Tio2 Photocatalysis for Transfer Hydrogenation

Review TiO2 Photocatalysis for Transfer Hydrogenation

Dongge Ma 1,* , Shan Zhai 1, Yi Wang 1, Anan Liu 2 and Chuncheng Chen 3

1 School of Science, Beijing Technology and Business University, Beijing 100048, China; [email protected] (S.Z.); [email protected] (Y.W.) 2 Basic Experimental Center for Natural Science, University of Science and Technology Beijing, Beijing 100083, China; [email protected] 3 Key Laboratory of Photochemistry, Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; [email protected] * Correspondence: [email protected]; Tel.: +86-010-68985573

Academic Editor: Yasuharu Yoshimi Received: 15 December 2018; Accepted: 15 January 2019; Published: 17 January 2019

Abstract: Catalytic transfer hydrogenation reactions, based on hydrogen sources other than gaseous H2, are important processes that are preferential in both laboratories and factories. However, harsh conditions, such as high temperature, are usually required for most transition-metal catalytic and organocatalytic systems. Moreover, non-volatile hydrogen donors such as dihydropyridinedicarboxylate and formic acid are often required in these processes which increase the difﬁculty in separating products and lowered the whole atom economy. Recently, TiO2 photocatalysis provides mild and facile access for transfer hydrogenation of C=C, C=O, N=O and C-X bonds by using volatile alcohols and amines as hydrogen sources. Upon light excitation, TiO2 photo-induced holes have the ability to oxidatively take two hydrogen atoms off alcohols and amines under room temperature. Simultaneously, photo-induced conduction band electrons would combine with these two hydrogen atoms and smoothly hydrogenate multiple bonds and/or C-X bonds. It is heartening that practices and principles in the transfer hydrogenations of substrates containing C=C, C=O, N=O and C-X bond based on TiO2 photocatalysis have overcome a lot of the traditional thermocatalysis’ limitations and ﬂaws which usually originate from high temperature operations. In this review, we will introduce the recent paragon examples of TiO2 photocatalytic transfer hydrogenations used in (1) C=C and C≡C (2) C=O and C=N (3) N=O substrates and in-depth discuss basic principle, status, challenges and future directions of transfer hydrogenation mediated by TiO2 photocatalysis.

Keywords: TiO2; transfer hydrogenation; photocatalysis; hydrogen donor

1. Introduction Hydrogenation of organic compounds is one of the basic transformations in organic synthesis [1–3]. In both laboratories and industries, hydrogenation processes are irreplaceable for producing bulk-chemicals, fine-chemicals, pharmaceuticals, agrochemicals and fragrances [4–6]. According to the types of hydrogen donor, hydrogenation can be roughly divided into two main categories: (i) Hydrogenation using gaseous dihydrogen [6]; (ii) transfer hydrogenation using hydrogen donors other than dihydrogen [7,8]. In consideration of the hazard and inconvenience to apply explosive gaseous dihydrogen cylinder, using safer hydrogen sources such as alcohols and amines is especially desired. Moreover, the activation of gaseous dihydrogen often requires expensive and toxic transition-metal complexes. These catalytic systems often need harsh conditions such as high reflux temperature and hydrogen pressure. Compared with hydrogenation using dihydrogen, transfer hydrogenation using alcohols and amines as hydrogen donor compounds (HDC) is safer and more convenient. Although the atom efficiency of hydrogenation using dihydrogen is higher than

Molecules 2019, 24, 330; doi:10.3390/molecules24020330 www.mdpi.com/journal/molecules Molecules 2019, 24, 330 2 of 22 transfer hydrogenation, the advantage in safety and mildness made the latter a more preferential choice in laboratory and industry for the reduction of organic compounds. Recently, transfer hydrogenations have been greatly developed. Among all of the current transfer hydrogenations, catalytic transfer hydrogenations have overwhelmingly come to dominate the field in place of stoichiometric transformations. Catalytic hydrogenation processes based on both use of H2 and other HDC can be briefly described as Scheme1[ 9,10]. In Scheme1a, transition-metal complexes such as the Ru complex heterolytically cleaves the dihydrogen H-H bond and the in-situ generated Ru-H complex attacks the carbonyl C=O in a nucleophilic manner yielding a Ru-alkoxide species. The following solvatolysis provides the alcohol product and regenerates the Ru complex. In Scheme1b, both the non-transition-metal mediated direct hydrogen transfer and the transition-metal catalyzed hydridic route for transfer hydrogenation is shown. The original version of the former (the top half of Scheme1b) was the aluminum isopropoxide mediated transfer hydrogenation named as Meerwein-Ponndorf-Verley (MPV) reduction [11–13]. In this case, the reaction mechanism is proposed to proceed through a six-membered transition state, without the involvement of metal hydride intermediates (the top half of Scheme1b). The process can also be run in the opposite direction, which is the well-known Oppenauer oxidation [14]. In the transition metal case (the bottom half of Scheme1b), it is believed that the reaction involves the formation of a metal hydride intermediate. In this case, the transition-metal complex catalyst facilitates the formation of metal-alkoxide with alcohol substrate. The alkoxide then undergoes a β-hydride elimination to give a metal-monohydride, which attacks another substrate ketone in a nucleophilic manner to realize the transfer hydrogenation [10,15]. Such a hydride intermediate has indeed been isolated in some transition-metal catalyzed transfer hydrogen reactions. Furthermore, according to the property of catalysts, catalytic transfer hydrogenations can be divided into homogeneous and heterogeneous categories. The former has garnered considerable success in the control of chemo-, regio- and even enantioselectivity [7,16]. As a significant branch of catalytic transfer hydrogenations, heterogeneous catalysis owns its distinct advantages: Easier separation and recyclization, less catalyst residue and non-decreased catalytic reactivity after multiple uses [17–21]. Heterogeneous catalysts play a pivotal role in the production of fine- and bulk-chemicals applying transfer hydrogenation. Specifically, heterogeneous catalytic systems have occupied a prominent status for transfer hydrogenation [22]. As a typical heterogeneous photocatalyst, TiO2 nanoparticle has been thoroughly investigated and applied in a broad range of energy and environmental fields [23]. For example, TiO2 nanocrystal materials have been widely applied in photocatalytic water-splitting process [24], dye-sensitized-solar-cells [25], perovskite solar-cells [26] and photocatalytic detoxification of water systems and air cleaning [27,28]. Recently, the potential of TiO2 in organic synthetic photoredox catalysis has been discovered [29–33]. Upon UV, sunlight or even visible-light irradiation, the photo-induced valence-band hole and conduction-band electron on TiO2 surface would participate in their separate oxidative or reductive reaction with suitable electron donors or acceptors (as shown in Scheme2a). Benefiting from this separated interfacial electron transfer, a number of TiO 2 photocatalytic organic transformations have been unearthed. If photo-induced conduction-band electrons are consumed with the suitable electron acceptors such as dioxygen, p-benzoquinone, Ag+ cation or H+ upon metallic Pt loading, valence-band holes would oxidize the organic substrate furnishing the oxidative transformations. TiO2 photocatalysis has demonstrated its potential in a series of oxidative transformations such as alcohol oxidation to aldehydes and ketones [34–37], amine oxidative coupling to imines [38–41] and sulfide oxidation to sulfoxides [42,43]. Furthermore, TiO2 photocatalysis could be applied in redox-neutral C-C bond formation reactions [44–46]. Under appropriate light irradiation, TiO2 photo-induced hole which is highly oxidative possessing a redox potential as high as 2.7 V vs. normal hydrogen electrode (NHE) is generated. The hole could cleave the organic compounds’ C-X/H bonds generating radical cation species. Theses radical cations can be further trapped by unsaturated compound participating in an addition reaction to construct C-C bonds or cross-coupled with another radical species (see Scheme2a) [ 44,45]. In these C-C construction transformations, Molecules 2019, 24, x FOR PEER REVIEW 2 of 21

convenient. Although the atom efficiency of hydrogenation using dihydrogen is higher than transfer hydrogenation, the advantage in safety and mildness made the latter a more preferential choice in laboratory and industry for the reduction of organic compounds. Recently, transfer hydrogenations have been greatly developed. Among all of the current transfer hydrogenations, catalytic transfer hydrogenations have overwhelmingly come to dominate the field in place of stoichiometric transformations. Catalytic hydrogenation processes based on both use of H2 and other HDC can be briefly described as Scheme 1 [9,10]. In Scheme 1a, transition-metal complexes such as the Ru complex heterolytically cleaves the dihydrogen H-H bond and the in-situ generated Ru-H complex attacks the carbonyl C=O in a nucleophilic manner yielding a Ru-alkoxide species. The following solvatolysis provides the alcohol product and regenerates the Ru complex. In Scheme 1b, both the non-transition- metal mediated direct hydrogen transfer and the transition-metal catalyzed hydridic route for transfer hydrogenation is shown. The original version of the former (the top half of Scheme 1b) was the aluminum isopropoxide mediated transfer hydrogenation named as Meerwein-Ponndorf-Verley Molecules 2019, 24, 330 3 of 22 (MPV) reduction [11–13]. In this case, the reaction mechanism is proposed to proceed through a six- membered transition state, without the involvement of metal hydride intermediates (the top half of bothScheme valence-band 1b). The process hole and can conduction-band also be run in electron the opposite half-reaction direction, are fruitful which for is synthesizing the well-known the ﬁnalOppenauer product. oxidation According [14] to. theIn the bond transition being cleaved, metal case the C-C (the bond bottom formation half of byScheme TiO2 photocatalysis1b), it is believed are dividedthat the intoreaction the following involves categories:the formation (1) Cleavageof a metal C-Si hydride bonds intermediate. [47]; (2) C-COOH In this bonds case, [ 48the,49 transition]. (3) C-H- bondmetal at complexα-position catalyst of tetrahydropyrrole facilitates the formation [50,51]. (4) of C-H metal bond-alkoxide at aldehyde with α a-positionlcohol substrate. [52]. (5) C-H The bondalkoxide at both then benzylic undergoes and a amine β-hydrideα-position elimination of N-arylisoquinoline to give a metal [53-monohydride,]. (6) inert sp 2 whichC-H bond attacks of pyridineanother substrateα-position ketone [54]. Apart in a nucleophilic from oxidative manner and redox-neutralto realize the transformations,transfer hydrogenation TiO2 photo-induced [10,15]. Such conduction-banda hydride intermediate electron with has indeeda redox potential been isolated of −0.5 in V some vs. NHE transition has been-metal proved catalyzed to be a mild transfer and selectivehydrogen catalyst reactions. for reductive Furthermore, transformation according [55 – to59 ]. the In theproperty presence of of catalysts, excess amount catalytic of alcohols transfer or amines,hydrogenations TiO2 photo-induced can be divided holes into would homogeneous migrate to the and surface heterogeneous and oxidize categories. the alcohols The and former amines has whichgarnered adsorbed considerable on TiO success2 surface in the and control be quenched. of chemo The-, regio depletion- and even of valence-band enantioselectivity holes increases[7,16]. As thea significant reaction ratebranch of conduction-bandof catalytic transfer electron’s hydrogenations, reductive heterogeneous transformations, catalysis since this owns consumption its distinct ofadvantages: holes decreases Easier the separation possibility and of recyclization, hole-electron less recombination. catalyst residue In this and way, non TiO-decreased2 photo-induced catalytic conduction-bandreactivity after multiple electrons uses would [17– have21]. Heterogeneous a much longer lifetime catalysts to participateplay a pivo intal the role interfacial in the production reduction of organicfine- and compounds. bulk-chemicals applying transfer hydrogenation. Specifically, heterogeneous catalytic systems have occupied a prominent status for transfer hydrogenation [22].

(a)

(b)

Scheme 1. Catalytic hydrogenation (a) activating gaseous H2 as a hydrogen source (b) activating

alcohols as a hydrogen source.

Compared with transition-metal catalyzed transfer hydrogenation, TiO2 photocatalysis could achieve similarly high selectivity and yield, but usually in much milder ambient conditions and even visible-light irradiation. In recent years, some studies have uncovered that under strictly controlling anaerobic conditions, photo-induced holes on TiO2 nanoparticle surface in the suspending solution have the capacity to oxidatively remove hydrogens from alcohols or amines and deliver these hydrogens to the conduction band of TiO2 where the hydrogens combined with the conduction-band electrons and further selectively transferred to the unsaturated compounds such as carbonyls, imines multiple bonds(see Scheme2b) [ 60–63]. It is heartening that practices and principles of TiO2 photocatalysis in these transfer hydrogenations of substrates containing C=C, C=O, N=O and C-X bond have overcome a lot of the traditional thermocatalysis’ limitations and ﬂaws originating from high temperature operations. Being environmentally benign, photo-, acid- and basic stable, extremely Molecules 2019, 24, x FOR PEER REVIEW 3 of 21

Scheme 1. Catalytic hydrogenation (a) activating gaseous H2 as a hydrogen source (b) activating alcohols as a hydrogen source.

As a typical heterogeneous photocatalyst, TiO2 nanoparticle has been thoroughly investigated and applied in a broad range of energy and environmental fields [23]. For example, TiO2 nanocrystal materials have been widely applied in photocatalytic water-splitting process [24], dye-sensitized- solar-cells [25], perovskite solar-cells [26] and photocatalytic detoxification of water systems and air cleaning [27,28]. Recently, the potential of TiO2 in organic synthetic photoredox catalysis has been discovered [29–33]. Upon UV, sunlight or even visible-light irradiation, the photo-induced valence- band hole and conduction-band electron on TiO2 surface would participate in their separate oxidative or reductive reaction with suitable electron donors or acceptors (as shown in Scheme 2a). Benefiting from this separated interfacial electron transfer, a number of TiO2 photocatalytic organic transformations have been unearthed. If photo-induced conduction-band electrons are consumed with the suitable electron acceptors such as dioxygen, p-benzoquinone, Ag+ cation or H+ upon metallic Pt loading, valence-band holes would oxidize the organic substrate furnishing the oxidative transformations. TiO2 photocatalysis has demonstrated its potential in a series of oxidative transformations such as alcohol oxidation to aldehydes and ketones [34–37], amine oxidative coupling to imines [38–41] and sulfide oxidation to sulfoxides [42,43]. Furthermore, TiO2 photocatalysis could be applied in redox-neutral C-C bond formation reactions [44–46]. Under appropriate light irradiation, TiO2 photo-induced hole which is highly oxidative possessing a redox potential as high as 2.7 V vs. normal hydrogen electrode (NHE) is generated. The hole could cleave the organic compounds’ C-X/H bonds generating radical cation species. Theses radical cations can be further trapped by unsaturated compound participating in an addition reaction to construct C-C bonds or cross-coupled with another radical species (see Scheme 2a) [44,45]. In these C-C construction transformations, both valence-band hole and conduction-band electron half-reaction are fruitful for synthesizing the final product. According to the bond being cleaved, the C-C bond formation by TiO2 Molecules 2019, 24, 330 4 of 22 photocatalysis are divided into the following categories: (1) Cleavage C-Si bonds [47]; (2) C-COOH bonds [48,49]. (3) C-H bond at α-position of tetrahydropyrrole [50,51]. (4) C-H bond at aldehyde α-

convenientposition [52]. in (4) separation C-H bond and at recyclization,both benzylic TiO and2 photocatalysisamine α-position seems of N to-arylisoquinoline be an ideal choice [53]. for (5) transfer inert hydrogenationssp2 C-H bond of if pyridine scaling-up α-position and enantioselectivity [54]. Apart from control oxidative issues areand solved. redox-neutral Moreover, transformations, accompanying withTiO2 thephoto-induced elucidation of conduction-band the detailed mechanism electron and with pathway a redox by trappingpotential theof reaction−0.5 V vs. intermediates NHE has been and determiningproved to be H/D a mild kinetic and isotope selective effects catalyst in the for process reductive of simultaneous transformation oxidation [55–59 of]. hole-scavengerIn the presence and of reductionexcess amount of target of alcohols organic substrate,or amines, the TiO efﬁciency2 photo-induced and the chemo-, holes would regio- migrate and even to enantioselectivity the surface and ofoxidize this methodology the alcohols and would amines be greatly which improved.adsorbed on In TiO this2 article,surface accordingand be quenched. to the unsaturated The depletion bond of beingvalence-band reduced byholes TiO2 photocatalyst,increases the this reaction review isra mainlyte of divided conduction-band into the following electron’s parts: (1)reductive Transfer hydrogenationtransformations, of since C=C andthis C ≡consumptionC (2) C=O and of C=Nholes (3) decreases N=O. As thethe hydrodehalogenation possibility of hole-electron by TiO2 photocatalysisrecombination. has In beenthis recentlyway, TiO reviewed2 photo-induced by Zhao etconduction-band al [64], this review electrons would notwould cover have this a section. much longer lifetime to participate in the interfacial reduction of organic compounds.

