meso-Bis(ethynyl) Versus meso-Bis(aryl) Calix[4]pyrroles

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Meso-bis(ethynyl) vs Meso-bis(aryl) Calix[4]pyrroles: Dimensionally Well-Modulated Receptors that can Regulate the Anion Binding Domains Ranjan Dutta, Srinivas Samala, Hongil Jo, Kang Min Ok, and Chang-Hee Lee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00639 • Publication Date (Web): 13 May 2019 Downloaded from http://pubs.acs.org on May 13, 2019

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The Journal of Organic Chemistry

Meso-bis(ethynyl) vs Meso-bis(aryl) Calix[4]pyrroles: Dimensionally Well-Modulated Receptors that can Regulate the Anion Binding Domains

Ranjan Dutta,† Srinivas Samala,† Hongil Jo,‡ Kang Min Ok,‡ and Chang-Hee Lee†* †Department

of Chemistry, Kangwon National University, Chun Cheon 24341, Korea, Email: [email protected], ‡Department of Chemistry, Sogang University, Seoul 121-742, Korea.

ABSTRACT Meso-substituted calix[4]pyrroles 2-6 containing direct meso-ethynyl linker displayed high binding affinities and unique conformational features on halide anion binding. A general conformational bias for the equatorial alignments of the meso-(aryl)ethynyl groups were observed in the host-halide complexes which was attributed to the repulsive anionalkyne interactions and released steric strain. Such conformational features of host-halide complexes persisted even in case of calix[4]pyrrole 6 bearing cationic meso-component, which displayed highest binding affinity for chloride anion among known meso-aryl calix[4]pyrroles. Synthetic details, conformational features and comparative halide anion binding properties of this series of calix[4]pyrroles are described. INTRODUCTION Calix[4]pyrroles based tetrapyrrolic macrocycles have found widespread application in the area of recognition, sensing, extraction and transportation of anionic species.1 Since the discovery of anion binding properties of parent octamethylcalix[4]pyrrole 1 by Sessler et al.2 different synthetic strategies have been developed for the modulation of anion binding properties of 1. Functionalization of meso-position is one of the route to generate new calix[4]pyrroles with strapping or pendant arms.3 Calix[4]pyrroles bearing various meso-aryl groups have been synthesized and explored for anion binding studies in recent years. Initial studies on the anion binding properties of mesobis-aryl calix[4]pyrroles were reported by Kohnke and coworkers. They concluded that presence of electron withdrawing group has a positive effect on anion binding affinity as observed in case of a meso-bis-(4-nitrophenyl) calix[4]pyrrole.4 We have reported differential anion selectivity of calix[4]pyrroles depending on the meso-aryl

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substituents using fluorescence dye displacement technique.5 Ballester and others have investigated energetics of anion-π interactions between anions and various meso-aryl groups of calix[4]pyrroles.6 Transmembrane nitrate anion transport activity and their correlation with the nature of meso-aryl groups were also studied in some cases.6a Attachments of hydrogen bond acceptors/donors at meso-positions were also reported to modulate anion binding properties. For instance, subtle geometrical differences were found in cases of fluoride and chloride complexes of a calix[4]pyrrole bearing 1,2-dichlorobenzimidazolyl groups as meso-component.7 Enhanced binding affinity for dihydrogen phosphate anion was reported for a meso-diacetyl calix[4]pyrrole taking advantage from the C=O•••H-O interactions.8 A meso-triazolyl calix[4]pyrrole displayed high binding affinity for chloride using additional triazole-C-H•••Cl interactions along with conventional NH•••Cl hydrogen bonds.9 Notably, axial alignment of meso-aryl groups were established as the most stable conformation in all host-anion complexes irrespective of nature of aryl groups. In all above cases, the tetrapyrrolic portion of the macrocycles usually adopted cone conformation and anion binding occurred in the pocket generated by the two diametrically positioned mesoaryl group. This trend of pocket site binding of anion persisted even in cases of mesotetra-aryl and meso-tetra-alkyl calix[4]pyrroles during anion complexation.10 Variety of acyclic and macrocyclic receptors containing arylethynyl linkages were well studied for various analyte detection, where the alkyne units served the role of a rigid linker as well as increased the conjugation of the host framework.11 Ballester and coworkers have reported synthesis of a bis-calix[4]pyrrole dimer connected through rigid alkyne linker for effective binding of ion-pair dimers and [2]pseudorotaxane formation.12 An expanded calix[4]pyrrole derivative bearing alkyne linker was synthesized by Cho et al. which showed relatively lower anion binding affinity.13 However, to the best of our knowledge, direct attachment of ethynyl groups at the meso-position of calix[4]pyrroles and their subsequent effects on anion binding properties have not been reported. Recently, we have demonstrated pseudo-equatorial conformation of meso-ethynyl extended aryl groups in the host-halide complexes of meso-arylethynyl calix[4]pyrroles 3 and 4 (Figure 1), which were unusual binding mode in the meso-substituted calix[4]pyrrole family.14 Herein, synthesis and a comparative studies on such unusual complexation geometry and effect of substituents


