Post-assembly modification of tetrazine-edged FeII4L6 tetrahedra

Article abstract of DOI:10.1021/jacs.5b05080

Post-assembly modification (PAM) is a powerful tool for the modular functionalization of self-assembled structures. We report a new family of tetrazine-edged Fe^II₄L₆ tetrahedral cages, prepared using different aniline subc

Full text of DOI:10.1021/jacs.5b05080

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Post-Assembly Modification of Tetrazine-Edged FeII L Tetra-
4 6
hedra
Derrick A. Roberts,‡ Ben S. Pilgrim,‡ Jonathan D. Cooper, Tanya K. Ronson, Salvatore Zarra, Jonathan R. Nitschke†
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Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
Supporting Information Placeholder
spread use as a synthetic bioconjugation reaction10
ABSTRACT: Post-assembly modification (PAM) is a
powerful tool for the modular functionalization of
and, more recently, for covalently modifying poly-
mers11 and metal-organic frameworks.12
self-assembled structures. We report a new family of
tetrazine-edged FeII L6 tetrahedral cages, prepared
4
The IEDDA reaction between a 3,6-disubstituted
1,2,4,5-tetrazine and an electron-rich dienophile is
an ideal reaction for PAM of a metallosupramolecu-
lar complex: it is efficient, produces N2 as an inert
by-product, does not interfere with metal–ligand
coordination, and is compatible with a range of
dienophiles.9 Conveniently, the D2h symmetry of the
tetrazine ring allows it to be incorporated in place of
the 1,4-disubstituted benzene moiety present in
many existing supramolecular complexes.13 We
therefore envisaged that IEDDA reactions could be
adapted to a range of existing supramolecular archi-
tectures, thus offering a general approach for the
rapid and facile functionalization of supramolecular
complexes through PAM.
using different aniline subcomponents, which un-
dergo rapid and efficient PAM by inverse electron-
demand Diels-Alder (IEDDA) reactions. Remarka-
bly, the electron-donating or -withdrawing ability of
the para-substituent on the aniline moiety influ-
ences the IEDDA reactivity of the tetrazine ring 11
bonds away. This effect manifests as a linear free
energy relationship, quantified using the Hammett
equation, between σpara and the rate of the IEDDA
reaction. The rate of PAM can thus be adjusted by
varying the aniline subcomponent.
Covalent post-assembly modification (PAM) has
recently developed into a useful tool for expanding
chemical functionality in supramolecular architec-
tures. To be most useful, a PAM reaction must pro-
ceed quantitatively under mild conditions as it is
often not possible to purify supramolecular mixtures
(e.g., by chromatography). Furthermore, the weaker,
dynamic linkages that hold together many metallo-
supramolecular complexes1 can be incompatible
with the aggressive reagents associated with the
formation of strong bonds under kinetic control.2
Consequently, only a limited number of reactions
have been successfully employed for supramolecular
PAM, including olefin metathesis,3 Williamson ether
synthesis,4 alkyne–azide cycloaddition,5 acylation
(acid anhydrides6 and active esters2b), imine reduc-
tion,7 Diels-Alder,8 and nucleophile-isocyanate cou-
pling.2c,8 The tetrazine-based inverse electron-
demand Diels-Alder (IEDDA) reaction also satisfies
the requirements of efficiency and mildness neces-
sary for successful PAM.9 This reaction has not yet,
however, been harnessed for PAM of a discrete su-
pramolecular complex although it has found wide-
Here we present a family of self-assembled met-
al-organic FeII L6 tetrahedral cages that contain te-
4
trazine moieties. These tetrazines react efficiently by
IEDDA with alkyne or alkyne-equivalent9b dieno-
philes. The design of dialdehyde subcomponent A,
based on an existing structural analog,14 integrates
tetrazine rings into the framework of the cage.
Strong electronic coupling is thus engendered be-
tween the aniline residues incorporated into the pe-
riphery and the tetrazine cores. This coupling mani-
fests through a linear free energy relationship
(LFER) between the IEDDA rate constant and the
Hammett parameter of the aniline para-substituent
(σpara). We thus demonstrate that the tetrazine moi-
ety can serve dual roles of being both a structural
element of the supramolecular architecture and a
useful reactive handle for introducing new chemical
functionality.
Subcomponent A was synthesized from commer-
cially available 5-bromo-2-iodopyridine efficiently in
five steps (Scheme 1; see SI, Section S3 for details).
