Synthesis of Structurally Diverse Emissive ... - ACS Publications

Article Cite This: J. Org. Chem. 2018, 83, 2570−2581

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Synthesis of Structurally Diverse Emissive Molecular Rotors with Four-Component Ugi Stators Ma. Carmen García-González,† Andrés Aguilar-Granda,† Angel Zamudio-Medina,‡ Luis D. Miranda,*,† and Braulio Rodríguez-Molina*,† †

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Ciudad de México 04510, Mexico ‡ Departamento de Ciencias Básicas, Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional, Av. Acueducto s/n Barrio la Laguna Ticomán, Ciudad de México 07340, Mexico S Supporting Information *

ABSTRACT: The use of the multicomponent Ugi reaction to rapidly prepare a library of dumbbell-like molecular rotors is highlighted here. The synthetic strategy consisted of the atom-economic access to 15 bulky and structurally diverse iodinated stators, which were cross-coupled to the 1,4-diethynylphenylene rotator. From those experiments, up to six rotors 1a−c and 1l−n were obtained, with yields ranging from 35 to 69% per coupled C−C bond. In addition to the framework diversity, five of these compounds showed aggregateenhanced emission properties thanks to their conjugated 1,4-bis(phenylethynyl)benzene cores, a property that rises by increasing the water fraction ( f w) in their THF solutions. The results highlight the significance of the diversity-oriented synthesis of rapid access to new molecular fluorescent rotors.

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precursors or final products with low yields or very low solubility. Furthermore, these problems are often discovered in the final steps, forcing the redesign of the synthetic routes.12 As the solubility and other properties of the molecules depend on the subtle differences in their molecular structures, a diversityoriented approach may be an appropriate alternative that can help us to fine-tune some properties of the rotors and avoid long synthetic procedures. In other words, it is highly desirable to find a synthetic alternative that allows a faster synthesis of molecular rotors, preferably with an increased variability of the frameworks. Along this line, it has been validated that multicomponent reactions (MCR) are a versatile tool to construct a vast range of molecular motifs in efficient and practical synthetic protocols. This approach has been useful to accelerate the discovery of new bioactive molecules, mainly in medicinal chemistry.13 One of the most appreciated features of this strategy is the feasibility to obtain large molecular complexity and diversity. Furthermore, the combination of a MCR with a postcondensation process gives access to diverse molecular libraries, offering the opportunity to vary the functional groups of the final products, normally in short synthetic sequences. Among the various MCRs,14 the four-component Ugi reaction stands out as a remarkable strategy due to its elegant simplicity.15 This approach is based on the reaction of four

INTRODUCTION In recent years, there has been great interest in the design and synthesis of artificial molecular machines (rotaxanes,1 catenanes,2 or motors3) that perform outstanding functions based on the ingenious combination of segmental motions. The inspiration for the envisioned properties in these compounds, whether in solution4 or in the solid state,5 has been drawn from biomolecular machines with synchronous motion in enzymes or from macroscopic objects, like the collective movement of gears. The relevance of this area was undoubtedly emphasized when the Nobel prize in chemistry was awarded to J.-P. Sauvage, F. Stoddart, and B. Feringa in 2016.6 Within this field, the synthesis of compounds that show rotary motion, known as molecular motors7 or rotors,8 remains very attractive to numerous research groups. It is generally considered that controlling the motion in these compounds could enable the discovery of new technological applications.9 Several reports10 have clearly pointed out that the rotation in these compounds could be favored when using a wheel-and-axis molecular architecture;11 that is, a relatively small group (termed rotator) linked to some voluminous groups with larger moments of inertia (termed stator). Usually, the construction of the rotors with this design can be carried out following a linear synthetic approach, based on several incremental steps, and sometimes the final products require lengthy purification procedures. Although clearly successful, such linear methodology renders rotors with limited structural diversity and may produce © 2018 American Chemical Society

Received: November 10, 2017 Published: February 19, 2018 2570

DOI: 10.1021/acs.joc.7b02858 J. Org. Chem. 2018, 83, 2570−2581

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The Journal of Organic Chemistry

THF−water fraction mixtures, as determined by fluorescence experiments. The aggregation was corroborated by dynamic light scattering (DLS), and a glimpse of the conformational changes that occur during this process was obtained by 1H NMR experiments carried out in THF/water mixtures.

commercially available compounds, which produce bulky aminoacyl amide derivatives (adducts): an aldehyde, an amine, a carboxylic acid, and an isocyanide. Furthermore, this reaction has other very appealing characteristics, for example: (1) the yields are typically high, (2) it can be carried out in onepot at room temperature, (3) only one molecule of water is obtained as the side product, and (4) the purification of the adduct is generally straightforward. Therefore, we envisioned that the use of MCRs would enable the rapid synthesis of diverse molecular rotors with a wheel-and-axle molecular architecture. Considering the above, in this work we describe the synthesis, optimization, and spectroscopic characterization of novel molecular rotors using Ugi adducts stators, which were coupled to 1,4-diethynylphenylene fragment 4, which includes the rotator and the axis (Figure 1). These molecular

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RESULTS AND DISCUSSION Synthesis and Characterization. The synthesis of the envisioned Ugi rotors could be carried out following the routes illustrated in Scheme 1. In the pathway A, we considered that either a conjugated dibenzaldehyde or dianiline could take part of the Ugi reaction, whereas in pathway B or C, a Sonogashira coupling would take place after the Ugi adducts were obtained. We explored pathway A by synthesizing either the dianiline 2a and dibenzaldehyde 2b, as described in detail in the Supporting Information. With the dianiline 2a in our hands, we explored the Ugi reaction using acetic acid, benzaldehyde, and cyclohexyl isocyanide as the additional components. Unfortunately, the desired molecular rotor was not obtained under any of the explored conditions, and only a partial transformation was observed. Mass spectra and TLC chromatography indicated mainly the formation of two compounds, which were identified as one-half of the expected Ugi condensation (monocoupled fragment) and one decomposition product (imine). The reaction did not show any progress even if the mixture was allowed to stir up to 5 days, so this pathway was not pursued further. We also attempted the Ugi reaction using the (p-diethynylphenylene)dibenzaldehyde 2b,16 but the very low solubility of this compound in methanol prevented any rotor formation (details provided in the Supporting Information). Next, we turned our attention to explore the alternative pathways B or C, which employ the Sonogashira coupling after synthesizing the Ugi adduct and differ only in the precursors (Scheme 1). It is important to mention that examples of these coupling reactions starting from Ugi adducts are relatively scarce, and they are limited to postcondensations, usually cyclizations.17 It was immediately noticed that one of the requirements for these routes to work was the inclusion of a halogen atom in Ugi structure, which could later be crosscoupled with an ethynyl moiety. To this end, commercial brominated and iodinated amines were used as starting materials. The Ugi adducts featuring bromide were obtained in moderate to good yields (see Supporting Information), but they presented exceedingly low reactivity toward the sub-

