Promoting the Furan Ring-Opening Reaction to Access New Donor–Acceptor Stenhouse Adducts with Hexafluoroisopropanol

Article abstract of DOI:10.1002/anie.202100115

Donor–acceptor Stenhouse adducts (DASAs) are visible-light-responsive photoswitches with a variety of emerging applications in photoresponsive materials. Their two-step modular synthesis, centered on the nucleophilic ring opening of an activated furan, ma

Full text of DOI:10.1002/anie.202100115

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10219–10227
International Edition: doi.org/10.1002/anie.202100115
German Edition: doi.org/10.1002/ange.202100115
Photoswitches
Promoting the Furan Ring-Opening Reaction to Access New Donor–
Acceptor Stenhouse Adducts with Hexafluoroisopropanol
Mich›le Clerc+, Friedrich Stricker+, Sebastian Ulrich, Miranda Sroda, Nico Bruns,*
Luciano F. Boesel,* and Javier Read de Alaniz*
Abstract: Donor–acceptor Stenhouse adducts (DASAs) are
visible-light-responsive photoswitches with a variety of emerg-
ing applications in photoresponsive materials. Their two-step
modular synthesis, centered on the nucleophilic ring opening of
an activated furan, makes DASAs readily accessible. However,
the use of less reactive donors or acceptors renders the process
slow and low yielding, which has limited their development. We
demonstrate here that 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) promotes the ring-opening reaction and stabilizes the
open isomer, allowing greatly reduced reaction times and
increased yields for known derivatives. In addition, it provides
access to previously unattainable DASA-based photoswitches
and DASA–polymer conjugates. The role of HFIP and the
photochromic properties of a set of new DASAs is probed
photochromic molecules requires easy accessibility, without
compromising their tunability. Therefore, high-yielding syn-
thetic approaches using readily available starting materials
for both small molecules and macromolecular systems
remains an important goal.
Donor–acceptor Stenhouse adducts (DASAs) are a new
class of visible-light-responsive photoswitches that were
developed in 2014.[7,8] DASAs exhibit a range of promising
properties for photochromic materials, such as negative
photochromism, visible-light activation, and modular syn-
thesis. Their architecture consists of a conjugated triene
connecting an amine donor and a carbon acid acceptor, which
upon irradiation can undergo a 4p-electrocyclization to
a closed cyclopentenone form (Figure 1a).[9,10] The “strength”
of the electron-donating or -withdrawing character of the
donor and acceptor groups largely governs the overall
switching properties, with structural modifications enabling
these properties to be readily tuned. For example, replacing
the dialkylamine donors from first generation derivatives
(2014)[7,8] with arylamines (second generation, 2016)[11,12]
provides access to DASAs with increased solvent compati-
bility, wavelength tunability, and tunable switching kinetics.
The introduction of strong carbon acid acceptors (third
generation, 2018)[13] retained the advantageous properties of
the second generation derivatives, while also providing better
control over the thermodynamic equilibrium in the dark. In
2018, Beves and co-workers also reported that minor steric
modifications to the dialkylamine donor (first generation)
dramatically improve the photoswitching properties of this
class of DASAs.[14] Similar to other classes of photoswitches,
however, most of these modifications have come with
increased difficulty in synthetic access.
1
using a combination of H NMR and UV/Vis spectroscopy.
The use of sterically hindered, electron-poor amines enabled
the dark equilibrium to be decoupled from closed-isomer half-
lives for the first time.
Introduction
In recent years, photochromic molecules have found
increased attention because of their ability to dynamically
control physical and chemical properties with high spatial and
temporal resolution.[1,2] The incorporation of these photo-
responsive molecules into materials has led to a range of
developments from molecular machines to life-science appli-
cations.[3–6] Critical to advancing these applications has been
the ability to optimize the photochromic properties, such as
absorption profile, quantum yield, and the thermal stability of
the metastable isomers through synthetic structural modifi-
cation. Although clearly beneficial, optimization often also
introduces more complicated synthetic strategies with longer
synthetic sequences and lower yields. The widespread use of
DASA photochromes are derived from furfural, which
serves as the precursor to the triene bridge, with the furan
[*] M. Clerc,[+] S. Ulrich, L. F. Boesel
M. Clerc,[+] N. Bruns
Empa, Swiss Federal Laboratories for Materials Science and
Technology, Laboratory for Biomimetic Membranes and Textiles
Lerchenfeldstrasse 5, 9014 St. Gallen (Switzerland)
E-mail: Luciano.Boesel@empa.ch
F. Stricker,[+] M. Sroda, J. Read de Alaniz
Department of Chemistry and Biochemistry
University of California
Santa Barbara, CA 93106 (USA)
E-mail: jalaniz@ucsb.edu
M. Clerc[+]
Department of Pure and Applied Chemistry
University of Strathclyde
Glasgow G1 1XL (UK)
E-mail: nico.bruns@strath.ac.uk
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification numbers for
some of the authors of this article can be found under:
https://doi.org/10.1002/anie.202100115.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Department of Chemistry, University of Fribourg
1700 Fribourg (Switzerland)
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corresponding degradation products. Common purification
methods such as column chromatography are often low-
yielding, predominantly because of the conversion between
the open and closed form that occurs during purification. This
challenge is highlighted by the low yields (typically
< 50%)[11,12] observed for the synthesis of second generation
DASAs. Decreasing the required reaction time, simplifying
the purification of DASAs, and expanding the design space to
enable the use of unreactive donors or acceptors would,
therefore, further expand the utility of this new class of
photochromes.
