catalysts

Review Transfer HydrogenationHydrogenation fromfrom 2-propanol2-propanol toto 6 Acetophenone CatalyzedCatalyzed byby [RuCl[RuCl22(η6--arene)P]arene)P] (P (P == monophosphine) and [Rh(PP)2]X (PP = diphosphine, monophosphine)− − and [Rh(PP) ]X (PP = diphosphine, X = ClCl-, BF, BF4-)4 Complexes) Complexes

Alberto Mannu 1,1,**, Arnald, Arnald Grabulosa Grabulosa 2,3 and2,3 and Salvatore Salvatore Baldino Baldino 4,* 4,*

1 DepartmentDepartment of of Chemistry, Chemistry, Materials Materials and and Chemical Chemical Engineering Engineering “G. “G. Natta”, Natta”, Politecnico Politecnico di di Milano, Milano, Piazza L.Piazza da Vinci L. da32, VinciMilano 32, 20133, Milano Italy 20133, Italy 2 DepartamentDepartament de de Química Química Inorgànica Inorgànica i iOrgànica, Orgànica, Secció Secció dede Química Química Inorgànica, Inorgànica, Universitat Universitat de de Barcelona, Barcelona, MartíMart ií Franquèsi Franquè s1– 1–11,11, E E-08028-08028 Barcelona, Barcelona, Spain Spain;; [email protected] [email protected] 3 InstitutInstitut de de Nanociència Nanociència i Nanotecnologia i Nanotecnologia (IN2UB), (IN2UB), Universitat Universitat de de Barcelon Barcelona,a, E E-08028,-08028, Barcelona, Barcelona, Spain Spain 4 DipartimentoDipartimento di di Chimica, Chimica, Università Universit àdidi Torino, Torino, Via Via Pietro Pietro Giuria, Giuria, 7, 7, I I-10125-10125 Torino, Torino, Italy Italy * Correspondence:Correspondence: [email protected] [email protected] (A.M.) (A.M.);; salvatore.b [email protected]@unito.it (S.B.) (S.B.) Received: 30 December 2019; Accepted: 26 January 2020; Published: date


Received: 30 December 2019; Accepted: 26 January 2020; Published: 1 February 2020
 Abstract: The reduction of ketones through homogeneous transfer hydrogenation catalyzed by Abstract: The reduction of ketones through homogeneous transfer hydrogenation catalyzed by transition metals is one of the most important routes for obtaining alcohols from carbonyl transition metals is one of the most important routes for obtaining alcohols from carbonyl compounds. compounds. The interest of this method increases when opportune catalytic precursors are able to The interest of this method increases when opportune catalytic precursors are able to perform the perform the transformation in an asymmetric fashion, generating enantiomerically enriched chiral transformation in an asymmetric fashion, generating enantiomerically enriched chiral alcohols. This alcohols. This reaction has been extensively studied in terms of catalysts and variety of substrates. reaction has been extensively studied in terms of catalysts and variety of substrates. A large amount of A large amount of information about the possible mechanisms is available nowadays, which has information about the possible mechanisms is available nowadays, which has been of high importance been of high importance for the development of systems with excellent outcomes in terms of for the development of systems with excellent outcomes in terms of conversion, enantioselectivity conversion, enantioselectivity and Turn Over Frequency. On the other side, many mechanistic and Turn Over Frequency. On the other side, many mechanistic aspects are still unclear, especially for aspects are still unclear, especially for those catalytic precursors which have shown only moderate those catalytic precursors which have shown only moderate performances in6 transfer hydeogenation. performances in transfer hydeogenation6 . This is the case of neutral [RuCl2( -arene)(P)] and cationic This is the case of neutral [RuCl2(η -arene)(P)] and cationic [Rh(PP)2]X (X = anion; P and PP = mono- [Rh(PP)2]X (X = anion; P and PP = mono- and bidentate phosphine, respectively) complexes. Herein, and bidentate phosphine, respectively) complexes. Herein, a summary of the known information a summary of the known information about the Transfer Hydrogenation catalyzed by these about the Transfer Hydrogenation catalyzed by these complexes is provided with a continuous focus complexes is provided with a continuous focus on the more relevant mechanistic features. on the more relevant mechanistic features. Keywords: transfer hydrogenation; ruthenium; rhodium; catalysis; ketone reduction Keywords: transfer hydrogenation; ruthenium; rhodium; catalysis; ketone reduction

1. Introduction 1. Introduction The hydrogen transfer reaction, also known as H-transfer or Transfer Hydrogenation (TH), has The hydrogen transfer reaction, also known as H-transfer or Transfer Hydrogenation (TH), has become, in particular since the 1990s, one of the most powerful methodologies to transform carbonyl become, in particular since the 1990s, one of the most powerful methodologies to transform carbonyl compounds into carbinols. It consists of the reduction of a polar carbon-heteroatom bond, usually compounds into carbinols. It consists of the reduction of a polar carbon-heteroatom bond, usually C=O. When this transformation takes place on a prochiral substrate, e.g., an unsymmetrical ketone, a C=O. When this transformation takes place on a prochiral substrate, e.g., an unsymmetrical ketone, a stereogenic center is generated and a chiral alcohol is produced. By employing opportune catalytic stereogenic center is generated and a chiral alcohol is produced. By employing opportune catalytic precursors equipped with an asymmetric environment, it is possible to obtain optically active precursors equipped with an asymmetric environment, it is possible to obtain optically active products. products. In that case, the reaction is addressed as Asymmetric Transfer Hydrogenation (ATH) [1] In that case, the reaction is addressed as Asymmetric Transfer Hydrogenation (ATH) [1] (Scheme1). (Scheme 1).

Scheme 1 1.. Synthesis of chiral alcohols from ketones.

Catalysts 20202020, 10, 162;x; doi: doi: FOR10.3390 PEER/catal10020162 REVIEW www.mdpi.com/journal/www.mdpi.com/journal/catalysts Catalysts 2020, 10, 162 2 of 19

The possibility to reduce ketones to alcohols in an enantioselective way through ATH represents a milestone in the asymmetric catalysis, as chiral alcohols are employed as intermediates, as well as end-products in many industries, including fragrancies and pharmaceutics [2]. In addition, the protocol can be extended to a general C=X polar substrate (X = O, N), allowing the synthesis of chiral alcohols [2], amines, and many corresponding derivatives [3]. Recent applications of such protocol have allowed the valorization of biomass by extracting lignin [4], or for the production of biofuels [5]. Historically, a milestone was reached in 1995, when Noyori reported the enantioselective reduction of prochiral ketones by employing as catalytic precursors [RuCl2(diphosphane)(diamine)] complexes in the presence of a base. The impact of these new catalytic systems for achieving alcohols with high optical purity has been very impressive, and since then an intensive and systematic research work has allowed the extension of the protocol to many substrates and catalysts [6]. The level of importance of such studies has been recognized in 2001 with the award of the Nobel prize in Chemistry [7]. The catalyzed reduction of ketones in homogenous phase has increased in popularity during the last 50 years and the corresponding literature is very rich. The reaction involves a formal transfer of hydrogen from a donor (usually an alcohol) to an acceptor carbonyl compound (usually a ketone). This protocol is not the only synthetic route for obtaining carbinols from carbonyl compounds but its operational simplicity, the elimination of safety measures associated with the use of gaseous dihydrogen, the low cost of the reducing agents and the availability of a large number of catalysts of high activity and selectivity for the process, make this process of high interest [8]. Many combinations of catalysts, hydrogen donors and acceptors have been developed during the last 25 years and most of them have been the objects of review articles [9]. Nowadays, a large number of catalytic precursors for the reduction of ketones with elevated Turn Over Number (TON), Turn Over Frequency (TOF) and excellent enantiomeric excess (e.e.) are available and most of the chemistry of such catalysts has been studied in detail, including many mechanistic aspects. Nevertheless, in order to open the way to the development of new and better performing systems, sometimes it is necessary to focus on the elemental aspects of a process. In general, in metal mediated catalysis, stable and robust complexes encounter difficulties in the activation step when they are employed as catalytic precursors. On the other hand, very reactive complexes can show high catalytic performances, but tend to decompose fast. The fine balance between stability of the catalyst and its activity and productivity represents the main task for most of the researchers involved in the implementation of new catalytic systems. In this survey, the most relevant literature regarding two catalytic systems will be discussed. The TH of carbonyl compounds in the presence of 2-propanol mediated by Ru-arene complexes bearing monodentate phosphorus ligands, and by mononuclear cationic Rh complexes stabilized by diphosphine ligands will be the object of this survey. A brief and general description of the TH, including an overview of the most common hydrogen donors available and the main accepted mechanisms will be provided. After that, the discussion 6 will move to the catalytic performances of catalytic precursors of the type [RuCl2(η -arene)(P)] and [Rh(PP)2]X (X = anion; P and PP = mono- and bidentate phosphine, respectively). A special focus on the mechanism characteristics of each class will be reported, especially in terms of activation of the C–H moiety of the donor agent (2-propanol) with the consequent formation of metal hydrides. Although the aforementioned systems are often less productive than the complexes featuring the combination of phosphino/amino functionalities [1], they can generate intermediate species within the catalytic cycle stable enough to be clearly detected and properly analyzed. As a matter of fact, both classes of Ru- and Rh-systems are straightforwardly prepared and their reactivity is easy to study, providing an ideal discussion field for gaining important mechanistic information which can also be exploited for more elaborated catalytic systems. Catalysts 2020, 10, 162 3 of 19

Catalysts2. Results 2020, 10, x FOR PEER REVIEW 3 of 18 Catalysts 2020, 10, x FOR PEER REVIEW 3 of 18 2.1. TH:One Generalities of the first andexample Applicationss of ketone reduction to alcohol was described in 1926 by Ponndorf and it is known as the Meerwein–Ponndorf–Verley reaction, or MPV process [10]. In the MPV process, OneOne of of t thehe firstfirst examplesexamples ofof ketoneketone reduction reduction to to alcohol alcohol was was described described in 1926in 1926 by by Ponndorf Ponndorf and and it is carbonyl compounds are reduced to the corresponding alcohols in the presence of aluminium 2- itknown is known as the as Meerwein–Ponndorf–Verley the Meerwein–Ponndorf–Verley reaction, reaction, or MPV or process MPV process [10]. In [ the10]. MPV In the process, MPV process, carbonyl propoxide through a six-membered transition state without involvement of metal hydride carbonylcompounds compounds are reduced are toreduced the corresponding to the corresponding alcohols in alcohols the presence in the of presence aluminium of aluminium 2-propoxide 2- intermediates [11]. propoxidethrough a six-memberedthrough a six transition-membered state transition without involvement state without of metal involvement hydride intermediates of metal hydride [11]. The opposite process to the MPV reduction was performed a few years later by Oppenauer and intermediatesThe opposite [11]. process to the MPV reduction was performed a few years later by Oppenauer has been employed for the oxidation of secondary alcohols to ketones (Oppenauer oxidation, Scheme andThe has opposite been employed process forto the the MPV oxidation reduction of secondary was performed alcohols a few to ketones years later (Oppenauer by Oppenauer oxidation, and 2) [12]. hasScheme been2 employed)[12]. for the oxidation of secondary alcohols to ketones (Oppenauer oxidation, Scheme 2) [12].

