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5,10-Diacylcalix[4]pyrroles: synthesis and anion binding studies† Sanjeev P. Mahanta and Pradeepta K. Panda* 5,10-Diacylcalix[4]pyrrole, a new positional isomer of the recently reported 5,15-diacylcalix[4]pyrrole, is synthesized as its two configurational isomers by acid catalysed condensation of meso-diacyltripyrrane with pyrrole. The solution phase anion binding of the two isomers of 5,10-diacylcalix[4]pyrrole was inves-
Received 28th September 2013, Accepted 22nd October 2013
tigated by 1H NMR spectroscopy in chloroform-d and isothermal titration calorimetry (ITC) in acetonitrile to gain insights into the positional and conformational effects of substituents on the macrocycle peri-
DOI: 10.1039/c3ob41966e
phery towards anion binding. During the investigation, a functionalized, stable pyrrole-2-carbinol was iso-
www.rsc.org/obc
lated and subsequently converted to the corresponding tripyrrane in situ.
Introduction The discovery of anion binding by meso-octamethylporphyrinogen 1 and its subsequent renaming as calix[4]pyrrole in analogy with the closely related calix[4]arenes by Sessler and coworkers drew wide attention from researchers towards this macrocycle.1 Subsequently, many transformations and modifications have been carried out on macrocycle 1 including mesosubstitution(s), β-substitution(s), single side strapping, core modification and core expansion.2 The design of a synthetic host for a specific guest relies on the optimal stabilization of the host–guest complex and this can be either driven by favourable enthalpy or entropy or a combination of both. In order to achieve enhanced selectivity towards a targeted guest, fine tuning of the interaction sites is required, which in turn requires appropriate functionalization such that better complementarity of the size and shape of the interacting sites between the receptor and the guest is achieved. In general most of the abiotic host–guest interactions are enthalpy driven.3 However, very recently Ursu and Schmidtchen reported that the selectivity can also be manipulated through appropriate design of hosts where host–guest complexation could be realized by overcoming an enthalpically unfavorable process by a highly entropy driven one.4 The larger size, enthalpy of hydration and accessibility in a very narrow pH
School of Chemistry, University of Hyderabad, Hyderabad, India. E-mail: [email protected], [email protected], [email protected]; Fax: (+)91-40-2301-2460 † Electronic supplementary information (ESI) available: Spectroscopic characterisation data, NMR titration data, ITC profile and DFT structure as well as X-ray crystallographic structure (CIF files) of compounds 5, 7, and cis-4. CCDC 909033–909035. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41966e
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range make anion recognition very difficult to achieve, compared to their cationic counterparts. The major challenge in anion recognition is to maximize the overall negative Gibb’s free energy change upon complexation (ΔG) through appropriate enthalpy–entropy compensation. Anion recognition chemistry has received growing attention in supramolecular chemistry due to its essential roles in biology, medicine, catalysis, and environmental science.5 Phosphates are one of the most important constituents of living systems as signaling units, energy storage and transduction.6 Furthermore, phosphates are industrially important components of both medicinal drugs and fertilizers. Phosphates are also responsible for hyperphosphatemia of patients with kidney failure and eutrophication of natural water resources.6 Therefore, selective binding of phosphates is of great importance to researchers and the challenges in phosphate binding chemistry have germinated a plethora of synthetic abiotic hosts in the literature.6 It is presumed that calix[4]pyrrole bearing preorganised and rigid binding domains will exhibit enhanced affinity
Fig. 1 Structures of meso-octamethylcalix[4]pyrrole 1 and deep cavity calixpyrroles 2.
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and selectivity towards anions (Fig. 1). In this regard, all the meso positions of calix[4]pyrrole were substituted by aryl groups (2a–b) to achieve a deep cavity and resulted in the formation of four configurational isomers. However, all of these isomeric receptors displayed a negative selectivity towards anions, compared to 1 owing to steric congestion.7 Separately, Namor and coworkers synthesized meso-tetramethyltetrakis(3-hydroxyphenyl)calix[4]pyrrole 2c and isolated its ααββ and αβαβ isomers and found that the ααββ isomer shows higher affinity for H2PO4− in acetonitrile while the αβαβ derivative prefers the F− ion.8 In another study, Ballester and coworkers used the αααα isomer of meso-tetrarylcalix[4]pyrrole receptors as a model to quantify chloride–π interaction in solution as a result of enforced proximity between the anion and the peripheral arenes.9 We envisaged that flexible anchors endowed with suitable functionality at the calixpyrrole periphery may enhance the affinity towards suitable anions. In this regard, recently we have demonstrated that the presence of two acyl substituents at the opposite meso-positions of 5,15-diacylcalix[4]pyrrole leads to only two configurational isomers, cis-3 and trans-3 (Fig. 2), where the former displays enhanced binding affinity towards a dihydrogenphosphate ion than 1, owing to favorable CvO⋯H–O hydrogen bonds between the anchoring acyl groups with the anion.10 Continuing our research endeavors towards the development of newer functionalized calix[4]pyrroles towards anion binding, herein we report the synthesis of 5,10-diacylated calix[4]pyrrole 4 (a positional isomer of 3), its solid state structure and anion binding studies. To the best of our knowledge, so far there has been no report on the synthesis of 5,10-meso-substituted calix[4]pyrrole and a study of the effect of substituents on the anion binding properties with respect to their positions on the calix[4]pyrrole periphery. Therefore, here we intend to understand the effect of the positional difference of the functional group and/or H-bonding functionality, i.e. acyl groups around the macrocycle periphery towards anion discrimination.
Paper
Results and discussion Compound 4 was synthesized by following a two-step protocol where the first step involves the synthesis of tripyrrane 7 followed by its acid catalyzed condensation with pyrrole in the presence of acetone. However, initial attempts to prepare 7 following Sessler’s protocol,11 i.e. with low acid concentration (0.025 equiv.), yielded dipyrromethane 6 (31%) along with a colorless liquid compound (Scheme 1). 1H NMR spectroscopic analysis displays a similar spectrum like dipyrromethane 6; however, an additional broad singlet appears at 4.59 ppm. Furthermore, the intensity ratio of α- and β-pyrrolic protons, NH and meso-methyl and acyl-methyl protons along with the new signal appears to be 1 : 2 : 1 : 3 : 3 : 1 (that in the case of 6 is 2 : 4 : 2 : 3 : 3 without the new signal). On the other hand, the corresponding 13C NMR spectrum shows the disappearance of the peak at 52.74 ppm (as observed in 6) with concomitant evolution of a new peak at 77.45 ppm. A deuterium exchange study revealed the exchangeable nature of the peak at 4.59 ppm and hence led us to tentatively presume the structure as a pyrrole-2-carbinol 5 (Scheme 1). LCMS did not provide any consistent data (m/z + 1 = 136 and m/z + 1 = 154), maybe owing to its instability during the operating conditions. In order to understand its structure unequivocally, we tried to grow a single crystal at low temperature. Fortunately, the solid state structure (crystals obtained by cooling at −20 °C) obtained via single crystal X-ray diffraction analysis at 100 K confirmed our presumption (Fig. 3). To the best of our knowledge, this is the first stable, structurally characterized pyrrole2-carbinol with alkyl substituents. Even though mono-alkyl and/or aryl pyrrole-2-carbinol are well known in porphyrinogen chemistry,12 the diaryl- or alkyl-functional group substituted pyrrole-2-carbinols are quite rare in the literature.13 Subsequently, we optimized the reaction conditions in order to obtain the desired tripyrrane which involves addition of a higher equivalent of trifluoroacetic acid (0.1 equiv.) to a
Scheme 1
Fig. 2 Structures of the four isomers of meso-diacylcalix[4]pyrrole. Top: 5,15-diacylcalix[4]pyrrole 3; bottom: 5,10-diacylcalix[4]pyrrole 4.
