One-pot synthesis of hetero[6]rotaxane bearing three different kinds of macrocycle through a self-sorting process† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc03232c Click here for additional data file.

A hetero[6]rotaxane bearing three different kinds of macrocycle is designed and successfully synthesized through a one-pot “click” reaction by employing a facile and efficient integrative self-sorting principle.


Introduction
In naturally occurring systems, the principles of reversible noncovalent self-assembly and self-sorting are widely used to construct complex architectures from several different building blocks to execute important tasks and specic functions. 1nspired by nature, a variety of complex and well-ordered multicomponent molecular or supramolecular systems have been constructed or assembled via noncovalent synthetic strategies. 2 Rotaxanes, 3,4 well-known for their unique structures consisting of mechanically interlocked threads and macrocycles, have attracted considerable attention in the past few decades due to their remarkable potential to evolve into molecular switches and molecular machines. 5Towards achieving multistate and multifunctional rotaxane-based molecular systems, chemists have been putting unremitting effort into the pursuit of increasing the structural complexity of mechanically interlocked molecules 6 and other chemical topological structures. 7Owing to the diversity of macrocycles and their host-guest systems, various rotaxanes bearing one or more types of macrocycle, also called hetero[n]rotaxanes, 8 have been successfully designed and constructed.
There have been some elegant examples of hetero [n]rotaxanes containing two different macrocycles, 9 which were constructed using efficient self-sorting and an orthogonal selfassembly synthetic approach.Schalley 6a and co-workers reported the self-sorting process of two classes of macrocyclic polyether, DB24C8 and B21C7, and two sorts of ammonium cation, dibenzylammonium (DBA) and benzylalkylammonium (BAA) ions, and then used the concept of integrative self-sorting to prepare a hetero[3]rotaxane.By precisely programming the association constants and steric hindrance, 6a,b,9b,c several hetero [n]rotaxanes with high structural complexity, for example, Liu's 9a twin-axle hetero[7]rotaxane, can be efficiently constructed by a facile one-pot route.Moreover, Stoddart 8a-c recently presented an effective "cooperative capture" strategy to construct a series of heterorotaxanes with two different kinds of macrocyclic ring, such as cucurbiturils and cyclodextrins or cucurbiturils and pillarenes, in good yields and high stereo-specicities.Goldup 9d and co-workers introduced a proof-ofconcept kinetic self-sorting approach for the efficient preparation of heterocircuit [3]rotaxanes.However, successful examples of heterorotaxanes bearing three or more different macrocycles have rarely been reported, 9e which would provide more possibilities for functionalization 10 towards more advanced and complex molecular systems.The major difficulty lies in the remarkably increased number of possible assembly modes in the presence of different kinds of macrocycle and guest molecule in a single system.The design of an ultimate specic and selective self-sorting system, 11 which can be introduced as a powerful tool for the efficient construction of complex hetero [n]rotaxanes bearing different kinds of macrocycle, is of great importance and highly desirable.
In this article, we present herein an efficient six-component integrative self-sorting process among three types of crown ether macrocycle and three types of guest molecule.Based on this well-established six-component integrative self-sorting process with good selectivity, a hetero[6]rotaxane bearing three different kinds of crown ether macrocycle was designed and successfully synthesized through a facile and efficient onepot threading-followed-by-stoppering strategy (Scheme 1).We envisage that this work will present an important advance in the design and construction of complicated mechanically interlocked structures.