The intrinsic similarities between the DASA furan ring-
opening reaction and the Stenhouse reaction[21] as well as aza-
Piancatelli rearrangement[22,23] might provide the key to
overcome some of the limitations currently associated with
DASA synthesis (Figure 1b). In 2007, Li and Batey rendered
the condensation/ring-opening/electrocyclization cascade re-
action between furfural and two equivalents of an amine
practical and synthetically useful by using lanthanide(III)
catalysts.[24] Subsequently, it was demonstrated by Read
de Alaniz and co-workers that rare-earth Lewis acids such
as dysprosium triflate (Dy(OTf)3) also serve as excellent
catalysts for the rearrangement of furylcarbinols with a range
of aniline nucleophiles.[23] Since these initial reports, a number
of Brønsted and Lewis acid catalysts have been shown to
promote the ring-opening reaction of furfural or 2-furylcar-
binols under mild conditions in the presence of a range of
nucleophilic amines.[23–29] A challenge remained to identify
conditions applicable to DASA synthesis that could simulta-
neously increase the rate of the furan ring-opening reaction
and inhibit the formation of the closed isomer during
synthesis to streamline the purification process and synthetic
access. Interestingly, Gandon and co-workers reported sev-
eral outstanding examples of the aza-Piancatelli rearrange-
ment, for which the Lewis acid catalyzed reaction proceeds in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at room temper-
ature in under an hour (selected substrates even reacted
without additional catalyst when HFIP was used as sol-
vent).[26] HFIP has recently gained much attention for
efficiently promoting a wide range of organic reactions
catalyzed by Lewis and Brønsted acids.[30,31]
Herein, we report the use of HFIP as a mild Lewis/
Brønsted acid in the synthesis DASA to promote the ring-
opening reaction of furan adducts for facile access to a broad
range of DASA photoswitches, including a range of new
DASA derivatives bearing deactivated amine donors that
were previously unreactive. Furthermore, we show that HFIP
shifts the DASA equilibrium to the open form through
hydrogen-bonding interactions, thereby simplifying work-up
and purification procedures and increasing the overall yields
of the isolated products. This method is also applied to
prepare DASA–polymer conjugates, with the required time
for functionalization reduced from days to several hours and
allowing the preparation of more structurally diverse DASA
materials.
Figure 1. Donor–acceptor Stenhouse adducts (DASAs). a) General
structures for open/colored triene and closed/colorless cyclopente-
none isomers. R’/R’’: alkyl or aryl; X: O or N; R: electron-withdrawing
group, five- or six-membered ring (a selection of donor and acceptor
structures are displayed in Figure 2). b) General DASA synthesis in
comparison to the closely related aza-Piancatelli rearrangement and
Stenhouse reaction.
oxygen atom forming the hydroxy group in the final
architecture. Using a straightforward, modular two-step syn-
thesis, furfural is attached to readily available carbon acid
acceptor moieties through a Knoevenagel condensation
followed by a ring-opening reaction of the furan core by
a secondary amine nucleophile, thereby resulting in the open-
form DASA photochrome (Figure 1b, proposed full mecha-
nism Figure S1). Despite the simplicity of this approach, some
synthetic challenges remain to enable general access to this
class of photochromes. Most importantly, the rate of the furan
ring-opening reaction strongly depends on the nucleophilicity
of the amine donor and the electrophilicity of the acceptor
group.[12,13,15,16] By introducing arylamines as donors (second
and third generation DASAs), reaction times can increase
drastically— from minutes to multiple hours.[12,13] The slow
rate is particularly problematic when polymers are involved
because of the concentration constraints and additional
deceleration caused by steric effects from the polymer
backbone. Here, reactions can take up to three weeks to
reach full conversion, even with moderately reactive furan
adducts derived from Meldrumꢀs acid.[17,18] Attempts to
promote the ring-opening reaction by using excess of the
amine component leads to partial degradation of the DASA.
