An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes

Ethyl- and propyl-prism[6]arenes are obtained in high yields and in short reaction times, independent of the nature and size of the solvent, in the cyclization of 2,6-dialkoxynaphthalene with paraformaldehyde. PrS[6]Et or PrS[6]nPr adopt, both in solution and in the solid state, a folded cuboid-shaped conformation, in which four inward oriented alkyl chains fill the cavity of the macrocycle. On these bases, we proposed that the cyclization of PrS[6]Et or PrS[6]nPr occurs through an intramolecular thermodynamic self-templating effect. In other words, the self-filling of the internal cavity of PrS[6]Et or PrS[6]nPr stabilizes their cuboid structure, driving the equilibrium toward their formation. Molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-fit mechanism. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer, PrS[5]. These results represent a rare example of a thermodynamically controlled cyclization process driven through an intramolecular self-template effect, which could be exploited in the synthesis of novel macrocycles.


Introduction
Since the birth of supramolecular chemistry, the eld of macrocyclic hosts and related host-guest complexes has grown considerably. 1,2 The internal cavity of macrocyclic hosts is reminiscent of the binding sites of natural bioreceptors and for this reason macrocycles have been the focus of biomimetic chemistry research. 3 The equilibrium of inclusion of a guest inside the host cavity is thermodynamically inuenced by many factors, such as host-guest desolvation processes, ion pair rupture, conformational control of the host and guest, and host/ guest weak interactions. 4,5 The strength of such non-covalent interactions in guest@host complexes plays a crucial role in overcoming the other unfavorable thermodynamic factors. [4][5][6] In general, an extended contact area 4,5 between the host and guest and a high level of preorganization of the host can lead to stronger complexation. Aromatic cyclophane 7 macrocycles, such as calixarenes, 8 resorcinarenes, 7 and pillararenes, 9 show a variety of deep cavities that can wrap the included guest. Recently, naphthol-based macrocycles with a deeper p-cavity have generated a great deal of interest. Thus, oxatubarenes, naphthotubes, and naphthocages were reported by Jiang and coworkers, which show interesting conformational properties and recognition abilities. [10][11][12][13][14][15][16] The scientic interest toward the design of new macrocyclic hosts 17 with deep cavities and conformational adaptive behavior 16 has recently prompted us to synthesize new examples of naphthol-based macrocycles named calix [2]naphth [2]arene 18 and prismarenes (Fig. 1). 19,20 The rst report on prismarenes was mainly focused on the synthesis and recognition properties of the pentameric PrS [5] Me macrocycle ( Fig. 1) constituted by 1,5-methylene bridged 2,6-dimethoxynaphthalene units. 19 With the aim to explore the supramolecular properties of the larger hexameric PrS [6] macrocycle, we decided to investigate its efficient synthesis by changing the solvent, templating agents, and alkoxy-chains. In this way, a rare and peculiar intramolecularly self-templated synthesis was discovered. 2,6-Dimethoxynaphthalene-based prism [n]arenes PrS[n] Me (Fig. 1) were obtained by a thermodynamically controlled cyclization process (Scheme 1). 21a,22 Starting from 4a, under the conditions reported in Scheme 1, the isomeric prismarenes PrS [5] Me and c-PrS [5] Me (the isomer with one 1,4 methylene bridge unit) were, respectively, the kinetic and the thermodynamic adduct.
Specically, the pentamer PrS [5] Me was formed faster than its confused isomer c-PrS [5] Me , and DFT calculations conrmed that the transition state for the formation of the confused isomer was higher in energy than that for PrS [5] Me . 19 In addition, DFT calculations conrmed the crucial role played by the solvent 1,2-DCE in the macrocyclization steps for the formation of the two isomeric PrS [5] Me and c-PrS [5] Me pentamers. 19 Under the conditions reported in Scheme 1, and in the presence of the solvent 1,2-DCE, the most stable product c-PrS [5] Me prevailed over time (Table 1, entry 1). When the template 5 2+ or 6 + (Scheme 1 and Table 1, entries 2 and 3) was added to the reaction mixture in 1,2-DCE, the formation of endo-cavity inclusion complexes, 5 2+ @PrS [5] Me or 6 + @PrS [6] Me , respectively, stabilized the desired product via supramolecular interactions, 19 and shied the equilibrium toward PrS [5] Me (Table 1, entry 2) or PrS [6] Me (Table 1, entry 3), respectively (thermodynamic templating 21b ). 19 The crucial factor which determines the greater thermodynamic stability of c-PrS [5] Me in the equilibrium mixture (Scheme 1), in the absence of guest 5 2+ or 6 + , is its ability to self-ll the internal cavity. 19 In fact, the 1,4-naphthalene ring assumes an orientation in which the 2-OMe group is inward oriented with respect to the cavity and completely lls it. 19 Considering these results, the question arises as to whether the pentamers and their confused isomers are still the kinetic and thermodynamic products, respectively, when starting from 4b-e bearing longer alkoxy groups. In other words, can the length of alkoxy substituents inuence the synthesis, the conformational, and supramolecular properties of prismarenes?