Results and discussion
Macrocyclic polyethers, 12 for example BPP34C10, DB24C8 and B21C7, have been widely employed in the fabrication of mechanically interlocked molecules and supramolecular polymers due to their host-guest interactions with versatile threadlike guests, such as, 4,4 0 -bipyridine dications (BPY 2+ ) and secondary DBA and BAA salts, respectively.BPP34C10, a larger macrocycle than DB24C8, could recognize viologen units by strong charge transfer and p-p stacking interactions (K a1 ¼ 240 M À1 in CH 3 CN), 12e while the affinity constant between DB24C8 and a viologen unit is K a2 ¼ 31 M À1 in CH 3 CN, 12f which is much smaller than that between BPP34C10 and a viologen unit.Meanwhile, the hydrogen bonding between DB24C8 and a DBA site (K a3 ¼ 420 M À1 in CH 3 CN) 12g was also proven to be stronger than that between BPP34C10 and a DBA site, and the binding constant for BPP34C10 and DBA is much weaker, 12h thus the elegant four-component self-sorting process between two macrocyclic rings (BPP34C10 and DB24C8) and two guest molecules (viologen and DBA) has been utilized in the orthogonal supramolecular polymerization of the two species of macrocycles and the two corresponding species of guest molecules. 13Moreover, the other four-component self-sorting process between DB24C8, B21C7, and DBA and BAA units has been demonstrated.6a Hence, herein our motivation is to integrate the above-mentioned two kinds of four-component selfsorting system into an unprecedented six-component selfsorting system based on macrocyclic polyethers, including three types of macrocycle, BPP34C10, DB24C8 and B21C7, and their three corresponding guest species, viologen, DBA and BAA units, then to utilize this unique self-sorting strategy to construct an unprecedented [6]rotaxane with three distinct macrocycles (Scheme 1).
The six-component self-sorting process was thoroughly investigated through a comparison of 1 H NMR spectra of the different combinations of crown ether rings and corresponding guest molecules (Fig. 1).Firstly, BPP34C10 and BPY 2+ were mixed in CD 3 CN in the same molar ratio, and the 1 H NMR spectrum (Fig. 1a   fully demonstrate the formation of pseudorotaxanes DB24C8 I DBA and B21C7 I BAA (Fig. 1b and c) respectively.Next, we focused on the six-component self-sorting process.Fig. 1d shows the 1 H NMR spectrum of the simple mixture of the three macrocyclic crown ether rings and the three corresponding guest molecules with different sizes and shapes.Interestingly, aer careful analysis, we found that the 1 H NMR spectrum (Fig. 1d) of an equal molar mixture of the six components showed the same pattern as the simple spectral overlap of Fig. 1a-c, evidenced by there being no obvious changes in the chemical shis of the protons H 2 -H 8 , which indicated that the pseudorotaxanes BPP34C10 I BPY 2+ , DB24C8 I DBA and B21C7 I BAA are the predominant species in this multicomponent self-assembly process.This unique self-sorting process could be attributed to the following encoded structural features: (i) BPP34C10 bears a larger binding constant with the BPY 2+ site compared to that of DB24C8, hence BPP34C10 binds to the BPY 2+ unit prior to DB24C8; 14 (ii) DB24C8 enjoys the biggest binding constant with the DBA site compared to with the BAA or BPY 2+ sites; 7c (iii) the binding behaviour between B21C7 and DBA is inhibited by the benzene rings of the DBA units, 6a,15 leading to the specic combination with the guest BAA units.These factors synergistically resulted in a highly selective six-component self-sorting process, as shown in Scheme 1.
Then, we demonstrated for the rst time the design and synthesis of a hetero[6]rotaxane bearing three different kinds of crown ether macrocycle via a facile and efficient one-pot strategy through a well-established self-sorting process among several types of host and guest species.As shown in Scheme 2, three macrocyclic polyethers with different cavity sizes, i.e.BPP34C10, DB24C8 and B21C7, were mixed with thread 1 and 5 according to the stoichiometric ratio in a single system.Although there were many possible assemblies among these precursors, only two types of assembly were formed in a specic and efficient self-sorting process, namely pseudo[4]rotaxane 6 consisting of BPP34C10, DB24C8 and thread 1, and [2]semirotaxane 7 composed of B21C7 and thread 5. Following the efficient self-sorting process which afforded pseudo[4]rotaxane 6 and [2]semi-rotaxane 7, a cascade-stopped hetero[6]rotaxane 8 could be obtained by a facile one-pot copper(I)-catalyzed alkyneazide cycloaddition (CuAAC) "click" reaction with a moderate yield of 49%.
