(1R,2S)‑Ephedrine: A New Self-Assembling Chiral Template for theSynthesis of Aluminophosphate FrameworksTeresa Alvaro-Munoz,† Fernando Lopez-Arbeloa,‡ Joaquín Perez-Pariente,† and Luis Gomez-Hortiguela*,†

†Instituto de Catalisis y Petroleoquímica, ICP-CSIC, C/Marie Curie 2, 28049 Madrid, Spain‡Departamento de Química Física, Universidad del País Vasco, Apartado 644, 48080 Bilbao, Spain

*S Supporting Information

ABSTRACT: (1R,2S)-(−)-Ephedrine is used as a new structure-directing agent for thesynthesis of nanoporous aluminophosphates. This molecule is selected based on the self-aggregating behavior through π−π type interactions between the aromatic rings and thepresence of H-bond-forming groups. Additionally, this molecule possesses two chiral centers,which could enhance a potential transfer of chirality to the inorganic framework. Synthesisresults showed that (1R,2S)-(−)-ephedrine is very efficient in directing the crystallization ofthe AFI-type structure in the presence of several catalytically active dopants. A combination offluorescence spectroscopy and molecular mechanics simulations shows that ephedrine displaysa great trend to self-assemble in water solution, establishing not only π−π type interactionsbetween the aromatic rings but also intermolecular H-bonds between NH2 and OH moietieswhich compete with the formation of H-bonds with water. These molecules are invariablyincorporated as aggregates within the AFI structure, regardless of the dopant introduced,showing a very strong trend to self-assemble within nanoporous frameworks as well. The stability of this supramoleculararrangement within the framework is due to a molecular recognition phenomenon based on the establishment of two H-bondsbetween the H atoms of the amino group and the O atoms of the hydroxyl group of the consecutive dimer, leading to an infinitesupramolecular π−π H-bonded chainlike arrangement within the AFI channels.

1. INTRODUCTION

Nowadays nanoporous materials, in particular zeolites, arefinding new applications in materials science since theirnanoscopic and crystalline structure and the associatedproperties allow their use to recognize and discriminatemolecules with precisions that can be fundamental in all fieldsof molecular recognition phenomena. In particular, the designof solid sorbents and heterogeneous catalysts from nanoporousmaterials which combine the shape selectivity characteristic ofthese materials and enantioselectivity represents one of thebiggest quests in zeolite science.Since the pioneering work of Barrer and Denny in the

1960s,1 organic compounds, particularly quaternary ammoniumsalts, have been extensively used in the hydrothermal synthesisof zeolite materials, which led to the discovery of a number ofnew framework structures and compositions.2 These organicmolecules are often referred to as structure-directing agents(SDAs), since they direct the crystallization pathway toward aparticular framework that would not be formed in itsabsence.3−7 The SDAs are encapsulated in the nanoporousstructure during its crystallization, developing strong non-bonding interactions with the framework and thus contributingto the final stability of the system. For an organic molecule tobe an efficient SDA, it has to fulfill a series of chemicalrequirements, like to have a moderate hydrophobicity, highsolubility in the synthesis media, moderate rigidity, and highhydrothermal stability, and should develop strong nonbondinginteractions with the nanoporous framework.8 The alumino-

phosphate family of zeotypes (AlPO4-n series),9−13 in whichthe network is composed of AlO4 and PO4 tetrahedral unitsarranged in a strict alternation, also almost invariably requirethe use of organic molecules in their synthesis. However, withthese AlPO frameworks, amines are used more often thanquaternary compounds.Synthesis of new large-pore zeolite-like structures is an

ultimate goal in zeolite science, particularly interesting forcatalysis for these structures will allow the processing of largeorganic molecules. In searching for novel large-pore nano-porous structures, increasingly larger, bulkier, and morecomplex SDAs have been extensively used, leading to thediscovery of a number of new zeolitic topologies.14 Using thisapproach, the first zeolitic materials containing 14-ring channelswere first reported in 1996; UTD-1 (DON)15−17 wassynthesized using a permethylated bis-cyclopentadienyl “sand-wich” complex of cobalt, and similarly CIT-5 (CFI structuretype)18,19 was prepared using a polycyclic amine. Recently, thefirst mesoporous chiral zeolite (ITQ-37) has been obtained byusing a very large, rigid, and complex organic SDA.20 However,such intensification of the size and complexity of organicspecies is severely restricted by the chemical requirements ofthe organic molecules to be efficient SDAs. On the other hand,the thermodynamically disfavored crystallization of very open

