Active ester functionalized azobenzenes as versatile building blocks

Article abstract of DOI:10.3390/molecules26133916

Azobenzenes are important molecular switches that can still be difficult to functionalize selectively. A high yielding Pd-catalyzed cross-coupling method under mild conditions for the introduction of NHS esters to azobenzenes and diazocines has been established. Yields were consistently high with very few exceptions. The NHS functionalized azobenzenes react with primary amines quantitatively. These amines are ubiquitous in biological systems and in material science.

Full text of DOI:10.3390/molecules26133916

molecules
Article
Active Ester Functionalized Azobenzenes as Versatile
Building Blocks
Sven Schultzke 1,2,† , Melanie Walther 1,2,† and Anne Staubitz 1,2,
*
1
Institute for Analytical and Organic Chemistry, University of Bremen, Leobener Straße 7,
D-28359 Bremen, Germany; schultzke@uni-bremen.de (S.S.); melanie.walther@uni-bremen.de (M.W.)
MAPEX Center for Materials and Processes, University of Bremen, Bibliothekstraße 1,
D-28359 Bremen, Germany
2
*
†
Correspondence: staubitz@uni-bremen.de; Tel.: +49-421-218-63210
These authors contributed equally to this work.
Abstract: Azobenzenes are important molecular switches that can still be difficult to functionalize
selectively. A high yielding Pd-catalyzed cross-coupling method under mild conditions for the intro-
duction of NHS esters to azobenzenes and diazocines has been established. Yields were consistently
high with very few exceptions. The NHS functionalized azobenzenes react with primary amines
quantitatively. These amines are ubiquitous in biological systems and in material science.
Keywords: azobenzene; diazocine; molecular switches; palladium-catalyzed carbonylation; photo-
switchable NHS ester; N-hydroxysuccinimide; chemical biology
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
1. Introduction
Citation: Schultzke, S.; Walther, M.;
Staubitz, A. Active Ester
Photoswitchable molecules add photoresponsiveness to diverse materials such as poly-
mers [1–6], dendrimers [7,8] or biomolecules [9–23]. By precise adjustment of the synthetic
Functionalized Azobenzenes as
Versatile Building Blocks. Molecules
2021, 26, 3916. https://doi.org/
10.3390/molecules26133916
strategy the switch can be incorporated into the target material and its switching properties
can be utilized. However, in many cases, it is exactly this tailored functionalization of the
photoswitch that is the major challenge and the bottleneck in a successful project.
Due to its fast and efficient photoswitching characteristics, as well as its high fatigue-
resistance [24], azobenzene is widely used in versatile applications such as molecular ma-
Academic Editors: Estelle Léonard
and Muriel Billamboz
chines [3,25–28], data storage materials [29–32], or photopharmacology [9–23]. Upon irra-
diation with UV-light, typical azobenzenes undergo isomerization from the thermodynam-
ically favored (E)-isomer to the less stable (Z)-isomer (Figure 1, left). The re-isomerization
can occur either by irradiation with light or by thermal relaxation [24,33]. The half-lives of
the latter strongly depend on the azobenzenes’ substitution pattern and are therefore tun-
able for the specific application [34]. The isomerization is accompanied by a change of sev-
Received: 31 May 2021
Accepted: 23 June 2021
Published: 26 June 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
eral physicochemical characteristics: the geometry [35,36], the end-to end-distance [35,36],
and the electronic properties [37] (e.g., absorption and dipole moment). The thermodynam-
ically favored (E)-form is planar [35] and without a dipole moment [37]. The (Z)-isomer on
the other hand has a bent geometry where the phenyl rings are twisted ~55◦ out of plane
to the azo group [36]. Moreover, the (Z)-isomer shows a dipole moment of 3.0 Debye [37].
