Article A Newmolecules Alkylation of Aryl Alcohols by Boron Trifluoride Etherate Article ANdze New Denis Jumbam, Alkylation Yamkela Maganga, of Aryl Wayiza Alcohols Masamba *, Nomthandazo by Boron I Mbunye, Esethu TrifluorideMgoqi and Sphumusa Etherate Mtwa Department of Chemical and Physical Sciences, Faculty of Natural Sciences, Walter Sisulu NdzeUniversity, Denis Jumbam, Nelson Yamkela Mandela Maganga, Drive, Mthatha Wayiza 511 Masamba7, South Africa; * , Nomthandazo [email protected] I. Mbunye, (N.D.J.); [email protected] Mgoqi and Sphumusa Mtwa (Y.M.); [email protected] (N.I.M.); [email protected] (E.M.), [email protected] (S.M.) Department of Chemical and Physical Sciences, Faculty of Natural Sciences, Walter Sisulu University, Nelson Mandela* Correspondence: Drive, Mthatha [email protected] 5117, South Africa; [email protected] (N.D.J.); [email protected] (Y.M.); [email protected] (N.I.M.); [email protected] (E.M.); [email protected] (S.M.) *AcademicCorrespondence: editor: Na [email protected] M. Garrido Received: 10 September 2019; Accepted: 9 October 2019; Published: date Academic Editor: Narciso M. Garrido Received:Abstract: 10 The September ethylation 2019; Accepted:of aryl alcohols 9 October by 2019; an Published:ethyl moiety 16 October of boron 2019 trifluoride etherate is Abstract:described.The The ethylation reaction proceeded of aryl alcohols cleanly by and an ethyl afforded moiety good of boronyields trifluorideof the corresponding etherate isdescribed. aryl ethyl Theethers. reaction It tolerated proceeded the presence cleanly of and functional afforded groups good yieldssuch as of aryl, the alkyl, corresponding halogens, arylnitro, ethyl nitrile, ethers. and Itamino. tolerated However, the presence the presence of functional of amino groups or nitro such groups as aryl, ortho alkyl, to a halogens, hydroxyl nitro, group nitrile, of an andaryl amino.compound However, drastically the presencereduced the of aminoyields of or the nitro an groupsticipated ortho products to a hydroxyldue to the group chelation of an of aryl the compoundaforementioned drastically functional reduced groups the with yields boron of the triflu anticipatedoride etherate. products A nitrogen due to atom the chelation in the aromatic of the aforementionedring system, as exemplified functional groups by hydroxypyridine with boron trifluoride and 8-hydroxyquinoline, etherate. A nitrogen completely atom in theinhibited aromatic the ringreaction. system, Resorcinol, as exemplified hydroquinone, by hydroxypyridine and aryl alcohols and 8-hydroxyquinoline, with aldehyde functions completely decomposed inhibited under the reaction.the reaction Resorcinol, conditions. hydroquinone, and aryl alcohols with aldehyde functions decomposed under the reaction conditions. Keywords: aryl alcohols; aryl ethyl ethers; boron trifluoride etherate; ethylation; functional groups Keywords: aryl alcohols; aryl ethyl ethers; boron trifluoride etherate; ethylation; functional groups 1. Introduction 1. IntroductionThe unprecedented ethylation reaction of carboxylic acids by an ethyl moiety of boron trifluoride etherateThe unprecedented(BTE) to form corresponding ethylation reaction ethyl of esters carboxylic in the acids absence by an of ethylethyl moiety alcohol of may boron have trifluoride opened etherateup a new (BTE) synthetic to form route corresponding for the formation ethyl of esters aryl inethyl the ethers, absence thanks of ethyl to the alcohol observed may havesimultaneous opened upformation a new synthetic of ethyl p route-ethoxybenzoate for the formation from p of-hydroxybenzoic aryl ethyl ethers, acid thanks [1]. to the observed simultaneous formationAryl ofethyl ethyl ethersp-ethoxybenzoate find varied applications from p-hydroxybenzoic in industry ranging acid [1]. from solvents, paints, cosmetics, and Arylpharmaceuticals ethyl ethers find[2]. variedFor example, applications p-ethoxyaniline in industry rangingis the precursor from solvents, for the paints, production cosmetics, ofand the pharmaceuticalsanalgesic phenacetin [2]. For [3,4], example, β-ethoxynaphthalenep-ethoxyaniline is(also the precursorknown as for nerolin) the production is used ofas thea fixative analgesic in phenacetinperfumery [[5]3,4 while], β-ethoxynaphthalene some derivatives of (also aryl knownethers exhibit as nerolin) antioxidative is used as properties a fixative in[6]. perfumery In light of [the5] whileaforementioned some derivatives properties of aryl of ethers aryl ethyl exhibit ethers antioxidative and their properties potential [applications6]. In light of in the the aforementioned chemical and propertiespharmaceutical of aryl industries, ethyl ethers we and set theirout to potential explore applicationsthe alkylation in of the