Received: November 12, 2013Revised: January 24, 2014Published: January 27, 2014

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frameworks, which are intrinsically less stable than denserframeworks, has to be compensated for by the establishment ofstrong nonbonding interactions with guest, SDAs in this case,species.Based on this, in a quest for new large and efficient organic

SDAs, new concepts in the design of the organic molecules areto emerge,21 especially involving the two main aspects of theSDA chemistry: (i) the increase of the SDA molecular sizewhile fulfilling the chemical requirements of the SDAs and (ii)the enhancement of the efficiency of the SDA molecules bymaximizing their nonbonding interactions with the frameworks.As previously mentioned, the increase of the SDA molecularsize is currently reaching a limit; this is so because their choiceas SDAs has almost invariably considered the features of singlemolecular units. Supramolecular chemistry has only rarely beenapplied in structure direction, in sharp contrast to the wide andvery successful use of supramolecular micelle arrangements ofsurfactants in the synthesis of mesoporous materials. In thiscontext, a new concept in structure direction has been recentlydeveloped by us22−26 and by Corma et al.;27 the strategyconsists of the use of molecules that self-assemble assupramolecular aggregates as SDAs, with the aggregates beingthe actual structure-directing entities. This concept permits theuse of relatively simple molecules with suitable size, hydro-phobicity, and basicity properties, to create more complex andlarger pore zeolite topologies due to their aggregation insupramolecular arrangements.One of the most common driving forces for the self-assembly

of organic molecules in aqueous solution is the presence ofaromatic rings that tend to aggregate due to the establishmentof π−π type interactions, which has been the main strategy wehave followed to date. On the other hand, the most commondriving force for molecular recognition phenomena is thedevelopment of intermolecular H-bonds between particulardonor/acceptor groups of different molecules. However, aspreviously mentioned, quaternary ammonium compounds,where no H atoms of amino groups susceptible of developingH-bonds are present, have been more often used in thesynthesis of zeolites. In contrast, amines with potentially H-bond-forming H atoms are more efficient for the synthesis ofnanoporous aluminophosphate frameworks. The possibility offorming H-bonds would in principle enable a supramolecularordering through molecular recognition phenomena among theSDA molecules occluded within nanoporous frameworks.Based upon these grounds, (1R,2S)-(−)-ephedrine (EPH)

has been used as SDA for the synthesis of hydrophilicaluminophosphate frameworks. This molecule has beenrationally selected based on the presence of aromatic ringswhich tend to self-assemble through π−π type interactions, HNand OH groups susceptible of developing intermolecular H-bonds, and high conformational flexibility due to the presenceof four rotatable bonds, which would facilitate the formation ofthose H-bonds. The synergy of these particular molecularfeatures in EPH will drive the molecule to develop a very strongself-assembling trend to form supramolecular aggregates inaqueous solution that will act as structure-directing species forthe crystallization of nanoporous aluminophosphate frame-works. Although this will not be particularly analyzed in thiswork, this molecule has also the advantage of having twoasymmetric C atoms, imparting a strongly asymmetric nature tothe molecule.

2. COMPUTATIONAL AND EXPERIMENTALMETHODOLOGIES

A. Computational Simulations. Molecular-mechanics-based simulations were performed to analyze the aggregationbehavior of ephedrine (EPH) in aqueous solution in order tounderstand the molecular features governing the supra-molecular chemistry that drives the formation of self-assembledaggregates in water. Molecular structures of ephedrine andwater molecules were described with the cvff force field.28 Dueto the strong basicity of ephedrine (pKa = 9.6)29 and the lowpH of the synthesis medium (5−6, see Tables S1, S2, and S3 inthe Supporting Information), protonated EPH (EPH+)molecules were studied. The atomic charge distribution ofEPH+ was obtained from DFT calculations, using the B3LYPhybrid functional and the ESP charge calculation method,setting the total net charge to +1. The positive charge of theEPH+ molecules was compensated by including an equalnumber of Cl− anions in the simulations. The atomic charges inwater molecules were −0.82 and +0.41 for oxygen andhydrogen, respectively.30

Due to the presence of four rotatable bonds, and theimportance of molecular flexibility when studying struture-directing and supramolecular aggregation issues,8,31 as well as inmolecular recognition phenomena, an initial conformationalanalysis was performed. The conformational space of DPGH+

was scanned by means of the Conformers Calculation Modulein Materials Studio,32 using a systematic grid scan searchmethod and optimizing the molecular structures for each set ofdihedral angles.The aggregation behavior of EPH+ molecules in water was

studied by means of molecular dynamics (MD) simulations,under periodic boundary conditions (PBC), using theDiscovery code as implemented in Material Studio.33 SixteenEPH+ molecules and 16 Cl− anions were included in thesimulation cell together with 640 water molecules. An initialequilibration period has been allowed, consisting of 100 ps ofMD simulations in the NPT ensemble at 25 °C. The density ofthe systems along this initial MD simulation was averaged, anda frame in the last steps of the MD trajectory with a densityclose to the averaged value was selected as the startingconfiguration for the subsequent NVT study. MD simulations(750 ps) were run, keeping the temperature constant at 298 K.Of this simulation time, the first 250 ps were assumed as theequilibration period, and only the last 500 ps of the MDsimulations were used for production. The aggregationbehavior of EPH+ molecules was studied by analyzing theradial distribution functions (RDFs) of different sets of atoms[gαβ(r)].

