Covalent Post-assembly Modification Triggers Multiple Structural Transformations of a Tetrazine-Edged Fe4L6 Tetrahedron

Article abstract of DOI:10.1021/jacs.8b05082

Covalent post-assembly modification (PAM) reactions are useful synthetic tools for functionalizing and stabilizing self-assembled metal-organic complexes. Recently, PAM reactions have also been explored as stimuli for triggering supramolecular structural transformations. Herein we demonstrate the use of inverse electron-demand Diels-Alder (IEDDA) PAM reactions to induce supramolecular structural transformations starting from a tetrazine-edged Fe^II₄L₆ tetrahedral precursor. Following PAM, this tetrahedron rearranged to form three different architectures depending on the addition of other stimuli: an electron-rich aniline or a templating anion. By tracing the stimulus-response relationships within the system, we deciphered a network of transformations that mapped different combinations of stimuli onto specific transformation products. Given the many functions being developed for self-assembled three-dimensional architectures, this newly established ability to control the interconversion between structures using combinations of different stimulus types may serve as the basis for switching the functions expressed within a system.

Full text of DOI:10.1021/jacs.8b05082

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Article
Covalent post-assembly modification triggers multiple
II4
6
structural transformations of a tetrazine-edged FeL tetrahedron
Derrick A. Roberts, Ben S. Pilgrim, Giedre Sirvinskaite, Tanya K Ronson, and Jonathan R. Nitschke
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05082 • Publication Date (Web): 08 Jul 2018
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Covalent post-assembly modification triggers multiple structural
transformations of a tetrazine-edged Fe tetrahedron
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‡
‡
Derrick A. Roberts , Ben S. Pilgrim , Giedre Sirvinskaite, Tanya K. Ronson, and Jonathan R. Nitschke*
Department of Chemistry, University of Cambridge, Lensfield Road CB2 1EW Cambridge, UK
ABSTRACT: Covalent post-assembly modification (PAM) reactions are useful synthetic tools for functionalizing and stabilizing self-assem-
bled metal-organic complexes. Recently, PAM reactions have also been explored as stimuli for triggering supramolecular structural transfor-
mations. Herein we demonstrate the use of inverse electron-demand Diels-Alder (IEDDA) PAM reactions to induce supramolecular structural
II
transformations starting from a tetrazine-edged Fe
4
6
L tetrahedral precursor. Following PAM, this tetrahedron rearranged to form three differ-
ent architectures depending on the addition of other stimuli – an electron-rich aniline or a templating anion. By tracing the stimulus-response
relationships within the system, we deciphered a network of transformations that mapped different combinations of stimuli onto specific trans-
formation products. Given the many functions being developed for self-assembled three-dimensional architectures, this newly-established abil-
ity to control the interconversion between structures using combinations of different stimulus types may serve as the basis for switching the
functions expressed within a system.
In this study, we develop inverse electron-demand Diels-Alder
INTRODUCTION
The functions of many proteins are regulated through well-de-
fined structural transformations in response to signals. These trans-
(
IEDDA) PAM reactions to trigger the rearrangement of self-assem-
II
bled metallocomplexes. Tetrazine-edged Fe L tetrahedron 1a
4
6
1
(Figure 1) is the point of departure for all the transformations de-
formations range from local conformational changes to whole-pro-
tein reorganization. A diverse array of biological phenomena are thus
enabled, including gas binding, catalysis, vision, and intracellular
scribed herein. It was designed to react efficiently with alkyne dieno-
philes to afford the corresponding pyridazine-edged tetrahedron.
Our investigations into the reactivity of 1a towards cyclooctyne in
1
8
2
transport. Many stimuli can trigger these transformations, including
CH CN revealed a sequence of structural rearrangements that led to
3
light absorption, guest binding, and covalent post-translational mod-
ifications. Efforts to synthetically emulate biological structural trans-
formations have led to insights into the mechanisms of these natural
processes, while also informing the designs of artificial stimuli-re-
the formation of three different cyclooctylpyridazine-edged archi-
II
II
II
tectures: Fe L tetrahedron 2, Fe L helicate 3, and Fe L twisted-
4
6
2
3
8
12
square-prism 4 (Figure 1). Additional stimuli, 4-methoxyaniline and
−
PF
semble in different ways via orthogonal subcomponent exchange
SE) and anion templation (AT) pathways, respectively. Detailed
6
, were observed to induce structures within the network to reas-
3
sponsive molecules and materials. Consequently, supramolecular
structural transformations have been used to construct novel switch-
(
4
5
able catalysts, guest capture-and-release systems, responsive soft
analysis of the individual stimulus-response relationships enabled us
to decipher how each combination of stimuli drives the system to a
different major transformation product. Using this information, we
constructed a hierarchical network that maps each architecture onto
the stimuli that led to its formation (Figure 1). Thus, different archi-
tectures within the system could be induced to interconvert by com-
bining covalent PAM with SE and AT co-stimuli in a sequence-de-
pendent manner.
