A Switchable Catalyst Duo for Acyl Transfer Proximity Catalysis and Regulation of Substrate Selectivity

Article abstract of DOI:10.1002/chem.202004416

Enzymes are encoded with a gamut of information to catalyze a highly selective transformation by selecting the proper reactants from an intricate mixture of constituents. Mimicking biological machinery, two switchable catalysts with differently sized cavities and allosteric control are conceived that allow complementary size-selective acyl transfer in an on/off manner by modulating the effective local concentration of the substrates. Selective activation of one of two catalysts in a mixture of reactants of similar reactivity enabled upregulation of the desired product.

Full text of DOI:10.1002/chem.202004416

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Accepted Article
Accepted Article
Title: A Switchable Catalyst Duo for Acyl Transfer Proximity Catalysis
and Regulation of Substrate Selectivity
Authors: Michael Schmittel, Abir Goswami, and Sudhakar Gaikwad
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To be cited as: Chem. Eur. J. 10.1002/chem.202004416
Link to VoR: https://doi.org/10.1002/chem.202004416
01/2020

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COMMUNICATION
A Switchable Catalyst Duo for Acyl Transfer Proximity Catalysis
and Regulation of Substrate Selectivity
Abir Goswami,‡ Sudhakar Gaikwad‡ and Michael Schmittel*
Abstract: Enzymes are encoded with a gamut of information to
catalyze a highly selective transformation by selecting the proper
reactants from an intricate mixture of constituents. Mimicking
biological machinery, two switchable catalysts with differently sized
cavities and allosteric control are conceived that allow complemen-
tary size-selective acyl transfer in an on/off manner by modulating
the effective local concentration of the substrates. Selective
activation of one of two catalysts in a mixture of reactants of similar
reactivity enabled upregulation of the desired product.
form homoleptic complexes with copper(I) ions due to the bulk in
2- and 9-position and thus remain coordinatively frustrated in the
form of [Cu(phenAr2)]+.[12] However, these copper(I) sites still
allow HETeroleptic PYridine and Phenanthroline (HETPYP) type
[13]
complexes
with sterically undemanding monodentate ligands
or substrates. Thus, substrates pyridin-4-yl-methanol (A1) and
1-acetylimidazole (B) were chosen that should weakly coor-
dinate to the copper(I)-loaded phenAr2 binding sites of ligands 3
and 4 (see SI, Fig. S41).
Many metalloenzymes use the proximity effect to control precise
docking of substrates thereby activating processes with astound-
ding selectivity.[1,2] Inspired by such mode of action, chemists
have designed fascinating catalysts and catalytic machinery for
controlling rate and selectivity.[3,4] However, almost all of those
prototypes were conceived as stand-alone molecular devices
operating only as individuals. Enzymes, in contrast, do not need
spatial isolation because each of them is encoded with highly
specific information for their mode of action. Conversely, encryp-
ting information into multiple switchable manmade catalysts for
achieving selectivity in mixtures of similar substrates still repre-
sents a major challenge.[5] Indeed, only a handful of systems is
known showing clear-cut ON/OFF regulation[6] or selectivity swit-
ching.[7] Even more difficult is control of selectivity when sub-
strates of similar reactivity but different size need to be differen-
tiated,[3b,5a] requiring proximity catalysis.[8] Herein, we describe
the switchable catalysts 1 and 2 (Figure 1) that were reversibly
toggled between four different states upon sequential addi-
tion/removal of copper(I) and iron(II) ions. Alike in natural machi-
nery,[9] ON/OFF control of catalysis and substrate selectivity in
acyl transfer reaction is possible by using allosteric effects[10] and
by selectively activating only one catalyst in a mixture of two.
A)
B)
[Cu2(3)]2+
[Cu(4)]+
60
40
20
0
0
100
200
300
Time / min
I)
II)
Figure 2. (A) Lewis-acid catalysis in the acyl transfer reactions I and II using
model catalysts 3 and 4. (B) Formation of C1 in presence of [Cu2(3)]2+ and
[Cu(4)]+ as catalyst (50 °C).
The spatial arrangement of both copper(I) ions in [Cu2(3)]2+ was
expected to pre-organize the substrates in close proximity within
the cavity thus increasing their effective concentration. To test
the catalytic activity of [Cu2(3)]2+, our chosen model, a mixture of
ligand 3 (3 mM), [Cu(CH3CN)4]PF6, reactants A1 and B in a
1:2:10:10 ratio in CD2Cl2/CD3CN (5:1, v/v) was heated at 50 °C
for 2 h furnishing pyridin-4-ylmethyl acetate (C1) in 33% yield (SI,
Fig. S44). In the absence of [Cu2(3)]2+, under otherwise identical
reaction conditions, no product formation was observed (SI, Fig.
