Hydrogen bonding directed self-assembly of small-molecule amphiphiles in water

Article abstract of DOI:10.1021/ol501841f

Compounds comprising one or two quadruply hydrogen bonding units, 2-ureido-4[1H]-pyrimidinone (UPy) and tris(tetraethylene glycol monomethyl ether) moieties, were reported to form highly stable hydrogen-bonded assemblies in water. Compound 1, containing o

Full text of DOI:10.1021/ol501841f

Letter
pubs.acs.org/OrgLett
Hydrogen Bonding Directed Self-Assembly of Small-Molecule
Amphiphiles in Water
Jiang-Fei Xu,†,‡ Li-Ya Niu,† Yu-Zhe Chen,† Li-Zhu Wu,† Chen-Ho Tung,† and Qing-Zheng Yang*,†
†Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing 100190, P. R. China
‡University of the Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: Compounds comprising one or two quadruply
hydrogen bonding units, 2-ureido-4[1H]-pyrimidinone (UPy)
and tris(tetraethylene glycol monomethyl ether) moieties,
were reported to form highly stable hydrogen-bonded
assemblies in water. Compound 1, containing one UPy,
assembles into vesicles, and compound 2, containing two UPy
units, forms micelles. The aggregates disassemble reversibly
when the solution pH is raised to 9.0 or above. The results
demonstrate the utility of hydrogen bonding to direct the self-
assembly of small-molecule building blocks in aqueous media.
a
Scheme 1. Synthesis of Compounds 1−3
ydrogen bonding drives the assembly of highly ordered
Hstructures in biology and plays a key role in maintaining
their function. Examples include the DNA double helix and the
3D structures of proteins and enzymatic reactive centers.1
Hydrogen bonding is also widely exploited in the preparation of
functional materials, such as supramolecular polymers,2
dendrimers,3 and foldamers.4 Using hydrogen bonding to
drive self-assembly in aqueous media, however, remains a
challenge because polar solvents, such as water, weaken or
destroy hydrogen bonds.
A possible strategy to maintain the hydrogen bonding in
aqueous media is to exploit multivalent H-bonding motives,
such as those provided by 2-ureido-4[1H]-pyrimidinone
(UPy), in combination with other noncovalent interactions,
such as hydrophobic effect.5 For example, hydrogen bonding in
the interiors of water-soluble proteins is protected by the
hydrophobic microenvironments of the polypeptides.1b,c
Water-soluble polymers such as poly(ethylene glycols)
(PEGs) end-functionalized with UPy were reported to
assemble and manifest dynamic properties in water.6 In such
systems, 3D networks formed by interactions between long
PEG chains (Mn 2−35 kDa) were cross-linked by UPy units to
form fibrous assemblies and hydrogels. Hydrogen bonding
played a modest role in self-assembly of such polymers because
of the low weight fraction of the hydrogen-bonding units.
Herein we exploited the quadruple hydrogen bonding of UPy
in cooperation with hydrophobic interaction to drive the
assembly of small molecules 1 and 2 (Scheme 1) in aqueous
media. We used the low molecular weight tetraethylene glycol
(TEG) monomethyl ether chains as polar blocks to make
molecules highly water soluble. The hydrogen-bonding units in
compounds 1 and 2 were shielded by hydrophobic groups to
yield stable aggregates.7 In neutral or acidic aqueous solutions,
a
TEG: tetraethylene glycol monomethyl ether. DMPA: 2, 2-
dimethoxy-2-phenylacetophenone. Hydrophilic parts of the molecules
are shown in blue, hydrophobic in red.
compound 1 (one UPy per molecule) formed vesicles while
compound 2 (two UPy units per molecule) formed micelles. In
basic solutions, both the micelles and the vesicles disassembled,
releasing guest molecules.
