Synthesis of Azaylide-Based Amphiphiles by the Staudinger Reaction

Article abstract of DOI:10.1002/anie.202105094

Catalyst- and reagent-free reactions are powerful tools creating various functional molecules and materials. However, such chemical bonds are usually hydrolysable or require specific functional groups, which limits their use in aqueous media. Herein, we report the development of new amphiphiles through the Staudinger reaction. Simple mixing of chlorinated aryl azide with a hydrophilic moiety and various triarylphosphines (PAr3) gave rise to azaylide-based amphiphiles NPAr3, rapidly and quantitatively. The obtained NPAr3 formed ca. 2 nm-sized spherical aggregates (NPAr3)_n in water. The hydrolysis of NPAr3 was significantly suppressed as compared with those of non-chlorinated amphiphiles nNPAr3. Computational studies revealed that the stability is mainly governed by the decrease in LUMO around the phosphorus atom owing to the o-substituted halogen groups. Furthermore, hydrophobic dyes such as Nile red and BODIPY were encapsulated by the spherical aggregates (NPAr3)_n in water.

Full text of DOI:10.1002/anie.202105094

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Accepted Article
Title: Synthesis of Azaylide-Based Amphiphiles by Staudinger Reaction
Authors: Masahiro Yamashina, Hayate Suzuki, Natsuki Kishida,
Michito Yoshizawa, and Shinji Toyota
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10.1002/anie.202105094
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Azaylide-Based Amphiphiles by Staudinger Reaction
Masahiro Yamashina,[a]* Hayate Suzuki,[a] Natsuki Kishida,[b] Michito Yoshizawa,[b] and Shinji Toyota[a]*
Abstract: Catalyst- and regent-free reactions are powerful tools
creating various functional molecules and materials. However, such
chemical bonds are usually hydrolysable or require specific
functional groups, which limits their use in aqueous media. Here we
report that the development of new amphiphiles through the
Staudinger reaction. Simple mixing of chlorinated aryl azide with a
hydrophilic moiety and various triarylphosphines (PAr3) gave rise to
azaylide-based amphiphiles NPAr3, rapidly and quantitatively. The
under mild conditions. However, the formed azaylide is readily
hydrolyzed to primary amine and phosphine oxide once existing
water. Taking advantage of this hydrolysis, the Staudinger
reaction has been usually employed in the biochemical field,[19–
22]
as initiated by Bertozzi and co-workers[23]. Recently, Yan,[24]
Xi,[25] Yoshida, and Hosoya[26] found the “non-hydrolysis”
Staudinger reaction for a biolabeling, in which halogen atoms on
the aryl azide significantly improve the hydrolytic stability of
azaylide.[27,28] This unusual stability prompted us to utilize the
azaylide formation for various supramolecular materials in water.
The advantage of this method is: (i) a variety of trisubstituted
phosphine compounds are commercially available[29] and
reported,[30] and (ii) their triaryl moieties can be utilized for
hydrophobic parts directly. Here we for the first time present the
development of azaylide-based amphiphiles through the
Staudinger reaction, as it is simple mixing of the hydrophilic
subcomponent and various hydrophobic triarylphosphines
(PAr3), and their self-assembly behaviors in water (Figure 1d).
obtained NPAr3 formed ca.
2 nm-sized spherical aggregates
(NPAr3)n in water. The hydrolysis of NPAr3 was significantly
suppressed as compared with those of non-chlorinated amphiphiles
nNPAr3. Computational study revealed the stability is mainly
governed by the LUMO modulation around phosphorus atom due to
the o-substituted halogen groups. Furthermore, hydrophobic dyes
such as Nile red and BODIPY were encapsulated by the spherical
aggregates (NPAr3)n in water.
An amphiphilic molecule, which can self-aggregate and
encapsulate guest molecules in water, has been greatly
attracted in the various fields.[1,2] Such amphiphiles have well-
segregated hydrophobic and hydrophilic parts in the molecule.