The ve-component self-sorting process which involves 1 and 5 and three kinds of crown ether was investigated using 1 H NMR spectroscopy (Fig. 2).The 1 H NMR spectrum of compound 1 in CD 3 CN was shown in Fig. 2a.Upon the addition of one molar equivalent of macrocycle BPP34C10, the strong hostguest interaction between BPP34C10 and the viologen unit on component 1 drove the efficient formation of the pseudo[2] rotaxane shown in Fig. 2b.Compared to the proton peaks exhibited in Fig. 2a, the aromatic protons H a and H b of the viologen unit in 1 were shied upeld 16 with Dd ¼ 0.25 ppm for H a and Dd ¼ 0.05 ppm for H b , which was attributed to the deshielding effect exerted by the macrocycle BPP34C10.No obvious change was observed for the signal peaks of the H g , H d , H f and H h protons in the DBA moieties.All of these results indicate that the BPP34C10 ring rested on the viologen sites of 1 instead of on the DBA sites.
In the mixture of thread 1, BPP34C10 and DB24C8 with a molar ratio of 1 : 1 : 2, pseudo[4]rotaxane 6 was formed, as evidenced by the 1 H NMR spectrum in Fig. 2c.In contrast to that shown in Fig. 2b, the H b proton signal split into two different peaks and one of them shied upeld with a Dd value of 0.36 ppm.H a split into three different peaks, one of which shied upeld with a Dd value of 0.20 ppm, while the other two shied downeld with Dd ¼ 0.06 and 0.35 ppm respectively, due to the deshielding effect of the oxygen atoms on DB24C8 and the incomplete combination of DB24C8 and the dibenzylammonium unit. 14For the same reason, the resonance signal of H c split into three different peaks.Since H g and H h did not directly interact with DB24C8, their chemical shis were barely changed.H d and H f shied downeld to Dd values of about 0.59 and 0.43 ppm, respectively.H d and H f also shied due to the deshielding effect of the oxygen atoms from DB24C8.
Scheme 2 Schematic representation of the preparation of compound C1 from 1 and 5 and hetero[6]rotaxane 8 from a five-component modularized self-sorting process of 1 and 5 and BPP34C10, DB24C8 and B21C7.
On the other hand, the 1 : 1 mixture of B21C7 and component 5 in CD 3 CN could afford [2]semi-rotaxane 7, 9b which was demonstrated by the downeld shi of the resonance peaks of H m and H p shown in Fig. 2e and S5 in the ESI.† It is worth mentioning that, upon mixing [2]semi-rotaxane 7 with pseudo [4]rotaxane 6 in a 1 : 1 molar ratio, no peak shi is observed in Fig. 2d, compared to either [2]semi-rotaxane 7 (Fig. 2e) or pseudo[4]rotaxane 6 (Fig. 2c).It should be noted that simultaneously mixing the ve corresponding threads and macrocycles in one-pot at a molar ratio of 1 : 2 : 2 : 1 : 2 (BPP34C10 : DB24C8 : B21C7 : 1 : 5) in CD 3 CN (Fig. S6 †) gave the same 1 H NMR spectral pattern as that in Fig. 2d.Such a result suggests the strong independence between these two types of assembly despite the dynamic nature of pseudo[4] rotaxane 6 and [2]semi-rotaxane 7.These results indicated a highly selective self-sorting process among these ve classes of component including three different kinds of macrocyclic polyether.This unique self-sorting process gave rise to the efficient and specic formation of pseudo[4]rotaxane 6 and [2] semi-rotaxane 7, which could provide an effective preassembly template for the one-pot facile synthesis of target hetero[6]rotaxane 8 via a subsequent CuAAC stoppering reaction.
