Post-assembly functionalization of organoplatinum(II) metallacycles via copper-free click chemistry

Article abstract of DOI:10.1021/ja3070073

We describe the use of a strain-promoted copper-free click reaction in the post-self-assembly functionalization of organoplatinum(II) metallacycles. The coordination-driven self-assembly of a 120° cyclooctyne-tethered dipyridyl donor with 60° and 120° di-Pt(II) acceptors forms molecular rhomboids and hexagons bearing cyclooctynes. These species undergo post-self-assembly [3+2] Huisgen cycloaddition with a variety of azides to give functionalized ensembles under mild conditions.

Full text of DOI:10.1021/ja3070073

Communication
pubs.acs.org/JACS
Post-assembly Functionalization of Organoplatinum(II) Metallacycles
via Copper-free Click Chemistry
Rajesh Chakrabarty* and Peter J. Stang*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S
* Supporting Information
copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC)
reactions.4 However, the application of click chemistry to
ABSTRACT: We describe the use of a strain-promoted
copper-free click reaction in the post-self-assembly
functionalization of organoplatinum(II) metallacycles.
The coordination-driven self-assembly of a 120° cyclo-
octyne-tethered dipyridyl donor with 60° and 120° di-
Pt(II) acceptors forms molecular rhomboids and hexagons
bearing cyclooctynes. These species undergo post-self-
assembly [3+2] Huisgen cycloaddition with a variety of
azides to give functionalized ensembles under mild
conditions.
functionalize discrete assemblies has received much less
attention. In a rare example, Zhou et al.5 described the
functionalization of porous nanocages bearing free alkyne
groups via the CuAAC reaction with azide-terminated PEG to
transform the nanocages into water-stable colloids, which
showed controlled release of the anticancer drug 5-fluorouracil.
However, the use of CuAAC reactions in living systems is
limited due the cytotoxicity of the Cu(I) catalyst toward living
cells. Copper-free strain-promoted azide−alkyne cycloaddition
(SPAAC) reactions6 recently developed between cyclooctynes
and azides have found wide utility in chemical biology, such as
labeling of biomolecules (glycans,7 proteins,8 lipids,9 and
nucleotides,10), modification of oligonucleotides11 and en-
zymes,12 and cell and tissue surface engineering.13 In the field
of material science, SPAAC reactions have been used for
surface functionalization of dendrimers,14 polymers,15 nano-
particles,16 and nanowires,17 surface patterning,18 and cross-
linking of polymers and hydrogels.19
he functionalization of supramolecular assemblies has
Tbeen extensively investigated over the past few years with
an aim to develop nanoscale ensembles that can find
applications in diverse fields such biological systems, host−
guest chemistry, cavity-directed synthesis, catalysis, photonics,
redox activity, magnetic behavior, self-organization, and
sensing.1 Although various functionalized nanoscopic systems
have been developed through conventional covalent synthesis,
the control of functional groups and structural precision, the
ability to perform selective encapsulation, and synthetic ease
and building-block versatility make coordination-driven self-
assembly a powerful tool to assemble functional supramolecules
with relative simplicity. However, potential incompatibilities
and interferences by various functional groups with the self-
assembly process often limit the library and scope of the
functionalized tectons. Thus, post-self-assembly modification of
supramolecular ensembles through transformation of the
organic component of the assemblies may be a way to
circumvent the problem. We have recently been able to achieve
post-assembly functionalization of metallosupramolecular
prisms via covalent modifications to incorporate new
functionalities under mild conditions.2 The free amino groups
tethered on the edges of the prisms allowed facile reactions
with isocyanate or maleic anhydride. Similarly, the free
malemide groups tethered on the edges of these prisms
underwent Diels−Alders reaction with anthracenyl ferroce-
noate. However, the range and scope of using an amino group
as a handle to introduce various functional groups is limited.
