nanomaterials

Article Supramolecular Organogels Based on N-Benzyl, N0-Acylbispidinols

Alexey V. Medved’ko 1, Alexander I. Dalinger 1, Vyacheslav N. Nuriev 1, Vera S. Semashko 1, Andrei V. Filatov 2, Alexander A. Ezhov 3,4 , Andrei V. Churakov 5, Judith A. K. Howard 6, Andrey A. Shiryaev 7,8 , Alexander E. Baranchikov 1,5 , Vladimir K. Ivanov 5,9 and Sergey Z. Vatsadze 1,* 1 Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] (A.V.M.); [email protected] (A.I.D.); [email protected] (V.N.N.); [email protected] (V.S.S.); [email protected] (A.E.B.) 2 Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia; fi[email protected] 3 Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russia; [email protected] 4 Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russia 5 Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (A.V.C.); [email protected] (V.K.I.) 6 Department of Chemistry, University of Durham, Durham DH1 3LE, UK; [email protected] 7 Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 119071 Moscow, Russia; [email protected] 8 Institute of Geology of Ore Deposits, Petrography, Mineralogy and Geochemistry, Russian Academy of Sciences, 119017 Moscow, Russia 9 Faculty of Material Science, Lomonosov Moscow State University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-903-748-7892



Received: 10 December 2018; Accepted: 3 January 2019; Published: 11 January 2019
 Abstract: The acylation of unsymmetrical N-benzylbispidinols in aromatic solvents without an external base led to the formation of supramolecular gels, which possess different thicknesses and degrees of stability depending on the substituents in para-positions of the benzylic group as well as on the nature of the acylating agent and of the solvent used. Structural features of the native gels as well as of their dried forms were studied by complementary techniques including Fourier-transform infrared (FTIR) and attenuated total reflection (ATR) spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and small-angle X-ray scattering and diffraction (SAXS). Structures of the key crystalline compounds were established by X-ray diffraction. An analysis of the obtained data allowed speculation on the crucial structural and condition factors that governed the gel formation. The most important factors were as follows: (i) absence of base, either external or internal; (ii) presence of HCl; (iii) presence of carbonyl and hydroxyl groups to allow hydrogen bonding; and (iv) presence of two (hetero)aromatic rings at both sides of the molecule. The hydrogen bonding involving amide carbonyl, hydroxyl at position 9, and, very probably, ammonium N-H+ and Cl− anion appears to be responsible for the formation of infinite molecular chains required for the first step of gel formation. Subsequent lateral cooperation of molecular chains into fibers occurred, presumably, due to the aromatic π−π-stacking interactions. Supercritical carbon dioxide drying of the organogels gave rise to aerogels with morphologies different from that of air-dried samples.

Keywords: organic nanomaterials; bispidines; supramolecular gels; SEM; TEM; AFM study; X-ray diffraction; FTIR spectroscopy; ATR spectroscopy; SAXS

Nanomaterials 2019, 9, 89; doi:10.3390/nano9010089 www.mdpi.com/journal/nanomaterials Nanomaterials 2019, 9, 89 2 of 17

1. Introduction Positron emission tomography (PET) is one of the widely used molecular imaging methods enabling early and high-resolution diagnostics of various diseases including oncological, neurological and cardiovascular [1,2]. In recent years, there has been growing interest in the field of new radiopharmaceuticals (RPs) with non-conventional PET radionuclides, for example, 86Y (14.7 h), 89Zr (78.4 h), and 64Cu (12.7 h) [3–5]. Among others, 64Cu is one of the most promising isotopes for PET usage because it possesses the smallest average energy of positrons, and its half-life allows delivery to local clinics [6,7]. Unlike conventional PET radionuclides (15O, 13N, 11C, 18F), the incorporation of metal isotopes into RPs requires the use of poly/multifunctional chelating agents that should form covalent bonds with various biomolecules/vectors possessing high specificity and selectivity toward certain targets [5,8–11]. 3,7-Diazabicyclo [3.3.1]nonanes (hereafter called bispidines) are one of the privileged scaffolds in medicinal chemistry [12] due to the number of advantages, for example, (i) high basicity and solubility in water and/or organic solvents [13,14]; (ii) the ability of diverse functionalization including chiral derivatives [15–20]; and (iii) deeply studied conformational features which allow the application of some rigid conformation [21–23]. Our recent works have shown the potential of using bispidine scaffolds for the design of inhibitors of serine proteases [24,25]. At the same time, bispidines are well-known ligands with a high affinity to Cu(II) and other bivalent metals [26–29]. Therefore, we focused on creating new potent ligands for 64Cu PET based on a number of unsymmetrically substituted bispidine-9-ols. During our work with ligands for serine proteases, it was necessary to find a way to insert bulky groups into pockets of the active site [24,25]. The acylation reaction is one of the obvious ways to functionalize the secondary amine group in N-benzylbispidinols; the resulting N-benzyl, N0-acylbispidinols allow subsequent transformations like the reduction of the amide group or the removal of the protecting benzylic group followed by the diverse functionalization of the formed secondary amine. In the course of our work, we discovered an interesting phenomenon, namely, the formation of gels during the acylation of N-benzylbispidinols in benzene. Supramolecular gels belong to a broad family of supramolecular materials [30]. Since the beginning of supramolecular gel investigation in the mid-1990s, this area attracts significant interest due to the many exciting and unique features exhibited by this soft matter [31–41]; see also the special issue of the Beilstein Journal of Organic Chemistry [42] and the Tetrahedron Symposium-in-Print Number 130 [43]; vol. 256 of Topics in Current Chemistry [44]; the special issue of Gels (https://www. mdpi.com/journal/gels/special_issues/supramol_gels), and a monograph [45]. The uniqueness of supramolecular gels in manifested in their intrinsic stimuli-responsive nature [46]. Their properties span from high porosity [47] to mechanically robust materials [48]; they can form unexpected composites with polymers [39] and photopatterned materials [49]; they are known for their self-sorting properties [50] and can be used as photophysical materials with unique properties [51,52]. Additionally, they can be exploited as pollutant removers [53] and for programmed cell growth [54]. The synthesis of a family of unsymmetrically N,N0-disubstituted bispidine-9-ol derivatives, gelling properties of their HCl salts, and a possible explanation of such behavior will be discussed in this manuscript. The main advantages and features of a new family of organogelators, namely, N,N0-disubstituted bispidine-9-ols, may be briefly emphasized as follows. Both (hetero)aromatic groups Ar1 and Ar2 can be independently varied to allow their introduction into the organogels and, hence, into their aerogel forms, offering a wide diversity of substituents with many useful properties. For example, we began studying in our labs the possibility of obtaining luminescent gels and gels capable of metal ion recognition. The presence of basic nitrogen atoms in N,N0-disubstituted bispidine-9-ols allows researchers to study acid/base interactions and their effects on gel stability.

