Thermally responsive dendrons and dendrimers based on reversible furan-maleimide diels-alder adducts

Article abstract of DOI:10.1021/ol0101281

(Equation presented) Benzyl aryl ether dendrons and dendrimers containing thermally reversible furan-maleimide Diels-Alder adducts were prepared up to the third generation. The covalent cleavage and reassembly of the dendrons and dendrimers were evaluated by ¹H NMR.

Full text of DOI:10.1021/ol0101281

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2681-2683
Thermally Responsive Dendrons and
Dendrimers Based on Reversible
Furan-Maleimide Diels−Alder Adducts
,†
James R. McElhanon* and David R. Wheeler
Organic Materials Department, Sandia National Laboratories,
Albuquerque, New Mexico 87185
jrmcelh@sandia.goV
Received June 11, 2001
ABSTRACT
Benzyl aryl ether dendrons and dendrimers containing thermally reversible furan-maleimide Diels−Alder adducts were prepared up to the third
generation. The covalent cleavage and reassembly of the dendrons and dendrimers were evaluated by 1H NMR.
Dendrimers1 comprise a family of synthetic macromolecules
that are considered to be prime nanometer-scale building
blocks for materials that may serve as chemical sensors,2
molecular recognition devices,3 chemical delivery systems,4
separations devices,5 etc. Recently, the alteration of the
structure of novel dendritic architectures through control of
covalent and noncovalent interactions and conditions has
attracted much attention. Examples include dendritic systems
that can be assembled,6 degraded,7 and configurationally8 or
conformationally9 altered. We report here the preparation and
initial investigations of thermally cleavable/reassembling
dendrons and dendrimers based on furan-maleimide Diels-
Alder (DA) reactions. Other examples10 of dendrimer
construction using DA chemistry exist. To our knowledge,
this represents the first covalent thermally reversible design
strategy in a dendritic system.
Reversible DA reactions between reactive dienes and
dienophiles are well studied.11 In particular, the reaction
between substituted furans and maleimides has been fre-
(6) (a) Zheng, F.; Zimmerman, S. C. Chem. ReV. 1997, 97, 1681-1712.
(b) Percec, V.; Johansson, G.; Heck, J.; Ungar, G.; Batty, S. V. J. Chem.
Soc., Perkin Trans. 1 1993, 1411-1420. (c) Newkome, G. R.; Guther, R.;
Moorefield, C. N.; Cardullo, F.; Echegoyen, L.; Perez-Cordero, E.;
Luftmann, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2023-2026. (d)
Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V. Science
1996, 271, 1095-1098. (e) Chechik, V.; Mingqi, Z.; Crooks, R. M. J. Am.
Chem. Soc. 1999, 121, 4910-4911. (f) Yamaguchi, N.; Hamilton, L. M.;
Gibson, H. W. Angew Chem. 1998, 37, 3275-3279.
(7) (a) Tully, D. C.; Trimble, A. R.; Fre´chet, J. M. J. AdV. Mater. 2000,
12, 1118-1122. (b) Smet, M.; Liao, L.-X.; Dahaen, W.; McGrath, D. V.
Org. Lett. 2000, 2, 511-513.
(8) (a) Li, S.; McGrath, D. V. J. Am. Chem. Soc. 2000, 122, 6795-
6796. (b) Junge, D. M.; McGrath, D. V. Chem. Commun. 1997, 9, 857-
858. (c) Junge, D. M.; McGrath, D. V. J. Am. Chem. Soc. 1999, 121, 4912-
4913.
† Current address: Sandia National Laboratories, Materials Chemistry
Department, Livermore, CA 94551-9402.
(1) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic
Molecules. Concepts, Syntheses, PerspectiVes; VCH: Cambridge, 1996. (b)
Zeng, F.; Zimmerman, S. C. Chem. ReV. 1997, 97, 1681. (c) Emrick, T.;
Fre´chet, J. M. J. Curr. Opin. Colloid Interface Sci. 1999, 4, 15. (d)
Zimmerman, S. C. Curr. Opin. Colloid Interface Sci. 1997, 2, 89. (e)
Tomalia, D. A.; Majoros, I. Supramolecular Polymers; Marcel Dekker: New
York, 2000; p 359.
(2) (a) Adronov, A.; Fre´chet, J. M. J. Chem. Commun. 2000, 18, 1701-
1710. (b) Balzani, V.; Ceroni, P.; Gestermann, S.; Kauffmann, C.; Gorka,
M.; Vo¨gtle, F. Chem. Commun. 2000, 10, 853-854.
(3) (a) Baars, M.; Meijer, E. W. Top. Curr. Chem. 2000, 210, 131-182
and references therein. (b) Bahr, A.; Felber, B.; Schneider, K.; Diedrich, F.
HelV. Chim. Acta 2000, 83, 1346-1376.
(9) Gitsov, I.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1996, 118, 3785-
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(10) (a) Morgenroth, F.; Berresheim, A. J.; Wagner, M.; Mu¨llen, K.
Chem. Commun. 1998, 10, 1139-1140. (b) Morgenroth, F.; Ku¨bel, C.;
Mu¨llen, K. J. Mater. Chem. 1997, 7, 1207-1211. (c) Morgenroth, F.; Ku¨bel,
C.; Mu¨ller, M.; Wiesler, U. M.; Berresheim, A. J.; Wagner, M.; Mu¨llen,
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(4) (a) Yoonkyung, K.; Zimmerman, S. C. Curr. Opin. Chem. Biol. 1998,
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10.1021/ol0101281 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/01/2001

