Negative and Positive Confinement Effects in Chiral Separation

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Negative and Positive Confinement Effects in Chiral Separation Chromatography Monitored with Molecular-Scale Precision by In-Situ Electron Paramagnetic Resonance (EPR) Techniques Martin Wessig, Martin Spitzbarth, Alexander Klaiber, Malte Drescher, and Sebastian Polarz Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b02713 • Publication Date (Web): 09 Oct 2017 Downloaded from http://pubs.acs.org on October 12, 2017

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Negative and Positive Confinement Effects in Chiral Separation Chromatography Monitored with Molecular-Scale Precision by In-Situ Electron Paramagnetic Resonance (EPR) Techniques Martin Wessig, Martin Spitzbarth, Alexander Klaiber, Malte Drescher, Sebastian Polarz* University of Konstanz, Department of Chemistry, D-78457 Konstanz, Germany.

KEYWORDS:

Nanoporous

Materials,

Host-Guest

Interactions,

Functional

Surfaces,

Organosilica, Hybrid Materials

ABSTRACT Separation of compounds using liquid chromatography is a process of enormous technological importance. This is true in particular for chiral substances, when one enantiomer has the desired set of properties and the other one may be harmful. The degree of development in liquid chromatography is extremely high, but still there is a lack in understanding based on experimental data how selectivity works on a molecular level directly at the surfaces of a porous

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host material. We have prepared amino-acid containing organosilica as such host materials. Watching the rotational dynamics of chiral spin probes using electron paramagnetic resonance spectroscopy allows us to differentiate between surface adsorbed and free guest species. Diastereotopic selectivity factors were determined, and the influence of chiral surface group density, chemical character of the surface groups, pore-size and temperature was investigated. We found higher selectivity values in macroporous solids with a rather rigid organosilica network and at lower temperature, indicating the significant effect of confinement effects. In mesoporous materials features are opposed with regards to the T-dependent behavior. From EPR imaging techniques and the resulting (macroscopic) diffusion coefficients, we could confirm that the correlations found on the microscopic level transform also to the macroscopic behavior. Thus, our study is of value for the development of future chromatography materials by design.

1. INTRODUCTION The existence of homochirality in biology makes it necessary that the stereochemistry and purity of synthetic components coming into contact with organisms must be defined to a highest level. Thalidomide, the active component of a drug with the trade-name Contergan, has gained notoriety. The (R)-enantiomer is a powerful immunomodulatory drug used in cancer treatment or as a sedative. Unfortunately, it was applied for the treatment of nausea in pregnant women half a century ago,1 and the (S)-enantiomer caused severe birth defects or even stillbirth. Despite the amazing advance of organic chemistry in asymmetric synthesis,2 in general, a desired stereoisomer is for its direct use still obtained in insufficient excess in most of the cases. Postpreparative purification is necessary, what makes chiral chromatography the method of choice. As a matter of fact, chiral chromatography has proven to be a versatile and cost-effective method


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for separation of racemates, even advantageous compared to the demanding direct synthesis and application of chiral auxiliaries during catalysis.3 An extensive description about the enormous progress of liquid chromatography with chiral, stationary phases made during several decades was given by Lämmerhofer in 2010.4 He analyzes that a molecular understanding of the recognition mechanisms on chiral surfaces is still scarce, in particular regarding their dynamic aspects. Since then, theoretical methods have helped to gain deeper insights, but still there is a gap in experimental data.5 The prevalent empirical character impedes the rational development of new stationary phases. Analytical techniques for studying directed diffusion as in chromatography can be divided into two complementary categories addressing either macroscopic or microscopic diffusion.6 Methods are designated as microscopic if the diffusion path length is smaller than the particle size of the porous host.7 The most popular technique to study microscopic diffusion is pulsed field gradient nuclear magnetic resonance (PFG-NMR).8 PFG-NMR was used to characterize diffusion in the presence of porous silica as a stationary phase.9-10 Besides the fact that NMR is an established technique, an obvious advantage is that countless compounds contain NMR active nuclei, and the interested reader is referred to one of the recent, excellent review articles by Kaerger et al.8,

11-12

The investigation of compound mixtures or solutions is much more

demanding, because now the NMR activity of the surrounding matrix becomes a disadvantage.13 Magic angle spinning (MAS) PFG NMR is needed for observing sufficiently resolved spectra for the different components, and so far only few molecules and their diffusion in solvents could be studied in this manner,14-16 in particular dissolved species inside a solid, porous hosts.17 Guenneau et. al. applied MAS PFG NMR to study the diffusion of diluted Ibuprofen in ethanol confined to MCM-41 with 3.5 and 11.6 nm pore diameter.18 A comprehensive investigation was


