Synthesis of large-pore zeolites from chiral structure-directing agents with two L-prolinol units

In this work, we perform an in-depth experimental and computational study about the structure-directing effect of two new chiral organic quaternary ammonium dications bearing two N-methyl-prolinol units linked by a xylene spacer in para or meta relative orientation, displaying four enantiopure stereogenic centers in (S) configuration. Synthesis results show that the para-xylene derivative is an efficient structure-directing agent, promoting the crystallization of ZSM-12 (in pure-silica composition), beta zeolite (as pure-silica, or in the presence of Al or Ge), and a mixture of polymorphs C, A and B of zeolite beta (in the presence of Ge). In contrast, the meta-xylene derivative showed a much poorer structure-directing activity, yielding only amorphous materials unless Ge is present in the gel, where beta and polymorph C (together with A and B) zeolites crystallized. Molecular simulations showed that the para-xylene dication displays a cylindrical shape suitable for confining in zeolite pores, while the meta-xylene derivative has an angular shape that shifts from the typical dimensions required for 12MR zeolite channels. Despite enantio-purity of the para-xylene dication with (S,S,S,S) configuration, no enrichment in polymorph A of the zeolite beta samples obtained was observed by Transmission Electron Microscopy. With the aid of molecular simulations, the failure in transferring chirality to the zeolite is explained by the loose fit of this SDA in the large-pores of zeolite beta, and a lack of close geometrical fit with the chiral element of polymorph A, as evidenced by the very similar interaction of the cation with the two enantiomorphic space groups of polymorph A. Nevertheless, the molecular-level knowledge gained in this work can provide insights for the future design of more efficient SDAs towards the synthesis of chiral zeolites.


Introduction
Zeolite materials have three-dimensional frameworks with pores and cavities of molecular dimensions that provide a confinement effect to guest species occluded within their framework, promoting their characteristic shape-selective and molecular sieve properties. 1,2 Combined with their cationicexchange and catalytic properties, this has stimulated the use of zeolite materials in a wide range of applications in the chemical industry, especially as catalysts for different types of reactions with high selectivity towards desired products. 3,4 Confinement effects associated to zeolite microporous frameworks enable the discrimination between guest species (sorbates, reactants, transition states or products) with small steric differences. 5 This has been widely exploited in catalytic uses, but it is also essential during the synthesis of these materials where guest extra-framework species are confined within the zeolite pores and cavities during the crystallization process. 6 In particular, the addition of organic cations with particular geometric properties (size and shape) to the zeolite synthesis gels has enabled to gain control on the zeolite porous architecture that crystallizes through host-guest chemistry and, in turn, confinement effects. These organic species, which are usually referred as structure-directing agents (SDA), direct the crystallization process towards a particular framework type through a geometric relationship between the size and shape of the organic species and that of the porosity of the zeolite framework. [7][8][9][10] One of the greatest challenges in zeolite science is the development of enantiomerically pure chiral zeolites -or at least enriched in one of the two enantiomorphic crystals. [11][12][13] These chiral zeolites should be able to perform enantioselective operations, both in adsorption and catalysis processes, because of an asymmetric confinement of guest species in the chiral pores and/or cavities. [14][15][16][17][18] Indeed, several chiral zeolite frameworks do actually exist. 12,[19][20][21][22][23] However, they usually crystallize as mixtures of crystals with the two handednesses, either as racemic mixtures of enantiopure crystals (like STW, that can crystallize in P6 1 22 or P6 5 22 enantiomorphic space groups) 24 or as intergrown polymorphs of chiral frameworks, like zeolite beta where polymorph A is chiral (and can crystallize in P4 1 22 or P4 3 22 space groups). 19 Once again, confinement in a restricted space is crucial for developing enantiodiscriminating properties, not only for potential applications but also during crystallization in the presence of organic SDAs. In this context, the usual host-guest geometrical relationship between organic SDAs and zeolite frameworks provides a straightforward tool to promote the crystallization of chiral zeolite frameworks through the use of chiral organic species as SDAs. 11,25 For this imprint of chirality to occur, a true template effect, in the sense of establishing a close geometrical relationship between the guest molecular shape and the host framework walls, should be established. Although this strategy has been used for very long, only very recently a single successful example of enantio-enrichment of a chiral zeolite (STW) through the use of a rationally-designed chiral organic SDA has been reported. 26 In this context, an in-depth knowledge at molecular level of the structure-directing role played by chiral SDAs during crystallization of zeolite frameworks is vital for successfully promoting a transfer of chirality from organic guests to the zeolite host framework.
In recent years, we have successfully studied several organic SDAs prepared from chiral precursors derived from the chiral pool, on the one hand from chiral alkaloids (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, [27][28][29][30][31][32] and on the other from Lprolinol (derived from L-proline aminoacid). 33-38 L-prolinol is a useful chiral precursor since it provides a rigid ring with an N atom that can be quaternized with two different alkyl substituents, providing an additional stereogenic centre. Interestingly, a careful selection of the synthesis protocol during the alkylation reactions enables a preferential attack by one particular side of the molecule, leading to enantiopure stereogenic N atoms in addition to the enantiopure C atoms of the original L-prolinol units. 33 In previous works, we studied the structure-directing effect of N-methyl-N-benzyl-prolinol, and observed the crystallization of several zeolite materials, including MTW, 33 MWW 38 and FER frameworks, 36 as a function of the synthesis conditions. Another report with similar but smaller prolinol derivatives with methyl and ethyl substituents showed the production of layered precursors of CDO zeolite. 39 In order to maximize the transfer of chirality to zeolite frameworks, it is essential to adapt the chiral dimension of the organic SDAs, which is expressed at a molecular level, to that of the zeolite frameworks, which is usually expressed at a longrange level in the form of helicoidal channels. Based upon these grounds, in this work we build new SDAs based on two L-prolinol units linked by a xylene ring in different positions, resulting in large SDAs with four enantiopure stereogenic centres that should enhance the asymmetry of the organic species (Scheme 1). In order to understand from a molecular level the structuredirecting activity of these SDAs, we perform a combined experimental and computational study of the zeolite materials obtained.