Synthesis of ethoxy-and propoxy-prismarenes
As previously reported, when methoxy-derivative 4a (ref. 19) was reacted in the presence of paraformaldehyde and TFA in 1,2-DCE as the solvent, c-PrS [5] Me and its PrS [5] Me isomer were formed in 40% and 0.3% yield ( Table 1, entry 1), respectively, while no trace of PrS [6] Me hexamer was detected in the reaction mixture. 19 We showed that under these conditions, c-PrS [5] Me was the thermodynamic product, while PrS [5] Me was the kinetic one and its formation was templated by the 1,2-DCE solvent. Thus, under these conditions, 1,2-DCE didn't act as a template for the prism [6]arene methoxy derivative. 19 Differently, when 2,6-diethoxynaphthalene 4b was reacted in 1,2-DCE (Table 1, entry 4), unexpectedly, the PrS[6] Et hexamer was formed in a very high yield (75%) aer 45 min. Analogously, when 2,6dipropoxynaphthalene 4c was used as the precursor, the PrS [6] nPr hexamer was again the favored product (65% yield) aer 90 min (Table 1, entry 5). These results were unexpected because, according to the data previously reported by Ogoshi 22 and by us, 19 the 1,2-DCE solvent does not play any role as a template for the larger pillar [6]arene and prism [6]arene methoxy-derivatives. The formation of ethoxy-and propoxyprismarenes PrS[n] R (n ¼ 5 and 6, R ¼ Et and nPr) as described in Scheme 1 and Table 1 was monitored as a function of time by  HPLC (ESI †). The formation of the cyclic oligomers proceeded through many linear intermediate compounds that, aer being initially formed, were then consumed as the cyclization reaction progressed.
In the case of 4b in 1,2-DCE (Scheme 1 and Table 1, entry 4), PrS [6] Et was formed faster than the pentamer PrS [5] Et (ESI †). In fact, the hexamer started to appear aer 10 min and remained the favored product over time, whereas an equilibrium value of 75% was reached aer 45 min. HPLC analysis (ESI †) revealed that the pentamer appeared aer 15 min but vanished aer 30 min. Analogous results were obtained by monitoring the formation of PrS [6] Et and PrS [5] Et over time using different solvents (ESI †), such as chloro-cyclohexane (Cl-CyHex, Table 1 20). Independent of the nature and size of the solvent, the hexamer PrS [6] Et is always kinetically and thermodynamically favored with respect to PrS [5] Et , and its formation occurs in very high yields (71-76%) in short reaction times (30-45 min). Similar results were observed for the reaction in Scheme 1 starting from propoxy precursor 4c. In this case, the hexamer PrS [6] nPr is the kinetically and thermodynamically favored product independent of the nature of the solvent (Table 1, entries 5, 13, 16, 19, and 21). These results are surprising; in fact, as reported in the literature, only halogenated solvents play a fundamental role as templates in the formation of p-electron rich macrocycles as in the synthesis of pillararenes. 22,23 To conrm the thermodynamic nature of the hexamers, PrS [5] Et or PrS [5] nPr (vide infra) was heated to 70 C in 1,2-DCE, in the presence of TFA. Under these conditions, a conversion to PrS [6] Et and PrS [6] nPr in 83% and 85% yield, respectively, was observed aer 22 h, conrming their higher thermodynamic stability.
As previously reported, 19 starting from the methoxy-derivative 4a in 1,2-DCE c-PrS [5] Me is preferentially formed, while no evidence of the hexamer was detected in the reaction mixture ( Table 1, entry 1). Therefore, we further investigated whether PrS [6] Me would be formed using the more bulky cyclohexane or toluene as the solvent. Starting from methoxy-derivative 4a in toluene, the pentamer c-PrS [5] Me was formed in a very low yield (11%, Table 1, entry 14) in addition to a copious quantity of polymeric material. Analogous results were obtained in cyclohexane (7% of c-PrS [5] Me , Table 1, entry 17).
