Rings of rings: calixpyrrole cyclotrimers

Calixpyroles are a class of heteromacrocycles that have been a topic of considerable interest over the last two decades due to their rich host-guest chemistry as receptors for anions. A number of structures comprising more than one calixpyrrole unit have been reported as multitopic and multivalent receptors. Here we report the first syntheses of cyclotrimeric structures containing calixpyrrole rings (hence rings of rings) that can be obtained by the cyclo-oligomerization of either cis - or trans -1,3-meso -4-hydoxyphenyl-calix[4]pyrrole with 1,5-dichloro-2,4-dinitrobenzene via aromatic nucleophilic substitution reactions. The novel structures appear intriguing candidates for prospective molecular recognition studies


Introduction
4][5][6] These include selective anion binding and transport across membranes, 7,8 the development of novel optical sensors, [9][10] several examples as organocatalysts, [11][12][13] and the discovery of potential antitumor properties for some specifically modified structures. 146][17][18] Functionalisation at the meso positions has been exploited for the tuning of the calixpyrrole properties, [19][20][21][22][23][24] and to include chemical moieties that can respond to external stimuli (e.g.stilbene or azobenzene units undergoing cis/trans isomerization by UV irradiation and thermally) providing a means to control the stability of complexes, 25 the formation of capsular assemblies, 26 or to modulate the binding selectivity of bis-calix pyrrole receptors towards bis-anions (bis-carboxylates) of different sizes. 27ulti calixpyrrole systems are of particular interest for their ability to either bind larger molecular guests at different (distant) sites of interactions (e.g.29][30] However, few examples of multi (more than two) calixpyrrole systems have been described to date, especially if we exclude examples in which calixpyrrole units were grafted onto either polymers or surfaces.Notable examples of multicalixpyrrole structures (three or more calix units) have been reported by Ballester 31 , Aoyan 32 and Kohnke. 33s part of our work on the host-guest chemistry of bis-and tris-calix[4]pyrrole 27,33 receptors, we identified the anti-and syn-meso-1,3-(4-hydroxyphenyl)calix [4]pyrroles (anti-5 and syn-5 in Scheme 1) first reported by Lee 34 as useful precursors for the assembly of multi-component structures.The potential to exploit the phenolate anions of anti-5 and syn-5 for the assembly of oligomeric structures via nucleophilic aromatic substitution reactions emerged from the past experience of one of us (FHK) as a visiting researcher in Professors P. Hodge and H. M. Colquhoun team in Manchester, and from being involved in the studies on ringto-chain and chain-to-ring conversions of high performance polymers being conducted there at the time. 35,36oreover, phenol units grafted at the meso-position of calix[4]pyrroles were also used by Ballester in reactions with 1,2-difluoro-4,5-dinitrobenzene or 1,2-difluoro-4,5-dicyanobenzene to obtain calixpyrrole cavitands. 37Inspired by these findings, we decided to explore the outcome of condensation reactions involving either anti-5 or syn-5 and 1,5-dichloro-2,4-dinitrobenzene 9 under basic conditions.In this paper we illustrate the outcome of this investigation.

Results and Discussion
The synthesis of calix[4]pyrroles having different substituents at distal meso-positions can be approached by a two-step procedure in which a pyrrole is initially reacted with a suitable ketone (4-hydroxyacetophenone for compounds 5) to obtain the dipyrromethane 6, which can then be reacted with acetone (Scheme 1, dotted arrows).This is indeed the method reported by Lee 34 to obtain compounds 5.However, we found two major drawbacks with this method: i) the presence of the free phenolic unit contributes to the formation of tarry byproducts during the synthesis of 6 and of compounds 5 and ii) the prevalent formation of syn-5 (26%) compared to anti-5 (2%), this limiting the availability of the anti-stereoisomer for further synthetic studies.Therefore, we adopted the benzyl-ether protection strategy outlined in Scheme 1.Both the protection and deprotection steps proceeded with excellent yields, syn-and anti-4 were formed in equal amounts (ca 20% each) and these were found to be quite resistant to degradation/decomposition during the operations required for their separation from the crude mixture as single isomers.

