Review Interfacialcatalysts Processes—The Key Steps of Phase Transfer Catalyzed Reactions Review InterfacialMieczysław Mąkosza Processes—The 1,* and Michał Fedoryński 2 Key Steps of Phase Transfer1 Institute of Organic Catalyzed Chemistry, Polish Reactions Academy of Sciences, Kasprzaka 44/52, 01‐224 Warsaw, Poland 2 Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00‐664 Warsaw, Poland; Mieczysł[email protected] M ˛akosza 1,* and Michał Fedory ´nski 2 * Correspondence: [email protected]; Tel: +48‐22‐3432334 1 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland 2Received:Faculty 18 of November Chemistry, 2020; Warsaw Accepted: University 5 December of Technology, 2020; Published: Noakowskiego 8 December 3, 00-664 2020 Warsaw, Poland; [email protected] *Abstract:Correspondence: After short [email protected]; historical introduction, Tel.: + interfacial48-22-3432334 mechanism of phase transfer catalyzed
(PTC) reactions of organic anions, induced by aqueous NaOH or KOH in two‐phase systems is Received:formulated. 18 NovemberSubsequently 2020; experimental Accepted: 5 December evidence 2020; that Published: supports 8 the December interfacial 2020 deprotonation as the key initial step of these reactions is presented. Abstract: After short historical introduction, interfacial mechanism of phase transfer catalyzed (PTC) reactionsKeywords: of organiccarbanions; anions, dichlorocarbene; induced by aqueous sodium NaOH hydroxide; or KOH ininterfacial two-phase processes; systems is formulated.quaternary Subsequentlyammonium salts; experimental phase transfer evidence catalysis; that supports alkylation the interfacial deprotonation as the key initial step of these reactions is presented.
Keywords: carbanions; dichlorocarbene; sodium hydroxide; interfacial processes; quaternary ammonium 1.salts; Introduction phase transfer catalysis; alkylation Phase‐Transfer Catalysis (PTC) is presently widely applied in chemical industry based on organic synthesis, such as pharmaceutical, agrochemical, cosmetical etc. The importance of this 1.catalysis Introduction is illustrated by value of sales of the PT catalysts that, according to the report of Market & Market Company in 2019, was exceeding 1 billion USD [1]. A particularly valuable variant of PTC Phase-Transfer Catalysis (PTC) is presently widely applied in chemical industry based on organic are reactions of organic anions, mostly carbanions, but also O‐ and N‐anions, generated and carried synthesis, such as pharmaceutical, agrochemical, cosmetical etc. The importance of this catalysis out in the presence of concentrated aqueous NaOH or KOH, catalyzed by tetraalkylammonium is illustrated by value of sales of the PT catalysts that, according to the report of Market & Market (TAA) salts. In this review we would like to discuss mechanistic features of these reactions, Company in 2019, was exceeding 1 billion USD [1]. A particularly valuable variant of PTC are reactions particularly interfacial processes that are key steps of generation of the reacting anions. of organic anions, mostly carbanions, but also O- and N-anions, generated and carried out in the The first example of industrial application of such catalytic processes was manufacturing of presence of concentrated aqueous NaOH or KOH, catalyzed by tetraalkylammonium (TAA) salts. 2‐phenylbutyronitrile via reaction of phenylacetonitrile with ethyl chloride carried out in the In this review we would like to discuss mechanistic features of these reactions, particularly interfacial presence of 50% aqueous NaOH and benzyltriethylammonium chloride (TEBA), 1 mol %, without processes that are key steps of generation of the reacting anions. solvent, by small Polish company, Isopharm, started in 1960 [2] (Scheme 1). The first example of industrial application of such catalytic processes was manufacturing of It should be stressed that carbanions associated with TAA cations in lipophilic ion pairs 2-phenylbutyronitrile via reaction of phenylacetonitrile with ethyl chloride carried out in the presence entering the organic phase exhibit much higher nucleophilic activity than those associated with of 50% aqueous NaOH and benzyltriethylammonium chloride (TEBA), 1 mol %, without solvent, potassium, sodium or lithium cations in organic solvents, thus the reactions proceed rapidly in spite by small Polish company, Isopharm, started in 1960 [2] (Scheme1). of their low concentrations that cannot exceed concentrations of the TAA salts (usually 1% molar).
50% NaOH aq Ph CN + Cl + Ph CN TEBA Ph CN
90–95% 3–5% Scheme 1. Production of 2 2-phenylbutyronitrile‐phenylbutyronitrile according to Polish Patent 46,030 (1962).
ItThis should process be stressed was elaborated that carbanions on the basis associated of short with note TAA by a cations French in chemist lipophilic Jarrousse ion pairs [3]. entering At that thetime organic this nitrile phase was exhibit usually much manufactured higher nucleophilic via reaction activity of phenylacetonitrile than those associated with ethyl with bromide potassium, in sodium or lithium cations in organic solvents, thus the reactions proceed rapidly in spite of their low concentrationsCatalysts 2020, 10, x; that doi: cannotFOR PEER exceed REVIEW concentrations of the TAA salts (usuallywww.mdpi.com/jou 1% molar). rnal/catalysts This process was elaborated on the basis of short note by a French chemist Jarrousse [3]. At that time this nitrile was usually manufactured via reaction of phenylacetonitrile with ethyl bromide in the
Catalysts 2020, 10, 1436; doi:10.3390/catal10121436 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 1436 2 of 15 CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 1515 Catalysts 2020, 10, x FOR PEER REVIEW 2 of 15 presencethe presence of sodium of sodium amide amide in anhydrous in anhydrous toluene. toluene. Taking intoTaking account into costaccount of the cost starting of the materials, starting thethe presencepresence ofof sodiumsodium amideamide inin anhydrousanhydrous toluene.toluene. TakingTaking intointo accountaccount costcost ofof thethe startingstarting solventsmaterials, and solvents investment and investment assuring safe assuring operation safe with operation sodium with amide sodium and regenerationamide and regeneration of the solvent, of materials,materials, solventssolvents andand investmentinvestment assuringassuring safesafe operationoperation withwith sodiumsodium amideamide andand regenerationregeneration ofof costthe solvent, of the catalytic cost of the process catalytic was process below 30% was of below the cost 30% of of the the known cost of procedure. the known procedure. thethe solvent,solvent, costcost ofof thethe catalyticcatalytic processprocess waswas belowbelow 30%30% ofof thethe costcost ofof thethe knownknown procedure.procedure. Thus wewe can can presently presently celebrate celebrate 60 year60 year anniversary anniversary of introduction of introduction of PTC of into PTC chemical into chemical industry. ThusThus wewe cancan presentlypresently celebratecelebrate 6060 yearyear anniversaryanniversary ofof introductionintroduction ofof PTCPTC intointo chemicalchemical Thisindustry. patent This and patent subsequent and subsequent patents and publicationspatents and presentingpublications alkylation presenting of carbanions alkylation in of the carbanions presence industry.industry. ThisThis patentpatent andand subsequentsubsequent patentspatents andand publicationspublications presentingpresenting alkylationalkylation ofof carbanionscarbanions ofin aqueousthe presence NaOH of andaqueous TEBA NaOH catalyst and [4 –TEBA7] have catalyst not raised [4–7] wider have interest not raised to these wider catalytic interest processes. to these inin thethe presencepresence ofof aqueousaqueous NaOHNaOH andand TEBATEBA catalystcatalyst [4–7][4–7] havehave notnot raisedraised widerwider interestinterest toto thesethese Onlycatalytic the processes. 1969 report Only that the dichlorocarbene 1969 report that can dichlorocarbene be generated andcan be react generated efficiently and with react alkenes efficiently via catalyticcatalytic processes.processes. OnlyOnly thethe 19691969 reportreport thatthat dichlorocarbenedichlorocarbene cancan bebe generatedgenerated andand reactreact efficientlyefficiently treatmentwith alkenes of chloroform via treatment and of alkenes chloroform by concentrated and alkenes aqueous by concentrated NaOH in the aqueous presence NaOH of TEBA in [the8], withwith alkenesalkenes viavia treatmenttreatment ofof chloroformchloroform andand alkenesalkenes byby concentratedconcentrated aqueousaqueous NaOHNaOH inin thethe waspresence widely of recognizedTEBA [8], was and widely convinced recognized chemical and community convinced that chemical concentrated community aqueous that alkali concentrated and TAA presencepresence ofof TEBATEBA [8],[8], waswas widelywidely recognizedrecognized andand convincedconvinced chemicalchemical communitycommunity thatthat concentratedconcentrated catalystsaqueous inalkali two and immiscible TAA catalysts phase system in two is immiscible a general and phase effi systemcient way is a for general generation and efficient and reactions way for of aqueousaqueous alkalialkali andand TAATAA catalystscatalysts inin twotwo immiscibleimmiscible phasephase systemsystem isis aa generalgeneral andand efficientefficient wayway forfor carbanionsgeneration (Schemeand reactions2). of carbanions (Scheme 2). generationgeneration andand reactionsreactions ofof carbanionscarbanions (Scheme(Scheme 2).2). 1 2 R11 R22 RR1 RR2 R1 R2 R1 R2 50% NaOH aq R R + CHCl 50%50% NaOHNaOH aqaq R44 R33 + CHCl33 R4 R3 + CHCl3 TEBATEBA R R 4 R33 TEBA RR4 R3 ClCl ClCl R4 R Cl Cl SchemeScheme 2.2. SynthesisSynthesis ofof gemgem‐‐dichlorocyclopropanesdichlorocyclopropanes viavia additionaddition ofof dichlorocarbene,dichlorocarbene, generatedgenerated inin thethe Scheme 2. Synthesis of gem-dichlorocyclopropanes‐dichlorocyclopropanes via addition of dichlorocarbene, generated in the presencepresence ofof aqueousaqueous NaOHNaOH andand TAATAA catalyst,catalyst, toto alkenes.alkenes. presence ofof aqueousaqueous NaOHNaOH andand TAATAA catalyst,catalyst, to to alkenes. alkenes. Subsequently in 1971 Charles M. Starks reported that reactions of inorganic anions with SubsequentlySubsequently in inin 1971 19711971 Charles CharlesCharles M. StarksM.M. StarksStarks reported reportedreported that reactions thatthat reactionsreactions of inorganic ofof inorganicinorganic anions with anionsanions nonpolar withwith nonpolar organic compounds proceed efficiently in two phase systems: organic phase and inorganic organicnonpolarnonpolar compounds organicorganic compoundscompounds proceed e proceedproceedfficiently efficientlyefficiently in two phase inin twotwo systems: phasephase systems:systems: organic organicorganic phase and phasephase inorganic andand inorganicinorganic salt in salt in aqueous solution, when catalyzed by TAA salts and coined the term Phase Transfer Catalysis aqueoussaltsalt inin aqueousaqueous solution, solution,solution, when when catalyzedwhen catalyzedcatalyzed by TAA byby TAA saltsTAA salts andsalts coined andand coinedcoined the term thethe termterm Phase PhasePhase Transfer TransferTransfer Catalysis CatalysisCatalysis [9] [9] (Scheme 3). (Scheme[9][9] (Scheme(Scheme3). 