Scheme 2. MPV reduction and Oppenauer oxidation. SchemeScheme 2 2.. MPVMPV reduction reduction and and Oppenauer Oppenauer oxidation. oxidation. In the MPV process the hard Lewis acid Al3+, coordinates the ketone and the alcohol, allowing the two reagents to be close enough for the hydrogen3+ transfer. Additionally, the metal coordination InIn the the MPV MPV process process the the hard hard Lewis acid Al3+, ,coordinates coordinates the the ketone ketone and and the the alcohol alcohol,, allowing allowing allows the cyclic geometry of the six-members transition state (Scheme 2). More recently these two thethe two two reagents reagents to to be be close close enough enough for for the the hydrogen hydrogen transfer transfer.. Additionally, Additionally, the the metal metal coordination coordination processes have been revisited in combination with low-aggregation aluminium alkoxide that are able, allowsallows the the cyclic cyclic geometry geometry of of the the six six-members-members transition transition state state (Schem (Schemee 22)).. More recently these two even in catalytic amounts, to induce the hydrogen transfer across both directions [13–15]. On the processesprocesses have have been been revisited revisited in in combination combination with with low low-aggregation-aggregation aluminium aluminium alkoxide alkoxide that that are are able, able, other side, the first ATH was proposed by Doering and Young [16], who presented an asymmetric eveneven in catalytic amounts,amounts, to to induce induce the the hydrogen hydrogen transfer transfer across across both both directions directions [13– 15[13].– On15]. the On other the version of the MPV process [17]. otherside, theside, first the ATH first was ATH proposed was proposed by Doering by Doering and Young and [ 16Young], who [1 presented6], who presented an asymmetric an asymmetric version of In 1967 appeared the first report about the possibility to homogeneously catalyze the reduction versionthe MPV of processthe MPV [17 process]. [17]. of ketones by transfer hydrogenation in the presence of a transition metal complex [18,19]. Only in InIn 1967 1967 appeared appeared the the first first report report about about the the possib possibilityility to to homogeneously homogeneously catalyze catalyze the the reduction reduction the second half of the seventies the TH started to be studied and developed, when Sasson and Blum ofof ketones ketones by by transfer transfer hydrogenation hydrogenation in in the the presence presence of of a a transition transition metal metal complex complex [18,19 [18,19]].. Only Only in in demonstrated that [RuCl2(PPh3)3] could promote the reduction of ketones to alcohols in the presence thethe second second half half of of the the seventies seventies the the TH TH started started to to be be studied studied and and developed, developed, when when Sasson Sasson and and Blum Blum of 2-propanol in homogeneous phase [20]. These preliminary studies found their application a few demonstrateddemonstrated that that [RuCl [RuCl22(PPh(PPh33)3)]3 ]could could promote promote the the reduction reduction of of ketones ketones to to alcohols alcohols in in the the presence presence years later with the first examples of C=O reduction catalyzed by transition metals (Ru/DIOP catalytic ofof 2 2-propanol-propanol in in homogeneous homogeneous phase phase [ [2020]].. These These preliminary preliminary studies studies found found their their application application a a few few precursor) in homogeneous phase [21]. yearsyears later later with with the the first first examples examples of of C=O C=O reduction reduction catalyzed catalyzed by by transition transition metals metals (Ru/DIOP (Ru/DIOP catalytic catalytic Since then, the interest in the ATH has grown and different protocols have been developed for precursor)precursor) in in homogeneous homogeneous phase phase [ [2121]].. this reaction [22]. SinceSince then, then, the the interest interest i inn the the ATH ATH has has grown grown and and different different protocols protocols ha haveve been been developed developed for for Historically, ruthenium has been the more commonly used and studied metal in ATH, and its thisthis reaction reaction [ [2222]].. corresponding chiral complexes have become the catalysts of choice for the production of chiral Historically,Historically, ruthenium ruthenium has has been been the the more more commonly commonly used used and and studied studied metal metal in in ATH ATH,, and and its its alcohols through ATH [1]. correspondingcorresponding chiral chiral complexes complexes have have become become the the catalysts catalysts of of choice choice for for the the production production of of chiral chiral When a reduction of a ketone to an alcohol takes place, two hydrogen atoms are formally alcoholsalcohols through through ATH ATH [ 1].]. exchanged. The reducing agent acts as hydrogen donor and can be indicated as DH2. Once the WhenWhen a a reduction reduction of of a a ketone ketone to to an an alcohol alcohol takes takes place, place, two two hydrogen hydrogen atoms atoms are are formally formally reaction is completed the reducing agent is converted in its dehydrogenated counterpart, D. In turn, exchanged.exchanged. The reducing reducing agent agent acts acts as ashydrogen hydrogen donor donor and canand be can indicated be indicated as DH 2 as. Once DH2 the. Once reaction the the ketone acts as acceptor and undergoes the formation of two new bonds: O-H and C-H (Scheme reactionis completed is completed the reducing the reducing agent is convertedagent is converted in its dehydrogenated in its dehydrogenated counterpart, counterpart, D. In turn, D. the In ketone turn, 3). theacts ketone as acceptor acts as and acceptor undergoes and theundergoes formation the of formation two new of bonds: two new O-H bonds: and C-H O- (SchemeH and C3-).H (Scheme

3).

Scheme 3. Transfer Hydrogenation from a generic donor agent to acetone. Scheme 3. Transfer Hydrogenation from a generic donor agent to acetone.

The most commonScheme hydrogen3. Transfer Hydrogenation donors employed from in a thegeneric H-transfer donor agent are 2-propanolto acetone. and formic acid, The most common hydrogen donors employed in the H-transfer are 2-propanol and formic acid, including its salts. including its salts. The most common hydrogen donors employed in the H-transfer are 2-propanol and formic acid, The employment of 2-propanol has some advantages, such as its low price, good solubilization including its salts. capacity and the possibility of an easy recycling. As a matter of fact, it was observed that a large The employment of 2-propanol has some advantages, such as its low price, good solubilization number of catalysts have a life time in 2-propanol long enough to obtain high conversions. capacity and the possibility of an easy recycling. As a matter of fact, it was observed that a large number of catalysts have a life time in 2-propanol long enough to obtain high conversions.

Catalysts 2020, 10, 162 4 of 19

CatalystsThe 2020 employment, 10, x FOR PEER of REVIEW 2-propanol has some advantages, such as its low price, good solubilization4 of 18 Catalystscapacity 2020 and, 10, thex FOR possibility PEER REVIEW of an easy recycling. As a matter of fact, it was observed that a4 largeof 18 numberWhen of catalysts 2-propanol have-like alife hydro timegen in 2-propanol donors are long employed, enough to obtain the process high conversions. takes place under thermodynamicWhenWhen 2 2-propanol-like-propanol control:-like once hydro hydrogen 2-propanolgen donors donors is dehydrogenated, are are employed, employed, acetone the the process is process formed takes takes, which place place can under act under as thermodynamichydrogenthermodynamic acceptor control: control: and, in once oncemost 2 2-propanol-cases,propanol an equilibriumis is dehydrogenated, dehydrogenated, is generated. acetone acetone For isthis is formed formed, reason,, which whicha large can canexcess act act asof as hydrogen2hydrogen-propanol acceptor acceptoris usually and, and, required in in most most and cases, cases, very an an often equilibrium equilibrium it is indeed is is generated. generated.the solvent For Forof thethis this reaction. reason, reason, a Its a large large boiling excess excess point of of 2of2-propanol-pro 82 panol°C makes is is usually usually it a good required choice andand to perform veryvery oftenoften the itit reaction isisindeed indeed at the thereflux solvent solvent as well. of of the the reaction. reaction. Its Its boiling boiling point point of The extraction of dihydrogen from 2-propanol requires in most cases the presence of a base: of82 82◦C °C makes makes it it a gooda good choice choice to to perform perform the the reaction reaction at refluxat reflux as as well. well. hydroxidesTheThe extraction extraction or alkoxides of of dihydrogen dihydrogen of alkali metals from from are2 2-propanol-propanol commonly requires requires used in in inthis most most kind cases cases of reactions. the the presence presence The amountof of a abase: base: of hydroxidesbasehydroxides is generally or or alkoxides alkoxides between of of 5 alkali alkalito 20 metalsequivalents metals are are commonly commonlywith respect used used to inthe in this thismetal, kind kind although of of reactions. reactions. some The Thesystems amount amount have of of basebeenbase isreported is generally generally working between between properly 5 5 to to 20 20 equivalentswithout equivalents base with with [23 ]respect. respect In addition, to to the the metal,sometimes metal, although although the base some some is systems systemsnot innocent have have beenduringbeen reported reported the reaction, working working especially properly properly in withoutthe without ATH. base baseIn fact, [ [2233] ].after. In In addition, addition,long reaction sometimes sometimes times, thethe the baseenantiomeric base is is not not innocent innocent excess during(e.e.)during can the the decrease reaction, reaction, through especially especially the inaction in the the ATH. of ATH. the In Inbase fact, fact, [24 after after–27 ]long.long reaction reaction times, times, the the enantiomeric enantiomeric excess excess (e.e.)(e.e.) THcan can underdecrease decrease kinetic through through control the the action actioncan be of of achieved the the base base [24by [24 –– using2727]].. the formic acid or its salts as hydrogen donorTHTHs. under Inunder this kinetic case, control control the by can -productcan be be achieved achieved is gaseous by by using using CO the2 which theformic formic acid makes acidor its the or salts itsreaction as salts hydrogen as irreversible hydrogen donors.. donorAdditionally,s. In this formic case, acidthe by can-product be activated is gaseous with CO a2 which weak base makes like the triethylamine reaction irreversible (formic. In this case, the by-product is gaseous CO2 which makes the reaction irreversible. Additionally, formic Additionally,acid:triethyacid can belamine activated formic mixtures with acid aare can weak commercially be base activated like triethylamine available) with a and weak (formic sometimes base acid:triethylamine like it can triethylamine be usedmixtures in aqueous (formic are acid:triethysolutioncommercially or laminein biphasic available) mixtures systems. and are sometimes Unfortunately,commercially it can available)the be acidity used inand of aqueous formic sometimes acid solution can, it can in or severalbe in used biphasic cases, in aqueous systems. inhibit solutionorUnfortunately, decompose or in biphasic the the catalytic acidity systems. of species, formic Unfortunately, acidso its can, use inis severalthelimited acidity cases,to these of inhibitformic catalysts oracid decompose robustcan, in enoughseveral the catalytic cases,to survive inhibit species, in ortheseso decompose its conditions use is limited the [ 8catalytic]. to these species, catalysts so robustits use enoughis limited to to survive these incatalysts these conditions robust enough [8]. to survive in theseOn Onconditions the the short short [8 list] list. of of hydrogen hydrogen donors donors employed employed for for the the TH TH there there are are also also the the Hantzsch’s Hantzsch’s esters esters ((FigureFigureOn 1 1)the)[ [228 8short],], which list of have hydrogen been used donors as mimicsmimics employed ofof thethe for reactivityreactivity the TH ofthereof thethe are biofactorbiofactor also the NADH.NADH. Hantzsch’s esters (Figure 1) [28], which have been used as mimics of the reactivity of the biofactor NADH.

