Bifunctional Molecular Photoswitches Based on Overcrowded Alkenes for Dynamic Control of Catalytic Activity in Michael Addition Reactions

Article abstract of DOI:10.1002/chem.201604966

The emerging field of artificial photoswitchable catalysis has recently shown striking examples of functional light-responsive systems allowing for dynamic control of activity and selectivity in organocatalysis and metal-catalysed transformations. While o

Full text of DOI:10.1002/chem.201604966

A Journal of
Accepted Article
Title: Bifunctional Molecular Photoswitches based on Overcrowded
Alkenes for Dynamic Control of Catalytic Activity in Michael
Addition Reactions
Authors: Stefano F. Pizzolato, Beatrice S. L. Collins, Thomas van
Leeuwen, and Ben Lucas Feringa
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Bifunctional Molecular Photoswitches based on Overcrowded
Alkenes for Dynamic Control of Catalytic Activity in Michael
Addition Reactions
Stefano F. Pizzolato, Beatrice S. L. Collins, Thomas van Leeuwen, Ben L. Feringa*(a)
Abstract: The emerging field of artificial photoswitchable catalysis
has recently shown striking examples of functional light-responsive
systems allowing for dynamic control of activity and selectivity in
organocatalysis and metal-catalysed transformations. While our
group has already disclosed systems featuring first generation
molecular motors as the switchable central core, a design based on
second generation molecular motors is lacking. Herein, the
syntheses of two bifunctionalized molecular switches based on a
photoresponsive tetrasubstituted alkene core are reported. They
feature a thiourea substituent as hydrogen-donor moiety in the upper
half and a basic dimethyl amine group in the lower half. This
combination of functional groups offers the possibility for application
of these molecules in photoswitchable catalytic processes. The
lightresponsive central cores were synthesized via a Barton-Kellogg
coupling of the prefunctionalized upper and lower halves.
Derivatization via Buchwald-Hartwig amination and subsequent
introduction of the thiourea substituent afforded the target
compounds. Control of catalytic activity in the Michael addition
reaction between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione
is achieved upon irradiation of stable-(E) and stable-(Z) isomers of
the bifunctional catalyst 1. Both isomers display a decrease in
catalytic activity upon irradiation to the metastable state, providing
systems with the potential to be applied as ON/OFF catalytic
photoswitches.
different approaches by harnessing cooperative,6–12 steric13–20
and electronic effects21–25 of the photo-accessible isomers.
For instance, Hecht and co-workers developed a series of
photoswitchable catalysts, based on
a
3,5-disubstituted
azobenzene core featuring a piperidine base, in which the
modulation of steric shielding was used to control catalytic
activity (Scheme 1a).16 Upon photoswitching, the basic
piperidine nitrogen atom is exposed in the (Z)-isomer, allowing
enhancement of rate of the aza-Henry reaction of nitroethane to
p-nitroanisaldehyde compared to the (E)-isomer (kZ/kE = 35.5).
Rebek and co-workers introduced
a
light-responsive
cavitand/piperidinium complex that displayed switchable
catalytic activity for the Knoevenagel condensation of aromatic
aldehydes with malonitrile.17 The cavitand features an
azobenzene arm capable of competing with the piperidinium ion
for the cavity when irradiated with UV light, allowing reversible
control of the guest binding and reactivity. Imahori and co-
workers reported a bis(trityl alcohol)-substituted azobenzene as
a
cooperative bifunctional switchable catalyst capable of
reversible activity control when applied to a Morita– Baylis –
Hillman reaction of 3-phenylpropanal and 2-cyclopenten-1-one.10
The switchable catalyst was able to increase the yield of the
reaction after 2 h (background, 27%) from 37% using the less
active state (E)-isomer to 78% yield using the more active (Z)-
isomer. Pericás and co-workers developed
a switchable
azobenzene-thiourea organocatalyst, which was used to achieve
control of Michael addition reactions through reversible
hydrogen-bond shielding of the catalytic unit, enabled by a nitro
group as the blocking moiety.20 The (E)-isomer effectively
catalyses the Michael addition of 2,4-pentanedione to (E)-3-
bromo-β-nitrostyrene (full conversion was achieved after 19 h),
while the photogenerated (Z)-isomer, in which the nitro group
engages in hydrogen bonding interactions with the thiourea
moiety, leads to a significantly lower reaction rate (only 23%
conversion after 20 h). Chen and co-workers developed a
pseudo-enantiomeric pair of optically switchable helicenes
Introduction
External control of catalytic systems by light is a highly
challenging and still underdeveloped field of modern organic
chemistry. In the quest for responsive catalytic systems, many
advantages arise from the use of light as a clean, non-invasive
stimulus, where judicious choice of irradiation wavelength may
allow precise control over catalyst function, activity and
selectivity. A number of photoresponsive catalysts have been
developed over the last decade, exploiting the established
switching properties of azobenzenes, diarylethenes and
overcrowded alkenes.1–5 Promising results in photochemical
control of catalyst activity or selectivity have been achieved via
containing
a
catalytic 4-N-methylaminopyridine (MAP).26
Successful application was found in the enantiodivergent
Steglich rearrangement of O- to C-carboxylazlactones, with
formation of either enantiomer with up to 91% ee (R) and 94%
ee (S), respectively. Branda and co-workers developed various
systems for exploiting the characteristic switching of structural
and electronic properties of diarylethenes to allow for instance