B. Hydrothermal Synthesis of AFI materials. Nano-porous aluminophosphates were synthesized by hydrothermalmethods using (1R,2S)-ephedrine (Sigma Adrich, 98%) asSDA. Gel molar compositions and synthesis conditions weresystematically varied, as detailed in Tables S1, S2, and S3 in theSupporting Information. The incorporation of several catalyti-cally active metals, such us magnesium, silicon, cobalt, or zinc,has been studied. Pseudoboehmite (Pural SB-1 77.5% Al2O3,Sasol) and phosphoric acid (Sigma-Aldrich, 85%) were used assources of Al and P, respectively. A wide scan of theexperimental conditions (organic and water contents, presenceof dopants, temperature, and crystallization times) wasperformed in order to obtain pure phases.

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In a typical synthesis, pseudoboehmite and the correspond-ing metal source (Mg(CH3COO)2·4H2O (Sigma-Aldrich,99.5%), Co(CH3COO)2·4H2O (Sigma Aldrich 98%), Zn-(CH3COO)2·2H2O (Sigma-Aldrich, 99%), or tetraethylortho-silicate, TEOS (Merck, 98%)), were added to a phosphoric acidsolution, and the mixture was stirred for 1 h. (1R,2S)-Ephedrinewas then added to this mixture and was stirred for about 2 h toobtain a uniform gel. The gels were then transferred intoTeflon-lined stainless steel autoclaves with a capacity of 14 cm3,which where heated statically at the required temperature(130−180 °C) under autogenous pressure for a specific periodof time (from 3 to 120 h). The resulting solids were collectedby filtration, washed thoroughly with water and ethanol, anddried at room temperature.Aqueous solutions of (1R,2S)-ephedrine were prepared by

adding equimolar amounts of the amine and HCl. In this way,0.1, 0.05, 0.01, 0.001, and 0.0001 M aqueous solutions wereobtained and studied by fluorescence spectroscopy.C. Characterization. The obtained solids were charac-

terized by different physicochemical techniques. Powder X-raydiffraction (XRD) patterns of samples were recorded on aPhilips XPERT diffractometer using CuKα radiation with a Nifilter. The crystal morphology was studied by scanning electronmicroscopy (SEM) using a Hitachi TM-1000 Tabletopmicroscope. The organic content of the samples was studiedby thermogravimetric analysis (TGA) using a Perkin-ElmerTGA7 instrument. Chemical analyses were obtained by ICP-AES (Fluxy-30, Claisse). UV−visible diffuse reflectance spectrawere registered on a Cary 5000 Varian spectrophotometerequipped with an integrating sphere using the syntheticpolymer Spectralen as reference.MAS NMR spectra were recorded with a Bruker AV 400 WB

spectrometer, using a BL7 probe for 13C and a BL4 probe for31P. 1H to 13C cross-polarization spectra were recorded usingπ/2 rad pulses of 4.5 μs for 1H, a contact time of 5 ms, and arecycle delay of 3 s. For the acquisition of the 13C spectra, thesamples were spun at the magic angle (MAS) at a rate of 5−5.5kHz. For 31P, π/2 rad pulses of 4.25 μs and recycle delays of 80s were used; these spectra were recorded while spinning thesamples at ca. 11 kHz. 29Si CP MAS NMR was recorded with a4 mm probe spinning at 10 kHz. A π/2 pulse of 3 μs, contacttime of 6 ms, and recycle delay of 5 s were used.The aggregation state of the molecules in solution and in the

solid samples was studied by fluorescence spectroscopy. Liquidand solid state UV−visible fluorescence emission spectra wererecorded in a RF-5300 Shimadzu fluorimeter. The fluorescencespectra were registered in the front-face configuration by a solidsample holder in which the samples were oriented 30° and 60°with respect to the excitation and emission beams, respectively.Liquid solutions of the SDA samples were placed in 1-, 0.1-, or0.01-mm pathway quartz cells, depending on the concentrationof the EPH solution, whereas the fluorescence spectra of thesolid samples were recorded by means of thin films supportedon glass slides ellaborated by solvent evaporation from adichloromethane suspension of the solid AFI samples.