Synthesis of the organic structure directing agents
The organic SDAs, 1,1'-(1,X-phenylenebis(methylene))bis(2-(hydroxymethyl)-1-methylpyrrolidin-1-ium (where 'X' is '4' for the para-substituted and '3' for the meta-substituted derivatives, and will be referred as 'pDMDPx' and 'mDMDPx', respectively, see Scheme 1), were prepared through alkylation reactions from the chiral precursor L-prolinol. Quaternization of the N atoms with different substituents (methyl and xylene derivatives) raises new stereogenic centres on N, which could display (S) or (R) configuration, while the absolute configuration of the stereogenic C atoms in L-prolinol units invariably remains as (S). Therefore, in principle two types of diastereoisomers could be produced, with prolinol units in (S,S) or (S,R) configuration (where the first refers to C and the second to N stereogenic centres). The order of alkylation reactions is crucial in order to obtain pure diastereoisomers. In a previous work, we observed that for N-benzyl-N-methyl-prolinol cation, initial alkylation with the bulky aromatic derivative followed by methylation led to pure (S,S)-derivatives, while inversion of the order of alkylation reactions (first methyl and second benzyl groups) yielded a mixture of (S,S) and (S,R) isomers. 33 The same strategy has been followed here in order to obtain pure (S,S,S,S)-isomers (in this case the organic cations contain two Lprolinol units, see Scheme 1).
Synthesis of pDMDPx and mDMDPx was carried out by alkylation of (S)-2-pyrrolidinemethanol (L-prolinol) with Q QRdibromo-para-xylene or Q QR-3 -respectively. In a typical synthesis of pDMDPx, 10.00 g of (S)-2pyrrolidinemethanol were carefully added to a cooled solution of 13.05 g of Q QR-3 -! -in 350 mL of acetonitrile with 20.50 g of potassium carbonate (careful, exothermic reaction). The reaction mixture was kept refluxing overnight, after which the inorganic solids were removed by filtration, and the solvent was rotoevaporated, yielding a yellowish solid (14.30 g, yield 95 %). 13  13.70 g of this solid were dissolved in 300 mL of cooled acetonitrile, and 12.80 g of methyl iodide were added dropwise (careful, exothermic reaction). The mixture was kept at room temperature for 5 days, after which the solvent was Please do not adjust margins rotoevaporated, and the obtained yellow oil was washed with diethyl ether. The resulting product was 1,1'-(1,4phenylenebis(methylene))bis(2-(hydroxymethyl)-1-methylpyrrolidin-1-ium iodide (pDMDPx + I -) (20.70 g, yield 91 %). 13  In order to confirm the production of the (S,S,S,S)-isomer, the organic synthesis was also carried out by reverting the order of alkylation, first adding a methyl group to L-prolinol through the Leucart reaction, and then adding the dibromo-para-xylene derivative. In this case, we obtained a product where 13 C NMR signals corresponding to the C atoms directly attached to N were doubled ( Figure S1), evidencing the presence of the two isomers, (S,R,S,R) and (S,S,S,S), and confirming the isomeric purity of our original product.