for control of Lewis acidity/basicity,27,28 stereoselectivity8 and
substrate reactivity,29–33 Other approaches, including the
application of photoresponsive systems for controlling the rate of
ring-opening polymerizations,24,34–36 are summarized in
comprehensive recent reviews.1–5
[a]
Stefano F. Pizzolato, Beatrice S. L. Collins, Thomas van Leeuwen,
Ben L. Feringa*
Centre for Systems Chemistry, Stratingh Institute for Chemistry,
University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: b.l.feringa@rug.nl
Supporting information for this article is available on the WWW
under “link”
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Our group demonstrated stimuli-responsive control of the activity
and enantioselectivity of a catalyst via dynamic conformational
changes of a first generation molecular motor equipped with two
functional groups able to cooperatively accelerate a reaction
(Scheme 1b; for the switching process of the main core, see
Scheme 2a).9 The two pseudo-enantiomeric (Z)-isomers of the
molecular motor during its rotary cycle were shown to control the
stereochemical outcome of an organocatalytic thiol 1,4-addition,
allowing access to both enantiomers of the product depending
on the state of the catalyst. This organocatalyst bears a 2-
aminopyridine base and a weakly acidic thiourea functionality,
which were proposed to engage in bidentate coordination of the
substrates, leading to both accelerated reaction rates and high
levels of stereocontrol. Subsequently we extended the
application of this concept to an organocatalysed Henry reaction
upon structural modification of the chiral catalyst, improving its
versatility and efficiency through a more constrained catalytic
pocket.12
bifunctional organocatalyst43–47 based on the second generation
molecular motor core. Unlike the first generation molecular
motor (Scheme 2a),48 the second generation motor structure
features non-identical upper and lower halves, in which the
upper half contains the sole stereogenic center of the molecule
(Scheme 2b).49–54 Upon irradiation with UV-light the central
stilbene-type alkene can undergo
a
photochemical E-Z
isomerization that yields a metastable (MS) diastereoisomer
(top/right structures), which holds the opposite helical chirality to
the original stable (St) diastereoisomer (top/left structures). The
metastable species can subsequently undergo a thermally
activated isomerization in which the upper half moves along the
lower half, again resulting in an inversion of helicity, namely
thermal helix inversion (THI).50 In the resulting stable isomer
(bottom/right structures), the upper half has undergone a 180°
rotation with respect to the lower half.
Scheme 1. a) Photoswitchable azobenzene-based piperidine as light- and
heat-triggered catalyst to achieve rate control of Henry reaction via reversible
steric shielding of basic/nucleophilic site. b) Photoswitchable overcrowded
alkene-based light- and heat-triggered thiourea-DMAP bifunctional catalyst to
achieve control of rate and enantioselectivity in a Michael addition reaction via
reversible E-Z photoisomerization and thermal helix inversion.
Furthermore application of dynamic control of chirality with
responsive phosphine ligands
for
palladium-catalysed
enantioselective allylic substitution was demonstrated.37
A
similar chiral first generation molecular motor scaffold was
recently exploited in a light- and heat-responsive bis-urea
receptor capable of multi-state regulation of dihydrogen
phosphate ion binding affinity.38 A major difference in binding
affinity of the interchangeable isomers was observed, enabling
external control of substrate binding by the dynamic host.
Scheme 2. Isomerization processes leading to unidirectional rotation in: (a)
first generation molecular motor (four-stage cycle with four distinctive
stereoisomers); (b) second generation molecular motor (four-stage cycle with
only two distinctive stereoisomers in case of symmetrically substituted lower
half). St = stable isomer, MS = metastable isomer.
Having established the potential of molecular motors39–42 as
multiple switching elements in dynamic chemical systems for
stereoselective catalysis and anion recognition, we engaged in
the challenge of developing a prototype for a responsive
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possible products accessible by combining three starting components
(depicted as coloured spheres) in a chemo- and enantioselective fashion
(suggested handedness of the newly generated stereogenic centres indicated
on the connecting bond). By triggering the proper catalyst states, both
enantiomers of each diastereoisomer could be accessed.
In our previous study we showed that the combination of a 5-
membered ring in the lower half (fluorene) with a sulfur
containing 6-membered ring in the upper half (5,8-
dimethylthiochromene and benzo[f]thiochromene) resulted in
distinctive high energy activation barriers for the thermal
relaxation step in the rotary cycle of the second generation
molecular motors and consequently long half-lives of the
metastable species.50,55 More precisely, the THI energy barrier
dramatically increases due to the high conformational
constraints, resulting in an alternative and predominant thermal
relaxation process, known as thermal E-Z isomerization (TEZI)
While the ultimate goal remains the syntheses of tri-
functionalized bistable switches and their use as catalysts in
one-pot multistep reactions, initial studies have focused on the
feasibility of introducing well-established catalytic functional
groups onto the overcrowded alkene scaffold found in second
generation molecular motors. Herein we report the first
syntheses of two bifunctional molecular switches 1 and 2 based
on the second generation molecular motor scaffold (Figure 1a).