Figure 1. Hantzsch’s ester. FigureFigure 1 1.. Hantzsch’sHantzsch’s ester. ester. Even if some examples of reduction of aldehydes or ketones by 2-propanol or ethanol in absence Even if some examples of reduction of aldehydes or ketones by 2-propanol or ethanol in absence of anyEven catalyst if some at high examples temperature of reduction (225 ℃ of, aldehydes30 h) have beenor ketones reported by 2 [2-propanol9], the metal or ethanol catalyzed in absenceprocess of any catalyst at high temperature (225 °C, 30 h) have been reported [29], the metal catalyzed process is ofis any the catalyst best option at high for temperature the synthesis (225 of ℃ alcohols, 30 h) have by been reduction reported of the [29 ] corresponding, the metal catalyzed ketones. process The the best option for the synthesis of alcohols by reduction of the corresponding ketones. The mechanism ismechanism the best optionof the catalytic for the transfer synthesis hydrogenation of alcohols byis related reduction to the of catalyst the corresponding employed. Nowadays ketones. Thetwo of the catalytic transfer hydrogenation is related to the catalyst employed. Nowadays two general mechanismgeneral pathways of the catalyticare accepted: transfer the hydrogenation “direct hydrogen is related transfer” to the and catalyst the “hydridic employed. route”. Nowadays In a review two pathways are accepted: the “direct hydrogen transfer” and the “hydridic route”. In a review of 2004 generalof 2004 pathwaysMorris proposed are accepted: a classification the “direct of hydrogen TH reactions transfer” based and on the the “hydridicse two possible route”. mechanisms In a review Morris proposed a classification of TH reactions based on these two possible mechanisms [30]. of[30 2004]. Morris proposed a classification of TH reactions based on these two possible mechanisms In the direct hydrogen transfer the hydrogen donor and the substrate interact with the catalyst [30]. In the direct hydrogen transfer the hydrogen donor and the substrate interact with the catalyst at the same time to generate an adduct where the hydrogen is delivered as formal hydride by the at theIn same the direct time hydrogento generate transfer an adduct the hydrogenwhere the donor hydrogen and theis delivered substrate asinteract formal with hydride the catalyst by the donor to the acceptor in a concerted process, without the formation of metal hydrides. The metal atdonor the sameto the time acceptor to generate in a concerted an adduct process, where withoutthe hydrogen the formation is delivered of metal as formal hydrides. hydride The by metal the plays two key roles: firstly, it permits to the donor and the acceptor to lay in a geometric proximity donorplays twoto the key acceptor roles: firstly, in a concertedit permits process,to the donor without and thethe formationacceptor to of lay metal in a hydrides.geometric Theproximity metal that can favour the transfer of the hydride, and secondly it enhances the electrophilic character of the playsthat can two favour key roles: the transfer firstly, ofit permitsthe hydride, to the and donor secondly and the it enhances acceptor theto lay electrophilic in a geometric character proximity of the carbonyl group which will accept in a more favourable way the hydride. Catalysts capable of this thatcarbonyl can favour group t hewhich transfer will ofaccept the hydride, in a more and favourable secondly itway enhances the hydride. the electrophilic Catalysts charactercapable of of thisthe kind of reactivity are generally based on electropositive metals like Al or lanthanides, even if some carbonylkind of reactivity group which are generally will accept based in a on more electropositive favourable metalsway the like hydride. Al or lanthanides, Catalysts capable even ifof some this examples have been reported with Ir catalysts (Scheme4)[15,31–33]. kindexamples of reactivity have been are reported generally with based Ir catalysts on electropositive (Scheme 4 )metals [15,31 –like33] .A l or lanthanides, even if some examples have been reported with Ir catalysts (Scheme 4) [15,31–33].

Scheme 4. Direct hydrogen transfer. Scheme 4. Direct hydrogen transfer. Scheme 4. Direct hydrogen transfer.

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 18 Catalysts 2020, 10, 162 5 of 19 The MPV process, previously described, can be rationalized with the direct hydrogen transfer mechanism.The MPV In such process, a mechanism, previously a described,stereoselective can bereduction rationalized can be with achieved the direct only hydrogen by employing transfer an enantiopuremechanism. chiral In such H- adonor mechanism, capable a to stereoselective transfer the chiral reduction information can be achievedto the acceptor only by [15 employing]. an enantiopureOn the other chiral side, H-donor the hydridic capable route to transfer is the the usually chiral accepted information mechanism to the acceptor in the case [15]. of catalytic precursorsOn the based other side, on transition the hydridic metals. route A is the key usually aspect accepted of this pathway mechanism is in the the formation case of catalytic of an intermediateprecursors based metal on hydride transition active metals. species A key that aspect generally of this pathwayspeaking iscan the be formation a mono- ofhydride an intermediate complex (monometal hydride-hydridic active route) species or a di that-hydride generally complex speaking (di-hydridic can be a mono-hydrideroute). In both complex cases the (mono-hydridic H-donor and theroute) H-acceptor or a di-hydride interact complexseparately (di-hydridic with the metal route). and Inin different both cases steps the of H-donor the catalytic and the cycle. H-acceptor In most casesinteract the separately catalyst iswith not the introduced metal and in in di itsff erent hydridic steps form of the but catalytic is prepared cycle. In in most situ cases by reaction the catalyst of ais precursornot introduced with in an its opportune hydridic form hydrogen but is prepared donor in(pre situ-activation) by reaction during of a precursor a period with of an time opportune called “inductionhydrogen donorperiod” (pre-activation) (Scheme 5). during a period of time called “induction period” (Scheme5).

Scheme 5. Hydridic route pathway for the H-transfer from 2-propanol to acetophenone (inner sphere Scheme 5. Hydridic route pathway for the H-transfer from 2-propanol to acetophenone (inner sphere mechanism) [8]. mechanism) [8]. The active species 1, usually resulted from the reaction between the precursor and 2-propanol, The active species 1, usually resulted from the reaction between the precursor and 2-propanol, undergoes an intramolecular β-hydrogen abstraction to generate a metal-hydride 2 and acetone. The undergoes an intramolecular β-hydrogen abstraction to generate a metal-hydride 2 and acetone. The latter is then displaced by acetophenone to give the intermediate complex 3 and the ketone inserts latter is then displaced by acetophenone to give the intermediate complex 3 and the ketone inserts into the metal-hydrogen bond (migratory insertion) to give the alkoxy complex 4. Replacement of the into the metal-hydrogen bond (migratory insertion) to give the alkoxy complex 4. Replacement of the alkoxy ligand by a new molecule of 2-propanol permits delivery of the alcohol product and a restart of alkoxy ligand by a new molecule of 2-propanol permits delivery of the alcohol product and a restart the catalytic cycle. This catalytic cycle is also known as “inner sphere mechanism”, due to the fact that of the catalytic cycle. This catalytic cycle is also known as “inner sphere mechanism”, due to the fact both donor and acceptor species enter in the coordination sphere of the metal. that both donor and acceptor species enter in the coordination sphere of the metal. The understanding of the mono- or di-hydridic nature of the intermediate species involved in the The understanding of the mono- or di-hydridic nature of the intermediate species involved in catalytic cycle represents a very important aspect to find the best conditions for a specific catalytic the catalytic cycle represents a very important aspect to find the best conditions for a specific catalytic reduction. Bäckvall suggested a procedure to determine whether the mechanism proceeds through reduction. Bäckvall suggested a procedure to determine whether the mechanism proceeds through a a mono-hydridic or a di-hydridic pathway [27,33–35]. Using a α-deuterated α-phenylethanol in the mono-hydridic or a di-hydridic pathway [27,33–35]. Using a α-deuterated α-phenylethanol in the presence of acetophenone it is possible to track the hydrogen during the hydrogen transfer process. presence of acetophenone it is possible to track the hydrogen during the hydrogen transfer process. As a matter of fact, if a catalyst operates through a mono-hydridic mechanism, the hydrogen atoms As a matter of fact, if a catalyst operates through a mono-hydridic mechanism, the hydrogen atoms are transferred from the alcohol to the ketone, keeping their identity: the C-H and O-H hydrogen are transferred from the alcohol to the ketone, keeping their identity: the C-H and O-H hydrogen atoms on the donor will be delivered to the carbon and oxygen centres of the acceptor carbonyl moiety, atoms on the donor will be delivered to the carbon and oxygen centres of the acceptor carbonyl respectively. In contrast, if a catalyst operates through a di-hydridic mechanism, the two hydrogen moiety, respectively. In contrast, if a catalyst operates through a di-hydridic mechanism, the two atoms coming from the donor scramble. Once the di-hydride complex is formed the two hydrogens hydrogen atoms coming from the donor scramble. Once the di-hydride complex is formed the two are delivered from the active metal species to the carbonyl functionality indistinctly (Scheme6)[ 8,35]. hydrogens are delivered from the active metal species to the carbonyl functionality indistinctly (Scheme 6) [8,35].

