Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2021 Oct 11;23(21):8143–8146. doi: 10.1021/acs.orglett.1c02800

per-Hydroxylated Prism[n]arenes: Supramolecularly Assisted Demethylation of Methoxy-Prism[5]arene

Rocco Del Regno 1, Paolo Della Sala 1, Davide Picariello 1, Carmen Talotta 1, Aldo Spinella 1, Placido Neri 1, Carmine Gaeta 1,*
PMCID: PMC8576831  PMID: 34633199

Abstract

graphic file with name ol1c02800_0006.jpg

Methoxy-prism[5]arene PrS[5]Me is demethylated by a supramolecularly assisted reaction. In the presence of a tetramethylammonium cation, PrS[5]Me is demethylated by BBr3 in high yield, while in its absence a 55/40 mixture of PrS[5]OH/PrS[6]OH is formed. The dealkylation of prismarenes, such as PrS[6]R (R = Et, nPr) and c-PrS[5]Me, can be easily obtained in high yields in the presence of BBr3.

In the past few years, growing interest has been directed toward the synthesis of novel macrocycles1a starting with naphthalene1b−1e or anthracene2 monomers. Oxatubarenes,3 naphtocages,4 zorbarenes,5 naphthotubes,6 calix[2]naphth[2]arenes,7 and prismarenes8−10 are naphthalene-based emerging macrocycles, which are of great interest in supramolecular chemistry due to their peculiar structural properties and π-rich deep cavities. Recently, our group reported the prism[n]arenes8−10 (PrS[n]R, n = 5 and 6, R = Me, Et, nPr, Figure 1), a novel class of macrocyclic hosts constituted by 1,5-methylene-bridged naphthalene units, obtained by one-pot condensation of 2,6-dimethoxynaphthalene and paraformaldehyde in the presence of TFA.11 Very recently12 the saucer[n]arene macrocycles were reported by the one-pot condensation of 2,7-dimethoxynaphthalene and paraformaldehyde.12

Figure 1.

Figure 1

Open in a new tab

Prism[n]arene macrocycles.

Phenol and resorcinol-based macrocycles, such as calixarenes,13 resorcinarenes,14 and pillararenes,15 have become highly studied and attractive synthetic hosts in supramolecular chemistry because of their easy functionalization. In particular, the procedure of functionalization of pillararenes starts primarily by the dealkylation of alkoxy-substituted (−OR) aromatic units.16 In fact, per-hydroxylated macrocycles are considered as useful synthetic precursors to obtain chemically modified hosts with novel supramolecular properties with respect to the parent macrocycles.16,17 Based on these considerations, and with the aim to expand the potentialities of prismarene macrocycles as supramolecular hosts, we decided to investigate a convenient procedure for the synthesis of per-hydroxylated prism[n]arenes PrS[n]OH (n = 5 and 6, Figure 1).

Initially, we investigated the demethylation of PrS[5]Me under the conditions previously reported15 for methoxy-pillar[5]arene. Thus, PrS[5]Me was treated with BBr3 in dry CH2Cl2 at 25 °C for 12 h. The FT ICR MALDI mass spectrum of the crude product of this reaction unambiguously revealed the presence of a mixture of per-hydroxylated PrS[5]OH and PrS[6]OH derivatives. PrS[6]OH was separated in 40% yield from PrS[5]OH (55%) by precipitation from ethyl acetate.