2. Materials and Methods

Synthesis. General Methods Compounds 1–3 were synthesized according to procedures described in [24,55,56]. Nanomaterials 2019, 9, 89 3 of 17

A solution of acyl halide (1 eq.) in dry benzene was added dropwise to a suspension of bispidine 3 (1 eq.) in dry benzene under vigorous stirring. In most cases, a gel-like substance started to form after the first several drops of the acyl halide solution. Then the mixture was refluxed under vigorous stirring for 3.5 hours. To obtain the hydrochloride product, the resulting gelatinous mass (precipitate or colloidal solution) was centrifuged for 10–15 min (6000 rpm) or filtered on a Schott filter (por.40) and then air dried with subsequent drying on a rotary evaporator. The free base was isolated from the aqueous solution of the formed solid hydrochloride by treatment with sodium bicarbonate (3 eq.) and characterized (Supplementary Materials, page 3–10). To study the native benzenogels, the reaction mixture was allowed to cool down to room temperature (see below). Supercritical carbon dioxide drying was performed using a home-made system (volumes 5 mL or 80 mL;, for details, see [57,58]). As per typical experiments, the working pressure and temperature were 80–90 bar and 40–50 ◦C, respectively. Small-angle X-ray scattering and diffraction (SAXS). SAXS patterns were acquired using a dedicated small-angle diffractometer SAXSess (Anton Paar, Graz, Austria) employing monochromatic Cu-Kα1 radiation (1.5412 A). The samples were placed into a standard glass capillary 1.5 mm in diameter and sealed. The measurements were performed in vacuum; scattered radiation was recorded using 2D imaging plates. Fourier-transform infrared (FTIR) spectra were acquired using a SpectrumOne spectrometer coupled with an AutoImage microscope (Perkin Elmer, Walthan, MA USA). The samples were placed on gold mirror and the spectra represented the superposition of absorption (dominant) and reflectance components. Atomic force microscopy (AFM). AFM measurements were made using a scanning probe microscope NTEGRA Prima (NT-MDT, Moscow, Russian Federation). Semi-contact mode was used. The amplitude of the “free air” probe oscillations was from 20 to 25 nm (peak-to-peak). High-resolution non-contact/semi-contact silicon AFM probes of the “Golden” NSG01 series (NT-MDT) were used. Topography, feedback error signal, and phase difference were registered simultaneously for the samples. The samples were prepared by drying the solution on silicon wafers. Transmission electron microscopy (TEM). TEM images were obtained using a transmission electron microscope LEO912 AB OMEGA (Carl Zeiss, Oberkochen, Germany) operating at 100 kV voltage. Samples were prepared by drying the solution droplets placed on copper grids coated by a Formvar film. Scanning electron microscopy (SEM). SEM images were obtained using a Carl Zeiss NVision 40 (Carl Zeiss, Oberkochen, Germany) workstation at 1 kV accelerating voltages using a secondary electron (SE2) detector. The preparation of the samples was the same as for the AFM measurements. X-Ray. Experimental intensities were measured using Bruker SMART 1K (for 4cb and 2c) and Bruker SMART APEX II (Brucker, Madison, WI, USA) diffractometers (for 4cb, 3c, 1b, 4da, and 5,7-dimethyl-1,3-diazaadamantan-6-one) using graphite monochromatized Mo-Kα radiation (λ = 0.71073 Å) in ω-scan mode. Absorption corrections based on measurements of equivalent reflections were applied. The structures were solved by direct methods and refined by full matrix least-squares on F2 with anisotropic thermal parameters for all non-hydrogen atoms (except the solvent benzene molecule in 4da)[59]. In 1b and 4da, all hydrogen atoms were placed in calculated positions and refined using a riding model. As for structures 4cb, 2c, 3a, and 1b, all protons were added geometrically and refined using a riding model, whereas all hydroxy- and amino-hydrogens were located from difference Fourier synthesis and refined isotropically. Finally, in 3c and 5,7-dimethyl-1,3-diazaadamantan-6-one, all protons were found from the difference map and their positional and thermal parameters were refined. The crystals of 4cb and 1b were racemically twinned with domain ratios 0.79/0.21 and 0.76/0.24, respectively. X-ray diffraction studies were performed at the Centre of Shared Equipment of the Institute of General and Inorganic Chemistry of the Russian Academy of Sciences (IGIC RAS). The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre (CCDC) as supplementary publications (for CCDC numbers, Nanomaterials 2019, 9, 89 4 of 17

Nanomaterials 2018, 8, x FOR PEER REVIEW 4 of 17 see Table S3). This information may be obtained free of charge from the Cambridge Crystallographic numbers, see Table S3). This information may be obtained free of charge from the Cambridge Data Centre website (www.ccdc.cam.ac.uk/data_request/cif). Crystallographic Data Centre website (www.ccdc.cam.ac.uk/data_request/cif). 3. Results 3. Results Compounds 1–3 were prepared according to protocols from [24,55,56]: the stereoselective ring Compounds 1–3 were prepared according to protocols from [24,55,56]: the stereoselective ring openingopening in in salts salts1 leads1 leads to to unsymmetrically unsymmetrically substitutedsubstituted bispidinols 22; ;the the deformy deformylationlation of of the the latter latter givesgives rise rise to to secondary secondary amino amino alcohols alcohols3 3(Scheme (Scheme1 1)). .

SchemeScheme 1. 1.Synthetic Synthetic routesroutes to the target amides amides 44. .

TheThe next next step, step, the the acylation acylation of ofthe the secondarysecondary amine group group in in 33, ,is is straightforward straightforward due due to tothe the presencepresence in thein the same same molecule molecule of aof tertiary a tertiary amine amine group group which which would would work work as an as internal an internal base base to accept to releasedaccept HCl.released It is HCl expected. It is expected that the resultingthat the resulting salts 4*HCl salts should4*HCl sh precipitateould precipitate from the from reaction the reaction mixture makingmixture the making isolation the easier. isolation Indeed, easier the. Indeed, tertiary the amine tertiary group amine worked group as worked the internal as the base internal during base the acylation,during the but acylation unexpectedly,, but unexpectedly, instead of the instead precipitation, of the precipitation the acylation, the ofacylation molecules of molecule3 in benzenes 3 in in mostbenzene cases (except in most for cases4aa , (except4ba, and for4ca 4aa) led, 4ba to, theand formation 4ca) led to of opaquethe formation to almost of opaque transparent to almost gel-like materials—verytransparent gel viscous-like materials substances—very with viscous the eventual substances presence with ofthe crystalline eventual presence admixtures of crystalline (see Figures S1–S7).admixture Similars ( resultssee Figure weres obtainedS1–S7). Similar when we results used were nitrobenzene, obtained ethoxybenzene, when we used or nitrobenzene, mesitylene (in ethoxybenzene, or mesitylene (in this case, the least stable gels if any were produced) instead of this case, the least stable gels if any were produced) instead of benzene for the synthesis of 4ab*HCl benzene for the synthesis of 4ab*HCl and 4ae*HCl. and 4ae*HCl. The target amides 4 were finally obtained by gentle base treatment of the salts 4*HCl The target amides 4 were finally obtained by gentle base treatment of the salts 4*HCl (Supplementary Materials, page 3–6). It was found that the choice of the base is crucial to obtaining (Supplementary Materials, page 3–6). It was found that the choice of the base is crucial to obtaining the amides 4: using a strong base like alkali leads to de-acylation instead of the formation of target 4 theamino amides-amides.: using Presumably, a strong basethis is like due alkali to the leads spatial to de-acylationproximity of an instead amino of lone the pair formation and an ofamide target amino-amides.function. Finally, Presumably, we were able this to is isolate due to and the characterize spatial proximity 12 new of amino an amino-amides lone 4 which pair and differed an amide by function.substituents Finally, Ar1 we and were Ar2 (see able Scheme to isolate 1). and characterize 12 new amino-amides 4 which differed by 1 2 substituentsIn order Ar andto Ar understand(see Scheme the1 ).structural features of the gels with general formulae benzene@4*HClIn order to understand, several phy thesical structural-chemical features methods of the providing gels with information general formulae about variousbenzene@4*HCl structural , severallevels physical-chemicalof supramolecular gels methods [30–32,60,61] providing were applied: information on the about molecular various scale structural (X-ray diffraction, levels of supramolecularIR spectroscopy), gels nano [30–scale32,60 ,(SAXS,61] were SEM, applied: TEM, AFM)on the, and molecular macroscopic scale scale (X-ray (IR diffraction, and NMR IR spectroscopy),spectroscopy, nanoscale SAXS, DLS, (SAXS, DSC, SEM, POM, TEM, rheology AFM),). andSome macroscopic of the applied scale methods (IR and NMRfailed spectroscopy, to provide SAXS,useful DLS, information. DSC, POM, For rheology). example, Some we of werethe applied unable methods to obtain failed reasonable to provide results useful information. from the ForNMR example,-spectroscopic we were titration unable o tof solution obtain reasonableof 3 by acyl resultschloride from solution the NMR-spectroscopicsince all signals appeared titration to be of solutionquite broad. of 3 by Rheological acyl chloride studies solution applied since to all sample signals benzene@4ce*HCl appeared to be quite showed broad. that Rheological this was indeed studies applieda gel [62] to sample, but no quantitativebenzene@4ce*HCl informationshowed emerged that ( thisTable wass S1 indeedand S2, aFigure gel [s62 S],8 and but S no9). quantitative informationIn order emerged to understand (Tables S1possible and S2, mechanisms Figures S8 of and the S9). intermolecular interactions that would lead to In gel order formation, to understand we applied possible the mechanisms single-crystal of the X-ray intermolecular technique to interactions those samples that would that were lead to gelcrystalline. formation, The we c appliedhemical theconnectivity single-crystal scheme X-ray for structurally technique tocha thoseracterized samples samples that were4cb, 2c crystalline., 3a, 3c, and 4da*HCl is presented in Scheme 2a, whereas their molecular structures are shown in Figures The chemical connectivity scheme for structurally characterized samples 4cb, 2c, 3a, 3c, and 4da*HCl

