catalysts

Article Urea Activation by an External Brønsted Acid: Breaking Self-Association and Tuning Catalytic Performance

Isaac G. Sonsona 1,2 ID , Eugenia Marqués-López 1 ID , Marleen Häring 2, David Díaz Díaz 2,3,* and Raquel P. Herrera 1,* ID

1 Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH) CSIC-Universidad de Zaragoza, C/ Pedro Cerbuna 12, 50009 Zaragoza, Spain; [email protected] (I.G.S.); [email protected] (E.M.-L.) 2 Institut für Organische Chemie, Universität Regensburg Universitätsstr. 31, 93053 Regensburg, Germany; [email protected] 3 Institute of Advanced Chemistry of Catalonia-Spanish National Research Council (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain * Correspondence: [email protected] (D.D.D.); [email protected] (R.P.H.); Tel.: +49-941-943-4373 (D.D.D.); Tel.: +34-976-761-190 (R.P.H.)


Received: 8 July 2018; Accepted: 25 July 2018; Published: 28 July 2018


Abstract: In this work, we hypothesize that Brønsted acids can activate urea-based catalysts by diminishing its self-assembly tendency. As a proof of concept, we used the asymmetric Friedel–Crafts alkylation of indoles with nitroalkenes as a benchmark reaction. The resulting 3-substituted indole derivatives were obtained with better results due to cooperative effects of the chiral urea and a Brønsted acid additive. Such synergy has been rationalized in terms of disassembly of the supramolecular catalyst aggregates, affording a more acidic and rigid catalytic complex.

Keywords: Brønsted acids; Friedel-Crafts; organocatalysis; self-association; synergy; urea

1. Introduction Asymmetric organocatalysis has become a powerful synthetic strategy over the last decade, being crucial for the development of new catalytic processes [1–13]. Among different families of organocatalysts [14], those acting by hydrogen bond interactions represent a noteworthy part of the overall developed organocatalysts [15–17]. One of the main organocatalytic structures covering this large group are (thio)urea derivatives [18–34]. After the pioneering work of Curran’s group on the use of urea as an organocatalyst [35,36], a number of considerable efforts have been devoted to the design and synthesis of new (thio)urea structures as suitable catalysts for a series of important enantioselective processes [18–34]. It is remarkable that the works reported by Etter’s group, where they were able to get co-crystal complexes with a urea and a variety of hydrogen bond acceptors, were the real starting point for the development of this field [37–40]. Most of the works in this field have so far focused on the development of more reactive catalytic systems in order to overcome disadvantages exhibited by organocatalysis [41], such as the necessity of high catalyst loadings and ensuing low turnover rates [42]. In this sense, progress has been made on modification of the (thio)ureas skeleton in order to increase their acidity. Within this context, more efficient catalysts were prepared, on introducing internal acidic elements (Figure1). For instance, taking our catalyst 1a [43–51] as a model, subsequent analogues 2 [52], 3 [53] and 4 [54] were designed and have been proved to increase catalytic activity. Using this approach, the authors changed the most

Catalysts 2018, 8, 305; doi:10.3390/catal8080305 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 305 2 of 21 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 21 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 21 changed the most acidic moiety of the model catalyst (i.e., 3,5-bis-CF3-phenyl group) for different acidicchanged moiety the most of the acidic model moiety catalyst of (i.e., the 3,5-bis-CFmodel catalyst3-phenyl (i.e., group) 3,5-bis-CF for different3-phenyl acidic group) moieties, for different while acidic moieties, while retaining the aminoindanol structure (Figure 1) [55,56]. retainingacidic moieties, the aminoindanol while retaining structure the aminoindanol (Figure1)[55 ,structure56]. (Figure 1) [55,56].

Figure 1. Comparative variation of acidity in (thio)urea structures. Figure 1. Comparative variation of acidity in (thio)urea structures. Figure 1. Comparative variation of acidity in (thio)urea structures. In this respect, Sigman and co-workers demonstrated that both the reaction rate and the In this respect, Sigman and co-workers demonstrated that both the reaction rate and the enantioselectivityIn this respect, could Sigman be correlated and co-workers to catalyst demonstrated acidity and that it could both be the efficiently reaction rate used and for the enantioselectivity could be correlated to catalyst acidity and it could be efficiently used for the enantioselectivitytuning and designcould of new be catalyst correlated structures to catalyst for hydrogen-bond-catalyzed acidity and it could be efficiently enantioselective used for the reactions tuning tuning and design of new catalyst structures for hydrogen-bond-catalyzed enantioselective reactions and[57]. design of new catalyst structures for hydrogen-bond-catalyzed enantioselective reactions [57]. [57]. Among the the most most appealing appealing organocatalyzed organocatalyzed reactions, reactions, the the Friedel-Crafts Friedel-Crafts alkylation alkylation reaction reaction has Among the most appealing organocatalyzed reactions, the Friedel-Crafts alkylation reaction hasreceived received great great attention attention and and is a is very a very efficient efficient strategy strategy for for C–C C–C bond bond formation formation [ 58[58–61].–61]. BasedBased on has received great attention and is a very efficient strategy for C–C bond formation [58–61]. Based on our previous experience using (thio)urea catalysts [43–51,62–66], [43–51,62–66], we reported a pioneering concept our previous experience using (thio)urea catalysts [43–51,62–66], we reported a pioneering concept regarding the the cooperative cooperative effect effect between between a Brønsted a acid Brønsted additive acid and additivea chiral thiourea and a organocatalyst chiral thiourea [45]. regarding the cooperative effect between a Brønsted acid additive and a chiral thiourea organocatalystIn this work, we [45]. hypothesize In this work, that we similar hypothesize beneficial that effects similar could beneficial take place effects with could urea organocatalyststake place with organocatalyst [45]. In this work, we hypothesize that similar beneficial effects could take place with ureain combination organocatalysts with a in Brønsted combination acid, which with could a Brønsted activate acid, the urea which by could diminishing activate significantly the urea by its urea organocatalysts in combination with a Brønsted acid, which could activate the urea by diminishingself-association significantly tendency and, its self-association therefore, increasing tendency its acidity. and, therefore, increasing its acidity. diminishing significantly its self-association tendency and, therefore, increasing its acidity.

2. Results and Discussion 2. Results and Discussion 2.1. Cooperative Effect in the Mixture (Urea Catalyst + Brønsted Acid) 2.1. Cooperative Effect in the Mixture (Urea Catalyst + Brønsted Acid) 2.1. Cooperative Effect in the Mixture (Urea Catalyst + Brønsted Acid) We havehave previouslypreviously studiedstudied bothboth (thio)urea-catalyzed(thio)urea-catalyzed Friedel-Crafts-typeFriedel-Crafts-type alkylation reactions We have previously studied both (thio)urea-catalyzed Friedel-Crafts-type alkylation reactions (Figure2 2))[ [43–51].43–51]. However, the poorer results obtained with the ureas in comparison with thiourea (Figure 2) [43–51]. However, the poorer results obtained with the ureas in comparison with thiourea analogues made us discard this family of structuresstructures inin successivesuccessive studies.studies. The unfavorable results foundanalogues with made ureas us have discard been this explained family basedof structures on the mostin successive acidic N-H studies. protons The in unfavorable the thioureas results [67] found with ureas have been explained based on the most acidic N-H protons in the thioureas [67] found with ureas have been explained based on the most acidic N-H protons in the thioureas [67] and their less tendency to self-aggregate due due to lower electron density on on the the sulfur sulfur atom atom [68–70]. [68–70]. and their less tendency to self-aggregate due to lower electron density on the sulfur atom [68–70]. Hence, it is not surprising to findfind more thiourea-basedthiourea-based organocatalysts than ureas reported in the Hence, it is not surprising to find more thiourea-based organocatalysts than ureas reported in the literature [[16].16]. literature [16].

Figure 2. Thiourea and urea catalysts previously tested in Friedel-Crafts-type alkylation reactions. Figure 2. Thiourea and urea catalysts previously tested in Friedel-Crafts-type alkylation reactions.reactions. As a matter of fact, self-association of ureas has been identified as the major drawback for As a matter of fact, self-association of ureas has been identified as the major drawback for hydrogen-bondingAs a matter of organocatalysis fact, self-association (Figure of ureas 3, I) has [71,72]. been Our identified previous asthe results major obtained drawback with for hydrogen-bonding organocatalysis (Figure 3, I) [71,72]. Our previous results obtained with hydrogen-bondingthioureas motivated organocatalysis us to investigate (Figure whether3, I)[71 , the72]. Our addition previous of a results Brønsted obtained acid with hampers thioureas the thioureas motivated us to investigate whether the addition of a Brønsted acid hampers the motivatedhydrogen-bonding us to investigate pattern whether of the urea, the addition allowing of an a Brønsted equilibrium acid with hampers free the molecules hydrogen-bonding in solution hydrogen-bonding pattern of the urea, allowing an equilibrium with free molecules in solution and/or smaller and soluble aggregates. In addition, molecules of “free” urea could be activated by a and/or smaller and soluble aggregates. In addition, molecules of “free” urea could be activated by a

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Catalysts 2018, 8, x FOR PEER REVIEW 3 of 21 pattern of the urea, allowing an equilibrium with free molecules in solution and/or smaller and soluble aggregates. In addition, molecules of “free” urea could be activated by a stronger proton donor (II), stronger proton donor (II), disrupting the interactions between neighboring urea molecules and, disrupting the interactions between neighboring urea molecules and, thus, increasing their efficiency thus, increasing their efficiency as a hydrogen-bonding organocatalyst (Figure 3). In principle, the as a hydrogen-bonding organocatalyst (Figure3). In principle, the activation mode III should also be activation mode III should also be considered, since it was proposed by others when using thiourea considered, since it was proposed by others when using thiourea catalysts and carboxylic acids [73–78]. catalysts and carboxylic acids [73–78].

Figure 3. Mechanistic hypothesis. Figure 3. Mechanistic hypothesis.

To this aim, we explored in detail the Friedel-Crafts alkylation of indole 6a with nitrostyrene 7a To this aim, we explored in detail the Friedel-Crafts alkylation of indole 6a with nitrostyrene 7a using urea catalyst 1b, both in the absence and in the presence of an external Brønsted acid (Scheme using urea catalyst 1b, both in the absence and in the presence of an external Brønsted acid (Scheme1). 1).

Scheme 1. Exploring the urea-catalyzed Friedel-Crafts-type alkylation reaction in the presence of a Scheme 1. Exploring the urea-catalyzed Friedel-Crafts-type alkylation reaction in the presence of a Brønsted acid. Brønsted acid.

We were delighted to observe a positive effect when using 1b in the presence of acid We were delighted to observe a positive effect when using 1b in the presence of acid (±)-mandelic ()-mandelic acid (9a). Interestingly, the enantiomer S (product 8aa) obtained when using complex 9a 8aa 1b ± acid1b ( ()-mandelic). Interestingly, acid (9a the) was enantiomer the same S when (product using only) obtained urea 1b when. using complex ( )-mandelic acid (9a) was the same when using only urea 1b. At this point, we decided to explore the different parameters that could influence this activation At this point, we decided to explore the different parameters that could influence this activation mode. Thus, we first studied the effect of the solvent, since polarity might play an important role in mode. Thus, we first studied the effect of the solvent, since polarity might play an important role in governing the interaction between catalysts and reagents (Table 1). governing the interaction between catalysts and reagents (Table1).

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TableTable 1. 1.Screening Screeningof ofcatalytic catalyticcomplex complex1b 1b·(·(±)-9a in different solvents.solvents. a.