3. RESULTSA. Aggregation of EPH+·Cl− in Aqueous Solution.

Fluorescence Spectroscopy. Figure 1 displays the fluorescencespectra of aqueous solutions of ephedrine hydrochloride(EPH+Cl−) at increasing concentrations. At the lowestconcentration studied (10−4 M, black line), a main fluorescenceband is observed centered at 282 nm, which is assigned to the

emission from the aromatic system of ephedrine monomers,since at this low concentration the presence of EPH monomersshould be predominant. A progressive increase of theconcentration results in the appearance of a new broad bandat longer wavelengths (between 325 and 425 nm, centered at360 nm), which becomes the predominant band as theconcentration rises to 0.1 M (pink line). The occurrence ofthis new band with the increase in the concentration of themolecules led us to assign it to the fluorescent emission fromEPH molecules in an aggregated state; π−π type interactions inthe aggregated state cause a stabilization of the electronic levelsleading to the observed bathochromic shift in the emissionband.Worth noting is the different fluorescence behavior observed

for ephedrine compared to other self-assembling aromaticamines previously studied by us (benzylpyrrolidine, BP, and(S)-N-benzyl-2-pyrrolidinemethanol, BPM).23,25 A much largershift toward higher wavelengths is observed for ephedrinemolecules upon an increase in the concentration (BP and BPMshift occurred from 282 nm, monomers, to 322 nm,aggregates). This shows that the interaction between theEPH aromatic rings in aggregates is much stronger than that forBP and BPM. On the other hand, supramolecular aggregationfor the latter molecules was only predominant at aconcentration of 1 M; in contrast, EPH aggregates are alreadyobserved at concentrations as low as 10−3 M (Figure 1, blueline) and are the predominant species at a concentration of 0.1M (pink line). Both observations suggest a much strongersupramolecular self-assembly behavior for EPH molecules.

Molecular Dynamics Simulations. We then analyzed theEPH behavior in aqueous solution by MD simulations tocharacterize the configuration of the supramolecular aggregates.Due to the conformational flexibility of EPH, and theimportance in structure-direction and molecular-recognitionphenomena, we first performed a conformational analysis(Figure 2). Out of the 140 conformational configurationsanalyzed, only seven different conformers were found to bestable. Figure 2 shows the most stable ones, where intra-molecular H-bonds are established; the other three conformers,

Figure 1. Fluorescence spectra of ephedrine·HCl of increasingconcentrations (M) in aqueous solution. Spectra of solutions with0.1 and 0.05 M concentrations have been smoothed because of the lowsignal-to-noise ratio due to the low optical pathway of the used cell.

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where no H-bonds are developed, are much less stable (relativeenergies of 9−17 kcal/mol with respect to conformer 1). Of thefour H-bonded conformations, three of them (1, 2, and 3)develop intramolecular H-bonds with one of the H atoms ofthe amino group (hereafter called hn1), while conformer 4develops the intramolecular H-bond with the other H (hn2).Looking at the relative energy differences, it becomes clear thatthe most stable intramolecular H-bond is developed with hn1,which in fact has a slightly smaller charge (0.324 e for hn1 vs

0.361 for hn2). This shows that the higher stability of such H-bond is due to a more favored spatial configuration.We next studied the behavior of EPH in aqueous solution at

a concentration similar to that in the aqueous synthesis gels(Figure 3). Initially a conformational analysis in water wasperformed by analyzing intramolecular RDFs (Figure 3A). Weobserved a very intense signal indicative of the formation of H-bonds between the O atom of the hydroxyl group and the hn1atom of the amino group (red line), much stronger than thatcorresponding to hn2 (green line), showing that suchintramolecular H-bonds are maintained during all thesimulation in most of the EPH+ molecules. Moreover, a veryprominent signal at 3.0 Å for the c3−h distance is observed(blue line). These results clearly indicate that the most stableconformer in vacuum, conformer 1 (Figure 2), is also thepredominant one in aqueous solution, evidencing a notablerigidity of the molecule despite the presence of four rotatablebonds and of water molecules that would compete for theformation of H-bonds with the polar groups of EPH. Theseintramolecular H-bonds must enhance the asymmetric natureof EPH molecules, reducing their conformational flexibility.Conformational flexibility can reduce the degree of asymmetryduring crystallization of host−guest materials.Supramolecular aggregation was then analyzed; Figure 3B

shows the intermolecular RDF between aromatic C atoms(cp−cp, black line). The high-intensity peak between 4 and 6 Åindicates a preferential location of the aromatic C atoms at suchdistances, showing a strong π−π stacking, and hence a strong

Figure 2. Most stable conformers of EPH+, with correspondingrelative energy (in kcal/mol); H-bonds are shown as dashed blue lines.Other less stable conformers without intramolecular H-bonds havebeen omitted. Distinguishable C(CH3)−O(OH) distances are high-lighted with yellow dashed arrows.

Figure 3. Intramolecular (A) and intermolecular (B and C) radial distribution functions (RDFs) of different sets of atoms during the MDsimulations of EPH+Cl− in aqueous solution (w indicates water molecules). (A) includes the molecular structure and atom types of EPH+. (D)Snapshot (t = 375 ps) of the arrangement of EPH+ aggregates, showing the formation of intermolecular H-bonds (dashed blue lines) and the π−πtype interactions (dashed yellow lines) (water molecules have been omitted for clarity).

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supramolecular aggregation through the aromatic rings,between EPH+ molecules, in agreement with the fluorescenceresults. In consequence, no interaction between the aromatic Hatoms with water molecules is observed (hcp−ow, gray line). Astrong peak at 1.7 Å between the H atom of the hydroxyl groupof EPH+ and O atoms of water is observed (ho−ow, blue line),much stronger than that corresponding between the O atom ofEPH+ and H atoms of water (oh−hw, red line), indicating theformation of H-bonds between the H-atom of the EPH+

hydroxyl group and the water O atom. H-bonds between Hatoms of EPH+ amino group and water O atom are alsoobserved, which are stronger with hn2 (dark cyan line) thanwith hn1 (green line) (see Figure 3A for nomenclature). Incontrast, no interaction of the amino N atom with water Hatoms is appreciated (n−hw, orange line).We then analyzed the intermolecular interaction between the

polar groups of EPH+ (Figure 3C). No H-bond intermolecularinteraction was observed between the amino groups (blackline) of different EPH+ molecules nor between the hydroxylgroups (blue). In contrast, a clear H-bond intermolecularinteraction at a distance of 1.8 Å is observed between the Hatoms of the amino group and the O of the hydroxyl group (redand green lines, hn1−oh and hn2−oh, respectively). At thesame time, as previously observed, one of the H atoms of theamino group (hn1) is involved in an intramolecular H-bondwith the O atom of the hydroxyl group within the samemolecule (Figure 3A, red line); such intramolecular H-bond ismostly developed with hn1 (rather than with hn2). Figure 3Dshows a snapshot (at time = 375 ps) of the type of aggregatesformed, where two self-assembling driving forces are present,π−π type interactions between the aromatic rings (dashedyellow lines) and intra- and intermolecular H-bonds betweenthe H atom of the amino group and the O atom of the hydroxylgroup. On the other hand, H atoms of the hydroxyl group (ho)and of the hn2 amino group interact preferentially with Oatoms of water (Figure 3B). Therefore, the type of supra-molecular aggregates found here suggests a molecularrecognition phenomenon of EPH molecules in water, both atan intramolecular level (through the H-bonds between O andH−N, determining the conformation) and at an intermolecularlevel (through π−π interactions on the one side and H-bondsbetween O and H−N atoms, determining the type ofaggregate).B. Hydrothermal Synthesis of AFI Materials. The use of

(1R,2S)-ephedrine as SDA under different gel compositionsand hydrothermal conditions has enabled the crystallization ofAFI-type materials (Figure S1 and Tables S1, S2, and S3 in theSupporting Information). The AFI-type structure is composedby one-dimensional noninterconnected 12-membered ringcylindrical channels. The synthesis results indicate that(1R,2S)-ephedrine is only able to direct the synthesis towardAFI-type materials in the presence of dopants. It was notpossible to synthesize undoped AlPO-5 since in the absence ofdopants a low-dimensional unknown framework with a highorganic content (which we refer to as phase X), AEN (as aresult of EPH degradation, at high temperatures and longcrystallization times), or a trydimite-like dense AlPO frameworkcrystallize (see Table S1). However, the incorporation ofdopants such as Co2+, Zn2+, Mg2+, or Si4+ drives thecrystallization at high temperatures toward AFI-type materials(see Tables S2 and S3 in the Supporting Information). Ingeneral, compositions of 0.925 Al2O3:0.15 MeO:1 P2O5:2EPH:100 H2O allowed for the crystallization of MgAPO-5,

CoAPO-5, SAPO-5, and ZnAPO-5 pure materials, which werefurther characterized. SEM (Figure S2 in the SupportingInformation) showed two different kinds of crystallinemorphologies: SAPO-5 crystallizes as large hexagonal prisms,with a crystal length close to 50 μm; in contrast, MgAPO-5,CoAPO-5, and ZnAPO-5 are obtained as aggregates of longneedles.The incorporation of organic molecules was studied by

thermogravimetric analysis and 13CP MAS NMR. The TGAprofiles of the samples studied (Figure S3 in the SupportingInformation) show four different weight loss steps. The firstweight loss, at temperatures below 200 °C, can be attributed towater desorption. The other weight losses are due to thedecomposition of the template, which occurs in several steps.The chemical integrity of EPH inside the framework wasverified by 13CP MAS NMR (Figure 4), showing that themolecule is incorporated intact within the structure in thedifferent materials (see assignments of the different bands inFigure 4).

The incorporation of dopants into the AFI structure wasverified by different techniques. 31P MAS NMR demonstratedthe incorporation of Mg and Zn within the AFI framework(Figure S4 in the Supporting Information). The spectra ofthese samples consists of a peak at −30 ppm, which ischaracteristic of tetrahedral P atoms in a P(4Al) configurationin the AFI network.34 In addition, two peaks at −24 and −22ppm are observed in MgAPO-5 and ZnAPO-5, respectively,due to the presence of P (1Mg, 3Al)35 and P (1Zn, 3Al)36

environments. The incorporation of Si was evidenced by 29SiMAS NMR. The spectrum of SAPO-5 (Figure S5 in theSupporting Information) consists of a broad band between −85and −105 ppm, which involves the different Si environments(Si−(OAl)n(OSi)4−n. These multiple Si environments occur asa result of the combination of the single P by Si substitutionmechanism with the simultaneous substitution of a pair ofneighboring Al and P atoms by two Si atoms. Finally, theincorporation of Co in the framework of the CoAPO-5 samplewas evidenced by UV diffuse reflectance spectroscopy by thepresence of three bands between 500 and 700 nm (Figure S6 inthe Supporting Information), characteristic of the 4A2(F) →4T1(P) transition of tetrahedral Co(II).37 The dopant content,

Figure 4. 13C CP MANMR of the different AFI materials studied andassignment of the different signals.

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calculated by ICP, was 1.1 Mg/u.c., 0.8 Si/u.c., 1.0 Zn/u.c., and1.3 Co/u.c. for MgAPO-5, SAPO-5, ZnAPO-5, and CoAPO-5,respectively.C. Aggregation of EPH within the AFI Materials. After

characterizing the aggregation state of EPH in solution, westudied their aggregation state inside the AFI framework. Solidstate UV−visible fluorescence spectroscopy results arepresented in Figure 5. Fluorescence results evidence the

complete absence of monomers in all the materials (there is noemission band at around 280 nm). Regardless of the dopant

introduced in the framework, a broad band between 300 and500 nm is observed, which corresponds to the presence of SDAaggregates occluded inside the AFI pores.23,24 Remarkably, andin contrast with previous results with benzylpyrrolidine and(S)-1-benzyl-2-pyrrolidinemethanol,23 we observed that EPH isalways incorporated as aggregates within the AFI structure,showing a very strong trend to self-assemble also withinnanoporous frameworks. Different maxima in the aggregatesemission range can be observed as a function of the dopantintroduced. Due to the confinement effect of the AFI one-dimensional channels, we tentatively assign such different bandseither to distinct interactions of the molecules with the dopantsincorporated or to slightly different π−π stackings in theaggregates (different distances/orientations between thearomatic C atoms).

4. DISCUSSION

In this work, (1R,2S)-ephedrine, an alkaloid derivative found invarious plants and commercially available, has been shown as anew chiral organic SDA with a great trend to self-assemblewhen directing the crystallization of nanoporous aluminophos-phates. A combination of fluorescence spectroscopy andmolecular simulations shows a great potential of this moleculeto self-aggregate in aqueous solution through the aromatic ringsby π−π type interactions. Such interactions are much strongerfor EPH than for our previously studied aromatic amines,benzylpyrrolidine (BP) and (S)-N-benzyl-2-pyrrolidinemetha-nol (BPM),23 as evidenced by the longer red-shift of EPH uponan increase in the concentration, and consequently aggregation,of the molecules. This implies a stronger trend of EPH to self-assemble in water, as confirmed by the predominance ofaggregates at a concentration of 0.1 M, at which BP and BPM

Figure 5. Solid state fluorescence spectra of the different AFI materialsobtained with EPH.

Figure 6. Molecular structure (A) and intermolecular RDFs between aromatic C atoms (B) and between H-bonded-to-N and O atoms of differentmolecules related to EPH (C).