Molecules 2019, 24, x FOR PEER REVIEW (a) 4 of 21

(b)

SchemeScheme 2. 2. (a(a) )TiO TiO2 2photo-inducedphoto-induced valence-band valence-band holes holes and and conduction-band conduction-band electrons electrons for for different different interfacialinterfacial reactions reactions under under irradiation irradiation (b ()b TiO) TiO2 photocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation using using alcohol alcohol as hydrogenas hydrogen donor donor compound compound for carbonyl for carbonyl C=O an C=Od imine and imineC=N reduction C=N reduction to alcohol to alcoholand amine and compounds.amine compounds.

2. Transfer Hydrogenation of C=C and C≡C Bonds Compared with transition-metal catalyzed transfer hydrogenation, TiO2 photocatalysis could achieveCatalytic similarly reduction high selectivity of C=C and to yield, C-C bondsbut usually are veryin much important milder ambient transformations conditions in and synthetic even visible-lightorganic chemistry irradiation. [65,66 In]. recent In drugs, years, agrochemicals some studies and have ﬁne-chemicals uncovered that structure, under strictly sp3C-sp controlling3C moiety anaerobicis ubiquitous conditions, and indispensable photo-induced [ 67holes,68]. on SaturatedTiO2 nanoparticle cyclic structures surface in becomethe suspending more and solution more haveimportant the capacity in the discoveryto oxidatively of new remove drug moleculeshydrogens [ 69from]. With alcohols the requirement or amines forand eco-sustainable deliver these hydrogenschemistry, to green the conduction and mild catalytic band of hydrogenation TiO2 where the process hydrogens of C=C combined to C-C bondswith the is conduction-band extremely desired. electronsHeterogeneous and further TiO2 selectivelyphotocatalysis transferred provides to athe feasible unsaturated plan. compounds such as carbonyls, imines multiple bonds(see Scheme 2b) [60–63]. It is heartening that practices and principles of TiO2 photocatalysis in these transfer hydrogenations of substrates containing C=C, C=O, N=O and C-X bond have overcome a lot of the traditional thermocatalysis’ limitations and flaws originating from high temperature operations. Being environmentally benign, photo-, acid- and basic stable, extremely convenient in separation and recyclization, TiO2 photocatalysis seems to be an ideal choice for transfer hydrogenations if scaling-up and enantioselectivity control issues are solved. Moreover, accompanying with the elucidation of the detailed mechanism and pathway by trapping the reaction intermediates and determining H/D kinetic isotope effects in the process of simultaneous oxidation of hole-scavenger and reduction of target organic substrate, the efficiency and the chemo-, regio- and even enantioselectivity of this methodology would be greatly improved. In this article, according to the unsaturated bond being reduced by TiO2 photocatalyst, this review is mainly divided into the following parts: (1) Transfer hydrogenation of C=C and C≡C (2) C=O and C=N (3) N=O. As the hydrodehalogenation by TiO2 photocatalysis has been recently reviewed by Zhao et al [64], this review would not cover this section.

2. Transfer Hydrogenation of C=C and C≡C Bonds Catalytic reduction of C=C to C-C bonds are very important transformations in synthetic organic chemistry [65,66]. In drugs, agrochemicals and fine-chemicals structure, sp3C-sp3C moiety is ubiquitous and indispensable [67,68]. Saturated cyclic structures become more and more important in the discovery of new drug molecules [69]. With the requirement for eco-sustainable chemistry, green and mild catalytic hydrogenation process of C=C to C-C bonds is extremely desired. Heterogeneous TiO2 photocatalysis provides a feasible plan. Not much later than Fujishima’s groundbreaking report on TiO2 photocatalysis application in water-splitting [70], Boonstra et al. discovered that TiO2 could act as a catalyst for the photohydrogenation of gaseous ethylene and acetylene [71]. They described that when TiO2 powder

Molecules 2019, 24, 330 5 of 22

Not much later than Fujishima’s groundbreaking report on TiO2 photocatalysis application in water-splitting [70], Boonstra et al. discovered that TiO2 could act as a catalyst for the photohydrogenationMolecules 2019, 24, x FOR ofPEER gaseous REVIEW ethylene and acetylene [71]. They described that when TiO2 powder5 of 21 was degassed with ethylene or acetylene and illuminated by near-UV (ultra-violet) light, hydrogenated paraffinwas degassed products with were ethylene generated. or The acetylene authors and demonstrated illuminated that by surface near-UV Ti-O-H（ ultra provided-violet reductive） light, H-specieshydrogenated to hydrogenate paraffin products acetylene were and ethylene.generated. Kubokawa The authors et al. demonstrated discovered that that after surface water Ti vapor-O-H provided reductive H-species to hydrogenate acetylene and ethylene. Kubokawa et al. discovered adsorption, TiO2 became a more effective catalyst for photohydrogenation of short-chain alkynes and alkenes.that after The water main vapor products adsorption, were alkanesTiO2 became and bond a more fission effective products. catalyst Although for photohydrogenation the efficiency and of short-chain alkynes and alkenes. The main products were alkanes and bond fission products. selectivity were fairly low, this report spurred the further research on TiO2 photocatalyzed transfer hydrogenationAlthough the efficiency of unsaturated and selectivity compounds were (as fairly shown low, in Scheme this report3)[72 spurred]. the further research on TiO2 photocatalyzed transfer hydrogenation of unsaturated compounds (as shown in Scheme 3) [72].

Scheme 3. TiO2 photocatalyzed transfer hydrogenation of ethylene and acetylene using water vapor Scheme 3. TiO2 photocatalyzed transfer hydrogenation of ethylene and acetylene using water vapor as a hydrogen source. as a hydrogen source. Further investigation over the reaction process by electron-paramagnetic-resonance (EPR) Further investigation over the reaction process by electron-paramagnetic-resonance (EPR) experiments and other mechanistic studies proved that it was H2O not surface Ti-OH which reduced experiments and other mechanistic studies proved that it was H2O not surface Ti-OH which reduced alkynes and alkenes [73]. Furthermore, Anpo et al. discussed the influence of Pt-loading to the alkynes and alkenes [73]. Furthermore, Anpo et al. discussed the influence of Pt-loading to the efficiency and product distribution of this reaction using water vapor as a hydrogen donor [74]. efficiency and product distribution of this reaction using water vapor as a hydrogen donor [74]. Using Using Pt-loaded TiO2 powder as the photocatalyst, much less bond fission occurred, since in-situ Pt-loaded TiO2 powder as the photocatalyst, much less bond fission occurred, since in-situ evolved evolved hydrogen atoms transferred into substrates more easily on Pt nanoparticles than on TiO2 hydrogen atoms transferred into substrates more easily on Pt nanoparticles than on TiO2 surface (as surface (as shown in Scheme4). By preparing much smaller TiO 2 nanoparticles with diameters shown in Scheme 4). By preparing much smaller TiO2 nanoparticles with diameters~50 Å , an ~50 Å, an apparent quantization effect appeared. The photohydrogenation efficiency of CH3C≡CH apparent quantization effect appeared. The photohydrogenation efficiency of CH3C≡CH and HC≡CH and HC≡CH was greatly enhanced with smaller TiO2 nanoparticles in comparison with bulk TiO2 was greatly enhanced with smaller TiO2 nanoparticles in comparison with bulk TiO2 particles [75]. particles [75]. The quantum yield was measured and the experimental result showed that as TiO2 The quantum yield was measured and the experimental result showed that as TiO2 nanoparticle nanoparticle became smaller, the quantum yield of the photohydrogenation of alkynes increased became smaller, the quantum yield of the photohydrogenation of alkynes increased greatly. greatly. Yamataka et al. discovered that when hydrogen donor was changed from water vapor to Yamataka et al. discovered that when hydrogen donor was changed from water vapor to alcohols alcohols such as ethanol or propan-2-ol, using platinized TiO2 as photocatalyst, much enhanced yield such as ethanol or propan-2-ol, using platinized TiO2 as photocatalyst, much enhanced yield could could be achieved for long-chain alkenes and alkynes transfer hydrogenation to alkanes [76]. This is a be achieved for long-chain alkenes and alkynes transfer hydrogenation to alkanes [76]. This is a major major advance for transfer hydrogenation by TiO2 photocatalysis. advance for transfer hydrogenation by TiO2 photocatalysis. Apart from Pt-loaded TiO2, Baba et al. designed and synthesized the bimetal-deposited TiO2 and used it as an effective photocatalyst for transfer hydrogenation of ethylene with water vapor as HDC [77]. They discovered that a noble metal component such as Pt or Pd could act as hydrogen evolution and hydrogenation catalyst, while the second metallic component such as Ni or Cu acted as an efficient adsorbent for ethylene. Thus, bimetallic photocatalyst such as Pt/TiO2/Cu or Pd/TiO2/Ni was synthesized demonstrating higher selectivity for ethylene photohydrogenation to ethane other than C=C fission to CH4 and H2 (as shown in Scheme5).

Scheme 4. The different reaction pathways on TiO2 photocatalyzed hydrogenation of alkynes and alkenes on unloaded and Pt-loaded TiO2.

Apart from Pt-loaded TiO2, Baba et al. designed and synthesized the bimetal-deposited TiO2 and used it as an effective photocatalyst for transfer hydrogenation of ethylene with water vapor as

Molecules 2019, 24, x FOR PEER REVIEW 5 of 21 was degassed with ethylene or acetylene and illuminated by near-UV （ ultra-violet ） light, hydrogenated paraffin products were generated. The authors demonstrated that surface Ti-O-H provided reductive H-species to hydrogenate acetylene and ethylene. Kubokawa et al. discovered that after water vapor adsorption, TiO2 became a more effective catalyst for photohydrogenation of short-chain alkynes and alkenes. The main products were alkanes and bond fission products. Although the efficiency and selectivity were fairly low, this report spurred the further research on TiO2 photocatalyzed transfer hydrogenation of unsaturated compounds (as shown in Scheme 3) [72].

Scheme 3. TiO2 photocatalyzed transfer hydrogenation of ethylene and acetylene using water vapor as a hydrogen source.

Further investigation over the reaction process by electron-paramagnetic-resonance (EPR) experiments and other mechanistic studies proved that it was H2O not surface Ti-OH which reduced alkynes and alkenes [73]. Furthermore, Anpo et al. discussed the influence of Pt-loading to the efficiency and product distribution of this reaction using water vapor as a hydrogen donor [74]. Using Pt-loaded TiO2 powder as the photocatalyst, much less bond fission occurred, since in-situ evolved hydrogen atoms transferred into substrates more easily on Pt nanoparticles than on TiO2 surface (as shown in Scheme 4). By preparing much smaller TiO2 nanoparticles with diameters~50 Å , an apparent quantization effect appeared. The photohydrogenation efficiency of CH3C≡CH and HC≡CH was greatly enhanced with smaller TiO2 nanoparticles in comparison with bulk TiO2 particles [75]. The quantum yield was measured and the experimental result showed that as TiO2 nanoparticle became smaller, the quantum yield of the photohydrogenation of alkynes increased greatly. Yamataka et al. discovered that when hydrogen donor was changed from water vapor to alcohols such as ethanol or propan-2-ol, using platinized TiO2 as photocatalyst, much enhanced yield could beMolecules achieved2019, for24, 330long-chain alkenes and alkynes transfer hydrogenation to alkanes [76]. This is a major6 of 22 advance for transfer hydrogenation by TiO2 photocatalysis.

MoleculesMolecules 20192019,, 24 24,, x x FORFOR PEERPEER REVIEW REVIEW 66 ofof 2121

HDC.HDC.[77][77] TheyThey discovereddiscovered thatthat aa noblenoble metalmetal componentcomponent suchsuch asas PtPt oror PdPd couldcould actact asas hydrogenhydrogen evolutionevolution andand hydrhydrogenationogenation catalyst,catalyst, whilewhile thethe secondsecond metallicmetallic componentcomponent suchsuch asas NiNi oror CuCu actedacted asas an an efficient efficient adsorbent adsorbent for for ethylene. ethylene. Thus, Thus, bimetallic bimetallic photocatalyst photocatalyst such such as as Pt/TiO Pt/TiO22/Cu/Cu or or Scheme2 4. The different reaction pathways on TiO photocatalyzed hydrogenation of alkynes and Pd/TiOPd/TiO2/Ni/Ni waswas synthesizedsynthesized demonstratingdemonstrating higherhigher2 selectivityselectivity forfor ethyleneethylene photohydrogphotohydrogenationenation toto Scheme 4. The different reaction pathways on TiO2 photocatalyzed hydrogenation of alkynes and alkenes on unloaded and Pt-loaded TiO . ethane other than C=C fission to CH44 and2 H22 (as shown in Scheme 5). ethanealkenes other on than unloaded C=C fissionand Pt- loadedto CH TiO and2. H (as shown in Scheme 5).

Apart from Pt-loaded TiO2, Baba et al. designed and synthesized the bimetal-deposited TiO2 and used it as an effective photocatalyst for transfer hydrogenation of ethylene with water vapor as

Scheme 5. Bimetal nanoparticle-loaded-TiO2 photocatalyzed transfer hydrogenation of ethylene. 2 SchemeScheme 5.5. BimetalBimetal nanoparticlenanoparticle--loadedloaded--TiOTiO2 photocatalyzedphotocatalyzed transfertransfer hydrogenationhydrogenation ofof ethylene.ethylene. Kuntz et al. discovered that using poly-vinyl alcohol as a hydrogen donor, an electron-transfer Kuntz et al. discovered that using poly-vinyl alcohol as a hydrogen donor, an electron-transfer reagentKuntz MoO et2 −al.acted discovered as co-catalyst, that using acetylene poly-vinyl transfer alcohol hydrogenation as a hydrogen to ethane donor, by TiOan elephotocatalysisctron-transfer 4 2− 2 reagentreagent MoO MoO442− actedacted as as co co--catalyst,catalyst, acetylene acetylene transfer transfer hydrogenation hydrogenation2− to to ethane ethane by by TiO TiO22 could be furnished (as shown in Scheme6)[ 78]. They described that MoO4 ion adsorbing on TiO2 photocatalysis could be furnished (as shown in Scheme 6) [78]. They described that MoO422−− ion colloidalphotocatalysis particle could surface be would furnished promote (as shown the adjacent in Scheme Ti(III) 6) sites [78] to. They execute described four-electron that MoO reduction4 ion adsorbing on TiO2 colloidal particle surface would promote the adjacent Ti(III) sites to execute four- ofadsorbing acetylene on through TiO2 colloidal an electron-relay particle surface effect. would Molybdenum promote the played adjacent a similar Ti(III) sites role to as execute noble-metal four- electron reduction of acetylene through an electron-relay effect. Molybdenum played a similar role platinumelectron reduction to catalyze of the acetylene hydrogen through generation an electron and hydrogenation.-relay effect. Molybdenum Later on, the played same group a similar further role asas noblenoble--metalmetal platinumplatinum toto catalyzecatalyze thethe hydrogenhydrogen generationgeneration andand hydrogenation.hydrogenation. LaterLater on,on, thethe samesame unearthed the mechanism behind the polynuclear Mo2 and Mo3 oxo species in assisting colloidal TiO2 group further unearthed the mechanism behind the polynuclear Mo2 and Mo3 oxo species in assisting nanoparticlesgroup further to unearthed hydrogenate the mechanism acetylene [79 behind]. the polynuclear Mo2 and Mo3 oxo species in assisting colloidalcolloidal TiOTiO22 nanoparticlesnanoparticles toto hydrogenatehydrogenate acetyleneacetylene [79][79]..