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performed by Pemberton et. al., who studied the diffusion of a range of substances dissolved in a mixture of CHCl3 and CH2I2.19 It is possible to also use 2D HETCOR solid state NMR experiments for surface interaction studies.20-21 For example Guo et al. studied the interaction of alanine on fumed silica nanoparticles.21 However, these experiments are very demanding and time consuming and need special equipment. One key disadvantage of PFG NMR spectroscopy remains. Due to the inherent, slow timescales can only resolve processes with a spatial resolution of several micrometers.22-25 It cannot reveal the very initial steps, when diffusion and discrimination of two dissolved molecules starts on the nanometer or molecular scale on a surface. Lately we demonstrated that electron paramagnetic resonance (EPR) is a suitable technique to address these problems.26-28 Continuous wave (CW) EPR spectroscopy in combination with nitroxide spin probes is the ideal method to study dynamics inside porous hosts since it is very sensitive for the microenvironment and delivers information about rotational dynamics and surface interactions under thermal equilibrium.26, 29-31 Because typically the porous matrix and relevant solvents are EPR-silent, this method is very suitable to track guests and species confined inside porous hosts.26,

32-34

We

showed that EPR spectroscopy cannot only be applied for the determination of diffusion coefficients of dissolved molecules confined to porous organosilica hosts, but it was also proven one spots the processes with molecular precision.26-28 Among the different materials used as chiral selectors in chromatography like metal-organic frameworks (MOFs), organic polymers, metal nanomaterials modified with chiral organic groups, carbon nanotubes, organosilica materials have a leading position.35-37 Organosilica can not only be structured into numerous types of porous solids,38 equipped with all sorts of organic groups,39 also the silica network and the Si-C linkage is very robust. At present, cyclodextrine


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derivatives, polysaccharide derivatives, dinitrobenzoyl derivatives of synthetic chiral molecules (Pirkle phases) or certain antibiotics like teicoplanin or vancomycin are used as chiral selectors attached to silica materials because of their broad applicability and chemical stability under chromatographic conditions.40-41 Chen et al. extensively studied substituted L-amino acid monolithic silica columns for enantiomeric separation of dansyl amino acids and hydroxyl acids in different chromatographic techniques.42-44 High selectivity was observed for materials or analytes with large substituents like phenyl, e.g. materials with L-phenylalanine attached to the surface or dansyl-phenylalanine as analyte. But for the majority of other systems the separation factor (defined as the quotient of the retention time of the enantiomers) is close to one.43-44 Recently Zhao and coworkers showed that a glutathione-functionalized monolithic silica is also capable of separation of various enantiomers.45 Among other examples for porous organosilica materials with chiral surfaces,46 another type of chiral, amino acid functionalized organosilica material was developed in our group, using a family of special silsesquioxane precursor containing substituted benzene as a bridging unit, the so-called UKON materials.47-48 The chirality of the material surface was proven successfully by a self-developed chiral physisorption method using (R)- and (S)-propylene oxide as a chiral gas.48 Considering our mentioned, preliminary work there is now the possibility to investigate the behavior of chiral, EPR-active spin-probes in porous materials with surfaces containing appropriate, chiral functionalities. The set of materials used for the current study is summarized in Fig. 1. In addition, pure silica (SiO2) materials were also used as a non-chiral reference. The pore structure, the nature and also the density of functional groups imbedded in the surface are varied leading to a matrix of different host materials. We have then synthesized a chiral spinprobe in the form of two enantiomers (Fig. 1a), which are infiltrated into the pore systems. The


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molecular scale dynamics of those spin-probes is studied by applying the methodology developed by us before.26,

28

Finally, we use EPR imaging techniques27 to check for the

consistency between the diffusive behavior on molecular and macroscopic scale.

Figure 1. Overview for the porous materials used in the current study about the confined diffusion of different enantiomers of 3-carboxy-2,2,5,5-tetramethyl-piperidin-1-oxyl (3CP) (a): Mesoporous materials and a representative TEM image (b; scalebar = 25 nm); macroporous aerogels and a representative SEM image (c; scalebar = 1µm); chemical structure of the organosilica frameworks within the study (d).


