Selective Reduction of Ketones and Aldehydes in Continuous-Flow Microreactor—Kinetic Studies

catalysts

Article Selective Reduction of Ketones and Aldehydes in Continuous-Flow Microreactor—Kinetic Studies

Katarzyna Maresz 1,*, Agnieszka Ciemi˛ega 1 and Julita Mrowiec-Biało ´n 1,2

1 Institute of Chemical Engineering Polish Academy of Sciences, Bałtycka 5, 44-100 Gliwice, Poland; [email protected] (A.C.); [email protected] (J.M.-B.) 2 Department of Chemical Engineering and Process Design, Silesian University of Technology, Ks. M. Strzody 7, 44-100 Gliwice, Poland * Correspondence: [email protected]; Tel.: +48-32-231-08-11

Received: 24 April 2018; Accepted: 18 May 2018; Published: 22 May 2018

Abstract: In this work, the kinetics of Meerwein–Ponndorf–Verley chemoselective reduction of carbonyl compounds was studied in monolithic continuous-flow microreactors. To the best of our knowledge, this is the first report on the MPV reaction kinetics performed in a flow process. The microreactors are a very attractive alternative to the batch reactors conventionally used in this process. The proposed micro-flow system for synthesis of unsaturated secondary alcohols proved to be very efficient and easily controlled. The microreactors had reactive cores made of zirconium-functionalized silica monoliths of excellent catalytic properties and flow characteristics. The catalytic experiments were carried out with the use of 2-butanol as a hydrogen donor. Herein, we present the kinetic parameters of cyclohexanone reduction in a flow reactor and data on the reaction rate for several important ketones and aldehydes. The lack of diffusion constraints in the microreactors was demonstrated. Our results were compared with those from other authors and demonstrate the great potential of microreactor applications in fine chemical and complex intermediate manufacturing.

Keywords: Meerwein–Ponndorf–Verley reduction; kinetics; ﬂow microreactor

1. Introduction A reduction of carbonyl bond is a widespread route for the synthesis of alcohols. However, the reaction, classically catalyzed by noble metals and carried out in the presence of molecular hydrogen, reveals signiﬁcant limitations, including low selectivity, high sensitivity to sulfur-containing substrates, and high-pressure requirements. The pharmaceutical industry is concerned with the purity of its products. The Meerwein–Ponndorf–Verley (MPV) reaction is an attractive method of synthesizing unsaturated alcohols from ketones or aldehydes using secondary alcohols instead of gaseous hydrogen. According to a generally accepted mechanism of the MPV reaction, the carbonyl group acts as a hydrogen acceptor and alcohol as a hydrogen source. The hydrogen transfer occurs when both substrates are simultaneously coordinated to the same Lewis acidic site (Scheme1). The formation of a six-membered transition state ring is considered to be a determining step in the reaction rate.

Catalysts 2018, 8, 221; doi:10.3390/catal8050221 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 221 2 of 8 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 8

SchemeScheme 1. 1.The The mechanism mechanism of of Meerwein–Ponndorf–Verley Meerwein–Ponndorf–Verley (MPV) (MPV) reduction. reduction.

InexpensiveInexpensive andand non-toxic hydrogen hydrogen donors donors an andd catalysts, catalysts, mild mild reaction reaction conditions, conditions, and exceptional chemoselectivity render this method of reduction favorable over alternatives. Among and exceptional chemoselectivity render this method of reduction favorable over alternatives. Among many active species, such as Zr [1,2], Al [3,4], Mg [3,5], and B [6,7], which are considered to be active many active species, such as Zr [1,2], Al [3,4], Mg [3,5], and B [6,7], which are considered to be catalysts for MPV reduction, zirconium has been shown to be one of the most promising. In the active catalysts for MPV reduction, zirconium has been shown to be one of the most promising. literature, batch processes are predominantly described with the use of numerous catalysts, e.g., In the literature, batch processes are predominantly described with the use of numerous catalysts, homogeneous alkoxides [8,9], zeolites [10,11], mesoporous sieves [12–14], and hydrotalcite [15]. e.g., homogeneous alkoxides [8,9], zeolites [10,11], mesoporous sieves [12–14], and hydrotalcite [15]. Nevertheless, the tedious separation of homogenous catalysts at the end of the process leads to its Nevertheless, the tedious separation of homogenous catalysts at the end of the process leads to its deactivation and non-reusability. Powdered catalysts ensure significant benefits over its deactivation and non-reusability. Powdered catalysts ensure significant benefits over its homogeneous homogeneous counterparts. However, filtration is an additional time- and cost-consuming step in counterparts. However, filtration is an additional time- and cost-consuming step in the technological the technological line. Flow microreactors allow one to overcome these drawbacks and have line. Flow microreactors allow one to overcome these drawbacks and have additional advantages, additional advantages, i.e., high surface-to-volume ratio, improved reaction parameter control, a i.e., high surface-to-volume ratio, improved reaction parameter control, a small equipment size, and a small equipment size, and a flexibility of module arrangement. flexibility of module arrangement. Flow chemistry is perspective and still not explored field in the area of chemoselective MPV Flow chemistry is perspective and still not explored field in the area of chemoselective MPV reduction. Battilocchio et al. reported the protocol for synthesizing various alcohols from aromatic reduction. Battilocchio et al. reported the protocol for synthesizing various alcohols from aromatic and and aliphatic carbonyl compounds using a packed-bed reactor filled with zirconium hydroxide aliphatic carbonyl compounds using a packed-bed reactor filled with zirconium hydroxide catalyst [16]. catalyst [16]. In our previous works [17–19], we demonstrated excellent activity of zirconium-doped In our previous works [17–19], we demonstrated excellent activity of zirconium-doped silica monolithic silica monolithic microreactors in cyclohexanone reductions and their improved performance microreactors in cyclohexanone reductions and their improved performance compared with the batch compared with the batch process. It was shown that zirconium species terminated with propoxy process. It was shown that zirconium species terminated with propoxy ligands featured the highest ligands featured the highest activity in MPV reduction among various Lewis centers immobilized activity in MPV reduction among various Lewis centers immobilized onto monoliths’ surfaces used onto monoliths’ surfaces used as reactive cores in microreactors. Extensive studies of structural, as reactive cores in microreactors. Extensive studies of structural, physicochemical, and catalytic physicochemical, and catalytic properties revealed the high efficiency of the proposed microreactors. properties revealed the high efficiency of the proposed microreactors. In this work, we present the kinetic studies of MPV reduction with the use of various carbonyl In this work, we present the kinetic studies of MPV reduction with the use of various carbonyl compounds and 2-butanol as a hydrogen donor. The experiments were performed in compounds and 2-butanol as a hydrogen donor. The experiments were performed in continuous-flow continuous-flow zirconium-propoxide-functionalized microreactors of different lengths. zirconium-propoxide-functionalized microreactors of different lengths. We determined the kinetic parameters, hardly presented for the MPV reduction process carried We determined the kinetic parameters, hardly presented for the MPV reduction process carried out in a flow regime. The results of the flow and batch reactors were compared with those of other out in a flow regime. The results of the flow and batch reactors were compared with those of other authors. The kinetic data are crucial to determine the optimum process conditions through the authors. The kinetic data are crucial to determine the optimum process conditions through the selection selection of appropriate catalysts and reaction parameters. The knowledge of basic issues related to of appropriate catalysts and reaction parameters. The knowledge of basic issues related to the course of the course of reactions allows one to set new, more effective paths for conducting processes. Despite reactions allows one to set new, more effective paths for conducting processes. Despite the possibility of the possibility of theoretical computer simulation of the behavior of the reaction system, the theoretical computer simulation of the behavior of the reaction system, the experimental determination experimental determination of the kinetic equation parameters is still necessary for the development of the kinetic equation parameters is still necessary for the development of the reactor model. of the reactor model. 2. Results 2. Results The characterization of siliceous monolithic microreactors functionalized with zirconium species and theirThe catalyticcharacterization properties of weresiliceous described monolithic in our previousmicroreactors papers functionalized [17,18]. Kinetic with studies zirconium were performedspecies and in their the microreactorscatalytic properties featured were by describe the exceptionallyd in our previous low back-pressure. papers [17,18]. It resultedKinetic studies from thewere unique performed structure in ofthe cylindrical-shape microreactors featured monoliths by appliedthe exceptionally as reactive low cores back-pressure. [20]. Briefly, monolithsIt resulted werefrom characterized the unique bystructure a continuous, of cylindrical-shape macroporous flow-throughmonoliths applied structure as (macroporesreactive cores in the[20]. range Briefly, of 30–50monolithsµm), extendedwere characterized with mesopores by a continuous, of bimodal macroporous size distributions flow-through (3/20 nm) structure and a high (macropores surface area in (340the mrange2·g− of1) (Figure30–50 μ1m),). The extended monoliths with weremesopores functionalized of bimodal with size zirconium distributions propoxide (3/20 nm) to obtainedand a high surface area (340 m2·g−1) (Figure 1). The monoliths were functionalized with zirconium propoxide to obtained Lewis acid sites on the silica surface. The zirconium cations were terminated by propoxy/hydroxo ligands, which appeared to be very active catalytic centers [18,19]. The

