Synthesis and Gelling Abilities of Polyfunctional Cyclohexane-1,2-dicarboxylic Acid Bisamides: Influence of the Hydroxyl Groups

molecules Article Synthesis and Gelling Abilities of Polyfunctional Cyclohexane-1,2-dicarboxylic Acid Bisamides: Influence of the Hydroxyl Groups Bernat Pi-Boleda 1, María Campos 2, Marta Sans 1,3 , Antonio Basavilbaso 2, Ona Illa 1, Vicenç Branchadell 1,*, Juan Carlos Estévez 2,* and Rosa M. Ortuño 1,* 1 Department de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain; [email protected] (B.P.-B.); [email protected] (M.S.); [email protected] (O.I.) 2 CIQUS (Centro Singular de Investigación en Química Biológica y Materiales Moleculares), Departamento de Química Orgánica Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] (M.C.); [email protected] (A.B.) 3The Hamburg Center for Ultrafast Imaging (CUI), Luruper Chaussee 149, 22761 Hamburg, Germany *Correspondence: [email protected] (V.B.); [email protected] (J.C.E.); [email protected] (R.M.O.); Tel.: +34-935-811-602 (R.M.O.) Received: 8 January 2019; Accepted: 18 January 2019; Published: 19 January 2019   Abstract: New enantiomerically pure C 16 -alkyl diamides derived from trihydroxy cyclohexane-1, 2-dicarboxylic acid have been synthesized from ( − )-shikimic acid. The hydroxyl groups in these compounds are free or, alternatively, they present full or partial protection. Their gelling abilities towards several solvents have been tested and rationalized by means of the combined use of Hansen solubility parameters, scanning electron microscopy (SEM), and circular dichroism (CD), as well as computational calculations. All the results allowed us to account for the capability of each type of organogelator to interact with different solvents and for the main mode of aggregation. Thus, compounds with fully protected hydroxyl groups are good organogelators for methanol and ethanol. In contrast, a related compound bearing three free hydroxyl groups is insoluble in water and polar solvents including alcohols but it is able to gelate some low-polarity solvents. This last behavior can be justified by strong hydrogen bonding between molecules of organogelator, which competes advantageously with polar solvent interactions. As an intermediate case, an organogelator with two free hydroxyl groups presents an ambivalent ability to gelate both apolar and polar solvents by means of two aggregation patterns. These involve hydrogen bonding interactions of the unprotected hydroxyl groups in apolar solvents and intermolecular interactions between amide groups in polar ones. Keywords: polyfunctional cycloalkane bisamides; organogelator; self-assembly; chirality; hydrogen bonds 1. Introduction Low molecular weight organogelators (LMWOGs) are soft materials widely used at present in several fields that include products employed as lubricants, cosmetics, drug delivery systems, tissue regeneration materials, biosensors, molecular electronic devices or chiral catalysts [ 1 – 5 ]. Very recently, applications of supramolecular gels as materials for environmental remediation [ 6 ] or for practical and eco-friendly oil spill recovery [7,8] have been reported. The gelling ability of molecules in different solvents has been the subject of a number of studies. However, the ultimate reasons for the hierarchical self-assembling of a gelator in a specific solvent still remain incomplete [ 9 , 10 ]. Therefore, there is a lack of prediction tools. Rationalization of the gelling Molecules 2019,24, 352; doi:10.3390/molecules24020352 www.mdpi.com/journal/molecules Molecules 2019,24, 352 2 of 17 power of a LMWOG has been attempted based on various solubility indicators [ 11 – 15 ]. Among them, Hansen solubility parameters (HSPs) [ 13 , 16 ] have been applied to elucidate the behavior of LMWOGs towards solvents and to reduce the number of trials usually involved during the identification of a suitable gelator for a particular application [17–19]. Amides have been reported as functional groups present in some of the simplest LMWOGs that have been described [ 20 ]. We have previously developed good LMWOGs of peptide nature based on chiral β -cyclobutane amino acids [ 21 , 22 ], or hybrid peptides presenting a cyclobutane β -amino acid joined in alternation with linear residues [ 23 ]. In both cases, a model to explain the self-assembly of the individual molecules to produce the gel was suggested by means of computational calculations. More recently, we reported a combined experimental and computational study to investigate and rationalize the gelling ability of diastereomeric 1,2-disubstituted carbocyclic compounds ( 1 , Figure 1) [ 24 ]. The influence of the cis/trans relative configuration of the monomers in their hierarchical self-assembly was analyzed and their gelling behavior compared well with that of trans-cyclohexane-1,2-diamine derivatives described by Hanabusa et al. [ 25 ] and van Esch et al. [ 26 ] suggesting that regiochemistry does not play a relevant role in the gelation process. It was remarkable that chiral aggregates were observed even from meso molecules cis1 as an example of stochastic symmetry breaking induced by sonication. Otherwise, regarding polyhydroxylated organogelators, only few results on modified carbohydrate or cholestane derivatives have been described and their ability to gelate organic solvents has been interpreted by using different techniques in each case [ 27 – 30 ]. Nevertheless, as far as we know, there is neither information in the literature on polyhydroxylated simple cycloalkane derivatives nor on compounds susceptible of additional hydrogen-bonding promoted by further functional groups such as amides. In this paper, we describe the investigation of five new polyhydroxylated cyclohexane bisamides (cisand trans2 , 3 – 5 , Figure 2), prepared from ( − )-shikimic acid. All of them bear two long alkyl