Presumably, this results from nucleophilic attack on the triene
and/or 1,4-addition to the cyclopentenone closed form.[19,20]
Besides long reaction times, purification can also be a major
challenge. Purification of DASA photochromes often relies
on trituration or precipitation of the more hydrophobic open
form, which takes advantage of the solubility differences
between the open and closed form of DASAs and the
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Results and Discussion
HFIP as Promoter in DASA Synthesis
Initial attempts to promote the ring-opening reaction
commenced with the use of Lewis acid catalysts such as
dysprosium triflate (Dy(OTf)3), a commonly used catalyst in
the aza-Piancatelli reaction.[23,27] Unfortunately, all our at-
tempts to use metal-based Lewis acids in DASA synthesis
resulted in degradation of the product or starting materials.
Inspired by the work of Gandon and co-workers and their
successful application of HFIP in the aza-Pinacatelli rear-
rangement,[26,31] we next explored the use of HFIP as a mild
Lewis/Brønsted acid in DASA synthesis. HFIP has a high
polarity and ionization potential as well as moderate acidity
(pKa = 9.3) in combination with low nucleophilicity and
a strong hydrogen bond donating ability, which could possibly
provide a way of assisting in the electrophilic activation of the
furan adduct and stabilizing charged intermediates.[30,31]
Furthermore, as a consequence of its low boiling point (b.p.:
598C)[30] HFIP can be easily separated from the reaction
mixture by evaporation in vacuo before purification. Initial
experiments were conducted on the effect of HFIP as
a cosolvent with dichloromethane for the reaction of 4,4’-
dimethoxydiphenylamine with the furan adduct derived from
Meldrumꢀs acid. 4,4’-Dimethoxydiphenylamine is unreactive
under the standard reported conditions for DASA formation
with this acceptor.[13] In contrast, rapid color formation was
observed by the naked eye, thus supporting the formation of
DASA-1 and the promising ability of HFIP to promote the
synthesis of DASAs. 1HNMR and UV/Vis kinetic studies
were then used to confirm this qualitative evaluation. For this
we utilized the third generation CF3-pyrazolone-derived
furan adduct 1 and N-methylaniline (Figure 2a) as readily
available starting materials that provided good signal sepa-
ration in the 1HNMR spectrum. The reaction progress in the
synthesis of DASA-2 was monitored by continuous in situ
analysis in deuterated dichloromethane in the presence and
absence of HFIP. Dichloromethane is a suitable cosolvent for
HFIP as it is inert under acidic conditions and does not form
hydrogen-bonded complexes with HFIP. As shown in Fig-
ure 2b, a drastic rate increase was observed using only 0.2 and
1 vol% of HFIP (corresponding to 1 and 5 equivalents
relative to 1), with second-order rate constants (k) increasing
from 3 Æ 1mÀ1 hÀ1 to 11.6 Æ 0.2 and 56 Æ 5 mÀ1 hÀ1, respectively
(Table S1). The accelerating effect was strongly enhanced at
higher concentrations (Figure S2) and, importantly, no signs
of the formation of side products or degradation were
Figure 2. Effect of HFIP on the reaction rate and yields in DASA
synthesis. a) Reaction scheme of the ring opening of CF3-pyrazolone-
derived furan adduct 1 and N-methylaniline. b) Conversion plots from
in situ 1H NMR experiments of the reaction displayed in (a) on
applying different amounts of HFIP in deuterated dichloromethane at
258C. The second-order rate constant increases from 3Æ1 mÀ1 hÀ1
(0 vol%) to 11.6Æ0.2 mÀ1 hÀ1 (0.2 vol%, 1 equivalent relative to 1) to
56Æ5 mÀ1 hÀ1 (1 vol%, 5 equivalents relative to 1). c) Comparison of
yields of isolated product and reaction time in the synthesis of a series
of DASAs under traditionally used reaction conditions and by applica-
tion of 20 vol% HFIP in dichloromethane. Yields obtained under
uncatalyzed conditions for DASA-3 and DASA-4 were taken from the
literature.[13]
1
detectable by HNMR spectroscopy, even when going up to
Encouraged by this initial result, we next explored the
generality of this method toward the synthesis of various
other first, second, and third generation DASAs. The syn-
thesis of first generation DASAs bearing strongly basic alkyl
amines (as compared to anilines used for second and third
generation DASAs) were inhibited by the addition of HFIP
(Figure S3). Presumably, this is due to the basicity of the
secondary alkylamines, which are known to form stable
hydrogen-bonding complexes with HFIP, which leads to an
adverse effect on the reaction rate.[32–34] In contrast, the
synthesis of both second and third generation DASAs greatly
20 vol% HFIP, while also improving the yields of the isolated
products (Figure 2c). Utilizing higher amounts of HFIP
accelerated the reaction further, however, degradation of
the product and starting material could be observed at
concentrations > 50 vol% (Figure S2). In this study, a max-
imum of 20 vol% HFIP (1 to 10 equivalents relative to the
furan adduct) was, therefore utilized, for all syntheses.
