molecules Article
KOtBu as a Single Electron Donor? Revisiting the Halogenation of Alkanes with CBr4 and CCl4 Katie J. Emery
ID
, Allan Young, J. Norman Arokianathar, Tell Tuttle *
ID
and John A. Murphy *
ID
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK;
[email protected] (K.J.E.);
[email protected] (A.Y.);
[email protected] (J.N.A.) * Correspondence:
[email protected] (T.T.);
[email protected] (J.A.M.); Tel.: +44-(0)141-548-2389 (J.A.M.) Academic Editor: John C. Walton
Received: 8 April 2018; Accepted: 26 April 2018; Published: 1 May 2018
Abstract: The search for reactions where KOt Bu and other tert-alkoxides might behave as single electron donors led us to explore their reactions with tetrahalomethanes, CX4 , in the presence of adamantane. We recently reported the halogenation of adamantane under these conditions. These reactions appeared to mirror the analogous known reaction of NaOH with CBr4 under phase-transfer conditions, where initiation features single electron transfer from a hydroxide ion to CBr4 . We now report evidence from experimental and computational studies that KOt Bu and other alkoxide reagents do not go through an analogous electron transfer. Rather, the alkoxides form hypohalites upon reacting with CBr4 or CCl4 , and homolytic decomposition of appropriate hypohalites initiates the halogenation of adamantane. Keywords: halogenation; potassium tert-butoxide; alkanes; dihalocarbenes; hypohalite
1. Introduction Recent reports have described transition-metal-free reactions, such as the coupling of haloarenes with arenes [1–4], that are promoted by a combination of KOt Bu and an organic additive. The reactions proceed by a radical mechanism, with a single electron transfer (SET) step initiating the formation of the radicals. It has previously been reported that KOt Bu is capable of reductively activating a range of substrates via single electron transfer [5,6], and this led some authors to propose that tert-butoxide anion is responsible for the initiation of these coupling reactions, either alone or in complexation with an additive, such as 1,10-phenanthroline, in the ground state [2,3,7–11]. However, recent publications have shown that the KOt Bu base reacts with the organic additive to form an electron donor in situ. SET from this electron donor then initiates the radical chain mechanism, not SET from tert-butoxide anion [12–14]. The investigations begged the question: “under what circumstances would KOt Bu behave as a single electron donor?” To answer that question, we were drawn to the research of Schreiner and Fokin et al., who reduced CBr4 using aqueous NaOH and a phase-transfer catalyst in a two-phase system that led to the bromination of adamantane [15,16]. They demonstrated that reaction of hydroxide anion with CBr4 led to the tribromomethyl radical 4, and concluded that this reflected direct electron transfer from hydroxide to CBr4 (Scheme 1). This tribromomethyl radical 4 undergoes a chain reaction, where it abstracts a hydrogen atom from adamantane 5 to form the alkyl radical 7 and bromoform 6. The adamantyl radical 7 abstracts a bromine atom from CBr4 , forming adamantyl bromide 8 and regenerating the tribromomethyl radical 4 [15]. The reactions of the tribromomethyl radical show diagnostic high selectivities for abstracting tertiary CH hydrogen atoms (to ultimately form 1-bromoadamantane) over secondary (CH2 ) counterparts (which would ultimately form 2-bromoadamantane). Molecules 2018, 23, 1055; doi:10.3390/molecules23051055
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tertiary CH hydrogen atoms (to ultimately form 1-bromoadamantane) over secondary (CH2) tertiary CH hydrogen atoms (to ultimately form 1-bromoadamantane) over secondary (CH2) counterparts (which would ultimately form 2-bromoadamantane). t Buform ◦ C, 96 h) to afford counterparts would ultimately 2-bromoadamantane). Recently,(which we showed reacts with CBr CBr44 and and adamantane adamantane (40 (40 °C, Recently, we showed that that KO KOtBu reacts with 96 h) to afford t Recently, we showed that KO Bu reacts to with CBrthe 4 and adamantane (40 °C, 96 h) to afford bromoadamantane—in aa reaction reaction that appears mirror work of of Schreiner Schreiner and and Fokin Fokin et et al.—with al.—with bromoadamantane—in that appears to mirror the work t Bu in bromoadamantane—in a reaction that appears to mirror the work of Schreiner and Fokin et al.—with NaOH, although although phase-transfer phase-transfer conditions conditions were were not not used used [17]. [17]. The The oxidation NaOH, oxidation potential potential of of KO KOtBu in tBu in NaOH, although phase-transfer conditions were not used [17]. The oxidation potential of KO DMF (0.10 V vs. SCE) [8] is not too different from the reduction potential of CBr in DMF ( − 0.31 V DMF (0.10 V vs. SCE) [8] is not too different from the reduction potential of CBr4 in4 DMF (−0.31 V vs. t Bu DMF (0.10 V vs. SCE)therefore [8] is notproposed too different from themight reduction potential of CBr 4 in DMF (−0.31 V vs. vs. SCE) [18]. It was that KO reduce CBr through an electron transfer t SCE) [18]. It was therefore proposed that KO Bu might reduce CBr4 4through an electron transfer SCE) [18]. Itbut was therefore proposed that KOtBu might reduce CBr 4 through an electron transfer mechanism, investigation. The aim of of thisthis paper is toisexplore the mechanism, but the the door doorwas wasleft leftopen opentotofurther further investigation. The aim paper to explore t mechanism, but the door was left open to further investigation. The aim of this paper is to explore t chemistry of KO Bu and related tertiary alkoxides in this context. the chemistry of KO Bu and related tertiary alkoxides in this context. the chemistry of KOtBu and related tertiary alkoxides in this context.
Scheme Scheme 1. 1. The TheSchreiner–Fokin Schreiner–Fokin mechanism mechanism for for the the bromination bromination of of alkanes alkanes from from reaction reaction of of hydroxide hydroxide Scheme 1. The Schreiner–Fokin mechanism for the bromination of alkanes from reaction of hydroxide with carbon tetrabromide [1]. with carbon tetrabromide [15]. with carbon tetrabromide [1].
2. 2. Results Results 2. Results The analogy of the proposed reaction of KOtBu with 4 or CCl4 (Scheme 2) to the Schreiner– t Bu CBr The analogy analogyofofthethe proposed reaction oftBu KO with CBr CCl4 2) (Scheme 2) to the 4 4 or The proposed reaction of KO with CBr 4 or CCl (Scheme to the Schreiner– Fokin reaction of reaction NaOH with this halide is striking (Scheme 1). (Scheme Upon donation of an electron, Schreiner–Fokin of NaOH with this halide is striking 1). Upon donation ofthe an Fokin reaction of NaOH with this halide is striking (Scheme 1). Upon donation of an electron, the alkoxide anion 9 would form the corresponding alkoxyl radical 10, which can undergo either electron, the alkoxide anion 9 would form the corresponding alkoxyl radical 10, which can undergo alkoxide anion 9 would form the corresponding alkoxyl radical 10, which can undergo either hydrogen atom transfer (HAT) to form 11, or β-scission to form the derived ketone 12 (for appropriate either hydrogen atom transfer to form 11, or β-scission form the derived ketone 12 (for hydrogen atom transfer (HAT) to(HAT) form 11, or β-scission to form thetoderived ketone 12 (for appropriate R). Either the alkoxyl radical 10 or the methyl radical can abstract a hydrogen atom from adamantane; appropriate R). Either the alkoxyl radical 10 or the methyl radical can abstract a hydrogen atom from R). Either the alkoxyl radical 10 or the methyl radical can abstract a hydrogen atom from adamantane; the adamantyl radical would then propagate the reaction as in Scheme 1. In order to detect the adamantane; the adamantyl radical would then propagate the reaction as in Scheme 1. In order to the adamantyl radical would then propagate the reaction as in Scheme 1. In order to detect the product from the β-scission of the alkoxyl radical 10, and bearing in mind the volatility of acetone detect thefrom product from the β-scission of theradical alkoxyl 10, andin bearing in mind the volatility of product the β-scission of the alkoxyl 10,radical and bearing mind the volatility of acetone from β-scission of tert-butoxyl radicals, we synthesized potassium 2-phenylpropan-2-olate 14 and acetone from β-scission of tert-butoxyl radicals, we synthesized potassium 2-phenylpropan-2-olate 14 from β-scission of tert-butoxyl radicals, we synthesized potassium 2-phenylpropan-2-olate 14 and used it as a base to explore a range of reaction conditions (Table 1). and used as a base to explore a range of reaction conditions (Table used it as it a base to explore a range of reaction conditions (Table 1). 1).
Scheme 2. The proposed mechanism for single electron transfer (SET) from tert-alkoxides to CBr4. Scheme transfer (SET) (SET) from from tert-alkoxides tert-alkoxides to to CBr CBr4.. Scheme 2. 2. The The proposed proposed mechanism mechanism for for single single electron electron transfer 4
Surprisingly, and in contrast to the case for KOtBu, exposure of 14 to CBr4 in dichloromethane Surprisingly, and in contrast to the case for KOttBu, exposure of 14 to CBr4 in dichloromethane solvent at 40 °C ledand to no bromination ofcase adamantane (Table 1, entry The products (2,2-dibromoSurprisingly, in contrast to the for KO Bu, exposure of 1). 14 to CBr 4 in dichloromethane solvent at 40 °C led to no bromination of adamantane (Table 1, entry 1). The products (2,2-dibromo◦ 1-methylcyclopropyl)benzene 16, methylstyrene 17 and (2,2-dichloro-1-methylcyclo-propyl)benzene solvent at 40 C led to no bromination of adamantane (Table 1, entry 1). The products (2,2-dibromo1-methylcyclopropyl)benzene 16, methylstyrene 17 and (2,2-dichloro-1-methylcyclo-propyl)benzene
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19 were observed, in addition to 2-phenylpropanol 15 and unreacted adamantane 18 (Table 1, entry 1-methylcyclopropyl)benzene 16, methylstyrene and (2,2-dichloro-1-methylcyclo-propyl)benzene 1). To avoid the complexity of having compounds17bearing different halogens in the reaction mixture, 19 were observed, in addition to 2-phenylpropanol 15 adamantane 18 (Table 1, entry 1). the reaction was repeated in dichloromethane using and CClunreacted 4 as the reagent, instead of CBr4 (Table 1, To avoid complexity of having compounds bearing different in the entry 2). the Although we had no evidence of light-sensitivity, wehalogens conducted thisreaction and allmixture, future the reaction was repeated in dichloromethane using CCl as the reagent, instead of CBr4 (Table 1, 4 experiments in foil-covered flasks [19]. The reaction yielded (2,2-dichloro-1-methylcyclopropyl)entry 2). Although hadproduct. no evidence of light-sensitivity, we conducted this and all future experiments benzene 19 as the we major Note that a blank reaction in dichloromethane (absence of CX4) in foil-covered flasks [19]. The reaction yielded (2,2-dichloro-1-methylcyclopropyl)-benzene 19 as resulted in the formation of product, bis((2-phenylpropan-2-yl)oxy)methane (20, 52%) (Table 1, entry the major product. Note that a blank reaction in dichloromethane (absence of CX ) resulted in the 4 3) [20]. formation of product, bis((2-phenylpropan-2-yl)oxy)methane (20, 52%) (Table 1, entry 3) [20]. Table 1. The reaction of the potassium 2-phenylpropan-2-olate 14 in dichloromethane at 40 °C a. Table 1. The reaction of the potassium 2-phenylpropan-2-olate 14 in dichloromethane at 40 ◦ C a .