Entry SolventEntry Solvent Time Time (Days) (Days) Yield (%) Yieldb (%)ee (%)b c ee (%) c 1 d CHCl3 d 3 46 36 1 CHCl3 3 46 36 2 CHCl32 CHCl3 3 3 88 88 55 55 3 d Toluene3 d Toluene 3 3 10 10 18 18 4 Toluene4 Toluene 3 3 38 38 42 42 5d Xylene 4 18 28 5d Xylene 4 18 28 6 Xylene 4 95 47 6 Xylene d 4 e 95 47 7 CH3CN 10 n.r. _ d f e 7 CH3CN8 CH3CN 10 4 n.d. n.r. 8 _ d e 8 CH3CN9 THF 4 10 n.r. n.d. f _ 8 e 9 d THF 10 THF 10 10 n.r. n.r. e _ _ d AcOEt 10 n.r. e _ 10 THF11 10 n.r. e _ 12 AcOEt 10 n.r. e _ 11 d AcOEt 10 n.r. e _ a12Unless specified, AcOEt see Experimental Section; b After 10 isolation by column chromatography; n.r. e c Determined by chiral _ d HPLCa Unless analysis specified, (Chiralpak see IA, Experimental Hex:iPrOH 90:10, Section; 1 mL/min); b AfterReaction isolation performed by column in the absence chromatography; of mandelic acid; c e n.r. = Not reaction observed; f n.d. = Not determined. Determined by chiral HPLC analysis (Chiralpak IA, Hex:iPrOH 90:10, 1 mL/min); d Reaction Aperformed lack of reactivityin the absence in polar of mandelic solvents, acid; with e n.r. high = Not complexing reaction observed; character, f n.d. was = Not observed determined. even when the solubility of the urea was certainly higher in those solvents (Table1, entries 7–12). Thus, the rupture or weakeningA lack of ofreactivity the hydrogen in polar interactions solvents, with between high the complexing catalyst and character, the reagents was seemsobserved to be even higher when in thesethe solubility solvents, of hampering the urea was the reaction.certainly Inhigher sharp in contrast, those solvents good results (Table were 1, entries achieved 7–12). on usingThus, lessthe rupture or weakening of the hydrogen interactions between the catalyst and the reagents seems to be coordinating solvents, such as toluene and xylene (Table1, entries 4–6). Finally, CHCl 3 provided the besthigher results in these (Table solvents,1, entry hampering 2) and, we hencethe reaction. selected In this sharp solvent contrast, for further good results studies. were It is achieved remarkable on that,using in less all cases,coordinating better results solvents, were such obtained as toluene in terms and of enantioselectivityxylene (Table 1, entries and reactivity 4–6). Finally, using catalyst CHCl3 1bprovidedin the presencethe best results of mandelic (Table acid 1, entry (±)-9a 2)(e.g. and, entries we hence 2, 4, selected 6, 8 vs. entriesthis solvent 1, 3, 5, for 7). further Interestingly, studies. the It sameis remarkable enantiomeric that, product in all cases,S was obtained better results with thiourea were obtained1a and urea in terms1b, as of well enantioselectivity as with a mixture and of  ureareactivity1b and using Brønsted catalyst acid 1b (in± )-the9a .presence These results of mandelic suggest acid that ( urea)-9a catalyst,(e.g. entries and 2, not 4, 6, the 8 Brønstedvs. entries acid, 1, 3, 5, 7). Interestingly, the same enantiomeric product S was obtained with thiourea 1a and urea 1b, as drives the enantioselectivity of the process. well as with a mixture of urea 1b and Brønsted acid ()-9a. These results suggest that urea catalyst, Furthermore, we extended the exploration of this catalytic system using different Brønsted acids. Schemeand not 2the shows Brønsted the results acid, drives obtained the withenantioselectivity representative of derivativesthe process. of acetic acid as the structural Furthermore, we extended the exploration of this catalytic system using different Brønsted core of the mandelic acid (±)-9a. acids.The Scheme results 2 shown shows in the Scheme results2 revealed obtained a cooperative with representative effect between derivatives urea 1b ofand acetic all external acid as acids the structural core of the mandelic acid ()-9a. used, although without a clear correlation with the pKa of the acid (Scheme S1). (R)- and (S)-mandelic acid 9a were tested in order to explore the match and mismatch effect. In both cases, the S enantiomer and the same results were obtained, suggesting that chirality is induced only by catalyst 1b. With this experiment, we discarded activation mode III (Figure3), since in such case the chirality of the acid would be expected to influence the absolute configuration of the final products. In contrast, these results are in agreement with the activation mode II (Figure3), where Brønsted acid could be activating urea 1b. Remarkably, (S)-9c and (±)-9d also presented similar results than (±)-9a. However, further studies were done using mandelic acid since, being the cheaper acid, its structure seems to be one of the most influential on urea self-aggregation, providing good results in terms of enantioselectivity and reactivity. Table2 summarizes the effect of temperature on the behavior of the complex 1b·(±)-mandelic acid (9a).

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Scheme 2. Screening of acids using urea catalyst 1b.

The results shown in Scheme 2 revealed a cooperative effect between urea 1b and all external acids used, although without a clear correlation with the pKa of the acid (Scheme S1). (R)- and (S)-mandelic acid 9a were tested in order to explore the match and mismatch effect. In both cases, the S enantiomer and the same results were obtained, suggesting that chirality is induced only by catalyst 1b. With this experiment, we discarded activation mode III (Figure 3), since in such case the chirality of the acid would be expected to influence the absolute configuration of the final products. In contrast, these results are in agreement with the activation mode II (Figure 3), where Brønsted acid could be activating urea 1b. Remarkably, (S)-9c and ()-9d also presented similar results than ()-9a. However, further studies were done using mandelic acid since, being the cheaper acid, its structure seems to be one of the most influential on urea self-aggregation, providing good results in terms of enantioselectivity and reactivity. Table 2 summarizes the effect of temperature on the behavior of the complex 1b·()-mandelic Scheme 2. Screening of acids using urea catalyst 1b. acid (9a). Scheme 2. Screening of acids using urea catalyst 1b.

The results shown in Scheme 2 revealed a cooperative effect betweena urea 1b and all external TableTable 2.2. EffectEffect ofof temperaturetemperature ofof modelmodel reaction.reaction. a acids used, although without a clear correlation with the pKa of the acid (Scheme S1). (R)- and (S)-mandelic acid 9a were tested in order to explore the match and mismatch effect. In both cases, the S enantiomer and the same results were obtained, suggesting that chirality is induced only by catalyst 1b. With this experiment, we discarded activation mode III (Figure 3), since in such case the chirality of the acid would be expected to influence the absolute configuration of the final products. In contrast, these results are in agreement with the activation mode II (Figure 3), where Brønsted acid could be activating urea 1b. Remarkably,◦ (S)-9c and ()-9d also presentedb similarc results than Entry Acid Entry T (°C) Acid T ( C) Time Time(Days) (Days) Yield Yield (%) (%)ee b (%) ee (%) c ()-9a. However, further studies were done using mandelic acid since, being the cheaper acid, its 1 - 1 15 - 15 5 5 24 24 46 46 structure seems to be one of the dmost influential on urea self-aggregation, providing good results in 2 9a d 2 15 9a 15 4 4 60 60 62 62 terms of enantioselectivity3 and9a reactivity.e 15 4 77 60 3 9a e 15 4 77 60 Table 2 summarizes4 the effect9a f of temperature15 on 4 the behavior 82of the complex 57 1b·()-mandelic 4 9a f 15 4 82 57 acid (9a). 5 - -25 5 15 57 5 - 6 -259a e -25 5 5 23 15 68 57 e 6 9a -25 5 a 23 68 a To a mixture of catalyst 1bTable(20 mol%, 2. Effect 0.02 mmol), of temperature (±)-mandelic of model acid 9a reaction.(20 mol%, 0.02 mmol), and nitroalkene a  7a To(0.1 a mmol)mixture at of 15 catalyst or −25 ◦ C,1b indole (20 mol%,6a (0.15 0.02 mmol) mmol), was ( added;)-mandelicb After acid isolation 9a (20 by mol%, column 0.02 chromatography; mmol), and cnitroalkeneDetermined by7a chiral (0.1 mmol) HPLC analysis at 15 or (Chiralpak −25 °C, IA, indole Hex: i6aPrOH (0.15 90:10, mmol) 1 ml/min); was added;d 2 equiv. b After of acid isolation (0.04 mmol); by ecolumn3 equiv. chromatography; of acid (0.06 mmol); cf Determined4 equiv. of acid by (0.08 chiral mmol). HPLC analysis (Chiralpak IA, Hex:iPrOH 90:10, 1 ml/min); d 2 equiv. of acid (0.04 mmol); e 3 equiv. of acid (0.06 mmol); f 4 equiv. of acid (0.08 mmol). The results demonstrated that the effect of Brønsted acid on the urea-based catalysis is maintained even at lower temperatures (15 and −25 ◦C), although a gradual drop in the reaction yield was observed. On the other hand, it seems that the effect of the external Brønsted acid decreases at a b c lowerEntry temperature, Acid where T presumably(°C) the Time formation (Days) of urea aggregates Yield (%) prevails and increases ee (%) the insolubility1 of the- acid. 15 5 24 46 d At2 this point,9a and since15 our goal was to test 4 this alternative approach 60 to improve the efficiency 62 of e the urea3 catalyst,9a we explored15 the substrate scope 4 at room temperature (Scheme 77 3). 60 4 9a f 15 4 82 57 5 - -25 5 15 57 6 9a e -25 5 23 68 a To a mixture of catalyst 1b (20 mol%, 0.02 mmol), ()-mandelic acid 9a (20 mol%, 0.02 mmol), and nitroalkene 7a (0.1 mmol) at 15 or −25 °C, indole 6a (0.15 mmol) was added; b After isolation by column chromatography; c Determined by chiral HPLC analysis (Chiralpak IA, Hex:iPrOH 90:10, 1 ml/min); d 2 equiv. of acid (0.04 mmol); e 3 equiv. of acid (0.06 mmol); f 4 equiv. of acid (0.08 mmol).

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The results demonstrated that the effect of Brønsted acid on the urea-based catalysis is maintained even at lower temperatures (15 and −25 °C), although a gradual drop in the reaction yield was observed. On the other hand, it seems that the effect of the external Brønsted acid decreases at a lower temperature, where presumably the formation of urea aggregates prevails and increases the insolubility of the acid. Catalysts 2018At this, 8, 305point, and since our goal was to test this alternative approach to improve the efficiency 6 of 21 of the urea catalyst, we explored the substrate scope at room temperature (Scheme 3).

Scheme 3. Scope of the Friedel-Crafts alkylation reaction. The purple values are obtained in the Scheme 3. Scope of the Friedel-Crafts alkylation reaction. The purple values are obtained in the presence of 1b·(±)-9a and the black values are obtained in the absence of acid (±)-9a. The yields are presence of 1b·(±)-9a and the black values are obtained in the absence of acid (±)-9a. The yields are obtained after isolation by column chromatography and the ee is determined by chiral HPLC obtained after isolation by column chromatography and the ee is determined by chiral HPLC analysis. analysis.

InIn order order to to compare compare the the resultsresults obtained obtained with with 1b·HA1b·HA andand the thesole sole catalyst catalyst 1b, the1b reactions, the reactions were were stoppedstopped after after three three days. days. The The results results shown shown in in Scheme Scheme3 3indicate indicate that that the the working working hypothesishypothesis was valid usingvalid different using different substituted substituted nitroalkenes nitroalkenes7a–i and 7a–i indoles and indoles6a–d, 6a–d affording, affording the corresponding the corresponding adducts 8 adducts 8 with higher yields and enantioselectivities compared to reactions in the absence of an with higher yields and enantioselectivities compared to reactions in the absence of an external acid. external acid. The absolute configuration of adducts 8 was assigned by comparison of their optical The absolute configuration of adducts 8 was assigned by comparison of their optical rotation with rotation with those reported in the literature for the same compounds. those reported in the literature for the same compounds. 2.2. Effect of Brønsted Acid on Urea Aggregation and Mechanistic Hypothesis 2.2. Effect of Brønsted Acid on Urea Aggregation and Mechanistic Hypothesis The foregoing results suggest two important facts to be considered when adding an external acidThe to foregoingthe reaction results medium: suggest first, the two plausible important rupture facts of to self-assembled be considered ureas when byadding the acid; an and external acidsecond, to the the reaction activation medium: of the “free” first, urea the through plausible coordination ruptureof by self-assembledthe acid. The fragmentation ureas by the of urea acid; and second,aggregates, the activation affording of a thehigher “free” concentration urea through of “free” coordination urea (or by smaller the acid. soluble The aggregates) fragmentation in of ureasolution, aggregates, could explain affording the aenhancement higher concentration of the reaction of “free”yield, but urea not (or necessarily smaller solublean increase aggregates) of the in solution,ee. However, could explain a concurrent the enhancement activation of of the the urea reaction with yield, the disassembly but not necessarily process could an increase positively of the ee. However,influence a both concurrent the yield activation and the enantioselectivity of the urea with of the the disassembly process, as shown process in Scheme couldpositively 2. influence both theWith yield this and in mind the enantioselectivity and in order to gain of additional the process, insight as shown on the coordination in Scheme2. mode between the Brønsted acid and the urea, we tested some additional key catalysts and additives (Table 3). With this in mind and in order to gain additional insight on the coordination mode between the Brønsted acid and the urea, we tested some additional key catalysts and additives (Table3).

