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catalysts Article

Selective Reduction of Ketones and Aldehydes in Continuous-Flow Microreactor—Kinetic Studies Katarzyna Maresz 1, *, Agnieszka Ciemi˛ega 1 and Julita Mrowiec-Białon´ 1,2 1 2

*

Institute of Chemical Engineering Polish Academy of Sciences, Bałtycka 5, 44-100 Gliwice, Poland; [email protected] (A.C.); [email protected] (J.M.-B.) 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 (Scheme 1). 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

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Scheme1.1.The Themechanism mechanismofofMeerwein–Ponndorf–Verley Meerwein–Ponndorf–Verley(MPV) (MPV)reduction. reduction. Scheme

Inexpensive and non-toxic hydrogen donors and catalysts, mild reaction conditions, and Inexpensive and non-toxic hydrogen donors and catalysts, mild reaction conditions, 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 The catalytic characterization siliceous monolithic microreactors with zirconium and their propertiesofwere described in our previous papersfunctionalized [17,18]. Kinetic studies were species and their catalytic properties were described in our previous papers [17,18]. Kinetic studies performed in the microreactors featured by the exceptionally low back-pressure. It resulted from were performed in of thecylindrical-shape microreactors featured by applied the exceptionally back-pressure. It resulted the unique structure monoliths as reactivelow cores [20]. Briefly, monoliths fromcharacterized the unique by structure of cylindrical-shape monoliths applied as (macropores reactive cores [20].range Briefly, were a continuous, macroporous flow-through structure in the of monoliths were characterized by a continuous, macroporous flow-through structure (macropores 30–50 µm), extended with mesopores of bimodal size distributions (3/20 nm) and a high surface areain 2 ·g−of 1 ) (Figure the m range 30–50 μm), extended with mesopores of bimodal sizezirconium distributions (3/20 nm) a high (340 1). The monoliths were functionalized with propoxide toand obtained 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

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Catalystsacid 2018, 8, x FOR PEERsilica REVIEW Lewis onPEER the surface. Catalysts 2018, sites 8, x FOR REVIEW

3 of 8 The zirconium cations were terminated by propoxy/hydroxo 3 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 determined byofICP MS analysis, was 7.03 wt MS % (in relation to7.03 the wt mass ofrelation silica support) in all concentration zirconium, determined by ICP analysis, was % (in to the mass of silica support) in all studied microreactors. silica support) in all studied microreactors. studied microreactors.

Figure1.1.(a) (a) SEMimage image of silica monolith structure; (b) nitrogen adsorption/desorption isotherm Figure monolith structure; (b) (b) nitrogen adsorption/desorption isotherm and Figure 1. (a) SEM SEM imageofofsilica silica monolith structure; nitrogen adsorption/desorption isotherm and size poredistribution size distribution (insert). pore (insert). and pore size distribution (insert).

Material functionalization with zirconium precursor did not considerably influence the Material functionalization functionalizationwith with zirconium precursor did not considerably the zirconium precursor did not considerably influenceinfluence the structural structural properties of the support. Only a small decline of the surface area and mesopore volume structural properties of the support. a small the and surface area and mesopore volume properties of the support. Only a smallOnly decline of thedecline surfaceofarea mesopore volume was observed. was observed. All features have been preserved after multiple reaction cycles. wasfeatures observed. Allbeen features have been after multiple All have preserved afterpreserved multiple reaction 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 with with2-butanol. 2-butanol.First, First, checked whether diffusion or activation the wewe checked whether diffusion or activation controlscontrols the reaction reaction rate. External mass transfer limitations are a common phenomenon in porous materials. To reaction rate. External masslimitations transfer limitations are aphenomenon common phenomenon in porousTo materials. To rate. External mass transfer are a common in porous materials. exclude the exclude the impact of diffusional effects on the reaction kinetics, the performance of microreactors exclude impact ofeffects diffusional the reaction kinetics, the microreactors impact ofthe diffusional on the effects reactiononkinetics, the performance of performance microreactorsof with monolithic with monolithic cores of different lengths were compared with respect to the same residence time, with of different lengths were compared withsame respect to the same cores monolithic of differentcores lengths were compared with respect to the residence time, residence equal to 5time, min. equal to 5 min. Similar conversions of cyclohexanone, about 40%, were achieved in all microreactors equal toconversions 5 min. Similar of cyclohexanone, about 40%, were achieved in all microreactors Similar of conversions cyclohexanone, about 40%, were achieved in all microreactors of a 1–8 cm of a 1–8 cm length, which evidenced the lack of transport constraints (Figure 2). of a 1–8which cm length, whichthe evidenced the lack of transport (Figure constraints length, evidenced lack of transport constraints 2). (Figure 2).