16 (%)
17 (%)
18 (%)
19 (%)
15 (%)
20 (%)
Substrate 18 (mmol)/Additive (mmol) 16 (%) 17 (%) 18 (%) 19 (%) EntryEntry Substrate 18 (mmol)/Additive (mmol) 15 (%) 20 (%) Yields Based on 0.5 mmol Yields Based on [14] 2 mmol Yields Based on 0.5 mmol Yields Based on [14] 2 mmol 1 18 (0.5)/CBr (0.5) 31 10 82 14 82 1 18 (0.5)/CBr4 (0.5)4 31 10 82 14 82 2 18 (0.5)/CCl4 (0.5) 3 76 50 67 3 2 18 (0.5)/CCl (0.5) - 3 2 76 90 50 67 55 3 24 3 18 4(0.5)/3 18 (0.5)/2 90 55 24 a All yields are calculated using 1,3,5-trimethoxybenzene as the internal standard (10 mol %) in 1 H-NMR unless a All yields are calculated using 1,3,5-trimethoxybenzene as the internal standard (10 mol %) in 1Hstated in the experimental information. As a precaution, reactions were conducted in foil-covered flasks. The yields NMR unless stated inusing the experimental a precaution, were conducted of 16–19 were calculated adamantane 18information. as the limiting As reagent (0.5 mmol). reactions However, the yields of 15 and in 20 were calculated basedThe on the alkoxide 14 used (2 mmol). foil-covered flasks. yields of 16–19 were calculated using adamantane 18 as the limiting reagent
(0.5 mmol). However, the yields of 15 and 20 were calculated based on the alkoxide 14 used (2 mmol).
We propose that both (2,2-dibromo-1-methylcyclopropyl)-benzene 16 and (2,2-dichloro-1We propose that both19(2,2-dibromo-1-methylcyclopropyl)-benzene 16 and (2,2-dichloro-1methylcyclopropyl)benzene are formed from methylstyrene 17. The formation of methylstyrene is methylcyclopropyl)benzene from methylstyrene 17. The formation of methylstyrene is therefore greatly encouraged19inare theformed presence of CBr , consistent with the conversion of the alkoxide 4 therefore greatly encouraged in the presence of CBr3A). 4, consistent with the conversion of the alkoxide to a leaving group (i.e., a hypobromite) (Scheme It is known that hypobromites are formed t to a leaving group (i.e., a hypobromite) (Scheme 3A). It is that known that hypobromites are formed from from reaction of KO Bu with halogens, X2 [21] (and hypohalites are precursors to alkene t reaction of KOby Buradical with halogens, X2 [21] (and so that hypohalites are precursors to alkene halogenation halogenation mechanisms [21,22]), this reaction shows that they also form from reaction by radical mechanisms [21,22]), so this reaction shows that they also form from reaction with with tetrahalomethanes. The potassium 2-phenylpropan-2-olate 14 nucleophilically attacks a molecule tetrahalomethanes. The potassium 2-phenylpropan-2-olate 14 nucleophilically attacks a molecule of of CBr4 to form the hypobromite 21 and eliminate a CBr3 anion 22. The hypobromite 21 then undergoes CBr 4 to form the hypobromite 21 and eliminate a CBr3 anion 22. The hypobromite 21 then undergoes an elimination to form methylstyrene 17. The formation of (2,2-dibromo-1-methylcyclopropyl)benzene an elimination to form methylstyrene 17. The formation of (2,2-dibromo-1-methylcyclopropyl)benzene 16 occurs by decomposition of the tribromomethyl anion to CBr2 23, which attacks methylstyrene 17 16 occurs3A). by decomposition of the tribromomethyl anion to CBr2 23, which attacks methylstyrene 17 (Scheme (Scheme 3A). Analogous to the formation of (2,2-dibromo-1-methylcyclo-propyl)benzene 16, the isolation Analogous to the formation of (2,2-dibromo-1-methylcyclo-propyl)benzene theCCl isolation of of (2,2-dichloro-1-methylcyclo-propyl)benzene 19 means that carbenes (in this 16, case, 2 27) are (2,2-dichloro-1-methylcyclo-propyl)benzene 19 means case, CCl2 the 27) are formed formed under the reaction conditions (Scheme 3B). that Thecarbenes carbene (in 27 this forms when potassium under the reaction conditions (Scheme 3B). The carbene 27 forms when the potassium 22-phenylpropan-2-olate 14 deprotonates the solvent, CH2 Cl2 , and the resulting CHCl2 anion 24 phenylpropan-2-olate 14 deprotonates the solvent, CH 2Cl2, and the resulting CHCl2 anion 24 undergoes halogen exchange with CBr4 to form bromodichloromethane 25. A second deprotonation undergoes exchange with CBr4 to form26, bromodichloromethane 25. Aanion second deprotonation would leadhalogen to the bromodichloromethyl anion and decomposition of this would lead to the would lead to the bromodichloromethyl anion 26, and decomposition of this anion would lead to the dichlorocarbene 27. dichlorocarbene In the blank27. reaction (without CBr4 ) (Table 1, entry 3), bis((2-phenylpropan-2-yl)oxy)methane In the blank reaction (withoutdisplacement CBr4) (Table 1, 3), bis((2-phenylpropan-2-yl)oxy)methane 20 20 is formed by the nucleophilic of entry chloride from dichloromethane by two molecules is formed by the nucleophilic displacement of chloride from dichloromethane by two molecules of of potassium 2-phenylpropan-2-olate 14 (Scheme 4) [23,24]. The fact that bis((2-phenylpropan-2potassium 2-phenylpropan-2-olate (Scheme 4) of[23,24]. The factthat that yl)oxy)methane 20 is only observed 14 in the absence CBr4 suggests thebis((2-phenylpropan-2reaction of potassium yl)oxy)methane 20 is only observed in the absence of CBr 4 suggests that the reaction of potassium 22-phenylpropan-2-olate 14 with dichloromethane is slower than the reaction with CBr4 . phenylpropan-2-olate 14 with dichloromethane is slower than the reaction with CBr4.
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Scheme 3. (A) (A) The The proposed proposed mechanism mechanism for the formation of methylstyrene 17 and (2,2-dibromo-1Scheme 3. proposed Scheme 3. (A) The mechanism for for the the formation formation of of methylstyrene methylstyrene 17 17 and and (2,2-dibromo-1(2,2-dibromo-1methylcyclopropyl)-benzene 16 and (B) the CCl 2 carbene 27, that is used to form (2,2-dichloro-1methylcyclopropyl)-benzene 16 16 and and (B) (B) the the CCl CCl22 carbene carbene 27, 27, that that is is used used to to form form (2,2-dichloro-1(2,2-dichloro-1methylcyclopropyl)-benzene methylcyclopropyl)benzene 19 (not (not shown). shown). methylcyclopropyl)benzene 19 methylcyclopropyl)benzene 19 (not shown).
Scheme 4. 4. Formation of of bis((2-phenylpropan-2-yl)oxy)methane 20. 20. Scheme Scheme 4. Formation Formation of bis((2-phenylpropan-2-yl)oxy)methane bis((2-phenylpropan-2-yl)oxy)methane 20.
Reflecting on on the the fact fact that that potassium potassium 2-phenylpropan-2-olate 2-phenylpropan-2-olate 14 14 did did not not give give rise rise to to halogenation halogenation Reflecting Reflecting on the fact that potassium 2-phenylpropan-2-olate 14KO didtBu notwas giveused rise to halogenation of adamantane (Table 1), while halogenation was observed when as the alkoxide alkoxide t of adamantane (Table 1), while halogenation was observed when KOtBu was used as the of adamantane (Table 1), while halogenation was observed when KO Bu was used as the alkoxide (the ratio of adamantane 18:1-bromoadamantane 31:2-bromoadamantane 51 was determined to be be (the ratio of adamantane 18:1-bromoadamantane 31:2-bromoadamantane 51 was determined to (the ratio of adamantane 18:1-bromoadamantane 31:2-bromoadamantane 51 was determined to 39:3.3:1 [17]), [17]), this this suggests suggests that that either either the the two two alkoxide alkoxide bases bases do do not not react react with with CBr CBr44 through through 39:3.3:1 be 39:3.3:1 [17]), this suggests that either the two alkoxide bases do not react with CBr through 4 14 was analogous mechanisms, mechanisms, or or that that the the halogenation halogenation reaction reaction was was intercepted intercepted and and inhibited inhibited when when analogous 14 was analogous mechanisms, or that the halogenation reaction was intercepted and inhibited when 14 used. Interception could occur if methylstyrene 17—formed in the reaction from potassium 2used. Interception could occur if methylstyrene 17—formed in the reaction from potassium 2was used. Interception14—shuts could occur if methylstyrene 17—formed inTo theprobe reaction from potassium phenylpropan-2-olate down the radical chain pathway. this possibility, the phenylpropan-2-olate 14—shuts down the radical chain pathway. To probe this possibility, the 2-phenylpropan-2-olate 14—shuts down the radical chain pathway. To probe this possibility, the reaction of KO KOttBu Bu with with CBr CBr 4 and adamantane 18 was repeated in the presence of methylstyrene 17 (1 reaction of 4 and adamantane 18 was repeated in the presence of methylstyrene 17 (1 t reactionScheme of KO Bu equiv., 5). with CBr4 and adamantane 18 was repeated in the presence of methylstyrene 17 equiv., Scheme 5). (1 equiv., Scheme The addition addition5). of methylstyrene methylstyrene 17 17 completely completely inhibited inhibited the the bromination bromination of of adamantane, adamantane, which which The of The addition ofshut methylstyrene 17 completely inhibited the by bromination ofpreferential adamantane, which suggests that it can down the radical mechanism, perhaps acting as a source of suggests that it can shut down the radical mechanism, perhaps by acting as a preferential source of suggests that it can shut down the radical mechanism, perhaps by acting as a preferential source hydrogen atoms, atoms, relative relative to to adamantane adamantane 18, 18, for for the the radical radical intermediates intermediates in in the the reaction. reaction. hydrogen of hydrogen atoms, relative to adamantane 18, for theand radical intermediates in the reaction. Computationally, the competition between methylstyrene adamantane as a source of H atoms Computationally, the competition between methylstyrene and adamantane as a source of H atoms Computationally, the competition between methylstyrene and adamantane as a source of H atoms was modeled modeled using using CBr CBr33 radicals, radicals, which which showed showed that that hydrogen hydrogen atom atom abstraction abstraction by by the the CBr CBr33 radical radical was ǂ = 10.7 kcal/mol and ΔGrxn = −7.7 kcal/mol) is thermodynamically and from methylstyrene 17 (ΔG ǂ from methylstyrene 17 (ΔG = 10.7 kcal/mol and ΔGrxn = −7.7 kcal/mol) is thermodynamically and
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5 of 16
was modeled Molecules 2018, 23,using x FORCBr PEER REVIEW which showed that hydrogen atom abstraction by the CBr3 radical 5 of 16 3 radicals, from methylstyrene 17 (∆G}than = 10.7 kcal/mol and ∆G = ǂ−=7.7 kcal/mol) thermodynamically and kinetically more favorable from adamantane 18rxn (ΔG 13.9 kcal/molisand ΔGrxn = 1.1 kcal/mol) } ǂ = 13.9 kcal/mol and ΔGrxn = 1.1 kcal/mol) kinetically more favorable than from adamantane 18 (ΔG kinetically more favorable than from adamantane 18 (∆G = 13.9 kcal/mol and ∆Grxn = 1.1 kcal/mol) (see Supplementary Materials). (see Supplementary Supplementary Materials). Materials). (see
Scheme 5. Using methylstyrene 17 to block the bromination of adamantane. Scheme 5. Using methylstyrene 17 to block the bromination of adamantane. Scheme 5. Using methylstyrene 17 to block the bromination of adamantane.
