Synthesis of macrocycle isomers via metathesis cyclization and their self-assembly from aqueous solutions

Article abstract of DOI:10.1021/ol801881k

(Graph Presented) Novel triangular macrocycle isomers were synthesized through metathesis cyclization with high yield (77%). HPLC and MALDI-TOF showed that the purity of the macrocycles was higher than 99%, while ¹H NMR clearly showed that these macrocycles contain C₂ and C₃ isomers in a ratio of 1:3. AFM and TEM showed that they spontaneously formed vesicular structures in a chloroform/water system with an average diameter of 460 nm, which was corroborated by DLS results.

Full text of DOI:10.1021/ol801881k

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4393-4396
Synthesis of Macrocycle Isomers via
Metathesis Cyclization and Their
Self-Assembly from Aqueous Solutions
Jing Jiang and Gregory N. Tew*
Department of Polymer Science and Engineering, UniVersity of Massachusetts,
Amherst, Massachusetts 01003
tew@mail.pse.umass.edu
Received June 10, 2008
ABSTRACT
Novel triangular macrocycle isomers were synthesized through metathesis cyclization with high yield (77%). HPLC and MALDI-TOF showed
1
that the purity of the macrocycles was higher than 99%, while H NMR clearly showed that these macrocycles contain C2 and C3 isomers in
a ratio of 1:3. AFM and TEM showed that they spontaneously formed vesicular structures in a chloroform/water system with an average
diameter of 460 nm, which was corroborated by DLS results.
Carbon-rich macrocycles remain of great interest to both
synthetic and theoretical chemists due to their unique
structures and interesting properties.1,2 However, macrocycle
synthesis has generally required heroic synthetic efforts
including the low-yielding “ultradilution” macrocyclization
reaction in the final stages of synthesis. Therefore, reports
of metathesis reactions leading to high synthetic yields of
macrocycles (up to 85%) were received with great enthusi-
asm.3 However, all of these macrocycles were based on
symmetrical monomers resulting in a single macrocyclic
product. We previously reported a series of novel, singly
substituted, ortho-substituted phenylene ethynylene macro-
cycles (see M0 in Figure 1) which formed order mesophases
and self-assembled into vesicular structures, for the first
time.4,5a These were prepared by ultradilution methods,6 and
consequently, only very small sample sizes were available.
To increase the quantity of available materials, we considered
(1) (a) Moore, J. S. Acc. Chem. Res. 1997, 30, 402. (b) Ho¨ger, S. J.
Polym. Sci. Part A: Polym. Chem. 1999, 37, 2685. (c) Youngs, W. J.;
Tessier, C. A.; Bradshaw, J. D. Chem. ReV. 1999, 99, 3153. (d) Kehoe,
J. M.; Kiley, J. H.; English, J. J.; Johnson, C. A.; Peterson, R. C.; Haley,
M. M. Org. Lett. 2000, 2, 969. (e) Yamaguchi, Y.; Kobayashi, S.;
Wakamiya, T.; Matsubara, Y.; Yoshida, Z. J. Am. Chem. Soc. 2000, 122,
7404. (f) Laskoski, M.; Steffen, W.; Morton, J. G. M.; Smith, M. D.; Bunz,
U. H. F. Angew. Chem., Int. Ed. 2002, 41, 2378. (g) Li, Y.; Zhang, J.;
Wang, W.; Miao, Q.; She, X.; Pan, X. J. Org. Chem. 2005, 70, 3285. (h)
Ho¨ger, S. Angew. Chem., Int. Ed. 2005, 44, 3806
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(3) (a) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416.
(b) Zhang, W.; Moore, J. S. J. Am. Chem. Soc. 2004, 126, 12796. (c) Zhang,
W.; Moore, J. S. Macromolecules 2004, 37, 3973. (d) Zhang, W.; Moore,
J. S. J. Am. Chem. Soc. 2005, 127, 11863. (e) Zhang, W.; Brombosz, S. M.;
(2) (a) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,
118, 1019. (b) Shetty, A. S.; Fischer, P. R.; Stork, K. F.; Bohn, P. W.;
Moore, J. S. J. Am. Chem. Soc. 1996, 118, 9409. (c) Zhang, J.; Moore,
J. S. J. Am. Chem. Soc. 1994, 116, 2655. (d) Venkataraman, D.; Lee, S.;
Zhang, J.; Moore, J. S. Nature 1994, 371, 591. (e) Zhang, J.; Moore, J. S.
Mendoza, J. L.; Moore, J. S. J. Org. Chem. 2005, 70, 10198
(4) Seo, S. H.; Jones, T. V.; Seyler, H.; Peters, J. O.; Kim, T. H.; Chang,
J. Y.; Tew, G. N. J. Am. Chem. Soc. 2006, 128, 9264
.
J. Am. Chem. Soc. 1992, 114, 9701
.
.
10.1021/ol801881k CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society