The azide−alkyne-based “click” reactions are attractive
alternatives in this context since they usually involve weakly
polarized reactants, minimizing undesired side reactions, and
thus could be an efficient method for expanding the range of
chemical functionalities that can be tethered onto the
metallosupramolecules. Post-synthetic modification of metal−
organic frameworks3 has been achieved in recent years through
Herein we report post-self-assembly functionalization of
supramolecular ensembles through “copper-free click chem-
istry”. The 120° cyclooctyne-tethered dipyridyl donor was
synthesized via the amide coupling reaction of 3,5-bis(4-
pyridylethynyl)aniline with 1-cyclooctyne-3-glycolic acid20 in
dichloromethane, leading to the formation of the cyclooctyne-
tethered donor 1 (Supporting Information, Scheme S1).
Stirring a mixture of 120° cyclooctyne-tethered donor 3 and
the 60° organoplatinum(II) acceptor, 3,6-bis[trans-Pt-
(PEt3)2(NO3)2]phenanthrene (4), in a 1:1 ratio in CD2Cl2
for 8 h led to the formation of self-assembled [2+2]
metallacyclic rhomboid 6. Similarly, self-assembled [3+3]
hexagon 7 was prepared by mixing the 120° donor ligand 3
with organoplatinum(II) acceptor, 4,4′-[trans-Pt-
(PEt3)2(NO3)2]diphenyl ketone (5), in a 1:1 ratio in CD3OD
1
for 8 h (Scheme 1). Multinuclear NMR (31P and H) of the
reaction products supports the formation of discrete, highly
symmetric assemblies. These metallacycles contain a pendant
cyclooctyne moiety at their vertices. The 31P{1H} NMR spectra
of 6 and 7 displayed sharp singlets at 12.7 and 14.1 ppm with
concomitant 195Pt satellites corresponding to a single
phosphorus environment (Figure 1). The peaks were shifted
upfield from those of their respective platinum acceptors 4 and
5 by approximately 6.4 and 5.1 ppm, respectively. The upfield
shift as well as the decrease in coupling constant (ΔJ) for the
Received: July 17, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3070073 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Self-Assembly of Discrete Metallacyclic
Rhomboids and Hexagons Bearing Cyclooctyne
Functionality
1
Figure 2. Partial H NMR spectra (in CD2Cl2) of (a) Pt(II) acceptor
4, (b) cyclooctyne-tethered donor 3, and (c) rhomboid 6.
distribution. In the ESI-MS of 7, no parent ion peak was
observed due to fragmentation. However, unique fragments
were observed that support the formation of the hexagonal
structure when analyzed in conjunction with the NMR spectra
(Supporting Information).
In order to gain structural information about the metalla-
cycles, single-point density functional theory (DFT) energy
minimizations were performed using the Gaussian09 package.22
All calculations were performed using the B3LYP hybrid DFT
functional23,24 and a split basis set wherein the 6-31G** basis
set25 was used for C, H, N, O, and P atoms, while the
LANL2DZ basis set26 and pseudopotential were used for Pt.
To minimize the computational cost, PEt3 ligands were
modeled as PH3. In rhomboid 6, the two cyclooctyne moieties
at the vertices lie above and below the plane of the central
metallacyclic core (Figure 3). The cyclooctyne groups adopt a
more stable boat conformation.27 The alkyne bonds in the
cyclooctynes are bent from linearity. Previous studies28 using
Figure 1. 31P{1H} NMR spectra of (a) rhomboid 6 and (b) hexagon 7.
195Pt satellites is consistent with back-donation from the
1
platinum atoms. In the H NMR spectrum of 6, signals due to
the α- and β-protons of the pyridine rings showed the expected
downfield shifts relative to those of 3 due to the loss of electron
density that occurs upon coordination of the pyridyl N-atom to
the Pt(II) metal center. As shown in Figure 2, the α- and β-
protons on the pyridine rings are split into two sets of two
doublets upon coordination, which is consistent with previous
observations of similar Pt-based rhomboids.21 The signal for
the α-pyridyl protons of cyclooctyne-tethered donor 3, which
appears as a doublet at 8.62 ppm, splits into two doublets at
9.34 and 8.68 ppm. Similarly, the β-pyridyl proton signal (δ =
7.42 ppm) is split into two doublets at 7.96 and 7.81 ppm. The
signal at δ = 9.18 ppm was assigned to the amide proton. In the
1H NMR spectrum of 7, sharp signals corresponding to
coordinated α- and β-pyridyl protons were identified at 8.89
and 7.87 ppm with downfield shifts relative to 3 (Figure 2).
