Tandem Reactivity of a Self-Assembled Cage Catalyst with Endohedral Acid Groups

Article abstract of DOI:10.1021/jacs.8b03984

Self-assembly of a carboxylic acid-containing ligand into an Fe₄L₆ iminopyridine cage allows endohedral positioning of the acid groups while maintaining a robust cage structure. The cage is an effective supramolecular catalyst, providing up to 1000-fold rate enhancement of acetal solvolysis. This enhanced reactivity allows a tandem deprotection/cage-to-cage interconversion that cannot be achieved with other acid catalysts. The combination of rate enhancements and sequestration of the reactive function confers both activity and selectivity on the process, mimicking enzymatic behavior.

Full text of DOI:10.1021/jacs.8b03984

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Communication
Tandem Reactivity of a Self-Assembled
Cage Catalyst with Endohedral Acid Groups
Lauren R. Holloway, Paul M. Bogie, Yana A Lyon, Courtney
Ngai, Tabitha F. Miller, Ryan R Julian, and Richard J. Hooley
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03984 • Publication Date (Web): 18 Jun 2018
Downloaded from http://pubs.acs.org on June 18, 2018
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Tandem Reactivity of a Self-Assembled Cage Catalyst with Endohedral
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Lauren R. Holloway, Paul M. Bogie, Yana Lyon, Courtney Ngai, Tabitha F. Miller, Ryan R. Julian and
Richard J. Hooley*
Department of Chemistry, University of California-Riverside, Riverside, CA 92521, U.S.A.
Supporting Information Placeholder
“structural” M-L interaction is essential. Appending unre-
active groups is not an issue, but carboxylic acids are good
ligands for metals, and are the structural components of
many metal-organic frameworks.14 Fortunately, Fe(II)-
iminopyridine-based self-assembly is tolerant to similar
groups such as sulfates.15 Here we describe the synthesis
of an Fe4L6 tetrahedral cage with internalized acid groups,
and its application towards tandem catalytic processes.
ABSTRACT: Self-assembly of a carboxylic acid-containing
ligand into an Fe4L6 iminopyridine cage allows endohedral
positioning of the acid groups while maintaining a robust cage
structure. The cage is an effective supramolecular catalyst,
providing up to 1000-fold rate enhancement of acetal solvoly-
sis. This enhanced reactivity allows a tandem deprotec-
tion/cage-to-cage interconversion that cannot be achieved
with other acid catalysts. The combination of rate enhance-
ments and sequestration of the reactive function confers both
activity and selectivity on the process, mimicking enzymatic
behavior.
Biomimetic catalysis with self-assembled cage complex-
es1 is a long-standing target, whether the cages are based
on self-complementary hydrogen bonds,2 hydrophobic
forces3 or metal-ligand interactions.4 As the inner shells of
most self-assembled cages are unfunctionalized, the most
effective reactions are reagentless, either unimolecular
rearrangements or cycloadditions.5 In some special cases,
the host superstructure can be involved in the reaction:
electron-rich aromatic panels can participate in internal
substitution reactions,6 charged cages can exploit localized
hydroxide ions to accelerate pH-responsive reactions,7 and
acidic CH bonds in the architecture allow guest activation.8
Cages with endohedrally oriented functional groups
would allow reagent-controlled reactions to be performed
on the cavity interior. Functionalized cages could also per-
form reactions that are incompatible with the external
milieu, or sequester reactive species, allowing compart-
mentalization and tandem processes.9 The challenge lies in
the synthesis: presenting functionality to the interior of a
self-assembled cage complex is still quite rare. Most exam-
ples are supercontainers or nanospheres with large inter-
nal spaces.10 Some of these large systems have been used
to promote internal reactions, such as Au-catalyzed cycli-
zations controlled by cooperativity between bound sub-
strates and internal groups.11 Also, metal-organic super-
containers12 with amine-functionalized walls can catalyze
internal Knoevenagel condensations.13 However, in each
case, the cavities are extremely large and selectivity in
guest binding can be limited; they are better described as
discrete nanophases10a rather than biomimetic hosts.
Figure 1. Ligand synthesis and multicomponent self-assembly
into tetrahedral cage complexes 1 and 2.
