Conformational Analysis and Binding Properties of a Cavity Containing Porphyrin Catalyst Provided with Urea Functions

Article abstract of DOI:10.1002/ejoc.201600627

Urea-functionalized porphyrin catalysts containing a cavity, which are used for the processive epoxidation of polymers, are thoroughly characterized and their binding properties and other supramolecular features disclosed. Intramolecular coordination of the urea side chains to the metal center of the porphyrin moiety is unveiled through NMR, IR, UV, and fluorescence spectroscopy studies. This intramolecular coordination appears to be essential in order to facilitate catalysis in a pseudo-rotaxane fashion, i.e. by preventing the use of an excess of bulky axial ligands. The current investigation provides information on how to modulate in a dynamic fashion the catalytic activity of supramolecular systems, which is of interest for the design of increasingly efficient processive catalysts.

Full text of DOI:10.1002/ejoc.201600627

DOI: 10.1002/ejoc.201600627
Full Paper
Metalloenzyme Mimics
Conformational Analysis and Binding Properties of a Cavity
Containing Porphyrin Catalyst Provided with Urea Functions
[
a]
[a]
[a]
Pilar Hidalgo Ramos, Pattama Saisaha, Johannes A. A. W. Elemans,*
Alan E. Rowan,*[ and Roeland J. M. Nolte*
a,b]
[a]
Abstract: Urea-functionalized porphyrin catalysts containing a appears to be essential in order to facilitate catalysis in a
cavity, which are used for the processive epoxidation of poly- pseudo-rotaxane fashion, i.e. by preventing the use of an excess
mers, are thoroughly characterized and their binding properties of bulky axial ligands. The current investigation provides infor-
and other supramolecular features disclosed. Intramolecular co- mation on how to modulate in a dynamic fashion the catalytic
ordination of the urea side chains to the metal center of the activity of supramolecular systems, which is of interest for the
porphyrin moiety is unveiled through NMR, IR, UV, and fluores- design of increasingly efficient processive catalysts.
cence spectroscopy studies. This intramolecular coordination
Introduction
taining a metal center and a substrate binding site have been
synthesized, mimicking the action of enzymes in terms of rate
[
2]
Over the years Nature has served as a continuous source of and selectivity. These man-made systems are relatively simple
inspiration for the design of novel molecular systems displaying and in that sense contrast with the complex structural and func-
properties and functions similar to the chemical architectures tional properties of biological molecules, which are thought to
[
1]
found in living systems. For instance, catalytic systems con- be essential to achieve the unique features of biological trans-
Figure 1. (a) Schematic representation of the cavity-containing manganese porphyrin catalyst, which epoxidizes polybutadiene in a pseudo-rotaxane fashion.
[
6]
(
b) Molecular structures of MnP and MnUPC.
[
a] Radboud University, Institute for Molecules and Materials,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
E-mail: J.Elemans@science.ru.nl
formations. In order to increase their level of sophistication an
in depth analysis and study of the structural features and supra-
molecular behavior of the man-made systems are essential.
A.Rowan@science.ru.nl
R.Nolte@science.ru.nl
www.ru.nl/imm
b] Australian Institute for Bioengineering and Nanotechnology (AIBN), Corner
College and Cooper Rds. (Bldg. 75), The University of Queensland,
Brisbane, Queensland, 4072, Australia
Inspired by naturally occurring processive enzymes, e.g. DNA
[
3]
polymerase III and λ-exonuclease, which move along a DNA
chain while modifying it, we designed a toroidal enzyme mimic
based on a manganese porphyrin appended to a glycoluril
[
[
4]
clip. This catalyst was capable of binding to a polymer, i.e.
polybutadiene, and move along it, while epoxidizing the dou-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600627.
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1
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ble bonds of the polymer chain in a pseudo-rotaxane fashion ular symmetry of the compound since equivalent signals for
(
Figure 1, a). In order to force the catalytic reaction to take place the protons of the four different alkylurea substituents were
inside the cavity of the porphyrin catalyst, a large excess of observed (Figure 3). Compared to those of the reference com-
a bulky pyridine ligand was applied. This ligand also prevents pound, 1-ethyl-3-(3-phenoxypropyl)urea (1), the resonances of
decomposition of the catalyst, which has been proposed to the alkylurea chains were shifted upfield due to the shielding
take place via the formation of an unreactive μ-oxo bridged effect of the porphyrin ring current (Table 1). Interestingly, each
IV
[5]
[6]
Mn -porphyrin dimer. In a separate paper we have de- pair of diastereotopic protons of the alkylurea groups (H-15, 17
scribed a urea-functionalized cavity porphyrin MnUPC that and 20; see Figure 3 and Table 1) gives rise to two different
turned out to be a better catalyst for oxidizing polybutadiene resonances suggesting a slow exchange process on the NMR
than MnP while it did not require an additional outside axial timescale. This feature can possibly be caused by a hindered
[
6]
ligand (Figure 1, b). We anticipated that the urea functions rotation of the C–O–C bonds, due to their ortho-substitution
exerted an effect on the catalytic activity of the manganese with respect to the porphyrin plane, or by an intramolecular
porphyrin by coordinating to the metal center, just as the bulky interaction, viz. hydrogen bonding, between the urea groups.
pyridine did. In order to further investigate this feature we The latter explanation, which we propose to be the main rea-
present here the structural characterization of the free-base and son, is supported by the observation of two NH stretching
–1
zinc derivatives of MnUPC and discuss their host–guest binding bands of similar intensities, at 3403 cm (free NH) and
3330 cm– (H-bonding NH), in the FT-IR spectrum of a 1 m
1
M
properties with nitrogen ligands and viologen guests.