Received: June 25, 2014
Published: July 18, 2014
© 2014 American Chemical Society
4016
dx.doi.org/10.1021/ol501841f | Org. Lett. 2014, 16, 4016−4019

Organic Letters
Letter
Compounds 1 and 2 were synthesized by thiol−ene and
thiol−yne reactions in 64% and 92% yields in two steps,
respectively (Scheme 1).8 Compound 3 without hydrogen-
bonding units was synthesized as a control. The compounds
were fully characterized by NMR spectroscopy and high-
resolution ESI-MS (for details of synthesis and characterization,
see the Supporting Information). The UPy NH signals in the
1H NMR spectra of 1 and 2 in CDCl3 were shifted downfield
(to 10−14 ppm), suggesting the formation of quadruple
hydrogen-bonded UPy dimers.
Compounds 1−3 are water-soluble, where they self-assemble
with the critical aggregation concentration (CAC), determined
by the pyrene method,9 of 22, 1.4, and 120 μM, respectively
(Figure S4−S6, Supporting Information). The change in CAC
across the series 3 > 1 > 2 is consistent with the important
contribution of H bonding to self-assembly of compounds 1−3
in water. For example, despite the similar weight fraction of
hydrophobic parts of compounds 1 and 3 (wHP = molar mass of
the hydrophobic part/molar mass of the whole molecule, wHP‑1
= 0.431, wHP‑2 = 0.557, wHP‑3 = 0.456),10 the CAC of 1 (1 UPy
per molecule) is ∼5.5 times lower than that of 3 (no UPy).
Increasing the number of UPy units from one in 1 to two in 2
1
further lowers the CAC (from 22 to 1.4 μM). The H NMR
Figure 2. TEM image (a) and cryo-TEM image (b) of the vesicles
formed by 1 in water, (c) TEM image of the micelles formed by 2 in
water, and (d) DLS measurements of the micelles of 2 and vesicles of
1 in water. Scale bar: 100 nm.
spectrum of 1 in H2O/D2O (95/5, v/v) manifested signals at
shifts (10 and 14 ppm) typical for hydrogen-bonded protons in
UPy dimers and identical to shifts recorded in CDCl3,
confirming the formation of hydrogen bonding between
molecules of 1 in water (Figure 1). In contrast, the resonances
Scheme 2. Tentative Models for the Self-Assembly of
Amphiphiles 1 and 2 in Water To Form Vesicles and
Micelles
1
Figure 1. H NMR spectra (400 MHz) of 1 in (a) H2O/D2O (95/5,
v/v, ∼10 mM) and (b) CDCl3.
of the TEG protons of 2 in D2O were considerably broadened
and signals of aliphatic and aromatic protons were absent
(Figure S9, Supporting Information). This result suggests the
distinct assembly behavior of the two compounds, as discussed
below.
Stained TEM images of dried aqueous solutions of 2 revealed
well-dispersed micelles with diameters of 10−15 nm (Figure
2c). DLS measurement gave a mean diameter of 20 nm (Figure
2d). This slightly larger diameter, compared with TEM
observations, is consistent with DLS measuring the hydro-
dynamic diameter of fully hydrated micelles whereas TEM
measures dry collapsed micelles.12 We assume that unlike
compound 1, which tends to dimerize, 2 with its two UPy units
forms random-coiled supramolecular polymers, which aggre-
gate into micelles. The UPy units, sequestered into the
hydrophobic cores of such micelles, may cross-link with each
other via quadruple hydrogen bonds, thus contributing to the
compactness and stability of the micelles (Scheme 2). Such a
putative structure would be consistent with the ill-defined
NMR spectra as it would restrict molecular tumbling.13 The
shape and size of the micelles remained unchanged after the
solution was stored for 4 months.