Electrospray ionization mass spectroscopic (ESI-MS) studies
further supports the formation of discrete supramolecular
assemblies. The ESI mass spectrum for rhomboid 6
(Supporting Information) showed peaks at m/z = 1560.5,
corresponding to [M − 2NO3]2+, and m/z = 1019.02,
attributable to [M − 3NO3]3+. All the peaks were isotopically
resolved and agreed very well with the calculated theoretical
Figure 3. DFT-optimized structure of metallacyclic rhomboid 6. Color
code: gray, C; light gray, H; blue, N; red, O; orange, P; green, Pt.
B
dx.doi.org/10.1021/ja3070073 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
DFT-based models for the 1,3-dipolar cycloaddition of
cyclooctynes with azides have shown that such deviation
from linearity distorts the cyclooctynes toward the transition-
state geometry, thus requiring less distortion energy to reach
their preferred transition-state geometry relative to a linear
alkyne.
The metallacyclic rhomboid 6 was tested for post-assembly
functionalization via “copper-free click chemistry”. The
rhomboid 6 undergoes efficient [3+2] Huisgen-type SPAAC
reactions with a variety of functionalized azides to give
functionalized metallacycles under mild conditions (Scheme
2). Molecular rhomboids 8a−c were obtained upon treatment
In conclusion, we have demonstrated that copper-free strain-
promoted azide−alkyne cycloaddition reactions can be
effectively used to functionalize metallacycles having pendant
cyclooctyne groups. In contrast to other methodologies for
construction of functionalized supramolecules where a pre-
functionalized unit is used, this method provides a facile way to
incorporate a wide range of chemical functionalities on
appropriate supramolecular assemblies with relative synthetic
ease. The ready access to a multi-biotin scaffold permits the
formation of a biotin multimeric structure for potential
enhancement of avidin−biotin assays. Since a multivalent
biotin scaffold allows many biotin binding proteins to dock
simultaneously and form larger complexes,30 these conjugates
may recruit more detection molecules to bind at the site of an
analyte that can have a direct effect on the sensitivity of
immunoassays, fluorescent detection, enzyme-linked immuno-
sorbent assays, and Western blotting procedures. Use of this
methodology to functionalize three-dimensional supramolecu-
lar cages, having large cavities, with biologically relevant homing
devices may lead to better drug delivery devices. Investigation
along these lines is currently underway in our laboratory.
Scheme 2. Post-assembly Modification of Discrete
Metallacyclic Rhomboids with Different Azides via Copper-
Free Click Chemistry
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all
metallacyclic assemblies; complete ref 22. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
stang@chem.utah.edu
■
Notes
The authors declare no competing financial interest.
of 6 with azidomethylbenzene, 1-(azidomethyl)pyrene, and 2-
(azidoethyl)biotinamide, respectively, in a 1:5 ratio in CD2Cl2
for 2 h at room temperature. In all cases, the only products
observed were the two regioisomeric 1,4,5-trisubstituted 1,2,3-
triazoles in varying ratios, as identified from 1H NMR spectra of
8a−c. The 31P{1H} NMR spectra for all the assemblies
remained unchanged, with the peaks appearing at about the
same positions relative to those of their unfunctionalized
counterparts. The 31P{1H} NMR spectra of the functionalized
rhomboids 8a−c show sharp singlets at 12.7 ppm, identical to
ACKNOWLEDGMENTS
P.J.S. thanks the NIH (Grant GM-057052) for financial
support.
■
REFERENCES
■
(1) Chakrabarty, R.; Mukherjee, P. S.; Stang, P. J. Chem. Rev. 2011,
111, 6810 and references therein.