The end-to-end distance of the (E)- and (Z)-isomer differs by ~3.5 Å [35
systems, azobenzenes bind typically in an elongated confirmation; its biological activity
is controllable via the switching process [ ]. The isomerization to the (Z)-isomer occurs
by irradiation with UV-light, which might harm cells and tissues [38 40]. Therefore, a
red-shifting of the absorption wavelength is desirable and in biological applications may
be even necessary [ ]. In addition, a separation of the absorption spectra of both isomers
is important to avoid mixtures of isomers. Starting from 2009, ortho-substituted azoben-
zenes [41 50] and ethylene-bridged azobenzenes, the so-called diazocines [51 52], have
been discovered to be promising candidates to overcome the two limitations of a typical
,36]. In biological
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conditions of the Creative Commons
Attribution (CC BY) license (https://
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Molecules 2021, 26, 3916
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azobenzene. Depending on the substituents in ortho-position, not only the absorption
is shifted towards longer wavelength but also the thermal half-life may be drastically
extended due to steric and electronic interactions [48]. Diazocines are also a particularly
important class of azobenzenes, because the bent (Z)-isomer is thermodynamically favored
due to the ring strain of the eight-membered ring (Figure 1, right). The isomerization of di-
azocines is in both directions possible using visible light; the isomerization to the elongated
(E)-form occurs upon irradiation with light in the range of 400 nm, the re-isomerization to
(Z) with 530 nm [51].
azobenzene
ortho-azobenzene
diazocine
E
F
F
N
N
(Z)
(Z)
(E)
F
F
N N
N N
h
kBT(h )
h
kBT(h )
h
kBT(h )
1
2
1
2
1
2
365 nm >400 nm
>500 nm
410 nm
400 nm
530 nm
F
F
N
N
N
(E)
(E)
(Z)
N
N N
F
F
Figure 1. Isomerization of azobenzene [24], tetra-ortho-fluorinated azobenzene [48] and diazocine [51].
To incorporate such azobenzenes into a larger system, a suitable functional group
is necessary that reacts selectively with the specific target position of the material. N-
Hydroxysuccinimide (NHS) esters react selectively under mild conditions with primary
amines, which can be found for example in commercially available polymers but of course
also in all proteins and peptides as well as in nucleic acids. Due to the ubiquity of primary
amines, NHS esters are versatile building blocks for instance in peptide synthesis [53–55],
bioconjugate chemistry [56–60] as well as functionalized materials and polymers [61–71].
The use of NHS esters for the formation of amides has several advantages: NHS esters are
comparatively easy to prepare. They are the only active esters that can be isolated [72].
In comparison to the coupling reaction of a primary amine with a carboxylic acid using a
0
carbodiimide coupling agent such as N,N -dicyclohexylcarbodiimide (DCC), NHS esters are
less toxic. They can be used under physiologic or slightly basic conditions [72]. Moreover,
the products of their transformations are easier to purify as water-soluble NHS is released
during the amide formation [53].
Traditionally, NHS esters are synthesized by a coupling reaction of the carboxylic acid
with NHS in the presence of a carbodiimide coupling agent [73,74], which is known to have
an allergenic potential and to form urea as byproduct. Thus, the product purification might
be challenging [72]. The carboxylic acid can also be activated by using anhydrides and their
analogues for example N,N0-disuccinimidyl carbonate (DSC) [75]. More recently, coupling
reactions of alcohols [76] and aldehydes [77] with NHS under oxidizing conditions have been
investigated. Carbonylative cross-coupling reactions represents another synthetic strategy
towards NHS esters [78,79]. Until recently, a carbon monoxide atmosphere was needed for
this type of reaction prohibiting a safe and easy-to-handle implementation of the reaction.
By using NHS formate as CO surrogate this drawback could be avoided and an efficient
protocol on Pd-catalyzed carbonylation reactions under mild conditions developed [78].