quently utilized in the preparation of thermally responsive
polymers.12 This is primarily due to ease of adduct formation
and dissociation. Adduct formation typically occurs at room
temperature, and adduct dissociation occurs at elevated
temperatures (>90 °C) (Scheme 1).
Scheme 2a
Scheme 1
Our convergent approach toward designing thermally
responsive dendritic architectures involved preparing den-
drons with substituted furan-maleimide DA adducts located
at the dendron focal point. We required a disubstituted furan
that could serve as an AB2 monomer and an N-substituted
maleimide with a reactive hydroxyl focal point.
AB2 furan monomer 213 was prepared in one step through
LiAlH4 reduction of commercially available dimethyl 3,4-
furandicarboxylate (1). N-(4-Hydroxyphenyl)maleimide14 (4)
was chosen as our reactive dienophile (Scheme 2). First
through third 3,4-substituted furan dendrons 3a-c were
prepared by reaction of 2 with the appropriate dendritic
bromide15 in the presence of NaH in DMF or KH in THF.
First through third DA dendrons 5a-c were prepared by
reacting the appropriate furan dendron with 4 at either
ambient temperature or 65 °C in ether/ethyl acetate solution.
First generation 5a precipitated from the reaction mixture
as pure exo isomer, while second and third generation
dendrons 5b and 5c, respectively, were each obtained as a
33%/66% mixture of endo/exo isomers as determined by 1H
NMR.
First through third generation dendrimers 6a-c were
prepared by reaction of 1,3,5-benzenetricarbonyl trichloride
central linker with the appropriate DA dendron in the
presence of Et3N in THF. To our delight, thermal isomer-
ization16 of exo/endo mixtures of second and third generation
dendrons and dendrimers gave pure exo isomers after heating
5 and 6 a-c neat at 65 °C for 48 h.
The reversible DA reaction for all dendrons and dendrim-
ers was evaluated by 1H NMR spectroscopy. NMR samples
(DMF-d7) of identical concentrations17 of dendrons 5a-c
were heated at 110 °C for 48 h. The NMR resonance at δ
9.99, corresponding to the phenolic proton of the DA
dendrons, proved diagnostic in determining percent dendron
dissociation. As the dendron samples were heated, a new
a Reaction conditions: (a) LiAlH4, Et2O, 88%; (b) NaH, DMF,
and 2 equiv either (i) BnBr, 84% or (ii) [G-1]-Br, 66%; KH, 2
equiv [G-2]-Br, THF, 74%; (c) either Et2O/EtOAc or EtOAc, rt or
65 °C; (d) benzene-1,3,5-tricarbonyltrichloride, Et3N, THF, 67%,
87%, and 73%, respectively.
(12) (a) Gousse´, C.; Gandini, A.; Hodge, P. Macromolecules 1998, 31,
314-321. (b) Laita, H.; Boufi, S.; Gandini, A. Eur. Polym. J. 1997, 33,
1203-1211. (c) Kuramoto, N.; Hayashi, K.; Nagai, K. J. Polym. Sci. Polym.
Chem. Ed. 1994, 32, 2501-2504.
(13) 2 and 3a are known compounds; see: Meissner, R.; Garcias, X.;
Mecozzi, S.; Rebek, J., Jr. J. Am. Chem. Soc. 1997, 119, 77.
(14) Compound 4 was prepared according to the literature: Park, J. O.;
Jang, S. H. J. Polym. Sci. Polym. Chem. Ed. 1992, 30, 723-729.
(15) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(16) Cooley, J. H.; Williams, R. V. J. Chem. Educ. 1997, 74, 582-585.
(17) Dendron concentration was 9.62 × 10-2 M.
singlet appeared at δ 9.95, corresponding to the phenolic
resonance of N-(4-hydroxyphenyl)maleimide (4) generated
during the retro DA reaction. The ratio of these peaks
revealed that approximately 40% of dendrons 5a-c had
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Org. Lett., Vol. 3, No. 17, 2001