Under these conditions, no hexamer PrS [6] Me was detected. When the reaction in Scheme 1 was performed using a monomer with even longer alkyl chains than propyl, namely 2,6dibutoxy-and 2,6-dipentoxynaphthalene 4d and 4e in 1,2-DCE, hexamers PrS [6] nBu and PrS [6] nPent were formed in lower yields of 30% and 8%, respectively (Table 1, entries 10 and 11). Thus, in summary, in the presence of small methoxy groups, the hexamer PrS [6] Me is not formed in any solvent (CyHex, toluene, or 1,2-DCE), whereas in the presence of ethoxy and propoxy groups the hexamer PrS [6] R is always formed in high yields (75 and 65%) independent of the nature and size of the solvent. Interestingly, the yield of prism [6]arene decreases (from 75% to 8%) as the chain length increases (entries 4, 5, 10, and 11) from ethoxy (4b, entry 4, Table 1) to pentoxy (4e, entry 11, Table 1). In addition, the pentamer PrS [5] Me is the kinetically favored product while its confused isomer prevails under thermodynamic conditions. Differently, in the presence of ethoxy and propoxy functions the hexamers PrS [6] R are both kinetically and thermodynamically favored products. These results led us to conclude that the length of the alkyl chains on the rims of prismarenes plays a "special role", driving their cyclization process. In detail, we can invoke a kinetically and thermodynamically self-templating effect by the Et and nPr alkyl chains in the synthesis of prismarene hexamers. At this point, we studied the role of the ammonium templates 5 2+ and 6 + in the formation of the ethoxy and propoxy prismarenes. In fact, we previously showed that the cation 5 2+ acted as a template for the synthesis of the methylated pentamer PrS [5] Me (47%, Table 1, entry 2). 19 Differently, starting from 4b, under the conditions in Scheme 1 and in the presence of 5 2+ $2I À , the hexamer PrS [6] Et was preferentially formed in 35% yield aer 22 h (thermodynamic conditions), while the pentamer PrS [5] Et was obtained in 10% yield ( Table 1, entry 6). HPLC analysis of the reaction mixture (Scheme 1) (ESI †) showed that aer 60 min the hexamer was formed faster than PrS [5] Et , which was not detected in the reaction mixture. Aer 70 min, PrS [6] Et started to decrease slightly, while PrS[5] Et increased.
Starting from propoxy derivative 4c, the hexamer was still the kinetically favored product, while aer 3 h the concentration of the pentamer PrS [5] nPr started to increase, and aer 22 h an equilibrium value of 1/1 was reached ( Table 1, entry 8). By comparison between the data in Table 1 (entry 2) 19 and the new results (entries 6 and 8), we can conclude that the cation 5 2+ is surely less effective as a thermodynamic template in the synthesis of ethoxy and propoxy pentamers. In detail, the thermodynamic effect of the host-guest complexation invoked for the synthesis of PrS [5] Me , 19 is overcome by the intramolecular "self-templating" effect of the ethyl and propyl chains. At this point, we investigated the role of 6 + in the synthesis of PrS [6] Et starting from 4b in 1,2-DCE (Scheme 1).
As previously reported, 19 6 + is an effective template for the synthesis of PrS [6] Me (Table 1, entry 3). 19 We monitored the progress of the reaction, and in the presence of 6 + $I À aer 45 min the yield of PrS [6] Et was <10%, signicantly lower than that obtained aer the same time (75%,  19 the ammonium cation 6 + has a negative inuence on the kinetics of the formation of prismarene hexamers PrS [6] Et and PrS [6] nPr . This is demonstrated by lower yields over longer reaction times. In other words, kinetically and thermodynamically self-templating by the Et and nPr alkyl chains in the synthesis of prismarene hexamers is veried by the higher yield (65-75%) of the product and a shorter reaction time, in the absence of cations. With these results in hand, we investigated the nature of the self-templating effect from the alkyl chains by detailed X-ray, DFT, and 2D NMR studies.
Structural properties of ethoxy-and propoxy-prismarenes in the solid state: the role of the alkyl chains The structure assumed by prismarenes were studied experimentally, both in solution and in the solid state, by single crystal X-ray diffraction (Fig. 2) and NMR techniques (ESI †), respectively, and theoretically by DFT calculations (Fig. 3 and ESI †).
Detailed structural models of the series PrS[6] R and PrS[5] R (R ¼ Et and n-Pr) were obtained by single crystal X-ray diffraction experiments ( Fig. 2 and ESI †) using synchrotron radiation and cryo-cooling techniques (see the ESI †). All four centrosymmetric crystal structures are composed of a racemic mixture of inherently 24-27 chiral macrocyclic molecules, in which the naphthalene moieties are 1,5 connected, with the alkoxy groups at the 2,6-positions (Fig. 2). The ethyl derivatives, PrS[6] Et (Fig. 2a) and PrS [5] Et (Fig. 2c), show two crystallographic independent molecules in the asymmetric units, while the propyl derivatives, PrS[6] nPr (Fig. 2b) and PrS [5] nPr (Fig. 2d), contain a half molecule which lies on a two-fold crystallographic axis and one entire macrocyclic molecule, respectively. The prism [6] arene derivatives show a common dissymmetric conformation for the independent molecules, with a pseudo-D 2 point symmetry of the macro-ring (Fig. 2e).