various chemical phenols and pharmaceutical using this new industries,ethylating weagent. set out to explore the alkylation of various phenols using this new ethylating agent. TheThe traditionaltraditional WilliamsonWilliamson etherether synthesis,synthesis, outlinedoutlined inin FigureFigure1 ,1, involves involves the the S SNN22 reactionreaction ofof anan aryloxidearyloxide withwith aa primaryprimary alkylalkyl halide,halide, or or of of an an E EARARS reaction ofof anan alkoxidealkoxide withwith anan arylaryl halidehalide [[7],7], inin thethe presencepresence [[8,9]8,9] oror absenceabsence ofof aa solventsolvent [[10].10]. Figure 1. Conventional Williamson ether synthesis of alkyl aryl ethers. Molecules2019, 24, x;doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Though effective and generally considered to be the method of choice, the Williamson ether synthesis suffers from some drawbacks such as the toxicity of the associated alkyl halides and Molecules 2019, 24, 3720; doi:10.3390/molecules24203720 www.mdpi.com/journal/molecules Molecules 2019, 24, 3720 2 of 8 dimethyl and diethyl sulfate. In addition, some alkyl halides involved in this reaction are prone to elimination under basic reaction conditions. The Cu-promoted Ullmann ether synthesis [11] and its variants [8,12,13] are a useful alternative method, but is limited to certain reactive substrates and only takes place in high boiling polar solvents. The Mitsunobu protocol, whereby the relevant phenol and alcohol are condensed in the presence of diethyl azodicarboxylate and triphenylphosphine, smoothly allows access to the expected alkyl aryl ethers in good to excellent yields [14]. However the resultant triphenylphosphine oxide poses tremendous challenges during product purification. Recently, an alternative version of the Williamson ether synthesis using dialkyl carbonates and imidazole carbamates as the alkylating agents [4,15–17] has been proposed. Because BTE is mostly used as catalyst at low temperatures, its capacity to act as an alkylating agent has eluded the attention of organic chemists until now. We wish to report here our findings on its high temperature reaction with variously substituted phenols. 2. Results and Discussion The results obtained in the reaction of various aryl alcohols with boron trifluoride etherate (BTE) are summarized in Figure2 below. Various aryl alcohols were ethylated under the above reaction conditions affording the corresponding ethers in low to excellent yield depending on the substitution on the aromatic ring. The reaction tolerated certain substituents such as, alkyl (compounds 7–9), halogens (compounds 2, 3, 5, and 6), nitro (compound 4), nitrile (compound 13) and amino (compound 10). The influence of some substituents, such amino, hydroxyl and nitro, on the overall outcome of the reaction depended on its nature and its position relative to the reaction center. Thus, while p-nitrophenol was converted to p-ethoxynitrobenzene (compound 4), its ortho isomer (o-nitrophenol) failed to react under the same reaction conditions, most likely due to the steric hindrance brought about by the proximity of the nitro to the hydroxyl group. The amino group on the other hand showed a somewhat different trend: p-aminophenol was ethylated, albeit in low yield (compound 10) after refluxing overnight. Its ortho isomer (o-aminophenol), on the other hand, formed the corresponding ether only in trace amounts and the slow reaction could also be attributed to the steric hindrance between the two adjacent groups (amino and hydroxyl). All three isomeric hydroxyphenols led to decomposition products, forming tarry materials. A nitrogen atom forming part of the aromatic ring system completely inhibited the ethylation reaction as exemplified by p-hydroxypyridine and 8-hydroxyquinoline, probably due to the chelation of the nitrogen atom onto the Lewis acid, leading to the formation of resinous materials. The presence of a nitrile group slowed down the ethylation reaction considerably (compound 13) and only 20% of the anticipated product was obtained after refluxing the reaction overnight. As in all the cases where low yields are obtained, the starting material was not recovered and was completely converted into tars. All three isomers of hydroxybenzaldehyde decomposed and formed resinous materials. The decomposition of p-hydroxybenzyl alcohol, on the other hand, may not be surprising given that hydroxybenzyl alcohols are prone to polymerization under acidic conditions [18]. BTE promotes the formation of a carbocation with aliphatic hydroxyl groups, which subsequently undergo alkene formation if β-hydrogen atoms are present [19]. The alkenes formed in the process are likely to polymerize under the above reaction condition