The assembly of 1 and 2 in aqueous solution was investigated
by transmission electron microscopy (TEM), cryo-TEM, and
dynamic light scattering (DLS). The TEM image of the
aggregates of 1 revealed spherical vesicles with diameters of
50−150 nm, which showed an obvious color contrast between
the peripheries and centers of the spheres (Figure 2a). The
average hydrodynamic diameter (Dh) of the vesicles deter-
mined by DLS measurements was ∼90 nm (Figure 2d), in
accord with the TEM observation. Cryo-TEM images of the
vesicles revealed the average thickness of the wall of 6−7 nm
(Figure 2b), approximately equal the length of the quadruple
hydrogen-bonded dimer of 1. These results suggest that in H2O
1 dimerizes through H bonding into a bolaform amphiphile,
which self-assembles into vesicles (Scheme 2).11
4017
dx.doi.org/10.1021/ol501841f | Org. Lett. 2014, 16, 4016−4019

Organic Letters
Letter
Because hydrogen bonding is sensitive to pH, as H donor
sites can be deprotonated or H acceptor sites can be
protonated,14,6c we considered that the aggregates of 1 and 2
could be reversibly disassembled by changing the solution pH,
thus making them potentially suitable for applications in
controlled release. We used Nile Red (NR) as a model guest
molecule.15 NR (1.0 μg/mL), encapsulated into the micelles
formed by 2 (0.05 mM), strongly fluoresces at 630 nm, which is
the typical emission wavelength of NR in hydrophobic
environment. Acidifying the solution with HCl to pH ∼2
slightly decreased the fluorescence intensity without changing
the wavelength (Figure 3b), suggesting that NR remained
band to 650 nm, suggesting the disruption of micelles and an
almost complete release of encapsulated NR. The collapse of
micelles may result from deprotonation of hydroxyl group in
the enol tautomer of UPy to the enolate (Figure 3a). The loss
of H bonding and electrostatic repulsion between negatively
charged enolates may be responsible for the dissolution of the
micelles. The dissociation of micelles in basic solutions was also
confirmed by DLS measurement, in which a decreased Dh of
3.8 nm was revealed at pH 10.0 (Figure S14, Supporting
Information), which was the approximate size of single
molecule of compound 2. The disassembly and assembly of
micelles is reversible, as evidenced by the recovery of NR
emission upon neutralization of the solution with acid (Figure
3c). It should be mentioned that the speed of release and
encapsulate of NR from micelles was very fast; the red color of
the encapsulated NR in micelles faded dramatically within ∼1−
3 s when NaOH was added and recovered in similar speed
upon neutralizing the solutions. This result suggested that the
kinetics of the reversible disassembly and assembly of micelles
were quite fast, which may attributed to the fast reaction rate of
deprotonation and protonation of UPy units.
We also studied the controlled release of NR from micelles
and from vesicles in buffered solutions (Figures S16 and S17,
Supporting Information). In a solution of micelles formed by 2
in glycine−NaOH buffer (pH 9.0), about 66% of the
encapsulated NR was released immediately as determined by
the changes in fluorescence intensity. At pH 10.0, about 85% of
NR released. For the NR encapsulated in vesicles formed by 1,
82% and 90% of them was released at pH 9.0 and pH 10.0,
respectively.
In conclusion, we report highly stable hydrogen-bonded
assemblies from small-molecule amphiphiles in aqueous
solution. Combination of quadruple hydrogen bonding unit
UPy as a hydrophobic part and short TEG chains as a
hydrophilic part enables the formation of stable hydrogen
bonds. The number of UPy units per molecule influenced the
behavior of assembly dramatically. Compound 1 with one UPy
unit formed bolaform amphiphilic hydrogen-bonded dimers,
which tended to form vesicles, whereas compound 2 formed
micellar structures in which building blocks may be cross-linked
by intermolecular hydrogen bonding. The correlation between
CAC and the number of H-bonding UPy moieties per molecule
further suggests that hydrogen bonding is a key contributor to
self-assembly of these small-molecule amphiphiles in H2O.
Increasing the solution pH to ∼9 disassembled both the
micelles and the vesicles and released guest molecules,
suggesting potential applications in drug delivery. Subsequently
decreasing the pH to <7 leads to reassembly of the structures.
Our studies could facilitate the development of new hydrogen-
bonded assemblies as novel functional materials.
Figure 3. (a) Tautomerizations of UPy unit, (b) fluorescence spectra
of Nile Red encapsulated in micelles formed by 2 upon addition of
acid or base, and (c) recovery of the fluorescence after the
neutralization of the base, λex = 550 nm.