Nanomaterials 2019, 9, 89 5 of 17 is presented in Scheme2a, whereas their molecular structures are shown in Figures S10–S17. Selected geometricalNanomaterials features 2018, are 8, x FOR listed PEER in REVIEW Table 1 . The main geometrical parameters of the bispidine5 skeletonof 17 in all studiedS10-S17 compounds. Selected geometrical are close tofeatures the values are listed reported in Table and1. The discussed main geometrical for numerous parameters bispidines of the and their saltsbispidine in [63 ] skeleton and references in all studied cited compounds therein. are close to the values reported and discussed for numerous bispidines and their salts in [63] and references cited therein.

(a) (b)

SchemeScheme 2. (a) Chemical2. (a) Chemical connectivity connectivity scheme scheme for for structurally structurally characterized characterized samples. samples. (b) Distances (b) Distances and deviations.and deviations. In all presented cases, both piperidine cycles of bicyclic skeleton adopt a chair conformation In all presented cases, both piperidine cycles of bicyclic skeleton adopt a chair conformation with involuntarily shortened N…N separations (see Table 1). In all five bispidine structures, with involuntarilybenzyl-substituted shortened nitrogen N atoms... N(NBz separations) are almost (see tetrahedral Table 1 with). In the all sum five of bispidine C-NBz-C angles structures, benzyl-substitutedranging from nitrogen 330.0 to 332.1°. atoms Benzyl (NBz) substituents are almost always tetrahedral occupy axial with positions the sum with of C-NBz-C respect to angles rangingsix from-membered 330.0 to piperidine 332.1◦. cycles Benzyl (exo substituents- to the concave always surface occupy of an axialeight-membered positions cycle). with respect Of to six-memberedinterest, piperidine hydroxyl groups cycles at (exo- C9 to positions the concave are oriented surface in of the an eight-membered same direction as cycle).the benzyl Of interest, substituents. As expected, amido nitrogen atoms in 2c, 3c, and 4da*HCl are almost planar due to hydroxyl groups at C9 positions are oriented in the same direction as the benzyl substituents. 2 their sp nature and do not participate in hydrogen bonding. In contrast, secondary amine N atoms2 As expected,in 3a and amido 3c are nitrogen tetrahedral atoms with inthe2c sum, 3c of, andangles4da*HCl nearly equalare almostto 325°. planarTheir hydrogen due to atoms their spare nature and doendo not- participateoriented due into intramolecular hydrogen bonding. hydrogen In bonding. contrast, secondary amine N atoms in 3a and 3c are tetrahedral withThe most the intriguing sum of angles feature nearly of the bispidine equal to derivativ 325◦. Theires is the hydrogen conformational atoms flexibility are endo -orientedof both due to intramolecularpiperidine cycles. hydrogen In general bonding., they can adopt chair-chair, chair-boat, or boat-boat conformations The[22,64] most. S intriguingearch in the featureCambridge of theStructural bispidine Database derivatives (CSD, ver. is 5.39, the Feb conformational 2018) [65] for struc flexibilitytures of of both neutral organic flexible bispidine derivatives with sp3- hybridized carbon atoms within an piperidine cycles. In general, they can adopt chair-chair, chair-boat, or boat-boat conformations [22,64]. eight-membered cycle produced 121 entries (136 molecules). Several additional structures with Search inadditional the Cambridge fused rigid Structural cycles were Database rejected. (CSD, Examination ver. 5.39, of Feb the 2018)nitrogen [65–]nitrogen for structures separation of neutral 3 organicdistribution flexible bispidine reveals derivativesthat the widely with used sp - N…N hybridized distance carbon is an atomsinappropriate within parameter an eight-membered for cycle producedconformational 121 entries analysis (136 of molecules). bispidines. In Several close proximity additional to structuresthe intermediate with additionalpoint (half-chair fused rigid cycles werearrangement rejected. with Examination one almost planar of the N ato nitrogen–nitrogenm), significant shifts separation of the nitrogen distribution atom (perpendi revealscular that the widely usedto the Nmain... planeN distance of the cycle) is an inappropriatedo not lead to noticeable parameter change for conformationals in N…N distances analysis (Scheme of 2 bispidines.b). Therefore, the mutual distribution of C9…N distances was analyzed (Figure 1). Regions In closecorresponding proximity to t theo chair intermediate-chair and chair point-boat (half-chair conformations arrangement are clearly separated with one on almost this scatterplot. planar N atom), significantThe shiftschair-chair of the arrangement nitrogen atomdominates: (perpendicular 87 vs. 49 cases. to theInterest mainingly plane, in the of crystalline the cycle) state do, not the lead to noticeableboat changes-boat conformat in N ...ion Nis absent distances. Thus, (Scheme other criteria2b). Therefore,should be used the to mutual distinguish distribution chair-chair of and C9 ... N distanceschair was-boat analyzed conformations: (Figure namely,1). Regions the absolute corresponding value of to the chair-chair difference between and chair-boat C9…N distances conformations are clearly(Figure separated S18-S19). on The this approximate scatterplot. value The 0.17 chair-chair Å may be arrangement used as a threshold dominates: between 87 vs. these 49 cases. conformations. Interestingly, in the crystalline state, the boat-boat conformation is absent. Thus, other criteria should In structures 4cb, 3c, and 4da, one of the two nitrogen atoms bears a H atom available for be usedhydrogen to distinguish bonding. chair-chair It is of interest and chair-boat that, in all conformations: cases, these atoms namely, are the involved absolute in strong value of the differenceintra betweenmolecular C9 hydrogen... N distances bonding (Figure NH…N. S18-S19). Obviously The, such approximate hydrogen bonding value 0.17 is assistedÅ may be by used as a thresholdconformational between thesepreorientation conformations. of the bispidine scaffold. In structuresThus, all4cb five, 3c bispidinol, and 4das, one contain of the just two one nitrogen “active” hydroxyl atoms bears hydrogen a H atom atom available suitable for for the hydrogen bonding.formation It is of interest of intermolecular that, in all hydrogen cases, these bonds. atoms Additionally, are involved all these in strong molecules intramolecular contain several hydrogen acceptors of hydrogen bond at the opposite side, promoting the formation of the H-bonded chains. bonding NH ... N. Obviously, such hydrogen bonding is assisted by conformational preorientation of the bispidine scaffold. Thus, all five bispidinols contain just one “active” hydroxyl hydrogen atom suitable for the formation of intermolecular hydrogen bonds. Additionally, all these molecules contain several Nanomaterials 2019, 9, 89 6 of 17 Nanomaterials 2018, 8, x FOR PEER REVIEW 6 of 17