Reactions can be performed in the open air. Importantly,
removing HFIP by evaporation in vacuo enables purification
by trituration, similar to previously reported procedures.[7,12]
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benefited from the addition of HFIP (Figure 2c). For
example, a fivefold increase in yield was achieved for the
synthesis of DASA-4 within a fraction of the usual reaction
time: 67% in 1 h vs. 13% in 16 h. This demonstrates that the
use of low concentrations of HFIP with a cosolvent improves
access to DASA-based photoswitches in terms of yield and
reaction time, while also expanding the accessible DASA
design space.
36.6)[39] led to mostly the closed form (Figure S17). These
results support that HFIP is unique amongst the protic polar
solvents for its ability to stabilize the open form of DASA
photochromes. To further investigate the effects of solvent on
the open form, we analyzed solvatochromic shifts[40] of first,
second, and third generation DASAs (DASA-4–DASA-6) as
well as a non-hydroxy DASA analogue in solvents of different
polarity (Figure 3 and Figures S18–S21). HFIP showed a clear
To better understand the role of HFIP in mediating the
ring-opening reaction of the furan adduct, we monitored the
rate of DASA-2 formation with other polar solvents and
alcohols by 1HNMR spectroscopy and investigated the
electronic ground-state properties of the furan adduct by
UV/Vis spectroscopy in various solvents. Analogous NMR
kinetic experiments were conducted with 2-propanol instead
of HFIP (Figures S4–S9). As previously observed for polar
protic solvents,[13,16] we found an accelerating effect for 2-
propanol (k: 9 mÀ1 hÀ1 for 2 vol%), but it was substantially
smaller than that of its fluorinated analogue (k: 56 mÀ1 hÀ1 for
1 vol%). More interestingly, using the methyl ether of HFIP
(HFIPMe) instead of HFIP had only minor effects on the
reaction rate (k: 5 mÀ1 hÀ1 for 3 vol%). HFIPMe is compara-
bly polar to HFIP (relative dielectric constant: eHFIP = 17.8,[35]
eHFIPMe = 15.4[36]), exhibits similar hydrogen bond acceptor
properties, but lacks the hydrogen bond donor ability that is
suspected to be responsible for the promotion of activity seen
in many other organic transformations.[37] UV/Vis spectro-
scopic analysis of the CF3-pyrazolone-derived furan adduct
1 revealed that the spectral properties are largely insensitive
to polarity differences of a variety of protic and aprotic
solvents but are strongly altered in HFIP (Figures S10 and
S11). These results suggest that the hydrogen bonding of
HFIP with the furan adduct plays a role in the observed rate
increase, potentially by increasing their electrophilic charac-
ter. However, the specific mechanism at play here requires
further study, as it is likely that multiple effects (polarity,
hydrogen bond donor ability, possibly acidity) contribute to
the observed promotion of the reaction. Moreover, other
effects such as off-cycle binding of the amine nucleophile with
HFIP (of relevance for strongly basic alkyl amines, Figure S3)
and product inhibition (see below) further complicate the full
mechanistic picture.
Figure 3. DASA solvatochromic shift analysis. a) Solvatochromic shifts
using the Dimroth–Reichardt ENT solvent polarity scale for first to third
generation DASAs and a non-hydroxy analogue in solvents of different
polarity. A deviation from nonlinearity is observed only for DASAs in
HFIP, which indicates the presence of hydrogen bonding interactions
with the triene hydroxy group. b) Chemical structures of the DASAs in
(a).
deviation from the linear trend in terms of the solvatochromic
shifts observed with the other solvents, thus indicating the
presence of additional specific interactions in HFIP. Of note,
the non-hydroxy DASA analogue (DASA-7) showed a linear
trend in its solvatochromic shift in all solvents, including
HFIP, which shows that the hydroxy group is likely respon-
sible for the nonlinear behavior of regular DASA compounds.
