Metathetical Redox Reaction of (Diacetoxyiodo)Arenes and Iodoarenes

Article Metathetical Redox Reaction of (Diacetoxyiodo)arenes and Iodoarenes

Antoine Jobin-Des Lauriers and Claude Y. Legault *

Received: 25 November 2015 ; Accepted: 15 December 2015 ; Published: 17 December 2015 Academic Editors: Wesley Moran and Arantxa Rodríguez

Centre in Green Chemistry and Catalysis, Department of Chemistry, University of Sherbrooke, 2500 boul. de l’Université, Sherbrooke, QC J1K 2R1, Canada; [email protected] * Correspondence: [email protected]; Tel./Fax: +1-819-821-8017

Abstract: The oxidation of iodoarenes is central to the ﬁeld of hypervalent iodine chemistry. It was found that the metathetical redox reaction between (diacetoxyiodo)arenes and iodoarenes is possible in the presence of a catalytic amount of Lewis acid. This discovery opens a new strategy to access (diacetoxyiodo)arenes. A computational study is provided to rationalize the results observed.

Keywords: hypervalent iodine; (diacetoxyiodo)arenes; metathesis

1. Introduction In the recent years, the development of hypervalent iodine-mediated synthetic transformations has been receiving growing attention [1–5]. This is not surprising considering the importance of improving oxidative reactions and reducing their environmental impact. Hypervalent iodine reagents are a great alternative to toxic heavy metals often used to effect similar transformations [6–10]. Among the plethora of iodine(III) compounds [11], it is undeniable that the (diacetoxyiodo)arenes remain the most common and used ones [12]. They are usually stable solids and can serve as precursors to numerous other iodanes, such as other (diacyloxyiodo)arenes and [hydroxy(tosyloxy) iodo]arenes [13,14]. Access to (diacetoxyiodo)arenes is, of course, usually accomplished by the oxidation of the corresponding iodoarene substrate. The traditional method involves peracetic acid oxidation in acetic acid [15]. One unexploited strategy to access these specific reagents is the metathetical redox reaction between (diacetoxyiodo)arenes and related iodoarenes (Scheme1a). While it is widely accepted that the ligands on iodane species are typically easily exchanged, the interconversion of oxidation states between λ3-iodane and iodoarenes is much rarer. The first example of such a metathetical redox reaction was reported by Koser et al., using [hydroxy(tosyloxy)-iodo] benzene (HTIB) as the oxidant, enabling transfer to a variety of iodoarenes (Scheme1b) [16]. Two applications of this initial method were subsequently reported, including one example using [bis(trifluoroacetoxy)iodo]benzene (BTI) [17,18]. More recently, Ciufolini et al. have reported the iodonium salt metathesis reaction with iodoarenes (Scheme1c) [19]. To the best of our knowledge, the metathetical redox reaction between (diacetoxyiodo)arenes and iodoarenes has never been reported. Expanding the scope of iodane metathesis to these commonly used reagents would be of great interest as an alternative synthetic method. Herein we report a protocol to achieve such a metathesis of (diacetoxyiodo)benzene and iodoarenes. We also provide a computational study to determine the origin of the observed reactivity.

Molecules 2015, 20, 22635–22644; doi:10.3390/molecules201219874 www.mdpi.com/journal/molecules Molecules 2015, 20, 22635–22644 Molecules 2015, 20, page–page

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SchemeScheme 1. Concept 1. Concept and and examples examples of of metathetical metathetical re redoxdox reactions reactions of ofiodanes iodanes and and iodoarenes. iodoarenes. Scheme 1. Concept and examples of metathetical redox reactions of iodanes and iodoarenes. 2. Results and Discussion 2. Results and Discussion 2. ResultsTheScheme reactivity and Discussion 1. Concept of HTIB and and examples (diacetoxyiodo)ben of metathetical rezenedox (DIB)reactions toward of iodanes iodo andarenes iodoarenes. was evaluated, The reactivity of HTIB and (diacetoxyiodo)benzene (DIB) toward iodoarenes was evaluated, usingThe conditions reactivity analogous of HTIB toand Koser’s (diacetoxyiodo)ben successful iodanezene metathesis(DIB) toward with iodo HTIBarenes [16]. was We evaluated,submitted using2. conditionsResults and analogous Discussion to Koser’s successful iodane metathesis with HTIB [16]. We submitted usingp-methyliodobenzene conditions analogous and p-bromoiodobenzene to Koser’s successful to iodane metathesismetathesis withwith HTIB HTIB (Scheme [16]. We 2a) submitted and DIB p-methyliodobenzenepat-methyliodobenzene roomThe temperaturereactivity andof (SchemeandHTIBp-bromoiodobenzene p-bromoiodobenzene and 2b). (diacetoxyiodo)ben In accordance to wiiodane iodanethzene the metathesis (DIB)metathesisresults toward reported with with iodo HTIB by HTIBarenes Koser,(Scheme (Scheme was equilibrium 2a) evaluated, and2a) andDIB is DIB at roomusingatachieved room temperature conditions temperature for the reactionanalogous (Scheme (Scheme with2 tob). 2b).HTIBKoser’s In Inaccordance within accordance successful 96 h. withInwiiodane thcontrast, the metathesis results results no metathesis reported reported with HTIB bywas by Koser, [16].observed Koser, Weequilibrium equilibriumsubmitted after 72 ish is achievedpachievedwith-methyliodobenzene forDIB. thefor the reaction reaction and with withp-bromoiodobenzene HTIB HTIB within within 9696 h. h.to Iniodane contrast, contrast, metathesis no no metathesis metathesis with HTIB was was(Scheme observed observed 2a) after and after 72DIB h 72 h withatwith DIB. room DIB. temperature (Scheme 2b). In accordance with the results reported by Koser, equilibrium is achieved for the reaction with HTIB within 96 h. In contrast, no metathesis was observed after 72 h with DIB.