Synthesis of zeolite materials
Zeolite materials were prepared by hydrothermal method using pDMDPx and mDMDPx as SDA under different synthesis conditions in fluoride medium. The molar composition of the synthesis gels was 0.25R:(1-x)SiO 2 :xGeO 2 :yAl 2 O 3 :0.5HF:wH 2 O, where R stands for the organic SDA. Pure-silicate, aluminosilicate and germanosilicate materials were prepared with different compositions, as explained in the corresponding section. In a typical preparation, the corresponding amounts of the organic hydroxide and GeO 2 were mixed and stirred for 30 minutes, after which tetraethylorthosilicate (TEOS) and aluminium isopropoxide were added and stirred until all the ethanol coming up from the hydrolysis of TEOS and the required amount of water to achieve the desired composition were evaporated. HF (48 %) was then added and manually stirred (with the help of a spatula) until a homogenous thick gel was obtained. The gels were introduced into 60 ml Teflon lined stainless steel autoclaves and heated statically at different temperatures under autogenous pressure for selected periods of time. The resulting solids were separated by filtration, thoroughly washed with ethanol and water and dried at room temperature overnight.

Characterization of zeolite materials
The obtained solids were characterized by powder X-Ray Diffraction (XRD), using a Philips X´PERT diffractometer with WQ radiation with a Ni filter. Thermogravimetric analyses (TGA) were registered using a Perkin-Elmer TGA7 instrument (heating rate = 20°C/min) under air flow. Liquid NMR spectra were recorded with a Bruker Avance III-HD Nanobay 300MHz spectrometer, using a 5mm HBO 1H/X probe. Solid State MAS-NMR spectra of the solid samples were recorded with a Bruker AV 400 WB spectrometer, using a BL7 probe. 1 H to 13 C Cross-Polarization spectra were recorded using Z) rad pulses of 2.75 s for 1 H, a contact time of 3 ms and a recycle delay of 4 s. The spectra were recorded while spinning the samples at ca 11.2 kHz.
Electron microscopy analyses were carried out in a cold FEG JEOL GrandARM 300 operated at 300 kV. The microscope was equipped with a double spherical aberration (Cs) corrector from JEOL Company. Images were recorded under low-dose conditions to minimize the electron beam damage using an annular dark field detector (ADF). Prior to observation, the samples were deeply crushed using mortar and pestle dispersed in ethanol and few drops of the suspension were placed onto holey carbon copper grids.

Computational details
In order to understand the structure-directing role of the two chiral SDAs and the effect of their molecular structure, molecular simulations based on a combination of molecular mechanics (Dreiding forcefield) and quantum mechanics (DFT) were carried out. Calculations of the stability of different conformers in vacuum were performed at ab-initio level with the CASTEP code, 40 using DFT+D and plane waves (with an energy cut-off of 571.4 eV), and the PBE functional (including the Grimme dispersion term). 41 Molecular structures of the organic cations and their interaction with the different zeolite frameworks were simulated using the Dreiding force-field 42 and an atomic charge distribution obtained by the ESP charge calculation method at DFT+D level; our results showed that such Dreiding-ESP model reproduced well the conformational energy landscape of the organic cations studied at DFT+D level. The atomic coordinates of the different zeolite frameworks were kept fixed during all the calculations. Different supercell systems were built as a function of the particular framework type; details will be given in the corresponding section. The organic cations were manually loaded in different conformations and orientations, and the most stable system was obtained through simulated annealing calculations. Interaction energies were calculated by subtracting the energy of the cations in vacuum to the total energy of the system; all energies are expressed in kcal/mol of SDA.
Calculation of the NMR chemical shielding of the different isomers was carried out with the gauge-including projector augmented-wave method (GIPAW) developed by Pickard and Mauri, 43 as implemented in the CASTEP code, using a [ ref value of 176 ppm, the same as in our previous works. 29,32,44 The conformational behaviour of the SDA cations in water was studied by NVT Molecular Dynamics simulations, in the same way as reported in our previous works. 35 8 SDA cations,16 Cl-anions (for charge-compensation) and 160 water molecules were included in the simulation cell, and 10 ns of MD simulations in NVT ensemble were run at 423 K.