[
7]
solution of H UPC in CHCl . Based on the results of the NMR
2
3
and FT-IR studies, we conclude that the urea-containing substit-
Results and Discussion
uents of H UPC are situated above the porphyrin plane and,
2
most likely, are engaged in intramolecular hydrogen bonding
Structural Analysis
[8]
via their urea moieties to generate a pseudo-cavity structure.
The free-base derivative of MnUPC (designated as H UPC; see
Figure 2) was synthesized as described in our previous paper.
The insertion of a zinc ion into H UPC to give ZnUPC caused
considerable line broadening and some noticeable differences
2
2
[
6]
ZnUPC was obtained in 94 % yield by reacting H UPC with in the pattern and chemical shift of the signals of the alkylurea
2
Zn(OAc) ·4H O in a mixture of chloroform and methanol.
groups (Figure 4 and Table 1). The observed downfield shifts of
2
2
The structure of H UPC was investigated with the help of protons H-19 and H-20 imply that the alkylurea groups are not
2
NMR spectroscopy. All proton resonances could be unambigu- directly located on top of the porphyrin center. The diastereo-
1
ously assigned after a COSY experiment. The H NMR spectrum topic protons H-16 and H-19, which in the case of H
UPC
2
of H UPC in CDCl at room temperature reveals the C molec- showed two different resonances, appear as one broad signal
2
3
2v
Figure 2. Molecular structures of H
2
P, ZnP, ZnOHP, H
2
UPC, ZnUPC, H
2
BocPC, ZnBocPC, model compound 1, py, tbpy, bipy, DABCO and V.
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2

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Figure 3. Assignments in the 400 MHz 1H NMR spectrum of H
UPC (M = 2H) in CDCl ; asterisks correspond to solvent signals.
2 3
Table 1. Chemical shifts[a] and Δδ values (in ppm) of the 3-(3-ethylureido)-
2
propoxy substituents of compounds H UPC and ZnUPC relative to those of
model compound 1.
δ
H
δ
δ
δ
1
Δδ
H
2
Δδ
[
b]
UPC[c] ZnUPC
[d]
2
UPC
ZnUPC
ZnUPC
H-14a
H-14b 3.94
H-15
H-16a
3.98
3.97
3.91
1.16
2.24
2.18
3.48
3.16
2.01
2.01
0.07
–0.01
–0.02
0.04
–0.17
–0.01
–0.01
0.11
0.18
0.36
0.17
4.03
4.03
2.01
3.38
3.38
4.51
4.24
3.17
3.17
1.10
–0.06
–0.10
–0.88
–0.97
–1.19
–1.02
–1.19
–1.33
–1.52
–1.20
–0.06
–0.12
–0.85
–1.14
–1.21
–1.03
–1.08
–1.15
–1.15
–1.03
1.13
2.41
H-16b 2.19
H-17
H-18
H-19a
H-19b 1.65
H-20 –0.10
3.49
3.05
1.84
[
a] A negative Δδ value corresponds to an upfield shift (400 MHz, 298 K,
CDCl /CD CN, 1:1, v/v). [b] Δδ(ZnUPC) δ(ZnUPC) δ(H UPC). [c]
Δδ(H UPC) = δ(H UPC) – δ(1). [d] Δδ(ZnUPC) = δ(ZnUPC) – δ(1). For proton
3
3
=
–
2
2
2
numbering see Figure 3.
Figure 4. (a) Selected regions in the 1H NMR spectra of free-base porphyrin
at room temperature as well as at 238 K. This is indicative of a
process with a large entropy of activation and characteristic of
a flexible system that switches between one or more strictly
H UPC and (b) of its zinc derivative ZnUPC. The most important changes are
2
3
indicated by dashed lines; (400 MHz, 298 K, CDCl ; asterisks correspond to
solvent signals – water, and n-heptane which remained after precipitation).
See Figure 3 for proton numbering.
[
9]
defined conformations. An intense band in the free NH
–1
stretching region (3391 cm ) and a weaker band in the
–1
hydrogen-bonded NH stretching region (3330 cm ), which is Soret band (Δλ = 1–1.5 nm) compared to this band in the UV/
visible in the FT-IR spectrum of ZnUPC in CHCl , reveal that the Vis spectra of its analogues ZnP and ZnOHP where such an
3
intramolecular hydrogen bonding between the alkylurea tails is interaction is absent.
still present, just as in H UPC.
To get more insight in this possible intramolecular coordina-
2
In the literature, several examples of metal porphyrin com- tion, the precursor porphyrin cages of H UPC and its zinc deriv-
2
plexes displaying a coordination bond between oxygen-based ative (designated as H BocPC and ZnBocPC, respectively) were
2
functionalities within the molecule itself and the metal center also studied. Compared to ZnUPC, the intramolecular hydrogen
[
10]
have been reported.