All yields were calculated using 1,3,5-trimethoxybenzene as the internal standard (10 mol %) in All yieldsThe were calculated using 1,3,5-trimethoxybenzene internal standard (10 mol in the 1H-NMR. yield of 18 was calculated based on recovery as of the adamantane 18, the yield of 16%) and All yields were calculated using 1,3,5-trimethoxybenzene as the internal standard (10 mol %) in 1H-NMR. the The yield of 18 was based on recovery of adamantane 18, the yield of 16 and 19 was calculated based on CBr 4. calculated (Note that alkoxide (4 eq.) is capable of forming methylstyrene 17.) the 1 H-NMR. The yield of 18 was calculated based on recovery of adamantane 18, the yield of 16 and 19 was calculated based on CBr 4. (Note that alkoxide (4 eq.) capable ofbromination forming methylstyrene 17.) With the knowledge that methylstyrene 17 is capable ofis preventing of adamantane, 19 was calculated based on CBr4 . (Note that alkoxide (4 eq.) is capable of forming methylstyrene 17.) t knowledge that methylstyrene of preventing of adamantane, why With does the bromination succeed when KO Bu17 29is+capable CBr4 alone are used? bromination The two hypobromites, tertWith the knowledge that methylstyrene is capable of preventing bromination of adamantane, tBu17 why does bromination succeed when KO 29 + CBr 4 alone are used? The two hypobromites, tertbutyl hypobromite and 21, may undergo elimination at different rates; additionally, 2-methylpropene why does bromination succeed when KOt Bu 29 + CBr4 alone are used? The two hypobromites, tert-butyl butyl hypobromite 21, may at different rates; additionally, 2-methylpropene (b.p. −6.9 °C) exists and as a gas at theundergo reactionelimination temperature. Such a volatile product would likely be found hypobromite and 21, may undergo elimination at different rates; additionally, 2-methylpropene (b.p. (b.p. −6.9 °C) exists as a gas at the reaction temperature. Such a volatile product would likely be found principally in the headspace above the reaction, rather than in solution, and therefore halogenation − 6.9 ◦ C) exists as headspace a gas at theabove reaction temperature. Such a volatile product would likely be found principally in the the reaction, rather than in solution, and therefore halogenation of adamantane 18 could occur. principally in the above the reaction, rather than in solution, and therefore halogenation of of adamantane 18headspace could occur. As mentioned earlier, Wirth et al. [19] used tert-butyl hypobromite to achieve the bromination adamantane 18 could occur.Wirth et al. [19] used tert-butyl hypobromite to achieve the bromination As mentioned earlier, of alkanes (while Walling [20] used tert-butyl hypochlorite to achieve chlorination) and proposed that As mentioned earlier, Wirth et tert-butyl al. [19] used tert-butyl hypobromite to achieve the of of alkanes (while Walling [20] hypochlorite to achieve chlorination) andbromination proposed the mechanism was initiated used via homolysis of the O–Br bond of tert-butyl hypobromite. Eitherthat the alkanes (while Walling [20] used hypochlorite achieve chlorination) and proposed the mechanism initiated via tert-butyl homolysis of the O–Br to bond tert-butyl hypobromite. Eitherthat the bromine radical was or the tert-butoxyl radical could abstract the H of atom from adamantane. Propagation the mechanism was initiated via homolysis of the O–Br bond of tert-butyl hypobromite. Either the bromine radical the tert-butoxyl radical couldabstracts abstract athe atomfrom fromCBr adamantane. Propagation could then occurorwhen the adamantyl radical BrH atom 4 [15] or from tert-butyl bromine radical or the tert-butoxyl radical could abstract the H atom from adamantane. Propagation could then occur hypobromite [23].when the adamantyl radical abstracts a Br atom from CBr4 [15] or from tert-butyl could then occur when the adamantyl radical abstracts a Br atom from CBr4 [13] or from tert-butyl hypobromite To gain[23]. further information on mechanism, an alternative alkoxide, potassium hypobromite [23].further information on mechanism, an alternative alkoxide, potassium To gain triphenylmethanolate 30, was prepared and subjected to the reaction conditions with CBr4 and To gain further information mechanism, alternative potassium triphenylmethanolate triphenylmethanolate 30, was on prepared and an subjected to alkoxide, the reaction conditions with CBr4 and adamantane 18 (Table 2). 30, was prepared and subjected to the reaction conditions with CBr4 and adamantane 18 (Table 2). adamantane 18 (Table 2). Table 2. The reaction of potassium triphenylmethanolate 30 in dichloromethane at 40 °C a. Table 2. The reaction of potassium triphenylmethanolate 30 in dichloromethane at 40 ◦ C aa. Table 2. The reaction of potassium triphenylmethanolate 30 in dichloromethane at 40 °C .
Entry
Additive (mmol) (%) 33 (%) 34 (%) Entry Additive (mmol) 1818(%) 31 31 (%)(%) 33 (%) 34 (%) 32 (%)32 (%) 11 18(0.5) (0.5) CBr CBr 49 7 33 5(%)5 3412 Entry Additive (mmol) (%) 31 7(%) (%)12 3288 (%) 88 44 (0.5) 18 (0.5) 1849 21 18 (0.5) 87 0 1 0 81 18 (0.5) 49 70 51 12 88 2 18 CBr (0.5)4 (0.5) 87 0 81 aa All 1 H-NMR 2 calculated 18using (0.5) 87 0(10 mol %) 81inmol yieldswere were calculated 1,3,5-trimethoxybenzene the1internal standard (10 in the All yields using 1,3,5-trimethoxybenzene as0theas internal standard the%) a1 All yields unless stated in thestated experimental information. Theinformation. yields of 18, 31, 33,yields 34 were using adamantane as were calculated using 1,3,5-trimethoxybenzene as the internal molcalculated %) in18the H-NMR unless in the experimental The ofcalculated 18,standard 31, 33, 34(10 were the limiting reagent. However, the yield of 32 was calculated based on the alkoxide 30. 1
H-NMR unless stated thelimiting experimental information. Theyield yieldsofof3218, 31,calculated 33, 34 were calculated using adamantane 18 asinthe reagent. However, the was based on the using adamantane 18 as the limiting reagent. However, the yield of 32 was calculated based on the alkoxide 30. Reaction of potassium triphenylmethanolate 30 with adamantane in the presence of CBr4 afforded alkoxide 30.