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2. EXPERIMENTAL SECTION 2.1. Synthesis part. AlaSil-x. The series was prepared using the bridged silsesquioxane sol-gel precursor reported in the literature.48 Co-condensation was achieved using Si(OEt)4 (TEOS); see also the SerSil1-x series described below. SerSil1 sol-gel precursor. 0.972 g L-Fmoc-Serine-OH (3.99 mmol) was dissolved in a mixture of 12 mL DMF and 12 mL DCM. The solution was cooled down to -12 °C and 2.97 mL Nmethylmorpholine (1M in DCM, 2.97 mmol) followed by 2.97 mL n-butylchloroformate (1M in DCM, 2.97 mmol) was added. After 20 min a solution of 1.49 g 3,5-bis-triisopropylsilylaniline in 15 mL DMF, 15 mL DCM and 2.97 mL N-methylmorpholine (1M in DCM) was added at -12 °C. The mixture was stirred overnight while it has been warmed up to room temperature. The solvent was removed under vacuum. 20 mL pentane was added and non-soluble volatiles were removed by centrifugation. The resulting gel was purified by column chromatography in DCM/EE 10:1 → 6:1. Finally 1.30 g L-1,3-bis-triisoporpoxysilylaniline-Ser-NH-Fmoc (1.60 mmol, 54%) was received as a colorless gel. 1

H-NMR (400.1 MHz, Toluol-D8): δ [ppm] = 1.27 (d, 36H, 3J = 6.16 Hz, iPr-CH3); 3.22 (s,

1H, Ser-OH); 3.41, 3.80 (m, 2 x 1H, Ser-CH2); 3.95 (t, 1H, 3J = 6.71 Hz, Fmoc-CH); 4.12 (ddd, 1H, Ser-CH); 4.27 (m, 2H, Fmoc-CH2); 4.40 (sept, 6H, 3J = 6.06 Hz, iPr-CH); 5.97 (d, 1H, J = 5.52 Hz, Ser-NH); 7.12 (2x t separated by 1.24 Hz, 2H, 3J = 7.44 Hz), 7.18 (2x t separated by 0.57 Hz, 2H, 3J = 7.42 Hz), 7.39 (d, 1H, 3J = 7.68 Hz), 7.42 (d, 1H, 3J = 7.46 Hz), 7.51 (d, 2H, 3J = 7.49 Hz) (all Fmoc-arom. H); 8.13 (s, 1H, p-arom. H); 8.34 (s, 2H, o-arom H); 8.83 (s, 1H, Anilin-NH).


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C-NMR (100.6 MHz, Toluol-D8): δ [ppm] = 25.78 (iPr-CH3); 47.48 (Fmoc-CH); 56.32 (Ser-

CH); 62.85 (Ser-CH2); 65.82 (iPr-CH); 67.51 (Fmoc-CH2); 120.14, 125.34, 127.37, 127.88 ppm (arom. Fmoc-CH); 128.22 (o-Anilin-C); 133.96 (m-Anilin-C); 137.57 (Anilin C-N); 137.72 (pAnilin-C); 141.69, 141.73 (Fmoc-tert-C); 144.16, 144.26 (Fmoc-tert-C); 157.25 (Fmoc-C=O); 169.03 (Ser-C=O). ESI-MS (positive): m/z: main peaks at 849.36 (MK+), 833.39 (MNa+), 811.40 (MH+, theoret.: 811.39). meso-SerSil1-x series. The mesoporous materials were prepared by using the amphiphilic block-copolymer are a structure-directing agent, and the degree of functionalization was controlled by co-condensation with TEOS (tetraethylorthosilicate). A Fmoc protected derivative of the sol-gel precursor was used (see also Supporting Information Scheme S1). A typical protocol is described for meso-SerSil1-10%. 0.294 g L-1,3-bis-triisopropoxysilylaniline-Ser-NHFmoc (0.362 mmol) with 0.583 g Pluronic P123 were dissolved in 1.20 mL of ethanol. 0.523 g 1 M HCl were slowly added. The solution was kept at 60 °C for 2 h. 0.755 g tetraethylorthosilicate (TEOS) was added and the sol was reacted for further 5 min at 60 °C. The sol was solidified for 6d at room temperature in an open glass container. Finally, the resulting gel was condensed for 6h at 80 °C. The template was removed by extraction in 30 g ethanol and 30 g HCl (konz.) at 60 °C for 4 d. The material was dried and 10 mL piperidine in 35 mL toluene were added. The suspension was kept at 60 °C for 2 d under slightly stirring. The solvent was removed and the material was extracted at 60 °C by toluene for 2 d followed by THF for 1 d. mesoSerSil2-x series. The synthesis was performed in two steps: First a co-condensation of TEOS and 3-Aminopropyltriethoxysilane (APTES) was performed as described in literature.49 Afterwards the material was postfunctionalized with Fmoc-Ser-OPfp (see below) according to