6
7
materials, and molecular mechanical actuators.
Various stimuli have been used to control supramolecular struc-
8
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tural transformations, including guest binding, ligand and metal
1
1
substitution, photo-isomerization reactions, and environmental
changes (e.g., pH, temperature, and concentration). There are,
however, few reports that use ligand-centered covalent post-assem-
1
2
1
3
bly modification (PAM) reactions to drive supramolecular trans-
1
4
formations. One reason for the uncommon use of PAM in this con-
text may be the narrow range of covalent reactions that cleanly func-
tionalize metallosupramolecular structures without compromising
their stabilities. Recently, however, new PAM strategies have pro-
vided mild and modular ways to covalently derivatize and stabi-
lize self-assembled complexes, and to generate complex molecular
topologies. These new PAM protocols can alter the electronic and
steric parameters of self-assembled complexes. Such alterations may
induce, in turn, well-defined structural transformations.
RESULTS AND DISCUSSION
Covalent PAM gates structural transformations. In the trans-
formation network of Figure 1, covalent PAM is the primary stimu-
lus that activates tetrazine-edged 1a towards subsequent structural
rearrangements. Control experiments revealed that neither SE nor
AT could drive transformation of 1a in the absence of PAM (see
Supporting Information (SI), Section S5 for details). Thus, covalent
PAM is the gateway stimulus for the network, producing a critical
change in the ligand framework of tetrahedron 1 that renders it sus-
ceptible to structural rearrangements.
1
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Figure 1. Stimulus-response map depicting the major products expressed by the system following the addition of different stimulus combinations.
1
Covalent PAM of 1a was studied by in situ H NMR spectros-
After several hours at room temperature, helicate 3a partially re-
copy. Treating 1a with cyclooctyne in CD
3
CN at 293 K resulted in
verted to tetrahedron 2a, indicating a dynamic equilibrium between
these complexes, 3a + 3a ⇌ꢀ2a, with an equilibrium constant (K):
the rapid (<20 min) formation of cyclooctylpyridazine-edged tetra-
1
hedron 2a. The H NMR spectrum of 2a confirmed its T-symmetric
[
ꢂꢃ]
tetrahedral configuration, and DOSY NMR indicated a slightly
larger hydrodynamic radius than 1a (Figure 2d). Further NMR anal-
ysis revealed that 2a was metastable, however, undergoing rear-
rangement into a new species over 1-2 h at room temperature. Heat-
ing 2a to 333 K for 2 h drove this rearrangement to completion, af-
fording a single species, 3a, with a smaller DOSY hydrodynamic ra-
ꢁ =
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ(1)
[
ꢄꢃ]ꢅ
Similar helicate–tetrahedron equilibria have been observed in
2
0
other bis-bidentate ligand systems, including geometrically
2
1
1
strained 2-iminopyridine chelates. Variable temperature H NMR
experiments allowed us to measure the temperature dependence of
K between 293 K and 333 K (Figure 3a); below 293 K, the rate of
equilibration was too slow to permit analysis (SI, Figure S25). Pro-
vided that the standard enthalpy and entropy changes of intercon-
version reaction are constant over this temperature range, Van ’t
Hoff analysis of these data (Figure 3b) gave:
dius than either 1a or 2a. High-resolution ion mobility/ESI mass
spectrometry (IM-MS) analysis revealed 3a to have an Fe
II
2
3
L stoi-
chiometry consistent with a dinuclear triple helicate structure (SI,
Section S6). MM2 molecular mechanics modeling of 3a in both chi-
ral (with both metal centers having the same configuration) and
achiral/meso (with metal centers having opposing configurations)
variants predicted strained structures requiring significant bending
of the ligands bridging the iron(II) ions (SI, Figure S23).