With this result in hand, we attempted the demethylation of PrS[5]Me by lowering the reaction temperature. Thus, PrS[5]Me was reacted with BBr3 under the conditions reported in Scheme 1, at −78 °C for 1 h and 0 °C for 3 h, but analogously, a mixture of per-hydroxylated PrS[5]OH (55%) and PrS[6]OH (40%) derivatives was obtained. Chromatographic analysis and HR FT ICR mass spectrometry evidenced that, during the demethylation of PrS[5]Me in the presence of BBr3, the hexamer PrS[6]Me started to appear after 15 min through the formation of linear oligomers (Figure 2), and successively the mixture of PrS[5]Me and PrS[6]Me was demethylated. This is not a surprising result for us; in fact, previously8,10 we reported examples of conversion processes between pentamer and hexamer, upon treatment with trifluoracetic acid (TFA) at 70 °C in 1,2-dichloroethane (1,2-DCE) as solvent, in which the conversions occurred by an acid-catalyzed ring opening and macrocyclization mechanism.8,10 With the aim to study this conversion under the conditions of solvent and temperature reported in Scheme 1, PrS[5]Me was treated in CH2Cl2 at −78 °C for 1 h at 0 °C and for 3 h in the presence of TFA. 1H NMR analysis of the crude product revealed the presence of PrS[6]Me and PrS[5]Me in a 1:1 ratio (Figure S16).18 On the basis of these results, we can assume that, under the conditions reported in Scheme 1, PrS[5]Me was first converted to PrS[6]Me (Figure 2) and finally, the mixture of pentamer and hexamer was demethylated.19 In other words, the conversion of PrS[5]Me to PrS[6]Me is kinetically favored with respect to its dealkylation.19 To confirm the role of BBr3 in promoting the interconversion in Figure 2, we observed that, in its absence, PrS[5]Me was stable under the conditions of demethylation in Scheme 1.

Scheme 1. Dealkylation of PrS[5]Me.

Scheme 1

Open in a new tab

Figure 2.

Figure 2

Open in a new tab

Proposed mechanism for the conversion of PrS[5]Me to PrS[6]Me and their demethylation. Reaction conditions in Scheme 1: BBr3, dry CH2Cl2, 1 h at −78 °C and 3 h at 0 °C.

At this point we studied the stability of PrS[5]OH under acid conditions. Interestingly, per-hydroxylated PrS[5]OH was stable up to 24 h in the presence of TFA in 1,2-DCE as solvent (at 70 °C), while polymeric insoluble products were formed in the presence of BBr3 in dichloromethane (1 h at −78 °C and 3 h at 0 °C). In both instances, no hint of hexamer PrS[6]OH was detected in the reaction mixtures, and this result clearly indicated that the conversion of pentamer to hexamer in Figure 2 occurred in the presence of BBr3, through the methylated macrocycle, while per-hydroxylated PrS[5]OH did not convert to hexamer PrS[6]OH.

As known,8,10 under acid equilibrium conditions the distribution of prismarene macrocycles (pentamer or hexamer) is influenced by the presence of ammonium guests: in the literature this process is named, in a general way, as thermodynamic template effect.20

In detail, starting with 2,6-dimethoxynaphthalene and paraformaldehyde, in the presence of TFA in 1,2-DCE as solvent at 70 °C, c-PrS[5]Me (Figure 1) was obtained in 40% yield (thermodynamic adduct), while its D5-isomer PrS[5]Me and hexamer PrS[6]Me were isolated from the equilibrium mixture by adding as template 1+ and 4+, respectively.8 An analogous effect was observed by Chen and co-workers with saucerarenes; in fact, by adding 1,1-dimethylpiperidin-1-ium as the template, saucer[4]arene was selectively obtained.12

On this basis, we envisioned studying the demethylation of PrS[5]Me in the presence of +N(Me)4 cation 1+.8 In particular, we speculated that the formation of the 1+@PrS[5]Me complex can affect the PrS[5]Me/PrS[6]Me ratio and the successive demethylation with BBr3.8 Thus, PrS[5]Me was treated (Scheme 2) with BBr3 in dry CH2Cl2 (1 h at −78 °C and 3 h at 0 °C) in the presence of 1+ as iodide salt (1 equiv), and under these conditions PrS[5]OH was selectively obtained in 90% yield. This result is particularly surprising; in fact, the presence of 1+ strongly improves the selectivity of the demethylation reaction of PrS[5]Me. Probably the formation of 1+@PrS[5]Me complex kinetically favors the demethylation of PrS[5]Me with respect to its conversion to PrS[6]Me. In fact, as previously reported by us,10 upon inclusion of the guest 1+, the PrS[5]Me macrocycle adopts an open conformation, in which the methoxy groups are sterically more accessible with respect to the closed conformation10 of PrS[5]Me in the free state (Figure S20). These results clearly indicated that the demethylation of PrS[5]Me is supramolecularly driven by the tetramethylammonium guest, which forms the complex 1+@PrS[5]Me that is easily demethylated.21

Scheme 2. Supramolecularly Assisted Dealkylation of PrS[5]Me in the Presence of Template Agent 1+–4+ as Iodide Salts.