chains and three hydroxyl groups with different degrees of protection. These new polyfunctional LMWOGs have been compared with their parent compounds cisand trans1 focusing the attention on the influence of the polar functional groups at the ring, especially the free hydroxyl groups, on their gelling power and aggregation mode in different solvents. With this purpose, the complementary results obtained from several experimental techniques (use of Hansen parameters, SEM and CD spectroscopy) as well as from computational calculations have been taken into account to understand and rationalize the main interactions involved in each case. Molecules 2019, 24, x 2 of 17 gelling power of a LMWOG has been attempted based on various solubility indicators [11–15]. Among them, Hansen solubility parameters (HSPs) [13,16] have been applied to elucidate the behavior of LMWOGs towards solvents and to reduce the number of trials usually involved during the identification of a suitable gelator for a particular application [17–19]. Amides have been reported as functional groups present in some of the simplest LMWOGs that have been described [20]. We have previously developed good LMWOGs of peptide nature based on chiral β-cyclobutane amino acids [21,22], or hybrid peptides presenting a cyclobutane β-amino acid joined in alternation with linear residues [23]. In both cases, a model to explain the self-assembly of the individual molecules to produce the gel was suggested by means of computational calculations. More recently, we reported a combined experimental and computational study to investigate and rationalize the gelling ability of diastereomeric 1,2-disubstituted carbocyclic compounds (1, Figure 1) [24]. The influence of the cis/trans relative configuration of the monomers in their hierarchical self-assembly was analyzed and their gelling behavior compared well with that of trans-cyclohexane-1,2-diamine derivatives described by Hanabusa et al. [25] and van Esch et al. [26] suggesting that regiochemistry does not play a relevant role in the gelation process. It was remarkable that chiral aggregates were observed even from meso molecules cis-1 as an example of stochastic symmetry breaking induced by sonication. Otherwise, regarding polyhydroxylated organogelators, only few results on modified carbohydrate or cholestane derivatives have been described and their ability to gelate organic solvents has been interpreted by using different techniques in each case [27–30]. Nevertheless, as far as we know, there is neither information in the literature on polyhydroxylated simple cycloalkane derivatives nor on compounds susceptible of additional hydrogen-bonding promoted by further functional groups such as amides. In this paper, we describe the investigation of five new polyhydroxylated cyclohexane bisamides (cisand trans-2, 3–5, Figure 2), prepared from (−)-shikimic acid. All of them bear two long alkyl chains and three hydroxyl groups with different degrees of protection. These new polyfunctional LMWOGs have been compared with their parent compounds cisand trans-1 focusing the attention on the influence of the polar functional groups at the ring, especially the free hydroxyl groups, on their gelling power and aggregation mode in different solvents. With this purpose, the complementary results obtained from several experimental techniques (use of Hansen parameters, SEM and CD spectroscopy) as well as from computational calculations have been taken into account to understand and rationalize the main interactions involved in each case. Figure 1. Previously studied LMWOGs (cisand trans-1) [16] and new LMWOGs investigated in this work (2–5). Figure 1. Previously studied LMWOGs (cisand trans1 ) [ 16 ] and new LMWOGs investigated in this work (2–5). Molecules 2019,24, 352 3 of 17 2. Results and Discussion 2.1. Synthesis of Organogelators 2–5 The synthesis of polysubstituted 1,2-cyclohexanedicarboxamides 2 – 5 was achieved from polysubstituted lactone 6 and 2-nitromethylcyclohexanecarboxylic acid methyl ester ( 9 ). respectively, previously obtained from commercially available (−)-shikimic acid (Scheme 1) [31]. For the preparation of 1,2-cyclohexanedicarboxamides cis2 , 3 and 5 , lactone 6 was transformed into acid 7 in 76% yield through a Nef reaction conducted under remarkably mild conditions, with sodium nitrite and acetic acid using dimethylsulfoxide as solvent and carefully controlling the pH (not lower than 3) in order to preserve the acetonide protecting group (Scheme 1). The resulting acid 7 was then condensed with hexadecylamine, using PyBop as coupling agent and diisopropylethylamine (DIEA) as a base, to give amide 8 in 98% yield. Subsequent reaction with a second equivalent of hexadecylamine in the presence of 2-hydroxypyridine afforded diamide 3 in 30% yield. In turn, 3 was transformed into fully protected derivative cis2 by protection of the free hydroxyl group as tert-butyldimethylsilyl ether by treatment with tert-butyldimethylsilyl chloride and imidazole (74% yield). Alternatively, aqueous trifluoroacetic acid-promoted hydrolysis of the acetonide in 3 afforded product 5in 42% yield. Following a similar route, nitroester 9 was transformed into amide 11 in 41% yield, for the two steps. This intermediate afforded diamide trans2 in 30% yield, when reacted with hexadecylamine and 2-hydroxypyridine as catalyst. The acetonide in fully protected diamide trans2 was removed as described before giving diamide 4 in 47% yield, which surprisingly preserved the silyl ether group that was inert under several conditions. Molecules 2019, 24, x 3 of 17 2. Results and Discussion 2.1. Synthesis of Organogelators 2–5 The synthesis of polysubstituted 1,2-cyclohexanedicarboxamides 2–5 was achieved from polysubstituted lactone 6 and 2-nitromethylcyclohexanecarboxylic acid methyl ester (9). respectively, previously