The structure of hetero[6]rotaxane 8 was conrmed by a variety of characterization tools, including 1 H NMR, HRMS (Fig. S31-S35 †), 1 H-1 H COSY (Fig. S9 †) and 1 H-1 H NOESY (Fig. S10 †).The major signal peaks in the HRMS spectrum of hetero[6]rotaxane 8 are found at m/z 1939.7592, 1244.8542,897.3967, 688.9200, and 549.9410, which   as shown in Fig. 3a and b, we can nd the chemical shi changes of several peaks, which can be attributed to the fact that BPP34C10 and BPY 2+ , DB24C8 and DBA, and B21C7 and BAA could bind to each other via p-p stacking and hydrogenbonding interactions.Owing to the deshielding effect of the combination of BPP34C10 and the viologen unit of BPY 2+ , the signals of H b and H a shied upeld with Dd ¼ À0.14 and À0.60 ppm, respectively.Meanwhile, due to the shielding effect of BPP34C10, the proton peaks of H c shied upeld with a Dd value of about À0.09 ppm.The signals of H g shied upeld with a Dd value of about À0.20 ppm, due to the shielding effect of the complexation of DB24C8 and the DBA unit.The signals of H d and H f shied downeld with Dd ¼ 0.56 and 0.35 ppm, respectively, owing to the deshielding effect of DB24C8.The signals of H m and H o were shied downeld with Dd ¼ 0.21 and Dd ¼ 0.44 ppm, respectively, due to the shielding effect of the combination of B21C7 and the BAA unit.Hence the comparison of the 1 H NMR spectra of C1 and 8 provided further evidence for the conrmation of the proposed structure of hetero[6]rotaxane 8.

Experimental
General methods 1 H NMR spectra were recorded at 298 K using a Brüker AV-400 spectrometer at a frequency of 400 MHz and are reported as parts per million (ppm) using CD 3 CN (d H 1.94 ppm) as an internal reference. 13C NMR spectra were recorded at 298 K using a Brüker AV-400 spectrometer at a frequency of 100 MHz and are reported as parts per million (ppm) using CD 3 CN (d H 1.94 ppm) as an internal reference.The electronic spray ionization (ESI) mass spectra were obtained using an LCT Premier XE mass spectrometer.

Conclusions
In conclusion, by precisely programming the association constants, steric hindrance and size-matching of different macrocyclic rings and their corresponding guest molecules, we have developed and constructed a novel six-component selfsorting system.The self-sorting strategy as a key tool ensures this highly selective self-assembly process in a multicomponent system and gives rise to the formation of specic rotaxane precursors.Based on this well-organized self-sorting process, a novel hetero[6]rotaxane 8 with three different crown ether macrocycles, a BPY 2+ recognition site and two secondary ammonium recognition sites was efficiently constructed via a classical CuAAC stoppering reaction.Such work has not only successfully developed a novel hetero[6]rotaxane 8, which will enrich the family of mechanically interlocked molecules, but also provides a good supplement for the self-sorting concept that can be used for the construction of complex supramolecular systems and materials with increasing complexity both in terms of structure and function.
Scheme 1 (a) Schematic representation of the six-component selfsorting process to predominantly form three interlocked species: BPP34C10 I BPY 2+ , DB24C8 I DBA and B21C7 I BAA.(b) Molecular structure and cartoon picture of the hetero[6]rotaxane 8 which has three different crown ether macrocycles, namely BPP34C10, DB24C8 and B21C7.
correspond to the target product aer the loss of 2, 3, 4, 5 and 6 PF 6 À ions, i.e. [M-2PF 6 ] 2+ , [M-3PF 6 ] 3+ , [M-4PF 6 ] 4+ , [M-5PF 6 ] 5+ and [M-6PF 6 ] 6+ , respectively.The 1 H-1 H NOESY spectrum of hetero[6]rotaxane 8 shows cross peaks (CP1 and CP2) between the protons of the BPP34C10 ring and the protons of the BPY 2+ unit (H b and H a ).The cross peaks CP3 and CP5 suggest the correlation between the protons of the DB24C8 ring and the aromatic protons H u and H s .The cross peak CP4 illustrates the relationship between the protons of the B21C7 ring and the aromatic protons H L .This means that we have successfully synthesized hetero[6]rotaxane via a self-sorting strategy using a one-pot mild CuAAC "click" reaction.In order to gain deeper insight into the self-sorting process and further verication of the formation of the interlocked molecular hetero[6]rotaxane 8, the axle compound C1 (Scheme S1 †) was also synthesized.Compounds 1, 2 and Cu(CH 3 CN) 4 PF 6 were mixed in CH 3 CN and stirred under the protection of argon at room temperature for 48 h, and the axle compound C1 was obtained in a moderate yield of 37%.Compound C1 was characterized by 1 H NMR and13 C NMR spectroscopy and HRMS (Fig.S27-S30 †).By comparing the 1 H NMR spectra of C1 and 8,