dissociated to maleimide 4 and furan dendron 3 after 1 h of
heating, at which point equilibrium was established and no
further changes were observed by NMR. Similarly, the
reassembling of dendrons 5a-c was evaluated by heating
the samples at 65 °C. As anticipated, the reassembly process
was much slower; approximately 82% dendron formed after
5 days. Concentration of 5a-c and heating (65 °C, 48 h)
of DMF and subsequent reaction with the esterified dendritic
core. Michael addition19 through amine attack upon free
maleimide is less likely since no degradation is observed in
dendrons 5a-c.
Similar NMR experiments were performed in DMSO-d6
with substantially less dendrimer degradation. Dendrimers
6a-c again readily dissociated at 110 °C. The extent of
dendrimer dissociation cannot be calculated accurately, as
three DA adducts are present. Fortunately, percent furan
dendron formed could be calculated through comparison of
characteristic 1H NMR resonances.20 First, second, and third
generation dendrimers yielded 80%, 70%, and 86% furan
dendron, respectively, after heating for 24 h. The dendrimer
reassembly process was examined after concentration and
1
regenerated dendrons 5a-c completely as observed by H
NMR (Figure 1).
1
heating at 65 °C for 48 h. H NMR revealed complete
reassembly of first generation dendrimer 6a (exo). Reas-
sembly was incomplete for second generation 6b and third
generation 6c with 58% and 80% dendron, respectively, still
present. Incomplete reassembly of 6b and 6c may be due to
a combination of steric and entropic influences.
The present work represents the first examples of thermally
cleavable/reassembling dendrons and dendrimers via the
reversible DA reaction between furan and maleimide. We
hope to demonstrate application as chemical delivery and/
or encapsulant systems in our future studies.
Acknowledgment. This work was supported by the
United States Department of Energy under contract DE-
AC04-94AL85000. Sandia is a multiprogram laboratory
operated by Sandia Corporation, a Lockheed Martin Com-
pany, for the US DOE. The authors thank Dominic V.
McGrath for helpful discussions and Duane Schneider for
GPC work.
Figure 1. 1H NMR spectra (DMF-d7) of [G-2]-DA dendron 5a
(a) before heating, (b) after heating (110 °C) for 48 h (42%
dissociation), and (c) after concentration and heating (65 °C) for
48 h (100% dendron).
Supporting Information Available: Synthetic details
and characterization data for all compounds reported and
dendrimer molecular weight determination by GPC. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Identical NMR experiments were performed with den-
drimers 6a-c.18 Dissociation of 6a-c was clearly evident;
however, degradation of the samples occurred upon pro-
longed heating (110 °C) in DMF-d7. This is presumably due
to amine generated through partial thermal decomposition
OL0101281
(19) Okumoto, S.; Yamabe, S. J. Org. Chem. 2000, 65, 1544-1548.
(20) Percent furan dendron formed was calculated through a ratio of peaks
(δ 9.06) corresponding to the three protons of the central core with (a) the
singlet (δ 4.39) corresponding to four methylene protons of the [G-1] furan
dendron (for [G-1] dendrimer) or (b) the singlet (δ 5.02) corresponding to
eight benzyl protons of the [G-2] or [G-3] furan dendron (for [G-2] and
[G-3] dendrimers).
(18) Dendrimer concentration was 1.05 × 10-2 M.
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