Article 3 ∞ [Cu2(mand)2(hmt)]–MOF: A Synergetic Effect between Cu(II) and in the Henry Reaction

1 1 1 2 2, Horat, iu Szalad , Natalia Candu , Bogdan Cojocaru , Traian D. Păsătoiu , Marius Andruh * and Vasile I. Pârvulescu 1,* 1 Department of Organic Chemistry, Biochemistry and Catalysis, Catalysis and Catalytic Processes Research Centre, Faculty of Chemistry, University of Bucharest, Bd. Regina Elisabeta nr. 4-12, 020462 Bucharest, Romania; [email protected] (H.S.); [email protected] (N.C.); [email protected] (B.C.) 2 Faculty of Chemistry, University of Bucharest, Department of Inorganic Chemistry, 23 Dumbrava Ro¸sie Street, sector 2, 020462 Bucharest, Romania; [email protected] * Correspondence: [email protected] (M.A.); [email protected] (V.I.P.)

 Received: 9 January 2020; Accepted: 12 February 2020; Published: 13 February 2020 

3 Abstract: [Cu2(mand)2(hmt)] H2O (where mand is totally deprotonated (racemic ∞ · mixture) and hmt is hexamethylenetetramine) proved to be a stable metal–organic framework (MOF) structure under thermal activation and catalytic conditions, as confirmed by both the in situ PXRD (Powder X-ray diffraction) and ATR–FTIR (Attenuated total reflection-Fourier-transform infrared spectroscopy) haracterization. The non-activated MOF was completely inert as catalyst for the Henry reaction, as the accessibility of the substrates to the channels was completely blocked by H-bonded water to the mand entities and CO2 adsorbed on the Lewis basic sites of the hmt. Heating at 140 ◦C removed these molecules. Only an insignificant change in the relative ratios of the XRD facets due to the capillary forces associated to the removal of the guest molecules from the network has been observed. This treatment afforded the accessibility of nitromethane and various aldehydes (4-bromobenzaldehyde, 4-nitrobenzaldehyde, and p-tolualdehyde) to the active catalytic sites, leading to conversions up to 48% and selectivities up to 98% for the desired nitroaldol products. The behavior of the catalyst is -sensitive. Protic completely inhibited the reaction due to the above-mentioned strong H-bonds. Accordingly, very good results were obtained only with aprotic solvents such as acetonitrile and 1,4-dioxane. The synthesized MOF is completely recyclable as demonstrated for five successive cycles.

Keywords: metal–organic frameworks; Henry reaction; heterogeneous basic catalysis; Lewis basic sites

1. Introduction As catalysts, metal–organic frameworks (MOFs) are a class of materials that stand at the boundary between zeolites and enzymes. Zeolites, with surface areas around 800 m2/g, can fade in comparison to MOFs when the porosity and channel regularity are taken into consideration. MOFs may provide an ultra-high porosity with some notable examples as DUT-32 [1], MOF-210 [2], or NU-100 [3]. The synthetic approach to achieve materials with such extreme values of the fraction of void volume to total volume is not complicated. An increase in the length of the organic linker could facilitate such molecular architectures [4,5], but this can also generate a decrease of the stability. On the other side, short and rigid linkers usually facilitate high thermal and chemical stability [6], and their textural properties can be tuned by branching the linking organic ligand [7,8]. Moreover, MOFs may also be designed to contain a variety of organic functional groups that decorate the channels. In a good

Chemistry 2020, 2, 50–61; doi:10.3390/chemistry2010006 www.mdpi.com/journal/chemistry Chemistry 2020, 2 51 resemblance with enzymes, such moieties can be effective in catalysis, influencing the overall catalytic selectivity due to the steric constraints introduced by the morphology of the channels [9]. However, to be used as catalysts or adsorbents, MOFs should be firstly evacuated for the adsorbed guest molecules without any collapse of the structure [10]. To achieve such stability, the literature suggested the necessity of either M+III or M+IV nodes with a high polarizing capability [11–13] or organic linkers with high pKa values [14]. In the case of M+II-supported MOFs, the stability may be improved by framework interpenetration [15], yet this generates a noticeable decrease in the specific surface area. In terms of catalytic activity, slight framework degradation without total collapse can be beneficial, as this may take place with the generation of defects [16]. Thus, MOFs may afford a very efficient transition from the classical homogeneous catalysis with metal complexes or from more recently organocatalysis to heterogeneous catalysis. The metallic nodes act as a backbone for the overall structure [17] but also regulate the acidity/basicity of the accessible sites [18–20]. For the specific case of the base catalyzed reactions, to date, several reports highlighted the efficient participation of the MOFs Lewis basic sites for fine organic syntheses such as the Hantzsch coupling reaction [21,22], Friedländer reaction [23], Knoevenagel condensation [24–26], aza-Michael condensation [27], or the Henry reaction [28–30]. Based on this state of the art, the aim of this study 3 was to extend the investigation of [Cu2(mand)2(hmt)] H2O (where mand is totally deprotonated ∞ · mandelic acid, and hmt is hexamethylenetetramine) [31] as a robust framework MOF for another important catalytic reaction, namely the Henry reaction, in the nitroaldol C–C coupling reaction, taking as substrates nitromethane and several derivatives.

2. Materials and Methods The reagents: copper(II) perchlorate hexahydrate (98%), mandelic acid (99%), hexamethylenetetramine ( 99%), nitromethane ( 95%), 1-nitropropane ( 98.5%), benzaldehyde ≥ ≥ ≥ ( 99%), 4-bromobenzaldehyde (99%), 4-nitrobenzaldehyde (99%), p-tolualdehyde (97%), ≥ 2-fluorobenzaldehyde ( 97%), and salycilaldehyde (98%) were obtained from Sigma-Aldrich (St. ≥ Louis, MI, USA) and were used without further purification. With these, the MOF catalyst has been prepared following a reported synthetic method [31]. The organic ligands have been dissolved in , and the copper(II) salt has been dissolved in DMF. All the components have been mixed together in a (1:1:1) molar ratio, and the green crystals were separated after a week by filtration, washed with methanol, and air-dried. The activation of the framework has been done firstly by drying at 110 ◦C for 24 h and then by raising the temperature with a rate of a 1.5 ◦C/min until 140 ◦C, where it was maintained for another 24 h. The resulted MOF has been exhaustively characterized by using TG-DTA (thermogravimetric-differential thermal analysis), PXRD, Raman, ATR–FTIR and diffuse reflectance infrared Fourier transform (DRIFT) analysis. Thermogravimetry was performed with a Shimadzu DTG-60 instrument (Kyoto, Japan) under a dry flow (50 mL/min) with a Pt crucible. Differential thermal analysis was conducted with a Shimadzu DTA-60 instrument. Powder X-ray diffraction (XRD) patterns were recorded using a Schimadzu XRD-7000 diffractometer (Kyoto, Japan) with Cu Kα radiation (λ = 1.5418 Å, 40 kV, 40 mA) at a step of 0.2 and a scanning speed of 2 degrees per minute in the 0–60 (2θ) range. Attenuated total reflection Fourier transformed infrared spectra were recorded using a PerkinElmer Spectrum Two spectrometer having an ATR cell equipped with 1 a diamond plate (Pike Technologies, Madison, WI, USA). The spectra were recorded with a 4 cm− resolution at 20 scans. DRIFT (diffuse reflectance infrared Fourier transform) analysis was carried out using a Brucker Tensor II with a Paraying Mantis accessory. A mirror was used as reference. 1 Raman spectra were acquired in the extended spectral region from 150 to 4000 cm− using a Horiba JobinYvon-Labram HR UV-Visible-NIR Raman Microscope Spectrophotometer (Kyoto, Japan), exciting with a laser at 488 nm. The activity tests were carried out in a glass reactor. First, 10 mg of catalyst were added to a solution of nitromethane (10 mmol), benzaldehyde derivatives (4-bromobenzaldehyde, 4-nitrobenzaldehyde Chemistry 2020, 2 52 Chemistry 2020, 2, x 3 and4‐nitrobenzaldehydep-tolualdehyde) (0.5and mmol),p‐tolualdehyde) and 3 mL (0.5 of solventmmol), withand 3 di mLfferent of solvent dielectric with constants different (deionized dielectric water,constants dried (deionized isopropyl alcoholwater, (IPA),dried 1,4-dioxane, isopropyl dichloromethane,alcohol (IPA), 1,4 dichloroethane,‐dioxane, dichloromethane, , or acetonitrile).dichloroethane, The chloroform, mixture has or been acetonitrile). stirred for 24The h atmixture 50 ◦C. has After been that stirred it has been for 24 filtered, h at 50 evaporated, °C. After andthat thenit has purified been filtered, by a silica evaporated, gel column and using then a mixturepurified of by petroleum a silica gel ether column and ethyl using acetate a mixture (6:1) asof eluent.petroleum Finally, ether the and resulted ethyl acetate solution (6:1) was as evaporated eluent. Finally, at room the temperature, resulted solution and the was identification evaporated ofat theroom evolved temperature, compounds and wasthe identification realized with aof GC-MS the evolved Carlo Erbacompounds Instruments was QMDrealized 1000 with (Milan, a GC Italy)‐MS equippedCarlo Erba with Instruments a Factor FourQMD VF-5HT 1000 (Milan, column. Italy) equipped with a Factor Four VF‐5HT column.