Figure 1. Molecular rotors described in this work, based on a multicomponent stator synthesized from an Ugi reaction.

components were selected to complement the Ugi stators for two main reasons: (1) the size of the 1,4-phenylene ring would be considerably smaller than the bulky aminoacyl amide derivatives, fulfilling the wheel-and-axle design, and (2) they would extend the conjugation of the resulting molecules, rendering compounds with emissive properties. To our knowledge, the use of this synthetic strategy has not been reported before and enabled the expedited synthesis of six diverse molecular rotors, showing yields from 35% to 69% per coupled carbon−carbon bond formed. Furthermore, five of these rotors showed aggregation-enhanced emission (AEE) in

Scheme 1. Retrosynthetic Strategies To Obtain Ugi Molecular Rotors

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The Journal of Organic Chemistry Scheme 2. Synthesis of Ugi Adduct 3a and Its Corresponding Molecular Rotor 1a

Table 1. Survey of Reaction Conditions for Molecular Rotor 1a entry

palladium catalysta

CuI

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 PdCl2(PPh3)2 Pd((C6H5)3P)4 Pd((C6H5)3P)4 Pd((C6H5)3P)4 Pd((C6H5)3P)4 Pd((C6H5)3P)4 Pd((C6H5)3P)4 Pd((C6H5)3P)4 PdCl2, PPh3

b b b

THF THF THF

c b b b b b b

THF CH3CN CH3CN CH3CN toluene toluene toluene toluene toluene toluene DMF THF

b b b

solvent

base

T (°C)

time (h)

yieldd (%)

Et3N Et3N Et3N Et3N Et3N Et3N DIPEA DIPEA DIPEA Et3N DIPA Et3N DIPA Cs2CO3 Cs2CO3 Et3N

rt 50 reflux rt rt rt rt rt reflux rt rt rt rt rt rt rt

14 14 14 72 72 14 14 108 12 72 72 72 72 72 72 72

15 traces traces nr 18 22 33 34 nr nr nr nr nr nr nr nr

10 mol %. b5 mol %. c10 mol %. dIsolated yield after purification by flash column chromatography, rt = room 22 °C, nr = no reaction, entry 14 PPh3 5%. a

higher amount of CuI (10% mol) caused only a minor improvement of the yield (18%, entry 5). When the reaction solvent was changed from THF to acetonitrile, the rotor 1a was obtained in a slightly better yield of 22% (entry 6). Complementarily, the use of diisopropylethylamine (DIPEA) instead of triethylamine as a base showed the best improvement in the yield (33%), which corresponds to a 58% yield per coupled C−C bond (entry 7). Since a small amount of starting material was still observed in this experiment, the reaction time was increased up to 108 h (entry 8), but the yield did not change significantly. Carrying out the reaction with different sources of Pd(0) or using other bases (entries 9−16) did not show any product. Finally, and inspired by the reported Sonogashira couplings under ballmilling conditions,19 we explored the mechanochemical activation of the reaction using a planetary mill, obtaining very low yields (see the Supporting Information). After we found the best reaction conditions for the synthesis of rotor 1a, we explored the scope of this protocol. We first focused on the synthesis of the several Ugi adducts 3, carrying out the reaction at room temperature in methanol in 24 h with moderate to good yields (47−98%). In this way, we prepared

sequent Sonogashira cross-coupling. After several attempts, we decided to use the iodide derivatives, which were also obtained in moderate to good yields (vide infra). To explore the synthesis of a molecular rotor following this approach, we used the adduct 3a as a test case, which was prepared in good yield (58%), starting from 4-iodoaniline 7, benzaldehyde 8, benzoic acid 9, and cyclohexyl isocyanide 10 (Scheme 2). With the adduct 3a in hand, we carried out the double Sonogashira cross-coupling using PdCl2(PPh3)2 as catalyst, CuI as cocatalyst, Et3N, and dry THF at room temperature to give the desired rotor 1a in 15% yield (Table 1, entry 1). After this promising result, we explored the effect of the temperature in this reaction. However, when the reaction was carried out at 50 °C or higher, only traces of the desired compound were observed, and only a dehalogenated Ugi adduct was obtained (entries 2 and 3). One well-known difficulty in this reaction is that the copper in the mixture could induce the free alkyne to react with itself, yielding the Glaser product (homocoupling).18 To explore the effect of the copper iodide, the Sonogashira cross coupling was carried out in the absence of this cocatalyst, but the desired product was not obtained (entry 4). Conversely, the use of a 2572


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Figure 2. Iodinated Ugi adducts that were synthesized and examined as voluminous stators.

Figure 3. Molecular rotors with four-component Ugi stators reported here.

(Figure 2). Another four Ugi adducts (3j and 3m−o) were prepared using the iodide atom appended to the carboxylic acid (Figure 2). All synthesized compounds were fully characterized

15 (3a−o) Ugi adducts, 11 of them (3a−i and 3k−l) using benzaldehyde, tert-butyl isocyanide, or cyclohexyl isocyanide, the corresponding carboxylic acid, and a halogenated amine 2573


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Figure 4. (a) Comparison of the fluorescence emission spectra of the molecular rotors reported here (1 × 10−6 M in THF). Emission of rotors with different THF/water fractions and the corresponding excitation wavelengths: (b) compound 1n (λexc = 340 nm), (c) compound 1a (λexc = 340 nm), (d) compound 1l (λexc = 325 nm).

by spectroscopic methods (NMR and IR) as well as highresolution mass spectrometry. Having the Ugi adducts in our hands, we focused on the synthesis of the rotors by a double Sonogashira reaction. Although all of the Ugi adducts were cross-coupled with the 1,4-diethynylphenylene compound 4, some of the resulting rotors showed low yields or persistent impurities difficult to remove by column chromatography. These side products were in some cases traces of starting materials or traces of dehalogenated adducts, and those rotors are not reported in detail here. Among the successful attempts, the molecular rotor 1b was obtained in a modest yield of 12% (35% per coupled carbon− carbon bond formed), starting from the Ugi adduct 3b. Comparatively, an electron-withdrawing group in the carboxylic precursor 3c afforded the molecular rotor 1c with a much better yield of 47% (68% per coupled carbon−carbon bond formed). Subsequently, we found that the position of the halogen in the Ugi precursor is of great importance because when the adduct 3k was used, which was obtained from 2iodoaniline, only degradation products were observed. Conversely, when the compound 3l was employed, which was obtained from 3-iodoaniline, the desired rotor 1l was obtained