Featuring catalytic functions, each switch was obtained both as
(E)- and (Z)-stereoisomers (only (E)-isomer shown). Related to
analogous examples,9,16 these switches may allow for dynamic
control of activity as ON/OFF or OFF/ON catalysts (Figure 1b).
Moreover, the present preliminary study is a stepping stone for
future synthesis of more complex trifunctional photoswitchable
catalysts for multi-step synthesis (see Scheme 3).
(for 5,8-dimethylthiochromene: Δ‡G°THI (100 °C, 1 atm)
=
138 kJ・mol−1, Δ‡G°TEZI (100 °C, 1 atm) = 129 kJ・mol−1, t
½
(20 °C, 1 atm) = 75 years; for benzo[f]thiochromene: Δ‡G°THI
(100 °C, 1 atm) = 140 kJ・ mol−1, Δ‡G°TEZI (100 °C, 1 atm) =
129 kJ ・ mol−1,
t
(20 °C, 1 atm)
=
4300 years). We
½
demonstrated that these overcrowded alkene systems could be
used as thermally highly stable and selective photoswitchable
bistable systems, both important requirements for reliable
photoresponsive catalysts, where each state should be
selectively addressable with a high photostationary state (PSS)
ratio while remaining stable over time.
An interesting aspect of the second generation molecular motor
scaffold is the possibility of functionalizing the otherwise
symmetrical lower half with two different catalytically active
moieties (depicted as A and B in Scheme 3), which could
dynamically cooperate with the single functionality (C) on the
upper half. Through this design two distinct bifunctional catalytic
pairs could be accessed. Notably these two pairs of catalytic
functional groups would also be addressed with two opposite
helical chirality, P or M, upon irradiation and thermal relaxation.
We envision such a design as a feasible future route for stimuli-
responsive switchable catalysts in multi-tasking systems and
Results and Discussion
Design. In order to address high switching performance and
thermal stability, the aforementioned bistable switch core was
chosen (thiopyran upper half – fluorene lower half, Figure 1a).
one-pot multi-step diastereo- and enantioselective reactions.2–
4,9,37,56–60
Scheme 3. Proposed design of a trifunctional light- and heat-responsive
organocatalyst for diastereo- and enantioselective one-pot multi-step systems.
The catalyst is envisioned to be switchable between four different states, each
displaying a different combination of active cooperative catalytic pair (AC or
BC) and helicity (P or M). In the scheme are displayed only two of the four
Figure 1. (a) Bifunctional molecular switches 1 and 2 ((Z)-isomers omitted).
(b) General scheme for photoswitching of bifunctional catalyst and potential
application as an OFF/ON catalyst. c) Retrosynthetic analysis of 1 and 2.
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Our prototypes feature a thiourea substituent in the upper half, a
1,4-addition reaction with methacrylic acid afforded the sulfide 8
(38%). The thiopyranone ring was finally constructed via a two-
step procedure from acid 8 via conversion to the more reactive
acyl chloride with oxalyl chloride followed by intramolecular
Friedel-Craft acylation to afford 9 (93%). All steps could be
performed on gram-scale with an overall yield of 26% over five
steps from commercial starting material.
well-established
hydrogen-donor
moiety
in
organocatalysis,47,61,62 and a basic dimethyl amine group in the
lower half. These functionalities were chosen to reflect
commonly encountered functional groups within the field of
organocatalysis47,62–68 and to avoid synthetic compatibility issues
associated with the Barton-Kellogg coupling,69,70 the signature
synthetic step for this family of overcrowded alkenes. The
reaction conditions required to synthesize the thioketone and
diazo coupling partners (Figure 1c) impose challenges to the
synthetic design. For instance, the established methodology
commonly adopted to generate the thioketone includes the use
of Lawesson’s reagent or P4S10 at high temperatures for
prolonged reaction times, which may cause problems with other
functionalities present in the molecule. In line with these
considerations, we chose to install a dimethylamine substituent
in the lower half, which is expected to tolerate the conditions for
thioketone formation. On the other hand, the more sensitive
thiourea motif in the upper half is to be installed after the
construction of the tetrasubstituted alkene and amination of the
upper half via a Buchwald-Hartwig coupling (Figure 1c).71
Synthesis. The synthesis of (E)-1 and (Z)-1 is outlined in
Schemes 4 and 5. The lower half coupling partner was
synthesized from commercially available 2-aminofluorene
(Scheme 4). Methylation of the aniline moiety via reductive
amination with formaldehyde and sodium cyanoborohydride
provided 3 (89%). Oxidation of the fluorene was then achieved
under an atmosphere of air using the trialkyl ammonium salt
Triton B as a catalyst in pyridine (89%). Fluorenone 4 was
converted into the reactive thioketone 5 via thionation with P4S10
in moderate yield (33%), where experimental observations
indicate a subtle balance between conversion of starting
material and decomposition of product in this step, both highly
dependent on temperature and reaction time.
Scheme 5. Synthesis of the upper half of molecular switch 1.
Ketone 9 was converted to the corresponding hydrazone 10
(42%) via condensation with hydrazine monohydrate (Scheme
6). The hydrazone 10 could be transformed into the required
diazo coupling partner 11 for the Barton-Kellogg coupling
reaction via rapid in situ oxidation at low temperature with
[bis(trifluoroacetoxy)iodo]-benzene. Reaction with thioketone 5
yielded a mixture of episulfides, (E)-12 and (Z)-12, which were
readily converted via desulfurization with triphenylphosphine to
the overcrowded alkenes (E)-13 and (Z)-13. The two isomers
could be separated by flash column chromatography to provide
(E)-13 and (Z)-13 in 35% and 21% yield, respectively, starting
with hydrazone 10. The geometry of isomers (E)-13 and (Z)-13,
obtained in their stable states only, was assigned on the basis of
1
the H NMR chemical shifts of the absorptions corresponding to
the dimethylamine substituent and the protons in position 1 or 8
on the fluorenyl lower half (highlighted in Scheme 6) in line with
previously reported analogous second generation molecular
motor scaffolds (for example: St-(E)-13, δ (-NMe2) = 3.07 ppm,
St-(Z)-13, δ (-NMe2) = 2.69 ppm; St = stable form; see
Supplementary Material for further details). Initial attempts to
install the benzophenone imine moiety on bromides 13 via
Buchwald-Hartwig amination failed, with no detectable
conversion even after prolonged reaction times. A halide
exchange to the iodide species before the Buchwald-Hartwig
reaction, however, allowed us to successfully continue the
synthesis. Bromides (E)-13 and (Z)-13 were converted
separately via aromatic Finkelstein reaction to the corresponding
iodides (E)-14 and (Z)-14 using a combination of copper iodide
and potassium iodide. High temperatures and long reaction
times were required, providing (E)-14 in good yield (90%) and
Scheme 4. Synthesis of lower half of switches 1 and 2.
The synthesis of the upper half started from commercially
available 2-bromo-1,4-dimethylbenzene (Scheme 5). By reacting
with chlorosulfuric acid, the aryl halide was first converted to the
corresponding arylsulfonyl chloride
reduction with zinc powder and sulfuric acid provided a 1.0 : 0.6
mixture of 4-bromo-2,5-dimethylbenzenethiol and the
6
(90%). Subsequent
7
corresponding disulfide (82% overall), which was converted
quantitatively to pure 7 by reduction with sodium borohydride. A
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(Z)-14 as a mixture of product and unconverted bromide starting
material ((Z)-14 : (Z)-13 = 8 : 1, 48%). The more reactive iodide
species were then submitted to the Buchwald-Hartwig amination
bis(diphenylphosphino)ferrocene catalytic system to install the
benzophenone imine moiety ((E)-15: 36%, (Z)-15: 63%).
reaction
using
a
palladium(II)
acetate
–
1,1’-
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Scheme 6. Synthesis of molecular switches (E)-1 and (Z)-1. Note: (E)-13 and (Z)-13 were assigned via the 1H NMR chemical shifts of the absorption peaks
corresponding to the dimethylamine substituent and the protons in position 1 or 8 on the fluorenyl lower half in line with previously reported analogous second
generation molecular motor scaffolds (see Supplementary Material for further details).
After hydrolysis to the free amine 16 ((E)-16: 80%, (Z)-16: 91%),
nucleophilic addition to 3,5-bis(trifluoromethyl)phenyl
isothiocyanate afforded the target thiourea-functionalized
switches ((E)-1: 85%, (Z)-1: 90%).
The related switches (E)-2 and (Z)-2 were synthesized via an
analogous route starting from 6-bromo-2-naphthol as shown in
Schemes 7 and 8.
Photoswitching process. The switching properties of (E)-1,
(Z)-1, (E)-2 and (Z)-2 were monitored by UV-vis absorption
spectroscopy (Figure 2) and H NMR spectroscopy (illustrated
1
for (E)-1 in Figure 3 and (Z)-1 in Figure 4, vide infra). Solutions
of stable (E)-1, (Z)-1, (E)-2 and (Z)-2 in tetrahydrofuran (1.0-
2.0·10−5 M) in 1 cm quartz cuvettes were irradiated at room
temperature under stirring for a few minutes towards the
metastable state using UV light ((E)-1 and (Z)-1, 312 nm; (E)-2
and (Z)-2, 365 nm). The photochemical E-Z isomerizations were
found to be characterized by clear isosbestic points, indicating
the absence of side-reactions. All four switches exhibited a
decrease in intensity of the absorption bands at 300–350 nm
upon irradiation at 312 nm or 365 nm and the appearance of a
new absorption band in the region 350–480 nm, characteristic of
the generated metastable isomers. The metastable isomers
were shown to be highly thermally stable, exhibiting no
degradation or back-isomerisation upon standing at room
temperature for extended periods of time.
1
The PSS ratios for all four switches were determined using H
and 19F NMR spectroscopy. In a general procedure, the
compound (approximately 0.5 mg) was dissolved in CD2Cl2
(0.7 mL) and the sample was irradiated in an NMR tube at
312 nm at room temperature. The isomerization process was
monitored over time by means of 1H NMR spectroscopy (see
Figure 3 for St-(E)-1). No further changes were observed after
15 min of irradiation. Both isomers, St-(E)-1 and MS-(Z)-1 were
assigned using two dimensional COSY and NOESY NMR
experiments (see Supplementary Material for further details).