Cage 1a was then prepared by subcomponent self-
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assembly15 of A with 4-fluoroaniline and iron(II)
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bis(trifluoromethane)sulfonimide (Fe(NTf2)2). ESI-
MS confirmed the formation of an FeII L6 complex in
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solution (SI, Section S4), and NMR spectra were
consistent with the expected tetrahedral symmetry
(Figure 1b). Single-crystal X-ray diffraction analysis
(Figure 2a) confirmed the tetrahedral structure of 1a
in the solid state.
9
We tested the reactivity of cage 1a towards nor-
bornadiene (NBD) as a model IEDDA reaction.
NBD, upon reacting with a tetrazine and after retro-
Diels-Alder elimination of dinitrogen (Figure 1a, I
and II), gives a dihydropyridazine intermediate that
spontaneously rearomatizes via a second retro-
Diels-Alder reaction to expel a molecule of cyclo-
pentadiene.9b The reaction between 1a and NBD (2
equiv. per tetrazine) in CD3CN resulted in the clean
formation of pyridazine-paneled 2a within 4 h at
50 °C, as verified by NMR and ESI-MS analyses (SI,
Section S5), together with a stoichiometric quantity
of cyclopentadiene (Figure 1). By UV-Vis spectros-
copy, we found that the reaction kinetics were first-
order in tetrazine (SI, Section S7), indicating that
the six tetrazine sites on a given cage react non-
cooperatively. It is therefore remarkable that the
conversion of 1a to 2a occurs cleanly and without
degradation of the assembled complex.
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i
aConditions: (i) PrMgCl, DMF, THF, −15 °C, 99%; (ii)
ethylene glycol, pTsOH, toluene, reflux, 99%; (iii)
K4Fe(CN)6, PdCl2, Na2CO3, DMA, 120 °C, 86%; (iv)
NH2NH2, S8, EtOH, reflux, then
tBuONO,
CHCl3/EtOH, rt, 65%; (v) THF/HCl(aq), 60 °C, 45%; (vi)
Fe(NTf2)2 5H2O, CH3CN, 60 °C, 5 h; (vii) CH3CN, 50 °C,
4 h; (viii) CDCl3, rt, 30 min.
Scheme 1. Synthesis of subcomponent A, self-
assembly of tetrazine-edged cages 1a-1i, and
subsequent post-assembly modification by
IEDDA.a
During the course of PAM, desymmetrization of
the cage signals was observed (Figure 1c); however,
persistence of the signals from protons He and Hf
and the absence of signals of the free subcompo-
nents suggested that the ligands do not dissociate
from the cage during the IEDDA reaction sequence.
Crossover experiments using a mixture of two te-
trazine-edged cages (1a and 1f) revealed that the
rate of ligand dissociation is much slower than the
IEDDA reaction (SI, Figures S25–S27). We therefore
conclude that the IEDDA reactions occur on the
intact cage rather than as part of a dissociation–
IEDDA–reassociation sequence. Although IEDDA
reactions are known to proceed through distorted
transitory bicyclic intermediates (structures I and II,
Figure 1), the distortion is in a direction that is
mostly perpendicular to the long-axis of the ligand
in 1a (SI, Figure S28), thus preventing strain-
induced disassembly of the cage.
In order to probe the both the solvent and sub-
strate scopes of post-assembly modification, we pre-
pared chloroform-soluble decylaniline-substituted
cage 1i, and investigated the IEDDA reaction using
commercially-available (1R,8S,9s)-bicyclo[6.1.0]non-
4-yn-9-ylmethanol (BCNM) as an alternative dieno-
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phile. The strained cycloalkyne of BCNM is reported
constants (σpara) between –0.37 (-OH) and +0.06 (-F)
(SI section S5).19 The reaction of NBD with each cage
was chosen as a model system for analyzing the ki-
netics of IEDDA due to its moderate rate, clean con-
version, and the high symmetry of the resulting
product cages (2a–2h), which enabled facile charac-
terization. NMR and mass spectra were consistent
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to react cleanly with tetrazines to give ring-fused
pyridazines, and its –OH group is a useful point of
attachment for other functional groups.16 As shown
in Scheme 1, cage 1i was observed to react with
BCNM in CDCl3 at 25 °C, yielding hexafunctional-
ised cage 3 as the major product of the reaction (SI,
Section S6).
with the formation of pyridazine-containing FeII L6
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cages 2a–2h (SI, Section S5), and X-ray diffraction
confirmed the tetrahedral structure of product cage
2e (Figure 2b).