Catalysts 2018, 8, 221 3 of 8

Catalysts 2018, 8, x FOR PEER REVIEW 3 of 8 CatalystsLewis acid2018, sites8, x FOR on PEER thesilica REVIEW surface. The zirconium cations were terminated by propoxy/hydroxo3 of 8 ligands, which appeared to be very active catalytic centers [18,19]. The concentration of zirconium, concentration of zirconium, determined by ICP MS analysis, was 7.03 wt % (in relation to the mass of concentrationdetermined by of ICPzirconium, MS analysis, determined was 7.03by ICP wt MS % (inanalysis, relation was to 7.03 the wt mass % (in of relation silica support) to the mass in allof silica support) in all studied microreactors. silicastudied support) microreactors. in all studied microreactors.

Figure 1. (a) SEM image of silica monolith structure; (b) nitrogen adsorption/desorption isotherm Figure 1.1. ((aa)) SEMSEM image image of of silica silica monolith monolith structure; structure; (b) ( nitrogenb) nitrogen adsorption/desorption adsorption/desorption isotherm isotherm and and pore size distribution (insert). poreand pore size distributionsize distribution (insert). (insert).

Material functionalization with zirconium precursor did not considerably influence the Material functionalizationfunctionalization with with zirconium zirconium precursor precursor did not did considerably not considerably inﬂuence influence the structural the structural properties of the support. Only a small decline of the surface area and mesopore volume propertiesstructural properties of the support. of the Only support. a small Only decline a small of the decline surface of area the andsurface mesopore area and volume mesopore was observed. volume was observed. All features have been preserved after multiple reaction cycles. Allwas features observed. have All been features preserved have been after preserved multiple reaction after multiple cycles. reaction cycles. Detailed studies of the kinetic experiment were performed for the MPV reduction of Detailed studies of the kinetic experiment were performed for the MPV reduction of cyclohexanone with 2-butanol. First, we checked whether diffusion or activation controls the cyclohexanone withwith 2-butanol. 2-butanol. First, First, we we checked checke whetherd whether diffusion diffusion or activation or activation controls controls the reaction the reaction rate. External mass transfer limitations are a common phenomenon in porous materials. To reactionrate. External rate. External mass transfer mass limitations transfer limitations are a common are a phenomenon common phenomenon in porous materials. in porous To materials. exclude theTo exclude the impact of diffusional effects on the reaction kinetics, the performance of microreactors excludeimpact of the diffusional impact of effects diffusional on the effects reaction on kinetics, the reaction the performance kinetics, the of performance microreactors of with microreactors monolithic with monolithic cores of different lengths were compared with respect to the same residence time, withcores monolithic of different cores lengths of different were compared lengths were with respectcompared to thewith same respect residence to the same time, residence equal to 5 time, min. equal to 5 min. Similar conversions of cyclohexanone, about 40%, were achieved in all microreactors equalSimilar to conversions5 min. Similar of conversion cyclohexanone,s of cyclohexanone, about 40%, were about achieved 40%, were in all achieved microreactors in all microreactors of a 1–8 cm of a 1–8 cm length, which evidenced the lack of transport constraints (Figure 2). oflength, a 1–8 whichcm length, evidenced which the evidenced lack of transport the lack of constraints transport (Figureconstraints2). (Figure 2).

Figure 2. Conversion of cyclohexanone in microreactors of different lengths for a residence time of Figure 2. Conversion of cyclohexanone in microreactors of different lengths for a residence time of 5 min. 5 min. The results of kinetic experiments for cyclohexanone reduction are depicted in Figure 3. The results of kinetic experiments for cyclohexanone reduction are depicted in Figure 3. FigureThe 3a results shows of the kinetic single experiments experimental for run cyclohexanone carried out reductionfor 6 h at are95 °C depicted in a 6 cm in Figurelong microreactor.3. Figure3a Figure 3a shows the single experimental run carried out for◦ 6 h at 95 °C in a 6 cm long microreactor. showsThe reaction the single rate experimental constant (Figure run carried 3c) was out determin for 6 h ated 95 by Cassuming in a 6 cm the long firs microreactor.t order kinetics The and reaction was The reaction rate constant (Figure 3c) was determined by assuming the first order kinetics and was ratecalculated constant using (Figure Equation3c) was (1): determined by assuming the ﬁrst order kinetics and was calculated using calculated using Equation (1): Equation (1): ln(C0/C) = kτ (1) ln(Cln(C00/C)/C) = k τ (1)(1) where C0 [mmol·cm−3] is the initial concentration of ketone, C [mmol·cm−3] the substrate where C0 [mmol·cm−3] is the initial concentration of ketone, C [mmol·cm−3] the substrate concentration after the reaction in the microreactor of a fixed length, k [min−1] the rate constant, concentration after the reaction in the microreactor of a fixed length, k [min−1] the rate constant, τ [min] the residence time. τ [min] the residence time.

Catalysts 2018, 8, 221 4 of 8

−3 −3 where C0 [mmol·cm ] is the initial concentration of ketone, C [mmol·cm ] the substrate concentration after the reaction in the microreactor of a ﬁxed length, k [min−1] the rate constant, Catalysts 2018, 8, x FOR PEER REVIEW 4 of 8 CatalystsCatalysts 2018 ,2018 8,τCatalysts Catalystsx[min] ,FOR 8, x FORPEER 20182018 the PEER ,REVIEW, residence 88,, xx REVIEW FORFOR PEER PEER time. REVIEWREVIEW 4 of 84 of 8 44 ofof 88

FigureFigure Figure3. (3.a) (Conversion a3.) ConversionFigure(Figurea) Conversion 3.3. 3.of ( (a ( aacyclohexanone)of)) Conversion Conversion Conversioncyclohexanone of cyclohexanone of of ofin cyclohexanone cyclohexanone cyclohexanone thein the 6-cm-longin 6-cm-longthe 6-cm-long in in themicroreactor.in thethemicroreactor. 6-cm-long 6-cm-long6-cm-longmicroreactor. microreactor.(b) (microreactor.microreactor.Catalyticb) Catalytic(b) Catalytic (resultsb) Catalyticresults ((bb) ) resultsforCatalyticCatalytic for results for results results for MPV forfor ◦ ◦ ◦ ◦ MPVMPV reductionMPV reduction reduction reductionatMPVMPV 65at 65reduction°Creductionat °C at65( 65(°C ), C(at75at( ), 657565),°C ), 75 °C°C75( C( ((°C ), ),85( ), ), 85 758575°C ), C( °C°C85( ), ),(°C andand ), ( ), ),and 95 ),859585 C(and 95°C°C )°C(95( in ), )), the( °C inandand ) microreactor(inthe )9595 thein microreactor °C°C themicroreactor (( microreactor )(points—experiments, ) inin thethe microreactormicroreactor lines-model). (c) Plot of ln (C /C)0 versus contact time. (points—experiments,(points—experiments,(points—experiments,(points—experiments,(points—experiments, lines-model). lines-model). lines-model). (c) Plot( lines-model).clines-model).) Plot (ofc) 0 ln Plotof (C ln of /C)(C ln((0cc /C))versus ) (C PlotPlot 0versus/C) ofof contactversus lnln contact (C(C00 /C) /C)contacttime. versusversustime. time. contactcontact time.time.

