Communication Selenium-Epoxy ‘Click’ Reaction and Se-Alkylation—Efficient Access to Organo-Selenium and Selenonium Compounds Taejun Eom and Anzar Khan * Department of Chemical and Biological Engineering, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul 02841, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-3290-4859 Received: 3 September 2020; Accepted: 29 September 2020; Published: 5 October 2020 Abstract: This work establishes the ‘click’ nature of the base-catalyzed oxirane ring opening reaction by the selenolate nucleophile. The ‘click’-generated ß-hydroxy selenide can be alkylated to afford cationic selenium species. Hemolytic studies suggest that selenonium cations do not lyse red blood cells even at high concentrations. Overall, these results indicate the future applicability of the developed organo-selenium chemistry in the preparation of a new class of cationic materials based on the seleno-ether motif. Keywords: ‘click’ chemistry; oxirane ring opening reaction; organo-selenium; organo-selenonium 1. Introduction Selenium was discovered in early 1800 [1,2]. The chemistry of organo-selenium nucleophiles, however, only began in 1973 with Sharpless and Lauers’ report on the preparation of phenylselenolate and its application in converting epoxides into allylic alcohols [3]. Since then a wide range of reactions based on nucleophilic selenium reagents have been developed for use in organic synthesis [1,2]. Inspired by Sharpless’ selenium reagent and the growing interest in organoselenium materials [4], we began to examine the full scope of the ring opening reaction of epoxides by the selenolates in context of ‘click’ chemistry—another area of research pioneered by Sharpless [5]. ‘Click’ chemistry entails modular and wide in scope reactions that can be carried out under simple experimental conditions and produce quantitative yields and inoffensive byproducts [6]. This philosophy has been quickly adapted in the arena of materials science and application of ‘click’ reactions has revolutionized the way functional soft materials are being created [7–12]. The copper catalyzed azide-alkyne cycloaddition reaction has been at the forefront of this revolution since its advent in 2002 [6]. However, other potential ‘click’ processes originally identified by Sharpless, such as thiol and amine-based ring opening of the epoxide group, are also making a considerable impact in the protective-group-free synthesis of reactive and functionalizable polymers [13], hydrogels [14] and patterned surfaces [15]. The addition of selenium to this list would enhance the repertoire of nucleophilic ring opening ‘click’ reactions. Simple and efficient access to the ß-hydroxy selenide motif would also help in evaluating its applicability in terms of creating new bio-relevant materials. In examining previous studies, it becomes clear that the most successful method to access ß-hydroxy selenides relies on stoichiometric amounts of metal-hydrides (e.g., LiAlH4, NaH, LiBEt3H, Na/NH3, Bu3SnH, NaBH4) or reducing agents such as zinc metal to create selenolate from diselenide precursors [16–20]. Often, selenolate is used in excess, reaction times range in hours at elevated temperatures (>50 ◦C), the isolated yields are moderate to high (<90%) and inert conditions are required. A strong reducing atmosphere also compromises functional group tolerance in such reactions. These attributes do not satisfy the ‘click’ chemistry criteria. Chemistry 2020, 2, 827–836; doi:10.3390/chemistry2040054 www.mdpi.com/journal/chemistry Chemistry 2020, 2, x 2 required.Chemistry 2020 A, 2strong reducing atmosphere also compromises functional group tolerance in such828 reactions. These attributes do not satisfy the ‘click’ chemistry criteria. Since selenols possess a relatively low pKa (5.2) [21], we hypothesized that simple organic and Since selenols possess a relatively low pKa (5.2) [21], we hypothesized that simple organic and inorganicinorganic bases bases such such as as triethylamine triethylamine (TEA), (TEA), di diazabicycloundeceneazabicycloundecene (DBU) (DBU) or or lithium lithium hydroxide hydroxide (LiOH)(LiOH) may may catalyze catalyze selenolate selenolate formation formation under under mild mild conditions conditions and and may may lead lead to to the the development development ofof simple simple protocols protocols in in epoxide epoxide ring ring opening opening reactions. reactions. Herein, Herein, we we show show that that indeed indeed small small amounts amounts (0.01–0.05(0.01–0.05 eq./SeH) eq./SeH) of of the the aforementioned aforementioned bases bases in an in organic an organic or aqueous or aqueous medium medium can catalyze can catalyze regio- selective formation of ß-hydroxy selenides in >95% yield in 15 min of reaction time