obtained from commercially available (−)-shikimic acid (Scheme 1) [31]. For the preparation of 1,2-cyclohexanedicarboxamides cis-2, 3 and 5, lactone 6 was transformed into acid 7 in 76% yield through a Nef reaction conducted under remarkably mild conditions, with sodium nitrite and acetic acid using dimethylsulfoxide as solvent and carefully controlling the pH (not lower than 3) in order to preserve the acetonide protecting group (Scheme 1). The resulting acid 7 was then condensed with hexadecylamine, using PyBop as coupling agent and diisopropylethylamine (DIEA) as a base, to give amide 8 in 98% yield. Subsequent reaction with a second equivalent of hexadecylamine in the presence of 2-hydroxypyridine afforded diamide 3 in 30% yield. In turn, 3 was transformed into fully protected derivative cis-2 by protection of the free hydroxyl group as tert-butyldimethylsilyl ether by treatment with tert-butyldimethylsilyl chloride and imidazole (74% yield). Alternatively, aqueous trifluoroacetic acid-promoted hydrolysis of the acetonide in 3 afforded product 5 in 42% yield. Following a similar route, nitroester 9 was transformed into amide 11 in 41% yield, for the two steps. This intermediate afforded diamide trans-2 in 30% yield, when reacted with hexadecylamine and 2-hydroxypyridine as catalyst. The acetonide in fully protected diamide trans-2 was removed as described before giving diamide 4 in 47% yield, which surprisingly preserved the silyl ether group that was inert under several conditions. Scheme 1. Synthesis of diamides 2–5. 2.2. Gelation Studies The gelling ability of compounds 2–5 was studied using 14 protic or aprotic solvents with different polarity. Compounds cisand trans-2, 3 and 4 were soluble in water whereas 5 was insoluble; formation of hydrogels was not observed in any case. Results for organic solvents are summarized in Table 1 where data for related compounds cisand trans-1 [24] are also shown for comparison. Scheme 1. Synthesis of diamides 2–5. 2.2. Gelation Studies The gelling ability of compounds 2 – 5 was studied using 14 protic or aprotic solvents with different polarity. Compounds cisand trans2 , 3 and 4 were soluble in water whereas 5 was insoluble; formation of hydrogels was not observed in any case. Results for organic solvents are summarized in Table 1 where data for related compounds cisand trans-1[24] are also shown for comparison. Molecules 2019,24, 352 4 of 17 The gels produced were stable at room temperature but unstable at 37 ◦ C. Thus, a gel became a solution by heating with a hand. Once the solution was left to cool down to room temperature, the gel was formed again and remained unaltered for weeks (see the Experimental Section for details on the gel preparation). Compounds 2 – 5 presented a different behavior with respect to cisand trans1 , as expected, clearly indicating that the additional substitution of the ring plays a significant role. Compounds cisand trans2 , and 4 are able to gelate alcohols contrariwise to cisand trans1 that are insoluble as well as trihydroxylated compound 5 . In addition, cis2 also promotes the formation of gels in pentane, ethyl acetate and isopropanol although with higher mgc (minimum gelation concentration) values. Nevertheless, the differences between these diastereoisomers are not very remarkable in contrast with the behavior of isomers 1, being trans-1a much better gelator than the cis diastereomer (Table 1) [24]. Table 1. Gelling behavior of previously known LMWOG 116 and of the new compounds 2 – 5 in common organic solvents a, b, c. Pentane 1,4-Dioxane Toluene Et2O CHCl3EtOAc THF CH2Cl2iPrOH Acetone EtOH MeOH CH3CN cis-116 30 51 100 ISIIIIIIII (48) (82) (161) O O O trans116 I 3 7 I 18 IIIIIIII (5) (11) (29) T T T cis-2 83 S S S S 100 S S 100 S 21 17 S (101) (122) (122) (26) (21) C O O O O trans-2S S S S S S S S S S 50 16 S (61) (19) T O 3I 51 102 S S S S S S S S S S (72) (144) T T 4 54 61 64 70 S 45 S S S 22 56 70 S (69) (78) (82) (90) (58) (28) (72) (90) O O T O O O O O 5I 102 82 I 82 IS S IIIII (193) (156) (156) O T T a Dielectric constant increases from left to right; b mgc (minimum gelation concentration) in mg mL −1 . mgc values in mM in parentheses; c I: insoluble (precipitates before formation of a gel), S: soluble, C: clear, O: opaque, T: translucent. Compound 3 is a bad organogelator because it is soluble in nearly all solvents tested, except in 1,4-dioxane and toluene, but it exhibits very high mgc values. Compound 3 is related to cis2 but with a free hydroxyl group; comparing their behavior, it seems clear that having an unprotected alcohol disfavors the gelling ability especially in methanol and ethanol. Compound 4 , bearing two free hydroxyl groups, gelates a large variety of solvents of very different dielectric constants and it is a good organogelator for acetone. Comparison with trans2 suggests that the structural features of 4 exert a significant influence on its properties allowing it to gelate plenty more solvents. Compound 5 has all three hydroxyl groups unprotected. Its behavior is similar to that of disubstituted cyclohexanes cisand trans1 as it forms gels in 1,4-dioxane, toluene and chloroform and it is insoluble in most other solvents (except in THF and dichloromethane), although the mgc values are significantly higher for 5 . It is noteworthy that, although this compound bears three free hydroxyl groups, it is insoluble in all the alcohols tested (methanol, ethanol and isopropanol) as well as in water. Some rational behind these observations will be discussed below. 