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Synthesis of pyrrole-2-carbinol 5.
Fig. 3 Single crystal X-ray structure of compound 5. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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Scheme 2
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Synthesis of tripyrrane 7.
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Scheme 4
Scheme 3
Dehydration of pyrrole-2-carbinol 5.
mixture of pyrrole and 2,3-butanedione (molar ratio 3 : 1) and stirring it for 3 h followed by quenching with excess triethylamine. The column chromatographic isolation yielded tripyrrane 7 (16%) along with dipyrromethane 6 (Scheme 2). This observation led us to conclude that at higher acid concentration, the pyrrole-2-carbinol to azafulvene intermediate conversion (Scheme 3) is more facile, which resulted in the formation of the desired tripyrrane.14 The unexpected stability of compound 5 may be attributed to the presence of a strong intermolecular O–H⋯O hydrogen bonding (ESI†). In order to check the fate of the reaction, we monitored the acid catalysed homo-condensation reaction of the pyrrole-2-carbinol with mass spectroscopy, which clearly provides the mass of some azafulvene intermediates (ESI†) indicating that the reaction proceeds via the formation of an azafulvene intermediate and at low acid concentration (with 0.05 equiv. of TFA), the pyrrole2-carbinol 5 to azafulvene 8 conversion (i.e. the dehydration process) is not efficient (Scheme 3). Single crystals of tripyrrane 7 were grown by keeping the oily material at low temperature and the solid state structure reveals that both the acyl groups reside on the same side, i.e. cis orientation, while the pyrrole NHs orient away from each other, clearly indicating the crystallisation of the meso-stereoisomer (Fig. 4). A careful investigation of the 1H and 13C NMR spectra and single crystals of compound 7 reveals the presence of the meso-stereoisomer only, which indicates that other stereoisomers are comparatively less stable and probably decompose under the
Fig. 4 Single crystal X-ray structure of compound 7. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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Synthesis of meso-diacylated calix[4]pyrroles 4.
reaction conditions and/or during purification. With the desired precursor in hand, finally we could successfully carry out the condensation of the tripyrrane 7 with pyrrole and acetone using BF3·OEt2 as a catalyst in dichloromethane solvent at room temperature to obtain the desired macrocycle 5,10-diacylcalix[4]pyrrole 4 as a mixture of two configurational isomers, designated (like the 5,15-analogues) as cis-4 (same side) and trans-4 (opposite side) (Scheme 4).10 We have performed the reaction for a longer time (12 h), such that sufficient acidolysis occurs in order to yield both the isomers in reasonably good quantity.15 Subsequent purification by silica gel column chromatography of the reaction mixture resulted in the isolation of trans-4 (7%) followed by the cis-4 (10%) as white solids as the more polar fractions (Scheme 4), along with the first four fractions meso-octamethylcalix[4]pyrrole 1, mono-meso-acylcalix[4]pyrrole and the two configurational isomers of 5,15-diacylcalix[4]pyrrole 3 as the side products (formed due to acidolysis).15 Interestingly, at the initial stage of the reaction several spots appeared in TLC, rendering their isolation almost impossible. However, the emergence of a much more resolved TLC pattern after continuing the reaction for a sufficiently longer time again confirms our previous observation during the formation of 7, i.e. during acidolysis, some of the products undergo decomposition. Both the isomers of compound 4 were characterized by 1H and 13C NMR, mass, IR and elemental analysis. 1H NMR spectra of both isomers reveal the presence of three types of N–H protons, thereby indicating the asymmetric nature of their H-bonding cavity (ESI†). Further, the structural integrity of the cis-isomer (crystals grown by slow evaporation of an ethyl acetate solution) could be unequivocally assigned in the solid state via X-ray diffraction analysis (Fig. 5). The structure clearly
Fig. 5 Single crystal X-ray structure of cis-4 showing clearly 1,3-alternate conformation of the pyrrole moieties. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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reveals the cis-orientation of the meso-acyl substituents with respect to the calix[4]pyrrole moiety, along with the regular 1,3-alternate conformation of the pyrrole units. Interestingly, one acyl moiety orients towards the binding domain of the calix[4]pyrrole, while the other one resides away, probably to minimize the nonbonding repulsive interaction between them. Further, the crystal packing displays intermolecular hydrogen bonding between the two acyl oxygens with the N–Hs of an adjacent macrocycle, while its two N–Hs (directed away from the acyl groups) form H-bonding with the two acyl oxygens of another calixpyrrole moiety, to form a two-dimensional helical network (ESI†). Unfortunately all our efforts to obtain a good quality single crystal of trans-4 did not find any success. Preliminary anion binding studies were carried out on both the calix[4]pyrrole isomers using 1H-NMR titration studies in CDCl3 (due to the poor solubility of trans-isomers in acetonitrile) with various anions (F−, Cl−, Br−, I−, H2PO4−, HSO4−, ClO4− and NO3−) as their tetrabutyl ammonium (TBA) salts. It is observed that both isomers show a general preference towards the fluoride ion among the halides and the H2PO4− ion among the studied oxoanions. As expected, quantitative 1 H NMR titration studies showed a distinct downfield shift for NH and an upfield shift for β-CH proton signals with gradual addition of an anion (ESI†). It also displayed evidence of very fast complexation–decomplexation equilibrium in the case of cis-4-F−, trans-4-F− and cis-4-H2PO4− complexes, since addition of approximately 0.2 equiv. of the corresponding salts resulted in the broadening of the pyrrole N–H signals and subsequent disappearance until addition of ∼1 equiv. of these salts (ESI†). On the other hand, in the case of cis-4-Cl−, cis-4-Br− and trans4-H2PO4− complexes, the NH signals remain intact, indicating the occurrence of rather slow complexation–decomplexation equilibrium on the NMR time scale. The formation of more than one singlet corresponding to the NH resonances, both in the case of cis-4 and trans-4 upon complexation with anions, reflects the retention of the asymmetric nature of their H-bonding core in the resulting complexes. Further, the 1H NMR study reveals that the observed anisochronicity of the binding domain is higher in the case of the trans-isomer than in its cisanalogue. For example, in the case of trans-4, addition of H2PO4− separated the NH resonances by almost 1 ppm (∼8.5 ppm and ∼9.5 ppm); on the other hand, in the case of the cis-isomer the difference between them is negligible (Fig. 6 and 7). In addition, in the case of cis-4, the β-pyrrolic protons which resonate at 5.90–6.00 ppm appear as asymmetric multiplets; however, the addition of 1.0 equiv. of TBAF split it into four equivalent singlets which are not visualized in the case of its trans-counterpart, supporting our above-mentioned notion. Further detailed studies to determine the thermodynamic parameters and binding constants were performed by isothermal titration calorimetry (ITC) in acetonitrile. In contrast to NMR spectroscopic analysis, ITC allows one to study the overall heat change of the system, including solvent contribution. Thus, it provides direct access to the energetics of the binding event without retreating to a structural probe that may
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Fig. 6 Change in 1H NMR spectra of cis-4 upon the addition of tetrabutylammonium salts of different anions: (a) pure cis-4, (b) cis-4 in the presence of TBAF, (c) cis-4 in the presence of TBACl, (d) cis-4 in the presence of TBAH2PO4 and (e) cis-4 in the presence of TBABr.