3. Results Let usus remindremind here here of of several several structural structural features features of of the the MOF MOF under under investigation investigation [30 ],[30], which which are 3 3 relevantare relevant for this for work. this work.[Cu2 (mand)∞ [Cu2(mand)2(hmt)]2(hmt)]H2O is∙H a2O 3D is coordination a 3D coordination polymer that polymer is constructed that is ∞ · fromconstructed binuclear from alkoxido-bridged binuclear alkoxido neutral‐bridged nodes, neutral {Cu2(mand) nodes,2 {Cu}, which2(mand) are2}, connected which are by connected hmt spacers by throughhmt spacers two outthrough of their two four out nitrogen of their atoms.four nitrogen The copper(II) atoms. The ions copper(II) show a coordination ions show numbera coordination of five, withnumber square of five, pyramidal with square geometry pyramidal (Figure 1geometry). Channels (Figure filled with1). Channels water molecules, filled with which water can molecules, be easily removed,which can follow be easily the removed, crystallographic follow ctheaxis. crystallographic The two uncoordinated c axis. The nitrogen two uncoordinated atoms from nitrogen the hmt spaceratoms from provide the Lewis hmt spacer basic sites,provide which Lewis are basic of interest sites, which for catalysis. are of interest for catalysis.

3 Figure 1. Perspective views of [Cu3 2(mand)2(hmt)] (the hmt molecules are drawn in blue): the channels Figure 1. Perspective views ∞of ∞ [Cu2(mand)2(hmt)] (the hmt molecules are drawn in blue): the (yellow)channels hosting (yellow) the hosting water molecules, the water which molecules, are not which shown are (left not); view shown along (left the); crystallographic view along the b axiscrystallographic emphasizing b the axis hmt emphasizing molecules (blue) the hmt each molecules one with two(blue) uncoordinated each one with nitrogen two uncoordinated atoms (right). 3.1. Characterizationnitrogen atoms (right of the). Catalysts

3.1. CharacterizationThe structure of of the the fresh Catalysts green MOF crystals has been checked from the recorded X-Ray diffraction pattern by comparison with the simulated one (Figure2). The identity of the recorded positions of the diffractionThe structure lines confirmed of the fresh the purity green of MOF the obtained crystals MOF. has been However, checked the difromfferent the intensity recorded ratios X‐Ray of thesediffraction indicated pattern a di ffbyerent comparison percentage with of the the di simulatedfferent facets. one A (Figure slight loss 2). The in crystallinity identity of was the measured recorded afterpositions the thermal of the diffraction treatment lines at 140 confirmed◦C for 24 the h (activated purity of the MOF) obtained (Figure MOF.2). Such However, an e ff ectthe hasdifferent been causedintensity by ratios the removal of these of theindicated guest moleculesa different from percentage the channels of the of different the framework, facets. whichA slight as aloss result in hascrystallinity led to a minorwas measured amorphization, after the which thermal is a treatment source of at beneficial 140 °C for defects 24 h (activated from the catalyticMOF) (Figure point 2). of view.Such an However, effect has the been XRD patternscaused by confirm the removal that the of overall the guest crystallinity molecules is preserved from the bychannels the activated of the MOFframework, with lines which located as a in result the same has positionsled to a minor as for theamorphization, fresh one. which is a source of beneficial defectsRaising from thethe temperature catalytic point at 160 of ◦view.C (Figure However,3) produced the XRD an importantpatterns confirm loss of thethat crystallinity the overall evidencedcrystallinity by is thepreserved less intense by the lines activated of the MOF facets with of the lines MOF located with in a totalthe same collapse positions at 180 as◦C. for XRD the patternsfresh one. collected at this temperature indicated the transformation of the MOF into a monoclinic Cu2O phase. Thus, lines at (2θ) 36 and 43 specific to the (110) and (111) crystalline facets of this phase clearly appeared in this pattern [32].

Chemistry 2020, 2, x 4

Chemistry 2020, 2 53 Chemistry 2020, 2, x 4

Figure 2. The XRD powder patterns for the simulated, as synthesized, activated, and recovered MOF.

Raising the temperature at 160 °C (Figure 3) produced an important loss of the crystallinity evidenced by the less intense lines of the facets of the MOF with a total collapse at 180 °C. XRD patterns collected at this temperature indicated the transformation of the MOF into a monoclinic Cu2O phase. Thus, lines at (2θ) 36 and 43 specific to the (110) and (111) crystalline facets of this phase clearly appeared in this pattern [32]. Figure 2.2. TheThe XRD XRD powder powder patterns patterns for for the the simulated, simulated, as synthesized, as synthesized, activated, activated, and recovered and recovered MOF. MOF.

Raising the temperature at 160 °C (Figure 3) produced an important loss of the crystallinity evidenced by the less intense lines of the facets of the MOF with a total collapse at 180 °C. XRD patterns collected at this temperature indicated the transformation of the MOF into a monoclinic Cu2O phase. Thus, lines at (2θ) 36 and 43 specific to the (110) and (111) crystalline facets of this phase clearly appeared in this pattern [32].

Figure 3. The in-situ PXRD analysis for the metal–organic framework (MOF). The sample has been Figure 3. The in‐situ PXRD analysis for the metal–organic framework (MOF). The sample has been treated at 100 ◦C for 2 h (red line), 120 ◦C for 2 h (blue line), 140 ◦C for 2 h (green line), 160 ◦C for 2 h treated at 100 °C for 2 h (red line), 120 °C for 2 h (blue line), 140 °C for 2 h (green line), 160 °C for 2 h (pink line), and 180 ◦C for 2 h (yellow line). The black line corresponds to the simulated pattern. (pink line), and 180 °C for 2 h (yellow line). The black line corresponds to the simulated pattern. To confirm the unhindered presence of the linkers in the framework of the activated MOF, comparativeTo confirm ATR–FTIR the unhindered spectra were presence recorded of the for bothlinkers the in fresh the andframework activated of MOF the activated (Figure4). MOF, They comparative ATR–FTIR spectra were recorded for both the fresh and activated MOF (Figure1 4). show identical vibrations bands characteristic to the monosubstituted ring at 680 cm− and They show1 identical vibrations bands characteristic to the monosubstituted1 benzene1 ring at 680 cm −1 790 cm− , to the alkoxido –O− group of the mandelic acid at 1060 cm− and 1370 cm− , and to the carbonyl and 790 cm−1, to the alkoxido –O1 − group of the mandelic acid at 1060 cm−1 and 1370 cm−1, and to the –C=OFigure acidic 3. bond The in at‐situ 1610 PXRD cm− analysis. Identical for bandsthe metal–organic were also detectedframework for (MOF). hexamethylenetetramine The sample has been with carbonyl –C=O acidic bond at 1610 cm−1. 1 Identical bands were also detected for vibrationstreated for at 100 tertiary °C for amino 2 h (red groups line), 120 at ν°C1220 for 2 cmh (blue− . For line), the 140 activated °C for 2 h and (green recovered line), 160 MOF, °C for the 2 h new hexamethylenetetramine with vibrations1 for tertiary amino groups at ν 1220 cm−1. For the activated bands(pink at 1615, line), 1400, and 180 and °C 1000 for 2 cmh (yellow− are specificline). The to black the Cline=C corresponds and C=N in-planeto the simulated vibrations pattern. (Figure 4). Besides the in situ PXRD and ATR–FTIR, the thermal stability of the MOF has been investigated by TG–DTA.To confirm The the TG–DTA unhindered analysis presence of the as-synthesized of the linkers sample in the (Figureframework5, left) of shows the activated that the MOFMOF, startscomparative losing moistureATR–FTIR at 50spectra◦C, this were weight recorded loss being for both associated the fresh with and an evidentactivated endothermic MOF (Figure eff ect.4). −1 TheThey MOF show retains identical its framework vibrations bands integrity characteristic up to 195 ◦ C,to atthe which monosubstituted temperature benzene it rapidly ring collapses. at 680 cm The strongand 790 exothermic cm−1, to the DTA alkoxido profile –O of− this group region of the corresponds mandelic toacid the at thermal 1060 cm decomposition−1 and 1370 cm of−1, the and organic to the ligands.carbonyl The –C=O sample acidic shows bond a weight at loss 1610 up tocm 74−1 wt. %Identical of its original bands mass. were also detected for hexamethylenetetramine with vibrations for tertiary amino groups at ν 1220 cm−1. For the activated

Chemistry 2020, 2, x 5

−1 Chemistryand recovered2020, 2 MOF, the new bands at 1615, 1400, and 1000 cm are specific to the C=C and C=N54 in‐plane vibrations (Figure 4).

Figure 4. ATR–FTIR spectra of the as-synthesized MOF (black), the activated MOF (red), and the Figure 4. ATR–FTIR spectra of the as‐synthesized MOF (black), the activated MOF (red), and the Chemistryrecovered 2020 MOF, 2, x (blue). 6 recovered MOF (blue).

