The Influence of Copper on Halogenation/Dehalogenation

catalysts

Review The Inﬂuence of Copper on Halogenation/Dehalogenation Reactions of Aromatic Compounds and Its Role in the Destruction of Polyhalogenated Aromatic Contaminants

Tomáš Weidlich

Chemical Technology Group, Institute of Environmental and Chemical Engineering, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 53210 Pardubice, Czech Republic; [email protected]; Tel.: +420-46-603-8049

Abstract: The effect of copper and its compounds on halogenation and dehalogenation of aromatic compounds will be discussed in the proposed article. Cu oxidized to appropriate halides is an effective halogenation catalyst not only for the synthesis of halogenated benzenes or their derivatives as desired organic ﬁne chemicals, but is also an effective catalyst for the undesirable formation of thermodynamically stable and very toxic polychlorinated and polybrominated aromatic compounds such as polychlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans accompanied incineration of waste contaminated with halogenated compounds or even inorganic halides. With appropriate change in reaction conditions, copper and its alloys or oxides are also able to effectively catalyze dehalogenation reactions, as will be presented in this review.

Keywords: halogenation; oxybromination; oxychlorination; copper-catalyzed; arylation; Ullmann

Citation: Weidlich, T. The Inﬂuence reaction; coupling; hydrodehalogenation of Copper on Halogenation/Dehalogenation Reactions of Aromatic Compounds and Its Role in the Destruction of 1. Introduction Polyhalogenated Aromatic Aromatic carbon–halogen (Carom–X) bonds are common functional groups in organic Contaminants. Catalysts 2021, 11, 378. synthesis. They are frequently and widely applied in the preparation of numerous organic https://doi.org/10.3390/catal ﬁne chemicals. In many cases, halogenated aromatic compounds (Ar-Xs) are valuable 11030378 intermediates for subsequent Carom–R bonds formation. The broad application of Ar-Xs is joined, however, with a high risk of environmental pollution by almost non-biodegradable Academic Editor: Sónia Carabineiro and toxic Ar–Xs which need subsequent chemical treatment of polluted matter with the aim of converting Ar–Xs to more-biodegradable non-halogenated products. Due to this Received: 27 February 2021 reason, even the facile cleavage of C –X with the aim of producing nonhalogenated and Accepted: 11 March 2021 arom Published: 14 March 2021 usually more biodegradable Carom–H or Carom–R has been intensively studied. In this article, the research advances on the copper-catalyzed and mediated Carom–

Publisher’s Note: MDPI stays neutral X (X = F, Cl, Br, I) bond formation via direct Carom–H bond transformation and (hy- with regard to jurisdictional claims in dro)dehalogenation of Carom–X producing Carom–H or Carom–R, respectively. published maps and institutional affil- Copper and its salts exhibit broad catalytic activity mainly due to the easily accessible iations. and reasonable stability of Cu(0), Cu(I), Cu(II) and Cu(III) oxidation states. They are therefore effective catalysts not only for Carom–H bonds transformations by single electron transfer (SET) processes [1,2] but through using appropriate conditions even for Carom– halogen cleavage reactions by SET, two-electron transfer, or other mechanisms [3,4]. Copper also ranks among the cheap, earth-abundant first-row transition metals which are more Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. environmentally acceptable (relatively less toxic) metals in comparison with noble platinum This article is an open access article group metals, gold or silver. Copper-mediated reactions have also gained significant distributed under the terms and popularity in recent times. The excellent functional group tolerance of copper-mediated conditions of the Creative Commons reactions offers new opportunities for the synthesis of a large variety of organic compounds. Attribution (CC BY) license (https:// This review intends to cover most of the recent advances both on Cu-based halogena- creativecommons.org/licenses/by/ tion and dehalogenation reactions of aromatic compounds based on C–O and C–C bond 4.0/). formation.

Catalysts 2021, 11, 378. https://doi.org/10.3390/catal11030378 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, x FOR PEER REVIEW 2 of 36

This review intends to cover most of the recent advances both on Cu-based halogen-

Catalysts 2021, 11, 378 ation and dehalogenation reactions of aromatic compounds based on C–O and C–C 2bond of 34 formation.

2. Cu-Based Halogenations of Aromatic Compounds 2. Cu-Based Halogenations of Aromatic Compounds This section may be divided by subheadings. It should provide a concise and precise descriptionThis section of the may experimental be divided results, by subheadings. their interpretation It should provide as well a as concise the experimental and precise descriptionconclusions ofthat the can experimental be drawn. Aryl results, halides their ar interpretatione widely used asin wellorganic as thesynthesis experimental to form conclusionscarbon-carbon that and can carbon-heteroatom be drawn. Aryl halidesbonds un areder widely metal usedcatalysis in organicsuch as synthesisin Heck, So- to formnogashira, carbon-carbon Suzuki, and and Ullmann carbon-heteroatom coupling reactions bonds under [5]. Aryl metal halides catalysis are suchalso ashighly in Heck, ver- Sonogashira,satile synthetic Suzuki, intermediates and Ullmann for many coupling applications reactions in [5agrochemicals,]. Aryl halides pharmaceuticals are also highly versatileand materials synthetic [6,7]. intermediates Aryl iodides for are many generally applications more reactive in agrochemicals, in organic pharmaceuticalstransformations. andAlthough materials aryl [6chlorides,7]. Aryl or iodides aryl bromides are generally are relatively more reactive more in inert, organic they transformations. are much more Althoughcommonly aryl found chlorides in pharmaceuticals or aryl bromides and agrochem are relativelyicals, more in which inert, they they are are introduced much more to commonlymodify the foundphysical in pharmaceuticalsand biological properties and agrochemicals, of aromatic in rings which [8]. they are introduced to modifyTraditional the physical methods and biological for Ar–Xs properties syntheses ofinvolved aromatic two rings common [8]. preparatory routes: Traditional methods for Ar–Xs syntheses involved two common preparatory routes: direct halogenation via an electrophilic substitution reaction (SEAr) and a nucleophilic direct halogenation via an electrophilic substitution reaction (SEAr) and a nucleophilic aromatic substitution reaction (SNAr) especially of diazonium salts [9]. aromatic substitution reaction (SNAr) especially of diazonium salts [9]. Halogenation of aromatic compounds using highly toxic chlorine (Cl2) and bromine Halogenation of aromatic compounds using highly toxic chlorine (Cl2) and bromine (Br2) via electrophilic aromatic substitution (SEAr) reaction mechanism requires special (Br ) via electrophilic aromatic substitution (S Ar) reaction mechanism requires special caution2 with regards to handling and safety. InE addition, corresponding toxic and very caution with regards to handling and safety. In addition, corresponding toxic and very corrosive hydrogen halides (HXs) are produced as by-products during halogen-based hal- corrosive hydrogen halides (HXs) are produced as by-products during halogen-based ogenations in stoichiometric quantity. In addition, HX as an undesirable by-product (a) halogenations in stoichiometric quantity. In addition, HX as an undesirable by-product diminishes significantly X atom efficiency of halogenation processes based on X2 as a hal- (a) diminishes significantly X atom efficiency of halogenation processes based on X as ogenation agent (X atom economy is max. 50%) and (b) causes difficulties with subsequent2 a halogenation agent (X atom economy is max. 50%) and (b) causes difficulties with HX treatment. subsequent HX treatment. TheThe developmentdevelopment ofof convenientconvenient andand moremore efficientefficient methodsmethods usingusing aa sourcesource ofof halidehalide ionion combinedcombined withwith differentdifferent oxidantsoxidants forfor thethe synthesissynthesis ofof arylaryl andand heteroarylheteroaryl halideshalides hashas thereforetherefore attractedattracted increasingincreasing attentionattention [[10–20].10–20]. AA different wayway forfor increasingincreasing thethe ClCl atomatom economyeconomy inin thethe productionproduction ofof chlorinatedchlorinated aromatic compounds via SEAr exploiting gaseous Cl2 is based on the ex-situ oxidative aromatic compounds via SEAr exploiting gaseous Cl2 is based on the ex-situ oxidative treatmenttreatment ofof co-producedco-produced hydrogenhydrogen chloride.chloride. ElectrolyticElectrolytic andand catalyticcatalytic technologiestechnologies cancan bebe appliedapplied forfor thisthis purpose.purpose. HCl electrolysis isis basedbased onon thethe conversionconversion ofof aa 2222 wt.%wt.% HClHCl solution over graphite electrodes separated by a diaphragm to Cl2 and H2, respectively at solution over graphite electrodes separated by a diaphragm to Cl2 and H2, respectively at thethe anodeanode andand the the cathode. cathode. High High electricity electricity consumption consumption leads leads to to the the unfavorable unfavorable operating operat- costsing costs of this of this process process [21]. [21]. TheThe catalyticcatalytic optionoption isis basedbased onon thethe gas-phasegas-phase oxidationoxidation ofof HClHCl toto ClCl22 byby OO22 overover heterogeneousheterogeneous Cu-Cu- oror otherother transitiontransition metal-basedmetal-based catalystscatalysts [[22].22].

2.1.2.1. The Role of Cu-Catalyzed O22-Based Oxidation of Waste HCl Producing ClCl22

TheThe so-called Deacon Deacon process, process, Cu-bas Cu-baseded oxidation oxidation of of waste waste HCl HCl with with O2 Ois2 oneis one of the of theintensively intensively studied studied techniques techniques enabling enabling reuse reuse of chlorine of chlorine spent spent during during chlorination chlorination pro- processescesses from from HCl HCl by-product by-product (Scheme (Scheme 1) 1[23–25].)[23–25 ].

SchemeScheme 1.1. Cu-catalyzed oxidation ofof HClHCl atat 360–450360–450 ◦°CC (Deacon process) [[23–25].23–25].

TheThe DeaconDeacon processprocess isis catalyzedcatalyzed byby CuClCuCl22/CuO/CuO with a mechanism that isis generallygenerally acceptedaccepted involvinginvolving threethree stepssteps (Equations(Equations (1)–(3))(1)–(3)) [[24]:24]: 2 CuCl2 → 2 CuCl + Cl2 ( 1 ) → 2 CuCl + O2 → CuO + CuCl22 CuCl 2 2 CuCl( 2 ) + Cl2 (1) CuO + HCl → CuCl2 + H2O ( 3 ) 2 CuCl + O2 → CuO + CuCl2 (2)

CuO + HCl → CuCl2 + H2O (3) The Cu-based recycling of chlorine from waste HCl signiﬁcantly increases Cl atom efﬁciency of SEAr chlorination process and is an important part of chlorination technolo- Catalysts 2021, 11, x FOR PEER REVIEW 3 of 36

Catalysts 2021, 11, x FOR PEER REVIEW 3 of 36

Catalysts 2021, 11, 378 The Cu-based recycling of chlorine from waste HCl significantly increases Cl 3atom of 34 efficiency of SEAr chlorination process and is an important part of chlorination technolo- gies [25].The TheCu-based other disadvantagerecycling of chlorine of SEAr-based from waste synthetic HCl strategiessignificantly is the increases low regioselec- Cl atom tivityefficiency of this of halogenation SEAr chlorination and problems process and with is the an formationimportant of part more of chlorinationhalogenated technolo-products gies(Schemegies [[25].25]. 2). TheThe otherother disadvantagedisadvantage ofof SSEEAr-based synthetic strategies is thethe lowlow regioselec-regioselec- tivitytivity ofof thisthis halogenationhalogenation andand problemsproblems withwith thethe formationformation ofof moremore halogenatedhalogenated productsproducts (Scheme(Scheme2 ).2).

Scheme 2. Electrophilic aromatic substitution (SEAr) pathway.

SchemeProgress 2. Electrophilic for the aromaticselective substitution synthesis of(SE Ar)aryl pathway. and heteroaryl halides has recently at- Scheme 2. Electrophilic aromatic substitution (SEAr) pathway. tracted increased attention. Significant advances dealing with higher regioselectivity have occurredProgressProgress in the for for C thearom the selective–H selective halogenation synthesis synthesis catalyzed of arylof aryl and by and heteroaryl differ heteroarylent halidestransition halides has metals recently has recentlysuch attracted as Pd, at- increasedRh,tracted Ru, increasedAu attention. [26], Agattention. Signiﬁcant [27–29], Significant etc. advances In the advances dealing area of with dealingCarom higher–H with bond regioselectivity higher halogenation, regioselectivity have the occurred copper have incatalysisoccurred the Carom alsoin –Hthe serves halogenationCarom –Ha useful halogenation catalyzedutilization. catalyzed by As different a class by differ transition of cheapent transition metalsand simply such metals asavailable Pd,such Rh, as and Ru,Pd, AuwidelyRh, [26Ru,], used AgAu [[26],transition27–29 Ag], etc. [27–29], metal In the catalysts, etc. area In of the CCu-basedarom area–H of bond saltsCarom halogenation,–Hhave bond exhibited halogenation, the substantial copper the catalysis applica- copper alsotioncatalysis servesin Carom also a–H useful serves bond utilization. functionalizationa useful utilization. As a class in ofrecentAs cheap a classye andars of owing simply cheap to availableand their simply distinct and available widely advantages used and transitionsuchwidely as usedlow metal toxicity, transition catalysts, high metal Cu-basedstability catalysts, and salts flexibleCu-based have exhibited forms salts of have substantial presence exhibited [30–34]. application substantial in C applica-arom–H bondtion Aerobicin functionalization Carom–H oxybromination bond functionalization in recent of arenes years catalyzedin owing recent to yeby theirars Cu(NO owing distinct3)2 towas advantagestheir achieved distinct using such advantages asHBr low as toxicity,asuch bromine as highlow source, toxicity, stability molecular high and ﬂexiblestability oxygen forms and as flexible the of presence oxid formsant and [30 of– presence34water]. as [30–34].a solvent with high selectivity.AerobicAerobic The oxybrominationcatalystoxybromination not only ofdemonstrates arenes catalyzed high chemoselectivityby by Cu(NO Cu(NO3)32) 2waswas forachieved achieved monobromination, using using HBr HBr as asbuta bromine a also bromine remarkable source, source, molecular regioselectivity molecular oxygen oxygen foras asthepa thera-isomers oxid oxidantant and [35]. and water waterThe as pr asaoposed solvent a solvent mechanism with with high high se- is selectivity.similarlectivity. to The the The catalystDeacon catalyst notprocess, not only only demonstratesbromine demonstrates is produced high high chemoselectivity chemoselectivity by O2-based Cu(II)-catalyzed for monobromination, oxida- buttionbut alsoofalso HBr remarkableremarkable (Scheme 3).regioselectivityregioselectivity forfor para-isomerspara-isomers [[35].35]. TheThe proposedproposed mechanismmechanism isis similarsimilar toto the the Deacon Deacon process, process, bromine bromine is producedis produced by by O2 -basedO2-based Cu(II)-catalyzed Cu(II)-catalyzed oxidation oxida- of tion HBr of (SchemeHBr (Scheme3). 3).

Cu(II) + 2 Br Cu(I) + Br2

Ar H + Br2 Ar Br + HBr Cu(II) + 2 Br Cu(I) + Br2 + Cu(I) + 1/2 O2 +2H Cu(II) + H2O Ar H + Br2 Ar Br + HBr Scheme 3. Proposed mechanism+ of oxybrominationCu(II) + [[35].35 H].O Cu(I) + 1/2 O2 +2H 2 SchemeThis 3. procedureProposed mechanism represents of an oxybromination attractiveattractive greengreen [35]. approachapproach toto brominatedbrominated aromaticsaromatics forfor several reasons: (i) it avoids the useuse andand handlinghandling ofof BrBr22;; (ii)(ii) nono VOCsVOCs (volatile(volatile organicorganic compounds)This procedure are used represents as solvents; an (iii)attractive the componentsco grmponentseen approach in the to reaction,reaction, brominated airair andand aromatics waterwater areare for non-toxic,several reasons: HBr is (i) much it avoids less toxic the thanuse and Br22, reagents reagentshandling are of non-flammable, non-flammable,Br2; (ii) no VOCs cheapcheap (volatile andand readilyorganicreadily available.compounds) Therefore, Therefore, are used this this as solvents;me methodthod offers(iii) the an co efficientefficientmponents system in the forfor reaction, thethe organicorganic air and solvent-freesolvent-free water are oxybromination of aromatics with high atom economy and selectivity. The Cu(OAc) oxybrominationnon-toxic, HBr is of much aromatics less toxic with than high Br at2,om reagents economy are non-flammable,and selectivity. The cheap Cu(OAc) and readily2 cat-2 catalyzedalyzedavailable. technique techniqueTherefore, for oxybromina forthis oxybromination methodtion offers of phenols an of phenolsefficient substituted substitutedsystem with for electron-donatingthe with organic electron-donating solvent-free (Edg) (Edg) groups using LiBr was published by Menini et al. [36]. The authors suggest a SET groupsoxybromination using LiBr of was aromatics published with by high Menini atom et economy al. [36]. The and authors selectivity. suggest The Cu(OAc)a SET mecha-2 cat- mechanismnismalyzed for technique this for bromination this for bromination oxybromina reaction.tion reaction. Similarly, of phenols Similarly, anilines substituted anilinessubstituted with substituted withelectron-donating both with Edg both and (Edg) Ewg Edg and Ewg were selectively brominated using Cu(OAc) catalyst [37] by a SET mechanism weregroups selectively using LiBr brominated was published using by Cu(OAc) Menini2 catalystet al. [36]. [37]2 The by aauthors SET mechanism suggest a SET(Scheme mecha- 4). A (SchemeThenism first for 4step ).this The consistsbromination first step of the consists reaction. formation of theSimilarly, of formation a Lewis anilines acid-base of a Lewis substituted complex acid-base with A complex between both Edg Cu(II) betweenand Ewgand Cu(II) and aniline or phenol. We then suggest the abstraction of a hydrogen atom and anilinewere selectively or phenol. brominated We then suggest using theCu(OAc) abstra2 ctioncatalyst of [37]a hydrogen by a SET atom mechanism and electron (Scheme trans- 4). electron transfer to Cu(II) resulting in radical B, Cu(I) and H+. Tautomeric cyclohexadienyl ferThe to first Cu(II) step resultingconsists of in the radical formation B, Cu(I) of a and Lewis H+ acid-base. Tautomeric complex cyclohexadienyl A between Cu(II)radical and C radical C reacts with Cu(II) bromide giving Cu(I) bromide and brominated product D, aniline or phenol. We then suggest the abstraction of a hydrogen atom and electron trans- whose tautomerization gives para-bromoaniline or para-bromophenol 2. Re-oxidation fer to Cu(II) resulting in radical B, Cu(I) and H+. Tautomeric cyclohexadienyl radical C of Cu(I) complexes by dioxygen readily occur in acetic acid solutions and complete the catalytic cycle (Scheme5).

Catalysts 2021, 11, x FOR PEER REVIEW 4 of 36 Catalysts 2021, 11, x FOR PEER REVIEW 4 of 36

reacts with Cu(II) bromide giving Cu(I) bromide and brominated product D, whose tau- reacts with Cu(II)tomerization bromide gives giving para-bromoaniline Cu(I) bromide and or para-bromophenol brominated product 2. Re-oxidation D, whose tau- of Cu(I) com- tomerizationplexes gives bypara-bromoaniline dioxygen readily or occur para-bromophenol in acetic acid solutions 2. Re-oxidation and complete of Cu(I) the com- catalytic cycle plexes by dioxygen readily occur in acetic acid solutions and complete the catalytic cycle Catalysts 2021, 11, 378 (Scheme 5). 4 of 34 (Scheme 5).

SchemeScheme 4.4.Regioselective Regioselective brominationbromination ofof anilines anilines and and phenols phenols [ 36[36,37].,37]. Scheme 4. Regioselective bromination of anilines and phenols [36,37].

