Isoindolinone-based molecular switches

Article abstract of DOI:10.1039/c2ob26679b

Switches are frequently used to provide external control over the conformation and function of organic and bio-organic molecules. While the use of bistable switches is widespread, multi-stable examples are observed relatively rarely. Reported here is a new class of molecular switch that is capable of forming three stable states of varied geometries, two of which can be induced to interconvert reversibly using either light or acid.

Full text of DOI:10.1039/c2ob26679b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 8770
www.rsc.org/obc
COMMUNICATION
Isoindolinone-based molecular switches†
Michael Lawson and Sara Eisler*
Received 26th August 2012, Accepted 4th October 2012
DOI: 10.1039/c2ob26679b
Switches are frequently used to provide external control over
the conformation and function of organic and bio-organic
molecules. While the use of bistable switches is widespread,
multi-stable examples are observed relatively rarely.
Reported here is a new class of molecular switch that is
capable of forming three stable states of varied geometries,
two of which can be induced to interconvert reversibly using
either light or acid.
The ability of molecular switches to reversibly alternate between
two states is frequently exploited to modulate the structure and
function of biomolecules,1 and organic materials.2 Dithienyl-
ethenes and overcrowded alkenes have been well studied in a
variety of systems that display the versatility of these moveable
units,3 but azobenzenes are still the most commonly used switch-
ing unit due to their tuneability,4 and their accessibility through a
variety of synthetic transformations.5 However, among the
choices available for incorporation into devices,6 multi-stable
switches are described relatively infrequently,7 yet a molecule’s
ability to revolve between many stable conformers/forms has sig-
nificant implications in applications such as information proces-
sing and biomaterials.8 An ideal multi-stable switch would
possess several states that differ in one or more physical and/or
electronic properties. It should be possible to interconvert
between these states using stimuli, preferably orthogonal, so that
each state is produced for a defined length of time; the most
desirable time scale would be based on the particular application.
The attainment of all of these properties in a single molecule is a
considerable challenge.
Scheme 1 Synthesis of enyne bis-isoindolinones.
of more functionalized structures, hindered our study of the
switching aspects of its properties. Our current interest is to
exploit and explore the photoswitching of the enyne isoindoli-
none core of 1 to make multi-stable molecular switches. This
general structure has three potential isomeric forms, ZZ–ZE–EE.
Switching between these isomers results in changes in end-to-
end distances from 2.5 to 6.0 Å, with the alkynyl arms oriented
at angles between ∼35° and 135°, features that are unique to this
isoindolinone motif. Therefore, we describe modifications to our
original synthetic route that have allowed the creation of new
enyne based isoindolinone derivatives that are more stable than
the unprotected derivative; their switching properties were then
explored and are described herein.
In our previous studies, terminal diyne 2 was subjected to
Hay/Glaser oxidative coupling conditions to produce bis-diyne
3.11 Cyclization was then induced with mild base, with concomi-
tant removal of the trimethylsilyl (TMS) groups, to give
extended bis-isoindolinone 1 as a 19 : 1 mixture of ZZ and ZE
isomers. Our initial goal was to synthesize derivatives with end-
capping groups that would not be removed under mildly basic
cyclization conditions.12 (Triisopropyl)silyl (TIPS) and Ph
groups were chosen as these bulky moieties have previously
been appended to extended π-conjugated systems to provide
stability.13 However, our initial attempt at making diynes 4 using
the same oxidative coupling/cyclization route as for 1 resulted in
failure. Butadiynes 3b and 3c could not be isolated using these
reaction conditions. We then turned to the Cadiot–Chodkiewicz
Isoindolinones (IINs) are a completely unexplored family of
molecular switches, despite observation of their photorespon-
siveness.9 In our recent work to develop an efficient synthetic
route toward π-extended isoindolinone systems,10 we further
noticed the sensitivity of a few bis-isoindolinone systems, such
as compound 1, to light (Scheme 1). However, the low thermal
stability of this carbon-rich molecule due to the lack of protective
group on the terminal alkyne, and limited synthetic accessibility
Department of Chemistry, University of New Brunswick, Fredericton,
NB, Canada. E-mail: seisler@unb.ca; Fax: +506 453 4981;
Tel: +506 238 5066
†Electronic supplementary information (ESI) available: Full charac-
terization for compounds 4a–b, 1H and 13C NMR and NOESY
spectra, details of switching experiments and Fig. S1–S5. See DOI:
10.1039/c2ob26679b
8770 | Org. Biomol. Chem., 2012, 10, 8770–8773
This journal is © The Royal Society of Chemistry 2012

View Article Online
Fig. 1 Computational modelling of (a) ZZ-4a, (b) ZE-4a, (c) EE-4a, and (d) EE-4a, top view.