Figure 2. Conversion of cyclohexanone in microreactors of different lengths for a residence time of Figure 2. Conversion residence time of Figure 2. Conversion of of cyclohexanone cyclohexanone in in microreactors microreactors of of different different lengths lengths for for aa residence time of 5 min. 55 min. 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. The3aresults kinetic experiments for run cyclohexanone depicted in Figure 3. Figure 3a Figure showsofthe single experimental carried outreduction for 6 h at are 95 °C in a 6 cm long microreactor. Figure 3a shows the single experimental run carried out for 95 °C in a 6 cm long microreactor. ◦ C 6inhaat shows the single experimental run carried out for 6 h at 95 6 cm long microreactor. The reaction The reaction rate constant (Figure 3c) was determined by assuming the first order kinetics and was The reaction rate constant (Figure 3c) was determined by assuming the first order kinetics and was rate constant (Figure 3c) was(1): determined by assuming the first order kinetics and was calculated using calculated using Equation calculated using Equation (1): Equation (1): ln(C0/C) = kτ (1) ln(C0 0/C) /C) = = kτ (1) ln(C kτ (1) −3 −3 where C0 [mmol·cm ] is the initial concentration of ketone, C [mmol·cm ] 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.

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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, Catalysts 2018, 8, x FOR REVIEW 4 of48of 84 of 8 Catalysts 8,PEER x FOR Catalysts 2018, 8, xxREVIEW FOR PEER PEER REVIEW of 88 Catalysts 2018,2018, 8,τ x[min] FOR PEER REVIEW Catalysts 2018, 8, FOR REVIEW 44 of thePEER residence time.

Figure 3. (a) Conversion of(a) cyclohexanone in the 6-cm-long microreactor. (b) (b) Catalytic results for Figure 3. ofof cyclohexanone in in the 6-cm-long microreactor. (b) Catalytic results for MPV Figure 3. Conversion (a) Conversion of cyclohexanone in 6-cm-long the 6-cm-long microreactor. (b) Catalytic forresults Figure 3. (a) Conversion of cyclohexanone in the the 6-cm-long microreactor. (b) results Catalytic results for Figure 3. (a) ofConversion cyclohexanone in the microreactor. Catalytic results for Figure 3. (a) Conversion cyclohexanone 6-cm-long microreactor. (b) Catalytic for ◦ ◦ ◦ ◦ reduction at 65 C ( ), 75 C ( ), 85 C ), and 95 C (  ) in the microreactor (points—experiments, MPV reduction at 65 °C ( ), 75 °C ( ), 85 °C ( ), and 95 °C ( ) in the microreactor reduction at °C 65 (°C at (), 65 75 ((°C (),), 75 85 ((°C), (),),and ), in°C MPV reduction at 65), °C °C 75), °C °C 85and °C °C ( ),),(°Cand and 95 °Cthe in the the microreactor microreactor MPVMPV reduction at 65 75 85 95 ) (in )95 the microreactor MPV reduction 85 °C (95 (( microreactor )) in lines-model). (c) Plot lnPlot (C /C) contact time. (points—experiments, lines-model). (c)of Plot of 0ln 0versus /C) versus time. (points—experiments, lines-model). (c) Plot (C 0versus /C)of versus contact (points—experiments, lines-model). (c) Plot ofcontact lncontact (C00/C) /C) versus contact time. time. (points—experiments, lines-model). (c) of(C lnof (Cln 0/C) time.time. (points—experiments, lines-model). (c) Plot ln (C versus contact

Figure 3b 3b confirms good between thethe experimental data and theand model prediction of ofprediction Figure 3bFigure confirms good agreement between the experimental data the prediction of Figure 3bagreement confirms good agreement between the experimental datamodel and the model prediction of Figure confirms good agreement between experimental data and the model prediction 3b confirms good agreement between the experimental data and the model of thethe first-order kinetics for the MPV process carried out at different temperatures and contact times in the first-order kinetics for the MPV process carried out at different temperatures and contact times in the first-order kinetics for the MPV process carried out at different temperatures and contact times in first-orderthe kinetics for the MPV process carried out atcarried different and contact times in first-order kinetics temperatures first-order kinetics for the MPV process outtemperatures at different temperatures and contact times in thethe range of 5–40 min. Each point corresponds to the average conversion obtained in microreactor the range of range 5–40 Each point corresponds to the average obtained in microreactor the range of 5–40 min. Each point corresponds corresponds toconversion theconversion averageobtained conversion obtained in microreactor microreactor range of the 5–40 min.min. Each point corresponds to the average in microreactor 5–40 min. average conversion of 5–40 min. Each point to the average conversion obtained in during 6-h-long tests. during 6-h-long tests. during 6-h-longtests. tests. during 6-h-long tests. tests. during 6-h-long TheThe linear relationship rate constant vs. theconstant contact time was observed through thethe whole The linear relationship rate constant vs. the contact time was observed through the whole The linear relationship rate constant vs. time was observed through the whole whole linear relationship rate constant vs. the contact time was observed through whole relationship rate constant vs. the contact time was whole The linear relationship rate vs. the contact observed through the temperature range used in the experiments. The experimental data are in line with those calculated temperature range in the experiments. experimental in line with those calculated temperature range used in the the experiments. experiments. The experimental experimental data are in line line with thosecalculated calculated temperature range usedused inrange the experiments. TheThe experimental datadata are are in line with those calculated calculated temperature used in The data are in with those from first-order kinetics equation. from first-order kinetics equation. from first-order kineticsequation. equation. from first-order kinetics equation. from first-order kinetics equation. first-order kinetics ◦65–95 Temperature dependence of the rate constant was examined the range 65–95 °C andand Temperature dependence of the rate constant was examined in the range of range 65–95 °C and is°C Temperature dependence of the rate constant was examined in the range ofis65–95 °C and is is Temperature dependence of the rate constant was examined in examined the range ofrange 65–95 Temperature dependence of the rate constant was the of and Temperature dependence of the rate constant wasin examined inof thein of °C 65–95 Cisand is shown shown in Figure 4. The activation energy was estimated from linear regression analysis, and it shown inin Figure activation energy was estimated from linear regression analysis, and shown in4. Figure 4. The The activation energy was estimated from linear regression analysis, and shown in Figure 4. in The activation energy was estimated from linear regression analysis, and it it and shown 4. activation energy was estimated from linear regression itit Figure 4.Figure The activation energy was estimated from regression analysis, and itanalysis, appeared to be −1.−−1 −to 1and 1 . ==−12.69 −1 −1factor appeared to be ,to frequency k∞ == 2.69 min −1 appeared tokJ·mol be·kJ·mol 52 −1 kJ·mol ,frequency and frequency factor = min 2.69 min . min appeared be 52 kJ·mol and frequency factor k∞ 2.69 min−1−1.. appeared to 52 be 52 , and frequency factor k∞ =k∞ 2.69 min appeared 52 kJ·mol ,, and frequency factor k∞ 52 kJ mol ,−1be and factor k∞ 2.69