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a TableTable 3. Effect 3. Effect of the of nature the nature of the catalyticof the catalytic complex. complex.a a TableTable 3. Effect 3. Effect of the of nature the nature of the of catalytic the catalytic complex. complex. a

b c Entry Entry Catalyst Catalyst Acid Yield (%) Yieldb (%)ee b (%) eec (%) c EntryEntry Catalyst Catalyst Acid Acid Yield Yield (%) (%) b ee (%) ee (%) c 1 1b - 46 36 1 1 1b1 1b 1b - - 4646 46 36 36 36 2 2 1b 1b (±)-)-9a 8888 55 55 2 2 1b 1b ()-9a( )-9a 88 88 55 55

3 3 1b 1b 8383 48 48 3 3 1b 1b 83 83 48 48

4 1b 57 40 4 4 1b4 1b 1b 5757 57 40 40 40

5 1b 55 37 5 5 1b5 1b 1b 5555 55 37 37 37

6 1b MeOH 68 40 6 6 1b6 1b 1b MeOH MeOH MeOH 6868 68 40 40 40 7 1c ()-9a 18d (13) d Rac. (Rac.)d d 7 7 1c 7 1c 1c ()-9a( ±)-)-9a 1818 (13) (13)d18 (13) Rac. d (Rac.) Rac.d (Rac.) Rac. (Rac.) d 8 1d ()-9a d 25d (7) d d Rac. (Rac.)d d 8 8 1d8 1d 1d ()-9a( ±)-)-9a 2525 (7) (7)25 (7)Rac. d (Rac.) Rac. (Rac.) Rac. (Rac.) d a a b b c c Unlessa Unless specified, specified, see Experimental see Experimental Section; Section; After b After isolation isolation by column by column chromatography; chromatography; c a Unless specified,Unless specified, see Experimental see Experimental Section; b After Section;isolation by column After isolation chromatography; by columnc Determined chromatography; by chiral Determined by chiral HPLC analysis (Chiralpak IA, Hex:iPrOH 90:10, 1 ml/min);d d values in HPLCDeterminedDetermined analysis by (Chiralpak chiral by chiral HPLC IA, Hex: HPLC analysisiPrOH analysis 90:10, (Chiralpak 1 ml/min); (Chiralpak IA,d values Hex: IA, iPrOH Hex: in parenthesisiPrOH 90:10, 90:10, 1have ml/min); been 1 ml/min); obtained values din values the in in parenthesis have been obtained in the absence of acid. absenceparenthesisparenthesis of acid. have beenhave obtainedbeen obtained in the in absence the absence of acid. of acid.

AdditionalAdditional important important aspects aspects can can also also be be concluded concluded from from the the results results disclosed disclosed in in TableTable3 .3. For AdditionalAdditional important important aspects aspects can also can bealso concluded be concluded from fromthe results the results disclosed disclosed in Table in Table 3. For 3. For For instance,instance, thethe presence of an an OH OH group group in in the the skeleton skeleton of 1b of 1bwithwith cis configurationcis configuration seems seems to be tocrucial instance,instance, the presence the presence of an ofOH an group OH group in the in skeleton the skeleton of 1b ofwith 1b withcis configuration cis configuration seems seems to be tocrucial be crucial be crucialfor both for the both enantioselectivity the enantioselectivity and the and reactivity the reactivity of the process of the process (compare (compare entry 2 entryagainst 2 entries against 7 and for bothfor theboth enantioselectivity the enantioselectivity and the and reactivity the reactivity of the of process the process (compare (compare entry entry 2 against 2 against entries entries 7 and 7 and entries8), 7which and 8), is in which good is agreement in good agreement with our previous with our observations previous observations with thioureas with [45]. thioureas When additives [45]. 8), which8), which is in goodis in good agreement agreement with withour previous our previous observations observations with withthioureas thioureas [45]. When[45]. When additives additives When9h additives, 9i or MeOH9h, 9i wereor MeOH used (entries were used 4–6), (entries the results 4–6), were the similar results to were those similar obtained to those with obtainedurea 1b alone 9h, 9i9h or, 9iMeOH or MeOH were wereused used(entries (entries 4–6), 4–6),the results the results were weresimilar similar to those to those obtained obtained with withurea 1burea alone 1b alone with(entry urea 1b 1) alonein terms (entry of selectivity, 1) in terms although of selectivity, a slightly although better yield a slightly was obtained better yield with wasthe additives. obtained This (entry(entry 1) in terms1) in terms of selectivity, of selectivity, although although a slightly a slightly better better yield yieldwas obtained was obtained with withthe additives. the additives. This This with thesupports additives. the scenario This supports in which the the scenario additive in whichcould break the additive urea interactions, could break generating urea interactions, more “free” supportssupports the scenario the scenario in which in which the additive the additive could could break break urea ureainteractions, interactions, generating generating more more “free” “free” generatingurea, although more “free” in urea,the absence although of inan the additional absence ofactivation, an additional since activation, only the OH since of onlythe carboxylic the OH of acid urea, urea,although although in the in absence the absence of an of additional an additional activation, activation, since sinceonly onlythe OH the ofOH the of carboxylic the carboxylic acid acid the carboxylicseems to acidbe responsible seems to be for responsible the activation for the of activationthe urea catalyst. of the urea The catalyst. effect observed The effect with observed catalysts 1c seemsseems to be toresponsible be responsible for the for activation the activation of the of urea the ureacatalyst. catalyst. The effectThe effect observed observed with withcatalysts catalysts 1c 1c with catalystsand 1d was1c andonly1d evidentwas only in the evident reactivity in the of reactivitythe process, of thesince process, both catalysts since both alone catalysts afforded alone racemic and 1dand was 1d onlywas onlyevident evident in the in reactivity the reactivity of the of process, the process, since sinceboth bothcatalysts catalysts alone alone afforded afforded racemic racemic affordedproducts racemic (entries products 7 and (entries 8). With 7 and these 8). With results, these we results, were we also were able also to able discard to discard the possible the possible mode of productsproducts (entries (entries 7 and 7 8).and With 8). Withthese these results, results, we were we werealso ablealso toable discard to discard the possible the possible mode mode of of modeactivation of activation in which in which both both urea urea and andacid acidsimultaneously simultaneously activate activate nitrostyrene, nitrostyrene, as previously as previously proposed activationactivation in which in which both bothurea andurea acid and simultaneouslyacid simultaneously activate activate nitrostyrene, nitrostyrene, as previously as previously proposed proposed proposedby other by other authors authors [79], [since79], since in this in case this the case yield the yieldshould should be higher be higher than thanthat achieved that achieved with withthe use of by otherby other authors authors [79], since[79], sincein this in case this thecase yield the yield should should be higher be higher than thanthat achievedthat achieved with withthe use the of use of the useacid of ( acid)-9a (± alone)-9a alone(Scheme (Scheme 1, 30%).1, 30%). acid (acid)-9a ( alone)-9a alone (Scheme (Scheme 1, 30%). 1, 30%). Next,Next, we analyzed we analyzed the effect the effect on both on eeboth and ee reaction and reaction yield usingyield using progressive progressive amounts amounts of (±)- of9a ()-9a Next,Next, we analyzed we analyzed the effect the effect on both on bothee and ee reactionand reaction yield yield using using progressive progressive amounts amounts of ( )-of9a ( )-9a with respectwith respect to urea to 1burea(0.02 1b mmol)(0.02 mmol) (Figure (Figure4). 4). with withrespect respect to urea to 1burea (0.02 1b (0.02mmol) mmol) (Figure (Figure 4). 4).

Catalysts 2018, 8, x FOR PEER REVIEW 8 of 21 Catalysts 2018, 8, 305 8 of 21 Catalysts 2018, 8, x FOR PEER REVIEW 8 of 21

Figure 4. Effect of the addition of acid ()-9a using 20 mol% of urea 1b. FigureFigure 4.4. EffectEffect ofof thethe additionaddition ofof acidacid ((±)-9a using 20 mol% of urea 1b.. The results indicated that ca. 20–40 mol% of acid is optimal for the activation effect. Higher amountsTheThe resultsofresults acid indicated furtherindicated increased that that ca. ca. 20–40 the 20–40 mol%yield, mol% ofbut acid causedof isacid optimal ais slightly optimal for the decrease for activation the activationin effect.the ee Higherof effect. the product, amounts Higher ofbecauseamounts acid further the of acidactivation increased further of theincreased the yield, reaction butthe causedthroughyield, but a the slightly caused acid decreasealone a slightly could in decrease the also ee take of thein place,the product, ee givingof the because product,rise to the a activationracemicbecause product.the of theactivation reaction of through the reaction the acid through alone could the acid also alone take place, could giving also take rise toplace, a racemic giving product. rise to a racemicSince product. NMR NMR techniques techniques can can provide provide important important information information on self-assembly on self-assembly processes processes in solution in andsolution inSince order and NMR to in support order techniques the to supportfragmentation can provide the fragmentation of urea important aggregates of information urea in the aggregates presence on self-assembly of in acid, the different presence processes1 H-NMR of acid, in experimentsdifferentsolution 1 andH-NMR were in order performed.experiments to support We were thus the performed. studied fragmentation the We variation thus of ureastudied in the aggregates signalsthe variation of in the the ureain presencethe catalyst signals 1b of of after acid, the different 1H-NMR experiments were performed. We thus studied the variation in the signals of the progressiveurea catalyst addition 1b after ofprogressive acid (±)-9a additionin CDCl of3 (Tableacid (4 )-and9a in Figures CDCl3 S1–S8). (Table 4 and Figures S1–S8). urea catalyst 1b after progressive addition of acid ()-9a in CDCl3 (Table 4 and Figures S1–S8). Table 4.4. EffectEffect ofof thethe acidacid onon thethe 11H NMR signals ofof thethe ureaurea catalyst.catalyst. aa Table 4. Effect of the acid on the 1H NMR signals of the urea catalyst. a CF3 CF3 O H Hb d Hc O H Hb d Hc Hd' N N CF3 Hd' N N CF3 OH H Ha OH H Ha ()-9a (±)-9a δNHa δδHHb b δHδHc c δHδHd d δHδHd’ d’ RatioRatio Integrals Integrals Entry Entry δNHa (ppm) (mmol)()-9a (mmol) (ppm) (ppm)(ppm)δHb (ppm)(ppm)δHc (ppm)(ppm)δHd (ppm)(ppm)δHd’ Urea:StandardUrea:StandardRatio Integrals Entry δNHa (ppm) 1 (mmol) 01 0 7.937 7.937 5.553(ppm) 5.553 4.691(ppm) 4.691 3.238(ppm) 3.238 2.976(ppm) 2.976 Urea:Standard 0.22:1 0.22:1 21 0.01 02 0.01 7.888 7.937 7.888 5.818 5.818 5.553 4.670 4.670 4.691 3.219 3.219 3.238 2.949 2.949 2.976 0.37:1 0.37:1 0.22:1 3 0.02 7.852 5.971 4.635 3.177 2.923 0.62:1 32 0.02 0.01 7.852 7.888 5.971 5.818 4.635 4.670 3.177 3.219 2.923 2.949 0.62:1 0.37:1 3 0.024 0.03 7.852 7.852 6.030 5.971 4.629 4.635 3.173 3.177 2.926 2.923 0.70:1 0.62:1 4 0.035 0.04 7.852 7.844 6.032 6.030 4.630 4.629 3.176 3.173 2.923 2.926 0.79:1 0.70:1 54 0.04 0.036 0.06 7.844 7.852 7.845 6.034 6.032 6.030 4.625 4.630 4.629 3.167 3.176 3.173 2.920 2.923 2.926 0.78:1 0.79:1 0.70:1 65 0.06 0.047 0.08 7.845 7.844 7.770 5.960 6.034 6.032 4.554 4.625 4.630 3.093 3.167 3.176 2.820 2.920 2.923 0.82:1 0.78:1 0.79:1 76 0.08 0.068 0.1 7.770 7.845 7.844 6.035 5.960 6.034 4.631 4.554 4.625 3.169 3.093 3.167 2.920 2.820 2.920 0.88:1 0.82:1 0.78:1 7a 0.08 7.770 5.960 4.554 3.093 2.820 0.82:1 8 To a solution 0.1 of urea 1b (0.02 7.844 mmol) in CDCl 6.0353 (0.5 mL) and 4.631 mesitylene 3.169 (0.0075 mmol), 2.920 as internal standard, 0.88:1 acid 8a ± 0.1 7.844 1 6.035 4.631 3.169 2.920 0.88:1 ( To)-9a a issolution added after of urea each measure1b (0.02 ofmmol)H NMR. in CDCl3 (0.5 mL) and mesitylene (0.0075 mmol), as internal standard,a To a solution acid ( of)- 9aurea is added1b (0.02 after mmol) each in measure CDCl3 (0.5of 1H mL) NMR. and mesitylene (0.0075 mmol), as internal Amongstandard, these acid ( NMR)-9a is spectra,added after we each only measure observed of 1H oneNMR. species of the urea due to the fact that the chemicalAmong these exchange NMR betweenspectra, we the only self-assembled observed one and species non-self-assembled of the urea due species to the fact is rapid that the on thechemical NMRAmong exchange timescale. these NMRbetween Additionally, spectra, the self-assembled we with only the observed addition and non-self-assembled one of species acid, urea of the signals speciesurea showdue is torapid sharper the onfact the peaks that NMR the in comparisontimescale.chemical exchange Additionally, with broader between with peaks the the self-assembled foundaddition when of acid, it and is mainly ureanon-self-assembled signals aggregated show sharper (see species supporting peaks is rapid in informationoncomparison the NMR Figurewithtimescale. broader S1–S8). Additionally, peaks This isfound because with when the when it addition is ureamainly is of aggregated,aggregated acid, urea the(seesignals major supporting show part sharper of information the signals peaks belongsinFigure comparison S1–S8). to the NMR-silentThiswith isbroader because (entry peaks when 1, found ratiourea integralswhenis aggregated, it is ureas:standard) mainly the aggregated major [part80]. (see of In contrast,thesupporting signals when belongsinformation urea to self-association the Figure NMR-silent S1–S8). is progressively(entryThis is 1, because ratio brokenintegrals when withurea ureas:standard) theis aggregated, addition [80]. of the acid, In majorcontrast, the integrals part when of the of urea thesignals self-association urea belongs increase to in istherelation progressively NMR-silent to the standardbroken(entry 1, with ratio (ratio the integrals integrals addition ureas:standard) ureas:standard). of acid, the integrals [80]. It was In of alsocontrast, the observed urea when increase that urea the in self-association NHrelationa signal to the of ureaisstandard progressively for a given(ratio concentration (0.02 mmol/0.5 mL CHCl ), when the equilibrium is shifted in favor of the aggregates integralsbroken with ureas:standard). the addition Itof wasacid, also the observedintegrals3 thatof the the urea NH increasea signal ofin urearelation for ato given the standard concentration (ratio a (0.02integrals mmol/0.5 ureas:standard). mL CHCl3 ),It whenwas also the observed equilibrium that is the shifted NH signalin favor of ureaof the for aggregates a given concentration (entry 1), is (0.02 mmol/0.5 mL CHCl3), when the equilibrium is shifted in favor of the aggregates (entry 1), is