Actually, such chains formed by OH…O=C or OH…N bonds were observed in the structures of the acceptorsNanomaterialsNanomaterials of hydrogen2018 2018, 8, 8x, FORx FOR bond PEER PEER atREVIEW REVIEW the opposite side, promoting the formation of the H-bonded6 of6 chains.17of 17 Actually,neutral such bispidinol chainss formed4cb, 2c by, 3a OH, and... 3cO=C (Fig orure OHs 2...–6)N. In bonds contrast, were the observed structure inthe of structures salt 4da*HCl of the neutralcontainsActually,Actually, bispidinols an such suchinsular chains chains4cb 0D, formed2c hydrformed, 3aogen, andby by -OH…O=C bonded3cOH…O=C(Figures motif or2– OH…N 6due). In to contrast, the bondsbonds OH…Cl were were the observed structurehydrogen observed in ofbondin the saltthe s tructures(Fig s4da*HCltructuresure S14 of contains).ofthe the anneutral insularneutral bispidinol0D bispidinol hydrogen-bondeds s4cb 4cb, ,2c 2c, , 3a3a motif, , andand due3c3c (Fig(Fig to theures OH 2–6)6) .. . . In In Cl cont cont hydrogenrast,rast, the thebond structure structure (Figure of of salt S14). salt 4da 4da*HCl*HCl containscontains an an insular insular 0D 0D hydr hydrogenogen-bonded-bonded motifmotif due to thethe OH…ClOH…Cl hydrogen hydrogen bond bond (Fig (Figureure S14 S14). ).

Figure 1. Hydrogen-bonded chains in structure 4cb . FigureFigure 1. 1.Hydrogen-bonded Hydrogen-bonded chains chains in in structure structure 4cb4cb. . Figure 1. Hydrogen-bonded chains in structure 4cb.

Figure 2. Hydrogen-bonded chains in structure 2c. FigureFigure 2. 2.Hydrogen-bonded Hydrogen-bonded chains chains in in structure structure 2c.2c .

Figure 2. Hydrogen-bonded chains in structure 2c.

Figure 3. Hydrogen-bonded chains in structure 3a.

Nanomaterials 2018, 8, x FOR PEER REVIEW 7 of 17 Nanomaterials 2019, 9, 89 7 of 17 Figure 3. Hydrogen-bonded chains in structure 3a.

FigureFigure 4. Hydrogen-bondedHydrogen-bonded chains in structure 3c.3c. It should be noted that 3c is isostructural with its chlorine analogue LEFFIN (3b)[66]. It should be noted that 3c is isostructural with its chlorine analogue LEFFIN (3b) [66]. Table 1. Selected geometric parameters for bispidines 4cb, 2c, 3a, 3c, 4da.

Table 1. Selected4cb geometric parameters 2c for bispidines 3a 4cb, 2c, 3a, 3c3c, 4da. 4da*HCl

R1, R2 p-FC4cb6 H4CH2-, p-FC2c 6H4CH2-, 3aC 6H4CH2-, 3cp-FC 6H4CH2-,4dap-BrC*HCl 6H4CH2-, R3R1, R2 p-FC—p-ClC6H4C(=O)-6H4CH2-, — p-FC6H—-CH(=O)4CH2-, — C6H4CH2-,—H — p-FC6H4CH2—H-, — p-BrC6HHC6H4C(=O)-4CH2-, H C-OHR3 p-ClC6H4C(=O)1.423(3)- -CH(=O) 1.472(6)* H 1.4195(12)H 1.4178(12)C6H4C(=O) 1.416(12)- av N-CendoC-OH ** 1.423(3)1.469(3) 1.472(6)* 1.458(3) 1.4195(12) 1.4695(15) 1.4178(12) 1.4691(14) 1.416(12) 1.458(14) NBz-C ** 1.465(3) 1.471(3) 1.4653(14) 1.4658(13) 1.505(13) av N-Cendo ** 1.469(3) 1.458(3) 1.4695(15) 1.4691(14) 1.458(14) N-CO ** 1.339(3) 1.331(3) — — 1.375(13) NBz-C ** 1.465(3) 1.471(3) 1.4653(14) 1.4658(13) 1.505(13) ΣC-NBz-C *** 330.3 330.0 331.4 331.9 332.1 ΣC-Namid-CN-CO ** *** 1.339(3)359.4 1.331(3) 359.5 — —— —1.375(13) 353.7 Σ ang C-NBz NH- ***C *** 330.3 —330.0 —331.4 325.0331.9 325.8332.1 —  C-Namid-C *** 359.4 359.5 — R2HN, — R2HN, 353.7 X, O . . . X **** =O, 2.784(3) =O, 2.665(5) Cl-, 3.049(10)  ang NH *** — — 325.02.7250(12) 325.82.7157(12) — N . . .X, Nintra O…X ********* =O, 2.784(3)2.825(3) =O, 2.665(5) 2.830(4) R2HN, 2.7250(12) 2.8372(13) R2HN, 2.7157(1 2.8309(13)2) Cl-, 3.049(10) 2.790(14) * forN…Nintra major component ***** of disorder.2.825(3) ** average2.830(4) distances between2.8372(13) nitrogen and carbon2.8309(13) atoms (N-Cendo—between2.790(14) secondary* for major amine component nitrogen atoms of disorder and skeleton. ** carbon average atoms; distances NBz-C—between between benzyl nitrogen substituted and carbon nitrogen atoms atoms and(N-Cendo skeleton— carbonbetween atoms; secondary N-CO—between amine nitrogen amide nitrogen atoms and atoms skeleton and carbonyl carbon carbon atoms; atoms). NBz- ***C— thebetween sum of C-N-C angles (NBz—benzyl substituted nitrogen atom; Namid—amide nitrogen atom; NH—secondary amine nitrogenbenzyl substitutedatom). **** length nitrogen of hydrogen atoms bonds. and skeleton***** intramolecular carbon atoms; distance N between-CO—between nitrogen atoms. amide nitrogen atoms and carbonyl carbon atoms). *** the sum of C-N-C angles (NBz—benzyl substituted nitrogen . Structureatom; Namid1c —comprisesamide nitrogen both ketoneatom; NHand— itssecondary bis-diol amine forms. nitrogen The molecular atom) **** structures length of of the hydrogen bonds. ***** intramolecular distance between nitrogen atoms. diazaadamantane derivatives 1c and 1c+H2O are shown in Figures S15 and S17. The main geometrical featuresStructure of the diazaadamantane1c comprises both scaffold ketone in both and compounds its bis-diol areforms. close The to those molecular found for structures hydrochloride of the ofdiazaadamantan the parent compounde derivatives [63]. Notably, 1c and this1c+H is2 onlyO are the shown third known in Fig exampleures S15 of and the cocrystallizationS17. The main ofgeomet ketonerical and features its hydrate of the [diazaadamantan67,68]. Surprisingly,e scaffold the conformationsin both compounds of both are forms close to are those very found close tofor eachhydrochloride other. In of1c+H the parent2O, the compound diol form [63] is. stabilized Notably, this by hydrogenis only the bondingthird known with example the adjacent of the chlorinecocrystallization anions and of ketone water and molecules its hydrate (Figure [67,68] S15).. Surprisingly, This hydrogen-bonded the conformations system of is finite,both forms and thisare structurevery close represents to each other. the 0D In network. 1c+H2O, It the should diol be form noted is stabilized that the bezylation by hydrogen of one bonding of the nitrogens with the inadjacent 5,7-dimethyl-1,3-diazaadamantan-6-one chlorine anions and water molecules (X-ray-derived (Figure S15). structureThis hydrogen shown-bonded in Figure system S16) leadsis finite to, theand inequivalence this structure ofrepresents CH2-N bonds the 0D in network. both 1c and It should1c+H2 Obe: thenoted one that connected the bezylation to N+ became of one longerof the (1.546/1.565nitrogens in Å)5,7- thandimethyl the initial-1,3-diazaadamantan one in the starting-6-one diazaadamantanone (X-ray-derived structure (1.466 Å), shown whereas in Fig theure second S16) bondleads becameto the inequivalence slightly shorter of CH (1.422/1.4372-N bonds Å). in Thisboth is1c a and consequence 1c+H2O: the ofthe one n Nconnected– σ*N–C anomeric to N+ became type electroniclonger (1.546/1.565 interaction Å ) already than the mentioned initial one in in [69 the]. starting diazaadamantanone (1.466 Å ), whereas the secondThe bond infinite became hydrogen-bonded slightly shorter chains (1.422/1.437 in solid-state Å ). This structures is a consequence is a common of the motifnN – σ for*N–C2c, anomeric 3c, 4cb. Intype the electronic case of the interaction amine 3c already, the secondary mentioned nitrogen in [69]. lone pair serves as a hydrogen bond acceptor,