The relative integration of the absorptions of the two isomers
revealed a PSS ratio (312 nm) in CD2Cl2 of St-(E)-1 : MS-(Z)-
1 = 18:82.
Scheme 7. Synthesis of the upper half of molecular switch 2 from commercial
starting material in 70% yield over five steps.
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Scheme 8. Synthesis of molecular switches (E)-2 and (Z)-2.
Figure 3. (a) 1H NMR spectra of St-(E)-1 (approximately 0.5 mg in CD2Cl2,
0.7 mL), with magnification of corresponding 19F NMR spectra as inserts.
(b) 1H NMR spectra after irradiation with 312 nm light of St-(E)-1 to the
metastable state MS-(Z)-1 affords a PSS mixture of St-(E)-1 : MS-(Z)-1 = 18 :
82, with magnification of corresponding 19F NMR spectra. Spectral region of
solvent residual peak (5.30–5.10 ppm) cut for clarity.
Figure 2 UV-vis spectra of the switching process of 1 and 2. Experimental UV-
vis absorption spectra in black of stable forms of (E)-1, (Z)-1, (E)-2, and (Z)-2
(THF, 1.0–2.5·10−5 M). Irradiation of (E)-1 (312 nm), (Z)-1 (312 nm), (E)-2
(365 nm), and (Z)-2 (365 nm) to the metastable isomers affords a PSS shown
in blue with five intermediate moments in the process (total irradiation time: 5-
10 min) shown in red (St : MS ratio: (E)-1, 18:82; (Z)-1, 10:90; (E)-2, 20:80;
(Z)-2, 16:84, ratios as determined by 1H and 19F NMR spectroscopy in CD2Cl2,
vide infra). Similar results were also obtained when CH2Cl2, toluene or
acetonitrile were used as solvent.
An analogous experiment with St-(Z)-1 was performed (Figure 4).
A PSS ratio of St-(Z)-1 : MS-(E)-1 = 10 : 90 was achieved after
irradiation at 312 nm in CD2Cl2 for 15 min.
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Figure 5. The different intermediates or substructures of target compound 1
studied to investigate the role of the amine substituents in the reversibility of
the photoswitching process.
Figure 4. (a) 1H NMR spectra of St-(Z)-1 (approximately 0.5 mg in CD2Cl2,
0.7 mL), with magnification of corresponding 19F NMR spectra as inserts.
(b) 1H NMR spectra after irradiation with 312 nm light of (Z)-1 to the
metastable state MS-(E)-1 affords a PSS mixture of St-(Z)-1 : MS-(E)-1 =
10:90, with magnification of corresponding 19F NMR spectra. Arrows indicate
absorption peaks of corresponding hydrogen atoms in St-(Z)-1 and MS-(E)-1.
It was hypothesized that the lone pair of the dimethylamine
substituent might be responsible for the deactivation of the
switching process, originating from a detrimental difference
between the absorbances and quantum yields of the stable and
metastable isomers. Hence, the addition of a Bronsted acid may
result in a recovery of the reversible switching properties,
providing the possibility for a pH-gated photo-responsive system.
Solutions of St-(E)-1 and St-(Z)-1 (THF, 1.0–2.5·10−5 M) were
irradiated with UV-light (365 nm and 395 nm) before and after
the addition of excess of acid or base (respectively, aliquots of
2M aq. HCl and 2M aq. NaOH) (see Supplementary Material for
further details). Large changes in the UV-vis spectra profiles and
shift of the isosbestic points during irradiation cycles were
observed upon addition of aliquots of both base and acid (365
nm in presence of base, 395 nm in presence of acid). This
observation could be explained by activation of the backward
switching path upon protonation of the dimethylamine
substituent. However, degradation could not be excluded as
alternative reasoning for the observed change in the UV-vis
spectra during the backward irradiation, as the original spectra
could not be recovered upon multiple irradiation cycles.
Nevertheless, such observation opens new insights for future
development of pH-gated photo-responsive systems based on
molecular motors/switches.
Comparable results were obtained for St-(E)-2 and St-(Z)-2,
affording, upon irradiation with 365 nm light, a PSS ratio of St-
(E)-2 : MS-(Z)-2 = 20 : 80 and St-(Z)-2 : MS-(E)-2 = 16 : 84,
respectively (see Supplementary Material for further details).
Interestingly, irradiation at longer wavelength (395 nm for 1 and
420 nm for 2) gave PSS mixtures consisting mostly of the
metastable isomer,72 even though this isomer absorbs more
strongly at these wavelengths, and led to no, or minimal, change
in the UV-vis spectra.73 Similar results were also obtained when
dichloromethane, toluene or acetonitrile were used as solvent.
Notably, the corresponding unfunctionalized molecular switches
constituting the light-responsive core of 1 and 2 have been
shown to undergo efficient reversible switching with 312/365 nm
and 420/450 nm light over multiple cycles with no evidence of
fatigue.55 Moreover, the thiourea moiety was present in our
previous successful examples of functionalized molecular
motors employed in photoresponsive catalytic and anion binding
systems.9,12,38 From
a parallel series of irradiation tests
performed on compounds 13, 16 and 28 (an analogous
compound of 13 lacking the amine moiety in the lower half)
(Figure 5), the reduced photoswitching behaviour appears to
arise due to the detrimental influence of the dimethylamine
substituent. Compound 28 was in fact the only compound in this
study which displayed efficient reversible photo-isomerization
(see Supplementary Material for further details).
This lack of reversible switching considerably mitigates the
possibility of using these switches as efficient reversible
ON/OFF catalysts and future studies will aim to discern what
functional groups, specifically what functional groups with
potentially catalytic capabilities, are compatible with efficient
reversible photoisomerization.
Catalytic activity. Having investigated the photoresponsive
dynamic motion of bifunctionalized switches 1-2, we next studied
their ability as photoswitchable cooperative catalysts. Wang and
co-workers reported
a
BINAM-based catalyst bearing
a
combination of an aromatic dimethylamine substituent as the
active nucleophilic group and a thiourea as the H-bond donor
moiety displaying promising activity as a catalyst for the Morita-
Baylis-Hillman (MBH) reaction.67 Despite the literature claims,
our attempts to catalyse the reaction between 2-cyclohexen-1-
one and 3-phenylpropionaldehyde by either (E)-1, (Z)-1, (E)-2,
(Z)-2 or the original literature catalyst did not lead to any
conversion to the desired Michael adduct as determined by
1H NMR spectroscopy (Scheme 9). We postulate that these
disappointing results are due to the limited catalytic activity of
the dimethylaniline moiety, both in terms of the low
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nucleophilicity of the aryl amine and the structurally constrained
nature of the tertiary amine within the catalyst. Future studies
will focus on the introduction of alternative, more nucleophilic,
aliphatic amine functionalities (e.g. aliphatic amine) into the
lower half, in line with the majority of successful catalysts
reported for the asymmetric organocatalysed MBH reaction.74–78
reaching only 19% conversion after 18 h (v0 = 1.08·10-3 M·h-1).
These results are highly supportive of a model similar to those
described by Hecht and Pericás, in which shielding in one
geometric isomer inhibits the activating abilities of a key catalytic
functionality in the molecule. Additionally, the catalyst St-(E)-1
could be switched to the less active state MS-(Z)-1 during the
course of the reaction by irradiation of the sample after 4 h. In
the presence of 3 mol% of St-(Z)-1, an increase of the reaction
rate compared to the blank reaction was observed, with 40%
conversion reached after 18 h (v0 = 2.94·10-3 M·h-1). Remarkably,
when the reaction was performed under the same conditions
with a PSS mixture (312 nm) of St-(Z)-1 : MS-(E)-1 = 12 : 88 as
catalyst, the rate of the reaction decreased, reaching less than
16% conversion after 18 h (v0 = 1.02·10-3 M·h-1). Contrary to
expectations, the deactivated isomer St-(Z)-1 showed moderate
catalytic activity, while the expected active isomer MS-(E)-1
provided only minimal increase in reaction rate beyond the
observed background reaction. Similar to St-(E)-1, St-(Z)-1 could
also be switched to the less active state during the course of the
reaction by irradiation of the sample after 4 h. It should be noted
that no degradation of the catalyst occurred during the irradiation
process, as well as no thermal decay of the metastable species
was detected, as determined by 1H NMR spectroscopy
throughout the kinetic experiments.
Scheme 9. Attempted catalysis of the Morita-Baylis-Hillman reaction between
2-cyclohexen-1-one and 3-phenylpropionaldehyde using either (E)-1, (Z)-1,
(E)-2 and (Z)-2; no conversion to the desired Michael adduct was observed by
1H NMR spectroscopy.
While our initial model of cooperative catalysis induced by
photocontrolled geometrical changes appears to be completely
unsuccessful, other recent reports led us to reassess the
molecular photoswitches (E)-1, (Z)-1, (E)-2 and (Z)-2. Studies by
both Hecht and Pericás has addressed the possibility of
shielding a catalytic moiety, in one photoaccessible isomer,
either by simple steric interactions (Hecht) or through hydrogen
bonding interactions (Pericás).16,20 Analysis of the photoswitches
(E)-1, (Z)-1, (E)-2 and (Z)-2 suggests that the catalytically active
hydrogen bonding thiourea moiety could be analogously
deactivated in both the St-(Z) or MS-(Z) isomers either through
steric shielding of the thiourea moiety by the dimethylamine
group or through hydrogen bonding interactions. In order to
investigate these ideas further we tested out system in the
Michael addition reaction (as described by Pericás) between (E)-
3-bromo-β-nitrostyrene and 2,4-pentanedione, in which we
postulated that the thiourea moiety in the upper half could
engage in hydrogen bonding with the nitro-substituent of the
substrate, activating it towards nucleophilic attack. The
dimethylaniline moiety in the lower half was anticipated to allow
control on the activity of the thiourea moiety by steric hindrance
or hydrogen bonding interactions, thus causing a difference in
catalytic activity between the more accessible (E)-isomers
(either St-(E) or MS-(E)) and the corresponding blocked (Z)-
isomers (either MS-(Z) or St-(Z)). Each distinct case could then,
respectively, represent a successful example of ON/OFF (St-(E)
to MS-(Z)) or OFF/ON (St-(Z) to MS-(E)) catalytic switches.
Figure 6 illustrates the progress of the conversion, monitored by
1H NMR spectroscopy, of the Michael reaction between (E)-3-
bromo-β- nitrostyrene and 2,4-pentanedione, mediated by
different forms of the thiourea catalysts in combination with
trimethylamine. When the reaction was conducted in the
absence of catalyst, only 10% conversion was observed after
18 h (v0 = 5.56·10-4 M h-1), in line with the results reported by
Pericás and co-workers. In the presence of 3 mol% of St-(E)-1, a
clear acceleration of the reaction was observed, with 60%
conversion reached after 18 h (v0 = 5.33·10-3 M·h-1). Interestingly,
when the reaction was performed under the same conditions
with a PSS mixture (312 nm) of St-(E)-1 : MS-(Z)-1 = 20 : 80 as
catalyst, the rate of the reaction was substantially decreased,
Due to the limited activity displayed by the catalysts, the
background blank reaction may still play an important role in the
conversion of the substrate. Assuming that the background
blank reaction still affords 10% conversion during 18 h (v0
=
5.56·10-4 M·h-1) even in the presence of the catalyst, the sole
contribution of the catalysts can then be calculated as follows in
terms of conversion (퐶표푛푣., equation 1), initial reaction rate (푣0,
equation 2), and turnover frequency (TOF, equation 3):
푪풐풏풗.풄풂풕풂풍풚풛풆풅 = 푪풐풏풗.푻푶푻− 푪풐풏풗.풃풍풂풏풌
(1)
(2)
(3)
풗ퟎ
= 풗ퟎ푻푶푻 − 풗ퟎ
풃풍풂풏풌
풄풂풕풂풍풚풛풆풅
⁄
푻푶푭 = 풗ퟎ
풄풐풏풄.풄풂풕풂풍풚풔풕
풄풂풕풂풍풚풛풆풅
In the case of St-(E)-1, by subtracting the contribution of the
background reaction, a 50% conversion (v0 = 5.33·10-3 M·h-1
-
0.56·10-3 M·h-1 = 4.77·10-3 M·h-1, TOF = 1.59 h-1) can be
attributed to the sole catalyst action. In the case of the
corresponding PSS mixture of St-(E)-1 : MS-(Z)-1 = 20 : 80, a
mere 9% conversion (v0 = 1.08·10-3 M·h-1 - 0.56·10-3 M·h-1
=
0.52·10-3 M·h-1, TOF = 0.173 h-1) can be attributed to the catalyst
mixture. Notably, this value appears to be proportional to the
fraction of St-(E)-1 present in the catalyst mixture (stable-(E)-1 =
20%), if compared to the former not-irradiated sample (i.e. St-
(E)-1 = 100%). Similar behavior is encountered in the second set
of experiments involving St-(Z)-1 and MS-(E)-1. By subtracting
the background reaction contribution, pure St-(Z)-1 appears to
give 30% conversion after 18 h (v0 = 2.94·10-3 M·h-1 - 0.56·10-3
M·h-1 = 2.38·10-3 M·h-1, TOF = 0.793 h-1), while the PSS mixture
of St-(Z)-1 : MS-(E)-1 = 12 : 88, afforded only 6% conversion (v0
= 1.02·10-3 M·h-1 - 0.56·10-3 M·h-1 = 0.46·10-3 M·h-1, TOF =
0.153 h-1).
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Figure 6. (a) Photoswitching of catalytic activity of (E)-1 in Michael addition: background blank reaction - no cat. (black); catalysed by St-(E)-1 (red); catalysed by
PSS mixture of St-(E)-1 : MS-(Z)-1 = 18 : 82 upon UV irradiation (312 nm) of St-(E)-1 (green); catalysed by St-(E)-1 upon intermediate irradiation (indicated with
orange bar) after 4 h (blue). (b) Photoswitching of catalytic activity of (Z)-1 in Michael addition: background blank reaction - no cat. (black); catalysed by St-(Z)-1
(red); catalysed by PSS mixture of St-(Z)-1 : MS-(E)-1 = 10 : 90 upon UV irradiation (312 nm) of St-(Z)-1 (green); catalysed by St-(Z)-1 upon intermediate
irradiation (indicated with orange bar) after 4 h (blue). (c) Reaction scheme of Michael addition. (d) Comparison between the net activity (yield (%) indicated above
corresponding bar, contribution of background reaction subtracted) of (E)-1 and (Z)-1 as not irradiated (blue) and pre-irradiated mixture (red). For reaction
conditions, irradiation and monitoring procedure, see Supplementary Material.
As shown by the experimental results, both stable isomers
displayed significant loss of catalytic activity upon irradiation to
the metastable state. As opposed to our assumption, this
behavior does not seem predominantly regulated by shielding of
the thiourea moiety by the amine substituent, either through
steric or hydrogen bonding interactions (vide infra,
Computational study), but apparently other veiled parameters
play a key role.