A detailed study on the interpretation of solvatochromic
shifts in terms of delocalization of the electronic ground-state
structure for different DASA generations was recently
published.[41] To also evaluate the effects of HFIP on the
switching properties, DASA-2 was placed in a solution of
dichloromethane with 0.5 vol% HFIP and irradiated with
light of l = 530 nm (Figure S22). In the presence of HFIP,
DASA-2 undergoes only an 11% decrease in absorption upon
irradiation, followed by rapid recovery to the open form in the
dark. In contrast, in pure dichloromethane, a substantially
increased photothermal stationary state (PTSS, equilibrium
between the light-driven forward reaction and the purely
thermal back reaction;[42] 81% closed isomers) and a notice-
ably slower recovery rate were observed. These results
HFIP as Modulator of Thermodynamic Equilibrium and
Photoswitching
We then investigated the impact of HFIP on the thermo-
dynamic equilibrium between the open and closed form of
DASAs. Previous studies showed that protic solvents (e.g.
methanol) and polar solvent (e.g. acetonitrile) afford a mix-
ture of open and closed isomers, which renders the purifica-
tion more difficult and, in general, results in lower yields of
isolated products (often only the more hydrophobic open
form can be isolated in high yield by trituration).[8,38] 1HNMR
spectroscopic analysis revealed that in the presence of HFIP,
minimal formation of the closed form occurred, despite the
polarity and acidity of HFIP (Figures S12–S16). Analogous
experiments in a polar solvent such as acetonitrile (e =
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overall switching kinetics of DASA compounds.[43,44] To test
this idea, we explored the role of HFIP in toluene, in which an
excellent PTSS performance (> 95% closed isomers at PTSS
for most DASA derivatives) and a slower thermal recovery
than in chlorinated solvents is observed.
As highlighted in Figure 4b, the closed-form half-life of
DASA-2 is reduced from 94 s to 2.5 s upon the addition of
only 0.1–0.5 vol% HFIP, and reaches a lower value than the
corresponding substantially more electron-rich 2-methylindo-
line derivative (DASA-5, 40 s in toluene).[13] This demon-
strates a facile pathway to externally modulate DASA
switching kinetics through addition of a simple hydrogen
bond donor, thus opening the door to systems relying on
finely controlled switching kinetics.
New DASA Derivatives
Figure 4. Hydrogen bonding interaction of HFIP and the DASA open
form and the effect of photoswitching. a) General scheme for the
proposed hydrogen bonding in DASAs in the presence and absence of
HFIP. b) The use of time-dependent UV/Vis spectroscopy to observe
the photochromic behavior of DASA-2 (10 mm) in toluene and toluene/
HFIP followed at lmax (625 nm).
To further illustrate the advantage of this new method, we
sought to expand the scope of DASAs by including highly
unreactive amine donors to prepare previously unattainable
DASA derivatives (Figure 5a). Previously reported DASAs
were limited to considerably nucleophilic amine donors with
pKa values of their conjugated acid above about 4.8. One
exception is 4,4’-dimethoxydiphenylamine (pKa conjugated
acid of ca. 2.2) that only reacted with a highly electron poor
and unusually reactive CF3-isoxazolone-derived furan ad-
duct.[13] Herein, we present a number of DASAs bearing
extremely non-basic amine donor moieties whose conjugate
acids have pKa values approaching 0.5 (Figure 5a). Driven by
the increased light penetration depth and biological compat-
ibility of near-IR light, we initially focused on arylamine
derivatives with the potential ability to red-shift the lmax
through hyperconjugation. Using 20 vol% HFIP in dichloro-
methane provided access to a range of new DASA derivatives
for the first time, including derivatives bearing aniline with
highlight that the thermodynamic equilibrium and PTSS
clearly shift to the open form in the presence of HFIP, even at
low concentrations. We propose that a hydrogen bond donor
interaction between the hydroxy group on the triene back-
bone and HFIP must be critical for stabilizing the open form
and controlling the thermodynamic equilibrium and PTSS. A
possible hydrogen bond donor interaction is shown in Fig-
ure 4a.[43]
Building on this hypothesis, we speculated that a modu-
lation of the intramolecular hydrogen bond strength in the
open form could also be exploited to systematically shape the
Figure 5. New DASAs bearing weak amine donors that were synthesized using HFIP. a) Different secondary amine donors examined previously
and herein for DASA synthesis ordered according to the pKa values of their corresponding acid (calculated with SciFinderꢁ), which correlate well
with the reactivity in the furan ring-opening reaction. b) Chemical structures of the new DASAs and their lmax in chloroform. Note: some of the
DASAs display split absorption bands (Figure S23–S36).
