Letter Cite This: Org. Lett. 2017, 19, 5509-5512
pubs.acs.org/OrgLett
Calix[n]triazoles and Related Conformational Studies Illan Kim,†,# Kyoung Chul Ko,‡,# Woo Ram Lee,§,# Jihee Cho,†,# Jong Hun Moon,‡ Dohyun Moon,∥ Amit Sharma,⊥ Jin Yong Lee,*,‡ Jong Seung Kim,*,⊥ and Sanghee Kim*,† †
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea § Department of Chemistry, Sejong University, Seoul 05006, Korea ∥ Beamline Division, Pohang Accelerator Laboratory, Pohang 790-784, Korea ⊥ Department of Chemistry, Korea University, Seoul 02841, Korea ‡
S Supporting Information *
ABSTRACT: Calix[n]triazoles are developed as new derivatives in the calixarene family. Calixtriazole compounds 2−4 are synthesized using an iterative convergent strategy including an inter-/intramolecular copper(I)-catalyzed azide−alkyne cycloaddition reaction. Solid-state structures are clearly refined to give 1,2-alternate and partial cone conformations for calix[4]triazole and calix[5]triazole, respectively. Theoretical studies based on density functional theory (DFT) calculations indicated that intermolecular interactions are crucial in determining the conformers of the crystals, and the most stable conformers of calix[4]triazole, calix[5]triazole, and calix[6]triazole in the monomeric forms are 1,3-alternate, 1,3-alternate, and 1,3,5-alternate, respectively.
B
5 D) and chemical stability.4,5 We found that triazole groups in calix[2]triazole[2]arene could participate in interactions with guest molecules.6 While the bulky tert-butyl substituted phenol unit restricts the conformations to some extent since no rotation is allowed through the annulus, the relatively small triazole rings are able to rotate around the methylene bridge to become more stable in a given environment.7 This triazole rotation led to the changes in the three-dimensional structures and cavities. We were thus inspired to investigate the conformational properties of the heterocalixarenes composed of only rotatable triazole rings and to explore their potentials as a new molecular platform in the field of supramolecular chemistry. In this paper, we therefore envision a new heterocalixarene composed of triazole rings that have either four, five, or six rings linked by a methylene bridge. A convergent synthesis of calix[n]triazoles (2, 3, and 4, Figure 1) and their three-dimensional structures are herein reported. The desired calix[n]triazoles were synthesized by an iterative convergent strategy involving a copper(I)-catalyzed azide− alkyne cycloaddition (CuAAC) reaction.8−10 Monotriazole 5 was used as the basic building block for our synthetic sequences and was readily obtained by the CuAAC of propargyl alcohol and propargylic azide 6.11 The hydroxyl group of 5 was converted to an azide group via a two-step sequence of Appel bromination followed by nucleophilic displacement by the azide ion to give monotriazole azide 7. In contrast, the TIPS protecting group on 5
ecause of their functional and structural beauty, calixarenes have been the subject of intense research over the past several decades.1 Currently, considerable effort has been devoted to expanding the scope of classical calixarene chemistry.2 This includes the development of next-generation materials that incorporates carefully crafted supramolecular properties to engender and enhance functionality. One approach is to replace the traditional phenolic units in calixarenes scaffolds with heteroaromatic rings. Due to the presence of the physicochemically different heteroaromatic rings, these modified calixarenes, known as heterocalixarenes, display unique cavity structure and binding properties. The family of heterocalixarenes includes calixpyrroles, calixfurans, calixpyridines, and caliximidazoles.3 In our work toward developing new types of calixarenes, we have previously reported calix[2]triazole[2]arene (1, Figure 1) in which two phenolic units of classical calix[4]arene are replaced with a 1,2,3-triazole ring. Our interest in the fusion of a calixarene with a triazole ring stemmed from the distinct physicochemical properties of 1,2,3-triazoles, such as their high dipole moment (ca.
Figure 1. Chemical structures of calix[2]triazole[2]arene (1) and calix[n]triazoles (2, 3, and 4). © 2017 American Chemical Society
Received: August 18, 2017 Published: October 11, 2017 5509
DOI: 10.1021/acs.orglett.7b02557 Org. Lett. 2017, 19, 5509−5512
Letter
Organic Letters was removed and the hydroxyl group of 8 was in turn converted to a bromide to give the dual-functionalized building block 9 (Scheme 1).