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The synthesis of NHS functionalized azobenzenes has been, so far, mainly performed
via the traditional coupling approach of the corresponding carboxylic acid with NHS and
a carbodiimide coupling agent [80
carboxylic acid moiety can be obtained via Mills reaction [85
symmetric ones via a reductive coupling of nitrobenzoic acid [70
–
84] (Scheme 1a). Unsymmetric azobenzenes with a
86] or azo coupling [68 81 84],
84 87 89]. Only a few
,
,
–
,
, –
examples exist with the NHS ester in meta-position and even fewer are reported for the ortho-
position [80]. However, NHS functionalized azobenzenes with other ortho-substituents
that shift the absorption wavelength in the region of visible light have not been reported
so far. In case of the diazocines, their incorporation into materials is often performed
via peptide coupling of an amine functionalized diazocine [90–92]. Only one example
of a diazocine with an NHS ester in meta-position to the azo group has been reported
(Scheme 1b) [93]. Here, the final diazocine was obtained in an overall yield of 3% after
five steps. The carbonyl function was connected to the phenyl rings of the diazocine
with a methylene bridge allowing more rotational degrees of freedom compared to a
direct linkage [93].
Scheme 1. Synthetic approach towards NHS functionalized azobenzenes [80] (a) and diazocine [93] (b).
We could recently show that cross-coupling reactions are a versatile tool for late-stage
functionalization of para-substituted azobenzene derivatives [94]. For diazocines, only few
examples on cross-coupling reactions with differing yields have been reported, mainly
Buchwald-Hartwig cross-coupling [95] or Stille reactions [11,96].
We report an efficient Pd-catalyzed carbonylation protocol, based on previously work
of Barré et al. [78], to transform iodinated azobenzenes into the corresponding active NHS
ester under mild conditions with NHS formate as CO surrogate. The iodinated precursors
are easily accessible and a high tolerance of functional groups was achieved, including other
halogen substituents. The usefulness of the obtained NHS functionalized azobenzenes was
demonstrated in two examples by coupling the NHS esters with an amino acid.
2. Results
The combination of palladium acetate as catalyst and Xantphos as ligand was demon-
strated to be a high yielding synthetic method in the literature for Pd-catalyzed carbony-
lation reactions [78
,79]. Therefore, we started our investigation with this catalytic system
for the functionalization of mono-iodinated azobenzenes
1
(Scheme 2). Although other
possible ligands were screened, the combination of palladium acetate with Xantphos was
shown to be the best condition for the catalytic carbonylation of iodinated azobenzenes. In
this way, mono-iodinated azobenzenes, at first without further substituents were reacted
1
with NHS formate (
2
). H NMR analysis with an internal reference revealed a quantitative
conversion to the desired para- 3a and meta-derivative 3b. Unfortunately, no conversion

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to the ortho-functionalized azobenzene 3c was detected; and the starting material was
completely recovered. It is very common that the functionalization of azobenzenes by
cross-coupling is low yielding or entirely unsuccessful. It also aligns with our own findings
that cross-coupling reactions at ortho-position of azobenzenes are rarely possible [94]. Next,
azobenzene derivatives with further substitutions were tested (3d–3n). A wide range
of functional groups was tolerated: Starting with a hydroxy group in para-position, 3d
was obtained in an isolated yield of 95%. Also, an amine function on the azobenzene
did not cause problems even though it might have been possible that the formed NHS
ester directly reacts with this aromatic primary amine; 3e could be isolated in 92%. The
acetamide functionalized azobenzene 3f was isolated in a yield of 86%. However, the
conversion was determined by 1H NMR analysis to be over 95%. Moreover, azobenzene
derivatives containing an electron withdrawing group, such as 4-nitro-40-iodoazobenzene
(
1g), were converted to the corresponding NHS ester in quantitative yield. Even the
vinylated species 1h was successfully transformed to 3h and isolated in a yield of 60%.
Moreover, the functionalization of three additional azobenzene derivatives proofs the
versatility of the demonstrated reaction: In particular, an azobenzene with both an ether
and a primary hydroxyl group (3i, 79%), an alkoxylated tetra-ortho-azobenzene (3j, 94%)
and a unique sterically hindered azobenzene with a naphthalene motif (3k, 74%) were all
successfully synthesized.