Catalysts 2020, 10, x FOR PEER REVIEW 6 of 18 Catalysts 2020, 10, 162 6 of 19 Catalysts 2020, 10, x FOR PEER REVIEW 6 of 18

SchemeScheme 6. M 6.onoMono-- and and di-hydridic di-hydridic mechanism mechanism for the for hydridic the hydridic route pathway. route pathway. Scheme 6. Mono- and di-hydridic mechanism for the hydridic route pathway. TheThe determination of of a a mono- mono- oror di-hydride di-hydride route route based based on on the the hydride hydride tracking tracking is not is not completely reliablecompletelyThe in determination thereliable case in of the Ru-based case of aof mono Ru complexes,-based- or complexes, di which-hydride have which route shown have based toshown prefer on to the theprefer hydride di-hydride the di - trackinghydride formation is not in completelytheformation case of in Ru-dichloridereliable the case in of the Ru -case catalyticdichloride of Ru precursors, -catalyticbased complexes, precursors, while a mono-hydridewhichwhile ahave mono shown-hydride route to has routeprefer been has the observedbeen di-hydride for formationRu-arene-basedobserved for in Ru the-arene catalysts case-based of Ru [8 catalysts].-dichloride [8]. catalytic precursors, while a mono-hydride route has been observedNoyoriNoyori for proposed proposedRu-arene [36- [based36], in], inthe catalysts the case case of the[ of8]. themono mono-hydride-hydride pathway pathway with Ru with com Ruplexes complexes containing containing ligandsNoyori bearing bearing proposed a aprotic protic [group36 group], in (such the (such case as alcohol asof alcoholthe monoor amino), or-hydride amino), an alternative anpathway alternative mechanism with mechanismRu com calledplexes “outer called containing “outer sphere mechanism” more widely known by the term “metal-ligand bifunctional catalysis” [37]. When ligandssphere mechanism”bearing a protic more group widely (such known as byalcohol the term or amino), “metal-ligand an alternative bifunctional mechanism catalysis” called [37]. “outer When the hydride is delivered from the mono-hydride intermediate species, the other hydrogen is donated spherethe hydride mechanism” is delivered more from widely the known mono-hydride by the term intermediate “metal-ligand species, bifunctional the other catalysis” hydrogen [ is37 donated]. When by the ancillary group present in the ligand (Scheme 7). theby thehydride ancillary is delivered group present from the in themono ligand-hydride (Scheme intermediate7). species, the other hydrogen is donated by the ancillary group present in the ligand (Scheme 7).

Scheme 7. Metal-ligand bifunctional catalysis [6].

Scheme 7 7.. MetalMetal-ligand-ligand bifunctional bifunctional catalysis catalysis [ 6]]..

Catalysts 2020, 10, 162 7 of 19

Catalysts 2020, 10, x FOR PEER REVIEW 7 of 18 A different catalytic proposal has been reported by Hounjet et al. in the case of the TH catalysed A different catalytic proposal6 has been reported by Hounjet et al. in the case of the TH catalysed by phosphine-anilido [RuR(η -p-cymene)(P,N-Ph2PAr)] complexes (R = H, Et, Ar =o-C6H4NMe). The by phosphine-anilido [RuR(6-p-cymene)(P,N-Ph2PAr)] complexes (R = H, Et, Ar =o-C6H4NMe). The drop of catalytic activity of the parent hydride complex pushed the authors to explore the possibility of drop of catalytic activity of the parent hydride complex pushed the authors to explore the possibility a mechanism different from the hydridic route, which could be similar to the one typical of the MPV of a mechanism different from the hydridic route, which could be similar to the one typical of the process [38]. MPV process [38]. 2.2. TH Catalyzed by Ru-arene Complexes Stabilized by Phosphines 2.2. TH Catalyzed by Ru-arene Complexes Stabilized by Phosphines At present, many highly efficient Ru-phosphorus systems for the TH reduction of ketones and At present, many highly efficient Ru-phosphorus systems for the TH reduction of ketones and aldehydes in the presence of 2-propanol and other H-donors (i.e., HCOOH/NEt3 mixtures, HCOONa, aldehydes in the presence of 2-propanol and other H-donors (i.e., HCOOH/NEt3 mixtures, HCOONa, HCOONH4) have been reported. Within these catalytic systems, stand out the precursors developed byHCOONH Noyori et4) have al. containing been reported the BINAP. Within motif these [39 catalytic–41] as well systems, as Ru stand complexes out the bearing precursors cyclometallated developed phosphinesby Noyori et [al.42 ,containing43], or other the ligandsBINAP motif as fluoroacetate [39–41] as well [44], as bi- Ru andcomplexes tridentate bearing nitrogen cyclometallated ligands in combinationphosphines [ with42,43] mono-, or other [45] ligandsor diphosphines, as fluoroacetate developed [44], by bi Baratta- and tridentate et al. [46– 49 nitrogen]. The association ligands in ofcombination chiral phosphorus with mono ligands- [45] withor diphosphines, (chiral) primary developed or secondary by Baratta amine et al. functionalities [46–49]. The association (bifunctional of catalysts)chiral phosphorus often results ligands in elevated with (chiral) enantioselectivities primary or [ secondary50]. On the amine other hand, functionalities limiting the (bifunctional discussion tocatalysts) Ru-arene often complexes results in containing elevated onlyenantioselectivities monophosphorus [50 ligands,]. On the the other most hand, representative limiting the and discussion studied to Ru-arene complexes containing only monophosphorus ligands, the most represent6 ative and family is that of neutral monomeric arene-Ru catalytic precursors of the type [RuCl2(η -arene)(P)] 6 (Figurestudied2 ).family is that of neutral monomeric arene-Ru catalytic precursors of the type [RuCl2( - arene)(P)] (Figure 2).

6 Figure 2. Overview of [RuCl2(η6 -arene)(P)] catalytic precursors. Figure 2. Overview of [RuCl2( -arene)(P)] catalytic precursors. 6 The simplest complex (in terms of ligands) of such family is represented by [RuCl2(η -p- The simplest complex (in terms of ligands) of such family is represented by [RuCl2(6-p- cymene)(PPh3)]. It has been employed as catalytic precursor for the reduction of ketones through cymene)(PPh3)]. It has been employed as catalytic precursor for the reduction of ketones through TH, TH, as in the reduction of acetophenone [51,52]. Successful reduction of cyclohexanone has been as in the reduction of acetophenone [51,52]. Successful reduction of cyclohexanone has been achieved η6 achieved employing as catalytic precursors the parent complexes [RuCl6 2( -p-cymene)(PMePh2)] [53] employing as6 catalytic precursors the parent complexes [RuCl2( -p-cymene)(PMePh2)] [53] and and [RuCl2(η -benzene)(PAr3)] [54] (Ar = Ph, p-An and p-CF3Ph). [RuCl2(6-benzene)(PAr3)] [54] (Ar = Ph, p-An and p-CF3Ph). Reduction of acetophenone in enantioselective fashion was described by Grabulosa et al. [55] Reduction of acetophenone in enantioselective fashion was described by Grabulosa6 et al. [55] and Aznar et al. [56] employing several catalytic precursors of the family [RuCl2(η -p-cymene)(P*)] and Aznar et al. [56] employing several catalytic precursors of the family [RuCl2(6-p-cymene)(P*)] stabilized by P-stereogenic monodentate ligands. These P-stereogenic ligands can be obtained in pure stabilized by P-stereogenic monodentate ligands. These P-stereogenic ligands can be obtained in pure chiral form through the Evans [53], or the Jugé-Stephan [57–59] methods. Both the synthetic pathways chiral form through the Evans [53], or the Jugé-Stephan [57–59] methods. Both the synthetic pathways have been extensively reported and discussed in the literature [60]. In general, such complexes are have been extensively reported and discussed in the literature [60]. In general, such complexes are not as effective catalytic precursors as the nitrogen-containing ones reported above. In fact, they not as effective catalytic precursors as the nitrogen-containing ones reported above. In fact, they are are formally saturated and in order to give rise to active species they must undergo some kind of formally saturated and in order to give rise to active species they must undergo some kind of dissociative process. This, in principle, is not favoured by the presence of the monophosphine, which dissociative process. This, in principle, is not favoured by the presence of the monophosphine, which is a strong-coordinating ligand, especially in the case of the phosphines obtained through the Evans is a strong-coordinating ligand, especially in the case of the phosphines obtained through the Evans methodology, which bring three alkyl substituents, the -basicity is elevated, making it extremely difficult for the corresponding Ru-complex to generate a vacant site on the metal centre through

Catalysts 2020, 10, 162 8 of 19 methodology, which bring three alkyl substituents, the σ-basicity is elevated, making it extremely Catalysts 2020, 10, x FOR PEER REVIEW 8 of 18 Catalysts 2020, 10, x FOR PEER REVIEW 8 of 18 difficultCatalysts for the 2020 corresponding, 10, x FOR PEER REVIEW Ru-complex to generate a vacant site on the metal centre through 8 of 18 Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 8 of 18 phosphineCatalysts decoordination. 2020, 10, x FOR PEER The REVIEW observation of moderate enantioselectivity for some of the mono 8 of 18 phosphine decoordination. The observation of moderate enantioselectivity for some of the mono phosphinesphosphine (vide infra) decoordination. proves that theThe ligand observation remains of coordinated moderate toenantioselectivity the Ru atom, since for this some is the of only the mono phosphinephosphines decoordination.(vide infra) proves The that observation the ligand of remains moderate coordinated enantioselectivity to the Ru for atom, some since of thethis mono is the sourcephosphines of chirality. (v Indeed,ide infra) some proves families that of the phosphines, ligand remains for example coordinated those to bearing the Ru the atom, 2-biphenylyl since this is the phosphinesonly source (v ofideide chirality. infra)infra) provesproves Indeed, thatthat some thethe ligandligand families remainsremains of phosphines, coordinatedcoordinated for toto example thethe RuRu atom,atom, those sincesince bearing thisthis the isis the the 2- substituentonly tendsource to ofgive chirality. higher enantioselectivities, Indeed, some families a fact of that phosphines, bodes well for for example future developments. those bearing the 2- onlybiphenylyl source substituent of chirality. ten Indeed,d to give some higher families enantioselectivities of phosphines,, fora fact example that bodes those well bearing for thefuture 2-- In spitebiphenylyl of this, partial substituent phosphine ten dissociationd to give higher cannot enantioselectivities be completely ruled, out,a fact as shown that bodes by Dyson well and for future biphenylyldevelopments. substituent In spite ten of d this, toto partial give give higher higher phosphine enantioselectivities enantioselectivities dissociation cannot,, a fact be that completely bodes well ruled for out future, as Chaplindevelopments. [61,62]. In spite of this, partial phosphine dissociation cannot be completely ruled out, as developments.shown by Dyson InIn and spite spite Chaplin of of this, this, [61 partial,62]. phosphine dissociation cannot be completely ruled out,, as Nevertheless,shown by Dyson at 80 andC, Chaplin in the presence [61,62]. of a base, and after some time (usually from 3 to 24 h), shownNevertheless, by Dyson and◦ at 80Chaplin °C, in [[the61,,62 presence].]. of a base, and after some time (usually from 3 to 24 h), these complexesNevertheless, show catalytic at 80 activity°C, in the for presence the TH of of ketones a base, inand the after presence some of time 2-propanol. (usually Infrom Table 3 to1 24 h), theseNevertheless, complexes show at 80 catalytic °C, in the activity presence for the of THa base, of ketones and after in thesome presence time (usually of 2-propanol. from 3 toIn 24Table h), some indicativethese complexes examples show are catalytic reported. activity for the TH of ketones in the presence of 2-propanol. In Table these1these some complexescomplexes indicative showshow examples catalyticcatalytic are activityreported.activity forfor thethe THTH ofof ketonesketones inin thethe presencepresence ofof 22--propanol. In Table 1 some indicative examples are reported. 1 some indicative examples are reported. Table 1. Acetophenone reduction thorough Transfer Hydrogenation catalyzed by [RuCl (η6-arene)(P)] 2 6 Table 1. Acetophenone reduction thorough Transfer Hydrogenation catalyzed by [RuCl2(6- Table 1. Acetophenone reduction thorough Transfer Hydrogenation catalyzed by [RuCl2(6- complexesTable in the 1. presenceAcetophenone of 2-propanol. reduction Selected thorough examples. Transfer Hydrogenation catalyzed by [RuCl2(6- Tablearene)(P)] 1. complexesAcetophenone in the reduction presence of thorough 2-propanol. Transfer Selected Hydrogenation examples. catalyzed by [RuCl2(66- Tablearene)(P)] 1. complexesAcetophenone in the reduction presence of thorough 2-propanol. Transfer Selected Hydrogenation examples. catalyzed by [RuCl22(( -- arene)(P)] complexes in the presence of 2-propanol. Selected examples. arene)(P)]Entry complexes Catalytic in the Precursor presence of 2 Conversion--propanol. Selected (%) examples. e.e. (%) Reference Entry Catalytic precursor Conversion (%) e.e. (%) Reference Entry Catalytic precursor Conversion (%) e.e. (%) Reference Entry Catalytic precursor Conversion (%) e.e. (%) Reference