The synthesis of amphiphiles is usually conducted in two steps:
(i) construction of hydrophobic parts, (ii) introduction of
hydrophilic chains[3–5] (Figure 1a). Inspired by the green
chemistry,[6] we envisioned that in situ preparation by simple
mixing of the hydrophilic/hydrophobic part and hydrophobic part
with optimum hydrophilic-lipophilic balance would be a powerful
strategy for development of various supramolecular materials[7–
11]. Actually, amphiphiles produced by this concept has been
studied by using noncovalent interactions such as host-guest
system[12,13] and coordination bonding[14,15] (Figure 1b). In the
case of covalent bonding, dynamic covalent bonds[16] and
copper-free click reaction[17] are well studied as catalyst- and
reagent-free reactions. However, despite the micellization is only
performed in water, these covalent bonds are very fragile toward
water or require specific functional groups. Therefore, in situ
method for the development of facile, versatile, and reliable
synthetic methodology for aqueous materials is still challenging
task, so far.
(a) synthetic technique
synthesis of
hydrophobic part
introduction of
hydrophilic part
hydrophilic
part
hydrophobic part
(b)
(c)
hydrophilic
host
N3
N
PPh3
–N2
PPh3
azaylide
metal
ion
NH2 O=PPh3
H2O
i. noncovalent
bonding
ii. coordination
bonding
hydrolyzed products
(d)
this work
hydrophobic part
hydrophilic part
Staudinger
reaction
N
P
+
P
–N2
N3
azaylide-based
amphiphiles
triarylphosphines
subcomponent
The Staudinger reaction is a click-type reaction of an azide
with a phosphine to form an iminophosphorane, so-called
azaylide, which is first reported by Staudinger and Meyer in
1919 (Figure 1c).[18] This reaction rapidly undergoes in high yield
Figure 1. Schematic representations of (a) typical synthetic methodology of
amphiphiles, (b) amphiphiles prepared by noncovalent bonding and
coordination bonding, (c) the Staudinger reaction, and (d) azaylide-based
amphiphiles prepared through the Staudinger reaction.
[a]
[b]
Dr. M. Yamashina, H. Suzuki, Prof. Dr. S. Toyota
Department of Chemistry, School of Science
Tokyo Institute of Technology
2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551, Japan
E-mail: yamashina@chem.titech.ac.jp
We first prepared the hydrophilic subcomponent 1 based on
the previous literatures (Figures S1-S10).[26,31] Subcomponent 1
(0.060 mmol) was then mixed with 0.060 mmol of tris(p-
tolyl)phosphine (PTol3) in CH3CN (5.0 mL) at 60 ºC for 3 min to
form NPTol3 in over 99% yield (Figure 2a, Figures. S19-S24).
The azaylide-based molecules can be switched by combination
of hydrophilic and hydrophobic parts. Indeed, mixing of 1 with
triphenylphosphine (PPh3) and tris(p-anisyl)phosphine (PAni3)
gave rise to corresponding azaylides (NPAr3) such as NPPh3
and NPAni3, respectively (Figures S25-S32). Non-chlorinated
E-mail: stoyota@chem.titech.ac.jp
N. Kishida, Prof. Dr. M. Yoshizawa
Laboratory for Chemistry and Life Science
Institute of Innovative Research, Tokyo Institute of Technology
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202105094
Angewandte Chemie International Edition
COMMUNICATION
nNPAr3 was also synthesized from non-chlorinated 2 and PAr3
(Figure 2a, Figures S11-18, S33-44). Colorless single crystals of
NPPh3I, in which the counter anion was replaced with I–, were
obtained by slow diffusion of Et2O into a solution of NPPh3I in
CH3CN. In the crystalline state, two phenyl groups were
disordered due to their rotation, and one phenyl group was
placed perpendicular to be trans-stilbene-like structure (Figures
2b, S45). NPPh3I and phenyl azaylide[32] indicated similar
dihedral angles in the CA-P-N-CB as 160o and 177o, respectively
Cl–
(a)
N+
d
c
b
a
O
Cl
O
N
P
H2O
Cl
A
C
B
(Figure S46). As
a result of the similar corn angle with
NPTol3
(NPTol3)n
triphenylphosphine, trident NPAr3 would be suitable to form
finite aggregates (Figure S46). The optimized structure of
NPAr3’ with a methyl ester group instead of the hydrophilic
chain was also supported the chemical structure of azaylide
(Figures 2c and S47).
(b)
a
A
B
d
C
b
c
log
(m2/s)
–10.0
–9.5
ppm
(a)
8.0
(c)
7.0
6.0
5.0
4.0
(d)
3.0
2.0
Cl–
N+
Cl–
N+
Cl–
N+
3
3
2
2
1
1
5
0
5
0
5
0
O
O
O
N
O
O
30
Y
PAr3
– N2
O
dav = 2.1 nm
20
10
0
CH3CN
N
Y
Y
Y
N
Y
Y
60 ºC
3 min
quant.
