Fluorenylidene-pyrroline biomimetic light-driven molecular switches

Article abstract of DOI:10.1021/jo802792j

(Chemical Equation Presented) A new family of biomimetic photoactivated molecular switches based in the retinal chromophore is described. Expedient synthesis allows a library of compounds with a different substitution pattern, including chiral substituent

Full text of DOI:10.1021/jo802792j

Fluorenylidene-Pyrroline Biomimetic Light-Driven Molecular
Switches
Laura Rivado-Casas,† Diego Sampedro,*,† Pedro J. Campos,† Stefania Fusi,§
Vinicio Zanirato,‡ and Massimo Olivucci§,|
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La Rioja, Unidad
Asociada al C.S.I.C., Madre de Dios, 51, 26006 Logron˜o, Spain, Dipartimento di Scienze Farmaceutiche,
UniVersita` di Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy, Dipartimento di Chimica,
UniVersita` di Siena, Via Aldo Moro 2, I-53100 Siena, Italy, and Chemistry Department, Bowling Green
State UniVersity, Bowling Green 43403, Ohio
diego.sampedro@unirioja.es
ReceiVed January 2, 2009
A new family of biomimetic photoactivated molecular switches based in the retinal chromophore is
described. Expedient synthesis allows a library of compounds with a different substitution pattern, including
chiral substituents, to be obtained. The effect of substitution, solvent, and light source on the
photoisomerization step has been assessed. The absorption maximum has been red-shifted ca. 50 nm
with respect to related systems and rotation is now easily achieved by using visible light.
Introduction
or to trigger folding/unfolding of oligopeptides.8-13 In this
context, preparation of novel switches differing from azobenzene
in size, polarity, and isomerization mechanism represents an
attractive target yielding alternative building blocks that could
Molecular switches based on photochemical E/Z isomeriza-
tions have been employed in different contexts to convert light
energy into “mechanical” motion at the molecular level.1-3 For
instance, switches based on azobenzene have been used to
control ion complexation,4,5 electronic properties,6 and catalysis7
(6) Jousselme, B.; Blanchard, P.; Gallego-Planas, N.; Delaunay, J.; Allain,
M.; Richomme, P.; Levillain, E.; Roncali, J. J. Am. Chem. Soc. 2003, 125, 2888–
2889.
(7) Cacciapaglia, R.; Stefano, S. D.; Mandolini, L. J. Am. Chem. Soc. 2003,
125, 2224–2227.
(8) Behrendt, R.; Renner, C.; Schenk, M.; Wang, F.; Wachtveitl, J.; Oesterhelt,
D.; Moroder, L. Angew. Chem., Int. Ed. 1999, 38, 2771–2774.
(9) Bredenbeck, J.; Helbing, J.; Sieg, A.; Schrader, T.; Zinth, W.; Renner,
C.; Behrendt, R.; Moroder, L.; Wachtveitl, J.; Hamm, P. Proc. Natl. Acad. Sci.
U.S.A. 2003, 100, 6452–6457.
† Universidad de La Rioja.
§ Universita` di Siena.
‡ Universita` di Ferrara.
| Bowling Green State University.
(1) Balzani, V.; Credi, A.; Venturi, M. Molecular DeVices and Machines. A
journey into the nanoworld; Wiley-VCH: Weinheim, Germany, 2003.
(2) Drexler, K.-E. Nanosystems: Molecular Machinery, Manufacturing and
Computation; John Wiley: New York, 1992.
(10) Renner, C.; Behrendt, R.; Spo¨rlein, S.; Wachtveitl, J.; Moroder, L.
Biopolymers 2000, 54, 489–500.
(3) Sauvage, J.-P. Molecular Machines and Motors; Springer Verlag:
Heidelberg, Germany, 2001.
(4) Shinkai, S.; Kusano, Y.; Manabe, O.; Nakaji, T.; Nishida, Y.; Ogawa, T.
J. Am. Chem. Soc. 1980, 102, 5860–5865.
(5) Shinkai, S.; Minami, T.; Kusano, Y.; Manabe, O. J. Am. Chem. Soc.
1983, 105, 1851–1856.
(11) Rudolph-Bo¨hner, S.; Kru¨ger, M.; Oesterhelt, D.; Moroder, L.; Na¨gele,
T.; Wachtveitl, J. J. Photochem. Photobiol. A 1997, 105, 235–248.
(12) Spo¨rlein, S.; Carstens, H.; Satzger, H.; Renner, C.; Behrendt, R.;
Moroder, L.; Tavan, P.; Zinth, W.; Wachtveitl, J. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 7998–8002.
(13) Ulysse, L.; Cubillos, J.; Chmielewski, J. J. Am. Chem. Soc. 1995, 117,
8466–8467.
4666 J. Org. Chem. 2009, 74, 4666–4674
10.1021/jo802792j CCC: $40.75  2009 American Chemical Society
Published on Web 06/01/2009