The DFT-optimized PrS [6] nPr molecule ( Fig. 3) is very similar to the corresponding experimental solid-state structure as demonstrated by a rmsd value of 0.34Å (ESI †) obtained by superimposing the two macrocyclic models (excluding the mobile alkyl chains).
The macro-ring is folded into a nearly square cuboid-shape (Fig. 2a, e and 3a) with the side-faces dened by the six naphthalene planar groups. Each aromatic planar group makes an angle of about 90 with respect to the contiguous naphthalene moieties (see ESI, Table S6 †). Two opposite naphthalene rings (A and A 0 of Fig. 2e at a 12.0Å distance) dene the square faces of the prism with about 6.5 A side lengths. A twofold symmetry axis passes through the centers of these naphthalene rings. Thus, these two naphthalene units show a canting angle q value of about 90 (see ESI, Table S5 †). 28 A second orthogonal twofold axis passes through two opposite methylene bridges of naphthalene moieties located on two edges of elongated faces of the parallelepiped. These naphthalene moieties show supplementary canting angles of ca. 40 /140 for the B/B 00 and B 000 /B 0 couples ( Fig. 2e and Table S5 †). The third orthogonal twofold axis passes through the two open edges of the prism (Fig. 2e). The four inward oriented alkyl chains of the naphthalene moieties located on the elongated faces of the prism ll the cavity of the macrocycle (Fig. 3). These chains, organized in couples oriented in an antiparallel fashion, establish C-H/p interactions with the aromatic walls and various inter-chain van der Waals interactions (Fig. 3).
In detail, four strong C-H/p interactions are present with a C-H/p centroid distance of 2.9Å and a C-H/p centroid angle of 148 . Clearly, this self-lling of the central cavity of the hexamer (Fig. 3) plays a crucial role in the thermodynamic stabilization of the hexameric skeleton, and it is relevant with respect to the conformational properties in solution and recognition abilities within the family PrS [6] nPr , PrS [6] Et , and PrS [6] Me . In addition, the inward oriented alkyl chains enhance the rigidity of the cuboid scaffold, as evidenced by NMR studies (vide infra). All three independent molecules of the prism [5]arene derivatives show a pseudo-C 2 point symmetry of the macro-ring and  therefore a similar dissymmetric conformation (Fig. 2c, d and f). This pseudo-symmetry was also observed in the three pseudopolymorphic crystal forms of PrS [5] Me . 19 The superimposition of the DFT-optimized PrS [5] nPr molecule with the solid-state structure shows a rmsd value of 0.07Å. The pseudo-twofold symmetry axis passes through the methylene bridge connecting the C and C 0 rings and the barycenter of the opposite naphthalene moiety (A in Fig. 2f). The canting angles reported in Table S5 † reect this situation. The dihedral angles of the B/B 0 and C 0 /C couples (see Fig. 2f) are supplementary angles (ca. 70 /110 for B/B 0 and ca. 40 /140 for C 0 /C), while the A angle is ca. 90 . In this way, two adjacent naphthalene rings (ESI †) are tilted in a way to give a self-lling of the cavity with their chains (ESI †). To gain insight into the structural features of the potential cavities of the prism[n]arenes (n ¼ 5 and 6), the surfaces and volumes of the ideal prismatic solids enclosed by the aromatic walls were evaluated (ESI † shows the comparison with the analogous pillararene and pagodarene 17 ). The geometrical parameters used for these calculations were obtained from the CCDC database as mean values of distances and angles observed in the X-ray structures containing the relevant monomeric unit (see Fig. S107 † for details).