Scheme 6. Molybdenum modiﬁed TiO2 photocatalyzed transfer hydrogenation of acetylene. 2 SchemeScheme 6.6. MolybdenumMolybdenum modifiedmodified TiOTiO2 photocatalyzedphotocatalyzed transfertransfer hydrogenationhydrogenation ofof acetylene.acetylene. Both Mo2 and Mo3 oxo species promoted the photohydrogenation of acetylene to ethane by a Both Mo2 and Mo3 oxo species promoted the photohydrogenation of acetylene to ethane by a 4- 4-electronBoth Mo process2 and onMo TiO3 oxo2 colloidal species promoted particle surface. the photohydrogenation Besides, Mo2 oxo of speciesacetylene also to enhancedethane by thea 4- electron process on TiO2 colloidal particle surface. Besides, Mo2 oxo species also enhanced the ethyleneelectron to process ethane on2-electron TiO2 colloidal photoreduction particle process. surface. In Besides, further studies, Mo2 oxo they spec designedies also a more enhanced efﬁcient the molybdenum-sulfurethyleneethylene to to ethane ethane 2 2co-catalyst--electronelectron photoreduction photoreduction other than molybdenum-oxo process. process. In In further further for acetylene studies, studies, photohydrogenation they they designed designed a a more more by efficient molybdenum-sulfur 2− co-catalyst other than molybdenum2− -oxo for acetylene TiOefficient2 colloidal molybdenum particle [80].-sulfur MoS4 coand-catalyst the dimeric other Mo 2S4 than(C2H 4S molybdenum2)2 co-catalysts-oxo provided for acetylene a higher photohydrogenation by TiO2 colloidal particle [80]. MoS42−2− and the dimeric Mo2S4(C2H4S2)22−2− co- turn-overphotohydrogenation number and by quantum TiO2 colloidal yield in particle comparison [80]. with MoS its4 molybdenum-oxoand the dimeric Mo analogues.2S4(C2H4S In2)2 their co- endingcatalystscatalysts work providedprovided on this a a theme, higher higher Kuntz turn turn-- etoverover al. designednumber number and and prepared quantum quantum the yield yield optimal in in comparison comparison molybdenum-based with with its its molybdenum-oxo analogues. In their ending work on this theme, Kuntz et al. designed and prepared co-catalystmolybdenum for- acetyleneoxo analogues. photohydrogenation In their ending towork ethane on this by TiO theme,2 colloidal Kuntz particleet al. designed [81]. They and combined prepared the optimal molybdenum-based co-catalyst for acetylene photohydrogenation to ethane by TiO2 thethe advantages optimal molybdenum of both Mo-oxo-based and co-catalyst Mo-sulfur for co-catalysts acetylene photohydrogenation and synthesized a dimeric to ethane co-catalyst by TiO2 colloidal particle2− [81]. They combined the advantages of both Mo-oxo and Mo-sulfur co-catalysts and Mocolloidal2OxSx(cys) particle2 . [81] A greatly. They combined improved quantumthe advantages yields of as both high Mo as 9.21%-oxo and was Mo achieved-sulfur co with-catalysts the record and synthesized a dimeric co-catalyst Mo2OxSx(cys)22−2−. A greatly improved quantum yields as high as highsynthesized turn-over a numberdimeric (TONco-catalyst = 32.9) Mo for2O acetylenexSx(cys)2 . photohydrogenation A greatly improvedto quantum ethylene yields by TiO as2 catalyst high as system.9.21%9.21% was Thewas reason achieved achieved for this with with high the the catalytic record record activity high high was turn turn that--overover the number number processes (TON (TON of electrons = = 32.9) 32.9) accepting for for acetylene acetylene from Ti photohydrogenation to ethylene by TiO2 catalyst system. The reason for this high catalytic activity (III)photohydrogenation sites and electrons to donating ethylene to by the TiO substrates2 catalyst bound system. to The TiO 2reasonsurface for were this both high greatly catalytic enhanced activity waswas that that the the processes processes of of electrons electrons accepting accepting from from Ti Ti (III) (III) sites sites and and electrons electrons donating donating to to the the substrates substrates boundbound to to TiO TiO22 surfacesurface were were both both greatly greatly enhanced enhanced by by this this co co--catalyst.catalyst. This This co co--catalystcatalyst provided provided comparablecomparable catalytic catalytic possibility possibility as as platinum platinum for for th thisis multi multi--electronelectron transfer transfer process process of of TiO TiO22 photocatalyzedphotocatalyzed transfertransfer hydrogenation.hydrogenation. AsAs an an environmentally environmentally benign benign photocatalyst, photocatalyst, TiO TiO22 hashas little little bio bio--toxicitytoxicity and and no no secondary secondary pollution.pollution. However,However, sincesince TiOTiO22 nanoparticlenanoparticle surfacesurface isis extremelyextremely hydratedhydrated andand possespossessesses numerousnumerous polarpolar Ti Ti--OHOH groups, groups, this this material material is is extremely extremely hydrophilic. hydrophilic. Effectively Effectively adsorbing adsorbing and and converting converting nonnon--polarpolar andand weakweak--polarpolar functionalfunctional groupgroup onon TiOTiO22 surfacesurface isis veryvery challenging.challenging. ForFor hydrogenationhydrogenation ofof olefinsolefins withwith onlyonly C=CC=C olefinicolefinic functionalfunctional grougroup,p, barebare TiOTiO22 photocatalystphotocatalyst withoutwithout metalmetal coco--catalystcatalyst loadingloading is is generally generally considered considered to to be be futile. futile. Although Although the the benzene benzene ring ring has has weak weak adsorption adsorption interactioninteraction onon polarpolar TiOTiO22 surfacesurface byby thethe coordinationcoordination ofof unoccupiedunoccupied TiTi 3d3d orbitalorbital withwith benzenebenzene ππ-- electronelectron cloud cloud,, TiO TiO22 photophoto--inducedinduced conduction conduction--bandband electrons electrons commonly commonly could could not not photoreduce photoreduce benzenebenzene C=C C=C bond, bond, because because of of its its extreme extreme inertness inertness against against the the reductive reductive transformation transformation of of the the benzenebenzene ring.ring. However,However, whenwhen C=CC=C bondbond isis conjugatedconjugated toto anotheranother polarpolar functionalfunctional grougroupp suchsuch asas C=OC=O

Molecules 2019, 24, 330 7 of 22 by this co-catalyst. This co-catalyst provided comparable catalytic possibility as platinum for this multi-electron transfer process of TiO2 photocatalyzed transfer hydrogenation. As an environmentally benign photocatalyst, TiO2 has little bio-toxicity and no secondary pollution. However, since TiO2 nanoparticle surface is extremely hydrated and possesses numerous polar Ti-OH groups, this material is extremely hydrophilic. Effectively adsorbing and converting non-polar and weak-polar functional group on TiO2 surface is very challenging. For hydrogenation of oleﬁns with only C=C oleﬁnic functional group, bare TiO2 photocatalyst without metal co-catalyst loading is generally considered to be futile. Although the benzene ring has weak adsorption interaction on polar TiO2 surface by the coordination of unoccupied Ti 3d orbital with benzene π-electron cloud, TiOMolecules2 photo-induced 2019, 24, x FOR conduction-bandPEER REVIEW electrons commonly could not photoreduce benzene C=C7 bond, of 21 because of its extreme inertness against the reductive transformation of the benzene ring. However, whenbond, C=Cthe polarity bond is and conjugated redox potential to another of polarC=C bond functional is increased group suchby a ascertain C=O bond,degree, the because polarity of andthe redoxconjugation potential and of induction C=C bond effect is increased of C=O bybond. a certain In this degree, way, the because 1,4-conjugate of the conjugation hydrogenations and induction of C=C effectbond ofby C=OTiO2bond. photocatalysis In this way, become the 1,4-conjugate possible if hydrogenationschemoselectivity of can C=C be bond successfully by TiO2 photocatalysiscontrolled. As becomeshown in possible Scheme if 7, chemoselectivity Walton et al. reported can be successfullythat under UV controlled. light excitation, As shown P25 in TiO Scheme2 could7, Waltoncatalyze et the al. reportedtransformation that under of maleimides UV light excitation,and maleic P25 anhydride TiO2 could to succinimides catalyze the transformationand succinic anhydride of maleimides using andmethanol maleic as anhydride a hydrogen to donor succinimides achieving and good succinic to excellent anhydride yields using (yields methanol ranging as afrom hydrogen 60% to donor 94%) achieving[82]. good to excellent yields (yields ranging from 60% to 94%) [82].

Scheme 7. P25-TiO2 photocatalyzed transfer hydrogenation of maleimides and maleic anhydride using Scheme 7. P25-TiO2 photocatalyzed transfer hydrogenation of maleimides and maleic anhydride ethanol as a hydrogen source. using ethanol as a hydrogen source. Compared with earlier work by Kubokawa [72] and Anpo [74,75], the main development in this Compared with earlier work by Kubokawa [72] and Anpo [74,75], the main development in this work was using alcohols instead of water vapor as hydrogen donors. This modification extremely work was using alcohols instead of water vapor as hydrogen donors. This modification extremely enhanced the yield of hydrogenated products and chemoselectivity. Moreover, pristine maleimide enhanced the yield of hydrogenated products and chemoselectivity. Moreover, pristine maleimide bearing NH group can be selectively converted to succinimide with NH group intact. Furthermore, bearing NH group can be selectively converted to succinimide with NH group intact. Furthermore, the authors expanded the substrate scope to N-aryl maleimide. Prolonged irradiation time was required the authors expanded the substrate scope to N-aryl maleimide. Prolonged irradiation time was and decreased isolated yield was obtained (9–79%). The key to the success of this transformation was required and decreased isolated yield was obtained (9–79%). The key to the success of this the appropriate choice of a suitable class of olefin, i.e. maleimides, which has C=O group conjugated transformation was the appropriate choice of a suitable class of olefin, i.e. maleimides, which has to C=C bond, leading to the non-polar olefinic bond’s diffusion, approaching and adsorption to TiO C=O group conjugated to C=C bond, leading to the non-polar olefinic bond’s diffusion, approaching2 surface catalytic sites much easier, which greatly promoted the hydrogen transfer process. Moreover, and adsorption to TiO2 surface catalytic sites much easier, which greatly promoted the hydrogen suitable choice of hydrogen donor and solvent was also pivotal for the success of this reaction. transfer process. Moreover, suitable choice of hydrogen donor and solvent was also pivotal for the Methanol hole-scavenger acted as the hydrogen donor, while the addition of acetonitrile decreased the success of this reaction. Methanol hole-scavenger acted as the hydrogen donor, while the addition of nucleophilicity of methanol, thus reduced the possibility of the ring-opening side-reaction caused by acetonitrile decreased the nucleophilicity of methanol, thus reduced the possibility of the ring- methanol and methoxide species’ nucleophilic attack. opening side-reaction caused by methanol and methoxide species’ nucleophilic attack. If C=C bond is not conjugated to C=O bond, its reduction becomes much more challenging due to If C=C bond is not conjugated to C=O bond, its reduction becomes much more challenging due the much-reduced redox potential [83,84]. Although pristine TiO2 photocatalyst could not initiate the to the much-reduced redox potential [83,84]. Although pristine TiO2 photocatalyst could not initiate reduction of styrene C=C bond, Pd-loaded TiO2 could realize this transformation achieving nearly the reduction of styrene C=C bond, Pd-loaded TiO2 could realize this transformation achieving nearly quantitative yield [83]. In this case, Pd-H species played a very significant role to reduce C=C bond, quantitative yield [83]. In this case, Pd-H species played a very significant role to reduce C=C bond, since it possessed strong reducing power. However, the functional group tolerability of this method since it possessed strong reducing power. However, the functional group tolerability of this method was not fully investigated. was not fully investigated. Although TiO2 photocatalysis has accumulated some success in the transfer hydrogenation of C=C olefinic bond in maleimides, maleic anhydride and styrene, the reaction and substrate scopes are still very limited. The expansion of this method to the world of complex pharmaceutical and natural products synthesis still has long way to go. In the chemical markets, there are many desirable products used as pharmaceuticals, drugs and agrochemicals such as imatinib, bortezomib and imidacloprid, which are often required to be synthesized from the selective hydrogenation of unsaturated carbocyclic or heterocyclic structures of available precursors. Thus, developing more general methodology especially adapted to inactivated alkenes with an easily-reducible functional group is urgently needed. Moreover, to achieve selectivity including chemo-, regio- and enantioselectivity is also the future direction for transfer hydrogenations of C=C and C≡C bonds via TiO2 photocatalysis. To realize these goals, modification and crystal engineering of TiO2 nanomaterials, hybridizing TiO2 with other nanomaterials and the synergistic use of different catalysis modes would provide possible solutions.

Molecules 2019, 24, 330 8 of 22

Although TiO2 photocatalysis has accumulated some success in the transfer hydrogenation of C=C oleﬁnic bond in maleimides, maleic anhydride and styrene, the reaction and substrate scopes are still very limited. The expansion of this method to the world of complex pharmaceutical and natural products synthesis still has long way to go. In the chemical markets, there are many desirable products used as pharmaceuticals, drugs and agrochemicals such as imatinib, bortezomib and imidacloprid, which are often required to be synthesized from the selective hydrogenation of unsaturated carbocyclic or heterocyclic structures of available precursors. Thus, developing more general methodology especially adapted to inactivated alkenes with an easily-reducible functional group is urgently needed. Moreover, to achieve selectivity including chemo-, regio- and enantioselectivity is also the future direction for transfer hydrogenations of C=C and C≡C bonds via TiO2 photocatalysis. To realize these goals, modiﬁcation and crystal engineering of TiO2 nanomaterials, hybridizing TiO2 with other nanomaterials and the synergistic use of different catalysis modes would provide possible solutions.

3. Transfer Hydrogenation of C=O and C=N Bonds Transfer hydrogenations of C=O bonds are extremely important since a variety of pharmaceuticals, agrochemicals and natural products are required to possess the bioactive asymmetric C-OH center, which can be conveniently prepared from the enantioselective reduction of the corresponding carbonyl compounds. Compared with transfer hydrogenations of C=C and C≡C bonds, TiO2 photocatalyzed transfer hydrogenations of C=O bonds have garnered more successes. The reason lies in that the hydrophilic TiO2 surface could effectively adsorb polar organic compounds by hydrogen bonds and coordination interaction of C=O lone-pair electrons with Ti 3d empty orbitals. In this way, polar C=O bonds could be facilely converted to C-OH bonds by interfacial electron/proton transfer, hydride transfer or hydrogen atom transfer delivered by HDC such as methanol, ethanol, i-propanol or triethylamine on TiO2 nanoparticle surface. Kohtani’s group has conducted a series of excellent work on TiO2 photocatalytic transfer hydrogenations of aryl carbonyl compounds using alcohols as hydrogen donors [55,85–90]. In their most recent work, even moderate enantioselectivity for aryl ketones’ conversion to chiral secondary aryl alcohols was realized (as shown in Scheme8)[ 56]. Although previous work of König’s group had proved that the combination of TiO2 photocatalysis and imine organocatalysis could facilitate the asymmetric aliphatic aldehyde α-alkylation using α-bromomalonate as alkylating reagent [52], Kohtani’s discovery was the pioneering work in realizing heterogeneous asymmetric photocatalysis by fabricating a chiral TiO2 surface and directly deploying this surface for the asymmetric induction. In König’s work, TiO2 photocatalyst only acted as photo-redox catalyst without participating in chiral control [52]. However, Kohtani et al. accomplished the preparation of chiral TiO2 surface and applied this chiral surface for enantioselective control [56]. By adsorbing the chiral R-mandelic acid on TiO2 nanoparticle surface, the semiconductor surface became discriminative in transfer hydrogenation of acetophenone. This asymmetric transformation was furnished with 33% ee value. Although this ee value was not ideal, it demonstrated the possibility of fabricating asymmetric active sites on the TiO2 surface by adsorbing appropriate chiral molecules [52,56,91,92]. In this way, the asymmetric catalytic sites would impose the inﬂuence on transfer hydrogenations by providing sterically differentiated environment for ketone substrate to access these sites. Namely, the direction of attack from both photo-induced holes and electrons was of asymmetry. Molecules 2019, 24, x FOR PEER REVIEW 8 of 21

3. Transfer Hydrogenation of C=O and C=N Bonds Transfer hydrogenations of C=O bonds are extremely important since a variety of pharmaceuticals, agrochemicals and natural products are required to possess the bioactive asymmetric C-OH center, which can be conveniently prepared from the enantioselective reduction of the corresponding carbonyl compounds. Compared with transfer hydrogenations of C=C and CC bonds, TiO2 photocatalyzed transfer hydrogenations of C=O bonds have garnered more successes. The reason lies in that the hydrophilic TiO2 surface could effectively adsorb polar organic compounds by hydrogen bonds and coordination interaction of C=O lone-pair electrons with Ti 3d empty orbitals. In this way, polar C=O bonds could be facilely converted to C-OH bonds by interfacial electron/proton transfer, hydride transfer or hydrogen atom transfer delivered by HDC such as methanol, ethanol, i-propanol or triethylamine on TiO2 nanoparticle surface. Kohtani’s group has conducted a series of excellent work on TiO2 photocatalytic transfer hydrogenations of aryl carbonyl compounds using alcohols as hydrogen donors [55,85–90]. In their most recent work, even moderate enantioselectivity for aryl ketones’ conversion to chiral secondary aryl alcohols was realized (as shown in Scheme 8) [56]. Although previous work of König’s group had proved that the combination of TiO2 photocatalysis and imine organocatalysis could facilitate the asymmetric aliphatic aldehyde α-alkylation using α-bromomalonate as alkylating reagent [52], Kohtani’s discovery was the pioneering work in realizing heterogeneous asymmetric photocatalysis by fabricating a chiral TiO2 surface and directly deploying this surface for the asymmetric induction. In König’s work, TiO2 photocatalyst only acted as photo-redox catalyst without participating in chiral Moleculescontrol 2019[52],.24 However,, 330 Kohtani et al. accomplished the preparation of chiral TiO2 surface and applied9 of 22 this chiral surface for enantioselective control [56].