Figure 4. Arrhenius plotplot for the the MPV ofMPV cyclohexanone. Figure 4. Arrhenius plot for MPV thereduction MPV of cyclohexanone. Figure 4. Arrhenius Arrhenius plot forreduction the MPV reduction ofcyclohexanone. cyclohexanone. Figure 4. Arrhenius for reduction of cyclohexanone. cyclohexanone. Figure 4. plot for the reduction of

TheThe studies of of the MPV reduction in in thereduction flow process were extended to other The studies of the MPV reduction in the flow process were extended to ketones other ketones The studies of the the MPV reduction in the the flow process were extended toand other ketones and and studies the MPV reduction the flow process were extended to other ketones andand The studies of MPV in flow process were extended to other ketones The studies of the MPV reduction in the flow process were extended to other ketones and aldehydes, andand the results, i.e.,the the conversion, productivity, and reaction rate constant are aldehydes, and the results, i.e., the conversion, productivity, and reaction rate constant are aldehydes, and the results, i.e., the the conversion, productivity, and reaction rate constant are aldehydes, the results, i.e., the conversion, productivity, and reaction rate constant are aldehydes, and results, i.e., conversion, productivity, and reaction rate constant are aldehydes, and the results, i.e., the conversion, productivity, and reaction rate constant are summarized summarized in Table 1. Analysis of these data shows that aldehydes are easier to be reduced than summarized in Table 1. Analysis of these data shows that aldehydes are easier to be reduced than summarized in Table 1. Analysis of these data shows that aldehydes are easier to be reduced than summarized in in Table Table 1. 1. Analysis shows aldehydes are easier to are be summarized in Tableof1. Analysis of thesethat data shows that aldehydes easier tothan be than reduced than Analysis ofthese thesedata data shows that aldehydes are easier to reduced be reduced ketones. −1, −1 −1, while −1 ketones. TheThe reaction rate constant ofrate benzaldehyde waswas 0.212 min while that for −1 ketones. The reaction rate constant of benzaldehyde reduction was 0.212 min that for that ketones. The reaction rate constant of reduction benzaldehyde reduction was 0.212 min ,for while that for for ketones. reaction rate constant of benzaldehyde reduction 0.212 min , while that ketones. The reaction constant of benzaldehyde reduction was 0.212 min , while − 1 The reaction rate constant of benzaldehyde reduction was 0.212 min , while that for cyclohexanone cyclohexanone was twice lower. Battilocchio et Battilocchio al. also that aldehydes, compared with cyclohexanone was twice lower. Battilocchio et also al.found also that aldehydes, compared with cyclohexanone was twice lower. Battilocchio et found al. that also found that aldehydes, compared with cyclohexanone was twice lower. Battilocchio et al. found aldehydes, compared with cyclohexanone was twice lower. et al. also found that aldehydes, compared with was twice lower. Battilocchio et al. also found that aldehydes, compared with aliphatic ketones, aliphatic ketones, required a shorter reaction time for complete conversion to alcohols [16]. Steric aliphatic ketones, required arequired shorter time for complete conversion to alcohols [16]. Steric aliphatic ketones, shorter reaction time for complete conversion to alcohols [16]. Steric Steric aliphatic ketones, required a shorter reaction time for complete conversion toconversion alcohols [16]. Steric aliphatic ketones, required aareaction shorter reaction time for complete to alcohols [16]. hindrance is a prevalent factor that affects the reactivity of the substrates. Citral is a mixture of cishindrance is a prevalent factor affects the reactivity of the substrates. Citral aCitral mixture cis- of isfactor prevalent factor that affects the reactivity of the the substrates. Citral is acisaof mixture of ciscishindrance is hindrance ahindrance prevalent thatthat affects the reactivity of the substrates. Citral is a is mixture of is aa prevalent factor that affects the reactivity of substrates. is mixture andand trans-isomers signified as neral and geranial, respectively. The MPV reduction of citral reveals and trans-isomers signified as neral and geranial, respectively. The MPV reduction of citral reveals and trans-isomers signified as neral and geranial, respectively. The MPV reduction of citral reveals trans-isomers signified as neral and as geranial, respectively. The MPV reduction of reduction citral reveals and trans-isomers signified neral and geranial, respectively. The MPV of citral reveals thethe preferential formation of its trans yield ofyield geraniol waswas 20% higher than nerol. The the preferential formation oftrans itsproduct. trans The of geraniol 20% higher than nerol. Thenerol. theformation preferential formation ofproduct. itsThe trans product. The yield ofwas geraniol was 20% higher than nerol. The The preferential of formation its product. The yield of geraniol 20% higher than nerol. The the preferential of its trans product. The yield of geraniol was 20% higher than orientation of the carbonyl group to the molecular in geranial reduces steric limitations forfor orientation of the carbonyl group to the molecular chain in geranial steric limitations for orientation of the carbonyl group tochain the molecular chain in reduces geranial reduces steric limitations for orientation oforientation the carbonyl group to the molecular chain in geranial reduces steric limitations of the carbonyl group to the molecular chain in geranial reduces steric limitations for binding between the Zr center and C=O. binding between the Zr center and C=O. binding between the Zr center and C=O. binding between the Zr center the andZr C=O. binding between center and C=O.