Scheme 5. The suggested single electron transfer (SET) mechanism for the bromination of anilines Scheme 5. TheScheme suggested 5. The singleor suggestedphenols electron [36,37]. single transfer electron (SET) transfer mechanism (SET) for mechanism the bromination for the ofbromination anilines or of phenols anilines [36 ,37]. or phenols [36,37]. ApartApart fromfrom solublesoluble Cu(II)-salts,Cu(II)-salts, thethe heterogeneousheterogeneousCu-based Cu-basedhalogenation halogenation variantvariant Apart withfromwith Cu-phtalocyanine Cu-phtalocyaninesoluble Cu(II)-salts, encapsulated encapsulated the heterogeneous on on zeolite zeol iteCu-based was was published published halogenation using using hydrogen hydrogenvariant peroxide peroxide or oxygen as an oxidant [38]. with Cu-phtalocyanineor oxygen as encapsulated an oxidant [38] on. zeolite was published using hydrogen peroxide Stahl and co-workers distinguished the mechanisms of the regioselective Cu-catalyzed or oxygen as an oxidantStahl and [38] co-workers. distinguished the mechanisms of the regioselective Cu-cata- chlorination and bromination of arenes and heteroarenes in 2009 [39]. Good to excellent Stahl andlyzed co-workers chlorination distinguished and bromination the mechanisms of arenes and of theheteroarenes regioselective in 2009 Cu-cata- [39]. Good to ex- yields of the corresponding mono-halogenated products were obtained by using lithium lyzed chlorinationcellent yieldsand bromination of the corresponding of arenes and mono-hal heteroarenesogenated in 2009products [39]. wereGood obtained to ex- by using cellent yieldshalides of the and corresponding O2 as the halogen mono-hal sourcesogenated and the products terminal were oxidant, obtained respectively. by using The bromina- lithium halides and O2 as the halogen sources and the terminal oxidant, respectively. The tions occurred more readily than the corresponding chlorinations and in some cases, the lithium halidesbrominations and O2 as theoccurred halogen more sources readily and than the terminalthe corresponding oxidant, respectively. chlorinations The and in some brominationslatter occurred required more higher readily amounts than (eventhe corresponding superstoichiometric) chlorinations of CuCl and2. The in regioselectivitiessome cases, the latter required higher amounts (even superstoichiometric) of CuCl2. The regi- obtained therein matched those expected of an electrophilic halogenation which is con- cases, the latteroselectivities required obtainedhigher amou thereinnts (evenmatched superstoichiometric) those expected of of an CuCl electrophilic2. The regi- halogenation trolled by sterics. The authors also noted that the bromination reactions turned red-brown oselectivitieswhich obtained is controlled therein matched by sterics. those The expected authors ofalso an notedelectrophilic that the halogenation bromination reactions in color upon heating, in addition to the fact that cyclooctene undergoes dibromination in which is controlledturned red-brown by sterics. in Thecolor authors upon heating, also noted in ad ditionthat the to thebromination fact that cyclooctene reactions undergoes a trans fashion under the reaction conditions. Electrophilic aromatic substitution (SEAr) turned red-browndibromination in color uponin a trans heating, fashion in ad underdition the to reacthe facttion that conditions. cyclooctene Electrophilic undergoes aromatic sub- dibrominationwas in proposed a trans fashion for the under bromination the reac reactionstion conditions. proceeding Electrophilic via direct aromatic attack sub- of Br2 which is producedstitution (S fromEAr) CuBr was proposedunder the for reaction the bromination conditions (Scheme reactions3). proceeding The mechanism via direct of the attack chlo- stitution (SEAr) was proposed for2 the bromination reactions proceeding via direct attack rinationof Br2 which was inis contrastproduced proposed from CuBr to occur2 under via the electron reaction transfer conditions from the(Scheme electron-rich 3). The arenemech- of Br2 whichanism is produced of the chlorinationfrom CuBr2 underwas in the contrast reaction prop conditionsosed to occur (Scheme via electron3). The mech- transfer from the anism of theto chlorination CuCl2. Analogously, was in contrast Yang reported proposed the to sameoccur mechanism via electron during transfer a parafrom bromination the of electron-rich arene to CuCl2. Analogously, Yang reported the same mechanism during a aniline using CuBr2 in combination with Oxone as the oxidant [40]. electron-rich arene to CuCl2. Analogously, Yang reported the same mechanism during a para bromination of aniline using CuBr2 in combination with Oxone as the oxidant [40]. para bromination2.2. The of Role aniline of Directing using CuBr Groups2 inin combination Regioselective with Cu-Catalyzed Oxone as Halogenationthe oxidant [40]. of Aromatic Compounds2.2. The Role of Directing Groups in Regioselective Cu-Catalyzed Halogenation of Aromatic 2.2. The Role of Directing Groups in Regioselective Cu-Catalyzed Halogenation of Aromatic CompoundsHighly regioselective ortho-halogenations of substituted 2-phenylpyridines catalyzed Compounds by Cu(II)Highly salts regioselective were described ortho-halogenation by several researchs of groupssubstituted [41–44 2-phenylpyridines]. Pyridine works ascata- a Highlymonodentatelyzed regioselective by Cu(II) directing ortho-halogenationsalts were group described in thiss casebyof sevesubstituted (Schemeral research6). 2-phenylpyridines Each groups of these [41–44]. methods cata- Pyridine is based works on lyzed by Cu(II)oxyhalogenationas a saltsmonodentate were described of directing accessible by group seve halideral in using researchthis case either groups(Scheme strong [41–44]. chemical6). Each Pyridine of oxidant these works (CrOmethods3 in methodis based as a monodentateA) or oxygen directing at elevatedgroup in temperaturethis case (Scheme (methods 6). Each B–D. of Surprisingly, these methods 1,2-dihalogenoethane is based or 1,1,2,2-tetrahalogenoethane (PHE, method B) or benzoyl chloride (method C) play an important role as the source of halogenating agent, although, they are usually used as

alkylating (PHE) or acylating (PhCOCl) agents. This could be explained by the mechanism given in Scheme7, both mentioned PHE and PhCOCl are sources of halide for Cu(II) catalyzed halogenation, presumably. In addition, benzoic acid anhydride formed Catalysts 2021, 11, x FOR PEER REVIEW 5 of 36

on oxyhalogenation of accessible halide using either strong chemical oxidant (CrO3 in method A) or oxygen at elevated temperature (methods B-D. Surprisingly, 1,2-dihalogenoethane or 1,1,2,2-tetrahalogenoethane (PHE, method B) or benzoyl chloride (method C) play an important role as the source of halogenating agent, although, they are usually used as alkylating (PHE) or acylating (PhCOCl) agents. This could be explained by the mechanism given in Scheme 7, both mentioned PHE and PhCOCl are sources of halide for Cu(II) catalyzed halogenation, presumably. In addition, benzoic acid anhydride formed Catalysts 2021, 11, 378 by hydrolysis of PhCOCl works as the precursor of catalytically active Cu-complexes5 of 34 F (Scheme 7, X = Cl) and G (Scheme 7, where X = Cl and OCOPh) in halogenation according to Scheme 6, method C [43]. by hydrolysis of PhCOCl works as the precursor of catalytically active Cu-complexes F (Scheme7, X = Cl) and G (Scheme7, where X = Cl and OCOPh) in halogenation according to Scheme6, method C [43].

SchemeScheme 6. 6.Selective Selective ortho-halogenation ortho-halogenation of of phenyl phenyl ring ring bound bound in in 2-phenylpyridine 2-phenylpyridine [ 41[41–44].–44].

Scheme 7. Proposed mechanism of ortho-halogenation of 2-phenylpyridine catalyzed by CuX2 (X Scheme 7. Proposed mechanism of ortho-halogenation of 2-phenylpyridine catalyzed by CuX2 (X = bromide,= bromide, chloride chloride or anionor anio ofn carboxylicof carboxylic acid) acid) [41 [41–44].–44].

BothBoth SET SET mechanism mechanism [ 41[41]] and and two-electrontwo-electron transfer transfer with with the the dominant dominant role role of of Cu(III)Cu(III) speciesspecies [44[44]] were were proposed proposed as as the the main main mechanism mechanism for for these these ortho-halogenations ortho-halogenations using using CuXCuX22 dependingdepending onon thethe usedused reactionreactionconditions conditions(Scheme (Scheme7 ).7). InIn addition, addition, it it must must be be mentionedmentioned thatthat notnot onlyonly ortho-halogenationortho-halogenation occursoccurs usingusing con-con- ditionsditions described described in in Method Method B inB in Scheme Scheme6. The 6. Th additione addition of a suitableof a suitable source source of nucleophile of nucleo- enablesphile enables ortho-functionalization ortho-functionalization of the phenyl of the phenyl ring in 2-phenylpyridinering in 2-phenylpyridine structure, structure, especially es- ifpecially non-halogenated if non-halogenated solvent (DMSO, solvent CH (DMSO,3CN) was CH used3CN) insteadwas used of polychloroethane.instead of polychloro- Dif- ferentethane. sources Different of nucleophiles sources of nucl wereeophiles used, concretelywere used, I 2concretely(for ortho-iodination), I2 (for ortho-iodination), CH3SiCN (for ortho-cyanation), H2O (for ortho-hydroxylation), organic disulﬁdes (for corresponding ortho-thioether formation, etc.). In all these above-mentioned Carom–H halogenation protocols with pyridine as the monodentate directing group (MDG), the chemo-selectivity remained a challenge since either mixed mono- and dihalogenated products or only one of the two potential products could be acquired. In this regard, a synthetic approach allowing the tunable synthesis of mono- and dihalogenated products was highly desirable. Recently, Han and co-workers [45] successfully achieved this kind of tunable reaction via a CuX-mediated Carom–H halogenation with the assistance of N-halosuccinimide (NXS, where X = Cl or Br). The application of different organic acids, which participated in the in-situ formation of acyl hypohalites enabled the selective generation of mono- or di-halogenated products (Scheme8). Catalysts 2021, 11, x FOR PEER REVIEW 6 of 36

Catalysts 2021, 11, x FOR PEER REVIEW 6 of 36

CH3SiCN (for ortho-cyanation), H2O (for ortho-hydroxylation), organic disulfides (for cor- respondingCH3SiCN (for ortho-thioethe ortho-cyanation),r formation, H2O (for etc.). ortho-hydroxylation), organic disulfides (for cor- respondingIn all these ortho-thioethe above-mentionedr formation, Carom etc.).–H halogenation protocols with pyridine as the monodentateIn all these directing above-mentioned group (MDG), Carom the–H chemo-selectivity halogenation protocol remaineds with a pyridinechallenge as since the eithermonodentate mixed mono- directing and groupdihalogenated (MDG), productsthe chemo-selectivity or only one of remained the two potential a challenge products since couldeither bemixed acquired. mono- In and this dihalogenated regard, a syntheti productsc approach or only allowing one of the the two tunable potential synthesis products of mono-could be and acquired. dihalogenated In this regard,products a synthetiwas highlyc approach desirable. allowing Recently, the Han tunable and synthesisco-workers of [45]mono- successfully and dihalogenated achieved thisproducts kind of was tunable highly reaction desirable. via Recently,a CuX-mediated Han and Carom co-workers–H halogenation[45] successfully with the achieved assistance this of kind N-halosuccinimide of tunable reaction (NXS, via where a CuX-mediated X = Cl or Br). Carom The–H appli- halo- Catalysts 2021, 11, 378 cationgenation of differentwith the organicassistance acids, of N which-halosuccinimide participated (NXS, in the wherein-situ Xformation = Cl or Br). of acylThe hypo-appli- 6 of 34 halitescation ofenabled different the organic selective acids, generation which participatedof mono- or di-halogenatedin the in-situ formation products of (Scheme acyl hypo- 8). halites enabled the selective generation of mono- or di-halogenated products (Scheme 8).

Scheme 8. Tunable ortho-halogenation of 2-phenylpyridine catalyzed by CuX in co-action of dif- Scheme 8. TunableferentScheme ortho-halogenation carboxylic 8. Tunable acids ortho-halogenation [45]. of 2-phenylpyridine of 2-phenylpyridi catalyzed byne CuX catalyzed in co-action by CuX of different in co-action carboxylic of dif- acids [45]. ferent carboxylic acids [45]. The heterogeneousThe heterogeneous Cu-MnO-catalyzed Cu-MnO-catalyzed option of selective option monohalogenation of selective monohalogenation of aro- of aro- maticThe compounds heterogeneousmatic compoundswith NXS Cu-MnO-catalyzed in with the presence NXS in the optionof presencemolecular of selective of oxygen, molecular monohalogenation under oxygen, irradiation under of with irradiationaro- with visiblematic compounds light,visible was alsowith light, reported. NXS was in also the Monochlorination, reported.presence of Monochlorination, molecular bromination, oxygen, bromination, underand iodinations irradiation and iodinations werewith were achievedvisible light, in achieveda quitewas also selective in reported. a quite fashion selective Monochlorination, [46]. fashion [46]. bromination, and iodinations were achievedApart in from a quite Apartthe selective issue from of thefashionselectivity, issue [46]. of selectivity,another major another challenge major in challenge the MDG-assisted in the MDG-assisted C– C–H H activationApart fromactivation lied thein the issue lied removal inof theselectivity, of removal the MDG, another of the which MDG, major undermined which challenge undermined thein the efficiency MDG-assisted the efﬁciency of the syn- ofC– the synthetic theticH activation procedure.procedure. lied inTo the alternate removal To alternate the of hardly the the MDG, hardly removable which removable underminedMDG of MDG the thepyridine ofthe efficiency pyridine ring, of Carretero ring,the syn- Carretero and andthetic co-workers procedure.co-workers [47] To discoveredalternate [47] discovered the highly hardly highly regi removableoselective regioselective MDG Cu-catalyzed of Cu-catalyzed the pyridine ortho-monochlorina- ortho-monochlorination ring, Carretero and tionand co-workersand monobrominationmonobromination [47] discovered of of anilineshighly anilines regi containingcontainingoselective aa removableCu-catalyzed removableN -(2-pyridyl)sulfonylN ortho-monochlorina--(2-pyridyl)sulfonyl (SO 2Py) auxil- (SOtion2 Py)and auxiliary. monobrominationiary. In In the the presence presence of ofanilines theof the copper(II) copper(II)containing halide halide a catalyst removable catalyst and NXS,andN-(2-pyridyl)sulfonyl NXS, a class a of classo-chloro/bromoanilines of o- chloro/bromoanilines(SO2Py) auxiliary.was efﬁciently In thewas presence efficiently provided of under providedthe copper(II) aerobic under conditions halide aerobic catalyst conditions (Scheme and9 ).NXS, (Scheme The a SO class2 9).Py ofThe group o- could be SOchloro/bromoanilines2Py groupremoved could be by wasremoved treatment efficiently by withtreatment provided elemental with under magnesiumelemental aerobic magnesium conditions in methanol. (Schemein methanol. 9). The SO2Py group could be removed by treatment with elemental magnesium in methanol.

Scheme 9. Ortho-halogenationScheme 9. Ortho-halogenation of anilines acylated of anilines by SO acylated2Py used by asSO monodentate2Py used as monodentate directing group directing with subsequentgroup of withScheme subsequent 9. Ortho-halogenation of SO2Py using of magnesium anilines acylated in methanol by SO 2[47].Py used as monodentate directing group SO2Py using magnesium in methanol [47]. with subsequent of SO2Py using magnesium in methanol [47]. More recently,More Shi recently, and co-workers Shi and co-workers[48] reported [48 the] reported ortho-C–H the orthohalogenation-C–H halogenation of arylof aryl-2- 2-carboxamidesMore recently,carboxamides using Shi (2-(pyridine-2-yl)isopropylamineand using co-workers (2-(pyridine-2-yl)isopropylamine [48] reported the ortho(PIP)-C–H as (PIP) a halogenation bidentate as a bidentate directing of aryl- directing group group2-carboxamides (BDG).(BDG). The using copper The (2-(pyridine-2-yl)isopropylamine copper catalyst catalyst combined combined with NXS with (X = NXS(PIP) Cl, Br, (X as I) = aand Cl, bidentate a Br, proper I) and directing additive a proper additive promotedgroup (BDG). smoothlypromoted The copper the smoothly synthesis catalyst the ofcombined synthesisvarious witho-haloaryl-2-carboxamides of various NXS (Xo -haloaryl-2-carboxamides= Cl, Br, I) and (Schemea proper 10).additive (Scheme This 10). This Catalysts 2021, 11, x FORpromoted PEER REVIEW smoothly the synthesis of various o-haloaryl-2-carboxamides (Scheme 10). This 7 of 36 synthetic protocolsynthetic tolerated protocol not tolerated only carbon not only aryls, carbon but also aryls, various but also heteroaryls various heteroarylssuch as such as thiophene,synthetic protocol furanthiophene, and tolerated pyridine furan not and in onlythe pyridine amide carbon in component. thearyls, amide butcomponent. also various heteroaryls such as thiophene, furan and pyridine in the amide component. O O C NXS/CuX C NH NH Z Z Zn(OAc)2 N N ClCH2CH2Cl X 120 oC Z = CH=CH or N=CH or S or O X = Cl, Br, I

SchemeScheme 10.10.Ortho-halogenation Ortho-halogenation of of aromatic aromatic or or heterocyclic heterocyclic carboxylic carboxylic acids acids derivatized derivatized to to appropri- appro- atepriate amide amide working working as a as bidentate a bidentate directing direct grouping group (BDG) (BDG) using using the PIPthe PIP group group [48]. [48].

In the optimization process, Zn(OAc)2 additive reveals a beneficial effect on the reaction yield as well as on monoselectivity. Common functional groups such as F, Cl, Br, NO2 and CN are well tolerated. Apart from PIP as BDG, Li with co-workers described Cu(OAc)2 catalyzed selective aerobic oxidative ortho-chlorination of benzamides with tri- chloroacetamide using 1-(2-Aminophenyl)-1H-pyrazole as a less expensive, removable BDG [49]. The used BDG was removed readily with cerium ammonium nitrate oxidation (Scheme 11).

Scheme 11. Ortho-halogenation of benzoic amides containing 1-(2-aminophenyl)-1-H-pyrazole as BDG with subsequent oxidative cleavage [49].

Liu, Wan, and Du achieved a CuO-catalyzed, one-pot N-acylation with subsequent C5–H halogenation of 8-aminoquinolines by direct employment of acyl halides as both the acylation and the halogenation reagent by co-action of air [50] (Scheme 12). The 8- Aminoquinoline skeleton works as both the substrate for acylation with acyl halide and after acylation of NH2-group as BDG. This remarkable reaction is a representative example of 100% atom economy.

Catalysts 2021, 11, x FOR PEER REVIEW 7 of 36

O O C NXS/CuX C NH NH Z Z Zn(OAc)2 N N ClCH2CH2Cl X 120 oC Z = CH=CH or N=CH or S or O X = Cl, Br, I

Catalysts 2021, 11, 378 7 of 34 Scheme 10. Ortho-halogenation of aromatic or heterocyclic carboxylic acids derivatized to appropriate amide working as a bidentate directing group (BDG) using the PIP group [48].

In the optimizationIn the optimizationprocess, Zn(OAc) process,2 additive Zn(OAc) reveals2 additive a beneficial reveals effect a on beneﬁcial the reac- effect on the tion yield as reactionwell as on yield monoselectivity. as well as on monoselectivity.Common functional Common groups functional such as F, groupsCl, Br, NO such2 as F, Cl, Br, and CN areNO well2 and tolerated. CN are wellApart tolerated. from PIP Apart as BDG, from Li PIP with as BDG, co-workers Li with co-workersdescribed described Cu(OAc)2 catalyzedCu(OAc) selective2 catalyzed aerobic selective oxidative aerobic ortho-chlorination oxidative ortho-chlorination of benzamides ofwith benzamides tri- with chloroacetamidetrichloroacetamide using 1-(2-Aminophenyl)-1 using 1-(2-Aminophenyl)-1H-pyrazole asH a-pyrazole less expensive, as a less removable expensive, removable BDG [49]. TheBDG used [49 BDG]. The was used removed BDG was readily removed with readilycerium withammonium cerium ammoniumnitrate oxidation nitrate oxidation (Scheme 11).(Scheme 11).

Scheme 11. Ortho-halogenationScheme 11. Ortho-halogenation of benzoic amides of benzoic containing amides 1-(2-aminophenyl)-1- containing 1-(2-aminophenyl)-1-H-pyrazole asH BDG-pyrazole with as subsequent oxidative cleavageBDG [with49]. subsequent oxidative cleavage [49].

Liu, Wan, andLiu, Du Wan, achieved and Du a CuO-catalyzed, achieved a CuO-catalyzed, one-pot N-acylation one-pot N-acylationwith subsequent with subsequent C5–H halogenationC5–H halogenation of 8-aminoquinolines of 8-aminoquinolines by direct employment by direct employment of acyl halides of acylas both halides as both the acylationthe and acylation the halogenation and the halogenation reagent by co-action reagent by of co-actionair [50] (Scheme of air [50 12).] (Scheme The 8- 12). The 8- AminoquinolineAminoquinoline skeleton works skeleton as both works the substrate as both the for substrate acylation for with acylation acyl halide with and acyl halide and after acylationafter of acylationNH2-group of NHas BDG.2-group This as remarkable BDG. This remarkable reaction is reactiona representative is a representative exam- example ple of 100% atomof 100% economy. atom economy. In the ﬁrst step, acylation of amino group proceeds with contemporary formation of HX which subsequently reacts with CuO catalyst and corresponding Lewis acid-base complex E between N-acyl-8-aminoquinoline and CuX2 is generated. After single electron transfer from Cu(II) cation to aromatic ring radical cation RC is formed and subsequent halide migration causes formation of the probably most stable radical R. Radical R de- composes to the 5-halogenated N-acyl 8-amino-quioline P, hydrogen radical and CuX. Hydrogen radical reduces CuX2 producing hydrogen halide and CuX. CuX2 is recycled by aerobic oxidation of CuX and can take part in the repeated catalytic cycle.