S43). A further control experiment using the same set of con-
ditions proved that 20 mol% of [Cu(4)]+ was unable to afford any
competitive amount of C1 (in-situ yield = 2%) (SI, Fig S45). Such
finding suggested the existence of a proximity effect in the
doubly copper(I)-loaded complex [Cu2(3)]2+.
To pre-access the proposed acyl transfer reaction (A + B → C +
D),[11] we first prepared as model the bis-phenanthroline ligand 3
(Figure 2, for synthesis see SI, Scheme S2) to evaluate its po-
tential for proximity catalysis. As reported earlier, sterically shiel-
ded phenanthrolines (phenAr2) like 4 are kinetically impeded to
To probe proximity catalysis in an ON/OFF manner, we decided
to block and re-open one of the [Cu(phenAr2)]+ binding site by a
competing stronger complexation such as the HETeroleptic Ter-
pyridine And Phenanthroline (HETTAP) motif.[13] We thus de-
signed nanoswitch 1 and implemented four distinct switching
states by addition and removal of copper(I) and iron(II) ions
(Figure 3).[14] Synthesis and characterization of nanoswitch 1 are
detailed in the supporting information (SI, Scheme S1). When a
solution of 1 in dichloromethane-d2 was treated with one equiv.
of copper(I) ions, formation of the intramolecular complex
Figure 1. Chemical Structures of nanoswitch 1 and 2.
[a]
A. Goswami, M.Sc., Dr. S. Gaikwad and Prof. Dr. M. Schmittel
Center of Micro and Nanochemistry and Engineering, Organische
Chemie I, University of Siegen, Adolf-Reichwein Str. 2, 57068
Siegen, Germany
E-mail: schmittel@chemie.uni-siegen.de
Supporting information and the identification number (ORCID) of
one author is provided under http://dx.doi.org/10.1002/.
Abir Goswami and Sudhakar Gaikwad contributed equally.
‡
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1
[Cu(1)]+ (= State I1) was confirmed by 1H NMR, H-1H COSY,
9
7/4
d
e
4/7
g/f
5+6
f/g
electrospray ionization mass spectrum (ESI-MS), and elemental
analysis. Two sets of phenanthroline signals (1:1, complexed vs.
uncomplexed) in the H NMR spectrum of [Cu(1)]+ clearly indi-
8/3
3/8
D)
a
b
n
c
[Fe(1)2]2+
1
cated presence of an intramolecular HETTAP complex that
desymmetrized both phenanthroline sites. The characteristic up-
field shifted signal of the mesityl protons 9-H at the complexed
phenAr2 from 6.94 to 6.41 ppm due to shielding by the terpyri-
dine unit attested the formation of [Cu(1)]+. This assignment was
further supported by the simultaneous upfield shift of the ter-
pyridine proton signal for a-H and b-H from 8.66 and 7.28 ppm
to 7.68 and 7.12 ppm, respectively (SI, Fig S22). The ESI-MS of
the resultant complex displayed a molecular ion peak at m/z =
1478.0 that is diagnostic for the [Cu(1)]+ due to the experimental
isotopic splitting matching the computed one (SI, Fig S66).
9
C)
B)
A)
[FeCu4(1)2]6+
9c
9u
9
[Cu2(1)2]2+
[Cu(1)]+
9
9.2
8.8
8.4
8.0
7.6
7.2
6.8
6.4
Figure 4. Partial 1H NMR (400 MHz, 298 K) of (a) [Cu(1)]+ in CD2Cl2 (State I1);
(b) [(Cu2(1)]2+ in CD2Cl2 (State II1); (c) [FeCu4(1)2]6+ in CD2Cl2:CD3CN (5:1)
(State III1); (d) [Fe(1)2]2+ in CD2Cl2:CD3CN (5:1) (State IV1).
A)
B)
[FeCu4(1)2]6+
0.8
0.6
0.4
0.2
0
[Cu2(1)]2+ [FeCu4(1)2]6+
0.05
0.03
0.01
576 nm
[Cu2(1)]2+
240
340
440
540
640
0
0.5
1
1.5
2
Wavelength / nm
No. of cycles
Figure 5. (A) UV-vis spectra and observable color of [Cu2(1)]2+ (1.25 × 10–4 M)
and [FeCu4(1)2]6+ (1.25 × 10–4 M) in CD2Cl2. (B) Two reversible switching
cycles (between [Cu2(1)]2+ and [FeCu4(1)2]6+) and changes in absorbance at λ
= 576 nm.