Scheme 1. Synthetic Route of Macrocycle Isomers
Figure 1. Macrocycles via different cyclization methods.
metathesis macrocyclization;6 however, due to the unsym-
metrical nature of our precursors, a mixture of isomers was
expected. The critical question was whether this mixture of
macrocycles would assemble into similar vesicular structures
previously discovered from the more labor intensive but
“pure” macrocycles. In this letter, we demonstrate that
metathesis does lead to the expected isomers (see Figure 1
and Scheme 2), and of critical importance, this mixture of
isomers readily assembles into vesicles, which appear to be
identical to those previously discovered. These findings lead
to the conclusion that metathesis produced isomers can still
assemble with excellent fidelity yet provide the added
advantage of greatly reducing the synthetic effort required
to obtain these important building blocks.
was performed in an argon glovebox due to the sensitivity
of the molybdenum catalyst to nitrogen, oxygen, and moisture.
Monomer 5, molybdenum catalyst, ligand, and 4-nitrophenol,
were dissolved in carbon tetrachloride and stirred overnight at
40 °C.3 The mixture was filtered to remove the precipitate, and
the solvent was removed using rotary evaporation. The crude
product was purified by flash chromatography to give the final
product as a viscous yellow oil in 77% total isolated yield.
The formation of regioisomers instead of a single mac-
rocycle is also outlined. Due to the unsymmetric structure
of monomer 5, there are eight possible macrocycles obtained
via metathesis cyclization (M6 to M13, Scheme 2). However,
careful analysis shows that M6 and M7 are identical, related
by a C2 axis as shown. Similarly, M8 to M13 are all identical,
related by either a C2 axis or a perpendicular C3 axis (see
Scheme 2). Because each macrocycle should be formed in
equal quantities, the expected ratio is 1:3.
We synthesized the TEG substituted ortho-phenylene
ethynylene triangular macrocycles (M1 and M2) through
metathesis cyclization in 77% yield. The final product was
isolated as a mixture of two regioisomers that were charac-
1
terized by HPLC, H NMR, and MALDI-TOF. Although
these isomers are inseparable using HPLC, 1H NMR signals
could be attributed to distinct isomers. Importantly, we found
that the mixture displayed self-assembling properties similar
to the pure, single isomer samples previously made via
ultradilution. For example, AFM and TEM confirmed the
self-assembly of this mixture of isomers in a chloroform/
water solvent system and showed that they formed vesicular
structures with an average diameter of 460 nm, which is
similar to that of the macrocycles obtained through the
traditional cyclization. Scheme 1 outlines the synthesis of
the macrocycle isomers. Starting from 3,4-diiodobenzoic
acid,7 esterification with triethylene glycol monomethyl ether
gave TEG ester 2 in 81% yield. This ester was then coupled
with (trimethylsilyl)acetylene by Sonogashira conditions8 to
afford 3 in 95% yield. The trimethylsilyl (TMS) protecting
groups were removed using potassium fluoride dihydrate in
DMF to give diacetylene 4, which was reacted with 4-ben-
zoyl-4′-bromobiphenyl to afford the metathesis precursor,
monomer 5, as yellow needles. The metathesis cyclization
The obtained macrocycles were characterized by HPLC,
1
MALDI-TOF, and H NMR. The HPLC chromatogram of
the isolated isomer mixture showed a single peak indicating
the isomers are inseparable and are more than 99% pure
(Figure 2a). The MALDI-TOF spectrum shown in Figure
2b has only one main peak at m/z ) 908 corresponding to
M + K+, with no detectable starting materials or oligomers.
Both of these methods clearly indicated the purity of the
isomers was very high.
1
The H NMR aromatic regions of the precursor and the
macrocycle regioisomers are shown in Figure 3a and 3b,
respectively. In Figure 3a, the narrow doublet at 8.14 ppm
(5) (a) Seo, S. H.; Chang, J. Y.; Tew, G. N. Angew. Chem., Int. Ed.
2006, 45, 7526. (b) Rehm, T.; Stepanenko, V.; Zhang, X.; Wurthner, F.;
Grohn, F.; Klein, K.; Schmuck, C. Org. Lett. 2008, 10, 1469. (c) Cristiano,
A.; Lim, C. W.; Rozkiewicz, D. I.; Reinhoudt, D. N.; Ravoo, B. J. Langmuir
2007, 23, 8944. (d) Houmadi, S.; Coquiere, D.; Legrand, L.; Faure, M. C.;
Goldmann, M.; Reinaud, O.; Remita, S. Langmuir 2007, 23, 4849.
(6) Ruggli, P. Liebigs. Ann. Chem. 1912, 392, 92.
(J ) 1.5 Hz), the doublet of doublets at 7.92 ppm (J1,2
)
1.5 Hz, J1,3 ) 8.1 Hz), and the wide doublet at 7.53 ppm (J
) 8.1 Hz) correspond to Ham, Hbm, and Hcm of the precursor,
respectively, and are characteristic of this substitution
pattern.9 This simple NMR spectrum is contrasted with the
one collected from the macrocycles shown in Figure 3b.
Initial inspection shows the macrocycle’s NMR aromatic
(7) Klemme, C. J.; Hunter, J. H. J. Org. Chem. 1940, 5, 227.
(8) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
46, 4467.
4394
Org. Lett., Vol. 10, No. 20, 2008