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highly deactivating groups, sterically hindered aromatic
amines, and new acyclic and cyclic aromatic amines (Fig-
ure 5b). To compare the properties of the DASAs synthesized
from these new donors, the CF3-pyrazolone-derived furan
adduct 1 was primarily used as the acceptor compound. For
the weakest donor, 2,2’-dinaphthylamine, a more reactive
CF3-isoxazolone-derived acceptor (S4) was used to yield
DASA-9. These furan adducts were synthesized by Knoeve-
nagel condensation of the respective carbon acids with
furfural in a first step according to previously reported
procedures.[8,13] The furan ring-opening reactions of the furan
adducts in 20 vol% HFIP can be conducted under ambient
conditions, open to air, and after completion, evaporation of
the solvents in vacuo enables isolation of the desired com-
pounds as solids that can be filtered and purified by
trituration with diethyl ether. For example, 1 reacted in 16 h
with iminostilbene to afford DASA-11, which was isolated in
good yield (65%) after trituration with diethyl ether. Full
characterization data of all the compounds can be found in
the Supporting Information.
the corresponding N-methylaniline derivatives.[12] In analogy
to the previous study,[12] density functional theory (DFT)
calculations at the B3LYP-GD3BJ/6-31G(d) level of theory
were used for geometry optimizations of the open-form
DASAs to compare dihedral angles between the acceptor and
donor groups in this new series (Figure 6b, Table S2, Figures
S41 and S42). In agreement with the literature,[12] a dihedral
angle of FD-A ꢀ 408 between the triene acceptor system and
the aryl donor group on the opposite side of the hydroxy
group was found for the acyclic amine donors, whereas the
indoline-derivative (DASA-5) is completely planar. The
second aryl group in DASA-1 and DASA-9 was predicted
to be even more twisted (FD-A ꢀ 608) and, therefore, is
expected to contribute even less to the homoconjugation and
the bathochromic absorption shift (Figure 6b). The iminos-
tilbene moiety in DASA-11 adopts a boat-like conformation
similar to the experimentally determined solid-state struc-
tures[45] of iminostilbene derivatives, with both phenyl rings
substantially out-of-plane (FD-A ꢀ 608), which explains the
hypsochromic shift observed relative to the corresponding N-
methylaniline derivative (DASA-2). A 11 nm red-shift can be
achieved with commercially available and stable p-nitroindo-
line in DASA-10 (lmax = 656 nm, Figures S31 and S32)
relative to the respective 2-methylindoline derivative (DA-
SA-5).[13] Since the planarity of the aryl groups of the donors
are critical for increasing the conjugation and extending the
absorption maximum wavelength, we attempted to utilize
other cyclic amines, including acridone and carbazole deriv-
atives. However, it was found that these amines, whose
conjugated acids have pKa values < 0, are either unreactive
under the optimized reaction conditions or result in unstable
adducts that prevented product characterization.
Absorption Properties of New DASAs
With access to a range of new DASA scaffolds, we
explored their absorption profiles by UV/Vis spectroscopy
(Figure 6a and Figures S23–S36). In general, these DASA
derivatives have similar properties to the previously reported
second and third generation DASAs, despite notable struc-
tural differences.[7,12,13] For example, the two 4-methoxyphen-
yl substituents in DASA-1 resulted in the same maximum
absorption wavelength of about 590 nm in chloroform as the
respective unsubstituted indoline derivative that formally
provides only one phenyl ring (DASA-3).[12,13] Presumably,
this is due to the substantial out-of-plane twist of both aryl
substituents on the acyclic amine donors and, therefore,
reduced HOMO overlap/conjugation. This phenomenon was
extensively investigated before to explain the bathochromic
shift of about 30 nm observed for cyclic indoline relative to
Photoswitching of New DASAs
Expanding the scope towards more electron-deficient
amines allowed us to compare the effect of these weakly
donating groups on the photoswitching behavior with the
Figure 6. UV/Vis absorption properties of new DASAs. a) Absorption spectra (chloroform) of DASA-1 and DASA-9 compared to previously
reported DASA derivatives.[12,13] b) Computational density functional theory modeling of DASA-1 to determine the HOMO orbital overlap and
dihedral angles between the donor and acceptor (FD-A) in comparison to the respective second generation DASA[12] bearing only one phenyl
substituent.
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arylamines introduced previously.[12,13] For this, time-depen-
dent UV/Vis spectroscopic analysis of the overall switching
kinetics and 1HNMR spectroscopic analysis of the dark state
were carried out (Figures S43–S56, S62–S73).