Scheme 2. Evaluation of the reactivity of DIB toward the metathetical redox process. Scheme 2. Evaluation of the reactivity of DIB toward the metathetical redox process. TheseScheme results 2. demonstrateEvaluation of the the very reactivity different of DIB reac towardtivity profiles the metathetical of DIB and redox HTIB. process. The origin of this reactivityThese resultsScheme dichotomy demonstrate 2. Evaluation was investigated. theof the very reactivity different In aof re DIB centreac toward tivitycomputational theprofiles metathetical of study, DIB redox and we haveHTIB.process. suggested The origin that of Thesethisreaction reactivity results with HTIBdichotomy demonstrate would was involve, theinvestigated. very at room different In temp a reerature,cent reactivity computational iodonium proﬁles intermediates, study, of DIB we and have through HTIB. suggested The a ligand originthat of this reactivityreactiondissociationThese with dichotomyresults mechanism HTIB demonstrate would was [20]. involve, investigated.Due the to veryat theroom different large temp In differ aerature, reac recentencetivity iodoniumin computational profiles effective intermediates,of electronegativity DIB and study, HTIB. through we The between have origina ligand suggested the of that reactionthisdissociationhydroxy reactivity and with mechanismtosyloxy dichotomy HTIB groups would [20]. was on Dueinvestigated. involve, HTIB, to the ionization large at In room a differre incent solution temperature,ence computational in iseffective achievable iodonium study,electronegativity at room we intermediates,have temperature suggested between [21,22] that throughthe In contrast, (diacetoxyiodo)arenes have identical ligands involved in the three-center four-electron a ligandreactionhydroxy dissociation withand tosyloxy HTIB mechanismwould groups involve, on HTIB, [20 at]. room ionization Due temp to in theerature, solution large iodonium is difference achievable intermediates, inat room effective temperature through electronegativity a ligand[21,22] dissociationbonding, and mechanism thus dissociation [20]. Due is expectedto the large to bediffer difficultence in [23]. effective We have electronegativity evaluated the betweenenergetic the of betweenIn contrast, the hydroxy (diacetoxyiodo)arenes and tosyloxy have groups identical on HTIB, ligands ionization involved in the solution three-center is achievable four-electron at room hydroxydissociation and for tosyloxy HTIB, groupsDIB, and on diphenyliodoniumHTIB, ionization in saltsolution 4 (see is the achievable computational at room details temperature in Section [21,22] 4), temperaturebonding, [21and,22 thus]. dissociation In contrast, is (diacetoxyiodo)arenesexpected to be difficult [23]. have We identical have evaluated ligands the involvedenergetic of in the Indissociationthe contrast, results are (diacetoxyiodo)arenesfor illustrated HTIB, DIB, in and Scheme diphenyliodonium have 3. identical ligands salt 4 (see involved the computational in the three-center details four-electronin Section 4), three-center four-electron bonding, and thus dissociation is expected to be difﬁcult [23]. We have bonding,the results and are thusillustrated dissociation in Scheme is expected 3. to be difficult [23]. We have evaluated the energetic of evaluateddissociation the energeticfor HTIB, DIB, of dissociationand diphenyliodonium for HTIB, salt DIB, 4 (see and the computational diphenyliodonium details in salt Section4 (see 4), the computationalthe results are details illustrated in Section in Scheme4), the 3. results are illustrated in Scheme3.

Scheme 3. Energetics of ligand dissociation on DIB, 4, and HTIB (energies reported in kcal/mol). Scheme 3. Energetics of ligand dissociation on DIB,2 4, and HTIB (energies reported in kcal/mol).

2 SchemeScheme 3. Energetics 3. Energetics of ligandof ligand dissociation dissociationon on DIB,DIB, 4,, and and HTIB HTIB (energies (energies reported reported in kcal/mol). in kcal/mol). 2

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Molecules 2015, 20, page–page As suspected, the dissociation of the tosyloxy group is calculated to be endergonic, but feasible.

DissociationMoleculesAs 2015suspected, of, the20, page–page triflate the dissociation anion in the of diphenyliodoniumthe tosyloxy group is saltcalculated4 is predicted to be endergonic, to be even but more feasible. facile at roomDissociation temperature. of the In contrast,triflate anion the in calculations the diphenyliodonium suggest that salt dissociation 4 is predicted of to an be acetoxy even more group facile on DIB at roomat roomMolecules temperatureAs suspected, temperature. 2015, 20, would page–pagethe Indissociation contrast, be too difficult. theof thecalculations tosyloxy grousuggestp is thatcalculated dissociation to be endergonic, of an acetoxy but group feasible. on DissociationTheDIB at dissociation room oftemperature the energiestriflate would anion seem inbe to thetoo be diphenyliodoniumdifficult. correlated to the intrinsicsalt 4 is predicted reactivity to ofbe these even iodanesmore facile toward As suspected, the dissociation of the tosyloxy group is calculated to be endergonic, but feasible. metathesis.at roomThe Wetemperature. dissociation postulated energiesIn thatcontrast, the seem key the to to calculationsbe the correlated metathetical suggest to the redoxintrinsicthat dissociation process reactivity might ofof anthese occur acetoxy iodanes by group the toward formation on Dissociation of the triflate anion in the diphenyliodonium salt 4 is predicted to be even more facile of anDIBmetathesis. iodonium at room We temperature intermediate. postulated would that If the itbe key is too the to difficult. the case, metathetical this could redox be process achieved might with occur DIB by by the promoting formation the of anatThe roomiodonium dissociation temperature. intermediate. energies In contrast, seem If it tois thebethe correlated calculationscase, this tocould thesuggest intrinsic be achievedthat reactivity dissociation with of DIB these of byan iodanes promotingacetoxy toward group the on dissociation of an acetoxy group through the use of a Lewis acid. We elected to use BF3¨ OEt2, metathesis.dissociationDIB at room We of anpostulated temperature acetoxy groupthat would the through key be to too thethe difficult. metatheticaluse of a Lewis redox acid. process We elected might to occur use BF by3·OEt the 2formation, as it was as it was shown in numerous methodologies to be a proficient and compatible Lewis acid with ofshown an iodonium inThe numerous dissociation intermediate. methodologies energies If itseem is to the tobe be case,a correlatedproficie this couldnt andto the be compatible intrinsicachieved reactivity Lewiswith DIB acid of by thesewith promoting iodanesDIB [24,25]. towardthe DIB [24,25]. DFT Calculations, using BF ¨ OMe as a model, suggest that this Lewis acid would permit dissociationDFTmetathesis. Calculations, of anWe acetoxyusing postulated BF group3·OMe that through2 asthe a key3model the to theuse, suggest2 metatheticalof a Lewis that this acid. redox Lewis We process electedacid would might to use permit occur BF3·OEt theby 2 the,formation as formationit was the formationshownof anof iodoniuman in iodoniumnumerous of an intermediate iodonium intermediate.methodologies intermediate at room If toit te isbemperature, thea at proficie roomcase, thisasnt temperature, illustratedand could compatible be inachieved asScheme illustrated Lewis with4. acid DIB inwith Schemeby DIBpromoting [24,25].4. the DFTdissociation Calculations, of usingan acetoxy BF3·OMe group2 as througha model ,the suggest use of that a Lewis this Lewis acid. Weacid elected would topermit use BF the3·OEt formation2, as it was of anshown iodonium in numerous intermediate methodologies at room te mperature,to be a proficie as illustratednt and compatible in Scheme Lewis 4. acid with DIB [24,25]. DFT Calculations, using BF3·OMe2 as a model, suggest that this Lewis acid would permit the formation of an iodonium intermediate at room temperature, as illustrated in Scheme 4.