products 1-bromoadamantane 31 (7%) and triphenylmethanol 32 (88%), as two additional Reaction of potassium triphenylmethanolate 30 with adamantane inwell the as presence of CBr4 products, benzophenone 33 (5%) and 4-benzhydrylphenol 34 (12%) (Table 2, entry 1). When Reaction of potassium triphenylmethanolate 30 triphenylmethanol with adamantane 32 in (88%), the presence ofasCBr CBr afforded products 1-bromoadamantane 31 (7%) and as well two44 was not present in the reaction mixture, 32 (81%) was34 isolated following workup, afforded products 1-bromoadamantane 31 (7%) triphenylmethanol 32 (88%), as well as two additional products, benzophenone 33 triphenylmethanol (5%) and and 4-benzhydrylphenol (12%) (Table 2, entry 1). together with a trace (1%) of benzophenone 33 (Table 2, entry 2). Further analysis of the starting additional products, benzophenone 33 (5%) and 4-benzhydrylphenol 34 (12%) (Table 2, entry 1). When CBr4 was not present in the reaction mixture, triphenylmethanol 32 (81%) was isolated When CBrworkup, 4 was not present in athe reaction triphenylmethanol 32 (81%) was analysis isolated following together with trace (1%) ofmixture, benzophenone 33 (Table 2, entry 2). Further following workup, togethershowed with a trace of benzophenone 33 (Table 2, entry 2). Furthersupplied analysis of the starting material trace(1%) amounts of 33 present in the commercially of the starting material showed trace amounts of 33 present in the commercially supplied
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triphenylmethanol 32. Background formation of benzophenone 33, in trace amounts from heterolytic material showed amounts 33 present in the commercially supplied triphenylmethanol 32. fragmentation of trace similar tertiaryofalkoxides with expulsion of a phenyl anion, is also precedented Background formation of benzophenone 33, in trace amounts from heterolytic fragmentation of similar [25,26]. tertiary with expulsion of a phenyl anion,inisthe alsopresence precedented Thealkoxides important difference between the reaction of CBr[25,26]. 4 and in its absence (Table 2, The important difference between the reaction in the presence of CBr and in itscan absence (Table 2, entry 1 and entry 2, respectively) is the formation of 4-benzhydrylphenol 434, which arise through entry 1 and entry 2, respectively) is the formation of 4-benzhydrylphenol 34, which can arise through the hypobromite 35 (Scheme 6). Potassium triphenylmethanolate 30 reacts with CBr4 to generate the the hypobromite 35 (Scheme 6). Potassium triphenylmethanolate 30the reacts CBr 4 to generate hypobromite 35. This hypobromite can react by three pathways (1) OBrwith anion leaves to form the the hypobromite 35. This hypobromite can react by three pathways (1) the OBr anion leaves form stabilized cation 36; (2) the O–Br bond fragments ionically with simultaneous migration of ato phenyl the stabilized thethe O–Br bond fragments ionically with migration of aa moiety to formcation cation36; 38; (2) or (3) O–Br bond undergoes homolysis to simultaneous form alkoxyl radical 40 and phenyl moiety to form cation 38; or (3) the O–Br bond undergoes homolysis to form alkoxyl radical bromine radical, for which there is literature precedent [23]. If pathway (1) is followed, the 40 and a bromine there is literature precedent [23]. If pathway (1) is30followed, carbocation 36 is radical, attackedfor bywhich another molecule of potassium triphenylmethanolate and, duethe to carbocation is attacked another molecule of potassium triphenylmethanolate and, due to steric effects,36the alkoxide by attacks at the para position of one of the benzene rings. In30doing so, the steric effects, alkoxidewhich, attacksfollowing at the paratautomerism position of one of the benzene workup, rings. In doing species 37 istheformed, and hydrolytic leads so, to the 34. species 37 is formed, which, following tautomerism and hydrolytic workup, leads to 34. Alternatively, Alternatively, 36 affords triphenylmethanol 32 on workup. Pathways (2) and (3) ultimately lead to 36 triphenylmethanol 32 on (2) the andformation (3) ultimately lead to the formation theaffords formation of benzophenone 33; workup. pathway Pathways (2) involves of intermediate 38, which of benzophenone 33; pathway (2) involves the formation of intermediate 38, which reacts(3) with water reacts with water on workup to form 39 and, ultimately, benzophenone 33. Pathway involves on workupoftothe form 39 and, ultimately, benzophenone 33.O–Br Pathway (3) involves of the formation alkoxyl radical 40, which could form via homolysis of 35 or,formation alternatively, by alkoxyl radical 40, which could form via O–Br homolysis of 35 or, alternatively, by SET from potassium SET from potassium triphenylmethanolate 30 to a molecule of CBr4. This alkoxyl radical might triphenylmethanolate to abenzophenone molecule of CBr This alkoxyl radical might to form 4 . However, undergo β-scission to 30 form 33. alternatively, theundergo radical β-scission 40 could undergo benzophenone However, alternatively, the radical 40 could neophyl-like rearrangement a neophyl-like 33. rearrangement to form radical 41 (Scheme 6) undergo [27]. Thea product 43 forms when the to form radical 41 (Scheme 6) [27]. The product 43 forms when the radical 42 abstracts a bromine radical 42 abstracts a bromine atom from either CBr4 or the hypobromite 35, and 43, in turn, upon atom from either CBra4hydrolytic or the hypobromite 35,toand 43, in turn, upon workup, undergoes a hydrolytic workup, undergoes conversion benzophenone 33. Previous fragmentations of related conversion to benzophenone 33. Previous of related of alkoxyl radicals have alkoxyl radicals have been studied [28–32].fragmentations The enhanced formation benzophenone 33 inbeen the studied [28–32]. The enhanced formation of benzophenone 33 in the presence of CBr could occur 4 6B), or the presence of CBr4 could occur through either β-scission of the alkoxyl radical 40 (Scheme through either β-scission the alkoxyl radical 40 (Scheme 6B), or the ionic mechanism (Scheme 6A). ionic mechanism (Schemeof6A).
Scheme 6. 6. Proposed and 34 34 from from 30: 30: (A) (A) through through ionic ionic Scheme Proposed pathway pathway for for the the formation formation of of 32, 32, 33 33 and intermediates and (B) through radical intermediates. intermediates and (B) through radical intermediates.
The study above provides evidence for significant formation of hypohalites from alkoxides 14 The study above provides evidence for significant formation of hypohalites from alkoxides 14 and 30. However, it might be possible for the OtBu anion in KOtBu to behave differently. The absence and 30. However, it might be possible for the Ot Bu anion in KOt Bu to behave differently. The absence of electron-withdrawing aryl groups would render it more electron-rich, and, therefore, it might be a better candidate than the other alkoxides to undergo electron transfer.
energy of reactions. (The calculations were conducted using the M06-2X functional [35,36] with the 6-311++G(d,p) basis set [37–41] on all atoms, except for the bromine. Bromine was modeled with the MWB28 relativistic pseudo-potential and associated basis set [42]. All calculations were carried out using the C-PCM implicit solvent model [43,44] with the dielectric constant for dichloromethane (ε = 8.93) or 2018, carbon tetrachloride (ε = 2.228) as appropriate. All calculations were performed in Gaussian09 Molecules 23, 1055 7 of 16 [45]). The energy barriers for SET from either KOtBu or potassium 2-phenylpropan-2-olate 14, to a of electron-withdrawing aryl groups would more electron-rich, and, therefore, it might be a molecule of CBr4 were calculated to be ΔGǂ render = +35.4 itkcal/mol and +36.1 kcal/mol, respectively (while better candidate than the other alkoxides to undergo electron transfer. the corresponding ΔGrxn values were +13.9 and +18.9 kcal/mol) (Figure 1). When the energy barrier probe for the the ability of alkoxides a single electron, computational was To calculated reactions with CCl4to , a donate similar energy profile was obtained for the modeling SET from t Bu and potassium was implemented to calculate the energy profile for the SET from both KO either of the two alkoxides to a molecule of CCl4 (see Supplementary Materials). The energy barriers tBu and potassium 2-phenylpropan-2-olate 14kcal/mol to CBr4 in 1) [33]. Our calculations calculated were ΔGǂ = 42.5 anddichloromethane 44.5 kcal/mol for(Figure SET to CCl 4 from KOprevious 2had been based on the 14, classical Nelsen four-point method [34], but, since that time, weCCl published a phenylpropan-2-olate respectively. These barriers for reactions of both CBr4 and 4 are not more accurate complexation method [33] for predicting the activation free energy and the relative accessible for a reaction performed at 40 °C, even as an initiation step. These computationally derived free energy of reactions. (The calculations were using M06-2X functional [35,36] with energy profiles for the SET step indicate that theconducted initiation for thisthe halogenation of adamantane 18 is the basis set [37–41] on allalternative atoms, except for the bromine. Bromine was modeledofwith not 6-311++G(d,p) via SET from the alkoxide; the likely radical pathway arises through homolysis the the MWB28 relativistic pseudo-potential and associated basis set [42]. All calculations were carried hypohalite intermediate [19]. (Importantly, our computation predicts a barrierless, but endergonic, out using C-PCM implicit solvent model [43,44] with with ΔG therxn dielectric constant for profile forthe homolysis of the O–Br bond in tBuO–Br = +27.6 kcal/mol [34].dichloromethane This is a highly t (ε = 8.93) or carbon tetrachloride (ε = 2.228) as appropriate. All calculations were performed endergonic reaction, but as it is simply an initiation step, few BuO–Br molecules are required in to Gaussian09 [45]). undergo homolysis).
Figure 1. Computational modelling of SET from alkoxides, KOtBu and potassium 2-phenylpropan-2Figure 1. Computational modelling of SET from alkoxides, KOt Bu and potassium 2-phenylpropan-2olate 14 to CBr4 in dichloromethane. olate 14 to CBr4 in dichloromethane.
The energy barriers for SET from either KOt Bu or potassium 2-phenylpropan-2-olate 14, to a molecule of CBr4 were calculated to be ∆G} = +35.4 kcal/mol and +36.1 kcal/mol, respectively (while the corresponding ∆Grxn values were +13.9 and +18.9 kcal/mol) (Figure 1). When the energy barrier was calculated for the reactions with CCl4 , a similar energy profile was obtained for the SET from either of the two alkoxides to a molecule of CCl4 (see Supplementary Materials). The energy barriers calculated were ∆G} = 42.5 kcal/mol and 44.5 kcal/mol for SET to CCl4 from KOt Bu and potassium 2-phenylpropan-2-olate 14, respectively. These barriers for reactions of both CBr4 and CCl4 are not accessible for a reaction performed at 40 ◦ C, even as an initiation step. These computationally derived
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energy profiles for the SET step indicate that the initiation for this halogenation of adamantane 18 is not via SET from the alkoxide; the likely alternative radical pathway arises through homolysis of the hypohalite intermediate [19]. (Importantly, our computation predicts a barrierless, but endergonic, profile for homolysis of the O–Br bond in t BuO–Br with ∆Grxn = +27.6 kcal/mol [34]. This is a highly endergonic reaction, but as it is simply an initiation step, few t BuO–Br molecules are required to undergo homolysis). 3. Experimental Section 3.1. Computational Methods The calculations were run using the M06-2X functional [35,36] with the 6-311++G(d,p) basis set [37–41] on all atoms except bromine. Bromine was modeled with the MWB28 relativistic pseudo-potential and associated basis set [42]. All calculations were carried out using the C-PCM implicit solvent model [43,44] as implemented in Gaussian09 [45]. 3.2. General Experimental Information All reagents were bought from commercial suppliers and used without further purification unless stated otherwise. All the reactions were carried out under argon atmosphere. Diethyl ether, tetrahydrofuran, dichloromethane and hexane were dried with a Pure-Solv 400 solvent purification system, marketed by Innovative Technology Inc. (Herndon, VA, USA). Organic extracts were, in general, dried over anhydrous sodium sulfate (Na2 SO4 ). A Büchi rotary evaporator was used to concentrate the reaction mixtures. Thin layer chromatography (TLC) was performed using aluminium-backed sheets of silica gel and visualized under a UV lamp (254 nm). The plates were developed using phosphomolybdic acid or KMnO4 solution. Column chromatography was performed to purify compounds by using silica gel 60 (200–400 mesh). The electron transfer reactions were carried out within a glove box (Innovative Technology Inc.) under nitrogen atmosphere, and performed in an oven-dried or flame-dried apparatus using anhydrous solvents, which were degassed under reduced pressure, then purged with argon and dried over activated molecular sieves (3 Å), prior to being sealed and transferred to the glovebox. All solvent or samples placed into the glovebox were transferred through the port, which was evacuated and purged with nitrogen 10 times before entry. When the reaction mixtures were prepared, the reaction vessel was removed from the glove box and the rest of the reaction was performed in a fumehood. Proton (1 H) NMR spectra were recorded at 400.13, 400.03 and 500.16 MHz on Bruker AV3, AV400 and AV500 spectrometers, respectively. Carbon (13 C) NMR spectra were recorded using broadband decoupled mode at 100.61, 100.59 and 125.75 MHz on Bruker AV3, AV400 and AV500 spectrometers, respectively. Spectra were recorded in either deuterated chloroform (CDCl3 ) or deuterated dimethyl sulfoxide (d6 -DMSO), depending on the solubility of the compounds. The chemical shifts are reported in parts per million (ppm), calibrated on the residual non-deuterated solvent signal, and the coupling constants, J, are reported in Hertz (Hz). The peak multiplicities are denoted using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; sx, sextet; m, multiplet; br s, broad singlet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets. Infrared spectra were recorded on an ATR-IR spectrometer. Melting points were determined on a Gallenkamp melting point apparatus. The mass spectra were recorded by either gas-phase chromatography (GCMS) or liquid-phase chromatography (LCMS), using various ionization techniques, as stated for each compound: atmospheric pressure chemical ionization (APCI), electron ionization (EI), electrospray ionization (ESI). GCMS data were recorded using an Agilent Technologies 7890A GC system coupled to a 5975C inert XL EI/CI MSD detector. Separation was performed using the DB5MS-UI column (30 m × 0.25 mm × 0.25 µm) at a temperature of 320 ◦ C, using helium as the carrier gas. LCMS data were recorded using an Agilent 6130 Dual source mass spectrometer with Agilent 1200, Agilent Poroshell 120ECC 4.6 mm × 75 mm × 2.7 um column.