Scheme 8. (Top): Chiral reagents modiﬁed-TiO2 photocatalyzed enantioselective transfer hydrogenationScheme 8. (Top of) acetophenone.: Chiral reagents (Bottom modified): Proposed-TiO2 photocatalyzed models for (left enantioselective) bidentate and transfer (right) mono-dentatehydrogenation adsorption of acetophenone. of (R)-mandelic (Bottom acid): Proposed (MA) and models interaction for ( betweenleft) bidentate aromatic and ketone (right and) mono MA- dentate adsorption of (R)-mandelic acid (MA) and interaction between aromatic ketone and MA on on the TiO2 surface. the TiO2 surface. In their earlier work, Kohtani et al. developed the transfer hydrogenation of aryl ketones and Molecules 2019, 24, x FOR PEER REVIEW 9 of 21 aldehydesBy adsorbing to aryl secondary the chiral andR-mandelic primary acid alcohols. on TiO In2 nanoparticle 2010, this group surface, initially the semiconductor reported the transfer surface became discriminative in transfer hydrogenation of acetophenone. This asymmetric transformation hydrogenationhydrogenation of ketones ketones by by TiO TiO22 photocatalysisphotocatalysis using using ethanol ethanol as as a ahydrogen hydrogen donor donor (as (as shown shown in was furnished with 33% ee value. Although this ee value was not ideal, it demonstrated the possibility inScheme Scheme 9).9 Using). Using ethanol ethanol or methanol or methanol as a ashydrogen a hydrogen donor donor is very is veryadvantageous, advantageous, since sincethese theseshort- of fabricating asymmetric active sites on the TiO2 surface by adsorbing appropriate chiral molecules short-chainchain molecules molecules are volatile are volatile and easy and to easy be separated to be separated from the from mixture the mixtureof the pr ofoduct the productby rotatory by [52,56,91,92]. In this way, the asymmetric catalytic sites would impose the influence on transfer rotatoryevaporation. evaporation. hydrogenations by providing sterically differentiated environment for ketone substrate to access these sites. Namely, the direction of attack from both photo-induced holes and electrons was of asymmetry. In their earlier work, Kohtani et al. developed the transfer hydrogenation of aryl ketones and aldehydes to aryl secondary and primary alcohols. In 2010, this group initially reported the transfer

Scheme 9. TiO22 photocatalyzed transfer hydrogenation of acetophenone derivatives.

Using commercial DegussaDegussa P25P25 TiOTiO22 as photocatalyst underunder >340>340 nm irradiation, benzaldehyde and several acetophenone derivativesderivatives were transformed into the corresponding alcohols with good yields,yields, respectivelyrespectively [[85]85].. Aryl carbonyl compounds with less stericsteric hindrancehindrance werewere hydrogenatedhydrogenated preferentially.preferentially. For For instance, tert tert-butyl-butyl and isoiso-propyl-propyl phenyl ketones were reduced much more sluggishly and and provided provided poorest poorest yields yields (7% and (7% 25%) and in prolonged 25%) in prolonged time compared time with compared unsubstituted with benzaldehydeunsubstituted benzaldehyde and acetophenone. and acetophenone. Moreover,this Moreover, method this could method be extended could be to extended a variety to of a acetophenonesvariety of acetophenones with electron-donating with electron and-donating electron-withdrawing and electron-withdrawing groups on phenylgroups ring on phenyl resulting ring in goodresulting to excellent in good yield.to excellent Besides, yield. bicyclic Besides, aryl ketonesbicyclic 2-acetonaphthalonearyl ketones 2-acetona couldphthalone also be reducedcould also with be thisreduced method with using this eithermethod ethanol using oreither i-propanol ethanol as or HDC. i-propanol However, as HDC. this method However, could this not method be extended could tonot aliphatic be extended ketones. to Cyclohexanone aliphatic ketones. did Cyclohexanone not convert at all did in this not photocatalytic convert at all system, in this due photocatalytic to its much greatersystem, electrondue to its density much andgreater much electro lowern density redox potential. and much For lower diaryl redox ketone potential. and aryl For cyclic diaryl aliphatic ketone ketone,and aryl this cyclic method aliphatic was ketone, proved this to be method valid providingwas proved yields to be ranging valid providing from 78% yields to >99%. ranging Later from on, insightful78% to >99%. mechanistic Later on, studies insightful for this mechanistic transformation studies were for conducted.this transformation The different were reduction conducted. modes The ofdifferent acetophenone reduction and modes2,2,2-triﬂuoroacetophenone of acetophenone and were 2,2,2 unveiled-trifluoroacetophenone by systematic kinetic were and unveiled adsorption by studiessystematic [86, 87kinetic]. Although and adsorption 2,2,2-triﬂuoroacetophenone studies [86,87]. Although possessed 2,2,2 higher-trifluoroacetophenone redox potential, its possessed reduction higher redox potential, its reduction was slower than acetophenone. This phenomenon mainly originated from the ketone-hemiketal-ketal equilibrium. The rate-determining-step of the reduction was the hemiketal-ketone tautomerization. Only ketone form could be adsorbed on TiO2 surface by C=O lone-pair electrons with Ti 3d empty orbital. In 2,2,2-trifluoroacetophenone, the hemiketal and ketal are the major species, while for acetophenone, the ketone form is the major species. This subtle difference was uncovered and exploited to design more efficient transfer hydrogenation catalyst systems. Apart from UV-light excited transfer hydrogenation of ketones, visible-light could also be applied for hydrogenation of aryl ketones to secondary aryl alcohols. For example, Kohtani et al. reported that fluorescein and rhodamine B dye-sensitized TiO2 semiconductor photocatalyst could mediate the transfer hydrogenations of acetophenones and fluoro-substituted acetophenone derivatives under visible-light irradiation (as shown in Scheme 10) [55]. Initially, the dye molecules were anchored on the surface of TiO2 nanoparticles through carboxylate or phenolic linking groups. These adsorbed dye molecules were excited by the visible-light irradiation and the excited-state electrons on dye LUMO were injected into TiO2 conduction band. These electrons on TiO2 conduction band reduced acetophenones C=O group coupled with protons, while triethylamine substrates were oxidized by the ground state dye radical cations to continuously supply protons and electrons. Furthermore, the efficiency of this visible-light-sensitized protocol was greatly increased by the introduction of more absorptive dyes. A series of pristine and thiophene-modified coumarin derivatives were chosen as the photosensitizers for visible-light driven TiO2 photocatalytic transformation of acetophenone to 1-phenyl-ethanol [88]. The irradiation time to reach the same conversion was greatly shortened compared with the previous dye-sensitized system when appropriate hydrogen donor was chosen. Moreover, the author studied the kinetics of this

Molecules 2019, 24, 330 10 of 22 was slower than acetophenone. This phenomenon mainly originated from the ketone-hemiketal-ketal equilibrium. The rate-determining-step of the reduction was the hemiketal-ketone tautomerization. Only ketone form could be adsorbed on TiO2 surface by C=O lone-pair electrons with Ti 3d empty orbital. In 2,2,2-trifluoroacetophenone, the hemiketal and ketal are the major species, while for acetophenone, the ketone form is the major species. This subtle difference was uncovered and exploited to design more efficient transfer hydrogenation catalyst systems. Apart from UV-light excited transfer hydrogenation of ketones, visible-light could also be applied for hydrogenation of aryl ketones to secondary aryl alcohols. For example, Kohtani et al. reported that fluorescein and rhodamine B dye-sensitized TiO2 semiconductor photocatalyst could mediate the transfer hydrogenations of acetophenones and fluoro-substituted acetophenone derivatives under visible-light irradiation (as shown in Scheme 10)[55]. Initially, the dye molecules were anchored on the surface of TiO2 nanoparticles through carboxylate or phenolic linking groups. These adsorbed dye molecules were excited by the visible-light irradiation and the excited-state electrons on dye LUMO were injected into TiO2 conduction band. These electrons on TiO2 conduction band reduced acetophenones C=O group coupled with protons, while triethylamine substrates were oxidized by the ground state dye radical cations to continuously supply protons and electrons. Furthermore, the efficiency of this visible-light-sensitized protocol was greatly increased by the introduction of more absorptive dyes. A series of pristine and thiophene-modified coumarin derivatives were chosen as the photosensitizers for visible-light driven TiO2 photocatalytic transformation of acetophenone to 1-phenyl-ethanol [88]. The irradiation time to reach the same conversion was greatly shortened compared with the previous dye-sensitized system when appropriate hydrogenMolecules 2019 donor, 24, x FOR was PEER chosen. REVIEW Moreover, the author studied the kinetics of this transformation10 of in21 detail [87]. Seven acetophenone derivatives were systematically investigated for this reductive transformation in detail [87]. Seven acetophenone derivatives were systematically investigated for transformation. Their redox potential, adsorptive energy on TiO2 surface and electron transfer efficiencythis reductive were transformation. compared. From Their these redox experimental potential, adsorptive and theoretical energy results, on TiO a plausible2 surface and mechanism electron transfer efficiency were compared. From these experimental and theoretical results, a plausible was proposed. The Ti defect sites of TiO2 photocatalyst acted both as the adsorption and the electronmechanism transfer was proposed. sites. The reactionThe Ti defect rate and sites yield of TiO were2 photocatalyst mainly determined acted both by theas the redox adsorption potential and of acetophenones,the electron transfer as well sites. as The the adsorptionreaction rate interaction. and yield were Furthermore, mainly determined the same groupby the discoveredredox potential that of acetophenones, as well as the adsorption interaction. Furthermore, the same group discovered that 2-fluoroacetophenone showed different product distribution in the TiO2 photocatalyzed transfer hydrogenation2-fluoroacetophenone with fluoro-substituted showed different productacetophenones distribution in spite in the of TiOtheir2 photocatalyzed similar structures transfer [89]. 2-fluoroacetophenonehydrogenation with fluoro provided-substituted defluorinated acetophenones acetophenone, in spite whileof their 2,2,2-trifluoroacetophenone similar structures [89]. 2- yieldedfluoroacetophenone 2,2,2-trifluoro-1-phenylethanol provided defluorinat and 2,2-difluoroacetophenoneed acetophenone, while formed 2,2,2- bothtrifluoroacetophenone the defluorinated andyielded the hydrogenated2,2,2-trifluoro- products.1-phenylethanol To explain and this2,2-difluoroacetophenone phenomenon, the plotting formed of the both reaction the defluorinated rate versus theand redox the hydrogenated potential of differentproducts. fluorinated To explain acetophenonesthis phenomenon, was the conducted. plotting of The the experimental reaction rate resultsversus showedthe redox that potential the redox of different potential fluorinated of fluorinated acetophenones acetophenone was determined conducted. the The chemoselectivity experimental results of this transfershowed reduction.that the redox The potential chemoselective of fluorinated transfer acetophenone hydrogenation determined of ketones the and chemoselectivity aldehydes to alcohols of this providedtransfer reduction. feasible functional The chemoselective group interconversion transfer hydrogenation and the derivatization of ketones methods and aldehydes of pharmaceutically to alcohols interestingprovided molecules. feasible functional group interconversion and the derivatization methods of pharmaceutically interesting molecules.

Scheme 10. Dye-sensitized-TiO2 photocatalyzed transfer hydrogenation of acetophenones under Scheme 10. Dye-sensitized-TiO2 photocatalyzed transfer hydrogenation of acetophenones under visible-light irradiation. visible-light irradiation.

Aldehydes could also be directly transformed to primary alcohols by TiO2 photocatalyzed transfer hydrogenation [93]. Li et al. reported that in the presence of HDC such as ethanol or i- propanol, both aromatic aldehydes and aliphatic aldehydes could be reduced to the corresponding primary alcohols in a TiO2 suspending solution under near-UV irradiation (as shown in Scheme 11) [93]. By the comparison of the isotope tracing experiments results and kinetics curve analysis of different functionalized benzaldehyde derivatives, they demonstrated that this reaction proceeded through a stepwise SET (single electron transfer) mechanism accompanied with simultaneous protonation other than direct hydrogen atom transfer pathway. Besides alcohols, oxidable amines are also excellent hole-scavenger and hydrogen source for some dye-modified TiO2 photocatalytic system with lower redox potential and oxidability, since amines are usually easier to donate electron than alcohols.

Scheme 11. TiO2 photocatalyzed transfer hydrogenation of benzaldehyde.

Not only carbonyl C=O could be effectively reduced to the corresponding C-OH bonds, but imine C=N bonds could also be photohydrogenated by TiO2 photocatalyst. Ohtani et al. reported that under UV irradiation in a Pt-TiO2 suspending solution, N-benzylidenebenzylamine and N- benzylideneaniline could be hydrogenated to the corresponding secondary amine dibenzylamine and N-benzylaniline with the simultaneous photo-oxidation of 2-propanol by TiO2 photo-induced hole, respectively, in high selectivity and yield (as shown in Scheme 12) [60].

Molecules 2019, 24, x FOR PEER REVIEW 10 of 21

transformation in detail [87]. Seven acetophenone derivatives were systematically investigated for this reductive transformation. Their redox potential, adsorptive energy on TiO2 surface and electron transfer efficiency were compared. From these experimental and theoretical results, a plausible mechanism was proposed. The Ti defect sites of TiO2 photocatalyst acted both as the adsorption and the electron transfer sites. The reaction rate and yield were mainly determined by the redox potential of acetophenones, as well as the adsorption interaction. Furthermore, the same group discovered that 2-fluoroacetophenone showed different product distribution in the TiO2 photocatalyzed transfer hydrogenation with fluoro-substituted acetophenones in spite of their similar structures [89]. 2- fluoroacetophenone provided defluorinated acetophenone, while 2,2,2-trifluoroacetophenone yielded 2,2,2-trifluoro-1-phenylethanol and 2,2-difluoroacetophenone formed both the defluorinated and the hydrogenated products. To explain this phenomenon, the plotting of the reaction rate versus the redox potential of different fluorinated acetophenones was conducted. The experimental results showed that the redox potential of fluorinated acetophenone determined the chemoselectivity of this transfer reduction. The chemoselective transfer hydrogenation of ketones and aldehydes to alcohols provided feasible functional group interconversion and the derivatization methods of pharmaceutically interesting molecules.

Scheme 10. Dye-sensitized-TiO2 photocatalyzed transfer hydrogenation of acetophenones under Molecules 2019, 24, 330 11 of 22 visible-light irradiation.