3).3). H O HH22OO n-Cn-C8HH17ClCl ++ NaCNNaCN 2 n-Cn-C8HH17CNCN n-C 8H 17Cl + NaCN R N++Cl–– n-C 8H 17CN 8 17 R44N+ Cl– 8 17 R4N Cl SchemeScheme 3.3. NucleophilicNucleophilic substitutionsubstitution inin alkylalkyl halideshalides byby inorganicinorganic anions,anions, catalyzedcatalyzed byby TAATAA saltssalts inin Scheme 3.3. Nucleophilic substitution in alkyl halides by inorganic anions, catalyzed by TAA salts in twotwo‐‐phasephase systems.systems. two-phasetwo‐phase systems. TheThe valuevalue ofof thethe catalyticcatalytic liquidliquid‐‐liquidliquid twotwo‐‐phasephase systemssystems forfor reactionsreactions ofof inorganicinorganic andand organicorganic The value of the catalytic liquid-liquidliquid‐liquid two-phasetwo‐phase systems for reactions of inorganic and organic anions,anions, catalyzedcatalyzed byby TAATAA salts,salts, waswas immediatelyimmediately recognizedrecognized asas indicatedindicated byby reviewsreviews publishedpublished inin anions, catalyzed by TAA salts,salts, waswas immediatelyimmediately recognized as indicatedindicated by reviewsreviews publishedpublished in 19731973 [10][10] andand 19741974 [11][11] andand plenaryplenary lecturelecture atat FirstFirst IUPACIUPAC ConferenceConference onon OrganicOrganic SynthesisSynthesis inin 19741974 19731973 [[10]10] and and 1974 1974 [ 11[11]] and and plenary plenary lecture lecture at at First First IUPAC IUPAC Conference Conference on Organicon Organic Synthesis Synthesis in 1974 in 1974 [12]. [12].[12]. [12]. The main question was therefore how the catalytic system operates. There were no doubts that TheThe mainmain questionquestion waswas thereforetherefore howhow thethe catalyticcatalytic systemsystem operates.operates. ThereThere werewere nono doubtsdoubts thatthat reactingThe anions,main question organic was or inorganic,therefore how are continuouslythe catalytic system introduced operates. into There organic were phase no doubts in form that of reactingreacting anions,anions, organicorganic oror inorganic,inorganic, areare continuouslycontinuously introducedintroduced intointo organicorganic phasephase inin formform ofof lipophilicreacting anions, ion pairs organic with TAAor inorganic, cations supplied are continuously by the catalyst, introduced thus the into key organic question phase that in should form beof lipophiliclipophilic ionion pairspairs withwith TAATAA cationscations suppliedsupplied byby thethe catalyst,catalyst, thusthus thethe keykey questionquestion thatthat shouldshould bebe answeredlipophilic ision how pairs these with ion TAA pairs cations are formed. supplied by the catalyst, thus the key question that should be answeredanswered isis howhow thesethese ionion pairspairs areare formed.formed. answeredThe PT is catalyzedhow these reactions ion pairs ofare inorganic formed. anions Y−− with e.g., alkyl halides RX proceed between The PT catalyzed reactions of inorganic anions Y − with e.g., alkyl halides RX proceed between The PT catalyzed reactions of inorganic anions Y− with e.g., alkyl halides RX proceed between sodiumThe or PT potassium catalyzed salts reactions of Y−− inof forminorganic of aqueous anions solutionY with ande.g., RXalkyl neat halides or dissolved RX proceed in a nonpolar between sodium or potassium salts of Y − in form of aqueous solution and RX neat or dissolved in a nonpolar sodium or potassium salts of Y− in form of aqueous solution and RX neat or dissolved in a nonpolar solvent.sodium or The potassium reactions salts proceed of Y thanksin form to of continuous aqueous solution transfer and of RX Y−− neatfrom or aqueous dissolved into in the a nonpolar organic solvent. The reactions proceed thanks to continuous transfer of Y − from aqueous into the organic solvent. The reactions proceed thanks to continuous transfer+ of Y− from aqueous into the organic phasesolvent. in formThe reactions of ion pairs proceed with lipophilic thanks to TAA continuous cations, Q transferY−+. These− of Y lipophilic from aqueous ion pairs into are the formed organic via phasephase inin formform ofof ionion pairspairs withwith lipophiliclipophilic TAATAA cations,cations, QQ+YY−.. TheseThese lipophiliclipophilic ionion pairspairs areare formedformed phase in form of ion pairs with lipophilic TAA cations, Q+Y−. These lipophilic ion pairs are formed continuousvia continuous ion exchangeion exchange between between inorganic inorganic salts salts dissolved dissolved in the in aqueous the aqueous phase phase and lipophilic and lipophilic TAA via continuous+ ion exchange between inorganic salts dissolved in the aqueous phase and lipophilic saltsvia continuous (Q X−) in+ the−ion organicexchange phase. between The overallinorganic substitution salts dissolved process in inthe shown aqueous on Schemephase and4. lipophilic TAATAA saltssalts (Q(Q+XX−)) inin thethe organicorganic phase.phase. TheThe overalloverall substitutionsubstitution processprocess inin shownshown onon SchemeScheme 4.4. TAA salts (Q+X−) in the organic phase. The overall substitution process in shown on Scheme 4. Q++X–– + Na++Y–– Q++Y–– + Na++X–– (a) Q+ X–orgorg + Na+ Y–aqaq Q+ Y–orgorg + Na+ X–aqaq (a) Q X org + Na Y aq Q Y org + Na X aq (a) Q++Y–– + R—X R—Y + Q++X–– (b) Q+ Y–orgorg + R—Xorgorg R—YR—Yorgorg ++ QQ+XX–orgorg (b)(b) Q Y org + R—Xorg org org SchemeScheme 4.4. EquilibriumEquilibrium ofof ionion exchangeexchange betweenbetween aqueousaqueous andand organicorganic phasesphases decidesdecides aboutabout PTPT Scheme 4.4. EquilibriumEquilibrium of of ion exchange between aqueous and organic phases decides about PT catalyzedcatalyzed nucleophilicnucleophilic substitutionsubstitution byby inorganicinorganic anions.anions. ((aa)) IonIon exchangeexchange betweenbetween thethe aqueousaqueous andand catalyzed nucleophilic substitution by inorganic anions. ( a) Ion exchange between the aqueous and organicorganic phases; phases;phases; ( ((bbb))) nucleophilic nucleophilicnucleophilic substitution substitutionsubstitution in inin the thethe organic organicorganic phase phasephase organic phases; (b) nucleophilic substitution in the organic phase
Catalysts 2020, 10, x 1436 FOR PEER REVIEW 33 of of 15 Catalysts 2020, 10, x FOR PEER REVIEW 3 of 15 This extraction mechanism was formulated by Starks [9]. Depending on the lipophilicity of This extraction mechanism was formulated by Starks [9]. Depending on the lipophilicity of Q+X−,This the ion extraction exchange mechanism can proceed was via formulated its partial migration by Starks into [9]. the Depending aqueous phase on the or lipophilicityat the interface of Q++X−, the ion exchange can proceed via its partial migration into the aqueous phase or at the interface betweenQ X−, the the ion phases. exchange From can this proceed scheme via it its is partialevident migration that success into of the the aqueous PTC nucleophilic phase or at substitution the interface between the phases. From this scheme it is evident that success of the PTC nucleophilic substitution withbetween inorganic the phases. anions From depends this scheme on the it is equilibrium evident that (Scheme success of 4a) the governed PTC nucleophilic by relation substitution of the with inorganic anions depends on the equilibrium (Scheme 4a) governed by relation of the hydrationwith inorganic energy anions of ions depends X− and on Y− the. Iodide equilibrium anions have (Scheme low4 hydrationa) governed energy by relation therefore of the alkyl hydration iodides hydration energy of ions X− and Y−. Iodide anions have low hydration energy therefore alkyl iodides cannotenergy be of ionsused X as− andalkylating Y−. Iodide agents. anions have low hydration energy therefore alkyl iodides cannot be cannot be used as alkylating agents. usedThe as alkylating reactions agents. of carbanions (and other organic anions) carried out in the presence of The reactions of carbanions (and other organic anions) carried out in the presence of concentratedThe reactions aqueous of carbanions NaOH are (and more other complicated organic anions) because carried they out embrace in the presenceinitial deprotonation of concentrated of concentrated aqueous NaOH are more complicated because they embrace initial deprotonation of theaqueous carbanion NaOH precursors. are more Simple complicated extraction because mechanism—ion they embrace exchange initial deprotonation of TAA salt ofwith the NaOH carbanion and the carbanion precursors. Simple extraction mechanism—ion exchange of TAA salt with NaOH and transferprecursors. of SimpleTAA hydroxide extraction mechanism—ioninto organic phase, exchange where of TAAthe saltdeprotonation with NaOH takes and transferplace—is of transfer of TAA hydroxide into organic phase, where the deprotonation takes place—is unacceptableTAA hydroxide due into to organic high phase,hydration where energy the deprotonation of hydroxide takes anions, place—is thus unacceptable unfavorable dueextraction to high unacceptable due to high hydration energy of hydroxide anions, thus unfavorable extraction equilibriumhydration energy (Scheme of hydroxide 5). anions, thus unfavorable extraction equilibrium (Scheme5). equilibrium (Scheme 5). Q+X– + Na+OH– Q+OH– + Na+X– Q+X–org + Na+OH–aq Q+OH–org + Na+X–aq org aq org aq Scheme 5. 5. UnfavorableUnfavorable anion anion exchange exchange equilibrium equilibrium for formation for formation of TAA hydroxides of TAA hydroxides in two‐phase in Scheme 5. Unfavorable anion exchange equilibrium for formation of TAA hydroxides in two‐phase systems.two-phase systems. systems. Moreover, thethe extraction extraction mechanism mechanism is unacceptable is unacceptable because because attempts attempts of generation of generation and reactions and Moreover, the extraction mechanism is unacceptable because attempts of generation and reactionsof dichlorocarbene of dichlorocarbene by treatment by treatment of a mixture of a of mixture chloroform of chloroform and alkene and with alkene separately with separately prepared reactions of dichlorocarbene by treatment of a mixture of chloroform and alkene with separately preparedanhydrous anhydrous TAA hydroxide TAA failedhydroxide [8]. Generatedfailed [8]. carbeneGenerated rapidly carbene reacted rapidly with reacted water produced with water via prepared anhydrous TAA hydroxide failed [8]. Generated carbene rapidly reacted with water produceddeprotonation via deprotonation of chloroform of in chloroform the organic phase.in the organic Therefore, phase. interfacial Therefore, mechanism interfacial was mechanism proposed: produced via deprotonation of chloroform in the organic phase. Therefore, interfacial mechanism wasdeprotonation proposed: deprotonation of CH acids takes of CH place acids at takes the interface place at betweenthe interface the immisciblebetween the phases, immiscible organic phases, and was proposed: deprotonation of CH acids takes place at the interface between the immiscible phases, organicconcentrated and concentrated aqueous NaOH aqueous solution. NaOH The solution. produced The carbanions produced carbanions are associated are withassociated sodium with or organic and concentrated aqueous NaOH solution. The produced carbanions are associated with sodiumpotassium or potassium cations hence cations cannot hence enter cannot organic enter nor organic aqueous nor phases. aqueous Ion phases. exchange Ion exchange with TAA with salt sodium or potassium cations hence cannot enter organic nor aqueous phases. Ion exchange with TAAdissolved salt dissolved in the organic in the phase organic proceeds phase proceeds at the interface. at the interface. The produced The produced lipophilic lipophilic ion pairs ion enter pairs the TAA salt dissolved in the organic phase proceeds at the interface. The produced lipophilic ion pairs enterorganic the phase organic where phase the where reactions the reactions proceed [ 12proceed] (Scheme [12]6 ).(Scheme 6). enter the organic phase where the reactions proceed [12] (Scheme 6).