(2) Wang, M.; Lan, W.-J.; Zheng, Y.-R.; Cook, T. R.; White, H. S.;
Stang, P. J. J. Am. Chem. Soc. 2011, 133, 10752.
(3) Cohen, S. M. Chem. Rev. 2012, 112, 970. (b) Wang, Z.; Cohen, S.
M. Chem. Soc. Rev. 2009, 38, 1315. (c) Song, Y.-F.; Cronin, L. Angew.
Chem., Int. Ed. 2008, 47, 4635.
(4) (a) Goto, Y.; Sato, H.; Shinkai, S.; Sada, K. J. Am. Chem. Soc.
2008, 130, 14354. (b) Gadzikwa, T.; Lu, G.; Stern, C. L.; Wilson, S. R.;
Hupp, J. T.; Nguyen, S. T. Chem. Commun. 2008, 5493. (c) Gadzikwa,
T.; Farha, O. K.; Malliakas, C. D.; Kanatzidis, M. G.; Hupp, J. T.;
Nguyen, S. T. J. Am. Chem. Soc. 2009, 131, 13613. (d) Savonnet, M.;
Bazer-Bachi, D.; Bats, N.; Perez-Pellitero, J.; Jeanneau, E.; Lecocq, V.;
Pinel, C.; Farrusseng, D. J. Am. Chem. Soc. 2010, 132, 4518.
(e) Kawamichi, T.; Inokuma, Y.; Kawano, M.; Fujita, M. Angew.
Chem., Int. Ed. 2010, 49, 2375.
1
the spectrum of the unfunctionalized rhomboid 7. The H
NMR spectra of the ensembles showed additional peaks
attributable to benzyl, pyrenyl, and biotinyl protons (Support-
1
ing Information). In the H NMR spectrum of 8a, the phenyl
protons originating from the benzyl azide appear as a multiplet
at 7.38 ppm, while the benzylic protons appear at 5.60 ppm and
are consistent with previous observations.29 The pyrenyl
protons in 8b appear as a multiplet at 8.27−8.11 ppm, with
the benzylic proton appearing at 6.38 ppm.
ESI-MS data provided further evidence for the formation of
the discrete functionalized species. The ESI mass spectrum for
8a showed isotopically resolved peaks at m/z = 1693.6,
corresponding to [M − 2NO3]2+, and m/z = 1108.1, attribut-
able to [M − 3NO3]3+ (Supporting Information). Similarly,
isotopically resolved peaks due to [M − 2NO3]2+ and [M −
3NO3]3+ were observed at m/z = 1817.6 and 1190.8
respectively, in the ESI-MS spectrum of 8b. The ESI-MS
spectrum of biotin-functionalized species 9c also showed an
isotopically resolved peak at m/z = 1228.1, corresponding to
[M − 3NO3]3+.
(5) Zhao, D.; Tan, S.; Yuan, D.; Lu, W.; Rezenom, Y. H.; Jiang, H.;
Wang, L.-Q.; Zhou, H.-C. Adv. Mater. 2011, 23, 90.
(6) Reviews: (a) Sletten, E. M.; Bertozzi, C. R. Angew. Chem., Int. Ed.
2009, 48, 6974. (b) Best, M. D. Biochemistry 2009, 48, 6571. (c) Becer,
C. R.; Hoogenboom, R.; Schubert, U. Angew. Chem., Int. Ed. 2009, 48,
4900. (d) Jewett, J. C.; Bertozzi, C. R. Chem. Soc. Rev. 2010, 39, 1272.
(e) Debets, M. F.; van der Doelen, C. W. J.; Rutjes, F. P. J. T.; van
Delft, F. L. ChemBioChem 2010, 11, 1168. (f) Sletten, E. M.; Bertozzi,
C. R. Acc. Chem. Res. 2011, 44, 666. (g) Best, M. D.; Rowland, M. M.;
Bostic, H. E. Acc. Chem. Res. 2011, 44, 686. (h) Debets, M. F.; van
C
dx.doi.org/10.1021/ja3070073 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Berkel, S. S.; Dommerholt, J.; Dirks, A. J.; Rutjes, F. P. J. T.; van Delft,
F. L. Acc. Chem. Res. 2011, 44, 805.
(22) Frisch, M. J.; et al. Gaussian09, Revision C.01; Gaussian, Inc.:
Wallingford, CT, 2010.