SchemeScheme 4. Energetics 4. Energetics of ligand of ligand dissociation dissociation on on DIB DIB withwith BF3·OMe¨ OMe2 (energies2 (energies reported reported in kcal/mol). in kcal/mol).

WithScheme this 4. in Energetics mind, we of testedligand dissociationthe iodane onmetathesis DIB with betweenBF3·OMe2 DIB(energies and preported-bromoiodobenzene in kcal/mol). (1b) With this in mind, we tested the iodane metathesis between DIB and p-bromoiodobenzene (1b) in the presence of 5 mol % of BF3·OEt2 (Equation (1)). To our delight, the metathetical redox process in theproceeded presenceWithScheme this cleanly of in 5 molmind,4. Energeticsto %attain we of tested BF ofequilibrium3 ¨ligandOEt the2 iodanedissociation(Equation within metathesis on67 (1)). DIB h. To withThebetween our BFcalculated3 delight,·OMe DIB2 (energiesand free the p-bromoiodobenzene metatheticalenergy reported of inreaction kcal/mol). redox (was1bprocess ) proceededinpredicted the presence cleanly to be of+0.5 to 5 attainmol kcal/mol, % equilibriumof BF which3·OEt 2is (Equation in within good agreement (1)). 67 h. To Theour with delight, calculated the experimentally the metathetical free energy measured redox of reaction process value was predictedproceededof +0.24 toWith bekcal/mol. cleanly +0.5 this kcal/mol,in toThe mind, attain reacti we equilibrium whichon tested did is thealso in iodanewithin goodproceed agreementmetathesis67 withh. The p-methyliodobenzene betweencalculated with the DIB experimentallyfree and energy p-bromoiodobenzene (1a ),of but reaction measured formation was ( value 1b ) of +0.24predictedof ain kcal/mol.suspension the presenceto be +0.5 pointed The of kcal/mol, 5 reactionmol to % a whichofFr didBFiedel-Crafts3 ·OEtis also in2 good(Equation proceed side agreement reaction (1)). with To p with of-methyliodobenzeneour 1a thedelight, with experimentally activated the metathetical DIB, measured (1a and), redox but was value formation process not proceeded cleanly to attain equilibrium within 67 h. The calculated free energy of reaction was of aofinvestigated suspension +0.24 kcal/mol. further. pointed The toreacti a Friedel-Craftson did also proceed side reactionwith p-methyliodobenzene of 1a with activated (1a), DIB,but formation and was not predicted to be +0.5 kcal/mol, which is in good agreement with the experimentally measured value investigatedof a suspension further. pointed to a Friedel-Crafts side reaction of 1a with activated DIB, and was not investigatedof +0.24 kcal/mol.further. The reaction did also proceed with p-methyliodobenzene (1a), but formation of a suspension pointed to a Friedel-Crafts side reaction of 1a with activated DIB, and was not investigated further. (1)

(1)

With these promising results in hand, the reaction mechanism was investigated using DFT(1) calculations (see computational details in Section 4). A single electron transfer (SET) redox process (1) betweenWith the these iodonium promising intermediate results in and hand, the theiodoar reactionene was mechanism considered was (Equation investigated (2)). The using transfer DFT

calculationsWithwas found these to (see promisingbe energeticallycomputational results too details costly in hand, into Sectionoccur the re reaction4)adily. A singleat room mechanism electron temperature. transfer was Ininvestigated (SET) accordance redox withprocess using the DFT calculationsbetweencalculations, With (seethe iodoniumit computationalthese was found promising intermediate that light detailsresults had and in inno the Sectionhand, effect iodoar onthe4). enethe reaction A ratewas single ofconsidered mechanismreaction electron in (Equation transferthewas conditions investigated (SET)(2)). Thedescribed redox transferusing process inDFT betweenwasEquationcalculations found the iodonium (1), to befurther (seeenergetically computational intermediatesuggesting too that costly anddetails the to theprocess occur in iodoarene Section re doesadily 4)not .at wasA involveroom single considered temperature. aelectron SET. (Equationtransfer In accordance (SET) (2)). redox with The process the transfer was foundcalculations,between to be theit energetically was iodonium found that intermediate too light costly had tono and occur effect the readilyoniodoar the rateene at roomwasof reaction considered temperature. in the (Equation conditions In accordance (2)). described The transfer with in the calculations,Equationwas found it(1), was further to found be energetically suggesting that light that too had thecostly no process effect to occur does on re the notadily rate involve at ofroom reaction a SET.temperature. in the conditions In accordance described with the in calculations, it was found that light had no effect on the rate of reaction in the conditions described in Equation (1), further suggesting that the process does not involve a SET. Equation (1), further suggesting that the process does not involve a SET. (2)

(2)

An ionic mechanism was thus considered. The intermediates evaluated are illustrated in Scheme 5.(2) This mechanism has similarities to the one proposed by Ciufolini et al. for diaryliodonium salt metathesisAn ionic [19], mechanis with them wasexception thus considered. of the transfe Therred intermediates group being evaluated easily dissociated. are illustrated For in the Scheme sake of5. (2) Thissimplicity, mechanism the aryl has (Ar) similarities group in theto intermediatesthe one proposed is a simple by Ciufolini phenyl etgroup al. for and diaryliodonium the initial iodane salt is metathesisDIB. TheAn transition [19], ionic with mechanis states the exception leadingm was thus to of the considered.the different transferred intermediatesThe groupintermediates being described easily evaluated dissociated. were are not illustrated studied, For the inas sake Schemeit was of 5. An ionic mechanism was thus considered. The intermediates evaluated are illustrated in simplicity,assumedThis mechanism that the these aryl (Ar)processes has group similarities of in association the intermediatesto the and one disso proposed isciation a simple doby phenyl notCiufolini require group et large al.and foractivation the diaryliodonium initial energies. iodane is salt et al. SchemeDIB.5metathesis .The This transition mechanism [19], stateswith has theleading exception similarities to the of different the to thetransfe oneintermediatesrred proposed group described being by Ciufolini easily were dissociated. not studied,for diaryliodoniumFor as the it wassake of salt metathesisassumedsimplicity, that [19 these the], with aryl processes the(Ar) exceptiongroup of association in the of intermediates the and transferred dissociation is a group simple do not being phenylrequire easily grouplarge dissociated.activation and the initial energies. For iodane the sake is of simplicity,DIB. The the transition aryl (Ar) states group leading in the intermediatesto the different3 intermediates is a simple phenyl described group were and not the studied, initial as iodane it was is assumed that these processes of association and dissociation do not require large activation energies. 3

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DIB. The transition states leading to the different intermediates described were not studied, as it was assumedMolecules that 2015 these, 20, page–page processes of association and dissociation do not require large activation energies.