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Figure 2. Depictions of the X-ray crystal structures of
(a) tetrazine-edged cage 1a, and (b) pyridazine-edged
cage 2e. Key: yellow = fluorine, orange = iron, blue =
nitrogen. Disorder and anions have been omitted for
clarity
Pseudo-first-order rate constants (kobs) for the re-
actions of cages 1a-1h with excess NBD (450 equiv.)
were determined by measuring the decrease in the
MLCT absorption band of the tetrazine cages over
the 2 h following the addition of NBD. We could not
monitor the reaction directly using the weaker te-
trazine n→π* band (λlit. = 510–530 nm, εlit. = 1000 M-
1 cm-1)20 as it overlapped substantially with the more
intense MLCT absorptions (450–650 nm). However,
we observed the intensity of the MLCT band of each
tetrazine cage (λmax ~ 630 nm) to decrease monoex-
ponentially during the IEDDA reaction, consistent
with the pseudo-first-order kinetics expected for the
consumption of tetrazine.21 This observation sug-
gests that the IEDDA reaction of a tetrazine moiety
directly influences the electronics of the adjacent
tris(2-pyridylimine)iron(II) chromophore. Conse-
quently, we were able to use the MLCT bands of
cages 1a–1h as spectroscopic probes for the IEDDA
reaction (see SI, Section S7 for details of kinetics
analyses).
Figure 1. In situ 1H NMR monitoring of the reaction (a)
between cage 1a (6.90 × 10−4 M) and NBD (2 equiv per
1
tetrazine) to give cage 2a. (b) H NMR spectrum of 1a.
1
(c) H NMR spectrum of the reaction mixture at 1 h.
Green circles denote NBD signals; purple triangles de-
note cyclopentadiene signals. (d) 1H NMR spectrum of
the reaction mixture at 4 h, revealing clean formation
of cage 2a and cyclopentadiene. (e) 1H DOSY spectrum
of the reaction mixture after 4 h. Units of D are cm s-1.
1
The H NMR spectrum of 3 was broad, which we
attribute to the presence of a mixture of low-
symmetry diastereomers that arise from the random
relative orientations of BCNM stereocenters within
each cage. Variable temperature NMR studies were
also consistent with a mixture of configurationally
complex diastereomers (SI, Section S6). Despite the
complexity, features characteristic of 3 were identi-
1
fied in H and DOSY NMR spectra (SI, Figure S39),
and HRMS confirmed its formation (SI, Section S41–
S44). PAM with BCNM thus serves as a novel means
of breaking cage symmetry,17 where stereochemical
complexity could influence cage function.13d,18
Measuring kobs values for the set of IEDDA reac-
tions shown in Figure 3a revealed that these reac-
tions follow the Hammett equation, whereby
log10(kobs) increased linearly with σpara: more elec-
tron-withdrawing substituents gave faster rates
(Figure 3b). Weaker correlations were observed be-
Cages 1a-1h were used to elucidate the influence
of the aniline para-substituent on the rate of the
IEDDA reaction. These cages were prepared from
anilines bearing para-substituents with Hammett
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1062283). This material is available free of charge via
the Internet at http://pubs.acs.org.
tween log10(kobs) and the Hammett resonance effect
parameters (σ+ or σ−),19 which is consistent with the
absence of significant charge build-up at any center
during the reaction (Figure S58).9a The positive
Hammett reaction constant (ρ = +0.47) is consistent
with a decrease in the tetrazine LUMO energy as the
electron-withdrawing power of the substituent in-
creases. Remarkably, the magnitude of ρ is compa-
rable to values measured for IEDDA reactions in
non-supramolecular systems in which the substitu-
ent is much closer to the reaction site (5 bonds22 vs.
11 bonds in the present case). We attribute this sen-
sitivity to the unimpeded conjugation pathway be-
tween the aniline para-substituent and the tetrazine
ring—an effect also reflected in the influence of the
tetrazine moiety over MLCT absorption, as noted
above.
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AUTHOR INFORMATION
Corresponding Author
†E-mail: jrn34@cam.ac.uk
Author Contributions
‡D.A.R. and B.S.P. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the UK Engineering and
Physical Sciences Research Council (EPSRC). The au-
thors thank Diamond Light Source (UK) for synchro-
tron beamtime on I19 (MT8464), the Department of
Chemistry NMR facility, University of Cambridge, and
the EPSRC UK National Mass Spectrometry Facility at
Swansea University. D.A.R. acknowledges the Gates
Cambridge Trust for Ph.D. funding. B.S.P. acknowl-
edges the Herchel Smith Research Fellowship from the
University of Cambridge and the Fellowship from Cor-
pus Christi College, Cambridge.