Catalysts 2018, 8, 305 9 of 21 Catalysts 2018, 8, x FOR PEER REVIEW 9 of 21 sensitive(entry to 1), the is presence sensitive of to acid the presenceand is progressively of acid and highfield is progressively shifted highfieldwith the addition shifted with of acid. the additionThis is in ofagreement acid. This with is inobservations agreement made with observationsby other authors made in bydifferent other authorsself-assembly in different systems self-assembly [81,82]. Thesesystems facts could [81,82 relate]. These to factsthe presence could relate of more to the free presence molecules of more of urea free or molecules smaller ofaggregates urea or smaller in solutionaggregates and, therefore, in solution support and, therefore,the disruption support of urea the disruptionself-assembly of ureawith self-assembly the presence of with acid. the Other presence signalsof acid.of the Otherurea are signals also affected of the ureaby the are presence also affected of acid, by as the shown presence in Table of acid,4. When as shown5 equivalents in Table 4. of acidWhen are 5 addedequivalents (entry of 8), acid the are signals added of (entry the 8), urea the catalysts signals of move the urea in the catalysts opposite move direction in the opposite (to downfield).direction This (to downfield).could be in agreement This could with be in the agreement equilibrium with shifted the equilibrium to a predominant shifted toactivation a predominant of the ureaactivation molecules, of the and urea therefore, molecules, with and the therefore, ensuing withacidification the ensuing of the acidification signals. A ofmajor the signals.variation A in major ureavariation signals is in observed urea signals with is the observed addition with of 0.02 the additionmmol of of acid, 0.02 as mmol in the of catalytic acid, as inreactions, the catalytic a plateau reactions, is morea plateau or less is reached more or lessafter reached that, and after increasing that, and the increasing amount the ofamount acid does of acidnot doesstrongly not stronglyaffect the affect shiftingthe shiftingof the signals. of the signals.A DOSY A NMR DOSY experiment NMR experiment [83–85] also [83 –supports85] also supportsthe coordination the coordination of the acid of the to theacid urea, tothe since urea, it is since possible it is possible to find totwo find different two different aggregate aggregate species species in a given in a given sample sample (urea·acid (urea· acid 0.02 0.02mmol:0.02 mmol:0.02 mmol): mmol): the urea the ureaself-assembled self-assembled and andthe urea·acid the urea· acidcomplex complex (Figure (Figure 5). 5).

Figure 5. DOSY NMR experiment in CDCl3 (300 MHz). Figure 5. DOSY NMR experiment in CDCl3 (300 MHz).

We also performed a mass spectrum of the mixture urea 1b·acid ()-9a (0.02 mmol:0.02 mmol) We also performed a mass spectrum of the mixture urea 1b·acid (±)-9a (0.02 mmol:0.02 mmol) in 0.5 mL of CHCl3 (Figure 6), since ESI-MS has been incorporated as an important technique for in 0.5 mL of CHCl (Figure6), since ESI-MS has been incorporated as an important technique for mechanistic studies of 3 organic reactions [86]. In the cationic ESI spectra obtained directly from mechanistic studies of organic reactions [86]. In the cationic ESI spectra obtained directly from solution solution to the gas phase, we found different species, and among them the remarkable mass peak of to the gas phase, we found different species, and among them the remarkable mass peak of the the active complex proposed in this manuscript (catalyst 1b + mandelic acid ()-9a) (M + K = 595.1). active complex proposed in this manuscript (catalyst 1b + mandelic acid (±)-9a) (M + K = 595.1). Other superior species related to the previous one have also been found in the mixture. Interestingly, Other superior species related to the previous one have also been found in the mixture. Interestingly, we we could not observe mass from the union of two or more ureas, although we cannot discard the could not observe mass from the union of two or more ureas, although we cannot discard the presence presence of this complex in the mixture of reaction. It could be due to the impact of this technique of this complex in the mixture of reaction. It could be due to the impact of this technique that they split that they split into free molecules of urea. into free molecules of urea.

Catalysts 2018, 8, 305x FOR PEER REVIEW 10 of 21

CatalystsIntens. 2018, 8, x FOR PEER REVIEW 10 of 21 2500 427.2

Intens. 2500 427.2

2000

2000

1500 1500

443.1 443.1

10001000 O O CF3 OH CF3 OH O OK O K N N CF3 O H H N N CF3 H H O O Chemical Formula: C34H29F6KN2O5 500 Exact Mass:Chemical 698.162 Formula: C34H29F6KN2O5 Molecular Weight: 698.693 500 Exact Mass: 698.162 Molecular Weight: 698.693

595.1 682.2

595.1 682.2 698.0

573.3 698.0

573.3 0 300 350 400 450 500 550 600 650 700 750 800 m/z 0_B2\1: +MS 0 300 350 400 450 500 550 600 650 700 750 800 m/z 0_B2\1: +MS Figure 6. Cationic ESI-MS spectra experiment in CHCl3. Figure 6. Cationic ESI-MS spectra experiment in CHCl3. Figure 6. Cationic ESI-MS spectra experiment in CHCl3. Based on these evidences and the results of our previous investigations [45,46], TSI is proposed as the plausible mode of activation between Brønsted acid, urea 1b and the reagents (Figure 7). Based on these evidencesevidences andand thethe resultsresults of of our our previous previous investigations investigations [45 [45,46],,46], TSI TSI is proposedis proposed as asthe the plausible plausible mode mode of activationof activation between between Brønsted Brønsted acid, acid, urea urea1b 1band and the the reagents reagents (Figure (Figure7). 7).

Figure 7. Proposed transition states for the [ureaacid]-catalyzed Friedel-Crafts reaction.

1b·HA complex could be identified as the most reactive species due to the increased acidity of NH in ureaFigure 1b after 7. Proposed synergic transition coordination states withfor the Brønsted [ureaacid]-catalyzed acid. Furthermore, Friedel-Crafts improvement reaction. in Figure 7. Proposed transition states for the [urea·acid]-catalyzed Friedel-Crafts reaction. enantioselectivity could be attributed to the formation of a more rigid assembly (on combination of both structures1b·HA complex after breaking could beurea identified self-association) as the mostin the reactive transition species state. Thisdue modeto the of increased activation acidity of supportsNH 1b in · ureaHAthe fact complex1b that after the could observed synergic beidentified enantiomer coordination as is a the result with most of Brønsted the reactive chirality acid. species of the Furthermore, dueorganocatalyst to the increased improvement used. acidity in Furtherenantioselectivityof NH computational in urea 1b couldafter calculations synergicbe attributed could coordination shedto the light formation on with this Brønsted singular of a more mode acid. rigid of Furthermore, activation. assembly (on improvement combination of in bothenantioselectivity structures after could breaking be attributed urea self-association) to the formation in ofthe a transition more rigid state. assembly This (onmode combination of activation of 2.3. Effect of Brønsted Acids on the Stability of Urea Aggregates supportsboth structures the fact after that breakingthe observed urea enantiomer self-association) is a result in the of transition the chirality state. of the This organocatalyst mode of activation used. supports the fact that the observed enantiomer is a result of the chirality of the organocatalyst used. Further computational calculations could shed light on this singular mode of activation. Further computational calculations could shed light on this singular mode of activation. 2.3. Effect of Brønsted Acids on the Stability of Urea Aggregates

Catalysts 2018, 8, 305 11 of 21

2.3. Effect of Brønsted Acids on the Stability of Urea Aggregates

When the reaction was performed in CH2Cl2 or CHCl3 using urea 1b alone, the formation of Catalysts 2018, 8, x FOR PEER REVIEW 11 of 21 dense gel-like aggregates was observed, which was in agreement with our previous studies about the self-assemblyWhen the behaviorreaction was of these performed ureas in in CH solution2Cl2 or [CHCl47]. The3 using viscosity urea 1b of alone, the mixture the formation was visually of decreaseddense upongel-like the aggregates addition was of acid observed,9a, which which could was theoreticallyin agreement bewith in our agreement previous with studies a weakening about of thethe self-assembled self-assembly behavior network, of spontaneouslythese ureas in solution generated [47]. The by theviscosity urea of catalyst the mixture and, hence,was visually with our mechanisticdecreased assumptions upon the addition from of the acid catalytic 9a, which experiments. could theoretically This be hypothesis in agreement was with demonstrated a weakening by analyzingof the theself-assembled thermal stability, network, flow spontaneously properties andgenerated morphological by the urea features catalyst of and, the supramolecularhence, with our gel mademechanistic of urea 1b assumptionsin the absence from or the presence catalytic of experiments. various acid This additives hypothesis at different was demonstrated molar ratios by urea analyzing the thermal stability, flow properties and morphological features of the supramolecular 1b:acid (i.e. 0.1, 0.3, 0.9). Two solvents (i.e. chloroform—solvent used in the reactions—and toluene) gel made of urea 1b in the absence or presence of various acid additives at different molar ratios urea were used in this study for comparative purposes. In general, gels were transparent in appearance, 1b:acid (i.e. 0.1, 0.3, 0.9). Two solvents (i.e. chloroform—solvent used in the reactions—and toluene) althoughwere used some in systems this study prepared for comparative in chloroform purposes. were In slightlygeneral, gels translucent were transparent (Figure8 ).in Mostappearance, studies in this sectionalthough were some conducted systems prepared with gels in chloroform prepared were within slightly approximately translucent 30(Figure min 8). of theMost corresponding studies in criticalthis gelation section were concentrations conducted with (CGC) gels of prepared1b, which within were approximately previously established 30 min of the in 7 corresponding g/L (chloroform) and 3critical g/L (toluene)gelation concentrations [47]. The detrimental (CGC) of 1b effect, which of thewere acid previously additives established was considerably in 7 g/L (chloroform) more evident for theand gels 3 g/L in (toluene) chloroform [47]. than The indetrimental toluene. Therefore,effect of the and acid for additives the sake was of clarity,considerably the most more relevant evident data refereedfor the to gels the gelsin chloroform in chloroform than in are toluene. included Therefore, in this and section, for the whereas sake of mostclarity, data the derivedmost relevant from the systemsdata inrefereed toluene to arethe providedgels in chloroform in Supporting are included Information in this section, (Table S1).whereas The firstmost signdata ofderived the weakening from effectthe that systems the acid in additive toluene are has provided on the physical in Supporting gel network Information formed (Table by self-assembled S1). The first ureasign ofmolecules the weakening effect that the acid additive has on the physical gel network formed by self-assembled was a partial gel-to-sol phase transition, visible to the naked eye (Figure8B–E). In general, the amount urea molecules was a partial gel-to-sol phase transition, visible to the naked eye (Figure 8B–E). In of expelled fluid usually increased with increasing amounts of acid. general, the amount of expelled fluid usually increased with increasing amounts of acid.