Besides the in situ PXRD and ATR–FTIR, the thermal stability of the MOF has been investigated by TG–DTA. The TG–DTA analysis of the as‐synthesized sample (Figure 5, left) shows that the MOF starts losing moisture at 50 °C, this weight loss being associated with an evident endothermic effect. The MOF retains its framework integrity up to 195 °C, at which temperature it rapidly collapses. The strong exothermic DTA profile of this region corresponds to the thermal decomposition of the organic ligands. The sample shows a weight loss up to 74 wt % of its original mass. The analysis done for the thermally activated sample (Figure 5, right) shows that in the first portion of the analysis, there is no weight loss associated to desolvation. A very weak signal appears on the DTA profile, which is associated with a very small amount of atmospheric water retained by the material. The activated material appears stable up to 185 °C, at which point it Figure 5. The TG–DTA profiles for the as‐synthesized MOF (left) and the activated MOF (right). rapidlyFigure collapses. 5. The This TG–DTA sample profiles decomposes for the as-synthesized up to 54% of MOF its original (left) and mass, the activated indicating MOF that (right during). the activationTheTo analysis procedure, investigate done athe partial for nature the decomposition thermally of the slight activated amorphization of the sampleframework during (Figure takes the5, place.thermal right) Figure shows activation, 5, that right Raman in theconfirms first portionthe importancespectroscopy of the analysis, of has the been activation there employed is no at weight (Figure140 °C. loss 6). Under associatedIn the thesecase toof conditions, desolvation.the as‐synthesized as Aboth very sample, TG weak and the signal DTA Raman appearsprofiles lines at 998 cm−1 and 1052 cm−1 correspond to C–N vibrations, those at 1597 cm−1 and 1697 cm−1 onshowed, the DTA almost profile, 20% which of the is mass associated corresponding with a very to the small molecules amount ofretained atmospheric during water the synthesis retained are by removed,correspond also affording to C=O and the C–N access vibrations, of the andreacting those moleculesat 2182 cm− 1during, 2975 cm the−1, andcatalytic 3056 cmreaction.−1 correspond the material.to the C–H The vibrations activated [33,34]. material At appearslower wavenumbers, stable up to the 185 line◦C, at 256 which cm− point1 is specific it rapidly to Cu–O collapses. This samplevibrations decomposes [35]. Raman up spectra to 54% of of the its sample original heated mass, at indicating 180 °C for that2 h does during not the contain activation any specific procedure, a partialline of decomposition the organic linkers. of the However, framework new takesvery intense place. and Figure broad5, right lines confirmswith maxima the at importance 1350 to 1590 of the activationcm−1 appeared. at 140 ◦C. These Under signals these are conditions, specific to the as bothD (disordered) TG and DTA band profiles and G (graphitic) showed, almostband specific 20% of the massto corresponding carbon materials. to theEven molecules more, the retainedbroad line during at 2800 the cm synthesis−1 is specific are to removed, the 2D band also of a ffsimilarording the accessmaterials of the reacting [36]. Thus, molecules the recorded during Raman the catalytic spectra suggest reaction. a minor graphitization of the material. DuringTo investigate the solvent the release, nature the of capillary the slight forces amorphization may break the during coordination the thermal bonds, leaving activation, behind Raman spectroscopydangling hasligands. been These, employed as they (Figure are no6). longer In the susceptive case of the to as-synthesized the same polarization sample, and the network Raman lines energies1 as the unhindered1 ligands, are more prone to thermal decomposition.1 1 at 998 cm− and 1052 cm− correspond to C–N vibrations, those at 1597 cm− and 1697 cm− correspond 1 1 1 to C=O and C–N vibrations, and those at 2182 cm− , 2975 cm− , and 3056 cm− correspond to the C–H 1 vibrations [33,34]. At lower wavenumbers, the line at 256 cm− is specific to Cu–O vibrations [35]. Raman spectra of the sample heated at 180 ◦C for 2 h does not contain any specific line of the organic linkers. However, new very intense and broad lines with maxima at 1350 to 1590 cm 1 appeared. −

Figure 6. The Raman spectra recorded for MOF samples exposed to different thermal treatments.

3.2. Catalytic Behaviour of MOF The investigation of the catalytic behaviour of the activated MOF has been done in several experimental steps. The first aspect considered is the solvent effect, as the interaction of these molecules with the channels will deactivate the framework by a channel fill. The ideal solvent

Chemistry 2020, 2, x 6

Figure 5. The TG–DTA profiles for the as‐synthesized MOF (left) and the activated MOF (right).

To investigate the nature of the slight amorphization during the thermal activation, Raman spectroscopy has been employed (Figure 6). In the case of the as‐synthesized sample, the Raman lines at 998 cm−1 and 1052 cm−1 correspond to C–N vibrations, those at 1597 cm−1 and 1697 cm−1 correspond to C=O and C–N vibrations, and those at 2182 cm−1, 2975 cm−1, and 3056 cm−1 correspond Chemistryto the C–H2020, 2vibrations [33,34]. At lower wavenumbers, the line at 256 cm−1 is specific to Cu–O55 vibrations [35]. Raman spectra of the sample heated at 180 °C for 2 h does not contain any specific line of the organic linkers. However, new very intense and broad lines with maxima at 1350 to 1590 Thesecm−1 appeared. signals are These specific signals to the are D (disordered) specific to the band D (disordered) and G (graphitic) band band and specificG (graphitic) to carbon band materials. specific 1 Evento carbon more, materials. the broad Even line atmore, 2800 the cm broad− is specific line at to2800 the cm 2D−1 band is specific of similar to the materials 2D band [36 of]. similar Thus, thematerials recorded [36]. Raman Thus, spectra the recorded suggest aRaman minor graphitizationspectra suggest of a the minor material. graphitization During the of solvent the material. release, theDuring capillary the solvent forces may release, break the the capillary coordination forces bonds, may leavingbreak the behind coordination dangling ligands.bonds, leaving These, asbehind they aredangling no longer ligands. susceptive These, to as the they same are polarization no longer susceptive and network to energiesthe same as polarization the unhindered and network ligands, areenergies more proneas the tounhindered thermal decomposition. ligands, are more prone to thermal decomposition.

FigureFigure 6.6. TheThe RamanRaman spectraspectra recordedrecorded forfor MOFMOF samplessamples exposedexposed toto didifferentfferent thermal thermal treatments. treatments. 3.2. Catalytic Behaviour of MOF 3.2. Catalytic Behaviour of MOF The investigation of the catalytic behaviour of the activated MOF has been done in several The investigation of the catalytic behaviour of the activated MOF has been done in several experimental steps. The first aspect considered is the solvent effect, as the interaction of these molecules experimental steps. The first aspect considered is the solvent effect, as the interaction of these with the channels will deactivate the framework by a channel fill. The ideal solvent found for this molecules with the channels will deactivate the framework by a channel fill. The ideal solvent system was acetonitrile. This has been further employed in the investigation of the substituent effect upon the benzaldehyde derivatives transformation. In addition, the size capacity of the framework has been studied by the employ of 1-nitropropane as a substrate. The last aspect to be confirmed was the reaction mechanism, which has been easily confirmed via a DRIFT study. In the absence of the catalyst, no nitroaldol reaction occurred. The carboxyl functional groups of the mandelic acid linker provide connectivity for the {Cu2(mand)2} binuclear nodes and the channel exposed oxygen atoms of these functionalities, which interacted with the guest molecules. Accordingly, with the protic solvents such as water or isopropanol, the framework oxygen atoms of the MOF network interact stronger as H-acceptors, hence blocking the channel. Therefore, with these solvents, the MOF did not yield any results. Interestingly enough, also no reaction products were observed when using chlorinated solvents such as chloromethane, chloroethane, or chloroform as a solvent. A possible explanation is the non-covalent interaction of these solvent molecules with the O atoms through halogen bonding [37]. The activated MOF showed a good activity for the Henry reaction with aprotic solvents (Table1). With 1,4-dioxane, despite its very low polarity (ε = 2.25), acceptable values of conversion and selectivity were obtained. The increase of the polarity of the solvent was accompanied by an increase of the conversion. The selectivity of the reaction is also solvent sensitive. Basic solvents such as acetonitrile blocked the Lewis acidity of the metal, allowing increased selectivities to nitroaldol (Table1). Chemistry 2020, 2, x 7

found for this system was acetonitrile. This has been further employed in the investigation of the substituent effect upon the benzaldehyde derivatives transformation. In addition, the size capacity of the framework has been studied by the employ of 1-nitropropane as a substrate. The last aspect to be confirmed was the reaction mechanism, which has been easily confirmed via a DRIFT study. In the absence of the catalyst, no nitroaldol reaction occurred. The carboxyl functional groups of the mandelic acid linker provide connectivity for the {Cu2(mand)2} binuclear nodes and the channel exposed oxygen atoms of these functionalities, which interacted with the guest molecules. Accordingly, with the protic solvents such as water or isopropanol, the framework oxygen atoms of the MOF network interact stronger as H-acceptors, hence blocking the channel. Therefore, with these solvents, the MOF did not yield any results. Interestingly enough, also no reaction products were observed when using chlorinated solvents such as chloromethane, chloroethane, or chloroform as a solvent. A possible explanation is the non-covalent interaction of these solvent Chemistry 2020, 2 56 molecules with the O atoms through halogen bonding [37]. The activated MOF showed a good activity for the Henry reaction with aprotic solvents (Table 1). WithThe 1,4-dioxan free linkerse, anddespite the metallicits very specieslow polarity have also(ε = been2.25), testedacceptable as organo- values and of conversion metal catalysts and (Tableselectivity2). The were mandelic obtained. acid showedThe increase no activity, of the while polarity with of hexamethylenetetramine, the solvent was accompanied the conversion by an ofincrease nitroalkane of the was conversion. of 31% and The with selectivity a high selectivity of the re toaction nitroalkene is also (96%).solvent Cu(ClO sensitive.) 6H BasicO showed solvents a 4 2· 2 highersuch as conversion acetonitrile (64%) blocked of nitro-alkane the Lewis but acidity with aof selectivity the metal, tonitroaldol allowing ofincreased only 23%, selectivities the rest being to thenitroaldol nitroalkene. (Table Thus,1). both the linker and the copper salt favorize the dehydration of nitroaldol to alkene. The fresh MOF did not show any catalytic activity. Table 1. The effect of the solvent on the catalytic performance of the activated MOF (10 mmols Tablenitromethane 1. The and effect 0.5 of mmols the solvent benzaldehyde on the catalytic. 24 h 50 °C performance 10 mg of catalyst). of the activated MOF (10 mmols

nitromethane and 0.5 mmols benzaldehyde. 24 h 50 ◦C 10 mg of catalyst).