The prism [6]arene shows a cavity opening of 52.4Å 2 almost twice that (27.3Å 2 ) of the prism [5]arene, and, analogously, a 2 : 1 volume cavity ratio was calculated for the two prisms (490Å 3 /255 A 3 ). Another important geometric feature is the internal potential contact surface areas (A) derived from the total area of the rectangular prism faces. The ratio between the contact surface areas of prism [6]arene and prism [5]arene is 252Å 2 /186Å 2 ¼ 1. 35. In fact, a close inspection of the 1 H NMR spectrum of PrS [6] nPr revealed the presence of 3 aromatic AX/AB systems (COSY) at 8.28/7.35 (9.6 Hz), 7.91/7.01 (9.6 Hz), and 7.52/6.35 (9.6 Hz) ppm ( Fig. S29c and e †), and two singlets at 4.82 and 4.42 ppm in a 2 : 1 ratio, attributable to the methylene-bridged groups. In addition, the OCH 2 groups showed three diastereotopic AB systems at 4.25/4.23, 4.17/3.95, and 3.00/2.29 ppm (Fig. S29c,  d and f †). The presence of diastereotopic resonances for the OCH 2 groups of PrS[6] nPr (Fig. 4a and S29c, d, f †) is due to the planar chirality of the macrocycle, in agreement with the considerations previously reported by Ogoshi and coworkers 24 for pillar [5]arenes. Thus, this 1D and 2D NMR analysis indicates that in solution PrS [6] nPr also adopts a conformation with a pseudo-D 2 point symmetry. The presence of shielded 1 H NMR signals at negative chemical shi values (Fig. 4a), attributable to the terminal methylene and methyl groups of the propyl-chains (CH 3 : À0.6 ppm, 12H, ESI †), clearly corroborates the nding that PrS [6] nPr also adopts in solution the cuboid structure depicted in Fig. 3a and 5a, in which there is a folding of the propyl chains inside the cavity. The 1D and 2D NMR spectra of PrS [6] Et show analogous features that conrm its cuboid structure in solution. A broad singlet is present in the 1 H NMR spectrum of PrS [6] Et in CD 2 Cl 2 at 298 K at À1.12 ppm (12H), attributable to the methyl groups belonging to the four ethyl groups folded inside the cavity. Impressively, these OCH 2 CH 3 methyl groups experienced an up-eld shi of Od ¼ d macrocycle À d monomer-4b ¼ À2.74 ppm, signicantly larger than that shown by the methyl groups of PrS [6] nPr of À1.67 ppm. This is evident from the close inspection of the X-ray structures in Fig. 5a and d. In Fig. 5b, the terminal methyl group of the chains of PrS [6] nPr are outward oriented, while the four ethyl groups of PrS [6] Et are entirely included inside the cavity of the macrocycle. The CPK visualization of the ethyl chains in Fig. 5d clearly reveals that they are close-packed inside the cavity, and ll the inner space more efficiently than the propyl chains of PrS[6] nPr in Fig. 5b. To quantify the differences in the self-lling of PrS [6] Et and PrS [6] nPr , the free volume of each enclosed internal cavity was evaluated from accessible surface area calculations  (see the ESI † and Fig. 5). The smaller cavity volume of 49Å 3 obtained for PrS [6] Et with respect to 77Å 3 for PrS [6] nPr indicates the more efficient packing of this ethyl derivative ( Fig. 5c and f).
These results support the hypothesis that the nature of the alkyl chains plays a crucial role in the thermodynamically controlled cyclization of the hexamer. The cyclization process of the prism [6]arene hexamer is thermodynamically controlled by the alkyl chains on the rims and by their ability to ll the internal cavity of the macrocycle. In particular, the ethyl chains show a better steric complementarity with the internal cavity of the prism [6]arene and ll it in a more effective way (90%) than the propyl chains (84%). Consequently, PrS [6] Et is obtained in higher yields (about 75%) than PrS [6] nPr independent of the used solvent. Longer butyl and pentyl chains are less effective at self-lling the internal cavity and consequently the yield of the hexamer is lower.
Analogously, no evidence of the hexamer was detected in the reaction mixture starting from 2,6-dimethoxynaphthalene 4a; in this case, the methyl groups is too small to produce an effective lling of the internal cavity of the hexamer. Consequently, the equilibrium of formation of the methoxy-prismarenes is shied toward the confused prism [5]arene c-PrS [5] Me , which shows a more effective self-lling of the internal cavity. When the 5 2+ or 6 + cation is present, the lling of the PrS[5] Me or PrS [6] Me cavity with the formation of the host-guest complex stabilizes the pentamer or hexamer respectively, which remains the preferential product over time.
On these bases, we can invoke an intramolecular thermodynamic self-templating effect in which the formation of the prism [6]arene is not driven by an external templating agent (e.g.: solvent) but by "intramolecular self-templating" 29 of the alkyl chains. In other words, the self-lling of the internal cavity of PrS [6] Et or PrS [6] nPr stabilizes their cuboid structure driving the equilibrium toward their formation. This represents a rare example of a documented thermodynamically controlled cyclization process driven through an intramolecular self-template effect.