Catalysts 2021, 11, 378 8 of 34 Catalysts 2021, 11, x FOR PEER REVIEW 8 of 36

1 1 R R H X O O CuO (40 mol.%) C RCX + H N R N 2 H X =Br,Cl N N P

R1 H O +HX +CuO H2O C R N H N CuX2 +air HX

H+CuX 1 1 R SET R H H O O X C C R N R N H 2+ 1 H + Cu N SET R Cu N X X H X O R E + C X migration R N H Cu+ N X X RC

Scheme 12. AcylationScheme of 12. 8-aminoquinoline Acylation of 8-aminoquinoline accompanied by accompanied selective Cu-catalyzed by selective halogenation Cu-catalyzed with halogenation proposed reaction mechanism [50].with proposed reaction mechanism [50].

In the first Chenstep, acylation and co-workers of amino developed group proceeds CuX-mediated with contemporary selective monohalogenation formation of of 2- HX whichmethylquinolines subsequently reacts producing with CuO corresponding catalyst and heterobenzylcorresponding halides Lewis [51acid-base] (Scheme 13). It complex E shouldbetween be N-acyl-8-ami noted that traditionalnoquinoline methods and CuX for2 is halogenation generated. After at the single heterobenzyl electron position Catalysts 2021, 11, x FOR PEER REVIEW 9 of 36 transfer fromwith Cu(II) NCS, cation NBS, orto NISaromatic result ring in mixtures radical ofcation the monohalogenated RC is formed and product subsequent and the dihalo- halide migrationgenated causes side product. formation of the probably most stable radical R. Radical R de- composes to the 5-halogenated N-acyl 8-amino-quioline P, hydrogen radical and CuX. Hydrogen radical reduces CuX2 producing hydrogen halide and CuX. CuX2 is recycled by aerobic oxidation of CuX and can take part in the repeated catalytic cycle. Chen and co-workers developed CuX-mediated selective monohalogenation of 2- methylquinolines producing corresponding heterobenzyl halides [51] (Scheme 13). It should be noted that traditional methods for halogenation at the heterobenzyl position with NCS, NBS, or NIS result in mixtures of the monohalogenated product and the dihalogenated sideSchemeScheme product. 13.13. Cu-catalyzedCu-catalyzed α α-halogenation-halogenation ofof 2-methylquinolines2-methylquinolines [[51].51].

InIn recentrecent years,years, thethe formationformation ofof C–FC–F chemicalchemical bondsbonds receivedreceived globalglobal researchresearch interestinterest duedue to the the particular particular functions functions of ofmany many fluorinated ﬂuorinated chemicals chemicals [2]. Accordingly, [2]. Accordingly, C–H fluor- C–H ﬂuorinationination reactions reactions also become also become an issue an of issue broad of concern broad concern as such asa transformation such a transformation provides a straightforward route for rapid synthesis of diversity-enriched fluorinated products. Daugulis and co-worker [52] established a Cu(I) catalyzed Carom–H ortho-fluorination of N-(quinolin-8-yl)benzamides (Scheme 14). The mono- and/or difluorination took place in the presence of CuI, N-methylmorpholine N-oxide (NMO) and pyridine by using DMF as the medium and AgF as the fluorine source, providing mono- or difluorinated products, respectively. This method manifests excellent functional group tolerance and provides a novel route for the preparation of ortho-fluorinated benzoic acids. As occurred in most cases involving the activation of two identical C–H bonds, the unsatisfactory chemo- selectivity in forming mixed products in many entries continued to be a problem to address [52] (Scheme 14).

Scheme 14. CuI/AgF based ortho-fluorination of benzamides bearing quinoline-based BDG [52].

2.3. Alternative Methods Applicable for Cu-Catalyzed Syntheses of Ar-Xs In 2002, Subramanian reported the conversion of aromatics to monofluoroaromatics using a CuF2 catalyst [53] (Scheme 15). The CuF2 oxidatively fluorinates the aromatic substrate with concomitant formation of HF and Cu metal. The latter is reoxidized to the active CuF2 species by two equivalents of HF and a half equivalent of O2, generating one equivalent of water as the sole by-product in the process. Despite the high temperatures and narrow scope of this process, it served as an important starting point for more advanced catalytic methods of halogenation using copper.

Catalysts 2021, 11, x FOR PEER REVIEW 9 of 36

Scheme 13. Cu-catalyzed α-halogenation of 2-methylquinolines [51]. Scheme 13. Cu-catalyzed α-halogenation of 2-methylquinolines [51]. In recent years, the formation of C–F chemical bonds received global research interest due to the particular functions of many fluorinated chemicals [2]. Accordingly, C–H fluor- In recent years, the formation of C–F chemical bonds received global research interest Catalysts 2021, 11, 378 ination reactions also become an issue of broad concern as such a transformation provides9 of 34 due to the particular functions of many fluorinated chemicals [2]. Accordingly, C–H fluor- a straightforward route for rapid synthesis of diversity-enriched fluorinated products. ination reactions also become an issue of broad concern as such a transformation provides Daugulis and co-worker [52] established a Cu(I) catalyzed Carom–H ortho-fluorination a straightforward route for rapid synthesis of diversity-enriched fluorinated products. of N-(quinolin-8-yl)benzamides (Scheme 14). The mono- and/or difluorination took place Daugulisprovides and co-worker a straightforward [52] established route a forCu(I) rapid catalyzed synthesis Carom of–H diversity-enriched ortho-fluorination fluorinated in the presence of CuI, N-methylmorpholine N-oxide (NMO) and pyridine by using DMF of N-(quinolin-8-yl)benzamidesproducts. (Scheme 14). The mono- and/or difluorination took place as the medium and AgF as the fluorine source, providing mono- or difluorinated prod- in the presence ofDaugulis CuI, N-methylmorpholine and co-worker [52] N-oxide established (NMO) a Cu(I) and catalyzed pyridine C byarom using–H ortho-fluorination DMF ucts, respectively. This method manifests excellent functional group tolerance and pro- as the mediumof N-(quinolin-8-yl)benzamides and AgF as the fluorine source, (Scheme providing 14). The mono- mono- or and/or difluorinated difluorination prod- took place vides a novel route for the preparation of ortho-fluorinated benzoic acids. As occurred in ucts, respectively.in the presenceThis method of CuI, manifests N-methylmorpholine excellent functional N-oxide group (NMO) tolerance and and pyridine pro- by using most cases involving the activation of two identical C–H bonds, the unsatisfactory chemo- vides a novelDMF route as for the the medium preparation and AgF of ortho-fluorinated as the fluorine source, benzoic providing acids. As mono-occurred or difluorinatedin selectivity in forming mixed products in many entries continued to be a problem to ad- most cases involvingproducts, the respectively. activation of This two method identical manifests C–H bonds, excellent the unsatisfactory functional group chemo- tolerance and dress [52] (Scheme 14). selectivity inprovides forming a mixed novel routeproducts for the in preparationmany entries of continued ortho-fluorinated to be a problem benzoic acids. to ad- As occurred dress [52] (Schemein most 14). cases involving the activation of two identical C–H bonds, the unsatisfactory chemo-selectivity in forming mixed products in many entries continued to be a problem to address [52] (Scheme 14).

Scheme 14. CuI/AgF based ortho-fluorination of benzamides bearing quinoline-based BDG [52]. SchemeScheme 14. 14.CuI/AgF CuI/AgF based based ortho-fluorination ortho-fluorination of of benzamides benzamides bearing bearing quinoline-based quinoline-based BDG BDG [52 [52].]. 2.3. Alternative Methods Applicable for Cu-Catalyzed Syntheses of Ar-Xs 2.3. Alternative MethodsIn 2002, Applicable Subramanian for Cu-Catalyzed reported the Syntheses conversi ofon Ar-Xs of aromatics to monofluoroaromatics 2.3.using Alternative a CuF2 catalyst Methods [53] Applicable (Scheme for 15). Cu-Catalyzed The CuF2 oxidatively Syntheses of fluorinates Ar-Xs the aromatic sub- In 2002, Subramanian reported the conversion of aromatics to monofluoroaromatics strateIn with 2002, concomitant Subramanian formation reported of the HF conversion and Cu metal. of aromatics The latter to is monofluoroaromatics reoxidized to the ac- using a CuF2 catalyst [53] (Scheme 15). The CuF2 oxidatively fluorinates the aromatic sub- usingtive CuF a CuF2 speciescatalyst by two [53 ]equivalents (Scheme 15 of). TheHF and CuF a halfoxidatively equivalent fluorinates of O2, generating the aromatic one strate with concomitant 2formation of HF and Cu metal. The latter2 is reoxidized to the ac- substrateequivalent with of water concomitant as the sole formation by-product of HF in and the Cu process. metal. Despite The latter the is high reoxidized temperatures to the tive CuF2 species by two equivalents of HF and a half equivalent of O2, generating one activeand narrow CuF species scope of by this two process, equivalents it served of HF as and an a important half equivalent starting of Opoint, generating for more one ad- equivalent of water as2 the sole by-product in the process. Despite the high temperatures2 equivalentvanced catalytic of water methods as the of sole halogenation by-product using in the copper. process. Despite the high temperatures and narrow scope of this process, it served as an important starting point for more ad- and narrow scope of this process, it served as an important starting point for more advanced vanced catalytic methods of halogenation using copper. catalytic methods of halogenation using copper.

Scheme 15. High-temperature CuF2 catalyzed ﬂuorination with subsequent recycling of CuF2 by oxyﬂuorination of produced copper [53].

Transition metal-catalyzed or transition metal-mediated halogen exchange has recently been emerging as a promising pathway for the production of otherwise not readily available Ar-Xs [54–57]. Aryl iodides (Ar–Is) have recently attracted increased attention due to their high reactivity in comparison with the corresponding Ar-Cls or Ar-Brs and the possibility of producing valuable hypervalent iodine-based reagents applicable as oxidants, etc. [58,59]. Cu-catalyzed decarboxylative iodination of 2-nitrobenzoic acids to the corresponding 2-nitro-iodobenzenes was published by Stang et al. (Scheme 16)[60]. Catalysts 2021, 11, x FOR PEER REVIEW 10 of 36

Scheme 15. High-temperature CuF2 catalyzed fluorination with subsequent recycling of CuF2 by oxyfluorination of produced copper [53].

Transition metal-catalyzed or transition metal-mediated halogen exchange has recently been emerging as a promising pathway for the production of otherwise not readily available Ar-Xs [54–57]. Aryl iodides (Ar–Is) have recently attracted increased attention due to their high re- Catalysts 2021, 11, x FOR PEER REVIEWactivity in comparison with the corresponding Ar-Cls or Ar-Brs and the possibility of10 pro- of 36 ducing valuable hypervalent iodine-based reagents applicable as oxidants, etc. [58,59]. Cu-catalyzed decarboxylative iodination of 2-nitrobenzoic acids to the correspond- Catalysts 2021, 11, 378 ing 2-nitro-iodobenzenes was published by Stang et al. (Scheme 16) [60]. 10 of 34 Scheme 15. High-temperature CuF2 catalyzed fluorination with subsequent recycling of CuF2 by oxyfluorination of produced copper [53]. Scheme 16. Cu(II)-catalyzed decarboxylative iodination of 2-nitrobenzoic acid [53]. Transition metal-catalyzed or transition metal-mediated halogen exchange has re- centlyA general been emerging method asfor a thepromising interconversion pathway offor different the production aromatic of otherwisehalogen derivatives not readily (so-called aromatic Finkelstein reaction) was also described converting aryl chlorides or available Ar-Xs [54–57]. bromides into the corresponding aryl iodides or aryl fluorides using the corresponding Aryl iodides (Ar–Is) have recently attracted increased attention due to their high re- Cu(I) halogenide as the catalyst and N,N′-dimethyl-cyclohexane-1,2-diamine L1 (Figure activity in comparison with the corresponding Ar-Cls or Ar-Brs and the possibility of pro- 1) as a ligand [61] (Scheme 17). ducing valuable hypervalent iodine-based reagents applicable as oxidants, etc. [58,59]. Cu-catalyzed decarboxylative iodination of 2-nitrobenzoic acids to the corresponding 2-nitro-iodobenzenes was published by Stang et al. (Scheme 16) [60]. SchemeScheme 16.16.Cu(II)-catalyzed Cu(II)-catalyzed decarboxylativedecarboxylative iodination iodination of of 2-nitrobenzoic 2-nitrobenzoic acid acid [ 53[53].].

AA generalgeneral methodmethod forfor thethe interconversion interconversion ofof different different aromatic aromatic halogen halogen derivatives derivatives (so-called(so-called aromaticaromatic FinkelsteinFinkelstein reaction)reaction) waswas alsoalso described describedconverting converting arylaryl chlorides chlorides or or bromidesbromides intointo thethe correspondingcorresponding arylaryl iodidesiodides oror arylaryl ﬂuorides fluorides using using the the corresponding corresponding Cu(I)Cu(I) halogenidehalogenide as as the the catalyst catalyst and and N,N N,N0-dimethyl-cyclohexane-1,2-diamine′-dimethyl-cyclohexane-1,2-diamine L1 L1(Figure (Figure1) Schemeas1) aas ligand a 17.ligand CuI [61 catalyzed][61] (Scheme (Scheme aromatic 17). 17). halogen-exchange reaction (aromatic Finkelstein reaction) [61].

Scheme 16. Cu(II)-catalyzed decarboxylative iodination of 2-nitrobenzoic acid [53].

A general method for the interconversion of different aromatic halogen derivatives

(so-called aromatic Finkelstein reaction) was also described converting aryl chlorides or bromides into the corresponding aryl iodides or aryl fluorides using the corresponding Scheme 17. CuI catalyzed aromatic halogen-exchange reaction (aromatic Finkelstein reaction) [61]. Cu(I) halogenide as the catalyst and N,N′-dimethyl-cyclohexane-1,2-diamine L1 (Figure FigureFigure 1. 1. StructuresStructures of of ligands ligands used used for for arom aromaticatic Finkelstein Finkelstein reaction reaction [55,61–63]. [55,61–63]. 1) as a ligand [61] (Scheme 17).

A wide array of substrates, including sterically hindered aryl bromides and heteroaryl bromides were well tolerated under the reaction conditions which employ inexpensive CuI, excess of NaI and a commercially available racemic diamine as a supporting ligand [55]. Buchwald and co-workers reported a potentially scale-up attractive variation to the above described Cu-catalyzed aromatic Finkelstein reaction which used a continuous flow reactor [62]. Remarkably, it was observed that the reaction of PhBr performed

Figure 1. Structures of ligands used for aromatic Finkelstein reaction [55,61–63]. SchemeScheme 17. 17.CuI CuI catalyzedcatalyzed aromatic aromatic halogen-exchange halogen-exchange reaction reaction (aromatic (aromatic Finkelstein Finkelstein reaction) reaction) [ 61[61].].

AA widewide array array of of substrates, substrates, including including sterically sterically hindered hindered aryl bromidesaryl bromides and heteroaryl and het- bromideseroaryl bromides were well were tolerated well tolerated under the under reaction the reaction conditions conditions which employ which employ inexpensive inex- CuI,pensive excess CuI, of excess NaI and of NaI a commercially and a commercially available available racemic racemic diamine diamine as a supportingas a supporting lig- Catalysts 2021, 11, x FOR PEER REVIEWligand [55]. Buchwald and co-workers reported a potentially scale-up attractive variation11 of 36 and [55]. Buchwald and co-workers reported a potentially scale-up attractive variation to to the above described Cu-catalyzed aromatic Finkelstein reaction which used a continu- the above described Cu-catalyzed aromatic Finkelstein reaction which used a continuous ous flow reactor [62]. Remarkably, it was observed that the reaction of PhBr performed ﬂow reactor [62]. Remarkably, it was observed that the reaction of PhBr performed with KI catalyzedwith KI catalyzed by CuI/1,10-phenanthroline by CuI/1,10-phenanthroline in DMF atin 110oCDMF at resulted 110oC inresulted the rapid in the formation rapid for- of

iodobenzenemation of iodobenzene in good yields in good [63]. yields The subsequent [63]. The subsequent kinetics studies, kinetics conducted studies, byconducted reacting anby equimolarreactingFigure 1. anStructures mixture equimolar ofof PhBrligands mixture and used KI of for or PhBr PhIarom andandatic KBr, KIFinkelstein or both PhI afforded andreaction KBr, a[55,61–63]. mixtureboth afforded with an aidentical mixture composition (20% PhBr and 80% PhI), thereby indicating the existence of thermodynamic with an identical composition (20% PhBr and 80% PhI), thereby indicating the existence equilibriumof thermodynamicA wide between array equilibrium of PhI substrates, and PhBr betw including (Schemeeen PhI 18 andsterically). PhBr (Schemehindered 18). aryl bromides and heteroaryl bromides were well tolerated under the reaction conditions which employ inexpensive CuI, excessL2 (10 of NaI mol%) and a commercially available racemic diamine as a supporting ligand [55]. BuchwaldCuI (5 and mol%) co-workers reported a potentially scale-up attractive variation Phto the Br above + KI described Cu-catalyzedPh aromaticI + KBr Finkelstein reaction which used a continuous flow reactor [62].DMF Remarkably,80 it was % observed that the reaction of PhBr performed 110 oC, 48 h

Scheme 18.18. CuI catalyzed halide exchange reactionreaction [[63].63].

The interconversion of different aromatic iodo- or bromo derivatives into Ar-Br or Ar-Cl was also described. Utilization of ionic liquid 1-butyl-3-methylimidazolium bromide (BMIMBr) as the solvent by co-action of copper halide salts enables, for example, this halogen-exchange reaction (Scheme 19) [64].

Scheme 19. CuX based iodide exchange reaction in ionic liquid BMIMBr [64].

Another method bypassing the usage of high excess of expensive ionic liquid in the dual role of the reaction solvent and liquid ion-exchanger is based on Cu2O-catalyzed conversion of aryl and heteroaryl bromides to the corresponding chlorides by cheap Me4NCl as the halide source in ethanol (Scheme 20) using L3 as the ligand (Figure 1). This reaction provides good to excellent yields of the aryl and heteroaryl chloride products when 20 mol % of [Cu] is employed [65].

Scheme 20. Cu2O catalyzed bromide exchange reaction using quaternary ammonium chloride [65].

These interconversion methods make potentially possible in-situ preparation of reactive Ar-I derivatives from common and simply available Ar-Cl or Ar-Br derivatives for subsequent nucleophilic aromatic substitution of halogen. These reactions are described in the following chapters. It can be stated that Cu-based halogenations of aromatic compounds enable the modern regioselective formation of a wide range of Ar-Xs which are applicable as intermediates for the synthesis of organic fine chemicals. Massive production and broad utilization of halogenated aromatic compounds are also joined with the production of hazardous waste streams often contaminated with stable polychlorinated by-products which could cause long-term contamination of the environment.

CatalystsCatalysts 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 1111 ofof 3636

withwith KIKI catalyzedcatalyzed byby CuI/1,10-phenanthrolineCuI/1,10-phenanthroline inin DMFDMF atat 110oC110oC resultedresulted inin thethe rapidrapid for-for- mationmation ofof iodobenzeneiodobenzene inin goodgood yieldsyields [63].[63]. TheThe subsequentsubsequent kineticskinetics studies,studies, conductedconducted byby reactingreacting anan equimolarequimolar mixturemixture ofof PhBrPhBr andand KIKI oror PhIPhI andand KBr,KBr, bothboth affordedafforded aa mixturemixture withwith anan identicalidentical compositioncomposition (20%(20% PhBrPhBr andand 80%80% PhI),PhI), therebythereby indicatingindicating thethe existenceexistence ofof thermodynamicthermodynamic equilibriumequilibrium betwbetweeneen PhIPhI andand PhBrPhBr (Scheme(Scheme 18).18).

L2L2 (10(10 mol%) mol%) CuICuI (5 (5 mol%) mol%) PhPh Br Br + + K KII PhPh II ++ KBr KBr DMF DMF 8080 % % Catalysts 2021, 11, 378 110110 ooC,C, 48 48 h h 11 of 34

SchemeScheme 18.18. CuICuI catalyzedcatalyzed halidehalide exchangeexchange reactionreaction [63].[63].