2.3. Hansen Solubility Parameters (HSPs) Inspection of the data in Table 1makes evident that the gelling properties observed for the studied LMWOGs do not only depend on the dielectric constant of the solvents but also other factors need to be considered for their understanding. Molecules 2019,24, 352 5 of 17 Plotting the HSPs of each solvent, a 3D space is generated and the solvents are sorted over the space depending on three parameters: δd , which accounts for dispersive interactions that dominate for low polarity solvents; δp , which is related to polar interactions, and δh that arises from hydrogen bonding interactions. The representation of the HSPs for 4 shows two areas of solvents corresponding to those gelated by this organogelator, which are highlighted in blue, and those in red in which it is soluble (Figure 2a,b). In order to better observe the two areas, the plane δp - δd was also represented showing that there are two clusters of gelling solvents which can be related to two different aggregation patterns. One area corresponds to apolar solvents with low δp and high δd and the other to aprotic (acetone) or protic (alcohols) polar solvents, with higher δp and also higher δh in the case of methanol and ethanol (Figure 2a). These results suggest that 4could interact with the solvent both through the unprotected hydroxyl groups and through hydrogen bonding between the amide groups. These facts resulting in two types of aggregates as corroborated by SEM (see below). Molecules 2019, 24, x 5 of 17 2.3. Hansen Solubility Parameters (HSPs) Inspection of the data in Table 1 makes evident that the gelling properties observed for the studied LMWOGs do not only depend on the dielectric constant of the solvents but also other factors need to be considered for their understanding. Plotting the HSPs of each solvent, a 3D space is generated and the solvents are sorted over the space depending on three parameters: δd, which accounts for dispersive interactions that dominate for low polarity solvents; δp, which is related to polar interactions, and δh that arises from hydrogen bonding interactions. The representation of the HSPs for 4 shows two areas of solvents corresponding to those gelated by this organogelator, which are highlighted in blue, and those in red in which it is soluble (Figure 2a,b). In order to better observe the two areas, the plane δp-δd was also represented showing that there are two clusters of gelling solvents which can be related to two different aggregation patterns. One area corresponds to apolar solvents with low δp and high δd and the other to aprotic (acetone) or protic (alcohols) polar solvents, with higher δp and also higher δh in the case of methanol and ethanol (Figure 2a). These results suggest that 4 could interact with the solvent both through the unprotected hydroxyl groups and through hydrogen bonding between the amide groups. These facts resulting in two types of aggregates as corroborated by SEM (see below). Figure 2. (a,c) HSPs representation and (b,d) 2D representation of δp vs. δd for the gelation study of compounds 4 (a,b) and 5 (c,d). Red: Solvents in which 4 or 5 are soluble; blue: solvents gelled. Despite bearing three unprotected hydroxyl groups, compound 5 is insoluble in polar solvents, especially in alcohols and also in water. One could have expected that the interaction of the three free hydroxyl groups of 5 should be favorable for solubility or gelation through hydrogen bonding. Instead, as shown in Figure 2, compound 5 is only soluble in apolar solvents while the solvents gelled are clustered in the region with the highest δd and lowest δp in the HSPs space (Figure 2d). This result suggests that the hydroxyl groups in 5 do not interact with solvents but they are Figure 2. ( a , c ) HSPs representation and ( b , d ) 2D representation of δp vs. δd for the gelation study of compounds 4(a,b) and 5(c,d). Red: Solvents in which 4or 5are soluble; blue: solvents gelled. Despite bearing three unprotected hydroxyl groups, compound 5 is insoluble in polar solvents, especially in alcohols and also in water. One could have expected that the interaction of the three free hydroxyl groups of 5 should be favorable for solubility or gelation through hydrogen bonding. Instead, as shown in Figure 2, compound 5 is only soluble in apolar solvents while the solvents gelled are clustered in the region with the highest δd and lowest δp in the HSPs space (Figure 2d). This result suggests that the hydroxyl groups in 5 do not interact with solvents but they are preferably involved in inter-gelator interactions. Only few examples on the fact that gelling solvents for polyhydroxylated compounds are clustered in a region of lower δp and δh but high δd have been described in the Molecules 2019,24, 352 6 of 17 literature [ 17 ]. These observations were fully supported by the results of computational calculations and CD (see below). 2.4. Scanning Electron Microscopy SEM experiments were carried out to investigate the morphology of some of the gels produced at the mgc for each compound. The micrographs were taken from the corresponding xerogels and selected examples are shown in Figure 3. Molecules 2019, 24, x 6 of 17 preferably involved in inter-gelator interactions. Only few examples on the fact that gelling solvents for polyhydroxylated compounds are clustered in a region of lower δ p and δ h but high δ d have been described in the literature [17]. These observations were fully supported by the results of computational calculations and CD (see below). 