The coupling reaction proceeded chemo-selectively in excellent yields when azoben-
zene derivatives were used that had both, an iodine and a bromine substituent. Thus,
the obtained NHS functionalized azobenzene derivatives 3l–n enable potential further
functionalization reactions by cross-coupling strategies.
Considering the latest research trends to use azobenzene derivatives that can be
switched with visible light and to incorporate these into different types of applications,
we were interested to transfer our results for mono-iodinated azobenzenes to di-iodinated
azobenzenes (Scheme 3). This posed no problems for 5a and 5b (Scheme 3), which were
synthesized in excellent yields. The synthesis of 5a was additionally performed on a
2.00 mmol scale leading to a comparable yield as the 100 µmol batch (96%). Here, the
reaction setup was slightly modified: A pressure tube was used as a reaction vessel which
was closed quickly after the addition of triethylamine. However, difficulties occurred for
5c and 5d. For 5c, we initially observed that the reaction was incomplete. A mixture of
mono-substituted NHS ester-azobenzene and di-substituted NHS ester-azobenzene was
detected. We hypothesized that the solubility of the iodinated azobenzene 4c might be
too low. Therefore, we changed the solvent to the more polar DMF, as this solvent was
reported to lead to comparable yields as THF [78]. However, DMF is slightly basic [97
]
and thus initializes the decomposition of the NHS formate ( ). Traces of dimethylamine,
2
a common impurity in DMF [98], can enhance this decomposition. The concomitant
release of carbon dioxide increased the pressure inside the vial so much that a subsequent
addition of triethyl amine via syringe was difficult. Without the additional base, however,
the decomposition of
2 was not sufficient for a full conversion. Changing the solvent to
DMSO instead, resolved this problem. The conversion of 4c increased drastically for the
tetra-ortho-methoxylated-azobenzene; 5c was synthesized in a yield of 91%.
Unfortunately, the tetra-ortho-fluorinated azobenzene 4d was only converted in traces
1
to 5d as detected by H NMR analysis. Even the change to a more polar solvent did
not increase the yield. Instead, there were so many reaction products that they could
not be further analyzed. In these rare cases, in which the cross-coupling approach fails,
alternative strategies need to be developed. In this instance, we were able to synthesize the
fluorinated target molecule 5d by the coupling of the carboxylic acid
6 with NHS (7) using
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl) and 4-dimethylaminopyridine
(DMAP) as coupling agent (Scheme 4). The yield could not be improved by using other
coupling agents such as DCC, HATU, HSPyU, 1,10-carbonyldiimidazol (CDI) or 2,4,6-
trichlorobenzoic acid (TCBC).

Molecules 2021, 26, 3916
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H
O
O
O
N
2
O
(2.0 equiv)
Pd(OAc)2 (3 mol %)
Xantphos (2.5 mol%)
NEt3 (1.1 equiv)
O
O
R
I
N
THF, 60 °C, 17 h
R
O
O
1
3
N
N
N
N
N
N
a
a
a
3a
3b
3c
99% (>95% )
94% (>95% )
(no conversion )
N
N
N
N
N
N
O
Me
N
H
H2N
HO
a
a
a
3d
3e
3f
95% (95% )
92% (95% )
86% (>95% )
N
N
N
N
N
N
C9H18
HO O
O2N
O
b
a
a
3g
99%
3h
3i
60% (69% )
79% (90% )
C6H13
O
Me
Me
N
N
N
N
C9H19
Me
O
Me
Br
O
O
Me
a
a
3j
3l
94% (95% )
95% (>95% )
N
O
N
Me
N
N
Br
N
N
O
Br
a
a
O
3m
3n
95% (>95% )
83% (90% )
a
3k
74% (95% )
C6H13
a
Scheme 2. Scope of the Pd-catalyzed NHS functionalization of mono-iodinated azobenzenes. Yields in brackets were
determined by using 1,3,5-trimethoxybenzene as internal reference for 1H NMR analysis; all other yields are isolated yields.
b
In DMSO.