TheTheThe interconversioninterconversioninterconversion ofofof differentdifferentdifferent aromaticaromaticaromatic iodo-iodo-iodo- ororor bromo bromobromo derivatives derivativesderivatives into intointo Ar-Br Ar-BrAr-Br or oror Ar-ClAr-ClAr-Cl was waswas also alsoalso described. described.described. Utilization UtilizationUtilization of ionicofof ionicionic liquid liquidliquid 1-butyl-3-methylimidazolium 1-butyl-3-methylimidazolium1-butyl-3-methylimidazolium bromide bro-bro- (BMIMBr)midemide (BMIMBr)(BMIMBr) as the asas solvent thethe solventsolvent by co-action byby co-actionco-action of copper ofof coppercopper halide halidehalide salts enables,saltssalts enables,enables, for example, forfor example,example, this halogen-exchangethisthis halogen-exchangehalogen-exchange reaction reactionreaction (Scheme (Scheme(Scheme 19)[ 64 19)19)]. [64].[64].

SchemeSchemeScheme 19. 19.19. CuX CuXCuX based basedbased iodide iodideiodide exchange exchangeexchange reaction reactionreaction in inin ionic ionicionic liquid liquidliquid BMIMBr BMIMBrBMIMBr [ [64].64[64].].

AnotherAnotherAnother method methodmethod bypassing bypassingbypassing the thethe usage usageusage of ofof high highhigh excess excessexcess of ofof expensive expensiveexpensive ionic ionicionic liquid liquidliquid in inin the thethe dualdualdual rolerole of of thethe reactionreaction reaction solventsolvent solvent andand and liquidliquid liquid ion-exchangerion-exchanger ion-exchanger isis basedbased is based onon CuCu on22 CuO-catalyzedO-catalyzed2O-catalyzed con-con- conversionversionversion ofof arylaryl of aryl andand heteroaryl andheteroaryl heteroaryl bromidesbromides bromides toto thethe to correspondingcorresponding the corresponding chlorideschlorides chlorides byby cheapcheap by MeMe cheap44NClNCl Measas the4theNCl halidehalide as the sourcesource halide inin source ethanolethanol in (Scheme ethanol(Scheme (Scheme 20)20) usingusing 20 L3L3) using asas thetheL3 ligandligandas the (Figure(Figure ligand 1). (Figure1). ThisThis 1 reactionreaction). This reactionprovidesprovides provides goodgood toto goodexcellentexcellent to excellent yieldsyields ofof yields thethe arylaryl of theandand aryl heteroarylheteroaryl and heteroaryl chloridechloride chlorideproductsproducts products whenwhen 2020 whenmolmol %% 20 ofof mol [Cu][Cu] % isis of employedemployed [Cu] is employed [65].[65]. [65].

SchemeSchemeScheme 20. 20.20. Cu CuCu222OO catalyzedcatalyzed bromidebromide exchange exchanexchangege reaction reactionreaction using usingusing quaternary quaternaryquaternary ammonium ammoniumammonium chloride chloridechloride [ 65]. [65].[65]. These interconversion methods make potentially possible in-situ preparation of re- activeTheseThese Ar-I derivatives interconversioninterconversion from methods commonmethods andmakemake simply potentiallypotentially available possiblepossible Ar-Cl in-situin-situ or Ar-Br preparationpreparation derivatives ofof for re-re- subsequentactiveactive Ar-IAr-I derivatives nucleophilicderivatives fromfrom aromatic commoncommon substitution andand simpsimp oflyly halogen. availableavailable These Ar-ClAr-Cl reactions oror Ar-BrAr-Br are derivativesderivatives described forfor in thesubsequentsubsequent following nucleophilicnucleophilic chapters. aromaticaromatic substitutionsubstitution ofof halogen.halogen. TheseThese reactionsreactions areare describeddescribed inin thetheIt following canfollowing be stated chapters.chapters. that Cu-based halogenations of aromatic compounds enable the modern regioselectiveItIt cancan bebe statedstated formation thatthat Cu-basedCu-based of a wide halogenationshalogenations range of Ar-Xs ofof aromaticaromatic which are compoundscompounds applicableas enableenable intermediates thethe mod-mod- forernern the regioselectiveregioselective synthesis of formationformation organic ﬁne ofof aa chemicals. widewide rangerange Massive ofof Ar-XsAr-Xs production whichwhich areare and applicableapplicable broad utilizationasas intermedi-intermedi- of halogenatedatesates forfor thethe synthesissynthesis aromatic of compoundsof organicorganic finefine are chemicchemic also joinedals.als. MassiveMassive with the productionproduction production andand of hazardous broadbroad utilizationutilization waste streamsofof halogenatedhalogenated often contaminated aromaticaromatic compoundscompounds with stable areare polychlorinated alsoalso joinedjoined withwith by-products thethe productionproduction which ofof could hazardoushazardous cause long-term contamination of the environment. wastewaste streamsstreams oftenoften contaminatedcontaminated withwith stabstablele polychlorinatedpolychlorinated by-productsby-products whichwhich couldcould cause long-term contamination of the environment. 2.4.cause Cu-Mediated long-term Formationcontamination of Polychlorinated of the environment. Aromatic Pollutants Disposal of hazardous wastes containing chlorinated aromatic compounds in a way that minimizes the environmental hazards has become an urgent issue. Conventional incineration of these wastes produces harmful compounds, such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and polychlorinated naphtalenes (PCNs); even in slight concentrations, their stability, bioaccumulation ability and toxicity are enormous. Generally, PCNs, PCBs and PCDD/Fs are always emitted from thermal-related industries and these chemicals all have similar physicochemical properties, biological effects and toxic mechanisms [66]. Their formation is connected with Cu-catalyzed O2-based oxidation of HCl (Deacon reaction) and Cu-catalyzed C-O coupling [67,68] (Scheme 21). Catalysts 2021, 11, x FOR PEER REVIEW 12 of 36

2.4. Cu-Mediated Formation of Polychlorinated Aromatic Pollutants Disposal of hazardous wastes containing chlorinated aromatic compounds in a way that minimizes the environmental hazards has become an urgent issue. Conventional incineration of these wastes produces harmful compounds, such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and polychlorinated naphtalenes (PCNs); even in slight concentrations, their stability, bioaccumulation ability and toxicity are enormous. Generally, PCNs, PCBs and PCDD/Fs are always emitted from thermal-related industries and these chemicals all have Catalysts 2021, 11, 378 similar physicochemical properties, biological effects and toxic mechanisms [66].12 Their of 34 formation is connected with Cu-catalyzed O2-based oxidation of HCl (Deacon reaction) and Cu-catalyzed C-O coupling [67,68] (Scheme 21).

SchemeScheme 21. 21.Cu-catalyzed Cu-catalyzed de-novo de-novo synthesis synthesis of of chlorinated chlorinated aromatic aromatic compounds compounds (Ar–Cl) (Ar–Cl) [ 67[67–74].–74].

ItIt has has been been suggested suggested in in several several studies studies that that the the so-called so-called de de novo novo synthesis synthesis of of PCBs, PCBs, PCNsPCNs and and PCDD/Fs PCDD/Fs occursoccurs inin thermal-relatedthermal-related industriesindustries fromfrom thethe coupling coupling of of phenoxy phenoxy radicalsradicals (formed (formed from from chlorinated chlorinated phenols) phenols) or or from from the the degradation degradation of of polycyclic polycyclic aromatic aromatic hydrocarbonshydrocarbons followedfollowed by their repeated repeated chlorination chlorination at at a atemperature temperature above above 300 300 °C ◦andC andthe theco-action co-action of oxygen. of oxygen. Chlorination Chlorination can be can catalyzed be catalyzed by transition by transition metal metal species, species, espe- especiallycially copper copper compounds compounds (Scheme (Scheme 21), which21), which are known are known to have to havestrong strong catalytic catalytic effects effects[69–74]. [69 These–74]. Thesechemicals chemicals all have all similar have similar physicochemical physicochemical properties, properties, biological biological effects effectsand toxic and mechanisms toxic mechanisms [66]. It [was66]. Itobserved, was observed, for example, for example, that unexpectedly that unexpectedly high concen- high concentrationstrations of PCNs of PCNswere formed were formed on fly onash fly from ash a from secondary a secondary copper copper smelting smelting process process at 250– ◦ at450 250–450 °C [74].C[ 74]. ForFor the the above-mentioned above-mentioned reasons, reasons, dehalogenation dehalogenation reactions reactions of Ar-Xsof Ar-Xs not not only only play play an importantan important role forrole the for transformation the transformation of Ar–Xs of Ar–Xs to the desiredto the desired organic organic fine chemicals fine chemicals (drugs, pesticides,(drugs, pesticides, etc.) but etc.) even but for ev theen transformation for the transformation of harmful of harmful and non-biodegradable and non-biodegradable Ar-Xs toAr-Xs the dehalogenatedto the dehalogenated and obviously and obviously readily readily biodegradable biodegradable non-halogenated non-halogenated products. prod- Copper-baseducts. Copper-based catalysis catalysis plays anplays important an important role even role ineven this in field. this field. Due to Due the to focus the focus of this of articlethis article on the on applicabilitythe applicability of copper of copper in contextin context with with the the solution solution of of the the environmental environmental aspectsaspects ofof application application of of halogenated halogenated aromatic aromatic compounds, compounds, only only Cu-catalyzed Cu-catalyzed C-C C-C and and C-O couplings together with reductive dehalogenation reactions are reviewed as the crucial processes for the possible chemical degradation of polyhalogenated oxygen heterocycles and their above-mentioned precursors.

3. Cu-Catalyzed Dehalogenation of Carom-X Bond 3.1. The Role of Cu in Nucleophilic Substitutions of Halogens in Ar-Xs Cu-catalyzed arylation reactions devoted to the formation of C–C and C–heteroatom bonds (Ullmann type couplings) have acquired great importance in the last two decades. From the environmental chemistry point of view, arylation reactions converting Ar-Xs to the corresponding non-halogenated products are also an uncoverable way for effective chemical destruction of very stable and almost non-biodegradable and toxic halogenated aromatic compounds. The scope of Cu-catalyzed cross-coupling reactions is increasing, Catalysts 2021, 11, 378and seems to be somewhat complementary to that of Pd-based methodologies. Finally, in 13 of 34 many cases, Cu-catalyzed reactions work well without any ligand, and when required, the ligands are usually structurally quite simple and inexpensive (ligands for Pd chemistry are often complex,and seems expensive to be somewhat and air-sensitive) complementary [75,76]. to that of Pd-based methodologies. Finally, in As the ligandsmany cases, applicable Cu-catalyzed for complexation reactions work of catalytically well without active any ligand,Cu(I) complexes and when required, the applicable forligands C-heteroatom are usually bonds structurally formation, quite differe simplent secondary and inexpensive (N,N′-dimethylethane- (ligands for Pd chemistry are diamine (DMEDA),often complex, N,N′-dimethylcyclohexane-1,2-diamine expensive and air-sensitive) [75, 76L1].) or tertiary 1,2-diamines (1,10-phenanthrolineAs theL2 ligandsor N,N,N applicable′,N′-tetramethylethanediamine for complexation of catalytically (TMEDA)), active enamines, Cu(I) complexes ap- oximes, phosphines,plicable aminoacids for C-heteroatom (proline bonds L3,formation, N,N-dimethylglycine different secondary L7), thiofene-2-carbox- (N,N0-dimethylethanediamine ylic acid, 1,3-dicarbonyl(DMEDA), N,Ncompounds,0-dimethylcyclohexane-1,2-diamine or diols (ninhydrin, in someL1) orcases tertiary even 1,2-diamines monosacha- (1,10-phenanth rides) were demonstratedroline L2 or N,N,N for the0,N effective0-tetramethylethanediamine course of the above-mentioned (TMEDA)), enamines, C-C or C-het- oximes, phosphines, eroatom formationaminoacids [77,78] (proline (FiguresL3 ,1 N,N-dimethylglycine and 2). Two differentL7 ),roles thiofene-2-carboxylic were attributed to acid, the 1,3-dicarbonyl used additivescompounds, for Cu-catalyzed or diols Ar-Xs (ninhydrin, substitu intion some reactions. cases even The monosacharides) formation of more were sol- demonstrated uble cuprate speciesfor the and/or effective stabilization course of of the crucial above-mentioned Cu(I) active species C-C or for C-heteroatom subsequent cou- formation [77,78] pling reaction(Figures was suggested1 and2) .and/or Two different an additive roles would were attributed facilitate toan theoxidative used additives addition for of Cu-catalyzed Ar-X to the CuAr-Xs atom, substitution thus accelerating reactions. the The coupling formation [79]. of more soluble cuprate species and/or stabiliza- The maintion drawback of crucial of Cu(I) this activetype of species coupling for subsequent reaction is couplingthe known reaction inertness was suggestedof aryl and/or an chlorides to theadditive Cu-catalyzed would facilitate nucleophilic an oxidative substitution addition in ofmost Ar-X cases, to the typically Cu atom, only thus the accelerating the aryl iodides andcoupling sometimes [79]. bromides are applicable for the described arylation reactions.

Figure 2.Figure Commonly 2. Commonly used ligands used applied ligands appliedfor Cu-catalyzed for Cu-catalyzed Ullmann Ullmann reactions. reactions. The main drawback of this type of coupling reaction is the known inertness of aryl 3.2. Reactions of Ar-Xs with O-Nucleophiles chlorides to the Cu-catalyzed nucleophilic substitution in most cases, typically only the 3.2.1. Cu-Catalyzedaryl iodides Syntheses and sometimesof Phenols bromides are applicable for the described arylation reactions. Phenols are important building blocks in chemical, pharmaceutical and material sciences [80]. One3.2. of Reactions the main of methods Ar-Xs with used O-Nucleophiles for the synthesis of functionalized phenols includes halogenation3.2.1. Cu-Catalyzed of substituted Syntheses benzene derivatives of Phenols followed by the nucleophilic substitution of activatedPhenols aryl halides are important (alkali hydrolysis). building blocks Recently, in chemical, several homogeneous pharmaceutical and and material sciences [80]. One of the main methods used for the synthesis of functionalized phenols includes halogenation of substituted benzene derivatives followed by the nucleophilic substitution of activated aryl halides (alkali hydrolysis). Recently, several homogeneous and heterogeneous catalysts based on copper complexes were reported for the cross- coupling of aryl halides with hydroxide salts. The possibility of performance of Cu-catalyzed synthesis of phenols by nucleophilic substitution of Ar-Xs by OH- in aqueous solutions emphasizes the applicability of this type of reaction in the green chemistry area. Application of water as an eco-friendly solvent enables not only utilization of common water-soluble bases such as sodium or potassium hydroxides or carbonates and sometimes even saccharides or glycolic acid as the suitable ligands but also utilization of water as the source of the nucleophile. For these purposes, CatalystsCatalysts 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 1515 ofof 3636

heterogeneousheterogeneous catalystscatalysts basedbased onon coppercopper complexescomplexes werewere reportedreported forfor thethe cross-couplingcross-coupling ofof arylaryl halideshalides withwith hydroxidehydroxide salts.salts. TheThe possibilitypossibility ofof performanceperformance ofof Cu-catalCu-catalyzedyzed synthesissynthesis ofof phenolsphenols byby nucleophilicnucleophilic substitutionsubstitution ofof Ar-XsAr-Xs byby OHOH-- inin aqueousaqueous solutionssolutions emphasizesemphasizes thethe applicabilityapplicability ofof thisthis typetype ofof reactionreaction inin thethe greengreen chemistrychemistry area.area. ApplicationApplication ofof waterwater asas anan eco-friendlyeco-friendly sol-sol- ventvent enablesenables notnot onlyonly utilizationutilization ofof commoncommon water-solublewater-soluble basesbases suchsuch asas sodiumsodium oror potas-potas- siumsium hydroxideshydroxides oror carbonatescarbonates andand sometimessometimes eveneven saccharidessaccharides oror glycolicglycolic acidacid asas thethe suitable ligands but also utilization of water as the source of the nucleophile. For these Catalysts 2021, 11, 378 suitable ligands but also utilization of water as the source of the nucleophile. For14 these of 34 purposes,purposes, aqueousaqueous solutionssolutions ofof dimethyldimethyl sulfsulfoxideoxide (DMSO)(DMSO) serveserve asas thethe bio-basedbio-based organicorganic andand withwith waterwater fullyfully misciblemiscible solventsolvent [81–85].[81–85]. TheThe applicationapplication ofof Cu(II)Cu(II) saltsalt usingusing glucoseglucose asas thethe ligandligand forfor nucleophilicnucleophilic aromaticaromatic aqueoussubstitutionsubstitution solutions ofof halogenhalogen of dimethyl inin differentdifferent sulfoxide Ar–XsAr–Xs (DMSO) byby OHOH-serve- nucleophilenucleophile as the bio-based waswas publishedpublished organic (Scheme(Scheme and with 22)22) water[83].[83]. fully miscible solvent [81–85]. The application of Cu(II) salt using glucose as the ligand for nucleophilic aromatic sub- - stitution of halogen in different Ar–Xs by OH nucleophile was published (Scheme 22)[83].

SchemeSchemeScheme 22. 22.22. Formation FormationFormation ofof phenol-basedphenol-based onon Cu-catalyzedCu-catalyzed nucleophilic nucleophilic aromaticaromatic substitutionsubstitution usingusing using glucoseglucoseglucose as asas the thethe ligand ligandligand [ [83].83[83].].

ArylArylAryl iodidesiodidesiodides andandand bromides bromidesbromides 1 11 were werewere reacted reactedreacted with withwith excess excessexcess potassium potassiumpotassium hydroxide hydroxidehydroxide (4 (4(4−−−888 equivalences)equivalences)equivalences) in inin the thethe presence presencepresence of ofof copper(II) copper(II)copper(II) acetate acetacetateate (5 (5(5 mol molmol %) %)%) and andand glucose glucoseglucose (5 (5(5 mol molmol %) %)%) to toto give givegive goodgoodgood to toto excellent excellentexcellent yields yieldsyields of ofof the thethe corresponding correspondingcorresponding phenols phenolsphenols 2. 2.2. TheTheThe reactivity reactivityreactivity of ofof aryl arylaryl chlorides chlorideschlorides depended dependeddepended on onon the thethe nature naturenature of ofof the thethe electron-withdrawing electron-withdrawingelectron-withdrawing groupgroupgroup withwithwith substratessubstratessubstrates containingcontainicontainingng a a nitro nitro group group providing providing anan excellentexcellent yieldyield yield ofof of phenolphenol phenol 22 2[81].[81].[81]. Similarly,Similarly,Similarly, using usingusing proline prolineproline as asas the thethe ligand, ligand,ligand, dihydroxyterephtalic dihydroxyterephtalicdihydroxyterephtalic acid acidacid is isis produced producedproduced from fromfrom corresponding sodium salt of dihalogenated terephtalic acid using CuBr as a catalyst in correspondingcorresponding sodiumsodium saltsalt ofof dihalogenateddihalogenated terephtalicterephtalic acidacid usingusing CuBrCuBr222 asas aa catalystcatalyst inin ananan alkaline alkalinealkaline aqueous aqueousaqueous solution solutionsolution (Scheme (Scheme(Scheme 23 23)23))[ [82]82[82]]...

SchemeSchemeScheme 23. 23.23. Cu-catalyzed Cu-catalyzedCu-catalyzed formation formationformation of ofof 2,5-dihydroxyterephtalic 2,5-dihydroxyter2,5-dihydroxyterephtalicephtalic acid acidacid from fromfrom 2,5-dihalogenoterephtalic 2,5-dihalogenotereph-2,5-dihalogenotereph- acidtalictalic [ acid82acid]. [82,107].[82,107].