Aldehydes could also be directly transformed to primary alcohols by TiO2 photocatalyzed Aldehydes could also be directly transformed to primary alcohols by TiO2 photocatalyzed transfer hydrogenationtransfer hydrogenation [93]. Li et[93] al.. Li reported et al. reported that in the that presence in the presence of HDC such of HDC as ethanol such as or ethanol i-propanol, or i- bothpropanol, aromatic both aldehydes aromatic aldehydes and aliphatic and aldehydesaliphatic aldehydes could be reducedcould be toreduced the corresponding to the corresponding primary primary alcohols in a TiO2 suspending solution under near-UV irradiation (as shown in Scheme 11) alcohols in a TiO2 suspending solution under near-UV irradiation (as shown in Scheme 11)[93]. By[93] the. By comparison the comparison of the isotopeof the isotope tracing tracing experiments experiments results and results kinetics and curve kinetics analysis curve of analysis different of functionalizeddifferent functionalized benzaldehyde benzaldehyde derivatives, derivatives, they demonstrated they demonstrated that this that reaction this proceededreaction proceeded through athrough stepwise a SET stepwise (single SET electron (single transfer) electron mechanism transfer) mechanism accompanied accompanied with simultaneous with simultaneous protonation otherprotonation than direct other hydrogen than direct atom hydrogen transfer atom pathway. transfer Besides pathway. alcohols, Besides oxidable alcohols, amines oxidable are also amines excellent are also excellent hole-scavenger and hydrogen source for some dye-modified TiO2 photocatalytic hole-scavenger and hydrogen source for some dye-modiﬁed TiO2 photocatalytic system with lower redoxsystem potential with low ander redox oxidability, potential since and amines oxidability, are usually since easieramines to are donate usually electron easier than to donate alcohols. electron than alcohols.

Scheme 11. TiO2 photocatalyzed transfer hydrogenation of benzaldehyde. Scheme 11. TiO2 photocatalyzed transfer hydrogenation of benzaldehyde. Not only carbonyl C=O could be effectively reduced to the corresponding C-OH bonds, but imine Not only carbonyl C=O could be effectively reduced to the corresponding C-OH bonds, but C=N bonds could also be photohydrogenated by TiO2 photocatalyst. Ohtani et al. reported that under imine C=N bonds could also be photohydrogenated by TiO2 photocatalyst. Ohtani et al. reported that UV irradiation in a Pt-TiO2 suspending solution, N-benzylidenebenzylamine and N-benzylideneaniline under UV irradiation in a Pt-TiO2 suspending solution, N-benzylidenebenzylamine and N- could be hydrogenated to the corresponding secondary amine dibenzylamine and N-benzylaniline benzylideneaniline could be hydrogenated to the corresponding secondary amine dibenzylamine with the simultaneous photo-oxidation of 2-propanol by TiO2 photo-induced hole, respectively, in high and N-benzylaniline with the simultaneous photo-oxidation of 2-propanol by TiO2 photo-induced selectivityMolecules 2019 and, 24,yield x FOR (asPEER shown REVIEW in Scheme 12)[60]. 11 of 21 hole, respectively, in high selectivity and yield (as shown in Scheme 12) [60].

Scheme 12. TiO2 photocatalyzed transfer hydrogenation of Schiff bases. Scheme 12. TiO2 photocatalyzed transfer hydrogenation of Schiff bases. This transfer photo-hydrogenation occurred in a stepwise SET followed by protonation pathway This transfer photo-hydrogenation occurred in a stepwise SET followed by protonation pathway the same as the previous Li’s example for benzaldehydes. They discussed the influence of Pt-loading, the same as the previous Li’s example for benzaldehydes. They discussed the influence of Pt-loading, the addition of desiccating reagents, acid and the preparation condition of the photocatalysts to the addition of desiccating reagents, acid and the preparation condition of the photocatalysts to the the overall selectivity and yield. An earlier report by Kagiya et al. demonstrated that both the overall selectivity and yield. An earlier report by Kagiya et al. demonstrated that both the symmetrical, unsymmetrical secondary and the tertiary amine could be synthesized by the Pt-TiO2 symmetrical, unsymmetrical secondary and the tertiary amine could be synthesized by the Pt-TiO2 photocatalyzed transfer hydrogenations of in-situ formed imine intermediate which were generated photocatalyzed transfer hydrogenations of in-situ formed imine intermediate which were generated from the condensation of primary amines and alcohols [94–96]. Apart from aldehyde and dihydrogen, from the condensation of primary amines and alcohols [94–96]. Apart from aldehyde and no other by-products were formed. With the introduction of an alcoholic solvent, unsymmetrical dihydrogen, no other by-products were formed. With the introduction of an alcoholic solvent, secondary and tertiary amines were synthesized from Pt-TiO2 photocatalyzed hydrogenation of unsymmetrical secondary and tertiary amines were synthesized from Pt-TiO2 photocatalyzed imines. In this case, imines were generated from the condensation of primary amines and aldehydes, hydrogenation of imines. In this case, imines were generated from the condensation of primary which were formed through oxidation of the alcohol solvent by photo-induced holes [94]. Moreover, amines and aldehydes, which were formed through oxidation of the alcohol solvent by photo- Ohtani et al. reported that α,ω-diamino carboxylic acids could be transformed to five- or six-membered induced holes [94]. Moreover, Ohtani et al. reported that α,ω-diamino carboxylic acids could be cyclic imino acids via Pt-TiO2 photocatalysis [95]. They described that α,ω-diamino carboxylic acids transformed to five- or six-membered cyclic imino acids via Pt-TiO2 photocatalysis [95]. They were initially oxidized by photo-induced holes to the corresponding α-keto acid or ω-aldehyde described that α,ω-diamino carboxylic acids were initially oxidized by photo-induced holes to the intermediates bearing carbonyl and amino groups. Condensation between carbonyl and amino groups corresponding α-keto acid or ω-aldehyde intermediates bearing carbonyl and amino groups. generated the cyclic imine intermediate. The following reduction by conduction band electrons in Condensation between carbonyl and amino groups generated the cyclic imine intermediate. The Pt-TiO2 along with protonation provided the final cyclic imino acid products. Pt-loaded TiO2 particles following reduction by conduction band electrons in Pt-TiO2 along with protonation provided the played two pivotal roles in these C=N transfer hydrogenations. The first was to act as proton reduction final cyclic imino acid products. Pt-loaded TiO2 particles played two pivotal roles in these C=N site to generate dihydrogen. The second was the hydrogenation site to help the dihydrogen molecule transfer hydrogenations. The first was to act as proton reduction site to generate dihydrogen. The reduce C=N bond to amino compounds. second was the hydrogenation site to help the dihydrogen molecule reduce C=N bond to amino When polar C=O was conjugated to non-polar C=C bond, Au/TiO or Pt/TiO could act as compounds. 2 2 chemoselective photocatalyst to reduce C=O bond to C-OH with C=C bond intact. Li et al. reported When polar C=O was conjugated to non-polar C=C bond, Au/TiO2 or Pt/TiO2 could act as chemoselective photocatalyst to reduce C=O bond to C-OH with C=C bond intact. Li et al. reported that under 365 nm UV irradiation, Pt/TiO2 photocatalyst provided excellent performance with record high apparent quantum yield (AQE) for photocatalytically selective reduction of cinnamaldehyde to cinnamyl alcohol (as shown in Scheme 13) [57]. Besides, Au/TiO2 also achieved satisfactory selectivity at high conversion under visible-light irradiation (> 420 nm).

Scheme 13. Au/Pt-TiO2 photocatalyzed transfer hydrogenation of cinnamaldehyde to cinnamyl alcohol.

They postulated a six-membered transition-state model to illustrate this chemoselectivity. Under UV or visible-light irradiation, TiO2 photo-induced holes oxidize the electron and hydrogen donor i-

Molecules 2019, 24, x FOR PEER REVIEW 11 of 21

Scheme 12. TiO2 photocatalyzed transfer hydrogenation of Schiff bases.

This transfer photo-hydrogenation occurred in a stepwise SET followed by protonation pathway the same as the previous Li’s example for benzaldehydes. They discussed the influence of Pt-loading, the addition of desiccating reagents, acid and the preparation condition of the photocatalysts to the overall selectivity and yield. An earlier report by Kagiya et al. demonstrated that both the symmetrical, unsymmetrical secondary and the tertiary amine could be synthesized by the Pt-TiO2 photocatalyzed transfer hydrogenations of in-situ formed imine intermediate which were generated from the condensation of primary amines and alcohols [94–96]. Apart from aldehyde and dihydrogen, no other by-products were formed. With the introduction of an alcoholic solvent, unsymmetrical secondary and tertiary amines were synthesized from Pt-TiO2 photocatalyzed hydrogenation of imines. In this case, imines were generated from the condensation of primary amines and aldehydes, which were formed through oxidation of the alcohol solvent by photo- induced holes [94]. Moreover, Ohtani et al. reported that α,ω-diamino carboxylic acids could be transformed to five- or six-membered cyclic imino acids via Pt-TiO2 photocatalysis [95]. They described that α,ω-diamino carboxylic acids were initially oxidized by photo-induced holes to the corresponding α-keto acid or ω-aldehyde intermediates bearing carbonyl and amino groups. Condensation between carbonyl and amino groups generated the cyclic imine intermediate. The following reduction by conduction band electrons in Pt-TiO2 along with protonation provided the final cyclic imino acid products. Pt-loaded TiO2 particles played two pivotal roles in these C=N transfer hydrogenations. The first was to act as proton reduction site to generate dihydrogen. The second was the hydrogenation site to help the dihydrogen molecule reduce C=N bond to amino Moleculescompounds.2019, 24 , 330 12 of 22 When polar C=O was conjugated to non-polar C=C bond, Au/TiO2 or Pt/TiO2 could act as chemoselective photocatalyst to reduce C=O bond to C-OH with C=C bond intact. Li et al. reported that under 365 nm UV irradiation, Pt/TiO2 photocatalyst provided excellent performance with record highthat under apparent 365 quantumnm UV irradiation, yield (AQE) Pt/TiO for photocatalytically2 photocatalyst prov selectiveided excellent reduction performance of cinnamaldehyde with record to high apparent quantum yield (AQE) for photocatalytically selective reduction of cinnamaldehyde to cinnamyl alcohol (as shown in Scheme 13)[57]. Besides, Au/TiO2 also achieved satisfactory selectivity atcinnamyl high conversion alcohol (as under shown visible-light in Scheme irradiation 13) [57]. Besides, (> 420 Au/TiO nm). 2 also achieved satisfactory selectivity at high conversion under visible-light irradiation (> 420 nm).

Scheme 13. Scheme 13. Au/PtAu/Pt-TiO-TiO2 ph2otocatalyzedphotocatalyzed transfer transfer hydrogenation hydrogenation of cinnamaldehyde of cinnamaldehyde to cinnamyl to cinnamylalcohol. alcohol.

They postulated a six-membered transition-state model to illustrate this chemoselectivity. They postulated a six-membered transition-state model to illustrate this chemoselectivity. Under Under UV or visible-light irradiation, TiO2 photo-induced holes oxidize the electron and hydrogen UV or visible-light irradiation, TiO2 photo-induced holes oxidize the electron and hydrogen donor i- donor i-propanol yielding active hydrogen species on metal particles. The C=O group adsorbed on

TiO2 surface and occupied the vicinal position to the metallic nanoparticle which adsorbed hydrogen. This vicinity facilitates the hydrogen transfer from metal to C=O group on TiO2 surface. Once alcohol is adsorbed on the TiO2 surface by hydrogen bonds, the photo-induced holes migrate to TiO2 surface and then oxidize these adsorbed alcohol molecules to generate protons and aldehyde product. The protons combine with TiO2 photo-induced electron on Au and Pt anchoring sites yielding hydrogen atoms or dihydrogen. These active hydrogen species generated by Au or Pt nanoparticle will reduce C=O bonds. Moreover, this article also indicated that alcohol oxidation and the simultaneous carbonyl reduction both occurred at the Au- or Pt-adsorbed TiO2 site. Apart from plasmonic metal-loaded TiO2 nanoparticles photocatalyst systems for chemoselective C=O reduction over thermodynamically more favorable C=C reduction [87], organic molecules-modified TiO2 nanoparticles could also solve this chemoselectivity issue. Dihydroxynaphthalene chelated TiO2 nanoparticles behaved as efficient photocatalyst for visible-light induced transfer hydrogenation reduction of benzaldehydes to the corresponding benzyl alcohols with the maintaining of easily-reducible functional group kept intact [97]. By a simple impregnation procedure, the as-synthesized dihyroxynaphthalene-modified TiO2 nanoparticles promoted the transfer hydrogenation of a variety of benzaldehydes with chloro, bromo, iodo, acetyl and cyano groups kept intact [97]. This high selectivity originated from attenuated reducing power of dye-sensitized conduction-band electrons compared with direct UV-light induced conduction-band electron. Using TiO2 and modified TiO2 nanomaterials, a series of compounds with C=O and C=N bonds could be photohydrogenated to the corresponding saturated alcohols and amines products, respectively. In this way, TiO2 photocatalysis provides one of the most important means for reductive transformation of polar unsaturated compounds to the corresponding saturated ones using short-chain alcohols or amines as hydrogen sources. This method could be applied in the production of alcohols and amines molecules, which are often very important products, key intermediates and candidates for drugs, agrochemicals, flavors and fragrances. The most economically interesting products such as chiral Molecules 2019, 24, x FOR PEER REVIEW 12 of 21

propanol yielding active hydrogen species on metal particles. The C=O group adsorbed on TiO2 surface and occupied the vicinal position to the metallic nanoparticle which adsorbed hydrogen. This vicinity facilitates the hydrogen transfer from metal to C=O group on TiO2 surface. Once alcohol is adsorbed on the TiO2 surface by hydrogen bonds, the photo-induced holes migrate to TiO2 surface and then oxidize these adsorbed alcohol molecules to generate protons and aldehyde product. The protons combine with TiO2 photo-induced electron on Au and Pt anchoring sites yielding hydrogen atoms or dihydrogen. These active hydrogen species generated by Au or Pt nanoparticle will reduce C=O bonds. Moreover, this article also indicated that alcohol oxidation and the simultaneous carbonyl reduction both occurred at the Au- or Pt-adsorbed TiO2 site. Apart from plasmonic metal-loaded TiO2 nanoparticles photocatalyst systems for chemoselective C=O reduction over thermodynamically more favorable C=C reduction [87], organic molecules-modified TiO2 nanoparticles could also solve this chemoselectivity issue. Dihydroxynaphthalene chelated TiO2 nanoparticles behaved as efficient photocatalyst for visible- light induced transfer hydrogenation reduction of benzaldehydes to the corresponding benzyl alcohols with the maintaining of easily-reducible functional group kept intact [97]. By a simple impregnation procedure, the as-synthesized dihyroxynaphthalene-modified TiO2 nanoparticles promoted the transfer hydrogenation of a variety of benzaldehydes with chloro, bromo, iodo, acetyl and cyano groups kept intact [97]. This high selectivity originated from attenuated reducing power of dye-sensitized conduction-band electrons compared with direct UV-light induced conduction- band electron. Using TiO2 and modified TiO2 nanomaterials, a series of compounds with C=O and C=N bonds could be photohydrogenated to the corresponding saturated alcohols and amines products, respectively. In this way, TiO2 photocatalysis provides one of the most important means for reductive transformation of polar unsaturated compounds to the corresponding saturated ones using short- chain alcohols or amines as hydrogen sources. This method could be applied in the production of Moleculesalcohols2019 and, 24 , amines 330 molecules, which are often very important products, key intermediates13 of and 22 candidates for drugs, agrochemicals, flavors and fragrances. The most economically interesting products such as chiral drugs with saturated heterocyclic structures could be synthesized by this drugs with saturated heterocyclic structures could be synthesized by this prospective methodology. prospective methodology. TiO2 photocatalyzed transfer hydrogenation strategies to reduce C=O and TiOC=N2 photocatalyzedbonds with other transfer sensitive hydrogenation and bio-active strategies groups tokept reduce intact C=O has andthe potential C=N bonds to enlarge with other the sensitivesynthetic and toolbox bio-active of building groups kept complex intact molecule, has the potential shorten to synthesis enlarge the steps synthetic and maximize toolbox of economic building complexbenefit. molecule, shorten synthesis steps and maximize economic benefit. 4. Transfer Hydrogenation of N=O Bonds 4. Transfer Hydrogenation of N=O Bonds The amino group plays pivotal role in many important drug molecules and agrochemicals [98]. The amino group plays pivotal role in many important drug molecules and agrochemicals [98]. The most convenient method to prepare the amino groups is the selective reduction of nitro groups. The most convenient method to prepare the amino groups is the selective reduction of nitro groups. However, this transformation is challenging due to the difficulty in controlling selectivity [99]. However, this transformation is challenging due to the difficulty in controlling selectivity [99]. Common reductant such as NaBH4 or LiAlH4 often leads to the mixture of nitroso, amino, azo, Common reductant such as NaBH4 or LiAlH4 often leads to the mixture of nitroso, amino, azo, azoxy azoxy and hydrazine products which are often difficult to separate requiring time-consuming column and hydrazine products which are often difficult to separate requiring time-consuming column chromatographic operations. Generally, thermocatalytic transformations of nitro to the amino group chromatographic operations. Generally, thermocatalytic transformations of nitro to the amino group often require noble metal catalysts Pd and explosive dangerous gaseous H2 [100]. To meet the demand often require noble metal catalysts Pd and explosive dangerous gaseous H2 [100]. To meet the and principle of green chemistry, TiO2 semiconductor photocatalysis provided a very promising demand and principle of green chemistry, TiO2 semiconductor photocatalysis provided a very means of nitro to amino compounds based on transfer hydrogenation mechanism (as shown in promising means of nitro to amino compounds based on transfer hydrogenation mechanism (as Scheme 14)[101]. shown in Scheme 14) [101].