Scheme 4. Synthesis of calix[6]triazole (4)
Scheme 1. Synthesis of the basic building blocks 7 and 9
CuAAC substrate 16 for calix[6]triazole (4) was prepared via an intermolecular CuAAC reaction between tri-triazole azide 11 and monotriazole alkyne 9 followed by azidonation. When 16 was subjected to the one-pot desilylation/CuAAC reaction conditions, calix[6]triazole (4) was obtained in excellent yield. From DFT calculations, the ring strain energies were estimated as 2.66, 0.01, and −0.11 kcal/mol for the most stable conformers of calix[n]triazole, respectively.13 It implies that the ring strain energies might not be considerably high to prohibit the intramolecular cyclization reaction under dilute conditions. These new heteroarenes compounds were fully characterized with various analytical techniques. The calixtriazoles (2−4) showed a single spectral peak in the Fast atom bombardment (FAB) mass spectrum with [M + H]+ signals at m/z 325.1392, 406.1719, and 487.2018, respectively. The 1H NMR spectra of 2, 3, and 4 in DMSO-d6 exhibited similar patterns, including a singlet for the proton of triazole C−H and another singlet for the bridged methylene protons (−CH2). When the spectra of individual calixtriazoles were compared, almost no differences in chemical shifts of the bridging methylene protons were observed. However, as shown in Figure S1, the signal of the triazole C−H was shifted downfield as the ring size increases. Calix[n]triazoles (2−4) can adopt several interconvertible conformations.14 According to the relative orientation (up or down) of the triazole C−H moieties, there exist four conformations for 2 and 3 and eight conformations for 4, as depicted in Tables S3−S5. Among the various conformations available to each compound, we tried to elucidate the most stable conformation based on the solid-state structures as well as DFT calculations. The crystalline structures of calix[4]triazole (2) and calix[5]triazole (3) were obtained by single crystal X-ray diffraction (SXRD) measurements with a PAL 2D-SMC beamline synchrotron by preparing micron-sized single crystals (Figures 2a, 2b and S2−S9). We found that the solvent molecules were
The intermolecular CuAAC reaction between 7 and 9 provided tri-triazole product 10 in good yield. The bromide of 10 was again converted to an azide group to give 11. To generate calix[4]triazole (2) from 11, reaction conditions for a one-pot desilylation/CuAAC were developed. Treatment of 11 with CuI (0.6 equiv), KF (10.0 equiv), and HBr (3.0 equiv) under highly dilute conditions (1.0 mM) in DMF at room temperature was found to effectively afford the desired macrocycle 2 (Scheme 2). In the absence of HBr, an allenic side product was the major product.12 Scheme 2. Synthesis of calix[4]triazole (2)
The syntheses of calix[5]triazole (3) and calix[6]triazole (4) were accomplished using the same synthetic strategy used for calix[4]triazole (2), as represented in Schemes 3 and 4. TetraScheme 3. Synthesis of calix[5]triazole (3)
Figure 2. (a) and (b) show three-dimensional crystal structures of calix[n]triazole (n = 4 and 5, respectively), while (c) shows a simulated structure (n = 6).