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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. Catalysts 2018, 8, FOR PEER REVIEW Catalysts2018, 2018,8, 8,xxxxFOR FORPEER PEERREVIEW REVIEW Catalysts 2018, 8, FOR PEER REVIEW Catalysts Catalysts Catalysts2018, 2018,8, 8,xx xFOR FORPEER PEERREVIEW REVIEW Catalysts 2018, 8, FOR PEER REVIEW

Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate

55 of of8888 of of 5555 5of of88 8 of

Table 1. Data from catalytic experiments.

Table 1. Data from catalytic experiments. Table1. 1.Data Datafrom fromcatalytic catalyticexperiments. experiments. Table 1. Data from catalytic experiments. Table 1, *catalytic 1, * 2 Table 1. Data from experiments. Table 1. Data from catalytic experiments. Conversion Productivity Productivity Productivity 3 1. Data from catalytic experiments. 1,* 1,* 2 3 Productivity Conversion Productivity K 11 [min−1−1 ]Table 1,* 1,*−1 2 3 −Productivity 1] 1Productivity −1 ] Productivity Conversion Productivity 1, 1, 1, 1, 222 ·gcat −Productivity 333 K [%] [mmol · g · h [mmol · h [mmol ·gcat −1 ·h−1 ] 1,* 1,* −1]] Productivity Productivity Conversion * Productivity * Productivity Conversion Productivity cat −1 −1 −1 −1 −1 −1 K111 [min [min−1 1, 1, 2 3 1, 1, 2 3 −1 0.106 0.106 0.106 0.106 0.106 0.106 0.106 0.106

88 8888 88 88 88 88 88

cat −1·h1,−1 [mmol·g Productivity ***]] Productivity cat ·h−1 [mmol·gcat Productivity −1 −1 −1 −1·h −1]] cat ·h [mmol·g [mmol·g cat−1 ·h [mmol·g cat−1 ·h−1−1]] [mmol·g cat−1·h−1] [mmol·gcat 2.22 2.22 2.22 2.22 2.22 2.22 2.22 2.22

0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021

35 3535 35 35 35 35 35

0.9 0.9 0.9 0.9 0.9 0.9 0.9

0.212 0.212 0.212 0.212 0.212 0.212 0.212 0.212

99 9999 99 99 99 99 99

2.64 2.64 2.64 2.64 2.64 2.64 2.64 2.64

1.14 [16] 1.14[16] [16] 1.14 [16] 1.14 [16] 1.14 1.14 1.14 [16] 1.14[16] [16]

0.081 0.081 0.081 0.081 0.081 0.081 0.081 0.081

80 8080 80 80 80 80 80

1.92 1.92 1.92 1.92 1.92 1.92 1.92 1.92

0.031/0.047 4444 4 0.031/0.047 0.031/0.047 0.031/0.047 0.031/0.047 4

4 0.031/0.047 0.031/0.047 44 0.031/0.047

46/61 46/61 46/61 46/61 46/61 46/61 46/61 46/61

0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9 0.48/0.9

0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026

40 40 40 40 40 40 40 40

0.96 0.96 0.96 0.96 0.96 0.96 0.96 0.96

−1]] K 111[min [min−1−1 K [min K K K 1 [min [min−1]]]

[%] Conversion Conversion [%] 1,*** Conversion [%] [%] [%] [%] [%]