+ – – + organic C Horg Q X org C Q + – – +org phaseorganic C Horg Q X org C Q org phase
interfacial + – – + + – – + + – C Hint + Na OH int H2Oint + C Na int + Q X C Q int + Na X int interfacial C H + Na+OH– H O – + + + –int – + Na+X– region int int 2 int + C Na int Q X int C Q int + int region
aqueous + – H O + – Na OH aq 2 aq Na X aq phaseaqueous Na+OH– H O Na+X– aq 2 aq aq phase Scheme 6. Interfacial mechanism of generation and transfer of carbanions in two‐phase systems. SchemeScheme 6.6. InterfacialInterfacial mechanismmechanism ofof generationgeneration andand transfertransfer ofof carbanionscarbanions inin two-phasetwo‐phase systems.systems. This initially speculative mechanism was subsequently supported experimentally and, on its ThisThis initiallyinitially speculativespeculative mechanismmechanism waswas subsequentlysubsequently supportedsupported experimentallyexperimentally and,and, onon itsits basis, specific features of reactions of carbanions and carbenes were rationalized. The experimental basis,basis, specificspecific featuresfeatures ofof reactionsreactions of of carbanions carbanions and and carbenes carbenes were were rationalized. rationalized. TheThe experimentalexperimental confirmation of the interfacial mechanism and its consequence are discussed in this review. confirmationconfirmation ofof thethe interfacial interfacial mechanism mechanism and and its its consequence consequence are are discussed discussed in in this this review. review. 2. Reactions of Carbanions at the Interface 2.2. ReactionsReactions ofof CarbanionsCarbanions atat thethe InterfaceInterface Interfacially generated carbanions cannot migrate into organic phase because they are InterfaciallyInterfacially generated generated carbanions carbanions cannot cannot migrate migrate into organicinto organic phase because phase theybecause are associated they are associated with sodium cations, nor into the aqueous phase because of strong salt out effect. Their withassociated sodium with cations, sodium nor intocations, the aqueous nor into phase the aqueous because phase of strong because salt out of estrongffect. Their salt out concentration effect. Their is concentration is small, and they are accessible with difficulty, so are unable to react with moderately small,concentration and they is are small, accessible and they with are di ffiaccessibleculty, so arewith unable difficulty, to react so withare unable moderately to react active with electrophiles moderately active electrophiles such as alkyl halides. Nevertheless, butyl iodide under somewhat elevated suchactive as electrophiles alkyl halides. such Nevertheless, as alkyl halides. butyl iodide Nevertheless, under somewhat butyl iodide elevated under temperature somewhat reacts elevated with temperature reacts with phenylacetonitrile at the interface with 50% aqueous sodium hydroxide phenylacetonitriletemperature reacts at with the interfacephenylacetonitrile with 50% at aqueous the interface sodium with hydroxide 50% aqueous [13]. Aromatic sodium aldehydeshydroxide [13]. Aromatic aldehydes are very active electrophiles, thus the addition of carbanions to the are[13]. very Aromatic active electrophiles, aldehydes are thus very the additionactive electrophiles, of carbanions thus to the the carbonyl addition group of carbanions proceeds rapidly. to the carbonyl group proceeds rapidly. However, the addition is a reversible process. Because of that However,carbonyl group the addition proceeds is a reversiblerapidly. However, process. Becausethe addition of that is reaction a reversible of aldehydes process. withBecause carbanions of that reaction of aldehydes with carbanions generated and located at the interface proceeds efficiently generatedreaction of and aldehydes located at with the interface carbanions proceeds generated efficiently and onlylocated when at athe fast interface subsequent proceeds reaction efficiently converts only when a fast subsequent reaction converts the initially formed aldol type anions into stable only when a fast subsequent reaction converts the initially formed aldol type anions into stable
Catalysts 2020, 10, 1436 4 of 15 Catalysts 2020, 10, x FOR PEER REVIEW 4 of 15 CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 44 ofof 1515 theproduct. initially For formed example, aldol addition type anions of benzaldehyde into stable product.to carbanion For of example, the Reissert addition compound of benzaldehyde generated toat product.product. ForFor example,example, additionaddition ofof benzaldehydebenzaldehyde toto carbanioncarbanion ofof thethe ReissertReissert compoundcompound generatedgenerated atat carbanionthe interface of theis followed Reissert by compound rapid intramolecular generated at rearrangement the interface is connected followed by with rapid rearomatisation intramolecular to thethe interfaceinterface isis followedfollowed byby rapidrapid intramolecularintramolecular rearrangementrearrangement connectedconnected withwith rearomatisationrearomatisation toto rearrangementform benzoate connected[14] (Scheme with 7). rearomatisation to form benzoate [14] (Scheme7). formform benzoatebenzoate [14][14] (Scheme(Scheme 7).7).
50% NaOHaq 50%50% NaOHNaOHaq PhCHOPhCHO N R N R aq NN RR PhCHO N R NN RR N R N R H CN NCNC OO H CNO CNCN OO NCPh OO H CNOO CN O Ph O orgorg int Ph O int org intint intint
N R = Ph, 89% NN O RR == Ph,Ph, 89%89% OO Ph O R PhPh OO RR orgorg org SchemeScheme 7. InterfacialInterfacial reaction reaction of the of Reissert the Reissert compound compound with aldehydes with aldehydes in the presence in the presence of aqueous of SchemeScheme 7.7. InterfacialInterfacial reactionreaction ofof thethe ReissertReissert compoundcompound withwith aldehydesaldehydes inin thethe presencepresence ofof aqueousaqueous aqueousNaOH. NaOH. NaOH.NaOH. HighlyHighly convincing convincing are resultsare results of the Darzensof the reaction Darzens of interfacially reaction generatedof interfaciallyα-chlorocarbanions generated HighlyHighly convincingconvincing areare resultsresults ofof thethe DarzensDarzens reactionreaction ofof interfaciallyinterfacially generatedgenerated withα‐chlorocarbanions aldehydes. The with reaction aldehydes. of α-chlorophenylacetonitrile The reaction of α‐chlorophenylacetonitrile with benzaldehyde proceedswith benzaldehyde efficiently α‐α‐chlorocarbanionschlorocarbanions withwith aldehydes.aldehydes. TheThe reactionreaction ofof α‐ α‐chlorophenylacetonitrilechlorophenylacetonitrile withwith benzaldehydebenzaldehyde withoutproceeds TAA efficiently catalyst without at the interface TAA catalyst between at benzene the interface solution between and 50% benzene aqueous solution NaOH. Moreover,and 50% proceedsproceeds efficientlyefficiently withoutwithout TAATAA catalystcatalyst atat thethe interfaceinterface betweenbetween benzenebenzene solutionsolution andand 50%50% stereochemicalaqueous NaOH. results Moreover, of the interfacial stereochemical reaction results and the of reaction the interfacial catalyzed reaction by TAA saltand thatthe proceedsreaction aqueousaqueous NaOH.NaOH. Moreover,Moreover, stereochemicalstereochemical resultsresults ofof thethe interfacialinterfacial reactionreaction andand thethe reactionreaction incatalyzed bulk solution by TAA are salt diff thaterent proceeds [15] (Scheme in bulk8). solution are different [15] (Scheme 8). catalyzedcatalyzed byby TAATAA saltsalt thatthat proceedsproceeds inin bulkbulk solutionsolution areare differentdifferent [15][15] (Scheme(Scheme 8).8). benzene Cl benbenzzeneene PhPh PhPh PhPh CNCN ClCl 50%50% NaOHNaOHaq Ph Ph Ph CN + PhCHO 50% NaOHaqaq H CN + H Ph Ph CN ++ PhCHOPhCHO (TEBA) HH O CNCN ++ HH O PhPh PhPh CNCN (TEBA)(TEBA) OO OO ratio with catalyst 8 : 92 ratioratio withwith catalystcatalyst 88 :: 9292 interfacialinterfacial 6868 :: 3232 interfacial 68 : 32 Scheme 8. Interfacial and TAA catalyzed reactions of α‐chloronitrile with aldehyde. SchemeScheme 8.8. InterfacialInterfacialInterfacial and and TAA TAA catalyzedcatalyzed reactions reactions of of α‐ α‐α-chloronitrilechloronitrilechloronitrile with with aldehyde. aldehyde. Similarly, synthesis of cyclopropanes can proceed via Michael addition of acrylonitrile to Similarly,Similarly, synthesis synthesis of of cyclopropanes cyclopropanes can can proceed proceed via via Michael Michael addition addition of of acrylonitrile acrylonitrile to to interfacially generated carbanion of α‐chlorophenylacetonitrile. Additionally in this case interfaciallyinterfacially generatedgeneratedgenerated carbanion carbanioncarbanion of α -chlorophenylacetonitrile.ofof α‐ α‐chlorophenylacetonitrile.chlorophenylacetonitrile. Additionally AdditionallyAdditionally in this case stereochemicalinin thisthis casecase stereochemical outcome of the interfacial reaction and the reaction catalyzed by TAA salt that stereochemicaloutcomestereochemical of the interfacialoutcomeoutcome ofof reaction thethe interfacialinterfacial and the reaction reactionreaction catalyzed andand thethe by reactionreaction TAA salt catalyzedcatalyzed that proceeds byby TAATAA in solution saltsalt thatthat is proceeds in solution is different [16] (Scheme 9). proceedsdiproceedsfferent [ inin16 solution]solution (Scheme isis9 different).different [16][16] (Scheme(Scheme 9).9). benzene benbenzzeneene NCNC CNCN NCNC HH ClCl 50% NaOHaq NC CN NC H Cl 50%50% NaOHNaOHaq ++ CNCN aq PhPh HH ++ PhPh CNCN Ph CN + CN (TEBA)(TEBA) Ph H + Ph CN PhPh CNCN (TEBA) ratio with catalyst 60 : 40 ratioratio withwith catalystcatalyst 6060 :: 4040 interfacialinterfacial 9393 :: 77 interfacial 93 : 7 SchemeScheme 9.9. InterfacialInterfacial andand TAATAA catalyzedcatalyzed reactionsreactions ofof α‐ α‐chloronitrilechloronitrile withwith acrylonitrile.acrylonitrile. SchemeScheme 9. 9. InterfacialInterfacial and and TAA TAA catalyzed catalyzed reactions reactions of of α‐α-chloronitrilechloronitrile with with acrylonitrile. acrylonitrile. Interesting results that support interfacial mechanism of hydroxide anion induced PTC InterestingInteresting resultsresults thatthat supportsupport interfacialinterfacial mechanismmechanism ofof hydroxidehydroxide anionanion inducedinduced PTCPTC reactionsInteresting of carbanions results that were support obtained interfacial in reactions mechanism with ofcharged hydroxide electrophiles. anion induced N‐alkylpyridinium PTC reactions reactionsreactions ofof carbanionscarbanions werewere obtainedobtained inin reactionsreactions withwith chargedcharged electrophiles.electrophiles. NN‐‐alkylpyridiniumalkylpyridinium ofsalts carbanions that are source were obtainedof lipophilic in reactions cations are with also charged active electrophiles, electrophiles. neverthelessN-alkylpyridinium they were salts used that as saltssalts thatthat areare sourcesource ofof lipophiliclipophilic cationscations areare alsoalso activeactive electrophiles,electrophiles, neverthelessnevertheless theythey werewere usedused asas arecatalysts source in of some lipophilic PTC cations reactions are also[17]. active Exposition electrophiles, of chloroform nevertheless solution they of were N‐benzhydryl used as catalysts‐ and catalystscatalysts inin somesome PTCPTC reactionsreactions [17].[17]. ExpositionExposition ofof chloroformchloroform solutionsolution ofof NN‐‐benzhydrylbenzhydryl‐ ‐ andand inN‐ some(2,4,6‐ PTCtrimethyl)benzylpyridinium reactions ([17], pp. 142–145). chlorides Exposition to 50% of aqueous chloroform NaOH solution resulted of Nin-benzhydryl- fast formation and of NN‐‐(2,4,6(2,4,6‐‐trimethyl)benzylpyridiniumtrimethyl)benzylpyridinium chlorideschlorides toto 50%50% aqueousaqueous NaOHNaOH resultedresulted inin fastfast formationformation ofof the stable adducts of trichloromethyl anion [18]. Using competitive experiments with strong, thethe stablestable adductsadducts ofof trichloromethyltrichloromethyl anionanion [18].[18]. UsingUsing competitivecompetitive experimentsexperiments withwith strong,strong,
Catalysts 2020, 10, 1436 5 of 15
N-(2,4,6-trimethyl)benzylpyridinium chlorides to 50% aqueous NaOH resulted in fast formation of the Catalystsstable adducts 2020, 10, x of FOR trichloromethyl PEER REVIEW anion [18]. Using competitive experiments with strong, noncharged5 of 15 electrophiles it was shown that the adducts were formed at the interface, no ion pairs of the pyridinium noncharged electrophiles it was shown that the adducts were formed at the interface, no ion pairs of cations with trichloromethyl anion were entering the organic phase (Scheme 10). the pyridinium cations with trichloromethyl anion were entering the organic phase (Scheme 10).