in a good 47% yield (69% per coupled carbon−carbon bond formed). Complementarily, the adduct 3m was used to obtain the molecular rotor 1m in 27% yield (52% per coupled carbon−carbon bond formed), and the compound 3n, allowed us to obtain the compound 1n in a moderated yield of 28% (53% per coupled carbon−carbon bond formed), as shown in Figure 3. Fluorescence and Structural Studies. Single-channel recording of fluorescence intensity has become a valuable tool for molecular rotors since fluorescence emission techniques are highly dependent and sensitive to dynamic rotations and conformational changes on the excited state.20 Once the six molecular rotors 1a−c and 1l−n were successfully characterized, we focused on their fluorescence properties resulting from the conjugated 1,4-bis(phenylethynyl)benzene core, a moiety that has been commonly employed in highly emissive molecules.21 The studies were performed in THF solutions of 1 × 10−6 M concentration at room temperature due to the high solubility of the rotors in this solvent (Figure 4a). Gratifyingly, three out of six rotors presented strong emissive properties, for example, the excitation at λexc = 340 nm afforded a well vibrationally resolved pattern with a peak of maximum intensity 2574


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The Journal of Organic Chemistry at λem = 350 nm for compound 1n (ϕf = 0.5). Using the same excitation wavelength, a peak was observed at λem = 410 nm for compound 1a (ϕf = 0.12). Using λexc = 325 nm, an emission at λem = 354 nm was observed for compound 1l (ϕf = 0.27). Conversely, the emission of compounds 1m (λexc = 340 nm, λem = 390 nm, ϕf = 0.05) and 1b (λexc = 335 nm, λem = 400 nm, ϕf = 0.04) was low. Unsurprisingly, the rotor 1c with deactivating (quenching) −NO2 groups was barely fluorescent (λexc = 340 nm, λem = 400 nm, ϕf = 0.007). The relevant optical properties have been compiled in Table 2.

an aggregation-induced emission (AIE) effect.22 With the aim of exploring the role of the particle formation in the emission properties, an AIE protocol was conducted for all of the rotors.23 Due to the insolubility of the rotors in water, a higher water fraction in their THF solution might force the formation of aggregates, possibly increasing the initial fluorescence. Therefore, all of the fluorescence experiments were carried out using different THF/water fraction mixtures (f w) as described in the Experimental Section. The water fraction experiments of compound 1n exhibited a slight increment in its relative emission intensity, as shown in Figure 4b, up to a THF/water fraction of 50%. Then, when the water fraction becomes higher than 50%, the emission decreases abruptly. This fluorescence quenching was attributed to the light-scattering caused by the formation of larger aggregates or to the fact that some aggregates precipitate and/ or they adhere to the walls of the cuvette. Gratifyingly, a more noticeable change was observed in compounds 1a and 1l (Figure 4c,d). These two rotors showed a significant emission enhancement when using water fractions from f w = 0 to 50% (1a) or from f w = 0 to 70% (1l), respectively. Again, higher water fractions caused fluorescence quenching, which was attributed to the above-mentioned reasons. Considering that the low emissive rotors (1b, 1c, and 1m) could also show analogous emission-enhancement properties, we carried out the corresponding THF/water fraction experiments (see the Supporting Information). Interestingly, rotor 1b showed very small emission enhancement in water fractions from f w = 0% to 60%, but a significant increase was observed

Table 2. Optical Properties of Compounds 1a−c and 1l−n (in Alphabetical order) compd 1a 1b 1c 1l 1m 1n

λmax abs (nm) 340 335 340 325 340 340

λem PL (nm)

Stokes shift (cm−1)

ϕf

410 400 400 354 390 350

× × × × × ×

0.12 0.04 0.007 0.27 0.05 0.50

1.42 1.53 1.66 3.44 2.08 1.00

05

10 1005 1005 1005 1005 1007

Despite the good observed emission of the three rotors 1n, 1a, and 1l, we pondered that the conformational changes and the intramolecular motion in these conjugated molecules could deactivate the excited states, thus reducing the emission intensity. If this hypothesis was correct, then any process in which the internal motion is reduced would increase the observed emission, as reported in numerous compounds with

Figure 5. 1H NMR of compound 1l in different THF-d8/D2O fractions at 300 MHz. The red asterisk indicates the signal corresponding to the central phenylene ring, and the blue dot shows the displacement of the −NH hydrogen. The insets highlight the changes in the chemical shifts of the protons in the phenylene and the amide group. 2575


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Figure 6. VT 1H NMR of 1l in pure THF-d8 at 300 MHz. The red asterisk indicates the signal corresponding to the central phenyl ring, and the blue dot shows the displacement of the −NH hydrogen. The inserts highlight the changes in the chemical shifts of the protons in the phenylene and the amide group.

compound is not soluble in water, at fractions above f w = 50% the particles were so large that they started to precipitate, and thus, the NMR signal was lost. Nevertheless, we were able to obtain the spectra using water fractions between 10% and 50%, as shown in Figure 5. As evidenced by the 1H NMR spectra of 1l, all of the signals showed large fluctuations of their chemical shifts immediately after the first addition of water (f w = 10%), as compared with the spectrum obtained in pure THF-d8. By using 2D NMR sequences (DEPT135, HETCOR, and FLOCK), it was possible to assign the signals corresponding to the central benzene ring as a singlet at 7.42 ppm and the one from the N− H group at 7.05 ppm. The insets in Figure 5 highlight the abrupt changes of these signals, which are easily distinguishable compared to other severely overlapped signals in the aromatic region. It seems possible to say that the interaction between neighboring Ugi stators is favored during aggregation, which could reduce the internal motion of the whole molecule, thus increasing the emission. Complementary variable-temperature 1H NMR experiments of rotor 1l in pure THF-d8 helped us to gain a deeper insight of the structural changes during the aggregation process caused by water. To better describe the structural changes, we used the signal coming from the central benzene ring as the main probe. The central protons are magnetically equivalent due to a chemical exchange that is faster than the time scale of the technique (at room temperature). If the frequency of this motional process is reduced at lower temperature, the signal would gradually become broader and smaller, until the chemical exchange becomes very slow, and the initial peak would split into two signals, as described in a decoalescence process.27