P
X
–
+
N
Ar
Ar
N3
P
5
X
X
1
2
(Y = Cl)
(Y = H)
Ar
0
0
2
4
6
8
1
0
1
2
1 4
NPAr3 or nNPAr3
0
3
6
9
12 nm
2.4 nm
(b)
(c)
Y = Cl
Figure 3. (a) Schematic representations of the self-assembly of (NPTol3)n in
water. (b) 1H NMR and DOSY spectra (500 MHz, 298 K, D2O, 4.0 mM based
on NPTol3) of (NPTol3)n. (c) DLS chart of (NPTol3)n (298 K, H2O, 4.0 mM
based on NPTol3). (d) Molecular modeling of the azaylide-based aggregate
NPTol3 (X = CH3)
NPPh3 (X = H)
NPAni3 (X = OCH3)
CB
(NPTol3)10
.
Y = H
nNPTol3 (X = CH3)
nNPPh3 (X = H)
nNPAni3 (X = OCH3)
The aggregation is further supported by nuclear Overhauser
effect spectroscopy (NOESY), where correlations are obviously
obtained between the terminal methyl and the interior phenyl
protons (HC–HA) (Figure S50). In addition, the concentration-
dependent 1H NMR spectra clearly showed the gradual upfield
shifting of HC and HB (Dd = up to 0.61 ppm), as the concertation
increased from 0.40 to 8.0 mM (Figures S64,65, Table S3).
Interestingly, in the range of 0.020 to 0.20 mM, all of the proton
signals became sharp without shifting because of the
monodispersity of NPTol3 (Figures S64,65). Thus, the critical
micelle concentration (CMC) of NPTol3 is estimated to be ~0.40
mM, which is relatively low as compared with those of classical
amphiphile (e.g., sodium dodecyl sulfonate (SDS) for 8.0 mM[33]).
In the same manner as NPTol3, the formation of (NPPh3)n and
(NPAni3)n was confirmed (Figures S53-62). It is noteworthy that
the CMC of NPPh3 shows ~2.0 mM which is 5-fold higher than
those of NPTol3 and NPAni3. (Figures S66-69, Tables S4,5).
This outcome implies that the presence of aromatic-alkyl CH-p
interaction leads to enforce the strong aggregation. In addition,
the in situ preparation of (NPAr3)n was successfully
demonstrated by mixing of 1 and corresponding PAr3 in pure
water even in heterogeneous system (Figure S63). Two chlorine
atoms probably contribute increasing the hydrophobicity since
the broad 1H NMR signal was not observed in non-chlorinated
nNPAr3 (Figures S73-75). (n)NPAr3 displayed absorption
CA
Figure 2. (a) Formation of azaylide through phosphazide in acetonitrile. (b)
The ORTEP drawing of NPPh3I which is an analogue of NPPh3. Counter
anions are omitted for clarity. (c) The optimized structure of NPTol3’ at the
B3LYP/6-31G (d,p) level with the conductor-like polarizable continuum model
(CPCM; H2O) (red ball: phosphorus, blue ball: nitrogen, green and light blue:
carbon, yellow: chlorine, pink: oxygen)
The supramolecular behavior of azaylide-based amphiphiles
was investigated in water. When NPTol3 (4.0 mmol) was
dissolved into water (1.0 mL), azaylide-based aggregate
(NPTol3)n was formed spontaneously (Figure. 3a). In the 1H
NMR spectrum of NPTol3 (4.0 mM in D2O), a set of signals for
tolyl moiety was considerably broadened and shifted upfield (Dd
= ~0.6 ppm) (Figure 3b, Figure S48). The 31P NMR signal
significantly defused in stark contrast to a sharp and strong
signal in CD3CN (Figure S49). These characteristic spectrum
changes arise from existing of dynamic behavior. The diffusion-
ordered spectroscopy (DOSY) NMR spectrum showed a single
band with D = 9.79 × 10–11 m2 s–1 (Figure 3b, Figures S51-52).
Dynamic light scattering (DLS) measurement provided relatively
small aggregates ~2 nm with a narrow distribution (Figure 3c,
Figure S60), which is comparable to a diameter of spherical
aggregates (NPTol3)10 (Figure 3d, Figures S61-62).