Molecules 2021, 26, 3916
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a
b
Scheme 3. Scope of the Pd-catalyzed NHS functionalization of di-iodinated azobenzenes. 2.00 mmol scale. Yields in
brackets were determined by using 1,3,5-trimethoxybenzene as internal reference for 1H NMR analysis; all other yields are
c
isolated yields. In DMSO.
Scheme 4. Alternative synthetic route to obtain the NHS functionalized tetra-ortho-fluorinated azobenzene.
In contrast to typical azobenzenes, the (Z)-isomer is thermodynamically favored in
diazocines making them a desirable molecule for applications. Moreover, the switching
is possible with visible light. Diazocines bearing a carboxyl group are demanding to
synthesize with moderate overall yields [99,100]. As iodinated diazocines can be easily
obtained [95], we were interested to transfer our method to diazocines. Analogously to the
difficulties for di-iodinated azobenzenes, the use of THF as solvent led only to a partial
conversion; in case of the di-iodinated diazocine, a mixture of mono- and di-functionalized
derivatives was obtained. Again, these problems were resolved by using DMSO as solvent
and diazocines 6a and 6b were obtained in near-quantitative yields (Scheme 5).
To demonstrate the usefulness of the obtained NHS ester derivatives for reactions with
a primary amine, azobenzene 2a and diazocine 8b were reacted with L-alanine tert-butyl
ester hydrochloride under slightly basic conditions yielding the corresponding amino acid
derivatives 9a and 9b in excellent to quantitative yield (Scheme 6).

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Scheme 5. Pd-catalyzed NHS functionalization of iodinated diazocines.
Scheme 6. Condensation reaction of NHS derivatives with L-alanine tert-butyl ester hydrochloride.
3. Discussion
This robust and high-yielding protocol enables new possibilities for the molecular
design of azobenzene and diazocines derivatives. A large scope of 14 mono-functionalized
and 5 di-functionalized azobenzenes and diazocines were prepared in high to excellent
yields. Iodinated azobenzenes are fairly easy to synthesize and a vast number of proto-
cols are available. In contrast to this, the traditional synthetic route requires a carboxyl
group on the azobenzene for the esterification to yield the NHS functionality. This is a
severe synthetic limitation. Indeed, the carboxylated analogous of 3g, 3k–l have not been
reported, but the corresponding NHS derivatives can now be synthesized via our synthetic
approach. These advantages are even more important considering that the solubility of
di-carboxylated azobenzenes in organic solvents is low. Furthermore, the synthesis of more
complex azobenzenes with a carboxyl-functionality requires many synthetical steps or are

Molecules 2021, 26, 3916
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unknown until today. The practicality of the approach was shown by the condensation of
two di-functionalized NHS esters with a protected amino acid.
4. Materials and Methods
All synthetic procedures and characterization data for all compounds and precursors
can be found in the supporting information.
4.1. General Information
For reactions under inert conditions, a nitrogen filled glovebox (Pure LabHE from
Inert, Amesbury, MA USA) and standard Schlenk techniques were used (Supplementary
Materials). All carbonylation reactions were performed in microwave reaction vials sealed
with a septum cap from Biotage (Biotage, Uppsala, Sweden). All glassware was dried in
◦
an oven at 200 C for several hours prior to use. NMR tubes were dried in an oven at
◦
110 C for several hours prior to use. NMR spectra were recorded on a Bruker Avance
Neo 600 (Bruker BioSpin, Rheinstetten, Germany) (600 MHz (1H), 151 MHz (13C{1H}), 565
MHz (19F) at 298 K. All 1H NMR and 13C{1H} NMR spectra were referenced to the residual
proton signals of the solvent (1H) or the solvent itself (13C{1H}). 19F NMR spectra were
referenced internally against trichlorofluoromethane. The exact assignment of the peaks
was performed by two-dimensional NMR spectroscopy such as 1H COSY, 13C{1H} HSQC
and 1H/13C{1H} HMBC when possible. High-resolution EI mass spectra were recorded
on a MAT 95XL double-focusing mass spectrometer from Finnigan MAT (Thermo Fisher
Scientific, Waltham, MA, USA) at an ionization energy of 70 eV. Samples were measured
by a direct or indirect inlet method with a source temperature of 200 ◦C. High-resolution
ESI and APCI mass spectra were measured by a direct inlet method on an Impact II mass
spectrometer from Bruker Daltonics (Bruker Daltonics, Bremen, Germany). ESI mass
spectra were recorded in the positive ion collection mode.