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SchemeScheme 5. Reaction 5. Reaction mechanism mechanism evaluated evaluated using DFT DFT calculations calculations (Ar (Ar = Ph = Phfor forsimplicity). simplicity).

The energetic properties of all these intermediates were calculated and are illustrated in an Scheme 5. Reaction mechanism evaluated using DFT calculations (Ar = Ph for simplicity). Theenergy energetic diagram properties(Scheme 6). ofAs all described these intermediatesin Scheme 6, formation were calculated of intermediate and are AIB illustrated+, following in an + energycomplexation diagramThe energeticScheme(Scheme by BF 5.properties3.OMe Reaction6).2, As was mechanism describedof found all these to evaluated be in intermedia an Scheme endergonic using6tes, DFT formation were but calculations feasiblecalculated of intermediateprocess(Ar =and Ph atforare room simplicity). illustrated temperature.AIB , in following an complexationenergyAt this point,diagram by BFthe 3(Scheme ïodoniumOMe2, 6). was intermediateAs found described to becan in an Schemeact endergonic as a Lewis6, formation but acid feasible toward of intermediate processan iodoarene at AIB room (in+, following temperature.this case The energetic properties of all these intermediates were calculated and are illustrated in an At thiscomplexationiodobenzene) point, the toby iodonium formBF3.OMe adduct2, was intermediate AIB found+·ArI . toAssociation becan an endergonic act of as the a AcOBF Lewisbut feasible3− acidcounterion process toward led at anroomto Int iodoarene temperature.1. By internal (in this energy diagram (Scheme 6). As described in Scheme 6, formation of intermediate AIB+, following AtLewis this acid point, migration, the iodonium Int2 would intermediate be accessed.+ can actThis as intermediate a Lewis acid can toward then anlead íodoarene to AIAr+ ·PhI(in this adduct, case case iodobenzene) to form adduct AIB ¨ ArI. Association of the AcOBF3 counterion led to Int1. complexation by BF3.OMe2, was found to be an endergonic but feasible process at room temperature. iodobenzene)which can liberate to form iodobenzene adduct AIB and+·ArI finally. Association provide, of by the transfer AcOBF of3− counterionBF3 to another led toDIB Int molecule,1. By internal the By internalAt this Lewis point, the acid iodonium migration, intermediateInt2 would can act be as accessed. a Lewis acid This toward intermediate an iodoarene can (in then this leadcase to Lewisnewly+ acidformed migration, (diacetoxyiodo)arene Int2 would be ( DIAraccessed.). The This calculations intermediate thus suggestcan then an lead ionic to mechanismAIAr+·PhI adduct,relying AIAr ïodobenzene)PhI adduct, to which form canadduct liberate AIB+·ArI iodobenzene. Association and of the finally AcOBF provide,3− counterion by transfer led to Int of1 BF. By3 tointernal another whichon the canasymmetry liberate iodobenzeneor activation and of finallythe iodane provide, moiety by transferto initiate of BFthe3 tometathetical another DIB redox molecule, process, the DIB molecule, the newly formed (diacetoxyiodo)arene (DIAr). The calculations thus suggest+ an ionic newlythroughLewis formed acida key migration, (diacetoxyiodo)areneiodonium Intintermediate.2 would (beDIAr accessed.). The calculations This intermediate thus suggest can then an ioniclead tomechanism AIAr ·PhI relying adduct, mechanismonwhich the asymmetry relyingcan liberate on or theiodobenzene activation asymmetry ofand the or finally activationiodane provide, moiety of by the to transfer iodaneinitiate of the moiety BF 3metathetical to another to initiate DIB redoxthe molecule, process, metathetical the redox process,newly formed through (diacetoxyiodo)arene a key iodonium (DIAr intermediate.).Int The calculationsInt thus suggest an ionic mechanism relying throughG a key iodonium intermediate. 1 2 on the asymmetry or activation of the iodane16.2 moiety16.2 to initiate the metathetical redox process, through a key iodoniumAIB intermediate.+ AIAr+ next Int1 Int2 G 11.7 11.7 catalytic 16.2 16.2 cycle + Int Int + next G AIB 11.6 1 2 11.6 AIAr + catalytic 11.7 AIB •ArI 16.2 16.2 AIAr+•PhI 11.7 cycle + + next DIB + BF AIB AIAr 3 11.6 11.6 11.7 catalytic 0.0 11.7 + AIB •ArI AIAr+•PhI cycle DIB + BF 11.6 11.6 3 + 0.0 -2.6 AIB •ArI AIAr+•PhI -2.6 -2.6 DIB•BF3 DIAr•BF3 DIAr + DIB + BF3 DIB•BF3 0.0 -2.6 -2.6 -2.6 DIB•BF DIAr•BF DIAr + Scheme 6. 3Energy diagram of the proposed mechanism (energies reported in kcal/mol).3 DIB•BF -2.6 -2.6 -2.63 DIB•BF3 DIAr•BF3 DIAr + PassageScheme through 6. Energy a non-symmetric diagram of the iodane proposed intermedia mechanismte could (energies explain reported the metathesis in kcal/mol). reported DIB•BF by Scheme 6. Energy diagram of the proposed mechanism (energies reported in kcal/mol). 3 Koser et al., in which iodoarene 5 is converted to its corresponding cyclic iodane 6 by the action of BTI, withoutPassage the need Schemethrough of a6. acatalyst Energy non-symmetric diagram (Equation of iodane the (3)) proposed [17]. intermedia mechanismte could (energies explain reported the metathesis in kcal/mol). reported by PassageKoser et al. through, in which a non-symmetriciodoarene 5 is converted iodane to intermediate its corresponding could cyclic explain iodane the 6 metathesisby the action reported of BTI, by Koserwithoutet al.Passage, inthe which need through of iodoarene a catalyst a non-symmetric (Equation5 is converted (3))iodane [17]. to intermedia its correspondingte could explain cyclic the iodane metathesis6 by reported the action by of Koser et al., in which iodoarene 5 is converted to its corresponding cyclic iodane 6 by the action of BTI, BTI, without the need of a catalyst (Equation (3)) [17]. without the need of a catalyst (Equation (3)) [17]. (3)

(3)