Fig. 7 Change in 1H NMR spectrum of trans-4 upon the addition of tetrabutylammonium salts of different anions: (a) pure trans-4, (b) trans4 in the presence of TBAF, (c) trans-4 in the presence of TBACl, (d) trans4 in the presence of TBAH2PO4 and (e) trans-4 in the presence of TBABr.
or may not reflect the entirety of the associative processes (e.g., an NMR spectroscopic signal).3h A glance at the binding constants obtained (Table 1) reveals a marginal difference in the overall affinity constant between the receptors 3 and 4, which is in the expected line owing to their inherent structural similarity. However, as a significant general trend, it was observed that cis-4 possesses a relatively higher binding ability than cis3 in the case of complexation with F−, Cl− and Br− ions, while in the case of the dihydrogenphosphate ion the opposite trend is noticed, which is otherwise higher than that reported for receptor 1. In all cases, a good fit to a 1 : 1 receptor–anion stoichiometry was obtained. A close look at the thermodynamic parameters obtained from the ITC experiments (Table 1) reveals that fluoride complexation is both enthalpically and entropically favoured, although the former contribution is relatively higher. On the other hand, in the case of other anions the complexation is entropically not favorable (except for cis4·Cl− and trans-3·H2PO4−). The favorable entropy observed upon complexation with the fluoride ion may be attributed to the release of the three water molecules from the hydrated TBA salt to the bulk solution. Further, the overall enthalpy–entropy compensation upon dihydrogenphosphate complexation is more in the case of the cis-isomers than chloride complexation, thereby resulting in their lower affinity towards dihydrogenphosphate than the chloride ion. On the other hand, transisomers display quite similar binding affinities towards the chloride and dihydrogenphosphate ions. However, the overall enthalpy–entropy penalty is lower in the case of both cis-3 and
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Table 1 Energetics of host–guest binding of the two isomers of 3 and 4 with different anions as their tetrabutylammonium salts in acetonitrile at 303 K as determined by isothermal titration calorimetry (ITC)
Aniona
Host
TΔS (kcal mol−1)
ΔH (kcal mol−1)
ΔG (kcal mol−1)
Ka (ITC) (M−1)
F−
cis-3 cis-4 trans-3 trans-4 1 cis-3b cis-4 trans-3b trans-4 1c cis-3b cis-4 trans-3 trans-4 1d cis-3b cis-4 trans-3b trans-4 1b
0.44 2.42 3.54 1.03 ND −1.29 2.53 −2.28 −2.46 −2.91 −5.24 −1.05 BDL BDL −3.56 −0.55 −2.75 2.26 −3.60 −3.27
−7.93 ± 0.15 −6.6 ± 0.05 −4.34 ± 0.03 −6.78 ± 0.08 ND −8.95 ± 0.12 −5.29 ± 0.02 −3.32 ± 0.44 −8.06 ± 0.20 10.16 ± 0.20 10.66 ± 0.94 −6.54 ± 0.29 BDL BDL −8.34 −7.94 ± 0.06 −9.72 ± 0.24 −3.32 ± 0.08 −9.12 ± 1.2 −9.77 ± 0.05
−8.37 −9.02 −7.88 −7.81 ND −7.66 −7.82 −6.60 −5.60 −7.29 −5.42 −5.49 BDL BDL −4.77 −7.40 −6.97 −5.58 −5.52 −6.50
1.11 ± 0.32 × 106 3.2 ± 0.86 × 106 4.77 ± 0.88 × 105 4.34 ± 0.79 × 105 ND 3.3 ± 0.66 × 105 4.45 ± 0.38 × 105 1.11 ± 0.09 × 104 1.09 ± 0.07 × 104 2.2 ± 0.2 × 105 8.02 ± 0.66 × 103 9.08 ± 0.84 × 103 BDL BDL 2.7 × 103 2.15 ± 0.15 × 105 1.05 ± 0.24 × 105 1.16 ± 0.08 × 104 1.23 ± 0.40 × 104 4.50 ± 0.16 × 104
Cl−
Br−
H2PO4−
ND: not determined by ITC; BDL: below the detection limit of ITC. a All the anions used were as their tetrabutylammonium salts. b From ref. 10. c From ref. 2f. d From ref. 16.
cis-4 calix[4]pyrrole isomers than 1, resulting in their higher affinity constants towards the dihydrogenphosphate ion. Although the exact nature of the host–guest interaction could not be ascertained owing to the lack of good quality diffraction grade crystals, the DFT optimized structure of the complexes confirms the above presumption (Fig. 8). Like cis-3, here also the enhanced affinity of cis-4 towards the dihydrogenphosphate ion (compared to 1) may be attributed
to the additional CvO⋯H–O hydrogen bonds between the carbonyl oxygen and hydrogens of the anion. Furthermore, the relatively higher affinity of cis-4 and cis-3 towards halides than 1 (Table 1) may be attributed to the weak C–H⋯X− interaction between the methyl groups of the acyl substituents to the anion due to the enforced proximity (ESI†).17 On the other hand, the lower affinity of cis-4 towards the dihydrogenphosphate ion than cis-3 may be attributed to the steric mismatch of the hydrogen bonding sites of the host and the anion (tetrahedral disposition between the two OHs of the anion, compared to almost right angled orientation of the two meso-acyl groups). The receptor trans-4 displays about an order lower affinity towards anions compared to its cis-analogue, probably due to the competition of the acyl group (directed away from the core) with the incoming anions of a neighbouring macrocycle,10 whereas the marginally higher binding affinity of trans4 than trans-3 towards chloride and dihydrogenphosphate ions may be ascribed to the additional weak interaction between the methyl hydrogens and the anion, apart from the relatively strong interaction between the anchoring acyl group directed towards the core and the anion (ESI†).10
Conclusions
Fig. 8 The space filling model of DFT-optimized structure of the model complexes. Top left: [cis-4·F]−; top right: [cis-4·H2PO4]−; bottom left: [cis-4·F]−; and bottom right: [trans-4·H2PO4]− (right), showing clearly the proposed H-bonding pattern. Colour code: cyan: fluorine, red: oxygen, blue: nitrogen, orange: phosphorus, grey: carbon, white: hydrogen.
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In conclusion, we have demonstrated the synthesis of a new positional isomer of the meso-diacylcalix[4]pyrroles. When the two acyl groups are placed at the 5,10-positions of the calix[4]pyrrole periphery, their preference towards halide ions increases (fluoride displays the largest enhancement). On the other hand, their placement at the 5,15-positions leads to higher affinity towards the dihydrogenphosphate ion. Further, the synthesis and structure of a stable pyrrole-2-carbinol (the
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first derivative containing alkyl and a functionalized group) and its subsequent in situ conversion to tripyrrane are also demonstrated. Also we have illustrated the first example of a one-pot synthesis of functionalized tripyrrane. This may spur the development of new functionalized building blocks leading to interesting porphyrinoids.