encapsulated in the hydrophobic core of micelles. The slight
decrease in fluorescence intensity may result from precipitation
of larger micelle aggregates as some hydrogen bonds between
the TEG chains and water molecules are disrupted.16 DLS
measurement of the micelle solution at pH 3.0 revealed an
increased Dh of 40 nm (Figure S14, Supporting Information),
which supported the hypothesized micelle aggregation. Similar
micelle aggregation phenomenon was also observed upon rising
temperature of the solution. At a raised temperature of 343 K,
the micelle solution became turbid and the Dh of the aggregates
increased to 115 nm (Figure S15, Supporting Information),
suggesting the formation of large aggregates. Such aggregation
was also related to the change of hydrogen bonds between
TEG chains and water molecules which the strength decreased
dramatically at raised temperatures.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, synthesis of compounds 1−3, NMR
spectra, determination of CACs, fluorescence spectra, DLS
measurements, and other materials. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
In contrast, increasing the pH of the solution to ∼11 greatly
decreased the fluorescence intensity and shifted the emission
*E-mail: qzyang@mail.ipc.ac.cn.
4018
dx.doi.org/10.1021/ol501841f | Org. Lett. 2014, 16, 4016−4019

Organic Letters
Letter
W.; Popa, E. R.; Fytas, G.; Meijer, E. W. Adv. Mater. 2012, 24, 2703.
(b) Kieltyka, R. E.; Pape, A. C. H.; Albertazzi, L.; Nakano, Y.; Bastings,
M. M. C.; Voets, I. K.; Dankers, P. Y. W.; Meijer, E. W. J. Am. Chem.
Soc. 2013, 135, 11159. (c) Bastings, M. M. C.; Koudstaal, S.; Kieltyka,
R. E.; Nakano, Y.; Pape, A. C. H.; Feyen, D. A. M.; van Slochteren, F.
J.; Doevendans, P. A.; Sluijter, J. P. G.; Meijer, E. W.; Chamuleau, S. A.
J.; Dankers, P. Y. W. Adv. Healthcare Mater. 2014, 3, 70. (d) Guo, M.;
Pitet, L. M.; Wyss, H. M.; Vos, M.; Dankers, P. Y. W.; Meijer, E. W. J.
Am. Chem. Soc. 2014, 136, 6969.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the 973 Program
(2013CB933800, 2013CB834505) and the National Natural
Science Foundation of China (21222210, 91027041,
21272243).
(7) (a) Menger, F. M.; Zhang, H. J. Am. Chem. Soc. 2006, 128, 1414.
(b) de Greef, T. F. A.; Nieuwenhuizen, M. M. L.; Stals, P. J. M.; Fitie,
C. F. C.; Palmans, A. R. A.; Sijbesma, R. P.; Meijer, E. W. Chem.
Commun. 2008, 44, 4306. (c) de Greef, T. F. A.; Nieuwenhuizen, M.
M. L.; Sijbesma, R. P.; Meijer, E. W. J. Org. Chem. 2010, 75, 598.
(d) Wong, C.-H.; Choi, L.-S.; Yim, S.-L.; Lau, K.-N.; Chow, H.-F.;
Hui, S.-K.; Sze, K.-H. Chem.Asian J. 2010, 5, 2249. (e) Besenius, P.;
van den Hout, K. P.; Albers, H. M. H. G.; de Greef, T. F. A.; Olijve, L.
L. C.; Hermans, T. M.; de Waals, B. F. M.; Bomans, P. H. H.;
Sommerdijk, N. A. J. M.; Portale, G.; Palmans, A. R. A.; van Genderen,
M. H. P.; Vekemans, J. A. J. M.; Meijer, E. W. Chem.Eur. J. 2011, 17,
5193. (f) Leenders, C. M. A.; Albertazzi, L.; Mes, T.; Koenigs, M. M.
E.; Palmans, A. R. A.; Meijer, E. W. Chem. Commun. 2013, 49, 1963.
(g) Pal, A.; Voudouris, P.; Koenigs, M. M. E.; Besenius, P.; Wyss, H.
M.; Degirmenci, V.; Sijbesma, R. P. Soft Matter 2014, 10, 952.
(8) (a) Hoogenboom, R. Angew. Chem., Int. Ed. 2010, 49, 3415.
(b) Peng, H.-Q.; Sun, C.-L.; Xu, J.-F.; Niu, L.-Y.; Chen, Y.-Z.; Wu, L.-
Z.; Tung, C.-H.; Yang, Q.-Z. Chem.Eur. J. 2014, DOI: 10.1002/
chem.201402955.