triazole 12, which is the requisite substrate for calix[5]triazole (3), was prepared from monotriazole azide 7. First, the intermolecular CuAAC reaction between 7 and propargyl alcohol gave bistriazole alcohol 13. After two-step azidonation/CuAAC, coupling with azide 14 and monotriazole alkyne 9 provided tetra-triazole 15. Nucleophilic displacement of 15 by azide gave tetra-triazole azide 12, which yielded calix[5]triazole (3) in excellent yield after a one-pot desilylation/CuAAC reaction. The penta-triazole
present in the unit cells of both 2 and 3. However, the solvent molecules in the unit cell of 2 were disordered and could not be modeled. In the unit cell of 3, there are four DMF and four water molecules involved in hydrogen bonding with each other. The ratio of 3/H2O/DMF was 1:1:1. Calix[5]triazole (3) and the H2O and DMF molecules in its unit cell were arranged asymmetrically (Figure S8). Because the growth of micron-size 5510
DOI: 10.1021/acs.orglett.7b02557 Org. Lett. 2017, 19, 5509−5512
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Organic Letters single crystals of 4 was unsuccessful, the structure of calix[6]triazole was further predicted using the Forcite module of MS modeling software with powder X-ray diffraction (PXRD) pattern data as described in Figures 2c and S10−S12. Several conformers exist for 2−4. To compare the stability of the different conformers, density functional theory (DFT) calculations were carried out (see SI for computational details). The calculated energies are listed in Tables S3−S5. The most stable conformational isomers have the maximum number of alternation of the lower side triazole C−H and upper side triazole C−H, i.e., 1,3-alternate-2, 1,3-alternate-3, and 1,3,5-alternate-4. This could be attributed to the reduced steric hindrance as well as repulsive dipole−dipole interactions between the triazole rings. The simulated 1H NMR spectra of these most stable isomers show almost exclusively singlets for the chemical shift of triazole C−H: 7.44 ppm, 8.14 ppm (with a slight splitting of 0.28 ppm), and 8.60 ppm for 2−4, respectively, which is consistent with the experimental spectra (see Figures S13−S15). However, the calculated most stable conformers of calix[4]triazole (2) and calix[5]triazole (3) are not consistent with those obtained from the X-ray crystallography data. In the crystal structures, 2 and 3 have 1,2-alternate-2 and partial cone-3 conformers, which are 0.601 and 1.016 kcal/mol higher than the most stable conformations of 1,3-alternate-2 and 1,3-alternate-3, respectively. As noted in the previous study, the inconsistency between the monomeric conformer and the condensed-phase conformer might be due to intermolecular interactions.15 To pinpoint this inconsistency between the monomeric conformers and crystal structures, we compared the energies of dimeric systems. Figure 3 shows the calculated dimeric forms for 1,2-alternate-2 and 1,3-alternate-2. In contrast with the monomer cases, the
Figure 4. Part of the crystal structure of 3 showing two trimer layers. The π−π and electrostatic interactions are shown in red and green, respectively. The numbers are distances in Å.
systems, a monomer interacting with a trimer layer, to compare the interactions in crystal structures (see Table S6). For such tetramer cases, the energy of partial cone-3 is calculated to be lower than that of 1,3-alternate-3 by 7.509 kcal/mol, which is consistent with our experimental results. The average distances between the N and H atoms responsible for the electrostatic interactions can explain this energy difference, i.e., 2.426 and 2.586 Å for partial cone-3 and 1,3-alternate-3, respectively. Further, we tried to understand the origin of the conformational preference in crystals based on the analysis of the natural bond orbital (NBO) charges and electrostatic potential map using 1,3-alternate-2 as an example (Figure 5). It was found that the
Figure 5. NBO charge distribution with color denoting the atomic charges ranging from −0.295 to +0.295 (a) and electrostatic potential map (b) for 1,3-alternate-2. The red and blue colors represent negatively and positively charged moieties, respectively.
carbon atom of the bridged methylenes (−CH2) and one of nitrogen atoms denoted with a star (−C−N*N−N−) in a triazole group have higher negative charges, whereas all the hydrogen atoms have higher positive charges. The electrostatic potential map also reflects these charge distributions. It is worth noting that the nitrogen atoms denoted by the star are in the outer part of the macrocycle, which can more easily interact with other molecules compared to a carbon atom at the backbone. Therefore, it can be speculated that the nitrogen atoms denoted by a star and all the hydrogen atoms play an important role in forming the strong electrostatic interactions. Consequently, strong electrostatic interactions as well as π−π interactions of the triazole groups might play a crucial role in the crystallization. Hence, the conformational preference for the crystallization may originate from the structural differences in these kinds of intermolecular interactions among the possible lower lying conformers. Despite our continued efforts to analyze the crystal structure of calix[6]triazole (4), its crystal structure has
Figure 3. Calculated dimeric structures for 1,2-alternate-2 and 1,3alternate-2. The expected electrostatic interactions and relevant distances are shown by green dotted lines with numbers in Å.