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the following procedure: 0.3 g of the material of step one was infiltrated under slight vacuum with a solution of 0.75 g Fmoc-Ser-OPfp in 7.5 mL DCM and 2.5 mL diethylamine. The suspension was stirred for 3 d at 25°C, centrifuged and dried. Now the material was extracted two times with 8 mL diethylamine in 18 mL toluene at 80 °C for 1d. Finally, the material was centrifuged and dried at 55 °C in vacuum. Fmoc-Ser-OPfp. 5.0 g of Fmoc-L-Serine-OH (15.28 mmol) was diluted in ethylacetateand colled down to 0°C. 2.81 g pentafluorophenol (15.28 mmol) was added and stirred for 30 min. Now 3.15 g dicyclohexyldicarbodiimide (15.28 mmol) was added. After 15 min the solution was allowed to warm up to room temperature and stirring was continued overnight. The precipitated was separated and the solvent was removed in vacuum yielding 6.4 g (12.97 mmol; 85 %) of the desired product. 1

H-NMR (400.1 MHz, CDCl3): δ [ppm] = 2.61 (s, 1H, Ser-OH), 4.03 & 4.22 (dd, je 1H, Ser-

CH2), 4.24 (t, 1H, Fmoc-CH), 4.46 (m, 2H, Fmoc-CH2), 4.82 (m, 1H, Ser-CH); 5.93 (d, 1H, NH); 7.30 (2x t separated by 1.26 Hz, 2H, 3J = 7.48 Hz), 7.39 (2x t separated by 0.54 Hz, 2H, 3J = 7.52 Hz), 7.52 (m, 2H), 7.76 (d, 1H, 3J = 7.46 Hz), 7.51 (d, 2H, 3J = 7.55 Hz) (Fmoc-arom.H). 13

C-NMR (100.6 MHz, CDCl3): δ [ppm] = 47.2 (Fmoc-CH); 56.0 (Ser-CH); 63.0 (Ser-CH2);

67.6 (Fmoc-CH2); 120.1, 125.1, 127.2, 127.9 (Fmoc-arom.-CH); 141.41, 141.45 (Fmoc-tert-C); 143.6, 143.7 (Fmoc-tert-C); 156.3 (Fmoc-C=O); 167.1 (Ser-C=O). 19

F-NMR (376.3 MHz, CDCl3): δ [ppm] = -152.2 (d, 2H, 3J = 17.12 Hz), -157.0 (t, 1H, 3J =

21.75 Hz), -161.8 (dd, 2H, 3J = 17.12 Hz, 21.75 Hz). Macroporous materials. Macroporous materials were prepared by adopting synthesis schemes suitable for the generation of aerogels.50 A typical protocol is described for macro-SerSil1-10%. 0.130 g L-1,3-bis-triisoporpoxysilylaniline-Ser-NH-Fmoc (0.161 mmol) were diluted in 0.384 g


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tetraisopropoxysilane (1.45 mmol) and 0.95 mL ethanol. 0.05 mL 1M HCl was added under slightly stirring. The sol was hydrolysed at 60 °C for 4.5 h. After cooling to room temperature 0.15 mL 1M ammonia was added dropwise. A part of the solution was transferred into EPR glass tubes for material synthesis and reacted for 1.5 d at room temperature. For extraction of the monolithic aerogel the material was overlaid with ethanol for 12 h. The supernatant was removed and extraction was repeated for 4 times. Now a solution of 40% v/v of piperidine in toluene was overlaid at 40 °C until the material was completely transparent. Afterwards the supernatant was exchanged several times, firstly by toluene followed by acetone for supercritical drying or ethanol for EPR measurements. Additional data about the macroporous materials are summarized in Supporting Information Fig. S1-11. Chiral spin probes. First, racemic 3-carboxy-2,2,5,5-tetramethyl-piperidin-1-oxyl (3CP) was prepared according to the method published by Yamada et al.51 See also Supporting Information Scheme 2 and Fig. S12,13. The separation of the enantiomers was managed by adopting the method published by Flohr et al. applying fractionated crystallization with (R)/(S) benzenemethanamine as a chiral auxilliary. An enantiomeric excess of 97% for (+)3CP respectively 94% for (-)3CP was received. 2.2. Materials characterization. Solid-State NMR spectra were recorded using a Bruker AVANCE III spectrometer operating at 400 MHz equipped with a 4 mm PH MAS DVT 400W1 BL4 N - P/H CGR probe head with magic angle gradient. FT-IR spectra were recorded by using a Perkin Elmer Spectrum 100 spectrometer using ATR unit. TEM images were performed on a Zeiss Libra 120 at 120 kV acceleration voltage. The TEM-samples were prepared by shortly dipping a carrier covered with a holey carbon foil (Plano company, S147) into a dispersion of the grinded materials in THF. Small-angle X-ray scattering (SAXS) measurements were conducted