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are presented in the ethynyl extended calix[4]pyrrole systems. Indeed, a general trend of pseudo-equatorial conformation of meso-ethynyl groups and enhanced halide anion binding affinity compared with the analogous meso-aryl congeners are established. The unusual conformational features as a consequence of repulsive anion-alkyne interactions and released steric strain are rationalized in case of a model calix[4]pyrrole receptor 5. Repulsive alkyne-anion interaction is proprosed to regulate the anion binding domains even in case of calix[4]pyrrole 6 bearing a positively charged meso-components. R

R N

H N

H N N H

H N

N H

H N

H N

1

H N N H

N N H H 2, R = ethynyl 3, R = H 4, R = F

N

H N

H N

H N

N H

N H

5

6

N H

N H

pyrrole

Acetone

BF3.Et2O Ac2O, THF

TFA (51%)

BF3.Et2O (11%)

(25%) 8

O

N H

N H

NH HN 9

H N

H N

2

10

Scheme 1. Synthetic route for calix[4]pyrrole 2 Si Si

pyrrole

Acetone

TFA (32%)

BF3.Et2O

O

NH HN

Si

Si H N

H N

N

H N

H N N H

N H 5

4-iodopyridine Pd(PPh3)2Cl2 CuI, NEt3 (62%)

THF (76%)

H N N H

13

12

11

N H

N H

(11%)

H N

TBAF

H N

H N N H

N H

N H 5

N

N

MeI, CHCl3 NH4PF6

N

H N

H N

(77%)

14

Scheme 2. Synthetic route for calix[4]pyrroles 5 and 6


N H

N H 6

N H 7

Figure 1. Chemical structures of receptors 1-7

nBuLi

H N


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RESULTS Synthesis of receptor 2-6 Synthesis of alkynyl extended calix[4]pyrrole 2 is outlined in Scheme 1. In brief, dipyrromethane 10 was synthesized from the reaction of corresponding ketone 9 with pyrrole in presence of catalytic amount of trifluoroacetic acid. Condensation of 10 with acetone in presence of BF3•Et2O catalyst afforded the desired calix[4]pyrrole 2 in 11% yield. Presence of three sets of meso-methyl protons with 1:1:1 ratio in 1H NMR spectrum confirmed the structural identity of cis-conformer of calix[4]pyrrole 2 unambiguously. Synthesis of 3, 4 and 7 have been reported previously.4a,14 The meso-bis-ethynyl calix[4]pyrrole 5 was also synthesized as shown in Scheme 2. Acid-catalyzed condensation of dipyrromethane 12 with acetone afforded the calix[4]pyrrole 13 in 11% yield and resulting desilylation gave corresponding calix[4]pyrrole 5 in 76% yield. We envisaged that a model receptor bearing simple meso-ethynyl substituents could serve as a reference system for in-depth understanding for the anion binding affinity and conformational bias in the mesoethynyl extended systems i.e. 2, 3 and 4. The structure of 13 was confirmed by single crystal X-ray crystallography which revealed a typical 1,3-alternate conformation of the tetrapyrrolic core (Figure 2). Structural identity of calix[4]pyrrole 5 was also confirmed by X-ray analysis. Typical 1,3-alternate conformation of pyrrole rings along with pseudo-axial arrangement of meso-ethynyl groups were visualized from the crystal structure analysis (Figure 2). The terminal alkyne groups of calix[4]pyrrole 5 opened up further opportunity to develop

new

meso-substituted

calix[4]pyrrole

receptors

through

covalent

functionalization. We sought to design an ethynyl extended calix[4]pyrrole containing positively charged meso-aryl groups which could affect the conformation by reducing the anion-alkyne repulsion. With the key precursor 5 in hand, Sonogashira coupling with 4-iodopyridine was carried out as shown in Scheme 2; this afforded the intermediate 4-pyridylethynyl calix[4]pyrrole 14 in 62% yields. Subsequent methylation and anion-exchange with NH4PF6 afforded the desired cationic calix[4]pyrrole 6.