under ambient regio-selective formation of ß-hydroxy selenides in >95% yield in 15 min of reaction time under conditions. Due to a mild and fast nature, the reaction tolerates a variety of electrophiles and ambient conditions. Due to a mild and fast nature, the reaction tolerates a variety of electrophiles and nucleophiles in the system. The selenium atom in the formed ß-hydroxy selenides can be nucleophiles in the system. The selenium atom in the formed ß-hydroxy selenides can be quantitatively quantitatively transformed into selenonium-based cationic species with full compatibility towards transformed into selenonium-based cationic species with full compatibility towards mammalian red mammalian red blood cells. Overall, these results indicate that the base-catalyzed selenium-epoxy blood cells. Overall, these results indicate that the base-catalyzed selenium-epoxy reaction meets reaction meets the requirements of a ‘click’ reaction. The strength of this chemistry is also the the requirements of a ‘click’ reaction. The strength of this chemistry is also the reactivity of the reactivity of the ‘click’-generated motif that allows for further installation of an alkyl group and ‘click’-generated motif that allows for further installation of an alkyl group and cationization of cationization of the structure. the structure. 2.2. Results Results 2.1.2.1. Selenol Selenol Nucleophile Nucleophile in in Organic Organic Medium Medium Initially,Initially, commerciallycommercially available available benzene benzene selenol selenol (1) and (1) glycidoland glycidol (2) were (2 chosen) were as chosen the precursors as the precursors(Scheme1)[ (Scheme22–25]. 1) The [22–25]. reaction The was reaction performed was pe underrformed ambient under ambient conditions conditions in chloroform in chloroform and the andcrude the reaction crude mixturereaction was mixture analyzed was withanalyzed the help with of 1theH-NMR help spectroscopyof 1H-NMR spectroscopy (Figure1, Figures (Figure S1–S3). 1, FiguresAmbient S1–S3). conditions Ambient were conditions chosen to were fulfill chosen one ofto fu thelfill criteria one ofof the ‘click’ criteria chemistry, of ‘click’ chemistry, which entails which the entailsreactions the toreactions be tolerant to be oftolerant moisture of moisture and oxygen. and oxygen. A 1:1 stoichiometryA 1:1 stoichiometry between between the reactants the reactants was wasemployed. employed. From From the the1H-NMR 1H-NMR data, data, it it became became clear clear that that prolonging prolonging thethe reactionreaction (from(from 15 min to to 3030 min) min) did did not not improve improve the the yield yield of ofthe the product product 3 significantly3 significantly (Table (Table 1).1 Instead,). Instead, thethe nature nature and and the amountthe amount of the of catalyst the catalyst influenced influenced the reaction the reaction in a more in a profound more profound way. The way. relatively The relatively stronger stronger bases, DBUbases, and DBU LiOH, and LiOH,led to 94 led and to 94 97% and ring 97% opening ring opening reaction reaction within within 15 min 15 of min reaction of reaction time with time with0.03 eq./SeH0.03 eq. /(4.76SeH mol%) (4.76 mol%) loading. loading. In all cases, In all diselenide cases, diselenide 4 (PhSeSePh)4 (PhSeSePh) was produced was produced as the side as product. the side Itproduct. appears It that appears stronger that catalysts stronger and catalysts short andreaction short times reaction are timesrequired are to required facilitate to a facilitate fast ring a opening fast ring reactionopening and reaction to hinder and tothe hinder formation the formation of diselenide of diselenide through oxidative throughoxidative dimerization dimerization of selenol of reactant selenol underreactant ambient under conditions. ambient conditions. SchemeScheme 1. 1. Base-catalyzedBase-catalyzed epoxide epoxide ring ring opening opening reaction reaction with with selenol selenol nucleophile. nucleophile. Chemistry 2020, 2 829 Chemistry 2020, 2, x 3 1 FigureFigure 1. H-NMR 1. 1H-NMR of the reactants of the reactants and the reaction and the mixture reaction (bottom) mixture in deuterated (bottom) in chloroform deuterated (CDCl 3). chloroform (CDCl3). Table 1. Ring opening reaction in chloroform. Selenol TableEpoxide 1. Ring opening reactionCatalyst in chloroform.Catalyst Time Ring Opening Entry Solvent Catalyst (1) (2) (mol%) (eq./SeH) (min) (%) Ring Selenol Epoxide Catalyst Catalyst Time Entry1 Solvent CHCl3 1 1Catalyst TEA 0.99 0.01 15Opening 75 2 CHCl (1)1 (2) 1 TEA(mol%) 0.99 (eq./SeH) 0.01 30(min) 77 3 (%) 3 CHCl3 1 1 TEA 2.91 0.03 15 81 14 CHCl CHCl33 11 1 1 TEA TEA 0.99 2.91 0.030.01 3015 8375 25 CHCl CHCl33 11 1 1 TEA TEA 0.99 4.76 0.050.01 1530 8777 6 CHCl 1 1 TEA 4.76 0.05