Figure 8. Representative photographs of undoped gels and gels doped with different additives Figure 8. Representative photographs of undoped gels and gels doped with different additives under under different conditions: (A) Undoped gel made of 1b in CHCl3 (c = 7 g/L; 1 mL); (B–D) doped gels differentmade conditions: of 1b in CHCl(A)3 Undoped(c = 7 g/L; 1 gel mL) made and ofmandelic1b in CHCl acid 3at( cdifferent= 7 g/L; molar 1 mL); ratios (B– D1b):acid: doped (B gels) 0.9, made(C) of 1b in0.3, CHCl (D)3 0.1;(c = (E 7) g/L;doped 1 gel mL) made and of mandelic 1b in CHCl acid3 ( atc = different7 g/L; 1 mL) molar andratios benzoic1b acid:acid: (molar (B) 0.9, ratios (C) 1b 0.3,:acid (D ) 0.1; (E) doped= 0.9); gel (F) madedoped of gel1b madein CHCl of 1b3 ( cin= CHCl 7 g/L;3 ( 1c mL)= 7 g/L; and 1 benzoicmL) and acid acetic (molar acid (molar ratios 1b ratio:acid 1b =:acid 0.9); = ( F0.9);) doped gel made(G) undoped of 1b in CHClgel made3 (c =of 7 1b g/L; in toluene 1 mL) and (c = acetic 3 g/L; acid 1 mL); (molar (H) ratiodoped1b gel:acid made = 0.9); of 1b (G in) undoped toluene ( gelc = 3 made of 1bg/L;in toluene 1 mL) and (c = mandelic 3 g/L; 1 mL);acid (molar (H) doped ratio gel1b:acid made = 0.9); of 1b (Iin) doped toluene gel ( cmade= 3 g/L; of 1b 1 in mL) toluene andmandelic (c = 3 g/L; acid (molar1 mL) ratio and1b :acidacetic = acid 0.9); (molar (I) doped ratio gel 1b made:acid = of 0.9).1b in toluene (c = 3 g/L; 1 mL) and acetic acid (molar ratio 1b:acid = 0.9).

Catalysts 2018, 8, 305 12 of 21

Catalysts 2018, 8, x FOR PEER REVIEW 12 of 21 This was also accompanied by a gradual decrease of the Tgel of the remaining gel phase (Figure9 ◦ and TableThis S1) inwas comparison also accompanied with theby aT gradualgel of the decrease pristine of gelthe T madegel of the of 1bremainingalone (~60 gel phaseC). A(Figure preliminary 9 designand of Table experiments S1) in comparison with chiral with Brønsted the Tgel of acids the pristine (e.g. mandelic gel made acid) of 1bshowed alone (60 no °C). significant A preliminary differences on thedesign above-mentioned of experiments effects with when chiral usingBrønsted either acids the (e.g. racemic mandelic mixture acid) of showed any of theno significant corresponding enantiomersdifferences (Table on the S1). above-mentioned Moreover, gelation effects kinetics when using of the either doped the racemicgels was mixture also notably of any of reduced the to corresponding enantiomers (Table S1). Moreover, gelation kinetics of the doped gels was also several hours in most cases, compared to pristine gels (Table S1). notably reduced to several hours in most cases, compared to pristine gels (Table S1). In termsIn terms of the of effect the effect of different of different acids, acids, the most the mostremarkable remarkable outcome outcome was observedwas observed with with mandelic acid,mandelic which prevented acid, which gelation prevented at molar gelation ratio at ( molar1b:acid) ratio = 0.9.(1b:acid) Taking = 0.9. experiments Taking experiments with mandelic with acid and benzoicmandelic acid acid as and representative benzoic acid as examples, representative molar examples, ratios (molar1b:acid) ratios of 0.6(1b:acid) and 0.9 of 0.6 gave and similar 0.9 gave results (Tablesimilar S1). Moreover, results (Table experiments S1). Moreover, using the experiments corresponding using methyl the corresponding ester caused methyl minor ester disruption caused in the gel, suggestingminor disruption the critical in the role gel, of thesuggesting free carboxylic the critical group role in of the the disassembly free carboxylic of the group supramolecular in the aggregates.disassembly These of results the supramolecular are in good agreement aggregates. with These the favorable results are effect in good observed agreement in reactions with theusing 1b and mandelicfavorable acideffectin observed equimolar in reactions amounts. using In 1b general, and mandelic other acids acid in such equimolar as acetic, amounts. phenylacetic, In general, benzoic other acids such as acetic, phenylacetic, benzoic and lactic acids also caused destabilization of the gel and lactic acids also caused destabilization of the gel network, albeit to a lesser extent. The results network, albeit to a lesser extent. The results suggest that the acidity of the carboxylic group (e.g., suggestmandelic that the acid acidity is the ofmost the acidic carboxylic among groupthese examples) (e.g., mandelic might acidplay isa more the most important acidic role among than these examples)structural might features. play a more important role than structural features.

Figure 9. Tgel of the gel made of 1b (c = 7 g/L) in CHCl3 and the effect caused by the incorporation of Figure 9. Tgel of the gel made of 1b (c = 7 g/L) in CHCl3 and the effect caused by the incorporation of selected acids at different ratios (molar ratio 1b:acid = 0.1, 0.3, 0.9). Abbreviations: AA = acetic acid; selected acids at different ratios (molar ratio 1b:acid = 0.1, 0.3, 0.9). Abbreviations: AA = acetic acid; PAA = phenylacetic acid; BA = benzoic acid; LA = lactic acid; MA = mandelic acid; MAE = mandelic PAA = phenylacetic acid; BA = benzoic acid; LA = lactic acid; MA = mandelic acid; MAE = mandelic acid acid methyl ester. The average values of at least two independent measurements are shown. methylEstimated ester. The error average 2 °C. values of at least two independent measurements are shown. Estimated error ±2 ◦C. The decrease in thermostability of supramolecular urea aggregates upon incorporation of the Theacid decrease was also inaccompanied thermostability by a detriment of supramolecular of their mechanical urea aggregates properties, upon as evidenced incorporation by of the acidoscillatory was also rheological accompanied measurements by a detrimentof selected gels of theirprepared mechanical in the absence properties, and presence as evidenced of the by acid. For instance, dynamic frequency sweep (DFS) measurements of gels based on 1b in chloroform oscillatory rheological measurements of selected gels prepared in the absence and presence of the showed that the incorporation of small amounts of mandelic acid (i.e. molar ratio 1b:acid = 0.1) acid. For instance, dynamic frequency sweep (DFS) measurements of gels based on 1b in chloroform caused a drop in the storage modulus G’ of 1.8 times compared to the undoped gel (i.e. G’ showed(undoped) that the  incorporation30493 Pa vs. G’ of (doped) small amounts17096 Pa) of (Figure mandelic 10A). acid In (i.e.addition, molar the ratio loss1b factor:acid or = tan 0.1) δ, caused a dropwhich in the represents storage mechanical modulus dampingG’ of ~1.8 or internal times comparedfriction of the to viscoelastic the undoped system, gel increased (i.e. G’ (undoped)from ~304930.180 Pa vs. (undoped)G’ (doped) to  ~170960.239 (doped). Pa) (Figure This indicates 10A). In that addition, the material the loss becomes factor more or tan dissipativeδ, which in represents the mechanicalpresence damping of the acid. or Both internal undoped friction and of doped the viscoelastic gels were very system, brittle increased in nature, as from shown ~0.180 by dynamic (undoped) to ~0.239strain (doped). sweep This (DSS) indicates measurements that the (i.e. material gel-to-sol becomes transition more occurred dissipative between in 9–10%the presence strain for of theall acid. Bothsamples) undoped (Figure and doped 10B). Dynamic gels were time very sweep brittle (DTS) in plots nature, showing as shown constant by dynamicmoduli values strain over sweep time (DSS) within the linear regime are provided in Supporting Information (Figure S45A). In concordance with measurements (i.e. gel-to-sol transition occurred between 9–10% strain for all samples) (Figure 10B). the minor effect that acids showed on the thermostability of toluene gels, additional rheological Dynamic time sweep (DTS) plots showing constant moduli values over time within the linear regime are provided in Supporting Information (Figure S45A). In concordance with the minor effect that acids showed on the thermostability of toluene gels, additional rheological experiments also showed a lower influence on the mechanical strength of the gels prepared in toluene (Figure S45B–D). Catalysts 2018, 8, x FOR PEER REVIEW 13 of 21

Catalysts 2018experiments, 8, 305 also showed a lower influence on the mechanical strength of the gels13 prepared of 21 in toluene (Figure S45B–D).

Figure 10. (A) DFS and (B) DSS measurements of undoped gel made of 1b in CHCl3 (c = 14 g/L), and dopedFigure gel made 10. (A of) DFS1b (c and = 14 (B g/L)) DSS and measurements mandelic acid of (molarundoped ratio gel1b made:acid of = 0.1)1b in in CHCl CHCl33 (c. = 14 g/L), and doped gel made of 1b (c = 14 g/L) and mandelic acid (molar ratio 1b:acid = 0.1) in CHCl3. Finally, the observed disrupting effect of the acids on the supramolecular aggregates of 1b Finally, the observed disrupting effect of the acids on the supramolecular aggregates of 1b could also be related to changes in the microstructure of the xerogels obtained by freeze-drying the could also be related to changes in the microstructure of the xerogels obtained by freeze-drying the corresponding gels. An entangled microfibrillar network over a dense and continuous structure corresponding gels. An entangled microfibrillar network over a dense and continuous structure was was observed for updoped xerogels (Figure 11), whereas the incorporation of 10 mol% of mandelic observed for updoped xerogels (Figure 11), whereas the incorporation of 10 mol% of mandelic acid acid (with respect to 1b) induced the formation of laminar and smoother structures (Figure 11A (with respect to 1b) induced the formation of laminar and smoother structures (Figure 11A vs. vs. Figure 11B). The discontinuous appearance of the doped xerogel could explain a less-effective Figure 11B). The discontinuous appearance of the doped xerogel could explain a less-effective immobilization of solvent molecules, which is in agreement with the observed lower Tgel and immobilization of solvent molecules, which is in agreement with the observed lower Tgel and mechanical strength of the bulk material. In contrast, FE-SEM images of the corresponding xerogels mechanical strength of the bulk material. In contrast, FE-SEM images of the corresponding xerogels showed little effect on the microstructure in comparison with the undoped network (Figure 11C vs. showed little effect on the microstructure in comparison with the undoped network (Figure 11C vs. Figure 11D). It is worth mentioning that the harmful effect of acids on the stability of supramolecular gel networks was not exclusive to urea 1b. Catalysts 2018, 8, x FOR PEER REVIEW 14 of 21

CatalystsFigure 201811D)., 8, It 305 is worth mentioning that the harmful effect of acids on the stability of supramolecular14 of 21 gel networks was not exclusive to urea 1b.

FigureFigure 11. RepresentativeRepresentative FE-SEM FE-SEM images images of ofxerogels xerogels derived derived from from (A) (pristineA) pristine gel made gel made of 1b of(c 1b= 7 g/L) in CHCl3, (B) doped gel made of 1b (c = 7 g/L) and mandelic acid (molar ratio 1b:acid = 0.1) in (c = 7 g/L) in CHCl3,(B) doped gel made of 1b (c = 7 g/L) and mandelic acid (molar ratio 1b:acid = 0.1) CHCl3, (c) pristine gel made of 1b (c = 3 g/L) in toluene, (D) doped gel made of 1b (c = 3 g/L) and in CHCl3,(C) pristine gel made of 1b (c = 3 g/L) in toluene, (D) doped gel made of 1b (c = 3 g/L) and mandelicmandelic acidacid (molar(molar ratioratio 1b1b:acid:acid == 0.1)0.1) inin toluene.toluene.