1 1 1 1 95% 95%1 5(S)[535(S] ) [53] 1 95%1 5(S) [53] 1 95%1 5(S) [53] 1 95%11 5(S)) [[53]]

1 1 2 2 93% 93%1 6(S)[536(S] ) [53] 2 93%1 6(S) [53] 2 93%1 6(S) [53] 2 93%11 6(S)) [[53]]

1 3 1 97%1 4(S) [53] 3 3 97% 97%1 4(S)[534(S] ) [53] 3 97%1 4(S) [53] 3 97%11 4(S)) [[53]]

1 4 66%1 - [53] 4 1 66%1 - [53] 4 4 66% 66%1 -[53-] [53] 4 66%11 -- [[53]]

1 5 58%1 - [53] 5 1 58%1 - [53] 5 5 58% 58%1 -[53-] [53] 5 58%11 -- [[53]]

1 73%1 20(S) 73%1 20(S) 6 1 73%1 20(S) [53] 6 73% 73%121 20(S) 20(S) [53] 6 6 73%43%2 [20(50(53]S)) [53] 6 2 43%2 50(S) [[53]] 6 43% 43%22 50(S) 50(S) [53] 43%2 50(S))

2 7 44%2 8(S) [53] 7 44%2 8(S) [53] 7 2 44%2 8(S) [53] 7 7 44% 44%22 8(S)[538(S] )) [[53]]

3 8 98%3 - [52] 8 98%3 - [52] 8 3 98%33 - [52] 8 8 98% 98%3 -[52--] [[52]]

3 9 96%3 - [52] 9 96%3 - [52] 9 96%33 - [52] 9 9 96% 3 96%3 -[52--] [[52]]

3 10 57%3 - [52] 10 57%3 - [52] 10 57%3 - [52] 10 57%33 -- [[52]]

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 18

phosphine decoordination. The observation of moderate enantioselectivity for some of the mono phosphines (vide infra) proves that the ligand remains coordinated to the Ru atom, since this is the only source of chirality. Indeed, some families of phosphines, for example those bearing the 2- biphenylyl substituent tend to give higher enantioselectivities, a fact that bodes well for future developments. In spite of this, partial phosphine dissociation cannot be completely ruled out, as shown by Dyson and Chaplin [61,62]. Nevertheless, at 80 °C, in the presence of a base, and after some time (usually from 3 to 24 h), these complexes show catalytic activity for the TH of ketones in the presence of 2-propanol. In Table 1 some indicative examples are reported.

Table 1. Acetophenone reduction thorough Transfer Hydrogenation catalyzed by [RuCl2(6- arene)(P)] complexes in the presence of 2-propanol. Selected examples.

Entry Catalytic precursor Conversion (%) e.e. (%) Reference

1 95%1 5(S) [53]

2 93%1 6(S) [53]

3 97%1 4(S) [53]

4 66%1 - [53]

5 58%1 - [53]

73%1 20(S) 6 [53] 43%2 50(S)

7 44%2 8(S) [53]

Catalysts 2020, 10, 162 9 of 19 8 98%3 - [52]

Table 1. Cont. 9 96%3 - [52] Entry Catalytic Precursor Conversion (%) e.e. (%) Reference

10 10 57% 3 57%3 -[52-] [52]

Catalysts 2020, 10, x FOR PEER REVIEW 9 of 18 CatalystsCatalysts 20 202020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 99 of of 18 18 Catalysts 2020, 10, x FOR PEER REVIEW 9 of 18 Catalysts 2020, 10, x FOR PEER REVIEW 9 of 18

3 3 11 11 43% 43%3 3 9(S)[529(]S) [52] 1111 43%43%3 9(9(SS) ) [52[52] ] 11 43%3 9(S) [52]

4 12 12 46% 4 46%4 414(R)[14(57]R) [57] 1212 46%46%4 14(14(RR) ) [57[57] ] 12 46%4 14(R) [57]

4 13 4 99%4 4 70(R) [57] 1313 13 99% 99%99%4 70(R)[70(5770(]RR) ) [57[57] ] 13 99%4 70(R) [57]

5 14 5 82%5 5 26(R) [59] 1414 14 82% 82%82%5 26(R)[26(5926(]RR) ) [59[59] ] 14 82%5 26(R) [59]

5 15 72%5 5 5(R) [59] 1515 5 72%72%5 5(5(RR) ) [59[59] ] 15 15 72% 72%5 5(R)[5(59R] ) [59]

5 16 94%5 5 23(R) [59] 1616 94%94%5 23(23(RR) ) [59[59] ] 16 16 94% 5 94%5 23(R)[23(59]R) [59]

17 99%1 12(R) [58] 1717 99%99%1 1 12(R)12(R) [58[58] ] 17 99%1 12(R) [58] 17 17 99% 1 99%1 12(R) [12(R)58] [58]