(9) Ding, Y.; Wang, Z.; Zhang, X. Chem. Commun. 2013, 49, 5580.
(10) Chebotareva, N.; Bomans, P. H. H.; Frederik, P. M.;
Sommerdijk, N. A. J. M.; Sijbesma, R. P. Chem. Commun. 2005, 41,
4967.
(11) (a) Wang, Y.; Xu, H.; Zhang, X. Adv. Mater. 2009, 21, 2849.
(b) Yu, G.; Xue, M.; Zhang, Z.; Li, J.; Han, C.; Huang, F. J. Am. Chem.
Soc. 2012, 134, 13248. (c) Yao, Y.; Xue, M.; Chen, J.; Zhang, M.;
Huang, F. J. Am. Chem. Soc. 2012, 134, 15712.
REFERENCES
■
(1) (a) Saenger, W. In Principles of Nucleic Acid Structure; Springer:
New York, 1984. (b) Creighton, T. E. In Proteins, Structures and
Molecular Properties; Freeman: New York, 1984. (c) Prediction of
Protein Structure and the Principles of Protein Conformation; Fasman, G.
D.., Ed; Plenum: New York, 1990.
(2) (a) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P.
Chem. Rev. 2001, 101, 4071. (b) Fouquey, C.; Lehn, J.-M.; Levelut, A.-
M. Adv. Mater. 1990, 2, 254. (c) Sijbesma, R. P.; Beijer, F. H.;
Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.;
Lowe, J. K. L.; Meijer, E. W. Science 1997, 278, 1601. (d) Park, T.;
Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 13986. (e) Todd, E.
M.; Zimmerman, S. C. J. Am. Chem. Soc. 2007, 129, 14534. (f) Chen,
S.-G.; Yu, Y.; Zhao, X.; Ma, Y.; Jiang, X.-K.; Li, Z.-T. J. Am. Chem. Soc.
2011, 133, 11124. (g) Shi, Z.-M.; Wu, C.-F.; Zhou, T.-Y.; Zhang, D.-
W.; Zhao, X.; Li, Z.-T. Chem. Commun. 2013, 49, 2673. (h) Yan, X.; Li,
S.; Pollock, J. B.; Cook, T. R.; Chen, J.; Zhang, Y.; Ji, X.; Yu, Y.;
Huang, F.; Stang, P. J. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 15585.
(i) Yan, X.; Li, S.; Cook, T. R.; Ji, X.; Yao, Y.; Pollock, J. B.; Shi, Y.; Yu,
G.; Li, J.; Huang, F.; Stang, P. J. J. Am. Chem. Soc. 2013, 135, 14036.
(j) Xu, J.-F.; Chen, Y.-Z.; Wu, D.; Wu, L.-Z.; Tung, C.-H.; Yang, Q.-Z.
Angew. Chem., Int. Ed. 2013, 52, 9738. (k) Yan, X.; Jiang, B.; Cook, T.
R.; Zhang, Y.; Li, J.; Yu, Y.; Huang, F.; Yang, H.-B.; Stang, P. J. J. Am.
Chem. Soc. 2013, 135, 16813. (l) Yan, X.; Cook, T. R.; Pollock, J. B.;
Wei, P.; Zhang, Y.; Yu, Y.; Huang, F.; Stang, P. J. J. Am. Chem. Soc.
2014, 136, 4460. (m) Peng, H.-Q.; Xu, J.-F.; Chen, Y.-Z.; Wu, L.-Z.;
Tung, C.-H.; Yang, Q.-Z. Chem. Commun. 2014, 50, 1334.
(3) (a) Zimmerman, S. C.; Zeng, F. W.; Reichert, D. E. C.;
Kolotuchin, S. V. Science 1996, 271, 1095. (b) Zeng, F.; Zimmerman,
S. C. Chem. Rev. 1997, 97, 1681. (c) Frechet, J. M. J. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 4782. (d) Ma, Y.; Kolotuchin, S. V.; Zimmerman,
S. C. J. Am. Chem. Soc. 2002, 124, 13757. (e) Zhang, H.; Fu, Y.; Wang,
D.; Wang, L.; Wang, Z.; Zhang, X. Langmuir 2003, 19, 8497. (f) Sun,
H.; Kaifer, A. E. Org. Lett. 2005, 7, 3845.