3.3. MaterialsMaterials andand MethodsMethods

3.1.3.1. ExperimentalExperimental DetailsDetails

AllAll commerciallycommercially availableavailable solventssolvents and and reagentsreagents werewere usedused asas received.received. CHClCHCl33 waswas filteredfiltered throughthrough basicbasic aluminaalumina priorprior toto useuse toto avoidavoid thethe presencepresence ofof trace trace amounts amounts of of acid. acid.1 1H-NMRH-NMR spectraspectra werewere recorded recorded atat 300300 MHz.MHz. CDClCDCl33 waswas used used as as a a deuterateddeuterated solvent.solvent. ChiralChiral ureaurea catalystscatalysts werewere obtainedobtained following following literature literature procedures: procedures:1b 1b[47 ],[47],1c [ 471c], [47],1d [47 1d] and[47]1e and[87 ].1e1 H[87]. and 113HC and NMR 13C spectra NMR forspectra compounds for compounds8aa [43 ],8aa8ab [43],[88 ],8ab8ac [88],[88 ],8ac8ad [88],[88 8ad], 8ae [88],[88 8ae], 8af [88],[89 8af], 8ag [89],[90 8ag], 8ah[90],[ 888ah], 8ai[88],[88 8ai], 8ba[88],[ 438ba], 8ca[43],[47 8ca] and [47]8ba and[ 538ba] are [53] consistent are consistent with valueswith values previously previously reported reported in the in literature. the literature.

3.2.3.2. GeneralGeneral ProcedureProcedure forfor thethe 1b1b·HA·HA-Catalyzed-Catalyzed Friedel–CraftsFriedel–Crafts AlkylationAlkylation ReactionReaction ToTo aa mixture of urea urea 1b1b (20(20 mol%), mol%), ( ()-mandelic±)-mandelic acid acid 9a 9a(20(20 mol%), mol%), and and nitroalkene nitroalkene 7a–i7a (0.1–i ◦ (0.1mmol) mmol) at 25 at °C 25 inC a in test a test tube tube CHCl CHCl3 (filtered3 (filtered through through basic basic alumina, alumina, 0.5 0.5 mL) mL) was was added and thenthen indoleindole 6a–d6a–d (0.15(0.15 mmol).mmol). AfterAfter 33 days,days, thethe residueresidue waswas purifiedpurified byby liquidliquid chromatographychromatography (SiO(SiO22; hexane/EtOAc,hexane/EtOAc, 8:2) 8:2) to to obtain the desired adducts 8.. Yields andand enantioselectivitiesenantioselectivities areare reportedreported inin SchemeScheme3 .3. SpectralSpectral andand analyticalanalytical datadata forfor compoundscompounds 8 are inin agreementagreement withwith thosethose previouslypreviously reportedreported inin thethe literature.literature. ((SS)-3-(2-Nitro-1-phenylethyl)-1)-3-(2-Nitro-1-phenylethyl)-1HH-indole-indole (8aa) (8aa)[43 ].[43]. Following Following the general the procedure, general compound procedure, 8aacompoundwas obtained 8aa was after obtained 3 days ofafter reaction 3 days at of room reaction temperature at room intemperature 88% yield. in The 88% ee yield. of the The product ee of was the determinedproduct was to determined be 55% by HPLCto be 55% using by a HPLC Daicel using Chiralpak a Daicel IA columnChiralpak (n- hexane/IA columni-PrOH (n-hexane/ = 90:10,i-PrOH flow −1 −1 24 24 rate= 90:10, 1 mL flow·min rate, λ1 =mL·min 254.0 nm):, λ =τ major254.0= nm): 15.3 τ min;major =τ minor15.3 min;= 14.0 τminor min. = [14.0α]D min.= +10.7 [α]D (c =0.40, +10.7 CH (c 20.40,Cl2, 24 24 55%CH2Cl ee)2, {lit.55% [ 53ee)], {lit. [α]D [53],+ [α] 25.3D (c +0.53, 25.3 CH(c 0.53,2Cl2 CH) for2Cl (S2)-) 8aafor ,(S 88%)-8aa ee}., 88% ee}. ((SS)-3-(1-(4-Chlorophenyl)-2-nitroethyl)-1)-3-(1-(4-Chlorophenyl)-2-nitroethyl)-1HH-indole-indole (8ab)(8ab)[ [88].88]. FollowingFollowing thethe generalgeneral procedure,procedure, compoundcompound 8ab waswas obtained obtained after after 3 3days days of ofreaction reaction at room at room temperature temperature in 94% in 94%yield. yield. The ee The of the ee ofproduct the product was determined was determined to be 55% toby beHPLC 55% using by a HPLC Daicel using Chiralpak a Daicel IA column Chiralpak (n-hexane/ IA columni-PrOH −1 −1 24 (=n- 90:10,hexane/ flowi-PrOH rate 1 = mL·min 90:10, flow, λ rate= 254.0 1 mL nm):·min τmajor, λ == 20.2 254.0 min; nm): τminorτmajor = 16.8= 20.2 min. min; [α]τDminor = +1.5= 16.8 (c min.0.53, 24 20 20 [CHα]D2Cl=2, 55% +1.5 ee). (c 0.53, {lit. CH[88],2Cl [α]2,D 55% + 7.5 ee). (c {lit. 1.2, [ 88CH],2 [Clα]2D), for+ ( 7.5S)-8ab (c 1.2,, 82% CH ee}.2Cl2 ), for (S)-8ab, 82% ee}. ((SS)-3-(1-(4-Bromophenyl)-2-nitroethyl)-1)-3-(1-(4-Bromophenyl)-2-nitroethyl)-1HH-indole-indole (8ac)(8ac) [[88].88]. FollowingFollowing thethe generalgeneral procedure,procedure, compoundcompound 8ac waswas obtained obtained after after 3 3days days of ofreaction reaction at room at room temperature temperature in 95% in 95%yield. yield. The ee The of the ee of the product was determined to be 55% by HPLC using a Daicel Chiralpak IA column

Catalysts 2018, 8, 305 15 of 21

−1 (n-hexane/i-PrOH = 90:10, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 21.2 min; τminor = 17.6 min. 24 20 [α]D = −4.2 (c 0.47, CH2Cl2, 55% ee) {lit. [88], [α]D − 1.7 (c 1.0, CH2Cl2), for (S)-8ac, 90% ee}. (S)-3-(2-Nitro-1-p-tolylethyl)-1H-indole (8ad) [88]. Following the general procedure, compound 8ad was obtained after 3 days of reaction at room temperature in 80% yield. The ee of the product was determined to be 54% by HPLC using a Daicel Chiralpak IA column (n-hexane/i-PrOH = 90:10, flow −1 25 rate 1 mL·min , λ = 254.0 nm): τmajor = 14.4 min; τminor = 13.0 min. [α]D = +5.1 (c 0.43, CH2Cl2, 54% 20 ee) {lit. [88], [α]D + 16.4 (c 0.9, CH2Cl2), for (S)-8ad, 81% ee}. (S)-3-(1-(4-methoxyphenyl)-2-nitroethyl-1H-indole (8ae) [88]. Following the general procedure, compound 8ae was obtained after 3 days of reaction at room temperature in 62% yield. The ee of the product was determined to be 48% by HPLC using a Daicel Chiralpak IB column −1 (n-hexane/i-PrOH = 80:20, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 22.4 min; τminor = 24.3 min. 25 20 [α]D = +14.4 (c 0.19, CH2Cl2, 48% ee) {lit. [88], [α]D + 26.4 (c 1.1, CH2Cl2), for (S)-8ae, 81% ee}. (R)-3-(1-(2,4-dichlorophenyl)-2-nitroethyl)-1H-indole (8af) [89]. Following the general procedure, compound 8af was obtained after 3 days of reaction at room temperature in 97% yield. The ee of the product was determined to be 53% by HPLC using a Daicel Chiralpak IA column (n-hexane/i-PrOH = 90:10, −1 25 flow rate 1 mL·min , λ = 254.0 nm): τmajor = 14.1 min; τminor = 12.7 min. [α]D = +32.5 (c 0.27, CH2Cl2, 53% ee). (R)-3-(1-(2-Bromophenyl)-2-nitroethyl)-1H-indole (8ag) [90]. Following the general procedure, compound 8ag was obtained after 3 days of reaction at room temperature in 94% yield. The ee of the product was determined to be 54% by HPLC using a Daicel Chiralpak IB column (n-hexane/i-PrOH = 80:20, −1 25 flow rate 1 mL·min , λ = 254.0 nm): τmajor = 26.7 min; τminor = 18.4 min. [α]D = +56.4 (c 0.20, CH2Cl2, 22 54% ee) {lit. [90], [α]D − 99.9 (c 1.3, CH2Cl2), for (S)-8ag, 96% ee}. (S)-3-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-indole (8ah) [88]. Following the general procedure, compound 8ah was obtained after 3 days of reaction at room temperature in 68% yield. The ee of the product was determined to be 52% by HPLC using a Daicel Chiralpak IA column −1 (n-hexane/i-PrOH = 90:10, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 19.1 min; τminor = 17.2 min. 24 20 [α]D = +10.6 (c 0.46, CH2Cl2, 52% ee) {lit. [88], [α]D + 24.3 (c 1.0, CH2Cl2), for (S)-8ah, 82% ee}. (S)-3-(1-(furan-2-yl)-2-nitroethyl)-1H-indole (8ai) [88]. Following the general procedure, compound 8ai was obtained after 3 days of reaction at room temperature in 58% yield. The ee of the product was determined to be 50% by HPLC using a Daicel Chiralpak IB column (n-hexane/i-PrOH = 80:20, flow rate −1 25 1 mL·min , λ = 254.0 nm): τmajor = 16.7 min; τminor = 12.6 min. [α]D = −16.4 (c 1.24, CH2Cl2, 50% ee) 20 {lit. [88], [α]D − 78 (c 1.0, CH2Cl2, for (S)-8ai, 78% ee}. (S)-5-chloro-3-(2-nitro-1-phenylethyl)-1H-indole (8ba) [43]. Following the general procedure, compound 8ba was obtained after 3 days of reaction at room temperature in 36% yield. The ee of the product was determined to be 50% by HPLC using a Daicel Chiralpak IA column −1 (n-hexane/i-PrOH = 90:10, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 13.3 min; τminor = 12.1 min. 25 20 [α]D = −14.7 (c 0.83, CH2Cl2, 50% ee) {lit. [91], [α]D − 27.8 (c 1.1, CH2Cl2, for (S)-8ba, 90% ee}. (S)-5-fluoro-3-(2-nitro-1-phenylethyl)-1H-indole (8ca) [47]. Following the general procedure, compound 8ca was obtained after 3 days of reaction at room temperature in 43% yield. The ee of the product was determined to be 53% by HPLC using a Daicel Chiralpak IA column −1 (n-hexane/i-PrOH = 90:10, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 13.7 min; τminor = 12.2 min. 25 26 [α]D = +6.3 (c 0.92, CHCl3, 53% ee) {lit. [47], [α]D + 11 (c 0.38, CHCl3, for (S)-8ca, 86% ee}. (S)-5-methoxi-3-(2-nitro-1-phenylethyl)-1H-indole (8da) [53]. Following the general procedure, compound 8da was obtained after 3 days of reaction at room temperature in 98% yield. The ee of the product was determined to be 55% by HPLC using a Daicel Chiralpak IA column −1 (n-hexane/i-PrOH = 90:10, flow rate 1 mL·min , λ = 254.0 nm): τmajor = 20.4 min; τminor = 17.1 min. 23 20 [α]D = −15.5 (c 0.34, CH2Cl2, 55% ee) {lit. [53], [α]D − 28.4 (c 1.0, CH2Cl2, for (S)-8da, 98% ee}. Catalysts 2018, 8, 305 16 of 21

