Cation templated improved synthesis of pillar[6]arenes

Abstract

Improved high yield syntheses of the larger pillar[6]arenes (P[6]) bearing different alkoxy substituents through cation templated syntheses using a series of small organic and organometallic cations is reported. Yields of P[6] up to 38% and P[6]/P[5] ratios as high as 5 : 1 were achieved.

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In the past decade a new class of macrocyclic aromatic host molecules called pillararenes has been disclosed by Ogoshi based on the condensation reaction between para-bis-alkoxy benzene derivatives and paraformaldehyde. The reaction is catalyzed by the presence of a Lewis or Brønsted acid, leading to the formation of macrocyclic structures containing five¹ or six² arene rings. Since its discovery, this class of molecules showed impressive host–guest properties due to the semi-rigid, symmetric and electron-donating cavity that promotes selective binding of unusual neutral molecules,³ observing important effects due to both size and length of the alkoxy substituents. Similarly to cyclodextrins, resorcin[n]arenes and calix[n]arenes, the recently discovered pillar[n]arenes represent a new class of molecules with great potentialities^4,5 ranging from the preparation of supramolecular polymers,⁶ pseudorotaxanes,⁷ application as channels for direct methanol fuel cells,⁸ inhibition of acetylcholine hydrolysis⁹ and other biological applications¹⁰ to mention most recent achievements. Therefore great attention has been focused on the optimization of the syntheses of pillar[5]arenes (P[5]), pillar[6]arenes (P[6])¹¹ and more recently on 7–15 membered arenes.¹² Most of the procedures reported higher yields for the smaller macrocycle, with ratios P[5]/P[6] ranging from 30 to 1.5. Only a few very recent examples in the literature reported an inversion of the ratio, with the formation of higher amounts of P[6] derivatives using (i) particularly bulky para disubstituted bis-alkoxy-benzene units with chloro-cyclohexane as templating solvent¹³ or (ii) polar solvents¹⁴ or (iii) solvent free conditions¹⁵ as well as (iii) naphthalene diimide as templating electron poor unit.¹⁶

Templated synthesis is a common strategy to steer product selectivity in a chemical reaction towards a particular molecule exploiting its recognition properties towards the templating unit. Examples of this strategy are the synthesis of crown ethers¹⁷ or catenanes¹⁸ based on metal ion chelates, cyclotrimers¹⁹ with a porous coordination framework, paracyclophanes²⁰ with covalently bond template as well as materials like mesoporous silica MCM-41 using surfactants.²¹

In the present contribution we report an improved synthesis of P[6] carried out with the templating approach based on the right selection of cationic guests characterized by proper size and shape to bind through cation–π interaction preferentially into the electron rich cavity of P[6] rather than P[5] (Scheme 1).

Scheme 1 Synthesis of P[5] and P[6] with FeCl₃ as catalyst in the presence of different cationic templating units T1–T4.

Starting from simple reagents like para-bis-alkoxy-benzene derivatives with formaldehyde and FeCl₃ as catalyst in the presence of tetramethylammonium chloride (TMAC) and bis(cyclopentadienyl)cobalt(III) hexafluorophosphate ([CoCp₂][PF₆]) as templating units, P[6] was obtained as main product with isolated yields up to 38% and P[5]/P[6] as low as 0.2.

In order to select possible templating guests, we investigated by ¹H NMR the interaction of a series of cationic species like T1, T2, T3, T4, with both P2[5] and P2[6] following the effect of the addition of the templating species on the resonances of the two pillararenes (see ESI†). We observed that T4 turned out to be a suitable guest for the smaller macrocycle P2[5] with no evidence of binding to P2[6] in agreement with recent reports for other similar ionic liquids.²² On the contrary, T2 and T3 turned out to bind into the cavity of P2[6] and not to that of P2[5], as reported in Fig. 1.

Fig. 1 (A) Bottom to top, ¹H NMR spectra of the progressive addition of equivalent amounts of T2 to P2[6], (B) Bottom to top, ¹H NMR spectrum of a progressive addition of equivalent amounts of T3 to P2[6].

The affinity between T2 and P2[6] was investigated in detail by means of ¹HNMR titration following the aromatic resonance of host that changed from 6.47 ppm in the absence of the guest up to 6.85 ppm under saturation conditions with excess of guest. The fitting of the Δδ as a function of the ratio between the concentration of the guest and the host was interpolated with a 1 : 1 binding mode observing a K_ass of 1.2 × 10⁴ M⁻¹ (ESI†). The value observed is indicative of a good affinity between the cationic guest and the larger host P2[6] and it is comparable to what observed for the interaction between a similar pillar[6]arene and ferrocenium.²³

In order to better investigate the contact between T2 as guest and the two host structures P2[5] and P2[6] at a semiempirical PM3 level (ESI†). According to symmetry considerations it would be expected a better templating effect imparted by the pentagonal T2 on the pentagonal P2[5] rather than on the hexagonal P2[6] analogue. Nevertheless, molecular modelling of T2@P₂[5] and T2@P₂[6] show that the templating molecule T2 barely fits in the cavity of P₂[5] and this is further evidenced by the forced eclipsed conformation that the cobaltocenium guest has to assume in order to fit within the cavity. Conversely, the larger cavity of P₂[6] allows the more favoured staggered conformation of T2, without contacts with the inner walls of the cavity (Fig. 2).