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are predominantly still forming monomers; it is only at 1 Mconcentration that these molecules form mostly aggregates.In an attempt to unravel the molecular features governing

such strong trend to self-assemble of EPH, MD simulations ofrelated molecules were performed (Figure 6), where the effectsof the amino substitution (Me-ephed and ephed(nh3)), of theseparation between the aromatic and the amino moieties(ephed(n-1)), of the presence of the hydroxyl group (ephed-(noOH)), and of having bulky and rigid N-substituents(ephed(cyc5)) (see Figure 6A) were analyzed. We firstconsidered the effect on the π−π-driven self-assembly throughthe aromatic rings (by analyzing the RDFs between aromatic Catoms and comparing with that of ephedrine, black line inFigure 6B). As expected, the presence of the hydroxyl groupdoes not alter the π−π-driven self-aggregation (ephed(noOH),dark yellow line); ephed (black line) and ephed(noOH) displaythe highest π−π aggregation. The increase of the steric volumeon the polar side of the molecule by adding another methylgroup (Me-ephed, red line) or a five-membered ring (ephed-(cyc5), purple line) reduces the π−π self-aggregation, possiblybecause of a steric repulsion generated by the presence of thesebulky groups. Removal of the methyl substituent in EPH(ephed(nh3), green line) involves a further reduction of theπ−π self-aggregation. In this case, analysis of the different RDFssuggests that this lower π−π self-assembly is caused by a higherinteraction of the unsubstituted (and more polar) R−NH3amino group with O atoms of water molecules, as evidenced bythe higher intensity of the RDF between the H atom of theamino group and water O atom in both the first (at 1.9 Å) andespecially the second (at 3.3 Å) shells (see Figure S7 in theSupporting Information). Such stronger hydrophilic interactionand stronger water coordination shell might compete with and

reduce the π−π self-aggregation. Finally, the lowest π−π self-assembly is observed for the EPH derivative with one less Catom between the aromatic ring and the N atom (ephed(n-1),blue line). In this case, this weaker π−π self-aggregation is dueto the shorter separation between the aromatic (hydrophobic)and the polar (amino and hydroxyl groups) sides of themolecule, which does not enable an effective interaction of eachside with the corresponding species of similar chemical nature(other aromatic rings for the former and water or polar sides ofother molecules for the latter). In summary, the trend to π−πself-assemble of these molecules follows the order ephed ∼ephed(noOH) > Me-ephed ∼ ephed(cyc5) > ephed(nh3) >ephed(n-1).Next we analyzed self-assembly through the formation of

intermolecular H-bonds between the amino and hydroxylgroups (Figure 6C; ephed(noOH) was not studied due to theabsence of O atoms). Surprisingly, we observed that EPH is theonly molecule where effective intermolecular H(N)···O H-bonds are formed in aqueous solution. Any alteration of theEPH molecular structure involves the disappearance of thistype of H-bond-driven self-assembly. Introduction of bulkysubstituents on N, in Me-ephed and ephed-cyc5 (red andpurple lines, respectively), prevents the formation of such H-bonds by steric reasons. Reduction of the chain length inephed(n-1) (blue line) probably impedes an effectiveseparation and orientation of the polar and apolar molecularsides. Finally, removal of the methyl substituent (ephed(nh3),green line) possibly brings more strong H-bond interactionswith water molecules, thus competing with the formation of H-bonds with adjacent organic molecules. In summary, our resultsdemonstrate that EPH has a very particular molecular structurewhich imparts a very strong trend to self-assemble through π−π

Figure 7. Geometry-optimized molecular structure of BPM (A) and EPH (C) aggregates within the AFI channels and intermolecular RDFs betweenH-bonded-to-N atoms (B, hn1 for EPH) and between H-bonded-to-N and O atoms (D, hn1 for EPH). C, H, N, and O atoms are displayed in gray,white, blue, and red, respectively.

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type interactions on the aromatic side and through H-bondinteractions on the polar molecular side, providing potentiallyan intense molecular-recognition capacity.We finally studied the correlation of this particular self-