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High-resolution mass spectrometry (HRMS) was performed at the University of Wales, Swansea, in the EPSRC National Mass Spectrometry Centre. Accurate mass was obtained using atmospheric pressure chemical ionization (APCI), chemical ionization (CI), electron ionization (EI), electrospray ionization (ESI) or nanospray ionization (NSI) with a LTQ Orbitrap XL mass spectrometer. 3.3. Synthesis of Alkoxide, Potassium 2-Phenylpropan-2-Olate 14 Potassium hydride (586 mg, 15 mmol, 1.0 eq.) was added to a flame-dried three-necked flask, equipped with a vacuum tap. Under an argon atmosphere, at −78 ◦ C, a solution of 2-phenylpropanol 15 (2.04 g, 15 mmol) in anhydrous diethyl ether (20 mL), as added and the reaction mixture, was stirred at −78 ◦ C for 1 h, then at RT overnight. The solvent was removed under vacuum and the crude material was dried for 1 h to obtain potassium 2-phenylpropan-2-olate 14 (2.46 g, 14.1 mmol, 93%) as an off-white solid m.p. 128–132 ◦ C; (Found: (GCMS-EI) C9 H11 O (M-K) 135.08); νmax (film)/cm−1 3503, 2972, 1663, 1444, 1433, 1236, 1161, 1067, 1029, 955, 881, 861, 764; 1 H-NMR (400 MHz, d6 -DMSO) δ 1.41 (6 H, s, 2 × CH3 ), 7.15–7.19 (1 H, m, ArH), 7.26–7.30 (2 H, m, ArH), 7.45–7.47 (2 H, m, ArH); 13 C-NMR (100 MHz, d6 -DMSO) δ 31.9 (2 × CH3 ), 70.5 (C), 124.4 (2 × CH), 125.8 (CH), 127.7 (2 × CH), 150.5 (C). The product was put under an argon atmosphere and transported into the glovebox immediately. 3.4. Blank Reaction (No KOt Bu) of CBr4 with Adamantane 18 Adamantane 18 (68 mg, 0.5 mmol), CBr4 (166 mg, 0.5 mmol, 1.0 eq.) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. 1 H-NMR (400 MHz, CDCl3 ) δ 1.76–1.75 (12 H, m, CH2 ), 1.88 (4 H, br s, CH); 13 C-NMR (100 MHz, CDCl3 ) δ 28.5 (6 × CH2 ), 37.9 (4 × CH). (The yield of adamantane 18 [46] (93%) was determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR). These signals are consistent with the literature values and reference samples. 3.5. Reactions of Potassium 2-Phenylpropan-2-Olate 14 with Adamantane 18 and CBr4 /CCl4 3.5.1. Table 1, Entry 1 Potassium 2-phenylpropan-2-olate 14 (349 mg, 2 mmol, 4.0 eq.), adamantane 18 (68 mg, 0.5 mmol), CBr4 (166 mg, 0.5 mmol, 1.0 eq.) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube, and the reaction mixture was stirred at 40 ◦ C for 90 h. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of 2-phenylpropanol 15 (66%), (2,2-dibromo-1-methylcyclopropyl)-benzene 16 (33%), methylstyrene 17 (18%), adamantane 18 (91%) and (2,2-dichloro-1-methylcyclopropyl)benzene 19 (17%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.60 (6 H, s) for 2-phenylpropanol 15; δ 1.72 (3 H, s), 1.78 (1 H, d, J = 7.6 Hz), 2.17 (1 H, d, J = 7.6 Hz) for (2,2-dibromo-1-methylcyclopropyl)benzene 16; δ 2.16 (3 H, s), 5.09 (1 H, s), 5.37 (1 H, s) for methylstyrene 17; δ 1.75–1.77 (12 H, m), 1.88 (4 H, br s) for adamantane 18; δ 1.68 (3 H, s), 1.96 (1 H, d, J = 7.2 Hz) for (2,2-dichloro-1-methylcyclopropyl)benzene 19; 13 C-NMR (100 MHz, CDCl3 ) δ 31.9, 72.7, 124.5, 126.8, 128.4 for 2-phenylpropanol 15; δ 27.9, 33.9, 128.5, 128.6 for (2,2-dibromo-1-methylcyclopropyl)-benzene 16; δ 22.0, 112.5 for methylstyrene 17; δ 28.5, 37.9 for adamantane 18; δ 25.7, 36.6 for (2,2-dichloro-1-methylcyclo-propyl)benzene 19. These signals are consistent with the literature values and reference samples. The compounds 16 and 19 were inseparable, so pure samples of 16 and 19 were prepared for comparison- see below.
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3.5.2. Preparation of 16 KOt Bu 29 (224 mg, 2 mmol, 4.0 eq.), HCBr3 (0.04 mL, 0.5 mmol, 1.0 eq.) and methylstyrene 17 (0.07 mL, 0.5 mmol) were added to an oven-dried pressure tube. Dichloromethane (3.13 mL) was added and the reaction mixture was stirred at 40 ◦ C for 90 h. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The crude material was purified by column chromatography (100% hexane) to give (2,2-dibromo-1-methylcyclopropyl)benzene 16 [18] (82.4 mg, 57%) as a colorless oil [Found: (GCMS-CI) C10 H11 Br2 + (M + H)+ 288.7]; νmax (film)/cm−1 1496, 1445, 1426, 1060, 1019, 763, 691; 1 H-NMR (400 MHz, CDCl3 ) δ 1.72 (3 H, s, CH3 ), 1.78 (1 H, d, J = 7.6 Hz, CH2 ), 2.17 (1 H, d, J = 7.6 Hz, CH2 ), 7.29–7.38 (5 H, m, ArH); 13 C{1 H}-NMR (100 MHz, CDCl3 ) δ 27.9 (CH3 ), 33.8 (CH2 ), 35.9 (C), 36.9 (C), 127.4 (CH), 128.5 (2 × CH), 128.6 (2 × CH), 142.5 (C); m/z (CI) 292.6 [(M + H)+ , 81 Br81 Br, 61%), 290.6 [(M + H)+ , 79 Br81 Br, 100), 288.7 [(M + H)+ , 79 Br79 Br, 70)]. 3.5.3. Preparation of 19 KOt Bu 29 (224 mg, 2 mmol, 4.0 eq.), HCCl3 (0.04 mL, 0.5 mmol, 1.0 eq.) and methylstyrene 17 (0.07 mL, 0.5 mmol) were added to an oven-dried pressure tube. Dichloromethane (3.13 mL) was added and the reaction mixture was stirred at 40 ◦ C for 90 h. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The crude material was purified by column chromatography (100% hexane) to give (2,2-dichloro-1-methylcyclopropyl)benzene 19 [18] (63.7 mg, 63%) as a colorless oil [Found: (HRMS-EI) 200.0157. C10 H10 Cl2 (M)•+ requires 200.0160]; νmax (film)/cm−1 1497, 1446, 1425, 1075, 1033, 1026, 936, 868, 772, 754, 697, 595; 1 H-NMR (400 MHz, CDCl3 ) δ 1.60 (1 H, d, J = 7.2 Hz, CH2 ), 1.68 (3 H, s, CH3 ), 1.96 (1 H, d, J = 7.2 Hz, CH2 ), 7.27–7.38 (5 H, m, ArH); 13 C-NMR (100 MHz, CDCl3 ) δ 25.7 (CH3 ), 32.0 (CH2 ), 36.6 (C), 66.0 (C), 127.4 (CH), 128.6 (2 × CH), 128.7 (2 × CH), 141.4 (C); m/z (CI) 203.9 ((M)•+ , 37 Cl37 Cl, 12%), 201.9 ((M)•+ , 35 Cl37 Cl, 70), 199.9 ((M)•+ , 35 Cl35 Cl, 100). 3.5.4. Table 1, Entry 2 Potassium 2-phenylpropan-2-olate 14 (349 mg, 2 mmol, 4.0 eq.), adamantane 18 (68 mg, 0.5 mmol), CCl4 (0.05 mL, 0.5 mmol, 1.0 eq.) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of 2-phenylpropanol 15 (67%), methylstyrene 17 (3%), adamantane 18 (76%), (2,2-dichloro-1-methylcyclopropyl)benzene 19 (50%) and bis((2-phenylpropan-2-yl)oxy)-methane 20 (3%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.60 (6 H, s) for 2-phenylpropanol 15; δ 2.17 (3 H, s), 5.10 (1 H, s), 5.38 (1 H, s) for methylstyrene 17; δ 1.76–1.78 (12 H, m), 1.89 (4 H, br s) for adamantane 18; δ 1.68 (3 H, s), 1.97 (1 H, d, J = 7.2 Hz) for (2,2-dichloro-1-methylcyclopropyl)benzene 19; δ 4.51 (2 H, s), 7.20–7.24 (2 H, m) for bis((2-phenylpropan-2-yl)oxy)methane 20; 13 C-NMR (100 MHz, CDCl3 ) δ 31.9, 72.7, 124.5, 126.8, 128.4 for 2-phenylpropanol 15; δ 22.0, 112.6 for methylstyrene 17; δ 28.5, 37.9 for adamantane 18; δ 25.6, 36.6 for (2,2-dichloro-1-methylcyclopropyl)benzene 19. These signals are consistent with the literature values and reference samples. 3.5.5. Table 1, Entry 3 Potassium 2-phenylpropan-2-olate 14 (349 mg, 2 mmol, 4.0 eq.), adamantane 18 (68 mg, 0.5 mmol) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture
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was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of 2-phenylpropanol 15 (39%), methylstyrene 17 (1%), adamantane 18 (84%) and bis((2-phenylpropan-2-yl)oxy)methane 20 (52%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.60 (6 H, s) for 2-phenylpropanol 15; δ 2.16 (3 H, s), 5.09 (1 H, s), 5.37 (1 H, s) for methylstyrene 17; δ 1.75–1.77 (12 H, m), 1.88 (4 H, br s) for adamantane 18; δ 4.51 (2 H, s), 7.20–7.24 (2 H, m) for bis((2-phenylpropan-2-yl)oxy)methane 20; 13 C-NMR (100 MHz, CDCl3 ) δ 31.9, 72.7, 124.5, 149.2 for 2-phenyl-2-propanol 15; δ 28.5, 37.9 for adamantane 18; δ 29.5, 77.7, 86.8, 146.9 for bis((2-phenylpropan-2-yl)oxy)methane 20. These signals are consistent with the literature values and reference samples. This crude material was purified by column chromatography (0–5% ethyl acetate in hexane) to give bis((2-phenylpropan-2-yl)oxy)methane 20 (44.7 mg, 26%) as a colorless oil (Found: (HRMS-ESI) 302.2118. C19 H28 O2 N (M + NH4 )+ requires 302.2115); νmax (film)/cm−1 2978, 2934, 1493, 1447, 1381, 1364, 1258, 1153, 1072, 1018, 991, 818, 762; 1 H-NMR (400 MHz, CDCl3 ) δ 1.59 (12 H, s, 4 × CH3 ), 4.50 (2 H, s, CH2 ), 7.20–7.23 (2 H, m, ArH), 7.27–7.31 (4 H, m, ArH), 7.38–7.40 (4 H, m, ArH); 13 C-NMR (100 MHz, CDCl3 ) δ 29.5 (4 × CH3 ), 77.7 (2 × C), 86.8 (CH2 ), 125.9 (4 × CH), 126.9 (2 × CH), 128.2 (4 × CH), 146.9 (2 × C). 