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Figure 2. Crystal structures of (a) calix[4]pyrrole 13: 1,3-alternate conformation of tetrapyrrolic core with bound acetone solvent was observed and (b) calix[4]pyrrole 5: 1,3alternate conformation of tetrapyrrolic core with bound dichloromethane solvent was observed. Solution state halide binding studies Qualitative halide anion binding studies of receptor 2 were performed by 1H NMR in CD3CN at 298 K. When a solution of TBAF (~0.28 equiv.) was added to 2 (8.32 mM in CD3CN), appearance of a new N-H signal was observed with large downfield shift (ca. Δδ = ~5.40 ppm) (SI). Signals corresponding to the parent NH signal disappeared completely upon addition of ~1.0 equiv. of TBAF indicating a slow complexationdecomplexation kinetics with 1/1 binding stoichiometry. Notably, slight downfield shift of aryl-CH proton was observed, whereas the corresponding meso-methyl protons (set a) endured downfield shift. These observation clearly suggest no anion-π interaction between meso-arylethynyl groups and bound fluoride anion, which is usually associated with up-field shift of the corresponding aryl-CH protons. Thus, the meso-methyl group must be in axial orientation and the meso-arylethynyl groups must adopt the equatorial conformation. Similar spectral changes were noted during titration of 2 with chloride anion. For instance, appearance of new NH peak (Δδ = 3.80 ppm) was observed upon addition of ~0.27 equiv. of Cl- to the solution of 2 (5.86 mM) in CD3CN (SI). Slow complexation-decomplexation kinetics was evident from the spectral pattern. Furthermore, downfield shift of aryl-CH and meso-methyl protons confirmed equatorial alignment of meso-arylethynyl groups. Broadening of NH signal was noted during gradual addition of bromide anion to a solution of 2 (8.63 mM) in CD3CN, which was reappeared after addition of ca. 1 equiv. of bromide (Δδ = 3.20 ppm) (SI). Small yet observable downfield shifts of pyrrole N-Hs were observed



during titration of 2 with iodide anion (SI). All the solution state 1H NMR titration studies clearly indicated that the meso-arylethynyl groups adopt the pseudo-equatorial conformation upon halide anion complexation. This pseudo-equatorial orientation persisted in case of the meso-ethynyl substituted calix[4]pyrrole 5 during complexation with halide anions. For example, 1H NMR titration of 5 (8.92 mM) with TBACl resulted in appearance of new peak corresponding to the pyrrole NHs with large downfield shift (Δδ = 3.30 ppm). Slow complexation-decomplexation kinetics was evident from the spectral pattern. Notably, simultaneous downfield shift (Δδ = 0.24 ppm) of meso-methyl protons (set a) and small upfield shift (Δδ = 0.02 ppm) of ethynyl protons clearly indicated the equatorial conformation of meso-ethynyl groups (SI). Similar spectral changes were recorded during titration of 5 with TBAF (SI). Gradual downfield shift of pyrrole N-Hs were observed during titration of 5 with TBABr (SI). The spectral pattern indicated a fast complexation-decomplexation kinetics and equatorial orientation of meso-ethynyl groups. Notably, similar spectral pattern were observed during titration of 6 with different halide anions. For example, addition of TBACl (in CD3CN) to a solution of 6 (6.63 mM) in CD3CN resulted appearance of new NH peak with large downfield shift (Δδ = 3. 68 ppm) (SI). The parent NH peak (7.84 ppm) was completely disappeared upon addition of ~1 equiv. of Cl- anion which indicated slow complexation-decomplexation kinetics with high binding affinity. Notably, pyridyl-CH protons also endured downfield shift during gradual addition of Cl- indicating presence of CH•••anion interaction rather than anion-π interactions. At the same time, meso-methyl protons (set a) also shifted downfield, clearly suggesting equatorial alignment of meso-N-methylpyridyl groups. 1H

NMR spectral changes with fluoride and bromide also indicated equatorial

conformation of meso-N-methylpyridyl groups of 6 (SI). The adaptation of this pseudo-equatorial orientation of meso-ethynyl or mesoarylethynyl groups are sharp contrast with the fact that directly attached meso-aryl groups occupy diaxial position and the bound anion resides between the two axially positioned aryl groups (cf. 7). Thus, the meso-ethynyl linkages must play a primary role to dictate the conformations of the host-halide complexes irrespective of the presence of any aryl groups. These dramatic differences in the conformation of the halide-host complexes are attributed to the steric repulsion between meso-aryl groups


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and β–pyrrolic protons (7eq, Scheme 3). In the case of the aryl akynyl group, the anion-π repulsion is predicted in 3ax which favor the equilibrium towards 3eq. No steric repulsion is expected when the triple bonds occupy the equatorial positions (3eq). Notably, repulsion between triple bond and anion dictates the conformational orientations even in case of calix[4]pyrrole 6 containing positively charged mesocomponent.