Scheme 2. Possible Macrocycle Isomers Obtained via
Cyclization of the Asymmetric Monomer 5
Figure 3.
1H NMR spectrum of precursor and macrocycle isomers.
(a) Aromatic region of the 1H NMR spectrum of the precursor. (b)
Aromatic region of the 1H NMR spectrum of macrocycle isomers.
′
′′
be three of each of these protons (3-Hc2, 3-Hc2 , 3-Hc2 ).
Therefore, the expected ratio of Hc protons should be 1:1:
1:1. The initial inspection of the NMR aromatic region shows
the Hc region between 7.42 and 7.45 ppm to include what
appears to be three sets of doublets in a ratio of 1:2:1.
However, careful inspection of the coupling constants shows
that these are not three doublets, but four. For example, the
coupling constant for peaks 1-2, 3-4, and 5-6 is 3.0 Hz
which does not agree with any values measured for this spin
system.9a However, the coupling constants for peaks 1-3,
2-4, 3-5, and 4-6 are 8.4 Hz, in very good agreement
with previously measured values for this Hc proton,4,9a,10
and consistent with four unique, but chemically similar, Hc
protons. A similar trend is observed for the Hb protons
between 7.90 and 7.87 ppm in which the four doublet of
doublets overlap with the highest intensity located in the
center. Due to the more complicated splitting, a definite
assignment is not possible; nevertheless, the pattern and
clearly measurable coupling constants are completely con-
sistent with expectations.
Figure 2
.
(a) HPLC trace of macrocycle isomers in acetonitrile
monitored at 290 nm along with (b) the MALDI-TOF spectrum.
region to be more complicated, although still apparently
containing three main sets of signals for the Ha, Hb, and Hc
protons. From the expected isomers shown in Figure 1, one
would expect M1 to have three identical Hc1 protons (3-
Hc1) due to the C3 symmetry. In contrast, M2 would have
Having confirmed that metathesis generated the expected
regioisomers, we wondered if this would impact the spon-
taneous self-assembly previously observed for the pure
macrocycle. The samples for both AFM and TEM were
prepared as previously reported.5a Briefly, in a small vial, 5
mL of water was added to 5 mL of a 1 mM solution of
macrocycles in chloroform. After shaking for a few minutes,
′
′′
three unique Hc protons, Hc2, Hc2 , and Hc2 , but because
of the expected ratios of each macrocycle (1:3), there should
(9) (a) Slutsky, M. M.; Jones, T. V.; Tew, G. N. J. Org. Chem. 2007,
72, 342. (b) Jones, T. V.; Slutsky, M. M.; Laos, R.; de Greef, T. F. A.;
Tew, G. N. J. Am. Chem. Soc. 2005, 127, 17235. (c) Jones, T. V.; Blatchly,
R.; Tew, G. N. Org. Lett. 2003, 5, 3297.
(10) Khan, A.; Hecht, S. J. Polym. Sci. Part A: Polym. Chem. 2006,
44, 1619
.
Org. Lett., Vol. 10, No. 20, 2008
4395