(23) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(24) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(25) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257.
(26) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
(27) Schoenebeck, F.; Ess, D. H.; Jones, G. O.; Houk, K. N. J. Am.
Chem. Soc. 2009, 131, 8121.
(28) (a) Gordon, C. G.; Mackey, J. L.; Jewett, J. C.; Sletten, E. M.;
Houk, K. N.; Bertozzi, C. R. J. Am. Chem. Soc. 2012, 134, 9199.
(b) Ess, D. H.; Jones, G. O.; Houk, K. N. Org. Lett. 2008, 10, 1633.
(29) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R.
A.; Ferringa, B. L. Org. Biomol. Chem. 2008, 6, 3461.
(30) Xu, H.; Regino, C. A. S.; Koyama, Y.; Hama, Y.; Gunn, A. J.;
Bernardo, M.; Kobayashi, H.; Choyke, P. L.; Brechbiel, M. W.
Bioconjugate Chem. 2007, 18, 1474.
(7) (a) Prescher, J. A.; Bertozzi, C. R. Cell 2006, 126, 851. (b) Chang,
P. V.; Prescher, J. A.; Hangauer, M. J.; Bertozzi, C. R. J. Am. Chem. Soc.
2007, 129, 8400. (c) Baskin, J. M.; Prescher, J. A.; Laughlin, S. T.;
Agard, N. J.; Chang, P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi,
C. R. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 16793. (d) Laughlin, S. T.;
Baskin, J. M.; Amacher, S. L.; Bertozzi, C. R. Science 2008, 320, 664.
(e) Ning, X.; Guo, J.; Wolfert, M. A.; Boons, G.-J. Angew. Chem., Int.
Ed. 2008, 47, 2253. (f) Chang, P. V.; Prescher, J. A.; Sletten, E. M.;
Baskin, J. M.; Miller, I. A.; Agard, N. J.; Lo, A.; Bertozzi, C. R. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 1821. (g) Baskin, J. M.; Dehnert, K.
W.; Laughlin, S. T.; Amacher, S. L.; Bertozzi, C. R. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 10360. (h) Dehnert, K. W.; Beahm, B. J.; Huynh, T.
T.; Baskin, J. M.; Laughlin, S. T.; Wang, W.; Wu, P.; Amacher, S. L.;
Bertozzi, C. R. ACS Chem. Biol. 2011, 6, 547.
(8) (a) Link, A. J.; Vink, M. K. S.; Agard, N. J.; Prescher, J. A.;
Bertozzi, C. R.; Tirrell, D. A. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
10180. (b) Tanrikulu, I. C.; Schmitt, E.; Mechulam, Y.; Goddard, W.
A., III; Tirrell, D. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 15285.
(c) Uttamapinant, C.; White, K. A.; Baruah, H.; Thompson, S.;
́ ́
Fernandez-Suarez, M.; Puthenveetil, S.; Ting, A. Y. Proc. Natl. Acad.
Sci. U.S.A. 2010, 107, 10914. (d) Plass, T.; Milles, S.; Koehler, C.;
Schultz, C.; Lemke, E. A. Angew. Chem., Int. Ed. 2011, 50, 3878.
(e) Yao, J. Z.; Uttamapinant, C.; Poloukhtine, A. A.; Baskin, J. M.;
Codelli, J. A.; Sletten, E. M.; Bertozzi, C. R.; Popik, V. V.; Ting, A. Y. J.
Am. Chem. Soc. 2012, 134, 3720.
́ ́ ́
(9) (a) Fernandez-Suarez, M.; Baruah, H.; Martínez-Hernandez, L.;
Xie, K. T.; Baskin, J. M.; Bertozzi, C. R.; Ting, A. Y. Nat. Biotechnol.