0.9

cat −1·h −1 cat −1·h −1 [mmol·g [mmol·g Productivity Productivity Productivity Productivity 2]] 3]] cat ·h−1 cat ·h−1 [mmol·g [mmol·g Productivity Productivity −1 −1 −1 −1 −1 −1 −1·h −1·h −1]] −1]] cat ·h cat ·h [mmol·g [mmol·g cat cat [mmol·g [mmol·g cat−1 cat−1 ·h ·h [mmol·g [mmol·g cat−1 ·h−1−1]] cat−1 ·h−1−1]] [mmol·g [mmol·g cat−1·h−1] cat−1·h−1] [mmol·gcat [mmol·gcat -2.28 [21] 2.28 [21] 2.28[21] [21] 2.28 [21] 2.28 ----2.28 2.28 [21] 2.28[21] [21]

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0.11 [15] 0.11[15] [15] 0.11 [15] 0.11 0.11 0.11 [15] 0.11[15] [15]

0.11 [15]

0.36 [10] 0.36[10] [10] 0.36 [10] 0.36 0.36 0.36 [10] 0.36[10] [10]

0.36 [10]

0.66 [16] 0.48 [5] 0.66[16] [16] 0.66 [16] 0.48 0.48[5] [5] 0.66 [16] 0.48 [5] 0.66 0.66 0.48 0.66 [16] 0.48 [5] 0.66[16] [16] 0.48[5] [5]

0.48 [5]

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-

-

0.48 [16] 0.48[16] [16] 0.48 [16] 0.48 0.48 0.48 [16] 0.48[16] [16] 0.48 [16]

0.54 [5] 0.54[5] [5] 0.54 [5] 0.54 0.54 0.54 [5] 0.54[5] [5]

0.54 [5]

0.12 [22] 0.12[22] [22] 0.12 [22] 0.12 0.12 0.12 [22] 0.12[22] [22]

0.12 [22]

0.08 80 2.1 --0.08 80 2.1 0.08 80 2.1 0.08 80 2.1 0.08 80 2.1 --------0.08 80 2.1 0.08 0.08 80 80 2.1 2.1 0.041 56 1.32 -0.72 [23] 0.041 56 1.32 0.72[23] [23] 0.041 56 1.32 0.72 [23] 0.041 56 1.32 0.72 1.32 ----- 3 0.72 [23] 0.041 56 1.32 0.72 [23] 1 this work (reaction 0.041 2 in56 0.041 56 1.32 0.72 [23] 0.041 56 1.32 95 °C), the flow process (data form literature), in the batch process 1 this work (reaction temp. 2 3 temp. 95 °C), in the flow process (data form literature), in the batch process 2 3 111 this 2 3 2 in 3 in this work (reaction temp. 95 °C), in the flow process (data form literature), in the batch process work (reaction temp. 95 °C), the flow process (data form literature), the batch process 11 this 4 nerol/geraniol; (reaction 95 flow (data literature), this work workliterature); (reaction temp. temp. 95 °C), °C), 222 in in the the flow process (data form form literature), 333 in in the the batch batch process process 1 this *the data forprocess the 4-cm-long microreactor. (data form 4 work (reaction temp. 95 °C), in flow process (data form literature), in the batch process

1 (data * data for the 4-cm-long form literature); 444 nerol/geraniol; this work (reaction temp. 95 ◦ C), 2 in the flow process (datamicroreactor. form literature), 3

nerol/geraniol; ****data data for the 4-cm-long microreactor. (data form literature); 44 nerol/geraniol; nerol/geraniol; data for the 4-cm-long microreactor. (data form literature); for microreactor. (data data for the 4-cm-long microreactor. (data form 4 nerol/geraniol; 4literature); nerol/geraniol; data forthe the 4-cm-long 4-cm-long microreactor. (data form form literature); literature); literature); nerol/geraniol; * data for *the 4-cm-long microreactor.

0.72 [23]