2.4. Scanning Electron Microscopy SEM experiments were carried out to investigate the morphology of some of the gels produced at the mgc for each compound. The micrographs were taken from the corresponding xerogels and selected examples are shown in Figure 3. Figure 3. SEM images of xerogels at the mgc of: (a,b) cis-2 from methanol; (c,d) trans-2 from methanol; (e,f) 4 from acetone; (g,h) 4 from pentane, at two magnifications each (200 and 50 μm). SEM images show that compounds cisand trans-2 present different morphologies despite having a similar gelling behavior in methanol. Compound cis-2 forms fibers of different lengths, some of which are very long (around 200 μm) (Figures 3a and b). Its diastereoisomer, trans-2, also forms big aggregates but in this case in the shape of fibrous platelets (Figures 3c and d). Therefore, this confirms that in this case, as well as for diastereomers cis/trans-1, [24] the cis/trans stereochemistry plays a role on the pattern of aggregation. Compound 4 was studied in two different solvents, acetone (Figure 3e,f) and pentane (Figure 3g,h). The appearance of the micrographs is quite different; in acetone the aggregates form disorganized shapes while in pentane the compound forms clear platelets. Therefore, the presence of the free hydroxyl groups also influences the morphology of aggregates in different solvents, which agrees with the results from consideration of the Hansen solubility parameters as discussed above. 2.5. Computational Calculations and Circular Dichroism In earlier studies of other LMWOGs, we used IR and 1 H-NMR spectroscopies to gain information about the aggregation process [21–23]. Nevertheless, in the present case in which different groups can contribute to the gel formation, we thought that the combined results from computational calculations and CD spectroscopy would be better to provide an overall view and a more reliable interpretation. Indeed, CD allowed us to obtain information about the hierarchical organization of the molecules in the aggregates and to corroborate the predictions from calculations that, in turn, led us to better understand the structure of the gels and their formation mode. Figure 3. SEM images of xerogels at the mgc of: ( a , b )cis2 from methanol; ( c , d )trans2 from methanol; (e,f)4from acetone; (g,h)4from pentane, at two magnifications each (200 and 50 µm). SEM images show that compounds cisand trans2 present different morphologies despite having a similar gelling behavior in methanol. Compound cis2 forms fibers of different lengths, some of which are very long (around 200 µ m) (Figure 3a,b). Its diastereoisomer, trans2 , also forms big aggregates but in this case in the shape of fibrous platelets (Figure 3c,d). Therefore, this confirms that in this case, as well as for diastereomers cis/trans1 , [ 24 ] the cis/trans stereochemistry plays a role on the pattern of aggregation. Compound 4 was studied in two different solvents, acetone (Figure 3e,f) and pentane (Figure 3g,h). The appearance of the micrographs is quite different; in acetone the aggregates form disorganized shapes while in pentane the compound forms clear platelets. Therefore, the presence of the free hydroxyl groups also influences the morphology of aggregates in different solvents, which agrees with the results from consideration of the Hansen solubility parameters as discussed above. 2.5. Computational Calculations and Circular Dichroism In earlier studies of other LMWOGs, we used IR and 1 H-NMR spectroscopies to gain information about the aggregation process [ 21 – 23 ]. Nevertheless, in the present case in which different groups can contribute to the gel formation, we thought that the combined results from computational calculations and CD spectroscopy would be better to provide an overall view and a more reliable interpretation. Indeed, CD allowed us to obtain information about the hierarchical organization of the molecules in the aggregates and to corroborate the predictions from calculations that, in turn, led us to better understand the structure of the gels and their formation mode. Computational calculations of compounds 2 – 5 were carried out using the M06-2X/6-31G(d) level of theory for the optimization of the geometry of Molecules 2019,24, 352 7 of 17 the monomer and the tetramer and using minimizations of the energy with molecular mechanics for the structure of the hexamer and the octamer (see Supplementary Materials for details). By means of calculations we found that monomers can aggregate according to two types of interactions. The first one, which is the only observed for 2 and 3 , occurs through the formation of –NH···OC– hydrogen bonds in one dimension (1-D) involving the amide groups (α-type aggregates). In turn, monomers with free hydroxyl groups can interact by additional –OH ··· OH– hydrogen bonding to give β -type aggregates. These aggregates formed by two kinds of directional bonding interactions would be dimers of α-ones (Figure 4) and have been predicted for gelators 4and 5. Molecules 2019, 24, x 7 of 17 Computational calculations of compounds 2–5 were carried out using the M06-2X/6-31G(d) level of theory for the optimization of the geometry of the monomer and the tetramer and using minimizations of the energy with molecular mechanics for the structure of the hexamer and the octamer (see Supplementary Materials for details). By means of calculations we found that monomers can aggregate according to two types of interactions. The first one, which is the only observed for 2 and 3, occurs through the formation of –NH···OC– hydrogen bonds in one dimension (1-D) involving the amide groups (α-type aggregates). In turn, monomers with free hydroxyl groups can interact by additional –OH···OH– hydrogen bonding to give β-type aggregates. These aggregates formed by two kinds of directional bonding interactions would be dimers of α-ones (Figure 4) and have been predicted for gelators 4 and 5. Figure 4. Cartoon representing the spatial disposition of monomers in αand β-aggregates. Predicted structures of the octamers from compounds cisand trans-2, and 3 are shown in Figure 5. As it can be observed, due to the presence of the TBDMS group and the relative cis configuration of the two amide groups, compound cis-2 shows a significantly curved vertical aggregate. Otherwise, compounds trans-2 and 3 form a right-handed helical aggregate where the chains are placed in such a way that maximizes the Van der Waals interactions. Figure 5. Front