Scheme 3. Possible binding modes and mechanism of representative receptors 3 and 7 In order for quantitative assessment of above finings, isothermal titration calorimetry (ITC) measurement were carried out for 2 with different halide anions in acetonitrile at 298 K. Binding constants and Gibbs free energy changes were summarized in table S1 (SI). Highest binding constant was obtained for fluoride anion which was benefited from a favorable entropic contribution. The observed chloride binding affinity was found to be twenty five fold larger than that of calix[4]pyrrole 7 which contains no meso-ethynyl spacer (Table 1). Notably, analogous receptors 3 and 4 also displayed similar binding affinity enhancement compared to 7 (Table 1). Eleven fold increment in bromide binding affinity was obtained for 2 than 7. Slightly higher chloride binding affinity of 2 compared to octamethylcalix[4]pyrrole 1 is likely originated from the presence of aryl-CH•••anion interactions resulted from biased conformations. These results indicated that, direct ethynyl linker exerted positive effect on anion binding affinity in general. Moderate binding constant value (Ka = 52.5) was calculated for iodide anion from 1H NMR titration. Furthermore, the positive effect of electron



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withdrawing substituents in 2 and 4 was evident from the slightly higher anion binding affinity compared to those of 3. Binding affinities and thermodynamic parameters for calix[4]pyrrole 5 with various halide anions were also calculated from ITC measurement in acetonitrile at 298 K (SI). The observed binding affinities for chloride and

bromide

anions

were

found

to

be

comparable

with

that

of

octamethylcalix[4]pyrrole 1. As expected, calix[4]pyrrole 6 displayed highest binding affinity for halides among this ethynyl extended calix[4]pyrrole family (Table 1). In fact, the observed chloride binding affinity (Ka = 4.50 x 106) is highest among reported meso-aryl calix[4]pyrroles.6b Presence of stronger CH•••anion interactions between the positively charged N-methylpyridyl CH protons and halides contributes to the observed high binding affiniy. Anion selectivity studies of this particular receptor is currently

under

active

investigation.

However,

all

the

meso-arylethynyl

calix[4]pyrroles displayed higher binding affinities than that of calix[4]pyrrole 5. We concluded that presence of CH•••anion interactions between aryl-CH and halide anions are contributed to the observed higher binding affinities in 2, 3, 4 and 6. Table 1. Comparative chloride and bromide binding affinities for 1, 2, 3, 4, 5, 6 and 7 in CH3CN as determined by isothermal titration calorimetry at 298 K Binding constants (Ka) Ka(TBACl)

1a

2

3b

4b

5

6

7c

2.2 x 105

4.25 x 105

5.73 x 105

3.6 x 103

7.15 x 103

1.10 x 104

1.16 x 105 ± 4.85 x 103 1.93 x 103 ± 0.95 x102

4.50 x 106 ± 1.01 x 106 4.57 x 105 ± 3.51 x 104

2.65 x 104

Ka(TBABr)

6.71 x 105 ± 3.30 x 104 9.17 x 103 ± 1.08 x 102

avalue

0.8 x 103

from ref. 2b. bvalue from ref. 14. cvalue from ref. 6b

Solid state structural analysis Structural identity of anion bound calix[4]pyrroles having equatorial meso(aryl)ethynyl groups was unequivocally established from single crystal X-ray structure analysis. Crystals of complex 1 (2•TBAF) were obtained by slow evaporation of an acetonitrile solution of 2 in the presence of excess TBAF. Structural analysis of complex 1 revealed that one fluoride anion is bound to the cone shaped tetrapyrrolic core by four point hydrogen bonding interactions (Figure 3). The N•••F- distances ranges from 2.73 to 2.75 Å, whereas the N-H•••F- angles varies from 169 to 174o. Notably, the meso-(4-ethynylphenyl)ethynyl arms occupied the equatorial positions whereas the meso-methyl groups were axially positioned. The TBA cation occupied