Selectivity for Selectivity for Solvent Conversion (%) SelectivityNitroaldol for (%) SelectivityNitroalkene for (%) Solvent Conversion (%) Nitroaldol (%) Nitroalkene (%) H2O (deionized) None None None IsopropylH2O (deionized) alcohol None None None None None None DichloromethaneIsopropyl alcohol None None None None None None Dichloroethane None None None DichloromethaneChloroform NoneNone None None None None DichloroethaneAcetonitrile None 40 None 91 None 9 1,4-dioxaneChloroform None 30 None 83 None 17 Acetonitrile 40 91 9 1,4-dioxane 30 83 17 Turnover numbers (TONs) were calculated to compare the performances of HMT and investigated MOFThe by consideringfree linkers theand participationthe metallic species of the have also of been the aminetested networksas organo- as and the metal active catalysts sites. In acetonitrile,(Table 2). The the TONmandelic of HMT acid was showed of 2.36, whileno acti forvity, MOF, while this was with more hexamethylenetetramine, than double (5.91). However, the inconversion the less polar of nitroalkane 1,4-dioxane, thewas TON of of31% MOF, and although with a still high superior selectivity to HMT, to hasnitroalkene been reduced (96%). to 4.41.Cu(ClO This4)2· increase6H2O showed in activity a higher for MOF conversion compared (64%) to HMT of mightnitro-alkane be assigned but towith both a anselectivity effect of theto Cu–Nnitroaldol interaction of only and 23%, a betterthe rest availability being the of nitroa the activelkene. sites. Thus, both the linker and the copper salt favorizep-Toluene-aldehyde, the dehydration asof nitroaldol the methyl to substituent, alkene. The exhibits fresh MOF an weak did not electron-releasing show any catalytic effect activity. with no real eTurnoverffect on the numbers conversion (TONs) and selectivity. were calculated Accordingly, to compare the calculated the TONperformances (5.65) and of the HMT selectivity and areinvestigated very close MOF to that by ofconsidering the benzaldehyde. the participation However, of thethe othernitrogens investigated of the aromatic networks substituents as the exhibitedactive sites. a very In acetonitrile, strong effect the on TON the TON of HMT and selectivity.was of 2.36, Thus, while for for the MOF, para this nitro was substituted more than substrate, double the(5.91). TON However, had a slight in the increase less polar to 6.97. 1,4-dioxane, However, the the TON effect of was MOF, more although evident forstillp -bromo-benzaldehydesuperior to HMT, has which,been reduced due to to the 4.41. predominant This increase resonance in activity activated for MOF the compared aromatic ring,to HMT led tomight a considerable be assigned increase to both ofan theeffect TON of the to 8.47. Cu–N In interaction addition, the and probability a better availability for the formed of the nitroaldolactive sites. to be in the proximity of a conjugated acid species NH+ increases, producing an enhanced dehydration. With 2-fluorobenzaldehyde as a substrate, the reaction followed a different pathway. Instead of the regular dehydration, both C-C coupling and elimination of the NO2 functional group [38] have been evidenced. This pathway was also observed for the -Br substitued substrate, with a selectivity to the secondary product of 13%. For the much more electronegative F, the conversion was total, and the selectivity was fully shifted to the secondary product. Salycilaldehyde was also employed as a subtrate in the Henry reaction, yet the results showed low values of conversion (12%). The reaction was also totally selective for the nitroaldol. To investigate the size control efficiency of the synthesized MOF, a larger nitroalkane substrate has also been employed. Thus, 1-nitro-propane has been used as a substrate in the reaction with benzaldehyde under the same experimental conditions (aldehyde: nitroalkane molar ratio of 1:20, 10 mg of catalyst, 50 ◦C, 24 h, solvent acetonitrile). The conversion suffered a noticeable decrease to 12%, with a TON calculated value of 1.75. In addition, it is to be noted that the nitroaldol selectivity has decreased to 74%. Such a decrease in the catalytic activity can be attributed to both the morphology Chemistry 2020, 2 57