IR spectra were recorded on a Nicolet i510 FT-IR spectrometer from Thermo Fisher
Scientific (Thermo Fisher Scientific, Waltham, MA, USA) with a diamond window in an
−1
area from 500–4000 cm with a resolution of 4 cm−1. All samples were measured 16 times
against a background scan. Melting points were recorded on a Büchi Melting Point M-560
(Büchi, Essen, Germany) and are reported corrected. Thin layer chromatography (TLC)
was performed using TLC Silica gel 60 F254 from Merck (Merck, Darmstadt, Germany) and
compounds were visualized by exposure to UV light at a wavelength of 254 nm. Column
chromatography was performed either manually using silica gel 60 (0.015–0.040 mm)
from Merck (Merck, Darmstadt, Germany) or by using a PuriFlash 4250 column machine
(Interchim, Mannheim, Germany). Silica gel columns of the type CHROMABOND Flash
RS 15 SPHERE SiOH 15 µm (Macherey-Nagel, Düren, Germany) were used. The sample
was applied via dry load with Celite® 503 (Macherey-Nagel, Düren, Germany) as column
material. If stated, Celite® 503 (Macherey-Nagel, Düren, Germany) was used as filtration
aid. The use of abbreviations follows the conventions from the ACS Style guide [101].
4.2. General Procedures
4.2.1. General Procedure 1 Carbonylation
(a) Mono-iodinated molecular switch
Under inert conditions, the corresponding mono-iodinated molecular switch (200
2.00 equiv), Pd(OAc)2 (1.35 mg, 6.00 mol, 3 mol%), Xantphos (2.89 mg, 5.00
2.5 mol%) and 2,5-dioxopyrrolidin-1-yl formate (57.2 mg, 400 mol, 4.00 equiv) were dis-
solved in dry THF (3 mL) in a pressure reaction vial. A solution of 1,3,5-trimethoxybenzene
(16.8 mg, 100 mol) as an internal standard in dry THF (1 mL) was added. The vial was
sealed and heated to 60 ◦C. A solution of triethyl amine (22.2 mg, 220
mol, 2.20 equiv) in
µmol,
µ
µmol,
µ
µ
µ
dry THF (1 mL) was quickly added. Fast gas evolution was observed and the reaction was
stirred for 17 h at 60 ◦C. After cooling to 21 ◦C, the solvent was removed under reduced
pressure. The residue was re-dissolved in DCM (10 mL), filtered through Celite® and the
solvent removed under reduced pressure.

Molecules 2021, 26, 3916
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(b) Di-iodinated molecular switch
Under inert conditions, the corresponding di-iodinated molecular switch (100 µmol,
1.00 equiv), Pd(OAc)2 (1.35 mg, 6.00
and 2,5-dioxopyrrolidin-1-yl formate (57.2 mg, 400
THF (3 mL) in a pressure reaction vial. A solution of 1,3,5-trimethoxybenzene (16.8 mg,
100 mol) as an internal standard in dry THF (1 mL) was added. The vial was sealed and
heated to 60 ◦C. A solution of triethyl amine (22.2 mg, 220
mol, 2.20 equiv) in dry THF
µmol, 6 mol%), Xantphos (2.89 mg, 5.00
µmol, 5 mol%)
µmol, 4.00 equiv) were dissolved in dry
µ
µ
(1 mL) was quickly added. Fast gas evolution was observed and the reaction was stirred
for 17 h at 60 ◦C. After cooling to 21 ◦C, the solvent was removed under reduced pressure.