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10.1002/anie.202105094
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COMMUNICATION
bands around 320 nm and indicated a weak blue emission in
water or acetonitrile (Figures S70-72, Table S6).
To obtain further insight into the unusual hydrolytic stability of
the azaylide, we carried out density functional theory (DFT)
calculation in water for chlorinated NPTol3’ and non-chlorinated
nNPTol3’ without the hydrophilic chain as model compounds.
The calculated HOMO of NPTol3’ shows low energy level in
comparison with nNPTol3’ (Figure S82). This fact indicated that
two chlorine atoms stabilized the HOMO leading to a decrease
of basicity of nitrogen atom. Visualization of the molecular
orbitals (MOs) is given in Figure S82. The LUMOs of aryl ester
(Hyd) and triarylphosphine (Aryl) moieties between NPTol3’ and
nNPTol3’ show precisely different distribution; the fragment
composition of Hyd to Aryl was 66% : 24% for NPTol3’ and
25% : 64% for nNPTol3’, estimated by MO analysis (Figure 4f,
Figures S82-83).34 As a result of these differences, the LUMO
around phosphorus atom in NPTol3’ was remarkably reduced
by 40% compared to nNPTol3’ (Figure S84). Likewise, other
azaylides NPPh3’ and NPAni3’ show similar tendencies in
comparison with those of non-chlorinated ones (Figures S82-84).
Thus, the LUMO modulation around phosphorus atom arose
electron withdrawing chlorine atoms stabilized the azaylide
moiety because nucleophilic addition of water on phosphorus
atom has become a rate-determined step (Scheme S1).[35,36]
Steric protection effect may be related in this system as well.
Encouraged by the finding of those supramolecular
aggregations, we next investigated the stability of the azaylide-
based amphiphile toward water. An azaylide moiety is generally
sensitive to water and organic solvents such as CS2.[24] Indeed,
the non-chlorinated nNPTol3 was rapidly hydrolyzed in water at
293 K affording the corresponding primary amine and phosphine
oxide after a few hours (Figure 4a bottom and 4b, Figure S73).
The half-life of nNPTol3 in water at 293 K was calculated to be
~12 h by monitoring the 1H NMR signals (Figures S73,79, Table
S7). In contrast, the chlorinated NPTol3 came out to be
consistently tolerated under the same conditions (Figure. 4a top
and 4c, Figure S76). NPPh3 and NPAni3 were more stable than
the corresponding non-chlorinated derivatives nNPPh3 and
nNPAni3, respectively (Figures. S74,75,77-79, Table S7). This
unique stability was also observed under the monodispersity
state (Figures S80,81). These results clearly revealed that two
chlorine atoms remarkably enhanced the tolerance of azaylide
for hydrolysis. The water content ratio in the solvent is strongly
related to the rate of hydrolysis, where the reaction accelerated
as the water ratio increased in the solvent. To the best of our
knowledge, this is first example in which azaylides successfully
demonstrated the tolerance test in pure water.[24,26]
Finally, we carried out experiments for the guest
encapsulation within the azaylide-based aggregates in water.
Whereas polyaromatic amphiphiles capable of uptaking
hydrophobic molecules have been reported,[37] amphiphiles
containing a triarylphosphine core are rarely reported so far.[38, 39]
Thus, the host capability of triarylphosphine core is obscure.
When Nile red (NR, excess) as hydrophobic organic dye was
mixed with 8.0 mM aqueous solution of NPTol3 (0.5 mL)
overnight at room temperature, the solution color changed from
colorless to a bright pink (Figure 5a). After removal the excess
NR by filtration, the formation of the host-guest complex was
confirmed by NMR, UV-vis, fluorescence, and DLS
measurements. As a result of NMR analysis, ~0.1 mM of NR
was found in 4.0 mM of NPTol3 aqueous solution (Figure S85).
The UV-vis spectrum shows a broad absorption band around
493 and 562 nm, which indicates that hydrophobic NR is
dissolved in water through encapsulation (Figure 5b). In the
fluorescence spectrum, intense fluorescence of NR significantly
O
Cl–
O
(a)
N+
Y
O
NPTol3
(Y = Cl)
Cl–
H2N
Y
N+
Y
O
r.t., H2O
O
P
N
Y
P
nNPTol3
(Y = H)
(b)
0 h
(c)
0 h
(d)
1 00 0.