We previously proposed that the carb- bonding possibilities in ZnBocPC should be reduced due to the
onyl groups of the urea moieties in ZnUPC could also act as absence of the urea functions and the presence of the bulky
[
6]
axial ligands. Evidence for such an intramolecular coordina- tert-butyloxycarbonyl (Boc) groups, but the intramolecular coor-
tion was obtained from the UV/Vis spectrum of ZnUPC in dination of the carbonyl group to the zinc metal ion should
1
CHCl /CH CN (1:1 v/v), which showed a somewhat red-shifted still be possible. The H NMR spectrum of H BocPC in CDCl
3
3
2
3
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is practically identical to that of H UPC, except for the signal
2
corresponding to the Boc group (Figure 5, a). Upon insertion of
zinc, the spectrum showed an overall broadening and a higher
number of resonances (Figure 5, b). Notably, the signal of only
one of the Boc groups displayed a large upfield shift (Δδ =
–
1.74 ppm), which is proposed to be the effect of the intramo-
lecular coordination of a carbonyl group to the zinc metal ion.
In the intramolecular bound state, which slowly exchanges with
the unbound state, the methyl protons of the Boc group are
non-equivalent and as a result one of these groups is substan-
tially shielded. Moreover, this coordination also causes a defor-
mation of the whole cavity scaffold, as many resonances corre-
sponding to protons of the glycoluril-based cavity appeared
split or broadened (Figure 5). This is in agreement with the
distortion of the whole structure as predicted by molecular
modelling (Figure 6).
Figure 7. (a) Schematic representation of the competitive binding of pyridine
to ZnBocPC. (b) The titration curve of ZnBocPC (displaying the shift of pro-
1
ton 4a) with py as recorded by H NMR (400 MHz, 298 K, CDCl
3
).
This ligand binds inside the cavity and coordinates to the Zn
[
11]
center.
Upon this binding the coordination of the carbonyl
moiety is proposed to be weakened. Indeed, the NMR spectra
show that upon increasing amounts of pyridine the Boc groups
become on average less shielded and the signal at δ =
–
0.6 ppm shifts downfield (Figure 8). In the presence of an ex-
cess of pyridine, the spectrum of the ZnBocPC–py complex is
very similar to that of the free base analogue H BocPC, except
2
for the shifts observed for the signals of the glycoluril frame-
work, the cavity side-wall and the crown ethers, which change
because of the coordination of pyridine to the zinc metal inside
the cavity. The calculated apparent association constant of the
1
Figure 5. (a) H NMR spectrum of H
2
2
BocPC. (b) Idem, of ZnBocPC (400 MHz,
ZnBocPC–py complex is about two orders of magnitude
3
98 K, CDCl ). The most important changes are indicated by dashed lines;
asterisks correspond to solvent signals – water and n-heptane which re-
mained after precipitation. See Figure 3 for proton numbering.
weaker than that of the ZnP–py complex (Kpy,app = 5.7 × 103
M
–1
5
–1
[11]
vs. Kpy,app = 1.1 × 10
M
for ZnP–py),
which is due to the
above mentioned competition between the intramolecular
zinc–carbonyl coordination and the coordination of the pyr-
idine ligand (Figure 7).
Figure 6. (a) Molecular modelling image of a porphyrin in which one Boc-
protected aminoalkyloxy chain is coordinated to the zinc center (the remain-
ing three substituents and the glycoluril-based cavity are not shown for clar-
ity reasons). (b) Molecular modelling of ZnBocPC showing the coordination
of the carbonyl group of one of the chains to the zinc center and the result-
ing distortion of the porphyrin cavity scaffold.
Further evidence for the intramolecular coordination of the
carbonyl moiety was obtained from a 1H NMR titration of
Figure 8. From top to bottom: 1H NMR spectra of ZnBocPC at increasing
ZnBocPC in CDCl with a competing pyridine (py) ligand (Fig-
3
concentrations of pyridine (400 MHz, 298 K, CDCl ). See Figure 3 for proton
3
ure 7).
numbering.
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Binding Properties
ligand with the intramolecular zinc–oxygen coordination of the
urea carbonyl groups.
Binding of Monodentate Ligands
1
A number of H NMR titrations were carried out in CD Cl/CD CN Binding of Bidentate Ligands
3
3
(
1:1 v/v) to investigate the binding of pyridine derivatives to
The addition of linear bidentate ligands to ZnUPC was investi-
host ZnUPC. Upon the addition of pyridine, the broad signals
in the H NMR spectrum of ZnUPC sharpened (Figure 9), indi-
cating a replacement of the proposed intramolecular zinc–urea
oxygen coordination by the intermolecular coordination of the
pyridine ligand. The upfield shifts of the signals of cavity side-
wall protons H-5 and crown ether protons H-6 reveal that this
gated in order to study the possibility of self-assembly of the
1
[
12]
porphyrin host into dimeric species.
Two molecules of
ZnUPC should be able to dimerize head to head, at least in
principle, by forming hydrogen bonds between the urea func-
tions, and this process may be facilitated by the addition of
a bidentate nitrogen base that bridges the two zinc centers.
Molecular modelling studies suggested that 4,4′-bipyridine
[
10c,11]
complexation predominantly took place inside the cavity.
(
bipy) is the best ligand to bridge the distance between two
1
ZnUPC hosts. Surprisingly, the H NMR spectra of ZnUPC in the
presence and in the absence of 0.5 equiv. of bipy in CDCl3/
CD CN (1:1, v/v) were not significantly different, which suggests
3
that dimer formation does not occur (Figure 10, a–b). Appar-
ently the urea-containing substituents prefer to form intramo-
lecular hydrogen bonds. The fact that no bipy signals are visible
in the NMR spectrum may indicate that the ligand binds weakly
[
13]
inside the cavity of the ZnUPC host, via π–π interactions and
is in rapid equilibrium with free bipy in solution. This explana-
tion was confirmed by the addition of dimethylviologen (V) to
the solution, which strongly binds in the cavity of the host (see
Table 2, entries 1 and 9) resulting in the displacement of bound
bipy and the appearance of non-bound bipy proton signals (δ =
8.68 and 7.61 ppm) as well as a sharpening of the signals (Fig-
ure 10, c). The further addition of bipy to the sample only re-
Figure 9. 1H NMR spectra obtained upon the addition of increasing amounts
of pyridine to ZnUPC [from (a) to (c); 0, 0.5, and 1 equiv. of py; 400 MHz,
2
3 3
98 K, CDCl /CD CN, 1:1, v/v]. See Figure 3 for proton numbering.
On the contrary, the bulky 4-tert-butylpyridine (tbpy) ligand sulted in an increase in the intensity of the uncomplexed bipy
is too large to fit inside the cavity and as a result its coordina- proton signals. In a separate experiment the UV/Vis spectrum
[
11]
–6
tion to the zinc ion can only take place on the outside.
The of a ca. 10
M
ZnUPC solution in CHCl /CH CN (1:1, v/v) in the
3 3
association constant of tbpy with ZnUPC is relatively low, as presence of 1.5 equiv. V was measured. The latter compound
expected, and even lower than the value obtained for ZnP in was added because it may increase the binding of a N-donor
–
1
the same solvent mixture (K = 110
M
for ZnUPC and K = ligand to the porphyrin host by allosteric interactions (vide in-
a
a
–
1
[14]
400
M
for ZnP, Table 2, entries 5 and 6). These low values are, fra). The UV/Vis spectrum only showed a very small red shift
in general, due to the absence of additional stabilizing interac- (<0.2 nm) of the Soret band upon the addition of a large excess
[
11]
tions by the cavity and, in the particular case of ZnUPC, due of bipy (> 10,000 equiv.), confirming that virtually no metal–
to the steric interactions with the alkylurea substituents on the bipy coordination takes place on the “top face” of ZnUPC.
“
top face” of the porphyrin and the competition of the tbpy These observations further support the idea that in ZnUPC one
a a
(M
–1) and Gibbs binding free energies ΔG (kJ mol–1) for the complexation of ZnUPC and ZnP with various ligands L or
Table 2. Association constants K
guests G in the absence and presence of varying concentrations of ligands L or guests G at 298 K. All measurements were performed in duplicate or triplicate
1
in a mixture of CHCl
3
/CH
3
CN (1:1, v/v) in the case of the fluorescence and UV/Vis measurements, and CDCl
3 3
/CD CN (1:1, v/v) in the case of the H NMR
measurements. Estimated errors in K
a
: 20 %.
a]
GAM
L
[b]
Entry
1[
Host
L or G
fixed
L or G
varied
Without G
With G
ΔΔG [
a
K
a
ΔG
a
K
a
ΔG
a
c]
7
7
2
3
7
7
2
ZnUPC
ZnP
ZnUPC
ZnP
ZnUPC
ZnP
ZnUPC
ZnP
V
V
V
V
tbpy (500 equiv.)
tbpy (500 equiv.)
dabco (500 equiv.)
dabco (10 equiv.)
V (1.5 equiv.)
V (1.5 equiv.)
V (10 equiv.)
V (10 equiv.)
–
2.2 × 10
9 × 10
–42
–34
–42
–34
–12
–15
–22
–27
–36
–33
2.3 × 10
–42
–37
–44
–36
–13
–29
–25
–32
n.d.
n.d.
0
–3
–2
–2
–1
–14
–3
–5
n.d.
n.d.
1
3
2
2
2
250
4
8
n.d.
n.d.
[
[
[
[
[
c][f]
c]
5
6
2
3
4
5
6
7
8
9
1
3 × 10
2.2 × 10
5.3 × 10
c]
5
6
9 × 10
2 × 10
d]
tbpy
tbpy
dabco
dabco
V
1.1 × 10
2.2 × 10
d]
2
5
4 × 10
1 × 10
[d]
4[e]
5[e]
6.2 × 10
5.0 × 10
2.0 × 10
6.0 × 10
2.3 × 10
4.0 × 10
n.d.
[
[
f]
c]
4[d]
6
H
H
2
UPC
P
0[c,g]
V
–
5
n.d.
2
a a a L a a
= (ΔG for L with G) – (ΔG = (K of L with G)/(K of L without G). [c] Measured by
for L without G). [b] Allosteric magnification defined as GAM
[
a] ΔΔG
1
[14]
[11]
fluorescence titration. [d] Measured by H NMR titration. [e] Measured by UV/Vis titration. [f] Values taken from ref.
[g] Values taken from ref.
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of the urea carbonyl groups coordinates to the zinc center, very ties, which have high association constants with V substrates
6
–1 [18]
effectively competing with the binding of a ligand.
(K ≈ 10 M ), the possibility of having a dipole-cation inter-
a
action between the urea groups and the viologen moiety
1
should also be taken into account. H NMR experiments, how-
ever, did not indicate any relevant interaction between ZnUPC
and a second V molecule.
The formation of the complex between ZnUPC and V can
also be monitored by fluorescence spectroscopy, since the
binding of the guest inside the cavity leads to quenching of
the fluorescence emitted by the porphyrin. It was observed that
V binds strongly to ZnUPC in an 1:1 host-guest ratio with an
7
–1
association constant of K = 2.2 × 10
M
, which is an order of
a
magnitude higher than that for the binding of V in the non-
5
–1
modified host ZnP (K = 9.0 × 10
M
) (Table 2, entries 1 and
a
2
).
Figure 10. Downfield region of the 1H NMR spectra of ZnUPC (a), after the
addition of 0.5 equiv. of bipy (b), and subsequently 1 equiv. (c) and 1.5 equiv.
In previous papers we reported on the effect of V as an allo-
[
14]
steric effector on the binding of tbpy to ZnP. This guest was
shown to have a significant positive allosteric effect, with also
the viologen guest binding being two orders of magnitude
(
3 3
d) of V; [400 MHz, 298 K, CDCl /CD CN (1:1), v/v].
To further investigate any possible dimerization of ZnUPC,
[19]
larger in the presence of the ligand. Analogous experiments
a smaller but more basic bidentate ligand than bipy, i.e., 1,4-
diazabicyclo[2.2.2]octane (DABCO), was tried as a linker be-
tween the zinc centers. In contrast to our previous studies with
ZnP and other examples in the literature in which the addition
of only half an equivalent of DABCO leads to the formation of
were performed with ZnUPC as the host. Titrations of ZnUPC
with tbpy in CDCl /CD CN (1:1 v/v) in the absence and presence
3
3
of 1.5 equiv. of V gave, within experimental error, similar associ-
2
–1
ation constants, i.e. K (ZnUPC–tbpy complex) = 1.1 × 10
M
a
2
–1
and K (ZnUPC–tbpy–V complex) = 2.2 × 10
M
(Table 2, entry
a
[
14,15]
zinc porphyrin dimers,
sation behavior, as was also confirmed by a 1D- H NMR and a
D-DOSY NMR measurement. Furthermore, upfield shifted
ZnUPC did not exhibit any dimeri-
5
), revealing that there is no cooperative effect of V on the
1
binding of tbpy to ZnUPC. This result can be explained by the
fact that the urea carbonyl groups coordinate to the zinc center
of the porphyrin and hence determine the binding profile of
the host. Hence, the presence or absence of tbpy has little or
no effect on the host-guest binding of viologen.
2
DABCO signals at around –5 ppm, which characterize the for-
mation of zinc-porphyrin–DABCO–zinc-porphyrin sandwich
[
16]
complexes, were not observed (vide infra).
Binding of Dimethylviologen and Cooperative Binding
Effects
In separate experiments the binding affinity of V for H UPC
2
was compared with the binding affinity for its analogue H P in
2
order to evaluate what conformational effect the introduction
of the urea groups has on the binding of V in the cavity of the
As already mentioned above, dimethylviologen (V) is a guest
that strongly binds in the cavity of ZnUPC. To further study this
1
former porphyrin host. The association constant of the H UPC–
binding, a H NMR titration experiment with ZnUPC and V in
2
V complex was 3.3 times higher than that of the H P–V complex
CDCl /CD CN (1:1 v/v) was carried out. The side-wall protons H-
2
3
3
(
entries 9 and 10), corresponding to a difference in binding
5
displayed an upfield complexation induced shift (Figure 11),
–1
energy of ΔΔG = 3 kJ mol . A possible explanation for the
observed difference might be the presence of the intramolecu-
lar hydrogen bonding network between the urea moieties,
which may lead to torsion of the meso-phenyl groups of the
revealing that V is clamped in between the cavity side-walls in
an edge-to-face geometry with respect to the porphyrin plane,
which is the same binding geometry as in the complex of V
[
14,17]
with ZnP.
Based on reported examples of porphyrin recep-
tors functionalized at their meso-positions with diarylurea moie- porphyrin and hence to a conformational change in the recep-
Figure 11. From top to bottom: 1H NMR spectra of ZnUPC in the absence and in the presence of increasing amounts of guest V (400 MHz, 298 K, CDCl
CD CN 1:1, v/v). See Figure 3 for proton numbering.
/
3
3
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1
Figure 12. H NMR spectra of: (I) free ZnUPC, (II) and (III) ZnUPC in the presence of 0.5 equiv. and 1 equiv. of DABCO, respectively, and (IV) after the subsequent
addition of 1 equiv. of V (500 MHz, 298 K, CDCl
DABCO, respectively.
3 3
/CD CN, 1:1, v/v). See Figure 3 for proton numbering; “V“ and “D” indicate proton assignments of V and
tor part of the molecule, which is attached to the porphyrin, spectrum, suggesting that a well-defined species was predomi-
leading to a higher binding constant.
nantly present in solution (Figure 12, IV).
As mentioned above the addition of the bidentate ligand
The formation of the pentameric complex V–ZnUPC–
DABCO did not facilitate the formation of head-to-head dimers DABCO–ZnUPC–V could not be detected in solution, in contrast
[
14]
from ZnUPC. We decided to investigate if the presence of V in to the situation when ZnP was used as a host. In the case of
the cavity would change this and induce a heterotropic cooper- ZnUPC the absence of the pentameric complex was concluded
ative effect on the coordination of DABCO leading to a subse- from the fact that two different chemical shifts were observed
quent dimerization of ZnUPC. Just as observed for the ternary for the DABCO methylene protons, at 0.83 and –2.67 ppm, re-
[
14]
complex ZnP–V–DABCO, the porphyrin proton resonances of spectively, and no signal corresponding to a possible sandwich
ZnUPC bound and unbound to DABCO indicated a process of complex at ca. –5 ppm.
fast exchange on the NMR timescale, which changed into a
slow exchange process when V was added (Figure 12). This indi-
cates that V has a positive cooperative effect on the binding
Conclusions
event between ZnUPC and DABCO. The allosteric magnifica-
G
tion, defined as AM = (K of complex with DABCO in the pres- Previously we reported that MnUPC is a better epoxidation cat-
L
a
ence of V)/(K of complex with DABCO in the absence of V), alyst than MnP and that this compound, in contrast to the latter
a
amounted to 4, and ΔΔGa = –3 kJ mol–1 (Table 2, entry 7). one, requires no axial pyridine ligand for activation. We tenta-
Molecular modelling calculations for the ZnUPC–V–DABCO tively explained this feature from the fact that the carbonyl
complex revealed that the alkylurea substituents can wrap groups of the urea functions of MnUPC were coordinated to
themselves around the zinc-coordinated DABCO molecule, in the metal center making that no additional axial ligand is
such a way that the second nitrogen atom of DABCO interacts needed. All the studies on the zinc derivative ZnUPC presented
with the urea groups via hydrogen bonding. According to this in this paper, confirm this explanation. They clearly show that
molecular modelling the DABCO molecule has the appropriate the urea functions on the porphyrin roof of this compound bind
dimensions to fit inside the pseudo-cavity formed by the alkyl- to the metal center and hence can take over the role of a pyr-
urea groups on top of ZnUPC. 2D-NOESY NMR measurements, idine ligand as the metal-activating species for catalysis. This
however, could not provide evidence for this proposed geome- conclusion is further supported by the NMR measurements and
try because the four alkylurea groups are in rapid dynamic ex- binding studies of the precursor of ZnUPC, ZnBocPC, which
[6]
1
change. The H NMR spectrum obtained when ZnUPC, V, and also possesses carbonyl groups located on the porphyrin roof
DABCO were mixed in a 1:1:1 ratio, indicated a more symmetric that can coordinate to the zinc center.
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Host ZnUPC can thus be regarded as a double “picket fence” 3.73 (d, J = 15.7 Hz, 4 H, ArCH
N in, H4a), 3.55–3.40 (m, 8 H, ArOCH ,
2
2
NH, H6b,17), 3.38–3.19 (m, 4 H, ArOCH , H ), 3.16 (br. s, 4 H, NH, H ),
porphyrin, with one side shielded by a guest binding cavity and
the other side protected by a pseudo-cavity formed by metal
binding urea groups that are linked by hydrogen bonds. This
feature makes the manganese analogue of ZnUPC an ideal pro-
cessive catalyst for the epoxidation of polymer substrates, as
confirmed by our previous studies.
2
6a
18
2
.34–2.08 (m, 8 H, CH NHCO, H ), 2.10–1.94 (m, 8 H, NHCH CH ,
2 16 2 3
H ), 1.24–1.08 (m, 8 H, CH CH CH , H ), 0.12–0.02 (m, 12 H, CH ,
H ) ppm. C NMR (75 MHz, CDCl ): δ = 159.88, 159.74, 158.04,
19
2
2
2
15
3
13
20
3
1
1
1
57.11, 150.23, 150.03, 146.72, 133.74, 131.06, 130.89, 130.21,
30.09, 128.72, 128.61, 128.22, 121.79, 115.86, 111.98, 105.91,
05.84, 84.92, 77.36, 67.41, 67.17, 44.50, 36.78, 33.95, 29.46, 14.81
ppm. MALDI-ToF MS: m/z calculated for C108H110N O Zn: 1982.8,
16
18
+
found 1982.8 ([M ]). UV/Vis [CHCl /CH CN, 1:1 v/v; λmax/nm, (log ε/
3
3
Experimental Section
–1
–1
M
cm )]: 428 (5.6), 560 (4.2), 599 (3.1). IR (neat): ν˜ = 3400, 3343,
+
1
700, 1641, 1564, 1515, 1458, 1247, 1108. HR-MS [ESI (m/z)] calcd.