Molecules 2019, 24, x FOR PEER REVIEW 13 of 21

Scheme 14. TiO2 photocatalyzed transfer hydrogenation of nitrobenzenes using alcohol as a hydrogenScheme 14. source. TiO2 photocatalyzed transfer hydrogenation of nitrobenzenes using alcohol as a hydrogen source. As early as 1993, Li et al. discovered that when TiO2 nanoparticles suspended in an ethanol solution,As early nitrobenzenes as 1993, Li could et al. be discovered transformed that into when the TiO corresponding2 nanoparticles amino suspended compounds in an in ethanol good isolatedsolution, yields nitrobenzenes under UV couldirradiation be transformed [102]. The high into efficiency the corresponding and selectivity amino was compounds thermodynamically in good controlledisolated yields by the difference under UV of reduction irradiation potential [102]. between The high nitro compounds efficiency and and TiO select2 conductionivity was bandthermodynamically electrons. The conductioncontrolled by band the difference potentialof of TiOreduction2 (−0.85 potential V versus between SCE) in nitro acetonitrile, compounds is more and negativeTiO2 conduction than p–nitroacetophenone band electrons. The (–0.1 conduction V versus SCE). band potential of TiO2 (−0.85 V versus SCE) in acetonitrile,Brezová iset more al. negative systematically than p–nitroacetophenon studied the solvente (–0.1 influences V versus SCE). on the efficiency of TiO2 photocatalyzedBrezová et chemoselective al. systematically 4-nitrophenol studied thereduction solvent to influences4-aminophenol on the [61 ]. efficiency They discovered of TiO2 thatphotocatalyzed viscosity, polarity, chemoselective polarizability 4-nitrophenol and polarity/polarizability reduction to 4-aminophenol ratio all [61] influence. They discovered the efficiency. that Aviscosity, solvent polarity, with the polarizability minimum viscosity, and polarity/polarizability the maximum polarity, ratio polarizability all influence theand efficiency. the highest A polarity/polarizabilitysolvent with the minimum ratio, namely,viscosity, methanol the maximum provided polarity, the highest polarizability reaction rates and when the highest other conditionspolarity/polarizability were identical. ratio, namely, methanol provided the highest reaction rates when other conditionsFerry etwere al. conductedidentical. the studies to confirm the real reducing species of TiO2 photocatalyzed aromaticFerry nitro et al. and conducted aliphatic the nitro studies compounds to confirm reduction: the real Alkylhydroxy reducing spec radicalsies of TiO or TiO2 photocatalyzed2 conduction bandaromatic electrons nitro and [63,103 aliphatic]. From nitro the carboncompounds and nitrogenreduction: mass-balance Alkylhydroxy experiments, radicals or theyTiO2 discoveredconduction thatband hydroxylamine electrons [63,103] may. From possibly the becarbon the pivotal and nitrogen intermediates. mass-balance By comparing experiments, the kinetics they discovered curve of nitrothat hydroxylamine compounds with may different possibly substitution be the pivotal groups, intermediates. the authors deduced By comparing a counterintuitive the kinetics point curve that of nitro compounds with different substitution groups, the authors deduced a counterintuitive point that nitro compounds with electron-withdrawing group would retard the transformation of nitro to the amino group. Moreover, from the kinetics plot of the reaction rate of nitro compounds versus the redox potential of different alcohols such as methanol and i-propanol, TiO2 conduction band or trapped-state electrons other than α-alkylhydroxy should be known as responsible for reductive transformation, albeit different nitro compounds showed almost the same kinetics constant in the presence of either methanol or i-propanol. Using electron-paramagnetic-resonance (EPR) techniques as the characterization tool, [62] Brezová et al. studied a number of key intermediates in the TiO2 photocatalytic transfer hydrogenation of nitrosobenzene derivatives. Taking nitrosobenzene as an example, they demonstrated the mechanism of TiO2 photocatalytic transfer hydrogenation of aromatic nitroso compounds by i-propanol as HDC, in which the radical species were characterized during the photocatalysis process. (as shown in Scheme 15). Initially, photo-induced electrons on TiO2 conductor band reduce nitrosobenzene to form mono-valence radical anion along a SET route. After protonation, N-OH• radical was generated. During the EPR measurements, no spin-trapping adducts of alkoxy, hydroxylalkyl and alkyl free-radicals were observed. Moreover, deuterium labelling experiments using CD3OD/toluene mixed solvent with other conditions identical were conducted. In agreement with the authors’ proposition, N-OH• was characterized by its different hyperfine splitting in comparison with N-OH•.

Molecules 2019, 24, 330 14 of 22 nitro compounds with electron-withdrawing group would retard the transformation of nitro to the amino group. Moreover, from the kinetics plot of the reaction rate of nitro compounds versus the redox potential of different alcohols such as methanol and i-propanol, TiO2 conduction band or trapped-state electrons other than α-alkylhydroxy should be known as responsible for reductive transformation, albeit different nitro compounds showed almost the same kinetics constant in the presence of either methanol or i-propanol. Using electron-paramagnetic-resonance (EPR) techniques as the characterization tool, Brezová et al. [62] studied a number of key intermediates in the TiO2 photocatalytic transfer hydrogenation of nitrosobenzene derivatives. Taking nitrosobenzene as an example, they demonstrated the mechanism of TiO2 photocatalytic transfer hydrogenation of aromatic nitroso compounds by i-propanol as HDC, in which the radical species were characterized during the photocatalysis process. (as shown in Scheme 15). Initially, photo-induced electrons on TiO2 conductor band reduce nitrosobenzene to form mono-valence radical anion along a SET route. After protonation, N-OH• radical was generated. During the EPR measurements, no spin-trapping adducts of alkoxy, hydroxylalkyl and alkyl free-radicals were observed. Moreover, deuterium labelling experiments using CD3OD/toluene mixed solvent with other conditions identical were conducted. In agreement with the authors’ proposition, N-OH• was characterized by its different hyperﬁne splitting in comparison Moleculeswith N-OH 2019,• 24. , x FOR PEER REVIEW 14 of 21

Scheme 15. Mechanism of aromatic nitroso compounds transfer reduction by TiO2 photo-generated Scheme 15. Mechanism of aromatic nitroso compounds transfer reduction by TiO2 photo-generated electron and proton in i-PrOH as demonstrated by the EPR studies. electron and proton in i-PrOH as demonstrated by the EPR studies. Furthermore, the authors studied other nitrosobenzene derivatives (2-nitrosobenzene, nitrosodurene,Furthermore, the 2,3,4,5-tetramethylnitrosobenzene, authors studied other nitrosobenzene 2,4,6-tritert-butylnitrosobenzene, derivatives (2-nitrosobenzene, nitrosodurene,3,5-dibromo-4-nitrosobenzenesulfonate 2,3,4,5-tetramethylnitrosobenzene, and 2-methyl-2-nitrosopropane) 2,4,6-tritert-butylnitrosobenzene, photo-induced 3,5-dibromo transfer-4- nitrosobenzenesulfonate and 2-methyl-2-nitrosopropane) photo-induced transfer hydrogenation hydrogenation reductions with alcohol (methanol, ethanol and i-propanol) in TiO2 slurry by reductionsEPR technique. with alcohol All the (methanol, results obtained ethanol the and similar i-propanol) conclusion in TiO of2 slurry transfer by hydrogenation,EPR technique. All that the is, resultsphoto-induced obtained hole the oxidation similar conclusion of alcohols producesof transfer protons hydrogenation, and corresponding that is, photo aldehydes-induced products hole oxidationin terms ofof 2e-ET,alcohols while produces the photo-induced protons and corresponding electrons reduced aldehydes nitrosobenzenes products in along terms a of stepwise 2e-ET, whileSET route. the photo-induced electrons reduced nitrosobenzenes along a stepwise SET route. Makarova et al. prepared surface modified TiO2 nanomaterials with L-arginine, lauryl sulfate Makarova et al. prepared surface modified TiO2 nanomaterials with L-arginine, lauryl sulfate and salicylic acid as modifiermodifier [[104104––106106]].. After After surface surface modificmodificationation with arginine, nitrobenzene adsorption on TiO2 surface was enhanced and the transformation of nitrobenzene to aniline was adsorption on TiO2 surface was enhanced and the transformation of nitrobenzene to aniline was greatly accelerated by by this this modification modification strategy. strategy. From From 10 10 K, K, 120 120 K and 200 K varied varied-temperature-temperature EPR experiments, experiments, the the authors authors un uncoveredcovered that that upon upon surface surface arginine arginine modification, modification, the the surface surface trapped trapped electron signals were absent in the EPR spectra, which differed greatly with bare TiO2 and other two electron signals were absent in the EPR spectra, which differed greatly with bare TiO2 and other two modifiedmodified samples. This This phenomenon phenomenon was was mainly mainly reasoned reasoned to to derive derive from from the the fairly fairly good e electronlectron coupling between TiO2 and arginine through the anchoring group of ammonium and carboxylate group of L-arginine with TiO2 surface oxygen lone-pair electron of Ti-O and Ti 3d unoccupied orbital. This electron coupling interaction facilitated TiO2 trapped electrons transfer to nitrobenzene more efficiently, leading to the highest yield for arginine modified TiO2. Tada et al. loaded Ag clusters onto TiO2 nanoparticles surface to realize a reasonable delivery photocatalytic reaction system (RDPRS) for the transformation of nitrobenzene to aniline [107]. They discovered that upon Ag cluster loading, the activity and the aniline product selectivity were both drastically increased. From the adsorption experiments investigation, the authors discovered that nitrobenzene was selectively adsorbed on Ag cluster rather than on bare TiO2 and the aniline product was neither adsorbed by Ag nor by TiO2. This difference in adsorptivity facilitated the desorption of aniline from TiO2 surface against further unselective over-oxidation. Also, the surface plasmonic effect of Ag particles enhanced the electron transfer from TiO2 conduction band to the nitrobenzene compounds, which accelerated the hole oxidation by means of the rapid transfer of conduction band electron. Zhang et al. systematically investigated different factors influencing the yield and selectivity of p-chloronitrobenzene reduction to p-chloroaniline [108]. They discovered that solvent played pivotal role in increasing product yield of p-chloroaniline. HCOOH/i-propanol as a hydrogen donor and solvent provided the best results achieving quantitative yield (99.2%). i-propanol is the best solvent and hydrogen donor, since i-propanol has the largest steric hindrance and highest redox potential among small molecule alcohols. This means that the TiO2 photo-induced hole oxidation of i-propanol is more difficult and slower than other hydrogen donor, which possibly provided a milder reduction condition and thus received good selectivity and yield of the transfer hydrogenation.

Molecules 2019, 24, 330 15 of 22

coupling between TiO2 and arginine through the anchoring group of ammonium and carboxylate group of L-arginine with TiO2 surface oxygen lone-pair electron of Ti-O and Ti 3d unoccupied orbital. This electron coupling interaction facilitated TiO2 trapped electrons transfer to nitrobenzene more efficiently, leading to the highest yield for arginine modified TiO2. Tada et al. loaded Ag clusters onto TiO2 nanoparticles surface to realize a reasonable delivery photocatalytic reaction system (RDPRS) for the transformation of nitrobenzene to aniline [107]. They discovered that upon Ag cluster loading, the activity and the aniline product selectivity were both drastically increased. From the adsorption experiments investigation, the authors discovered that nitrobenzene was selectively adsorbed on Ag cluster rather than on bare TiO2 and the aniline product was neither adsorbed by Ag nor by TiO2. This difference in adsorptivity facilitated the desorption of aniline from TiO2 surface against further unselective over-oxidation. Also, the surface plasmonic effect of Ag particles enhanced the electron transfer from TiO2 conduction band to the nitrobenzene compounds, which accelerated the hole oxidation by means of the rapid transfer of conduction band electron. Zhang et al. systematically investigated different factors influencing the yield and selectivity of p-chloronitrobenzene reduction to p-chloroaniline [108]. They discovered that solvent played pivotal role in increasing product yield of p-chloroaniline. HCOOH/i-propanol as a hydrogen donor and solvent provided the best results achieving quantitative yield (99.2%). i-propanol is the best solvent and hydrogen donor, since i-propanol has the largest steric hindrance and highest redox potential among small molecule alcohols. This means that the TiO2 photo-induced hole oxidation of i-propanol is more difficult and slower than other hydrogen donor, which possibly provided a milder reduction condition and thus received good selectivity and yield of the transfer hydrogenation. Kominami et al. studied the TiO2 photocatalytic reduction of nitrobenzene using oxalic acid as green transfer hydrogenation reagent in aqueous solution [109]. They discovered that in the presence of a small partial pressure O2 (5%), higher yield of aniline was achieved than in the absence of O2. Although the authors did not provide the essential role of this small amount of O2, we proposed that the low partial pressure O2 possibly acted as an electron shuttle or energy transfer reagent through ROS species that facilitated the electron and energy transfer processes during the total photocatalytic transfer hydrogenation. With the optimal conditions in hand, an excellent 95% yield of aniline was realized using oxalic acid hydrogen source in the aqueous solution. The only by-product was the oxidation product of oxalic acid-CO2. Shiraishi et al. utilized rutile TiO2 nanoparticles as a photocatalyst for effective nitrobenzene 3+ reduction. (as shown in Scheme 16)[110]. For rutile TiO2, more Ti species on the surface of TiO2 were generated upon UV irradiation than anatase. The Ti3+ species played a dual role both as the nitrobenzene adsorption and the electron trapping sites. In the presence of alcohol as a hydrogen source,Molecules a2019 variety, 24, x FOR of nitrobenzene PEER REVIEW derivatives could be transformed into the corresponding anilines16 of 21 in excellent yield (>94%) and quantum yield (25%) with another reducible functional group intact (asnitrobenzene shown in Tablerings1 kept). intact under the standard photoreduction conditions. Moreover, this method provided an excellent yield for anilines.

Scheme 16. Rutile-TiO photocatalyzed nitrobenzenes transfer hydrogenation to anilines. Scheme 16. Rutile-TiO2 photocatalyzed nitrobenzenes transfer hydrogenation to anilines.

Using TiO2 photocatalytic transfer hydrogenation for the transformation of nitro to amino compounds has already gained great advances since the beginning of the 1990s. A number of nitrobenzene derivatives could be transformed into the corresponding anilines under UV, sunlight or even visible-light irradiation under pristine TiO2, meta-loaded TiO2 and dye-sensitized TiO2 nanomaterials. EPR and surface-sensitive spectrometry such as attenuated total reflection infrared (ATR-FTIR) and diffuse reflectance infrared Fourier transform spectroscopy (DRITS-FTIR) provided much information on the reaction pathways of this heterogeneous photocatalytic reaction [62,63,103,104]. However, there are yet some challenging issues in this field to be addressed. For instance, how to enhance the optimal yield, utilize the total solar spectrum to near-infrared region and meliorate the functional group tolerability and extend the application to more complex molecules are interested in medicinal chemistry and natural product chemistry. All of these called for a more insightful understanding of the reaction mechanism.