the mixture was left undisturbed for 2-3 h until it separated
into two clear phases. The organic layer was transferred to
another small vial, and a carbon-coated copper grid was
dipped into this solution. The grid was placed on filter paper
and dried under a stream of nitrogen prior to collecting the
AFM image shown in Figure 4a. This image shows spherical
TEM. These TEM images show imperfectly circular struc-
tures unlike those previously observed from the pure mac-
rocycle; however, this may be a drying artifact, so we prefer
not to speculate further. The most important observation in
our opinion is vesicle formation despite the presence of
isomers.
Novel ortho-phenylene ethynylene triangular macrocycles
were successfully synthesized via metathesis cyclization with
a high yield of 77% compared to that of the ultradiluted
cyclization reaction, which typically yielded 20% of the
macrocycle. 1H NMR shows that these macrocycles contain
two regioisomers with a ratio of 1:3, while the sample is
more than 99% pure as shown by HPLC and MALDI-TOF.
DLS, AFM, and TEM were used to characterize the self-
assembly of these isomers into vesicles with an average
diameter of ∼440 nm. These results indicated that a mixture
of isomers obtained through high-yielding metathesis mac-
rocyclization can still be well characterized and behave
similarly to other single isomer macrocycles. Understanding
the structural limitations of metathesis macrocyclization is
important so that one knows when it is necessary to pursue
the more time-consuming ultradilution methods.
Figure 4. Tapping-mode AFM and TEM images of vesicles formed
by macrocycle isomers on carbon-coated copper grid: (a) AFM
phase image; (b) TEM images without staining.
aggregates on the carbon-coated copper grid with an average
diameter of about 460 nm, which is in good agreement with
DLS results (440 nm) collected from the organic phase. The
combination of DLS and AFM confirms that the AFM
images are representative of the bulk structure and that no
significant drying artifacts are present. More important, these
AFM images support formation of vesicles based on previous
literature.5 However, since AFM cannot determine whether
the aggregates are solid or hollow, it is impossible to
precisely confirm vesicle formation by AFM, and so TEM
experiments were carried out. TEM images (Figure 4b) of
the same sample used for AFM confirmed the structures were
vesicular by the presence of a dark outer ring and light
interior, which is typical for 2D projections of vesicles in
Acknowledgment. We thank the NSF for financial support
(NSF CAREER CHE-0449663). G.N.T. thanks the ARO and
ONR Young Investigator programs in addition to the PECASE
program, 3M Nontenured faculty grant, and DuPont Young
Faculty Award for generous support. We thank Prof. J. S. Moore
and Dr. W. Zhang at University of Illinois, Urbana-Champaign,
for their help with metathesis cyclization.
Supporting Information Available: Complete synthetic
procedures for preparation of monomers 1-5 and metathesis
cyclization. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801881K
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Org. Lett., Vol. 10, No. 20, 2008