Nanomaterials 2018, 8, x FOR PEER REVIEW 8 of 17

Nanomaterials 2019, 9, 89 8 of 17 The infinite hydrogen-bonded chains in solid-state structures is a common motif for 2c, 3c, 4cb. In the case of the amine 3c, the secondary nitrogen lone pair serves as a hydrogen bond acceptor, whereas inin thethe amides 2c and 4cb,, carbonyl oxygensoxygens play thisthis role. The structure of the salt 4da*HCl differsdiffers dramatically, sincesince twotwo typestypes ofof intermolecularintermolecular hydrogen bonds can be distinguished within it.it. The firstfirst one binds the protonated tertiary amine hydrogen and carbonyl oxygen of the adjacent centro-symmetricallycentro-symmetrically linked molecule forming the dimers. Each Each organic molecule is also linked to the chloride anion by the second intermolecular hydrogen bond involving the hydroxyl hydrogen at position 9,9, which servesserves asas aa hydrogenhydrogen bondbond donordonor asas inin 2c2c,, 3c3c,, andand 4cb4cb.. On the basis of thesethese findingsfindings for thethe drieddried materials,materials, we cancan tentativelytentatively suggest that the main structural motif that links molecules into the 1D supramolecular polymer within the supramolecularsupramolecular gel isis thethe hydrogenhydrogen bond bond between between the the hydroxyl hydroxyl at at position position 9 and9 and the the hydrogen hydrogen bond bond donor, donor, which which can becan either be either a halogenide a halogenide anion anion or a carbonyl or a carbonyl oxygen oxygen atom.The atom. involvement The involvement of the hydroxyl of the hydroxyl and carbonyl and groupscarbonyl in hydrogen groups in bonding hydrogen is confirmed bonding by is FTIR confirmed spectra of by the FTIR native spect gelsrabenzene@4ce*HCl of the native gelsand benzene@4de*HClbenzene@4ce*HCl and(Figure benzene@4de*HCl S25). (Figure S25). It shouldshould be be stressed stressed here here that that upon upon the removalthe removal of benzene of benzene and ethoxybenzene, and ethoxyb theenzene gel, structure the gel undergoesstructure undergoes irreversible irreversible changes clearlychanges seen clearly in theseen carbonyl in the carbonyl and hydroxyl/NH and hydroxyl/NH regions regions of the IRof spectrathe IR spectra (Figure (7Figure). These 7) changes. These changes indicate indicate heavy structural heavy structural rearrangement rearrangement of the gel of which the gel leads which to thelead insolubilitys to the insolubility of the dried of the sample dried evensample in hoteven benzene, in hot benzene which was, which attempted was attempted in order in to order prepare to aprepare gel from a gel the from solid the4*HCl solid. This4*HCl can. This be explainedcan be explained as follows: as follows the removal: the removal of the solventof the solvent moves previouslymoves previously loosely looselypacked packedmolecular molecular chains into chains close into proximity close proximity with the with formation the formation of stronger of interchainstronger inter attractivechain interactions;attractive interactions; another explanation another explanation can be found can in thebe changes found in in the intermolecular changes in H-bondingintermolecular (see H below-bonding in Discussion). (see below in Discussion).

Figure 5. The changes in ATR spectra of 4ab during solvent removal. Benzene peaks are shown in blue. SeeFigure text 5. for The details. changes in ATR spectra of 4ab during solvent removal. Benzene peaks are shown in blue. See text for details. The xerogel organization at the nanoscale level of type 4*HCl obtained by direct benzene evaporationThe xerogel was studiedorganization by AFM, at the SEM, nanoscale and TEM level (Figure of type8, Figures4*HCl S20–S24).obtained by The direct data benzene clearly showevaporation the existence was stud ofied long byand AFM, thin SEM nanofibers, and TEM as (Fig a mainure 8, structural Figures S motif20–S24 of). theThe xerogels, data clearly which show is typicalthe existence for supramolecular of long and thin gels nanofibers [32]. In some as a main cases, structural the nano-crystalline motif of the additives xerogels, are which observed. is typical In somefor supramolecular extreme cases, gelsthewidth [32]. In of thesome nanofibers cases, the is nanoless than-crystalline 100 nm. additives are observed. In some extreme cases, the width of the nanofibers is less than 100 nm.

Nanomaterials 2019, 9, 89 9 of 17 NanomaterialsNanomaterials 2018 ,2018 8, x ,FOR 8, x FORPEER PEER REVIEW REVIEW 9 of 917 of 17

Figure 6. AFM, SEM, and TEM images for the dried gel benzene@4ce*HCl. FigureFigure 6. AFM, 6. AFM, SEM SEM, and, andTEM TEM images images for the for driedthe dried gel benzene@4ce*HCl gel benzene@4ce*HCl. . The sample of benzenogel benzene@4cb*HCl was subjected to different solvent The sample of benzenogel benzene@4cb*HCl was subjected to different solvent removal removalThe sample procedures. of benzenogel benzene@4cb*HCl was subjected to different solvent removal proceduresprocedures. .

a) a) b) b)

c) c) d) d)