Scheme 2

Open in a new tab

Reaction conditions: BBr3, dry CH2Cl2, 1 h at −78 °C and 3 h at 0 °C: (a) 1+; (b) 22+; (c) 32+; (d) 4+.

With these results in hand we attempted the demethylation of PrS[5]Me in the presence of 1,4-dihexyl-DABCO 32+, as iodide salt (Scheme 2). As previously reported,8 the 32+@PrS[5]Me complex shows an association constant value of 3.9 × 107 M–1 which is significatively higher than that for 1+@PrS[5]Me (6.4 × 104 M–1). When PrS[5]Me was reacted with BBr3 in dry CH2Cl2 (1 h at −78 °C and 3 h at 0 °C) in the presence of 32+ as iodide salt (1 equiv), the hexamer PrS[6]OH was obtained in 55% yield, while the pentamer PrS[5]OH was obtained in 40% yield (Scheme 2). This result clearly indicates that in the presence of 32+@PrS[5]Me complex the demethylation is kinetically underdog with respect to the conversion of PrS[5]Me to PrS[6]Me, probably due to steric reasons. In fact, inspection of a 32+@PrS[5]Me model (Figure S21) suggests that the two methoxy-rims are hindered by the presence of hexyl chains.8 To confirm this assumption, PrS[5]OH was again the favored product (80%, Scheme 2) when the demethylation was performed in the presence of 1,4-dimethyl-DABCO 22+ bearing less encumbering methyl groups.

Among the ammonium guests so far explored for the endo-cavity complexation with prismarene hosts,8,10 tetraethylammonium 4+ shows the higher PrS[6]Me/PrS[5]Me selectivity ratio (S = K2@[6]/K2@[5]= 2700/90 = 30).8 For this reason, we studied the demethylation of PrS[5]Me in the presence of tetraethylammonium 4+ (Scheme 2), which shows low affinity for PrS[5]Me.8 When the demethylation reaction of PrS[5]Me was performed with BBr3 in dry CH2Cl2 (Scheme 2) in the presence of 4+ as iodide salt, PrS[6]OH was favored (65%) over PrS[5]OH (25%). Under these conditions (d in Scheme 2), initially the conversion of PrS[5]Me in PrS[6]Me was kinetically favored with respect to its demethylation. Then the 4+@PrS[6]Me complex was formed and quickly demethylated.

Considering these results, the question arises as to whether PrS[6]Me itself can be easily demethylated: in other words, does demethylation of PrS[6]Me lead to the formation of a mixture of PrS[6]OH/PrS[5]OH? To investigate this aspect, PrS[6]Me was reacted with BBr3 in dry CH2Cl2 (Scheme 3, 1 h at −78 °C and 3 h at 0 °C), and PrS[6]OH was obtained in 93% yield. No hint of PrS[5]OH was detected in the reaction mixture, and this result suggests that no conversion of PrS[6]Me to PrS[5]Me occurs. In order to confirm this assumption, PrS[6]Me was treated with TFA under the usual conditions of solvent and temperature reported in Scheme 3. Thin layer chromatography and 1H NMR analysis (Figure S18) clearly indicated the absence of PrS[5]Me, while confused c-PrS[5]Me began to appear by prolonging the reaction time.22 In conclusion, in the presence of TFA in CH2Cl2, PrS[5]Me is first converted to PrS[6]Me and, in the long-run, to c-PrS[5]Me,8 while when starting with PrS[6]Me its slow conversion to c-PrS[5]Me occurs (Figure S19), and no PrS[5]Me is formed. These results are in full accord with the data previously reported by us8 that indicated PrS[6]Me as a kinetic intermediate and c-PrS[5]Me as the thermodynamic macrocycle (Figure 1). Accordingly, when c-PrS[5]Me was demethylated in the presence of BBr3 in CH2Cl2, c-PrS[5]OH was formed in 93% yield and no conversion to other prismarenes was observed.