1 tBuOK, 24h, 80 °C; 2 tBuOK, 24h, 40 °C; 3 tBuOK, 30 min., 80 °C; 4 tBuOK, 5 h, 80 °C; 5 tBuOK, 3 h, 80 °C. 1 1t BuOK,tBuOK, 24h, 24h, 80 80 °C; °C; 2 2t BuOK,tBuOK, 24h, 24h, 40 40 °C; °C; 3 3t BuOK,tBuOK, 30 30 min., min., 80 80 °C; °C; 4 4t BuOK,tBuOK, 5 5 h, h, 80 80 °C; °C; 5 5t BuOK,tBuOK, 3 3 h, h, 80 80 °C. °C. 1 tBuOK, 24h, 80 °C; 2 tBuOK, 24h, 40 °C; 3 tBuOK, 30 min., 80 °C; 4 tBuOK, 5 h, 80 °C; 5 tBuOK, 3 h, 80 °C. 1 1 tBuOK, 24h, 802 °C; 2 tBuOK, 24h, 340 °C; 3 tBuOK, 30 min.,4 80 °C; 4 tBuOK, 5 h, 80 °C; 5 tBuOK, 3 h, 80 °C. tBuOK,tBuOK, 24h, 24h, 80 ◦C; 80 °C;tBuOK, tBuOK, 24h, 40 24h,◦C;6 40tBuOK, °C; t 30BuOK, min., 30 80 ◦min.,C; t BuOK,80 °C; 5t h,BuOK, 80 ◦C; 5 th,BuOK, 80 °C; 3 h,t 80BuOK,◦C. 3 h, 80 °C. Table 1 shows that [RuCl2(6-6arene)(P)] are latent catalysts for TH and ATH in the presence of TableTable 1 1 shows shows that that [RuCl [RuCl2(2(6-arene)(P)]-arene)(P)] are are latent latent catalysts catalysts for for TH TH and and ATH ATH in in the the presence presence of of Table 1 shows that [RuCl2(6-arene)(P)] are latent catalysts for TH and ATH in the presence of 2-propanolTable 1 asshows hydrogen that [RuCl donor.6 2( Many-arene)(P)] of them are worklatent properlycatalysts for only TH at and high ATH temperatures in the presence and are of Table22-propanol-propanol1 shows as that as hydrogen hydrogen [RuCl 2( η donor. donor.-arene)(P)] Many Many are of of latentthem them work catalysts work properly properly for TH onlyonly and at ATH at high high in temperatures the temperatures presence of and and are are 2affected-propanol by a as drop hydrogen of the donor.enantioselectivity. Many of them Nevertheless, work properly some onlyof these at highcatalytic temperatures precursors and can arebe 2-propanolaffectedaffected as hydrogenby by a a drop drop donor.of of the the enantioselectivity. enantioselectivity. Many of them work Nevertheless, Nevertheless, properly onlysome some at of of high these these temperatures catalytic catalytic precursors precursors and are can can be be affectedactivated by at a40 drop °C, resultingof the enantioselectivity. in a good and moderate Nevertheless, e.e. and some moderate of these conversion catalytic precursors (entries 6 andcan 7).be affectedactivatactivat by aed droped at at 40 of 40 the°C, °C, enantioselectivity.resulting resulting in in a a good good Nevertheless,and and moderate moderate some e.e. e.e. and and of thesemoderate moderate catalytic conversion conversion precursors (entries (entries can be6 6 and and 7). 7). activatIn addition,ed at 40some °C, specificresulting ligands in a good like and the moderatedibenzothiophenylphosphine e.e. and moderate conversion of entry 13(entries give relatively 6 and 7). activatedInIn addition, ataddition, 40 ◦C, resultingsome some specific specific in a goodligands ligands and like like moderate the the dibenzothiophenylphosphine dibenzothiophenylphosphine e.e. and moderate conversion of of entry (entriesentry 13 13 6give give and relatively 7).relatively Inhigh addition, enantioselectivities, some specific suggesting ligands like that the with dibenzothiophenylphosphine the appropriate ligands useful of entrylevels 13of selectivitygive relatively may In addition,highhigh enantioselectivities, enantioselectivities, some specific ligands suggesting suggesting like the that dibenzothiophenylphosphine that with with the the appropriate appropriate ligandsligands ligands of useful entry useful 13levels levels give of of relatively selectivity selectivity may may highbe attained. enantioselectivities, suggesting that with the appropriate ligands useful levels of selectivity may high enantioselectivities,bebe attained. attained. suggesting that with the appropriate ligands useful levels of selectivity may be attained.Some speculations have been reported about the possible mechanism for the TH catalyzed by be attained.SomeSome speculations speculations have have been been reported reported about about the the possible possible mechanism mechanism for for the the TH TH catalyzed catalyzed by by Some6 speculations have been reported about the possible mechanism for the TH catalyzed by [RuClSome2(6-6arene)(P)] speculations catalytic have been precursors. reported Asabout discussed the possible above, mechanism the generation for the TH of catalyzed vacancies by is [RuCl2 2(6 -arene)(P)] catalytic precursors. As discussed above, the generation of vacancies is [RuCl2(6-arene)(P)] catalytic precursors. As discussed above, the generation of vacancies is [RuClmandatory2(6-arene)(P)] in order to catalytic activate precursors. the catalysis As. Additionally, discussed above,considering the an generation inner sphere of vacanciesmechanism, is mandatorymandatory in in orde order rto to activate activate the the catalysis catalysis.. .Additionally,Additionally, Additionally, considering considering an an inner inner sphere sphere mechanism, mechanism, mandatorythe availability in orde of otherr to activate vacancies the duringcatalysis the.. Additionally,Additionally, catalytic cycles considering is fundamental an inner in ordersphere to mechanism, rationalize thethe availability availability of of other other vacancies vacancies during during the the catalytic catalytic cycles cycles is is fundamental fundamental inin in orderorder order toto to rationalize rationalize thethe hydrideavailability formation of other and vacancies the substrate during coordination the catalytic (Scheme cycles is 8 fundamental). in order to rationalize thethe hydride hydride formation formation and and the the substrate substrate coordination coordination (Scheme (Scheme 8 8).). the hydrideRegard ingformation the enantioselectivity, and the substrate in coordination some cases the (Scheme tethered 8). complex results are more selective RegardRegardinginging thethe the enantioselectivity,enantioselectivity, enantioselectivity, inin in somesome some casescases cases thethe the tetheredtethered tethered complexcomplex complex resultsresults results are are more more selective selective comparedRegard toing the the untethered enantioselectivity, counterpart in ,some as in casesthe case the oftethered raw 2 complexvs 6 (Table results 1). This are increasemore selective in e.e. comparedcompared to to the the untethered untethered counterpart counterpart,, ,as as in in the the case case of of raw raw 2 2 vs vs 6 6 ( T(Tableable 1) 1).. .This This increase increase in in e.e. e.e. comparedcan be rationalized to the untethered by considering counterpart the reduced,, as in theavailable case of space raw 2for vs the 6 ( Tacetophenoneable 1).. This increaseapproach in to e.e. II cancan be be rationalized rationalized by by considering considering the the reduced reduced available available space space for for the the acetophenone acetophenone approach approach to to II II canand bein rationalizedthe consequent by consideringstereospecific the formation reduced ofavailable III (Scheme space 8) for in the the acetophenone case of a tethered approach geometry. to II andand in in the the consequent consequent stereospecific stereospecific formation formation of of III III ( S(Schemecheme 8) 8) in in the the case case of of a a tethered tethered geometry. geometry. andUnfortunately, in the consequent this behavior stereospecific has not formation been confirmed of III ( Sforcheme other 8) catalyticin the case precursors of a tethered as, e.g., geometry. 1 vs 5 Unfortunately,Unfortunately, this this behavior behavior has has n notot been been confirmed confirmed for for other other catalytic catalytic precursors precursors as as,, ,e.g., e.g.,e.g., 1 1 vs vs 5 5 Unfortunately,(Table 1), hinting this that behavior the specific has n parametersot been confirmed influencing for otherthe observed catalytic enantioselectivity precursors as,, e.g.,e.g., for 1 these vs 5 (T(Tableable 1), 1), hinting hinting that that the the specific specific parameters parameters influencing influencing the the observed observed enantioselectivity enantioselectivity for for these these (systemsTable 1), are hinting still poorly that the understood. specific parameters influencing the observed enantioselectivity for these systemssystems are are still still poorly poorly understood. understood. systems are still poorly understood.

Catalysts 2020, 10, 162 10 of 19

Some speculations have been reported about the possible mechanism for the TH catalyzed by 6 [RuCl2(η -arene)(P)] catalytic precursors. As discussed above, the generation of vacancies is mandatory in order to activate the catalysis. Additionally, considering an inner sphere mechanism, the availability of other vacancies during the catalytic cycles is fundamental in order to rationalize the hydride formation and the substrate coordination (Scheme8). Regarding the enantioselectivity, in some cases the tethered complex results are more selective compared to the untethered counterpart, as in the case of raw 2 vs 6 (Table1). This increase in e.e. can be rationalized by considering the reduced available space for the acetophenone approach to II and in the consequent stereospecific formation of III (Scheme8) in the case of a tethered geometry. Unfortunately, this behavior has not been confirmed for other catalytic precursors as, e.g., 1 vs 5 (Table1), hinting that the specific parameters influencing the observed enantioselectivity for these Catalystssystems 20 are20, 10 still, x FOR poorly PEER understood. REVIEW 10 of 18

Scheme 8 8.. PProposedroposed inner inner sphere dissociative catalytic cycle for for transfer transfer hydrogenation mediated by neutral [RuCl (η6-arene)(P)] complexes [52]. neutral [RuCl2(6-arene)(P)] complexes [52]. The decoordination of chloride is an obvious way to free up coordination positions and explain The decoordination of chloride is an obvious way to free up coordination positions6 and explain the catalytic TH of acetophenone in the presence of 2-propanol and [RuCl2(η -arene)(P)] catalytic 2 6 the catalytic TH of acetophenone in the presence of 2-propanol and [RuCl ( -arene)(P)]6 catalytic precursors. An attempt to verify this possibility was carried out for some [RuCl2(η -arene)(P)] precursors. An attempt to verify this possibility was carried out for some [RuCl2(6-arene)(P)] complexes (arene = p-cymene, benzene; P = triphenylphosphine, (R)-monophos, and (S)-binepine) [52]. complexes (arene = p-cymene, benzene; P = triphenylphosphine, (R)-monophos, and (S)-binepine) The effect of induction time, temperature, amount of base, catalyst/substrate ratio, and the ability to [52]. The effect of induction time, temperature, amount of base, catalyst/substrate ratio, and the ability to generate hydride species were explored. The presence of the base resulted mandatory during the activation period for unlocking the latent active species. An adverse effect of an excess of chlorine was also observed, which supports the proposed mechanism. Nevertheless, another reaction pathway could indeed be in place. In fact, the generation of vacancies during the catalytic cycle could be ensured by the partial decoordination of the arene moiety, from 6 to 4, as shown in Scheme 9 [55].

Catalysts 2020, 10, 162 11 of 19 generate hydride species were explored. The presence of the base resulted mandatory during the activation period for unlocking the latent active species. An adverse effect of an excess of chlorine was also observed, which supports the proposed mechanism. Nevertheless, another reaction pathway could indeed be in place. In fact, the generation of vacancies during the catalytic cycle could be ensured by the partial decoordination of the arene moiety, fromCatalystsη6 20to20η, 104,,as x FOR shown PEER in REVIEW Scheme 9[55]. 11 of 18

Scheme 9 9.. DDissociativeissociative pathways pathways involving involving arene arene partial partial decoordination. decoordination.

TheThe generation of vacant sites sites through through a a dissociative dissociative step step involving involving the the -Cl -Cl moiety moiety has has been been also also relatedrelated toto thethe anticancer activity activity of of such such complexes. complexes. Dinda Dinda et et al. al. discussed discussed this this topic topic for for ruthenium(II) ruthenium(II) 6 0/+1 1 2 piano-stoolpiano-stool [Ru( [Ru(η6--p-cymene)(L)Cl]-cymene)(L)Cl]0/+1 (L=κ(L=1κ- -or or κκ2-1,1-1,1-bis(diphenylphosphino)-methane,-bis(diphenylphosphino)-methane, 1,1 1,1-bis--bis- 1 (diphenylphosphino)methane(diphenylphosphino)methane oxide, oxide, κκ1-mercaptobenzothiazole)-mercaptobenzothiazole) complexes complexes [63 [63]. ].DFT DFT calculations calculations revealedrevealed the the possibility possibility that that the the presence presence of water of water generates generate intermediates intermediate species species through through an associative an pathway,associative by pathway, generating by vacantgenerating sites vacant on the sites metal on as the a result metal of as a a possible result of change a possible of the change apticity of (fromthe 6 4 2 ηapticityto η and(fromη )6 of to the 4 and metal-arene 2) of the bond metal [-63arene]. bond [63]. Thus,Thus, thethe alternative mechanism mechanism reported reported in in S Schemecheme 99 cannot cannot be be discarded discarded a apriori. priori. In In fact, fact, the the manymany di differencesfferences in in the the catalytic catalytic outcome outcome reported reported for neutral for neutral Ru complexes Ru complexes bearing bearing different different aromatic units,aromatic or withinunits, or the within same the family, same the family, half sandwichthe half sandwich architecture architecture is compared is compared with the with parent the parent tethered onetethered (Table one1). (Table In this 1). line, In this the labilityline, the of lability the arene of the ring arene also ring has also an ehasffect annot effect only not in only catalysis in catalysis [64] but also[64] onbut the also cytotoxicity on the cytotoxicity of Ru-arene of Ru complexes-arene complexes with anticancer with anticancer activity activity [65]. Papish [65]. Papish et al. [et64 al.] studied [64] 6 6 thestudied influence the influence of the arene of the in arene systems in systems of the type of the [RuCl type2( η[RuCl-arene)(NHC)]2( -arene)(NHC)] in TH. Theyin TH. found They thefound more the more labile the arene, the higher the catalytic activity, and suggested a mechanism involving complete arene decoordination and substitution by 2-propanol molecules, forming the active species. In spite of this, they also suggested that for more tightly bound arenes (i.e. C6Me6) the cycle can proceed with species with a ring-slipped arene, as in Scheme 9. More likely, a mixed mechanism, which includes chlorine decoordination and partial change in the hapticity of the arene unit, could better explain the mechanism of the TH of ketones by 2-propanol catalyzed by neutral [RuCl2(6-arene)P] complexes. With simple tertiary phosphines and other