Figure 7. SEM micrographs of dry gel samples obtained by different solvent removal methods from FiguFigure 7.re SEM 7. SEM micrographs micrographs of dry of geldry samplesgel samples obtained obtained by different by different solvent solvent removal removal methods methods from from benzene@4cb*HCl:(a) bulk xerogel; (b) gel coated on the glass surface; (c) liquid CO2 washing; benzene@4cb*HClbenzene@4cb*HCl: (a) :bulk (a) bulk xerogel xerogel; (b) ; gel(b) coatedgel coated on the on glassthe glass surface; surface; (c) liquid (c) liquid CO2 COwashing;2 washing; (d) (d) (d) sc-CO2 washing. Scale bar is 1 micrometer. sc-COsc2- COwashing.2 washing. Scale Scale bar isbar 1 mis icrometer1 micrometer. . The drying regime drastically affects the microstructure of the gels. Figure9 shows scanning The Thedrying drying regime regime dra sticallydrastically affects affects the themicrostructure microstructure of the of thegels gels. Figure. Figure 9 shows 9 shows scanning scanning electron microscopy images of benzene@4cb*HCl gels dried under different conditions. Drying electronelectron microscopy microscopy images images of benzene@ of benzene@4cb*HCl4cb*HCl gels gels dried dried under under different different conditions. conditions. Drying Drying under ambient conditions results in dense structures ranging from strongly interwoven to partially underunder ambient ambient conditions conditions results results in dense in dense structures structures ranging ranging from from strongly strongly interwov interwoven toen pa tortially partially conglutinated fiber-like particles (Figure9a,b). Drying in supercritical CO 2 resulted in a loose structure conglutinatedconglutinated fiber fiber-like- like particles particles (Figure (Figure 9a,b) 9.a,b) Drying. Drying in supercriticalin supercritical CO 2 CO resulted2 resulted in a in loose a loose possessing a lower aggregation degree of individual fibers (Figure9d). Presumably the difference is structurestructure possessing possessing a lower a lower aggregation aggregation degree degree of individual of individual fibers fibers (Fig (ureFig ure9d). 9 Presumablyd). Presumably the the due to the contribution of capillary forces. Drying under ambient conditions (xerogels) results in a differencedifference is due is due to the to contributionthe contribution of capi of capillaryllary forces. forces. Drying Drying under under ambient ambient conditions conditions (xerogels) (xerogels) strong coalescence of the particles upon the removal of liquid benzene and a movement of menisci into resultsresults in a instrong a strong coalescence coalescence of the of particlesthe particles upon upon the removalthe removal of liquid of liquid benzene benzene and and a movement a movement of menisciof menisci into into the thesample sample monolith. monolith. The The supercritical supercritical drying drying almost almost levels levels the theeffects effects from from the the

Nanomaterials 2019, 9, 89 10 of 17 Nanomaterials 2018, 8, x FOR PEER REVIEW 10 of 17 Nanomaterials 2018, 8, x FOR PEER REVIEW 10 of 17 thecapcapillary sampleillary forces f monolith.orces and and results The results supercritical in in loose loose un drying unaggregatedaggregated almost monoliths. levels monoliths. the effects The The c fromhemical chemical the capillarycomposition composition forces of of andthe the resultsbenzene@4cb*HClbenzene@4cb*HCl in loose unaggregated xerogel xerogel sample sample monoliths. is is in in Theagreement agreement chemical with with composition its its chemical chemical of thestructure: structure:benzene@4cb*HCl indeed, indeed, the the xerogelsample sample samplecontainscontains is Cl inCl and agreementand F. F. with its chemical structure: indeed, the sample contains Cl and F. Unusual structures were formed upon washing the gel using liquid CO2 with subsequent UnusualUnusual structures structures werewere formed formed uponupon washingwashing thethe gel gel using using liquid liquid CO CO2 2with with subsequent subsequent solventsolvent removal removal ( (Figure Figures(Figures9 c).9 9c)c). The .The The gel’s ge gel’sl’s fiber-like f iberfiber-like-like structure structure structure looks looks looks almost almost almostdisrupted, disrupted, disrupted, andand and thethe the samplesample sample consistsconsists of of strongly strongly coalesced coalesced particles particles with with a a crystalcrystal-like crystal-like-like shape shape;shape; ;some somesome particles particles particles are are are even even even faceted. faceted.faceted. Such an appearance may be due to the substance’s partial dissolution in liquid CO2 followed by SuchSuch an an appearance appearance may may be be due due to to the the substance’s substance’s partial partial dissolution dissolution in in liquid liquid CO CO2 2followed followed by by re-crystallization and fast desorption of CO2 from the sample surface, resulting in the disruption of re-crystallizationre-crystallization and and fast fast desorption desorption of of CO CO2 2from from the the sample sample surface, surface, resulting resulting in in the the disruption disruption of of fibersfibersfibers and and the the formationformation formation of of dendrite-likedendrite dendrite-like-like particles.particles particles. .The The same same observations observations were were found found forfo for r samples samples preparedprepared from from ethoxebenzeneethoxebenzene ethoxebenzene (Figure(Fig (Figureure S24)S24 S24) ) AnAn investigationinvestigation investigation of of the the xerogel xerogel sample sample using using aa back-scatteredback back-scattered-scattered electron electron detector detector (BSE(BSE-mode) (BSE-mode)-mode) (Figure(Fig(Figureure 10 10) ) reveals reveals inclusions inclusions of of a a secondary secondary phase phase with with a a density density notably notably higher higher than than that that of of the the matrix.matrix. ThisThis This finding fi findingnding is isin is agreementin in agreement agreement with with withPOM POM POMdata (Figure data data (Figure ( S7).Figure This S7 S7) can.) . This This be explainedcan can be be explained explainedby the formation by by the the offormationformation some nano-crystalline of of some some nano nano-crystalline domains-crystalline within domains domains the within amorphous within t hethe amorphous amorphous gel fibers. gel gel fibers. fibers.

aa) ) bb) )

Figure 8. SEM micrographs of the benzene@4cb*HCl xerogel sample obtained for the same area by FigureFigure 8. 8.SEM SEM micrographs micrographs of of the thebenzene@4cb*HCl benzene@4cb*HClxerogel xerogel sample sample obtained obtained for for the the same same area area by by (a) SE2 and (b) BSE detectors. Scale bar is 2 μm. (a()a SE2) SE2 and and (b (b) BSE) BSE detectors. detectors Scale. Scale bar bar is is 2 2µ μm.m.

SSimilarSimilarimilar differences differences were were observed observed upon upon drying drying the the benzene@4ce*HCl benzene@4ce*HCl sample sample under under ambient ambient conditions and in supercritical CO2 (Figure 9). conditionsconditions and and in in supercritical supercritical CO CO2 2(Figure (Figure9 ).9).

a)a) b)b)

Figure 9. SEM micrographs of dry gel samples obtained by different solvent removal methods from Figure 9. SEM micrographs of dry gel samples obtained by different solvent removal methods from benzene@4ce*HCl:Figure 9. SEM micrographs(a) direct air-drying;of dry gel samples (b) sc-CO obtained2 drying. by Scale different bar is solvent 1 µm. removal methods from benzene@4ce*HCl: (a) direct air-drying; (b) sc-CO2 drying. Scale bar is 1 μm. benzene@4ce*HCl: (a) direct air-drying; (b) sc-CO2 drying. Scale bar is 1 μm.

Nanomaterials 2019, 9, 89 11 of 17

Nanomaterials 2018, 8, x FOR PEER REVIEW 11 of 17 The nanoscale structure of the gels leads to a highly heterogeneous spatial distribution of electron density reflectedThe nanoscale by intense structure small-angle of the X-ray gels leadsscattering to a (SAXS)highly heterogeneous caused by scatterers spatial larger distribution than 60 of nm. The sampleselectronbenzene@4ce*HCl density reflected by intenseand benzene@4de*HCl small-angle X-ray scatteringalso possess (SAXS) crystallographic caused by scatterers ordering larger with than 60 nm. The samples benzene@4ce*HCl and benzene@4de*HCl also possess crystallographic interlayer spacings of 2.47, 1.16, and 0.75 nm (benzene@4ce*HCl) and 2.4+2.7 (double peak), 1.16, and ordering with interlayer spacings of 2.47, 1.16, and 0.75 nm (benzene@4ce*HCl) and 2.4+2.7 (double 0.75 nmpeak) (benzene@4de*HCl, 1.16, and 0.75 nm )(benzene@4de*HCl (Figure 10). ) (Figure 10).