Scheme 1
Notably, compounds 4 can be described as 'super aryl extended calixpyrroles', never previously reported, and they are potentially intriguing molecular receptors.We noted that syn-4 formed a molecular complex with adventitious formate ions present in the mass spectrometer much more efficiently than for anti-4 or any of the other calixpyrrole derivatives reported here (see Figure S3d).The relative stereochemistries of compounds 4 were easily assigned from their 1 H NMR spectra, as the resonances are consistent with a time-averaged planar conformation of the macrocycle; the geminal methyl groups are equivalent in the anti-isomer and different in the C2v symmetric syn-isomer.All other NMR signals were consistent with the indicated structure.Since the catalytic hydrogenation for the deprotection of the phenol units was conducted on isomerically pure anti-4 or syn-4 there was no ambiguity for the stereochemistry of compounds 5, which can nevertheless be confirmed by their 1 H and 13 C NMR spectra on the basis of the same considerations made for compounds 4 (see Figures S2a, S2b, S3a, S3b for compounds 4, and S4a, S4b, S5a, S5b for compounds 5).
Before exploring the reactions of compounds 5 with 1,5-dichloro-2,4-dinitrobenzene 9, we decided to prepare the bis-calixpyrrole 10 (Scheme 2) using meso-(4-hydroxypheny)calixyrrole 8.This compound was expected to provide a tool to aid the identification of the NMR signals in the more complex mixtures that can arise from the reaction of compounds 5 with 9.This required the synthesis of meso-(4hydroxypheny)calixyrrole 8, for which we decided to use dipyrromethane 3 as starting material via the intermediate 7, since protection/deprotection strategy of the phenolic unit had proven to be advantageous.Compound 8 exhibits very different 1 H NMR spectra in CDCl3 and DMSO-d6 (compare Figures.S7a vs S7e).In DMSO the NH resonances are shifted downfield (from  7.23 and 7.30 to 9.37 and 9.51 respectively) indicating a strong hydrogen-bonding interaction with the solvent, the AB system associated with the pyrrole -CH is considerably narrower, the AA'BB' system of the aryl unit is also very narrow, and the resonances of the geminal methyl groups that are closely packed in CDCl3 appear much more spaced out in DMSO.
Scheme 2. The letters correlate to 1 H NMR assignments shown in Figure 1.
A variety of polar solvents and bases have been used for the nucleophilic substitution reaction of halogenated nitrobenzenes with phenols. 37In this initial investigation we selected acetonitrile and either K2CO3 or CS2CO3.The reaction of 9 with two molar equivalents of 8 gave bis-calixpyrrole 10 as the main product, albeit in moderate yield (25%).The 1 H NMR spectrum in CD2Cl2 (Figure 1, see Figure S8a for the 1 H NMR spectrum in DMSO-d6) shows the presence of a singlet for the aryl proton placed between the nitrogroups at 8.71 ppm, but the resonance for the other proton on this ring is overlapping part of the AA'BB' system for the psubstituted aryl rings and one of the two signals for the two different sets of pyrrole NH units.This can be seen in the HSQC spectrum (Figure S8e) by the presence of a correlation with the carbon atom at 121.6 ppm.Five resonances are visible for the different sets of methyl groups (a broad signal between 1.57 and 1.53 ppm is ascribed to residual water) and the spectrum is consistent with a dynamically mediated conformation having a -plane perpendicular to the central aryl unit and passing across its CH groups.The new bis-calixpyrrole 10 has the potential to behave as a ditopic receptor for anions.Moreover, the nitrogroups can be subjected to a number of chemical transformations (e.g.reduction and derivatization) for the construction of complex and fascinating multi-or polycalixpyrrole systems.