in the batch process (data form

The impact of both the steric and electronic effect can be observed in the case of The impact impact of of both both the the steric steric and and electronic electronic effect effect can can be be observed observed in in the the case case of of The The impact of both the steric and electronic effect can be observed in the case of The impact of both the steric and electronic effect can be observed in the case of The impact of both the steric and electronic effect can be observed in the case of cinnamaldehyde reduction. The low activity can be attributed to the presence of a bulky chain in this The impact reduction. of both The the low steric and can electronic effecttocan be observed in the case of cinnamaldehyde activity be attributed the presence of a bulky chain in this cinnamaldehyde reduction. The low activity can be attributed to the presence of bulky chain in this cinnamaldehyde reduction. Thesteric lowactivity activity canbe beattributed attributed tothe the presence of aaaain bulky chain inthis this cinnamaldehyde reduction. The low can to presence of cinnamaldehyde reduction. The low activity can be attributed to the presence of bulky chain in this The impact of both the and electronic can be observed thechain case in of cinnamaldehyde substrate and double bond. The productivity in the reduction process of cinnamaldehyde was cinnamaldehyde reduction. The low activity can be attributed to the presence a bulky bulky chain in this substrate and double double bond. The productivity in the theeffect reduction process ofof cinnamaldehyde was substrate and bond. The productivity in reduction process of cinnamaldehyde was substrate and double bond. The productivity in the reduction process of cinnamaldehyde was substrate and double bond. The productivity in the reduction process of cinnamaldehyde was substrate and and double bond.that The productivity in the the reduction process ofbulky cinnamaldehyde wassubstrate and significantly lower than for benzaldehyde. The reduction of unsaturated ketone, substrate double bond. The productivity in reduction process of cinnamaldehyde was reduction. The low activity can be attributed to the presence of a chain in this significantly lower lower than than that that for for benzaldehyde. benzaldehyde. The The reduction reduction of of unsaturated unsaturated ketone, ketone, significantly significantly lower than for benzaldehyde. The of unsaturated ketone, significantly lower than that for benzaldehyde. The reduction of unsaturated ketone, 2-cyclohexen-1-on, is difficult without affecting the conjugated C=C bond. A significant decrease in significantly lower than that that for benzaldehyde. The reduction reduction of unsaturated ketone, 2-cyclohexen-1-on, is difficult without affecting the conjugated C=C bond. A significant decrease in double bond. The productivity in the reduction process of cinnamaldehyde was significantly lower 2-cyclohexen-1-on, is difficult without affecting the conjugated C=C bond. A significant decrease in 2-cyclohexen-1-on, is is difficult difficult without without affecting affecting the the conjugated conjugated C=C C=C bond. bond. A A significant significant decrease decrease in 2-cyclohexen-1-on, in 2-cyclohexen-1-on, is difficult without affecting the conjugated C=C bond. A significant decrease in conversion was observed compared to the saturated cyclic carbonyl compound (cyclohexanone); 2-cyclohexen-1-on, is difficult without affecting the conjugated C=C bond. A significant decrease in conversion was observed compared to the saturated cyclic carbonyl compound (cyclohexanone); than that for benzaldehyde. The reduction of unsaturated ketone, 2-cyclohexen-1-on, is difficult conversion was observed compared to the saturated cyclic carbonyl compound (cyclohexanone); conversion was was observed observed compared compared to to the the saturated saturated cyclic cyclic carbonyl carbonyl compound compound (cyclohexanone); (cyclohexanone); conversion conversion was observed compared to saturated cyclic compound (cyclohexanone); nevertheless, the product was obtained with 100% selectivity. Aromatic ketones, compared with conversion was compared to the the saturated cyclic carbonyl carbonyl compound nevertheless, theobserved product was was obtained obtained with 100% selectivity. selectivity. Aromatic ketones,(cyclohexanone); compared with with nevertheless, the product with 100% Aromatic ketones, compared nevertheless, the product was obtained with 100% selectivity. Aromatic ketones, compared with without affecting the difficult conjugated C=C bond. A significant decrease incompared conversion was observed nevertheless, the product was obtained with 100% selectivity. Aromatic ketones, with nevertheless, the product was obtained with 100% selectivity. Aromatic ketones, compared with cyclic ketones, are more to reduce due to the resonance and inductive effect of the benzene nevertheless, the product was obtained with 100% selectivity. Aromatic ketones, compared with cyclic ketones, are more difficult to reduce due to the resonance and inductive effect of the benzene cyclic ketones, are more difficult to reduce due to the resonance and inductive effect of the benzene cyclic ketones, are more difficult to reduce due to the resonance and inductive effect of the benzene cyclic ketones, are more difficult to reduce due the resonance and inductive effect of the benzene compared the cyclic carbonyl compound (cyclohexanone); nevertheless, the product was cyclic ketones, are more difficult to reduce due to the resonance and inductive effect of the benzene ring [22]. ItItto explains the difference conversions acetophenone. cyclic ketones, aresaturated more difficult toin reduce due to to of thecyclohexanone resonance andand inductive effect ofNo theproducts benzene ring[22]. [22]. explains thedifference difference in conversions of cyclohexanone and acetophenone. No products ring It explains the in conversions of cyclohexanone and acetophenone. No products ring [22]. It explains explains the difference in conversions of cyclohexanone and acetophenone. No products ring [22]. It the difference in conversions of cyclohexanone and acetophenone. No products ring [22]. It explains the difference in conversions of cyclohexanone and acetophenone. No products obtained with 100% selectivity. Aromatic ketones, compared with cyclic ketones, are more difficult to arising from the Tischenko cross reaction or from the aldol condensation [24], were detected for any ring [22]. It explains the difference in conversions of cyclohexanone and acetophenone. No products arisingfrom fromthe theTischenko Tischenkocross crossreaction reactionor orfrom fromthe thealdol aldolcondensation condensation[24], [24],were weredetected detectedfor forany any arising arising from the Tischenko cross reaction or from the aldol condensation [24], were detected for any arising from the Tischenko cross reaction or from the aldol condensation [24], were detected for any arising from the Tischenko cross reaction or from the aldol condensation [24], were detected for any of the investigated substrates. This evidenced the excellent selectivity of the proposed catalyst. arising from the Tischenko cross reaction or from the aldol condensation [24], were detected for any reduce due to thesubstrates. resonance and inductive effect ofselectivity the benzene [22].catalyst. It explains the difference ofthe theinvestigated investigated substrates. This evidenced theexcellent excellent selectivity ofthe thering proposed catalyst. of This evidenced the of proposed of the investigated substrates. This evidenced the excellent selectivity of the proposed catalyst. of the substrates. This evidenced the excellent selectivity of the proposed catalyst. of the investigated substrates. This evidenced the excellent selectivity of the proposed catalyst. ItItinvestigated should furthermore be highlighted that alcohols produced by the selective hydrogenation of the investigated substrates. This evidenced the excellent selectivity of the proposed catalyst. should furthermore be highlighted that alcohols produced by the selective hydrogenation of inofconversions of cyclohexanone and acetophenone. No products arising from the Tischenko cross It should furthermore be highlighted that alcohols produced by the selective hydrogenation of It should should furthermore furthermore be be highlighted highlighted that that alcohols alcohols produced produced by by the the selective selective hydrogenation hydrogenation of ItIt of should furthermore be