Scheme 3. Dealkylation of PrS[6]R.

Scheme 3

Open in a new tab

With these results in hand, we attempted the synthesis of per-hydroxylated prismarenes starting with ethoxy PrS[n]Et and propoxy PrS[n]nPr derivatives. As previously reported, PrS[6]Et and PrS[6]nPr are obtained in high yields,10 and could be very convenient to investigate a procedure of dealkylation starting with these derivatives. When PrS[6]Et and PrS[6]nPr were dealkylated in the presence of BBr3 in CH2Cl2, under the conditions reported in Scheme 3, per-hydroxylated PrS[6]OH was selectively obtained in 93% and 96% yield, respectively. The selectivity observed in the dealkylation reactions of PrS[6]Et and PrS[6]nPr in the presence of BBr3 can be reasonably explained on the basis of their thermodynamic stability in solution under acid conditions.8,10 As previously shown,10 the crucial factor which determines the stability of ethoxy- and propoxy-prismarenes under acid conditions is the self-filling of their cavity by intramolecular effects of the alkyl chains.10 Consequently, in the presence of BBr3 in CH2Cl2, PrS[6]Et and PrS[6]nPr were efficiently dealkylated and no hint of other cyclooligomers was present in the reaction mixture.

Differently, when PrS[5]Et and PrS[5]nPr were treated with BBr3 in CH2Cl2, the hexamer PrS[6]OH was obtained in very high yield (90%), while PrS[5]OH was detected in very low yield (<10%), to confirm that, under acid conditions in the presence of BBr3, PrS[5]Et and PrS[5]nPr convert to the more stable hexamers. Clearly, under these conditions the conversion of pentamers PrS[5]Et and PrS[5]nPr to their respective hexamers is kinetically favored with respect to dealkylation of ethyl and propyl chains.

When the dealkylation of PrS[5]Et with BBr3 was performed in the presence of 1+ as iodide salt, then the pentamer PrS[5]OH was detected in 24% yield, while PrS[6]OH was formed in 69% yield. This result confirms that the formation of the 1+@PrS[5]Et complex accelerates the dealkylation with respect to free PrS[5]Et.

In conclusion, here is described the supramolecularly assisted dealkylation of methoxy-prism[5]arene PrS[5]Me. The conversion of the pentamer PrS[5]Me to hexamer is kinetically favored with respect to the demethylation. Differently, when the complex 1+@PrS[5]Me is formed then the reaction of demethylation becomes kinetically favored with respect to the conversion pentamer → hexamer. The dealkylation of prismarenes, such as PrS[6]R (R = Et, nPr) and c-PrS[5]Me, can be easily obtained in high yields in the presence of BBr3. The per-hydroxylated prismarenes described here can be considered as useful synthetic precursors to obtain novel prismarene hosts with intriguing supramolecular properties. Finally, we believe that the procedure of supramolecularly assisted demethylation described here for prism[5]arene could be useful for other macrocycles.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c02800.

  • Detailed synthetic procedures, 1D and 2D NMR spectra of per-hydroxylated prismarenes, HR mass spectra. (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol1c02800_si_001.pdf (2.2MB, pdf)