A number of factors must be addressed when creating a
tetrahedral assembly for supramolecular catalysis. The
ligand must be large enough to allow a suitably sized cavi-
ty, as well as possessing the correct coordination angle.
Linear ligands favor tetrahedral structures, but do not al-
low simple internalization of functional groups. V-shaped
ligands allow endohedral functions,16 but invariably favor
assemblies with a smaller, and entropically favored M2L3
stoichiometry.17 Also, the use of octahedral metals can lead
to metal- and ligand-based stereoisomerism.18 2,7-
Diaminofluorene has been shown to assemble into an iso-
meric mixture of M4L6 tetrahedra,18 although the cavity is
too small for effective molecular recognition. The coordi-
nation angle is ideal, however, so we focused on an ex-
tended 2,7-dianilino-fluorene scaffold for the creation of a
functionalized cage (Figure 1). Two ligands were synthe-
sized, unfunctionalized C, and diacid E. Suzuki coupling
To synthesize cages with reactive endohedral groups,
ensuring compatibility between the catalytic group and
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between A and 4-boc-aminophenylboronic acid, followed do the DOSY NMR spectra. All peaks for both 1 and 2 dif-
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by deprotection gives C in 84 % yield. To access the acid
ligand, A was treated with α-bromoethylacetate and KOtBu,
giving diester B. Suzuki coupling, Boc removal and hydrol-
ysis of the esters followed by neutralization gave ligand E
in 43 % overall yield (4 steps).
fuse at the same rate, and the diffusion constants are near-
ly identical (D(1) = 3.01 x 10-10 m/s2, D(2) = 3.09 x 10-10
m/s2).
Molecular modeling (semi-empirical, AM1 forcefield) of
the two isomers of acid 2 (Figure 2b) shows that in both
cases, the acid groups are mostly positioned towards the
internal cavity, and that rotation of the fluorenyl groups to
exohedrally orient the acids is unfavorable. NOESY NMR
shows intra-ligand NOE correlations that are likely due to
free rotation of the phenyl spacers. This does not rule out
rotation of the fluorenyl moiety, but if any rotation does
occur, the barrier is low, and the acids can easily be orient-
ed to the cavity interior at 23 °C (for further structural
discussion, see Supporting Information). As such, cage 2
passes the first test: it has acidic groups on the ligands, and
they can be oriented endohedrally. Is it capable of exploit-
ing these reactive groups for biomimetic catalysis?
Ligands C and E were treated with 2-formylpyridine
(PyCHO) and Fe(NTf2)2 in acetonitrile, to give cages 1 and 2
respectively. ESI-MS analysis of cage 2 showed only peaks
for ions corresponding to an Fe4L6 stoichiometry, plus
fragments (Figure 2a, see Table S-2 for full assignment).
The dominant peak was for [2-1H]7+, with other ions [2-
2H]6+ and [2-3H]5+ present, indicating that the acids in cage
2 are generally protonated, despite the overall cationic
nature of the cage. The ESI-MS spectrum for 1 gave similar
stoichiometry, with a [1]8+ base peak and peaks for the
[1•NTf2]7+ and [1•(NTf2)4]4+ ions (plus fragments) clearly
observable (Fig S-24).
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Figure 3. Peak deconvolutions of the downfield (imine CH)
regions of the 1H NMR spectra of 1 and 2 (600 MHz, 298 K,
CD3CN).
Figure 2. Characterization of cage 2. a) ESI-MS spectrum (L =
The challenge in using Fe-iminopyridine cages as cata-
lysts is that they can be somewhat fragile. Strongly coordi-
nating anions (e.g. Cl-) and other exogenous nucleophiles
are rarely tolerated,16,21 so to determine the effectiveness
of 2 as a catalyst, we initially focused on a mild acetal hy-
drolysis (Table 1). Aromatic acetals such as 3a-c were
treated with 4 % cage 2 and 6 equivalents of water in
CD3CN, and the reaction monitored by NMR. Solvolysis of
3a was rapid in the presence of cage 2, with 99 % conver-
sion after 5 h at 23 °C. The pyridyl equivalent 3b was less
reactive, and required heating to 77 °C for 14 h for com-
plete reaction. No decomposition of cage 2 was detected
during the solvolysis, and the cage-catalyzed reactions
showed significant rate enhancements over control pro-
cesses. The initial rates of the catalyzed hydrolyses of 3a
and 3b were determined to be V = 2410 and 440 x10-4
mM/min, respectively. Dibutylacetal 3c was solvolyzed at
the same rate as dimethyl acetal 3b: cage 2 cannot discrim-
inate between molecules of broadly similar size, due to its
large cavity. When 6 equivalents of control ligand F (i.e. an
equivalent number of COOH groups as used with 2) were
used as catalyst, only 1 % conversion of 3a was observed
ligand); b) calculated energy minimized structures of the two
observed isomers of 2 (C3, S4); c) H and 2D-DOSY NMR spec-
tra (600 MHz, 298 K, CD3CN, D(2) = 3.09 x 10-10 m/s2).