∆ꢆ⦵ = − 54 ± 2 ꢀꢇꢈꢀꢉꢊꢋꢌꢍꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
∆ꢎ⦵ = − 134 ± 5 ꢀꢈꢀꢁꢌꢍꢀꢉꢊꢋꢌꢍꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
The relief of ligand strain when converting from helicate to tet-
rahedron is thus enthalpically favorable, while the loss of transla-
tional freedom due to fusion of two smaller complexes into a single
larger one is entropically costly.
The strained geometry of helicate 3a was reflected in its
H NMR spectrum: signals corresponding to H and H were broad
and shifted downfield (Figure 2c) compared to analogous protons
in tetrahedra 1a and 2a (Figure 2a, b). VT-NMR analysis of 3a in
1
1
4
To assess which complex the system preferentially expresses at
equilibrium, we defined µsys,F as the proportion of building blocks
present in the helicate and tetrahedron populations:
CD CN revealed that a proportion of the iron(II) centers undergo a
3
transition to a high spin state as the temperature of the solution in-
creased from 243 K to 333 K (SI, Figure S24). This incipient spin-
crossover behavior is consistent with the strained geometry of the
2
[ꢂꢃ]
ꢏꢐꢑꢐ,ꢒ
=
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ(2)
1
9
helicate. We hypothesize that the N→Fe bonds elongate progres-
sively at higher temperatures to relieve ligand strain. This effect
weakens the iron(II) ligand field, leading to a higher proportion of
high-spin metal centers that contribute to the downfield shifts and
[ꢄꢃ]
We have employed µsys,F rather than the canonical thermody-
⦵
namic definition of favorability (i.e., the sign of ∆G ) because, at the
concentrations employed in these experiments ([1a] ≈ 1.5 mM),
over 99.5% of the system’s building blocks must be converted into
1
4
broadening of the H and H signals.
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⦵
helicate 3a before ∆G = 0 and there is a switchover in which side of
the equilibrium is favored (SI, Section S6.5). As this conversion will
happen only above 404 K, which exceeds the boiling point of
to 333 K for 2 h resulted in near-complete conversion to helicate 3b
(Figure 4c).
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CH CN, it is more useful to consider the extent to which the sys-
tem’s building blocks are distributed between helicate and tetrahe-
dron populations.
3
According to Equation 2, more than half of the system’s building
blocks constitute helicates when µsys,Fꢀ <ꢀ 1.ꢀ This threshold was
found at approximately 270 K at the concentrations employed
herein (SI, Section S6.4). Above this temperature, the system is thus
said to preferentially express helicate 3a over tetrahedron 2a.
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Figure 2. (a) The transformations of 1a following treatment with cy-
1
clooctyne were followed by NMR: H spectra of (b) Tetrahedron 1a
(1.5 mM); (c) Tetrahedron 2a (40 min); (d) Helicate 3a after equili-
Figure 3. Analysis of the temperature dependence of the equilibrium
between tetrahedron 2a and helicate 3a. (a) H NMR spectra of a mix-
ture of 2a and 3a at different temperatures, with incipient spin-crossover
behavior evident in 3a and, to a lesser extent, in 2a. (b) Van ’t Hoff anal-
ysis of the equilibrium.
bration at 333 K for 2 h (conversion complete within 20 min). (e) Over-
1
1
laid H DOSY NMR spectra of 1a, 2a and 3a, corresponding to spectra
–
6
2
–1
(
b)–(d). The units of D are 10 cm s .
Combining covalent PAM with subcomponent exchange.
We hypothesized that substitution of the electron-poor 4-fluoroan-
iline residues within tetrahedron 1a by more electron-rich 4-meth-
oxyaniline would increase the strength of the metal-ligand bonds
and thus influence the supramolecular product distribution follow-
ing PAM-induced rearrangement. The reaction of tetrahedron 1a
with 4-methoxyaniline furnished tetrahedron 1b (SI, Section S7). As
with 1a, 1b reacted with cyclooctyne (1.3 equiv. per tetrazine) in
The stronger N→Fe bonds in the structures containing meth-
oxyaniline residues also influenced the position of the helicate–tet-
rahedron equilibrium. Even after equilibration at 333 K for 2 h, peaks
corresponding to tetrahedron 2b were still visible by NMR (Figure
4
c). By contrast, the fluoroaniline system produced exclusively heli-
cate under similar conditions (Figure 3a). Incorporation of an elec-
tron-rich aniline thus shifted the helicate–tetrahedron equilibrium
in favor of the tetrahedron. This shift was also apparent at lower tem-
peratures, although the slower rate of interconversion precluded
quantitative study. We infer helicate formation to be less favorable
in the methoxyaniline system because the shorter N→Fe bonds
would exacerbate the ligand strain involved in helicate formation.