Figure 10. Small-angle X-ray scattering patterns of samples benzene@4ce*HCl (red) and benzene@4de*HClFigure 10. Sm(black).all-angle X-ray scattering patterns of samples benzene@4ce*HCl (red) and benzene@4de*HCl (black). The close similarity in scattering patterns of the two different samples undoubtedly indicates the similar nano-The and close macrostructural similarity in scattering organization patterns of of benzenogels the two different based samples on N-benzyl, undoubtedlyN’-acylbispidinols. indicates The existencethe similar ofthe nano crystallographic- and macrostructural ordering organization may be a result of ofbenzenog the orderingels based of gelator on N-benzyl molecules, withinN’ chains,-acylbispidi fibers,nols. and The bundles. existence It canof the also crystallographic point to the presence ordering ofmay nano-crystalline be a result of the domains ordering within of the wholegelator gel-like molecules material. within chains, fibers, and bundles. It can also point to the presence of nano-crystalline domains within the whole gel-like material. 4. Discussion 4. Discussion In previous sections we have shown that the acylation of secondary amines 3 in benzene by acyl In previous sections we have shown that the acylation of secondary amines 3 in benzene by acyl chlorideschlorides led to led the to formation the formation of supramolecular of supramolecular gels gels of generalof general formulae formulaebenzene@4*HCl benzene@4*HCl.. BeforeBefore we start towe speculate start to speculate on the structural on the structural features features of new of materials, new materials, some some additional additional information information and and data shoulddata be takenshould into be taken account: into account:

• the• gelsthe are gels formed are formed only only during during the the acylation acylation of of secondary secondary amines of of NN-benzylbispidine-benzylbispidine-9-ols,-9-ols, but notbut upon not upon purging purging the HClthe HCl gas gas through through the the solution/suspension solution/suspension of of isolated isolated amino amino-amides-amides 4 4 in benzene; in benzene; • during the removal of benzene from the gel, the latter undergoes some irreversible structural • duringrearrangements the removal ofwhich benzene lead to from the further the gel, insolubility the latter ofundergoes dried material some in benzene; irreversible structural rearrangements• the gels are whichformed lead neither to the in t furtherhe presence insolubility of the external of dried base material (e.g., triethylamine), in benzene; nor from • the gelsthe are chloroanhydrides formed neither of in picolinic the presence acids (beta of the or gamma) external or base pyrazole (e.g.,- triethylamine),containing acid chlorides; nor from the chloroanhydrides• the removal of of picolinicthe chloride acids anion (beta by or gamma) the action or of pyrazole-containing aqueous silver nitrate acid destroys chlorides; the • the removalsupramole ofcular the gel; chloride anion by the action of aqueous silver nitrate destroys the supramolecular• the gels are gel;not formed upon alkylation (e.g., by benzylchloride); • the gels are not formed upon alkylation (e.g., by benzylchloride);

Nanomaterials 20182019, 98, 89x FOR PEER REVIEW 1212 of of 17

• the gels are formed only from aromatic (benzoic, para-chlorobenzoic acid) or heteroaromatic • the(2-thiophencarboxylic gels are formed only acid) from acid aromatic chlorides, (benzoic, but para-chlorobenzoic not with the use acid) of aliphatic or heteroaromatic reagents (2-thiophencarboxylic(acetylchloride, chloroanhydride acid) acid, orchlorides, cyclopropanecarboxylic but not with acid) the; use of aliphatic reagents • (acetylchloride,the gels are formed chloroanhydride, also in nitrobenzene, or cyclopropanecarboxylic ethoxybenzene acid);, and mesitylene at elevated • thetemperatures gels are formed (nearly also 100 in ° nitrobenzene,C), but their stability ethoxybenzene, depends and on mesitylenethe substituents at elevated at acylating temperatures agents (nearly(SI pp. 6 100–9).◦ C), but their stability depends on the substituents at acylating agents (SI pp. 6–9). All these data indicate that for the formation of supramolecular gel gelss in our systems,systems, one needs the following following:: (i) (i) proton (in the form of a protonated tertially amino group, which was found in the crystal of of4da*HCl 4da*HCl);); (ii) (ii) chloride chloride anion anion (obviously, (obviously to form, to hydrogen form hydrogen bonds with bonds N-H+, with as N in-H+,4da*HCl as in, 4da*HClor O-H, as, or in O1c+H-H, as2 Oin); 1c (iii)+H carbonyl2O); (iii) carbonyl group (obviously, group (obviously, to form to infinite form infinite chains viachains hydrogen via hydrogen bonds withbonds O-H, with like O-H, those like found those infou thend crystalin the crystal structure structure of 4cd orof 2c4cd); (iv)or 2c two); (iv) aromatic two aromatic substituents substituent at boths atnitrogen both n atomsitrogen of atoms the bispidine of the bispidinescaffold (presumably, scaffold (presumably, to form the to lateral form intermolecular the lateral intermolecular bonding via bondingπ−π-stacking via π− interactions).π-stacking interactions). The combination combination of of all allfeatures features mentioned mentioned above above allows allowsus to formulate us to formulate the following the mechanism following mechanismof gel formation of gel upon formation acylation upon of acylation amines 3 of(Scheme amines3 ).3 (Scheme The possible 3). The participation possible participation of H-bonded of Hsupramolecular-bonded supramolecular polymers like polymers those found like those in the fou crystalsnd in ofthe3a crorystals3c is of not 3a discussed or 3c is not here discussed for simplicity, here foralthough simplicity, they although may play they some may role play in the some beginning role in ofthe the beginning process. of the process.

HO HO HO

N N O N N O N N H H H SM 1 1 Ar2 1 O Ar Cl Ar2 Ar Cl Ar polymeriz. Cl Ar2

ORGANOGEL

H H O O H O N N N N SOLV SOLV H H 1 O Ar1 O Ar N N 2 Cl SOLV Cl lateral H Ar H interactions H Ar1 O O O Cl SOLV H SOLV O N N N N H H 1 1 O SOLV Ar O SOLV Ar N N Ar2 Cl Cl H H Ar1 H O SOLV Cl H Ar2 - not shown for clarity

Scheme 3 3.. SchematicSchematic representation of a possible method of gel formation.

Scheme 33 accountsaccounts forfor allall ofof thethe factorsfactors andand featuresfeatures mentionedmentioned above.above. Indeed,Indeed, allall thethe requiredrequired items are presented in the scheme and all playplay crucialcrucial rolesroles forfor thethe gelgel formationformation process.process. At this momentmoment,, wewe lacklack enoughenough data data to to reveal reveal the the mechanism mechanism for for the the aggregation aggregation of species of species of molecular of molecular size, size,schematically schematically shown shown as a result as a of result supramolecular of supramolecular polymerization polymerization that includes that both includes the formation both the formationof H-bonds ofand H-bondsπ−π-stacks. and π−π The-stacks. role ofThe the role solvent of the insolvent these in processes these processes is also unclear, is also unclear but we, canbut weassume can assume the importance the importance of the donor/acceptor of the donor/acceptor properties properties of the of aromatic the aromatic solvent solvent as well as as well its stericas its steric demands. Indeed, in the case of nitrobenzene, the strongest gel is formed when the π-donor