3.6. Reaction of KOt Bu in Dichloromethane KOt Bu 29 (224 mg, 2 mmol, 4.0 eq.), CBr4 (166 mg, 0.5 mmol, 1.0 eq.), adamantane 18 (68 mg, 0.5 mmol) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The ratio of adamantane 18:1-bromoadamantane 31:2-bromoadamant-ane 51 was determined to be 39:3.3:1 from the 1 H-NMR spectrum of the crude mixture. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl ) δ 1.74–1.76 (12 H, m, CH × 6), 1.88 (4 H, br s, CH × 4) for adamantane 3 2 18; δ 1.73 (6 H, m, CH2 × 3), 2.10 (3 H, br s, CH × 3), 2.36 (6 H, m, CH2 × 3) for 1-bromoadamantane 31 [47]; δ 1.96–2.00 (2 H, m, CH2 ), 2.15 (2 H, br s, CH × 2), 2.33 (2 H, br s, CH × 2), 4.68 (1 H, br s, CH) for 2-bromoadamantane 51 [48]; 13 C-NMR (100 MHz, CDCl3 ) δ 28.5, 37.9 adamantane 18; δ 32.8, 35.7, 49.5 for 1-bromoadamantane 31; 36.6, 39.1 for 2-bromoadamantane 51. These signals are consistent with the literature values and reference samples. 3.7. Reactions of Adamantane 18 with CBr4 , Methylstyrene 17 and KOt Bu 29 (Scheme 5) KOt Bu 29 (224 mg, 2 mmol, 4.0 eq.), CBr4 (166 mg, 0.5 mmol, 1.0 eq.), methylstyrene 17 (0.07 mL, 0.5 mmol, 1.0 eq.), adamantane 18 (68 mg, 0.5 mmol) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of (2,2-dibromo-1-methylcyclopropyl)benzene 16 (59%), methylstyrene 17 (3%), adamantane 18 (75%) and (2,2-dichloro-1-methylcyclopropyl)benzene 19 (40%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.72 (3 H, s), 1.78 (1 H, d, J = 7.6 Hz) for (2,2-dibromo-1-methylcyclopropyl)benzene 16; δ 5.09 (1 H, s), 5.37 (1 H, s) for methylstyrene 17; δ 1.75–1.78 (12 H, m), 1.88 (4 H, br s) for adamantane 18; δ 1.60 (1 H, d, J = 7.2 Hz), 1.69 (3 H, s), 1.97 (1 H, d, J = 7.2 Hz) for (2,2-dichloro-1-methylcyclopropyl)benzene 19; 13 C-NMR (100 MHz, CDCl3 ) δ 27.9, 33.9, 36.9, 142.5 for (2,2-dibromo-1-methylcyclopropyl)benzene 16; δ 28.5, 37.9 for adamantane 18; δ 25.7, 32.0, 36.6, 141.4 for (2,2-dichloro-1-methylcyclopropyl)benzene 19. These signals are consistent with the literature values and reference samples [49,50].
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3.8. Synthesis of Alkoxide, Potassium Triphenylmethanolate 30 Potassium hydride (802 mg, 20 mmol, 1.0 eq.) was added to a flame-dried three-necked flask, equipped with a vacuum tap. Under an argon atmosphere, at –78 ◦ C, a solution of triphenylmethanol 32 (5.21 g, 20 mmol) in anhydrous tetrahydrofuran (25 mL) was added and the reaction mixture was stirred at −78 ◦ C for 1 h, then at RT overnight. The solvent was removed on the house vacuum line and the crude material was dried for 1 h to give potassium triphenylmethanolate 30 (5.07 g, 17 mmol, 85%) as an off-white solid, m.p. 238 ◦ C (dec.); (Found: (GCMS-EI) C19 H16 O (M)•+ 260.1 (under the MS analysis 30 is protonated to the alcohol)); νmax (film)/cm−1 3057, 3022, 1595, 1487, 1443, 1414, 1329, 1155, 1053, 1009, 891, 756; 1 H-NMR (400 MHz, d6 -DMSO) δ 6.93–6.98 (3 H, m, ArH), 7.04–7.08 (6 H, m, ArH), 7.34–7.37 (6 H, m, ArH); 13 C-NMR (100 MHz, d6 -DMSO) δ 84.7 (C), 123.6 (3 × CH), 126.0 (6 × CH), 128.2 (6 × CH), 157.6 (3 × C). The product was put under an argon atmosphere and transported into the glove box immediately. 3.9. Reactions of Potassium Triphenylmethanolate 30 at 40 ◦ C 3.9.1. Table 2, Entry 1 Potassium triphenylmethanolate 30 (597 mg, 2 mmol, 4.0 eq.), CBr4 (166 mg, 0.5 mmol, 1.0 eq.), adamantane 18 (68 mg, 0.5 mmol) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of adamantane 18 (49%), 1-bromoadamantane 31 (7%), triphenylmethanol 32 (88%), benzophenone 33 (5%) and 4-benzhydrylphenol 34 (12%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.75–1.78 (12 H, m), 1.88 (4 H, br s) for adamantane 18; δ 1.74 (6 H, m), 2.12 (3 H, br s), 2.38 (6 H, m) for 1-bromoadamantane 31 [47]; δ 7.27–7.34 (15 H, m) for triphenylmethanol 32; δ 7.49 (4 H, d, J = 8.0 Hz), 7.60 (2 H, d, J = 8.0 Hz), 7.82 (4 H, d, J = 8.0 Hz) for benzophenone 33 [51]; δ 5.49 (1 H, s), 6.73–6.77 (2 H, m), 6.97–7.00 (2 H, m) for 4-benzhydrylphenol 34 [52]; 13 C-NMR (100 MHz, CDCl3 ) δ 28.3, 37.7 for adamantane 18; δ 49.3, 35.5, 32.6 for 1-bromoadamantane 31; δ 82.2, 127.4, 128.0, 147.0 for triphenylmethanol 32; δ 56.1, 115.3, 144.3 for 4-benzhydroxylphenol 34. These signals are consistent with the literature values and reference samples. This crude material was purified by column chromatography (0%–10% ethyl acetate in hexane) to give both benzophen-one 33 [51] (7 mg, 4%) as a yellow oil (Found: (GCMS-EI) C13 H10 O (M)•+ 182.0); νmax (film)/cm−1 3057, 1655, 1597, 1445, 1275, 1175, 939, 918, 808, 762; 1 H-NMR (400 MHz, CDCl3 ) δ 7.49 (4 H, t, J = 8.0 Hz, ArH), 7.60 (2 H, t, J = 8.0 Hz, ArH), 7.82 (4 H, d, J = 8.0 Hz, ArH); 13 C-NMR (100 MHz, CDCl3 ) δ 128.2 (4 × CH), 130.2 (4 × CH), 132.6 (2 × CH), 137.5 (2 × C), 196.7 (C) and 4-benzhydrylphenol 34 [52] (18.9 mg, 7%) as a yellow oil (Found: (GCMS-EI) C19 H16 O (M)•+ 260.1); νmax (film)/cm−1 3366, 2361, 2336, 1595, 1508, 1491, 1449, 1238, 1173, 1103, 1030, 816, 800, 750, 735; 1 H-NMR (400 MHz, CDCl3 ) δ 4.82 (1 H, br s, OH), 5.49 (1 H, s, CH), 6.73–6.77 (2 H, m, ArH), 6.97–7.00 (2 H, m, ArH), 7.11–7.13 (4 H, m, ArH), 7.19–7.32 (6 H, m, ArH); 13 C-NMR (100 MHz, CDCl3 ) δ 56.1 (CH), 115.3 (2 × CH), 126.4 (2 × CH), 128.4 (4 × CH), 129.5 (4 × CH), 130.7 (2 × CH), 136.4 (C), 144.3 (2 × C), 154.1 (C). Triphenylmethanol 32 1 H-NMR (400 MHz, CDCl3 ) δ 2.79 (1 H, s, OH), 7.26–7.34 (15 H, m, ArH), 7.57 (2 H, d, J = 8.4 Hz, ArH); 13 C-NMR (100 MHz, CDCl3 ) δ 82.2 (C), 127.4 (CH), 128.1 (6 × CH), 147.0 (9 × C). These signals are consistent with a commercial sample used as a reference. 3.9.2. Table 2, Entry 2 Potassium triphenylmethanolate 30 (597 mg, 2 mmol, 4.0 eq.), adamantane 18 (68 mg, 0.5 mmol) and dichloromethane (3.13 mL) were added to an oven-dried pressure tube and the reaction mixture was stirred at 40 ◦ C for 90 h in the dark. The reaction mixture was cooled to RT and quenched with
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aqueous hydrochloric acid (1 M, 5 mL) and extracted with diethyl ether (4 × 10 mL). The organic phases were combined, dried over Na2 SO4 , filtered and concentrated in vacuo. The yield of adamantane 18 (87%), triphenylmethanol 32 (81%) and benzophenone 33 (1%) were determined by adding 1,3,5-trimethoxybenzene to the crude mixture as an internal standard for 1 H-NMR. The products were identified by the following characteristic signals; 1 H-NMR (400 MHz, CDCl3 ) δ 1.75–1.78 (12 H, m), 1.882018, (4 H,23,brx FOR s) for adamantane 18; δ 7.27–7.34 (15 H, m) for triphenylmethanol 32, δ 7.49 (4 d, Molecules PEER REVIEW 13 H, of 16 J = 8.0 Hz, ArH), 7.60 (2 H, d, J = 8.0 Hz, ArH), 7.82 (4 H, d, J = 8.0 Hz, ArH) for benzophenone 33; 13 C-NMR (100 MHz, CDCl ) δ 28.3, 37.7 for adamantane 18; δ 82.2, 127.4, 128.0, 147.0 triphenylmethanol 147.0 triphenylmethanol 32 3 [49]. These signals are consistent with the literature values and reference 32 [49]. These signals are consistent with the literature values and reference samples. samples. 4. Conclusions 4. Conclusions This This study study has has led led to to aa revision revision of of earlier earlier thoughts thoughts on on the the mechanism mechanism for for the the halogenation halogenation of of t Bu and CBr . It is proposed that the mechanism does adamantane 18 by using a combination of KO t 4 adamantane 18 by using a combination of KO Bu and CBr . It is proposed that the mechanism does not occur through through SET, SET, as was previously previously believed, believed, but but proceeds proceeds through through hypobromite hypobromite intermediates intermediates not occur as was (Scheme The alkoxide alkoxide in in the the reaction reaction mixture, mixture, 53, 53, forms forms aa hypobromite hypobromite in in the the presence of CBr (Scheme 7). 