3 and the size of the MOF channel. The pore size of [Cu2(mand)2(hmt)] is 7.9 Å [31], i.e., it is a very ∞ small value placing this MOF at the boundary between microporous and ultramicroporous materials. Another characteristic that has to be considered is the dipole-rich surface of such molecular materials, which inChemistry cotrast 2020 with, 2, x the small pore size, will limit the substrate diffusion as the size of the reacting8 molecule increases. Table 2. Catalytic results using the isolated MOF components and MOF as catalysts for the Henry Chemistry 2020,Table 2, x Chemistry 2. reactionCatalytic 2020, 2with, x results various using substrates the isolated(10 mmols MOF nitromethane components and 0.5 and mm MOFols benzaldehyde, as catalysts 24 forh, 50 the ºC, Henry88 10 mg of catalyst). reactionChemistry with various2020, 2, x substrates (10 mmols nitromethane and 0.5 mmols benzaldehyde, 24 h, 50 ºC,8 ChemistryTable 20202. Cataly, 2, x tic results using the isolated MOF components and MOF as catalysts for the Henry 8 Chemistry 2020, 2, x 8 10 mgChemistry of catalyst). 2020, 2, x 8 ChemistryChemistryreaction 2020 2020, 2with,, 2x, x various substrates (10 mmols nitromethane and 0.5 mmols benzaldehyde, 24 h, 50 ºC, 8 8 Table 2. Catalytic results using the isolated MOF components and MOF as catalysts for the Henry 10 Tablemg of 2.catalyst). Cataly tic results using the isolated MOF components and MOF as catalysts for the Henry TableTablereaction 2.2. CatalyCataly withtic ticvarious resultsresults substrates usingusing thethe (10 isolatedisolated mmols MOFMOF nitromethane compcomponentsonents and andand 0.5 MOFMOFmmols asas benzaldehyde, catalystscatalysts forfor thethe 24 HenryHenryh, 50 ºC, TableTablereaction 2. 2.Cataly Catalywithtic varioustic results results substrates using using the the (10 isolated isolated mmols MOF nitromethaneMOF comp componentsonents and and 0.5and MOFmm MOFols as asbenzaldehyde, catalysts catalysts for for the 24the Henryh, Henry 50 ºC, reactionreaction10 mg withwithof catalyst). variousvarious substratessubstrates (10(10 mmolsmmols nitromethanenitromethane andand 0.50.5 mmmmolsols benzaldehyde,benzaldehyde, 2424 h,h, 5050 ºC,ºC, Chemistryreactionreaction10 2020 mg, 2withof, withx catalyst). various various substrates substrates (10 (10 mmols mmols nitromethane nitromethane and and 0.5 0.5 mm mmolsols benzaldehyde, benzaldehyde, 24 24 h, h, 50 50 ºC, ºC, 8 1010 mg mg of of catalyst). catalyst). 1010 mg mg of of catalyst). catalyst). Table 2. Catalytic results using the isolated MOF components and MOF as catalysts for the Henry Selectivity Chemistryreaction 2020, 2with, x various substrates (10 mmolsCarbon nitromethaneyl Conversion and 0.5 mm ols Selectivitybenzaldehyde, for 24 h, 50 ºC, 8 Catalyst Solvent for 10 mg of catalyst). Substrate (%) Nitroaldol (%) Nitroalkene Table 2. Catalytic results using the isolated MOF components and MOF as catalysts for the Henry Carbonyl Conversion Selectivity for SelectivitySelectivity for ChemistryreactionCatalyst 2020, 2with, x various Solvent substrates (10 mmolsCarbon nitromethaneyl Conversion and 0.5 mm ols Selectivitybenzaldehyde, for 24 h, 50 ºC, 8 NoCatalyst catalyst 1,4-Dioxane Solvent Substrate (%)None NitroaldolNone (%) NitroalkeneNonefor 10 mg of catalyst). Substrate (%) Nitroaldol (%) NitroalkeneSelectivity Table 2. Catalytic results using the isolatedCarb onMOFyl componentsConversion and MOF as Selectivitycatalysts for forSelectivity the HenrySelectivity Catalyst Solvent Carbonyl Conversion Selectivity for SelectivitySelectivityfor MandelicCatalyst Acid SolventCarbonyl CarbSubstrateonyl Conversion Conversion (%)Selectivity SelectivityNitroaldol for for (%) Selectivityfor Catalyst NoreactionCatalystSolvent catalyst with various 1,4-Dioxane SolventEthanol substrates (10 mmolsCarbCarbSubstrateonon nitromethaneylyl ConversionNone ConversionandNone 0.5(%) mm ols Selectivitybenzaldehyde,Selectivity NoneNitroaldolNone for for (%) 24 h,forSelectivity None50for ºC, No(5.21CatalystCatalyst catalyst mg) 1,4-Dioxane Solvent SolventSubstrate SubstrateCarbonyl (%) ConversionNone(%) Nitroaldol NitroaldolSelectivityNone (%) (%) for NitroalkeneNoneforfor 10 Catalystmg of catalyst). Solvent Substrate (%) Nitroaldol (%) Nitroalkenefor SubstrateSubstrate (%)(%) NitroaldolNitroaldol (%) (%)Nitroalkene NitroalkeneNitroalkene NitroalkeneNitroalkene NoHMT catalyst 1,4-Dioxane None None None MandelicNo catalyst Acid 1,4-Dioxane 31None 4None Selectivity96None NoNo(2.4 catalyst catalyst mg) 1,4-Dioxane 1,4-DioxaneEthanolEthanol Carbonyl ConversionNoneNoneNone Selectivity NoneNoneNone for NoneNone No catalyst No1,4(5.21(5.21CatalystNo -catalystDioxane catalyst mg)mg) 1,4-Dioxane 1,4-DioxaneSolvent None NoneNone NoneNone None NoneNoneforNone Mandelic Acid Substrate (%) Nitroaldol (%) Cu(ClOMandelic4)2·6H Acid2O Ethanol None None NitroalkeneNone MandelicMandelicHMT(5.21 Acid Acidmg) EthanolEthanol 64None 23None 76None Mandelic(12.25HMT(5.21 mg) Acid mg) Ethanol None31 None4 SelectivityNone96 Mandelic Acid Mandelic(5.21(2.4 mg)mg) Acid EthanolEthanolEthanol Carbonyl Conversion31NoneNone Selectivity 4NoneNone for NoneNone 96 No(5.21(2.4Catalyst(5.21Ethanol catalyst mg) mg) mg) 1,4-Dioxane SolventEthanol None NoneNone NoneNone None NoneNoneforNone (5.21 mg) (5.21HMT mg) Substrate (%) Nitroaldol (%) ActivatedHMT MOF Ethanol 31 4 Nitroalkene96 Cu(ClOHMTHMT(2.44)2·6H mg) 2O 1,4-DioxaneEthanol 3031 83 4 1796 (10HMT(2.4HMT mg) mg) Ethanol 3164 234 9676 Cu(ClOMandelic(12.25(2.4 4mg)) mg)2 Acid6H 2O EthanolEthanol 3131 44 Selectivity9696 HMT (2.4(2.4 mg) mg)· EthanolEthanolEthanol Carbonyl Conversion64None31 Selectivity 23None4 for None 7696 No(12.25Cu(ClO(5.21CatalystEthanol (2.4catalyst mg) mg) mg)4)2 ·6H 2O 1,4-Dioxane Solvent 31 None 4 None 96Nonefor ActivatedCu(ClO 4MOF)2·6H 2O Ethanol Substrate (%)64 Nitroaldol23 (%) 76 (2.4 mg) Cu(ClOActivated4)2·6H MOF2O Ethanol 64 23 76 Cu(ClO(12.2544)22·6H mg)22O AcetonitrileEthanol 6440 2391 Nitroalkene769 Cu(ClO(10(12.25 mg)) 4·6H2 mg) O2 1,4-Dioxane 30 83 17 Cu(ClO(12.25(10HMT mg) mg)) ·6H O EthanolEthanol 6464 2323 7676 ActivatedMandelic(12.25(12.25 mg) mg) MOFAcid EthanolEthanol 3164 423 9676 Cu(ClO4)2·6H2O Activated(2.4(12.25 mg) mg) MOF 1,4-DioxaneEthanol 30None 83None None 17 ActivaNoActivated(5.21(10Ethanol catalystted mg) mg) MOF MOF 1,4-Dioxane1,4-Dioxane 64 None30 23 None83 76None 17 (12.25 mg) ActivatedActivated(10 MOFmg) MOF Acetonitrile1,4-Dioxane 4830 9883 2 17 Activated(10(10 mg) mg)MOF 1,4-DioxaneAcetonitrile 4030 9183 179 Cu(ClOActivated(10 4mg))2·6H MOF2O 1,4-Dioxane1,4-Dioxane 3030 8383 1717 (10(10HMT mg) mg) 1,4-DioxaneEthanol 6430 2383 7617 ActivatedMandelic(12.25Activated(10 mg)mg) MOFAcid MOF Ethanol 31 4 96 Activated MOF ActivaActivated(2.4ted mg) MOF MOF AcetonitrileEthanolAcetonitrile 40None40 91None91 None 9 9 ActivaActivated(5.21(10ted mg) mg) MOF Acetonitrile 40 91 9 ActivatedActivated1,4-Dioxane(10 MOFmg) MOF Acetonitrile 30 6640 83 1691 1771 9 (10 mg) ActivatedActivated(10(10 mg) mg)MOF MOF AcetonitrileAcetonitrile 4840 9891 29 Cu(ClO(10 4mg))2·6H 2O AcetonitrileAcetonitrile 4040 9191 9 9 (10(10HMT mg) mg) 1,4-Dioxane 30 83 17 ActivatedActiva(10(10 mg) mg)ted MOF MOF Ethanol 64 23 76 (12.25Activa mg)ted MOF AcetonitrileEthanolAcetonitrile 4831 48 984 98 96 2 2 Activated MOF Activa(2.4(10ted(10 mg)mg) mg)MOF Acetonitrile 48 98 2 ActivaActivaAcetonitrile(10tedted mg)MOF MOF Acetonitrile 40 6648 91 1698 9 712 ActivatedActiva(10 mg)ted MOF MOF AcetonitrileAcetonitrile 1004848 98098 202 (10 mg) Activated(10(10 mg) mg) MOF AcetonitrileAcetonitrile 4048 9198 9 2 Cu(ClOActiva(10(10 4mg)) 2mg)ted·6H MOF2 O 1,4-Dioxane 30 83 17 ActivatedActiva(10 mg)ted MOF MOF EthanolAcetonitrile 64 66 23 16 76 71 Activa(12.25ted(10 mg) mg)MOF AcetonitrileAcetonitrile 6666 1616 71 71 Activated MOF ActivaActiva(10(10tedted mg) mg)MOF MOF Acetonitrile 66 16 71 ActivaActiva(10ted mg)ted MOF MOF AcetonitrileAcetonitrile 6666 1616 7171 ActivatedAcetonitrile(10(10 mg) mg) MOF AcetonitrileAcetonitrile 48 1004866 98 98016 2 2071 (10 mg) ActivatedActiva(10(10ted mg) mg) MOFMO F Acetonitrile 40 91 9 (10 mg) 1,4-DioxaneAcetonitrile 1230 10083 170 Activa(10 mg)ted MOF Activa(10 mg)ted MOF Acetonitrile 100 0 0 Activated MOF ActivatedActivaActivated(10ted mg)MOF MOF Acetonitrile 100 0 0 ActivaActiva(10tedted mg)MOF MOF AcetonitrileAcetonitrileAcetonitrile 10010066100 01600 71 000 ActivatedAcetonitrile(10(10 mg)mg) MOF AcetonitrileAcetonitrile 66 10048100 16 980 0 71 20 0 (10 mg) Activa(10(10ted mg) mg) MO F Acetonitrile 40 91 9 Activa(10(10ted mg) mg) MO F Acetonitrile 12 100 0 (10 mg) Acetonitrile 39 89 11 (10 mg) ActivaActivatedted MOF MO F ActivaActivatedted MOF MO F AcetonitrileAcetonitrile 66 12 16100 71 0 Activated MOF Activa(10ted(10 mg) mg)MO F AcetonitrileAcetonitrile 1004812 980100 20 0 ActivatedActivaActiva(10(10ted tedmg) mg) MOFMO MO FF Acetonitrile 12 100 0 ActivaActivaAcetonitrile(10ted mg)ted MO MOF F AcetonitrileAcetonitrileAcetonitrile 100 121212 0 100100100 0 000 (10 mg) p(10(10-Toluene-aldehyde,(10 mg)mg) mg) AcetonitrileAcetonitrile as the methyl substituent, exhibits39 an12 weak electron-releasing89100 effect110 with (10(10 mg) mg) noActiva real tedeffect MOF on the conversion and selectivity. Accordingly, the calculated TON (5.65) and the ActivaActivatedted MOF MO F Activated MOF Acetonitrile 10066 160 710 selectivityActiva(10ted mg) areMO Fvery closeAcetonitrile to that of the benzaldehyde. However,39 the other investigated89 aromatic11 ActivaActivated(10ted mg)MO MOF F AcetonitrileAcetonitrile 3939 8989 1111 ActivatedActivaActivap-Toluene-aldehyde,(10tedted mg) MOFMO MO F F AcetonitrileAcetonitrile as the methyl substituent, exhibits12 39an weak electron-releasing10089 effect011 with substituents(10(10 mg) mg) exhibited AcetonitrileAcetonitrileAcetonitrile a very strong effect on the TON 39and3939 selectivity. 89Thus,8989 for the para 1111 nitro Activated MOF (10(10(10 mg)mg) mg) nosubstitutedActiva reAcetonitrileal tedeffect MOFsubstrate, on the conversionthe TON had and a slightselectivity. increase Accordingly, 12to 6.97. However, the calculated 100the effect TON was (5.65) more0 andevident the (10 mg) p-Toluene-aldehyde,Acetonitrile as the methyl substituent, exhibits100 an weak electron-releasing0 effect0 with forselectivityActiva p-bromo-benzaldehyde(10pted-Toluene-aldehyde, mg) areMO Fvery close to which, asthat the of methyldue the to benzaldehyde. substituent,the predomi exnant However,hibits resonance an weakthe activatedother electron-releasing investigated the aromatic aromaticeffect ring, with Activanop p-Toluene-aldehyde,re-Toluene-aldehyde,alted effect MOF onAcetonitrile the conversion asas thethe methylmethyl and substituent,substituent,selectivity. exAccordingly,exhibitshibits12 anan weakweak the electron-releasingcalculatedelectron-releasing100 TON (5.65) effecteffect0 and withwith the substituentsnop re(10-Toluene-aldehyde,p-Toluene-aldehyde,al mg) effect exhibited onAcetonitrile the a conversion veryas as the thestrong methyl methyl and effect substituent,selectivity. substituent, on the TONAccordingly,ex exhibitshibits and39 an anselectivity. weak weakthe electron-releasingcalculated electron-releasing Thus,89 forTON the (5.65) effectpara effect11 and nitrowith with the noled retoal(10 aeffect mg)considerable on the conversionincrease of and the selectivity.TON to 8. Accordingly,47. In addition, the thecalculated probability TON for (5.65) the andformed the nonoselectivity rerealal effecteffect are onon very thethe conversionconversionclose to that andand of selectivity.selectivity.the benzaldehyde. Accordingly,Accordingly, However, thethe calculatedcalculated the other TONTONinvestigated (5.65)(5.65) andand aromatic thethe nitroaldolsubstitutednoselectivity real effect to substrate, beare inon very the the proximitythe closeconversion TON to thathad of a anda ofconjugated slight the selectivity. benzaldehyde. increase acid Accordingly, speciesto 6.97. However, NHHowever,+ increases,the thecalculated the other effectproducing investigated TONwas more (5.65)an enhanced evident aromaticand the Activated MOFTo confirmselectivityselectivity the areare mechanism veryvery closeclose oftoto the thatthat reaction, ofof thethe benzaldehyde.benzaldehyde. the catalyst wasHowever,However, washed thethe with otherother the investigatedinvestigated nitromethane aromaticaromatic substrate, forselectivityselectivityActivasubstituentssubstituents pAcetonitrile-bromo-benzaldehydeted areMO are Fveryexhibitedexhibited very close close aato verywhich,tovery that that strongstrongof dueof the the to effecteffectbenzaldehyde. benzaldehyde.the predomionon thethe39 TONTON nant However, However, andresonanceand selectivity.selectivity. the the activatedother89 other Thus,Thus,investigated investigated the forfor aromatic thethe11 aromatic paraparaaromatic ring, nitronitro (10 mg) dehydration.substituentsActivated MO exhibitedF Acetonitrile a very strong effect on the TON and12 selectivity. Thus,100 for the para0 nitro then dried,substituentssubstituentssubstituted andp(10-Toluene-aldehyde, after mg) exhibitedexhibited that,substrate,Acetonitrile it was aa the veryasvery analyzed TONthe strongstrong methyl had effect byaeffect substituent,slight DRIFT onon increase thethe (Figure TONexTON hibitsto and6.97.7and).39 an A selectivity.However, selectivity.weak pure electron-releasing nitromethane the Thus,Thus,89 effect forfor was thethe sample more effectparapara11 evidentnitrowithnitro was used ledsubstituentssubstituted to(10 a mg)considerable substrate,exhibited increase thea very TON ofstrong had the a TON effectslight to onincrease 8. the47. TONIn to addition,6.97. and However, selectivity. the probability the Thus, effect for wasfor the themore para formed evident nitro nosubstitutedsubstituted real effect substrate,substrate, on the conversion thethe TONTON hadhad and aa slightslightselectivity. increaseincrease Accordingly, toto 6.97.6.97. However,However, the calculated thethe effecteffect TON waswas (5.65) moremore and evidentevident the 1 as a referencenitroaldolsubstitutedsubstitutedforfor top-bromo-benzaldehyde-bromo-benzaldehyde point to substrate, besubstrate, out in the its proximitythe characteristic the TON TON which,which, had of had a a conjugated duedueaslight vibration slight toto increase thethe increase acidpredomipredomi bands. speciesto to 6.97. 6.97.nant The NHHowever, signalsHowever,resonance+ increases, atthe theνactivated effect1390,producing effect wasν wasthe1410, more an aromaticmore enhanced and evident evident 1590 ring, cm − selectivityforforled pp-bromo-benzaldehyde-bromo-benzaldehyde to a areconsiderable very close increaseto which, which,that of of duedue thethe to tobenzaldehyde. TON thethe predomi predomito 8.47.nant nantHowever,In addition, resonanceresonance the the activatedotheractivated probability investigated thethe aromatic aromaticfor thearomatic formedring,ring, p-Toluene-aldehyde,are all characteristicdehydration.forforActivaled p -bromo-benzaldehydep -bromo-benzaldehydetoted a MOconsiderableas toFthe the methyl N–O increase which, stretches.substituent,which, ofdue duethe to Theto TONthe exhibitsthe spectrapredomi topredomi 8.47. annant obtained Innantweak addition,resonance resonance electron-releasing from the activated activated theprobability activated the the aromatic effectforaromatic MOF,the with formedring, ring, as in the led top-Toluene-aldehyde, a considerable increase as the ofmethyl the TONsubstituent, to 8.47. ex Inhibits addition, an weak +the electron-releasing probability for the effect formed with ledsubstituentslednitroaldol toto aa considerableconsiderable toexhibited be inAcetonitrile the increaseaincrease proximityvery strong ofof ofthethe aeffect conjugatedTONTON on toto the 8.8. 47.acid47. TON InIn species addition,addition,and39 selectivity.NH + the theincreases, probabilityprobability Thus,89 producing for for forthe the the paraan 11 formedenhancedformed nitro no real effect onnitroaldolled nitroaldol the (10to conversion amg) toconsiderable tobe be in inthe the andproximity proximityincrease selectivity. of of ofa conjugated thea conjugated Accordingly,TON to acid 8.acid47. species species In the addition, NH calculated NH+ increases, increases, the probability TON producing producing (5.65) for an an andtheenhanced enhanced formed the nosubstitutednitroaldoldehydration. real effect to substrate, be on in the the conversion theproximity TON had ofand aa conjugated slightselectivity. increase acid Accordingly, tospecies 6.97. However,NH the++ increases, calculated the effect producing TON was (5.65) more an enhanced andevident the nitroaldolnitroaldoldehydration. to to be be in in the the proximity proximity of of a aconjugated conjugated acid acid species species NH NH increases,+ increases, producing producing an an enhanced enhanced selectivity are verydehydration.forselectivitydehydration. p -bromo-benzaldehyde close are to very that close of theto which, that benzaldehyde. of due the to benzaldehyde. the predomi However,nant However, resonance the other the activatedother investigated investigated the aromatic aromatic aromatic ring, dehydration.dehydration. substituents exhibitedledsubstituents top-Toluene-aldehyde, a aconsiderable very exhibited strong increasea veryas effect the strong ofmethyl on the effect the TONsubstituent, TON on to the8. and47. TONex In hibits selectivity. addition,and an selectivity. weak the Thus,electron-releasing probability Thus, for for the for the parathe effectpara formed nitro nitrowith no real effect on the conversion and selectivity. Accordingly, the calculated TON (5.65) and the substituted substrate,nitroaldolsubstituted the to substrate,TON be in thehad proximitythe a TONslight had of increase a a conjugated slight toincrease 6.97. acid speciestoHowever, 6.97. NHHowever,+ increases,the effect the effectproducing was was more more an evidenenhanced evidentt forselectivity p-bromo-benzaldehyde are very close to which, that of due the to benzaldehyde. the predominant However, resonance the activatedother investigated the aromatic aromatic ring, for p-bromo-benzaldehydedehydration. which, due to the predominant resonance activated the aromatic ring, ledsubstituents to a considerable exhibited increasea very strong of the effect TON on to the8.47. TON In addition,and selectivity. the probability Thus, for for the the para formed nitro led to a considerablenitroaldolsubstituted increase to substrate, be in the of proximitythe the TON TON had of a toa conjugated slight 8.47. increase In acid addition, speciesto 6.97. NHHowever, the+ increases, probability the effectproducing for was the more an enhanced formed evident nitroaldol to be dehydration.forin thep-bromo-benzaldehyde proximity of a conjugated which, due acid to the species predomi NHnant+ increases, resonance producingactivated the an aromatic enhanced ring, dehydration. led to a considerable increase of the TON to 8.47. In addition, the probability for the formed nitroaldol to be in the proximity of a conjugated acid species NH+ increases, producing an enhanced dehydration. Chemistry 2020, 2, x 9