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with a Bruker AXS Nanostar. N2-physisorptions measurements were recorded on a Micromeritics Tristar. Mercury intrusion porosimetry was performed on a Micromeritics AutoPore IV. SEM images were obtained by a Zeiss 249 CrossBeam 1540XB. 2.3. EPR methodology. CW-EPR measurements have been performed on a Miniscope MS400 X-Band EPR spectrometer equipped with a variable temperature unit (TC-H03 Temperature Controller, magnetech GmbH). Prior of use, all materials and solutions have been degassed under argon by at least 10 pump-freeze-thaw cycles. For each measurement 50 mg of the representative material was infiltrated under argon over night by 2 mL of a 2 mM solution of (+)3CP or (-)3CP in ethanol. Subsequently the supernatant was removed and the material was washed three times with pure degassed ethanol. At every temperature the samples have been allowed to equilibrate at least 10 minutes prior of measuring the spectra. The following parameters have been used: 1.56 mW Microwave power, 100 kHz modulation frequency, 12 mT sweep width, 120 s scan time, 4096 data points, modulation amplitude was chosen between 1/5 and 1/3 of the line width of the low field transition of the mobile component. All spectra have been simulated using the free MATLAB toolbox easyspin52 with two components of different rotational correlation time τc. (+)3CP and (-)3CP spectra within the same material have been simulated in parallel using identical parameters when possible only with adapted fraction of the two components of different τc. For continuous wave EPR imaging a Bruker E 580 X-Band spectrometer equipped with an ER 4180 TMHS resonator at 20 °C has been used. Spatial resolution was provided by an E540 GCX2 gradient coil system. For EPR imaging, materials have been synthesized directly in sample tubes as written above. The material monoliths were filled with ethanol or isopropanol analogous to the used solvent in the diffusion experiment. For the measurement, any solvent on top of the monolith was removed and a solution of (-)3CP in


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the same solvent was added at the top of the material. In case of sample tubes with 3 mm inner diameter 20 µl of a 3CP solution was added, in case of 2 mm inner diameter 9 µl was added. After the measurement, the sample was extracted several times with pure solvent until the complete spin probe was removed out of the material. Then the sample was used again for monitoring the diffusion of (+)3CP. For diffusion measurement: The sample was placed in the resonator and a series of measurements were taken back to back over a duration of at least 14 h. The following parameters have been used: 0.40 mW Microwave power, 0.15 mT modulation amplitude, 100 kHz modulation frequency, 349.5 mT center field, 45.0 mT sweep width, 643 s scan time, points: 8192 data points, 78 ms conversion time, 328 ms time constant, 1.5 T/m magnetic field gradient in the direction of the sample axis. For each sample, an additional measurement was taken with the same parameters without magnetic field gradient to be used in deconvolution. Spectral-spatial imaging was not performed because the contribution of the nonadsorbed species to the spectral line shape was small enough to not affect the image reconstruction. Crack-free monolithic samples have to be used for the investigation. Because their synthesis is quite time-consuming and they cannot be reused after the experiment, each experiment was performed only once. The diffusion direction along the monolith from top to bottom is defined as y-axes (see also Supporting Information Fig. S14). The cylindrical symmetry of the samples allows the diffusion to be described in terms of the one-dimensional projection 1d , of the spin density , at a given time t and location y using the diffusion equation

, = macro 1d , 1d

(1)

macro is the macroscopic translational diffusion coefficient. For each sample a numerical solution of the diffusion equation was found with the initial condition

1d 0, = 0 and


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boundary condition

1d , bottom = 0 (Details can be found in ref.