Experimental section NMR spectra were recorded on a Bruker Avance-400 MHz FT NMR spectrometer using tetramethylsilane (TMS, δ = 0) as an internal standard at room temperature. Mass spectral determinations were carried out using a Shimadzu-LCMS-2010 mass spectrometer and elemental analyses were obtained through a Thermo Finnigan Flash EA 1112 analyzer. HRMS data were recorded using a Brucker Maxis spectrometer. Melting points were determined using open capillary tubes on a BIO-TECH, India apparatus. IR spectra were recorded on a JASCO-FT-IR model 5300 and a NICOLET 5700 FT-IR spectrometer. Microcalorimetric titrations were performed using an Isothermal Titration Calorimeter (ITC) purchased from Microcal Inc., MA. The Origin software provided by Microcal Inc. was used to calculate the binding constant (Ka) and the enthalpy change (ΔH). All tetrabutylammonium salts (of anions) for NMR and ITC titration were purchased from Sigma-Aldrich® and were directly used in the titration experiment (fluoride as its trihydrate). During 1H NMR titrations the receptor solutions were titrated by adding known quantities of a concentrated solution of the anions in question. The anion solution used to effect the titrations contained the receptor at the same concentration as the receptor solutions into which they were being titrated. The quantum mechanical DFT calculations were performed with the Gaussian 03 program package. The Becke three-parameter hybrid (B3)18 functional was used along with the Lee–Yang– Parr (LYP)19 correction. The 6-311++G(d,p) basis set is employed in all the reported calculations. General crystallographic details Data for 5 were collected on a BRUKER SMART-APEX CCD diffractometer at 100 K. Data for 7 and cis-4 were collected on an Oxford Gemini A Ultra diffractometer with a dual source at 298 K. Mo-Kα (λ = 0.71073 Å) radiation was used to collect the X-ray reflections of the crystal. CCDC numbers 909034 (5), 909035 (7) and 909033 (cis-4) contain the supplementary crystallographic data. Preparation of 3-hydroxy-3-(1H-pyrrol-2-yl)butan-2-one 5 Pyrrole (2.3 mL, 33 mmol, 3 equiv.) and 2,3-butanedione (1 mL, 11 mmol, 1 equiv.) were mixed in a 10 mL round bottom flask. The flask was immersed in a salt-ice bath and TFA (0.021 mL, 0.27 mmol, 0.025 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 3 h under a N2 atmosphere. The reaction mixture was quenched by adding triethylamine. The excess pyrrole was removed by vacuum distillation at ∼70–80 °C. The product was purified by
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silica gel column chromatography (20% EtOAc + 80% hexane). The first fraction obtained as a white oil (650 mg, 28%) upon solidification at low temperature (or dried under high vacuum) corresponds to meso-acyldipyrromethane 6. The second fraction (720 mg, 40%) which is obtained as a colourless liquid (at room temperature) corresponds to compound 5. Compound 5 crystallizes upon storing in a freezer at −20 °C. FT-IR data (KBr) – 3398, 1709 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 8.39 (br, s, 1H, NH), 6.73 (d, 1H, pyrrole CH, J = 1.6 Hz), 6.22 (m, 2H, pyrrole CH), 4.59 (s, 1H, OH), 2.21 (s, 3H, CH3), 1.72 (s, 3H, CH3); 13C NMR (in CDCl3, 100 MHz): δ in ppm 209.50, 131.33, 118.42, 108.79, 106.65, 77.45, 24.44, 23.01. LCMS m/z calcd for C8H11NO2 (M + H) 154, found 154; Elemental analysis for C8H11NO2 calcd (found); C 62.73 (62.86), H 7.24 (7.13), N 9.14 (9.21). Preparation of 3,3′-(1H-pyrrole-2,5-diyl)bis(3-(1H-pyrrol-2-yl)butan-2-one) (5,10-diacyltripyrrane) 7 Pyrrole (2.3 mL, 33 mmol, 3 equiv.) and 2,3-butanedione (1 mL, 11 mmol, 1 equiv.) were mixed in a 10 mL round bottom flask. The flask was immersed in a salt-ice bath and TFA (0.140 mL, 1.1 mmol, 0.1 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 3 h under a N2 atmosphere. The reaction mixture was quenched by adding triethylamine. The excess pyrrole was removed by vacuum distillation at ∼70–80 °C. The product was purified by silica gel column chromatography (20% EtOAc + 80% hexane). The first fraction obtained as a white oil (700 mg, 30%) corresponds to compound 6. The second fraction obtained as a colourless oil (315 mg, yield 16%) crystallizes at low temperature to yield compound 7. M.P. – 126–128 °C; FTIR data (KBr) – 3736.7, 3392.1, 1703.6 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 8.49–8.69 (br, m, 3H, NH), 6.74 (s, 2H, pyrrole CH), 6.16 (m, 2H, pyrrole CH), 5.95–6.01 (m, 4H, pyrrole CH), 2.10 (s, 3H, CH3), 1.81 (s, 3H, CH3). 13C NMR (in CDCl3, 100 MHz): δ in ppm 209.67, 132.81, 132.08, 118.05, 108.46, 106.83, 106.76, 52.66, 26.53, 25.00. LCMS m/z cald for C20H23N3O2 (M − H) 336, found 336; elemental analysis for C20H23N3O2 calcd (found); C 71.19 (71.28), H 6.87 (6.76), N 12.45 (12.56). Preparation of compound 4 5,10-Diacyltripyrrane 7 (900 mg, 2.7 mmol, 1 equiv.) was dissolved in a mixture of freshly distilled pyrrole (2 mL, 27 mmol, 10 equiv.), dry acetone (10 mL) and dry dichloromethane (200 mL) at room temperature under a nitrogen atmosphere and then BF3·OEt2 (0.083 mL, 0.7 mmol, 0.25 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1 M NaOH. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the combined organic layer was dried over anhydrous sodium sulphate. The solutions were evaporated under reduced pressure and the residue was purified by column chromatography using silica gel (eluent: 15% EtOAc + 85% hexanes) to afford the required
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5,10-diacylcalix[4]pyrroles with trans-4 (100 mg, 7%) and cis-4 (125 mg, 10%) isomers as white solids. trans-4 Isomer: M.P. – 210–212 °C; FT-IR data (KBr) – 3369.73, 3298.5, 1704.05 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 7.58 (br, s, 1H, NH), 7.54 (br, s, 2H, NH), 7.36 (br, s, 1H, NH), 5.95 (m, 6H, pyrrole CH), 5.91 (m, 2H, pyrrole CH), 2.11 (s, 6H, CH3), 1.71 (s, 6H, CH3), 1.52 (s, 12H, CH3); 13 C NMR (in CDCl3, 100 MHz): δ in ppm 207.20, 140.07, 138.20, 132.55, 130.66, 106.77, 106.25, 103.66, 103.42, 52.69, 35.34, 29.41, 28.97, 26.76, 25.10; LCMS m/z calcd for C30H36N4O2 (M + H) 485.63, found 485.25; elemental analysis for C30H36N4O2 calcd (found); C 74.35 (74.28), H 7.49 (7.58), N 11.56 (11.66). cis-4 Isomer: M.P. – >220 °C (with decomposition); FT-IR data (KBr) – 3408.22, 3364.38, 3287.67, 1693.15 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 7.65 (br, s, 2H, NH), 7.57 (br, s, 1H, NH), 7.33 (br, s, 1H, NH), 5.97 (m, 4H, pyrrole CH), 5.94 (d, 2H, pyrrole CH, J = 2.4 Hz), 5.91 (t, 2H, pyrrole CH, J = 2.8 Hz), 2.14 (s, 6H, CH3), 1.73 (s, 6H, CH3), 1.53 (s, 12H, CH3); 13 C NMR (in CDCl3, 100 MHz): δ in ppm 207.36, 140.10, 138.29, 132.714, 130.64, 106.48, 106.28, 103.69, 103.43, 52.58, 35.37, 29.61, 28.85, 26.73, 24.40; LCMS m/z calcd for C30H36N4O2 (M + H) 485.63, found 485.15; elemental analysis for C30H36N4O2 calcd (found); C 74.35 (74.51), H 7.49 (7.41), N 11.56 (11.48).
Organic & Biomolecular Chemistry
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Acknowledgements This work was supported by the Council of Scientific & Industrial Research (CSIR), India project no. 01/(2449)/10/EMR-II). SPM thanks CSIR (for a Senior Research Fellowship) and the School of Chemistry Development Fund, University of Hyderabad for financial support.