With 2‐fluorobenzaldehyde as a substrate, the reaction followed a different pathway. Instead of the regular dehydration, both C‐C coupling and elimination of the NO2 functional group [38] have been evidenced. This pathway was also observed for the ‐Br substitued substrate, with a selectivity to the secondary product of 13%. For the much more electronegative F, the conversion was total, and the selectivity was fully shifted to the secondary product. Salycilaldehyde was also employed as a subtrate in the Henry reaction, yet the results showed low values of conversion (12%). The reaction was also totally selective for the nitroaldol. To investigate the size control efficiency of the synthesized MOF, a larger nitroalkane substrate has also been employed. Thus, 1‐nitro‐propane has been used as a substrate in the reaction with benzaldehyde under the same experimental conditions (aldehyde: nitroalkane molar ratio of 1:20, 10 mg of catalyst, 50 °C, 24 h, solvent acetonitrile). The conversion suffered a noticeable decrease to 12%, with a TON calculated value of 1.75. In addition, it is to be noted that the nitroaldol selectivity has decreased to 74%. Such a decrease in the catalytic activity can be attributed to both the morphology and the size of the MOF channel. The pore size of ∞3[Cu2(mand)2(hmt)] is 7.9 Å [31], i.e., it is a very small value placing this MOF at the boundary between microporous and ultramicroporous materials. Another characteristic that has to be considered is the dipole‐rich surface of such molecular materials, which in cotrast with the small pore size, will limit the substrate diffusion as the size of the reacting molecule increases. To confirm the mechanism of the reaction, the catalyst was washed with the nitromethane substrate, then dried, and after that, it was analyzed by DRIFT (Figure 7). A pure nitromethane sample was used as a reference to point out its characteristic vibration bands. The signals at ν 1390, −1 Chemistryν 1410,2020 and, 2 1590 cm are all characteristic to the N–O stretches. The spectra obtained from the 58 activated MOF, as in the ATR–FTIR analysis, show vibration bands characteristic to hexamethylenetetramine at ν 1250 and 1420 cm−1 and mandelic acid at ν 1370 and 1620 cm−1. ATR–FTIRWashing analysis,with the shownitromethane vibration presented bands characteristic in these spectra to hexamethylenetetramineits characteristic vibration atbandsν 1250 even and 1 1 1420after cm 30− minand mandelicof exposure acid to atvacuum.ν 1370 However, and 1620 cmthe− exposure. Washing to withvacuum the nitromethaneled to a shift of presented the N–O in thesestretches spectra to itslower characteristic wavenumbers, vibration suggesting bands an even increase after in 30 the min strength of exposure of the interaction. to vacuum. However, the exposureThese results to vacuum are in led a togood a shift corroboration of the N–O with stretches the catalytic to lower data, wavenumbers, supporting suggestingthe reaction an increasemechanism in the described strength ofin the Figure interaction. 8.