Catalysts 2020, 10, 162 12 of 19 labile the arene, the higher the catalytic activity, and suggested a mechanism involving complete arene decoordination and substitution by 2-propanol molecules, forming the active species. In spite of this, they also suggested that for more tightly bound arenes (i.e. C6Me6) the cycle can proceed with species with a ring-slipped arene, as in Scheme9. More likely, a mixed mechanism, which includes chlorine decoordination and partial change in the hapticity of the arene unit, could better explain the mechanism of the TH of ketones by 2-propanol Catalysts 2020, 10, x FOR PEER REVIEW 12 of 18 Catalysts 2020,, 10,, xx FORFOR 6 PEERPEER REVIEWREVIEW 12 of 18 catalyzedCatalysts by neutral 2020 [RuCl, 10, x FOR2(η PEER-arene)P] REVIEW complexes. With simple tertiary phosphines and other innocent 12 of 18 ligands, i.e.,innocent without ligands any deprotonation, i.e., without siteany capabledeprotonation of proton site transfer, capable the of outer-sphereproton transfer mechanism, the outer-sphere innocent ligands,, i.e.,i.e., without any deprotonation site capable of proton transfer,, thethe outerouter-sphere seems unlikely.innocent ligands, i.e., without any deprotonation site capable of proton transfer, the outer-sphere mechanism seems unlikely. mechanism seems unlikely. 2.3. TH Mediated by Rh Complexes Stabilized by Phosphine Ligands 2.3. TH Mediated by Rh Complexes Stabilized by Phosphine Ligands 2.3. TH Mediated by Rh Complexes Stabilized by Phosphine Ligands The use of Rh-phosphine complexes as catalytic precursors for the transfer hydrogenation reaction The use of Rh-phosphine complexes as catalytic precursors for the transfer hydrogenation has been reportedThe a use few of times. Rh-phosphine As for the Ru-basedcomplexes catalytic as catalytic precursors precursors reported for above, the transfer the ability hydrogenation of reaction has been reported a few times. As for the Ru-based catalytic precursors reported above, the the complexreaction to generate has been hydrides reported in a the few presence times. As of for an opportunethe Ru-based donor catalytic represents precursors the key reported step for above, the ability of the complex to generate hydrides in the presence of an opportune donor represents the key catalytic applications.ability of the complex to generate hydrides in the presence of an opportune donor represents the key step for catalytic applications. Regardingstep for the catalytic reduction applications. of ketones, Rh-phosphine complexes have been successfully employed Regarding the reduction of ketones, Rh-phosphine complexes have been successfully employed as catalytic precursorsRegarding mainly the reduction in the presence of ketones, of molecular Rh-phosphine hydrogen complexes [66]. Activation have been of 2-propanolsuccessfully by employed as catalytic precursors mainly in the presence of molecular hydrogen [66]. Activation of 2-propanol Rh-phosphineas catalytic complexes precursors and the mainly achievement in the ofpresence TH under of molecular these conditions hydrogen has been[66]. reportedActivation for of few 2-propanol by Rh-phosphine complexes and the achievement of TH under these conditions has been reported complexesby such Rh-phosphine as those containing complexes amino-phosphines and the achievement [67– 70of]. TH Recently, under thethese TH conditions from 2-propanol has been to reported for few complexes such as those containing amino-phosphines [67–70].. Recently, Recently, the the TH TH from from 2 2- acetophenonefor few in the complexes presence such of mononuclear as those containing Rh complexes amino bearing-phosphines phosphine [67–70 ligands]. Recently, has been the also TH from 2- propanol to acetophenone in the presence of mononuclear Rh complexes bearing phosphine ligands describedpropanol (Table2)[ to71 acetophenone]. in the presence of mononuclear Rh complexes bearing phosphine ligands has been also described (Table 2) [71].. has been also described (Table 2) [71]. Table 2. Reduction of acetophenone in the presence of refluxing 2-propanol and tBuOK mediated by Table 2. Reduction of acetophenone in the presence of refluxing 2-propanol and tBuOK mediated by +Table 2. Reduction of acetophenone in the presence of refluxing 2-propanol and tBuOK mediated by [Rh(PP)2] TableX− catalytic 2. R+ eduction- precursors of acetophenone [71]. in the presence of refluxing 2-propanol and tBuOK mediated by [Rh(PP)2]+X-- catalytic precursors [71]. [Rh(PP)2]+X- catalytic precursors [71]. [Rh(PP)2]+X- catalytic precursors [71]. [Rh(PP)2] X catalytic precursors [71]. Entry Catalytic Precursor Formula 1 Conversion Entry Catalytic precursor Formula1 Conversion Entry Catalytic precursor Formula1 Conversion Entry Catalytic precursor Formula1 Conversion

1 1 [Rh(DPPP)[Rh(DPPP)2]Cl2]Cl 92.4% 92.4% 1 [Rh(DPPP)2]Cl 92.4% 1 [Rh(DPPP)2]Cl 92.4%

2 2 [Rh(DPPE)(DPPP)]Cl[Rh(DPPE)(DPPP)]Cl 58.7% 58.7% 2 [Rh(DPPE)(DPPP)]Cl 58.7%

3 [Rh(DPPE)2]Cl 49.4% 3 3 [Rh(DPPE)[Rh(DPPE)2]Cl2]Cl 49.4% 49.4% 3 [Rh(DPPE)2]Cl 49.4%

4 [Rh(DPPP)2]BF4 77.6% 4 4 [Rh(DPPP)[Rh(DPPP)]BF 2]BF477.6% 77.6% 4 [Rh(DPPP)2 4 2]BF4 77.6%

5 [Rh(DPPE)(DPPP)]BF4 36.0% 5 [Rh(DPPE)(DPPP)]BF4 36.0% 5 5 [Rh(DPPE)(DPPP)]BF[Rh(DPPE)(DPPP)]BF4 36.0%4 36.0%

6 [Rh(DPPE)2]BF4 3.6% 6 [Rh(DPPE)2]BF4 3.6% 6 [Rh(DPPE)2]BF4 3.6% 6 6 [Rh(DPPE)[Rh(DPPE)2]BF4 2]BF4 3.6% 3.6%

1 1 DPPP = 1,3-bis-diphenylphosphinepropane; DPPE = 1,2-bis-diphenylphosphinoethane. 1 DPPP = 1,3-bis-diphenylphosphinepropane; DPPE = 1,2-bis-diphenylphosphinoethane. 1 DPPP = 1,3-bis-diphenylphosphinepropane; DPPE = 1,2-bis-diphenylphosphinoethane. 1 DPPP DPPP= 1,3-bis-diphenylphosphinepropane; = 1,3-bis-diphenylphosphinepropane; DPPE = 1,2-bis-diphenylphosphinoethane. DPPE = 1,2-bis-diphenylphosphinoethane. A detailed mechanistic proposal on the catalytic activity of these complexes in TH has never A detailed mechanistic proposal on the catalytic activity of these complexes in TH has never A detailedbeen reported. mechanistic This is proposal mainly ondue the to the catalytic scarcity activity of specific of these data complexes available about in TH the has TH never of ketones in been reported. This is mainly due to the scarcity of specific data available about the TH of ketones in 2-propanol mediated by mononuclear cationic Rh(I) complexes of the type [Rh(PP)2]X. been reported.2-propanol This ismediated mainly due by mononuclear to the scarcity cationic of specific Rh(I) data complexes available of about the type the TH[Rh(PP) of ketones2]X. in 2-propanol mediated by mononuclear cationic Rh(I) complexes of the type [Rh(PP)2]X. 2-propanol mediatedIt is known by mononuclear that these cationic complexes Rh(I) complexes undergo oxidative of the type addition [Rh(PP) ]X. to form hexacoordinate It is known that these complexes undergo oxidative addition 2 to form hexacoordinate (octahedral) hydrides in the presence of H2 or HCl, and that the rate of such reaction is related to the (octahedral) hydrides in the presence of H2 or HCl, and that the rate of such reaction is related to the (octahedral) hydrides in the presence of H2 or HCl, and that the rate of such reaction is related to the length of the alkyl bridge of the diphosphine (PP = dppe, dppp, X = BF4) [72]. In this line, for length of the alkyl bridge of the diphosphine (PP = dppe, dppp, X = BF4) [72]. In this line, for length of the alkyl bridge of the diphosphine (PP = dppe, dppp, X = BF4) [72]. In this line, for complexes [Rh(PP)2][CF3SO3] (PP = dppe, dmpe, depe, depp, depx; with dmpe = 1,2- complexes [Rh(PP)2][CF3SO3] (PP = dppe, dmpe, depe, depp, depx; with dmpe = 1,2- complexes [Rh(PP)2][CF3SO3] (PP = dppe, dmpe, depe, depp, depx; with dmpe = 1,2- bis(dimethylphosphino)ethane; depe = 1,2-bis-(diethylphosphino)ethane; depp = 1,3-bis- bis(dimethylphosphino)ethane; depe = 1,2-bis-(diethylphosphino)ethane; depp = 1,3-bis- (diethylphosphino)propane; depx = 1,2-bis((diethylphosphanyl)methyl-benzene),, DuBois et al. (diethylphosphino)propane; depx = 1,2-bis((diethylphosphanyl)methyl-benzene), DuBois et al. correlated the rate of the oxidative addition of H2 and the bite angle of the diphosphine [73]. In correlated the rate of the oxidative addition of H2 and the bite angle of the diphosphine [73]. In correlated the rate of the oxidative addition of H2 and the bite angle of the diphosphine [73]. In addition, Mansel et al. found that while complexes containing dcpe (1,2- addition, Mansel et al. found that while complexes containing dcpe (1,2- bis(dicyclohexylphosphino)ethane) or dppe are not able to form hydrides, those containing depe, bis(dicyclohexylphosphino)ethane) or dppe are not able to form hydrides, those containing depe, dppp, or dmpe form an equilibrium mixture of hydrides.. FinallyFinally,, complexescomplexes containing depp or depx dppp, or dmpe form an equilibrium mixture of hydrides. Finally, complexes containing depp or depx were able to form quantitatively hydrides [74]. An additional issue regarding the reactivity of such were able to form quantitatively hydrides [74]. An additional issue regarding the reactivity of such