Scheme 3
The condensation of 9 with the bis-phenolic calixpyrroles (Scheme 3) was initially tested using syn-5.Intuitively, but wrongly, we assumed that anti-5 could not provide the 'concave' shape needed for macrocyclization.The selected reaction conditions were similar to those used for 10, but we adopted Cs2CO3 as the base.This base was chosen to benefit from its higher solubility in CH3CN compared to K2CO3 but we also hoped that the Cs + ions could favor the macrocyclization process by reducing the conformational flexibility of the calix[4]pyrrole units.In fact, calix[4]pyrroles may act as ditopic receptors, and host small cationic species (Cs + better suited than K + ) in the -electron rich cavity that is formed by the pyrrole rings when the calix adopts a cone conformation (NH units pointing to an anionic counterion).The CsCl formed in situ was expected to reduce the conformation mobility of the calixpyrrole units, hence rendering the cyclization reactions less entropically unfavorable.While these considerations on the selection of the base Cs2CO3 have still to be assessed quantitively (e.g.evaluating the yield with different bases) the use of Cs2CO3 as base appeared to give cleaner reactions (lower number of spots on t.l.c.) than K2CO3.We were surprised to find that the reaction of 9 with either anti-or syn-5 provided in both cases a crude mixture from which the only macrocyclization products that we were able to isolate by column chromatography were the cyclotrimers antianti-anti-11 and syn-syn-syn-11 respectively, although analysis of the other chromatographic fractions ( 1 H NMR) revealed the presence of linear oligomers.Yields of cyclotrimers 11 were very modest and were not optimized, but they might be increased by the use of high dilution techniques.The cyclic nature of these compounds is evident from their 1 H NMR spectra (Figures S9a-d and S10a-c).In fact, the calixpyrrole components maintain their symmetric properties (and hence their original pattern of proton resonances) only if included in a macroring (or equally derivatized at each phenolic oxygen).The trimeric structures were confirmed by mass spectrometry.These macrocycles were sparingly soluble in all organic solvents, and the acquisition of 13 C NMR spectra in which all carbon atoms are visible was severely compromised.However, close inspection of the observable carbon resonances in comparison with those of the related precursors allowed the assignment of most signals (see experimental section).The 1 H NMR of syn-syn syn-11 in DMSO-d6 shows all the resonances assignments in Figure S10a) that can be expected, including three well-resolved signals for the three sets of 'different' CH3 units.The NH resonances at low field indicate a strong hydrogen-bonding interaction with the DMSO solvent.Although we have not had the opportunity to undertake host-guest binding studies, we explored the effects of TBACl on the 1 H NMR spectrum of syn-syn syn-11 (Figure 2(b) and S10b).The presence of chloride produced remarkable complexation-induced shifts, most notably the NH resonances are shifted from 9.56 to 11.00 ppm, the aryl CH between the nitro groups is marginally affected (from 8.93 to 8.84 ppm) but the other aryl proton on the same aryl ring is shifted upfield (from 6.95 to 6.60 ppm).The overall number of resonances (general pattern) is unchanged in this chloride complex formed in the presence of a large excess of chloride.Therefore, the supramolecular chloride complex of syn-syn-syn-11 and the free receptor appear to retain a D3h symmetry which may result from either a dynamically mediated spectrum on the NMR time-scale or from a frozen conformation (the latter appears less likely).We speculate that three chloride ions are bound by syn-syn-syn 11 because the 'downfield effect' on the NH resonances for this interaction is consistent with that observed for typical 1:1 complexes of calix[4]pyrroles involving four NH units and one chloride.If only one chloride was involved in the formation of the complex with syn-syn-syn-11, one would expect the downfield effect to be smaller, being 'diluted' over three calix units (i.e. one or two chlorides spreading their effects over 12 NH units).

Conclusions
In this work we have demonstrated that calix[4]pyrrole derivatives containing nucleophilic phenol units at their distal meso-positions may be subjected to polymerization with 1,3-dichloro-4,5-dinitrobenzene to give both polymeric materials (not isolated and characterized in this study) and cyclooligomers.In this work only [3+3] cyclization products could be fully characterized.Surprisingly, both syn-and anti-5 gave cyclotrimers, as one would expect that anti-5, which lacks the 'convergent' nature of the reactive groups, should not form small macrocyclization products, and certainly not ones of the same size as syn-5.Preliminary molecular modeling studies indicate that cyclotrimers 11 are essentially strain-free, all bonds and angles being within the expected ranges.The synthesis of these novel 'rings of rings' here obtained in modest yields may be improved, now that we have found that they can be made.This would provide the means to explore their host-guest chemistry in detail.Their large cavities can host multiple anions and biologically important ones.We have previously explored the biological activity of calixpyrrole derivatives on cancer cells, and these new compounds are intriguing candidates.Finally, the presence of nitroaromatic units provides a means for the chemical elaboration of these structures and a route to resolve the encountered solubility issues.

General.
Starting reagents were purchased from commercial sources (Sigma-Aldrich and VWR International) and used as supplied.Solvents were dried/purified by conventional methods; pyrrole was distilled at reduced pressure shortly before use.Air/moisture sensitive reactions were conducted under Argon atmosphere.The progress of reactions was monitored by thin layer chromatography (t.l.c.) using Merck SiO2 60F254 plastic plates; compounds were visualized with I2 vapors and/or by examination under UV light.