Ogoshi reported that 1,2-DCE and chlorocyclohexane are thermodynamic template solvents in the synthesis of pillar [5] arenes. 22 In detail, DCE lls the pillar [5]arene cavity and its equilibrium of formation is driven by the thermodynamic effect of the complexation, solvent@host. 22 The same authors clearly showed that 1,2-DCE didn't play a template role in the synthesis of the pillar [6]arene. 22 In an attempt to examine if the solvents in Table 1 play a thermodynamic templating role for the selective formation of prism [6]arenes, by an endo-cavity inclusion process (solvent@PrS [6] R complexation), we performed 1 H NMR experiments following a standard procedure already reported for pillararenes. 22 The cuboid structure of the prism [6]arene shows an inaccessible closed-cavity (closed state, Fig. 5a, b and d, e) and consequently a conformational change of the prism [6] arene should be expected during an eventual endo-cavity inclusion of the solvent (vide infra).
The 1 H NMR spectra of PrS [6] nPr in Fig. 4b-d were acquired in non-deuterated solvents such as chloro-cyclohexane, decaline, and 1,2-DCE. As is evident, the 1 H NMR spectra in these solvents agree with the D 2 -symmetry of the cuboid structure.
This result clearly indicated that in the presence of these solvents, the prism [6]arene remains in a closed state (Fig. 4) and consequently the inclusion of solvent molecules inside the cavity doesn't occur. To conrm this assumption, 1 H NMR experiments were performed in which PrS [6] nPr and PrS [6] Et were titrated with 1 equiv. of solvent such as cyclohexane, chloro-cyclohexane, toluene, decaline, and 1,2-DCE and in no case was the shi of the solvent signals observed (ESI †), con-rming that the host cuboid structure was retained. From these results, it can be inferred that these solvents don't act as a thermodynamic template for prism [6]arene formation. These results are consistent with the nding that, independent of the nature and size of the solvent, the ethoxy-and propoxy-hexamers are always kinetically and thermodynamically favored with respect to the pentamer.
In order to investigate whether the solvent 1,2-DCE plays a role in the stabilization of the transition states (TSs) for the macrocyclization steps of the intermediate carbocation of PrS [6] Et , a preliminary DFT study (ESI †) was performed. The transition state holding the solvent molecule inside the cavity (ESI †) is predicted to lie above the one holding the ethyl group inside the cavity by 3.4 kcal mol À1 in terms of internal energy and 2.3 kcal mol À1 in terms of Gibbs free energy. Based on the reasonable hypothesis that a late transition state is involved in the rate-determining step, DFT results suggest that the ethyl group could indeed ll the cavity, thus acting as an internal kinetic templating agent.

Molecular recognition properties of ethoxy-and propoxyprism[n]arenes: the role of the alkyl chains
On the basis of these conformational aspects, a question arises as to whether PrS [6] nPr and PrS [6] Et are also capable of adopting a conformation with an open-cavity (open state) in the presence of appropriate guests. Due to the presence of p-electron rich cavities, 19 it is worth investigating the recognition abilities of PrS [6] nPr and PrS [6] Et hosts toward cationic ammonium guests (Scheme 2). The complexation of the N,N,N 0 ,N 0 -tetramethylpiperazonium 7 2+ cation (Scheme 2) showed very interesting features. The addition of 1 equiv. of 7 2+ as a barfate salt (BArF À ) 30,31 to a solution of PrS [6] nPr in CD 2 Cl 2 caused signicant changes in its 1 H NMR spectrum (Fig. 6), indicative of the formation of a 7 2+ @PrS [6] nPr complex with the cation hosted inside the cavity of PrS [6] nPr . Furthermore, in the presence of 7 2+ , a more symmetric conformation of PrS [6] nPr emerged in the 1D and 2D NMR spectra (ESI †). In fact, the 1 H NMR signals of the macrocycle in the 7 2+ @PrS [6] nPr complex (Fig. 6b) are in agreement with an average D 6 symmetry. 32 The most plausible rationalization of this behavior is that the introduction of the guest into the macrocycle cavity forces the cuboid scaffold to open. This assumption was corroborated by DFT calculations (Fig. 6 top). The optimized structure (ESI †) of the complex 7 2+ @PrS [6] nPr shows an opening of the cuboid scaffold (open state in Fig. 6), with the guest 7 2+ that occupies the central cavity in which the average plane of the cyclohexane ring is tilted by 20 with respect to the mean plane of the host methylene bridges. An association constant value of 1.2 Â 10 8 M À1 (Table 2, 298 K, CD 2 Cl 2 , see the ESI †) was determined for the 7 2+ @PrS [6] nPr complex by a series of competition experiments (ESI †). 33,34 The host-guest complex is stabilized by ion-dipole (N + /OR), cation/p, C-H/p, and van der Waals interactions.