dimer of 1,2-alternate-2 was calculated to be lower in energy than 1,3-alternate-2 by 4.347 kcal/mol. In the case of 1,2-alternate-2, monomers slid slightly off each other resulting in stronger electrostatic interactions. However, in 1,3-alternate-2, a cofacial dimer was formed with relatively weaker electrostatic interactions. In calix[5]triazole (3), it is not simple to predict dimeric forms to determine the intermolecular interactions. As seen in Figure 4, strong electrostatic interactions with 2.4−2.6 Å can be found in its crystal structure, where it was selected to look closely into the interactions between two trimer layers. In each trimer layer, π−π interactions between triazole groups with 3.492 Å separations can help to form the layer structure. Therefore, we designed tetramer 5511
DOI: 10.1021/acs.orglett.7b02557 Org. Lett. 2017, 19, 5509−5512
Letter
Organic Letters
(f) Kim, S. K.; Lynch, V. M.; Hay, B. P.; Kim, J. S.; Sessler, J. L. Chem. Sci. 2015, 6, 1404. (g) Kumar, R.; Lee, Y. O.; Bhalla, V.; Kumar, M.; Kim, J. S. Chem. Soc. Rev. 2014, 43, 4824. (h) Kim, H. J.; Lee, M. H.; Mutihac, L.; Vicens, J.; Kim, J. S. Chem. Soc. Rev. 2012, 41, 1173. (2) (a) Vystotsky, M.; Saadioui, M.; Böhmer, V. Calixarenes 2001; Kluwer Academic Publishers: Dordrecht, Netherlands, 2001; pp 250. (b) Kumar, S.; Paul, D.; Singh, H. Tetrahedron Lett. 1997, 38, 3607. (c) Chun, Y.; Singh, N. J.; Hwang, I.-C.; Lee, J. W.; Yu, S. U.; Kim, K. S. Nat. Commun. 2013, 4, 1797. (d) Yang, P.; Jian, Y.; Shou, X.; Li, G.; Deng, T.; Shen, H.; Yang, Z.; Tian, Z. J. Org. Chem. 2016, 81, 2974. (e) Ma, Y.X.; Han, Y.; Chen, C.-F. J. Inclusion Phenom. Macrocyclic Chem. 2014, 79, 261. (3) (a) Král, V.; Sessler, J. L.; Zimmerman, R. S.; Seidel, D.; Lynch, V.; Andrioletti, B. Angew. Chem., Int. Ed. 2000, 39, 1055. (b) Lee, G.-A.; Wang, W.-C.; Shieh, M.; Kuo, T.-S. Chem. Commun. 2010, 46, 5009. (c) Hong, J.; Son, M.; Ham, S. Bull. Korean Chem. Soc. 2009, 30, 423. (d) Nagarajan, A.; Ka, J.-W.; Lee, C.-H. Tetrahedron 2001, 57, 7323. (e) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. Rev. 2003, 240, 17. (f) Král, V.; Gale, P. A.; Anzenbacher, P.; Jursíková, K.; Lynch, V.; Sessler, J. L. Chem. Commun. 1998, 9. (4) For the physicochemical properties of 1,2,3-triazole, see: (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 2006, 51. (b) Juríček, M.; Kouwer, P. H. J.; Rowan, A. E. Chem. Commun. 2011, 47, 8740. (5) For representative examples of other related macrocycles involving 1,2,3-triazole, see: (a) Li, Y.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 12111. (b) White, N. G.; Carvalho, S.; Félix, V.; Beer, P. D. Org. Biomol. Chem. 2012, 10, 6951. (6) (a) Cho, J.; Lee, S.; Hwang, S.; Kim, S. H.; Kim, J. S.; Kim, S. Eur. J. Org. Chem. 2013, 2013, 4614. (b) Cho, J.; Pradhan, T.; Kim, J. S.; Kim, S. Org. Lett. 2013, 15, 4058. (c) Cho, J.; Pradhan, T.; Lee, Y. M.; Kim, J. S.; Kim, S. Dalton Trans. 2014, 43, 16178. (7) (a) Blas, J. R.; López-Bes, J. M.; Márquez, M.; Sessler, J. L.; Luque, F. J.; Orozco, M. Chem. - Eur. J. 2007, 13, 1108. (b) Alemán, C.; Casanovas, J. J. Phys. Chem. A 2005, 109, 8049. (8) For references of the CuAAC reaction, see: (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (9) For examples of iterative CuAAC methodologies, see: (a) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505. (b) Valverde, I. E.; Delmas, A. F.; Aucagne, V. Tetrahedron 2009, 65, 7597. (c) Spruell, J. M.; Dichtel, W. R.; Heath, J. R.; Stoddart, J. F. Chem. - Eur. J. 2008, 14, 4168. (d) Yuan, Z.; Kuang, G.