27

) and an influx of the

spin probe solution:

1d , top = exp− ∙ + +

(2)

with parameters , and and the one-dimensional projection of spin density 1D along the glass capillary. The simulated solution was convolved with the spectral line shape of the sample. This corresponds to a numerical simulation of the expected signal of the performed EPR imaging experiment. The parameters macro , , and were determined by least square minimization of the difference between the experimental data and the numerical simulation. Sample points near the top of the monolith have been ignored because they are affected by the distribution of 3CP within the material and of the supernatant solution due to the spectral line width that acts as a point spread function.

3. RESULTS AND DISCUSSION 3.1. Porous host synthesis and characterization. The first part of our study involves the generation of diverse porous materials for studying the host-guest interaction on confined chiral spin-probes (Fig. 1). One class of materials is represented by mesoporous solids (see Supporting Information Fig. S15-34), denoted with the pre-fix meso, characterized by pore-systems created by the liquid crystal templating method. AlaSil-100 was prepared as described in ref.48 Because of the bridged organosilsesquioxane solgel precursor used, these materials belong to the large class of so-called periodically ordered mesoporous organosilica materials (PMOs).53 We had also reported that bifunctional PMO materials are accessible via a simple co-condensation scheme.34, 54 Thus, for dilution of the chiral entity the respective silsequioxane precursor is co-condensated with Si(OEt)4 (TEOS) resulting


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in the AlaSil-x series (with x = the fraction of the organic modification in %) for instance. For enabling a more complex surface interaction with the spin-probe we have also prepared a new PMO material containing serine as a chiral component and the corresponding SerSil-x series. The mesoporous materials were all characterized by a set of analytical techniques including transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), nitrogen physisorption measurements, FT-IR spectroscopy,

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C and

29

Si- solid state nuclear magnetic

resonance (MAS-NMR). Representative data for the mesoporous materials used in this study are summarized in Supporting Information Fig. S15-34. All materials are characterized by poresize below 10 nm and high internal surface area. SerSil1-10 as a representative case has pores Dp = 5.0 nm in size and a surface area A = 876 m2/g. Materials with much larger pores are prepared via an aerogel route but with the same set of precursors compared to the mesoporous materials (see experimental part). For differentiation, these materials are denoted with a prefix macro. Analytical data for the macroporous materials are summarized in Supporting Information Fig. S1-11. Because of pore-sizes in the range 100 500 nm scanning electron microscopy (SEM) and mercury intrusion porosimetry were applied as additional characterization techniques. The resulting materials have a very open pore structure but also a polydisperse pore-size distribution (see Fig. 1c), which is typical for aerogels.55 3.2. Microscopic study of chiral spin probes in hosts with chiral interfaces. The EPR spectra of 3CP consists of three lines caused by the hyperfine interaction of the electron spin with the nuclear spin of 14N (I = 1) within the nitroxide group (see Fig. 2). Due to the anisotropy of the hyperfine interaction, the line shape of the 3CP spectra depends on the rotational correlation time τc.


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Figure 2. (a) Dynamic equilibrium between non-interacting 3CP spin probes and 3CP attached to the surface and the consequences on the rotational dynamics. (b) EPR spectra of the two extreme cases free 3CP (red) and immobile 3CP (blue) and the equilibrium situation as found in pores (black = experimental spectrum; grey = spectral fit). (c) Temperature-dependent EPR spectra for the different enantiomers of the spin-probe confined on the same porous silica host meso-AlaSil-100.


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This means that narrow signals are observed for 3CP free to move and to rotate. When 3CP is a guest inside a porous host, this species correlates to the non-interacting case as shown in Fig. 2a (red).26 If there are constraints to the rotational movement, as it is the case for 3CP attached to the surface (Fig. 2a, blue), there is a systematic broadening of the signal. In reality, there exists a dynamic equilibrium between those two species, and the spectrum reflects the superposition of both characteristics (Fig. 2b). There is a marked difference between (+)3CP compared to (-)3CP in the same chiral host. It is obvious that the fraction of surface-bound species is larger for (+)3CP indicating a stronger diastereotopic interaction with the L-amino acid (Alanine) of the organosilica matrix (Fig. 2c). Quantitative information about the relative amount of adsorbed and non-interacting 3CP can be obtained from full profile spectral simulation of the EPR data (Fig. 2b). In all cases, two components of different τc are needed for the description of the spin probe behavior. Spectra were taken at different temperature, because from the resulting correlation one can conclude about the interaction enthalpy.26 The quantitative evaluation of the fraction Ф of the surface adsorbed species to the overall spin probe is shown in Figure 3a,c. More importantly, from the surface adsorbed fraction Ф of the 3CP enantiomers, it is possible to calculate an adsorption selectivity factor α for a given temperature T (Figure 3b,d) defined as56 !"#

=

(3).

$!"#

A large α-value speaks for a significant difference in interaction, molecular mobility and high separation factor. From the set of porous materials used in the current study (Fig. 1) one can now check for the influence of temperature, confinement strength, density of chiral surface groups and chemical structure of the chiral surface group.


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Figure 3. Fraction of surface-adsorbed spin probes (hollow symbols = (-)3CP; solid symbols (+)3CP) in mesoporous (a) or macroporous hosts (c) with different network composition: Squares = AlaSil; circles = SerSil1; triangles = SerSil2; black = 100% organic modification; blue = 10% organic modification; red = 5% organic modification. The resulting selectivity factors for mesoporous (b) and macroporous hosts (d). The grey line indicates the behavior for a non-chiral reference material (pure SiO2). The overall tendency is that the fraction of surface-bound molecules decreases with increasing temperature. This is expected because temperature opposes the adsorption enthalpy caused by the rather strong acid-base interaction between the amino-groups on the surface and the acid group in 3CP. The higher the temperature, the more 3CP molecules are able to overcome this


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interaction and detach from the pore wall (see also Scheme 1). When both enantiomers are either predominantly attached at the pore surface (at low T) or do not interact anymore (at high T), it is clear that selectivity α remains close to 1. A dynamic equilibrium between adsorbed and free guest molecules is necessary for their effective differentiation. From Fig. 3 it becomes evident that confinement strength has a huge impact on this behavior. The fraction of adsorbed 3CP is influenced by the interaction strength and also by the probability of the guest to be near the pore wall. The latter is higher for high surface-to-volume ratio, which is typically found for the mesoporous solids (see Supporting Information Fig. S15-34). When the mean diffusion of 3CP is comparable to the confinement size, most of the trajectories will lead to a contact with the pore walls. As a result, the fraction of adsorbed 3CP is likely high. α increases with T, but overall it remains below 1.2. It is also not surprising to see a positive influence of the density of chiral surface groups on α within one class of materials (e.g. meso-AlaSil-10 → 100; meso-SerSil1-5 → 10). However, one also sees that the SerSil materials outperforms the AlaSil materials, and in particular meso-SerSil2 with serine pending into the pore volume shows the highest α values. The additional chiral OH-group in serine leads to higher differentiation between the 3CP enantiomers according to Fig. 3a. When the pores are larger as for the macroporous materials, the chance for 3CP for being located near the interface reduces, so does the fraction for bound molecules (Fig. 3c). It seems than one is now already at the right side from the selectivity maximum (scheme 1b) as α decreases with higher temperature (Fig. 3d). It is interesting to note that now also the influence of the chemical nature of the surface groups have turned around. macro-SerSil2 is not effective at all with α-values close to 1. The more rigid backbone in macro-SerSil-1 and macro-AlaSil has advantages and the enantioselectivity can become much higher (up to 2.75; Fig 3d) compared to


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the mesoporous analogues (Fig. 3b). Now, the additional OH-group in serine has an adverse effect as it seems to reduce the interaction with the chiral center at the surface. Macro-AlaSil shows notable selectivity values (2.05) even at higher temperatures (T = 303 K). It is also remarkable that the additional alkyl chain in SerSil2 has now an adverse effect compared to the situation in the mesoporous materials.

Scheme 1. (a) Temperature-dependent interaction scenarios for (+)3CP (grey) compared to (-)3CP (green) in porous hosts with chiral interfaces of the L-AlaSil type (blue) and the effect on discrimination between the two enantiomers (b).


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3.3. Macroscopic study of chiral spin probes in hosts with chiral interfaces. If our microscopic findings are correct, we expect that (+)3CP has a higher retention time on chromatographic columns made from L-AlaSil or L-SerSil materials, and separation works best for macro-AlaSil. EPR imaging is well suited to study macroscopic translational diffusion on a length scale of several millimeters.27 For the diffusion experiment either a (+)3CP or (-)3CP solution was added on top of a solvent filled monolith. Diffusion was observed by monitoring the spin density change within the monolith during the diffusion process. As a representative case the data obtained for macro-AlaSil1-10 is shown in Fig. 4. The diffusion process and EPR imaging experiment were modeled numerically using the diffusion equation (equation 1) followed by a convolution with the spectral line shape of the guest molecules. The whole procedure is described in detail in the experimental part. Each vertical slice corresponds to the concentration profile of 3CP within the sample. The 3CP molecules are initially located at the top of the sample (low values of t) and diffuse into the material during the experiment. Fig. 4c compares the macroscopic diffusion of (+)3CP and (-)3CP for the macroporous materials, we have described before. The trends found for the microscopic picture (Fig. 3d) are confirmed. The diffusion coefficient of (-3)CP is larger in all of the three cases. Macro-AlaSil-10 shows the best performance within the series, since (-)3CP moves 5-times faster through the monolithic material than (+)3CP.