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PAPER
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5,10-Diacylcalix[4]pyrroles: synthesis and anion binding studies† Sanjeev P. Mahanta and Pradeepta K. Panda* 5,10-Diacylcalix[4]pyrrole, a new positional isomer of the recently reported 5,15-diacylcalix[4]pyrrole, is synthesized as its two configurational isomers by acid catalysed condensation of meso-diacyltripyrrane with pyrrole. The solution phase anion binding of the two isomers of 5,10-diacylcalix[4]pyrrole was inves-
Received 28th September 2013, Accepted 22nd October 2013
tigated by 1H NMR spectroscopy in chloroform-d and isothermal titration calorimetry (ITC) in acetonitrile to gain insights into the positional and conformational effects of substituents on the macrocycle peri-
DOI: 10.1039/c3ob41966e
phery towards anion binding. During the investigation, a functionalized, stable pyrrole-2-carbinol was iso-
www.rsc.org/obc
lated and subsequently converted to the corresponding tripyrrane in situ.
Introduction The discovery of anion binding by meso-octamethylporphyrinogen 1 and its subsequent renaming as calix[4]pyrrole in analogy with the closely related calix[4]arenes by Sessler and coworkers drew wide attention from researchers towards this macrocycle.1 Subsequently, many transformations and modifications have been carried out on macrocycle 1 including mesosubstitution(s), β-substitution(s), single side strapping, core modification and core expansion.2 The design of a synthetic host for a specific guest relies on the optimal stabilization of the host–guest complex and this can be either driven by favourable enthalpy or entropy or a combination of both. In order to achieve enhanced selectivity towards a targeted guest, fine tuning of the interaction sites is required, which in turn requires appropriate functionalization such that better complementarity of the size and shape of the interacting sites between the receptor and the guest is achieved. In general most of the abiotic host–guest interactions are enthalpy driven.3 However, very recently Ursu and Schmidtchen reported that the selectivity can also be manipulated through appropriate design of hosts where host–guest complexation could be realized by overcoming an enthalpically unfavorable process by a highly entropy driven one.4 The larger size, enthalpy of hydration and accessibility in a very narrow pH
School of Chemistry, University of Hyderabad, Hyderabad, India. E-mail: [email protected], [email protected], [email protected]; Fax: (+)91-40-2301-2460 † Electronic supplementary information (ESI) available: Spectroscopic characterisation data, NMR titration data, ITC profile and DFT structure as well as X-ray crystallographic structure (CIF files) of compounds 5, 7, and cis-4. CCDC 909033–909035. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41966e
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range make anion recognition very difficult to achieve, compared to their cationic counterparts. The major challenge in anion recognition is to maximize the overall negative Gibb’s free energy change upon complexation (ΔG) through appropriate enthalpy–entropy compensation. Anion recognition chemistry has received growing attention in supramolecular chemistry due to its essential roles in biology, medicine, catalysis, and environmental science.5 Phosphates are one of the most important constituents of living systems as signaling units, energy storage and transduction.6 Furthermore, phosphates are industrially important components of both medicinal drugs and fertilizers. Phosphates are also responsible for hyperphosphatemia of patients with kidney failure and eutrophication of natural water resources.6 Therefore, selective binding of phosphates is of great importance to researchers and the challenges in phosphate binding chemistry have germinated a plethora of synthetic abiotic hosts in the literature.6 It is presumed that calix[4]pyrrole bearing preorganised and rigid binding domains will exhibit enhanced affinity
Fig. 1 Structures of meso-octamethylcalix[4]pyrrole 1 and deep cavity calixpyrroles 2.
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and selectivity towards anions (Fig. 1). In this regard, all the meso positions of calix[4]pyrrole were substituted by aryl groups (2a–b) to achieve a deep cavity and resulted in the formation of four configurational isomers. However, all of these isomeric receptors displayed a negative selectivity towards anions, compared to 1 owing to steric congestion.7 Separately, Namor and coworkers synthesized meso-tetramethyltetrakis(3-hydroxyphenyl)calix[4]pyrrole 2c and isolated its ααββ and αβαβ isomers and found that the ααββ isomer shows higher affinity for H2PO4− in acetonitrile while the αβαβ derivative prefers the F− ion.8 In another study, Ballester and coworkers used the αααα isomer of meso-tetrarylcalix[4]pyrrole receptors as a model to quantify chloride–π interaction in solution as a result of enforced proximity between the anion and the peripheral arenes.9 We envisaged that flexible anchors endowed with suitable functionality at the calixpyrrole periphery may enhance the affinity towards suitable anions. In this regard, recently we have demonstrated that the presence of two acyl substituents at the opposite meso-positions of 5,15-diacylcalix[4]pyrrole leads to only two configurational isomers, cis-3 and trans-3 (Fig. 2), where the former displays enhanced binding affinity towards a dihydrogenphosphate ion than 1, owing to favorable CvO⋯H–O hydrogen bonds between the anchoring acyl groups with the anion.10 Continuing our research endeavors towards the development of newer functionalized calix[4]pyrroles towards anion binding, herein we report the synthesis of 5,10-diacylated calix[4]pyrrole 4 (a positional isomer of 3), its solid state structure and anion binding studies. To the best of our knowledge, so far there has been no report on the synthesis of 5,10-meso-substituted calix[4]pyrrole and a study of the effect of substituents on the anion binding properties with respect to their positions on the calix[4]pyrrole periphery. Therefore, here we intend to understand the effect of the positional difference of the functional group and/or H-bonding functionality, i.e. acyl groups around the macrocycle periphery towards anion discrimination.
Paper
Results and discussion Compound 4 was synthesized by following a two-step protocol where the first step involves the synthesis of tripyrrane 7 followed by its acid catalyzed condensation with pyrrole in the presence of acetone. However, initial attempts to prepare 7 following Sessler’s protocol,11 i.e. with low acid concentration (0.025 equiv.), yielded dipyrromethane 6 (31%) along with a colorless liquid compound (Scheme 1). 1H NMR spectroscopic analysis displays a similar spectrum like dipyrromethane 6; however, an additional broad singlet appears at 4.59 ppm. Furthermore, the intensity ratio of α- and β-pyrrolic protons, NH and meso-methyl and acyl-methyl protons along with the new signal appears to be 1 : 2 : 1 : 3 : 3 : 1 (that in the case of 6 is 2 : 4 : 2 : 3 : 3 without the new signal). On the other hand, the corresponding 13C NMR spectrum shows the disappearance of the peak at 52.74 ppm (as observed in 6) with concomitant evolution of a new peak at 77.45 ppm. A deuterium exchange study revealed the exchangeable nature of the peak at 4.59 ppm and hence led us to tentatively presume the structure as a pyrrole-2-carbinol 5 (Scheme 1). LCMS did not provide any consistent data (m/z + 1 = 136 and m/z + 1 = 154), maybe owing to its instability during the operating conditions. In order to understand its structure unequivocally, we tried to grow a single crystal at low temperature. Fortunately, the solid state structure (crystals obtained by cooling at −20 °C) obtained via single crystal X-ray diffraction analysis at 100 K confirmed our presumption (Fig. 3). To the best of our knowledge, this is the first stable, structurally characterized pyrrole2-carbinol with alkyl substituents. Even though mono-alkyl and/or aryl pyrrole-2-carbinol are well known in porphyrinogen chemistry,12 the diaryl- or alkyl-functional group substituted pyrrole-2-carbinols are quite rare in the literature.13 Subsequently, we optimized the reaction conditions in order to obtain the desired tripyrrane which involves addition of a higher equivalent of trifluoroacetic acid (0.1 equiv.) to a
Scheme 1
Fig. 2 Structures of the four isomers of meso-diacylcalix[4]pyrrole. Top: 5,15-diacylcalix[4]pyrrole 3; bottom: 5,10-diacylcalix[4]pyrrole 4.