Fig. 2 Minimized (semiempirical PM3) structures of T2@P₂[5] (top left: front view stick; top right: front view space filling) and of T2@P₂[6] (bottom left: front view stick; bottom right: front view space filling).

The recent synthesis of the pillar[n]arenes²⁴ with FeCl₃ as a low cost, environmentally friendly catalyst starting from para-bis-alkoxy-benzene derivatives was investigated in the presence and absence of the selected templating cationic species T1–T4. Reactions carried out without templates with all the para-bis-alkoxy-benzene derivative employed led to conversions comparable to that reported in the literature but not in terms of isolated yields (Table 1).²⁵

Table 1 Synthesis of P[5] and P[6] with different starting monomers (M1 methoxy-, M2 ethoxy-, M3 butoxy-) and different templating agents: T1 and T4 15 mol%, T2 and T3 25 mol%

#	Monomer	Template	Conversion (%)	P[6]^a/P[5]^a
a Isolated % yields.
1	M1	—	27	7/3
2	M2	—	29	6/3
3	M3	—	12	5/traces
4	M1	T1	100	13/30
5	M2	T1	100	19/24
6	M3	T1	27	15/12
7	M1	T2	100	6/5
8	M2	T2	100	38/7
9	M3	T2	59	32/28
10	M1	T3	100	1/22
11	M2	T3	100	6/19
12	M3	T3	8	7/10
13	M1	T4	10	2/8
14	M2	T4	94	13/13
15	M3	T4	<2	—

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Subsequently, all the cationic guests T1–T4 were employed as templating species in the reaction between M1–M3 derivatives and paraformaldehyde with FeCl₃. Using M1 as substrate and in the presence of T1 the reaction led to quantitative conversion of the aromatic substrate and formation of P1[5] and P1[6] in 30% and 13% isolated yields, respectively (Table 1, entry 4).

The presence of the cationic template favored both the reaction, since higher overall yields of macrocycles were observed as well as the selectivity towards P1[6]. Switching from the dimethoxy M1 to the diethoxy M2 reagent, an increase of the amount of the corresponding P2[6] product was observed. The longer butoxy M3 substrate displayed incomplete conversion, but the amount of P3[6] isolated was slightly higher than that of P3[5]. The same trend was observed with the cationic species T3 observing quantitative conversions with the smaller aromatic substrate and a P[6]/P[5] ratio that increased with the longer substituted substrates. Nevertheless, in all cases the corresponding P[5] was isolated as the major isomer, with a maximum 7% yield. The use of T4 as templating unit did not provide good results, since for all the substrates investigated the yield of the corresponding macrocycles were rather low, in some cases due also to reduced conversions of the reagents.

When the reaction was carried out with T2, the best result was obtained employing M2 as substrate with quantitative conversion of the reagent and 38% and 7% yields for P2[6] and P2[5], respectively. With the longer M3 quite good yields but with lower selectivity towards P3[6] were obtained (Table 1, entry 9).

Since T2, as anticipated from ¹H NMR titration experiments, turned out to be the best templating unit to favour the synthesis of the larger macrocycles P2[6], the effect of its amount on the reaction was further investigated using M2 as substrate (Table 2). It was observed that conversion and even more importantly yields of P2[6] and P2[5] were not much affected by the mol% amounts of the templating cation. Overall, the best conditions were observed using 25 mol% of T2 leading to 38% isolated yield of P2[6].

Table 2 Synthesis of P2[5] and P2[6] with different molar amounts of T2

#	Template (mol%)	Conversion (%)	P2[6]^a/P2[5]^a
a Isolated yields.
1	20	93	37/6
2	25	100	38/7
3	30	83	34/5

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In order to ascertain the scalability of the reaction, the synthesis of P2[6] templated by T2 under conditions as in Table 2 entry 8 was repeated on 7 mmol of M2. The reaction led to quantitative conversion of the aromatic reagent and formation of the corresponding P2[6] macrocycle in 38% isolated yield corresponding to isolation of 472 mg of the host. Since the synthesis of M2 from hydroquinone is a quantitative reaction, the two step synthesis of P2[6] from hydroquinone is possible with an overall yield of 38%.

Conclusions

In conclusion, we reported high yielding template syntheses of the hexameric pillararenes P[6] from 1,4-disubstituted alkoxy benzene derivatives and paraformaldehyde with FeCl₃ as Lewis acid in the presence of templating cationic guests T1–T4. Among other P[6] selective syntheses,^13–16 our approach is rather straightforward, it uses an economic and environmentally friendly catalyst and requires a templating unit used in substoichiometric amount.

Acknowledgements

The authors acknowledge Università Ca’ Foscari di Venezia and M.I.U.R. for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: experimental synthetic procedures and NMR titrations. See DOI: 10.1039/c6ra07164c

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