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the π-rich cavity. Notably, similar spatial alignment of meso-arylethynyl groups were observed in the crystal structures of halide complexes of 3 and 4.14 Intermolecular CH•••Cl- interactions was clearly observed in case of chloride complex of 3 in solid state.14 Crystals of chloride bound calix[4]pyrrole 5 (Complex 2) were also obtained from an acetonitrile solution of 5 and excess TBACl. Four point NH•••Cl- hydrogen bonding interactions and pseudo-equatorial alignment of meso-ethynyl groups were clearly seen from the crystal structure analysis (Figure 3). Thus, this unique spatial orientation is found to be general trend in cases of meso-ethynyl extended calix[4]pyrroles. Further, the primary role of ethynyl groups was confirmed to dictate the conformation of host-guest complexes irrespective of presence of any aryl substitution.

Figure 3. Crystal structures of TBAF complex of 2 and TBACl complex of 5. Steric and electronic effects provided by the meso-ethynyl linkers led to such unique conformation of meso-groups in cases of 2, 3, 4, 5 and 6. Repulsive anion-ethynyl interactions between the halides and π-cloud of triple bond could favor the equilibrium towards the more stable meso-equatorial conformer (Scheme 3). The steric repulsion between β-pyrrolic protons and meso-aryl groups in cone conformation dictate the axial conformations of meso-aryl groups in cases of 7 and analogous meso-aryl calix[4]pyrroles.6 Lesser steric repulsion due to ethynyl extension in cases of mesoethynyl extended systems could also contribute to observed spatial orientation. CONCLUSION In summary, a series of meso-substituted calix[4]pyrroles bearing various mesoethynyl extended aryl groups were developed. Calix[4]pyrrole 5 bearing terminal ethynyl funtionality offers convenient scope to access meso-substitued calix[4]pyrroles



Page 10 of 18

such as 6. Synthesized receptors displayed higher halide anion binding affinity and unique host-guest complexation features. We have established these calix[4]pyrroles as superior halide anion receptors as evident from their higher binding affinities compared

to

the

analogous

meso-aryl

calix[4]pyrroles

and

simple

octamethylcalix[4]pyrrole. In particular, calix[4]pyrrole 6 displayed highest binding affinity for chloride anion among known meso-aryl calix[4]pyrroles. Distinct steric and electronic effects of meso-ethynyl spacers were reflected from the observed binding mode. Equatorial alignment of meso-(aryl)ethyny groups was unambiguously established as the preferred conformation for these series of calix[4]pyrroles. Solution state halide binding studies alongwith solid state structural evidences corroborated the above findings. Thus, regulation of the anion binding site in diametrically mesosubstituted calix[4]pyrrole which inherently possessing two different binding sites, is visualized. EXPERIMENTAL SECTION Materials and methods All reagents and solvents were perchased from commercial sources and were used as received. Reactions for air-senstive compounds were carried out under inert atmosphere. Synthesized compounds were purified by silica gel (230–400 mesh, MN) column chromatography. 1H NMR spectra of synthesized compounds were receorded on Bruker 400 MHz NMR, whereas

13C

NMR spectra were recorded at either 150.9

MHz or 100.6 MHz NMR. Mass spectroscopy were carreid out on either Voyager DESTR MALDI-TOF or JEOL JMS-700 GC mass spectrometer. Binding constants corresponding to the host-guest interaction were determined using isothermal titration calorimetry (ITC). For the ITC measurements, the host compound was dissolved in acetonitrile to give 0.401-0.892 mM stock solutions. These host solutions were titrated into tetrabutylammonium salt solutions (2.46 – 8.945 mM) of the anion in question contained in the insulated cell (1.4584 mL) of a fully computer operated VP-ITC MicroCalorimeter. Synthesis of 4-(4-ethynylphenyl)but-3-yn-2-one (9): n-butyllithium (2.5 M, 0.6 mL, 1.5 equiv.) was added to a solution of 0.126 g (1 mmol) of 1,4-diethynyl benzene in 25 mL of tetrahydrofuran at -78 °C under N2 atmophere. The reaction was allowed to