-C.; Clark, R. J.; Zhu, L. Org. Lett. 2012, 14, 2590. (e) Hatit, M. Z. C.; Sadler, J. C.; McLean, L. A.; Whitehurst, B. C.; Seath, C. P.; Humphreys, L. D.; Young, R. J.; Watson, A. J. B.; Burley, G. A. Org. Lett. 2016, 18, 1694. (10) For examples of iterative CuAAC reaction in synthesis, see: (a) Opsteen, J. A.; Van Hest, J. C. M. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 2913. (b) Meudtner, R. M.; Hecht, S. Angew. Chem., Int. Ed. 2008, 47, 4926. (c) Galibert, M.; Piller, V.; Piller, F.; Aucagne, V.; Delmas, A. F. Chem. Sci. 2015, 6, 3617. (d) Lewis, J. E. M.; Winn, J.; Cera, L.; Goldup, S. M. J. Am. Chem. Soc. 2016, 138, 16329. (e) Li, K.; Jiang, G.; Zhou, F.; Li, L.; Zhang, Z.; Hu, Z.; Zhou, N.; Zhu, X. Polym. Chem. 2017, 8, 2686. (11) White, N. G.; Carvalho, S.; Felíx, V.; Beer, P. D. Org. Biomol. Chem. 2012, 10, 6951. (12) (a) Masters, J.-S.; Wallesch, M.; Bräse, S. J. J. Org. Chem. 2011, 76, 9060. (b) Tabuchi, S.; Hirano, K.; Miura, M. Chem. - Eur. J. 2015, 21, 16823. (13) The ring strain energies were calculated based on eq 5 in the reference: Dudev, T.; Lim, C. J. Am. Chem. Soc. 1998, 120, 4450. (14) (a) Gutsche, C. D.; Bauer, L. J. J. Am. Chem. Soc. 1985, 107, 6052. (b) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713. (c) Boulet, B.; Joubert, L.; Cote, G.; Bouvier-Capely, C.; Cossonnet, C.; Adamo, C. J. Phys. Chem. A 2006, 110, 5782. (15) Kim, S. J.; Jo, M.-G.; Lee, J. Y.; Kim, B. H. Org. Lett. 2004, 6, 1963.
not been defined. This might be due to the existence of diverse lower lying conformers and higher rotational flexibility of the triazole groups as seen in the calculated structures of 4 shown in Table S5. In summary, a series of calix[n]triazoles 2−4 have been synthesized using an iterative convergent strategy with an inter-/ intramolecular copper(I)-catalyzed azide−alkyne cycloaddition. Crystal structures for 1,2-alternate calix[4]triazole and partial cone calix[5]triazole have been successfully assigned. While there were no differences in the chemical shifts of the bridged methylene protons in the 1H NMR spectra, we found the triazole C−H signals shifted downfield as the ring expanded. Unlike what we observed in their solid-state structures, DFT calculation revealed the most stable conformers of calix[4]triazole, calix[5]triazole, and calix[6]triazole are 1,3-alternate, 1,3-alternate, and 1,3,5-alternate, respectively. This study provides insights into the distinctive properties and conformational differences of each calix[n]triazole compared to conventional calix[4]arenes. Furthermore, investigations on their applications in anion binding studies are underway.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02557. Experimental procedures, characterization data, and DFT calculations (PDF) X-ray data for compound 2 (CIF) X-ray data for compound 3 (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Kyoung Chul Ko: 0000-0003-4386-9112 Jin Yong Lee: 0000-0003-0360-5059 Jong Seung Kim: 0000-0003-3477-1172 Sanghee Kim: 0000-0001-9125-9541 Author Contributions #
I.K., K.C.K., W.R.L., and J.C. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by 2016R1A2A1A05005375 (S.K.), Nos. 2009-0081566 and 2010-0020209 (J.S.K.), and NRF2017R1C1B5018060 (W.R.L.) of National Research Foundation (NRF) grant funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea. This work was also supported by No. KSC-2016-C3-0070 (J.Y.L.) of the supercomputing application research of KISTI supercomputing center.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02557 Org. Lett. 2017, 19, 5509−5512