coupling, a method that is often used to create unsymmetrical
butadiynes.14 Reaction of terminal acetylene 2 with the appropri-
ate alkynyl bromides provided, in one step, enyne-containing
isoindolinones 4a–b in 61% and 54% yield, respectively. In both
cases, the ZZ isomers were produced as the main product, as
confirmed by NOESY experiments, which showed correlations
between the vinyl and the aromatic protons. The ZE isomers
were observed to be 5% and 13% of the product mixture for the
TIPS and phenyl derivatives, respectively.15
In preliminary work with terminal diyne 1, evidence of an EE
1
isomer was observed in the H NMR spectrum after exposure of
the ZZ-1–ZE-1 mixture to 365 nm light.16 As the presence of the
end-capping Ph and SiiPr3 groups might hinder the formation of
this sterically hindered isomer, we carried out some modeling
studies to determine the relative stabilities of the isomers of 4a.17
Shown in Fig. 1 are the energy-minimized structures of the three
possible isomers of 4a with their Erel values. It was determined
that ZZ-4a-and ZE-4a are of similar energies, with only a
0.90 kcal mol−1 difference. Somewhat surprisingly, the ZE form
seems to be the most stable. As can be seen in Fig. 1a, the
alkynyl moieties on ZZ-4a are slightly strained and are bent by
∼4° due to the bulkiness of the butyl chains on the amide. For
ZE-4a, rotation of one of the alkynyl arms into the E confor-
mation allows for relief of strain on that alkyne, which in this
isomer results in one completely linear alkynyl unit. It is known
that bending of alkynes by up to 20° leads to only minimal
increases in strain, explaining the only small difference in energy
between ZZ and ZE.18 However, it is difficult to confirm that the
ZE isomer is the thermodynamically most stable isomer using
these results, due to the relatively small difference in energy
found via the calculations.
Fig. 2 Switching properties of IIN-4a as monitored by 1H NMR in
CDCl3. (a) Scheme summarizing switching properties, (b) ZZ (95%)
isomer, (c) mixture of ZE–EE and traces of ZZ after exposure to 365 nm
light for 6 h, (d) primarily ZE isomer after exposure to 470 nm light for
2 h.
Not surprisingly, EE-4a is more strained than both the ZZ and
ZE isomers as a result of steric interactions between the two
SiiPr3 groups. To accommodate the bulk these groups provide,
the alkynyl units bend by an average of 7°. As alkynyl groups
can bend fairly easily without causing significant increases in
energy, and as the ZZ and ZE isomers also experience slight
deformation in this moiety, it is likely that strain caused by the
adjacent TIPS groups is accommodated in another way. Shown
in Fig. 1d is the top view of the energy-minimized structure of
EE-4b. The isoindolinone backbone is twisted by about 5°,
while for ZZ-4a and ZE-4a it is completely planar. Considering
the rather strained appearance of EE-4a, it is actually quite sur-
prising that so little a difference in energy, 5 kcal mol−1, is
observed between the EE and EZ isomers of 4a. However, this
small difference in energy was promising for the switching
experiments, indicating that the EE isomer might be accessible.
A series of photochemical experiments was subsequently
carried out, the results of which are summarized in Fig. 2a.
Depending on the wavelength of light used, the olefins in struc-
ture ZZ-4a can be isomerized to give an approximately equal
mixture of the ZE and EE forms, which can then be transformed
to give 95% of the ZE isomer; the ZE–EE and ZE forms can be
interconverted reversibly. The isomerisation were carried out as
1
follows. In Fig. 2b is an expansion of the H NMR spectrum of
the starting mixture of ZZ-4a (95%) : ZE-4a (5%); the majority
presence of the ZZ isomer was confirmed via a NOESY experi-
ment. Upon exposure of this mixture to 365 nm light, the vinyl
resonance of ZZ-4a at δ 5.88 ppm gradually diminishes. Corre-
spondingly, two vinyl resonances at δ 5.92 ppm and δ 5.65 ppm
appear. After 6 h a state is reached where two isomers that are
not ZZ-4a dominate the mixture, Fig. 2c. In addition to the vinyl
peaks, four new resonances also appear in the aromatic region, at
δ 9.41, 8.91, 8.26 ppm and 8.25 ppm. The presence of NOESY
correlations between the vinyl resonance at δ 5.92 ppm and the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8770–8773 | 8771

View Article Online
The phenyl-substituted 4b, similarly to 4a, responds to a
range of wavelengths. However, this derivative does not operate
as a switch in the same way as 4a. As shown in Fig. S2,†
365 nm light can be used to switch the primarily ZZ mixture of
4b. After 6 h of exposure at this wavelength, a photostationary
state is reached with a 1 : 5 : 5 mixture of ZZ–ZE–EE-4b,
Fig. S2.† Despite the observance of some light sensitivity in this
mixture, cycling between the ZE and the ZE–EE mixture was not
possible. Although the energy-minimized structures of 4b share
similar features to 4a, Fig. S3,† namely small deformations in
the alkynyl bond angle in the ZZ,ZE and EE isomers, and twist-
ing of the isoindolinone backbone in the EE form, there are no
significant differences in energy between the three isomers of
4b. In addition, the UV-Visible absorption spectrum of 4b,
Fig. S4,† shows that the ZZ isomer and the 1 : 5 : 5 mixture of
ZZ–ZE–EE-4b share very similar broad absorption features,
possibly explaining the lack of individual response to light. In
addition, prolonged exposure of 4b to TFA resulted only in
decomposition, not isomerisation to one isomer, as for TIPS-pro-
tected 4a. In this case, extension of the conjugation and removal
of the bulky TIPS groups appear to be detrimental to the switch-
ing properties.