Regarding the C-H/p interactions, Natural Bond Orbital (NBO) 35,36 (ESI †) and Non-Covalent Interactions (NCI) calculations (ESI †) revealed that a signicant contribution to the stabilization energy of the 7 2+ @PrS [6] nPr complex was provided by the four equatorial C-H groups of the guest and the aromatic naphthalene walls (26%, see RDG based NCI analysis in the ESI †), while the axial C-H groups give a negligible contribution (3.0%). Finally, the + NCH 3 group also establishes cationic C-H/p interactions with the aromatic walls of the host, as conrmed by RDG-based NCI analysis (ESI †).
An analogous conformational change from a closed to an open conformation was also revealed for the PrS[6] Et host aer endo-cavity complexation with 7 2+ . Attempts to obtain crystals of 7 2+ @PrS [6] nPr or 7 2+ @PrS [6] Et complexes were unsuccessful. However diffracting crystals of 6 + @PrS [6] Me $BArF 19 were obtained and the X-ray structure of this complex (Fig. 7a) provides interesting structural details regarding the open state of the prism [6]arene skeleton. The symmetric PrS [6] Me host lies on the crystallographic two-fold axis passing through the center of two opposite naphthalene rings of the host. The internal guest results in an opening of the cuboid arrangement towards the formation of a hexagonal prism. This is reected by the supplementary canting angles of the B/B 00 and B 000 /B 0 couples, which change from ca. 40 /140 of free PrS[6] R to ca. 60 /120 in the complex (Table S7 †), closer to the ideal angle of 90 of a regular hexagonal prism.
Furthermore, the interior dihedral angles between the naphthalene planes increase from an averaged value of 90 observed in free PrS[6] R molecules to an averaged value of 105 , closer to the ideal angle of 120 of a regular hexagonal prism. A close inspection of the solid state structure of the 6 + @PrS [6] Me $BArF complex reveals the important role of cationic C-H/p interactions in the host-guest complexation. Analogously, PrS [5] nPr undergoes a conformational change from a closed to an open state upon endo-cavity complexation with Scheme 2 Schematic complexation equilibrium of PrS[n] R with ammonium guests 5 2+ -10 + as barfate salts.  the cationic guest 7 2+ . When PrS [5] nPr was mixed with N,N,N 0 ,N 0tetramethylpiperazonium salt 7 2+ $(BArF) 2 , in CD 2 Cl 2 at room temperature, drastic changes were observed in the 1 H NMR spectrum (Fig. 8). The presence of upeld shied signals of 7 2+ methylene H atoms to negative values (Fig. 8b) is indicative of the inclusion of 7 2+ inside the cavity, shielded by the PrS [5] nPr walls. An AB system is observed at À0.82/À1.04 ppm (J ¼ 11.5 Hz). Furthermore, the Dd value between the aromatic doublets experiences a variation from 1.18 (Dd ¼ 8.07 À 6.89 ¼ 1.18) for the free host (Fig. 8a) to 1.62 ppm (Dd ¼ 8.82 À 7.20 ¼ 1.62) (Fig. 8b) upon complexation. This result clearly indicates an opening of the folded structure of PrS [5] nPr (closed state in Fig. 8) that upon complexation with 7 2+ adopts the open state in Fig. 8 in which the PrS [5] nPr host shows a D 5 symmetry.
In this conformation, the aromatic walls adopt canting angle values of about 90 and therefore dene a regular pentagonal prism (Fig. 8). 37 Thus, in the open state the aromatic H atoms move away from the cavity and experience a down-eld shi ( Fig. 8b) with respect to the closed state (Fig. 8a). The attempts to obtain crystals of 7 2+ @PrS [5] nPr or 7 2+ @PrS [5] Et complexes were also unsuccessful in this case. However diffracting crystals of 7 2+ @PrS [5] Me $BArF and 10 + @PrS [5] Me $BArF were obtained and the X-ray structures of these complexes (Fig. 7b and c) provide structural details regarding the open state of the prism [5]arene skeleton (see also the DFT optimized structure of the 7 2+ @PrS [5] nPr complex in Fig. 8 and the ESI †). The crystal structure of 7 2+ @PrS [5] Me $(BArF) 2 (Fig. 7b) shows the guest located at the center of the prismatic host with the chair's plane perpendicular to the mean plane of methylene bridges of the macrocycle (85.8 ). The pseudo-two-fold symmetry axis of 7 2+ , orthogonal to the chair's plane, forms an angle of about 50 with a crystallographic two-fold axis, thereby resulting in a twoposition statistical disorder of the 7 2+ ion.