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Synthesis of pyrrole-2-carbinol 5.
Fig. 3 Single crystal X-ray structure of compound 5. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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Scheme 2
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Synthesis of tripyrrane 7.
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Scheme 4
Scheme 3
Dehydration of pyrrole-2-carbinol 5.
mixture of pyrrole and 2,3-butanedione (molar ratio 3 : 1) and stirring it for 3 h followed by quenching with excess triethylamine. The column chromatographic isolation yielded tripyrrane 7 (16%) along with dipyrromethane 6 (Scheme 2). This observation led us to conclude that at higher acid concentration, the pyrrole-2-carbinol to azafulvene intermediate conversion (Scheme 3) is more facile, which resulted in the formation of the desired tripyrrane.14 The unexpected stability of compound 5 may be attributed to the presence of a strong intermolecular O–H⋯O hydrogen bonding (ESI†). In order to check the fate of the reaction, we monitored the acid catalysed homo-condensation reaction of the pyrrole-2-carbinol with mass spectroscopy, which clearly provides the mass of some azafulvene intermediates (ESI†) indicating that the reaction proceeds via the formation of an azafulvene intermediate and at low acid concentration (with 0.05 equiv. of TFA), the pyrrole2-carbinol 5 to azafulvene 8 conversion (i.e. the dehydration process) is not efficient (Scheme 3). Single crystals of tripyrrane 7 were grown by keeping the oily material at low temperature and the solid state structure reveals that both the acyl groups reside on the same side, i.e. cis orientation, while the pyrrole NHs orient away from each other, clearly indicating the crystallisation of the meso-stereoisomer (Fig. 4). A careful investigation of the 1H and 13C NMR spectra and single crystals of compound 7 reveals the presence of the meso-stereoisomer only, which indicates that other stereoisomers are comparatively less stable and probably decompose under the
Fig. 4 Single crystal X-ray structure of compound 7. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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Synthesis of meso-diacylated calix[4]pyrroles 4.
reaction conditions and/or during purification. With the desired precursor in hand, finally we could successfully carry out the condensation of the tripyrrane 7 with pyrrole and acetone using BF3·OEt2 as a catalyst in dichloromethane solvent at room temperature to obtain the desired macrocycle 5,10-diacylcalix[4]pyrrole 4 as a mixture of two configurational isomers, designated (like the 5,15-analogues) as cis-4 (same side) and trans-4 (opposite side) (Scheme 4).10 We have performed the reaction for a longer time (12 h), such that sufficient acidolysis occurs in order to yield both the isomers in reasonably good quantity.15 Subsequent purification by silica gel column chromatography of the reaction mixture resulted in the isolation of trans-4 (7%) followed by the cis-4 (10%) as white solids as the more polar fractions (Scheme 4), along with the first four fractions meso-octamethylcalix[4]pyrrole 1, mono-meso-acylcalix[4]pyrrole and the two configurational isomers of 5,15-diacylcalix[4]pyrrole 3 as the side products (formed due to acidolysis).15 Interestingly, at the initial stage of the reaction several spots appeared in TLC, rendering their isolation almost impossible. However, the emergence of a much more resolved TLC pattern after continuing the reaction for a sufficiently longer time again confirms our previous observation during the formation of 7, i.e. during acidolysis, some of the products undergo decomposition. Both the isomers of compound 4 were characterized by 1H and 13C NMR, mass, IR and elemental analysis. 1H NMR spectra of both isomers reveal the presence of three types of N–H protons, thereby indicating the asymmetric nature of their H-bonding cavity (ESI†). Further, the structural integrity of the cis-isomer (crystals grown by slow evaporation of an ethyl acetate solution) could be unequivocally assigned in the solid state via X-ray diffraction analysis (Fig. 5). The structure clearly
Fig. 5 Single crystal X-ray structure of cis-4 showing clearly 1,3-alternate conformation of the pyrrole moieties. Thermal ellipsoids are scaled to the 25% probability level. Colour code: red: O, blue: N, grey: C, white: H.
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reveals the cis-orientation of the meso-acyl substituents with respect to the calix[4]pyrrole moiety, along with the regular 1,3-alternate conformation of the pyrrole units. Interestingly, one acyl moiety orients towards the binding domain of the calix[4]pyrrole, while the other one resides away, probably to minimize the nonbonding repulsive interaction between them. Further, the crystal packing displays intermolecular hydrogen bonding between the two acyl oxygens with the N–Hs of an adjacent macrocycle, while its two N–Hs (directed away from the acyl groups) form H-bonding with the two acyl oxygens of another calixpyrrole moiety, to form a two-dimensional helical network (ESI†). Unfortunately all our efforts to obtain a good quality single crystal of trans-4 did not find any success. Preliminary anion binding studies were carried out on both the calix[4]pyrrole isomers using 1H-NMR titration studies in CDCl3 (due to the poor solubility of trans-isomers in acetonitrile) with various anions (F−, Cl−, Br−, I−, H2PO4−, HSO4−, ClO4− and NO3−) as their tetrabutyl ammonium (TBA) salts. It is observed that both isomers show a general preference towards the fluoride ion among the halides and the H2PO4− ion among the studied oxoanions. As expected, quantitative 1 H NMR titration studies showed a distinct downfield shift for NH and an upfield shift for β-CH proton signals with gradual addition of an anion (ESI†). It also displayed evidence of very fast complexation–decomplexation equilibrium in the case of cis-4-F−, trans-4-F− and cis-4-H2PO4− complexes, since addition of approximately 0.2 equiv. of the corresponding salts resulted in the broadening of the pyrrole N–H signals and subsequent disappearance until addition of ∼1 equiv. of these salts (ESI†). On the other hand, in the case of cis-4-Cl−, cis-4-Br− and trans4-H2PO4− complexes, the NH signals remain intact, indicating the occurrence of rather slow complexation–decomplexation equilibrium on the NMR time scale. The formation of more than one singlet corresponding to the NH resonances, both in the case of cis-4 and trans-4 upon complexation with anions, reflects the retention of the asymmetric nature of their H-bonding core in the resulting complexes. Further, the 1H NMR study reveals that the observed anisochronicity of the binding domain is higher in the case of the trans-isomer than in its cisanalogue. For example, in the case of trans-4, addition of H2PO4− separated the NH resonances by almost 1 ppm (∼8.5 ppm and ∼9.5 ppm); on the other hand, in the case of the cis-isomer the difference between them is negligible (Fig. 6 and 7). In addition, in the case of cis-4, the β-pyrrolic protons which resonate at 5.90–6.00 ppm appear as asymmetric multiplets; however, the addition of 1.0 equiv. of TBAF split it into four equivalent singlets which are not visualized in the case of its trans-counterpart, supporting our above-mentioned notion. Further detailed studies to determine the thermodynamic parameters and binding constants were performed by isothermal titration calorimetry (ITC) in acetonitrile. In contrast to NMR spectroscopic analysis, ITC allows one to study the overall heat change of the system, including solvent contribution. Thus, it provides direct access to the energetics of the binding event without retreating to a structural probe that may
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Fig. 6 Change in 1H NMR spectra of cis-4 upon the addition of tetrabutylammonium salts of different anions: (a) pure cis-4, (b) cis-4 in the presence of TBAF, (c) cis-4 in the presence of TBACl, (d) cis-4 in the presence of TBAH2PO4 and (e) cis-4 in the presence of TBABr.