MethylatedMethylatedMethylated monosaccharidemonosaccharidemonosaccharide quebrachitolquebrachitolquebrachitol waswawass successfullysuccessfullysuccessfully testedtestedtested asasas thethethe ligand ligandligand of ofof choicechoicechoice using usingusing Cu CuCu22O2OO andandand NaOHNaOHNaOH forforfor effectiveeffectiveeffective hydroxylation hydroxylationhydroxylation of ofof aryl arylaryl iodides iodidesiodides in inin boiling boilingboiling water waterwater ororor aq. aq.aq. ethanol ethanolethanol on onon air airair [ [85]85[85]]... InInIn addition, addition,addition, Cu(CH Cu(CHCu(CH33CN)3CN)CN)44X4XX and andand Cu(NH Cu(NHCu(NH33)3)4)44XX complexescomplexescomplexes (X (X(X = == PF PFPF66,6,, HSO HSOHSO444))) werewerewere proved provedproved Catalysts 2021, 11, x FOR PEER REVIEWasas effective effective catalysts catalysts for for hydroxylation hydroxylation of of o-bromo- o-bromo- or or o-chlorobenzoic o-chlorobenzoic acid acid in in an an alkaline alkaline16 of 36 as effective catalysts for hydroxylation of o-bromo- or o-chlorobenzoic acid in an alkaline aqueousaqueousaqueous solution. solution.solution. TheTheThe mainmainmain rolerolerole of ofof these thesethese complexes complexescomplexes is isis in inin the thethe increasing increasingincreasing of ofof a aa catalytically catalyticallycatalytically actingactingacting Cu(I) Cu(I)Cu(I) ions ionsions concentration concentrationconcentration ininin an anan aqueous aqueousaqueous reaction reactionreaction medium, medium,medium, as asas was waswas documented documenteddocumented by byby SaphierSaphier Saphier et etet al. al.al. (Scheme (Scheme(Scheme 24 24)24))[ [86]86[86]]...

SchemeScheme 24. 24.Cu-catalyzed Cu-catalyzed formationformation salicylic salicylic acid acid from from 2-halogenobenzoic 2-halogenobenzoic [ 87[87].].

ArylAryl bromidesbromides and and even even aryl aryl chlorides chlorides were were converted converted to to the the corresponding corresponding phenols phenols inin anan alkaline alkaline aqueousaqueous DMSODMSO solutionsolution usingusing CsOHCsOH asas aa base base under under argon argon after after several several daysdays ofof heatingheating at at 130 130◦oCC usingusing 8-hydroxyquinoline-N-oxide8-hydroxyquinoline-N-oxide asas thetheligand ligand[ 87[87]].. One of the most efficient copper-based catalytic systems for hydroxylation of even aryl chlorides based comprising copper(II) acetylacetonate and N,N′-bis(4-hydroxy-2,6- dimethylphenyl)-oxalamide in DMSO/H2O mixture using LiOH or KOH was described by Ma et al. [88]. Another possibility for the effective performance of different Ar–I or Ar–Br substitution reactions in the aqueous reaction medium requires phase-transfer catalysis (PTC) conditions using a two-phase (aqueous-organic) reaction mixture. In this case, CuI nanoparticles were used with co-action of Bu4NOH as the source of nucleophile [89]. In conclusion, even Cu-catalyzed hydroxylation of Ar-Xs is feasible in green solvents as are DMSO/H2O and cheap bases as are potassium or sodium hydroxides, carbonates or phosphates, only a few examples of effective utilization of Ar-Cls were published using entirely different ligands. In this case, the high potential of tandem catalysis to transform non-reactive Ar-Cl to reactive Ar-I that is subsequently hydroxylated to the corresponding Ar-OH could be expected.

3.2.2. Cu-Catalyzed Syntheses of Aryl Ethers from Ar-Xs Cu-catalyzed nucleophilic substitution of halogen (especially I or Br) in Ar-X by aliphatic alcoholates are usually performed in polar aprotic solvents such as N,N-dimethyl- formamide (DMF). The mechanism of the Ar-Xs substitution by sodium methanolate as O-nucleophile was studied, CuOCH3 (or NaCu(OCH3)2, respectively) was proposed as the key intermediate in anisole synthesis from bromobenzene by Aalten and others [90]. Methanolysis is applicable even for the preparation of sterically hindered derivatives which has been shown by Righi et al. in the case of the flavonoide Mosloflavone synthesis (Scheme 25) [91].

Scheme 25. Cu-catalyzed methoxylation of sterically hindered 6-bromo-5-hydroxy-7-methoxyfla- vone [91].

1,10-Phenanthroline L2 was tested as a simple and cheap ligand suitable for the preparation of an effective CuI-based catalyst for the reaction of primary and secondary alcohols with iodoarenes under quite mild reaction conditions enabling the preparation of optically pure chiral ethers (Scheme 26) [92].

Catalysts 2021, 11, x FOR PEER REVIEW 16 of 36

Scheme 24. Cu-catalyzed formation salicylic acid from 2-halogenobenzoic [87].

Catalysts 2021, 11, 378 Aryl bromides and even aryl chlorides were converted to the corresponding phenols15 of 34 in an alkaline aqueous DMSO solution using CsOH as a base under argon after several days of heating at 130oC using 8-hydroxyquinoline-N-oxide as the ligand [87]. One of the most efficient copper-based catalytic systems for hydroxylation of even One of the most efﬁcient copper-based catalytic systems for hydroxylation of even aryl chlorideschlorides basedbased comprisingcomprising copper(II)copper(II) acetylacetonateacetylacetonate andand N,NN,N0′-bis(4-hydroxy-2,6--bis(4-hydroxy-2,6- dimethylphenyl)-oxalamide in DMSO/H2O mixture using LiOH or KOH was described dimethylphenyl)-oxalamide in DMSO/H2O mixture using LiOH or KOH was described by MaMa etet al.al. [[88]88].. Another possibility for for the the effective effective performance performance of of different different Ar–I Ar–I or or Ar–Br Ar–Br substitu- substi- tutiontion reactions reactions in in the the aqueous aqueous reaction reaction medium medium requires requires phase-transfer catalysis (PTC)(PTC) conditionsconditions usingusing a a two-phase two-phase (aqueous-organic) (aqueous-organic) reaction reaction mixture. mixture. In In this this case, case, CuI CuI nanopar- nano- particles were used with co-action of Bu4NOH as the source of nucleophile [89]. ticles were used with co-action of Bu4NOH as the source of nucleophile [89]. InIn conclusion,conclusion, eveneven Cu-catalyzedCu-catalyzed hydroxylationhydroxylation ofof Ar-XsAr-Xs isis feasiblefeasible inin greengreen solventssolvents as are DMSO/H2O and cheap bases as are potassium or sodium hydroxides, carbonates or as are DMSO/H2O and cheap bases as are potassium or sodium hydroxides, carbonates or phosphates,phosphates, only aa fewfew examplesexamples ofof effectiveeffective utilizationutilization ofof Ar-ClsAr-Cls werewere publishedpublished usingusing entirelyentirely differentdifferent ligands.ligands. InIn thisthis case,case, thethe highhigh potentialpotential ofof tandemtandem catalysiscatalysis toto transformtransform non-reactive Ar-ClAr-Cl toto reactive reactive Ar-I Ar-I that that is is subsequently subsequently hydroxylated hydroxylated to to the the corresponding correspond- Ar-OHing Ar-OH could could be expected. be expected.

3.2.2. Cu-Catalyzed Syntheses of Aryl EthersEthers fromfrom Ar-XsAr-Xs Cu-catalyzed nucleophilic nucleophilic substitution substitution of of halogen halogen (especially (especially I or I orBr) Br) in Ar-X in Ar-X by ali- by aliphaticphatic alcoholates alcoholates are are usually usually performed performed in in polar polar aprotic solventssolvents suchsuch as as N,N-dimethylfo N,N-dimethyl- rmamideformamide (DMF). (DMF). The The mechanism mechanism of of the the Ar-Xs Ar-X substitutions substitution by by sodium sodium methanolate methanolate as O-as nucleophileO-nucleophile was was studied, studied, CuOCH CuOCH3 (or3 (or NaCu(OCH NaCu(OCH3)32),2, respectively) respectively) was was proposed proposed asas thethe key intermediateintermediate inin anisoleanisole synthesissynthesis fromfrom bromobenzenebromobenzene byby AaltenAalten andand othersothers [[90]90].. Methanolysis isis applicableapplicable eveneven forfor thethe preparation ofof sterically hinderedhindered derivativesderivatives whichwhich hashas beenbeen shownshown byby RighiRighi etet al.al. in the casecase of the ﬂavonoideflavonoide MosloﬂavoneMosloflavone synthesissynthesis (Scheme(Scheme 2525))[ [91]91]..

Scheme 25. 25. Cu-catalyzedCu-catalyzed methoxylation methoxylation of sterically of hindered sterically 6-bromo-5-hydroxy-7-methoxyfla- hindered 6-bromo-5-hydroxy-7- methoxyﬂavonevone [91]. [91].

1,10-Phenanthroline L2L2 waswas tested tested as as a simple a simple and and cheap cheap ligand ligand suitable suitable for the for prep- the preparationaration of an of effective an effective CuI-based CuI-based catalyst catalyst for the for reaction the reaction of primary of primary and secondary and secondary alco- Catalysts 2021, 11, x FOR PEER REVIEW 17 of 36 alcoholshols with with iodoarenes iodoarenes under under quite quite mild mild reacti reactionon conditions conditions enabling enabling the the preparation ofof optically purepure chiralchiral ethersethers (Scheme(Scheme 2626))[ [92]92]..

SchemeScheme 26.26. CuICuI catalyzed catalyzed coupling coupling of of chiral chiral sec-phenethyl sec-phenethyl alcohol alcohol with with retention retention of configuration of conﬁgura- tion[92]. [ 92].

ItIt isis knownknown thatthat thethe additionaddition ofof suitablesuitable ligandsligands toto thethe Cu(I)Cu(I) saltsalt enables enables increasingincreasing solubilitysolubility andand stabilizationstabilization ofof catalyticallycatalytically activeactive Cu(I)Cu(I) speciesspecies andand facilitatesfacilitates aromaticaromatic substitutionsubstitution byby O-nucleophiles.O-nucleophiles. ThisThis factfact sometimessometimes enablesenables thethe utilizationutilization ofof commoncommon aromaticaromatic hydrocarbonshydrocarbons (toluene,(toluene, xylene)xylene) oror alcoholsalcohols asas thethe solventssolvents andand lowerlower reactionreaction temperaturetemperature forfor highlyhighly efﬁcientefficient preparationpreparation of of Ar–ORs Ar–ORs (Scheme (Scheme 27 27).).

Scheme 27. Cu(I)-catalyzed coupling of aliphatic alcohols with Ar-Xs (X = Br, I) [93–96].

Using 3,4,7,8-tetramethyl-1,10-phenanthroline L4 as the ligand with KF/Al2O3 as the base (in the presence of a large excess of phenol), the coupling of alcohols with aryl iodides has also been realized [93]. Using amino acids L3, L7, L11 (Figure 2) as ligands provides interesting results, but here the issue of having the nucleophile (the alcohol) in excess re- mains [94]. Especially L4 was proved to be a highly efficient ligand, which enables this reaction to be carried out with aryl iodides under mild conditions [95,96]. Their method is particularly noteworthy for not needing a large excess of alcohol and for being remarkably selective for O-arylation when amino alcohols are involved. In the case of preparation of diphenyl ethers, a mild heterogeneous system (reaction at 50–60 °C) based on copper nanoparticles (0.1 eq. of nano Cu (18 nm)), for the coupling of aryl iodides and aryl bromides with phenols was developed by Kidwai et al. (Scheme 28) [97].

Scheme 28. Copper-catalyzed coupling of phenols with Ar-Xs (X = Br, I) [97–105].

The reactions take place without any added ligand and the system is reusable, although a decrease in yield is observed and a longer time reaction is required for each subsequent run. With the requirement of utilizing non-polar solvents, however, there are only limited reports of Cu-catalyzed O-arylation reactions being performed in toluene or xylene [98]. Mao and Wang [99] recently reported that a diamine-type ligand anchored to silica and chelated to copper, efficiently promotes the synthesis of diaryl ethers from aryl iodides, aryl bromides, or even activated aryl chlorides at 130 °C.

Catalysts 2021, 11, x FOR PEER REVIEW 17 of 36 Catalysts 2021, 11, x FOR PEER REVIEW 17 of 36

Scheme 26. CuI catalyzed coupling of chiral sec-phenethyl alcohol with retention of configuration Scheme 26. CuI catalyzed coupling of chiral sec-phenethyl alcohol with retention of configuration [92]. [92]. It is known that the addition of suitable ligands to the Cu(I) salt enables increasing It is known that the addition of suitable ligands to the Cu(I) salt enables increasing solubility and stabilization of catalytically active Cu(I) species and facilitates aromatic solubility and stabilization of catalytically active Cu(I) species and facilitates aromatic substitution by O-nucleophiles. This fact sometimes enables the utilization of common substitution by O-nucleophiles. This fact sometimes enables the utilization of common Catalysts 2021, 11, 378 aromatic hydrocarbons (toluene, xylene) or alcohols as the solvents and lower reaction16 of 34 aromatic hydrocarbons (toluene, xylene) or alcohols as the solvents and lower reaction temperature for highly efficient preparation of Ar–ORs (Scheme 27). temperature for highly efficient preparation of Ar–ORs (Scheme 27).

Scheme 27. Cu(I)-catalyzed coupling of aliphatic alcohols with Ar-Xs (X = Br, I) [93–96]. SchemeScheme 27.27. Cu(I)-catalyzedCu(I)-catalyzed couplingcoupling ofof aliphaticaliphatic alcoholsalcohols withwith Ar-XsAr-Xs (X(X == Br,Br, I)I) [[93–96]93–96]..

UsingUsing 3,4,7,8-tetramethyl-1,10-phenanthroline3,4,7,8-tetramethyl-1,10-phenanthrolineL4 L4as as the the ligand ligand with with KF/Al KF/Al2OO3 asas thethe Using 3,4,7,8-tetramethyl-1,10-phenanthroline L4 as the ligand with KF/Al2 2O33 as the base (in the presence of a large excess of phenol), the coupling of alcohols with aryl iodides basebase (in(in thethe presencepresence ofof aa largelarge excessexcess ofof phenol),phenol), thethe couplingcoupling ofof alcoholsalcohols withwith arylaryl iodidesiodides has also been realized [93]. Using amino acids L3L3, L7L7, L11L11 (Figure 2) as ligands provides hashas alsoalso beenbeen realizedrealized [[93].93]. UsingUsing aminoamino acidsacids L3,, L7,, L11(Figure (Figure2 )2) as as ligands ligands provides provides interestinginteresting results, but but here here the the issue issue of of having having the the nucleophile nucleophile (the (the alcohol) alcohol) in inexcess excess re- interesting results, but here the issue of having the nucleophile (the alcohol) in excess re- remainsmains [94]. [94 ].Especially Especially L4L4 waswas proved proved to to be be a a highly highly efficient efﬁcient ligand, whichwhich enablesenables thisthis mains [94]. Especially L4 was proved to be a highly efficient ligand, which enables this reactionreaction toto bebe carried carried out out with with aryl aryl iodides iodides under under mild mild conditions conditions [95 [95,96].,96]. Their Their method method is reaction to be carried out with aryl iodides under mild conditions [95,96]. Their method particularlyis particularly noteworthy noteworthy for for not not needing needing a large a large excess excess of alcohol of alcohol and and for beingfor being remarkably remark- is particularly noteworthy for not needing a large excess of alcohol and for being remark- selectiveably selective for O-arylation for O-arylation when when amino amino alcohols alcohols are involved. are involved. ably selective for O-arylation when amino alcohols are involved. InIn the case of of preparation preparation of of diphenyl diphenyl et ethers,hers, a mild a mild heterogeneous heterogeneous system system (reaction (reac- In the case of preparation of diphenyl ethers, a mild heterogeneous system (reaction tionat 50–60 at 50–60 °C) based◦C) based on copper on copper nanoparticles nanoparticles (0.1 eq. (0.1 of nano eq.of Cu nano (18 nm)), Cu (18 for nm)), the coupling for the at 50–60 °C) based on copper nanoparticles (0.1 eq. of nano Cu (18 nm)), for the coupling couplingof aryl iodides of aryl and iodides aryl bromides and aryl bromides with phen withols was phenols developed was developed by Kidwai by et Kidwai al. (Scheme et al. of aryl iodides and aryl bromides with phenols was developed by Kidwai et al. (Scheme (Scheme28) [97]. 28)[97]. 28) [97].

SchemeScheme 28.28. Copper-catalyzedCopper-catalyzed couplingcoupling ofof phenolsphenols withwith Ar-XsAr-Xs (X(X == Br,Br, I)I) [[97–105].97–105]. Scheme 28. Copper-catalyzed coupling of phenols with Ar-Xs (X = Br, I) [97–105]. TheThe reactionsreactions take take place place without without any any added added ligand ligand and and the systemthe system is reusable, is reusable, although alt- The reactions take place without any added ligand and the system is reusable, alt- ahough decrease a decrease in yield isin observedyield is observed and a longer and timea longer reaction time is reaction required is for required each subsequent for each sub- run. hough a decrease in yield is observed and a longer time reaction is required for each sub- sequentWith run. the requirement of utilizing non-polar solvents, however, there are only limited sequent run. reportsWith of Cu-catalyzedthe requirement O-arylation of utilizing reactions non-polar being solvents, performed however, in toluene there are or only xylene limited [98]. With the requirement of utilizing non-polar solvents, however, there are only limited Maoreports and of Wang Cu-catalyzed [99] recently O-arylation reported reactions that a diamine-type being performed ligand in anchoredtoluene or to xylene silica and[98]. reports of Cu-catalyzed O-arylation reactions being performed in toluene or xylene [98]. chelatedMao and toWang copper, [99] efficiently recently reported promotes that the a synthesis diamine-type of diaryl ligand ethers anchored from arylto silica iodides, and Mao and Wang [99] recently reported that a diamine-type◦ ligand anchored to silica and arylchelated bromides, to copper, or even efficiently activated promotes aryl chlorides the sy atnthesis 130 C.of diaryl ethers from aryl iodides, chelated to copper, efficiently promotes the synthesis of diaryl ethers from aryl iodides, aryl Aminobromides, acids or wereeven successfullyactivated aryl tested chlorides as ligands at 130 for °C. Cu(I) catalyzed arylation of Ar-X. Although,aryl bromides, in principle, or even aactivated number ofaryl amino chlorides acids at could 130 facilitate°C. copper-catalyzed coupling of aryl halides and phenols, N,N-dimethylglycine L7 was found to be the best ligand for this biaryl ether formation. Ma et al. [100] described an efficient catalytic C–O coupling reaction at ambient temperature. A particular advantage of the ambient-temperature conditions used with this system is that the coupling can occur without any accompanying racemization of the tyrosine derivatives. Using the amino acid L7 as a supporting ligand with 30% copper loading, they could couple 2-bromotrifluoroacetanilide and L-tyrosine derivatives in high yields even at 25 ◦C[100]. It was observed in this reaction that an ortho- amide substituent (CF3CONH-) bound on the aryl halide (2-bromotrifluoroacetanilide) is required as MDG. The additional stabilization of the CuI center, provided by O coordination of this chelating ortho group, was proposed to be a key factor for the success of these reactions. The catalytic system based on beta-keto ester L8 as a supporting ligand affords the corresponding diaryl ethers from aryl bromides and iodides at mild temperatures in DMSO [101]. Similarly, the imine L9 and salicylaldoxime L10 (Figure2) are also very efficient at promoting the synthesis of diaryl ethers. In combination with 10% CuI and the inexpensive base K3PO4 (instead of commonly used Cs2CO3), these ligands allow for the Catalysts 2021, 11, 378 17 of 34

coupling of a large range of aryl bromides with phenols under mild conditions [102,103]. The coupling of phenols with aryl bromides is also possible with L2 as the supporting ligand. The latter was used in the presence of copper impregnated into charcoal under microwave irradiation [104]. Very effective Cu(I)-based catalysts soluble in common organic solvents were produced by complexing of Cu(Ph3P)3Br with 1,10-phenanthroline or neocuproine and evaluated for facile cleavage of Ar-Xs with different nucleophiles [105]. Even a ligand-free copper-catalyzed diaryl ether synthesis based on arylation of Ar–I or Ar–Br with phenols using the inexpensive base K3PO4 and phase transfer catalyst Bu4NBr are typically carried out in polar, aprotic solvents (DMF) after tens of hours of action at a temperature above 120 ◦C[106]. The arylation in 100 kg scale of 4-bromo-chlorobenzene using 4-methoxyphenol was reported under the above-described conditions using L7 (Figure2) as the cheap ligand of choice producing exclusively 4-chlorophenyl-40-methoxyphenylether. In this case, the ◦ coupling reaction worked well at 90 C in dioxane using Cs2CO3 as a base, and a wide range of aryl iodides, aryl bromides and phenols could be used as coupling partners [107]. Aryl chlorides are in general considered too inert for C-O cross-coupling with phenols. The comparison in the reactivity of different halogens in aryl halides was studied and compared using Cu(Ph3P)3X catalyst [108]. It was observed using the Cu(Ph3P)3I in the reaction of 4-chloro-bromobenzene with 4-methylphenol. The aryl chloride side is at least 30-times less reactive in comparison with the aryl bromide side of 4-chloro-bromobenzene. The obtained reaction mixture contains only 1.9% yield of 4-bromo-40-methyl-diphenylether and below 1% of double-coupled product bis-1,4-(4-methylphenoxy)benzene) and 66.9% yield of 4-chlorophenyl-40-methyl-phenylether. A signiﬁcant advance was achieved with the development of an efﬁcient method for the copper-catalyzed arylation of phenols by aryl chlorides (Scheme 10) using ligand Catalysts 2021, 11, x FOR PEER REVIEW 19 of 36 2,2,6,6-tetramethyl-3,5-heptadione L12 (Figure3). This reaction system is one of the few able to condense both activated and deactivated aryl chlorides. Although relatively harsh Catalysts 2021, 11, x FOR PEER REVIEW ◦ 19 of 36 conditions are used (135 C), this procedure has genuine economic advantages in that very inexpensive materials are used (Scheme 29)[109]. H N

H N N H L13 N H Figure 3. Ligands are applicable for coupling phenols with different Ar-Xs. L13

Figure 3. LigandsFigure 3. areLigands applicable are applicablefor coupling for phenols coupling with phenols different with Ar-Xs. different Ar-Xs.