REFERENCES
1. (a) Corbett, P. T., Leclaire, J., Vial, L., West, K. R., Wietor, J.-L.,
Sanders, J. K. M., Otto, S., Chem. Rev., 2006, 106, 3652-3711; (b)
Sarma, R. J., Nitschke, J. R., Angew. Chem., Int. Ed., 2008, 47, 377-380;
(c) Belowich, M. E., Stoddart, J. F., Chem. Soc. Rev., 2012, 41, 2003-
2024.
2. (a) Ma, Z., Han, S., Hopson, R., Wei, Y., Moulton, B., Inorg.
Chim. Acta, 2012, 388, 135-139; (b) Roberts, D. A., Castilla, A. M.,
Ronson, T. K., Nitschke, J. R., J. Am. Chem. Soc., 2014, 136, 8201-8204;
(c) Young, M. C., Johnson, A. M., Hooley, R. J., Chem. Commun.,
2014, 50, 1378-1380.
3. (a) Fuller, A.-M., Leigh, D. A., Lusby, P. J., Oswald, I. D. H.,
Parsons, S., Walker, D. B., Angew. Chem., Int. Ed., 2004, 43, 3914-
3918; (b) Kaucher, M. S., Harrell, W. A., Davis, J. T., J. Am. Chem.
Soc., 2005, 128, 38-39; (c) Fuller, A.-M. L., Leigh, D. A., Lusby, P. J.,
Slawin, A. M. Z., Walker, D. B., J. Am. Chem. Soc., 2005, 127, 12612-
12619; (d) Leigh, D. A., Lusby, P. J., McBurney, R. T., Morelli, A.,
Slawin, A. M. Z., Thomson, A. R., Walker, D. B., J. Am. Chem. Soc.,
2009, 131, 3762-3771.
Figure 3. Plot of log10(kobs) against σpara. Aniline para-
substituents are labeled in the diagram.
Chemical self-assembly has proven capable of
generating architectures of great structural23 and
functional24 complexity. The development of new
methods to cleanly modify and transform these as-
semblies can expand the amount of chemical space
accessible,25 as each new reactive motif (tetrazene,
in this study) may be incorporated into many previ-
ously reported structure types. Attractive features of
our method are its clean “click” nature,26 the ability
to incorporate new functionality via BCNM, and the
ability to adjust reaction rates through modular var-
iation of the aniline subcomponent. Future work
will seek to adapt this IEDDA methodology to other
supramolecular architectures in order to modulate
phenomena such as guest binding, reactivity and
structural transformations.
4. Schneider, M. W., Oppel, I. M., Griffin, A., Mastalerz, M., Angew.
Chem., Int. Ed., 2013, 52, 3611-3615.
5. (a) Chakrabarty, R., Stang, P. J., J. Am. Chem. Soc., 2012, 134,
14738-14741; (b) Barran, P. E., Cole, H. L., Goldup, S. M., Leigh, D. A.,
McGonigal, P. R., Symes, M. D., Wu, J., Zengerle, M., Angew. Chem.,
Int. Ed., 2011, 50, 12280-12284; (c) Han, S., Ma, Z., Hopson, R., Wei,
Y., Budil, D., Gulla, S., Moulton, B., Inorg. Chem. Commun., 2012, 15,
78-83; (d) Zhao, D., Tan, S., Yuan, D., Lu, W., Rezenom, Y. H., Jiang,
H., Wang, L.-Q., Zhou, H.-C., Adv. Mater., 2011, 23, 90-93.
6. Brega, V., Zeller, M., He, Y., Peter Lu, H., Klosterman, J. K.,
Chem. Commun., 2015, 51, 5077-5080.
7. (a) Mosquera, J., Zarra, S., Nitschke, J. R., Angew. Chem., Int. Ed.,
2014, 53, 1556-1559; (b) Acharyya, K., Mukherjee, P. S., Chem. Eur. J.,
2015, 21, 6823-6831.
8. Wang, M., Lan, W.-J., Zheng, Y.-R., Cook, T. R., White, H. S.,
Stang, P. J., J. Am. Chem. Soc., 2011, 133, 10752-10755.
ASSOCIATED CONTENT
Supporting Information. Synthetic details, charac-
terization data, NMR and mass spectra, kinetics anal-
yses, X-ray crystallography data. Crystallographic data
are deposited with the CCDC (numbers 1062282-
9. (a) Knall, A.-C., Slugovc, C., Chem. Soc. Rev., 2013, 42, 5131-5142;
(b) Foster, R. A. A., Willis, M. C., Chem. Soc. Rev., 2013, 42, 63-76.
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