References

  1. a Diederich F.; Stang P. J.; Tykwinski R. R.. Modern Supramolecular Chemistry: Strategies for Macrocycle Synthesis; Wiley-VCH: Weinheim, 2008. [Google Scholar]; b Yao H.; Jiang W.. Naphthol-Based Macrocycles. In Handbook of Macrocyclic Supramolecular Assembly; Liu Y., Chen Y., Zhang H. Y., Eds.; Springer: Singapore, 2019. [Google Scholar]; c Wang X.; Jia F.; Yang L.-P.; Zhou H.; Jiang W. Conformationally adaptive macrocycles with flipping aromatic sidewalls. Chem. Soc. Rev. 2020, 49, 4176–4188. 10.1039/D0CS00341G. [DOI] [PubMed] [Google Scholar]; d Gaeta C.; Wang D.-X. Editorial: New Macrocycles and Their Supramolecular Perspectives. Front. Chem. 2020, 8, 128. 10.3389/fchem.2020.00128. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Chen C.-F.; Han Y. Triptycene-Derived Macrocyclic Arenes: From Calixarenes to Helicarenes. Acc. Chem. Res. 2018, 51, 2093–2106. 10.1021/acs.accounts.8b00268. [DOI] [PubMed] [Google Scholar]
  2. Han X.-N.; Han Y.; Chen C.-F. Pagoda[4]arene and i-Pagoda[4]arene. J. Am. Chem. Soc. 2020, 142, 8262–8269. 10.1021/jacs.0c00624. [DOI] [PubMed] [Google Scholar]
  3. Jia F.; He Z.; Yang L.-P.; Pan Z.-S.; Yi M.; Jiang R.-W.; Jiang W. Oxatub[4]arene: A Smart Macrocyclic Receptor With Multiple Interconvertible Cavities. Chem. Sci. 2015, 6, 6731–6738. 10.1039/C5SC03251B. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. a Jia F.; Hupatz H.; Yang L.-P.; Schröder H. V.; Li D.-H.; Xin S.; Lentz D.; Witte F.; Xie X.; Paulus B.; Schalley C. A.; Jiang W. Naphthocage: A Flexible yet Extremely Strong Binder for Singly Charged Organic Cations. J. Am. Chem. Soc. 2019, 141, 4468–4473. 10.1021/jacs.9b00445. [DOI] [PubMed] [Google Scholar]; b Lu S.-B.; Chai H.; Ward J. S.; Quan M.; Zhang J.; Rissanen K.; Luo R.; Yang L.-P.; Jiang W. A 2, 3- dialkoxynaphthalene- based naphthocage. Chem. Commun. 2020, 56, 888–891. 10.1039/C9CC09585C. [DOI] [PubMed] [Google Scholar]
  5. Tran A. H.; Georghiou P. E.; Miller D. O. Synthesis and Complexation Properties of “Zorbarene”: A New Naphthalene Ring-Based Molecular Receptor. J. Org. Chem. 2005, 70, 1115–1121. 10.1021/jo0484427. [DOI] [PubMed] [Google Scholar]
  6. Yang L.-P.; Wang X.; Yao H.; Jiang W. Naphthotubes: Macrocyclic Hosts with a Biomimetic Cavity Feature. Acc. Chem. Res. 2020, 53, 198–208. 10.1021/acs.accounts.9b00415. [DOI] [PubMed] [Google Scholar]
  7. Del Regno R.; Della Sala P.; Spinella A.; Talotta C.; Iannone D.; Geremia S.; Hickey N.; Neri P.; Gaeta C. Calix[2]naphth[2]arene: A Class of Naphthalene–Phenol Hybrid Macrocyclic Hosts. Org. Lett. 2020, 22, 6166–6170. 10.1021/acs.orglett.0c02247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Della Sala P.; Del Regno R.; Talotta C.; Capobianco A.; Hickey N.; Geremia S.; De Rosa M.; Spinella A.; Soriente A.; Spinella A.; Neri P.; Gaeta C. Prismarenes: A New Class of Macrocyclic Hosts Obtained by Templation in a Thermodynamically Controlled Synthesis. J. Am. Chem. Soc. 2020, 142, 1752–1756. 10.1021/jacs.9b12216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Yang L.-P.; Jiang W. Prismarene: An Emerging Naphthol-Based Macrocyclic Arene. Angew. Chem., Int. Ed. 2020, 59, 15794–15796. 10.1002/anie.202003423. [DOI] [PubMed] [Google Scholar]