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warm from -78 °C to room temperature. The reaction was then cooled back to -78 °C, and 0.15 mL (1.2 equiv.) of BF3.Et2O was added. Acetic anhydride (0.13 mL, 1.4 equiv.) was added after 5.0 minute at the same temperature. The reaction was warmed gradually to room temperature over a period of 2 h. The reaction mixture was neutralized by 1 N aqueous NaOH solution. The mixture was extracted repeatedly with dichloromethane and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under vaccum and the crude was purified by column chromatography with hexane/dichloromethane as the eluent to afford the product 9 (42 mg, 0.25 mmol) as yellow solid in 25% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 7.46-7.52 (m, 4H, Ar-H), 3.22 (s, 1H, CH), 2.44 (s, 3H, CH3); 13C{1H} NMR (100 MHz, CDCl3) 184.5, 132.9, 132.4, 124.7, 120.3, 89.6, 89.3, 82.8, 80.4, 32.8 ppm; HMRS calcd. for C12H8O 168.0575 found 168.0577 (M+). Synthesis of dipyrromethane (10): To the mixture of 7 (50 mg, 0.3 mmol) and pyrrole (0.21 mL, 10 equiv.) kept under N2 atmosphere at 0°C, trifluoroacetic acid (0.022 mL, 1 equiv.) was added dropwise. The reaction mixture was quenched after 10 minute with 2M aqueous NaOH and extracted with CH2Cl2 (2 x 20 ml). The combined organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude was purified by silica gel column chromatography to afford dipyrromethane 10 (43 mg, 0.15 mmol) as yellow solid in 51% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.13 (brs, 2H, NH), 7.38-7.44 (m, 4H, Ar-H), 6.68-6.70 (m, 2H, pyr-H), 6.15-6.19 (m, 4H, pyr-H), 3.15 (s, 1H, CH), 1.99 (s, 3H, CH3); 13C{1H} NMR (CDCl3, 100 MHz) 134.5, 132.1, 131.7, 123.5, 122.0, 117.5, 108.5, 104.9, 83.2, 82.2, 79.0, 36.4, 30.1 ppm; HRMS calcd. for C20H16N2 284.1313 found 284.1315 (M+). Synthesis of calix[4]pyrrole 2: To a solution of compound 10 (0.45 g, 1.58 mmol) in acetone (250 mL) was added BF3.Et2O (0.195 mL, 1 equiv.) dropwise. The mixture was then stirred at room temperature for 6 h. The reaction was quenched by the addition of excess triethylamine. The excess volume of acetone was removed under reduced pressure and the resulting crude was extracted with CH2Cl2 (2 × 100 mL) and washed with water. The combined organic layer was dried with anhydrous Na2SO4, and the solvent was removed in vacuo. Column chromatography (silica gel; hexanes/dichloromethane = 2:1) afforded 2 (53 mg, 0.082 mmol) as foamy solid in 11% yield. 1H NMR (CD3CN, 400 MHz) δ ppm 7.89 (s, 4H, NH), 7.42-7.44 (m, 4H,



Ar-H), 7.38-7.42 (m, 4H, Ar-H), 6.01 (dd, J = 3.2 Hz, J = 2.8 Hz, 4H, pyr-H), 5.85 (dd, J = 3.2 Hz, J = 2.8 Hz, 4H, pyr-H), 3.47 (s, 2H, CH), 1.85 (s, 6H, CH3), 1.52 (s, 6H, CH3), 1.51 (s, 6H, CH3);

13C{1H}

NMR (CD3CN, 100 MHz) 140.5, 134.9, 133.1,

132.7, 124.8, 122.7, 105.1, 104.0, 96.0, 83.7, 82.2, 80.7, 36.8, 36.0, 29.1, 28.8, 28.6 ppm; MALDI-TOF calcd. for C46H40N4 648.3253 (exact mass) found 649.306 (M+H)+; HRMS found 648.3254 (M+). Synthesis of dipyrromethane (12): Trifluoroacetic acid (0.15ml, 2 mmol) was added dropwise to a mixture of pyrrole (1.38 ml, 20 mmol) and 11 (0.33 ml, 2 mmol) at 0oC under nitrogen atmosphere. The reaction was quenched with water after 10 minute and extracted with dichloromethane and finally washed with saturated aq. sodium bicarbonate solution. The combined organic layer was then dried over Na2SO4 and the solvent was concentrated in vacuo. The resulting crude was purified in silica gel using hexane/dichloromethane as eluent to afford 12 (164 mg, 0.64 mmol) as yellow viscous liquid in 32% yield. 1H NMR (CDCl3, 400 MHz) δ ppm 8.12 (brs, 2H, NH), 6.67-6.69 (m, 2H, pyr-H), 6.13-6.16 (m, 2H, pyr-H), 6.09-6.11 (m, 2H, pyr-H), 1.89 (s, 3H, CH3), 0.20 (s, 9H, CH3);