FigureFigure Figure3b 3bconfirms confirms 3bFigure Figureconfirms good 3good 3b3bb agreement confirms confirmsgoodconfirms agreement agreement good goodgood between between agreement agreementagreement between the the experimental between experimental thebetweenbetween experimental the thethe data experimental experimental experimentaldata and data and the and the model data datamodelthedata modelprediction and andand prediction the thethe prediction model modelmodel of of prediction predictionprediction of of ofof thethe first-order first-orderthe first-order kineticsthethe kinetics first-orderfirst-orderfirst-order kinetics for forthe the forMPV kineticskineticskinetics MPVthe process MPV process forforfor thetheprocessthe carried MPV MPVcarried carried out processprocess out at differentoutat carriedcarried different at different temperatures outout temperatures atat differenttemperaturesdifferent and temperaturestemperatures and contact and contact contact times times andand in times contact contactin in timestimes inin thethe range therange ofrange 5–40of the5–40the of min. range5–40rangerange min. Each min. ofofofEach 5–405–40point5–40 Each point min.min. min. correspondspoint corresponds EachEach corresponds pointpointpoint to correspondsthecorrespondstocorresponds the averageto theaverage average conversion toto conversion thethethe conversion averageaverageaverage obtained obtained conversionconversionconversion obtained in microreactorin microreactor obtainedobtainedobtainedin microreactor inin microreactormicroreactormicroreactor duringduringduring 6-h-long 6-h-long 6-h-longduring duringtests. tests. tests.6-h-long6-h-long tests.tests. TheThe linearThe linear linearrelationship relationshipTheThe relationship linearlinear rate relationshiprelationshipraterelationship constant rate constant constant vs. rateraterate vs.th e constantconstantvs.constantth contacte thcontacte contact vs.vs.vs.time timeth theth wase e time contact contactwas observed was observed time timeobserved throughwas was through observedobservedthrough the the whole throughthethroughwhole whole thethe wholewholewhole temperaturetemperaturetemperature range temperaturerangetemperature usedrange used in used thein rangerange the experiments.in theexperiments. usedused experiments. inin thethethe The experiments. experiments.experiments.The expe The experimental experimental rimental TheThe data experimentalexpe expedata are datarimentalrimental are in linearein line in with datadata linewith arethoseare with those inin calculatedlinelinethose calculated withwithwith calculated thosethose those calculatedcalculatedcalculated fromfrom first-orderfrom first-order first-order fromfromkinetics kinetics first-orderfirst-orderfirst-order kinetics equation. equation. equation. kineticskineticskinetics equation.equation. equation. TemperatureTemperatureTemperature dependenceTemperature Temperaturedependence dependence of dependence thedependenceofdependence the ofrate therate constant rate ofconstant ofof the constant thethe ratewa rate ratewas constant examined s constantwaconstant examineds examined was inwawa examined theinss examinedexaminedthe inrange therange in ofrange the in65–95inof range thethe65–95 of range°C65–95range of °C 65–95and andof°Cof is 65–95◦ 65–95and Cis and is °C°C is shownandand isis shownshownshown in inFigure Figureininshownshown Figure4. Figure The4. inThe in4 4. .activation Figure Figure TheThe activation activationactivation 4.4. energyTheThe energy energyactivationactivation energy was was wasesti was estienergyenergymated estimated matedesti mated fromwaswas from estiesti linearfrom linearmatedlinearmated linearregres regression regresfromfrom sionregres sionlinearlinear analysis, analysis,sion analysis, regresregres analysis, and andsionsion and it analysis, analysis,and appearedit it andand to be itit −1 −1 appearedappearedappeared to beto 52be52appeared appearedto kJ52 kJbe·· molkJmol 52·mol kJ− to,to1 ·andmol,− 1be andbe, and 52−52frequency1, frequency andkJkJfrequency··molmol frequency−−11 ,factor, andand factor factor frequencyfrequency kfactor∞ k ∞ k=∞ =2.69 =k 2.69 ∞2.69 factor minfactor= min2.69 min. − kkmin−1∞1∞. ==− 2.6912.69. minmin−−11..

FigureFigure 4.Figure Arrhenius 4. Arrhenius 4. ArrheniusFigureFigure plot plot 4.for4. Arrhenius Arrhenius plot forthe the MPVfor MPVthe reductionplotplot MPV reduction forfor reduction thethe of MPV MPVcyclohexanone. of cyclohexanone. reductionofreduction cyclohexanone. of of cyclohexanone.cyclohexanone.

The studiesThe studies of theThe ofMPV studies the reductionMPV of thereduction MPVin the reduction inflow the process flow in theprocess were flow extendedwere process extended towere other extendedto ketonesother ketonesto and other andketones and The studies Theof the studies MPV ofreduction the MPV in reductionthe flow process in the ﬂowflow were processprocess extended werewere to extendedextendedother ketones to otherother and ketonesketones and aldehydes,aldehydes, and aldehydes,the and results, the andresults, i.e., the the i.e.,results, conversion the conversioni.e., , theproductivity, conversion, productivity, ,and productivity, reaction and reaction rate and constant ratereaction constant arerate constantare are aldehydes, andaldehydes, the results, andand the thei.e., results, results,the i.e.,conversion thei.e., conversion, the, productivity,conversion productivity,, productivity, and andreaction reaction and rate ratereaction constant constant rate are constant summarized are summarizedsummarizedsummarized in summarizedTablesummarizedin Table in 1.Table Analysis1. Analysis 1.inin Analysis TableTable of theseof 1.1. these AnalysisofAnalysis data these data show data of ofshow thesetheses showthats that data dataaldehydess that aldehydes showshow aldehydesss arethatthat are easier aldehydesaldehydes areeasier toeasier beto arebereducedare to reduced easierbeeasier reduced than toto than bebe thanreducedreduced thanthan in Table1. Analysis of these data shows that aldehydes are easier−1 to be reduced than ketones. ketones.ketones. The reaction Theketones. reaction rate The constant ratereaction constant of rate benzaldehyde constantof benzaldehyde of reductionbenzaldehyde reduction was 0.212reduction was min0.212 was, min−while1 0.212−1, whilethat min for −−that11, while for that for ketones. TheTheketones. reaction reaction The rate rate reaction constant constant rate of of benzaldehydeconstant benzaldehyde of benzaldehyde reduction waswas reduction 0.2120.212 min min was−1,, while 0.212while that minthat for ,for cyclohexanonewhile that for cyclohexanonecyclohexanone wascyclohexanone twice was lower.twice was lower.Battilocchio twice Battilocchio lower. et alBattilocchio. alsoet al .found also et foundthatal. also aldehydes, that found aldehydes, thatcompared aldehydes, compared with compared with with cyclohexanonewascyclohexanone was twice twice lower. lower. was Battilocchio twiceBattilocchio lower. et al. Battilocchioet alsoal. also found found et that al. aldehydes,thatalso aldehydes,found comparedthat comparedaldehydes, with aliphaticwith compared ketones, with aliphaticaliphaticaliphatic ketones, ketones, aliphaticaliphaticketones, required required requiredketones,ketones, a shorter a shorter requiredarequired shorter reaction reaction aareaction shorter shortertime time for timereactionreaction forcomplete completefor completetimetime conversion forforconversion completecompleteconversion to alcoholsto conversionconversion alcohols to alcohols [16]. [16]. to toSteric [16].alcoholsalcohols Steric Steric [16].[16]. StericSteric hindrancehindrancehindrance is ais prevalent hindranceahindrance isprevalent a prevalent factor isis factor aa prevalent prevalent thatfactor that affects that affects factorfactor affectsthe the reactithatthat thereacti affectsaffectsvity reactivity of the vity thetheof thereacti reactisubstrates.of thesubstrates.vityvity substrates. ofof Citral thethe Citral substrates.substrates. isCitral ais mixture a ismixture a CitralCitral mixture of cis- ofisis acis-a of mixturemixture cis- ofof cis-cis- andand trans-isomersand trans-isomers trans-isomersandand signified trans-isomerstrans-isomers signified signified as neralas neral signifiedassignified and neral and geranial, and asgeranial,as neralneral geranial, respectively. and andrespectively. geranial,respectively.geranial, The respectively.respectively.The MPV The MPV reduction MPV reduction TheThe reduction MPVMPVof citralof reductioncitralreduction of reveals citral reveals reveals ofof citralcitral revealsreveals thethe preferential preferentialthe preferential theformationthe formation preferentialpreferential formation of itsof formationitstransformation of trans its product. trans product. ofof product. itsits The transtrans The yield The product.product.yield of yield geraniolof geraniol The Theof geraniol yieldyield was was of20%of was geraniolgeraniol20% higher 20% higher was higherwasthan than 20%20% nerol. than nerol. higherhigher Thenerol. The thanthan The nerol.nerol. TheThe orientationorientationorientation of theoforientationorientation the ofcarbonyl thecarbonyl carbonyl ofofgroup thethegroup carbonylcarbonylgroupto theto the tomolecular groupgroupthemolecular molecular toto chain thethe chain molecularmolecular inchain geranialin geranial in geranialchainchain reduces reduces inin reducesgeranialgeranial steric steric limitations steric reducesreduces limitations limitations stericsteric for for limitationslimitations for forfor bindingbindingbinding between between betweenbindingbinding the the Zr Zrthecenterbetweenbetween center Zr centerand thetheand C=O. ZrZrand C=O. centercenter C=O. and and C=O.C=O.