Experimental Results
the excellent crystallinity of the sample and where the existence of the structural defects is evidenced as a consequence of the intergrowth of both polymorphs of zeolite beta, polymorphs A and B. The Electron diffraction (ED) pattern (inset) obtained from the same crystal exhibits well-defined spots together with diffuse lines along c* axis produced as a consequence of the mixture of both polymorphs. Such types of images allowed the calculation of the relationship of both polymorphs on different zeolite crystallites, obtaining a ratio for this Al-beta sample of 40% of polymorph A and 60% of B. The stacking sequence is marked showing the zig-zag pillaring of PA in yellow, while the regions of polymorph B are marked by straight red lines.
In the case of Ge-containing materials obtained in the presence of pDMDPx, samples prepared with different Ge amounts (with 5 H 2 O molar ratio, Table 3) were analysed. For materials with a low Ge content (Si/Ge = 30), an excellent crystallinity was observed, displaying the typical morphology for zeolite beta, as shown in Figure 3b. This image allows the observation of several zeolite crystallites with truncated octahedral shaped particles of few hundreds of nm (the atomic resolution data of the framework, again along 'b' axis, is shown in the inset). As for the previous case, the stacking sequence can be also followed if the data is sufficiently good to distinguish the different polymorphs (Figure 3c). In this sample, a mixture of 50% of polymorph B, 49% of A and 1 % of C was observed ( Figure  3c uses the same colour code to denote the polymorphs, including green lines for polymorph C).
Very similar results were also obtained when the amount of Ge was increased to a Si/Ge of 15 (Figures 3d and 3e), obtaining a product with very good crystallinity where the predominant polymorphs were A and B (Figure 3d). In this case, polymorph A was found to be 42 % of the sample, while B was 54 % with a slight increment of polymorph C (3 %) (Figure 3e). In conclusion, no evidence of an enrichment in polymorph A is observed in the Ge-containing beta materials, while minor amounts of Cstacking sequences are observed, evidencing that the slightly increased peaks at 7 and 9.7° observed previously in the XRD patterns ( Figure 1D) are due to minor amounts of polymorph C.
Increasing the amount of Ge to Si/Ge = 5 made a significant influence on the structure and morphology of the materials obtained. Figure 3f shows the low magnification image of few particles representative of this material. The first difference in comparison with the previous zeolites is the particle size, which was much smaller, obtaining crystallites of sizes under 100 nm. The atomic resolution observation is depicted in Figure 3g, corresponding to a zeolite nanoparticle of ~50 nm with the different polymorphs marked. Interestingly, the increase of polymorph C is evident in this micrograph, reaching up to 18 %, being 44 % and 38 % for A and B, respectively. A closer look of the occurrence of the three polymorphs is displayed in Figure  3h, showing how the three polymorphs stack onto each other. From these observations, we conclude that Ge has a big influence on the final material obtained, where high Ge contents increases the amount of polymorph C while reducing the crystal size.
In terms of the relative crystallinity of the materials, no significant differences were observed for beta zeolites obtained with Si/Al = 15, Si/Ge = 30 or Si/Ge = 15, presenting in every case excellent crystallinities without the observation of amorphous phases. Despite no amorphous material was visualized for Si/Ge = 5 either, the crystallinity was not as good as for the others, although this aspect could be related to the small size of the particles obtained and maybe the entire structure was not completely formed along the particle. Nevertheless, most of the particles observed displayed a reasonable well-defined framework.

Characterization of the pDMDPx diastereomeric configuration
First, we wanted to confirm the diastereomeric configuration of the organic pDMDPx cation obtained. As explained below, the order of addition of the alkylation agents did lead to a pure isomer (by first addition of xylene and second of methyl group) or to a mixture of isomers (first methyl and second xylene group). In order to verify the diastereomeric configuration of our pure isomer, we calculated by DFT the theoretical 13 C chemical shifts of the (S,S,S,S) and (S,R,S,R) isomers (in their most stable conformation in aqueous solution, as explained below), and compared with the experimental results ( Figure  S1). The theoretical and experimental results are shown in Table  4; in the experimental data, '1' corresponds to the isomer produced pure (whose shifts are obtained from Figure S1-top), and '2' corresponds to the other one (whose bands are those in Figure S1-bottom that are not present in Figure S1-top). Theoretical NMR calculations show that C11, C6, C5 and C9 chemical shifts are those that differ mostly depending on the isomer, as expected since these are directly attached to N whose absolute configuration varies. Theoretical results show that change from (S) to (R) configuration of N involves a downfield shift of C11 and C9, and an upfield shift of C6 and C5. Interestingly, change from '1' to '2' isomer in the experimental data involves exactly the same type of shifts (in qualitative terms) of the bands associated to those C atoms (downfield in C11, C9, and upfield in C6, C5), clearly confirming that the pure pDMDPx isomer that we obtained had (S,S,S,S) configuration, as expected because of steric reasons (and the same for mDMDPx).