13C{1H}

NMR (CDCl3, 100 MHz) 134.6, 117.2, 108.5,

108.4, 104.7, 87.0, 36.7, 30.3, 0.2 ppm; HRMS calcd. for C15H20N2Si 256.1396 found 256.1398. Synthesis of calix[4]pyrrole 13: BF3.Et2O (0.14 ml, 1.13 mmol) was added dropwise to a solution of 12 (256 mg, 1.1 mmol) in acetone (140 ml). The reaction was allowed to stir at room temperature for 16 h under nitrogen atmosphere in dark. The reaction was quenched with triethylamine and excess acetone was removed in rotary. The crude was dissolved in dichloromethane and washed with water several times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified in silica gel using hexane/dichloromethane as eluent to afford calix[4]pyrrole 13 (33 mg, 0.056 mmol) as white solid in 11% yield. 1H NMR (CD3CN, 400 MHz) δ ppm 7.60 (s, 4H, NH), 5.94 (dd, J = 2.8 Hz, J = 6.4 Hz, 4H, pyr-H), 5.83 (dd, J = 2.8 Hz, J = 6.4 Hz, 4H, pyr-H), 1.71 (s, 6H, CH3), 1.49 (s, 6H, CH3), 1.47 (s, 6H, CH3), 0.13 (s, 18H, TMS);

13C{1H}

NMR (CD3CN, 100 MHz) 140.1, 134.6, 110.2, 105.0,

103.9, 86.5, 37.0, 35.9, 28.9, 28.8, 28.6 ppm (TMS peak merged with the reference); MALDI-TOF calcd. for C36H48N4Si2 592.342 (exact mass) found 593.353 (M+H)+.


Page 12 of 18

Page 13 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Synthesis of calix[4]pyrrole 5: Calix[4]pyrrole 13 (30 mg, 0.05 mmol) was dissolved in minimum volume of THF. Tetrabutylammonium fluoride (29 mg, 0.11 mmol) was added to it in one shot. The reaction was stirred for 30 min under nitrogen atmosphere. The solvent was removed in vacuo and the crude was purified in silica gel using hexane/dichloromethane as eluent to afford calix[4]pyrrole 5 (17 mg, 0.038 mmol) in 76% yield. 1H NMR (CD3CN, 400 MHz) δ ppm 7.74 (s, 4H, NH), 5.95 (t, 4H, J = 3.2 Hz, pyr-H), 5.82 (t, J = 3.2 Hz, 4H, pyr-H), 2.63 (s, 2H, CH), 1.76 (s, 6H, CH3), 1.50 (s, 6H, CH3), 1.48 (s, 6H, CH3);

13C{1H}

NMR (CD3CN, 100 MHz) 140.3, 134.7,

105.0, 103.8, 88.0, 71.5, 36.0, 35.9, 29.2, 28.5 ppm; MALDI-TOF calcd. for C30H32N4 448.263 (exact mass) found 449.308 (M+H)+. Synthesis of calix[4]pyrrole 6: Calix[4]pyrrole 2 (30 mg, 0.067 mmol), 4iodopyridine (30 mg, 2.2 equiv.), Pd(PPh3)2Cl2 (7 mg, 0.15 equiv.) and CuI (1.1 mg, 0.15 equiv.) was suspended in dry and degassed triethyamine (5 ml) under nitrogen atmosphere. The reaction mixture was then heated at 70°C for 16 h. It was then cooled to room temperature and the solvent was evaporated. The crude was then extracted with dichloromethane and

washed with water. The organic layer was dried over

Na2SO4 and evaporated to dryness. The crude was then purified in silica gel column chromatography in hexane/ethyl aceetate to afford the product 14 (25 mg, 0.041 mmol) in 62% yield. 1H NMR ((CD3)2CO, 400 MHz) δ ppm 8.76 (s, 4H, NH), 8.51 (q, 4H, J = 2.4 Hz, py-H), 7.30 (q, 4H, J = 2.8 Hz, py-H), 5.97 (t, 4H, J = 2.8 Hz, pyr-H), 5.79 (t, J = 2.8 Hz, 4H, pyr-H), 1.87 (s, 6H, CH3), 1.51 (s, 6H, CH3), 1.50 (s, 6H, CH3); 13C{1H}