Detailed results are tabulated in the Supporting Informa-
tion (Table S3). Similar to the introduction of arylamines
instead of alkylamines for barbituric acid and Meldrumꢀs acid
acceptors reported in 2016,[12] the use of even more electron-
deficient amines for pyrazolone and isoxazolone derivatives
increased the half-life of their closed form while maintaining
the red-shifted lmax wavelength that these acceptor groups
enable (e.g. DASA-5: 5 s, DASA-2: 13 s. DASA-11: 202 s).
Another similarity is the shift of the thermodynamic equilib-
rium towards the closed isomer with more weakly donating
amines, as observed for DASA-8 and DASA-10 (both < 5%
open at equilibrium in chloroform), which is in accordance
with previous studies.[11] This electronic effect on the equilib-
rium position can be compensated by introducing sterically
hindered groups, as was shown in 2018,[14] which is in line with
what we observed when utilizing amines with bulky secondary
phenyl moieties in DASA-1, DASA-9, and DASA-11 (32%,
> 95%, and 89% open at equilibrium in chloroform). This
allows the formation of DASAs with a large amount of open
form in the dark while exhibiting long-lived closed-form
isomers after photoswitching, which could previously not be
decoupled.[11–13]
One interesting exception to this trend is DASA-12, which
includes a sterically bulky methyl ester in the 2-position of an
indoline donor. Against expectation, the thermodynamic
equilibrium is massively shifted towards the closed form
when compared to the previously published 2-methylindoline
derivative (DASA-5), while the half-life of the closed form
after irradiation is greatly increased (> 3200 s vs. 5 s, Figures
7a,b). As a result of the increased stability of the closed form
of DASA-12, it could be shown by 2DNMR spectroscopy
(Figures S75 and S76) to be zwitterionic in chloroform. This is
the first report on the nature of the closed form of a DASA
with a third generation acceptor and aryl donor, and
demonstrates a clear difference to the second generation
Meldrumꢀs and barbituric acid derivatives that reside mostly
in the keto isomer closed form.[11,12,44] Presumably, the
increase in the half-life of the closed isomer of DASA-12 is
partially due to a hydrogen bond stabilization of the
protonated amine in the zwitterionic form by the carbonyl
ester moiety through formation of a five-membered ring
(Figure 7c). This shows an interesting design principle that
enables the intramolecular stabilization of a selected form of
the closed DASA isomer and its ability to influence overall
switching kinetics.[46]
Figure 7. Photochromic properties of DASA-12 compared to DASA-5.
a) The use of time-dependent UV/Vis spectroscopy to observe the
photochromism of DASA-5 and DASA-12 in chloroform at 10 mm
(initial absorbance: 0.9 and 0.1) followed at lmax (645 nm and
646 nm). Quantitative conversion of the open form to the closed form
under irradiation with light at 617 nm for 100 s and subsequent
thermal recovery in the dark can be observed. To ensure comparability,
this experiment was also performed at similar initial absorbances
(100 mm DASA-12, Figure S61). b) Comparison of the photochromic
parameters of DASA-5 and DASA-12 in chloroform.[13] c) Presumed
hydrogen bonding stabilizing the zwitterionic closed form of DASA-12.
upon excitation into the absorption bands that are character-
istic of the naphthyl groups (300–350 nm, Figures S77 and
S78). The shape and position of the fluorescence emission
band did not change, and the intensity of the emission was
found to change only slightly when the DASA was converted
into the closed form (Figure S78). This is in agreement with
DFT calculations that predicted a limited electronic coupling
between the naphthyl groups and the triene acceptor system
in the open form (Table S2). However, we cannot completely
exclude that trace amounts of highly fluorescent, free 2,2’-
dinaphthylamine is present, which could complicate the
fluorescence measurements. DASAs in general are weakly
fluorescent when excited at their maximum absorbance
wavelength (p-p* transition of open form), so that prior
examples of strongly fluorescent DASAs have been limited to
systems that are based on the attachment of separate
fluorophores.[47–50] Introducing easily accessible fluorescent
donors could thus enable further development of multifunc-
tional materials and easily identifiable DASA-functionalized
materials.
Fluorescence of DASA-9
Beyond controlling the half-life, new properties can be
introduced by the utilization of functional amines. Subjecting
fluorescent 2,2’-dinaphthylamine to furan adduct S4 in the
presence of 20 vol% HFIP in dichloromethane afforded
DASA-9. Interestingly, it was found that DASA-9 shows
a fluorescence emission with a maximum at about 400 nm
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Polymer Conjugation
Conclusion
The utility of HFIP to promote the formation of DASAs
was also explored beyond small molecules by investigating its
applicability to the synthesis of DASA–polymer conjugates.