Characterization of the conformational space of pDMDPx and mDMDPx
Next, we characterized the conformational behaviour of the two SDAs, and their geometrical properties as a function of the aromatic substitutional position. The main torsional angle that defines the conformational space is C11-N-C5-C1, which defines three different conformations with angles of 60, 180 and -60° (for each ring). Besides, the two L-prolinol units can be at opposite or the same side of the aromatic ring; Figure 4 shows the molecular shape of the different conformers with the two prolinol units in opposite sides. Different force-field/charge models were tried; we found that Dreiding and a DFT atomic charge distribution (ESP method) reproduced well the relative Please do not adjust margins Please do not adjust margins channels is higher than in the previous orientation. In any case, once again we did not find any evidence for an enrichment of polymorph A in this zeolite. Replacement of methyl by ethyl substituents did result in an increase of the enantiodiscrimination energy (to 1.51 kcal/mol) ( Figure S8), although in this case a very low interaction energy was found (-80.72 and -79.21 kcal/mol for P4 1 22 and P4 3 22, respectively), evidencing a poor fit of this cation in BEA.
We note that the crystallization of zeolite materials in the presence of mDMDPx invariably required the presence of Ge. Therefore, it seems that the main structure-directing agent in this system was provided by Ge rather than by mDMDPx, which might act more as a space-filling agent. The same as for the MTW framework, the low structure-directing efficiency of mDMDPx might be associated to the angular shape of this cation, which shifts away from the cylindrical shape typical of pore-based zeolites.
For the sake of completeness, we also studied the most stable location of these cations in polymorph C (BEC) ( Figure S9). Similar orientations of the SDAs were observed, with pDMDPx aligned with the [100] (or [010]) channels, and mDMDPx spanning the two types of channels along 'c' axis. On the other hand, the interaction energies of each SDA were also very similar as those for BEA.

Conclusions
In this work, we have performed a thorough study about the structure-directing effect of two chiral SDAs based on two Lprolinol quaternary ammonium units linked by a xylene ring in para-or meta-position. The synthesis protocol of the chiral SDAs ensures the production of pure enantiomers with a unique diastereomeric configuration, with the four resulting stereogenic centres in (S) absolute configuration. Our synthesis results indicate that the para-SDA is much more efficient in directing the crystallization of large-pore zeolites, being able to promote the formation of MTW in pure-silica composition, zeolite beta in the presence of Al, and mixtures of polymorphs A, B and C of zeolite beta in the presence of Ge. In contrast, the meta-derived SDA is a very poor SDA, only allowing the production of crystalline zeolite materials in the presence of Ge, probably acting more as a pore-filling agent than a true structure-director, and being Ge the actual structure-directing agent. A conformational study of the two SDAs suggests that the worse structure-directing efficiency of the meta-derivative is a consequence of its angular shape that fits worse in the tubular channels of zeolite frameworks; in contrast, the para-derivative displays a more cylindrical shape suitable to be confined in zeolite pores.
Because of the presence of the chiral polymorph A in zeolite beta, we analysed the stability of our enantiomerically-pure para-xylene SDA in the two enantiomorphic space groups, yielding a similar interaction energy in both cases. This might be associated to the large size of the BEA zeolite channels and the loose fit of the SDA, which prevents an effective transfer of the asymmetric nature of the chiral SDA to the stacking of beta sheets along the 'c' direction that determines the BEA chirality.
As a consequence, zeolite beta obtained in this work seems to have the usual proportion of A and B polymorphs. Nevertheless, our results suggest that larger substituents associated to the stereogenic centres should result in larger energy differences between the chiral polymorphs, providing clues about the future design of new chiral SDAs.

Conflicts of interest
There are no conflicts to declare.

Table of Contents
Enantiopure chiral organic dications based on two L-prolinol units linked by para-xylene units effectively structure-directs the crystallization of several zeolites including beta, while the meta-xylene derivative is much less efficient director.