views of central 6 molecules in octameric 1-D aggregates (amide hydrogen-bonds) of cisand trans-2, and 3. Non-polar hydrogen atoms have been omitted for clarity. Atoms in amide groups have been represented with red (oxygen), blue (nitrogen) and grey (carbon) spheres. CD spectra for cisand trans-2 were recorded both in methanol solution and as xerogels (dry gels) from methanol (Figure 6). In this way, more insight could be obtained on the transfer of chirality from a single molecule to the aggregates. Figure 4. Cartoon representing the spatial disposition of monomers in αand β-aggregates. Predicted structures of the octamers from compounds cisand trans2 , and 3 are shown in Figure 5. As it can be observed, due to the presence of the TBDMS group and the relative cis configuration of the two amide groups, compound cis2 shows a significantly curved vertical aggregate. Otherwise, compounds trans2 and 3 form a right-handed helical aggregate where the chains are placed in such a way that maximizes the Van der Waals interactions. Molecules 2019, 24, x 7 of 17 Computational calculations of compounds 2–5 were carried out using the M06-2X/6-31G(d) level of theory for the optimization of the geometry of the monomer and the tetramer and using minimizations of the energy with molecular mechanics for the structure of the hexamer and the octamer (see Supplementary Materials for details). By means of calculations we found that monomers can aggregate according to two types of interactions. The first one, which is the only observed for 2 and 3, occurs through the formation of –NH···OC– hydrogen bonds in one dimension (1-D) involving the amide groups (α-type aggregates). In turn, monomers with free hydroxyl groups can interact by additional –OH···OH– hydrogen bonding to give β-type aggregates. These aggregates formed by two kinds of directional bonding interactions would be dimers of α-ones (Figure 4) and have been predicted for gelators 4 and 5. Figure 4. Cartoon representing the spatial disposition of monomers in αand β-aggregates. Predicted structures of the octamers from compounds cisand trans-2, and 3 are shown in Figure 5. As it can be observed, due to the presence of the TBDMS group and the relative cis configuration of the two amide groups, compound cis-2 shows a significantly curved vertical aggregate. Otherwise, compounds trans-2 and 3 form a right-handed helical aggregate where the chains are placed in such a way that maximizes the Van der Waals interactions. Figure 5. Front views of central 6 molecules in octameric 1-D aggregates (amide hydrogen-bonds) of cisand trans-2, and 3. Non-polar hydrogen atoms have been omitted for clarity. Atoms in amide groups have been represented with red (oxygen), blue (nitrogen) and grey (carbon) spheres. CD spectra for cisand trans-2 were recorded both in methanol solution and as xerogels (dry gels) from methanol (Figure 6). In this way, more insight could be obtained on the transfer of chirality from a single molecule to the aggregates. Figure 5. Front views of central 6 molecules in octameric 1-D aggregates (amide hydrogen-bonds) of cisand trans2 , and 3 . Non-polar hydrogen atoms have been omitted for clarity. Atoms in amide groups have been represented with red (oxygen), blue (nitrogen) and grey (carbon) spheres. CD spectra for cisand trans2 were recorded both in methanol solution and as xerogels (dry gels) from methanol (Figure 6). In this way, more insight could be obtained on the transfer of chirality from a single molecule to the aggregates. Molecules 2019,24, 352 8 of 17 Molecules 2019, 24, x 8 of 17 Figure 6. Normalized CD spectra of cis-and trans-2, respectively, in methanol solution (2.4 mM for cis-2 and 2.7 mM for trans-2) and xerogel at the mgc in methanol in KBr (20 mM) at 25 °C. In solution, cisand trans-2 show a band in the CD spectrum. cis-2 Presents a negative band with a maximum at 222 nm and trans-2 shows a positive band with a maximum at 221 nm and a small negative lobule at 211 nm. The CD spectra of these organogelators in methanol solution were also computed giving predictions in very good agreement with the experimental spectra (see Figure S1 in Supplementary Materials). For the xerogels from methanol, the shape of the CD spectra is visibly different. For cis-2 as a xerogel from methanol, a bisignate Cotton effect was observed with a positive band at 215 and a negative one at 223 nm with zero crossing at 218 nm. The band of compound trans-2 presents a hypsochromic shift and it has a maximum at 207 nm. This shift is associated to the formation of H-type aggregates in which two or more monomers are arranged on the top of each other, i.e., the stacking due to amide π−π* interactions is oriented in a direction that is roughly perpendicular to the molecular plane; the band is moved to lower wavelengths because the absorption is more energetic than that of the monomer suggesting a strong interaction between the monomers [32,33]. In view of the CD spectra of the xerogels (Figure 6) and their predicted structures (Figure 5), it is important to remark that the bisignate spectrum of cis-2 is in agreement with a curved vertical aggregate whereas the monosignate band for trans-2 suggests a helical structure for its aggregates. This relationship is consistent with previous observations for compounds cisand trans-1, [24] and also applies for the other xerogels considered in this work. Compound 3 also differs in the shape of the CD spectra in solution and in the xerogel (Figure 7a). It is bisignate in solution while it shows a band for the xerogel, which is in agreement with the predicted structure of its aggregates that suggests a helical torsion as shown in Figure 5. Figure 7. (a) Normalized CD spectra of methanol solution (2.47 mM) and xerogel at the mgc from toluene in KBr (20 mM) of 3 at 25 °C; (b) Normalized CD spectra of methanol