SchemeScheme 29.29. (Nano)copper(Nano)copper catalysts-basedcatalysts-based couplingcoupling ofof arylaryl chlorideschlorides withwith phenolsphenols [ [109–112].109–112].

SchemeThe 29. (Nano)copperother publishedThe other catalysts-based methods published enable coupling methods Cu-catalyzed of enablearyl chlorides Cu-catalyzed coupling with phenols or coupling aryl [109–112]. chlorides or aryl with chlorides with phenols appliedphenols CuI applied nanoparticles CuI nanoparticles [110], CuI/sparteine [110], CuI/sparteine L13 [111], nanoL13 [Cu1112O], nano[112] Cuwere2O[ 112] were achievedThe other forachieved diaryl published ether for diarylmethods synthesi ether senable starting synthesis Cu-catalyzed from starting chlorobenzene. fromcoupling chlorobenzene. or aryl chlorides with phenolsIn appliedcomparison CuIIn comparison nanoparticleswith hydroxylation with [110], hydroxylation CuI/sparteineof aryl chlorides, of aryl L13 chlorides, above[111], nanomentioned above Cu mentioned2O copper-cata-[112] were copper-catalyzed achievedlyzed arylation for diarylarylation of etherphenols of synthesi phenols with Ar-Clss with starting Ar-Cls seems from to seems chlorobenzene.be more to be feasible more feasible due to the due broader to the broaderchoice choice of of effectiveIn comparisoneffective catalytic with catalytic systems, hydroxylation systems, though though ofworking aryl workingchlorides, in non-aqueous in above non-aqueous mentioned solvents. solvents. copper-cata-On Onthe theother other hand, in lyzedhand, arylation in the area of phenols of treatment with Ar-Cls methods seems applicable to be more for chemicalfeasible due destruction to the broader of toxic choice Ar-Cl ofderivatives effective catalytic are phenols systems, as reactants though much working more in expensive non-aqueous compared solvents. with On sodium the other or po- hand,tassium in the hydroxide, area of treatment carbonate methods or phosphate applicable applied for chemicalin hydroxylation destruction reactions. of toxic Ar-Cl derivativesAlthough are phenols the intramolecular as reactants C–Omuch coupling more expensive of aryl chloride compared with with aromatic sodium OH or group po- tassiumcatalyzed hydroxide, by copper(I) carbonate salts isor much phosphate easier appliedand is applicable in hydroxylation for the preparationreactions. of diben- zofuransAlthough (Scheme the intramolecular 30) [113], it could C–O be coupling the source of ofaryl undesirable chloride with PCDD/Fs aromatic as theOH by-prod- group catalyzeducts accompanying by copper(I) production salts is much of polychlorinated easier and is applicable phenols. for the preparation of dibenzofurans (Scheme 30) [113], it could be the source of undesirable PCDD/Fs as the by-products accompanying production of polychlorinated phenols.

Scheme 30. Formation of dibenzofurans by Cu(I) salt of thiophene-2-carboxylic acid (CuTC) catalyzed C–O coupling [113]. Scheme 30. Formation of dibenzofurans by Cu(I) salt of thiophene-2-carboxylic acid (CuTC) cata- lyzed3.3. C–OUtilization coupling of Ar-Xs[113]. in Cu-Mediated Biaryl Syntheses This chapter will deal with recent developments in aryl–aryl bond formation using 3.3.Ar–X Utilization as the starting of Ar-Xs material in Cu-Mediated and copper Biaryl and Syntheses its derivatives as reagents or catalysts. Cop- perThis is the chapter most ancient will deal transition with recent metal developments used for the synthesisin aryl–aryl of biarylsbond formation and it is still using em- Ar–Xployed as the at present.starting materialThese reactions and copper imply and the it suse derivatives of aromatic as reageniodidetss or or bromides catalysts. (some-Cop- pertimes is the even most chlorides) ancient transition as substrates metal and used coppe for rthe metal synthesis or copper of biaryls salt as and the it reagent. is still em- The ployedmechanism at present. of these These reductive reactions couplings imply the usually use of involves aromatic the iodide formations or bromides of a cuprate (some- as the timesintermediate even chlorides) and copper as substrates halide as anda byproduct copper metal (Scheme or copper31). salt as the reagent. The mechanism of these reductive couplings usually involves the formation of a cuprate as the intermediate and copper halide as a byproduct (Scheme 31).

Catalysts 2021, 11, x FOR PEER REVIEW 19 of 36

H N

N H L13

Figure 3. Ligands are applicable for coupling phenols with different Ar-Xs.

Scheme 29. (Nano)copper catalysts-based coupling of aryl chlorides with phenols [109–112].

The other published methods enable Cu-catalyzed coupling or aryl chlorides with phenols applied CuI nanoparticles [110], CuI/sparteine L13 [111], nano Cu2O [112] were achieved for diaryl ether synthesis starting from chlorobenzene. In comparison with hydroxylation of aryl chlorides, above mentioned copper-cata-

Catalysts 2021, 11, 378 lyzed arylation of phenols with Ar-Cls seems to be more feasible due to the broader18 choice of 34 of effective catalytic systems, though working in non-aqueous solvents. On the other hand, in the area of treatment methods applicable for chemical destruction of toxic Ar-Cl derivatives are phenols as reactants much more expensive compared with sodium or po- thetassium area ofhydroxide, treatment carbonate methods or applicable phosphate for applied chemical in hydroxylation destruction of toxicreactions. Ar-Cl derivatives areAlthough phenols the as intramolecular reactants much C–O more coupling expensive of aryl compared chloride with with sodium aromatic or potassium OH group hydroxide,catalyzed by carbonate copper(I) or salts phosphate is much applied easier an ind hydroxylation is applicable for reactions. the preparation of diben- zofuransAlthough (Scheme the intramolecular30) [113], it could C–O be couplingthe source of of aryl undesirable chloride withPCDD/Fs aromatic as the OH by-prod- group catalyzeducts accompanying by copper(I) production salts is much of polychlorinated easier and is applicable phenols. for the preparation of dibenzofurans (Scheme 30)[113], it could be the source of undesirable PCDD/Fs as the by-products accompanying production of polychlorinated phenols.

SchemeScheme 30.30.Formation Formation of of dibenzofurans dibenzofurans by by Cu(I) Cu(I) salt salt of of thiophene-2-carboxylic thiophene-2-carboxylic acid acid (CuTC) (CuTC) catalyzed cata- C–Olyzed coupling C–O coupling [113]. [113].

3.3.3.3. UtilizationUtilization ofof Ar-XsAr-Xs inin Cu-MediatedCu-Mediated BiarylBiaryl SynthesesSyntheses ThisThis chapterchapter willwill dealdeal withwith recentrecent developmentsdevelopments inin aryl–arylaryl–aryl bondbond formationformation usingusing Ar–XAr–X as as the the starting starting material material and and copper copper and and its it derivativess derivatives as as reagents reagen orts catalysts.or catalysts. Copper Cop- isper the is most the most ancient ancient transition transition metal metal used forused the for synthesis the synthesis of biaryls of biaryls and it isand still it employedis still em- atployed present. at present. These reactions These reactions imply the imply use of the aromatic use of iodidesaromatic or iodide bromidess or (sometimesbromides (some- even chlorides)times even as chlorides) substrates as and substrates copper metal and coppe or copperr metal salt or as copper the reagent. salt as The the mechanism reagent. The of Catalysts 2021, 11, x FOR PEER REVIEW 20 of 36 thesemechanism reductive of these couplings reductive usually couplings involves usually the formation involves ofthe a formation cuprate as of the a cuprate intermediate as the andintermediate copper halide and copper as a byproduct halide as (Scheme a byproduct 31). (Scheme 31).

SchemeScheme 31.31.Mechanism Mechanism ofof Cu-catalyzedCu-catalyzed couplingcoupling ofof Ar–XAr–X (Ullmann(Ullmann reaction) reaction) [ 114[114–117].–117].

TwoTwo molarmolar equivalentsequivalents ofof arylaryl halidehalide areare typicallytypically reactedreacted withwith oneone equivalentequivalent ofof ﬁnelyfinely divideddivided coppercopper atat highhigh temperaturetemperature (above(above 200200 ◦°C)C) toto formform aa biarylbiaryl andand aacopper copper halidehalide [[114–116].114–116]. ConsiderableConsiderable improvementsimprovements have have been been made made overover thethe lastlast century.century. PolarPolar aproticaprotic solventssolvents suchsuch asas DMF,DMF, DMSO DMSO or or N-methylpyrrolidonN-methylpyrrolidon (NMP) (NMP) are are the the solvents solvents that that permitpermit thethe useuse ofof lowerlower temperaturestemperatures andand aa lowerlower proportionproportion ofof copper.copper. InIn addition, addition, thethe useuse ofof anan activatedactivated formform ofof CuCu powder,powder, mademadeby bythe the reduction reductionof of copper(I) copper(I)iodide iodidewith with ◦ potassium,potassium, allows allows for for the the reaction reaction to to be be carried carried out out at evenat even lower lower temperatures temperatures (about (about 85 C) 85 with°C) with improved improved yields. yields. As the As reaction the reaction is heterogeneous, is heterogeneous, it can it be can accelerated be accelerated considerably consid- usingerably ultrasound using ultrasound halide [ 117halide]. Regarding [117]. Regard the relationshiping the relationship between between the structure the structure of an aryl of halidean aryl and halide its reactivity, and its reactivity, electron-withdrawing electron-withdrawing groups suchgroups as nitrosuch andas nitro carboxymethyl, and carbox- especiallyymethyl, especially in the ortho-position in the ortho-position to the halogen to the halogen atom, provide atom, provide an activating an activating effect. effect. The The presence of substituents that provide alternative reaction sites, such as amino, hydroxyl, and free carboxyl groups, greatly limit, however, or prevent the reaction. Symmetrical coupling of substituted benzene rings and aromatic heterocycles using copper as the reducing and coupling agent can be performed in both inter- and intramolecular reactions. Although steric hindrance can be a problem in Ullmann reactions, Hauser published C-C coupling of protected iodoresorcinol proceeded to afford the biphenyl in a good yield (73%) (Scheme 32) [118].

Scheme 32. Cu-mediated biaryl coupling of sterically hindered alkoxylated iodoresorcinol deriva- tive [118].

Meyers et al. reported that depending on the substituent, an aryl halide can be converted to a diastereomerically enriched product under equilibrating conditions and that diastereomerically enriched biaryls are formed using the harsh reaction conditions required for the performance of a Cu0 mediated biaryl synthesis [119–125]. A modern intramolecular version of Ullmann C-C bond formation under relatively mild reaction conditions was described recently. The formation of the Ar-CuBr compound was proposed as the key intermediate for the effective substitution of bromide in the Ar-

Catalysts 2021, 11, x FOR PEER REVIEW 20 of 36

Scheme 31. Mechanism of Cu-catalyzed coupling of Ar–X (Ullmann reaction) [114–117].

Two molar equivalents of aryl halide are typically reacted with one equivalent of finely divided copper at high temperature (above 200 °C) to form a biaryl and a copper halide [114–116]. Considerable improvements have been made over the last century. Polar aprotic solvents such as DMF, DMSO or N-methylpyrrolidon (NMP) are the solvents that permit the use of lower temperatures and a lower proportion of copper. In addition, the use of an activated form of Cu powder, made by the reduction of copper(I) iodide with potassium, allows for the reaction to be carried out at even lower temperatures (about 85 °C) with improved yields. As the reaction is heterogeneous, it can be accelerated considerably using ultrasound halide [117]. Regarding the relationship between the structure of

Catalysts 2021, 11, 378 an aryl halide and its reactivity, electron-withdrawing groups such as nitro and carbox-19 of 34 ymethyl, especially in the ortho-position to the halogen atom, provide an activating effect. The presence of substituents that provide alternative reaction sites, such as amino, hydroxyl, and free carboxyl groups, greatly limit, however, or prevent the reaction. presenceSymmetrical of substituents coupling that of provide substituted alternative benzen reactione rings and sites, aromatic such as heterocycles amino, hydroxyl, using andcopper free as carboxyl the reducing groups, and greatly coupling limit, agent however, can be or performed prevent the in reaction. both inter- and intramo- lecularSymmetrical reactions. coupling of substituted benzene rings and aromatic heterocycles using copperAlthough as the reducing steric hindrance and coupling can be agent a proble can bem performedin Ullmann in reactions, both inter- Hauser and intramolec- published ularC-C reactions.coupling of protected iodoresorcinol proceeded to afford the biphenyl in a good yield (73%)Although (Scheme steric 32) [118]. hindrance can be a problem in Ullmann reactions, Hauser published C-C coupling of protected iodoresorcinol proceeded to afford the biphenyl in a good yield (73%) (Scheme 32)[118].

SchemeScheme 32.32.Cu-mediated Cu-mediated biarylbiaryl couplingcoupling of sterically hindered alkoxylated iodoresorcinol deriva- deriva- tivetive [[118].118].

MeyersMeyers etet al. reported reported that that depending depending on on the the substituent, substituent, an anaryl aryl halide halide can canbe con- be convertedverted to a to diastereomerically a diastereomerically enriched enriched product product under under equilibrating equilibrating conditions conditions and andthat Catalysts 2021, 11, x FOR PEER REVIEW 21 of 36 thatdiastereomerically diastereomerically enriched enriched biaryls biaryls are areform formeded using using the theharsh harsh reaction reaction conditions conditions re- requiredquired for for the the performance performance of of a aCu Cu0 0mediatedmediated biaryl biaryl synthesis synthesis [119–125]. [119–125]. Catalysts 2021, 11, x FOR PEER REVIEW 21 of 36 AA modernmodern intramolecularintramolecular versionversion ofof UllmannUllmann C-CC-C bondbond formationformation underunder relativelyrelatively Br structure.mildmild Hydroxyl-bearing reactionreaction conditionsconditions amino waswas acid describeddescribed L11 (Figure recently.recently. 3) was The The identified formation formation as of of the the Ar-CuBrefficientAr-CuBr compoundcompound ligand for thiswaswas C-C proposed proposed coupling as as the(Scheme the key key intermediate 33)intermediate [126]. for for the the effective effective substitution substitution of of bromide bromide in thein the Ar-Br Ar- Br structure.structure. Hydroxyl-bearing Hydroxyl-bearing amino aminoacid L11 acid (FigureL11 (Figure 3) was3) identified was identiﬁed as the as efficient the efﬁcient ligand ligand for thisfor thisC-C C-Ccoupling coupling (Scheme (Scheme 33) [126].33)[126 ].

Scheme 33. Example of the modern variant of intramolecular Cu-catalyzed arylation [126].

SchemeAt least 33.33. Example some water-soluble of the modern variantarylhalidesvariant ofof intramolecularintram sucholecular as halogenated Cu-catalyzedCu-catalyzed aromatic arylationarylation sulfonic [[126].126]. acids and their salts (bromamine acid) are capable to react with copper powder via Ullmann biarylAt reaction least some evenAt leastwater-solublein aqueous some water-soluble solutions arylhalides (Scheme arylhalides such 34)as halogenated[127–129]. such as halogenated aromatic sulfonic aromatic acids sulfonic acids and their saltsand (bromamine their salts (bromamine acid) are capable acid) are to capablereact with to reactcopper with powder copper via powder Ullmann via Ullmann biaryl reactionbiaryl even reaction in aqueous even insolutions aqueous (Scheme solutions 34) (Scheme [127–129]. 34)[ 127–129].

Scheme 34. Cu-mediatedScheme 34. Cu-mediated Ullmann C–C Ullmann coupling C–C of bromamine coupling of acid bromamine (dye intermediate) acid (dye intermediate) in aqueous solution in aque- [127–129]. ous solution [127–129]. Scheme 34. Cu-mediated Ullmann C–C coupling of bromamine acid (dye intermediate) in aqueous solutionUsing copper(I)-thiophene-2-carboxylate [127–129]. (CuTC) as a promoter, Liebeskind et al. [130] reported a CuTC-mediated Ullmann-reductive coupling of substituted aromatic iodides Usingor bromides copper(I)-thiophene-2-carboxylate and 2-iodoheteroaromatics at (C roomuTC) temperature. as a promoter, The LiebeskindCuTC-mediated et al. biaryl[130] reportedreductive a coupling CuTC-mediated required Ullmann-reductive a polar, coordinating coupling solvent of such substituted as N-methylpyrrol- aromatic io- idinonedides or (NMP), bromides in all and probability 2-iodoheteroaromatics to generate reactive at room Cu(I) temperature. monomers The from CuTC-mediated the insoluble Cu(I)biaryl carboxylate reductive coupling polymer. required a polar, coordinating solvent such as N-methylpyrrol- idinoneThe (NMP),authors inassume all probability that the efficiency to generate of reactiveCuTC is Cu(I) probably monomers not due from to internal the insoluble coor- dinationCu(I) carboxylate from the sulfurpolymer. atom to the metal but may be due to the inherent ability of car- boxylateThe as authors a ligand assume to stabilize that the the efficiency oxidative of addition CuTC is productprobably (Scheme not due 35).to internal The CuTC- coor- mediateddination fromreaction the wassulfur quite atom general to the and metal tolera butnt may of various be due functional to the inherent groups. ability The ofintra- car- molecularboxylate asreductive a ligand coupling to stabilize has the also oxidative been successfully addition productstudied. (SchemeThe easy 35).preparation The CuTC- of CuTC,mediated its handling reaction wasin air, quite and general the high and yields tolera ofnt reductively of various functionalcoupled products groups. Theachieved intra- undermolecular mild reductivereaction conditions coupling hascould also make been Cu successfullyTC or other studied. Cu(I) carboxylates The easy preparation the reagents of ofCuTC, choice its for handling many Ullmann-like in air, and the reductive high yields coupling of reductively reactions [113,131].coupled products achieved under mild reaction conditions could make CuTC or other Cu(I) carboxylates the reagents of choice for many Ullmann-like reductive coupling reactions [113,131].

Catalysts 2021, 11, 378 20 of 34

Using copper(I)-thiophene-2-carboxylate (CuTC) as a promoter, Liebeskind et al. [130] reported a CuTC-mediated Ullmann-reductive coupling of substituted aromatic iodides or bromides and 2-iodoheteroaromatics at room temperature. The CuTC-mediated biaryl reductive coupling required a polar, coordinating solvent such as N-methylpyrrolidinone (NMP), in all probability to generate reactive Cu(I) monomers from the insoluble Cu(I) carboxylate polymer. The authors assume that the efﬁciency of CuTC is probably not due to internal coordination from the sulfur atom to the metal but may be due to the inherent ability of carboxylate as a ligand to stabilize the oxidative addition product (Scheme 35). The CuTC-mediated reaction was quite general and tolerant of various functional groups. The intramolecular reductive coupling has also been successfully studied. The easy preparation of CuTC, its handling in air, and the high yields of reductively coupled products achieved CatalystsCatalysts 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 2222 ofof 3636 under mild reaction conditions could make CuTC or other Cu(I) carboxylates the reagents of choice for many Ullmann-like reductive coupling reactions [113,131].

SchemeSchemeScheme 35. 35.35. Proposed ProposedProposed mechanism mechanismmechanism of ofof CuTC-based CuTC-basCuTC-baseded C–C C–CC–C coupling couplingcoupling catalysis catalysiscatalysis [ [130].130[130].].