Molecular switches that involve photo-isomerisation between
Z/E isomers often experience thermal conversion to the thermo-
dynamic minimum at rt. In our case, we observed that the ZZ,
ZE and EE forms of compound 4a are stable indefinitely at rt
when protected from light; we have yet to observe changes in
isomer ratios under these conditions. In addition, the mixture of
isomers shown in Fig. S1† was heated to 60 °C for 24 h in
CDCl3 with no change in isomer ratio, Fig. S5.† Heating to
120 °C for 24 h in DMF, however, minimally altered the product
ratio toward a decomposition product. The observed thermal
stability is a surprising result due to the thermal responsiveness
of hemi-thioindigo,6 which shares structural features with the
isoindolinone switch presented here.
Fig. 3 UV-Visible absorption spectra of ZZ–ZE–EE isomers of 4a. ZZ-
dotted line (⋯⋯), ZE-solid line (—), ZE–EE-dashed line (−−−).
aromatic resonance at δ 8.91 ppm, in addition to the correlation
between the vinyl resonance at δ 5.65 ppm and the methylene
group at δ 3.78 ppm, confirmed that ZE-4a is produced. No cor-
relation was observed between the new vinyl resonance at δ
5.65 ppm19 and the aromatic resonance at δ 9.41 ppm, which
was assigned to the aromatic proton ortho to the vinyl group of
EE via an HMBC experiment. However, after continued
exposure of the approx. 50 : 50 mixture to 365 nm light, no
further changes were observed, indicating the achievement of a
photostationary state. Irradiation of the mixture in Fig. 2c with
470 nm light for 2 h did lead, though, to further changes in the
isomer ratio.
As shown in Fig. 2d, the presence of ZE-4a now dominates
the 1H NMR spectrum. Irradiation of the ZE isomer with 411 nm
light for 2 hours again produced the ZE–EE mixture in Fig. 2c.
Alternating between 470 and 411 nm light led to cycling
between the primarily ZE mixture, Fig. 2d, and the approx.
50 : 50 mixture of ZE–EE, Fig. 2c.20 This result is comparable to
what is observed with many commonly used switches, which
reach photostationary states before full conversion. Ten cycles
were performed on 4a with 470/411 nm light and no fatigue was
observed.
Cycling back to the ZZ isomer proved to be difficult. As can
be seen in Fig. 3, the UV-Visible spectra did not provide much
help in this endeavor due to the broad absorption throughout the
235 nm to 450 nm range of all isomers, making it difficult to
target a particular absorbance in a single isomer. The ability to
convert the ZE–EE mixture in Fig. 2c to the primarily ZE isomer
in Fig. 2d with 470 nm light is likely due to the high wavelength
absorption tail that appears in the UV-Visible absorption spec-
trum in the ≥460 nm region of the ZE–EE mixture, Fig. 3
(dashed trace). This low-energy tail is not present in the UV-Vi-
sible spectra of just the ZZ and ZE isomers, dotted and solid
trace, respectively, and therefore must belong to the EE form.
Correspondingly, the ZZ and ZE structures do not respond to
light ≥460 nm. Interestingly, when a mixture of all three
isomers, produced by exposure of the ZZ isomer to 365 nm light
for 1 h, is treated to the equilibrating conditions of trifluoroacetic
acid (TFA), only the ZE isomer is produced, indicating that this
isomer is the thermodynamic minimum, Fig. S1.†
Conclusions
A new molecular switch has been realized using an isoindoli-
none motif. These structures are available in a few steps and
given proper substitution can reversibly alternate between two
isomeric forms using either light or acid. All isomers are ther-
mally stable at rt and at elevated temperatures. Future studies
will focus on a full photophysical examination and fine-tuning to
provide a fully reversible tri-stable switch.