Catalysts 2020, 10, 162 13 of 19

It is known that these complexes undergo oxidative addition to form hexacoordinate (octahedral) hydrides in the presence of H2 or HCl, and that the rate of such reaction is related to the length of the alkyl bridge of the diphosphine (PP = dppe, dppp, X = BF4)[72]. In this line, for complexes [Rh(PP)2][CF3SO3] (PP = dppe, dmpe, depe, depp, depx; with dmpe = 1,2-bis(dimethylphosphino)ethane; depe = 1,2-bis-(diethylphosphino)ethane; depp = 1,3-bis- (diethylphosphino)propane; depx = 1,2-bis((diethylphosphanyl)methyl-benzene), DuBois et al. correlated the rate of the oxidative addition of H2 and the bite angle of the diphosphine [73]. In addition, Mansel et al. found that while complexes containing dcpe (1,2-bis(dicyclohexylphosphino)ethane) or dppe are not able to form hydrides, those containing depe, dppp, or dmpe form an equilibrium mixtureCatalysts of 20 hydrides.20, 10, x FOR Finally,PEER REVIEW complexes containing depp or depx were able to form quantitatively13 of 18 hydrides [74]. An additional issue regarding the reactivity of such complexes is the role of the anion. complexes is the role of the anion. In the solid state such complexes are usually described as In the solid state such complexes are usually described as monomeric and cationic, and single-crystal monomeric and cationic, and single-crystal x-ray crystallography studies confirm a distorted square- x-ray crystallography studies confirm a distorted square-planar tetra-coordinated structure, with no planar tetra-coordinated structure, with no contact between cation and anion [75–77]. In contrast, this contactbehavior between is not cation so clear and in anion solution [75–77, at]. least In contrast, for some this of behavior these complexes. is not so clear James in solution,[72] and atAnderson least for some of these complexes. James [72] and Anderson [78] proposed that [Rh(PP) ]X complexes (X = Cl , [78] proposed that [Rh(PP)2]X complexes (X = Cl-, BF4-, PF6, SbF6) form ionic2 pairs when n = 2 and 3,− BF4while−, PF 6coordination, SbF6) form ionicof the pairs anion when can nbe =observed2 and 3, for while n = coordination 1 and 4. Very of recently the anion Mannu can be et observed al. [71] = forobserved n 1 and that 4. changing Very recently the anion Mannu Cl- with et al. BF [714−, ]the observed outcome that of the changing reduction the of anion acetophenone Cl− with in BF the4−, thepresence outcome of of 2- thepropanol reduction was different of acetophenone (Table 2), in revealing the presence a not negligible of 2-propanol role of was the di anionfferent when (Table these2), revealingcomplexes a not are negligible employed role as of catalytic the anion precursors when these in complexesTH. In the aresame employed contribution as catalytic [71], the precursors authors in TH.demonstrated In the same that contribution for such complexes [71], the, authors phosphine demonstrated exchange can that occur for such even complexes, at room temperature. phosphine exchangeDecoordination can occur of even diphosphine at room temperature. generates high Decoordinationly reactive intermediate of diphosphine species generates of the highly type reactive[Rh(PP)(solv.)] intermediate+ (solv. species = solvent), of the typealready [Rh(PP)(solv.)] detected for+ several(solv. = solventssolvent), and already diphosphines detected for[79 several]. Such solventsspecies and can diphosphines exist in [79 equilibrium]. Such species with can many exist in other equilibrium intermediates, with many including other intermediates, dinuclear + including[Rh2(diphosphine) dinuclear [Rh2(2-2Cl)(diphosphine)2] [79], trinuclear2(µ2-Cl) [Rh23][(DPPP)79], trinuclear3(μ3-OMe) [Rh2]+ [803(DPPP)], and mononuclear3(µ3-OMe)2] [Rh(PP)X][80], and mononuclear[81,82]. Recently, [Rh(PP)X] Baráth [81 [,8382]]. suggested Recently, a Bar catalyticáth [83 ]cycle suggested for the aTH catalytic reaction cycle mediated for the by TH dinuclear reaction mediated[Rh2(DPPP) by dinuclear2(2-Cl)2] ( [RhScheme2(DPPP) 10).2 ( µ2-Cl)2] (Scheme 10).

SchemeScheme 10. 10Adaptation. Adaptation of of the the catalytic catalytic cycle cycle for for TH TH from from 2-propanol 2-propanol toto acetophenoneacetophenone mediatedmediated by dinucleardinuclear [Rh [Rh2(PP)2(PP)2(µ2(2-Cl)2-Cl)2]2] complexes complexes [[8383].].

In the mechanism reported in Scheme 10, the typical hydride route has been considered as for the Ru complexes discussed above. The catalytic precursor undergoes activation by the action of the base and the 2-propanol. According to Pàmies findings [34], a mono-hydride route was proposed, as a selective deuterium transfer from the α-position of 2-propanol to the carbonyl carbon of the ketone was observed in the presence of Rh catalytic precursors. It is worth citing the reduction of carbonylic compounds (aldehydes and ketones) in the presence of 2-propanol, which was reported in biphasic water/alcohol conditions for the in situ generated catalytic system [{RhCl(COD)}2] (COD = 1,5-cyclooctadiene)/TPPTS [84] (Scheme 11).

Catalysts 2020, 10, 162 14 of 19

In the mechanism reported in Scheme 10, the typical hydride route has been considered as for the Ru complexes discussed above. The catalytic precursor undergoes activation by the action of the base and the 2-propanol. According to Pàmies findings [34], a mono-hydride route was proposed, as a selective deuterium transfer from the α-position of 2-propanol to the carbonyl carbon of the ketone was observed in the presence of Rh catalytic precursors. It is worth citing the reduction of carbonylic compounds (aldehydes and ketones) in the presence of 2-propanol, which was reported in biphasic water/alcohol conditions for the in situ generated catalyticCatalysts 20 system20, 10, x FOR [{RhCl(COD)} PEER REVIEW2] (COD = 1,5-cyclooctadiene)/TPPTS [84] (Scheme 11). 14 of 18

Scheme 11. TH from 2-propanol to acetophenone mediated by [Rh(COD)Cl]2/TPPTS complexes. Scheme 11. TH from 2-propanol to acetophenone mediated by [Rh(COD)Cl]2/TPPTS complexes. The system was extended not only to the reduction of acetophenone, but also to several ketones The system was extended not only to the reduction of acetophenone, but also to several ketones and aldehydes showing high conversions after 2 h at 80 ◦C in the presence of Na2CO3 as base. and aldehydes showing high conversions after 2 h at 80 °C in the presence of Na2CO3 as base. Additional detailed studies about the activity of the catalytic precursor [RhCl(mtppms)3] in the Additional detailed studies about the activity of the catalytic precursor [RhCl(mtppms)3] in the reduction of cinnamaldehyde in biphasic water/alcohol systems and in the presence of sodium formate reduction of cinnamaldehyde in biphasic water/alcohol systems and in the presence of sodium (HCOONa) were reported by Joò et al. [85,86]. formate (HCOONa) were reported by Joò et al. [85,86]. By comparing the effect on the catalytic outcome of several alcohols (methanol, ethanol, 2-propanol, By comparing the effect on the catalytic outcome of several alcohols (methanol, ethanol, 2- 2-ethoxyethanol, glycerol), an accelerating effect of 2-propanol was reported. Nevertheless, on the basis propanol, 2-ethoxyethanol, glycerol), an accelerating effect of 2-propanol was reported. Nevertheless, of experiments conducted in absence of formate, and considering the kinetic behavior of the systems, on the basis of experiments conducted in absence of formate, and considering the kinetic behavior of the possibility of 2-propanol acting as hydrogen donor was excluded. Instead, the accelerating effect the systems, the possibility of 2-propanol acting as hydrogen donor was excluded. Instead, the observed was related to an increased solubility of the substrate in such conditions. accelerating effect observed was related to an increased solubility of the substrate in such conditions. 3. Conclusions 3. Conclusions Catalytic reduction of ketones in homogeneous phase through transfer hydrogenation (TH), and its asymmetricCatalytic version reduction (ATH) of areketones processes in homogeneous of choice for thephase synthesis through of transfer several alcohols.hydrogenation Despite (TH), the large and numberits asymmetric of deeply version studied (ATH) catalytic are processes systems for of thischoice transformation, for the synthesis the rationalization of several alcohols. of the reactionDespite the large number of deeply studied catalytic systems for this transformation, the rationalization of mechanism is difficult in many cases. In particular, for TH promoted by neutral [RuCl2(arene)(P)] complexesthe reaction (P mechanism= generic monophosphine), is difficult in many the classical cases. hydridic In particular, route does for TH not promoted exhaustively by describe neutral the[RuCl catalysis.2(arene)(P)] For these compl systems,exes (P the = crucialgeneric point monophosphine is represented), by the the classical generation hydridic of vacant route sites do duringes not theexhaustively catalytic cycle. describe In the the case catalysis. of Ru-arene For complexes, these systems the decoordination, the crucial pointof chloride is represented as well as a changeby the ingeneration the hapticity of vacant of the arene sites unitduring can contribute the catalytic to the cycle. generation In the of case catalytic of Ru active-arene species. complexes, A mixed the decoordination of chloride as well as a change in the hapticity of the arene unit can contribute to the mechanism cannot be excluded. In the case of [Rh(PP)2]X catalytic precursors (PP = diphosphine, Xgeneration= anion), the of catalytic proposal active of a catalytic species. mechanism A mixed is mechanism even more cannotdifficult, be mainly excluded. due toIn the the variety case of intermediate[Rh(PP)2]X catalytic species pr thatecursors can be (PP formed = diphosphine, in situ. X = anion), the proposal of a catalytic mechanism is evenIt seemsmore difficult, clear that mainly the catalytically due to the activevariety species of intermediate in TH for species the Ru- that and can Rh-systems be formed presented in situ. hereinIt areseems metallic clear hydridesthat the catalytically which havebeen active detected species spectroscopically in TH for the Ru in- and many Rh cases.-systems In spite presented of this, theherein details are ofmetallic the mechanism hydrides arewhich not knownhave been for thedetected systems spectroscopically described in this in review. many Thecases. generation In spite of this, the details of the mechanism are not known for the systems described in this review. The generation of the required coordination vacancies is particularly intriguing. In the case of Ru-arene systems, some experimental data suggest halide decoordination, while other evidence suggests arene slippage. Similarly, in the case of cationic monomeric Rh complexes bearing diphosphines, a partial dissociation of one diphosphine “arm”, acting as labile ligand, cannot be excluded. Additionally, the active participation of the anion should be considered. What is clear is that much more in-depth mechanistic studies, both theoretical and experimental, are needed in order to clarify the catalytic cycle of the systems described in this review.

Funding: This research received no external funding.

Catalysts 2020, 10, 162 15 of 19 the required coordination vacancies is particularly intriguing. In the case of Ru-arene systems, some experimental data suggest halide decoordination, while other evidence suggests arene slippage. Similarly, in the case of cationic monomeric Rh complexes bearing diphosphines, a partial dissociation of one diphosphine “arm”, acting as labile ligand, cannot be excluded. Additionally, the active participation of the anion should be considered. What is clear is that much more in-depth mechanistic studies, both theoretical and experimental, are needed in order to clarify the catalytic cycle of the systems described in this review.

Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflicts of interest.

References and Note

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