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Figure 4. Diffusion of (+)3CP (a) and (-)3CP (b) through a monolith of macro-AlaSil-10 at 293 K. For evaluation of the data see also Supporting Information Fig. S14. (c) Macroscopic diffusion coefficients of (+)3CP and (-)3CP through the various amino acid functionalized monolithic aerogels measured by EPR imaging.

4. CONCLUSION Our study proves that the investigation of dynamic properties of guest molecules inside porous hosts using EPR spectroscopy is a powerful tool. The advantage of EPR spectroscopy compared to other methods used for the investigation of diffusion are manifold. The application to solid samples does not require special equipment or measurement techniques, and it can be used at


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technically relevant conditions (in solvents, higher pressures and ambient temperature). Due to the short time domain of EPR spectroscopy, it is ideal to reveal details about processes on the molecular scale, which are of particle importance for the initial steps of chiral separation in chromatography. It can resolve even subtle differences occurring during separation of enantiomers in chiral hosts during chromatography. Because of the molecular precision one can now investigate, how small changes in the molecular structure of the interface effect selectivity. Whereas the density of chiral group is also important, we found that diastereoselectivity is much more influenced by an interplay between the degree of confinement, temperature and molecular flexibility in proximity of the chiral surface center. Even small chemical changes, like the presence of an additional group next to the chiral center, may lead to substantial changes in selectivity. The example of a flexible linker attached to the chiral surface group as in the SerSil1,2 materials and the adverse effects in mesoporous and macroporous materials illustrates how complex the situation is. The conformation between the guest and the surface group is a very important factor. It can be speculated that it is more difficult to find the ideal conformation at a highly curved interface as occurring in very small pores. A chiral surface center attached to a flexible linker seems to be beneficial. The investigation of those neighboring group effects is highly interesting represents a promising topic for research in the future. The surface-to-volume ratio is a crucial parameter for guests inside porous materials too. Although it is impossible to gain full control over this parameter, the general trend is, the surface-to-volume ratio is higher for the mesoporous materials (see Supporting Information). Thus, our initial expectation was that diastereoselective discrimination should be better in smaller pores because guest species are closer to the surfaces. However, we found higher selectivity values for the macroporous organosilica hosts, and these could be confirmed by


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imaging EPR techniques resulting in macroscopic diffusion coefficients. The confinement strength is very important in determining the influence in temperature because of the different position of the selectivity range for each material as shown in scheme 1. Because in macroporous materials selectivity drops quickly with temperature, we propose a maximum in chiral separation performance can be reached for our porous materials at temperature slightly below ambient or with smaller sized macropores. A challenge for materials science is in this respect, the preparation of macroporous organosilica materials with a very narrow pore-size distribution function, unlike to the aerogels presented in the current study. It could be interesting to prepare inverted opals with organosilica as a matrix and use them in the future. An even bigger challenge for the future will be to derive a quantitative correlation between the molecular selectivity values and the macroscopic diffusion constants. While for macro-AlaSil-10 and macro-SerSil2-10 there is at least a qualitative agreement, according to the selectivity values of macro-SerSil1-10 we had expected a much more pronounced difference for the diffusion coefficient of (+)3CP compared to (-)3CP.

Electronic supplementary information: This material is available free of charge via the Internet at http://pubs.acs.org. Meso-SerSil1-x series; Synthesis of Fmoc-Ser-OPfp; Analytical data for the mesoporous materials; Analytical data for the macroporous materials; Enantiomers of the chiral spin probe 3CP; Diffusion studies using EPR imaging techniques. (PDF)

AUTHOR INFORMATION Corresponding Author


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*Email: [email protected] Author Contributions MW prepared all samples, recorded the EPR data and evaluated them. MS and MD performed the imaging EPR studies. AK measured SAXS data. SP supervised the research and wrote the paper. Funding Sources German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) ACKNOWLEDGMENT We acknowledge the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) for funding within the SPP 1570 (PO 780/14-1).


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TOC Figure


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Negative and Positive Confinement Effects in Chiral Separation

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