solution (2.56 mM) and xerogels at the mgc in acetone and pentane, respectively, in KBr (20 mM) of 4 at 25 °C; (c) Normalized CD spectra of 5 in methanol solution (2.17 mM) and xerogel at the mgc from toluene in KBr (20 mM) at 25 °C. 200 210 220 230 240 250 260 270 280 -1.0 -0.5 0.0 0.5 1.0 5(MeOH solution) 5(MeOH xerogel) 6(MeOH solution) 6(MeOH xerogel) Normalized [Φ] Wavelength (nm) cis-2 cis-2 trans-2 trans-2 200 210 220 230 240 250 260 270 -1.0 -0.5 0.0 0.5 1.0 Normalized [φ] Wavelength (nm) 8xerogel pentane 8solution methanol 8xerogel acetone 200 210 220 230 240 250 -1.0 -0.5 0.0 0.5 1.0 Normalized Wavelength (nm) 9xerogel 9solution 200 210 220 230 240 250 260 -1.0 -0.5 0.0 0.5 1.0 Normalized Δε Wavelength (nm) G xerogel G solution [φ] 7solution 7xerogel a) b) c) Normalized [Φ] 543 Figure 6. Normalized CD spectra of cis-and trans2 , respectively, in methanol solution (2.4 mM for cis2 and 2.7 mM for trans-2) and xerogel at the mgc in methanol in KBr (20 mM) at 25 ◦C. In solution, cisand trans2 show a band in the CD spectrum. cis2 Presents a negative band with a maximum at 222 nm and trans2 shows a positive band with a maximum at 221 nm and a small negative lobule at 211 nm. The CD spectra of these organogelators in methanol solution were also computed giving predictions in very good agreement with the experimental spectra (see Figure S1 in Supplementary Materials). For the xerogels from methanol, the shape of the CD spectra is visibly different. For cis2 as a xerogel from methanol, a bisignate Cotton effect was observed with a positive band at 215 and a negative one at 223 nm with zero crossing at 218 nm. The band of compound trans2 presents a hypsochromic shift and it has a maximum at 207 nm. This shift is associated to the formation of H-type aggregates in which two or more monomers are arranged on the top of each other, i.e., the stacking due to amide π−π * interactions is oriented in a direction that is roughly perpendicular to the molecular plane; the band is moved to lower wavelengths because the absorption is more energetic than that of the monomer suggesting a strong interaction between the monomers [32,33]. In view of the CD spectra of the xerogels (Figure 6) and their predicted structures (Figure 5), it is important to remark that the bisignate spectrum of cis2 is in agreement with a curved vertical aggregate whereas the monosignate band for trans2 suggests a helical structure for its aggregates. This relationship is consistent with previous observations for compounds cisand trans1 , [ 24 ] and also applies for the other xerogels considered in this work. Compound 3 also differs in the shape of the CD spectra in solution and in the xerogel (Figure 7a). It is bisignate in solution while it shows a band for the xerogel, which is in agreement with the predicted structure of its aggregates that suggests a helical torsion as shown in Figure 5. Molecules 2019, 24, x 8 of 17 Figure 6. Normalized CD spectra of cis-and trans-2, respectively, in methanol solution (2.4 mM for cis-2 and 2.7 mM for trans-2) and xerogel at the mgc in methanol in KBr (20 mM) at 25 °C. In solution, cisand trans-2 show a band in the CD spectrum. cis-2 Presents a negative band with a maximum at 222 nm and trans-2 shows a positive band with a maximum at 221 nm and a small negative lobule at 211 nm. The CD spectra of these organogelators in methanol solution were also computed giving predictions in very good agreement with the experimental spectra (see Figure S1 in Supplementary Materials). For the xerogels from methanol, the shape of the CD spectra is visibly different. For cis-2 as a xerogel from methanol, a bisignate Cotton effect was observed with a positive band at 215 and a negative one at 223 nm with zero crossing at 218 nm. The band of compound trans-2 presents a hypsochromic shift and it has a maximum at 207 nm. This shift is associated to the formation of H-type aggregates in which two or more monomers are arranged on the top of each other, i.e., the stacking due to amide π−π* interactions is oriented in a direction that is roughly perpendicular to the molecular plane; the band is moved to lower wavelengths because the absorption is more energetic than that of the monomer suggesting a strong interaction between the monomers [32,33]. In view of the CD spectra of the xerogels (Figure 6) and their predicted structures (Figure 5), it is important to remark that the bisignate spectrum of cis-2 is in agreement with a curved vertical aggregate whereas the monosignate band for trans-2 suggests a helical structure for its aggregates. This relationship is consistent with previous observations for compounds cisand trans-1, [24] and also applies for the other xerogels considered in this work. Compound 3 also differs in the shape of the CD spectra in solution and in the xerogel (Figure 7a). It is bisignate in solution while it shows a band for the xerogel, which is in agreement with the predicted structure of its aggregates that suggests a helical torsion as shown in Figure 5. Figure 7. (a) Normalized CD spectra of methanol solution (2.47 mM) and xerogel at the mgc from toluene in KBr (20 mM) of 3 at 25 °C; (b) Normalized CD spectra of methanol solution (2.56 mM) and xerogels at the mgc in acetone and pentane, respectively, in KBr (20 mM) of 4 at 25 °C; (c) Normalized CD spectra of 5 in methanol solution (2.17 mM) and xerogel at the mgc from toluene in KBr (20 mM) at 25 °C. 200 210 220 230 240 250 260 270 280 -1.0 -0.5 0.0 0.5 1.0 5(MeOH solution) 5(MeOH xerogel) 6(MeOH solution) 6(MeOH xerogel) Normalized [Φ] Wavelength (nm) cis-2 cis-2 trans-2 trans-2 200 210 220 230 240 250 260 270 -1.0 -0.5 0.0 0.5 1.0 Normalized [φ] Wavelength (nm) 8xerogel pentane 8solution methanol 8xerogel acetone 200 210 220 230 240 250 -1.0 -0.5 0.0 0.5 1.0 Normalized Wavelength (nm) 9xerogel 9solution 200 210 220 230 240 