In this reaction, rapid ligand exchange would lead to intermediate Int-A (Scheme 7). Due to(3) the large difference in effective electronegativity between the alkoxy and trifluoroacetoxy groups, dissociationIn this ofreaction, the latter rapid to fu ligandrnish the exchange iodonium would intermediate lead to Int-Bintermediate is conceivable. Int-A Furthermore,(Scheme 7). Duethe fact to (3) thethat large Int-B difference binds together in effective both I(I) electronegativity and I(III) partners between might facilitatethe alkoxy the and metathetical trifluoroacetoxy redox process. groups, In this reaction, rapid ligand exchange would lead to intermediate Int-A (Scheme 7). Due to Indissociation this reaction, of the latter rapid to ligandfurnish exchangethe iodonium would intermediate lead to Int-B intermediate is conceivable.Int-A Furthermore,(Scheme 7the). fact Due to thatthe Int-B large binds difference together in botheffective I(I) andelectronegativity I(III) partners betweenmight facilitate the alkoxy the metathetical and trifluoroacetoxy redox process. groups, the large difference in effective electronegativity between the alkoxy and triﬂuoroacetoxy groups, dissociation of the latter to furnish the iodonium intermediate Int-B is conceivable. Furthermore, the fact dissociationthat Int-B of thebinds latter together to furnish both I(I) the and iodonium I(III) partners intermediate might facilitateInt-B theis metathetical conceivable. redox Furthermore, process. 4

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4 Molecules 2015, 20, 22635–22644 the fact that Int-B binds together both I(I) and I(III) partners might facilitate the metathetical redoxMolecules process. 2015, 20, page–page Molecules 2015, 20, page–page

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SchemeScheme 7. Proposed7. Proposed intermediate intermediate to rationalize reactivity reactivity of ofBTI BTI toward toward 5. 5. Scheme 7. Proposed intermediate to rationalize reactivity of BTI toward 5. Calculations using t-BuOH as a model alcohol support this proposal, as described by the energetic Calculations using t-BuOH as a model alcohol support this proposal, as described by the valuesCalculations illustratedScheme usingin Scheme t -BuOH7. Proposed 8. Whileas a intermediatemodel dissociation alcohol to rationalize supportof a trifluoroacetate this reactivity proposal, of BTIgr asoup towarddescribed on the5. bysymmetric the energetic BTI energeticwasvalues calculated values illustrated illustrated to bein Schemetoo costly in 8. Scheme toWhile occur dissociation8 .at room While temperature. dissociationof a trifluoroacetate In ofcontrast, a triﬂuoroacetategr oupdue onto the lowersymmetric group effective BTI on the symmetricelectronegativitywas Calculationscalculated BTI was to using calculatedofbe thetoo t -BuOH tcostly-butoxy to asto be comparedaoccur model too at costly alcoholroom to the totemperature. support occurtrifluoroace this at room Inprtoxy oposal,contrast, temperature.group, as duedescribed the to dissociation the Inby lower contrast,the energeticeffective on the due to the lowernon-symmetricvalueselectronegativity effectiveillustrated tBTFIB electronegativity ofin Schemethe is t facilitated.-butoxy 8. While compared of dissociation the t -butoxyto the of trifluoroace a comparedtrifluoroacetatetoxy to group, the group triﬂuoroacetoxy the on dissociationthe symmetric group,on BTIthe the dissociationwasnon-symmetric calculated on the to non-symmetrictBTFIB be too is costly facilitated. to tBTFIBoccur at is room facilitated. temperature. In contrast, due to the lower effective electronegativity of the t-butoxy compared to the trifluoroacetoxy group, the dissociation on the non-symmetric tBTFIB is facilitated.

Scheme 8. Alcohol-promoted formation of an iodonium intermediate. SchemeScheme 8. Alcohol-promoted8. Alcohol-promoted formationformation of of an an iodonium iodonium intermediate. intermediate. This alternative activation mechanism raises an important point concerning the presence of waterThis in these alternative reactions.Scheme activation As 8. aAlcohol-promoted protic mechanism solvent similar raisesformation anto anofimportant analcohol, iodonium pointwater intermediate. concerningmight act as the an presenceactivator toof Thispromotewater alternativein theseacyloxy reactions. group activation dissociation.As a protic mechanism solvent The energetic similar raises valuesto an an importantalcohol, of water water exchange point might concerning andact aspossible an activator the acyloxy presence to of waterdissociationpromoteThis in theseacyloxyalternative were reactions. groupcomputed activation dissociation. for As bothmechanism a protic DIBThe andenergetic solvent raises BTI; thean values similar resultsimportant of are towater anillustratedpoint exchange alcohol, concerning in Schemeand water possiblethe might9. presence In theacyloxy act case of as an activatorofwaterdissociation DIB, to in even promotethese were the reactions. intermediatecomputed acyloxy As afor group protic species both solvent dissociation.DIB [hydroxy and similar BTI;(acetyloxy)iodo]benzene the to The anresults alcohol, energetic are illustratedwater values might (HAIB) in ofSchemeact would wateras an 9. activator notIn exchange the permit case to and possibledissociationpromoteof DIB, acyloxy even acyloxy of the dissociation the groupintermediate acetyloxy dissociation. were speciesgroup computed The to[hydroxy formenergetic forthe(acetyloxy)iodo]benzeneboth valuesiodonium DIB of water andintermediate BTI;exchange the(HAIB) at resultsand room would possible aretemperature. not illustrated acyloxy permit in SchemeIndissociation contrast,9. In the the were caseof calculationsthe ofcomputed DIB,acetyloxy even suggest for group theboth intermediatethat DIB to dissociat andform BTI; theion speciesthe iodoniumof results the [hydroxy(acetyloxy)iodo]benzenetrifluoroacetoxy are intermediate illustrated group inat Scheme room on the 9.temperature. Inanalogous the case (HAIB) would[hydroxy(trifluoroacetoxy)ioofIn notcontrast,DIB, permiteven the the dissociationcalculations intermediate do]benzenesuggest of species the that acetyloxy [hydroxy(HTFIB) dissociat intermediate(acetyloxy)iodo]benzene groupion of the to formtrifluoroacetoxy migh thet be iodoniumpossible (HAIB) group at intermediateroomwould on the temperature. not analogous permit at room dissociation of the acetyloxy group to form the iodonium intermediate at room temperature. temperature.In[hydroxy(trifluoroacetoxy)io essence, In even contrast, if BTI is the founddo]benzene calculations to be more(HTFIB) suggest stable intermediate than that HTFIB, dissociation migh thet be latter possible of would the at triﬂuoroacetoxy roompossess temperature. reactivity group similarIn contrast, to Koser’s the calculations reagent (HTIB). suggest The that main dissociat differionence of thebetween trifluoroacetoxy DIB, BTI, and group HTIB on canthe analogoussimply be on theIn analogousessence, even [hydroxy(triﬂuoroacetoxy)iodo]benzene if BTI is found to be more stable than HTFIB, (HTFIB) the latter intermediate would possess might reactivity be possible explained[hydroxy(trifluoroacetoxy)iosimilar to byKoser’s the better reagent nucleofugality (HTIB).do]benzene The of (HTFIB)main TsO −differ and intermediate CFence3CO between2− vs. migh AcO DIB,t −be. possibleBTI, and at HTIB room can temperature. simply be at room temperature. In essence, even if BTI is found to be more stable than HTFIB, the latter would Inexplained essence, by even the ifbetter BTI nucleofugalityis found to be ofmore TsO stable− and CFthan3CO HTFIB,2− vs. AcO the− . latter would possess reactivity possesssimilar reactivity to Koser’s similar reagent to Koser’s (HTIB). reagentThe main (HTIB). difference The between main difference DIB, BTI, betweenand HTIB DIB, can BTI,simply and be HTIB ´ ´ ´ can simplyexplained be explainedby the better by nucleofugality the better nucleofugality of TsO− and CF of3CO TsO2− vs. andAcO− CF. 3CO2 vs. AcO .