4.4.4. Cu-Based Cu-BasedCu-Based Hydrodehalogenation HydrodehalogenationHydrodehalogenation of ofof Aromatic AromaticAromatic Compounds CompoundsCompounds HydrodehalogenationHydrodehalogenationHydrodehalogenation (HDH) (HDH) involvesinvolves involves hydrogenolysishydrogenolysis hydrogenolysis ofof of C-XC-X C-X bonds,bonds, bonds, requiresrequires requires anan anex-ex- externalternalternal supplysupply supply ofof ofreductantreductant reductant (usually(usually (usually aa sourcesource a source ofof hydrogen)hydrogen) of hydrogen) andand is andis tytypicallypically is typically promotedpromoted promoted usingusing usingaa metalmetal a metal catalystcatalyst catalyst (Scheme(Scheme (Scheme 36)36) [132].[132]. 36)[ 132 ].

SchemeSchemeScheme 36. 36.36. Scheme SchemeScheme of ofof common commoncommon hydrodehalogenation hydrodehalogenationhydrodehalogenation (HDH) (HDH)(HDH) of ofof Ar-X. Ar-X.Ar-X.

AlthoughAlthoughAlthough HDH HDHHDH is isis used usedused as asas a aa reaction rereactionaction for forfor the thethe removal removalremoval of ofof halogen halogenhalogen used usedused as asas the thethe protecting protectingprotecting groupgroupgroup ininin organicorganic synthesis synthesis inin in somesome some casescases cases [133–137],[133–137], [133–137], HDHHDH HDH isis is primarilyprimarily primarily consideredconsidered considered aa devel-devel- a de- velopingopingoping technologytechnology technology forfor for thethe the degradationdegradation degradation ofof chlorinatedchlorinated of chlorinated aquaticaquatic aquatic pollutantspollutants pollutants [132,138].[132,138]. [132,138 ThisThis]. This pro-pro- processcesscess leadsleads leads toto chlorine-free tochlorine-free chlorine-free hydrogenatedhydrogenated hydrogenated compoundscompounds compounds whichwhich which allowallow allow forfor for aa considerableconsiderable a considerable re-re- reductionductionduction inin in effluenteffluent efﬂuent toxicity.toxicity. toxicity. Moreover,Moreover, Moreover, thethe the systemsystem system cancan can bebe be operatedoperated operated underunder under ambientambient ambient condi-condi- con- ditionstionstions withinwithin within aa awidewide wide rangerange range ofof of initialinitial initial pollutantpollutant pollutant concentrations.concentrations. concentrations. TheThe The mainmain main advantageadvantage advantage ofof hy-hy- of hydrodechlorinationdrodechlorinationdrodechlorination overover over advancedadvanced advanced oxidationoxidation oxidation tetechniques techniqueschniques (AOPs)(AOPs) (AOPs) isis isthethe the lowlow low consumptionconsumption consumption ofof ofexpensiveexpensive expensive reagents.reagents. reagents. AOPsAOPs AOPs usuallyusually usually requirerequire require pollpoll pollutantutantutant mineralizationmineralization mineralization forfor effectiveeffective for effective treatmenttreatment treatment(elimination(elimination (elimination ofof hazardoushazardous of hazardous adsorbableadsorbable adsorbable orgaorga organically-boundnically-boundnically-bound halogenshalogens halogens AOXAOX AOX by-products),by-products), whilewhilewhile the thethe HDH HDHHDH process processprocess only onlyonly changes changeschanges the thethe pollutant pollutantpollutant chemical chemicalchemical structure structurestructure to toto make makemake them themthem less lessless toxictoxictoxic and/or and/orand/or more more easily easily biodegradable. biodegradable. HDHHDHHDH isis an an effectiveeffective alternativealternative alternative procedureprocedure procedure especiallyespecially especially forfor for decomposingdecomposing decomposing ofof oflowlow low concen-concen- con- centrationstrationstrations ofof wastewaste of waste halogenatedhalogenated halogenated organicorganic organic compoucompou compoundsndsnds underunder under relativelyrelatively relatively mildmild mild conditionsconditions conditions with-with- withoutoutout thethe theformationformation formation ofof thethe of the toxictoxic toxic by-productsby-products by-products [[139].139]. [139 This].This This emergingemerging emerging tete techniquechniquechnique couldcould could havehave have aa ahighhigh high potentialpotential potential forfor for sustainablesustainable sustainable treatmenttreatment treatment ofof of contaminatedcontaminated waterwater streams streams andand solidsolid wastes.wastes. CatalyticCatalyticCatalytic hydrodechlorination hydrodechlorinationhydrodechlorination of of aof low aa lowlow concentration concentrationconcentration of halogenated ofof halogenatedhalogenated aromatic aromaticaromatic compounds com-com- inpoundspounds contaminated inin contaminatedcontaminated liquids such liquidsliquids as aqueous suchsuch asas solutions aqueousaqueous orsolutionssolutions mineral oror oils mineralmineral with noble-metal oilsoils withwith noble-noble- and transition-metal catalysts is a particularly simple and efﬁcient method [140]. Molecular metalmetal andand transition-metaltransition-metal catalystscatalysts isis aa particularlyparticularly simplesimple andand efficientefficient methodmethod [140].[140]. hydrogen is often used as a hydrogen source in catalytic dechlorination. Hydrogen- MolecularMolecular hydrogenhydrogen isis oftenoften usedused asas aa hydrogenhydrogen sourcesource inin catalyticcatalytic dechlorination.dechlorination. Hy-Hy- transferring reactions using hydrogen donors, such as secondary alcohols and formic drogen-transferringdrogen-transferring reactionsreactions ususinging hydrogenhydrogen donors,donors, suchsuch asas secondarysecondary alcoholsalcohols andand for-for- micmic acidacid salts,salts, havehave alsoalso beenbeen studiedstudied extensively.extensively. TheThe applicationapplication ofof noblenoble metalsmetals cata-cata- lystslysts isis limited,limited, however,however, duedue toto thethe rapidrapid deactivationdeactivation ofof thesethese catalystscatalysts [138,141].[138,141]. TheThe effectiveeffective rolerole ofof copper-basedcopper-based catalysiscatalysis inin hydrodechlorinationhydrodechlorination (HDC)(HDC) processesprocesses applicableapplicable forfor wasteswastes contaminatedcontaminated withwith lowlow concentrationsconcentrations ofof polychlorinatedpolychlorinated pollutantspollutants hashas beenbeen describeddescribed [142–158].[142–158].

4.1.4.1. Cu-CatalyzedCu-Catalyzed HDCHDC ofof ChlorinatedChlorinated BenzenesBenzenes DechlorinationDechlorination ofof polychlorinatedpolychlorinated benzenesbenzenes inin thethe presencepresence ofof coppercopper waswas studiedstudied byby GhaffarGhaffar andand TabataTabata [144][144] atat aa temperaturetemperature aroundaround 9090 °C°C usingusing isopropylalcoholisopropylalcohol andand aqueousaqueous NaOHNaOH and/orand/or Ca(OH)Ca(OH)22 inin thethe presencepresence ofof sulfursulfur andand flyfly ashash (Scheme(Scheme 37).37).

Catalysts 2021, 11, 378 21 of 34

acid salts, have also been studied extensively. The application of noble metals catalysts is limited, however, due to the rapid deactivation of these catalysts [138,141]. The effective role of copper-based catalysis in hydrodechlorination (HDC) processes applicable for wastes contaminated with low concentrations of polychlorinated pollutants has been described [142–158].

4.1. Cu-Catalyzed HDC of Chlorinated Benzenes Dechlorination of polychlorinated benzenes in the presence of copper was studied Catalysts 2021, 11, x FOR PEER REVIEW ◦ 23 of 36 by Ghaffar and Tabata [144] at a temperature around 90 C using isopropylalcohol and aqueous NaOH and/or Ca(OH)2 in the presence of sulfur and ﬂy ash (Scheme 37).

+OH Cu + S Cl H+ SH + OH i-PrOH Cln Cln Cln Cln H2O 90 oC

Cu + OH +SH - 3n HCl i-PrOH/H2O

G Gn G=H,OHorSH

Scheme 37. HDCScheme combined 37. HDC with combined nucleophilic with aromatic nucleophilic substitution aromatic of substitution chlorinatedbenzenes of chlorinated caused benzenes by the combined action

of Cu/ﬂy ashcaused with NaOH/S/Ca(OH) by the combined2 actionin aqueous of Cu/fly isopropanol ash with [NaOH/S/Ca(OH)144]. 2 in aqueous isopropanol [144].

The observedThe decrease observed in dechlorination decrease in dechlorination at a higher temperature at a higher temperature(120–150 °C) (120–150 was ◦C) was explained byexplained vaporization by vaporization of used solv ofents used accompanied solvents accompanied by a decrease by in a decreaseOH− and in SH OH− − and SH− − nucleophilesnucleophiles and by the possible and by the catalytic possible effe catalyticct of copper effect ofin copper co-action in co-action of produced of produced Cl− Cl ions ions and oxygenand which oxygen perform which perform the further the chlorination further chlorination of produced of produced less chlorinated less chlorinated ben- benzenes zenes at a higherat a highertemperature temperature [68]. [68].

4.2. High-Temperature4.2. High-Temperature Cu-Mediated Cu-MediatedPCDD/Fs Dechlorination PCDD/Fs Dechlorination Several researchSeveral groups research have demonstrated groups have demonstrated that copper-catalyzed that copper-catalyzed dechlorination dechlorinationof of PCDD/PCDF or other polychlorinated aromatic compounds proceeds on fly ash at a PCDD/PCDF or other polychlorinated◦ aromatic compounds proceeds on fly ash at a temperature abovetemperature 250 °C with above the exclusion 250 C with of oxygen the exclusion but without of oxygen the addition but without of an external the addition of an reductant. Theexternal observed reductant. dechlorination The observed proc dechlorinationess was explained process not wasonly explained by biaryl not for- only by biaryl formation via the Ullmann reaction on a copper surface, but even by the HDC reaction. mation via the Ullmann reaction on a copper surface, but even by the HDC reaction. In In this context, the carbon matrix presented in fly ash was proposed as the reductant this context, the carbon matrix presented in fly ash was proposed as the reductant funda- fundamental for low valent Cu(I) or Cu(0) capable of promoting HDC reaction at above mental for low valent Cu(I) or Cu(0) capable of promoting HDC reaction at above 120 °C 120 ◦C in the absence of oxygen [145–150]. in the absence of oxygen [145–150]. This catalytic property of copper compounds contained in fly ash might be applied This catalytic property of copper compounds contained in fly ash might be applied for decontamination of PCBs, PCNs and PCDD/Fs contaminated fly ash during industrial- for decontamination of PCBs, PCNs and PCDD/Fs contaminated fly ash during industrial- scale operations. scale operations. 4.3. Cu-Mediated HDC of Ar-Cls Dissolved in an Aqueous Solution 4.3. Cu-Mediated4.3.1. HDC HDC of ofAr-Cls Chlorinated Dissolved Phenols in an Aqueous Solution 4.3.1. HDC of Chlorinated(Poly)chlorinated Phenols phenols are common contaminants of industrial water streams due (Poly)chlorinatedto their intensive phenols production are common and contaminants application of as industrial biocides and water due streams to their due relatively high to their intensivesolubility production in water. and They application are in most as biocides cases produced and due to by their nucleophilic relatively aromatic high substitu- solubility in water.tion of They corresponding are in most chlorobenzenes cases produced which by nucleophilic are the next aromatic frequent substitution pollutant of industrial of corresponding chlorobenzenes which are the next frequent pollutant of industrial wastewaters. Iron particles covered with copper are popular in remediation chemistry for the HDC treatment of water streams contaminated with halogenated compounds. Zerovalent iron (ZVI) has been explored extensively over the last few decades for degrading and remediating a wide variety of halogenated compounds from an aqueous environment. The main drawback of the ZVI is the reported low reductive reactivity toward most of Ar–Xs. The precious metal (usually transition metal is known as effective hydrogenation catalyst Pd, Pt, Ni, Cu, etc.) appended to ZVI, resulted in the formation of infinite galvanic cells to accelerate atomic hydrogen production [151].

Catalysts 2021, 11, 378 22 of 34

wastewaters. Iron particles covered with copper are popular in remediation chemistry for the HDC treatment of water streams contaminated with halogenated compounds. Zerovalent iron (ZVI) has been explored extensively over the last few decades for degrading and remediating a wide variety of halogenated compounds from an aqueous environment. The main drawback of the ZVI is the reported low reductive reactivity toward most of Ar–Xs. The precious metal (usually transition metal is known as effective hydrogenation catalyst Pd, Pt, Ni, Cu, etc.) appended to ZVI, resulted in the formation of infinite galvanic cells to accelerate atomic hydrogen production [151]. Treatment of electropositive metals with more electronegative (precious) metal salts (e.g., Cu(II), Ag(I), Au(III)) can form a metal/metal galvanic cell via the cementation process (electropositive metal particles covered with a layer based on precious metal). In the metal/metal galvanic cell produced via the cementation process, the electropositive metal corrodes and transfer electrons to an electronegative metal surface where dehalogenation occurs. As one of the most abundant and low-cost metals, copper has been intensively studied for modifying zero-valent iron. Choi et al. documented that zero-valent iron (ZVI) is completely non-reactive in the case of 2,4,6-trichlorophenol (2,4,6-TCP) in 100 mg TCP/L aq. solution treated with 100 g 0 −2 −1 Fe /L. Iron metalized with Cu (Cu/Fe) causes HDC with kobs= 0.31 × 10 h under the same conditions. The HDC activity is explained by the acceleration of galvanic oxidation of Fe in Cu/Fe bimetal. Cu can accelerate the electrochemical reduction reaction mediated by Fe0 surface due to a large potential difference between Fe (E0 = −0.44 V) and Cu (E0 = 0.36 V) [152]. In agreement with the observed positive effect of copper deposited on an iron surface, Su et al. described the significant catalytical effect of the CuSO4 addition to the aqueous iron slurry for rapid dechlorination of hexachlorobenzene (HCB) in comparison with iron itself. The enhancement effect of the presence of Cu(II) ions on the significant increase of rate constant of HDC of HCB was attributed to the reduced Cu coating on iron particles together with the decrease in solution pH at the start of the experiments caused by the acidic CuSO4 addition [153]. In contrast, the high removal efficiency of pentachlorophenol from the aqueous solution after 2–3 days of Cu/Fe bimetal action was explained by chemisorption of chlorophe- nolates on the metal oxide surface of Cu/Fe by Kim and Carraway rather than the HDC reaction [154]. It was also observed by Duan et al. [155] that copper works as the hydrodechlorination −1 −1 agent for 4-chlorophenol (4-CP) more rapidly (with kobs= 1.37 × 10 h ) than bimetals Cu/Ni or Cu/Fe under conditions when 0.4 mM 4-CP was treated by 100 g/L of the respective metallic reductant. In addition, cyklohexanone and soluble Cu(II) salt are produced by HDC of 4-CP using Cu. HDC based on the action of Cu/Fe bimetal produces −3 −1 phenol na Fe(II) salt much more slowly (with kobs= 8.61 × 10 h ). The authors deduced different mechanisms of Cu and Cu/Fe actions based on these observations (Scheme 38). Apart from the above-mentioned co-action of Cu in HDC, the catalytic HDC action of copper was observed after the addition of sodium borohydride as the reductant. Rapid HDC of several chloroaromatics dissolved in aqueous solution (34 mg Ar–Cl/L) was observed using nanocopper (2.5 g Cu/L) and NaBH4 (1 g/L) (Scheme 39)[156]. Catalysts 2021, 11, x FOR PEER REVIEW 24 of 36

Treatment of electropositive metals with more electronegative (precious) metal salts (e.g., Cu(II), Ag(I), Au(III)) can form a metal/metal galvanic cell via the cementation process (electropositive metal particles covered with a layer based on precious metal). In the metal/metal galvanic cell produced via the cementation process, the electropositive metal corrodes and transfer electrons to an electronegative metal surface where dehalogenation occurs. As one of the most abundant and low-cost metals, copper has been intensively studied for modifying zero-valent iron. Choi et al. documented that zero-valent iron (ZVI) is completely non-reactive in the case of 2,4,6-trichlorophenol (2,4,6-TCP) in 100 mg TCP/L aq. solution treated with 100 g Fe0/L. Iron metalized with Cu (Cu/Fe) causes HDC with kobs = 0.31 × 10−2 h−1 under the same conditions. The HDC activity is explained by the acceleration of galvanic oxidation of Fe in Cu/Fe bimetal. Cu can accelerate the electrochemical reduction reaction mediated by Fe0 surface due to a large potential difference between Fe (E0 = −0.44 V) and Cu (E0 = 0.36 V) [152]. In agreement with the observed positive effect of copper deposited on an iron surface, Su et al. described the significant catalytical effect of the CuSO4 addition to the aqueous iron slurry for rapid dechlorination of hexachlorobenzene (HCB) in comparison with iron itself. The enhancement effect of the presence of Cu(II) ions on the significant increase of rate constant of HDC of HCB was attributed to the reduced Cu coating on iron particles together with the decrease in solution pH at the start of the experiments caused by the acidic CuSO4 addition [153]. In contrast, the high removal efficiency of pentachlorophenol from the aqueous solution after 2–3 days of Cu/Fe bimetal action was explained by chemisorption of chlorophe- nolates on the metal oxide surface of Cu/Fe by Kim and Carraway rather than the HDC reaction [154]. It was also observed by Duan et al. [155] that copper works as the hydrodechlorination agent for 4-chlorophenol (4-CP) more rapidly (with kobs = 1.37 × 10−1 h−1) than bimetals Cu/Ni or Cu/Fe under conditions when 0.4 mM 4-CP was treated by 100 g/L of the respective metallic reductant. In addition, cyklohexanone and soluble Cu(II) salt are produced by HDC of 4-CP using Cu. HDC based on the action of Cu/Fe bimetal produces phenol na Fe(II) salt much more slowly (with kobs = 8.61 × 10−3 h−1). The authors deduced different Catalysts 2021, 11, 378 mechanisms of Cu and Cu/Fe actions based on these observations (Scheme 38). 23 of 34

Catalysts 2021, 11, x FOR PEER REVIEW 25 of 36

Apart from the above-mentioned co-action of Cu in HDC, the catalytic HDC action of copper was observed after the addition of sodium borohydride as the reductant. Rapid HDC of several chloroaromatics dissolved in aqueous solution (34 mg Ar–Cl/L) was ob- Scheme 38. Proposed twoserved HDC using mechanisms nanocopper of 4-CP (2.5 using g Cu/L) a metallic and copper NaBH and4 (1bimetallic g/L) (Scheme Cu/Fe 39) system [156]. [155 ].

Scheme 38. Proposed two HDC mechanisms of 4-CP using a metallic copper and bimetallic Cu/Fe system [155].

Scheme 39. Cu-catalyzed HDC of chlorobenzene using NaBH4 as the reduction agent [156]. Scheme 39. Cu-catalyzed HDC of chlorobenzene using NaBH4 as the reduction agent [156]. Similar to the above mentioned HDC mediated by Cu using NaBH4 reductant, the HDCSimilar of DDT to (50 the ppm above in mentioned H2O) and 2,4,6-TCPHDC mediated (50 ppm by inCu H using2O) was NaBH achieved4 reductant, using the a mixtureHDC of ofDDT Devarda’s (50 ppm alloy in H2 (50%O) and Cu 2,4,6-TCP + 45% Al (50 + 5%ppm Zn in in H quantity2O) was achieved 0.5 g/L) andusing sodium a mix- ◦ borohydrideture of Devarda’s alloy (1alloy g NaBH (50%4 Cu/L) + at 45% 80–100 Al + 5%C[ 157Zn ].in quantity 0.5 g/L) and sodium boro- hydridePartial alloy HDC (1 g of NaBH polychlorinated4/L) at 80–100 benzenes °C [157]. and regioselective HDC of some chlorinated phenolsPartial and HDC chlorinated of polychlorinated anilines using benzenes Devarda’s and Al–Cu–Zn regioselective alloy inHDC an alkalineof some aqueous chlorin- solutionated phenols at room and temperature chlorinated was anilines studied using by Weidlich Devarda’s et al.Al–Cu–Zn [158]. The alloy HDC in activity an alkaline was explainedaqueous solution by the galvanic at room oxidation temperature of Al was from stud Devardaied by´ Weidlichs Al–Cu–Zn et al. alloy [158]. in anThe aqueous HDC ac- 1 wt.%tivity NaOH was explained solution. by the galvanic oxidation of Al from Devarda´s Al–Cu–Zn alloy in an aqueous 1 wt.% NaOH solution. 4.3.2. Cu-Catalyzed Hydrodebromination (HDB) of Polybrominated Phenols 4.3.2.Flame Cu-Catalyzed retardants Hydrodebromination are common organic (HDB) specialty of Polybrominated chemicals widely Phenols used to improve the flameFlame resistance retardants in circuitare common boards andorganic plastics. specialty Broadly chemicals used flame widely retardants used to based improve on brominatedthe flame resistance phenols (brominatedin circuit boards flame and retardants, plastics. Broadly BFRs) have used been flame of concernretardants recently based for on ourbrominated environment phenols because (brominated of their endocrine flame retardan disruptive,ts, BFRs) immune have toxicitybeen of andconcern risk recently of toxic for our environment because of their endocrine disruptive, immune toxicity and risk of toxic brominated byproducts formation. They are ubiquitously present in the electrical wastes (e-wastes) and persist at low concentrations [159–161]. Pyrolysis and combustion are often applied to dismantle e-wastes. The incineration of BFRs-containing e-wastes usually produces, however, polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs), which are highly toxic in the environment [162–164]. As a potential remediation technology, hydrodebromination (HDB) of persistent pollutant tetrabromobisphenol A (TBBPA) from both aqua and soil by zero-valent iron particles (nZVI) covered with transition metals was intensively investigated (Scheme 40) [165,166].