Nanomaterials 2019, 9, 89 13 of 17

Nanomaterials 2018, 8, x FOR PEER REVIEW 13 of 17 demands. Indeed, in the case of nitrobenzene, the strongest gel is formed when the π-donor thiophene thiopheneacid chloride acid is chloride applied. is On applied. the other On hand, the other the sterically hand, the demanding sterically demanding mesitylene formsmesitylene least forms stable leastgels amongstable gels this among row of solvents:this row of nitrobenzene, solvents: nitrobenzene, mesitylene, mesitylene, benzene, and benzene, ethoxybenzene. and ethoxybenzene. At the the same same time, time, assuming assuming that that the organogel the organogel building building block shown block shown in Scheme in 3Scheme indeed appeared3 indeed appearedduring the during gel formation, the gel formation, we can explain we can the explain changes the inchanges gel structure in gel structure during the during solvent the removal solvent re(seemoval Scheme (see4 ).Scheme At the molecular/supramolecular4). At the molecular/supramolecular level, one expectslevel, one the expect changes the in thechange main in H-bonded the main Hmotif-bonded from polymericmotif from chain polymeric to discreet chain dimers to discreet of type [ dimers4da*HCl of]2 . type This [ explains4da*HCl the]2. evolution This explains of the the IR evolutionspectra during of the the IRsolvent spectra evaporation: during the solvent both OH/NH evaporation: and C=O both regions OH/NH display and C=O remarkable regions changesdisplay remarkablein the corresponding changes in vibrations the corresponding (see above). vibrations Obviously, (see such above changes). Obviously will affect, such the changes nano/macro will a levelffect theof the nano/macro gel organization, level of and the different gel organization, solvent removal and different methods solvent will result removal in different methods morphologies will result in of differentthe final solids.morphologies of the final solids.

ORGANOGEL Cl XEROGEL H H O O H H O N N SOLV - H SOLV N N Ar1 O H N N Ar1 O Ar2 Cl H H 1 Ar1 O removal O Ar O H Cl SOLV of solvent/ H structural N N SOLV O change N N H H O Ar1 O N H N Ar2 Cl H H Ar1 O Cl SOLV Cl H Ar2 - not shown for clarity

SchemeScheme 4. Schematic4. Schematic representation representation of the of structural the structural changes changes upon solvent upon removalsolvent removalfrom the benzenogel. from the benzenogel. 5. Conclusions 5. ConclusionsIn conclusion, we have discovered a new family of low molecular weight gelators (LMWGs) basedIn on conclusion, the HCl salts we of have unsymmetrical discoveredN a-benzyl, new familyN’-acylbispidinols. of low molecular The weight first example gelators of the(LMWG aerogels) basedpreparation on the from HCl the salts supramolecular of unsymmetrical gel is N reported-benzyl, inN’ this-acyl manuscript.bispidinols. The The scope first example and limitations of the aerogelof the new preparation class of LMWGs from the is supramolecular the subject of our gel current is reported studies. in thisThe manuscriptinvestigation. The of copper scope and limitationszirconium complexes of the new of class new of ligands LMWG ands is theirthe subject gel forms of our for current possible studies. PET applications The investigation is also on of coourpper agenda. and zirconium complexes of new ligands and their gel forms for possible PET applications is alsoSupplementary on our agenda. Materials: The following are available online at http://www.mdpi.com/2079-4991/9/1/89/s1. Figure S1: Photo of 4ae*HCl in nitrobenzene, Figure S2: Photo of 4ae*HCl in ethoxybenzene, Figure S3: SupplementaryPhoto of 4ae*HCl Materials:in mesitylene, The following Figure S4: are Photo available of 4ab*HCl online atin www.mdpi.com/ nitrobenzene, Figurexxx/s1 S5:. Figure Photo S1: of 4ab*HClPhoto of 4ae*HClin ethoxybenzene, in nitrobenzene Figure, S6: Figure Photo S2: ofPhoto4ab*HCl of 4ae*HCin mesitylene,l in ethoxybenzene Figure S7:, POMFigure photomicrography, S3: Photo of 4ae*HCl Figure in mesityleneS8: Dependence, Figure of S4: viscosity Photo of on4ab*HCl shear rate,in nitrobenzene Figure S9:, Figure Dependence S5: Photo of theof 4ab*HCl loss and in accumulation ethoxybenzene modules, Figure on angular frequency, Figure S10: Molecular structure of 4cb, Figure S11: Molecular structure of 2c, Figure S6:S12: Photo Molecular of 4ab*HCl structure in mesitylene of 3a, Figure, Figure S13: S7: MolecularPOM photomicrography, structure of 3c Figure, Figure S8 S14:: Dependence Molecular of structureviscosity on of shear4da*HCl*(C rate, Figure6H6)2, S Figure9: Dependence S15: Hydrogen-bonded of the loss and finite accumulation motif in the modules structure on 1c+H2O angular ,frequency, Figure S16: Figure Molecular S10: Molecularstructure of structure 5,7-dimethyl-1,3-diazaadamantan-6-one, of 4cb, Figure S11: Molecular structure Figure of S17: 2c, TheFigure structures S12: Molecular a) and b) structure of ketone of and 3a, itsFigure diol S13:form inMolec theular crystal structure 1c, Figure of S18: 3c, Scatterplot Figure S14: of C9 Molecular... N separations structure in structures of 4da*HCl*(C of neutral6H6)2 organic, Figure flexible S15: Hydrogenbispidines,-bonded Figure S19: finite Histogram motif ofin absolute the structure differences 1c+H2O between, Figure C9 ... N S16: separations, Molecular Figure structure S20: TEM of 5,7-dimethyl-1,3-diazaadamantan-6-one, Figure S17: The structures a) and b) of ketone and its diol form in the crystal 1c, Figure S18: Scatterplot of C9…N separations in structures of neutral organic flexible bispidines, Figure S19: Histogram of absolute differences between C9…N separations, Figure S20: TEM micrograph of

Nanomaterials 2019, 9, 89 14 of 17 micrograph of 4bc*HCl, Figure S21–S23: AFM micrograph of 4bc*HCl, Figure S24: SEM micrographs of dry gel samples obtained by different solvent removal methods from ethoxybenzene@4ae*HCl, Figure S25: FTIR spectra of the native gels benzene@4de*HCl and benzene@4ce*HCl, Table S1: Dependence of shear rate on viscosity, Table S2: Dependence of the loss and storage moduli on angular frequency, Table S3: Crystal data, data collection, structure solution, and refinement parameters for 4cb, 2c, 3a, 3c, 1b, 5,7-dimethyl-1,3-diazaadamantan-6-one, and 4da. Author Contributions: S.Z.V., A.V.M., and V.N.N. conceived and designed the experiments; A.V.M., A.I.D., V.N.N., V.S.S., and A.V.F. performed the experiments; V.N.N. contributed to the NMR studies; V.S.S. contributed to the ATR studies; A.V.F. contributed to the POM, DLS, and DSC studies; A.A.E. contributed to the AFM studies; A.V.C., and J.A.K.H. contributed to the X-ray studies; A.A.S. contributed to the SAXS and FTIR studies; A.E.B. contributed to the SEM studies; S.Z.V, A.I.D., A.A.E., A.V.C., and V.K.I. wrote the paper; and S.Z.V. contributed to the general management. Funding: This work was supported by the Russian Science Foundation (Grant No. 16-13-00114). Acknowledgments: The X-ray diffraction studies were carried out within the State Assignment on Fundamental Research for the Kurnakov Institute of General and Inorganic Chemistry. The authors would like to thank S.S. Abramchuk (Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences) for assistance with the TEM measurements. The authors also thank A. Ryabchun for his help in the POM studies, A. Romanchuk for her help in the DLS studies, E. Raitman for her help in the DSC studies, and V. Maidannik for his help in the rheology investigation. Conflicts of Interest: The authors declare no conflict of interest.

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