highlighted that alcohols produced by the selective hydrogenation of carbonyl-bearing substrates are fine chemicals of primary interest. They are used as flavor additives, It should furthermore be highlighted that alcohols produced by the selective hydrogenation of carbonyl-bearing substrates are fine chemicals of primary interest. They are used as flavor additives, carbonyl-bearing substrates are fine chemicals of primary interest. They are used as flavor additives, reaction or from the aldol condensation [24], were detected for any of the investigated substrates. carbonyl-bearing substrates substrates are are fine fine chemicals chemicals of of primary primary interest. interest. They They are are used used as as flavor flavor additives, additives, carbonyl-bearing carbonyl-bearing substrates are fine of interest. They as flavor and intermediates in drug Products of the esterification of cinnamyl alcohol, carbonyl-bearing substrates areproduction. fine chemicals chemicals of primary primary They are are used used as flavor additives, additives, and intermediates intermediates in drug drug production. Products of interest. the esterification esterification of cinnamyl cinnamyl alcohol, and in production. Products of the of alcohol, and intermediates in drug production. Products of the esterification of cinnamyl alcohol, This evidenced the excellent selectivity of the proposed catalyst. and intermediates in drug production. Products of the esterification of cinnamyl alcohol, and intermediates in drug production. Products of the esterification of cinnamyl alcohol, indole-3-acetic acid, or α-lipoic acid were studied for antioxidant and anti-inflammatory and intermediates in drug production. Products of their the esterification of cinnamyl alcohol, indole-3-acetic acid, or α-lipoic acid were studied for their antioxidant and anti-inflammatory indole-3-acetic acid, or acid were studied for and anti-inflammatory indole-3-acetic acid, or or α-lipoic α-lipoic acid were studied studied for their their antioxidant antioxidant and anti-inflammatory anti-inflammatory indole-3-acetic acid, were and indole-3-acetic acid, or α-lipoic acid were studied for their antioxidant and anti-inflammatory It should furthermore beacid highlighted that for alcohols produced by selective hydrogenation of activity [25], and graniol was checked in colon cancer chemoprevention and treatment [26]. indole-3-acetic acid, or α-lipoic α-lipoic acid were studied for their their antioxidant antioxidant andthe anti-inflammatory activity [25],and and graniol waschecked checked in colon cancer chemoprevention andtreatment treatment [26]. activity [25], graniol was in colon cancer chemoprevention and [26]. activity [25], and graniol was checked in colon cancer chemoprevention and treatment [26]. activity [25], and graniol was checked in colon cancer chemoprevention and treatment [26]. activity [25], and graniol was checked in colon cancer chemoprevention and treatment [26]. Our results were compared to the literature data for flow and batch processes. To the best of our carbonyl-bearing substrates are fine chemicals of primary interest. They are used as flavor additives, activity andwere graniol was checked colon cancer chemoprevention and treatment [26]. Our[25], results compared tothe thein literature datafor for flowand andbatch batchprocesses. processes. Tothe the bestof ofour our Our results were compared to literature data flow To best Our results werecompared compared to the literature data for flow and batch processes. To the best of our Our results were to the literature data for flow and batch processes. To the best of our 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 Our results were compared to the literature data for flow and batch processes. To the best of our and intermediates in process drug production. Productspowdered of the esterification of cinnamyl knowledge, the MPV MPV process using heterogeneous heterogeneous powdered catalyst at at flow flow conditionsalcohol, has only onlyindole-3-acetic knowledge, the using catalyst conditions has knowledge, the MPV process using heterogeneous powdered catalyst at flow conditions has only knowledge, the MPV process using heterogeneous powdered catalyst at flow conditions has only knowledge, the MPV process using heterogeneous powdered catalyst at flow conditions has only been published in one paper [16]. The productivities of reactors toward benzyl alcohol, knowledge, the MPV process using heterogeneous powdered catalyst at flow conditions has only beenor published in onewere paperstudied [16]. The productivities of ZrO ZrO22222-based -based reactors toward benzyl alcohol, acid, α-lipoic acid for their antioxidant and anti-inflammatory activity [25], and graniol been published in one paper [16]. The productivities of ZrO -based reactors toward benzyl alcohol, been published in paper [16]. of 22-based reactors toward alcohol, been published in one paper [16]. The productivities of ZrO -based reactors toward benzyl alcohol, cinnamyl alcohol, and 1-phenylethanol are nearly 44 times lower than those achieved in the studied been published in one one paper [16]. The The productivities productivities of ZrO ZrO 2-based reactors toward benzyl benzyl alcohol, cinnamyl alcohol, and 1-phenylethanol are nearly times lower than those achieved in the studied cinnamyl alcohol, and 1-phenylethanol are nearly 4 times lower than those achieved in the studied was checked in colon cancer chemoprevention and treatment [26]. cinnamyl alcohol, and 1-phenylethanol 1-phenylethanol are nearly nearly 444 times times lower than than those those achieved in in the the studied studied cinnamyl alcohol, and are achieved cinnamyl alcohol, and are nearly lower than those achieved in studied monolithic microreactors. Table shows productivities from batch reactors obtained other cinnamyl and 1-phenylethanol 1-phenylethanol arethe nearly 4 times times lower lower those achieved in the theby studied monolithicalcohol, microreactors. Table 1111 shows shows the productivities fromthan batch reactors obtained by other monolithic microreactors. Table the productivities from batch reactors obtained by other monolithic microreactors. Table shows the productivities from batch reactors obtained by other monolithic microreactors. Table 1 shows the productivities from batch reactors obtained by monolithic microreactors. Table 1 shows the productivities from batch reactors obtained by other research. They are significantly than those obtained in the proposed flow system (except one monolithic microreactors. Tablelower 1 shows the productivities from batch reactors obtained by other other research. They are significantly lower than those obtained in the proposed flow system (except one research. They are significantly lower than those obtained in flow system one research. They They are are significantly significantly lower lower than than those those obtained obtained in in the the proposed proposed flow flow system system (except (except one one research. research. They are significantly lower than those obtained in the proposed flow system (except one case). ItIt was due to excellent mixing mass transfer conditions, offered by innovative monolithic research. They are significantly lowerand than those obtained in the the proposed proposed flow system (except (except one case). was due to excellent mixing and mass transfer conditions, offered by innovative monolithic case). It to and mass offered by monolithic case). It It was was due due to to excellent excellent mixing mixing and and mass mass transfer transfer conditions, conditions, offered offered by by innovative innovative monolithic monolithic case). case). It was due to excellent mixing and mass transfer conditions, offered by innovative monolithic microreactor characterized by high ratios. Application of the proposed case). It was was due due to excellent excellent mixing mixing andsurface-to-volume mass transfer transfer conditions, conditions, by innovative innovative microreactor characterized by high high surface-to-volume ratios. offered Application of the the monolithic proposed microreactor characterized by surface-to-volume ratios. Application of proposed microreactor characterized by high surface-to-volume ratios. Application of the proposed microreactor microreactor characterized characterized by by high high surface-to-volume surface-to-volume ratios. ratios. Application Application of of the the proposed proposed microreactor characterized by high surface-to-volume ratios. Application of the proposed