General: Dichloromethane and acetonitrile were distilled from CaH2
under atmospheric pressure. DMF (after stirring for 7 days with BaO)
was distilled under reduced pressure. K CO was dried in an oven
+
For [C108H110N O Zn + 2Na] = 2028.7207; found = 2028.72456
16
18
(
|Δ| = 1.24 ppm).
2
3
(
150 °C). All other chemicals were commercial products and used
as received. Flash column chromatography was performed using (0.25 g, 2.66 mmol) in dry DMF (2 mL) was added K
silica gel (0.035–0.075 mm) purchased from Acros or Merck. TLC 4.3 mmol). After stirring the solution for 30 min under a nitrogen
1-Ethyl-3-(3-phenoxypropyl)urea (1): To a solution of phenol
CO (0.6 g,
2
3
analyses were performed on silica 60 F254 coated glass either from
Merck or Acros. Molecular modeling calculations were performed
with the use of Spartan® (equilibrium geometry determination by
molecular mechanics using MMFF).
atmosphere, 3-bromo-1-tert-butoxycarbonylpropylamine (0.65 g,
2.73 mmol) was added. The mixture was stirred overnight at 60 °C.
After cooling, the solvent was evaporated and the residue dissolved
in dichloromethane. This solution was washed with water (3 ×), and
the organic phase was separated, dried with Na SO , filtered and
2
4
Syntheses
the solvents evaporated to dryness to yield 0.57 g (63 %) of tert-
butyl 3-phenoxypropylcarbamate as an oil. 1H NMR (400 MHz,
CDCl ): δ = 7.31–7.25 (m, 2 H, ArH ), 6.95 (tt, J = 7.4, 1.0 Hz, 1 H,
Zn-Tetrakis{o-3-[(tert-butoxycarbonyl)amino]propoxy}por-
phyrin Clip (ZnBocPC): To a degassed solution of cavity porphyrin
H BocPC (3.2 mg, 1.6 μmol) in a mixture of CHCl and MeOH (2:1,
3
3
2
3
ArH ), 6.89 (dd, J = 8.8, 1.0 Hz, 2 H, ArH ), 4.76 (br. s, 1 H, NHCO),
4
2
v/v; 2 mL) was added Zn(OAc) ·2H O (5 mg, 2.3 μmol). The mixture
4.02 (t, J = 6.0 Hz, 2 H, OCH ), 3.37–3.30 (m, 2 H, CH NH), 2.02–1.94
2
2
2
2
was excluded from light and refluxed under nitrogen for 3 h. After
cooling, the solvent was evaporated and the residue was dissolved
(m, 2 H, CH CH CH ), 1.44 (s, 9 H, CH ) ppm.
2
2
2
3
To tert-butyl 3-phenoxypropylcarbamate (0.42 g, 1.67 mmol) was
added a saturated solution of HCl in ethyl acetate (10 mL). After
stirring for 4 h, the white precipitate formed was filtered off and
in CH Cl2 (5 mL). The organic layer was washed with water (2 ×
2
5
mL) and concentrated in vacuo. After purification by preparative
TLC (silica, toluene/EtOAc/MeOH, 10:5:1, v/v/v) and filtration
dried under vacuum to yield 0.31 g (98 %) of 3-phenoxypropan-1-
through a short plug of silica (CHCl /MeOH, 98:2, v/v), the product
1
3
ammonium chloride as a white solid. H NMR (300 MHz, CD OD):
3
was dissolved in a minimal amount of CH Cl and this solution was
2
2
δ = 7.23 (dd, J = 8.8, 7.4 Hz, 1 H, ArH ), 6.88–6.81 (m, 4 H, ArH +
4
2
added dropwise to stirred n-heptane to yield, after centrifugation
ArH ), 4.12 (t, J = 5.80 Hz, 2 H, OCH ), 3.16 (t, J = 7.3 Hz, 2 H, CH NH),
3
2
2
and drying of the product under vacuum, 3.3 mg (99 %) of zinc
2
.24–2.08 (m, 2 H, CH CH CH ) ppm.
2 2 2
1
derivative ZnBocPC. H NMR (400 MHz, CDCl ); the non-symmetric
3
To 3-phenoxypropan-1-ammonium chloride (175 mg, 0.93 mmol),
dry dichloromethane (5 mL) and triethylamine (0.15 mL, 1.08 mmol)
were added. When the compound became soluble, ethyl isocyanate
conformation of the molecule gives rise to a high multiplicity of the
signals and therefore an accurate assignment of the spectrum was
not fully possible (see Figure 3 for numbering and Figure 5, b): δ =
(88 μL, 1.12 mmol) was added and the mixture was stirred over-
8
.68 (s, 8 H, pyrrole-ꢀH, H11,12), 7.75–7.62 (m, 4 H, ArH ), 7.12–7.02
9
night at room temperature under a nitrogen atmosphere. Dichloro-
methane (10 mL) was added to the solution and washed with water
(
m, 8 H, ArH8,10), 7.02–6.86 (m, 6 H, ArH1,2), 6.88–6.76 (m, 4 H, ArH3),
6
.30–6.12 (m, 4 H, ArH ), 4.86 + 4.43 (br., 2 H, NHBoc), 4.21 (d, J =
5
(3 × 25 mL). The organic phase was separated, dried with MgSO4,
1
5.8 Hz, 4 H, ArCH N out, H4b), 4.2–0.2 (several multiplets, 42 H,
2
filtered and the solvents evaporated to dryness to yield 200 mg
porphOCH2 + porphOCH2 + OCH CH + ArOCH2 + NHBoc +
2
2
1
(
0.90 mmol) of 1 as a white solid. H NMR (300 MHz, CDCl ): δ =
3
CH NHCO + CH CH CH, H7b,7a,14,6,17,16,15), 3.72 (d, J = 15.8 Hz, 4 H,
2
2
2
7
.31–7.24 (m, 2 H, ArH ), 6.92 (tt, J = 7.3, 1.0 Hz, 1 H, ArH ), 6.88
3
4
ArCH N in, H ), 1.40 + 1.35 + 1.25 (s, 27 H, CH , H ), –0.57 (s, 9 H,
2
4a
3
18
(
dd, J = 8.7, 1.0 Hz, 2 H, ArH ), 4.51 (br. s, 1 H, CH NH), 4.25 (br. s, 1
2
2
CH , H ) ppm. MALDI-ToF MS: m/z calculated for C116H122N O Zn
3
18
12 22
+
+
H, NHCH
2
CH
3
), 4.03 (t, J = 5.8 Hz, 2 H, OCH
2
), 3.41 (t, J = 6.5 Hz, 2
(
[
(
2098.8), found 2098.3 ([M ]). HR-MS [ESI (m/z)] calcd. For
C116H122N O Zn + 2Na] = 2144.78834; found = 2144.79889
+
H, CH NH), 3.19 (q, J = 7.2 Hz, 2 H, NHCH CH ), 2.04–1.94 (m, 2 H,
2 2 3
12
22
CH CH CH ), 1.10 (t, J = 7.2 Hz, 3 H, NHCH CH ) ppm. IR (neat): ν˜ =
2
2
2
2
3
|Δ| = 4.92 ppm).
–1
3
391, 3304, 1678, 1640, 1607, 1586, 1564, 1542, 1498, 1239 cm .
Zn-Tetrakis[3-(3-ethylureido)propoxy]porphyrin (ZnUPC): This
compound was synthesized following the same procedure as de-
Acknowledgments
This research was supported by the European Research Council
scribed for ZnBocPC. Starting from porphyrin clip H UPC, (20.8 mg,
2
1
0.8 μmol) and Zn(OAc) ·2H O (20 mg, 92 μmol) in CHCl /MeOH
2 2 3
(2:1 v/v, 2 mL), 20.1 mg (94 %) of ZnUPC was obtained after purifi-
(ERC) in the form of an Advanced Grant to R. J. M. N. (ALPROS-
cation by column chromatography (silica, MeOH/CH Cl , 3:97, v/v)
2
2
2
2
90886) and an ERC Starting grant to J. A. A. W. E. (NANOCAT-
59064). Further financial support was obtained from the Coun-
1
as a purple solid. H NMR (400 MHz, CDCl ; see Figure 3 for number-
3
ing): δ = 8.85 (s, 4 H, pyrrole-ꢀH, H ): δ = 8.79 (s, 4 H, pyrrole-ꢀH,
1
1
cil for the Chemical Sciences of the Netherlands Organization
for Scientific Research (CW-NWO) (Vidi Grant to J. A. A. W. E. and
H ), 7.71 (t, J = 8.3 Hz, 4 H, ArH ), 7.13–7.00 (m, 8 H, ArH8,10), 7.00–
12
9
6
4
.90 (m, 6 H, ArH1,2), 6.85–6.75 (m, 4 H, ArH ), 6.18 (s, 4 H, ArH ),
3 5
.22 (d, J = 15.7 Hz, 4 H, ArCH N out, H4b), 4.24–4.11 (m, 4 H, por- Vici Grant for A. E. R.) and from the Dutch Ministry of Education,
2
phOCH , H ), 4.10–3.86 (m, 12 H, porphOCH + OCH CH , H7a,14), Culture, and Science (Gravity program 024.001.035).
2
7b
2
2
2
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Keywords: Supramolecular chemistry · Rotaxanes ·
Metalloenzyme mimics · Porphyrinoids · Viologens ·
Manganese
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[19] It is proposed that a structural rearrangement of the host and/or electro-
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0
M.
[
Received: May 20, 2016
Published Online: ■
1
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Full Paper
Metalloenzyme Mimics
Diphenylglycoluril-based metallopor-
phyrin cavities functionalized with alk-
ylurea chains show intramolecular co-
ordination of one of these chains to
the metalloporphyrin. Its impact on
the binding of viologen guests inside
the cavity and coordination of axial li-
gands at the outside is described, and
allosteric binding effects are revealed.
P. Hidalgo Ramos, P. Saisaha,
J. A. A. W. Elemans,* A. E. Rowan,*
R. J. M. Nolte* .................................. 1–10
Conformational Analysis and Bind-
ing Properties of a Cavity Contain-
ing Porphyrin Catalyst Provided
with Urea Functions
DOI: 10.1002/ejoc.201600627
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