(4) (a) Forgan, R. S.; Sauvage, J.-P.; Stoddart, J. F. Chem. Rev. 2011,
111, 5434. (b) Zhang, D.-W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Chem. Rev.
2012, 112, 5271. (c) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J.-M.
Chem.Eur. J. 2001, 7, 2798. (d) Berl, V.; Huc, I.; Khoury, R. G.;
Lehn, J.-M. Chem.Eur. J. 2001, 7, 2810. (e) Zhu, J.; Lin, J.-B.; Xu, Y.-
X.; Shao, X.-B.; Jiang, X.-K.; Li, Z.-T. J. Am. Chem. Soc. 2006, 128,
12307. (f) Cai, W.; Wang, G.-T.; Du, P.; Wang, R.-X.; Jiang, X.-K.; Li,
Z.-T. J. Am. Chem. Soc. 2008, 130, 13450. (g) Guo, L.; Almeida, A. M.;
Zhang, W.; Reidenbach, A. G.; Choi, S. H.; Guzei, I. A.; Gellman, S. H.
J. Am. Chem. Soc. 2010, 132, 7868. (h) Gan, Q.; Ferrand, Y.; Bao, C.;
Kauffmann, B.; Grelard, A.; Jiang, H.; Huc, I. Science 2011, 331, 1172.
(i) Xiao, T.; Li, S.-L.; Zhang, Y.; Lin, C.; Hu, B.; Guan, X.; Yu, Y.;
Jiang, J.; Wang, L. Chem. Sci. 2012, 3, 1417.
(12) Zhang, S.; Zhao, Y. Macromolecules 2010, 43, 4020.
(13) Chen, S.; Ruan, Y.; Brown, J. D.; Gallucci, J.; Maslak, V.; Hadad,
́
C. M.; Badjic, J. D. J. Am. Chem. Soc. 2013, 135, 14964.
(14) Li, S.-L.; Xiao, T.; Xia, W.; Ding, X.; Yu, Y.; Jiang, J.; Wang, L.
Chem.Eur. J. 2011, 17, 10716.
(15) (a) Wang, C.; Wang, G.; Wang, Z.; Zhang, X. Chem.Eur. J.
2011, 17, 3322. (b) Wang, G.; Wang, C.; Wang, Z.; Zhang, X.
Langmuir 2011, 27, 12375.
(16) (a) Maeda, Y. Langmuir 2001, 17, 1737. (b) Lutz, J.-F.;
Weichenhan, K.; Akdermir, O.; Hoth, A. Macromolecules 2007, 40,
2503.
(5) (a) Brunsveld, L.; Vekemans, J. A. J. M.; Hirschberg, J. H. K. K.;
Sijbesma, R. P.; Meijer, E. W. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
4977. (b) Sijbesma, R. P.; Meijer, E. W. Chem. Commun. 2003, 39, 5.
(c) Li, M.; Yamato, K.; Ferguson, J. S.; Gong, B. J. Am. Chem. Soc.
2006, 128, 12628. (d) Obert, E.; Bellot, M.; Bouteiller, L.; Andrioletti,
F.; Lehen-Ferrenbach, C.; Boue, F. J. Am. Chem. Soc. 2007, 129, 15601.
(e) Cafferty, B. J.; Gallego, I.; Chen, M. C.; Farley, K. I.; Eritja, R.;
Hud, N. V. J. Am. Chem. Soc. 2013, 135, 2447. (f) Zhang, K.-D.; Ajami,
D.; Rebek, J. J. Am. Chem. Soc. 2013, 135, 18064.
(6) (a) Dankers, P. Y. W.; Hermans, T. M.; Baughman, T. W.;
Kamikawa, Y.; Kieltyka, R. E.; Bastings, M. M. C.; Janssen, H. M.;
Sommerdijk, N. A. J. M.; Larsen, A.; van Luyn, M. J. A.; Bosman, A.
4019
dx.doi.org/10.1021/ol501841f | Org. Lett. 2014, 16, 4016−4019