Catalysts 2018, 8, 221 5 of 8 required a shorter reaction time for complete conversion to alcohols [16]. Steric hindrance is a prevalent factor that affects the reactivity of the substrates. Citral is a mixture of cis- and trans-isomers signiﬁed as neral and geranial, respectively. The MPV reduction of citral reveals the preferential formation of its trans product. The yield of geraniol was 20% higher than nerol. The orientation of the carbonyl group to the molecular chain in geranial reduces steric limitations for binding between the Zr center and C=O.

CatalystsCatalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 55 ofof 88 CatalystsCatalysts 20182018,,, 88,,, xxx FORFORFOR PEERPEERPEER REVIEWREVIEWREVIEW 55 ofof 88 CatalystsCatalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW Table 1. Data from catalytic experiments. 55 ofof 88 TableTable 1.1. DataData fromfrom catalyticcatalytic experiments.experiments. TableTable 1.1. DataData fromfrom catalyticcatalytic experiments.experiments. TableTableConversion 1.1. DataData fromfrom1, * catalyticcatalyticProductivity experiments.experiments.1,* Productivity 2 Productivity 3 1 −1TableConversion 1. Data from1,* catalyticProductivity experiments. 1,* Productivity 2 Productivity 3 Substrate K 1 [min−1 ] Conversion 1,* Productivity 1,*− 1 −Productivity1 2 −1Productivity−1 3 −1 −1 Substrate K 1 [min −1] 1,1, · 1,1, · 22 · · 33 · · Substrate K [min ] ConversionConversion[%] 1, 1,** ProductivityProductivity[mmol−1 g 1,cat−1,*1* h ProductivityProductivity] [mmol−1 − 221 gcat ProductivityProductivityh ] −1 [mmol − 331 gcat h ] SubstrateSubstrate KK 11 [min[min−−11]] ConversionConversion[%] 1,** Productivity[mmolProductivity·gcat −1·h 1,−**1] [mmolProductivityProductivity·gcat −1·h −2 1 ] [mmolProductivityProductivity·gcat −1·h −3 1 ] SubstrateSubstrate KK 1 1 [min [min−−11]] Conversion[%] * Productivity[mmol·gcat−−11 ·h −−11*] [mmolProductivity·gcat−−11 ·h−− 11 ] [mmolProductivity·gcat−−11 ·h−− 11 ] Substrate K 1 [min−1] [%][%] [mmol[mmol···ggcatcatcat−−11···hh−−11]] [mmol[mmol···ggcatcatcat−−11···hh−−11]] [mmol[mmol···ggcatcatcat−−11···hh−−11]] Substrate K [min ] [%][%] [mmol[mmol··ggcatcat−1··hh−1]] [mmol[mmol··ggcatcat−1··hh−1]] [mmol[mmol··ggcatcat−1··hh−1]] [%] [mmol·gcat−1·h−1] [mmol·gcat−1·h−1] [mmol·gcat−1·h−1] 0.1060.106 8888 88 2.22 2.22 2.22 - - - 2.28 2.28 [21][21] 2.28 [21] 0.1060.106 8888 2.22 2.22 - - 2.28 2.28 [21][21] 0.1060.106 8888 2.22 2.22 - - 2.28 2.28 [21][21]

0.0210.021 3535 0.9 0.9 - - 0.11 0.11 [15][15] 0.0210.0210.021 3535 35 0.9 0.9 0.9 - - - 0.11 0.11 [15][15] 0.11 [15] 0.0210.021 3535 0.9 0.9 - - 0.11 0.11 [15][15]

0.2120.212 99 99 2.64 2.64 1.14 1.14 [16][16] 0.36 0.36 [10][10] 0.2120.2120.212 99 99 99 2.64 2.64 2.64 1.14 1.14 [16][16] 1.14 [16] 0.36 0.36 [10][10] 0.36 [10] 0.2120.212 99 99 2.64 2.64 1.14 1.14 [16][16] 0.36 0.36 [10][10]

0.081 80 1.92 0.66 [16] 0.48 [5] 0.0810.0810.081 80 80 80 80 1.92 1.92 1.92 1.92 0.66 0.66 0.66 [16] [16][16] 0.66 [16] 0.48 0.48 0.48 [5] [5][5] 0.48 [5] 0.0810.081 80 80 1.92 1.92 0.66 0.66 [16][16] 0.48 0.48 [5][5] 0.081 80 1.92 0.66 [16] 0.48 [5]

4 0.031/0.047 4 46/61 0.48/0.9 - 0.54 [5] 0.031/0.0474 4 4 46/61 0.48/0.9 - 0.54 [5] 0.031/0.0470.031/0.047 44 46/6146/6146/6146/61 0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9 - - - - 0.54 0.54 0.54 [5][5][5] 0.54 [5] 0.031/0.0470.031/0.047 4 46/6146/61 0.48/0.9 0.48/0.9 - - 0.54 0.54 [5][5]

0.0260.026 40 40 0.96 0.96 0.48 0.48 [16][16] 0.12 0.12 [22][22] 0.0260.026 40 40 0.96 0.96 0.48 0.48 [16][16] 0.12 0.12 [22][22] 0.0260.0260.026 40 40 40 0.96 0.96 0.96 0.48 0.48 [16][16] 0.48 [16] 0.12 0.12 [22][22] 0.12 [22]