1
Both cages 1 and 2 displayed somewhat complex 1H
NMR spectra indicative of the formation of multiple cage
isomers. The spectrum of 2 (Figure 2c) shows discrete
peaks in each expected region of the spectrum, but these
peaks are overlapped and clustered. There are a variety of
stereochemical possibilities for M4L6 tetrahedral struc-
tures. The most common is an all-fac coordination at the
metal centers, giving rise to three isomeric possibilities,
with either S4, C3, or T symmetry.19 Other possibilities exist
with mer coordination at the metal center, but these show
far more complex NMR spectra.20 Deconvolution of the
1
imine region of the H NMR spectrum of cage 2 (Figure 3)
shows the presence of only two isomers 2-C3 (45 %) and
2-S4(55 %), with no observed peaks for the T-symmetric
isomer. The unfunctionalized cage 1 shows 8 peaks in the
imine region, with the extra peak corresponding to the T-
symmetric isomer. The isomeric ratio is 48 % 1-C3, 11 % 1-
T, and 41 % 1-S4. 2D NMR and elemental analysis (see
Supporting Information) corroborates the assignment, as
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Journal of the American Chemical Society
after 24 h at 23 °C, with V = 2.26 x10-4 mM/min. Only 20 %
pling this reaction to a tandem process is challenging, as
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conversion was observed when heated at 50 °C for an ad-
ditional 24 h. Similarly, 3b only showed 6 % conversion
after 24 h at 77 °C, with V = 4.03 x10-4 mM/min. The rate
enhancement provided by internalizing the acid groups in
the cage cavity is 1070-fold for 3a, and 100-fold for 3b.
Unfunctionalized cage 1 was not an effective catalyst: no
solvolysis of acetals 3a, 3b or 3c occurred after 48 h with 4
% cage 1 at 23 °C. When the samples were heated, minimal
conversion (~1 %) was observed after 24 h.
the helicates are sensitive to acid, as well as carboxylate or
chloride ions. To perform both a deprotection of the 2-
formylpyridine acetal and the helicate aldehyde exchange
requires careful matching of conditions. Stronger acids
such as CF3COOH are effective catalysts for acetal solvoly-
sis, but also allow other side reactions to occur. Weak acids
do not destroy the helicates but are ineffective in depro-
tecting the acetal.
Acid cage 2 is perfectly suited to this tandem process. 4
% cage 2 was combined with 3b, water, and brominated
helicate 4•Br in CD3CN, and the tandem process monitored
at 77 °C (Figure 4c, Supporting Information). The solvoly-
sis of 3b and the incorporation of the resultant PyCHO into
4•Br occur rapidly: after only 30 mins, peaks for 4•Br
start to disappear. Peaks for PyCHO are not observed ini-
tially, only peaks for displaced BrPyCHO. As an excess of
the acetal is present, excess PyCHO builds up after 3 h. The
reaction achieves completion after 8 h, with a conversion
of 92 %. No decomposition of the helicates occurs, and
only the helicates, 2 and excess aldehydes are present after
the reaction. No incorporation of Br-PyCHO into cage 2 is
observed, as expected: even though 2 is an iminopyridine
cage, it is capable of catalyzing the displacement reactions
of other iminopyridine assemblies.
9
The rate enhancement is provided by the cage structure:
while NMR analysis showed that 3a-c are in fast exchange
with cage 2 and no discrete Michaelis complex is observed,
the acetals do have significant affinity for the cage. Stern-
Volmer analysis of the absorbance spectra (Supporting
Information) illustrated this strong host:guest affinity,
with KD(2•3a) = 76 μM and KD(2•3b) = 44 μM. No binding
was observed between 3a-c and control ligand F: the mo-
lecular recognition is driven by the multiple closely located
acid groups and the cationic nature of the cage host. Inter-
estingly, the unfunctionalized cage 1 also shows affinity for
guests, with KD(1•3c) = 10 μM. It is an ineffective catalyst,
however, as it has no reactive functional groups.
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Table 1. Supramolecular Catalysis of Acetal Solvolysis.
Initial Rate V,
Conversion,
Substratea t, h T, °C Catalystb
x10-4 mM/min
%
3a
3a
3b
3b
3c
3a
3a
3a
3b
3b
1
5
4
23
23
77
2
2
79
99
60
99
96
0
2410
440
2
14 77
14 77
48 23
24 23
24 23
48 77
24 77
2
2
418
n.d.
1
Fc
Fc + 1
1
2.26
2.87
n.d.
1
1
1
Fc
4.03
6
a [3a-c] = 12.3 mM, [H2O] = 74 mM, CD3CN; b [1/2] = 0.51 mM;
c [F] = 3.08 mM, i.e. 6 equivalents with respect to 2, to ensure
the same number of acidic groups in the system.
Cavity-containing catalysts have another advantage over
small molecules: compartmentalization. This is important
for a tandem, or “cascade” catalysis,22 an example of which
is shown in Figure 4. Cage-to-cage conversions of self-
assembled M2L3 helicates such as 4•Br can occur under
mild conditions by adding 2-formylpyridine and water to
the system. Aldehyde exchange occurs only if the process
is enthalpically favorable, i.e. if an electron poor aldehyde
is replaced by an electron rich aldehyde.23 However, cou-
Figure 4. Tandem catalysis with a) cage 2; b) controls. 1H
NMR spectra of the tandem reaction of acetal 3b (12.3 mM)
with helicate 4•Br (1.5 mM), H2O (61.5 mM) and c) cage 2
(0.51 mM); d) acid F (3.08 mM), CD3CN, 77 °C.
Cage 2 is a good catalyst for this tandem solvoly-
sis/displacement, whereas other acids are not (Figure 4d,
Supporting Information). No acetal solvolysis is observed
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mond, K. N.; Toste, F. D. J. Am. Chem. Soc. 2016, 138, 9682-9693.
with control acid F after 8 h, and decomposition of 4•Br
occurs after extended heating (120 h). Using a stronger
acid such as CF3CO2H led to rapid decomposition after only
10 mins at 77 °C. Acetal solvolysis was observed, but the
helicates were not tolerant of the strong acid, even at 23
°C. When cage 1 was used as catalyst, no acetal solvolysis
occurred, and 4•Br persisted even after extended reaction.
The combination of enhanced reactivity and compartmen-
talization of the acid groups in cage 2 allows it to be an
effective tandem catalyst: reactive enough to be functional,
but mild enough to work with sensitive tandem partners.
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In conclusion, we have shown that an endohedrally func-
tionalized cage complex is capable of 1000-fold accelera-
tions of acid-catalyzed reactions over non-assembled con-
trol acids, and this can be applied to tandem cage-to-cage
interconversions. The cage binds substrate strongly, and
releases the products rapidly, allowing good turnover. The
internally functionalized cage allows sequestration of reac-
tive species, reaction rate accelerations and concurrent
tandem reactions: the hallmarks of enzymatic catalysis.
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ASSOCIATED CONTENT
Supporting Information
New molecule synthesis, cage characterization and assign-
ment. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* E-mail: richard.hooley@ucr.edu
ACKNOWLEDGMENTS
The authors would like to thank the National Science Founda-
tion (CHE-1708019 to R.J.H.) and NIH (NIGMS grant
R01GM107099 to R.R.J.) for funding.
(21) Ma, S.; Smulders, M. M. J.; Hristova, Y.; Clegg, J. K.; Ronson, T. K.;
Zarra, S.; Nitschke, J. R. J. Am. Chem. Soc. 2013, 135, 5678-5684.
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ACS Paragon Plus Environment

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Journal of the American Chemical Society
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ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
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74x61mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
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83x78mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
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74x62mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
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35x14mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
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120x162mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
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29x9mm (300 x 300 DPI)
ACS Paragon Plus Environment