5. Conclusions

We have conducted a review of paragon examples of TiO2 photocatalyzed transfer hydrogenations. Although still in its budding period in comparison with its currently prevalent applications in water-splitting, dye-sensitized-solar-cell, aqua system and air atmosphere pollutant decomposition [111], TiO2 photocatalysis has already exhibited the potential in organic synthesis [112], especially in transfer hydrogenation based on safe and cheap HDC (hydrogen donor compounds). Various unsaturated bonds, including C=C, C≡C, C=O, C=N, N=O bond, could be transformed into the corresponding saturated C‐C, C-O, C-N and N-H bonds, respectively. Compounds with non-polar olefin and acetylene, polar aldehyde, ketone, imine and nitro functional groups can be smoothly reduced by TiO2 photocatalysis using transfer hydrogenating reagents, such as water, alcohols, and amines. By means of this strategy, these unsaturated bonds in functionalized organic substrates could be transformed into the useful saturated moieties in diverse complex organic functional molecules. This research topic has already become a hot and active area being focused by both photocatalytic and synthetic field. Comparing with homogeneous Ru-, Ir-polypyridyl complex and organic dye photocatalysts, however, TiO2 photocatalysis demonstrates a fairly narrow substrate scope and limited reaction types and still has much space to improve. Current transfer hydrogenations by TiO2 photocatalysis still lack selectivity, especially in enantioselectivity. The latter is the widest gap between the state-of-the-art TiO2 photocatalyzed transfer hydrogenation and the future requirement for this methodology. Although there are sparse reports of chiral TiO2 surface photocatalyzed transfer hydrogenation of acetophenone, the ee value is still very low. The scope of TiO2 photocatalyzed asymmetric transfer hydrogenation needs to be widened. Only by the continuous efforts in the optimization of reaction conditions and materials engineering of photocatalysts could this asymmetric photocatalyzed transfer hydrogenation be applied in

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The Theonly only by-product by-product was wasthe the oxidationoxidationrealized product using product ofoxalic oxalic of oxalicacid acid hydrogen acid-CO-CO. 2. source in the aqueous solution. The only by-product was the oxidationrealizedrealizedoxidation using product using productoxalic of oxalic oxalicacid of oxalic acidhydrogen acid hydrogen -acidCO2- .CO source 2. source in the in aqueousthe aqueous solution. solution. The Theonly only by-product by-product was wasthe the oxidationrealizedrealizedoxidation using product using productoxalic of oxalic oxalicacid of oxalicacidhydrogen acid hydrogen- acidCO2. - sourceCO 2 .source in the in aqueousthe aqueous solution. solution. The Theonly only by-product by-product was wasthe the oxidationoxidationShiraishiShiraishi product productet al. ofet utilizedoxalical. of utilized oxalic acid rutile -acid COrutile TiO2-.CO 2TiO 2nanoparticles. 2 nanoparticles as a as photocatalyst a photocatalyst for effectivefor effective nitrobenzene nitrobenzene oxidation product of oxalic acid2-CO2 2. 2 oxidationShiraishiShiraishi Shiraishiproduct et al. ofetet utilized oxalic al.al. utilizedutilized acid rutile- CO rutilerutile TiO2. 2 TiO TiOnanoparticles2 2 nanoparticlesnanoparticles as a as photocatalystas aa photocatalyst photocatalyst for effective forfor effectiveeffective nitrobenzene nitrobenzenenitrobenzene oxidationoxidationShiraishiShiraishi product etproduct al. ofet utilized oxalical. of utilized oxalic acid rutile -acid COrutile TiO-.CO 2TiO nanoparticles. 2 nanoparticles as a as photocatalyst a photocatalyst3+ 3+ for effectivefor effective nitrobenzene nitrobenzene reduction.reShiraishiduction.Shiraishi (as et shown(as al. etshown utilized al. in utilizedScheme in rutileScheme rutile16) TiO [110]16) 2TiO nanoparticles [110]. 2For nanoparticles. Forrutile rutile TiOas a2TiO , as photocatalystmore 2a, more photocatalyst Ti Tispecies3+ forspecies effectiveonfor theoneffective surfacethe nitrobenzene surface nitrobenzene of TiO of 2TiO 2 reduction.Shiraishi (as etshown al. utilized in Scheme rutile 16) 2TiO [110]2 nanoparticles. For rutile 2TiO as a2, photocatalystmore3+ Ti 3+ species for effectiveon the surface nitrobenzene of 2TiO2 reduction.Shiraishireduction. (as etshown (as al. shownutilized in Scheme in rutile Scheme 16) TiO [110] 16)2 nanoparticles .[110] For2 .rutile For rutile TiO as 2a ,TiO more photocatalyst2, more Ti3+ species Ti3+ for species oneffective the on surface the nitrobenzene surface of TiO of2 TiO2 reduction.reShiraishiduction.Shiraishi (as et shown(as al. etshown utilized al.in utilizedScheme in rutileScheme rutile16) TiO [110]16) TiO nanoparticles [110]. For nanoparticles. rutileFor rutile TiO as 2aTiO, as3+more photocatalyst 2a, 3+more photocatalyst Ti3+ speciesTi3+ forspecies oneffectivefor the oneffective surfacethe nitrobenzene surface nitrobenzene of TiO of 2TiO 2 rewereduction.werere generatedduction. generated (as shown(as upon shown upon inUV Scheme inUVirradiation Scheme irradiation 16) [110]16) than [110] .than Foranatase.. rutileForanatase. rutileThe TiO TheTi 2TiO, more Tispecies2, 3+more speciesTi playedspeciesTi3+ playedspecies aon dual thea on dual role surfacethe role bothsurface ofboth as TiO ofthe as 2TiO the2 reduction. (as shown in Scheme 16) [110]. For rutile 2TiO3+ 2, more3+ 3+ Ti species on the surface of 2TiO2 werereduction.were weregenerated generated generated(as shown upon upon upon inUV Scheme irradiation UVUV irradiationirradiation 16) [110] than .than thanForanatase. rutile anatase.anatase. The TiO TheTiThe2, 3+more speciesTiTi2 3+ Tispeciesspecies3+ playedspecies3+ playedplayed a on dual the aa dual dualrole surface rolebothrole of both bothas TiO the asas2 thethe2 rewereduction.werere generatedduction. generated (as shown (as upon shown upon inUV Scheme inirradiationUV Scheme irradiation 16) [110] 16)than [110] .than Foranatase.. rutileanatase.For rutileThe TiO TheTi TiO, 3+more Tispecies, 3+more speciesTi played speciesTi played species a on dual thea on dual role surfacethe role bothsurface ofboth as TiO theof as TiO the werenitrobenzenenitrobenzenewere generated generated adsorption upon adsorption upon UV and irradiationUV and theirradiation electronthe thanelectron than trappinganatase. trappinganatase. Thesites. ThesitTi In3+es. speciesTithe In3+ presencethespecies playedpresence played of a alcohol dualof aalcohol dual role as roleaboth ashydrogen aboth ashydrogen the as the nitrobenzenewerewerenitrobenzene nitrobenzenegenerated generated adsorption upon adsorptionadsorption upon UV and irradiationUV andthe andirradiation electron thethe than electronelectron than trappinganatase. trappinganatase.trapping Thesites. ThesitTisit In3+es.es. thespeciesTi InIn3+ presence speciesthespeciesthe played presencepresence played of aalcohol dual ofof a alcohol alcoholdual role as roleaboth ashydrogenas aboth a as hydrogenhydrogen the as the nitrobenzenesource,source,nitrobenzene a variety a varietyadsorption of adsorption nitrobenzene of nitrobenzene and andthe derivatives electronthe derivatives electron trapping could trapping could be sit transformed es.be sit transformedInes. the In presencethe into presence intothe of correspondingthe alcohol correspondingof alcohol as a asanilineshydrogen a anilineshydrogen in in source,nitrobenzenenitrobenzenesource,source, a variety a a variety adsorptionvariety of adsorption nitrobenzene of of nitrobenzene nitrobenzene and andthe derivatives electronthe derivatives derivativeselectron trapping could trapping could could be sit transformed es.be be sit transformed Intransformedes. the In presencethe into presence into theinto correspondingof the the alcohol ofcorresponding corresponding alcohol as a anilinesashydrogen a anilineshydrogenanilines in in in source,excellentexcellentsource, a varietyyield a varietyyield (>94%) of nitrobenzene(>94%) of and nitrobenzene andquantum quantum derivatives derivativesyield yield (25%) could (25%) couldwith be withtransformed anotherbe transformed another reducible intoreducible intothe functional corresponding the functional corresponding group group anilines intact anilines intact (as in (as in excellentsource,source,excellentsource,excellent a varietyyield aa variety varietyyieldyield (>94%) of nitrobenzene (>94%)(>94%) ofof and nitrobenzenenitrobenzene andquantumand quantumquantum derivatives yieldderivativesderivatives yieldyield (25%) could (25%)(25%) couldcouldwith be transformedwith withanother bebe transformedtransformed anotheranother reducible into reduciblereducible intotheinto functional corresponding thethe functionalfunctional correspondingcorresponding group groupgroup anilines intact anilinesanilines intactintact (as in (as (as inin excellentshownshownexcellent in yieldTa inble yieldTa (>94%) 1).ble (>94%) 1). and andquantum quantum yield yield (25%) (25%) with with another another reducible reducible functional functional group group intact intact (as (as shownexcellentexcellentshownshown in yieldTa ininble yield Ta Ta(>94%) 1).bleble (>94%) 1).1). and andquantum quantum yield yield (25%) (25%) with with another another reducible reducible functional functional group group intact intact (as (as shownshown in Ta inble Ta 1).ble 1). 2 2 Not Notonly only UV- UVlight-light could could induce induce the TiOthe TiO photocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes shownshownNot in onlyNot Ta inble onlyUVTa 1).ble- light UV 1).-light could could induce induce the TiO the2 TiO photocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes shownshownNot in only NotTa inble UVonlyTa 1).ble-light UV 1).- lightcould could induce induce the TiO the2 TiOphotocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes Not Notonly only UV- lightUV-light could could induce induce the TiO the 2TiO photocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of2 nitrobenzenes of2 nitrobenzenes to anilines,to anilines,Not but only alsobut UV alsolower-light lower energy could energy inducevisible visible thegreen TiOgreen light2 photocatalytic light could could excite excite transfer dye -dyesensitized hydrogenation-sensitized TiO TiO to ofcatalyze2 to nitrobenzenes catalyze this this to anilines,toNot anilines, Notonly but only UV alsobut- lightUV alsolower-light could lower energy could induce energy inducevisible the visible TiO greenthe 2TiO greenphotocatalytic light photocatalytic light could could excite transfer excite transfer dye hydrogenation -dyesensitized hydrogenation-sensitized TiO of2 TiO to nitrobenzenes catalyzeof2 to nitrobenzenes catalyze this this to anilines,Notto anilines, onlyNot but onlyUV also but- lightUV loweralso-light could lower energy could induce energy visibleinduce the visible TiO greenthe2 TiO photocatalyticgreen light2 photocatalytic lightcould could excite transfer excite transferdye hydrogenation- sensitizeddye hydrogenation-sensitized TiO of2 TiOto nitrobenzenes catalyzeof2 tonitrobenzenes catalyze this this to anilines,to anilines, but alsobut alsolower lower energy energy visible visible green green 2light2 light could3 could3 excite excite dye -dyesensitized-sensitized TiO 2TiO to catalyze2 to catalyze this this transformation.transformation. König Kö nig et al. et prepared al. prepared a TiO a TiO/Ru2-/RuN -metalN3 metal-oxide-oxide semiconductor/transition semiconductor/transition2 metal metal transformation.to anilines,totransformation. anilines, but also but Kö nigalso lower Kö etniglower energy al. et preparedenergy al. visible prepared visible agreen TiO agreen 2 TiOlight/Ru- 2lightN/Ru could3 -metalN could 3 excitemetal-oxide excite dye-oxide semiconductor/transition -dyesensitized semiconductor/transition-sensitized TiO 2TiO to catalyze to catalyze metal this metal this transformation.to anilines,totransformation. anilines, but alsobut Kö nigalsolower K ö etniglower energy al. et prepared energy al. visible prepared visible agreen TiO agreen 2/Rulight TiO- Nlight /Rucould3 metal- Ncould excite metal-oxide excite dye-oxide semiconductor/transition- dyesensitized semiconductor/transition-sensitized TiO2 TiO to catalyze2 to catalyze metal this metal this transformation.ion/dyeion/dyetransformation. ternary ternary composite König composite Kö nig et al. catalyst et prepared al.catalyst prepared system system a TiO[58] a 2.[58] TiO/Ru .-2 /RuN 3 -metalN3 metal-oxide-oxide semiconductor/transition semiconductor/transition metal metal ion/dyetransformation.transformation.ion/dye ternary ternary composite König composite Kö nig et al.catalyst et prepared al.catalyst preparedsystem system a TiO[58] a .2 TiO[58]/Ru -2. /RuN 3 -metalN3 metal-oxide-oxide semiconductor/transition semiconductor/transition metal metal ion/dyetransformation.transformation.ion/dye ternary ternary composite König composite Kö etnig al.catalyst et prepared al.catalyst preparedsystem system a [58] TiO a .2 TiO/Ru[58] -2.N/Ru 3 metal-N3 metal-oxide-oxide semiconductor/transition semiconductor/transition metal metal ion/dyeion/dye ternary ternary composite composite catalyst catalyst system system [58] .[58] . ion/dyeion/dyeion/dye ternary ternaryternary composite compositecomposite catalyst catalystcatalyst system systemsystem [58] . [58] [58] .. Molecules 2019,Table24, 330Table 1. Rutile 1. Rutile-TiO-2TiO photocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes with with i-propanol i-propanol. . 16 of 22 2 TableTableTable 1. Rutile 1. 1. Rutile Rutile-TiO2- -TiOphotocatalyticTiO2 photocatalytic photocatalytic transfer transfer transfer hydrogenation hydrogenation hydrogenation of nitrobenzenes of of nitrobenzenes nitrobenzenes with with iwith-propanol i i--propanolpropanol. . . Table 1. Rutile-TiO2 photocatalytic2 transfer hydrogenation of nitrobenzenes with i-propanol. TableTable 1. Rutile 1. Rutile-TiO2- TiOphotocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes with withi-propanol i-propanol. . TableTable 1. Rutile 1. Rutile-TiO2- TiOphotocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes with withi-propanol i-propanol. . TableTable 1. Rutile 1. Rutile-TiO2- TiOphotocatalytic2 photocatalytic transfer transfer hydrogenation hydrogenation of nitrobenzenes of nitrobenzenes with withi-propanol i-propanol. . EntryEntry EntryTableEntryEntry 1. Rutile-TiOSubstrateSubstrate photocatalytic SolventSolvent transfer hydrogenationt/ht/h t/ht/hConversion/% Conversion/% of nitrobenzenes ProductProduct with i-propanol. Yield/%Yield/% EntryEntry SubstrateSubstrate 2 SolventSolvent t/h t/hConversion/% Conversion/% ProductProduct Yield/%Yield/% EntryEntry SubstrateSubstrate SolventSolvent t/h t/hConversion/% Conversion/% ProductProduct Yield/%Yield/% EntryEntry SubstrateSubstrate SolventSolvent t/h t/ht/hConversion/% Conversion/% ProductProduct Yield/%Yield/% Entry Substrate Solvent Solvent t/h t/hConversion/% Conversion/% Product Product Yield/% Yield/% 1 1 i-PrOHi-PrOH 6 6 >99 >99 >99 >99 1 11 i-PrOHii--PrOHPrOH 6 66 >99 >99>99 >99 >99>99 1 1 i-PrOHi-PrOH 6 6 >99 >99 >99 >99 11 1 i-PrOHi-PrOHi-PrOH 6 6 6 >99 >99 >99 >99 >99 1 1 i-PrOHi-PrOH 6 6 >99 >99 >99 >99 2 2 i-PrOH/toluenei-PrOH/toluene (1/9) (1/9) 4 4 >99 >99 98 98 2 22 i-PrOH/tolueneii--PrOH/toluenePrOH/toluene (1/9) (1/9) (1/9)4 44 >99 >99>99 98 9898 2 2 i -PrOH/toluenei-PrOH/toluene (1/9) (1/9)4 4 >99 >99 98 98 22 2 i-i-PrOH/toluenePrOH/toluenei-PrOH/toluene (1/9) (1/9) (1/9)4 4 4 >99 >99 >99 98 98 2 2 i-PrOH/toluenei-PrOH/toluene (1/9) (1/9)4 4 >99 >99 98 98 3 3 i-PrOH/toluenei-PrOH/toluene (9/1) (9/1) 5 5 >99 >99 94 94 3 33 i-PrOH/tolueneii--PrOH/toluenePrOH/toluene (9/1) (9/1) (9/1)5 55 >99 >99>99 94 9494 3 3 i -PrOH/toluenei-PrOH/toluene (9/1) (9/1)5 5 >99 >99 94 94 33 3 i - i-PrOH/toluenePrOH/toluenei-PrOH/toluene (9/1) (9/1) (9/1)5 5 5 >99 >99 >99 94 94 3 3 i -PrOH/toluenei-PrOH/toluene (9/1) (9/1)5 5 >99 >99 94 94