Fig. 7 Change in 1H NMR spectrum of trans-4 upon the addition of tetrabutylammonium salts of different anions: (a) pure trans-4, (b) trans4 in the presence of TBAF, (c) trans-4 in the presence of TBACl, (d) trans4 in the presence of TBAH2PO4 and (e) trans-4 in the presence of TBABr.
or may not reflect the entirety of the associative processes (e.g., an NMR spectroscopic signal).3h A glance at the binding constants obtained (Table 1) reveals a marginal difference in the overall affinity constant between the receptors 3 and 4, which is in the expected line owing to their inherent structural similarity. However, as a significant general trend, it was observed that cis-4 possesses a relatively higher binding ability than cis3 in the case of complexation with F−, Cl− and Br− ions, while in the case of the dihydrogenphosphate ion the opposite trend is noticed, which is otherwise higher than that reported for receptor 1. In all cases, a good fit to a 1 : 1 receptor–anion stoichiometry was obtained. A close look at the thermodynamic parameters obtained from the ITC experiments (Table 1) reveals that fluoride complexation is both enthalpically and entropically favoured, although the former contribution is relatively higher. On the other hand, in the case of other anions the complexation is entropically not favorable (except for cis4·Cl− and trans-3·H2PO4−). The favorable entropy observed upon complexation with the fluoride ion may be attributed to the release of the three water molecules from the hydrated TBA salt to the bulk solution. Further, the overall enthalpy–entropy compensation upon dihydrogenphosphate complexation is more in the case of the cis-isomers than chloride complexation, thereby resulting in their lower affinity towards dihydrogenphosphate than the chloride ion. On the other hand, transisomers display quite similar binding affinities towards the chloride and dihydrogenphosphate ions. However, the overall enthalpy–entropy penalty is lower in the case of both cis-3 and
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Table 1 Energetics of host–guest binding of the two isomers of 3 and 4 with different anions as their tetrabutylammonium salts in acetonitrile at 303 K as determined by isothermal titration calorimetry (ITC)
Aniona
Host
TΔS (kcal mol−1)
ΔH (kcal mol−1)
ΔG (kcal mol−1)
Ka (ITC) (M−1)
F−
cis-3 cis-4 trans-3 trans-4 1 cis-3b cis-4 trans-3b trans-4 1c cis-3b cis-4 trans-3 trans-4 1d cis-3b cis-4 trans-3b trans-4 1b
0.44 2.42 3.54 1.03 ND −1.29 2.53 −2.28 −2.46 −2.91 −5.24 −1.05 BDL BDL −3.56 −0.55 −2.75 2.26 −3.60 −3.27
−7.93 ± 0.15 −6.6 ± 0.05 −4.34 ± 0.03 −6.78 ± 0.08 ND −8.95 ± 0.12 −5.29 ± 0.02 −3.32 ± 0.44 −8.06 ± 0.20 10.16 ± 0.20 10.66 ± 0.94 −6.54 ± 0.29 BDL BDL −8.34 −7.94 ± 0.06 −9.72 ± 0.24 −3.32 ± 0.08 −9.12 ± 1.2 −9.77 ± 0.05
−8.37 −9.02 −7.88 −7.81 ND −7.66 −7.82 −6.60 −5.60 −7.29 −5.42 −5.49 BDL BDL −4.77 −7.40 −6.97 −5.58 −5.52 −6.50
1.11 ± 0.32 × 106 3.2 ± 0.86 × 106 4.77 ± 0.88 × 105 4.34 ± 0.79 × 105 ND 3.3 ± 0.66 × 105 4.45 ± 0.38 × 105 1.11 ± 0.09 × 104 1.09 ± 0.07 × 104 2.2 ± 0.2 × 105 8.02 ± 0.66 × 103 9.08 ± 0.84 × 103 BDL BDL 2.7 × 103 2.15 ± 0.15 × 105 1.05 ± 0.24 × 105 1.16 ± 0.08 × 104 1.23 ± 0.40 × 104 4.50 ± 0.16 × 104
Cl−
Br−
H2PO4−
ND: not determined by ITC; BDL: below the detection limit of ITC. a All the anions used were as their tetrabutylammonium salts. b From ref. 10. c From ref. 2f. d From ref. 16.
cis-4 calix[4]pyrrole isomers than 1, resulting in their higher affinity constants towards the dihydrogenphosphate ion. Although the exact nature of the host–guest interaction could not be ascertained owing to the lack of good quality diffraction grade crystals, the DFT optimized structure of the complexes confirms the above presumption (Fig. 8). Like cis-3, here also the enhanced affinity of cis-4 towards the dihydrogenphosphate ion (compared to 1) may be attributed
to the additional CvO⋯H–O hydrogen bonds between the carbonyl oxygen and hydrogens of the anion. Furthermore, the relatively higher affinity of cis-4 and cis-3 towards halides than 1 (Table 1) may be attributed to the weak C–H⋯X− interaction between the methyl groups of the acyl substituents to the anion due to the enforced proximity (ESI†).17 On the other hand, the lower affinity of cis-4 towards the dihydrogenphosphate ion than cis-3 may be attributed to the steric mismatch of the hydrogen bonding sites of the host and the anion (tetrahedral disposition between the two OHs of the anion, compared to almost right angled orientation of the two meso-acyl groups). The receptor trans-4 displays about an order lower affinity towards anions compared to its cis-analogue, probably due to the competition of the acyl group (directed away from the core) with the incoming anions of a neighbouring macrocycle,10 whereas the marginally higher binding affinity of trans4 than trans-3 towards chloride and dihydrogenphosphate ions may be ascribed to the additional weak interaction between the methyl hydrogens and the anion, apart from the relatively strong interaction between the anchoring acyl group directed towards the core and the anion (ESI†).10
Conclusions
Fig. 8 The space filling model of DFT-optimized structure of the model complexes. Top left: [cis-4·F]−; top right: [cis-4·H2PO4]−; bottom left: [cis-4·F]−; and bottom right: [trans-4·H2PO4]− (right), showing clearly the proposed H-bonding pattern. Colour code: cyan: fluorine, red: oxygen, blue: nitrogen, orange: phosphorus, grey: carbon, white: hydrogen.
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In conclusion, we have demonstrated the synthesis of a new positional isomer of the meso-diacylcalix[4]pyrroles. When the two acyl groups are placed at the 5,10-positions of the calix[4]pyrrole periphery, their preference towards halide ions increases (fluoride displays the largest enhancement). On the other hand, their placement at the 5,15-positions leads to higher affinity towards the dihydrogenphosphate ion. Further, the synthesis and structure of a stable pyrrole-2-carbinol (the
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first derivative containing alkyl and a functionalized group) and its subsequent in situ conversion to tripyrrane are also demonstrated. Also we have illustrated the first example of a one-pot synthesis of functionalized tripyrrane. This may spur the development of new functionalized building blocks leading to interesting porphyrinoids.