3.3. Evaluation of the Stability of Urea Aggregates Thermoreversible gels (1 mL volume) were prepared at desired concentration by the gentle heating-cooling procedure, as previously described [47]. Unless stated otherwise, acid additives (from a stock solution) were mixed with the urea and the volume was then adjusted with pure solvent. The heating-cooling cycle was then applied and the formed gels were considered to be stable if they did not exhibit gravitational flow upon turning the vial upside-down. See Supporting Information for additional details. Unless indicated otherwise, gels were equilibrated for at least overnight at room temperature before thermal analysis. Tgel values were determined at desired times after gelation using a calibrated thermoblock, which was heated using an electric heating plate equipped with a temperature control ◦ couple at ~0.4 C/min [47]. The temperature at which the bulk gel started to break was defined as Tgel. Each measurement was randomly made at least twice and the average value was reported with an ◦ estimated error of ±2 C. Reported Tgel values correspond to the gel phase that supported the inversion of the vial, which enabled separation first of any liquid phase generated by the acid additive. Flow properties of our compounds were studied by oscillatory rheology using an AR 2000 Advanced rheometer (TA Instruments, Regensburg, Germany) equipped with a Julabo C cooling system (Regensburg, Germany). A 1000 mm gap setting and a torque of 5 × 10−4 N/m at 25 ◦C were employed for the measurements in a plain-plate (20 mm, stainless steel). The following experiments were performed for each sample, using 2 mL total gel volume: (a) Dynamic strain sweep (DSS) = variation of storage modulus G0 and loss modulus G” with strain from 0.01 to 100%; (b) dynamic frequency sweep (DFS) = variation of G0 and G” with frequency from 0.1 to 10 Hz at 0.1% strain; (c) dynamic time sweep (DTS) = variation of G0 and G” with time keeping the strain and frequency values constant and within the linear viscoelastic regime (i.e., strain = 0.1% strain; frequency = 1 Hz). Mechanical inertial effects of the measuring head were determined by the software package. In addition, fixed rest time after sample loading and pre-shearing to equilibrium at different shear rates were routinely made in order to minimize prehistory effects. Field Emission Scanning Electron Microscopy (FESEM) images of xerogels were recorded with a Zeiss Merlin, Field Emission Scanning Electron Microscope (Zaragoza, Spain) operated at an accelerating voltage of 10 kV. For visualization, samples were prepared by freeze-drying the corresponding gels. The obtained fibrous solids were placed on top of tin plates and shielded with Pt (40 mA during 30–60 s; film thickness = 5–10 nm). Images were taken at the University of Zaragoza (Servicio General de Apoyo a la Investigación-SAI)

4. Conclusions The results obtained in the Friedel-Crafts alkylation reaction suggest that the synergic effect between a Brønsted acid and a urea catalyst is higher than the effect promoted by each species separately. The experiments are also in agreement first, with the critical role played by the free carboxylic group in the disassembly of the supramolecular urea aggregates and secondly, in the activation of the “free” urea through coordination by the acid. This mechanism was demonstrated by analyzing the thermal and mechanical stability, as well as morphological properties of the supramolecular gel aggregates in the absence and presence of acid additives at different molar ratios. In terms of the effect of different acids, the most remarkable outcome (i.e., decrease of gel stability and significant changes in morphology) was observed with mandelic acid, which prevented the gelation at molar ratio of 0.9. In contrast, experiments using the corresponding methyl ester caused minor disruption in the gel, in good agreement with the observations made during the catalytic studies. The observed behavior is studied for the first time in the literature and could open a new interesting research line related to the effect of acid on urea-catalyzed reactions. Moreover, this contribution could become an important starting point for further investigations, since this study suggests that this phenomenon could be extended to other molecules with similar acidity and/or hydrogen-bonding ability. This possibility is currently being investigated in our laboratories. Catalysts 2018, 8, 305 17 of 21

Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/8/8/305/s1, Scheme S1: pKa values in waters, Figures S1–S8: Effect of the acid in the 1H NMR signals of the urea catalysts (500 MHz), Figures S9–S44: HPLC chromatograms, Figure S45: Gel measurements, Table S1: Effects of the addition of different additives on the aspect, gelation time and Tgel with respect to the pristine gels prepared in CHCl3 and in toluene. Author Contributions: Conceptualization, E.M.-L., D.D.D. and R.P.H.; Methodology, Software, Validation, Formal Analysis, Investigation, Resources, Data Curation, all authors; Writing-Original Draft Preparation, D.D.D. and R.P.H.; Writing-Review & Editing, all authors; Visualization, E.M.-L., D.D.D. and R.P.H.; Supervision, E.M.-L., D.D.D. and R.P.H.; Project Administration, E.M.-L., D.D.D. and R.P.H.; Funding Acquisition, E.M.-L., D.D.D. and R.P.H. Funding: This research was funded by Ministerio de Economía, Industria y Competitividad (CTQ2017-88091-P), Universidad de Zaragoza (JIUZ-2017-CIE-05) and Gobierno de Aragón-Fondo Social Europe (Research Groups E-07_17R). Acknowledgments: I. G. S. thanks the Obra Social de Ibercaja-CAI for mobility aid. D. D. D. thanks the Deutsche Forschungsgemeinschaft (DFG) for the Heisenberg Professorship Award. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Whiley-VHC: Weinheim, Germany, 2004. 2. Acc. Chem. Res. 2004, 37 (8). Special Issue on Organocatalysis; Houk, K.N., List, B., Eds.; American Chemical Society: Washington, DC, USA, 2004. 3. Enantioselective Organocatalysis; Dalko, P.I., Ed.; Whiley-VCH: Weinheim, Germany, 2007. 4. Chem. Rev. 2007, 107 (12). Special Issue on Organocatalysis; List, B., Ed.; American Chemical Society: Washington, DC, USA, 2007. 5. Recent Developments in Asymmetric Organocatalysis; Pellissier, H., Ed.; RSC Publishing: Cambridge, UK, 2010. 6. Asymmetric Organocatalysis; List, B., Ed.; Springer: Heidelberg, Germany, 2010. 7. Current Organic Chemistry, Volume 15, Number 13; Herrera, R.P., Ed.; Bentham Science: Soest, The Netherlands, 2011. 8. Science of Synthesis Asymmetric Organocatalysis; List, B.; Maruoka, K., Eds.; Thieme: Sttutgart, Germany, 2012. 9. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Application; Dalko, P.I., Ed.; Wiley-VCH: Weinheim, Germany, 2013. 10. De Figueiredo, R.M.; Christmann, M. Organocatalytic Synthesis of Drugs and Bioactive Natural Products. Eur. J. Org. Chem. 2007, 2007, 2575–2600. [CrossRef] 11. Marqués-López, E.; Herrera, R.P.; Christmann, M. Asymmetric organocatalysis in total synthesis—A trial by fire. Nat. Prod. Rep. 2010, 27, 1138–1167. [CrossRef][PubMed] 12. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774–793. [CrossRef][PubMed] 13. Marqués-López, E.; Herrera, R.P. Comprehensive Enantioselective Organocatalysis; Dalko, P., Ed.; Wiley-VCH: Weinheim, Germany, 2013; pp. 1359–1383. 14. Dalko, P.I.; Mosan, L. In the Golden Age of Organocatalysis. Angew. Chem. Int. Ed. 2004, 43, 5138–5175. [CrossRef][PubMed] 15. Berkessel, A. Organocatalysis by Hydrogen Bonding Networks in Organocatalysis; Reetz, M.T., List, B., Jaroch, H., Weinmann, H., Eds.; Springer: Berlin, Germany, 2008; Volume 2, pp. 281–297. 16. Hydrogen Bonding in Organic Synthesis; Pihko, P.M., Ed.; Wiley-VCH: Weinheim, Germany, 2009. 17. Kerstin, E.-E.; Berkessel, A. Noncovalent organocatalysis based on hydrogen bonding: elucidation of reaction paths by computational methods. Top. Curr. Chem. 2010, 291, 1–27. [CrossRef] 18. Schreiner, P.R. Metal-free organocatalysis through explicit hydrogen bonding interactions. Chem. Soc. Rev. 2003, 32, 289–296. [CrossRef][PubMed] 19. Takemoto, Y. Recognition and activation by ureas and thioureas: stereoselective reactions using ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 2005, 3, 4299–4306. [CrossRef][PubMed] 20. Connon, S.J. Organocatalysis Mediated by (Thio)urea Derivatives. Chem. Eur. J. 2006, 12, 5418–5429. [CrossRef][PubMed] 21. Taylor, M.S.; Jacobsen, E.N. Asymmetric Catalysis by Chiral Hydrogen-Bond Donors. Angew. Chem. Int. Ed. 2006, 45, 1520–1543. [CrossRef][PubMed] 22. Doyle, A.G.; Jacobsen, E.N. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 5713–5743. [CrossRef][PubMed] Catalysts 2018, 8, 305 18 of 21

23. Miyabe, H.; Takemoto, Y. Discovery and Application of Asymmetric Reaction by Multi-Functional Thioureas. Bull. Chem. Soc. Jpn. 2008, 81, 785–795. [CrossRef] 24. Zhang, Z.; Schreiner, P.R. (Thio)urea organocatalysis—What can be learnt from anion recognition? Chem. Soc. Rev. 2009, 38, 1187–1198. [CrossRef][PubMed] 25. Marqués-López, E.; Herrera, R.P. El renacer de un nuevo campo: La Organocatálisis Asimétrica. Tioureas como organocatalizadores. An. Quím. 2009, 105, 5–12. (In Spanish) 26. Takemoto, Y. Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions. Chem. Pharm. Bull. 2010, 58, 593–601. [CrossRef][PubMed] 27. Sohtome, Y.; Nagasawa, K. The Design of Chiral Double Hydrogen Bonding Networks and Their Applications to Catalytic Asymmetric Carbon-Carbon and Carbon-Oxygen Bond-Forming Reactions. Synlett 2010, 1–22. [CrossRef] 28. Sohtome, Y.; Nagasawa, K. Dynamic asymmetric organocatalysis: Cooperative effects of weak interactions and conformational flexibility in asymmetric organocatalysts. Chem. Commun. 2012, 48, 7777–7789. [CrossRef][PubMed] 29. Marqués-López, E.; Herrera, R.P. New Strategies in Chemical Synthesis and Catalysis; Pignataro, B., Ed.; Wiley-VCH: Weinheim, Germany, 2012; pp. 175–199. 30. Serdyuk, O.V.; Heckel, C.M.; Tsogoeva, S.B. Bifunctional primary amine-thioureas in asymmetric organocatalysis. Org. Biomol. Chem. 2013, 11, 7051–7071. [CrossRef][PubMed] 31. Xi, Y.; Shi, X. Cinchonine and thiourea. Chem. Commun. 2013, 49, 8583–8585. [CrossRef][PubMed] 32. Narayanaperumal, S.; Rivera, D.G.; Silva, R.C.; Paixão, M.W. Terpene-Derived Bifunctional Thioureas in Asymmetric Organocatalysis. ChemCatChem. 2013, 5, 2756–2773. [CrossRef] 33. Zhang, Z.; Bao, Z.; Xing, H. N,N0-Bis[3,5-bis(trifluoromethyl)phenyl]thiourea: a privileged motif for catalyst development. Org. Biomol. Chem. 2014, 12, 3151–3162. [CrossRef][PubMed] 34. Fang, X.; Wang, C.-J. Recent advances in asymmetric organocatalysis mediated by bifunctional amine–thioureas bearing multiple hydrogen-bonding donors. Chem. Commun. 2015, 51, 1185–1197. [CrossRef][PubMed] 35. Curran, D.P.; Kuo, L.H. Altering the Stereochemistry of Allylation Reactions of Cyclic. alpha.-Sulfinyl Radicals with Diarylureas. J. Org. Chem. 1994, 59, 3259–3261. [CrossRef] 36. Curran, D.P.; Kuo, L.H. Acceleration of a dipolar Claisen rearrangement by Hydrogen bonding to a soluble diarylˆurea. Tetrahedron Lett. 1995, 36, 6647–6650. [CrossRef] 37. Etter, M.C.; Panunto, T.W. 1,3-Bis(m-nitrophenyl)urea: An exceptionally good complexing agent for proton acceptors. J. Am. Chem. Soc. 1988, 110, 5896–5897. [CrossRef] 38. Etter, M.C.; Urbañczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T.W. Hydrogen bond-directed cocrystallization and molecular recognition properties of diarylureas. J. Am. Chem. Soc. 1990, 112, 8415–8426. [CrossRef] 39. Etter, M.C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23, 120–126. [CrossRef] 40. Kelly, T.R.; Kim, M.H. Relative Binding Affinity of Carboxylate and Its Isosteres: Nitro, Phosphate, Phosphonate, Sulfonate, and. delta.-Lactone. J. Am. Chem. Soc. 1994, 116, 7072–7080. [CrossRef] 41. Auvil, T.J.; Schafer, A.G.; Mattson, A.E. Design Strategies for Enhanced Hydrogen-Bond Donor Catalysts. Eur. J. Org. Chem. 2014, 2633–2646. [CrossRef] 42. Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Low-loading asymmetric organocatalysis. Chem. Soc. Rev. 2012, 41, 2406–2447. [CrossRef][PubMed] 43. Herrera, R.P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 6734–6737. [CrossRef][PubMed] 44. Herrera, R.P.; Monge, D.; Martín-Zamora, E.; Fernández, R.; Lassaletta, J.M. Organocatalytic Conjugate Addition of Formaldehyde N,N-Dialkylhydrazones to β,γ-Unsaturated α-Keto Esters. Org. Lett. 2007, 9, 3303–3306. [CrossRef][PubMed] 45. Marqués-López, E.; Alcaine, A.; Tejero, T.; Herrera, R.P. Enhanced Efficiency of Thiourea Catalysts by External Brønsted Acids in the Friedel—Crafts Alkylation of Indoles. Eur. J. Org. Chem. 2011, 3700–3705. [CrossRef] Catalysts 2018, 8, 305 19 of 21