Scheme 9. Water-promoted formation of iodonium intermediates. Scheme 9. Water-promoted formation of iodonium intermediates. These calculations support the non-reactivity observed for DIB even in non-anhydrous solvents. In contrast,These calculations we couldSchemeScheme expect support 9. 9.Water-promoted reactivityWater-promoted the non-reactivity from formationformationBTI evenobserved of ofat iodonium iodoniumroom for DIB temperature intermediates. even intermediates. in non-anhydrous under non-anhydrous solvents. conditions.In contrast, To we test could this hypothexpect esis,reactivity BTI was from let toBT reactI even with at roomp-bromoiodobenzene temperature under at room non-anhydrous temperature withoutconditions.These strict calculationsTo exclusion test this hypoth supportof water.esis, the For BTI non-reactivity comparis was let toon, react aob similarserved with experimentp for-bromoiodobenzene DIB even involving in non-anhydrous at5 molroom % temperature of solvents.BF3·OEt2 These calculations support the non-reactivity observed for DIB even in non-anhydrous solvents. wasInwithout contrast, also strictperformed. we exclusion could The expect of results water. reactivity are For illustrated comparis from BTon, inI Schemeaeven similar at 10. roomexperiment temperature involving under 5 mol non-anhydrous % of BF3·OEt2 In contrast, we could expect reactivity from BTI even at room temperature under non-anhydrous conditions.was also performed. To test this The hypoth resultsesis, are BTI illustrated was let to in react Scheme with 10. p-bromoiodobenzene at room temperature conditions.without strict To exclusion test this of hypothesis, water. For comparis BTI wason, a let similar to reactexperiment with involvingp-bromoiodobenzene 5 mol % of BF3·OEt at2 room temperaturewas also performed. without strict The results exclusion are illustrated of water. in Scheme For comparison, 10. a similar experiment involving 5 mol % of BF3¨ OEt2 was also performed. The results are illustrated in Scheme 10. 5 5 22639 5 Molecules 2015, 20, 22635–22644 Molecules 2015, 20, page–page

F3CCO2 I O2CCF3 I F3CCO2 I O2CCF3 I Additive Molecules 2015, 20, page–page

CDCl3 (1.0 M) F3CCO2 I O2CCF3 I rt, time F3CCO2 I O2CCF3 I Br Br Additive BTI 1b 7 Grxn (kcal/mol) found +1.2 CDCl (1.0 M) Additive 3 time (h) conv. (%) calculated +0.6 rt, time Br Br none 19 6 BTI 1b 7 Grxn (kcal/mol) 41 13 found +1.2 BFAdditive3•OEt2 (5 mol%) time19 (h) conv.25 (%) calculated +0.6 41 26 none 19 6 SchemeScheme 10. 10.Evaluation Evaluation of of BTI BTI toward toward uncatalyzeduncatalyzed41 and and catalyzed catalyzed13 iodane iodane metathesis. metathesis. BF3•OEt2 (5 mol%) 19 25 The experimental outcome of the iodane metathesis41 reactions26 with BTI is in agreement with the Thecalculation experimental results. Metathesis outcome ofoccurs the iodaneslowly in metathesis the absence reactions of a Lewis with acid; BTI equilibrium is in agreement could not with be the Scheme 10. Evaluation of BTI toward uncatalyzed and catalyzed iodane metathesis. calculationachieved, results. even after Metathesis 41 h. As occurswith DI slowlyB, the Lewis in the acid absence has a drastic of a Lewis effect acid;on the equilibrium rate of metathesis, could as not be achieved,equilibriumThe even experimental afteris attained 41 h. outcomewithin As with 19 of DIB,h. theAgain, theiodane Lewisthe metathesiscalc acidulated has freereactions a drasticenergy with of effect reaction BTIon is in theis agreement in rate good of agreement metathesis, with the as equilibriumwithcalculation the isexperimentally attainedresults. Metathesis within observed 19 occurs h. Again,conversion slowly the in (Scheme calculated the absence 10). free of a energy Lewis acid; of reaction equilibrium is in could good not agreement be withachieved, the experimentallyAs the even iodane after metathesis 41 observed h. As with reactions conversion DIB, the are Lewis under (Scheme acid th ermodynamichas 10 ).a drastic effect control, on the we rate selected of metathesis, a substrate as Asthatequilibriumthe would iodane favoris attained metathesis a complete within metathetical reactions 19 h. Again, are redoxthe under calc prulatedocess. thermodynamic freeWe performedenergy of control,reaction the iodane is we in metathesis selectedgood agreement a using substrate thatDIBwith would and the favorexperimentallyo-iodobenzoic a complete acid observed (o metathetical-I-BzOH) conversion as the redox (Schemeiodoarene process. 10). (Scheme We 11). performed The thermodynamic the iodane drive metathesis (i.e., entropic gain) of the reaction was predicted to lead to a complete conversion (ΔGrxn = −11.8 kcal/mol). using DIBAs and the iodaneo-iodobenzoic metathesis acid reactions (o-I-BzOH) are under as thethermodynamic iodoarene (Schemecontrol, we 11 ).selected The thermodynamic a substrate Additionally, o-I-BzOH enables the evaluation of the proximity effect of the iodine(I) and iodine(III) drivethat (i.e. would, entropic favor a gain)complete of metathetical the reaction redox was process. predicted We performed to lead the to iodane a complete metathesis conversion using partnersDIB and oon-iodobenzoic the rate of acidthe metathetical(o-I-BzOH) as redox the iodoarene reaction. (SchemeIndeed, 11).o-I-BzOH The thermodynamic can serve as an drive acyloxy (i.e., (∆Grxnligand.= ´11.8 We thus kcal/mol). performed Additionally, AcO/o-I-BzOo exchange-I-BzOH on enables DIB in thethe evaluationabsence of a ofLewis the acid. proximity Treatment effect of entropic gain) of the reaction was predicted to lead to a complete conversion (ΔGrxn = −11.8 kcal/mol). the iodine(I) and iodine(III) partners on the rate of the metathetical redox reaction. Indeed, o-I-BzOH ofAdditionally, an equimolar o-I-BzOH mixture enables of DIB the and evaluation o-I-BzOH ofin thechloroform, proximity followed effect of bythe AcOHiodine(I) removal and iodine(III) through can servehexanepartners as azeotrope, anon the acyloxy rate resulted of ligand. the inmetathetical a Weclean thus mixture redox performed of reaction. DIB, 8 AcO/, and Indeed, 9o -I-BzOin a o 1:2:1-I-BzOH exchange ratio, can indicative serve on DIB as of an inan acyloxy thealmost absence of a Lewisstatisticalligand. acid.We equilibrium. thus Treatment performed It is of AcO/important an equimolaro-I-BzO to exchangenote mixture that onno ofDIBiodobenzene DIB in the and ab senceowas-I-BzOH observed of a Lewis in chloroform,at acid. this point.Treatment followedThe by AcOHproximityof an equimolar removal effect of throughmixture the I(I) andof hexane DIB I(III) and partners azeotrope, o-I-BzOH did notin resulted chloroform,facilitate inin anya followed clean way the mixture by metathetical AcOH of removal DIB, redox8 ,through process and 9 in a 1:2:1inhexane ratio, the absence indicative azeotrope, of a ofLewisresulted an almostacid. in aTreatment clean statistical mixture of this equilibrium. of st DIB,atistical 8, and mixture It 9 is in important a of 1:2:1 [bis(a ratio,cyloxy)iodo]benzenes to indicative note that of no an iodobenzene almost with was observedastatistical catalytic equilibrium.quantity at this point.of BF It3 ·OEtis Theimportant2 resulted proximity toin notethe effect smooth that ofno an theiodobenzened clean I(I) andconversion I(III)was observed partners to the single at did this cyclic not point. facilitateiodane The in 10 and iodobenzene. The same efficient metathetical redox process could be done in one-pot by treating any wayproximity the metathetical effect of the I(I) redox and I(III) process partners in thedid absencenot facilitate of ain Lewisany way acid. the metathetical Treatment redox of this process statistical anin theequimolar absence quantityof a Lewis of acid. DIB Treatmentand o-I-BzOH of this with statistical 5 mol mixture% of BF 3of·OEt [bis(a2 forcyloxy)iodo]benzenes 4 h in dichloromethane. with mixtureCompound of [bis(acyloxy)iodo]benzenes 10 could be obtained in withessentially a catalytic quantitative quantity yield of BFby 3simple¨ OEt2 resultedremoval of in PhI the smoothby a catalytic quantity of BF3·OEt2 resulted in the smooth and clean conversion to the single cyclic iodane and clean conversion to the single cyclic iodane 10 and iodobenzene. The same efﬁcient metathetical trituration10 and iodobenzene. with hexane. The same efficient metathetical redox process could be done in one-pot by treating redox process could be done in one-pot by treating an equimolar quantity of DIB and o-I-BzOH with an equimolar quantity of DIB and o-I-BzOH with 5 mol % of BF3·OEt2 for 4 h in dichloromethane. 5 molCompound % of BF3 ¨10OEt could2 for be 4 hobtained in dichloromethane. in essentially quantitative Compound yield10 bycould simple be obtainedremoval of in PhI essentially by quantitativetrituration yield with by hexane. simple removal of PhI by trituration with hexane.