FigureFigure 7. 7.The The didiffuseffuse reflectancereflectance infraredinfrared Fourier transform transform (DRIFT) (DRIFT) spectra spectra recorded recorded for for the the nitromethanenitromethane reference reference (black), (black), the the activated activated MOF MOF (red), (red), MOF MOF washed washed by theby the substrate substrate (blue), (blue), and and MOF afterMOF 30 minafter evacuation 30 min evacuation (violet). (violet).

These results are in a good corroboration with the catalytic data, supporting the reaction mechanism describedChemistry in2020 the, 2, Figurex 8. 10

2+ FigureFigure 8. The8. The catalytic catalytic cycle cycle for for the the Henry Henry reaction reaction facilitated facilitated by by the the MOF MOF catalyst. catalyst. The The Cu Cu2+atoms atoms are illustratedare illustrated in green, in green, oxygen oxygen atoms atoms are illustrated are illustrated in red, in red, nitrogen nitrogen atoms atoms are are illustrated illustrated in blue,in blue, and carbonand carbon atoms areatoms illustrated are illustrate in gray.d in gray. Hydrogen Hydrogen atoms atoms have have been been omitted omitted for clarity.for clarity.

3.3. The Stability of the Catalyst

The investigated MOF has been five times recycled for the Henry coupling of benzaldehyde and p-nitro-benzaldehyde without any change in the conversion and selectivity. However, the activated MOF is moisture sensitive, and therefore, it cannot be left under atmospheric conditions for a long time. Thus, due to the adsorption of water, one week of exposure has as an effect a decrease of the conversion to only 15%, with selectivity for the nitroaldol of 56%. However, it completely recovered the initial activity after heating the sample at the same 140 °C. It is also important that the MOF preserved its crystallinity after five successive cycles.

5. Conclusions

The ∞[Cu2(mand)2(hmt)]·H2O MOF structure has been synthesized by assembling copper(II) ions with mandelic acid and hexamethylenetetramine in basic solution. The highly ordered channel morphology of this framework gives accessibility for two Lewis basic sites per hmt unit, while the Cu2+ nodes are coordinatively saturated, hence not being catalytically active. This MOF offers a heterogeneous alternative to a homogenous organocatalyst. The required Lewis base active catalytic sites for the nitroaldol reaction were provided by the amino groups of the hmt linker acting as a deprotonating agent for nitromethane. However, the reaction further proceeded to nitroalkene. This step has been catalyzed by the conjugated NH+ acid in situ generated during the reaction. The synthesized MOF proved to be stable up to 140 °C. Higher temperatures induced a continuous degradation of the framework, which was evidenced by PXRD and TG–DTA weight loss, with a total collapse at 180 °C. As Raman spectroscopy showed, finally, this decomposition occurred with the formation of a graphitic material. Non-activated MOF was completely inert from the catalytic point of view in the Henry reaction due to the blockage of the active sites by the polar molecules. However, after the thermal activation, and only with aprotic solvents, it showed an increased catalytic activity compared to HMT. Basic solvents such as acetonitrile blocked the generated Brønsted acidity, allowing increased selectivities to nitroaldol. Noteworthy, the synthesized MOF is completely recyclable. It is worth

Chemistry 2020, 2 59

3.3. The Stability of the Catalyst The investigated MOF has been five times recycled for the Henry coupling of benzaldehyde and p-nitro-benzaldehyde without any change in the conversion and selectivity. However, the activated MOF is moisture sensitive, and therefore, it cannot be left under atmospheric conditions for a long time. Thus, due to the adsorption of water, one week of exposure has as an effect a decrease of the conversion to only 15%, with selectivity for the nitroaldol of 56%. However, it completely recovered the initial activity after heating the sample at the same 140 ◦C. It is also important that the MOF preserved its crystallinity after five successive cycles.

4. Conclusions

The [Cu2(mand)2(hmt)] H2O MOF structure has been synthesized by assembling copper(II) ∞ · ions with mandelic acid and hexamethylenetetramine in basic solution. The highly ordered channel morphology of this framework gives accessibility for two Lewis basic sites per hmt unit, while the Cu2+ nodes are coordinatively saturated, hence not being catalytically active. This MOF offers a heterogeneous alternative to a homogenous organocatalyst. The required Lewis base active catalytic sites for the nitroaldol reaction were provided by the amino groups of the hmt linker acting as a deprotonating agent for nitromethane. However, the reaction further proceeded to nitroalkene. This step has been catalyzed by the conjugated NH+ acid in situ generated during the reaction. The synthesized MOF proved to be stable up to 140 ◦C. Higher temperatures induced a continuous degradation of the framework, which was evidenced by PXRD and TG–DTA weight loss, with a total collapse at 180 ◦C. As Raman spectroscopy showed, finally, this decomposition occurred with the formation of a graphitic material. Non-activated MOF was completely inert from the catalytic point of view in the Henry reaction due to the blockage of the active sites by the polar molecules. However, after the thermal activation, and only with aprotic solvents, it showed an increased catalytic activity compared to HMT. Basic solvents such as acetonitrile blocked the generated Brønsted acidity, allowing increased selectivities to nitroaldol. Noteworthy, the synthesized MOF is completely recyclable. It is worth mentioning here that this MOF is assembled easily from cheap starting materials, which makes it appealing for applications.

Author Contributions: V.I.P. and M.A.; methodology, N.C.; software, B.C.; validation, T.D.P.; formal analysis, H.S., N.C.; writing—original draft preparation, H.S., B.C., T.D.P.; writing—review and editing, V.I.P., M.A.; supervision, V.I.P., M.A.; project administration, V.I.P., M.A.; All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by UEFISCDI, grant number PNII-ID-PCCE-2011-2-0050. Traian D. Păsătoiu is grateful to UEFISCDI for a post-doctoral fellowship (grant umber PN-III-P1-1.1-PD-2016-1564). Conflicts of Interest: The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

1. Grünker, R.; Bon, V.; Müller, P.; Stoeck, U.; Krause, S.; Mueller, U.; Senkovka, I.; Kaskel, S. A new metal–organic framework with ultra-high surface area. Chem. Commun. 2014, 50, 3450–3452. [CrossRef][PubMed] 2. Furukawa, H.; Ko, N.; Go, Y.B.; Aratani, N.; Choi, S.B.; Choi, E.; Yazaydin, A.O.; Snurr, R.Q.; O’Keeffe, M.; Kim, J.; et al. Ultrahigh Porosity in Metal-Organic Frameworks. Science 2010, 329, 424–428. [CrossRef] [PubMed] 3. Farha, O.K.; Yazaydin, A.O.; Eryazici, I.; Malliakas, C.D.; Hauser, B.G.; Kanatzidis, M.G.; Nguyen, S.T.; Snurr, R.Q.; Hupp, J.T. De novo synthesis of a metal–organic framework material featuring ultrahigh surface area and gas storage capacities. Nat Chem. 2010, 2, 944–948. [CrossRef][PubMed] 4. Yuan, D.; Zhao, D.; Sun, D.; Zhou, H.C. An Isoreticular Series of Metal–Organic Frameworks with Dendritic Hexacarboxylate Ligands and Exceptionally High Gas-Uptake Capacity. Angew. Chem. Int. Ed. 2010, 49, 5357–5361. [CrossRef][PubMed] Chemistry 2020, 2 60