0.080.08 8080 2.1 2.1 - - - - 0.080.08 8080 2.1 2.1 - - - - 0.080.080.08 8080 80 2.1 2.1 2.1 ------0.041 56 1.32 - 0.72 [23] 0.041 56 1.32 - 0.72 [23] 0.0410.041 5656 1.32 1.32 - - 0.72 0.72 [23][23] 1 0.041 2 56 1.32 - 3 0.72 [23] 1 this work (reaction temp.0.041 95 °C), 2 in the 56 flow process (data 1.32 form literature), 3 in the - batch process 0.72 [23] 11 thisthisthis workworkwork (reaction(reaction(reaction temp.temp.temp. 959595 °C),°C),°C), 22 ininin thethethe flowflowflow processprocessprocess (data(data(data formformform literature),literature),literature), 33 ininin thethethe batchbatchbatch processprocessprocess 11 thisthis workwork (reaction(reaction temp.temp.4 9595 °C),°C), 22 inin thethe flowflow processprocess (data(data formform literature),literature), 33 inin thethe batchbatch processprocess (data1 this formwork literature);(reaction temp. 4 nerol/geraniol; 95 °C),◦ 2 in *the data flow for processthe 4-cm-long (data form microreactor. literature), 3 in the batch process 1(data form literature);4 4 nerol/geraniol;2 * data for the 4-cm-long microreactor. 3 (data(datathis form workform literature);literature); (reaction temp.44 nerol/geraniol;nerol/geraniol;nerol/geraniol; 95 C), in *** datadatadata the for flowforfor thethe process 4-cm-long4-cm-long (data microreactor.microreactor. form literature), in the batch process (data form (data(data formform literature);literature); 4 nerol/geraniol;nerol/geraniol; ** datadata forfor thethe 4-cm-long4-cm-long microreactor.microreactor. literature);(data form 4literature);nerol/geraniol; nerol/geraniol; * data for * the data 4-cm-long for the 4-cm-long microreactor. microreactor. The impact of both the steric and electronic effect can be observed in the case of TheThe impactimpact ofof bothboth thethe stericsteric andand electronicelectronic effecteffecteffect cancancan bebebe observedobservedobserved ininin thethethe casecasecase ofofof cinnamaldehydeTheThe impactimpact reduction.ofof bothboth Thethethe lowstericsteric activity andand canelectronicelectronic be attributed effecteffect to can canthe presencebebe observedobserved of a bulky inin the thechain casecase in this ofof cinnamaldehydecinnamaldehydecinnamaldehyde reduction. reduction.reduction. The TheThe low lowlow activity activityactivity can cancan be bebe attr attrattributedibutedibuted to toto the thethe presence presencepresence of ofof a aa bulky bulkybulky chain chainchain in inin this thisthis cinnamaldehydesubstratecinnamaldehydeThe impactand double reduction.reduction. of both bond. the TheThe The steric lowlow productivity activityactivity and electronic cancan beinbe attrattrtheibuted effectibutedreduction to canto thethe beprocess presencepresence observed of ofofcinnamaldehyde aa inbulkybulky the chainchain case in ofin thiswasthis cinnamaldehyde substratesubstratesubstrate andandand doubledoubledouble bond.bond.bond. TheTheThe productivityproductivityproductivity ininin thethethe reductionreductionreduction processprocessprocess ofofof cinnamaldehydecinnamaldehydecinnamaldehyde waswaswas reduction.substratesignificantlysubstrate andand The lowerdoubledouble low activitythanbond.bond. that TheThe can productivityforproductivity be benzalde attributed ininhyde. thethe to reductionreduction theThe presencereduction processprocess of ofof aof bulky cinnamaldehydecinnamaldehydeunsaturated chain inketone, thiswaswas substrate and significantlysignificantlysignificantly lowerlowerlower thanthanthan thatthatthat forforfor benzaldebenzaldebenzaldehyde.hyde. TheThe reductionreduction ofof unsaturatedunsaturated ketone,ketone, significantly2-cyclohexen-1-on,significantly lowerlower is difficultthanthan thatthat without forfor affectingbenzaldebenzalde thehyde.hyde. conjugated TheThe reductionreduction C=C bond. ofof A significantunsaturatedunsaturated decrease ketone,ketone, in double2-cyclohexen-1-on,2-cyclohexen-1-on,2-cyclohexen-1-on, bond. The isisis productivity difficultdifficultdifficult withoutwithoutwithout in affecting theaffectingaffecting reduction thethethe conjugatedconjugatedconjugated process C=CC=CC=C of cinnamaldehyde bond.bond.bond. AAA significantsignificantsignificant decreasewasdecreasedecrease significantly ininin lower 2-cyclohexen-1-on,conversion2-cyclohexen-1-on, was observed isis difficultdifficult compared withoutwithout to affectingaffecting the satura thetheted conjugatedconjugated cyclic carbonyl C=CC=C bond.bond. comp AA ound significantsignificant (cyclohexanone); decreasedecrease inin thanconversionconversionconversion that for waswaswas benzaldehyde. observedobservedobserved comparedcomparedcompared The tototo reduction thethethe saturasaturasaturatedtedted of cycliccyclic unsaturatedcyclic carbonylcarbonylcarbonyl ketone,compcompcompoundound 2-cyclohexen-1-on, (cyclohexanone);(cyclohexanone); is difficult conversionnevertheless,conversion waswas the observedobserved product comparedwascompared obtained toto the thewith saturasatura 100%tedted selectivity. cycliccyclic carbonylcarbonyl Aromatic compcomp ketones,oundound (cyclohexanone);(cyclohexanone); compared with withoutnevertheless,nevertheless, affecting thethe productproduct the conjugated waswas obtainedobtained C=C withwith bond. 100%100% selectivity.selectivity. A significant AromaticAromatic decrease ketones,ketones, in comparedcompared conversion withwith was observed nevertheless,cyclicnevertheless, ketones, thethe are productproduct more difficult waswas obtainedobtained to reduce withwith due 100% 100%to the selectivity.selectivity. resonance AromaticandAromatic inductive ketones,ketones, effect comparedcompared of the benzene withwith cycliccycliccyclic ketones,ketones,ketones, areareare moremoremore difficultdifficultdifficult tototo reducereducereduce dueduedue tototo thethethe resonanceresonanceresonance andandand inductiveinductiveinductive effecteffecteffect ofofof thethethe benzenebenzenebenzene comparedcyclicringcyclic [22]. ketones,ketones, Itto explains the areare saturatedmoremore the differencedifficultdifficult cyclic toto in reducereduce carbonylconversion duedue to compoundtos ofthethe cyclohexanone resonanceresonance (cyclohexanone); andand and inductiveinductive acetophenone. effecteffect nevertheless, ofof No thethe products benzenebenzene the product was ringringring [22]. [22].[22]. ItItIt explainsexplainsexplains thethethe difference differencedifference in inin conversionconversionconversionsss ofofof cyclohexanonecyclohexanonecyclohexanone andandand acetophenone.acetophenone.acetophenone. No NoNo productsproductsproducts obtainedringarisingring [22].