50% NaOHaq N R + CHCl3 N R + Cl3C N R Cl CCl3 ratio 28 : 1
R = Ph2CH, 92%
Scheme 10. InterfacialInterfacial addition addition of trichloromethyl trichloromethyl carbanion to N‐-benzhydrylpyridiniumbenzhydrylpyridinium chloride.
Moreover, nono catalytic catalytic generation generation and and reactions reactions of dichlorocarbene of dichlorocarbene was observed was observed in the presence in the presenceof these pyridinium of these pyridinium salts. The salts. experiments The experiments with these with pyridinium these pyridinium salts clarify salts clarify contribution contribution of the variantof the variant of the interfacial of the interfacial mechanism mechanism known as known modified as interfacialmodified interfacial mechanism mechanism (MIM) ([17 ],(MIM) pp. 95–97). [19]. According to MIM, TAA salts enter ion exchange with sodium hydroxide at the interface to produce TAA hydroxidehydroxide that that cannot cannot enter enter the organicthe organic phase phase and a ffandord deprotonationafford deprotonation of a carbanion of a carbanion precursor precursorto form directly to form lipophilic directly ionlipophilic pair at ion the pair interface. at the Suchinterface. interfacial Such interfacial ion exchange ion andexchange formation and formationof TAA hydroxide of TAA hydroxide cannot be excluded,cannot be howeverexcluded, it however is not the it main is not way the of main formation way of of formation carbanions. of carbanions.Moreover, it Moreover, was shown it that was halogen shown anionsthat halogen presented anions in the presented concentrated in the aqueous concentrated KOH coveraqueous its KOHsurface cover thus its preventing surface thus formation preventing of TAA formation hydroxide of TAA and excludinghydroxide MIM.and excluding This was MIM. experimentally This was experimentallyshown by experiments shown with N -benzhydryl-by andexperimentsN-(2,4,6-trimethyl)benzylpyridinium with N‐benzhydryl salts‐ as catalystsand Nand‐(2,4,6 electrophiles‐trimethyl)benzylpyridinium [18]. These salts dissolved salts as in catalysts a polar and solvent electrophiles in the absence [18]. ofThese carbanion salts dissolved precursors in aat polar the interface solvent addin the rapidly absence hydroxide of carbanion anions precursors that immediately at the interface decompose. add rapidly hydroxide anions that immediately decompose. 3. Inhibitory Effects of Bromide and Iodide Anions on PTC Reactions of Carbanions 3. InhibitoryIt is a general Effects phenomena of Bromide that and alkyl Iodide iodides, Anions in on spite PTC of Reactions their high of alkylation Carbanions activities, are as a ruleIt ineis affi generalcient alkylating phenomena agents that foralkyl PTC iodides, alkylation in spite of carbanionsof their high and alkylation substitution activities, by inorganic are as a ruleanions inefficient [9,12]. Thisalkylating situation agents is easily for PTC explained alkylation in PTC of carbanions reactions of and inorganic substitution anions by because inorganic the anionsreaction [9,12]. is controlled This situation by anion is exchange easily explained equilibria in between PTC reactions organic of and inorganic aqueous anions phases (Schemebecause 4thea). reactionDue to low is controlled energy of hydration by anion theexchange iodide anionsequilibria stay between preferentially organic in theand organic aqueous phase, phases therefore (Scheme the 4a).less lipophilicDue to low anions energy cannot of hydration enter the the organic iodide phase. anions Such stay simple preferentially and obvious in the rationalization organic phase, is thereforeinvalid to the explain less inhibitorylipophilic eanionsffect of cannot iodide andenter in the some organic cases bromidephase. Such anions simple for PTC and alkylation obvious rationalizationof carbanions because is invalid carbanions to explain are inhibitory much more effect lipophilic of iodide species and in some than iodidecases bromide anions. anions Moreover, for PTCin some alkylation cases PTC of alkylation carbanions of carbanionsbecause carbanions proceeds e ffiareciently much by more alkyl iodides—therelipophilic species are nothan inhibitory iodide anions.effects [ 19Moreover,–21]. These in apparently some cases controversial PTC alkylation observations of carbanions are readily proceeds explained efficiently on the basis by ofalkyl the iodides—thereinterfacial mechanism. are no inhibitory Thus, inhibition effects of [20–22]. the alkylation These byapparently iodide anions controversial is observed observations for carbanions are readilygenerated explained via deprotonation on the basis of of weak the CHinterfacial acids whereas mechanism. the alkylation Thus, inhibition of carbanions of the alkylation derived from by iodidestronger anions CH acidsis observed (and also for carbanions heteroacids) generated is not inhibited via deprotonation by iodide anions.of weak CH Moreover acids whereas since alkyl the alkylationiodides are of more carbanions active alkylating derived from agents stronger than chlorides, CH acids peculiar (and also regularities heteroacids) can be is observed—under not inhibited by iodidesimilar anions. conditions Moreover PTC alkylation since alkyl of some iodides strong are CH more acids active proceeds alkylating more effi agentsciently than by alkyl chlorides, iodide peculiarthan alkyl regularities chloride, whereascan be observed—under less acidic CH acids similar are conditions alkylated byPTC alkyl alkylation chlorides, of some but not strong by alkyl CH acidsiodides proceeds [22,23] (Schememore efficiently 11). by alkyl iodide than alkyl chloride, whereas less acidic CH acids are alkylated by alkyl chlorides, but not by alkyl iodides [23,24] (Scheme 11).
X X 50% NaOHaq + I CN TBAB, 20 °C CN
X 4‐MeO 4‐Me H 4‐Cl 3,4‐Cl2 2,4‐Cl2 pKa 23.8 22.9 21.9 20.5 18.7 17.5 conversion, % 4 10 17 45 55 90
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 15
noncharged electrophiles it was shown that the adducts were formed at the interface, no ion pairs of the pyridinium cations with trichloromethyl anion were entering the organic phase (Scheme 10).
50% NaOHaq N R + CHCl3 N R + Cl3C N R Cl CCl3 ratio 28 : 1
R = Ph2CH, 92% Scheme 10. Interfacial addition of trichloromethyl carbanion to N‐benzhydrylpyridinium chloride.
Moreover, no catalytic generation and reactions of dichlorocarbene was observed in the presence of these pyridinium salts. The experiments with these pyridinium salts clarify contribution of the variant of the interfacial mechanism known as modified interfacial mechanism (MIM) [19]. According to MIM, TAA salts enter ion exchange with sodium hydroxide at the interface to produce TAA hydroxide that cannot enter the organic phase and afford deprotonation of a carbanion precursor to form directly lipophilic ion pair at the interface. Such interfacial ion exchange and formation of TAA hydroxide cannot be excluded, however it is not the main way of formation of carbanions. Moreover, it was shown that halogen anions presented in the concentrated aqueous KOH cover its surface thus preventing formation of TAA hydroxide and excluding MIM. This was experimentally shown by experiments with N‐benzhydryl‐ and N‐(2,4,6‐trimethyl)benzylpyridinium salts as catalysts and electrophiles [18]. These salts dissolved in a polar solvent in the absence of carbanion precursors at the interface add rapidly hydroxide anions that immediately decompose.
3. Inhibitory Effects of Bromide and Iodide Anions on PTC Reactions of Carbanions It is a general phenomena that alkyl iodides, in spite of their high alkylation activities, are as a rule inefficient alkylating agents for PTC alkylation of carbanions and substitution by inorganic anions [9,12]. This situation is easily explained in PTC reactions of inorganic anions because the reaction is controlled by anion exchange equilibria between organic and aqueous phases (Scheme 4a). Due to low energy of hydration the iodide anions stay preferentially in the organic phase, therefore the less lipophilic anions cannot enter the organic phase. Such simple and obvious rationalization is invalid to explain inhibitory effect of iodide and in some cases bromide anions for PTC alkylation of carbanions because carbanions are much more lipophilic species than iodide anions. Moreover, in some cases PTC alkylation of carbanions proceeds efficiently by alkyl iodides—there are no inhibitory effects [20–22]. These apparently controversial observations are readily explained on the basis of the interfacial mechanism. Thus, inhibition of the alkylation by iodide anions is observed for carbanions generated via deprotonation of weak CH acids whereas the alkylation of carbanions derived from stronger CH acids (and also heteroacids) is not inhibited by iodide anions. Moreover since alkyl iodides are more active alkylating agents than chlorides, peculiar regularities can be observed—under similar conditions PTC alkylation of some strong CH Catalysts 2020, 10, 1436 6 of 15 acids proceeds more efficiently by alkyl iodide than alkyl chloride, whereas less acidic CH acids are alkylated by alkyl chlorides, but not by alkyl iodides [23,24] (Scheme 11).
X X 50% NaOHaq + I CN TBAB, 20 °C CN
Catalysts 2020, 10X, x FOR PEER REVIEW4‐MeO 4‐Me H 4‐Cl 3,4‐Cl2 2,4‐Cl26 of 15 pKa 23.8 22.9 21.9 20.5 18.7 17.5 Schemeconversion, 11. Effect % of CH acidity4 of the carbanion10 precursors17 on inhibition45 of their55 deprotonation90 by iodide anions.
Scheme 11. Effect of CH acidity of the carbanion precursors on inhibition of their deprotonation by iodideIt appears anions. therefore that inhibitory effect of iodide anions in PTC alkylation of carbanions is not due to competitive transfer of these anions into organic phase, but due to accumulation of iodide anionsIt appearson the thereforesurface of that the inhibitory aqueous ephase,ffect of iodidehence anionsits basicity in PTC is alkylationdiminished. of carbanionsIn this situation is not duedeprotonation to competitive of weak transfer CH of acids these does anions not into proceed, organic therefore phase, but alkylation due to accumulation of carbanions of iodide is inhibited, anions onwhereas the surface more of acidic the aqueous carbanion phase, precursors hence its basicityare deprotonated is diminished. and In the this produced situation deprotonation carbanions are of weakefficiently CH acids alkylated does notby active proceed, alkylating therefore agents—alkyl alkylation of carbanionsiodides. It iscan inhibited, be therefore whereas concluded more acidic that carbanionbasicity of precursors the interface are between deprotonated organic and phase the produced and 50% carbanions aqueous sodium are efficiently hydroxide alkylated is affected by active by alkylatingthe presence agents—alkyl of halogen anions iodides. that It canare beaccumulated therefore concluded at the surface that of basicity the aqueous of the interfacephase due between to low organichydration phase energy. and 50% aqueous sodium hydroxide is affected by the presence of halogen anions that are accumulated at the surface of the aqueous phase due to low hydration energy. 4. Specific Features of Generation and Reactions of Dichlorocarbene under PTC Conditions 4. Specific Features of Generation and Reactions of Dichlorocarbene under PTC Conditions Successful generation and reactions of dichlorocarbene (DCC) under action of aqueous NaOH on chloroformSuccessful generation[8] was really and surprising reactions of because dichlorocarbene all preceding (DCC) reports under stressed action of the aqueous necessity NaOH of onstrictly chloroform anhydrous [8] was conditions really surprising and even because use of all precedingsublimed reportspotassium stressed t‐butoxide the necessity as a base of strictly [25]. anhydrousEfficiency of conditions the PTC andsystem even is usedue of to sublimed a few reasons: potassium a) 50%t-butoxide (saturated) as a baseaqueous [24]. NaOH, Efficiency in which of the PTCapproximately system is due there to ais few one reasons: molecule a) of 50% water (saturated) for one aqueous ion, is in NaOH, fact a strong in which desiccation approximately agent, there hence is onethere molecule are no oftraces water of for water one ion, in isthe in organic fact a strong phase; desiccation b) upon agent, deprotonation hence there of are chloroform no traces of on water the ininterface the organic generated phase; trichloromethyl b) upon deprotonation anions are of chloroform introduced on into the organic interface phase generated as lipophilic trichloromethyl ion pairs anionswith TAA are introducedcation. Further into processes: organic phase reversible as lipophilic dissociation ion pairs of trichloromethyl with TAA cation. anions Further into processes:DCC and reversibleits addition dissociation to alkenes of proceeds trichloromethyl in the organic anions into phase DCC without and its contact addition with to alkenes water proceedsand hydroxide in the organicanions [26] phase (Scheme without 12). contact with water and hydroxide anions [25] (Scheme 12).
organic phase
+ – – + CHCl3 org CCl2 org + Q Cl org CCl3 Q org
interfacial region + – – + + – CCl –Q+ + Na+Cl– CHCl3 int + Na OH int H2Oint + CCl3 Na int + Q Cl int 3 int int
+ – CCl2 int + Na Cl int
+ – + – Na OH aq H2Oaq Na Cl aq
aqueous phase
Scheme 12. Mechanism of interfacially initiated generation of dichlorocarbene.