Light-DriVen Molecular Switches
SCHEME 1. NAIP and NAFP Switches
expand the applicability of the switch concept to diversified
molecular environments. A sophisticated application of the
above principle led to the preparation of chiral diarylidenes,
featuring a single isomerizable bond. These systems constitute
examples of light-driven molecular rotors14-18 where the chiral
framework imposes a preferential direction (either clockwise
or counterclockwise) of isomerization.
The retinal protonated Schiff base chromophore of rhodop-
sins19-21 constitutes an example of an E/Z switch shaped by
biological evolution that can be modeled with quantitative
computations.22 In bovine rhodopsin (Rh) a selective photoi-
somerization of the 11-cis chromophore (PSB11) occurs via
evolution of a single π f π* excited state (S1) that survives
for only 150 fs and yields, upon decay, the all-trans ground
state (S0) product with a 67% quantum yield.19,20 While these
properties make Rh an excellent reference for the design of E/Z
switches, irradiation of PSB11 in solution features an unselective
isomerization and a picosecond excited state lifetime20 prompt-
ing a search for artificial Rh-mimetic molecules.
Recently, we have been able to demonstrate that it is possible
to prepare and characterize23 an N-alkylated indanylidene-
pyrroline Schiff base (NAIP) that displays, in methanol solution,
excited state properties similar to those of Rh-embedded PSB11.
The synthetic strategy we have developed to set up the
polyconjugated iminium chromophore features a high-yielding
heterocyclization as the key step. We have shown that 4-inda-
nylidene pyrroline derivatives (IPs) are the products of an
intriguing multistep one-pot process we named “cyclopropyl
ring-opening/nitrilium ion ring-closing tandem reaction”.24 In
detail, when 1-cyclopropylindenium intermediates (i) react with
acetonitrile they undergo homoallyl rearrangement yielding the
corresponding nitrilium ions (ii). Then, the transient electrophilic
species collapse onto the internal olefine generating the desired
pyrroline derivatives IPs.
We could trigger the heterocyclization step both by treating
1-cyclopropylindanols IcP-OH in CH3CN with Tf2O and by
regioselective protonation with TfOH of indenyl cyclopropane
derivatives IcP in CH3CN. The effectiveness and versatility of
the synthetic approach permitted the access to several NAIPs,
structure NAIPa and NAIPb included (Scheme 1).
NAIPs are “chimerical” switches that incorporate into the
Feringa’s biarylidenes skeleton a protonated or alkylated Schiff
base function (see Scheme 1) that could potentially replicate
the dynamics of the PSB11 isomerization in Rh. This protein
features a S1 lifetime of ≈150 fs, a S0 transient (photorhodopsin)
appearance time of 180 fs, and a primary photoproduct
(bathorhodopsin) appearance time of ≈6 ps. Very recently we
have shown, through a highly interdisciplinary research effort,25
that a p-methoxy NAIP derivative (NAIPa, Scheme 1) is a
photochromic compound completing its Z f E and E f Z
photocycle in picoseconds. These time scales (ca. 0.3 ps for
Z-a) suggest that NAIP-based motors may complete a half-rotary
cycle in less than 10 ps,25 i.e., a few orders of magnitude faster
than the fastest (≈6 ms for half-cycle) known biarylidene.25,26
In spite of the remarkable properties of NAIPs, these switches
display absorption maxima in the near-UV region. Thus, the
parent compound NAIPb has an absorption maximum of 343
nm that is red-shited to 377 nm for NAIPa due to the electron-
releasing effect of its p-MeO group. Indeed, electron releasing
groups in the para and ortho position are predicted to stabilize
the spectroscopic (charge-transfer) state with respect to the
ground state and therefore lead to a red-shift.23 Unless deriva-
tives of this switch can be prepared that span absorption maxima
in the 343-420 nm range one still seeks homologues where
the absorption maximum of the parent (unsubstituted) system
is clearly in the visible. With this idea in mind we have pointed
to a replacement of the indanylidene unit of NAIPs with moieties
displaying a more expanded π-system.
(14) Feringa, B. L. Acc. Chem. Res. 2001, 34, 504.
(15) Feringa, B. L. J. Org. Chem. 2007, 72, 6635–6652.
(16) Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B. L. J. Am.
Chem. Soc. 2000, 122, 12005.
(17) Koumura, N.; Geertsema, E. M.; van Gelder, M. B.; Meetsma, A.;
Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 5037.
(18) Koumura, N.; Zijistra, R. W. J.; van Delden, R. A.; Harada, N.; Feringa,
B. L. Nature 1999, 401, 152.
(19) Kandori, H.; Shichida, Y.; Yoshizawa, T. Biochemistry (Moscow) 2001,
66, 1483–1498.
(20) Mathies, R. A.; Lugtenburg, J. In Handbook of Biological Physics;
Stavenga, D. G., de Grip, W. J., Pugh, E. N., Eds.; Elsevier: Amsterdam, The
Netherlands, 2000; Vol. 3, pp 56-90.
(21) Teller, D. C.; Okada, T.; Behnke, C. A.; Palczewski, K.; Stenkamp,
R. E. Biochemistry 2001, 40, 7761–7772.
In the present report we focus on switches where the
indanylidene unit has been replaced by a fluorenylidene unit.
(22) Andruniow, T.; Ferre´, N.; Olivucci, M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 17908–17913.
(23) Lumento, F.; Zanirato, V.; Fusi, S.; Busi, E.; Latterini, L.; Elisei, F.;
Sinicropi, A.; Andrunio´w, T.; Ferre´, N.; Basosi, R.; Olivucci, M. Angew. Chem.,
Int. Ed. 2007, 47, 414–420.
(25) Sinicropi, A.; Martin, E.; Ryasantsev, M.; Helbing, J.; Briand, J.; Sharma,
D.; Le´onard, J.; