Selective Carboxylate Recognition Using Urea-Functionalized Unclosed Cryptands: Mild Synthesis and Complexation Studies

Abstract

Herein we present the synthesis and evaluation of anion-binding properties of 12 new receptors from the unclosed cryptand family. Their core is built on the stable 26-membered tetraamidic macrocyclic scaffold, whereas various alkyl and aryl urea substituents were introduced after a yield-limiting macrocyclization step (65–98%). The receptors strongly bind anions, in particular carboxylates, even in a highly competitive solvent mixture (DMSO-d₆ + H₂O 95:5 v/v).

The Lehn’s concept of supramolecular chemistry¹ has allowed for effective planning of diverse synthetic macrocyclic compounds, able to selectively bind neutral and ion molecules.^2,3 When considering supramolecular systems, we must take into account the weak interactions, including π-stacking, hydrophobic effect, and most importantly, hydrogen bonding,⁴ between all molecules present in the system: host, guest, solvents, and other components of their environment. The directivity of the hydrogen bonds determines the geometry of the receptor; moreover, the geometry of the complexed object must also be taken into account.⁵ For a couple of years, one can observe progress in studies of anion binding receptors. This involves the designing of new specialized systems having both open-chain⁶ and macrocyclic structures.⁷ Thus, introducing efficient hydrogen bond donors, such as amide⁸ or especially urea groups,⁹ should help to form a strictly defined network of bonds, favorably affecting the receptor’s selectivity. Urea derivatives, due to their specific geometry, are capable of selectively binding the Y-shaped carboxylates.¹⁰ Urea functions can be introduced easily into the structure of most molecular receptors,¹¹ and its importance is demonstrated by the key role they play in catalysis;⁶ they are also often found in pharmaceuticals¹² and natural compounds.¹³

In an earlier paper, we presented a procedure for synthesizing macrocyclic tetralactams using sodium methoxide.¹⁴ Subsequently, we applied this procedure to synthesize “unclosed cryptands”, containing a flexible lariat arm comprising an amide function.^8,15 Postfunctionalization studies regarding the said arm allowed for the introduction of large substituents within it.¹⁶ In the work reported herein, we resolved to strengthen the host–guest interactions in the said receptors, which can be obtained, as mentioned above, by introducing the urea function, characterized by a high yield and easily available and inexpensive components.

We synthesized macrocyclic receptors with a urea function in the lariat arm following the postfunctionalization procedure discussed in our previous paper.¹⁵ The tert-butyloxycarbonyl group (Boc) is used to protect the amine function, as it can be easily removed under mild conditions. This multistep procedure requires only one chromatographic purification of macrocyclic product 3 obtained with 61% yield, whereas the total yield of the procedure was 47% (Scheme 1).

Scheme 1. Synthesis of N-Boc-Protected Macrocyclic Precursor 3 and Its Postfunctionalization to 4a–l.

Through the postfunctionalization of precursor 3, carried out under one-pot conditions (successively by deprotection of the amine function, followed by a reaction with the appropriate isocyanate), we obtained 12 urea derivatives in generally excellent yields. These compounds are characterized by diverse lariat arms, containing both aliphatic units (4a, 4b) and aromatic units (4c–l). Within the group of aromatic compounds, the following derivatives should be distinguished: 4d–f (with electron-donating substituents) and 4g–l (with electron-withdrawing substituents).

We selected five urea derivatives from among the receptors so obtained and examined their complexing properties in relation to four anions (Cl^–, MeCO₂^–, PhCO₂^–, and H₂PO₄^–). This choice was dictated by the structure of the lariat arm and was limited to the following compounds: 4a with an aliphatic substituent, 4c containing a phenyl substituent, as well as 4d with an electron-donating group, and 4g and 4l with electron-withdrawing groups. The stability constants of receptor complexes with the studied anions were determined by ¹H NMR titration in a DMSO-d₆ mixture with the addition of 0.5% H₂O (v/v). We maintained a constant receptor concentration (∼10^–2 M) in each experiment. In all titration experiments, the addition of anion resulted in downfield urea moieties signals. The stability constants were calculated on the basis of chemical shift changes upon the additions of the anion. The results obtained are summarized in Table 1, where we ignore the results for H₂PO₄^– because this anion showed a very complex stoichiometry complexation model, which precluded the determination of reliable association constants. Despite the fact that we could not match the binding model to obtained experimental data, the chemical shift values for urea group protons show a strong affinity of H₂PO₄^– toward the used receptors (see Supporting Information).

Table 1. Stability Constants K_a (M^–1) for Complexes of Hosts 4(a, c, d, g) with Anions in DMSO-d₆ + 0.5% H₂O at 298 K^a.

receptor	R	Cl–	MeCO2–	PhCO2–
4a	n-Bu	90	5970	5180
4c	Ph	140	>104	>104
4d	p-C6H4OMe	140	>104	>104
4g	p-C6H4NO2	310	b	b

^aDetermined by ¹H NMR titration experiments using HypNMR 2008 software¹⁷ for fitting; anions added as TBA salts; estimated errors <10%.

^bDeprotonation of the receptor.

The corresponding titration curves are consistent with the 1:1 binding model for all experiments presented in Table 1.¹⁸ Receptor 4a with the n-butyl substituent showed the lowest affinity for all anions used. Its association constants for both carboxylate anions, however, are noteworthy: 5970 M^–1 for MeCO₂^– and 5180 M^–1 for PhCO₂^–. In the case of receptors 4c and 4d, nonlinear curve fittings indicated that these receptors form complexes with acetate and benzoate with constants more than 10000 M^–1, while maintaining the 1:1 binding model, this helps to rationalize our results, as these high values indicate the strong affinity of the receptors used toward carboxylates. Strong binding of the anionic molecule and a well-defined hydrogen bonding network was corroborated by DFT calculations (Scheme 2).

Scheme 2. Energy-Minimized Structures of Free Receptor 4c and Its Complex with the Benzoate Anion.

The last of the receptors examined in this titration series, namely, 4g (with NO₂ as a substituent), shows the highest affinity, among the receptors studied, toward Cl^– (310 M^–1): more than 2 times that of receptor 4c with a phenyl substituent. Unfortunately, our examination of this receptor’s affinity toward carboxylate anions was unsuccessful because of its rapid deprotonation process. The literature shows that this is a common phenomenon in the complexation of anions by receptors containing a nitro group in their aromatic substituent adjacent to functions possessing acidic protons.¹⁹ We confirmed the process of deprotonation by UV–vis spectroscopy tests. The results of this experiment, as well as the postulated mechanism of proton transfer, are shown in Scheme 3. The acetate anion causes deprotonation of the urea group, which results in the delocalization of the negative charge on the electron-withdrawing NO₂ group. The changed color of the solution indicates the occurrence of intermolecular charge transfer (ICT). We observed a bathochromic shift of the absorption maximum by 30 nm. The absorption band at 360 nm disappeared, while a new band appeared at 390 nm. We observed the emergence of an isosbestic point at 370 nm.

Scheme 3. Carboxylate-Induced Deprotonation of the Receptor 4g and Corresponding Charge-Transfer Transition States.

In connection with the aforementioned impossibility of using the ¹H NMR titration technique, we carried out titration experiments with the use of more competitive solvent systems (DMSO-d₆ with 5% H₂O (v/v)) (Table 2).

Table 2. Stability Constants K_a (M^–1) for Complexes of Hosts 4(c, d, l) with Anions in DMSO-d₆ + 5% H₂O at 298 K^a.

receptor	R	Cl–	MeCO2–	PhCO2–
4c	Ph	b	1120	1780
4d	p-C6H4OMe	60	2400	4070
4l	3,5-C6H3(CF3)2	120	7940	6760

^aDetermined by ¹H NMR titration experiments using HypNMR 2008 software¹⁷ for fitting; anions added as TBA salts; estimated errors <10%.

^bNot determined.

Experiments carried out in this system allowed us to determine, in the measurable range below 10000 M^–1, the stability constants K_a of complexes of receptors 4c and 4d with carboxylates. Both receptors displayed a higher binding affinity for PhCO₂^– over the considerably more basic MeCO₂^– (K_a 1780 vs 1120 M^–1 and 4070 M^–1 vs 2400 M^–1, for 4c and 4d, respectively). This unusual anti-Hofmeister type selectivity of 4c and 4d probably results from favorable π–π interactions between aromatic subunits of the host and the phenyl ring of benzoate. The literature shows that this uncommon effect occurs for the receptors containing a hydrophobic pocket in their structures.^20,21 For compounds 4c and 4d, the aromatic part of the lariat arm is near flat and has a hydrophobic character with a large share of regions with a positive electrostatic surface potential (ESP). In contrast, the lariat arm of receptor 4l is deviated from the planarity due to double substitution at meta positions by CF₃ groups. This substitution increases the acidity of NH protons of the urea group but also reduces the number of regions with positive ESP located on the lariat arm, thus minimizing the number of noncovalent interactions with the flat phenyl ring of benzoate (see Supporting Information for details). This diminishes the benzoate selectivity of receptor 4l, although the relative binding constants for carboxylates are highest than for receptors 4c and 4d.

Nonetheless, we decided to compare the very high association constants of receptor 4d with the constants found for the earlier-obtained amide receptor 5, with an analogous structure (Figure 1).

Figure 1.

Structures of receptors 4d and 5.

In the highly competing solvent medium of DMSO-d₆ + 5% H₂O, receptor 5 displayed a very weak affinity toward carboxylate anions (7 M^–1 for MeCO₂^– and 10 M^–1 for PhCO₂^–, respectively). The approximately 400-fold difference in bonding strength of the compared receptors indicates how well the urea system is matched geometrically to carboxylate anions. Receptor 4l with two electron-withdrawing trifluoromethyl groups showed the strongest complexing properties. The stability constants of its complexes with carboxylic anions are 7940 M^–1 for MeCO₂^– and 6760 M^–1 for PhCO₂^–, respectively. Moreover, we obtained a monocrystal of receptor 4l, whose structure is shown in Figure 2. It displays a high degree of preorganization; all four amide protons in the macrocycle are directed toward the center of the gap, and only the urea protons are located outside the macroring plane. The structure contains multiple water molecules in the crystal lattice, from which one is bound in the host cavity by three hydrogen bond interactions (d = 2.86–3.07 Å). Moreover, an intramolecular hydrogen bond N–O (2.90 Å) is observed between amide proton N(3) and carbonyl oxygen O(1) of the urea group. In addition, one CF₃ group from the lariat arm moiety is positioned above the pyridine ring forming short intramolecular CF₃-π interactions (d_C–F···centroid(pyridine) = 3.25 Å).

Figure 2.

Crystal structure of receptor 4l, top (a) and side (b) views. Nonacidic protons and remaining disordered water molecules were omitted for clarity.

In conclusion, we have presented a development of the previously reported unclosed cryptand postfunctionalization method, which enabled us to obtain a broad array of 12 new macrocyclic systems with an incorporated urea group. The compounds selected for complexation studies showed a strong affinity for carboxylate anions even in a very competing solvent medium, namely, DMSO-d₆ with 5% H₂O (v/v).

Experimental Section

Materials and Methods

All of the reagents were used as received. The solvents were dried by distillation over the appropriate drying agents. All solvents were obtained from common suppliers and used as received. Column chromatography was carried out using Merck Kieselgel 60 (63–100 μm mesh size), and TLC was carried out on Merck Kieselgel F254 plates. Melting points were determined using a Boëtius M HMK hot-stage apparatus and were uncorrected. The NMR spectra are recorded on a Bruker Mercury 400 instrument. Chemical shifts are reported in ppm (δ) and are set to the solvent residue peak. J coupling constants values are reported in hertz (Hz). Mass spectral analyses were performed with the ESI-TOF technique on a Mariner mass spectrometer from PerSeptive Biosystem. The lowest energy conformation of the complex of receptor 4c with PhCO₂^– was found after conducting a conformational search analysis, and selected conformers with lowest energies were optimized without any constrains at the DFT/M06-2X/6-31G(d)/C-PCM:DMSO level of theory using program Spartan’18 Parallel Suite (see Supporting Information for details).²²⁻²⁴

tert-Butyl N-{4,11,17,24-Tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}carbamate 3

The product 3 was obtained as previously described.¹⁵

General Procedure A for Obtaining Receptors 4a–l

A suspension of macrocyclic compound 3 (0.140 g, 0.23 mmol) in anhydrous DCM (3 mL) in 0 °C 4 M HCl in dioxane (0.286 mL, 1.15 mmol) was added. Then the mixture was stirred at room temperature for 1 h. Subsequently, the mixture was cooled to 0 °C, and then N,N-diisopropylethylamine (0.288 mL, 1.65 mmol) and the corresponding isocyanate (0.46 mmol) were added. The mixture was stirred for a further 30 min, the solvent was evaporated under a vacuum, and the residue was purified employing column chromatography and using a DCM/methanol mixture [99:1 → 95:5, v/v] as the eluent. The obtained colorless oil was dissolved in methanol and then sonicated in water.

3-Butyl-1-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4a)

Following General Procedure A and using n-butyl isocyanate (52 μL, 0.46 mmol), the product 4a (91 mg, 0.15 mmol, 65%) was obtained as a colorless solid (mp 133–134 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.42 (t, J = 5.1 Hz, 2H), 8.44 (t, J = 5.4 Hz, 2H), 8.21–8.09 (m, 3H), 7.72 (s, 1H), 7.08 (t, J = 8.3 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 6.24 (t, J = 4.1 Hz, 1H), 4.53 (s, 4H), 3.30–3.24 (m, 4H), 3.23–3.16 (m, 4H), 2.79 (dd, J = 12.2, 6.4 Hz, 2H), 1.69–1.62 (m, 4H), 1.56–1.47 (m, 4H), 0.89–0.83 (m, 2H), 0.70 (dd, J = 14.4, 7.2 Hz, 2H), 0.48 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.3, 162.8, 156.4, 152.4, 148.8, 139.1, 125.9, 123.9, 116.1, 105.0, 66.6, 39.0, 38.0, 31.4, 29.3, 26.4, 26.3, 19.0, 13.3. HRMS (ESI, MeOH): m/z calcd for C₃₀H₄₁N₇O₇Na [M + Na]⁺, 634.2965; found, 634.2964.

1-Cyclohexyl-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4b)

Following General Procedure A and using cyclohexyl isocyanate (59 μL, 0.46 mmol), the product (142 mg, 0.22 mmol, 97%) was obtained as a colorless solid (mp 163–164 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (t, J = 6.1 Hz, 2H), 8.43 (t, J = 5.6 Hz, 2H), 8.19–8.11 (m, 3H), 7.72 (s, 1H), 7.07 (t, J = 8.4 Hz, 1H), 6.65 (d, J = 8.5 Hz, 2H), 6.11 (d, J = 6.7 Hz, 1H), 4.53 (s, 4H), 3.29–3.27 (m, 2H), 3.27–3.19 (m, 8H), 1.72–1.62 (m, 6H), 1.56–1.46 (m, 7H), 1.00–0.93 (m, 2H), 0.45 (dd, J = 23.7, 11.8 Hz, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.8, 155.5, 152.2, 148.9, 139.1, 125.7, 123.9, 116.0, 104.9, 66.6, 48.0, 37.7, 32.6, 26.4, 25.0, 24.4, 23.6. HRMS (ESI, MeOH): m/z calcd for C₃₂H₄₃N₇O₇Na [M + Na]⁺, 660.3122; found, 660.3126.

1-Phenyl-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4c)

Following General Procedure A and using phenyl isocyanate (50 μL, 0.46 mmol), the product 4c (141 mg, 0.22 mmol, 97%) was obtained as a colorless solid (mp 177–178 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.17 (t, J = 5.9 Hz, 2H), 8.86 (s, 1H), 8.23 (t, J = 5.0 Hz, 2H), 8.18–8.06 (m, 4H), 7.30 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 8.4 Hz, 1H), 6.71–6.61 (m, 4H), 6.41 (t, J = 7.2 Hz, 1H), 4.58 (s, 4H), 3.20 (s, 8H), 1.52 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.8, 153.3, 152.6, 148.8, 139.3, 138.9, 127.8, 126.3, 123.9, 121.3, 117.9, 115.4, 105.3, 66.9, 38.8, 37.9, 26.4, 26.2. HRMS (ESI, MeOH): m/z calcd for C₃₂H₃₇N₇O₇Na [M + Na]⁺, 654.2652; found, 654.2647.

1-(4-Methoxyphenyl)-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4d)

Following General Procedure A and using 4-methoxyphenyl isocyanate (60 μL, 0.46 mmol), the product 4d (145 mg, 0.22 mmol, 95%) was obtained as a colorless solid (mp 146–147 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (t, J = 6.0 Hz, 2H), 8.54 (s, 1H), 8.25 (t, J = 5.3 Hz, 2H), 8.17–8.08 (m, 3H), 8.04 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.12 (t, J = 8.4 Hz, 1H), 6.67 (d, J = 8.5 Hz, 2H), 6.23 (d, J = 9.0 Hz, 2H), 4.57 (s, 4H), 3.38 (s, 3H), 3.21 (d, J = 5.6 Hz, 8H), 1.54 (dd, J = 13.7, 6.3 Hz, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.8, 153.9, 153.5, 152.6, 148.7, 138.9, 132.3, 126.2, 123.8, 120.0, 115.5, 113.1, 105.2, 66.9, 54.6, 38.8, 37.8, 26.4, 26.2. HRMS (ESI, MeOH): m/z calcd for C₃₃H₃₉N₇O₈Na [M + Na]⁺, 684.2758; found, 684.2755.

1-(3-Methoxyphenyl)-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4e)

Following General Procedure A and using 3-methoxyphenyl isocyanate (60 μL, 0.46 mmol), the product 4e (143 mg, 0.22 mmol, 94%) was obtained as a colorless solid (mp 135–136 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.04 (t, J = 6.1 Hz, 2H), 8.83 (s, 1H), 8.24 (t, J = 5.3 Hz, 2H), 8.14–8.08 (m, 3H), 8.06 (s, 1H), 7.12 (t, J = 8.4 Hz, 1H), 7.05 (t, J = 2.0 Hz, 1H), 6.84 (d, J = 9.1 Hz, 1H), 6.70–6.61 (m, 3H), 6.10 (dd, J = 8.2, 2.2 Hz, 1H), 4.58 (s, 4H), 3.49 (s, 3H), 3.24–3.15 (m, 8H), 1.58–1.49 (m, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.8, 159.2, 153.3, 152.7, 148.7, 140.6, 138.8, 128.8, 126.4, 123.9, 115.3, 110.3, 106.6, 105.3, 103.7, 66.9, 54.5, 38.8, 38.0, 26.5, 26.3. HRMS (ESI, MeOH): m/z calcd for C₃₃H₃₉N₇O₈Na [M + Na]⁺, 684.2758; found, 684.2759.

1-(2-Methoxyphenyl)-1-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12(32),13,15,27,29-hexaen-31-yl}urea (4f)

Following General Procedure A and using 2-methoxyphenyl isocyanate (61 μL, 0.46 mmol), the product 4f (145 mg, 0.22 mmol, 95%) was obtained as a colorless solid (mp 135–136 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (bs, 2H), 8.67 (s, 1H), 8.39 (s, 1H), 8.32 (bs, 2H), 8.10 (s, 3H), 7.90 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 6.35 (t, J = 7.5 Hz, 1H), 5.86 (t, J = 7.5 Hz, 1H), 4.58 (s, 4H), 3.82 (s, 3H), 3.20 (s, 8H), 1.52 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.5, 162.8, 153.1, 152.5, 148.7, 147.3, 138.8, 128.2, 126.3, 123.8, 121.3, 119.3, 118.4, 115.3, 109.9, 105.1, 66.8, 55.5, 38.8, 38.0, 26.4, 26.1. HRMS (ESI, MeOH): m/z calcd for C₃₃H₃₉N₇O₈Na [M + Na]⁺, 684.2758; found, 684.2758.

1-(4-Nitrophenyl)-1-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12(32),13,15,27,29-hexaen-31-yl}urea (4g)

Following General Procedure A and using 4-nitrophenyl isocyanate (75 mg, 0.46 mmol), the product 4g (115 mg, 0.17 mmol, 74%) was obtained as a yellow solid (mp 176–177 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.62 (s, 1H), 9.05 (t, J = 6.0 Hz, 2H), 8.22 (d, J = 9.1 Hz, 1H), 8.18–8.09 (m, 3H), 7.90 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 9.1 Hz, 2H), 7.61 (s, 2H), 7.21 (t, J = 8.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 4.58 (s, 4H), 3.29–3.14 (m, 8H), 1.61–1.41 (m, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.3, 162.8, 153.9, 148.7, 146.1, 145.6, 141.5, 139.2, 128.6, 125.1, 124.0, 123.9, 118.0, 106.1, 102.0, 67.4, 38.0, 26.7, 26.4. HRMS (ESI, MeOH): m/z calcd for C₃₂H₃₆N₈O₉Na [M + Na]⁺, 699.2503; found, 699.2497.

1-(3-Nitrophenyl)-1-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12(32),13,15,27,29-hexaen-31-yl}urea (4h)

Following General Procedure A and using 3-nitrophenyl isocyanate (75 mg, 0.46 mmol), the product 4h (140 mg, 0.21 mmol, 90%) was obtained as a yellowish solid (mp 170–171 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.31 (s, 1H), 8.99 (t, J = 5.9 Hz, 2H), 8.34 (s, 1H), 8.30 (t, J = 5.1 Hz, 2H), 8.24 (s, 1H), 8.10–7.98 (m, 3H), 7.49 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 7.10 (d, J = 6.9 Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H), 6.70 (d, J = 8.5 Hz, 2H), 4.61 (s, 4H), 3.25 (d, J = 5.1 Hz, 4H), 3.16 (d, J = 6.0 Hz, 4H), 1.56 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.5, 162.6, 153.0, 152.5, 148.5, 147.2, 140.5, 138.7, 129.0, 126.8, 123.7, 115.7, 114.6, 111.8, 105.1, 66.8, 38.8, 38.1, 26.4, 26.2. HRMS (ESI, MeOH): m/z calcd for C₃₂H₃₆N₈O₉Na [M + Na]⁺, 699.2503; found, 699.2499.

1-(2-Nitrophenyl)-1-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12(32),13,15,27,29-hexaen-31-yl}urea (4i)

Following General Procedure A and using 2-nitrophenyl isocyanate (75 mg, 0.46 mmol), the product 4i (142 mg, 0.21 mmol, 91%) was obtained as a yellowish solid (mp 156–157 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.84 (s, 1H), 9.38 (s, 1H), 9.15 (t, J = 6.0 Hz, 2H), 8.28 (d, J = 8.3 Hz, 1H), 8.18 (t, J = 4.8 Hz, 2H), 8.15–8.11 (m, 3H), 7.79 (dd, J = 8.3, 1.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 6.64 (t, J = 7.6 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 4.59 (s, 4H), 3.25–3.15 (m, 8H), 1.51 (bs, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.7, 152.5, 152.5, 148.7, 139.0, 136.6, 134.8, 133.8, 127.0, 124.8, 124.0, 122.0, 121.5, 114.5, 105.1, 66.8, 38.7, 37.8, 26.3, 26.0. HRMS (ESI, MeOH): m/z calcd for C₃₂H₃₆N₈O₉Na [M + Na]⁺, 699.2503; found, 699.2498.

1-(4-Cyanophenyl)-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4j)

Following General Procedure A and using 4-cyanophenyl isocyanate (66 mg, 0.46 mmol), the product 4j (148 mg, 0.23 mmol, 98%) was obtained as a colorless solid (mp 171–172 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.28 (s, 1H), 9.14 (t, J = 6.1 Hz, 2H), 8.33 (s, 1H), 8.20 (t, J = 5.3 Hz, 2H), 8.15–8.10 (m, 3H), 7.42 (d, J = 8.7 Hz, 2H), 7.16 (t, J = 8.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 4.60 (s, 4H), 3.27–3.16 (m, 8H), 1.53 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.4, 162.7, 152.6, 152.4, 148.6, 143.7, 139.1, 132.2, 126.8, 123.8, 118.9, 117.5, 114.6, 105.1, 102.9, 66.7, 38.8, 38.0, 26.3, 26.1. HRMS (ESI, MeOH): m/z calcd for C₃₃H₃₆N₈O₇Na [M + Na]⁺, 679.2605; found, 679.2605.

3-{4,11,17,24-Tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}-1-[4-(trifluoromethyl)phenyl]urea (4k)

Following General Procedure A and using 4-(trifluoromethyl)phenyl isocyanate (66 μL, 0.46 mmol), the product 4k (148 mg, 0.21 mmol, 92%) was obtained as a colorless solid (mp 174–175 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.23 (t, J = 6.1 Hz, 2H), 9.14 (s, 1H), 8.32 (s, 1H), 8.15 (t, J = 5.4 Hz, 2H), 8.13–8.07 (m, 3H), 7.51 (d, J = 8.5 Hz, 2H), 7.16 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 4.59 (s, 4H), 3.21 (d, J = 3.1 Hz, 8H), 1.52 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.5, 162.8, 153.1, 152.6, 148.6, 143.1, 139.0, 126.7, 125.2, 123.9, 117.8, 114.9, 105.2, 66.8, 38.7, 37.9, 26.3, 26.1. HRMS (ESI, MeOH): m/z calcd for C₃₃H₃₆F₃N₇O₇Na [M + Na]⁺, 722.2526; found, 722.2520.

1-[3,5-Bis(trifluoromethyl)phenyl]-3-{4,11,17,24-tetraoxo-2,26-dioxa-5,10,18,23,32-pentaazatricyclo[25.3.1.1^12,16]dotriaconta-1(31),12,14,16(32),27,29-hexaen-31-yl}urea (4l)

Following General Procedure A and using 3,5-bis(trifluoromethyl)phenyl isocyanate (80 μL, 0.46 mmol), the product 4l (170 mg, 0.22 mmol, 96%) was obtained as a colorless solid (mp 164–165 °C). ¹H NMR (400 MHz, DMSO-d₆): δ 9.50 (s, 1H), 9.09 (t, J = 6.0 Hz, 2H), 8.30 (s, 1H), 8.19 (t, J = 5.3 Hz, 2H), 8.07 (s, 3H), 7.97 (s, 2H), 7.23 (s, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 4.60 (s, 4H), 3.21 (s, 8H), 1.53 (s, 8H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 167.5, 162.7, 153.1, 153.0, 148.6, 141.5, 138.7, 130.5, 127.0, 124.4, 123.8, 121.7, 121.6, 117.6, 114.6, 105.4, 67.0, 38.7, 37.9, 26.5, 26.2, 25.4. HRMS (ESI, MeOH): m/z calcd for C₃₄H₃₅F₆N₇O₇Na [M + Na]⁺, 790.2400; found, 790.2377.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.9b03082.

• Copies of ¹H and ¹³C NMR spectra of all of the compounds and Cartesian coordinates of calculated structures, X-ray crystallographic data, and titration experiments for receptors 4(a,c,d,g,l) and 5 (PDF)

• CIF file for compound 4l (CIF)

Accession Codes

CCDC 1854521 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cam-bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

Author Contributions

The authors contributed to the following: conceptualization, P.N., K.D., and J.J.; methodology, P.N., K.D., J.J., and M.M.; validation, P.N. and M.M.; formal analysis, P.N. and M.M.; investigation, P.N.; resources, J.J.; data curation, P.N. and M.M.; writing the original draft preparation, P.N., M.M., and J.J.; writing, review, and editing, P.N., M.M. and J.J.; visualization, P.N.; supervision, J.J.; project administration, J.J.; funding acquisition, J.J.

The authors declare no competing financial interest.