7). The presence of CBr44.. The hypobromite 54 can undergo reaction along two pathways. The first option is an elimination The hypobromite 54 can undergo reaction along two pathways. The first option is an elimination reaction alkene 57,57, which reacts withwith carbenes formed in the in reaction to afford product reaction to toform formthe the alkene which reacts carbenes formed the reaction tofinal afford final 58. The second pathway is the O–Br bond homolysis of the hypobromite 54. This forms the alkoxyl product 58. The second pathway is the O–Br bond homolysis of the hypobromite 54. This forms the radical and a 55 bromine radical intermediates perform a hydrogen abstraction alkoxyl 55 radical and a radical. bromineThese radical. These radical intermediates perform aatom hydrogen atom from adamantane 18 to form adamantyl radical 56 (alternatively, the hydrogen atom abstraction may abstraction from adamantane 18 to form adamantyl radical 56 (alternatively, the hydrogen atom occur at the C-2 position to ultimately give the 2-Br isomer). The radical 56 will abstract a bromine abstraction may occur at the C-2 position to ultimately give the 2-Br isomer). The radical 56 will from a hypobromite molecule 54, or from CBr4 , to54, form 31 and an4,alkoxyl CBr3 radical. abstract a bromine from a hypobromite molecule or from CBr to formradical 31 and55, an or alkoxyl radical The radical formed will propagate the chain pathway by hydrogen atom abstraction from adamantane 55, or CBr3 radical. The radical formed will propagate the chain pathway by hydrogen atom 18, thus creating a radical chain it appears that the search reactionsthat where abstraction from adamantane 18, mechanism. thus creating Thus, a radical chain mechanism. Thus,for it appears the t ground-state KO Bu where behavesground-state as an electron donor must continue. The outcomes of thiscontinue. project have tBu behaves search for reactions KO as an electron donor must The led us to reexamine the remaining claims [3,4] of this outcomes of this project have led us to reexamine thephenomenon. remaining claims [5,6] of this phenomenon.
Scheme for halogenation halogenation of of adamantane. adamantane. Scheme 7. 7. The The modified modified mechanism mechanism for Supplementary Materials: The following are available online, (i)Additional computational analysis and xyz coordinates relating to all computed structures (ii) Table S1 “The reaction of tert-butyl hypochlorite 46 in Supplementary Materials: The following are available online, (i)Additional computational analysis and xyz dichloromethane or carbon tetrachloride as solvent” Table tert-Butyl in bromination of coordinates relating to all computed structures (ii) (iii) Table S1 S2. “The reactionhypobromite of tert-butyl50hypochlorite 46 in adamantane 18; (iv) procesdures and spectroscopid in support of the experiments discussed dichloromethane or Experimental carbon tetrachloride as solvent” (iii) Table S2.data tert-Butyl hypobromite 50 in bromination of adamantane 18; (v) (iv)NMR Experimental and spectroscopid data in support of the experiments discussed in in those Tables spectra ofprocesdures key products. those Tables (v) NMR spectra of key products. Author Contributions: K.J.E., A.Y., J.N.A., T.T., J.A.M. conceived and designed the experiments; K.J.E., A.Y., Author Contributions: K.J.E., A.Y., J.N.A., T.T., J.A.M. conceived and designed the experiments; K.J.E., A.Y., J.N.A. J.N.A. performed the experiments, K.J.E., A.Y., J.N.A., T.T., J.A.M. analyzed the data, K.J.E., T.T., J.A.M. wrote performed the experiments, K.J.E., A.Y., J.N.A., T.T., J.A.M. analyzed the data, K.J.E., T.T., J.A.M. wrote the paper. the paper Acknowledgments: We thank the EPSRC and University of Strathclyde for the funding. Grant Number: Acknowledgments: We thank University Strathclyde Service for the Centre, funding.Swansea, Grant Number: EP/L505080/1. Further thanksthe to EPSRC EPSRC and National Mass of Spectrometry for the high-resolution mass spectra EP/L505080/1. Further thanksresults. to EPSRC National Mass Spectrometry Service Centre, Swansea, for the highresolutionofmass spectra results. Conflicts Interest: There are no conflicts to declare. Conflicts of Interest: There are no conflicts to declare.
References 1.
Schreiner, P.R.; Lauenstein, O.; Kolomitsyn, I.V.; Nadi, S.; Fokin, A.A. Selective C-H Activation of Aliphatic Hydrocarbons under Phase-Transfer Conditions. Angew. Chem. Int. Ed. 1998, 37, 1895−1897.
Molecules 2018, 23, 1055
14 of 16
References 1.
2.
3.
4. 5. 6.
7.
8.
9. 10. 11.
12.
13.
14. 15. 16. 17.
18.
19.
Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Potassiumt-Butoxide Alone Can Promote the Biaryl Coupling of Electron-Deficient Nitrogen Heterocycles and Haloarenes. Org. Lett. 2008, 10, 4673–4676. [CrossRef] [PubMed] Sun, C.L.; Li, H.; Yu, D.G.; Yu, M.; Zhou, X.; Lu, X.Y.; Huang, K.; Zheng, S.F.; Li, B.J.; Shi, Z.J. An efficient organocatalytic method for constructing biaryls through aromatic C–H activation. Nat. Chem. 2010, 2, 1044–1049. [CrossRef] [PubMed] Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. tert-Butoxide-mediated arylation of benzene with aryl halides in the presence of a catalytic 1, 10-phenanthroline derivative. J. Am. Chem. Soc. 2010, 132, 15537–15539. [CrossRef] [PubMed] Studer, A.; Curran, D.P. Organocatalysis and C-H Activation Meet Radical- and Electron-Transfer Reactions. Angew. Chem. Int. Ed. 2011, 50, 5018–5022. [CrossRef] [PubMed] Ashby, E.C.; Argyropoulos, J.N. Single electron transfer in the Meerwein-Ponndorf-Verley reduction of benzophenone by lithium alkoxides. J. Org. Chem. 1986, 51, 3593–3597. [CrossRef] Ashby, E.C.; Goel, A.B.; DePriest, R.N. Evidence for single electron transfer in the reations of alkali metal amides and alkoxides with alkyl halides and polynuclear hydrocarbons. J. Org. Chem. 1981, 46, 2429–2431. [CrossRef] Cuthbertson, J.; Gray, V.J.; Wilden, J.D. Observations on transition metal free biaryl coupling: Potassium tert-butoxide alone promotes the reaction without diamine or phenanthroline catalysts. Chem. Commun. 2014, 50, 2575–2578. [CrossRef] [PubMed] Yi, H.; Jutand, A.; Lei, A. Evidence for the interaction between tBuOK and 1,10-phenanthroline to form the 1,10-phenanthroline radical anion: A key step for the activation of aryl bromides by electron transfer. Chem. Commun. 2015, 51, 545–548. [CrossRef] [PubMed] Dai, P.; Ma, J.; Huang, W.; Chen, W.; Wu, N.; Wu, S.; Li, Y.; Cheng, X.; Tan, R.G. Photoredox C–F Quaternary Annulation Catalyzed by a Strongly Reducing Iridium Species. ACS Catal. 2018, 8, 802–806. [CrossRef] Gao, L.; Wang, L.; Gong, M.G.; Wang, W.; Yuan, R. Visible Light Photoredox Catalyzed Biaryl Synthesis Using Nitrogen Heterocycles as Promoter. ACS Catal. 2015, 5, 45–50. Ahmed, J.; Sreejyothi, P.; Vijaykumar, G.; Jose, A.; Raj, M.; Mandal, S.K. A new face of phenalenyl-based radicals in the transition metal-free C–H arylation of heteroarenes at room temperature: Trapping the radical initiator via C–C σ-bond formation. Chem. Sci. 2017, 8, 7798–7806. [CrossRef] [PubMed] Zhou, S.; Anderson, G.M.; Mondal, B.; Doni, E.; Ironmonger, V.; Kranz, M.; Tuttle, T.; Murphy, J.A. Organic super-electron-donors: Initiators in transition metal-free haloarene-arene coupling. Chem. Sci. 2014, 5, 476–482. [CrossRef] Zhou, S.; Doni, E.; Anderson, G.M.; Kane, R.G.; MacDougall, S.W.; Ironmonger, V.M.; Tuttle, T.; Murphy, J.A. Identifying the Roles of Amino Acids, Alcohols and 1,2-Diamines as Mediators in Coupling of Haloarenes to Arenes. J. Am. Chem. Soc. 2014, 136, 17818–17826. [CrossRef] [PubMed] Patil, M. Mechanistic Insights into the Initiation Step of the Base Promoted Direct C-H Arylation of Benzene in the Presence of Additive. J. Org. Chem. 2016, 81, 632–639. [CrossRef] [PubMed] Schreiner, P.R.; Lauenstein, O.; Kolomitsyn, I.V.; Nadi, S.; Fokin, A.A. Selective C-H Activation of Aliphatic Hydrocarbons under Phase-Transfer Conditions. Angew. Chem. Int. Ed. 1998, 37, 1895–1897. [CrossRef] Fokin, A.A.; Schreiner, P.R. Metal-Free, Selective Alkane Functionalizations. Adv. Synth. Catal. 2003, 345, 1035–1052. [CrossRef] Barham, J.P.; Coulthard, G.; Emery, K.J.; Doni, E.; Cumine, F.; Nocera, G.; John, M.P.; Berlouis, L.E.A.; McGuire, T.; Tuttle, T.; et al. KOtBu: A Privileged Reagent for Electron Transfer Reactions? J. Am. Chem. Soc. 2016, 138, 7402–7410. [CrossRef] [PubMed] Murayama, E.; Kohda, A.; Sato, T. Metal-catalysed organic photoreactions. Evidence for the long-range electron-transfer mechanism in the uranyl- or iron(III)-catalysed photoreactions of olefins. J. Chem. Soc. Perkin Trans. 1980, 1, 947–949. [CrossRef] Nishina, Y.; Ohtani, B.; Kikushima, K. Bromination of hydrocarbons with CBr4 , initiated by light-emitting diode irradiation. Beilstein J. Org. Chem. 2013, 9, 1663–1667. [CrossRef] [PubMed]
Molecules 2018, 23, 1055
20.