The residue was re-dissolved in DCM (10 mL), filtered through Celite® and the solvent
removed under reduced pressure.
4.2.2. General Procedure 2 Carbonylation
(a) Mono-iodinated molecular switch
Under inert conditions, the corresponding mono-iodinated switch (200
2.00 equiv), Pd(OAc)2 (1.35 mg, 6.00 mol, 3 mol%), Xantphos (2.89 mg, 5.00
2.5 mol%) and 2,5-dioxopyrrolidin-1-yl formate (57.2 mg, 400
dissolved in dry THF (4 mL) in a pressure reaction vial. The vial was sealed and heated
to 60 ◦C. A solution of triethyl amine (22.2 mg, 220
mol, 2.20 equiv) in dry THF (1 mL)
µmol,
µ
µmol,
µmol, 4.00 equiv) were
µ
was quickly added. Fast gas evolution was observed and the reaction was stirred for 17 h
at 60 ◦C. After cooling to 21 ◦C, the solvent was removed under reduced pressure. The
residue was re-dissolved in DCM (10 mL) and extracted with water (20 mL) and brine
(20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the
solvent removed under reduced pressure.
(b) Di-iodinated molecular switch
Under inert conditions, the corresponding di-iodinated switch (100
Pd(OAc)2 (1.35 mg, 6.00 mol, 6 mol%), Xantphos (2.89 mg, 5.00 mol, 5 mol%) and 2,5-
dioxopyrrolidin-1-yl formate (57.2 mg, 400 mol, 4.00 equiv) were dissolved in dry THF
(4 mL) in a pressure reaction vial. The vial was sealed and heated to 60 ◦C. A solution of
triethyl amine (22.2 mg, 220 mol, 2.20 equiv) in dry THF (1 mL) was quickly added. Fast
µmol, 1.00 equiv),
µ
µ
µ
µ
gas evolution was observed and the reaction was stirred for 17 h at 60 ◦C. After cooling
to 21 ◦C, the solvent was removed under reduced pressure. The residue was re-dissolved
in DCM (10 mL) and extracted with water (20 mL) and brine (20 mL). The combined
organic layers were dried over magnesium sulfate, filtered and the solvent removed under
reduced pressure.
4.2.3. General Procedure Condensation Reaction
Triethyl amine (2.20 equiv) was added to a solution of L-alanine tert-butyl ester
hydrochloride (2.20 equiv) in dry DMF. A solution of the corresponding di-NHS function-
alized molecular switch (1.00 equiv) in dry DMF was added and the resulting mixture was
◦
stirred at 21 C for 16 h. Water and ethyl acetate were added, and the mixture was washed
with brine (3 ). The combined organic phases were dried over magnesium sulfate, filtered
×
and the solvent removed under reduced pressure yielding the product.
Supplementary Materials: The following are available online: general information, a list of all
reagents and solvents, experimental procedures and analytical data, determination of 1H NMR yield,
images of all NMR spectra.
Author Contributions: Conceptualization, S.S. and M.W.; methodology, S.S. and M.W.; validation,
S.S., M.W. and A.S.; formal analysis, S.S. and M.W.; investigation, S.S., M.W. and A.S.; resources,
A.S.; data curation, S.S. and M.W.; writing—original draft preparation, S.S., M.W. and A.S.; writing—
review and editing, S.S, M.W. and A.S.; visualization, S.S. and M.W.; supervision, A.S.; project
administration, A.S.; funding acquisition, A.S. All authors have read and agreed to the published
version of the manuscript.

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Funding: This research was funded by the GERMAN RESEARCH FOUNDATION (DFG) within the
priority program SPP 2100 “Soft Material Robotic Systems”, Subproject STA1195/5-1, “Insect feet
inspired concepts soft touch grippers with dynamically adjustable grip strength”.
Institutional Review Board Statement: The data presented in this study are openly available in the
supporting information.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds may be available from the authors. Please contact
the authors for further details.
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