2007, 25, 1483. (b) Neef, A. B.; Schultz, C. Angew. Chem., Int. Ed.
2009, 48, 1498. (c) Bostic, H. E.; Smith, M. D.; Poloukhtine, A. A.;
Popik, V. V.; Best, M. D. Chem. Commun. 2012, 48, 1431.
(10) Marks, I. S.; Kang, J. S.; Jones, B. T.; Landmark, K. J.; Cleland,
A. J.; Taton, T. A. Bioconjugate Chem. 2011, 22, 1259.
(11) (a) Gutsmiedl, K.; Wirges, C. T.; Ehmke, V.; Carell, T. Org. Lett.
2009, 11, 2405. (b) Jayaprakash, K. N.; Peng, C. G.; Butler, D.;
Varghese, J. P.; Maier, M. A.; Rajeev, K. G.; Manoharan, M. Org. Lett.
2010, 12, 5410. (c) Sharma, A. K.; Heemstra, J. M. J. Am. Chem. Soc.
2011, 133, 12426. (d) Singh, I.; Heaney, F. Chem. Commun. 2011, 47,
2706. (e) Shelbourne, M.; Chen, X.; Brown, T.; El-Sagheer, A. H.
Chem. Commun. 2011, 47, 6257.
(12) Debets, M. F.; van Berkel, S. S.; Schoffelen, S.; Rutjes, F. P. J. T.;
van Hest, J. C. M.; van Delft, F. L. Chem. Commun. 2010, 46, 97.
(13) Wilson, J. T.; Krishnamurthy, V. R.; Cui, W.; Qu, Z.; Chaikof, E.
L. J. Am. Chem. Soc. 2009, 131, 18228.
(14) (a) Ornelas, C.; Broichhagen, J.; Weck, M. J. Am. Chem. Soc.
2010, 132, 3923. (b) Ledin, P. A.; Friscourt, F.; Guo, J.; Boons, G.-J.
Chem. Eur. J. 2011, 17, 839. (c) Huang, B.; Desai, A.; Zong, H.; Tang,
S.; Leroueil, P.; Baker, J. R., Jr. Tetrahedron Lett. 2011, 52, 1411.
(15) Canalle, L. A.; van Berkel, S. S.; de Haan, L. T.; van Hest, J. C.
M. Adv. Funct. Mater. 2009, 19, 3464.
(16) (a) Lallana, E.; Fernandez-Megia, E.; Riguera, R. J. Am. Chem.
Soc. 2009, 131, 5748. (b) Jølck, R. I.; Sun, H.; Berg, R. H.; Andresen,
T. L. Chem. Eur. J. 2011, 17, 3326.
(17) Henriksson, A.; Friedbacher, G.; Hoffmann, H. Langmuir 2011,
27, 7345.
(18) (a) DeForest, C. A.; Polizzotti, B. D.; Anseth, K. S. Nat. Mater.
2009, 8, 659. (b) DeForest, C. A.; Sims, E. A.; Anseth, K. S. Chem.
Mater. 2010, 22, 4783. (c) Orski, S. V.; Poloukhtine, A. A.; Arumugam,
S.; Mao, L.; Popik, V. V.; Locklin, J. J. Am. Chem. Soc. 2010, 132,
11024.
(19) (a) Johnson, J. A.; Baskin, J. M.; Bertozzi, C. R.; Koberstein, J.
T.; Turro, N. J. Chem. Commun. 2008, 3064. (b) Xu, J.; Filion, T. M.;
Prifti, F.; Song, J. Chem. Asian J. 2011, 6, 2730.
(20) Agard, N. J.; Baskin, J. M.; Prescher, J. A.; Lo, A.; Bertozzi, C. R.
ACS Chem. Biol. 2006, 10, 644.
(21) Pollock, J. B.; Cook, T. R.; Stang, P. J. J. Am. Chem. Soc. 2012,
134, 10607.
D
dx.doi.org/10.1021/ja3070073 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX