Cavitands as Reaction Vessels and Blocking Groups for Selective Reactions in Water

Article abstract of DOI:10.1002/anie.201602355

The majority of reactions currently performed in the chemical industry take place in organic solvents, compounds that are generally derived from petrochemicals. To promote chemical processes in water, we examined the use of synthetic, deep water-soluble cavitands in the Staudinger reduction of long-chain aliphatic diazides (C₈, C₁₀, and C₁₂). The diazide substrates are taken up by the cavitand in D₂O in folded, dynamic conformations. The reduction of one azide group to an amine gives a complex in which the substrate is fixed in an unsymmetrical conformation, with the amine terminal exposed and the azide terminal deep and inaccessible within the cavitand. Accordingly, the reduction of the second azide group is inhibited, even with excess phosphine, and good yields of the monofunctionalized products are obtained. In contrast, the reduction of the free diazides in bulk solution yields diamine products.

Full text of DOI:10.1002/anie.201602355

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602355
German Edition: DOI: 10.1002/ange.201602355
Supramolecular Chemistry
Cavitands as Reaction Vessels and Blocking Groups for Selective
Reactions in Water
Daniele Masseroni, Simone Mosca, Matthew P. Mower, Donna G. Blackmond,* and
Julius Rebek, Jr.*
Abstract: The majority of reactions currently performed in the
chemical industry take place in organic solvents, compounds
that are generally derived from petrochemicals. To promote
chemical processes in water, we examined the use of synthetic,
deep water-soluble cavitands in the Staudinger reduction of
long-chain aliphatic diazides (C , C , and C ). The diazide
8
10
12
substrates are taken up by the cavitand in D O in folded,
2
dynamic conformations. The reduction of one azide group to
an amine gives a complex in which the substrate is fixed in an
unsymmetrical conformation, with the amine terminal exposed
and the azide terminal deep and inaccessible within the
cavitand. Accordingly, the reduction of the second azide
group is inhibited, even with excess phosphine, and good yields
of the monofunctionalized products are obtained. In contrast,
the reduction of the free diazides in bulk solution yields
diamine products.
Figure 1. Chemical formula, conformation, and schematic representa-
tion of the deep, water-soluble cavitand 1.
Scheme 1. Staudinger reduction.
W
e recently developed new container molecules—deep,
a,w-diazides to monoamines within 1 by using trimethylphos-
water-soluble cavitands 1 (Figure 1) that function over a large
phine (PMe ) in D O. The reaction of azides and triaryl- or
3
2
[1]
pH range—as vessels for reagents reluctant to enter water.
trialkylphosphines reliably forms amines almost quantita-
tively under mild conditions through iminophosphorane
The containers are vase-shaped structures that use the
principles of molecular recognition to target molecules of
complementary sizes, shapes, and chemical surfaces. The key
to their function as receptors in water is the burial of
hydrophobic guests within the cavitand host. We demonstrate
here the advantages of folded guest shapes within cavitands to
dramatically alter the reactivities of two ends of a symmetrical
substrate. These molecular containers offer access to reaction
selectivities that are unknown in bulk solution. Specifically,
[
3]
intermediates. If the reaction is performed in aqueous
solvent, the iminophosphorane intermediates are readily
hydrolyzed to yield the primary amines and phosphine(V)
oxide. In our study, the differences in the folding conforma-
tions of the starting materials and the desired products within
the cavitand gave rise to exceptional product distributions.
Sonication of a,w-diazides with 1 gave stoichiometric
1
host–guest complexes, with their H NMR spectra showing
[2]
we applied the Staudinger reaction (Scheme 1) to reduce
characteristic upfield-shifted signals (Figure 2; see also the
Supporting Information). There are well-established exper-
imental and computational correlations between upfield
shifts and positions of nuclei within this and related cav-
[*] Dr. D. Masseroni, Prof. Dr. J. Rebek, Jr.
Department of Chemistry, Fudan University
[1]
itands. The eight aromatic panels of the container create
220 Handan Road, Shanghai 200433 (China)
a magnetic anisotropy that shields nuclei from the applied
magnetic field of the spectrometer. Nuclei in the deepest parts
of the cavitand experience the largest upfield shifts (Dd of ꢀ4
to ꢀ5 ppm) and those near the rim the smallest upfield shifts
Dr. S. Mosca
Department of Biotechnology and Biosciences
University of Milano-Bicocca
20126 Milano (Italy)
(Dd of ꢀ0.5 to 0 ppm). However, the diazides show signals
Dr. S. Mosca, M. P. Mower, Prof. Dr. D. G. Blackmond,
Prof. Dr. J. Rebek, Jr.
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute
clustered around 0 to ꢀ1.3 ppm (i.e. Dd of ꢀ1 to ꢀ2 ppm).
Accordingly, the methylene groups are not fixed at the top or
at the bottom of the cavity. Instead, they are in a rapid,
dynamic equilibrium, whereby a given methylene group
resides sometimes deep inside the cavitand (where it expe-
riences a Dd of ꢀ4 ppm) and sometimes outside (where no
shift occurs). A symmetrical compound must spend equal
times in the two environments, so the average Dd value of the
magnetic environments is about ꢀ2 ppm. This places the
signals for the nondescript methylene groups at around
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: blackmond@scripps.edu
jrebek@scripps.edu
Supporting information (synthesis and characterization of new
compounds, materials, methods for all experiments, kinetic model-
ing details, and additional spectral data) and the ORCID identifica-
tion number(s) for the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201602355.
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Figure 2. Left: Upfield portions of the H NMR spectra of a,w-diazide@cavitand 1 complexes (400 MHz, 298 K, D O): a) (diazide C )@cavitand;
2
8
b) (diazide C )@cavitand; c) (diazide C )@cavitand. Right: Schematic representations of diazide C , C and C12 in the cavitand as the rapidly
1
0
12
8
10
interconverting J-shaped conformations of the guest.
1
ꢀ
0.7 ppm, where they in fact appear. The H NMR spectra of
the diazides indicate time-averaged and unsymmetrical
J-shaped arrangements rather than fixed and symmetrical,
U-shaped ones. The situation is depicted in Figure 2 (see also
the Supporting Information). Attempts to freeze out the
motion at lowered temperatures were unsuccessful.
Treatment of the complexes in D O with an excess of
2
PMe (3 equivalents) in an NMR tube induces changes in the
3
spectra. Figure 3 shows, as an example, the changes for the
complex of C12 (for C and C , see the Supporting Informa-
10
4]
8
[
tion). Dimethylsulfone was used as an internal standard, and
the product distribution with time is shown in the stacked
spectra. The new resonances that appear match the signals of
authentic monoamine monoazide C12 inside the cavitand (see
the Supporting Information).
The methylene signals of both the monoamine and
diamine in the cavitand appear further upfield than those of
the diazide, and are consistent with static complexes. The
assignments shown in Figure 3 are based on COSY spectra
(
see the Supporting Information) and reflect the correlation
of the upfield shift (ꢀDd) with the depth of the nuclei in the
cavity. The diamine shows the typical upfield shifts of
[1]
a conventionally folded bola-amphiphile. Most informa-
tively, the methylene groups a and b to the monoazide are
shifted furthest upfield. The steric requirements of the narrow
N3 function apparently allow a sharp bend in its attached
chain that can penetrate deeply into the cavitand. The fixed
conformation of this complex buries the azide end inside the
cavity, thereby isolating it from the bulk solution and
Figure 3. Top: Illustration of the Staudinger reduction of the (diazide
C )@cavitand complex in D O, with suggested conformations of the
possible products inside the container. Bottom: Partial NMR spectra
of the reduction reaction of diazide C12 (exp. C12(a); see the Supporting
1
2
2
Information) chaperoned by cavitand 1 (400 MHz, 298 K, D O):
2
a) diazide C12 complex in D O; b) addition of 3 equiv of PMe to (a),
2
3
15 min; c) 30 min; d) 45 min; e) 60 min; f) 75 min; g) 90 min;
h) 105 min; i) 120 min; l) 135 min; m) 150 min; n) 210 min; o) 25 h;
preventing reaction with PMe . The addition of another
3
p) authentic C12 monoamine monoazide in cavitand 1 in D O;
2
three equivalents of phosphine to the reaction mixture after
q) authentic C12 diamine in cavitand 1 in D O.