Experimental section NMR spectra were recorded on a Bruker Avance-400 MHz FT NMR spectrometer using tetramethylsilane (TMS, δ = 0) as an internal standard at room temperature. Mass spectral determinations were carried out using a Shimadzu-LCMS-2010 mass spectrometer and elemental analyses were obtained through a Thermo Finnigan Flash EA 1112 analyzer. HRMS data were recorded using a Brucker Maxis spectrometer. Melting points were determined using open capillary tubes on a BIO-TECH, India apparatus. IR spectra were recorded on a JASCO-FT-IR model 5300 and a NICOLET 5700 FT-IR spectrometer. Microcalorimetric titrations were performed using an Isothermal Titration Calorimeter (ITC) purchased from Microcal Inc., MA. The Origin software provided by Microcal Inc. was used to calculate the binding constant (Ka) and the enthalpy change (ΔH). All tetrabutylammonium salts (of anions) for NMR and ITC titration were purchased from Sigma-Aldrich® and were directly used in the titration experiment (fluoride as its trihydrate). During 1H NMR titrations the receptor solutions were titrated by adding known quantities of a concentrated solution of the anions in question. The anion solution used to effect the titrations contained the receptor at the same concentration as the receptor solutions into which they were being titrated. The quantum mechanical DFT calculations were performed with the Gaussian 03 program package. The Becke three-parameter hybrid (B3)18 functional was used along with the Lee–Yang– Parr (LYP)19 correction. The 6-311++G(d,p) basis set is employed in all the reported calculations. General crystallographic details Data for 5 were collected on a BRUKER SMART-APEX CCD diffractometer at 100 K. Data for 7 and cis-4 were collected on an Oxford Gemini A Ultra diffractometer with a dual source at 298 K. Mo-Kα (λ = 0.71073 Å) radiation was used to collect the X-ray reflections of the crystal. CCDC numbers 909034 (5), 909035 (7) and 909033 (cis-4) contain the supplementary crystallographic data. Preparation of 3-hydroxy-3-(1H-pyrrol-2-yl)butan-2-one 5 Pyrrole (2.3 mL, 33 mmol, 3 equiv.) and 2,3-butanedione (1 mL, 11 mmol, 1 equiv.) were mixed in a 10 mL round bottom flask. The flask was immersed in a salt-ice bath and TFA (0.021 mL, 0.27 mmol, 0.025 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 3 h under a N2 atmosphere. The reaction mixture was quenched by adding triethylamine. The excess pyrrole was removed by vacuum distillation at ∼70–80 °C. The product was purified by
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silica gel column chromatography (20% EtOAc + 80% hexane). The first fraction obtained as a white oil (650 mg, 28%) upon solidification at low temperature (or dried under high vacuum) corresponds to meso-acyldipyrromethane 6. The second fraction (720 mg, 40%) which is obtained as a colourless liquid (at room temperature) corresponds to compound 5. Compound 5 crystallizes upon storing in a freezer at −20 °C. FT-IR data (KBr) – 3398, 1709 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 8.39 (br, s, 1H, NH), 6.73 (d, 1H, pyrrole CH, J = 1.6 Hz), 6.22 (m, 2H, pyrrole CH), 4.59 (s, 1H, OH), 2.21 (s, 3H, CH3), 1.72 (s, 3H, CH3); 13C NMR (in CDCl3, 100 MHz): δ in ppm 209.50, 131.33, 118.42, 108.79, 106.65, 77.45, 24.44, 23.01. LCMS m/z calcd for C8H11NO2 (M + H) 154, found 154; Elemental analysis for C8H11NO2 calcd (found); C 62.73 (62.86), H 7.24 (7.13), N 9.14 (9.21). Preparation of 3,3′-(1H-pyrrole-2,5-diyl)bis(3-(1H-pyrrol-2-yl)butan-2-one) (5,10-diacyltripyrrane) 7 Pyrrole (2.3 mL, 33 mmol, 3 equiv.) and 2,3-butanedione (1 mL, 11 mmol, 1 equiv.) were mixed in a 10 mL round bottom flask. The flask was immersed in a salt-ice bath and TFA (0.140 mL, 1.1 mmol, 0.1 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 3 h under a N2 atmosphere. The reaction mixture was quenched by adding triethylamine. The excess pyrrole was removed by vacuum distillation at ∼70–80 °C. The product was purified by silica gel column chromatography (20% EtOAc + 80% hexane). The first fraction obtained as a white oil (700 mg, 30%) corresponds to compound 6. The second fraction obtained as a colourless oil (315 mg, yield 16%) crystallizes at low temperature to yield compound 7. M.P. – 126–128 °C; FTIR data (KBr) – 3736.7, 3392.1, 1703.6 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 8.49–8.69 (br, m, 3H, NH), 6.74 (s, 2H, pyrrole CH), 6.16 (m, 2H, pyrrole CH), 5.95–6.01 (m, 4H, pyrrole CH), 2.10 (s, 3H, CH3), 1.81 (s, 3H, CH3). 13C NMR (in CDCl3, 100 MHz): δ in ppm 209.67, 132.81, 132.08, 118.05, 108.46, 106.83, 106.76, 52.66, 26.53, 25.00. LCMS m/z cald for C20H23N3O2 (M − H) 336, found 336; elemental analysis for C20H23N3O2 calcd (found); C 71.19 (71.28), H 6.87 (6.76), N 12.45 (12.56). Preparation of compound 4 5,10-Diacyltripyrrane 7 (900 mg, 2.7 mmol, 1 equiv.) was dissolved in a mixture of freshly distilled pyrrole (2 mL, 27 mmol, 10 equiv.), dry acetone (10 mL) and dry dichloromethane (200 mL) at room temperature under a nitrogen atmosphere and then BF3·OEt2 (0.083 mL, 0.7 mmol, 0.25 equiv.) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1 M NaOH. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the combined organic layer was dried over anhydrous sodium sulphate. The solutions were evaporated under reduced pressure and the residue was purified by column chromatography using silica gel (eluent: 15% EtOAc + 85% hexanes) to afford the required
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5,10-diacylcalix[4]pyrroles with trans-4 (100 mg, 7%) and cis-4 (125 mg, 10%) isomers as white solids. trans-4 Isomer: M.P. – 210–212 °C; FT-IR data (KBr) – 3369.73, 3298.5, 1704.05 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 7.58 (br, s, 1H, NH), 7.54 (br, s, 2H, NH), 7.36 (br, s, 1H, NH), 5.95 (m, 6H, pyrrole CH), 5.91 (m, 2H, pyrrole CH), 2.11 (s, 6H, CH3), 1.71 (s, 6H, CH3), 1.52 (s, 12H, CH3); 13 C NMR (in CDCl3, 100 MHz): δ in ppm 207.20, 140.07, 138.20, 132.55, 130.66, 106.77, 106.25, 103.66, 103.42, 52.69, 35.34, 29.41, 28.97, 26.76, 25.10; LCMS m/z calcd for C30H36N4O2 (M + H) 485.63, found 485.25; elemental analysis for C30H36N4O2 calcd (found); C 74.35 (74.28), H 7.49 (7.58), N 11.56 (11.66). cis-4 Isomer: M.P. – >220 °C (with decomposition); FT-IR data (KBr) – 3408.22, 3364.38, 3287.67, 1693.15 cm−1; 1H NMR (in CDCl3, 400 MHz): δ in ppm 7.65 (br, s, 2H, NH), 7.57 (br, s, 1H, NH), 7.33 (br, s, 1H, NH), 5.97 (m, 4H, pyrrole CH), 5.94 (d, 2H, pyrrole CH, J = 2.4 Hz), 5.91 (t, 2H, pyrrole CH, J = 2.8 Hz), 2.14 (s, 6H, CH3), 1.73 (s, 6H, CH3), 1.53 (s, 12H, CH3); 13 C NMR (in CDCl3, 100 MHz): δ in ppm 207.36, 140.10, 138.29, 132.714, 130.64, 106.48, 106.28, 103.69, 103.43, 52.58, 35.37, 29.61, 28.85, 26.73, 24.40; LCMS m/z calcd for C30H36N4O2 (M + H) 485.63, found 485.15; elemental analysis for C30H36N4O2 calcd (found); C 74.35 (74.51), H 7.49 (7.41), N 11.56 (11.48).
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Acknowledgements This work was supported by the Council of Scientific & Industrial Research (CSIR), India project no. 01/(2449)/10/EMR-II). SPM thanks CSIR (for a Senior Research Fellowship) and the School of Chemistry Development Fund, University of Hyderabad for financial support.
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