Facile synthesis of a chiral polymeric helix; folding by intramolecular hydrogen bonding

Judith J. van Gorp , Jef A. J. M. Vekemans and E. W. Meijer *
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands. E-mail: E.W.Meijer@tue.nl; Fax: +31-40-2474706; Tel: +31-40-2473101

Received (in Cambridge, UK) 8th October 2003 , Accepted 31st October 2003

First published on 25th November 2003


Abstract

In a single condensation step, a poly-ureidophthalimide is synthesized, which folds into a chiral, helical architecture according to circular dichroism spectroscopy.


The helix, being a fundamental structure in realizing the biological activity of naturally occurring macromolecules, is expected to lead to a broad range of applications, including molecular recognition, and molecular scaffold functions.1 Of the various synthetic helices,2 the foldamers3,4 are most similar to the natural α-helix, compared to helicenes5 or supramolecular helices.6 Aliphatic peptidometic homologues,7 as well as aromatic oligo-amides,8 have been demonstrated to adopt helical conformations through non-covalent intramolecular interactions.

Using para- instead of meta8-substituted aromatic units, urea9 based aromatic helices may also be formed with an estimated 6–8 units per turn (Scheme 1). Imide oxygens are suitable to orientate the para-positioned urea groups, while imide nitrogens allow the incorporation of any primary amine containing functionality. In this case, a chiral amine is incorporated to permit investigation of the chiral, helical architecture in dilute solution using circular dichroism spectroscopy. After a two step conversion of the amine into a monomer, a true polymer is formed in a single, swift condensation step. In addition, corresponding oligomers have been obtained by chromatographic separations.


Chemical structure of a turn of the designed polymeric helix, together with a diamino functionalized monomer.
Scheme 1 Chemical structure of a turn of the designed polymeric helix, together with a diamino functionalized monomer.

Backbone building block, 3,6-dinitrophthalic anhydride (1), was synthesized by nitration of 1,5-dinitronaphthalene and subsequent oxidation,10 followed by ring closure of the obtained diacid using acetic anhydride.11 Anhydride 1 was reacted with 1.6 equiv. of chiral 3,4,5-tris[(S)-3,7-dimethyloctyloxy]aniline (2) to obtain 3,6-dinitrophthalimide 3 (Scheme 2).12 Dinitro compound 3 was catalytically hydrogenated on Pd to diamino compound 4; diisocyanato monomer 5 was obtained by treating diamine 4 with an excess of phosgene. Equimolar amounts of diamino monomer 4 and diisocyanato monomer 5 were copolymerized in toluene using 4-dimethylaminopyridine as a catalyst, to afford poly-ureidophthalimide 6.


Synthesis of poly-ureidophthalimide 6. Reagents and conditions: a) acetonitrile, 80 °C; b) acetic anhydride, 100 °C; c) H2(g), Pd/C, THF–EtOH–water; d) phosgene in toluene, 110 °C; e) 4-dimethylaminopyridine, toluene, 80 °C.
Scheme 2 Synthesis of poly-ureidophthalimide 6. Reagents and conditions: a) acetonitrile, 80 °C; b) acetic anhydride, 100 °C; c) H2(g), Pd/C, THF–EtOHwater; d) phosgene in toluene, 110 °C; e) 4-dimethylaminopyridine, toluene, 80 °C.

Polymer 6 was subjected to column chromatography to divide the mixture into high (6a), intermediate (6b), and low (6c) molecular weight fractions. The average chain length of the mixtures 6a–c was determined by 1H-NMR endgroup analysis, using the integral ratio between the signals of the termini (amine protons at 5.18 ppm and aromatic phthalimide protons at 6.95 and 8.48 ppm) and the signals of the aromatic phthalimide protons in the main chain (8.73 ppm). For polymer 6a, an average value as high as 30 units was calculated. Average values of 7 and 3.5 units were calculated for 6b and 6c, respectively. The oligomers (dimer up to octamer 6d–j) were obtained by preparative, reversed phase HPLC13 (see Supplementary information for polydispersities).

The appearance of urea protons at 9.0 ppm is indicative of intramolecular hydrogen bonding. The chiral architectures were investigated in detail with CD-spectroscopy (Fig. 1). Polymer 6a (∼30 units) folds into a chiral structure with a very high degree of ordering in THF (g = −0.012). Remarkably, 6b (∼7 units) shows only a minor Cotton effect, while 6c (∼3.5 units) shows no Cotton effect at all. The dimer up to the hexamer 6d–h show no Cotton effects either, while the heptamer 6i and octamer 6j show minor effects.13


UV-Vis (bottom) and CD spectra (top) of ureidophthalimides 6a–c in THF (∼0.03 g ml−1), per mole monomeric units, together with the chain length dependence of the Cotton effect (inset).
Fig. 1 UV-Vis (bottom) and CD spectra (top) of ureidophthalimides 6a–c in THF (∼0.03 g ml−1), per mole monomeric units, together with the chain length dependence of the Cotton effect (inset).

Indeed, it is most likely that the poly-ureidophthalimide 6 folds into a helical architecture with a pitch of approximately 6–8 units. In agreement with earlier studied foldamers,4 only chains that complete one pitch of the helix (6b) can fold into a stable architecture in which chirality is transferred from the CD-silent peripheral side chains, to the accurately positioned, CD-active phthalimide chromophores. In longer systems, pitches become ‘sandwiched’ between turns below and above, and order is only increased (6a).