Previous syntheses of DASA–polymer conjugates relied on
first installing secondary amine precursors onto the polymer
and then a subsequent reaction with an excess of furan
adduct.[17,18,51,52] Although this approach provided access to
DASA–polymer conjugates, it suffered from slow reaction
and favored the use of electron-rich amine donors. As such,
we were pleased to discover that HFIP improved access to
DASA–polymer conjugates, reducing the reaction time from
days to hours (Figure 8a). For example, treatment of an N-
methylmethoxyaniline-functionalized simple model poly-
(butyl methacrylate) with an excess of the CF3-pyrazolone-
derived furan adduct in the presence of 20 vol% HFIP in
dichloromethane for 5 h yielded the new DASA polymer P1.
To further demonstrate the power and generality of this
HFIP-accelerated postfunctionalization approach, we sought
to broaden the process to diphenylamine as a weak amine
donor, which is largely unreactive under previously reported
reaction conditions. The polymer bearing diphenylamine
groups was synthesized by aminolysis of the activated ester
groups.[17] Treatment of this material with an excess of the
CF3-pyrazolone–furan adduct in the presence of 20 vol%
HFIP in dichloromethane overnight and subsequent purifi-
cation by size-exclusion chromatography gave DASA–poly-
mer conjugate P2 (characterization data for the polymers can
be found in the Supporting Information). Analysis by UV/Vis
spectroscopy confirmed the formation of the new DASA
adduct (Figure 8b). The DASA–polymer conjugates can be
converted into the closed form upon irradiation (PTSS of
40% closed form for P1 and 85% for P2 in toluene) and fully
recover their initial absorbance in the dark (Figures S57–S60).
These examples highlight that the new reaction conditions
improve the reaction rates and provide access to new DASA-
based functional materials with greater tunability of the
absorption wavelength and photoswitching response.
In conclusion, we have developed a practical solution for
accelerating the furan ring-opening reaction in the synthesis
of DASAs by using HFIP. Importantly, the new method can
be performed at ambient temperature and HFIP can be
readily removed from the reaction mixture by simple
evaporation. We demonstrate that the addition of HFIP
greatly shortens the reaction time and improves the yields of
new, as well as previously reported adducts, including DASA–
polymer conjugates. Furthermore, the method offers access to
a broader range of DASA photoswitches by enabling the use
of electron-deficient aromatic amines and new furan adducts.
The introduction of sterically hindered, electron-poor donors
allows the design of DASA derivatives with long closed-form
half-lives after photoswitching, while maintaining large
amounts of the open isomer in the dark. Moreover, the use
of HFIP allows more facile and faster access to DASA–
polymer conjugates, thus lowering the barrier of entry into the
growing field of functional DASA materials. The use of HFIP
as an external modulator of DASA photoswitching kinetics
will further enable the design of systems with tailored
responses for selected applications.
Acknowledgements
This work was supported by the Swiss National Science
Foundation through Grant no. 200021_172609 and through
grant no. 150638 for partial financial support of the NMR
hardware. This work was partially supported by the Office of
Naval Research through the MURI on Photomechanical
Material Systems through Grant No. ONR N00014-18-1-2624.
Views and conclusions are those of the authors and should not
be interpreted as representing official policies, either ex-
pressed or implied, of the U.S. Government. This work was
supported in part by NIH Shared Instrumentation Grant,
S10OD012077, for magnetic resonance instrumentation. F.S.
wants to thank the German National Merit Foundation for an
ERP-scholarship. We thank Dr. Daniel Rentsch (Empa) for
NMR measurements and support. We thank Dr. Dorina Opris
Figure 8. HFIP-promoted synthesis of DASA–polymer conjugates and properties of the resulting polymers. a) In situ absorbance monitoring at
lmax (open form DASA) of the furan ring-opening reaction to afford P1 in THF or using HFIP in dichloromethane. b) Absorption spectra
(chloroform) and chemical structures of DASA-functionalized poly(butyl methacrylate) polymers P1 and P2 (m: 4 mol%).
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Conflict of interest
The authors declare no conflict of interest.
Keywords: donor–acceptor Stenhouse adducts ·
hexafluoroisopropanol ·hydrogen bonds ·
photochromic materials ·photoswitches ·synthetic methods
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Manuscript received: January 4, 2021
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Accepted manuscript online: January 27, 2021
Version of record online: March 18, 2021
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