[22]. from It withIt explainsexplains the 100% Tischenko thethe selectivity. differencedifference cross reaction inin Aromatic conversionconversion or from ketones,ss oftheof cyclohexanonecyclohexanone aldol compared condensation andand with acetophenone.acetophenone. [24], cyclic were ketones, detected NoNo productsproducts for are any more difficult to arisingarisingarising fromfromfrom thethethe TischenkoTischenkoTischenko crosscrosscross reactionreactionreaction ororor fromfromfrom thethethe aldolaldolaldol condensationcondensationcondensation [24],[24],[24], werewerewere detecteddetecteddetected forforfor anyanyany reducearisingofarising the investigated from duefrom tothethe the TischenkoTischenko substrates. resonance crosscross This andreactionreaction evidenced inductive oror fromfrom the theexcellent effectthe aldolaldol of condensationselectivitycondensation the benzene of the [24],[24], ring proposed werewere [22 detecteddetected]. catalyst. It explains forfor anyany the difference ofof thethe investigatedinvestigated substrates.substrates. ThisThis evidencedevidenced ththeee excellent excellentexcellent selectivity selectivityselectivity of ofof the thethe proposed proposedproposed catalyst. catalyst.catalyst. ofof thetheIt investigated investigatedshould furthermore substrates.substrates. be ThisThishighlighted evidencedevidenced that thth alcoholsee excellentexcellent produced selectivityselectivity by oftheof thethe selective proposedproposed hydrogenation catalyst.catalyst. of in conversionsItItIt shouldshouldshould furthermorefurthermorefurthermore of cyclohexanone bebebe highlightedhighlightedhighlighted and thatthatthat acetophenone. alcoholsalcoholsalcohols producedproducedproduced No productsbybyby thethethe selectiveselectiveselective arising hydrogenationhydrogenationhydrogenation from the Tischenko ofofof cross carbonyl-bearingItIt shouldshould furthermorefurthermore substrates bebe are highlightedhighlighted fine chemicals thatthat of alcoholsalcohols primary producedproduced interest. byTheyby thethe are selectiveselective used as hydrogenationhydrogenation flavor additives, ofof reactioncarbonyl-bearingcarbonyl-bearingcarbonyl-bearing or from substrates substratessubstrates the aldol are areare condensation fine finefine chemicals chemicalschemicals of ofof [24 primary primaryprimary], were interest. interest.interest. detected They TheyThey for are areare anyused usedused ofas asas flavor flavor theflavor investigated additives, additives,additives, substrates. carbonyl-bearingandcarbonyl-bearing intermediates substratessubstrates in drug areare prod finefine uction. chemicalschemicals Products ofof primaryprimary of interest.interest.the esteri TheyTheyfication areare usedused of asascinnamyl flavorflavor additives,additives, alcohol, andandand intermediatesintermediatesintermediates ininin drugdrugdrug prodprodproduction.uction. ProductsProducts ofof thethe esteriesterificationficationfication ofofof cinnamylcinnamylcinnamyl alcohol,alcohol,alcohol, Thisandindole-3-aceticand evidencedintermediatesintermediates acid, the in in excellentor drugdrugα-lipoic prodprod selectivity aciduction.uction. were Products Products ofstudied the proposed forofof thetheirthe esteri esteri catalyst.antioxidantficationfication andofof cinnamylcinnamylanti-inflammatory alcohol,alcohol, indole-3-aceticindole-3-aceticindole-3-acetic acid,acid,acid, ororor αα-lipoic-lipoic-lipoic acidacidacid werewerewere studiedstudiedstudied forforfor theirtheirtheir antioxidantantioxidantantioxidant andandand anti-inflammatoryanti-inflammatoryanti-inflammatory indole-3-aceticactivityindole-3-aceticIt should [25], and acid, furthermoreacid, graniol oror αwasα-lipoic-lipoic checked be acidacid highlighted inwerewere colo nstudiedstudied cancer that forchemoprevention alcoholsfor theirtheir antioxidantantioxidant produced and andtreatment byand the anti-inflammatoryanti-inflammatory selective [26]. hydrogenation of activityactivityactivity [25], [25],[25], and andand graniol graniolgraniol was waswas checked checkedchecked in inin colo colocolonn cancercancer chemopreventionchemoprevention andand treatmenttreatment [26].[26]. carbonyl-bearingactivityactivityOur [25],[25], results andand were graniolgraniol substrates compared waswas checkedchecked areto the fine in inliterature colocolo chemicalsnn cancercancer data fo ofchemopreventionchemopreventionr primaryflow and batch interest. andprocesses.and treatmenttreatment They To are the [26].[26]. used best of as our flavor additives, OurOur resultsresults werewere comparedcompared toto thethe literatureliterature datadata foforrr flow flowflow and andand batch batchbatch processes. processes.processes. To ToTo the thethe best bestbest of ofof our ourour knowledge,OurOur resultsresults the wereMPVwere comparedcomparedprocess using toto thethe heterogeneous literatureliterature datadata powdered foforr flowflow andand catalyst batchbatch processes.atprocesses. flow conditions ToTo thethe bestbest has ofof only ourour andknowledge,knowledge, intermediates thethethe MPVMPVMPV in processprocess drugprocess production. usingusingusing heterogeneousheterogeneousheterogeneous Products powderedpowderedpowdered of the esterification catalystcatalystcatalyst atatat flowflowflow of cinnamyl conditionsconditionsconditions alcohol, hashashas onlyonlyonly indole-3-acetic knowledge,knowledge, thethe MPVMPV processprocess usingusing heterogeneousheterogeneous powderedpowdered2 catalystcatalyst atat flowflow conditionsconditions hashas onlyonly beenknowledge,been publishedpublished the ininMPV oneone process paperpaper [1[1 using6].6]. TheThe heterogeneous productivitiesproductivities powdered ofof ZrOZrO2-based-based catalyst reactorsreactors at flow towardtoward conditions benzylbenzyl has alcohol,alcohol, only acid,been orpublishedα-lipoic in acid one werepaper studied[16]. The for productivities their antioxidant of ZrO22-based-based and anti-inflammatory reactorsreactors towardtoward benzylbenzyl activity alcohol,alcohol, [25 ], and graniol beenbeen publishedpublished inin oneone paperpaper [1[16].6]. TheThe productivitiesproductivities ofof ZrOZrO22-based-based reactorsreactors towardtoward benzylbenzyl alcohol,alcohol, cinnamylbeen published alcohol, in andone 1-phenylethanolpaper [16]. The productivities are nearly 4 times of ZrO lower2-based than reactors those achieved toward benzyl in the alcohol,studied wascinnamylcinnamylcinnamyl checked alcohol,alcohol,alcohol, in colon andandand 1-phenylethanol1-phenylethanol1-phenylethanol cancer chemoprevention areareare nearlynearlynearly 444 timestimestimes and lowertreatmentlowerlower thanthanthan thosethose [those26]. achievedachievedachieved ininin thethethe studiedstudiedstudied cinnamylmonolithiccinnamyl alcohol,alcohol, microreactors. andand 1-phenylethanol1-phenylethanol Table 1 shows areare the nearlynearly producti 44 timestimesvities lowerlower from thanthan batch thosethose reactors achievedachieved obtained inin thethe by studiedstudied other monolithicmonolithic microreactors.microreactors. TableTable 11 showsshows thethe productiproductivitiesvities fromfrom batchbatch reactorsreactors obtainedobtained byby otherother monolithicresearch.monolithic They microreactors.microreactors. are significantly TableTable lower 11 showsshows than thethe those productiproducti obtainedvitiesvities in from fromthe proposed batchbatch reactorsreactors flow system obtainedobtained (except byby otherother one research.research.research. TheyTheyThey areareare significantlysignificantlysignificantly lowerlowerlower thanthanthan thosethosethose obobobtainedtainedtained ininin thethethe proposedproposedproposed flowflowflow systemsystemsystem (except(except(except oneoneone research.case).research. It was TheyThey due areare to significantlysignificantly excellent mixing lowerlower and thanthan mass thosethose transfer obobtainedtained conditions, inin thethe proposedproposed offered by flowflow innovative systemsystem (except (exceptmonolithic oneone case).case).case). ItItIt waswaswas dueduedue tototo excellentexcellentexcellent mixingmixingmixing andandand massmassmass transfertransfertransfer conditions,conditions,conditions, offeredofferedoffered bybyby innovativeinnovativeinnovative monolithicmonolithicmonolithic case).microreactorcase). ItIt waswas due duecharacterized toto excellentexcellent mixingmixingby high andand surface-to-volume massmass transfertransfer conditions,conditions, ratios. offeredofferedApplication byby innovativeinnovative of the monolithicmonolithicproposed microreactormicroreactor characterizedcharacterized byby highhigh surface-to-volumesurface-to-volume ratios.ratios. ApplicationApplication ofof thethe proposedproposed microreactormicroreactor characterizedcharacterized byby highhigh surface-to-volumesurface-to-volume ratios.ratios. ApplicationApplication ofof thethe proposedproposed

Catalysts 2018, 8, 221 6 of 8

Our results were compared to the literature data for flow and batch processes. To the best of our knowledge, the MPV process using heterogeneous powdered catalyst at flow conditions has only been published in one paper [16]. The productivities of ZrO2-based reactors toward benzyl alcohol, cinnamyl alcohol, and 1-phenylethanol are nearly 4 times lower than those achieved in the studied monolithic microreactors. Table1 shows the productivities from batch reactors obtained by other research. They are significantly lower than those obtained in the proposed flow system (except one case). It was due to excellent mixing and mass transfer conditions, offered by innovative monolithic microreactor characterized by high surface-to-volume ratios. Application of the proposed continuous-flow microreactor for the MPV process offers not only enhanced productivity, but also facilitates process handling by excluding contact with reaction media. The latter is of importance when working with dangerous substances.

3. Materials and Methods Microreactors were fabricated using silica monoliths as cores. The monoliths were obtained by combined sol-gel and phase separation methods described in details in [20]. Briefly, polyethylene glycol (PEG 35 000, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in 1 M nitric acid (Avantor, 65%, Gliwice, Poland). The mixture was cooled in the ice bath and subsequently tetraethoxysilane (TEOS, ABCR, 99%, Karlsruhe, Germany) was added dropwise. After 30 min of stirring, cetyltrimethylammonium bromide (CTAB, Sigma-Aldrich) was added. After complete dissolution, the sol was transferred to the polypropylene molds and stored at 40 ◦C for 8 days for gelation and aging. Next, rod-shaped monoliths were washed with deionized water and treated with 1 M ammonia solution (Avantor, 25%) for 8 h at 90 ◦C. Afterward, the materials were washed, dried at 40 ◦C for 3 days, and finally calcined at 550 ◦C for 8 h to remove organic templates. The prepared monoliths of diameter 4.5 mm were put into heat-shrinkable tubes and equipped with connectors to obtain flow microreactors. Zirconium propoxide moieties were grafted onto silica carriers, maintaining Zr/Si ratio fixed at 0.14 and using a solution of zirconium(IV) propoxide (Sigma Aldrich, 70% in 1-propanol) in anhydrous ethanol (Avantor, 99.8%). Reactive cores were impregnated with the solution and kept for 24 h at 70 ◦C. Finally, they were washed with ethanol and dried at 110 ◦C in nitrogen flow conditions. Structural properties were analyzed by electron microscopy (TM 30000, Hitachi, Chiyoda, Tokyo, Japan) and adsorption–desorption measurements (ASAP 2020, Micromeritics, Norcross, GA, USA). The continuous-flow microreactors were tested in the MPV reduction of various carbonyl compounds (cyclohexanone: Sigma Aldrich, 99%, benzaldehyde: Sigma-Aldrich, 99%, acetophenone: Acros, Geel, Belgium, 98%, cinnamaldehyde: Acros, 99%, citral: Roth, 95–98%, Karlsruhe, Germany, hexanal: Aldrich, Saint Louis, MO, USA, 98%, nonanal: Aldrich, 95%, 2-cyclohexen-1-one: Acros, 97%) with 2-butanol (Avantor 99%). The molar ratio of substrates was 1:52. The flow rate was changed in the range of 0.03–0.24 cm3·min−1. The progress and selectivity of the reaction were monitored by gas chromatography (FID detector, HP-5 column, 7890A, Agilent, Santa Clara, CA, USA). The kinetic experiments were carried out in setup shown in Figure5 for a flow rate fixed at 0.03 cm3·min−1, at the temperature range of 65–95 ◦C. The mass of the 1-cm-long microreactor was 0.0375 g. The length of reactive cores was changed from 1 to 8 cm (weight form 0.0375–0.3 g) and enabled the obtainment of data for different residence times, calculated using Equation (2):

m ·l·V 0.0375·l·V τ = k T = T (2) F F

−1 where mk is the mass of monolith per length unit [g·cm ], l is the microreactor length [cm], VT is the total pore volume, equal to −4 [cm3·g−1] (data from mercury porosimetry), and F is the ﬂow rate [cm3·min−1]. Catalysts 2018, 8, x FOR PEER REVIEW 6 of 8 continuous-flow microreactor for the MPV process offers not only enhanced productivity, but also facilitates process handling by excluding contact with reaction media. The latter is of importance when working with dangerous substances.

3. Materials and Methods Microreactors were fabricated using silica monoliths as cores. The monoliths were obtained by combined sol-gel and phase separation methods described in details in [20]. Briefly, polyethylene glycol (PEG 35 000, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in 1 M nitric acid (Avantor, 65%, Gliwice, Poland). The mixture was cooled in the ice bath and subsequently tetraethoxysilane (TEOS, ABCR, 99%, Karlsruhe, Germany) was added dropwise. After 30 min of stirring, cetyltrimethylammonium bromide (CTAB, Sigma-Aldrich) was added. After complete dissolution, the sol was transferred to the polypropylene molds and stored at 40 °C for 8 days for gelation and aging. Next, rod-shaped monoliths were washed with deionized water and treated with 1 M ammonia solution (Avantor, 25%) for 8 h at 90 °C. Afterward, the materials were washed, dried at 40 °C for 3 days, and finally calcined at 550 °C for 8 h to remove organic templates. The prepared monoliths of diameter 4.5 mm were put into heat-shrinkable tubes and equipped with connectors to obtain flow microreactors. Zirconium propoxide moieties were grafted onto silica carriers, maintaining Zr/Si ratio fixed at 0.14 and using a solution of zirconium(IV) propoxide (Sigma Aldrich, 70% in 1-propanol) in anhydrous ethanol (Avantor, 99.8%). Reactive cores were impregnated with the solution and kept for 24 h at 70 °C. Finally, they were washed with ethanol and dried at 110 °C in nitrogen flow conditions. Structural properties were analyzed by electron microscopy (TM 30000, Hitachi, Chiyoda, Tokyo, Japan) and adsorption–desorption measurements (ASAP 2020, Micromeritics, Norcross, GA, USA). The continuous-flow microreactors were tested in the MPV reduction of various carbonyl compounds (cyclohexanone: Sigma Aldrich, 99%, benzaldehyde: Sigma-Aldrich, 99%, acetophenone: Acros, Geel, Belgium, 98%, cinnamaldehyde: Acros, 99%, citral: Roth, 95–98%, Karlsruhe, Germany, hexanal: Aldrich, Saint Louis, MO, USA, 98%, nonanal: Aldrich, 95%, 2-cyclohexen-1-one: Acros, 97%) with 2-butanol (Avantor 99%). The molar ratio of substrates was 1:52. The flow rate was changed in the range of 0.03–0.24 cm3·min−1. The progress and selectivity of theCatalysts reaction2018, 8 ,were 221 monitored by gas chromatography (FID detector, HP-5 column, 7890A, Agilent,7 of 8 Santa Clara, CA, USA).

Figure 5. Scheme of the reaction setup.

4. ConclusionsThe kinetic experiments were carried out in setup shown in Figure 5 for a flow rate fixed at 0.03 cm3·min−1, at the temperature range of 65–95 °C. The mass of the 1-cm-long microreactor was 0.0375 g. TheThe length outstanding of reactive potential cores was of continuous-flow changed from 1 microreactors to 8 cm (weight in theform area 0.0375–0.3 of selective g) and reduction enabled of thecarbonyl obtainment compounds of data was for different demonstrated. residence Broad-range times, calculated and long-term using Equation experiments (2): were conducted to determine the kinetics of the MPV reaction of∙∙ cyclohexanone.∙∙ in the zirconium-functionalized flow = = microreactors. The lack of diffusion constraints in the microreactors was shown. The activation energy(2) was calculated to be 52 kJ·mol−1. Moreover, reaction rate constants for several ketones and aldehydes where mk is the mass of monolith per length unit [g·cm−1], l is the microreactor length [cm], VT is the weretotal pore collected. volume, The equal rate ofto the−4 process[cm3·g−1] is (data necessary from tomercury design porosimetry), the apparatus and and F reaction is the flow systems. rate [cmSignificant3·min−1]. differences in process efficiency were recorded for various carbonyl compounds. They were assigned to steric effects caused by bulky chains, electronic effects of an additional double bond, and an inductive effect of the benzene ring. We believe that the proposed system can be effectively exploited for fine chemical and pharmaceutical production.