2
2
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2
4 h (or to the authentic monoazide complex for control, see
reports of this reaction supports this assignment for complex
the Supporting Information) did not change the chemical
shifts or the integrals of the spectra, thus confirming that the
remaining azide group is inaccessible to the reducing agent.
The striking ability of the cavitand to suppress the rapid
interconversion of the two ends of the molecule in and out of
the cavitand once one azide has been reduced to an amine
rationalizes the excellent selectivity afforded by the chaper-
one.
I. Build up of this intermediate may be responsible for the
poor material balance based solely on diazide and mono-
amine during the early part of the reaction. As shown in
Figure 4, the kinetic model based on Equations (1) and (2)
provides a good fit to the temporal concentration data for the
substrate and product, thus allowing an estimate of the
temporal concentration of the presumed iminophosphorane
[
5]
intermediate.
Figure 4 shows the kinetic profile of the reaction of the C12
diazide within cavitand, taken from integration of the NMR
time course data in Figure 3. Rapid consumption of the
diazide to form an intermediate species suggested to be an
iminophosphorane is followed by quantitative conversion into
the monoamine product in less than three hours, with no
formation of the diamine product observed.
Similar results were obtained with the C10 diazide; nearly
quantitative yields were observed for the monoamine. An
accurate determination of the distribution of the molecular
species was not possible with the shorter diazide (C ). The
8
resonances of the guests became broadened after addition of
the phosphine. Nevertheless, integration of the monoamine
signals in the NMR spectrum after 24 h reaction gave a rough
estimate, with the yield around 50–60% (see the Supporting
Information). The deeper complex formed by the C diazide
8
(Figure 2) compared to C10 or C12 diazides could explain its
lowered reactivity toward PMe in solution.
3
Control experiments (without cavitand) were performed
both with diazides using [D ]2-propanol as cosolvent and with
8
the monoreduced azide in D O. The reaction outcomes were
2
1
monitored by H NMR spectroscopy (the Supporting Infor-
mation). In the absence of the cavitand, diazides and
monoaminoazides are both converted quantitatively into the
diamines, without any traces of the monoamine product,
again highlighting the striking ability of the cavitand to
suppress the second reduction step.
Table 1 summarizes the rate constants determined from
kinetic modeling studies of the reactions using COPASI
Figure 4. Product distribution and kinetic model curves for the reduc-
tion of diazide C12 with cavitand 1. Open circles represent experimental
data from three runs; lines represent the kinetic model of Equa-
[
5]
software with and without cavitand. Comparison of the
values of k to k ’ and k to k ’ supports the hypothesis that the
1
1
2
2
[
5]
tions (1) and (2).
kinetics of the sequential reaction of azide to amine is similar
with and without the cavitand, and the primary role of the
cavitand is to suppress the onward reaction of the monoamine
to the diamine product.
The sequential reaction can be modeled from the
experimental data according to Equations (1) and (2).
Formation of an intermediate (rate constant k ) precedes its
1
Table 1: Rate constants derived from kinetic modeling of the sequential
reactions according to Equations (1) and (2).
hydrolysis (rate constant k ) to the monoamine product. A
[a]
2
second sequential reaction converting the monoamine into
Substrate
Diazide with cavitand
Monoamine without cavitand
the diamine product (with k ’ and k ’) occurs only in the
1
2
[b]
[b]
[b]
[b]
k1
k2
k ’
k ’
2
1
absence of the cavitand.