All componentscomponents of of this this equilibrium equilibrium are solubleare soluble in the in organic the organic phase, hence phase, in thehence case in of the moderately case of + + − nucleophilicmoderately nucleophilic alkenes the carbene alkenes can the react carbene back can with react chloride back with anion chloride to form TAAanion toCCl form3− ion TAA pair, CCl so it3 canion pair, be kept so it ”ready can be for kept use”. ”ready This for was use”. confirmed This was experimentally confirmed experimentally because it was because shown it was that shown under that under PTC conditions overall rate of the consumption of chloroform correlates with rate of the addition of DCC, therefore is a function of nucleophilicity of alkenes [27]. On the other hand, under classical conditions: treatment of chloroform with t‐BuOK in strictly anhydrous solvent, DCC is generated irreversibly, because dissociation of trichloromethyl carbanion results in formation of insoluble KCl [25,26] (Scheme 13).
Catalysts 2020, 10, 1436 7 of 15
PTC conditions overall rate of the consumption of chloroform correlates with rate of the addition of DCC, therefore is a function of nucleophilicity of alkenes [26]. On the other hand, under classical conditions: treatment of chloroform with t-BuOK in strictly anhydrous solvent, DCC is generated irreversibly, because dissociation of trichloromethyl carbanion results in formation of insoluble Catalysts 2020, 10, x FOR PEER REVIEW 7 of 15 CatalystsKCl [24 2020,25], 10 (Scheme, x FOR PEER 13). REVIEW 7 of 15 Catalysts 2020, 10, x FOR PEER REVIEW 7 of 15 + – CHCl3 + t-BuOK K+CCl3– + t-BuOH CHCl3 + t-BuOK K +CCl – + t-BuOH CHCl3 + t-BuOK K CCl33 + t-BuOH + – K+CCl3– CCl2 + KCl K +CCl3 – CCl + KCl K CCl3 CCl22 + KCl Scheme 13. Irreversible generation of dichlorocarbene under action of t-BuOK in anhydrous Scheme 13. Irreversible generation of dichlorocarbene under action of t‐BuOK in anhydrous solvents.Scheme 13.13.Irreversible Irreversible generation generation of dichlorocarbeneof dichlorocarbene under under action action of t-BuOK of t in‐BuOK anhydrous in anhydrous solvents. solvents.solvents. TheThe strongly strongly promoted promoted extraction extraction mechanism, mechanism, namely namely ion ion exchange exchange between between TAA TAA chloride chloride and and The strongly promoted extraction mechanism, namely ion exchange between TAA chloride and sodiumsodiumThe hydroxide hydroxide strongly promoted producing producing extraction TAA TAA hydroxide hydroxide mechanism, that that enternamely enter the the ion organic organic exchange phase phase between where where TAAdeprotonation deprotonation chloride and of of sodium hydroxide producing TAA hydroxide that enter the organic phase where deprotonation of chloroformchloroformsodium hydroxide and and further further producing reactions reactions TAA take take hydroxide place, place, is is that excluded enter the for organic two reasons: phase where equi equilibriumlibrium deprotonation of of this this ion ion of chloroform and further reactions take place, is excluded for two reasons: equilibrium of this ion exchangeexchangechloroform is unfavorableandunfavorable further forreactionsfor TAATAA hydroxide, hydroxide,take place, and andis excluded particularly particularly for due twodue to reasons:to observation observation equilibrium that that attempts attempts of this to useion to exchange is unfavorable for TAA hydroxide, and particularly due to observation that attempts to useseparatelyexchange separately is prepared unfavorable prepared TAA for hydroxide TAA TAA hydroxide hydroxide, for generation for and generation particularly and reactions and due reactionsof DCCto observation gave of negativeDCC that gave results—theattempts negative to use separately prepared TAA hydroxide for generation and reactions of DCC gave negative resultscarbeneuse separately— isthe mostly carbene prepared hydrolyzed. is mostly TAA Reversibilityhydrolyzed. hydroxide Reversibil of for formation generationity ofof DCCformation and under reactions of PTC DCC conditionsof under DCC PTCgave is of conditions particularnegative results—the carbene is mostly hydrolyzed. Reversibility of formation of DCC under PTC conditions isvalueresults—the of particular in the case carbene value of slow isin mostlythe final case reaction, hydrolyzed. of slow e.g., final addition Reversibility reaction, of DCC e.g. of, to formationaddition alkenes of of of DCC moderate DCC to under alkenes nucleophilicity PTC of conditionsmoderate [27] is of particular value in the case of slow final reaction, e.g., addition of DCC to alkenes of moderate nucleophilicity(Schemeis of particular 14) or value [ insertion27] (Scheme in the into case 14) CH of or bond slow insertion [final28] (Scheme reaction, into CH 15 e.g., bond), that addition [28 thanks] (Scheme of to DCC PTC 15), to become alkenes that thanks synthetically of moderate to PTC nucleophilicity [28] (Scheme 14) or insertion into CH bond [29] (Scheme 15), that thanks to PTC becomeusefulnucleophilicity reactions. synthetically [28] (Scheme useful reaction 14) or sinsertion. into CH bond [29] (Scheme 15), that thanks to PTC becomebecome syntheticallysynthetically usefuluseful reactions.reactions. Ph 50% NaOHaq PhPh Ph 50% NaOHaq Ph Ph Ph + CHCl3 50% NaOHaq Ph Ph Ph ++ CHClCHCl3 TEBA Ph Ph 3 TEBATEBA Cl Cl ClCl ClCl
996%6% ((<10%<10% wwithith tt--BuOKBuOK [[19])24]) 96% (<10% with t-BuOK [19]) SchemeScheme 14. ReversibilityReversibility of of PTC PTC generation generation of of dichlorocarbene dichlorocarbene assures assures high high yields yields of of its its addition addition to to SchemeScheme 14.14. ReversibilityReversibility ofof PTCPTC generationgeneration ofof dichlorocarbenedichlorocarbene assuresassures highhigh yieldsyields ofof itsits additionaddition toto alkenesalkenes of of low low nucleophilicity. nucleophilicity. alkenesalkenes ofof lowlow nucleophilicity.nucleophilicity.
O 50% NaOH OO 50%50% NaOHNaOHaaqq O O Ph + CHCl aq OOOO PhPh ++ CHClCHCl3 O 3 TEBATEBA O TEBA PPhh CCHClHCl2 O Ph CHCl22 556%6% 56% Scheme 15. Reversibility of PTC generation of dichlorocarbene assures good yields of its insertion SchemeScheme 15. 15. ReversibilityReversibility of ofof PTC PTCPTC generation generationgeneration of ofof dichlorocarbene dichlorocarbenedichlorocarbene assures assuresassures good goodgood yields yieldsyields of its ofof insertion itsits insertioninsertion into into C-H bonds. intoC-Hinto CC bonds.‐‐HH bonds.bonds. TheThe PTC PTC conditions conditions are are applicable applicable also also for for generation generation and and reactions reactions of of other other dihalocarbenes: dihalocarbenes: TheThe PTCPTC conditionsconditions areare applicableapplicable alsoalso forfor generationgeneration andand reactionsreactions ofof otherother dihalocarbenes:dihalocarbenes: dibromocarbene,dibromocarbene, chlorofluorocarbene, chlorofluorocarbene, bromofluorocarbene bromofluorocarbene etc., from bromoform, etc., dichlorofluoromethane from bromoform, dibromocarbene,dibromocarbene, chlorofluorocarbene,chlorofluorocarbene, bromofluorocarbenebromofluorocarbene etc.,etc., fromfrom bromoform,bromoform, dichlorofluoromethaneand dibromofluoromethane and respectively. dibromofluoromethane However, the respectively. reactions ofHowever, dibromochloromethane the reactions with of dichlorofluoromethanedichlorofluoromethane andand dibromofluoromethanedibromofluoromethane respectively.respectively. However,However, thethe reactionsreactions ofof dibromochloromethanealkenes, carried out in thewith presence alkenes, of carried typical out TAA in the salts, presence such as of TEBA, typical results TAA salts, in the such formation as TEBA, of dibromochloromethanedibromochloromethane withwith alkenes,alkenes, carriedcarried outout inin thethe presencepresence ofof typicaltypical TAATAA salts,salts, suchsuch asas TEBA,TEBA, resultsa mixture in the of bromochloro-,formation of a dibromo- mixture andof bromochloro dichlorocyclopropanes.-, dibromo- and This dichlorocyclopropanes. undesired lack of selectivity This resultsresults inin thethe formationformation ofof aa mixturemixture ofof bromochlorobromochloro‐‐,, dibromodibromo‐ ‐ andand dichlorocyclopropanes.dichlorocyclopropanes. ThisThis undesiredis due to reversibilitylack of selectivity of the is dissociation due to reversibility of initially of generated the dissociation dibromochloromethyl of initially generated anions to undesiredundesired lacklack ofof selectivityselectivity isis duedue toto reversibilityreversibility ofof thethe dissociationdissociation ofof initiallyinitially generatedgenerated dibromochloromethylbromochlorocarbene and anions its reactions to bromochlorocarbene with halogen anions and [26 ].its On reactions the other with hand, halogen irreversible anions dissociation [26]. On dibromochloromethyldibromochloromethyl anionsanions toto bromochlorocarbenebromochlorocarbene andand itsits reactionsreactions withwith halogenhalogen anionsanions [27].[27]. OnOn theof dibromochloromethylother hand, irreversible anions dissociation generated of dibromochloromethyl in the presence of potassium anions generatedt-butoxide in assures the presence selective of thethe otherother hand,hand, irreversibleirreversible dissociationdissociation ofof dibromochloromethyldibromochloromethyl anionsanions generatedgenerated inin thethe presencepresence ofof potassiumformation oft-butoxide bromochlorocyclopropanes assures selective formation [24]. of bromochlorocyclopropanes [24]. potassiumpotassium tt‐‐butoxidebutoxide assuresassures selectiveselective formationformation ofof bromochlorocyclopropanesbromochlorocyclopropanes [25].[25]. TrichloromethylTrichloromethyl anionsanions areare generated generated at at the the interface, interface, where where they they enter enter fast fast ion exchangeion exchange with with TAA TrichloromethylTrichloromethyl anionsanions areare generatedgenerated atat thethe interface,interface, wherewhere theythey enterenter fastfast ionion exchangeexchange withwith TAAsalt to salt form to lipophilic form lipophilic ion pairs ion that pairs are entering that are the entering organic phase. the organic Nevertheless, phase. theNevertheless, trichloromethyl the TAATAA saltsalt toto formform lipophiliclipophilic ionion pairspairs thatthat areare enteringentering thethe organicorganic phase.phase. Nevertheless,Nevertheless, thethe trichloromethylanions can also dissociateanions can at also the interfacedissociate to at form theDCC. interface Interfacially to form locatedDCC. Interfacially DCC has no located possibility DCC to trichloromethyltrichloromethyl anionsanions cancan alsoalso dissociatedissociate atat thethe interfaceinterface toto formform DCC.DCC. InterfaciallyInterfacially locatedlocated DCCDCC has no possibility to react with alkenes that are insufficiently active nucleophiles, however hashas nono possibilitypossibility toto reactreact withwith alkenesalkenes thatthat areare insufficientlyinsufficiently activeactive nucleophiles,nucleophiles, howeverhowever trialkylamines, much stronger nucleophiles, can react with interfacially located DCC to form the trialkylamines,trialkylamines, muchmuch strongerstronger nucleophiles,nucleophiles, cancan reactreact withwith interfaciallyinterfacially locatedlocated DCCDCC toto formform thethe ammonium ylide. This ylide can migrate into the organic phase where it acts as a base to ammoniumammonium ylide.ylide. ThisThis ylideylide cancan migratemigrate intointo thethe organicorganic phasephase wherewhere itit actsacts asas aa basebase toto deprotonate chloroform. The generated trichloromethyl anion dissociates to form DCC that adds to deprotonatedeprotonate chloroform.chloroform. TheThe generatedgenerated trichloromethyltrichloromethyl anionanion dissociatesdissociates toto formform DCCDCC thatthat addsadds toto alkenes to give dichlorocyclopropane. Trialkylamines can therefore act as catalysts in PTC alkenesalkenes toto givegive dichlorocyclopropane.dichlorocyclopropane. TrialkylaminesTrialkylamines cancan thereforetherefore actact asas catalystscatalysts inin PTCPTC dichlorocyclopropanation [29,30] (Scheme 16). dichlorocyclopropanationdichlorocyclopropanation [30,31][30,31] (Scheme(Scheme 16).16).