with water fractions between f w = 70% and 90%, indicating that emissive aggregates are favored under high f w conditions. On the other hand, the rotor 1c which bears −NO2 groups in the stator did not show any emission improvement but only a complete quenching under those conditions. Finally, a slight enhancement was observed in rotor 1m only up to f w = 30%, but higher water fractions quenched the fluorescence. The significant enhanced-emission observed in the rotors 1a, 1l, and 1n (also in 1m to some extent) can be attributed to the aggregate formation.24 We further investigated the aggregation of the rotor 1l by means of dynamic light scattering (DLS), a technique that is commonly used to determine the size distribution of small particles in suspensions.25 For a better comparison, the DLS studies were carried out under the same concentration conditions of the PL experiments. The DLS analyses confirmed that when the rotor is completely dissolved in THF, there are no particles in the solution (see the Supporting Information). Subsequently, the addition of water gave rise to a bimodal distribution of particles, that is, the coexistence of minute particles of 3.21 nm and larger aggregates of 345 nm at f w = 20%. Larger particles with size of ca. 540 nm, were later obtained at higher water fractions ( f w = 30%). Finally, at f w = 60% the distribution of particles became monomodal, showing very large particles of 1774 nm in size (see the Supporting Information). Once we confirmed the particle formation, we carried out 1H NMR experiments of the rotor 1l to gain more information about the structural changes that may occur during aggregation.26 The experiments were carried out starting from a pure THF solution, and subsequently, D2O was gradually added in f w = 10% steps. Indeed, given the fact that the 2576


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and the use of other MCRs to construct new molecular rotors are currently underway.

In our experiments, this peak progressively shifted and became broader until it practically disappeared at 233 K, in complete agreement with the expected line shape change of a reduced rotational process, improving the planarization of the 1,4-bis(phenylethynyl)benzene core, thus increasing the emission (Figure 6). Very low temperatures would finally cause the anticipated splitting of the signal, which could allow us to extract a precise activation barrier to rotation of this molecular fragment; however, these experiments could not be carried out due to the low solubility of the rotor 1l at that temperature and due to limitations of our spectrometer. Similarly, the signal from the N−H group also shifted gradually (insert in Figure 6), suggesting that the low-temperature experiments also have an impact on the molecular conformation of the Ugi stators. It should be emphasized that although only these two signals (central benzene ring and N−H) are described here in a detailed fashion, all of the signals from the spectrum showed changes in their chemical shifts, indicating that the low temperature reduces the internal motion also in the Ugi stators. As described in the literature,28 this restriction also gives rise to an improvement of the emission properties. We corroborated the significant emission enhancement at lowtemperature by carrying out fluorescence experiments of the rotor 1l in pure THF from 293 to 253 K (see the Supporting Information). Considering all of the 1H NMR and fluorescence experiments together, is evident that the structural changes in THF− water mixtures are different than those observed at low temperature in pure THF. To assess the role of the water in this process, not only the aggregation but also the fluorescence studies could be carried out using a polar aprotic solvent miscible with THF, for example, DMF or acetone; unfortunately, the synthesized rotors were completely or partially soluble in those solvents, preventing further experiments.

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EXPERIMENTAL SECTION

Material and Methods. All reagents were purchased from SigmaAldrich and used as received. Flash column chromatography was performed using Aldrich silica gel 230−400 mesh, hexane, and ethyl acetate as eluents. Reactions were monitored by TLC on silica gel plates 60 F254 (Merck), and the spots were detected either by UV absorption or by using Seebach’s TLC stain followed by heating. 1H and 13C NMR spectra were recorded at ambient temperature using Bruker Fourier 300 and JEOL Eclipse 300 spectrometers, chemical shifts (δ) are reported in ppm relative to the solvent signal with an internal TMS standard, and NMR coupling constants are reported in hertz (Hz). The FT-IR spectral data were recorded with Bruker ATR in the 450−4000 cm−1 range. High-resolution mass spectra were recorded on a JEOL AccuTOF JMS-T100LC mass spectrometer with TOF mass analyzer. FAB+ mass spectra were obtained on a 3nitrobenzyl alcohol matrix in the positive ion mode on the MStation JMS-700 spectrometer, operated at an accelerating voltage of 10 kV by using Xenon atoms at 6 keV. Melting points were determined using Fisher Johns melting point apparatus (uncorrected). The absorption spectra were acquired in a Cary 50 spectrometer, and fluorescence spectra were acquired in a Cary Eclipse fluorimeter (Varian). The quantum yields (ϕf) were determined in cyclohexane using Coumarin 102 as the reference. DLS experiments were performed in a Malvern Instruments, Ltd. equipment with a laser NIBS (non-invasive back scattering) at 298 K, using a THF solution of 1l at 1 × 10−6 M and Milli-Q water. The solution was filtered through an inorganic Anatop membrane (Whatman) with a 0.02 μ pore size. Immediately after preparing the mixtures (THF/water), the cuvette was introduced into the DLS equipment provided with a laser diode (wavelength = 633 nm). The analyses of the hydrodynamic radius (RH) were performed with the Zetasizer software version 7.12. General Procedure for the Ugi Adducts. The Ugi 4-CR were carried out by mixing in one round-bottom flask the corresponding benzaldehyde (1.0 equiv), the appropriate amine (1.0 equiv), the benzoic acid derivative (1.0 equiv), and the isocyanide (1.0 equiv) in MeOH. The reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica using hexanes/ EtOAc as eluent to afford the corresponding Ugi adduct. General Procedure for Sonogashira Coupling. In a roundbottom flask were dissolved the Ugi adduct (2.0 equiv), 1,4diethynylbenzene (1.0 equiv), PdCl2(PPh3)2 (10% mol), and CuI (5% mol) in degassed acetonitrile. To this suspension was added degassed N,N-diisopropylethylamine, and the mixture was stirred to room temperature under nitrogen atmosphere from 24 to 48 h. After this reaction time, am aqueous solution of saturated NH4Cl was added to the mixture, and the organic layers were extracted with dichloromethane (3 × 20 mL). The organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column on silica with hexanes/EtOAc as eluents to afford the corresponding molecular rotor. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)benzamide (3a). Compound 3a was synthesized using 4-iodoaniline (0.60 g, 2.7 mmol), benzaldehyde (0.29 g, 2.7 mmol), benzoic acid (0.34 g, 2.7 mmol), and cyclohexyl isocyanide (0.3 g, 2.7 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (0.85 g, 58%, mp 220−222 °C). IR νmax: 3273, 2930, 2851, 1675, 1628, 1558, 1377 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.33−7.16 (m, 13H), 6.74 (d, 2H, J = 8.1 Hz), 6.22 (s, 1H), 5.67 (d, 1H, J = 8.0 Hz), 4.94−3.81 (m, 1H), 2.00−1.92 (m, 2H), 1.73−1.56 (m, 3H), 1.43−1.30 (m, 2H), 1.20−1.01 (m, 3H). 13C NMR (75 MHz, CDCl3) δ: 171.2, 168.5, 141.0, 137.5, 135.8, 134.7, 132.4, 130.3, 129.7, 128.7, 128.5, 127.9, 92.6, 66.0, 48.9, 32.9, 25.6, 24.8. HRMS (EI+): calcd for C27H27IN2O2 [M]+ 538.1117, found 538.1135.

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CONCLUSIONS We describe here for the first time a diversity-oriented synthesis to obtain six structurally diverse rotors with moderate to good yields (35−69% per coupled C−C bond formed). We started with the synthesis of 15 iodinated bulky stators that were then coupled to the 1,4-bis(phenylethynyl)benzene core. Most of the resulting rotors showed moderate to good fluorescence in THF solution, except the one bearing the deactivating −NO2 group, which was not emissive. Subsequently, we conducted an AIE protocol to increase the fluorescence of these rotors. Remarkably, stronger emissions were documented when using progressively higher water fractions in their THF solutions, causing the rotors to form aggregates, confirmed by DLS experiments. From these studies, it can be concluded that the presence of water forces the existence of highly emissive aggregates, favoring conformational changes of the whole molecule, as evidenced by 1H NMR experiments carried out in THF-d8/D2O. In summary, we have demonstrated that the use of multicomponent reactions is an excellent alternative to obtain diversity-oriented molecular rotors. This strategy significantly shortens the typical linear synthetic sequences and affords structures that could be subsequently modified, if desired. Our results highlight the significance of the synthesis of diversityoriented molecular rotors with enhanced emissive properties resulting from aggregation. Subsequent structural modifications 2577


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N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)4-methylbenzamide (3g). Compound 3g was synthesized using the following amounts: 4-iodoaniline (0.79 g, 3.6 mmol), benzaldehyde (0.38 g, 3.6 mmol), 3-methylbenzoic acid (0.49 g, 3.6 mmol), and cyclohexyl isocyanide (0.39 g, 3.6 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.45 g, 74%, mp 212−214 °C). IR νmax: 3438, 3277, 2929, 1662, 1626, 1552, 1385 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.35−7.19 (m, 10H), 6.97 (d, 2H, J = 8.11 Hz), 6.74g (d, 2H, J = 8.11 Hz), 6.20 (s, 1H), 5.69 (d, 1H, J = 8.3 Hz), 3.92−3.81 (m, 1H), 2.26 (s, 3H), 1.99−1.90 (m, 2H), 1.68−1.59 (m, 3H), 1.42− 1.27 (m, 3H), 1.20−1.04 (m, 3H). 13C NMR (75 MHz, CDCl3) δ: 171.2, 168.6, 141.4, 140.0, 137.5, 134.8, 133.4, 132.8, 130.2, 128.8, 128.7, 128.6, 92.5, 66.2, 48.9, 32.9, 25.6, 24.8, 21.3. HRMS (EI+) calcd for C28H29IN2O2 [M]+ 552.1274, found 552.1282. N-(2-tert-Butylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)-4methylbenzamide (3h). Compound 3h was synthesized using 4iodoaniline (0.79 g, 3.6 mmmol), benzaldehyde (0.38 g, 3.6 mmol), 3methylbenzoic acid (0.49 g, 3.6 mmol), and tert-butyl isocyanide (0.30 g, 3.6 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.04 g, 55%, mp 142−144 °C). IR νmax 3295, 3065, 2922, 1672, 1625, 1484, 1384, 1361 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.33−7.19 (m, 10H), 6.95 (d, 2H, J = 8.0 Hz), 6.74 (d, 2H, J = 8.0 Hz), 6.14 (s, 1H), 5.76 (s, 1H), 2.24 (s, 3H), 1.35 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 171.0, 168.6, 144.2, 141.3, 139.9, 137.9, 134.8, 132.7, 132.2, 130.0, 129.1, 128.7, 128.5, 128.4, 117.3, 92.4, 6.6, 51.7, 28.7, 21.4. HRMS (DART+) calculated for C26H28IN2O2 [M]+ 527.1195, found 527.1183. N-(2-((2,6-Dimethylphenyl)amino)-2-oxo-1-phenylethyl)-N-(4iodophenyl)benzamide (3i). Compound 3i was synthesized using 4iodoaniline (0.72 g, 3.2 mmol), benzaldehyde (0.34 g, 3.2 mmol), benzoic acid (0.40 g, 3.2 mmol), and 2,6-dimethylphenyl isocyanide (0.43 g, 3.2 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.67 g, 93%, mp 90−93 °C). IR νmax: 3264, 3030, 1645, 1526, 1481, 1340 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.39−7.35 (m, 2H), 7.33−7.27 (m, 7H), 7.22−7.12 (m, 4H), 7.08−7.02 (m, 3H), 7.27 (d, 2H, J = 8.1 Hz), 6.34 (s, 1H), 2.22 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 171.2, 168.1, 140.9, 137.5, 135.6, 135.5, 134.1, 133.4, 132.5, 130.3, 129.7, 129.0, 128.8, 128.4, 128.2, 127.8, 127.3, 92.7, 66.6, 18.5. HRMS (DART+) calcd for C29H26IN2O2 [M + H]+ 561.10389, found 561.10431. N-(2-(tert-Butylamino)-2-oxo-1-phenylenethyl)-N-(2-fluorophenyl)-4-iodobenzamide (3j). Compound 3j was synthesized using 2fluoroaniline (0.62 g, 3.6 mmol), benzaldehyde (0.38 g, 3.6 mmol), 4iodobenzoic acid (0.89 g, 3.6 mmol) and tert-butyl isocyanide (0.30 g, 3.6 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.38 g, 72%, mp 178−180 °C). IR νmax: 3310, 2969, 1656, 1624, 1551, 1360 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.48 (d, 2H, J = 6.3 Hz), 7.23− 7.19 (m, 5H), 7.0.3−7.69 (m, 4H), 6.67 (t, 2H, J = 7.8, 15.3 Hz), 6.15 (s, 1H), 5.58 (s, 1H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 170.2, 168.4, 162.9, 159.6, 136.8, 136.5, 136.4, 135.4, 134.5, 132.3, 132.2, 130.2, 130.1, 128.6, 115.4, 115.1, 96.0, 66.2, 51.8, 28.6. HRMS (DART+) calcd for C25H25FIN2O2 [M + H]+ 531.0944, found 531.0935. N-(2-(tert-Butylamino)-2-oxo-1-phenylethyl)-N-(2-iodophenyl)benzamide (3k). Compound 3k was synthesized using 2-iodoaniline (0.72 g, 3.2 mmol), benzaldehyde (0.34 g, 3.2 mmol), benzoic acid (0.40 g, 3.2 mmol), and tert-butyl isocyanide (0.27 g, 3.2 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (1.11 g, 68%, mp 150−152 °C). IR νmax: 3340, 2970, 1674, 1626, 1469, 1353 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.95 (d, 1H, J = 7.9 Hz), 7.47 (d, 3H, 7.3 Hz),7.36 (t, 3H, J = 6.2 Hz), 7.22−7.07 (m, 7H), 6.68 (t, 1H, J = 7.6 Hz), 6.16 (s, 1H), 1.39 (s, 7H). 13C NMR (75 MHz, CDCl3) δ: 170.8, 169.0, 142.2, 139.2, 136.1, 133.7, 132.9, 131.1, 130.1, 129.6, 129.2, 129.1, 128.9, 128.5, 128.4, 128.2, 128.1, 127.9, 127.5, 127.2, 103.6,

N-((2-tert-Butylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)benzamide (3b). Compound 3b was synthesized using 4-iodoaniline (0.79 g, 3.6 mmol), benzaldehyde (0.40 g, 3.6 mmol), benzoic acid (0.44 g, 3.6 mmol), and tert-butyl isocyanide (0.30 g, 3.6 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (1.64 g, 89%, mp 193−195 °C). IR νmax: 3426, 3279, 2966, 1675, 1627, 1384, 1358 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.31−7.27 (m, 4H), 7.24 (s, 5H), 7.20−7.14 (m, 3H), 6.75 (d, 2H, J = 9.0 Hz), 6.14 (s, 1H), 5.69 (s, 1H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 170.9, 168.5, 140.9, 137.3, 135.7, 134.7, 132.2, 130.1, 129.6, 128.6, 128.5, 128.5, 127.7, 92.4, 66.4, 51.7, 28.6. HRMS (EI+) calcd for C25H25IN2O2 [M]+ 512.0961, found 512.0960. N-(2-tert-Butylamino)-2-oxo-1-phenylethyl)-4-chloro-N-(4-iodophenyl)-3-nitrobenzamide (3c). Compound 3c was synthesized using 4-iodoaniline (0.62 g, 2.8 mmol), benzaldehyde (0.3 g, 2.8 mmol), 4chloro-3-nitrobenzoic acid (0.57 g, 2.8 mmol), and tert-butyl isocyanide (0.23 g, 2.8 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.65 g, 98%, mp 151−153 °C). IR νmax: 3306, 3232, 1683, 1633, 1540, 1359 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.82 (d, 2H, J = 2.1 Hz), 7.33−7.29 (m, 3H), 7.24−7.15 (m, 4H), 7.11−7.09 (m, 2H), 6.69 (s, 2H), 6.04 (s, 1H), 5.39 (s, 1H), 1.29 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 167.9, 167.2, 147.2, 139.6, 137.9, 135.6, 133.9, 132.8, 132.3, 131.4, 130.3, 129.0, 128.8, 128.4, 126.0, 93.6, 66.5, 52.0, 28.6. HRMS (DART+) calcd for C25H24ClIN3O4 [M + H]+ 592.0500, found 592.0506. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)3-methoxybenzamide (3d). Compound 3d was synthesized using 4iodoaniline (0.60 g, 2.7 mmol), benzaldehyde (0.29 g, 2.7 mmol), 3methoxybenzoic acid (0.41 g, 2.7 mmol), and cyclohexyl isocyanide (0.30 g, 2.7 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.29 g, 83%, mp 161−163 °C). IR νmax: 3264, 3065, 2928, 1646, 1590, 1556, 1336 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.34−7.19 (m, 8H), 7.09−6.97 (m, 1H), 6.87−6.80 (m, 2H), 6.77−6.71 (m, 2H), 6.19 (s, 1H), 5.68 (d, 2H, J = 8.2 Hz), 3.90−3.80 (m, 1H), 3.64 (s, 3H), 2.03−1.81 (m, 2H), 1.61 (m, 3H), 1.41−1.25 (m, 2H), 1.19− 1.00 (m, 3H). 13C NMR (75 MHz, CDCl3) δ: 170.9, 168.5, 159.0, 141.0, 137.5, 137.0, 134.5, 132.4, 130.3, 129.0, 128.7, 121.0, 116.3, 113.4, 92.7, 66.1, 55.3, 48.9, 32.9, 25.5, 24.8. HRMS (EI+) calcd for C28H29IN2O3 [M]+ 568.1223, found 568.1213. N-(2-(tert-Butylamino)-2-oxo-1-phenylethyl)-N-(4-iodophenyl)-3methoxybenzamide (3e). Compound 3e was synthesized using 4iodoaniline (0.79 g, 3.6 mmol), benzaldehyde (0.38 g, 3.6 mmol), 3methoxybenzoic acid (0.55 g, 3.6 mmol), and tert-butyl isocyanide (0.30 g, 3.6 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.54 g, 79%, mp 107−109 °C). IR νmax: 3284, 3078, 2963, 1680, 1628, 1559, 1382 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.33−7.20 (m, 8H), 7.06−7.01 (m, 1H), 6.86−6.82 (m, 2H), 6.77−6.72 (m, 2H), 6.10 (s, 1H), 5.65 (s, 1H), 3.64 (s, 3H), 1.35 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 170.8, 168.6, 159.0, 137.5, 137.0, 134.8, 132.3, 130.2, 129.0, 121.1, 116.3, 113.5, 92.6, 66.6, 55.3, 51.8, 28.7. HRMS (EI+) calcd for C26H27IN2O3 [M]+ 542.1066, found 542.1092. N-(2-(tert-Butylamino)-2-oxo-1-phenylethyl)-3-fluoro-N-(4iodophenyl)benzamide (3f). Compound 3f was synthesized using 4iodoaniline (0.72 g, 3.2 mmol), benzaldehyde (0.34 g, 3.2 mmol), 3fluorobenzoic acid (0.45 g, 3.2 mmol), and tert-butyl isocyanide (0.27 g, 3.2 mmol) and purified by flash column chromatography (eluent 80:20 hexane/EtOAc). The product was obtained as a white solid (1.46 g, 86%, mp 205−207 °C). IR νmax: 3281, 3072, 1679, 1630, 1555, 1439, 1358, 1225 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.35− 7.18 (m, 7H), 7.15−7.01 (m, 3H), 6.96−6.87 (m, 1H), 6.76 (d, 2H, J = 7.9 Hz), 6.14 (s, 1H), 5.65 (s, 1H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 169.9, 168.3, 163.6, 160.3, 140.3, 137.9, 137.5, 134.4, 132.3, 130.2, 129.5, 129.4, 128.7, 124.2, 116.8, 11.6, 115.8, 115.5, 92.9, 66.4, 51.8, 28.7. HRMS (DART+) calcd for C25H25FIN2O2 [M + H]+ 531.0944, found 531.0967. 2578