C12
C10
C8
36.4
26.6
–
0.026
0.029
–
30.4
13.4
13.1
0.032
0.044
0.045
k1
k2
diazide ƒ! intermediate ƒ! monoamine
ð1Þ
ð2Þ
[
c]
[c]
0
0
2
k
1
k
[5]
monoamine ƒ! intermediate ƒ! diamine
[a] Modeling studies carried out using COPASI software. [b] Units of
ꢀ1
ꢀ1
rate constants are M
h . [c] k and k for diazide C with cavitand could
1 2 8
not be calculated because of inaccurate integration measurements of the
NMR spectrum.
The function of the cavitand may be thought of as
a loosely held blocking group: once the first reduction step
occurs, the cavitand suppresses the rapid equilibration of the
two ends of the molecules, thus hiding the second azide site
and thereby altering the reaction product selectivity. The
formation and build up of the intermediate iminophosphor-
ane is not directly observed due to interference from other
signals in the NMR spectra of complex I under the reaction
conditions. However, the observation of signals attributed to
the iminophosphorane in the solution reaction (see the
Supporting Information) and consideration of literature
A variety of contorted alkane shapes are observed in
[
6]
closed systems such as capsules and open-ended systems
[7]
[8]
such as cyclodextrins and cucurbiturils. In earlier studies,
we used the folded conformations that bring the guest ends
close together to promote macrolactamization reactions in
[
9]
cavitands. Here, the cavitand plays a complementary and
contrasting role by inhibiting the further reactions of a folded
guest; this overcomes a general problem of the monofunc-
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Angewandte
Communications
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[
10]
tionalization of symmetrical compounds.
When the two
reaction sites on a molecule are remote such that they act
independently, statistically determined yields are obtained;
the yield of the desired monofunctionalized product under
these circumstances is < 50%, a common bane of such
reactions.
[
1] K.-D. Zhang, D. Ajami, J. V. Gavette, J. Rebek, Jr., J. Am. Chem.
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[
[
The cavitand plays two roles in the reactions in this study:
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[
11]
second, it behaves as a supramolecular protecting group in
which the mechanical barriers of the walls isolate reactive
functions from reagents in solution. The unprecedented effect
on the chemical selectivity of the present monofunctionaliza-
tion reaction requires use of the cavitand as a stoichiometric
agent to chaperone each substrate molecule. However, the
cavitand can be recovered by simple extraction for use in
further reactions (see the Supporting Information), and we
are working toward combining these processes toward the
goal of true catalysis with turnover.
1
[
5] S. Hoops, S. Sahle, R. Gauges, C. Lee, J. Pahle, N. Simus, M.
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1
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[
2015, 137, 14582 – 14585.
[
[
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Acknowledgements
This research was supported by the Thousand Talents
Program, Fudan University of Shanghai, China, the National
Science Foundation of the USA (CHE 1506266), and a Marie
Curie International Outgoing Fellowship within the 7th
European Community Framework Programme; Grant
PIOF-GA-2013-627403 provided a postdoctoral fellowship
1065; b) R. M. Yebeutchou, E. Dalcanale, J. Am. Chem. Soc.
2009, 131, 2452 – 2453; c) H. Ren, Z. Huang, H. Yang, H. Xu, X.
Zhang, ChemPhysChem 2015, 16, 523 – 527; d) B. Breiner, J. K.
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Smulders, J. R. Nitschke, Chem. Sci. 2012, 3, 785 – 788.
(
to S.M.).
Keywords: cavitands · diazides · selectivity ·
Staudinger reduction · supramolecular chemistry
Received: March 7, 2016
Published online: && &&, &&&&
4
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Communications
Supramolecular Chemistry
D. Masseroni, S. Mosca, M. P. Mower,
D. G. Blackmond,*
J. Rebek*
&&&& — &&&&
Cavitands as Reaction Vessels and
Blocking Groups for Selective Reactions
in Water
Reaction shutdown: A deep, water-solu-
ble cavitand allows the selective mono-
reduction of diazides to monoamines.
The unusual reaction pathway can be
explained by different folding conforma-
tions of the starting materials and prod-
ucts inside the container.
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