9
0.0
0.0
NPTol3
8
y
=
96.9e-4E-05x
0.1585
80
60
40
20
R²
=
7
6
0.0
0.0
5
4
3
0.0
0.0
0.0
60 h
60 h
nNPTol3
τ = 12 h
2
1
0.0
0.0
y = 96.3e-0.06x
decreased (FF
= 0.1%) because of the tight guest-guest
R²
=
0.9982
0
0.
0
1
0
2
0
3
0
4
0
5
0
6
0
7
0
8 0
0
ppm
aggregation (Figure 5b). DLS measurement revealed relatively
large aggregates with narrow size distribution which is
approximately 4.5 nm as a diameter (Figure S88). This size of
nanoparticle most probably corresponds to NR15•(NPTol3)40 as
estimated by molecular mechanics calculation (Figure 5c). The
increased the size of encapsulated micelle was the
consequence of strong guest-guest aggregation.[40] Similarly,
(NPTol3)n successfully encapsulated pyrromethene 546 (BP) in
water. The characteristic absorption band around 455 and 501
nm arose encapsulated (BP)n and significant low fluorescence
quantum yield (~0.1%) were confirmed as well as NR (Figure
S87). The encapsulated particle was displayed approximately
6.6 nm with a broad distribution (Figures S88,90), which is larger
than the encapsulated NR.[40] In the same manner, we
succeeded in encapsulation of NR and BP by using NPPh3 and
NPAni3, respectively (Figures S86,87,89). Interestingly, NPPh3
/ h
16 32 48 64
0
8.0
(e)
7.0
8.0
7.0
(f)
Hyd
25
Hyd
66
N 1
Hyd
N
P
P
10
N 3
P 7
Aryl
Aryl
64
Aryl
24
nNPTol3’
NPTol3’
nNPTol3’ NPTol3’
Figure 4. (a) Reaction scheme of the hydrolysis of NPTol3 and nNPTol3 in
water. 1H NMR spectra (500 MHz, 298 K, D2O) before and after 60 h of (b) 4.0
mM of nNPTol3 and (c) 4.0 mM of NPTol3. (d) Time-course of the
decomposition of NPTol3 and nNPTol3 in water for 60 h. (e) Visualization and
(f) fragment composition of the LUMOs for nNPTol3’ and NPTol3’.
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10.1002/anie.202105094
Angewandte Chemie International Edition
COMMUNICATION
[2]
Y. Moroi, Micelles: Theoretical and applied aspects, Plenum Press,
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has low uptake ability toward both NR and BP, although NPAni3
has strong affinity for NR as well as NPTol3 observed by UV-vis
absorption bands. Thus, this result also indicates that CH-p
interactions between host and guest molecules play an
important role in forming a robust host-guest complex in water.
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4.5 nm
3
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In conclusion, we have developed facile synthesis
methodology for amphiphiles through the Staudinger reaction.
Simple mixing of the hydrophilic subcomponent and hydrophobic
triarylphosphines gave rise to corresponding azaylide-based
amphiphiles rapidly and quantitatively. The amphiphiles form
spherical aggregates which are ~2.0 nm as a diameter in water
through p-p and CH-p interactions. Hydrolysable azaylide moiety
is significantly stabilized in water because of the LUMO
modulation around phosphorus atom arose electron withdrawing
chlorine atoms. Furthermore, the obtained amphiphiles provide
host capability toward hydrophobic organic dye in water. The
present azaylide formation serves as a new type of preparation
technique without catalysts and reagents, which will enable to
create further functional materials in aqueous media.
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Acknowledgements
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10.1002/anie.202105094
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Entry for the Table of Contents
COMMUNICATION
M. Yamashina,* H. Suzuki, N. Kishida,
M. Yoshizawa, and S. Toyota*
N3
N
P
micelles
hydrophilic
Page No. – Page No.
azide
azaylide-based
amphiphiles
+
Synthesis of Azaylide-Based
P
Amphiphiles by Staudinger Reaction
–N2
hydrophobic
triarylphosphines
in situ
Here we report new type of amphiphiles through the click-type Staudinger reaction,
which is in situ preparation by mixing of hydrophilic azide and hydrophobic
triarylphosphine. These azaylide-based amphiphiles are stable against hydrolysis
even in water and form ~2 nm spherical aggregates through self-assembly.
Furthermore, the obtained amphiphiles by our method are capable of encapsulation
of hydrophobic organic dyes in water.
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