On the other hand, in CHCl3, no Cotton effect is observed for ureidophthalimides 6a–c, suggesting a non-chiral conformation of the polymer chains in this solvent. This might be rationalized by interference of the intramolecular imideurea hydrogen bonding by CHCl3 (H-bond donor), while the ether oxygen of THF (H-bond acceptor) might increase the syn-coplanarity between two adjacent urea protons.14 Denaturation experiments show that the chiral, helical aggregates in THF are unusually insensitive to the addition of CHCl3.4 Finally, above 50 vol% CHCl3, a fairly sharp transition is observed, which corresponds to the unfolding of a highly ordered aggregate (Fig. 2).


Denaturation curve of helical polymer 6a.
Fig. 2 Denaturation curve of helical polymer 6a.

It is worth mentioning that hysteresis accompanies the folding process of the chiral helix. It takes a long time (1 h) before the system reaches equilibrium after the addition of more CHCl3. Also, order is hardly lost upon raising the temperature (45% at 55 °C, compared to 100% at 20 °C for 6a in THF), while upon cooling, the architectures need at least several hours to regain their maximal ordering. Apparently, order and stability are optimally balanced for this poly-ureidophthalimide, since stronger hydrogen bonding and π–π stacking interactions will occur at the expense of reversibility and flexibility of the helical architecture.15

Currently, we are unravelling the exact intra- and intermolecular ordering phenomena in more detail, but already we can conclude, that the highly ordered, poly-ureidophthalimide helix is an easily accessible, truly polymeric scaffold enclosing an interesting hollow core, with potential applications in biological or materials science.

Notes and references

  1. T. Nakano and Y. Okamoto, Chem. Rev., 2001, 101, 4013 CrossRef CAS.
  2. C. Schmuck, Angew. Chem., Int. Ed., 2003, 42, 2448 CrossRef CAS.
  3. D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell and S. H. Gellman, J. Am. Chem. Soc., 1996, 118, 13071 CrossRef CAS.
  4. D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes and J. S. Moore, Chem. Rev., 2001, 101, 3893 CrossRef CAS.
  5. B. Kiupel, C. Niederalt, M. Nieger, S. Grimme and F. Vögtle, Angew. Chem., Int. Ed., 1998, 37, 3031 CrossRef CAS; L. Vyklický, S. H. Eichhorn and T. J. Katz, Chem. Mater., 2003, 15, 3594 CrossRef CAS.
  6. J.-M. Lehn, J.-C. Homo and M. Schmutz, Angew. Chem., Int. Ed., 2000, 38, 233; V. Berl, M. J. Krische, I. Huc, J.-M. Lehn and M. Schmutz, Chem. Eur. J., 2000, 6, 1938 CrossRef CAS; F. Würthner, S. Yao and U. Beginn, Angew. Chem., Int. Ed., 2003, 42, 3247 CrossRef.
  7. R. P. Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101, 3219 CrossRef CAS; K. Gademann, A. Häne, M. Rueping, B. Jaun and D. Seebach, Angew. Chem., Int. Ed., 2003, 42, 1534 CrossRef CAS; D. Seebach, L. Schaeffer, M. Brenner and D. Hoyer, Angew. Chem., Int. Ed., 2003, 42, 776 CrossRef CAS.
  8. Y. Hamuro, S. J. Geib and A. D. Hamilton, J. Am. Chem. Soc., 1997, 119, 10587 CrossRef CAS; H. Jiang, J.-M. Léger and I. Huc, J. Am. Chem. Soc., 2003, 125, 3448 CrossRef CAS; C. Dolain, V. Maurizot and I. Huc, Angew. Chem., Int. Ed., 2003, 42, 2738 CrossRef CAS; V. Berl, I. Huc, R. G. Khoury, M. J. Krische and J.-M. Lehn, Nature, 2000, 407, 720 CrossRef CAS; X. Yang, A. L. Brown, M. Furukawa, S. Li, W. E. Gardiner, E. J. Bukowski, F. V. Bright, C. Zheng, X. C. Zeng and B. Gong, Chem. Commun., 2003, 56 RSC; B. Gong, Chem. Eur. J., 2001, 7, 4336 CrossRef CAS; R. D. Parra, B. Gong and X. C. Zeng, J. Phys. Chem., 2001, 115, 6036 Search PubMed.
  9. C. Hemmerlin, M. Marraud, D. Rognan, R. Graff, V. Semety, J.-P. Briand and G. Guichard, Helv. Chim. Acta, 2002, 85, 3692 CrossRef CAS; P. S. Corbin, S. C. Zimmerman, P. A. Thiessen, N. A. Hawryluk and T. J. Murray, J. Am. Chem. Soc., 2001, 123, 10475 CrossRef CAS.
  10. T. Momose and M. Torigoe, J. Pharm. Soc. Jpn., 1951, 71, 977 CAS.
  11. J. L. Meek, J. Chromatogr., 1983, 266, 401 CrossRef CAS.
  12. K. Pieterse, PhD Thesis: Electron deficient materials based on azaheterocycles, Technische Universiteit Eindhoven, Eindhoven, 2001 Search PubMed.
  13. Results to be published.
  14. Broadening of the 1H-NMR signals is much more pronounced in THF-d8 than in CDCl3, and disappears upon addition of HFIP. Infrared spectroscopy shows the urea NH stretch vibration at 3354 cm−1 in CHCl3 and at 3341 cm−1 in THF.
  15. J. J. van Gorp, J. A. J. M. Vekemans and E. W. Meijer, J. Am. Chem. Soc., 2002, 124, 14759 CrossRef CAS.

Footnote

Electronic Supplementary Information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b312407j/

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