4 4 i -PrOH/toluenei-PrOH/toluene (5/5) (5/5) 7 7 >99 >99 98 98 4 4 i -PrOH/toluenei-PrOH/toluene (5/5) (5/5)7 7 >99 >99 98 98 44 44 i -PrOH/toluenei-PrOH/toluenei-i-PrOH/toluenePrOH/toluene (5/5) (5/5) (5/5) (5/5)7 7 7 >99 >99>99 >99 98 9898 4 4 i - PrOH/toluenei-PrOH/toluene (5/5) (5/5)7 7 >99 >99 98 98 4 44 i -PrOH/tolueneii--PrOH/toluene (5/5) (5/5)7 77 >99 >99>99 98 9898

5 5 i-PrOH/toluenei-PrOH/toluene (1/9) (1/9) 6 6 >99 >99 94 94 5 55 i-PrOH/tolueneii--PrOH/toluenePrOH/toluene (1/9) (1/9) (1/9)6 66 >99 >99>99 94 9494 55 5 i-i-PrOH/toluenePrOH/toluenei-PrOH/toluene (1/9) (1/9) (1/9)6 6 6 >99 >99 >99 94 94 5 55 i-PrOH/toluene ii--PrOH/toluene (1/9) (1/9)6 66 >99 >99>99 94 9494 5 i-PrOH/toluene (1/9) 6 >99 94

66 6 ii--PrOH/tolueneii--PrOH/toluene (1/9) (1/9) 66 6 >99>99 >99 9797 97 66 6 i-PrOH/toluenei-PrOH/toluenei-PrOH/toluene (1/9) (1/9) (1/9)6 6 >99 >99 >99 97 9797 6 6 i -PrOH/toluenei-PrOH/toluene (1/9) (1/9)6 6 >99 >99 97 97 6 66 i- PrOH/tolueneii--PrOH/toluene (1/9) (1/9)6 66 >99 >99>99 97 9797

7 7 7 i-i-PrOH/toluenePrOH/toluenei-PrOH/toluene (1/9) (1/9) (1/9) 6 6 6 >99 >99 >99 94 94 7 77 i-PrOH/tolueneii--PrOH/toluenePrOH/toluene (1/9) (1/9) (1/9)6 66 >99 >99>99 94 9494 7 7 i-PrOH/toluene i-PrOH/toluene (1/9) (1/9)6 6 >99 >99 94 94 7 77 i-PrOH/toluene ii--PrOH/toluene (1/9) (1/9)6 66 >99 >99>99 94 9494 Reaction7 Reaction conditions: conditions: Substrate Substratei-PrOH/toluene µ (50 μmol),(50 μmol), rutile(1/9) rutile -TiO6 -2TiO catalyst2 catalyst>99 (10 mg),(10 mg), solvent solvent (5 mL), (5 mL), temperature temperature 94 Reaction conditions: Substrate (50 mol), rutile-TiO2 catalyst2 (102 mg), solvent (5 mL), temperature (303 K), N2 (1 atm), ReactionReactionReaction conditions: conditions:conditions: Substrate SubstrateSubstrate (50 μmol), (50(50 μmol),μmol), rutile rutile-rutileTiO2- -TiOcatalystTiO2 catalystcatalyst (10 mg), (10(10 mg),solventmg), solventsolvent (5 mL), (5(5 mL),temperaturemL), temperaturetemperature Reaction conditions: Substrate (50 μmol), rutile-TiO2 catalyst2 (10 mg), solvent (5 mL), temperature Xe lampReaction(303 ((303ReactionK),λ > N 300K),conditions:2 (1 nm).N atm),conditions:2 (1 atm), Xe Substrate lamp Xe Substrate lamp (λ >(50 300(λ μmol),>(50 nm).300 μmol), nm). rutile rutile-TiO2- TiOcatalyst2 catalyst (10 mg), (10 mg),solvent solvent (5 mL), (5 mL),temperature temperature Reaction conditions:2 Substrate (50 μmol), rutile-TiO catalyst (10 mg), solvent (5 mL), temperature Reaction(303 K),Reaction(303(303 N conditions:K), 2K), (1 N Natm),conditions:2 (1 (1 atm), atm),Xe Substrate lamp Xe Xe Substrate lamp lamp(λ >(50 300(λ (λ μmol), > (50>nm). 300 300 μmol), nm). nm).rutile rutile-TiO2- TiOcatalyst2 catalyst (10 mg), (10 mg),solvent solvent (5 mL), (5 mL),temperature temperature (303Reaction K),Reaction N conditions:2 (1 atm),conditions:2 Xe Substrate lamp Substrate (λ >(50 300 μmol), (50nm). μmol), rutile rutile-TiO2- TiOcatalyst2 catalyst (10 mg), (10 mg),solvent solvent (5 mL), (5 mL),temperature temperature (303 K),(303 N K),2 (1 N atm),2 (1 atm), Xe lamp Xe lamp (λ > 300(λ > nm). 300 nm). (303 K),(303 N K),2 (1 N atm),2 (1 atm), Xe lamp Xe lamp (λ > 300(λ > nm). 300 nm). 3 3 2 2 (303Under UnderK),(303 greenN K),2 (1 green N atm),-2light (1 atm),- Xelight or lamp sunlightXe or lamp (λsunlight > 300 (λ irradiation, > nm). 300 irradiation, nm). excited excited state state N dyeN 3 dyetransferred transferred its electrons its electrons to TiO to TiO 2 UnderUnder green green-light-light or sunlight or sunlight irradiation, irradiation, excited excited state state N3 dye N 3 dyetransferred transferred its electrons its electrons to TiO to 2TiO 2 UnderUnder green green-light- lightor sunlight or sunlight irradiation, irradiation, excited excited state stateN3 dye N3 transferreddye transferred its electrons its electrons to TiO to2 TiO2 NotUnder onlyUnder UV-lightgreen green-light could-light or sunlight or induce sunlight irradiation, the irradiation, TiO22photocatalytic excited2 excited state state N3 transfer dye N3 dyetransferred hydrogenationtransferred its electrons its electrons of nitrobenzenes to TiO to 2TiO 2 conductionconduction band, band, these these in-situ in- situgenerated generated TiO TiO conduction2 conduction band band electrons3 electrons reduced reduced the vicinalthe vicinal Pt, Pd Pt, Pd2 conductionconductionUnderUnder band,green greenband, -theselight- theselight orin -sunlightsitu orin - sunlightsitugenerated irradiation,generated irradiation, TiO 2TiO conductionexcited2 conductionexcited state band state N 3band dye electronsN dyetransferredelectrons transferred reduced reduced its theelectrons its vicinaltheelectrons vicinal to Pt, TiO toPd Pt, 2TiO Pd conductionUnderconductionUnder band,green greenband, -theselight- light these orin -sunlightsitu or in -sunlightgeneratedsitu irradiation,generated irradiation, TiO2 TiO conductionexcited conductionexcited state band state N3 band dye electronsN3 transferreddye electrons transferred reduced reduced its theelectrons its vicinal electronsthe vicinal to Pt, TiO Pdto Pt, 2TiO Pd2 to anilines,conductionor Auorconduction ionAu but toion band, alsothe to band, corresponding the lowerthese corresponding these in energy-situ in- situgenerated metal visible generated metal colloidal greenTiO colloidal 2TiO conduction lightparticles.2 conduction particles. could These band excite These band electronsmetal dye-sensitized metalelectrons particles reduced particles reduced behaved the behaved TiO vicinalthe as tovicinal reaction catalyzeasPt, reaction Pd Pt, Pd this orconduction Auconductionor ionAu toion band, the to band, corresponding thethese corresponding these in-situ in- situgenerated metal generated metal colloidal TiO colloidal 2TiO conduction particles.2 conduction particles. These band These band metalelectrons metalelectrons particles reduced particles reduced behaved the behaved vicinalthe 2as vicinal reaction asPt, reaction Pd Pt, Pd orconduction Auconductionor ion Au to ionband, the to band,corresponding thesethe correspondingthese in-situ in- generatedsitu metal generated metal colloidal TiO colloidal 2TiO conduction particles.2 conduction particles. These band Theseband metalelectrons electronsmetal particles reduced particles reduced behaved the behaved vicinal the as vicinalreaction asPt, reactionPd Pt, Pd transformation.orsites Ausitesor for ionAu hydrogen for toion hydrogen the Königto correspondingthe generation corresponding etgeneration al. prepared and metal andhydrogenation metal hydrogenation colloidal a TiO colloidal/Ru-N particles. of nitroparticles. of nitrometal-oxidebenzenes. Thesebenzenes. These metal Triethanolamine metal particles semiconductor/transitionTriethanolamine particles behaved actedbehaved acted as as reactionthe as finalthereaction final metal sitesor Auor sitesforsites ionAu hydrogen for for toion hydrogen hydrogenthe to correspondingthe generation corresponding generation generation and metal hydrogenationand and metal hydrogenation hydrogenationcolloidal colloidal2 particles. of nitro particles. of of3 nitro benzenes.nitro Thesebenzenes.benzenes. These metal Triethanolamine metal particlesTriethanolamine Triethanolamine particles behaved actedbehaved acted acted asas reactionthe asas as final reactionthe the final final sitessites for hydrogen for hydrogen generation generation and hydrogenationand hydrogenation of nitro of nitrobenzenes.benzenes.3 Triethanolamine3 Triethanolamine acted acted as the as final the final ion/dyeelectron/hydrogenelectron/hydrogensites ternary for hydrogen composite donor generation donor catalyst to regenerate to and regeneratesystem hydrogenation the [58 ]. the ground ground of nitro state benzenes. state N Ndye.3 Triethanolaminedye. This This visible visible-light acted-light-induced as- inducedthe final electron/hydrogensitessiteselectron/hydrogen for hydrogen for hydrogen generation donor generation donor to and regenerate to hydrogenationand regenerate hydrogenation the the ground of nitro ground of nitrobenzenes. state benzenes. state N3 Triethanolaminedye. N 3 Triethanolamine dye. This This visible visibleacted-light acted as-light- inducedthe as final- theinduced final electron/hydrogensites sitesforelectron/hydrogen hydrogen for hydrogen generation donor generation donor to and regenerate to hydrogenationand regenerate hydrogenation the ground the of nitro groundof nitrobenzenes. state benzenes. state N3 Triethanolamine dye. N Triethanolamine dye. This This visible acted visible-light acted as--light inducedthe as final -theinduced final electron/hydrogentransformationtransformationelectron/hydrogen demonstrated donor demonstrated donor to regenerate to good regenerate good substrate the substrate the ground tolerability ground tolerability state state withN3 withdye.N many3 dye.This many functional This visible functional visible-light groups-light -induced groups- induced on on transformationelectron/hydrogenUnderelectron/hydrogentransformation green-light demonstrated donor demonstrated or donor sunlight to regenerate to good irradiation, regenerate good substrate the substrate the ground excited tolerability ground tolerability state state withN 3 dye withdye. N many3 transferreddye. This many functional This visible functional visible its-light electrons groups-light- induced groups- induced on to TiOon transformationelectron/hydrogenelectron/hydrogentransformation demonstrated donor demonstrated donor to regenerate to good regenerate good substrate the substrate the ground tolerability ground tolerability state state with N3 dye. Nwith many3 dye. This many functional This visible functional visible-light groups-light- induced groups -induced on on 2 transformationtransformation demonstrated demonstrated good good substrate substrate tolerability tolerability with with many many functional functional groups groups on on conductiontransformationtransformationtransformation band, these demonstrated demonstrated demonstrated in-situ generated good good good substrate TiO substrate substrate2 conduction tolerability tolerability tolerability band with electrons with with many many many reduced functional functional functional the groups vicinal groups groups onPt, Pd on on or

Au ion to the corresponding metal colloidal particles. These metal particles behaved as reaction sites for hydrogen generation and hydrogenation of nitrobenzenes. Triethanolamine acted as the final electron/hydrogen donor to regenerate the ground state N3 dye. This visible-light-induced transformation demonstrated good substrate tolerability with many functional groups on nitrobenzene rings kept intact under the standard photoreduction conditions. Moreover, this method provided an excellent yield for anilines. Using TiO2 photocatalytic transfer hydrogenation for the transformation of nitro to amino compounds has already gained great advances since the beginning of the 1990s. A number of nitrobenzene derivatives could be transformed into the corresponding anilines under UV, sunlight or even visible-light irradiation under pristine TiO2, meta-loaded TiO2 and dye-sensitized TiO2 nanomaterials. EPR and surface-sensitive spectrometry such as attenuated total reflection infrared (ATR-FTIR) and diffuse reflectance infrared Fourier transform spectroscopy (DRITS-FTIR) provided much information on the reaction pathways of this heterogeneous photocatalytic reaction [62,63,103,104]. However, there are yet some challenging issues in this field to be addressed. For instance, how to enhance the optimal yield, utilize the total solar spectrum to near-infrared region and meliorate the functional group tolerability and extend the application to more complex molecules are interested in medicinal chemistry and natural product chemistry. All of these called for a more insightful understanding of the reaction mechanism.

5. Conclusions

We have conducted a review of paragon examples of TiO2 photocatalyzed transfer hydrogenations. Although still in its budding period in comparison with its currently prevalent applications in water-splitting, dye-sensitized-solar-cell, aqua system and air atmosphere pollutant decomposition [111], TiO2 photocatalysis has already exhibited the potential in organic synthesis [112], Molecules 2019, 24, 330 17 of 22 especially in transfer hydrogenation based on safe and cheap HDC (hydrogen donor compounds). Various unsaturated bonds, including C=C, C≡C, C=O, C=N, N=O bond, could be transformed into the corresponding saturated C-C, C-O, C-N and N-H bonds, respectively. Compounds with non-polar olefin and acetylene, polar aldehyde, ketone, imine and nitro functional groups can be smoothly reduced by TiO2 photocatalysis using transfer hydrogenating reagents, such as water, alcohols, and amines. By means of this strategy, these unsaturated bonds in functionalized organic substrates could be transformed into the useful saturated moieties in diverse complex organic functional molecules. This research topic has already become a hot and active area being focused by both photocatalytic and synthetic field. Comparing with homogeneous Ru-, Ir-polypyridyl complex and organic dye photocatalysts, however, TiO2 photocatalysis demonstrates a fairly narrow substrate scope and limited reaction types and still has much space to improve. Current transfer hydrogenations by TiO2 photocatalysis still lack selectivity, especially in enantioselectivity. The latter is the widest gap between the state-of-the-art TiO2 photocatalyzed transfer hydrogenation and the future requirement for this methodology. Although there are sparse reports of chiral TiO2 surface photocatalyzed transfer hydrogenation of acetophenone, the ee value is still very low. The scope of TiO2 photocatalyzed asymmetric transfer hydrogenation needs to be widened. Only by the continuous efforts in the optimization of reaction conditions and materials engineering of photocatalysts could this asymmetric photocatalyzed transfer hydrogenation be applied in laboratorial and industrial scales enantiomer’s synthesis. By more elaborate designing of TiO2 nanomaterials itself or artful choice of co-catalysts, additives, and reaction parameters, this research area will provide us with greener, safer, more environmentally benign, efficient designs and strategies to supplement the traditional transition-metal complexes catalysts and organocatalysts for transfer hydrogenation of unsaturated compounds.

Funding: This work was supported by the National Natural Science Foundation of China (21703005). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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