The X-ray structure of the 7 2+ @PrS [5] Me complex reveals a high steric complementarity between the PrS [5] Me cavity and the cationic 7 2+ guest that gives rise to relevant C-H/p interactions. The host resembles an almost regular pentagon prism with canting angles of 90.0 AE 3.2 and interior dihedral angles ranging from 104.6 to 110.5 , with an average angle of 107.9 , very close to the ideal 108 angle (Fig. 7b). Similarly, the crystal structure of 10 + @PrS [5] Me $BArF also evidences an opening of the prismatic host in both crystallographic independent hostguest complexes (see Tables S7 and S8 †) (Fig. 7c). The macrocycle adopts an almost regular pentagon prism with canting angles of 90.0 AE 3.3 and interior dihedral angles ranging from 102.1 to 113.7 , with an average angle of 108 , equal to the ideal angle (Fig. 7c).
The tetramethylammonium guests are well-centered in the PrS [5] Me cavity to give the important cationic C-H/p interactions (Fig. 7c). By a series of NMR competition experiments, an association constant value of 1.4 Â 10 9 M À1 (298 K, CD 2 Cl 2 ) was determined for the 7 2+ @PrS [5] nPr complex ( Table 2). This was conrmed by uorescence titration (K ass ¼ 1.7 Â 10 9 M À1 , see the ESI †). Interestingly, NBO analysis (ESI †) conducted on 7 2+ @PrS [5] nPr indicates that both axial and equatorial C-H/p interactions play a signicant role in the stabilization of the complex. In a similar way, PrS [5] nPr shows high affinity for dication N,N 0 -dihexyl-DABCO 5 2+ (ESI †). In fact, the 1 H NMR spectrum of PrS [5] nPr shows signicant changes upon addition of 5 2+ as a barfate salt (ESI †) and is indicative of the formation of pseudorotaxane 5 2+ @PrS [5] nPr . The association constant values for the formation of 5 2+ @PrS [5] R complexes (  Table 2 indicates that the longer alkyl chains of axle 5 2+ play a crucial role in the stabilization of pseudorotaxanes 5 2+ @PrS [5] R .

Conclusions
Prism [6]arenes bearing ethyl or propyl chains on their rims are obtained in high yields and in short reaction times, independent of the nature and size of the solvent. Differently, in the presence of small methoxy groups, the hexamer PrS[6] Me is not formed in any solvent (CyHex, toluene, or 1,2-DCE), and analogously the PrS[6] Pentyl derivative is formed in a very low yield. The reaction progress, monitored by HPLC, revealed that PrS [6] R (R ¼ nPr and Et) are the favored products, both kinetically and thermodynamically. Differently, as previously reported for methylated prismarenes, 19 the pentamer PrS [5] Me is the kinetically favored product, while its confused isomer c-PrS [5] Me prevails under thermodynamic conditions. Based on these results, we have invoked a kinetically and thermodynamically self-templating effect by the Et and nPr alkyl chains in the synthesis of prismarene hexamers. Insights into this effect were obtained by detailed X-ray and 1D and 2D NMR investigations supported by DFT calculations. These studies clearly showed that PrS [6] Et and PrS [6] nPr are folded into a square cuboid-shape with D 2 symmetry. In this conformation, four inward oriented alkyl chains of the naphthalene moieties, located on the elongated faces of the prism, ll the cavity of the macrocycle, and establish C-H/p interactions with the aromatic walls and various inter-chain van der Waals interactions. 1D and 2D NMR studies show that the cuboid structure of the hexamers is also maintained in solutions of different solvents, such as 1,2-DCE, CH 2 Cl 2 , decaline, and chloro-cyclohexane. On these bases, we propose that the synthesis of the ethyl and propyl prism [6]arenes occurs under an intramolecular thermodynamic self-templating effect in which the formation of the prism [6]arene is not driven by an external templating agent (e.g., solvent) but by intramolecular self-templating of the alkyl chains. In other words, the self-lling of the internal cavity of PrS [6] Et or PrS [6] nPr stabilizes their cuboid structure driving the equilibrium toward their formation.
The cuboid structure of the prism [6]arene shows an inaccessible closed cavity, and molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-t mechanism, which originates from the conformational exibility of the prismarene macrocycle. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer.
Thus, we here have described a rare example of a documented cyclization process kinetically and thermodynamically templated by intramolecular interactions. The in-depth investigation of the self-lling effects of the alkyl chains on the synthesis of prism [6] arenes, and on their conformational properties, could pave the way to the synthesis of macrocycles exploiting this novel thermodynamically controlled intramolecularly self-templated cyclization process, different from those currently known, based on the external effect of solvents or guests.

Conflicts of interest
There are no conicts to declare.