(ΔG ≈ 4 kcal mol-1) is the same for all isomers of 1. The
calculations also allow us to rule out the possibility of
intramolecular hydrogen bonding interactions between the
thiourea and dimethylaniline moieties, where the distances are
too large in all four isomers for hydrogen bonding. Future
research will focus on the investigation of a possible substantial
alteration of the electronic properties upon switching to the
metastable states, which could provide a plausible explanation
for the detrimental impact on the catalytic activity.
Computational study. Although the exact reason for the
observed decrease in catalytic activity upon irradiation remains
elusive, DFT calculations on various conformations of all four
isomers, St-(E)-1, MS-(Z)-1, St-(Z)-1 and MS-(E)-1, have
allowed us to gather further information to help interpret the
results. Conformational analysis on all four isomers allowed us
to identify the most stable cis and trans conformations of all the
possible ground state isomers of 1 (Figure 7), where cis and
trans describes the conformation of the thiourea motif.
Conclusions
We have described the design and synthesis of two
photoresponsive bifunctionalized catalysts based on an
overcrowded alkene core. The compounds show switching upon
irradiation with 312 nm light, forming the corresponding
metastable states with good photostationary states. Interestingly,
they do not exhibit reversible switching and further investigation
are required to determine the influence of the dimethylamine
group on the reversibility of the switching processes of bistable
switches based on overcrowded alkenes.
It was found in accordance with a previous study that the
presumably less catalytically active anti conformation of the
thiourea unit for each stable and metastable isomers of 1 lies
79
lower in energy.
However the Gibbs free energy difference
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Figure 7. DFT optimized structures of the cis (top) and trans (bottom) conformations adopted by the thiourea substituent for each stable and metastable isomer of
1 (from left to right, the order follows the switching cycle for second generation molecular motor as depicted in Scheme 2b: St-(E)-1, MS-(Z)-1, St-(Z)-1, and MS-
(E)-1.
the 1H, 13C and 19F NMR spectra are presented in the Supporting
Information.
Switches St-(E)-1 and St-(Z)-1 display properties of
photoswitchable catalytic activity control in the Michael addition
reaction
between
(E)-3-bromo-β-nitrostyrene
and
2,4-
pentanedione. From the experimental results, both isomers
displayed a decrease in catalytic activity upon irradiation to the Acknowledgements
metastable state, which could not be accredited to any
detectable decomposition of the catalysts. As opposed to our
initial assumption of controlling the activity of the thiourea moiety
by steric hindrance or hydrogen bonding interactions, both E-
and Z-isomers behave comparably as ON/OFF catalytic
switches upon photoisomerization with clear changes in reaction
rate and turnover frequency, regardless of the catalyst geometry.
Therefore such behavior does not seem predominantly
regulated by the steric hindrance exerted by the amine
substituent around the thiourea moiety. As demonstrated in this
work, an aromatic amine substituent was shown to be
detrimental for the photochemical reversibility of the switching
process and to be a poorly active catalytic moiety. These studies
provide valuable insight into the requirements for the design of
more effective and complex trifunctional molecular switches,
which may allow the photocontrol of catalyst activity and
selectivity in multicomponent reactions. Key to the successful
Financial support from The Netherlands Organization for
Scientific Research (NWO-CW), Foundation for Fundamental
Research on Matter (FOM, a subsidiary of NWO), the Zernike
Institute for Advanced Materials, The Royal Netherlands
Academy of Arts and Sciences (KNAW), The European
Research Council (Advanced Investigator Grant no 227897 to
B.L.F.), Ministry of Education, Culture and Science (Gravitation
program 024.001.035), and the University of Groningen are
acknowledged. The authors would like to thank Ing. P. van der
Meulen for the technical support during the kinetic NMR
spectroscopy experiments.
Keywords: molecular switches • photoisomerization •
photoswitchable catalysts • activity control • Michael addition
Abbreviations: photostationary state (PSS) • metastable (MS) •
thermal helix inversion (THI) • thermal E-Z isomerization (TEZI) •
turnover frequency (TOF) • density functional theory (DFT)
development of these future catalysts will be
a deeper
understanding of the effect of ancillary functional groups on
reversible photoswitching and the introduction of more active
catalytic groups to ensure higher catalyst performance.
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Entry for the Table of Contents
Layout 2:
FULL PAPER
Stefano F. Pizzolato, Beatrice S. L.
Collins, Thomas van Leeuwen, Ben L.
Feringa*
Page No. – Page No.
Bifunctional Molecular Photoswitches
based on Overcrowded Alkenes for
Dynamic Control of Catalytic Michael
Addition Reactions
The synthesis of two bifunctional molecular switches and the experimental study of
their photochemical and catalytic behaviour is presented. Dynamic control of
catalytic activity of the Michael addition reaction is achieved upon irradiation of
stable-(E)-1 and stable-(Z)-1. This demonstrates that both isomers display a
decrease in catalytic activity upon irradiation to the metastable state, providing
systems with the potential to be applied as ON/OFF catalytic photoswitches.
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