Scheme 11. Ligand exchange between DIB and o-I-BzOH followed by iodane metathesis.

6 SchemeScheme 11. 11.Ligand Ligand exchange exchange between between DIBDIB and oo-I-BzOH-I-BzOH followed followed by byiodane iodane metathesis. metathesis.

22640 Molecules 2015, 20, 22635–22644

Molecules 2015, 20, page–page There is a need to reconcile the fact that ligand exchange on DIB is facile at room temperature withoutThere the is need a need for to any reconcile activation, the whilefact that the ligand metathetical exchange redox on processDIB is facile is not at possible. room temperature The nature withoutof the exchange the need for processes any activation, needs to while be considered.the metathetical While redox the process calculations is not possible. suggest aThe mandatory nature of thedissociative exchange processprocesses through needs to anbe considered. iodonium Whil intermediatee the calculations to achieve suggest metathesis, a mandatory an dissociative associative processmechanism through could an still iodonium be considered intermediate for ligand to achiev exchangee metathesis, (Scheme an 12 associative). It was calculated mechanism that couldcis-DIB, still bea T-shaped considered isomer for ligand of DIB exchange in which (S bothcheme acetoxy 12). It ligands was calculated are cis to eachthat cis other,-DIB, would a T-shaped be energetically isomer of DIBaccessible in which at roomboth acetoxy temperature. ligands Thisare cis intermediate to each other, neutral would iodane be ener wouldgetically react accessible readily at with room a temperature.carboxylic acid This (AcOH intermediate was used neutral for simplicity),iodane woul throughd react readily proton with transfer, a carboxylic to afford acid in (AcOH return DIBwas usedin its for most simplicity), stable conformation, through proton bearing transfer, its two to affo mostrd electron in return withdrawing DIB in its most groups stable in conformation,trans relation. bearingAddition its of two iodobenzene most electron on ciswithdrawing-DIB cannot groups occur readily,in trans asrelation. it is not Addition a strong of enough iodobenzene donor to on stabilize cis-DIB cannotexpulsion occur of thereadily, acetoxy as it group. is not a strong enough donor to stabilize expulsion of the acetoxy group.

Scheme 12.12. Plausible mechanism for ligand exchangeexchange (energies(energies reportedreported inin kcal/mol).kcal/mol).

In summary, we have demonstrated that, with the simple action of a Lewis acid, it is possible to In summary, we have demonstrated that, with the simple action of a Lewis acid, it is achieve the metathetical redox reaction of (diacetoxyiodo)arenes and iodoarenes. Both the experimental possible to achieve the metathetical redox reaction of (diacetoxyiodo)arenes and iodoarenes. Both the results and computational insights draw a clearer picture of what is needed for these metathetical experimental results and computational insights draw a clearer picture of what is needed for redox reactions to proceed. The results presented herein open the way for further exploration. these metathetical redox reactions to proceed. The results presented herein open the way for further exploration. 3. Experimental Section 3. Experimental Section 3.1. General Information 3.1. General Information All glassware was stored in the oven and/or was flame dried prior to use under an inert atmosphereAll glassware of gas. CDCl was3 stored was dried in the over oven anhydrous and/or K was2CO3 ﬂamebut not dried thoroughly priorto dried. use Analytical under an thin-layerinert atmosphere chromatography of gas. (TLC) CDCl3 waswas performed dried over on precoated, anhydrous glass-backed K2CO3 but silica not gel thoroughly (Merck 60 dried. F254). VisualizationAnalytical thin-layer of the developed chromatography chromatogram (TLC) was was performed performed on by precoated, UV absorbance, glass-backed aqueous silica cerium gel molybdate,(Merck 60 F ethanolic254). Visualization phosphomolybdic of the developed acid, iodi chromatogramne, or aqueous waspotassium performed permanganate. by UV absorbance, Nuclear magneticaqueous resonance cerium molybdate, spectra (1H, ethanolic 13C, DEPT) phosphomolybdic were recorded either acid, on iodine, an Avance or aqueousIII HD 300 potassium (Bruker, Billerica,permanganate. MA, USA) Nuclear or Mercury+ magnetic 400 resonance (Agilent spectra Technology, (1H, 13 SantaC, DEPT) Clara, were CA, recorded USA) spectrometers. either on an ChemicalAvance III shifts HD 300for 1 (Bruker,H-NMR Billerica,spectra are MA, recorded USA) orin parts Mercury+ per million 400 (Agilent from tetramethylsilane Technology, Santa with Clara, the solventCA, USA) resonance spectrometers. as the internal Chemical standard. shifts Data for 1 H-NMRare reported spectra as follows: are recorded chemical in partsshift, multiplicity per million (sfrom = singlet, tetramethylsilane d = doublet, witht = triplet, the solvent q = quartet, resonance qn = quintet, as the internal sext = sextuplet, standard. m Data = multiplet are reported and br as = broad),follows: coupling chemical constant shift, multiplicity in Hz, integration. (s = singlet, Chemical d = doublet, shifts for t = 13 triplet,C-NMR q =spectra quartet, are qn recorded = quintet, in partssext = per sextuplet, million mfrom = multiplet tetramethylsilane and br = with broad), the couplingsolvent resonance constant as in Hz,the internal integration. standard. Chemical All spectra shifts werefor 13 obtainedC-NMR spectrawith complete are recorded proton indecoupling. parts per When million ambiguous, from tetramethylsilane proton and carbon with assignments the solvent wereresonance established as the using internal COSY, standard. NOESY, All HMQC spectra and were DEPT obtained experiments. withcomplete High resolution proton mass decoupling. spectra wereWhen recorded ambiguous, on a protonMaxis ESI-Q-Tof and carbon (Bruker, assignments Billerica, were MA, established USA) at the using Université COSY, de NOESY, Sherbrooke. HMQC and DEPT experiments. High resolution mass spectra were recorded on a Maxis ESI-Q-Tof (Bruker, 3.2.Billerica, Metathetical MA, USA) Redox at Reaction the Université of HTIB de and Sherbrooke. p-Methyliodobenzene To a round-bottom flask were added [hydroxy(tosyloxy)iodo]benzene (HTIB) (333.4 mg, 0.850 mmol), p-methyliodobenzene (185.3 mg, 0.850 mmol) and dichloromethane (1.7 mL, 0.5 M). The white suspension was stirred at room temperature.22641 Aliquots (5–10 μL) were taken from clear

7 Molecules 2015, 20, 22635–22644

3.2. Metathetical Redox Reaction of HTIB and p-Methyliodobenzene To a round-bottom ﬂask were added [hydroxy(tosyloxy)iodo]benzene (HTIB) (333.4 mg, 0.850 mmol), p-methyliodobenzene (185.3 mg, 0.850 mmol) and dichloromethane (1.7 mL, 0.5 M). The white suspension was stirred at room temperature. Aliquots (5–10 µL) were taken from clear dichloromethane supernatant after allowing the suspension to settle and diluted in HPLC-grade hexanes (500–750 µL) at various moments. Conversions were determined by GC-MS by integration of signals of iodobenzene and p-methyliodobenzene.

3.3. Lewis-Acid-Catalyzed Metathetical Redox Reaction of DIB and p-Bromoiodobenzene To a ﬂame-dried vial equipped with a septum, under an argon atmosphere, were added DIB (372.1 mg, 1.155 mmol), p-bromoiodobenzene (325.6 mg, 1.155 mmol) and CDCl3 (442 µL). Diluted BF3¨ Et2O (713 µL of a freshly made solution of BF3¨ Et2O [100 µL BF3¨ Et2O in 10 mL CDCl3], 0.058 mmol) was added for a total volume of 1.16 mL of CDCl3 (1 M). The solution was stirred at room temperature under inert atmosphere. Conversions were determined by integration of well-deﬁned 1H-NMR signals (5 s relaxation time) of the two (diacetoxyiodo)arenes present in solution. The free energies of reaction (Equation (1) and Scheme 10) were determined with the measured conversions (see Supplementary Materials for more details).

3.4. One-Pot Metathetical Redox Reaction of DIB and o-Iodobenzoic Acid To a ﬂame-dried vial, under argon, were added o-iodobenzoic acid (247.7 mg, 1.00 mmol), DIB (322.1 mg, 1.00 mmol) and a solution of BF3¨ Et2O (1.22 mL, [100 µL BF3¨ Et2O in 10 mL CH2Cl2], 0.012 mmol). The ﬁnal reaction concentration is 0.8 M. The solution was allowed to stir at room temperature for 4 h. The solvent was evaporated and the crude residue washed twice with hexane. The crude product was dried under vacuum to afford compound 10 in quantitative yield. The spectral data is consistent with the reported one in the literature [26].

4. Computational Details The geometry optimizations were done using the Gaussian 09 software package [27] with the M06-2X [28] density functional in combination with the 6-31+G(d,p) basis set [29,30] for all atoms except iodine, for which LANL2DZdp + ECP was used [31,32]. The structures were optimized with a solvation model (SMD) for chloroform [33]. Unless otherwise stated, a ﬁne grid density was used for numerical integration in the calculations. Conformational searches were done on all the species described throughout the mechanistic pathways. Harmonic vibrational frequencies were computed for all optimized structures to verify that they were either minima or transition states, possessing zero or one imaginary frequency, respectively. All the free energies are reported in kcal/mol and incorporate unscaled free energy corrections based on the vibrational analyses and temperature of 298 K.

Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/ 12/19874/s1. Cartesian coordinates, electronic and zero-point vibrational energies. Acknowledgments: This work was supported by the National Science and Engineering Research Council (NSERC) of Canada, the Canada Foundation for Innovation (CFI), the FRQNT Centre in Green Chemistry and Catalysis (CGCC), and the Université de Sherbrooke. Author Contributions: A.J.-D.L. and C.Y.L. conceived and designed the experiments; A.J.-D.L. performed the experiments; C.Y.L. performed the computational calculations; C.Y.L. wrote the paper; A.J.-D.L. helped with the correction of the paper. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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