CD
3
CN at 293 K to form cycloocytylpyridazine-edged tetrahedron
2
b (Figure 4b). Tetrahedron 2b also existed in equilibrium with
II
Fe
2
3
L helicate 3b. However, the rate of interconversion between 2b
and 3b was appreciably slower due to the stronger N→Fe bonds, al-
lowing 2b to persist as the dominant product for several hours at
2
93 K following PAM. This property permitted the analysis of both
complexes by IM–MS, which revealed significantly different drift
times in the gas phase (SI, Section S7). Heating the reaction mixture
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Unexpectedly, SE of the 2a/3a mixture with 4-methoxyaniline Deciphering the effects of three chemical stimuli. The trans-
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at 278 K initially led to disproportionately greater formation of heli-
formation network has so far been shown to respond to PAM and SE
stimuli to express tetrahedral and helicate structures. Targeting
more complex, higher-nuclearity architectures, however, requires
cate 3b than of tetrahedron 2b. A post-PAM initial µsys,F of 2.3 was
1
obtained, as determined by H NMR (SI, Figure S33), indicating
II
that more than twice the number of subcomponents were bound up
in the tetrahedron 2a population than in the helicate 3a population.
The SE reaction of 4-methoxyaniline with this mixture at 278 K pro-
ceeded slowly, requiring 7 days to approach completion. Helicate 3b
was initially observed to predominate over tetrahedron 2b, with an
initial µsys,OMe of the system of only 0.25, marking 3b as the kinetic
product of the transformation.
the Fe centers to adopt lower-symmetry meridional (mer) configu-
rations as opposed to higher-symmetry facial (fac) stereochemistry.
The presence of templating anions was observed to drive such a fac-
to-mer transition in this system, leading to the formation of a larger
complex, twisted square prism 4, containing exclusively mer-config-
II
ured Fe vertices.
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We first observed prism 4 when attempting to crystallize helicate
3a. Single crystals suitable for X-ray diffraction analysis were ob-
tained by the slow diffusion of benzene vapor into an acetonitrile so-
2[ꢂꢖ]
ꢏꢐꢑꢐ,ꢓꢔꢕ
=
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ(3)
[ꢄꢖ]
lution of 2a and 3a containing Bu
surprised when X-ray analysis revealed Fe
complex 4a (Figure 5) rather than the anticipated Fe
4
NPF (50 equiv). We were initially
6
The 2b/3b mixture then underwent slow rearrangement to ex-
press more tetrahedron 2b. This process required 3 weeks to ap-
proach equilibrium at 278 K, however.
II
8
L
12 twisted square prism
II
2
L helicate.
3
Prism 4a consists of two four-sided circular helicate rings con-
taining four metal centers and four equatorial ligands. The two
square rings are bridged by four axial ligands, and are twisted by
2
9 ± 2° with respect to each other (Figure 5b). The average metal-
II
to-metal distances both within and between the Fe
4
L rings are very
4
similar (11.7 ± 0.3 Å). All metal centers possess the same ∆ or Λ ste-
reochemistry within a given complex, lending the structure idealized
D point symmetry. Both enantiomers of 4a were present in the crys-
4
tal. The angles between the pyridine−pyridazine−pyridine ring cen-
troids were 161−173° and the dihedral angles between the pyridine
and pyridazine rings were 41−63°, indicating the presence of bend-
ing and twisting away from a linear and coplanar orientation.
Figure 4. (a) Transformations of 1b following treatment with cy-
1
clooctyne were followed by NMR: H spectra of (b) Tetrahedron 1b
(
1.5 mM); (c) Tetrahedron 2b, recorded 2 h after addition of cy-
clooctyne; (d) Helicate 3b, recorded after equilibration at 333 K for 2 h.