[Cu2(1)]2+ was instantly cleaved to yield the bishomoleptic iron(II)
complex [FeCu4(1)2]6+ (State III1), a quantitative transformation
that could easily be followed by the naked eye (Figure 5A). The
notable upfield shift of the terpyridine proton a-H from 7.69 to
7.13 ppm and b-H from 7.11 to 7.04 ppm unambiguously
corroborated clean formation of the dimeric iron(II) terpyridine
complex (Figure 4C). Further support for this assignment was
received from the downfield shifted signal of the mesityl protons
9-H from 6.38 to 6.97 ppm that is characteristic for coordinatively
frustrated [Cu(phenAr2)]+ complexes (SI, Fig S26). Additionally,
1H-1H COSY, ESI-MS, and elemental analysis verified the
formation of the desired complex [FeCu4(1)2]6+ (State III1).
Figure 3. Four-state switching of nanoswitch
copper(I) and iron(II) ions.
1 by addition/removal of
Addition of one more equiv. of copper(I) ions to the solution of
State I1 quantitatively furnished [Cu2(1)]2+ (= State II1), where the
additional equiv. of copper (I) was bound at the second shielded
phenanthroline site. The identity of the complex was corrobora-
ted by a correct elemental analysis and an ESI mass signal of
the resulting complex [Cu2(1)]2+ (peak at m/z = 770.1, see SI, Fig.
1
S67). In the H NMR, the HETTAP-free phenanthroline and its
mesityl protons (9u-H) showed the anticipated downfield shifts in
the 1H NMR (Figure 4B, and SI, Fig. S24). At room temperature,
the two distinct sets of phenanthroline signals clearly indicated
slow exchange of the terpyridine arm between both copper(I)-
loaded phenanthrolines. A cross-correlation between proton 9c-
H of the copper(I)-loaded phenanthroline (at 6.96 ppm) and
proton 9-H of the HETTAP-complexed phenanthroline signal (at
Then, copper(I) ions were removed to prepare [Fe(1)2]2+ (= State
IV1) by addition of 2.0 equiv. of cyclam (with respect to 1) as a
1
strong chelating agent. In the H NMR, the phenanthroline pro-
ton signal for 9c-H is upfield shifted to 6.87 ppm due to deme-
talation (Figure 4D; SI, Fig. S28). The formation of complex
[Fe(1)2]2+ was further evidenced by UV/vis, 1H-1H COSY, ESI-
MS spectroscopy and elemental analysis. Finally, 0.5 equiv. of
hexacyclen was added to remove iron(II) and 1.0 equiv. of
copper(I) was added to go back to the initial state, State I. After
the successful demonstration of the unidirectional cyclic
switching along the states I1→II1→III1→IV1→I1 (see SI, Fig. S39)
over two cycles, we verified the reversible switching between
1
6.38 ppm) in the H-1H ROESY experiment allowed measure-
ment of the slow exchange.[15] The activation parameters for the
exchange were determined at 298 K (k = 1.34 s–1 and ΔG⧧
=
298
72.6 kJ mol–1) (SI, Fig. S42).
Addition of iron(II) ions to State II1 was expected to furnish a
bishomoleptic complex at the tridentate terpyridine sites (State
III1 = [FeCu4(1)2]6+).[16] Indeed, upon addition of 0.5 equiv. of
iron(II) ions to complex ([Cu2(1)]2+), the HETTAP complex in
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States II1 and III1 by UV/vis (Figure 5B) due to its importance for
the ON/OFF-control of catalysis.
With nanoswitch 2 and its switching states being fully characteri-
zed, we investigated its ability to discriminate similar reactants
Since reversible toggling between States II1 and III1 was suc-
cessful, the catalytic activity of the individual switching states
was investigated. First, a mixture of nanoswitch 1 (3 mM in
CD2Cl2 / CD3CN = 5:1, v/v), [Cu(CH3CN)4]PF6, A1 and B
(1:2:10:10) representing State II1 was heated (50 °C, 2 h). By 1H
NMR criteria, the acyl-transferred product C1 was not formed (SI,
Fig. S47). As expected, blockage of one of the binding sites in
[Cu2(1)]2+ by HETTAP complexation is sufficient to suppress acyl
transfer. This finding suggested to regulate the reaction in an
ON/OFF manner by unmasking/masking the copper(I)-loaded
HETTAP site in [Cu2(1)]2+. Consequently, the ON state for acyla-
tion should be embodied by State III1, where both the copper(I)-
loaded phenanthrolines stations are available for catalysis. Thus,
a mixture of 1 (3.0 mM), [Fe(BF4)2]•6H2O, [Cu(CH3CN)4]PF6, A1
and B (2:1:4:20:20) was tested for its catalytic action. As expec-
ted, State III1 was catalytically active furnishing 33% of C1 after
2 h of heating at 50 °C (SI, Fig S48).
by size. Markedly, neither State II2 nor III2 was able to noticeably
catalyze the transformation of A1 + B. Even in the presence of
State III2 (= [FeCu4(2)2]6+; 5 mol%), where the copper(I) ions are
exposed, the reaction (50 °C, 2 h) between A1 (30.0 mM) and B
(30.0 mM) gave only 2% of the product C1 (SI, Fig. S51). In con-
trast, a mix of switch 2 (3 mM), [Fe(BF4)2]•6H2O, [Cu(CH3CN)4]-
PF6 (2:1:4) representing State III2 plus the large alcohol A2 & B
(20:20) furnished 26% of product C2 (SI, Fig. S50). As expected,
State II2 = [Cu2(2)]2+ (10 mol%) was unable to promote any re-
action between A2 (30.0 mM) and B (30.0 mM) (SI, Fig. S49).
For evaluating the larger alcohol in the smaller sized catalyst, we
studied the reaction of A2 and B in presence of model complex
[Cu2(3)]2+. Since no formation of product C2 was observed at the
same conditions (SI, Fig. S52), we concluded that the substrate
(4-(pyridin-4-yl)phenyl)methanol (A2) has an incompatible length
with the cavity of [Cu2(3)]2+ that is equally part of [FeCu4(1)2]6+
(State III1 of switch 1). This finding again clearly indicated that
the dimensions of the substrates had a significant effect on
catalysis and that preorganization of the substrate is not suffi-
cient. In essence, a good fit of substrate and cavity dimensions
is necessary to observe proximity effect.
Statistically, three possible combinations of bound substrates (A
and A, A and B, B and B) at both copper(I)-loaded phenan-
throlines of [Cu2(3)]2+ are possible. Obviously only the hetero-
combination of the reactants (A and B) will lead to increased
reaction rates. To evaluate the coordination preferences of the
substrates at the copper(I)-phenAr2 sites, we mixed ligand 3 (3
mM), [Cu(CH3CN)4]PF6, A1 and B in 1:2:1:1 ratio and compared
the results with those of the homo-combinations (1:2:2:0 and
1:2:0:2). All the pyridyl protons a-, b-, c-H and imidazole protons
d-, e-, f-H in hetero-combination (1:2:1:1 mixture) were upfield
1
shifted and became sharper in the H NMR compared to those
of the other two combinations (SI, Fig. S41). We hypothesized
that the hetero-combination of the substrates A1 and B
coordinated preferentially, better than the two homo arrange-
ments (A & A, B & B). A possible reason for this binding
preference is hydrogen bonding between the acetyl group of B
and the hydroxyl group of A1 that should lead to increased
effective local concentrations. Moreover, the corresponding
hemiacetal from A and B, although being a high energy interme-
diate, would fit perfectly into the cavity and thus could be re-
sponsible for the rate enhancement.
Figure 6. Four state switching scheme of nanoswitch 2 by addition/removal of
copper(I) and iron(II) ions.
After the concept of switchable proximity catalysis had been
established for switch 1, the larger nanoswitch 2 was prepared
in order to extend the study toward multi-catalyst systems and
their substrate selectivity. We selected a framework based on a
tetrahedral core (Figure 6)[17] because there the distance bet-
ween both copper(I)-loaded phenanthrolines is increased by 3.1
Å in comparison to that in switch 1 (d = 14.9 Å, see SI, chapter
8). Nanoswitch 2 was unambiguously characterized by spectral
data (for its preparation and data, see the SI, Scheme 3). At first,
we individually synthesized each of the switching States I2, II2,
III2 and IV2 in pure form for characterization by 1H, 1H–1H COSY,
ESI–MS, and elemental analysis (SI). Secondly, we confirmed
the clean in-situ four-state switching (State I2→II2→III2→IV2→I2)
of 2 by alternate addition and removal of copper(I) and iron(II)
ions (SI, Fig S40).
Next we individually evaluated the in-situ ON/OFF control of
proximity catalysis of the switches 1 (Figure 7A) and 2 (Figure
7B) by reversibly toggling between monomeric and dimeric
states. Switching was accomplished by addition and removal of
iron(II) ions.[18] A mixture of [(Cu2(1)]2+ (3.00 mM), substrates
pyridin-4-yl-methanol (A1) and 1-acetylimidazole (B) in 1:10:10
ratio in CD2Cl2:CD3CN (5:1) was heated at 50 °C for 2 h. No acyl
1
transfer was observed by H NMR spectroscopy (Catalysis OFF
in State II1; SI, Fig. S53a) which is readily justified on the basis
of one blocked copper site. Upon addition of 0.5 equiv. of
[Fe(BF4)2]•6H2O (relative to 1) to State II1, complex [FeCu4(1)2]6+
formed (State III1). Heating of the reaction mixture at 50 °C for 2
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