Article

The Journal of Organic Chemistry 66.2, 51.8, 28.7. HRMS (DART+) calcd for C25H26IN2O2 [M + H]+ 513.1038, found 513.1033. N-(2-(tert-Butylamino)-2-oxo-1-phenylethyl)-N-(3-iodophenyl)benzmide (3l). Compound 3l was synthesized using 3-iodoaniline (0.72 g, 3.2 mmol), benzaldehyde (0.34 g, 3.2 mmol), benzoic acid (0.40 g, 3.2 mmol), and tert-butyl isocyanide (0.27 g, 3.2 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (1.59 g, 97%, mp 159−161 °C). IR νmax: 3320, 3059, 2968, 1655, 1631, 1551, 1448, 1358, 1253 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.43−7.09 (m, 12H), 6.98 (d, 1H, J = 7.9 Hz), 6.69 (t, 1H, J = 7.7 Hz), 6.12 (s, 1H), 5.79 (s, 1H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 171.0, 168.5, 142.3, 139.0, 136.0, 135.7, 134.6, 130.1, 130.0, 129.7, 129.5, 128.7, 128.6, 128.5, 127.8, 92.8, 66.8, 51.8, 28.7. HRMS (DART+) calcd for C25H26IN2O2 [M + H]+ 513.1038, found 513.1043. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-4-iodobenzamide (3m). Compound 3m was synthesized using benzylamine (0.51 g, 4.8 mmol), benzaldehyde (0.51 g, 4.8 mmol), 4-iodobenzoic acid (1.2 g, 4.8 mmol), and tert-butyl isocyanide (0.4 g, 4.8 mmol) and purified by flash column chromatography (eluent 90:10 hexane/ EtOAc). The product was obtained as a white solid (1.79 g, 71%, mp 155−156 °C). IR νmax: 3306, 1659, 1638, 1545, 1438, 1410 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.67 (s, 1H), 7.47−7.08 (m, 10H), 6.98 (s, 1H), 5.51 (s, 1H), 4.72 (d, 1H, J = 17.1 Hz), 4,44, (d, 1H, J = 14.5 Hz), 1.32 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 172.3, 168.2, 137.6, 135.8, 129.7, 128.9, 128.7, 128.4, 128.3, 126.9, 107.0, 5.7, 28.6. HRMS (DART+) calcd for C26H28IN2O2 [M + H]+ 527.11954, found 527.11972. N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-2-iodobenzamide (3n). Compound 3n was synthesized using benzylamine (0.43 g, 4.0 mmol), benzaldehyde (0.42 g, 4.0 mmol), 2-iodobenzoic acid (1.0 g, 4.0 mmol), and tert-butyl isocyanide (0.33 g, 4.0 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (1.69 g, 82%, mp 132−135 °C). IR νmax: 3304, 3029, 2931, 1659, 1638, 1547, 1408 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.73−7.66 (m, 2H), 7.44−7.25 (m, 7H), 7.15−7.09 (m, 4H), 7.02−6.93 (m, 2H), 5.53 (s, 1H), 4.71 (d, 1H, J = 16.6 Hz), 4.43 (d, 1H, J = 16.6), 1.31 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 171.5, 168.3, 138.7, 138.5, 135.6, 135.1, 130.1, 129.8, 129.2, 129.0, 128.8, 128.4, 128.1, 127.0, 125.7, 94.3, 51.8, 28.69. HRMS (EI+) calcd for C26H27IN2O2 [M]+ 526.1117, found 526.1125. N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-2-iodobenzamide (3o). Compound 3o was synthesized using benzylamine (0.29 g, 2.7 mmol), benzaldehyde (0.29 g, 2.7 mmol), 2-iodobenzoic acid (0.68 g, 2.7 mmol), and cyclohexyl isocyanide (0.29 g, 2.7 mmol) and purified by flash column chromatography (eluent 80:20 hexane/ EtOAc). The product was obtained as a white solid (0.71 g, 47%, mp 121−124 °C). IR νmax: 3299, 3029, 2924, 1675, 1607, 1548, 1424 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.83−7.59 (m, 2H), 7.47−7.23 (m, 6H), 7.15 (m, 3H), 7.04−6.93 (m, 2H), 5.53 (s, 1H), 4.68 (d, 1H, J = 16.5 Hz), 4.45−4.40 (m, 1H), 3.89−3.71 (m, 1H), 1.98−1.70 (m, 2H), 1.68−1.51 (m, 3H), 1.40−1.23 (m, 2H), 1.19−0.92 (m, 3H). 13C NMR (75 MHz, CDCl3) δ: 171.5, 168.2, 138.7, 138.3, 135.7, 134.7, 130.1, 129.8, 129.0, 128.9, 128.5, 127.1, 125.6, 94.1, 64.4, 52.6, 48.8, 32.8, 25.5, 24.8. HRMS (EI+) calcd for C28H29IN2O2 [M]+ 552.1274, found 552.1268. N,N′-((1,4-Phenylenebis(ethyne-2,1-diyl))bis(4,1-phenylene))bis(N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)benzamide) (1a). Compound 1a was synthesized using Ugi adduct (0.4 g, 0.740 mmol), 1,4-diethynylbenzene (0.047g, 0.037 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), and CuI (0.0071g, 0.037 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow solid (0.23 g, yield 33%, mp 133− 135 °C). IR νmax: 3055, 2922, 1646, 1589, 1436 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.48−7.08 (m, 28H), 6.99 (d, 4H, J = 7.01 Hz), 6.27 (s, 2H), 5.87 (d, 1H, J = 8.1 Hz), 4.02−3.74 (m, 1H), 1.99−1.88 (m, 4H), 1.70−1.56 (m, 6H), 1.37−1.27 (m, 4H), 1.17−1.03 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 171.0, 168.4, 141.2, 135.8, 134.5, 132.3, 131.4, 131.3, 130.3, 130.1, 129.5, 128.5, 128.4, 127.6, 122.8, 121.4,