46. Roca-López, D.; Marqués-López, E.; Alcaine, A.; Merino, P.; Herrera, R.P. A Friedel–Crafts alkylation mechanism using an aminoindanol-derived thiourea catalyst. Org. Biomol. Chem. 2014, 12, 4503–4510. [CrossRef][PubMed] 47. Schön, E.-M.; Marqués-López, E.; Herrera, R.P.; Alemán, C.; Díaz, D.D. Exploiting Molecular Self-Assembly: From Urea-Based Organocatalysts to Multifunctional Supramolecular Gels. Chem. Eur. J. 2014, 20, 10720–10731. [CrossRef][PubMed] 48. Juste-Navarro, V.; Marqués-López, E.; Herrera, R.P. Thiourea-Catalyzed Addition of Indoles to Aliphatic β,γ-Unsaturated α-Ketoesters. Asian J. Org. Chem. 2015, 4, 884–889. [CrossRef] 49. Schiller, J.; Pérez-Ruiz, R.; Sampedro, D.; Marqués-López, E.; Herrera, R.P.; Díaz, D.D. Fluoride Anion Recognition by a Multifunctional Urea Derivative: An Experimental and Theoretical Study. Sensors 2016, 16, 658. [CrossRef][PubMed] 50. Gimeno, M.C.; Herrera, R.P. Hydrogen Bonding Networks in Chiral Thiourea Organocatalysts: Evidence on the Importance of the Aminoindanol Moiety. Cryst. Growth Des. 2016, 16, 5091–5099. [CrossRef] 51. Izaga, A.; Herrera, R.P.; Gimeno, M.C. Gold(I)-Mediated Thiourea Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis. ChemCatChem 2017, 9, 1313–1321. [CrossRef][PubMed] 52. Robak, M.T.; Trincado, M.; Ellman, J.A. Enantioselective Aza-Henry Reaction with an N-Sulfinyl Urea Organocatalyst. J. Am. Chem. Soc. 2007, 129, 15110–15111. [CrossRef][PubMed] 53. Ganesh, M.; Seidel, D. Catalytic Enantioselective Additions of Indoles to Nitroalkenes. J. Am. Chem. Soc. 2008, 130, 16464–16465. [CrossRef][PubMed] 54. So, S.; Burkett, J.A.; Mattson, A.E. Internal Lewis Acid Assisted Hydrogen Bond Donor Catalysis. Org. Lett. 2011, 13, 716–719. [CrossRef][PubMed] 55. Sonsona, I.G.; Marqués-López, E.; Herrera, R.P. The aminoindanol core as a key scaffold in bifunctional organocatalysts. Beilstein J. Org. Chem. 2016, 12, 505–523. [CrossRef][PubMed] 56. Fan, Y.; Kass, S.R. Enantioselective Friedel–Crafts Alkylation between Nitroalkenes and Indoles Catalyzed by Charge Activated Thiourea Organocatalysts. J. Org. Chem. 2017, 82, 13288–13296. [CrossRef][PubMed] 57. Jensen, K.H.; Sigman, M.S. Systematically Probing the Effect of Catalyst Acidity in a Hydrogen-Bond-Catalyzed Enantioselective Reaction. Angew. Chem. Int. Ed. 2007, 46, 4748–4750. [CrossRef] [PubMed] 58. Marqués-López, E.; Diez-Martinez, A.; Merino, P.; Herrera, R.P. The Role of the Indole in Important Organocatalytic Enantioselective Friedel-Crafts Alkylation Reactions. Curr. Org. Chem. 2009, 13, 1585–1609. [CrossRef] 59. You, S.-L.; Cai, Q.; Zeng, M. Chiral Brønsted acid catalyzed Friedel–Crafts alkylation reactions. Chem. Soc. Rev. 2009, 38, 2190–2210. [CrossRef][PubMed] 60. Terrasson, V.; de Figueiredo, R.M.; Campagne, J.M. Organocatalyzed Asymmetric Friedel–Crafts Reactions. Eur. J. Org. Chem. 2010, 2635–2655. [CrossRef] 61. Zeng, M.; You, S.-L. Asymmetric Friedel-Crafts Alkylation of Indoles: The Control of Enantio- and Regioselectivity. Synlett 2010, 1289–1301. [CrossRef] 62. Dessole, G.; Herrera, R.P.; Ricci, A. H-Bonding Organocatalysed Friedel-Crafts Alkylation of Aromatic and Heteroaromatic Systems with Nitroolefins. Synlett 2004, 2374–2378. [CrossRef] 63. Pettersen, D.; Herrera, R.P.; Bernardi, L.; Fini, F.; Sgarzani, V.; Fernández, R.; Lassaletta, J.M.; Ricci, A. A Broadened Scope for the Use of Hydrazones as Neutral Nucleophiles in the Presence of H-Bonding Organocatalysts. Synlett 2006, 239–242. [CrossRef] 64. Bernardi, L.; Fini, F.; Herrera, R.P.; Ricci, A.; Sgarzani, V. Enantioselective aza-Henry reaction using cinchona organocatalysts. Tetrahedron 2006, 62, 375–380. [CrossRef] 65. Alcaine, A.; Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R.P. Thiourea catalyzed organocatalytic enantioselective Michael addition of diphenyl phosphite to nitroalkenes. Org. Biomol. Chem. 2011, 9, 2777–2783. [CrossRef][PubMed] 66. Auria-Luna, F.; Marqués-López, E.; Mohammadi, S.; Heiran, R.; Herrera, R.P. New Organocatalytic Asymmetric Synthesis of Highly Substituted Chiral 2-Oxospiro-[indole-3,40-(10,40-dihydropyridine)] Derivatives. Molecules 2015, 20, 15807–15826. [CrossRef][PubMed] 67. Bordwell, F.G.; Algrim, D.J.; Harrelson, J.A., Jr. The relative ease of removing a proton, a hydrogen atom, or an electron from carboxamides versus thiocarboxamides. J. Am. Chem. Soc. 1988, 110, 5903–5904. [CrossRef] Catalysts 2018, 8, 305 20 of 21

68. This behavior can be also rationalized in terms of ab initio methods, which support differences in energy for the N-H···S compared with N-H···O interaction in the chain dimers, being weaker in thioureas than in ureas (Ref. 69 and 70). 69. Masunov, A.; Dannenberg, J.J. Theoretical Study of Urea. I. Monomers and Dimers. J. Phys. Chem. A 1999, 103, 178–184. [CrossRef] 70. Masunov, A.; Dannenberg, J.J. Theoretical Study of Urea and Thiourea. 2. Chains and Ribbons. J. Phys. Chem. B 2000, 104, 806–810. [CrossRef] 71. Berkessel, A.; Cleemann, F.; Mukherjee, S.; Müller, T.N.; Lex, J. Highly Efficient Dynamic Kinetic Resolution of Azlactones by Urea-Based Bifunctional Organocatalysts. Angew. Chem. Int. Ed. 2005, 44, 807–811. [CrossRef][PubMed] 72. Scheerder, J.; Engbersen, J.F.J.; Casnati, A.; Ungaro, R.; Reinhoudt, D.N. Complexation of Halide Anions and Tricarboxylate Anions by Neutral Urea-Derivatized p-tert-Butylcalix[6]arenes. J. Org. Chem. 1995, 60, 6448–6454. [CrossRef] 73. Weil, T.; Kotke, M.; Kleiner, C.M.; Schreiner, P.R. Cooperative Brønsted Acid-Type Organocatalysis: Alcoholysis of Styrene Oxides. Org. Lett. 2008, 10, 1513–1516. [CrossRef][PubMed] 74. Companyó, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R. Highly Enantio- and Diastereoselective Organocatalytic Desymmetrization of Prochiral Cyclohexanones by Simple Direct Aldol Reaction Catalyzed by Proline. Chem. Eur. J. 2009, 15, 6564–6568. [CrossRef][PubMed] 75. Reis, Ö.; Eymur, S.; Reis, B.; Demir, A.S. Direct enantioselective aldol reactions catalyzed by a proline–thiourea host–guest complex. Chem. Commun. 2009, 1088–1090. [CrossRef][PubMed] 76. El-Hamdouni, N.; Companyó, X.; Rios, R.; Moyano, A. Substrate-Dependent Nonlinear Effects in Proline–Thiourea-Catalyzed Aldol Reactions: Unraveling the Role of the Thiourea Co-Catalyst. Chem. Eur. J. 2010, 16, 1142–1148. [CrossRef][PubMed] 77. Klausen, R.S.; Jacobsen, E.N. Weak Brønsted Acid-Thiourea Co-catalysis: Enantioselective, Catalytic Protio-Pictet-Spengler Reactions. Org. Lett. 2009, 11, 887–890. [CrossRef][PubMed] 78. Xu, H.; Zuend, S.J.; Woll, M.G.; Tao, Y.; Jacobsen, E.N. Asymmetric Cooperative Catalysis of Strong Brønsted Acid–Promoted Reactions Using Chiral Ureas. Science 2010, 327, 986–990. [CrossRef][PubMed] 79. Shi, Y.-L.; Shi, M. Chiral Thiourea-Phosphine Organocatalysts in the Asymmetric Aza-Morita–Baylis–Hillman Reaction. Adv. Synth. Catal. 2007, 349, 2129–2135. [CrossRef] 80. Escuder, B.; LLusar, M.; Miravet, J.F. Insight on the NMR Study of Supramolecular Gels and Its Application to Monitor Molecular Recognition on Self-Assembled Fibers. J. Org. Chem. 2006, 71, 7747–7752. [CrossRef] [PubMed] 81. Schoonbeek, F.S.; van Esch, J.H.; Hulst, R.; Kellogg, R.M.; Feringa, B.L. Geminal Bis-ureas as Gelators for Organic Solvents: Gelation Properties and Structural Studies in Solution and in the Gel State. Chem. Eur. J. 2000, 6, 2633–2643. [CrossRef] 82. Jung, J.H.; Shinkai, S.; Shimizu, T. Spectral Characterization of Self-Assemblies of Aldopyranoside Amphiphilic Gelators: What is the Essential Structural Difference Between Simple Amphiphiles and Bolaamphiphiles? Chem. Eur. J. 2002, 8, 2684–2690. [CrossRef] 83. Morris, K.F.; Johnson, C.S., Jr. Diffusion-ordered two-dimensional nuclear magnetic resonance spectroscopy. J. Am. Chem. Soc. 1992, 114, 3139–3141. [CrossRef] 84. Price, W.S. Pulsed-field gradient nuclear magnetic resonance as a tool for studying translational iffusion: Part 1. Basic theory. Conc. Magn. Reson. 1997, 9, 299–336. [CrossRef] 85. Cohen, Y.; Avram, L.; Frish, L. Diffusion NMR Spectroscopy in Supramolecular and Combinatorial Chemistry: An Old Parameter—New Insights. Angew. Chem. Int. Ed. 2005, 44, 520–554. [CrossRef][PubMed] 86. Reactive Intermediates; Santos, L.S., Ed.; Wiley-VCH: Weinheim, Germany, 2010. 87. Liu, X.-G.; Jiang, J.-J.; Shia, M. Development of axially chiral bis(arylthiourea)-based organocatalysts and their application in the enantioselective Henry reaction. Tetrahedron: Asymmetry 2007, 18, 2773–2781. [CrossRef] 88. Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. Asymmetric Friedel-Crafts Alkylations of Indoles with Nitroalkenes Catalyzed by Zn(II)-Bisoxazoline Complexes. J. Org. Chem. 2006, 71, 75–80. [CrossRef][PubMed] 89. Meshram, H.M.; Rao, N.N.; Kumar, G.S. Boric Acid–Mediated Mild and Efficient Friedel–Crafts Alkylation of Indoles with Nitro Styrenes. Synth. Commun. 2010, 40, 3496–3500. [CrossRef] Catalysts 2018, 8, 305 21 of 21

90. Wu, J.; Li, X.; Wu, F.; Wan, B. A New Type of Bis(sulfonamide)-Diamine Ligand for a Cu(OTf)2-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction of Indoles with Nitroalkenes. Org. Lett. 2011, 13, 4834–4837. [CrossRef][PubMed] 91. Itoh, J.; Fuchibe, K.; Akiyama, T. Chiral Phosphoric Acid Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with Nitroalkenes: Cooperative Effect of 3 Å Molecular Sieves. Angew. Chem. Int. Ed. 2008, 47, 4016–4018. [CrossRef][PubMed]

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