Catalysts 2021, 11, 378 24 of 34

brominated byproducts formation. They are ubiquitously present in the electrical wastes (e-wastes) and persist at low concentrations [159–161]. Pyrolysis and combustion are often applied to dismantle e-wastes. The incineration of BFRs-containing e-wastes usually produces, however, polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs), which are highly toxic in the environment [162–164]. As a potential remediation technology, hydrodebromination (HDB) of persistent pollu- Catalysts 2021, 11, x FOR PEER REVIEWtant tetrabromobisphenol A (TBBPA) from both aqua and soil by zero-valent iron particles26 of 36

(nZVI) covered with transition metals was intensively investigated (Scheme 40)[165,166].

SchemeScheme 40.40. HydrodebrominationHydrodebromination (HDB) (HDB) of of TBBPA TBBPA in in contaminated contaminated aqueous aqueous solution solution using using an excessan ofexcess bimetallic of bimetallic particles. particles.

TheThe studystudy ofof LiLi etet al.al. demonstratesdemonstrates thatthat depositiondeposition ofof CuCu onon nZVInZVI surfacesurface drasticallydrastically improvedimproved thethe debrominationdebromination ofof tetrabromobisphenoltetrabromobisphenol AA (TBBPA)(TBBPA) [167[167].]. ThisThis techniquetechnique utilizesutilizes Fe(III)Fe(III) andand Cu(II)Cu(II) saltssalts asas metalmetal sourcessources andand NaBH4NaBH4 asas aa powerfulpowerful reductantreductant forfor thethe initialinitial preparationpreparation ofof nZVInZVI (Equation(Equation (4)),(4)), whichwhich isis subsequentlysubsequently coveredcovered byby reductivereductive depositiondeposition onon Fe(0)Fe(0) afterafter thethe additionaddition ofof Cu(II)Cu(II) saltsalt (Equation(Equation (5)).(5)). 4 Fe3+ + 3 BH4 -+ 9 H2O → 4 Fe0 3 H2BO3 - + 12 H+ + 6 H2 ( 4 ) 3+ − 0 − + 4Cu Fe 2+++ Fe 30 BH → 4Cu+0 + 9 Fe H22+O → 4 Fe 3 H 2BO3 + 12 H + 6 H2 ( 5 ) (4)

Cu2++ Fe0 → Cu0 + Fe2+ (5)

Cu-nZVI with a low dosage could rapidly and completely debrominate TBBPA into Cu-nZVI with a low dosage could rapidly and completely debrominate TBBPA into BPA. This is attributed to the above-mentioned excellent galvanic effect in the presence of BPA. This is attributed to the above-mentioned excellent galvanic effect in the presence of Cu. It was reported that the proper amount of Cu islets coating on the nZVI surface and Cu. It was reported that the proper amount of Cu islets coating on the nZVI surface and a a weakly acidic condition favored the fast rate (ca. 3.41 × 10−2 min−1) of debromination weakly acidic condition favored the fast rate (ca. 3.41 × 10−2 min−1) of debromination and and the great extent of TBBPA degradation. The oxidation of Fe0 and the elevation of pH the great extent of TBBPA degradation. The oxidation of Fe0 and the elevation of pH pro- promoted the co-precipitation of Fe(II) and Fe(III) and thus the formation of amorphous moted the co-precipitation of Fe(II) and Fe(III) and thus the formation of amorphous mag- magnetite on the Cu–nZVI surface. This study suggests that Cu–nZVI can be effectively netite on the Cu–nZVI surface. This study suggests that Cu–nZVI can be effectively used used to remove TBBPA from both water and soil, reducing the toxicological effects of to remove TBBPA from both water and soil, reducing the toxicological effects of TBBPA TBBPA in aquatic and edaphic environments [167]. in aquatic and edaphic environments [167]. Even sole copper nanoparticles are an effective debromination agent for reduction of TBBPAEven tosole BPA copper even nanoparticles in co-action with are an Fe(II) effective salts occurringdebromination in green agent rust. for Fe(II)reduction works of asTBBPA a reductant to BPA foreven the in regeneration co-action with of Fe(II) active salts Cu0 occurringspecies [168 in ].green This rust. observation Fe(II) works corre- as 0 spondsa reductant well for with the the regeneration above-mentioned of active reductive Cu species potential [168]. ofThis metallic observation copper corresponds for HDC of 4-CPwell [with155]. the above-mentioned reductive potential of metallic copper for HDC of 4-CP [155].Cu-based debromination of TBBPA was even observed during pyrolysis of electronic waste.Cu-based Cu has debromination a signiﬁcant catalytic of TBBPA effect was on even the observed pyrolysis during process pyrolysis and products. of electronic Cu canwaste. promote Cu has the a significant conversion catalytic of the pyrolytically effect on the produced pyrolysis organicprocess bromidesand products. such asCu bro- can promote the conversion of the pyrolytically produced organic bromides such as bromo- momethane, bromoethane, 2-bromophenol, and 2,4-dibromophenol to Br2 and HBr. The conversionmethane, bromoethane, mechanism of2-bromophenol, bromide species and is 2,4-dibromophenol simpliﬁed as the preferential to Br2 and adsorptionHBr. The con- of organicversion bromidesmechanism followed of bromide by the species coordination is simpli offied bromine as the preferential atoms and Cu.adsorption The electron of or- transferganic bromides results infollowed the cleavage by the of coordination the C–Br bond of andbromine the generationatoms andof Cu. Br 2Theor HBr.electron In contrast,transfer results Cu can in act the as cleavage a catalyst of to th promotee C–Br bond the debrominationand the generation reaction of Br through2 or HBr. the In con- Ull- manntrast, Cu crossing-coupling can act as a catalyst reaction. to promote Cu could the therefore debromination promote reaction wasteprinted through circuit the Ullmann boards pyrolysiscrossing-coupling and make reaction. the pyrolysis Cu could products therefore easier promote to dispose waste ofto printed some extentcircuit [ 169boards]. py- rolysisWe and observed make the that pyrolysis 2,4,6-tribromophenol products easi (2,4,6-TBP)er to dispose even of into asome quite extent high concentration[169]. dissolvedWe observed in alkaline that aqueous 2,4,6-tribro solutionmophenol (25 mM (2,4,6-TBP) of 2,4,6-TBP even in 1.5 in wt.%a quite aq. high NaOH) concentration underlies rapidlydissolved to in HDB alkaline using aqueous Devarda solution´s Al-Cu-Zn (25 mM alloy of 2,4,6-TBP (18 g/L) afterin 1.5 2 wt.% h at room aq. NaOH) temperature underlies rapidly to HDB using Devarda´s Al-Cu-Zn alloy (18 g/L) after 2 h at room temperature and phenol is produced quantitatively (Scheme 41). This reaction is slower than HDB promoted by Raney Al-Ni alloy but the efficiency is the same. In addition, copper is not as toxic an element in comparison with nickel. The filtrate obtained after neutralization which contains phenol is completely biodegradable by bacteria P. fluorescence or R. erythropolis, as we verified [170,171].

Catalysts 2021, 11, 378 25 of 34

and phenol is produced quantitatively (Scheme 41). This reaction is slower than HDB promoted by Raney Al-Ni alloy but the efficiency is the same. In addition, copper is not as toxic an element in comparison with nickel. The filtrate obtained after neutralization which Catalysts 2021, 11, x FOR PEER REVIEW 27 of 36 contains phenol is completely biodegradable by bacteria P. fluorescence or R. erythropolis, as we verified [170,171].

Scheme 41. Cu-catalyzedScheme 41. Cu-catalyzed HDB of 2,4,6-TBP HDB dissolved of 2,4,6-TBP in aq. dissolved NaOH mediatedin aq. NaOH by Devardasmediated Al–Cu–Znby Devardas alloy Al–Cu– [170,171]. Zn alloy [170,171]. 4.3.3. Cu-Catalyzed HDB of Polybrominated Diphenylethers 4.3.3. Cu-Catalyzed HDB of Polybrominated Diphenylethers Polybrominated diphenylethers (PBDEs) are well-known BFRs and are widely used Polybrominated diphenylethers (PBDEs) are well-known BFRs and are widely used in circuit boards, furniture, plastics, textiles, and other commercial products designed for in circuit boards, furniture, plastics, textiles, and other commercial products designed for fire protection [172]. PBDEs belong to a class of persistent organic pollutants (POPs), with fire protection [172]. PBDEs belong to a class of persistent organic pollutants (POPs), with potential toxicity to the liver, the reproductive system and the development of mammals. potential toxicity to the liver, the reproductive system and the development of mammals. PBDEs have been found in both, natural and artificial environments (such as sediments PBDEs have been found in both, natural and artificial environments (such as sediments from the rivers, lakes, and oceans) [173]. In addition, during pyrolysis of polybrominated from the rivers, lakes, and oceans) [173]. In addition, during pyrolysis of polybrominated diphenylethers (PBDEs), which are used as flame retardants in synthetic polymer blends, diphenylethers (PBDEs), which are used as flame retardants in synthetic polymer blends, polybrominated dibenzo-p-dioxins PBDDs and polybrominated dibenzofurans PBDFs are polybrominatedformed dibenzo-p-dioxins similarly to TBBPA PBDDs [174]. and polybrominated dibenzofurans PBDFs are formed similarlyThere to are TBBPA a number [174]. of studies on the degradation of PBDEs by chemical reduction There andare a many number in-depth of studies reaction on the mechanisms degradation have of beenPBDEs revealed. by chemical Compared reduction to a chemical and many reduction,in-depth reaction photolysis mechanisms for PBDE degradationhave been revealed. involves Compared the dissipation to a ofchemical a high amount of reduction, energyphotolysis and for is costlyPBDE [ 175degradation]. involves the dissipation of a high amount of energy and is costlyIn comparison, [175]. a chemical reduction is considered to be the most feasible solution to In comparison,the restoration a chemical of the reduction PBDEs-contaminated is considered area. to be Debrominationthe most feasible of solution PBDEs byto (nZVI) or the restorationiron-based of the bimetalsPBDEs-contaminated has become the area. primary Debromination mode of chemical of PBDEs reduction by (nZVI)(Scheme or 42) [176]. iron-basedAccording bimetals has to the become significantly the primary different mode debromination of chemical activity reduction of Fe/Cu (Scheme bimetal 42) in electri- [176]. Accordingcally conductive to the significantly water and different non-conductive debromination ethanol, activity the authors of Fe/Cu suggested bimetal that in the effect electricallyof conductive galvanic couplewater and formed non-conducti by coveringve ethanol, of Fe0 surface the authors with Cusuggested0 (electron-transfer) that the plays effect of galvanicthe dominant couple roleformed in 2,2 by0,4,4 covering0-tetrabromodiphenyl of Fe0 surface with ether Cu (BDE-47)0 (electron-transfer) debromination mech- plays the dominantanism. In role addition, in 2,2´,4,4´-tetrab Fe/Cu reducesromodiphenyl BDE-47 finally ether to (BDE-47) diphenylether debromination (DPE) and no toxic mechanism.dibenzofuran In addition, was Fe/Cu produced reduces during BDE-47 this finally process to [177diphenylether]. (DPE) and no toxic dibenzofuran was produced during this process [177].

Catalysts 2021, 11, 378 26 of 34 Catalysts 2021, 11, x FOR PEER REVIEW 28 of 36

SchemeScheme 42. HDBHDB of 2,2 of′,4,4 2,2′-tetrabromodiphenylether0,4,40-tetrabromodiphenylether (BDE-47) (BDE-47) using bimetallic using bimetallic Cu/Fe particles Cu/Fe particles[176–178]. [176 –178].

TheThe comparisoncomparison of HDB HDB kinetics kinetics determined determined the the high high debromination debromination activity activity of me- of metallictallic copper copper both both in the in the form form of Fe/Cu of Fe/Cu bimetal bimetal and andcopper copper in co-action in co-action of reductants of reductants such suchas H2 as or H NaBH2 or NaBH4. In addition,4. In addition, the determined the determined debromination debromination rate using rate Fe/Cu using is Fe/Cu lower isin lowercomparison in comparison with Fe/Pd with or Fe/Ag Fe/Pd but or Fe/Aghigher th butan higher the debromination than the debromination rate of Fe/Ni, rate Fe/Au of Fe/Ni,or Fe/Pt Fe/Au bimetals or Fe/Pt or Fe bimetals(ZVI) [178]. or Fe (ZVI) [178]. AlthoughAlthough metallicmetallic coppercopper inin fewfew casescases promotespromotes HDH HDH reaction reaction better better in in comparison comparison withwith Cu/ZVI,Cu/ZVI, in in most most cases cases effective effective application application of of metallic metallic copper copper in inco-action co-action of ofa re- a reductantductant such such as asiron, iron, aluminium aluminium or NaBH or NaBH4 is meanwhile4 is meanwhile the method the method of choice of for choice effective for effectiveHDH of HDH (poly)halogenated of (poly)halogenated phenols phenols in contaminated in contaminated aqueous aqueous solutions. solutions. Especially Especially com- combinationbination of copper of copper disposing disposing with withhigh specific high specific surface surface area and area powerful and powerful but in aqueous but in aqueous solution also enough stable reductant as is NaBH potentially offers options for solution also enough stable reductant as is NaBH4 potentially4 offers options for new find- newings findingsin HDH inprocesses. HDH processes. 5. Conclusions 5. Conclusions This review summarizes recent developments in the field of copper-catalyzed Carom– This review summarizes recent developments in the field of copper-catalyzed Carom– H halogenation and subsequent Carom–X transformation reactions, mainly focusing on H halogenation and subsequent Carom–X transformation reactions, mainly focusing on Carom–X substitution by O-nucleophiles, C-C couplings and hydrodehalogenation which areCarom most–X substitution significant in by the O-nucleophiles, chemical treatment C-C couplings of toxic polyhalogenated and hydrodehalogenation aromates such which as polybrominatedare most significant diphenyl in the etherschemical or polybrominatedtreatment of toxic phenol, polyhalogenated polychlorinated aromates biphenyls, such as polychlorinatedpolybrominated dibenzo-p-dioxins diphenyl ethers or and polybrom dibenzofurans.inated phenol, polychlorinated biphenyls, polychlorinatedCopper-catalyzed dibenzo-p-dioxins reactions have and gained dibenzofurans. significant attention because of its cost effec- tiveness,Copper-catalyzed low toxicity of Cureactions and perception have gained of copper significant as an attention environment-friendly because of its catalyst cost ef- widelyfectiveness, used inlow organic toxicity chemistry. of Cu and Moreover, perception it isof absolutelycopper as an clear environment-friendly from the reported work cata- thatlyst mostwidely of used the methods in organic belong chemistry. to cheaply-available Moreover, it is catalystsabsolutely such clear as from metallic the reported copper, copperwork that halides, most oxides of the andmethods copper belong acetate to aschea theply-available catalytic systems. catalysts The such Cu-catalyzed as metallic direct cop- Cper,arom copper–H halogenation halides, oxides reaction and hascopper emerged acetate as as a the powerful catalytic strategy systems. for The the Cu-catalyzed synthesis of adirect wide C varietyarom–H ofhalogenation halogenated reaction aromatic has compounds. emerged as a With powerful the utilization strategy for of anthe appropri- synthesis ateof a directing wide variety group, of Cu-catalyzed halogenated halogenationaromatic compounds. enables selective With the preparation utilization of stericallyan appro- hindered,priate directing but rarely group, accessible Cu-catalyzed ortho-halogeno-substituted halogenation enables aromatic selective compounds. preparation of steri- callyOne hindered, of the mostbut rarely important accessible Cu(II) ortho-halogeno-substituted catalyzed oxidation reactions aromatic influencing compounds. not only industrialOne of production the most important of Ar-Xs butCu(II) even catalyzed the undesirable oxidation formationreactions influencing of persistent not poly- only halogenatedindustrial production by-products of Ar-Xs is the but air oxidationeven the undesirable of HX (oxyhalogenation). formation of persistent This reaction polyhal- is responsibleogenated by-products for the formation is the air of stableoxidation and toxicof HX polyhalogenated (oxyhalogenation). aromatic This reaction compounds is re- suchsponsible as PCBs for the and formation PCDD/Fs of during stable and industrial toxic polyhalogenated thermal treatment aromatic processes compounds in the pres- such enceas PCBs of oxygen and PCDD/Fs (metal ores during sintering, industrial de novo thermal synthesis treatment during processes waste combustion,in the presence etc.). of Sinceoxygen the (metal formation ores ofsintering, undesirable de novo PCBs, synthesis PCDD/Fs during or PCNs wast ise combustion, based on the etc.). utilization Since the of theformation copper of surface, undesirable several PCBs, inhibitors PCDD/Fs of de or novo PCNs synthesis is based on have the beenutilization proven of e.g.,the copper some

Catalysts 2021, 11, 378 27 of 34

amines or sulfur-containing compounds which act as blockers and deactivators of the catalytically active copper surface [179–185]. The prospective application of these inhibitors could be potentially the crucial practice integrated into the key technological processes (waste incineration or metallurgy), which are at fault for PCDD/Fs or PCBs production, for minimization of PCBs, PCDD/Fs or PCNs genesis. In contrast, the catalytic activity of Cu and its salts at an elevated temperature permits straightforward cleavage of Carom–X bonds producing corresponding non-halogenated aromatic products not only in a synthesis of organic ﬁne chemicals but even in very effective dehalogenation processes applicable in the area of halogenated waste treatment and remediation processes. The discovery of the rate acceleration effect of organic ligands in promoting cross-coupling reactions has expanded the scope of copper catalysis to new areas, promising novel reactivities and selectivities. Aryl halides are the most explored substrates in transition metal-catalyzed cross-coupling reactions. Copper-based catalysts demonstrated good activity and selectivity for all types of Carom−X substitution reactions of aryl iodides. Overall, aryl bromides and heteroaryl bromides manifested moderate reactivities, while aryl chlorides have generally been considered inert to copper-based catalysts. The discovery of new ligands and the application of more reactive Cu-based nanocatalysts have enabled, however, cross-couplings to be achieved in some cases with aryl chlorides. In the future, the ultimate goal should be the design and further development of convenient copper-based catalysts for the activation of inert aryl chloride substrates. In this area, new methodologies employing tandem catalysis to transform unreactive aryl chloride into a more reactive aryl iodide as an intermediate that subsequently undergoes a variety of Cu-based coupling reactions could be a promising area not only in terms of the broader exploitation of copper-catalyzed reactions to large-scale synthesis of organic ﬁne chemicals [186,187], but even for the development of simpler destruction techniques available for the treatment of PCBs, PCNs or PCDD/Fs. Moreover, metallic copper in the co-action of appropriate reductants, especially NaBH4, Fe or Al, makes possible facile destruction of polybrominated and polychlorinated aromatic pollutants e.g., polyhalogenated phenols and polybrominated diphenyl ethers in contaminated soils and wastewater streams. A huge excess of reagents is still required, however, especially for effective hydrodechlorination of chlorinated aromatic pollutants. These research directions can therefore be a rich area for further future investigation.

Funding: This research received no external funding. Acknowledgments: This research was funded by the Faculty of Chemical Technology, University of Pardubice, within support of an excellent research team Chemical Technology Group. Conﬂicts of Interest: The author declares no conﬂict of interest.

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