstract [en]

To improve the radical-trapping capacity of the natural antioxidants, alkylthio-, alkylseleno-, and alkyltelluro groups were introduced into all vacant aromatic positions in β-, γ- and δ-tocopherol. Reaction of the tocopherols with electrophilic chalcogen reagents generated by persulfate oxidation of dialkyl dichalcogenides provided convenient but low-yielding access to many sulfur and selenium derivatives, but failed in the case of tellurium. An approach based on lithiation of the appropriate bromo-tocopherol, insertion of chalcogen into the carbon-lithium bond, air-oxidation to a dichalcogenide, and final borohydride reduction/alkylation turned out to be generally applicable to the synthesis of all chalcogen derivatives. Whereas alkylthio- and alkylseleno analogues were generally poorer quenchers of lipid peroxyl radicals than the corresponding parents, all tellurium compounds showed a substantially improved radical-trapping activity. Introduction of alkyltelluro groups into the tocopherol scaffold also caused a dramatic increase in the regenerability of the antioxidant. In a two-phase lipid peroxidation system containing N-acetylcysteine as a water-soluble co-antioxidant the inhibition time was up to six-fold higher than that recorded for the natural antioxidants.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-243231 (URN)10.1002/chem.201405895 (DOI)000348510400023 ()
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2017-12-05Bibliographically approved
3. Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
Open this publication in new window or tab >>Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
Show others...
2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 24, 12540-12544 p.Article in journal (Refereed) Published
Abstract [en]

Tellurobistocopherols 911 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 911 quenched linoleic-acid-derived peroxyl radicals much more efficiently than α-tocopherol in a chlorobenzene/water two-phase system. N-Acetylcysteine or tris(2-carboxylethyl)phosphine as co-antioxidants in the aqueous phase could regenerate the tellurobistocopherols and increase their inhibition times. Antioxidant 11 inhibited peroxidation for 7-fold longer than that recorded with α-tocopherol. Thiol consumption in the aqueous phase was monitored and found to be inversely related to the inhibition time.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-302464 (URN)10.1021/acs.joc.6b02450 (DOI)000390180100051 ()
Note

Authors in list of papers in thesis: Poon, J.; Yan, J.; Gates, P.; Engman, L.

Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2017-11-21Bibliographically approved
4. Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines
Open this publication in new window or tab >>Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines
Show others...
2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 36, 12891-12903 p.Article in journal (Refereed) Published
Abstract [en]

The synthesis of a variety of aromatic amines carrying an ortho-alkyltelluro group is described. The new antioxidants quenched lipidperoxyl radicals much more efficiently than α-tocopherol and were regenerable by aqueous-phase N-acetylcysteine in a two-phase peroxidation system. The inhibition time for diaryl amine 9 b was four-fold longer than recorded with α-tocopherol. Thiol consumption in the aqueous phase was found to correlate inversely to the inhibition time and the availability of thiol is the limiting factor for the duration of antioxidant protection. The proposed mechanism for quenching of peroxyl radicals involves O-atom transfer from peroxyl to Te followed by H-atom transfer from amine to alkoxyl radical in a solvent cage.

Keyword
antioxidants; amines; chain-breaking activity; organotellurium; regenerable
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-302460 (URN)10.1002/chem.201602377 (DOI)000383758200044 ()27484352 (PubMedID)
Funder
Swedish Research Council, 621-2011-4006
Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2017-11-21Bibliographically approved
5. In Search of Catalytic Antioxidants-(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols
Open this publication in new window or tab >>In Search of Catalytic Antioxidants-(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols
2013 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, no 12, 6008-6015 p.Article in journal (Refereed) Published
Abstract [en]

The quenching of peroxyl radicals by ortho-(alkyltelluro)phenols occurs by a more complex mechanism than formal H-atom transfer. In an effort to improve on this concept, we have prepared (alkyltelluro)resorcinols and bis(alkyltelluro)phenols and evaluated their catalytic chain breaking and preventive antioxidative properties. The in situ formed trianion produced from 2-bromophenol and 3 equiv of tert-butyllithiutn was allowed to react with dialkyl ditellurides to provide ortho-(alkyltelluro)phenols in low yields. 2-Bromoresorcinols after treatment with 4 equiv of tert-butyllithium similarly afforded 2-(alkyltelluro)resorcinols. Bis(alkyltelluro)phenols were accessed by allowing the trianion produced from the reaction of 2,6-dibromophenol with 5 equiv of tert-butyllithium to react with dialkyl ditellurides. The novel phenolic compounds were found to inhibit azo-initiated peroxidation of linoleic acid much more efficiently than alpha-tocopherol in a two-phase peroxidation system containing excess N-acetylcysteine as a stoichiometric thiol reducing agent in the aqueous phase. Whereas most of the (alkyltelluro)phenols and resorcinols could inhibit peroxidation for only 89-228 min, some of the bis(alkyltelluro)phenols were more regenerable and offered protection for >410 min. The novel (alkyltelluro)phenols were also evaluated for their capacity to catalyze reduction of hydrogen peroxide in the presence of thiophenol (glutathione peroxidase-like activity). (Alkyltelluro)resorcinols 7a-c were the most efficient catalysts with activities circa 65 times higher than those recorded for diphenyl diselenide.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-205014 (URN)10.1021/jo400703w (DOI)000320979500020 ()
Available from: 2013-08-13 Created: 2013-08-13 Last updated: 2017-12-06Bibliographically approved

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