250 260 -1.0 -0.5 0.0 0.5 1.0 Normalized Δε Wavelength (nm) G xerogel G solution [φ] 7solution 7xerogel a) b) c) Normalized [Φ] 543 Figure 7. ( a ) Normalized CD spectra of methanol solution (2.47 mM) and xerogel at the mgc from toluene in KBr (20 mM) of 3 at 25 ◦ C; ( b ) Normalized CD spectra of methanol solution (2.56 mM) and xerogels at the mgc in acetone and pentane, respectively, in KBr (20 mM) of 4 at 25 ◦ C; ( c ) Normalized CD spectra of 5 in methanol solution (2.17 mM) and xerogel at the mgc from toluene in KBr (20 mM) at 25 ◦C. Molecules 2019,24, 352 9 of 17 Compounds 4 and 5 were also computed. As was hypothesized when the HSPs were analyzed (see above), these compounds could present two different aggregation patterns depending on the predominant interactions in apolar or polar solvents. In α -type aggregates from 4 , the molecules are placed in a zig-zag disposition because of the intermolecular interactions between amide groups (see Figure S3). This type of interactions would be favored in polar solvents and, indeed, the CD spectrum of the xerogel from acetone (prepared at the mgc) is bisignate (Figure 7b). On the other hand, the predicted β -type structure (Figure S3) shows that compound 4 can self-assemble through hydrogen bonding interactions of the unprotected hydroxyl groups, and then forms an aggregate which shows a torsion that will produce some helicity (right-handed helix). This type of interaction is expected to be predominant in apolar solvents as confirmed by the monosignate CD spectrum of 4as a xerogel from pentane (Figure 7b). Therefore, the results from the consideration of HSPs for organogelator 4 are consistent with the CD spectra of the xerogels from polar or apolar solvents and can be explained by the predictions from computational calculations. In a similar manner, compound 5 can aggregate in two different ways. Figure 8shows the α -type and the β -type structure, where two α -aggregates are interacting with each other through hydrogen bond interactions between the unprotected hydroxyl groups. In this way, the free hydroxyl groups of the molecule would be used to form aggregates avoiding interactions with the solvent. This could explain the insolubility of 5 in alcohols. Moreover, if the polar head of this organogelator was strongly interacting with another polar head, the parts of the molecule available for aggregation would only be the amide groups and the long alkyl chains, which would explain why 5 behaves in a very similar manner to the non-substituted cyclohexane-based compounds cisand trans-1[24] (see Table 1). Molecules 2019, 24, x 9 of 17 Compounds 4 and 5 were also computed. As was hypothesized when the HSPs were analyzed (see above), these compounds could present two different aggregation patterns depending on the predominant interactions in apolar or polar solvents. In α-type aggregates from 4, the molecules are placed in a zig-zag disposition because of the intermolecular interactions between amide groups (see Figure S3). This type of interactions would be favored in polar solvents and, indeed, the CD spectrum of the xerogel from acetone (prepared at the mgc) is bisignate (Figure 7b). On the other hand, the predicted β-type structure (Figure S3) shows that compound 4 can self-assemble through hydrogen bonding interactions of the unprotected hydroxyl groups, and then forms an aggregate which shows a torsion that will produce some helicity (right-handed helix). This type of interaction is expected to be predominant in apolar solvents as confirmed by the monosignate CD spectrum of 4 as a xerogel from pentane (Figure 7b). Therefore, the results from the consideration of HSPs for organogelator 4 are consistent with the CD spectra of the xerogels from polar or apolar solvents and can be explained by the predictions from computational calculations. In a similar manner, compound 5 can aggregate in two different ways. Figure 8 shows the α−type and the β−type structure, where two α−aggregates are interacting with each other through hydrogen bond interactions between the unprotected hydroxyl groups. In this way, the free hydroxyl groups of the molecule would be used to form aggregates avoiding interactions with the solvent. This could explain the insolubility of 5 in alcohols. Moreover, if the polar head of this organogelator was strongly interacting with another polar head, the parts of the molecule available for aggregation would only be the amide groups and the long alkyl chains, which would explain why 5 behaves in a very similar manner to the non-substituted cyclohexane-based compounds cisand trans-1 [24] (see Table 1). Figure 8. (a) side view of central 6 molecules in octameric 1-D aggregate (amide hydrogen-bonds) 5-α. (b) side views of octameric 2-D aggregates (amide and hydroxyl hydrogen-bonds) 5-β. Non-polar hydrogen atoms have been omitted for clarity. Atoms in amide groups have been represented with red (oxygen), blue (nitrogen) and grey (carbon) spheres. Although compound 5 is rather insoluble in methanol, the low concentration required for CD spectroscopy, 2.17 mM in this case, allowed the spectrum to be recorded in this solvent. Thus, the normalized CD spectra (Figure 7c) show that while compound 5 presents a band in methanol solution, the spectrum for the xerogel is bisignate with zero crossing at 205 nm, which is consistent with the formation of a curved vertical aggregate. However, both predicted αand β-type structures Figure 8. ( a ) side view of central 6 molecules in octameric 1-D aggregate (amide hydrogen-bonds) 5-α . ( b ) side views of octameric 2-D aggregates (amide and hydroxyl hydrogen-bonds) 5-β . Non-polar hydrogen atoms have been omitted for clarity. Atoms in amide groups have been represented with red (oxygen), blue (nitrogen) and grey (carbon) spheres. 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