NMR (DMSO-d6, 150 MHz) 150.4, 140.2, 133.7, 132.0, 131.9, 131.2, 129.3,

129.2, 126.0, 104.2, 102.9, 100.2, 78.8, 35.9, 35.2, 30.5, 28.6, 28.2 ppm; MALDI-TOF calcd. for C40H38N6 602.316 (exact mass) found 603.476 (M+H)+. Subsequenly, calix[4]pyrrole 14 (35 mg) was dissolved in dry chloroform (10 ml) and MeI (0.49 ml, 100 equiv.) was added to it. The reaction mixture was then refluxed for 24 h. During this time a yellow viscous liquid seprated from the reaction mixture which was washed with chloroform and dissolved in small volume of acetonitrile. Saturated aqueous solution of NH4PF6 was then added slowly to it and stirred for 2 h. A yellow color precipitate of 6 (40 mg, 0.044 mmol) was obtained which was washed with water and dried in vaccum. Yield: 77%. 1H NMR ((CD3)2CO, 400 MHz) δ ppm 8.99 (q, 4H, J = 3.2 Hz, py-H), 8.76-8.75 (m, 4H, NH), 8.14 (q, 4H, J = 3.6 Hz, py-H), 6.04 (t, 4H, J =



3.2 Hz, pyr-H), 5.82 (t, J = 2.8 Hz, 4H, pyr-H), 4.53 (s, 6H, CH3), 1.91 (s, 6H, CH3), 1.50 (s, 6H, CH3), 1.49 (s, 6H, CH3);

13C{1H}

NMR ((CD3)2CO, 100 MHz) 146.5,

141.2, 140.9, 133.0, 130.5, 109.3, 105.8, 104.1, 78.7, 49.0, 37.5, 36.1, 29.2, 28.5 ppm; MALDI-TOF calcd. for [C42H44N6PF6]+ 777.3264 (exact mass) found 777.323 (M+PF6)+. ACKNOWLEDGEMENTS Support from the Basic Science Research Program (2015R1A2A1A10052586) funded by the National Research Foundation (NRF) under the Ministry of Science, ICT & Future Planning of Korea is acknowledged. The Central Laboratory at KNU and the University-Industry Cooperation Foundation at KNU (520160033, D1001560-01-01) are also acknowledged. ASSOCIATED CONTENT Supporting Information. NMR spectra, MS data, NMR titration and ITC data, notes on XRD data. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES 1. (a) Kim, D. S.; Sessler, J. L. Calix[4]pyrroles: versatile molecular containers with ion transport, recognition, and molecular switching functions. Chem. Soc. Rev. 2015, 44, 532-546. (b) Saha, I.; Lee, J. T.; Lee, C.–H. Recent Advancements in Calix[4]pyrrole‐Based Anion‐Receptor Chemistry. Eur. J. Org. Chem. 2015, 38593885. 2. (a) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. M. Calix[4]pyrroles: Old Yet New Anion-Binding Agents. J. Am. Chem. Soc. 1996, 118, 5140-5141. (b) Sessler, J. L.; Gross, D. E.; Cho, W.-S.; Lynch, V. M.; Schmidtchen, F. P.; Bates, G. W.; Light, M. E.; Gale, P. A. Calix[4]pyrrole as a Chloride Anion Receptor: Solvent and Countercation Effects. J. Am. Chem. Soc. 2006, 128, 12281-12288. 3. (a) Yoon, D.-W.; Gross, D. E.; Lynch, V. M.; Sessler, J. L.; Hay, B. P.; Lee, C.-H. Benzene-, Pyrrole-, and Furan-Containing Diametrically Strapped Calix[4]pyrroles— An Experimental and Theoretical Study of Hydrogen-Bonding Effects in Chloride


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isomers. Chem. Commun. 2016, 52, 11139–11142. (e) Kumar, C. D.; Sirisha, K.; Dhaked, D. K.; Lokesh, P.; Sarma, A. V. S.; Bharatam, P. V.; Kantevari, S.; Sripadi, P. Investigation of Anion−π Interactions Involving Thiophene Walls Incorporated Calix[4]pyrroles. J. Org. Chem. 2015, 80, 1746–1753. 7. Mulugeta, E.; Dutta, R.; He, Q.; Lynch, V. M.; Sessler, J. L.; Lee, C.-H. Anion‐Dependent

Binding‐Mode

Changes

in meso‐(5,6‐Dichlorobenzimidazole)

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an

easy-to-prepare,

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Graphical abstract X-

H H N

H N

H N

H H N

X-

X-

H N R

H N N H

N H


X-

H N R

H N

H N

H N

meso-Bis(ethynyl) Versus meso-Bis(aryl) Calix[4]pyrroles

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