These results suggest that SE proceeds more rapidly for helicate
a than for tetrahedron 2a. We infer the principal route of SE thus
3
to consist of conversion of helicate 3a into helicate 3b. Equilibration
between 2a and 3a then regenerates more 3a, leading to further
amine substitution via the helicate rather than the tetrahedron. Once
formed, the stronger N→Fe bonds in helicate 3b stall its conversion
into 2b at lower temperatures, allowing it to build up as an interme-
diate at 278 K.
–⊂4a.
Figure 5. Representations of the X-ray crystal structure of PF
6
Hydrogen atoms, disorder, solvent molecules and non-encapsulated
counterions are omitted for clarity. (a) 4a shown with its Fe framework
highlighted in orange. (Key: gray = carbon, blue = nitrogen, orange =
iron, green = fluorine). (b) Schematic structure of 4a illustrating average
II
The higher rate of helicate amine substitution can be under-
stood in terms of the longer and weaker N→Fe bonds in the strained
helicate structure, enabling faster SE than in the less-strained tetra-
hedron. These observations agree with recent findings by Hooley
and co-workers, which demonstrated how ligand strain can drasti-
cally influence amine substitution rates—and, thus, supramolecular
Fe–Fe distances and the twist angle between the square faces of the
–
prism. (c) Side view of 4a highlighting the positions of bound PF
6
ions.
Equatorial and axial ligands are colored blue and yellow, respectively.
d) View along the C axis of 4a, highlighting counter-ions bound
(
4
–
around the upper and lower rims of the prism. The central PF6 ion is
omitted in (d) to highlight the channel through the complex.
2
2
structural outcomes—in imine-containing metallocomplexes.
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26
Prism 4a encapsulated nine PF
6
anions in the crystal. Eight of
framework, and SE, which increased the strength of the N→Fe
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these are bound within partially-enclosed pockets within the two
circular helicate rings, and the ninth is held within the central
void of the prism. Close contacts between the cyclooctylpyridazine
rings and the PF ions suggested that anion-π interactions contrib-
ute to the stability of the observed host-guest complex.
bonds, were both required to overcome the entropic cost of forming
II
II
Fe
4
L
4
the larger Fe
8
L
12 architecture. Prior studies suggest that more elec-
tron-rich aniline residues produce stronger quadrupolar π-interac-
tions between the aniline and pyridine rings at the mer-verticies, thus
affording additional stabilization to the prism architecture.
–
6
23
27
–
The encapsulation of nine PF
6
anions within 4a in the solid state
led us to infer that the addition of suitable templating anions could
2
4
drive a helicate-to-prism transformation in solution. Treating a
–
–
–
2a/3a mixture with PF
6
,BF
4
orClO led to the appearance of mul-
4
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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9
0
tiple new H NMR signals, suggesting the formation of higher-nucle-
arity structures (SI, Figure S34). These structures might be larger
9
b, 25
prisms of the general formula Fe2x
L
3x (where x ≥ 4).
However,
these transformations were incomplete, yielding intractably compli-
cated mixtures rather than a discrete major product.
−
In the case of BF
4
, we obtained single crystals suitable for crys-
CN solu-
tion of the initial transformation library. X-ray diffraction analysis re-
tallography by slow diffusion of benzene vapor into a CH
3
II
−
vealed the formation of Fe
product, analogous to the PF
8
L
12 prism BF
4
⊂4a as the only observed
−
6
inclusion complex. The binding
−
pockets of BF
mixture of CH
4
⊂4a, however, exhibited partial occupancy with a
−
3
CN and BF
is a poor fit for the binding pockets of 4a compared to PF
The observation that 2a and 3a did not rearrange cleanly into
4
guests (SI, Figure S64), suggesting that
−
−
BF
4
6
.
twisted square prism 4a in solution suggests that AT alone could not
drive this transformation. We infer that in the solid state, crystal
packing provided the stabilization needed to selectively form 4a as
the only observed product. We anticipated that combining AT with
SE using more electron-rich 4-methoxyaniline could provide analo-
gous stabilization in solution by increasing the strengths of the
Figure 6. (a) Equilibration of a mixture of 2b and 3b at 293 K for 48 h
1
gave rise to H NMR spectrum (b) (500 MHz, 298 K, CD
3
CN), which
N→Fe bonds, thereby providing an additional enthalpic driving
transformed into spectrum (c), corresponding to twisted square prism
II
force for the formation of the larger Fe
8
L
12 architecture.