  10. Della Sala P.; Del Regno R.; Di Marino L.; Calabrese C.; Palo C.; Talotta C.; Geremia S.; Hickey N.; Capobianco A.; Neri P.; Gaeta C. An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes. Chem. Sci. 2021, 12, 9952–9961. 10.1039/D1SC02199K. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. For recent reports on prismarenes, see:; a Song Q.; Shang K.; Xue T.; Wang Z.; Pei Di; Zhao S.; Nie J.; Chang Y. Macrocyclic Photoinitiator Based on Prism[5]arene Matching LEDs Light with Low Migration Macromol. Macromol. Rapid Commun. 2021, 42, 2100299–306. 10.1002/marc.202100299. [DOI] [PubMed] [Google Scholar]; b Song Q.; Zhao K.; Xue T.; Zhao S.; Pei D.; Nie J.; Chang Y. Nondiffusion-Controlled Photoelectron Transfer Induced by Host– Guest Complexes to Initiate Cationic Photopolymerization. Macromolecules 2021, 54, 8314. 10.1021/acs.macromol.1c01457. [DOI] [Google Scholar]
  12. Chen C.-C.; Li J.; Zhou H.-Y.; Han Y. Saucer[n]arenes: Synthesis, Structure, Complexation and Guest Induced Circularly Polarized Luminescence Property. Angew. Chem., Int. Ed. 2021, 60, 21927–21933. 10.1002/anie.202108209. [DOI] [PubMed] [Google Scholar]
  13. Calixarenes and Beyond; Neri P., Sessler J. L., Wang M. X., Eds.; Springer Int Publishing: 2016. [Google Scholar]
  14. Cram D. J.; Cram J. M. In Container Molecules and Their Guests; Stoddart J. F., Ed.; Monographs in Supramolecular Chemistry; Royal Society of Chemistry: Cambridge, 1994. [Google Scholar]
  15. Ogoshi T.; Kanai S.; Fujinami S.; Yamagishi T.; Nakamoto Y. para-Bridged Symmetrical Pillar[5]arenes: Their Lewis Acid Catalyzed Synthesis and Host–Guest Property. J. Am. Chem. Soc. 2008, 130, 5022–5023. 10.1021/ja711260m. [DOI] [PubMed] [Google Scholar]
  16. Ogoshi T.; Aoki T.; Kitajima K.; Fujinami S.; Yamagishi T.-a.; Nakamoto Y. Rapid, Facile and High-Yield Synthesis of Pillar[5]arene from Commercially Available Reagents and Its X-ray Crystal Structure. J. Org. Chem. 2011, 76, 328–331. 10.1021/jo1020823. [DOI] [PubMed] [Google Scholar]
  17. Ma Y.; Chi X.; Yan X.; Liu J.; Yao Y.; Chen W.; Huang F.; Hou J.-L. per-Hydroxylated Pillar[6]arene: Synthesis, X-ray Crystal Structure, and Host−Guest Complexation. Org. Lett. 2012, 14, 1532–1535. 10.1021/ol300263z. [DOI] [PubMed] [Google Scholar]
  18. Under conditions of thermodynamic equilibrium, i.e. TFA in CH2Cl2 at reflux for 1 h, PrS[5]Me was completely converted to its c-PrS[5]Me isomer.
  19. As suggested by a reviewer, probably, in accordance to the Curtin–Hammett principle, the selectivity could be largely determined by the demethylation energy barriers and probably under the reaction conditions, the conversion of PrS[5]Me to PrS[6]Me occurs with a rate constant kconversion > kdealkylation.
  20. Furlan R. L. E.; Otto S.; Sanders J. K. M. Supramolecular templating in thermodynamically controlled synthesis. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 4801–4804. and reference cited therein 10.1073/pnas.022643699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. In other words, kconversion < kdealkylation for 1+@ PrS[5]Me
  22. Interestingly, when PrS[6]Me was reacted under conditions of thermodynamic equilibrium, in CH2Cl2, at reflux in the presence of TFA, its conversion to confused c-PrS[5]Me was complete after 2 h.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol1c02800_si_001.pdf (2.2MB, pdf)

Articles from Organic Letters are provided here courtesy of American Chemical Society

RESOURCES