Catalysts 2018, 8, 221

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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. Table 1 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 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. 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): τ=

mk ·l ·VT 0.0375·l ·VT = F F

(2)

where mk is the mass of monolith per length unit [g·cm−1 ], 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 ].

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 Catalysts 2018, 8,were 221 monitored by gas chromatography (FID detector, HP-5 column, 7890A, Agilent, 7 of 8 Santa Clara, CA, USA).

Figure Figure 5. 5. Scheme Scheme of of the the reaction reaction setup. setup.

The kinetic experiments were carried out in setup shown in Figure 5 for a flow rate fixed at 0.03 4. Conclusions 3 cm ·min−1, at the temperature range of 65–95 °C. The mass of the 1-cm-long microreactor was 0.0375 The outstanding potential of continuous-flow in the area of selective reduction of g. The length of reactive cores was changed from 1microreactors to 8 cm (weight form 0.0375–0.3 g) and enabled carbonyl compounds demonstrated. Broad-range and long-term experiments the obtainment of datawas for different residence times, calculated using Equation (2): were conducted to determine the kinetics of the MPV reaction of cyclohexanone in the zirconium-functionalized flow ∙∙ . ∙∙ = = microreactors was shown. The activation energy (2) microreactors. The lack of diffusion constraints in the was calculated be 52ofkJmonolith ·mol−1 . Moreover, rate−1],constants for several ketones aldehydes per lengthreaction unit [g·cm l is the microreactor length and [cm], VT is the where mk is thetomass were collected. The rate of the process is necessary to design the apparatus and reaction systems. total pore volume, equal to −4 [cm3·g−1] (data from mercury porosimetry), and F is the flow rate Significant differences in process efficiency were recorded for various carbonyl compounds. They were 3 −1 [cm ·min ]. 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, DEC-2017/01/X/ST8/00083), is gratefully acknowledged.

Poland (project no.

Conflicts of Interest: The authors declare no conflict of interest.

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