−
4b, upon addition of PF
6
. (d) Overlaid DOSY NMR spectra corre-
Heating a mixture of 2b and 3b with an excess of Bu
4
NPF
6
sponding to spectra (b) and (c), as indicated by the arrows, comparing
–
6
2 –1
(
20 equiv) to 333 K for 16 h gave a single major product, as deter-
the diffusivities of 2b, 3b and 4b. The units of D are 10 cm s .
1
mined by H NMR spectroscopy (Figure 6c). The spectrum of this
species reflected the symmetry of prism 4b, exhibiting three imine
and three methoxy proton environments characteristic of mer-con-
Establishing a stimulus hierarchy via sequential transfor-
mations. In the above discussion, we explored individual steps
within the transformation network to simplify our analysis of the
overall system. It is, however, possible to traverse different paths
within this network by the sequential addition of PAM, SE and AT
stimuli (SI, Section S10). Importantly, carrying out transformations
in sequence allowed us to ascertain the pathway dependence of the
network and thus sort the three stimulus types in order of their abil-
ity to drive discrete transformations within the system.
1
figured metal vertices (SI, Figure S36). H DOSY NMR analysis also
confirmed that this complex diffused at a slower rate than either tet-
rahedron 2b or helicate 3b (Figure 6d). Moreover, we observed ex-
cellent agreement between the calculated effective spherical radii of
the three complexes and their DOSY-determined hydrodynamic ra-
dii (SI, Figure S35). Diffraction-quality single crystals of 4b were ob-
tained by slow vapor diffusion of benzene into an acetonitrile solu-
Control experiments had demonstrated that no structural trans-
formations were possible without first adding cyclooctyne, empha-
sizing the role of PAM as the primary stimulus. We hypothesize that
the bulky cyclooctyl groups introduced through PAM caused the
central ring of the ligands to adopt a non-planar conformation that
promotes formation of the helicate and prism architectures. Ligand
non-planarity, both in the dihedral angles between rings and in the
angles between ring centroids, is noticeable in the crystal structures
of 4a and 4b (SI, Section S11) and the optimized geometries of
MM2 molecular models of helicates 3a and 3b. Conversely, the te-
trazine ligand does not have sufficient steric bulk to favor the ligand
geometries that lead to the helicate and prism.
tion of the complex containing excess Bu
4
NPF (50 equiv). X-ray
6
crystallography established the structure of the square prism in the
–
solid state, which was analogous to PF
6
⊂4a (SI, Figure S68).
Prism 4b was also prepared by combining pre-functionalised cy-
clooctylpyridazine dialdehyde (SI, Section S9), 4-methoxyaniline
and Fe(PF
6
)
2
in CD CN at 333 K for 48 h. Subsequent purification
3
of the reaction mixture by size-exclusion chromatography (SEC) re-
1
moved impurities to give a clean H NMR spectrum of 4b for high-
resolution NMR analysis (Figure 7a). A small amount of helicate 3b
co-eluted with 4b, but was readily distinguishable (Figure 6c). The
1
H NMR spectrum of purified 4b matched that of the product
−
formed following the treatment of a mixture of 2b and 3b with PF
6
.
SE is the next most important stimulus since, when combined
with PAM, it influenced the relative proportion of tetrahedron and
Prism 4b was only obtained as the major product in solution
when all three stimuli were present. We infer that AT, which pro-
II
vided stabilizing anion-πꢀ interactions within the Fe
8
L
12 prism
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Journal of the American Chemical Society
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helicate, as reflected in the different helicate ⇌ tetrahedron equilib-
structural transformations is thus an emerging application of PAM
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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5
6
that seeks to controllably introduce instability into self-assembled
architecture through covalent reactions. It is a challenge to develop
modifications that render a parent architecture sufficiently unstable
to undergo a rearrangement, but not so unstable as to destroy it com-
pletely. In this contribution, we have demonstrated an approach us-
ing the tetrazine-based IEDDA reaction to induce transformations
of a tetrazine-edged tetrahedral cage. The PAM stimulus (cy-
clooctyne) could be combined with additional co-stimuli (an elec-
tron rich aniline or an anion template) to influence the supramolec-
ular product distribution, thereby rendering the system responsive
to three unique stimulus types that operate together.
rium constants for the fluoroaniline and methoxyaniline-derived sys-
tems. Without initial PAM, however, SE was not observed to drive
structural transformation. SE could, however, result in the conver-
sion of tetrahedron 1a to 1b. Finally, AT required the presence of
both PAM and SE stimuli to influence the product distribution of
the system in solution. Thus, the hierarchical ordering of the ability
of the three stimuli to bring about change in the structure type is
PAM > SE > AT.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Different potential functions could be expressed by this system
or its derivatives following the applications of various combinations
of stimuli. Tetrahedral complexes can be employed as molecular
3
0
containers that bind cargoes, whereas most helicates have minimal
cavity volume for guest encapsulation but can interact with mole-
3
1
cules such as DNA. The inner channels of prisms such as 4b enable
3
2
them to act as pores through membranes. The ability to map differ-
ent combinations of stimuli to unique structural outcomes, to switch
33
from order in the system to disorder and back again, thus reveals
opportunities for tailoring their functions to unique combinations of
chemical stimuli.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Pub-
lications website.
1
Figure 7. Assigned H NMR spectrum (500 MHz, 298 K, CD
3
CN) of
prism 4b, synthesized directly from building blocks and purified by size
exclusion chromatography. A small amount of helicate 3b (marked with
asterisks) co-eluted with prism 4b.
PDF Supporting information containing experimental procedures, spec-
troscopic data, MM2 modelling and X-ray crystallography (PDF).
−
While the stimulus combinations discussed above generated dis-
crete products, one combination failed to produce a well-defined re-
X-ray data for PF
6
⊂4a (CCDC 1577717) (CIF).
−
X-ray data for BF ⊂4a (CCDC 1577718) (CIF).
4
−
sponse at all. The addition of PF
6
to a mixture of 2a and 3a led to
−
X-ray data for PF ⊂4b (CCDC 1577719) (CIF).
6
28
the system moving towards a more disordered state, as evidenced
by the broadness of its NMR spectrum (SI, Figure S59c). We attrib-
ute this disorder to the incipient formation of anion-templated struc-
tures, which nonetheless lack a sufficient driving force to produce a
single discrete complex. However, completing the required set of
stimuli by performing SE caused prism 4b to emerge from the disor-
dered mixture as the sole product (SI, Figure S59d). This observa-
tion highlights the pathway-dependent nature of the network,
whereby the order of stimulus addition does not affect the ultimate
outcome (4b), but does determine what intermediate ordered states
AUTHOR INFORMATION
Corresponding Author
*
jrn34@cam.ac.uk
Author Contributions
These authors contributed equally.
‡
All authors have given approval to the final version of the manuscript.
ACKNOWLEDGMENT
2
9
(
2a, 3a, 1b, 2b, or 3b) and disordered states are expressed by the
D.A.R. acknowledges the Gates Cambridge Trust. B.S.P. acknowledges
the Royal Commission for the Exhibition of 1851 Fellowship and Cor-
pus Christi College, Cambridge. This work was supported by the UK
system along the way.
In addition to elucidating the structures expressed by the system
after the various stimuli have been added, our investigations of these
transformation sequences also provided insight into the relative
rates of the various processes. PAM triggered a rapid structural trans-
formation, with IEDDA proceeding to completion on both 1a and
Engineering
and
Physical
Sciences
Research
Council
(EP/M01083X/1). The authors thank Diamond Light Source (UK)
(MT11397), University of Cambridge NMR facility, and the EPSRC
UK National Mass Spectrometry Facility at Swansea University. The au-
thors thank Dr Felix Rizzuto and Ms Marion Kieffer for recording
HRMS and IM-MS data.
1
b within 20 min at 293 K. Both the 2 ⇌ꢀ3 equilibria and subcom-
ponent exchange are slower processes at 293 K, taking hours to days,
as discussed above. Anion templation was the slowest of these pro-
cesses, as heating to 333 K was required for 24-48 h before prism 4b
emerged as the dominant product.
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1. Faulkner, A. D.; Kaner, R. A.; Abdallah, Q. M. A.; Clarkson, G.; Fox,
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