Catalysts 2020, 10, 1436 8 of 15 react with alkenes that are insufficiently active nucleophiles, however trialkylamines, much stronger nucleophiles, can react with interfacially located DCC to form the ammonium ylide. This ylide can migrate into the organic phase where it acts as a base to deprotonate chloroform. The generated trichloromethyl anion dissociates to form DCC that adds to alkenes to give dichlorocyclopropane. TrialkylaminesCatalysts 2020, 10, x can FOR therefore PEER REVIEW act as catalysts in PTC dichlorocyclopropanation [29,30] (Scheme 168 ).of 15 Catalysts 2020, 10, x FOR PEER REVIEW 8 of 15 + – CCl2 int + R3Nint R3+N—CCl– 2 int CCl2 int + R3Nint R3N—CCl2 int + – + – R3+N—CCl– 2 int R3+N—CCl– 2 org R3N—CCl2 int R3N—CCl2 org + – + – R3+N—CCl– 2 org + CHCl3 org R3+N—CHCl2 –CCl3 org R3N—CCl2 org + CHCl3 org R3N—CHCl2 CCl3 org + – +— – R3+N—CHCl2 –CCl3 org R3+N— CHCl2 Cl– org + CCl2 org R3N—CHCl2 CCl3 org R3N CHCl2 Cl org + CCl2 org
CCl2 org + CCl2 org + org org Cl Cl org org Cl Cl + – + – R3+N—CHCl2 Cl– org R3+N—CHCl2 Cl– int R3N—CHCl2 Cl org R3N—CHCl2 Cl int + + + – + – R +N—CCl + Na+Cl– + H O R3N—CHCl2 Cl– int + Na+ OH– int R 3N—CCl 2 int + Na+Cl– int + H 2O int R3N—CHCl2 Cl int + Na OH int 3 2 int int 2 int Scheme 16. Interfacially generated dichlorocarbene reacts with trialkyl amines. They can as PT Scheme 16.16. Interfacially generated dichlorocarbene reacts with trialkyltrialkyl amines.amines. They can actas PT as catalysts. PTcatalysts. catalysts. InterfaciallyInterfacially generated generated DCC DCC undergo undergo also also hydrolysis hydrolysis via reaction via reaction with hydroxide with hydroxide anions to anions produce to Interfacially generated DCC undergo also hydrolysis via reaction with hydroxide anions to chlorideproduce and chloride formate and anions. formate It should anions. be therefore It should clarified be whytherefore in the PTCclarified dichlorocyclopropanation why in the PTC produce chloride and formate anions. It should be therefore clarified why in the PTC thedichlorocyclopropanation hydrolysis is practically the negligible. hydrolysis Inis practically the experiment: negligible. chloroform In the experiment: (1 mol), styrene chloroform (1 mol), (1 dichlorocyclopropanation the hydrolysis is practically negligible. In the experiment: chloroform (1 TAAmol), chloride styrene (0.01(1 mol), mol) TAA and aqueous chloride NaOH (0.01 mol) (excess), and the aqueous first 3–5% NaOH of chloroform (excess), the was first hydrolyzed, 3–5% of mol), styrene (1 mol), TAA chloride (0.01 mol) and aqueous NaOH (excess), the first 3–5% of subsequentchloroform dichlorocyclopropanationwas hydrolyzed, subsequent proceeded dichlorocyclopropanation practically without hydrolysis proceeded [31 practically]. It was therefore without chloroform was hydrolyzed, subsequent dichlorocyclopropanation proceeded practically without concludedhydrolysis that [32]. produced It was therefore chloride concluded anions of lower that produced hydration chloride energy than anions hydroxide of lower anions hydration accumulate energy hydrolysis [32]. It was therefore concluded that produced chloride anions of lower hydration energy atthan the hydroxide interface and anions protect accumulate DCC against at the hydrolysis. interface and Formation protect ofDCC DCC against at the hydrolysis. interface, in Formation the absence of than hydroxide anions accumulate at the interface and protect DCC against hydrolysis. Formation of ofDCC TAA at catalyststhe interface, is also in confirmedthe absence by of the TAA reactions catalysts of is 3-alkenoic also confirmed acids. by These the reactions acids exposed of 3‐alkenoic to 50% DCC at the interface, in the absence of TAA catalysts is also confirmed by the reactions of 3‐alkenoic aqueousacids. These NaOH acids are obviouslyexposed to deprotonated 50% aqueous but NaOH the sodium are carboxylatesobviously deprotonated cannot enter thebut aqueousthe sodium nor acids. These acids exposed to 50% aqueous NaOH are obviously deprotonated but the sodium organiccarboxylates phases. cannot Thus, enter interfacially the aqueous generated nor organic DCC being phases. in close Thus, vicinity interfacially to these generated carboxylates DCC adds being to carboxylates cannot enter the aqueous nor organic phases. Thus, interfacially generated DCC being thein close double vicinity bond even to these in the carboxylates absence of the adds PT catalysts. to the double Addition bond of TAAeven salts in the only absence slightly of improves the PT in close vicinity to these carboxylates adds to the double bond even in the absence of the PT thecatalysts. yields Addition [32,33] (Scheme of TAA 17 salts). only slightly improves the yields [33,34] (Scheme 17). catalysts. Addition of TAA salts only slightly improves the yields [33,34] (Scheme 17). CO H CO 2H 1. 50% NaOH 2 CO2H 1. 50% NaOH aq CO2H + CHCl3 aq + CHCl3 2. H2SO4 2. H2SO4 Cl Cl Cl Cl 54% (62% with TEBA) 54% (62% with TEBA) Scheme 17. Interfacially generated dichlorocarbene adds to β,γ‐unsaturated acids. Scheme 17. Interfacially generated dichlorocarbene adds toto ββ,γγ‐-unsaturatedunsaturated acids. 5. Direct Observation of Interfacially Generated Carbanions 5. Direct Observation of Interfacially Generated Carbanions The presented and discussed earlier in this paper experimental verification of the interfacial The presented and discussed earlier in thisthis paperpaper experimentalexperimental verificationverification of the interfacialinterfacial mechanism of PTC reactions of carbanions generated in the presence of aqueous NaOH mechanism ofof PTC PTC reactions reactions of carbanions of carbanions generated generated in the presence in the of aqueouspresence NaOH of aqueous unambiguously NaOH unambiguously confirm that the deprotonation of the carbanion precursors occurs at the phase confirmunambiguously that the confirm deprotonation that the of deprotonation the carbanion of precursors the carbanion occurs precursors at the phase occurs boundary at the (in phase the boundary (in the interfacial region). Such generated carbanions cannot enter the organic nor boundary (in the interfacial region). Such generated carbanions cannot enter the organic nor aqueous phases and remain at the interface unless the catalyst—source of lipophilic cations—is aqueous phases and remain at the interface unless the catalyst—source of lipophilic cations—is introduced. Fast ion exchange with TAA salt in the interfacial region produces lipophilic ion pairs introduced. Fast ion exchange with TAA salt in the interfacial region produces lipophilic ion pairs
Catalysts 2020, 10, 1436 9 of 15 interfacial region). Such generated carbanions cannot enter the organic nor aqueous phases and remain at the interface unless the catalyst—source of lipophilic cations—is introduced. Fast ion exchange with TAA salt in the interfacial region produces lipophilic ion pairs
6. Phase Transfer Catalyzed Base Induced β-Elimination In the preceding sections the interfacial mechanism of PTC reactions in the presence of aqueous NaOH was unambiguously evidenced. Formulation of interfacial mechanism of reactions of carbanions and carbenes was based on two major circumstances, the most important of them is highly unfavorable ion exchange equilibria between hydroxide and halogen anions, hence negligible transfer of hydroxide anions into the organic phase. It was therefore well documented that transfer of hydroxide anions from the aqueous NaOH into organic phase proceeds in negligible degree. In this situation it appears that PTC cannot be an efficient tool for base induced β-elimination of hydrogen halides from haloalkanes to form alkenes. Nevertheless, there are many reports of successful PTC β-elimination of HCl and HBr in laboratory and industry ([17], pp. 420–423). It appears that these processes proceed at the interface, or by minute quantities of TAA hydroxide. Catalysts 2020, 10, 1436 10 of 15
Wehave supposed that the problem can be solved (at least partially) by use of cocatalysts—compounds Y-H that upon deprotonation at the interface with aqueous NaOH produce lipophilic anions Y− of high basicity but low nucleophilicity. These anions upon transfer into organic phase in form of ion pairs with TAA cations shall react with haloalkanes via β-elimination, not substitution pathway (Scheme 18). CatalystsCatalysts 2020 2020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 1010 ofof 1515
Y—H + Na++OH–– Y––Na++ + H O Y—Horgorg + Na OH aqaq Y Na intint + H22Oaqaq
Y––Na++ + Q++X–– Q++Y–– + Na++X–– Y Na intint + Q X orgorg Q Y orgorg + Na X aqaq
X H + Q++Y–– + Y—H + Q++X–– X H + Q Y orgorg + Y—Horgorg + Q X orgorg org org org org SchemeScheme 18. 18. Concept Concept of ofof cocatalysis cocatalysiscocatalysis in inin PTC PTCPTC β‐ β‐β-eliminationeliminationelimination reactions. reactions.reactions.
β UsingUsingUsing as asas a aa model modelmodel reaction reactionreaction β‐ β‐-eliminationeliminationelimination of of hydrogen hydrogen bromide bromide from fromfrom bromocyclohexane bromocyclohexane we wewe have havehave testedtestedtested this thisthis hypothesis hypothesishypothesis taking takingtaking a few aa fewfew alcohols alcoholsalcohols and phenolsandand phenolsphenols as the as potentialas thethe potentialpotential cocatalysts cocatalystscocatalysts [36]. Under [38].[38]. standard UnderUnder β standardconditionsstandard conditionsconditions shown on shownshown Scheme onon 19 SchemeScheme following 1919 followingfollowing degree of degree thedegree-elimination ofof thethe β‐ β‐eliminationelimination was observed. waswas observed.observed.
Br + Br Bu +NBr–– (5% mol), Y—H (5% mol) Bu44NBr (5% mol), Y—H (5% mol) 50% NaOHaq, PhCl, 40 °C, 45 min 50% NaOHaq, PhCl, 40 °C, 45 min
2 6 4 Y—HY—H nonenone nn‐‐BuOHBuOH PhPh2CHOHCHOH MesitolMesitol pp‐‐ClCClC6HH4OHOH yield,yield, %% 00 1515 4343 8282 3737 Scheme 19. Search for efficient cocatalyst in PTC β‐elimination. SchemeScheme 19. SearchSearch for for efficient efficient cocatalyst cocatalyst in PTC β‐β-elimination.elimination. Effectiveness of the cocatalyst depends on its OH acidity and basicity of the O‐anions. Thus EffectivenessEffectiveness ofof the the cocatalyst cocatalyst depends depends on itson OH its acidityOH acidity and basicity and basicity of the Oof-anions. the O‐anions. Thus t-BuOH Thus t‐BuOH and n‐BuOH of low acidity are converted into anions to negligible or low degree thus are tand‐BuOHn-BuOH and n of‐BuOH low acidity of low are acidity converted are converted into anions into to anions negligible to negligible or low degree or low thus degree are ine thusfficient are inefficient cocatalysts. On the other hand p‐chlorophenol, a strong OH acid, is fully converted into inefficientcocatalysts. cocatalysts. On the other On handthe otherp-chlorophenol, hand p‐chlorophenol, a strong OH a strong acid, isOH fully acid, converted is fully converted into anion into but anion but of low basicity thus is also inefficient as cocatalyst. Alcohols of higher acidity, containing anionof low but basicity of low thus basicity is also thus ine isffi alsocient inefficient as cocatalyst. as cocatalyst. Alcohols Alcohols of higher of acidity, higher containing acidity, containing aryl and aryl and perfluoroalkyl substituents are active cocatalysts. The most efficient is mesitol of reasonable arylperfluoroalkyl and perfluoroalkyl substituents substituents are active are cocatalysts. active cocatalysts. The most The emostfficient efficient is mesitol is mesitol of reasonable of reasonable OH OH acidity and basicity of its anion. It should be stressed that in this case ratio of competing OHacidity acidity and basicityand basicity of its anion.of its anion. It should It beshould stressed be thatstressed in this that case in ratio this ofcase competing ratio of substitutioncompeting substitution to β‐elimination is 1:164. It appears therefore that mesitol, readily available product, is substitutionto β-elimination to β‐elimination is 1:164. It appearsis 1:164. It therefore appears that therefore mesitol, that readily mesitol, available readily product,available isproduct, the most is the most recommended cocatalyst for β‐elimination. Surprisingly this simple and efficient therecommended most recommended cocatalyst for cocatalystβ-elimination. for β‐ Surprisinglyelimination. this Surprisingly simple and effithiscient simple cocatalytic and variantefficient of cocatalytic variant of PTC β‐elimination process has not found wider application in organic cocatalyticPTC β-elimination variant processof PTC has β‐ notelimination found wider process application has not in found organic wider synthesis. application in organic synthesis.synthesis. 7. PTC Fluorination 7.7. PTCPTC FluorinationFluorination Although this review is devoted to interfacial processes in PTC reactions induced by concentrated aqueousAlthoughAlthough sodium thisthis hydroxide, reviewreview it isis appears devoteddevoted appropriate, toto interfacialinterfacial following processesprocesses the preceding inin PTCPTC section, reactionsreactions to present inducedinduced another byby concentratedtypeconcentrated of cocatalytic aqueous aqueous PTC sodium sodium process. hydroxide,hydroxide, We would itit like appears appears to present appropriate, appropriate, this variant following following of PTC the becausethe precedingpreceding it offers section,section, perhaps toto presentthepresent most anotheranother efficient type solutiontype ofof cocatalytic ofcocatalytic a difficult PTCPTC and important process.process. WeWe question—PT wouldwould likelike catalyzed toto presentpresent nucleophilic thisthis variantvariant fluorination. ofof PTCPTC becauseDuebecause to high itit offersoffers charge perhapsperhaps density thethe and mostmost high efficientefficient energy ofsolutionsolution hydration, ofof aa liquid-liquiddifficultdifficult andand PTC importantimportant is not applicablequestion—PTquestion—PT for catalyzednucleophiliccatalyzed nucleophilicnucleophilic substitution fluorination.fluorination. with fluoride DueDue anions. toto highhigh There chargecharge are a few densitydensity variants andand of highhigh solid-liquid energyenergy PTCofof hydration,hydration, reactions liquidofliquid fluoride‐‐liquidliquid anions PTCPTC used isis notnot as applicableapplicable potassium for fluoride,for nucleophilicnucleophilic but of limited substitutionsubstitution application. withwith fluoride Thefluoride frequent anions.anions. disadvantage ThereThere areare of aa fewthesefew variantsvariants methods ofof is solidsolid undesired‐‐liquidliquidβ PTC-eliminationPTC reactionsreactions by ofof highly fluoridefluoride basic anionsanions fluoride usedused anions asas potassiumpotassium [37,38]. fluoride,fluoride, butbut ofof limitedlimitedWe application.application. have elaborated TheThe frequent afrequent simple disadvantage anddisadvantage efficient way ofof thesethese of PT methodsmethods catalyzed isis fluorinationundesiredundesired β‐ β‐ ofeliminationelimination alkyl halides byby highlyorhighly sulfonates basicbasic fluoridefluoride with solid anionsanions potassium [39,40].[39,40]. fluoride using a cocatalyst—a compound Y able to associate We have elaborated a simple and efficient way of PT catalyzed fluorination of alkyl halides or reversiblyWe have with elaborated fluoride anion a simple so salt and of efficient TAA with way lipophilic of PT catalyzed YF− can fluorination be readily transferred of alkyl halides into the or sulfonates with solid potassium fluoride using a cocatalyst—a compound Y able to associate sulfonatesorganic solution with solid to deliver potassium a source fluoride of fluoride using anion. a cocatalyst—a In the organic compound solution YFY −ablecan dissociateto associate to − reversiblyliberatereversibly highly withwith active fluoridefluoride fluoride anionanion anions soso saltsalt of orof TAA reactTAA with directlywith lipophiliclipophilic with alkyl YFYF− halides cancan bebe readily orreadily sulfonates transferredtransferred as a source intointo thethe of − organicnucleophilicorganic solutionsolution fluoride. toto deliverdeliver aa sourcesource ofof fluoridefluoride anion.anion. InIn thethe organicorganic solutionsolution YFYF− cancan dissociatedissociate toto liberateliberate highlyhighly activeactive fluoridefluoride anionsanions oror reactreact directlydirectly withwith alkylalkyl halideshalides oror sulfonatessulfonates asas aa sourcesource ofof nucleophilicnucleophilic fluoride.fluoride. 3 WeWe havehave foundfound thatthat PhPh3SnFSnF isis anan efficientefficient cocatalystcocatalyst thatthat reactsreacts withwith aa TAATAA saltsalt andand solidsolid KFKF toto 3 2− formform TAATAA saltsalt ofof PhPh3SnFSnF2− anion.anion. ThisThis saltsalt inin acetonitrileacetonitrile reactsreacts withwith alkylalkyl halideshalides oror sulfonatessulfonates toto affordafford nucleophilicnucleophilic fluorinationfluorination [41,42][41,42] (Scheme(Scheme 20).20).
Catalysts 2020, 10, 1436 11 of 15
We have found that Ph3SnF is an efficient cocatalyst that reacts with a TAA salt and solid KF to form TAA salt of Ph SnF anion. This salt in acetonitrile reacts with alkyl halides or sulfonates to Catalysts 2020, 10, x FOR PEER3 REVIEW2− 11 of 15 aCatalystsfford nucleophilic 2020, 10, x FOR fluorination PEER REVIEW [39 ,40] (Scheme 20). 11 of 15 CH CN Ph SnF + KF 3 Ph SnF –K+ 3 org solid CH3CN 3 2 – solid+ Ph3SnForg + KFsolid Ph3SnF2 K solid Ph SnF –K+ + Q+X– Ph SnF –Q+ + K+X– 3 2 – solid+ + org– 3 2 – org+ + solid– Ph3SnF2 K solid + Q X org Ph3SnF2 Q org + K X solid Ph SnF –Q+ + R—X R—F + Ph SnF + Q+X– 3 2 – org+ org org 3 org + org– Ph3SnF2 Q org + R—Xorg R—Forg + Ph3SnForg + Q X org
+ Ph SnF (10% mol), Bu NHSO – (10% mol) 3 4 + 4 – R—X + KF Ph3SnF (10% mol), Bu4NHSO4 (10% mol) R—F R—X + KF CH3CN, 85 °C R—F CH3CN, 85 °C
RX (yield, %): PhCH2Br (~100), n-C8H17OMs (90), RX (yield, %): PhCH2Br (~100), n-C8H17OMs (90), n-C6H13CH(CH3)OMs (82), CH3CH(OMs)CO2Et (89) n-C6H13CH(CH3)OMs (82), CH3CH(OMs)CO2Et (89) Scheme 20. Cocatalytic system for PTC nucleophilic fluorination of alkyl halides and sulfonates. SchemeScheme 20. 20.Cocatalytic Cocatalytic system system for for PTC PTC nucleophilic nucleophilic fluorination fluorination of of alkyl alkyl halides halides and and sulfonates. sulfonates. It should be stressed that under these catalytic conditions the substitution proceeds efficiently also inItIt the should should case be ofbe stressedalkyl stressed halides that that and under under sulfonates these these catalytic catalytic that in conditionsthe conditions reaction the thewith substitution substitution free fluoride proceeds proceeds anions eenter efficientlyfficiently side reaction—basealsoalso in in the the case case of inducedof alkyl alkyl halides β‐halideselimination. and and sulfonates sulfonates It appears that that in intherefore the the reaction reaction that with with the free freecatalytic fluoride fluoride process anions anions enterdoes enter side notside reaction—basereaction—base induced inducedβ β‐-elimination.elimination. It appearsIt appears therefore therefore that thethat catalytic the catalytic process process does not does proceed not proceed via dissociation of Ph3SnF2− anion to generate fluoride anions in the organic phase, but via − directviaproceed dissociation reaction via dissociation of of the Ph 3alkylSnF of2 − halidesPhanion3SnF 2 toand anion generate sulfonates to generate fluoride with fluoride anionsthis complex inanions the organic anionin the thatorganic phase, does butphase, not via exhibit but direct via basicity.reactiondirect reaction of the alkyl of the halides alkyl and halides sulfonates and sulfonates with this complex with this anion complex that doesanion not that exhibit does basicity. not exhibit basicity.It should be mentioned that potassium salt of Ph SnF anion is soluble in dipolar aprotic It should be mentioned that potassium salt of Ph33SnF2− anion is soluble in dipolar aprotic solvents—DMF,It should be sulfolane mentioned etc., thusthat potassium an alternative salt variant of Ph3SnF of PTC2− anion can beis realized,soluble in in dipolar which Ph aproticSnF solvents—DMF, sulfolane etc., thus an alternative variant of PTC can be realized, in which Ph3SnF + actssolvents—DMF, as a catalyst thatsulfolane continuously etc., thus transfers an alternative KF in variant form of of K PTCPh SnFcan be intorealized, the organic in which solution, Ph3SnF acts as a catalyst that continuously transfers KF in form of K+Ph3SnF3 2− into2− the organic solution, thus + − catalyzethusacts catalyzeas anucleophilic catalyst nucleophilic that fluorination continuously fluorination [43] transfers (Scheme [41] (Scheme KF 21). in form 21). of K Ph3SnF2 into the organic solution, thus catalyze nucleophilic fluorination [43] (Scheme 21). solvent Ph SnF + KF Ph SnF –K+ 3 org solid solvent 3 2 – org+ Ph3SnForg + KFsolid Ph3SnF2 K org Ph SnF –K+ + R—X R—F + Ph SnF + KX 3 2 – org+ org 3 Ph3SnF2 K org + R—Xorg R—F + Ph3SnF + KX
Ph3SnF (10% mol) R—X + KF Ph3SnF (10% mol) R—F + KX R—X + KF sulfolane R—F + KX sulfolane
RX (yield, %): PhCOCH2Br (92), n-C8H17OMs (90), RX (yield, %): PhCOCH2Br (92), n-C8H17OMs (90), n-C6H13CH(CH3)OTs (80) n-C6H13CH(CH3)OTs (80) SchemeScheme 21. NewNew type type of of solid solid-liquid‐liquid PTC PTC for for nucleophilic nucleophilic fluorination. fluorination. Scheme 21. New type of solid‐liquid PTC for nucleophilic fluorination.
These results suggest that the system Ph 3SnXSnX (X=F, (X=F, Cl) Cl) and and solid solid potassium potassium fluoride fluoride with with or withoutThese TAATAA results halide halide suggest is is an an effi efficient thatcient the source source system of soluble,of Ph soluble,3SnX nucleophilic (X=F, nucleophilic Cl) and but solid notbut strongly notpotassium strongly basic fluoride fluoridebasic fluoride with anion. or anion.without TAA halide is an efficient source of soluble, nucleophilic but not strongly basic fluoride 8.anion. Effect of the Size of Interface 8. EffectThe of key the steps Size of of PTC Interface reactions carried out in the presence of concentrated aqueous NaOH are 8. Effect of the Size of Interface interfacialThe key processes steps of of PTC deprotonation, reactions carried therefore out in of the crucial presence importance of concentrated is size of theaqueous interface. NaOH In are the interfacialThe keyprocesses steps ofof PTCdeprotonation, reactions carried therefore out of in crucialthe presence importance of concentrated is size of the aqueous interface. NaOH In the are PTCinterfacial reactions processes carried ofout deprotonation, under the common therefore batch of crucialconditions importance size of theis size interfacial of the interface. area depends In the mostlyPTC reactions on the speed carried of stirring.out under There the arecommon a few papersbatch conditionsin which relation size of ofthe the interfacial speed of stirringarea depends with themostly rate ofon the the chemical speed of reactionsstirring. There was studied are a few in papers order toin establishwhich relation mechanism of the ofspeed the process.of stirring Since with thethe first rate step of the of thechemical PTC reactions reactions of was carbanions studied andin order other to anions establish derived mechanism from weak of the organic process. acids Since is the first step of the PTC reactions of carbanions and other anions derived from weak organic acids is
Catalysts 2020, 10, 1436 12 of 15
PTC reactions carried out under the common batch conditions size of the interfacial area depends mostly on the speed of stirring. There are a few papers in which relation of the speed of stirring with the rate of the chemical reactions was studied in order to establish mechanism of the process. Since the Catalysts 2020, 10, x FOR PEER REVIEW 12 of 15 first step of the PTC reactions of carbanions and other anions derived from weak organic acids is interfacialinterfacial deprotonation deprotonation followed followed by by ion ion exchange exchange and and transfer transfer of of the the anions anions into into the the organic organic phase phase wherewhere they they enter enter further further reactions reactions it it appears appears that that the the observed observed rates rates of of the the reaction reaction should should depend depend onon thethe size size of of the the interface, interface, hence hence speed speed of of the the agitation. agitation. SituationSituation isis howeverhowever moremore complicated,complicated, becausebecause rate rate constant constant ofof the the reaction reaction in in the the organic organic phase phase can can be be the the deciding deciding factor. factor. InIn the the case case of of veryvery fast fast reactions reactions in in the the organic organic phase, phase, speed speed of of agitation agitation can can decide decide to to some some extent extent on on overall overall rate rate ofof the the reaction. reaction. OnOn thethe other other handhand whenwhen thethe rate rate constant constant ofof the the reaction reaction in in the the organic organic phase phase is is not not high,high, overall overall rate rate can can mimic mimic zero zero order order kinetics kinetics because because concentration concentration ofof the the reacting reacting anions anions in in the the organicorganic phase phase is is constant, constant, whereas whereas electrophilic electrophilic reagent reagent is is in in great great excess. excess. Thus, Thus, in in general, general, kinetic kinetic of of PTCPTC reactionreaction inin two immiscible phase phase systems systems in in correlation correlation with with speed speed of ofstirring, stirring, when when phases phases are areof various of various viscosity viscosity is isin inour our opinion opinion not not a a reliable reliable tool tool for for differentiation differentiation of thethe extractionextraction andand interfacialinterfacial mechanism. mechanism. AnAn important important factor factor that that a affectsffects e efficiencyfficiency of of the the PTC PTC reactions reactions of of carbanions carbanions in in the the liquid-liquid liquid‐liquid two-phasetwo‐phase systems systems is is e effectffect of of the the structure structure of of the the TAA TAA cations cations on on rate rate of of the the interfacial interfacial ion ion exchange exchange andand transfer transfer of of the the formed formed lipophilic lipophilic ionion pairspairs fromfrom thethe interfaceinterface intointo thethe bulkbulk ofof thethe organicorganic phase.phase. ThisThis very very complicated complicated problem problem was was studied studied and and thoroughly thoroughly discussed discussed by by Denmark Denmark [ 42[44].]. RecentlyRecently alternative alternative approaches approaches to assureto assure large sizelarge of interfacialsize of interfacial region between region two between immiscible two liquidimmiscible phases liquid are under phases investigation—reactions are under investigation—reactions carried out in microreactors carried out or continuous in microreactors microflow or systems.continuous Passing microflow two immiscible systems. Passing liquids two through immiscible narrow liquids tubing through can result narrow in laminar tubing or can turbulent result in flowlaminar depending or turbulent on density flow depending and viscosity on of density the liquids and viscosity and speed of of the flow. liquids Turbulent and speed flow assuresof flow. particularlyTurbulent flow large assures interfacial particularly surface. large This interfacial technique surface. was successfully This technique applied was successfully for a few reactions applied thatfor a proceed few reactions without that a PT proceed catalyst, without and also a PT PT catalyst, catalyzed and reactions, also PT catalyzed particularly reactions, for generation particularly and reactionsfor generation of dibromo- and reactions [43,44] andof dibromo dichlorocarbenes‐ [45,46] and [45 dichlorocarbenes] (Scheme 22). [47] (Scheme 22).
CHCl 3 Cl 35% NaOHaq Cl O Et NMe O O 2 cat. O 80 °C O continuous flow synthesis O 98%
SchemeScheme 22. 22. AdditionAddition of of PTC PTC generated generated dichlorocarbene dichlorocarbene to to alkenes alkenes in in continuous continuous flow flow system. system.
InIn these these papers papers specific specific features features of two of phasetwo phase reactions reactions in flow systemsin flow aresystems thoroughly are thoroughly discussed. discussed. 9. Asymmetric Synthesis via PT Catalyzed Reactions of Carbanions 9. AsymmetricParticularly Synthesis attractive via application PT Catalyzed of PTC Reactions in chemistry of Carbanions of carbanions is asymmetric synthesis inducedParticularly by chiral TAA attractive cations. application Carbanions of generated PTC in chemistry at the interface of carbanions with concentrated is asymmetric aqueous synthesis NaOH areinduced transferred by chiral into organicTAA cations. phase inCarbanions form of lipophilic generated ion at pairs the with interface TAA cations.with concentrated Chiral TAA aqueous cations canNaOH affect are stereochemical transferred into outcome organic of thephase reactions in form of of prochiral lipophilic carbanions ion pairs with with electrophilic TAA cations. partners Chiral thusTAA induce cations enantioselectivity. can affect stereochemical In the ion pairsoutcome carbanions of the arereactions associated of prochiral with TAA carbanions cations due with to electrostaticelectrophilic forces. partners In the thus transition induce enantioselectivity. states of the alkylation In the of prochiralion pairs carbanions theare negativeassociated charge with isTAA distributed cations on due the to alkylating electrostatic agents, forces. hence In the the di fftransitionerences of states free energies of the ofalkylation the diastereoisomeric of prochiral transitioncarbanions states the withnegative chiral charge TAA cationsis distributed become on negligible the alkylating and no agents, induction hence is observed. the differences The problem of free wasenergies successfully of the diastereoisomeric solved when chiral transition TAA cations states able with to chiral enter additionalTAA cations association become negligible with carbanions and no wereinduction used. Theis observed. key question The isproblem selection was of the successfully chiral TAA solved salts that when induce chiral high TAA enantioselectivity cations able to of enter the reactionsadditional of association the prochiral with carbanions. carbanions The were most used. common The TAA key question salts that is assure selection high enantioselectivityof the chiral TAA aresalts quaternized that induce cinchona high enantioselectivity alkaloids containing of athe variety reactions substituents of the ableprochiral to additionally carbanions. interact The withmost common TAA salts that assure high enantioselectivity are quaternized cinchona alkaloids containing a variety substituents able to additionally interact with the carbanions. Efficient PT catalysts that assure high enantioselectivity of reactions of carbanions are also spiro‐bis‐binaphthyl TAA salts, chiral analogues of crown ethers, bis‐TAA salts synthesized from tartaric acid etc. (Scheme 23).
Catalysts 2020, 10, 1436 13 of 15 the carbanions. Efficient PT catalysts that assure high enantioselectivity of reactions of carbanions are also spiro-bis-binaphthyl TAA salts, chiral analogues of crown ethers, bis-TAA salts synthesized from tartaric acid etc. (Scheme 23). Catalysts 2020, 10, x FOR PEER REVIEW 13 of 15
Br– Ar H N Ar O N N Br– Ar O Ar N O N 2 I– Ar Ar
SchemeScheme 23. 23. ExamplesExamples ofof eefficientfficient chiral chiral PT PT catalysts. catalysts.
ReviewsReviews ofof enantioselectiveenantioselective PTCPTC reactionsreactions catalyzedcatalyzed byby variousvarious typestypes ofof chiralchiral catalystscatalysts areare publishedpublished [[48–51].46–49]. A A systematic systematic search search for for TAA TAA salts salts as as efficient efficient asymmetric asymmetric PT PT catalysts catalysts based based on onquantitative quantitative structure structure activity activity-selectivity‐selectivity relationship relationship was was recently recently published published [52]. [50 Discussion]. Discussion in inall allthese these studies studies of ofenantioselective enantioselective PT PT catalyzed catalyzed reactions reactions of of carbanions carbanions was based onon interfacialinterfacial mechanismmechanism of of generation generation of of carbanions. carbanions.
10.10. ConcludingConcluding RemarksRemarks InIn thisthis short short review review a a variety variety of of experimental experimental results results is is presented presented that that unambiguously unambiguously confirmconfirm interfacialinterfacial mechanismmechanism ofof PTCPTC reactionsreactions ofof carbanions.carbanions. ThusThus itit waswas evidencedevidenced thatthat thethe initialinitial stepstep ofof thesethese reactionsreactions isis deprotonation deprotonation of of the the carbanion carbanion precursor precursor on on the the phase phase boundary boundary between between organicorganic phasephase and and concentrated concentrated aqueous aqueous NaOH NaOH followed followed by by ion ion exchange exchange of of interfacially interfacially located located carbanions carbanions andand TAATAA saltssalts toto form lipophilic ion pairs pairs that that enter enter organic organic phase. phase. It It was was also also shown shown that that basicity basicity of ofthe the surface surface of of the the NaOH NaOH aqueous aqueous solution solution can can be be modified modified by by presence of inorganicinorganic anionsanions andand cations.cations. ThisThis possibilitypossibility cancan extendextend applicabilityapplicability ofof thethe PTCPTC reactions reactions of of organic organic anions. anions.
AuthorAuthor Contributions: Contributions: M.M.M.M. andand M.F.M.F. contribute contribute equally. equally. AllAll authorsauthors havehave readread andand agreedagreed to to the the published published versionversion of of the the manuscript. manuscript.
Funding:Funding: ThisThis research research was was funded funded by Polishby Polish Academy Academy of Sciences of Sciences and Faculty and ofFaculty Chemistry, of Chemistry, Warsaw University Warsaw of Technology. University of Technology. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References References 1. Available online: https://www.marketsandmarkets.com/Market-Reports/phase-transfer-catalyst-market-
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