21. 22. 23.
24. 25. 26. 27. 28.
29. 30. 31.
32.
33. 34. 35.
36. 37. 38. 39. 40. 41.
42.
15 of 16
Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. Metathesis Reaction of Formaldehyde Acetals: An Easy Entry into the Dynamic Covalent Chemistry of Cyclophane Formation. J. Am. Chem. Soc. 2005, 127, 13666–13671. [CrossRef] [PubMed] Montoro, R.; Wirth, T. Direct Bromination and Iodination of Non-Activated Alkanes by Hypohalite Reagents. Synthesis 2005, 1473–1478. [CrossRef] Walling, C.; Jacknow, B.B. Positive Halogen Compounds. I. The Radical Chain Halogenation of Hydrocarbons by t-Butyl Hypochlorite1. J. Am. Chem. Soc. 1960, 82, 6108–6112. [CrossRef] Cornélis, A.; Laszlo, P. Clay-Supported Reagents; II1. Quaternary Ammonium-Exchanged Montmorillonite as Catalyst in the Phase-Transfer Preparation of Symmetrical Formaldehyde Acetals. Synthesis 1982, 1982, 162–163. [CrossRef] Dehmlow, E.V.; Schmidt, J. Anwendungen der phasen-transfer-katalyse 2.: Diaryloxymethane und formaldehydacetale. Tetrahedron Lett. 1976, 17, 95–96. [CrossRef] Swan, G.A. 286. The fission of non-enolisable ketones by potassium tert.-butoxide. J. Chem. Soc. 1948, 1408–1412. [CrossRef] Lea, T.R.; Robinson, R. CCCXIII.—The fission of some methoxylated benzophenones. J. Chem. Soc. 1926, 129, 2351–2355. [CrossRef] Salamone, M.; Bietti, M.; Calcagni, A.; Gente, G. Phenyl Bridging in Ring-Substituted Cumyloxyl Radicals. A Product and Time-Resolved Kinetic Study† . Org. Lett. 2009, 11, 2453–2456. [CrossRef] [PubMed] DiLabio, G.A.; Ingold, K.U.; Lin, S.; Litwinienko, G.; Mozenson, O.; Mulder, P.; Tidwell, T.T. Isomerization of Triphenylmethoxyl: The Wieland Free-Radical Rearrangement Revisited a Century Later. Angew. Chem. Int. Ed. 2010, 49, 5982–5985. [CrossRef] [PubMed] Bucher, G. Rearrangement of the Trityloxy Radical: Sherlock Holmes’ most recent case. Angew. Chem. Int. Ed. 2010, 49, 6934–6935. [CrossRef] [PubMed] Smeu, M.; DiLabio, G.A. Rearrangement of the 1,1-Diphenylethoxyl Radical Is Not Concerted but Occurs through a Bridged Intermediate. J. Org. Chem. 2007, 72, 4520–4523. [CrossRef] [PubMed] Li, J.; Zhang, X.; Shen, H.; Liu, Q.; Pan, J.; Hu, W.; Xiong, Y.; Chen, C. Boron Trifluoride·Diethyl Ether-Catalyzed Etherification of Alcohols: A Metal-Free Pathway to Diphenylmethyl Ethers. Adv. Synth. Catal. 2015, 357, 3115–3120. [CrossRef] Altimari, J.M.; Delaney, J.P.; Servinis, L.; Squire, J.S.; Thornton, M.T.; Khosa, S.K.; Long, B.M.; Johnstone, M.D.; Fleming, C.L.; Pfeffer, F.M.; et al. Rapid formation of diphenylmethyl ethers and thioethers using microwave irradiation and protic ionic liquids. Tetrahedron Lett. 2012, 53, 2035–2039. [CrossRef] Anderson, G.M.; Cameron, I.; Murphy, J.A.; Tuttle, T. Predicting the reducing power of organic super electron donors. RSC Adv. 2016, 6, 11335–11343. [CrossRef] Nelsen, S.F.; Blackstock, S.C.; Kim, Y. Estimation of inner shell Marcus terms for amino nitrogen compounds by molecular orbital calculations. J. Am. Chem. Soc. 1987, 109, 677–682. [CrossRef] Zhao, Y.; Truhlar, D.G. A new local density functional for main-group thermochemistry, transition metal bonding, thermochemical kinetics, and noncovalent interactions. J. Chem. Phys. 2006, 125, 194101. [CrossRef] [PubMed] Zhao, Y.; Truhlar, D.G. Density Functionals with Broad Applicability in Chemistry. Acc. Chem. Res. 2008, 41, 157–167. [CrossRef] [PubMed] Krishnan, R.; Binkley, J.S.; Seeger, R.; Pople, J.A. Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 1980, 72, 650–654. [CrossRef] Frisch, M.J.; Pople, J.A.; Binkley, J.S. Self-consistent molecular orbital methods 25. Supplementary functions for Gaussian basis sets. J. Chem. Phys. 1984, 80, 3265–3269. [CrossRef] McLean, A.D.; Chandler, G.S. Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z = 11–18. J. Chem. Phys. 1980, 72, 5639–5648. [CrossRef] Blaudeau, J.-P.; McGrath, M.P.; Curtiss, L.A.; Radom, L. Extension of Gaussian-2 (G2) theory to molecules containing third-row atoms K and Ca. J. Chem. Phys. 1997, 107, 5016–5021. [CrossRef] Clark, T.; Chandrasekhar, J.; Spitznagel, G.W.; Schleyer, P.V.R. Efficient diffuse function-augmented basis sets for anion calculations. III. The 3-21+G basis set for first-row elements, Li-F. J. Comput. Chem. 1983, 4, 294–301. [CrossRef] Bergner, A.; Dolg, M.; Küchle, W.; Stoll, H.; Preuß, H. Ab initio energy-adjusted pseudopotentials for elements of groups 13–17. Mol. Phys. 1993, 80, 1431–1441. [CrossRef]
Molecules 2018, 23, 1055
43. 44. 45. 46.
47. 48. 49. 50. 51. 52.
16 of 16
Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995–2001. [CrossRef] Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J. Comput. Chem. 2003, 24, 669–681. [CrossRef] [PubMed] Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09; Gaussian, Inc.: Wallingford, CT, USA, 2009. Dewanji, A.; Mück-Lichtenfeld, C.; Studer, A. Radical Hydrodeiodination of Aryl, Alkenyl, Alkynyl, and Alkyl Iodides with an Alcoholate as Organic Chain Reductant through Electron Catalysis. Angew. Chem. Int. Ed. 2016, 55, 6749–6752. [CrossRef] [PubMed] Denmark, S.E.; Henke, B.R. Investigations on transition-state geometry in the aldol condensation. J. Am. Chem. Soc. 1991, 113, 2177–2194. [CrossRef] Liu, Y.; Xu, Y.; Jung, S.H.; Chae, J. A Facile and Green Protocol for Nucleophilic Substitution Reactions of Sulfonate Esters by Recyclable Ionic Liquids [bmim][X]. Synlett 2012, 23, 2692–2698. [CrossRef] Clavier, H.; Jeune, K.L.; Riggi, I.D.; Tenaglia, A.; Buono, G. Highly Selective Cobalt-Mediated [6 + 2] Cycloaddition of Cycloheptatriene and Allenes. Org. Lett. 2011, 13, 308–311. [CrossRef] [PubMed] Dale, W.J.; Swartzentruber, P.E. Substituted Styrenes. V. Reaction of Styrene and α-Methylstyrene with Dihalocarbenes. J. Org. Chem. 1959, 24, 955–957. [CrossRef] Das, T.; Chakraborty, A.; Sarkar, A. Palladium catalyzed addition of arylboronic acid or indole to nitriles: Synthesis of aryl ketones. Tetrahedron Lett. 2014, 55, 7198–7202. [CrossRef] Sato, Y.; Aoyama, T.; Takido, T.; Kodomari, M. Direct alkylation of aromatics using alcohols in the presence of NaHSO4 /SiO2 . Tetrahedron 2012, 68, 7077–7081. [CrossRef]
Sample Availability: Samples of the compounds are not available. © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