Acknowledgements
We gratefully acknowledge the New Brunswick Innovation
Foundation (NBIF) and the Canada Foundation for Innovation
(CFI) for financial support. M. L. thanks NSERC for a USRA
Scholarship.
Notes and references
1 (a) M. Blanco-Lomas, S. Samanta, P. J. Campos, G. A. Woolley and
D. Sampedro, J. Am. Chem. Soc., 2012, 134, 6960; (b) U. Kusebauch,
S. A. Cadamuro, H.-J. Musiol, M. O. Lenz, J. Wachtveitl, L. Moroder
and C. Renner, Angew. Chem., Int. Ed., 2006, 45, 7015.
8772 | Org. Biomol. Chem., 2012, 10, 8770–8773
This journal is © The Royal Society of Chemistry 2012

View Article Online
2 (a) T. Ikeda, J.-i. Mamiya and Y. Yu, Angew. Chem., Int. Ed., 2007, 46,
506; (b) Z. Yu and S. Hecht, Angew. Chem., Int. Ed., 2011, 50, 1640;
(c) M. Natali and S. Giordani, Chem. Soc. Rev., 2012, 41, 4010.
3 (a) F. Nourmohammadian, T. Wu and N. R. Branda, Chem. Commun.,
2011, 47, 10954; (b) H. Tian and S. Yang, Chem. Soc. Rev., 2004, 33, 85;
(c) B. L. Feringa, R. A. van Delden, N. Koumura and E. M. Geertsema,
Chem. Rev., 2000, 100, 1789.
4 A. A. Beharry and G. A. Woolley, Chem. Soc. Rev., 2011, 40, 4422.
5 F. Hamon, F. Djedaini-Pilard, F. Barbot and C. Len, Tetrahedron, 2009,
65, 10105.
13 T. Luu, E. Elliott, A. Slepkov, S. Eisler, R. McDonald, F. A. Hegmann
and R. R. Tykwinski, Org. Lett., 2005, 7, 51.
14 P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes, ed.
H. G. Viehe, Dekker, New York, 1969, p. 597.
15 After column chromatography, isomer ratios changed to 12 : 1 ZZ–ZE for
4a and 2 : 1 ZZ–ZE for 4b.
16 The presence of the EE isomer at this early stage was indicated by the
presence of appropriate resonances and through space correlations in the
1H NMR and NOESY spectra, respectively.
17 Geometry optimization was undertaken at the B3LYP/6-31G* level using
Spartan ’10; Wavefunction, Inc., Irvine, CA, 2010.
6 W. Steinle and K. Rück-Braun, Org. Lett., 2003, 5, 141.
7 (a) P. Remón, M. Bälter, S. Li, J. Andréasson and U. Pischel, J. Am.
Chem. Soc., 2011, 133, 20742; (b) K. Higashiguchi, K. Matsuda and
M. Irie, Angew. Chem., Int. Ed., 2003, 42, 3537.
18 W. F. Maier, G. C. Lau and A. B. McEwen, J. Am. Chem. Soc., 1985,
107, 4724.
19 This resonance is overlapping with the E-vinyl resonance of
the ZE isomer. Integration indicates the presence of two vinyl
resonances from EE and one vinyl resonance from ZE. Any EE
vinyl-alkyl correlation is buried under the same correlation for the ZE
isomer.
20 Due to the broad absorption of 4a in the UV-Visible region, it was not
possible to target a specific absorption. Hence, 4a was exposed to a
number of wavelengths in the 300–470 nm region. 470/411 nm provided
the best results.
8 K. Szacilowski, Chem. Rev., 2008, 108, 3481.
9 V. Belluau, P. Noeureuil, E. Ratzke, A. Skvortsov, S. Gallagher,
C. A. Motti and M. Oelgemöller, Tetrahedron Lett., 2010, 51, 4738.
10 A. Bubar, P. Estey, M. Lawson and S. Eisler, J. Org. Chem., 2012, 77,
1572.
11 (a) G. Chen, I. Mahmud, L. N. Dawe, L. M. Daniels and Y. Zhao, Ibid,
2011, 76, 2701; (b) A. S. Hay, J. Org. Chem., 1962, 27, 3320.
12 K2CO3 will cause cyclization but will leave the TIPS groups of 3b.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8770–8773 | 8773