5. Deng, H.; Grunder, S.; Cordova, K.E.; Valente, C.; Furukawa, H.; Hmadeh, M.; Gandara, F.; Whalley, A.C.; Liu, Z.; Asahina, S.; et al. Large-Pore Apertures in a Series of Metal-Organic Frameworks. Science 2012, 336, 1018–1023. [CrossRef] 6. Tan, Y.X.; He, Y.P.; Zhang, J. Tuning MOF Stability and Porosity via Adding Rigid Pillars. Inorg. Chem. 2012, 51, 9649–9654. [CrossRef] 7. Marx, S.; Kleist, W.; Huang, J.; Maciejewskia, M.; Baiker, A. Tuning functional sites and thermal stability of mixed-linker MOFs based on MIL-53(Al). Dalton Tran. 2010, 39, 3795–3798. [CrossRef] 8. Wittmann, T.; Siegel, R.; Reimer, N.; Milius, W.; Stock, N.; Senker, J. Enhancing the Water Stability of

Al-MIL-101-NH2 via Postsynthetic Modification. Chem. Eur. J. 2014, 20, 314–323. 9. Lillerud, K.P.; Olsbye, U.; Tilset, M. Designing Heterogeneous Catalysts by Incorporating Enzyme-Like Functionalities into MOFs. Top Catal. 2010, 53, 859–868. [CrossRef] 10. Mondloch, J.E.; Karagiaridi, O.; Farha, O.K.; Hupp, J.T. Activation of metal–organic framework materials. CrystEngComm. 2013, 15, 9258–9264. [CrossRef] 11. Yuan, S.; Qin, J.S.; Lollar, C.T.; Zhou, H.C. Stable Metal–Organic Frameworks with Group 4 Metals: Current Status and Trends. ACS Cent. Sci. 2018, 4, 440–450. [CrossRef][PubMed] 12. Kang, I.J.; Khan, N.A.; Haque, E.; Jhung, S.H. Chemical and Thermal Stability of Isotypic Metal–Organic Frameworks: Effect of Metal Ions. Chem. Eur. J. 2011, 17, 6437–6442. [CrossRef][PubMed] 13. Kandiah, M.; Nilsen, M.H.; Usseglio, S.; Jakobsen, S.; Olsbye, U.; Tilset, M.; Larabi, C.; Quadrelli, E.A.; Bonino, F.; Lillerud, K.P. Synthesis and Stability of Tagged UiO-66 Zr-MOFs. Chem. Mater. 2010, 22, 6632–6640. [CrossRef] 14. Duan, J.; Jin, W.; Kitagawa, S. Water-resistant porous coordination polymers for gas separation. Coord. Chem. Rev. 2017, 332, 48–74. [CrossRef] 15. Jasuja, H.; Walton, K.S. Effect of catenation and basicity of pillared ligands on the water stability of MOFs. Dalton Trans. 2013, 42, 15421–15426. [CrossRef] 16. Canivet, J.; Vandichel, M.; Farrusseng, D. Origin of highly active metal–organic framework catalysts: Defects? Defects! Dalton Trans. 2016, 45, 4090–4099. [CrossRef] 17. Kitagawa, S.; Kitaura, R.; Noro, S. Functional Porous Coordination Polymers. Angew. Chem. Int. Ed. 2004, 43, 2334–2375. [CrossRef] 18. Burgoyne, A.R.; Meijboom, R. Knoevenagel Condensation Reactions Catalysed by Metal-Organic Frameworks. Catal. Lett. 2013, 143, 563–571. [CrossRef] 19. Cai, J.; Wang, H.; Wang, X.; Duan, X.; Wang, Z.; Cui, Y.; Yang, Y.; Chen, B.; Qian, G. An amino-decorated

NbO-type metal–organic framework for high C2H2 storage and selective CO2 capture. RSC Adv. 2015, 5, 77417–77422. [CrossRef] 20. An, J.; Geib, S.J.; Rosi, N.L. High and Selective CO Uptake in a Cobalt Adeninate Metal Organic Framework 2 − Exhibiting Pyrimidine- and Amino-Decorated Pores. J. Am. Chem. Soc. 2010, 132, 38–39. [CrossRef] 21. Rostamnia, S.; Xin, H. Basic isoreticular metal–organic framework (IRMOF-3) porous nanomaterial as a suitable and green catalyst for selective unsymmetrical Hantzsch coupling reaction. Appl. Organometal. Chem. 2014, 28, 359–363. [CrossRef] 22. Rostamnia, S.; Morsali, A. Basic isoreticular nanoporous metal–organic framework for Biginelli and Hantzsch coupling: IRMOF-3 as a green and recoverable heterogeneous catalyst in solvent-free conditions. RSC Adv. 2014, 4, 10514–10518. [CrossRef]

23. Pérez-Mayoral, E.; Cejka, J. [Cu3(BTC)2]: A Metal–Organic Framework Catalyst for the Friedländer Reaction. ChemCatChem. 2011, 3, 157–159. [CrossRef] 24. Gascon, J.; Aktav, U.; Hernandez-Alonso, M.D.; van Klink, G.P.M.; Kapteijin, F. Amino-based metal-organic frameworks as stable, highly active basic catalysts. J. Catal. 2009, 261, 75–87. [CrossRef] 25. Valvekensa, P.; Vandichelb, M.; Waroquierb, M.; Van Speybroeck, V.; De Vos, D. Metal-dioxidoterephthalate MOFs of the MOF-74 type: Microporous basic catalysts with well-defined active sites. J. Catal. 2014, 317, 1–10. [CrossRef] 26. Luan, Y.; Qi, Y.; Gao, H.; Andriamitantsoa, R.S.; Zhenga, N.; Wang, G. A general post-synthetic modification approach of amino-tagged metal–organic frameworks to access efficient catalysts for the Knoevenagel condensation reaction. J. Mater. Chem. A 2015, 3, 17320–17331. [CrossRef] Chemistry 2020, 2 61

27. Savonnet, M.; Aguado, S.; Ravon, U.; Bazer-Bachi, D.; Lecocq, V.; Bats, N.; Pinela, C.; Farrusseng, D. Solvent free base catalysis and transesterification over basic functionalised Metal-Organic Frameworks. Green Chem. 2009, 11, 1729–1732. [CrossRef] 28. Grupta, A.K.; Dea, D.; Bharadwaj, P.K. A NbO type Cu(II) metal–organic framework showing efficient catalytic activity in the Friedländer and Henry reactions. Dalton Trans. 2017, 46, 7782–7790. [CrossRef] 29. Yu, H.; Xie, J.; Zhong, Y.; Zhang, F.; Zhu, W. One-pot synthesis of nitroalkenes via the Henry reaction over amino-functionalized MIL-101 catalysts. Catal. Commun. 2012, 29, 101–104. [CrossRef] 30. Karmakar, A.; Martins, L.M.D.R.S.; Hazra, S.; da Silva, M.F.C.G.; Pombeiro, A.J.L. Metal Organic Frameworks − with Pyridyl-Based Isophthalic Acid and Their Catalytic Applications in Microwave Assisted Peroxidative Oxidation of Alcohols and Henry Reaction. Cryst. Growth Des. 2016, 16, 1837–1849. [CrossRef] 31. Ilyes, E.; Florea, M.; Madalan, A.M.; Haiduc, I.; Parvulescu, V.I.; Andruh, M. A Robust Metal–Organic Framework Constructed from Alkoxo-Bridged Binuclear Nodes and Hexamethylenetetramine Spacers: Crystal Structure and Sorption Studies. Inorg. Chem. 2012, 51, 7954–7956. [CrossRef][PubMed]

32. Yang, M.; Zhu, J.J. Spherical hollow assembly composed of Cu2O nanoparticles. J. Cryst. Growth 2003, 256, 134–138. [CrossRef] 33. Thamann, T.J.; Loehr, T.M. Raman spectra and normal coordinate analysis of the copper(II) and copper(III) complexes of biuret and oxamide. Spectrochim. Acta A 1980, 36, 751–760. [CrossRef] 34. Dhumal, N.R.; Singh, M.P.; Anderson, J.A.; Kiefer, J.; Kim, H.J. Molecular Interactions of a Cu-Based Metal–Organic Framework with a Confined Imidazolium-Based Ionic Liquid: A Combined Density Functional Theory and Experimental Vibrational Spectroscopy Study. J. Phys. Chem. C 2016, 120, 3295–3304. [CrossRef] 35. Escamilla-Roa, E.; Cartwright, J.H.E.; Sainz-Diaz, C.I. Chemobrionic Fabrication of Hierarchical Self-Assembling Nanostructures of Copper Oxide and Hydroxide. ChemSystemsChem 2019, 1, e190001. [CrossRef] 36. Ferrari, A.C.; Meyer, J.C.; Scardaci, V.; Casiraghi, C.; Lazzeri, M.; Mauri, F.; Piscanec, S.; Jiang, D.; Novoselov, K.S.; Roth, S.; et al. Raman Spectrum of Graphene and Graphene Layers. Phys. Rev. Lett. 2006, 97, 187401. [CrossRef] 37. Politzer, P.; Lane, P.; Concha, M.C.; Ma, Y.; Murray, J.S. An overview of halogen bonding. J. Mol. Model. 2007, 13, 305–311. [CrossRef] 38. Ballini, R.; Palmieri, A. Formation of Carbon-Carbon Double Bonds: Recent Developments via Nitrous Acid Elimination (NAE) from Aliphatic Nitro Compounds. Adv. Synth. Catal. 2019, 361, 5070–5097. [CrossRef]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).