91.3, 90.5, 89.7, 89.5, 66.1, 48.8, 32.7, 25.4, 24.6. HRMS (FAB+) calcd for C64H58N4O4 [M + H]+ 946.4458, found 946.4454. N,N′-((1,4-Phenylenebis(ethyne-2,1-diyl))bis(4,1-phenylene))bis(N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide) (1b). Compound 1b was synthesized using Ugi adduct (0.4 g, 0.780 mmol), 1,4-diethynylbenzene (0.049g, 0.390 mmol), PdCl2(PPh3)2 (0.055 g, 0.078 mmol), and CuI (0.039g, 0.039 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow oil (0.082 g, yield 12%, mp 124− 126 °C). IR νmax: 3329, 2963, 2922, 1683, 1634, 1513 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.37 (s, 2H), 7.32 (d, 2H, J = 6.0 Hz), 7.26− 7.22 (m, 5H), 7.20−7.11 (m, 5), 7.49 (d, 2H, J = 6.0 Hz), 6.17 (s, 1H), 5.73 (s, 1H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 171.0, 168.5, 141.3, 135.8, 134.7, 132.4, 131.5, 131.4, 130.3, 130.1, 129.6, 128.5, 128.4, 127.7, 122.8, 121.4, 90.6, 89.7, 66.6, 51.7, 28.6. HRMS (DART) calcd for C60H55N4O4 [M + H]+ 895.42233, found 895.42274. N,N′-((1,4-Phenylenebis(ethyne-2,1-diyl))bis(4,1-phenylene))bis(N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-4-chloro-3-nitrobenzamide) (1c). Compound 1c was synthesized using Ugi adduct (0.45 g, 0.760 mmol), 1,4-diethynylbenzene (0.048 g, 0.380 mmol), PdCl2(PPh3)2 (0.054 g, 0.077 mmol), and CuI (0.0072 g, 0.038 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow solid (0.376 g, yield 47%, mp 134−136 °C). IR νmax: 3066, 2961, 2923, 1642, 1536, 1514, 1343 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.92 (s, 1H), 7.42− 7.39 (m, 3H), 7.30 (d, 1H, J = 8.4 Hz), 7.27−7.18 (m, 7H), 7.02 (s, 2H), 6.15 (s, 1H), 5.52 (s, 1H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 168.0, 167.2, 147.1, 139.9, 135.8, 133.9, 132.8, 131.9, 131.5, 131.3, 130.5, 130.3, 128.9, 128.7, 128.3, 126.1, 122.8, 122.6, 90.4, 90.2, 66.6, 52.0, 28.6. HRMS (FAB+) calcd for C60H51Cl2N6O8 [M + H]+ 1053.3145, found 1053.3142. 4,4-(1,4-Phenylenebis(ethyne-2,1-diyl))bis(N-benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide) (1m). Compound 1m was synthesized using Ugi adduct (0.40 g, 0.760 mmol), 1,4diethynylbenzene (0.048 g, 0.380 mmol), PdCl2(PPh3)2 (0.054 g, 0.077 mmol), and CuI (0.0072 g, 0.038 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow solid (0.186 g, yield 27%, mp 160−162 °C). IR νmax: 3058, 3030, 2925, 1691, 1623, 1604, 1549, 1497, 1407 cm−1. 1 H NMR (300 MHz, CDCl3) δ: 7.70−7.64 (m, 3H), 7.55−7.46 (m, 9H), 7.28 (d, 2H, J = 9.0 Hz), 7.13 (s, 2H), 6.99 (s, 2H), 5.52 (s, 1H), 4.74 (d, 1H, J = 17.4 Hz), 4.46 (d, 1H, J = 16.8 Hz), 1.32 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: 172.5, 168.3, 136.1, 135.0, 131.6, 131.5, 129.6, 128.8, 128.6, 128.2, 126.9, 126.8, 124.4, 122.9, 90.6, 90.4, 51.6, 29.6, 28.5. HRMS (DART+) calcd for C62H59N4O4 [M + H]+ 923.45363, found 923.45294. 2,2′-(1,4-Phenylenebis(ethyne-2,1-diyl))bis(N-benzyl-N-(2-(tertbutylamino)-2-oxo-1-phenylethyl)benzamide) (1n). Compound 1n was synthesized using Ugi adduct (0.20 g, 0.38 mmol), 1,4diethynylbenzene (0.024 g, 0.19 mmol), PdCl2(PPh3)2 (0.027 g, 0.038 mmol), and CuI (0.0036 g, 0.019 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow solid (0.099 g, yield 28%, mp 99−102 °C). IR νmax: 3314, 3060, 2918, 2849, 1679, 1622, 1448, 1361 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.66 (s, 2H), 7.58−7.24 (m, 20H), 7.19−7.11 (m, 6H), 6.69 (s, 4H), 5.55 (s, 4H), 4.78 (d, 2H, J = 16.4 Hz), 4.50 (d, 2H, J = 16.4 Hz), 1.37 (s, 18H). 13C NMR (75 MHz, CDCl3) δ: 172.2, 168.3, 136.8, 135.1, 132.6, 131.6, 129.7, 128.8, 128.6, 128.3, 127.1, 126.9, 126.5, 90.4, 89.9, 51.7, 28.6. HRMS (FAB+) calcd for C62H59N4O4 [M + H]+ 923.4536, found 923.4541. 2,2′-(1,4-Phenylenebis(ethyne-2,1-diyl))bis(N-benzyl-N-(2-(tertbutylamino)-2-oxo-1-phenylethyl)benzamide (1l). Compound 1l was synthesized using Ugi adduct (0.28 g, 0.55 mmol), 1,4diethynylbenzene (0.035 g, 0.28 mmol), PdCl2(PPh3)2 (0.038 g, 0.055 mmol), and CuI (0.0052 g, 0.027 mmol) and purified by flash column chromatography (eluent 7:3 hexane/EtOAc). The product was obtained as a yellow solid (0.227 g, yield 47%, mp 118−120 °C). IR νmax: 3315, 3064, 2965, 1683, 1634, 1594, 1449, 1330 cm−1. 1H NMR (300 MHz, CDCl3) δ: 7.44 (s, 1H), 7.38−7.17 (m, 26H), 6.98 2579


Article

The Journal of Organic Chemistry (t, 2H, J = 7.5 Hz), 6.12 (s, 2H), 5.78 (2H), 1.40 (s, 18H). 13C NMR (75 MHz, CDCl3) δ: 171.0, 168.6, 141.6, 135.8, 134.8, 133.0, 132.4, 131.5, 130.3, 129.6, 128.6, 128.5, 128.4, 127.8, 123.3, 122.9, 90.4, 89.5, 67.2, 51.7, 28.6. HRMS (FAB+) calculated for C60H54N4O4 [M + H]+ 894.4145, found 894.4129.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02858. Synthetic procedures, spectroscopic 1H and 13C NMR data for all compounds, DLS measurements, VT 1H NMR data, and UV−vis and emission spectra of all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Braulio Rodríguez-Molina: 0000-0002-1851-9957 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support from PAPIIT-UNAM (IA201117) and CONACYT (238913). A.A.-G. thanks CONACYT (scholarship 279212). We thank B. Quiroz, A. Peña, and E. Huerta (NMR), L. Velasco and J. Pérez (MS), and R. Patiño (IR) for technical support. We thank Dr. Arturo Jimenez for his valuable scientific discussions. We also thank Dr. Alejandro Dorazco for the fluorescence experiments at low temperature.

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REFERENCES

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