Author Contributions: A.C. and K.M. conceived, designed, and performed the experiments; A.C., K.M., and J.M.-B. analyzed the data and wrote the paper. Funding: This research was funded by the National Science Centre, Poland: DEC-2017/01/X/ST8/00083. Acknowledgments: The financial support of the National Science Centre, Poland (project no. DEC-2017/01/X/ST8/00083), is gratefully acknowledged. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Liu, S.H.; Jaenicke, S.; Chuah, G.K. Hydrous zirconia as a selective catalyst for the Meerwein–Ponndorf– Verley reduction of cinnamaldehyde. J. Catal. 2002, 206, 321–330. [CrossRef] 2. Plessers, E.; Fu, G.X.; Tan, C.Y.X.; De Vos, D.E.; Roeffaers, M.B.J. Zr-based MOF-808 as Meerwein–Ponndorf– Verley reduction catalyst for challenging carbonyl compounds. Catalysts 2016, 6, 104. [CrossRef] 3. Axpuac, S.; Aramendía, M.A.; Hidalgo-Carrillo, J.; Marinas, A.; Marinas, J.M.; Montes-Jiménez, V.; Urbano, F.J.; Borau, V. Study of structure–performance relationships in Meerwein–Ponndorf–Verley reduction of crotonaldehyde on several magnesium and zirconium-based systems. Catal. Today 2012, 187, 183–190. [CrossRef] 4. Zapilko, C.; Liang, Y.C.; Nerdal, W.; Anwander, R. A general strategy for the rational design of size-selective mesoporous catalysts. Chem. Eur. J. 2007, 13, 3169–3176. [CrossRef][PubMed] 5. Aramendía, M.A.A.; Borau, V.; Jiménez, C.; Marinas, J.M.; Ruiz, J.R.; Urbano, F. Reduction of α,β-unsaturated

aldehydes with basic MgO/M2O3 catalysts (M=Al, Ga, In). Appl. Catal. A Gen. 2003, 249, 1–9. [CrossRef] 6. Uysal, B.; Oksal, B.S. A new method for the chemoselective reduction of aldehydes and ketones using boron i tri-isopropoxide, B(O Pr)3: Comparison with boron tri-ethoxide, B(OEt)3. J. Chem. Sci. 2011, 123, 681–685. [CrossRef]

7. Uysal, B.; Oksal, B.S. New heterogeneous B(OEt)3-MCM-41 catalyst for preparation of α,β-unsaturated alcohols. Res. Chem. Intermed. 2015, 41, 3893–3911. [CrossRef] 8. Meerwein, H.; Schmidt, R. Ein neues verfahren zur reduktion von aldehyden und ketonen. Justus Liebigs Ann. Chem. 1925, 444, 221–238. [CrossRef]

9. Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka, K. Zr(OBut)4 as an effective promoter for the Meerwein–Ponndorf–Verley alkynylation and cyanation of aldehydes: Development of new asymmetric cyanohydrin synthesis. Tetrahedron 2001, 57, 867–873. [CrossRef] Catalysts 2018, 8, 221 8 of 8

10. Wang, J.; Okumura, K.; Jaenicke, S.; Chuah, G.K. Post-synthesized zirconium-containing beta zeolite in Meerwein–Ponndorf–Verley reduction: Pros and cons. Appl. Catal. A Gen. 2015, 493, 112–120. [CrossRef] 11. Creyghton, E.J.; Downing, R.S. Shape-selective hydrogenation and hydrogen transfer reactions over zeolite catalysts. J. Mol. Catal. A Chem. 1998, 134, 47–61. [CrossRef] 12. Zhang, B.; Xie, F.; Yuan, J.; Wang, L.; Deng, B.X. Meerwein–Ponndorf–Verley reaction of acetophenone over

ZrO2-La2O3/MCM-41: Influence of loading order of ZrO2 and La2O3. Catal. Commun. 2017, 92, 46–50. [CrossRef] 13. Sushkevich, V.L.; Ivanova, I.I.; Tolborg, S.; Taarning, E. Meerwein–Ponndorf–Verley-Oppenauer reaction of crotonaldehyde with ethanol over Zr-containing catalysts. J. Catal. 2014, 316, 121–129. [CrossRef] 14. Rodriguez-Castellon, E.; Jimenez-Lopez, A.; Maireles-Torres, P.; Jones, D.I.; Roziere, J.; Trombetta, M.; Busca, G.; Lenarda, M.; Storaro, L. Textural and structural properties and surface acidity characterization of mesoporous silica-zirconia molecular sieves. J. Solid State Chem. 2003, 175, 159–169. [CrossRef] 15. Jimenez-Sanchidrian, C.; Ruiz, J.R. Tin-containing hydrotalcite-like compounds as catalysts for the Meerwein–Ponndorf–Verley reaction. Appl. Catal. A Gen. 2014, 469, 367–372. [CrossRef] 16. Battilocchio, C.; Hawkins, J.M.; Ley, S.V. A mild and efficient flow procedure for the transfer hydrogenation of ketones and aldehydes using hydrous zirconia. Org. Lett. 2013, 15, 2278–2281. [CrossRef][PubMed] 17. Koreniuk, A.; Maresz, K.; Mrowiec-Białoń,J. Supported zirconium-based continuous-flow microreactor for effective Meerwein–Ponndorf–Verley reduction of cyclohexanone. Catal. Commun. 2015, 64, 48–51. [CrossRef] 18. Ciemi˛ega,A.; Maresz, K.; Mrowiec-Białoń,J. Continuous-flow chemoselective reduction of cyclohexanone in i a monolithic silica-supported Zr(OPr )4 multichannel microreactor. Microporous Mesoporous Mater. 2017, 252, 140–145. [CrossRef] 19. Maresz, K.; Ciemi˛ega,A.; Mrowiec-Białoń,J. Meervein–Ponndorf–Vereley reduction of carbonyl compounds in monolithic siliceous microreactors doped with Lewis acid centers. Appl. Catal. A Gen. 2018, 560, 111–118. 20. Ciemi˛ega, A.; Maresz, K.; Malinowski, J.J.; Mrowiec-Białoń, J. Continuous-flow monolithic silica microreactors with arenesulfonic acid groups: Structure-catalytic activity relationships. Catalysts 2017, 7, 255. [CrossRef] 21. Li, G.; Fu, W.H.; Wang, Y.M. Meervvein–Ponndorf–Verley reduction of cyclohexanone catalyzed by partially crystalline zirconosilicate. Catal. Commun. 2015, 62, 10–13. [CrossRef] 22. Corma, A.; Domine, M.E.; Valencia, S. Water-resistant solid Lewis acid catalysts: Meerwein–Ponndorf–Verley and Oppenauer reactions catalyzed by tin-beta zeolite. J. Catal. 2003, 215, 294–304. [CrossRef] 23. Ruiz, J.R.; Jiménez-Sanchidrián, C.; Hidalgo, J.M.; Marinas, J.M. Reduction of ketones and aldehydes to alcohols with magnesium–aluminium mixed oxide and 2-propanol. J. Mol. Catal. A Chem. 2006, 246, 190–194. [CrossRef] 24. Aramendia, M.A.; Borau, V.; Jimenez, C.; Marinas, J.M.; Ruiz, J.R.; Urbano, F.J. Activity of basic catalysts in the Meerwein–Ponndorf–Verley reaction of benzaldehyde with ethanol. J. Colloid Interface Sci. 2001, 238, 385–389. [CrossRef][PubMed] 25. Theodosis-Nobelos, P.; Kourti, M.; Tziona, P.; Kourounakis, P.N.; Rekka, E.A. Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity. Bioorg. Med. Chem. Lett. 2015, 25, 5028–5031. [CrossRef][PubMed] 26. Carnesecchi, S.; Schneider, Y.; Ceraline, J.; Duranton, B.; Gosse, F.; Seiler, N.; Raul, F. Geraniol, a component of plant essential oils, inhibits growth and polyamine biosynthesis in human colon cancer cells. J. Pharmacol. Exp. Ther. 2001, 298, 197–200. [PubMed]

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