assembly behavior of EPH in water with its incorporationwithin the one-dimensional channels of the AFI structure andcompared it with the self-assembling molecule we previouslystudied, (S)-N-benzyl-2-pyrrolidine-methanol (BPM) (Figure7). Previous results showed a much weaker supramolecularaggregation of BPM within the AFI channels;23,24 this was atleast partially due to the electrostatic repulsion generated by theclose location of the positively charged H amino atoms inconsecutive dimers (Figure 7A) (indeed, loading of neutralBPM molecules showed a much stronger aggregation).26 Thisclose location of the positive charges is evidenced by theintense peak of the RDF between the H atoms of the aminogroups in consecutive aggregates (Figure 7B, black line).Indeed, a similar close location of the positively charged Hatoms of the amino groups, and hence a similar electrostaticrepulsion, occurs when consecutive EPH aggregates are packedwithin the AFI channels (Figure 7B, gray line) (a completestudy about the location and supramolecular arrangement ofEPH molecules within the AFI channels is out of the scope ofthe present work but will be provided in a forthcomingpublication). However, our fluorescence results evidence theinvariable incorporation of EPH molecules within the AFIchannels as aggregates (Figure 5), even though a similarelectrostatic repulsion would be expected. Therefore, itbecomes clear that some other interaction must be present inorder to compensate for such repulsion.Molecular simulations in aqueous solution showed a strong

intermolecular H-bond interaction between the O atom of thehydroxyl group and the H atoms of the amino group of EPHmolecules (Figure 3B). Interestingly, molecular simulationsresults show that these H-bond interactions are maintainedwithin the AFI framework between H(hn1) and O(H) atoms(Figure 7C). Indeed, a very strong H-bond interaction at adistance of 2.0 Å is observed between these atoms in EPH(Figure 7D, gray line). In fact, two intermolecular H-bonds aredeveloped between consecutive aggregates (Figure 7C, dashedblue lines). In contrast, similar H-bond interactions in BPM aremuch weaker (the intensity is much lower, and the H-bonddistance is larger, 2.4 Å, Figure 7D, black line), and in this case,only one H-bond per two BPM aggregates is developed.Therefore, this strong trend of EPH to self-assemble throughπ−π type and double H-bond interactions is responsible for thestrong supramolecular behavior observed when occluded withinthe nanoporous framework, which leads to the development ofinfinite supramolecular chains connected by π−π type and H-bond interactions within the one-dimensional channels of theAFI framework. Hence, our work shows a new SDA molecule,(1R,2S)-ephedrine, with a great potential of molecularrecognition, and consequently to self-assemble, and hence apotential ability to direct the crystallization of large-poreframeworks. In addition, it has the advantage of possessing twoasymmetric atoms, imparting an asymmetric character which isenhanced by the rigidity generated by the development ofintramolecular H-bonds in water (Figure 3C).

5. CONCLUSIONSIn this work (1R,2S)-(−)-ephedrine has been used as a newchiral structure-directing agent (SDA) for the synthesis ofnanoporous aluminophosphates with a great potential of self-

assembly and molecular recognition. A combination of UV−visfluorescence spectroscopy and molecular simulations hasshown that this molecule displays a very strong trend to self-assemble in aqueous solution through two types ofintermolecular interactions, through π−π type interactionsbetween aromatic rings, leading to a π−π stacking, and throughH-bonds between H-atoms of amino groups and O atoms ofhydroxyl groups of adjacent molecules. This leads to large self-assembled supramolecular aggregates.Interestingly, such double self-assembly behavior is repro-

duced when ephedrine molecules are occluded within the one-dimensional channels of the AFI framework. Fluorescenceresults show that only aggregates are incorporated within thechannels. The electrostatic repulsion generated by the closelocation of positively charged N atoms of protonated ephedrinemolecules in adjacent aggregates is compensated for by thedevelopment of two H-bonds between the H atoms of aminogroups and O atoms of hydroxyl groups of consecutiveaggregates. Indeed, our results show that (1R,2S)-(−)-ephe-drine has a very particular molecular structure that enables suchdouble self-assembling nature through aromatic rings andintermolecular H-bonds, which is canceled upon any slightmodification of the molecular structure. This leads tosupramolecular infinite ephedrine chains occluded within theAFI channels, stabilized by π−π type interactions betweenaromatic rings on the one side and H-bonds between aminoand hydroxyl groups on the other.

■ ASSOCIATED CONTENT*S Supporting InformationSynthesis experiments, X-ray diffraction patterns, SEM images,thermogravimetric analyses, 31P and 29Si MAS NMR, UV−visible diffuse reflectance spectra, and additional radialdistribution functions. This material is available free of chargevia the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: lhortiguela@icp.csic.es. Telephone: +34-91-5854785.Fax: +34-91-5854760.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe research leading to these results has received funding fromthe Spanish Ministry of Science and Innovation MICINN(projects MAT2009-13569 and MAT2012-31127) and theEuropean Research Council, under the Marie Curie CareerIntegration Grant program (FP7-PEOPLE-2011-CIG), GrantAgreement PCIG09-GA-2011-291877. L.G.-H. acknowledgesthe Spanish Ministry of Education and Science for a Juan de laCierva contract.

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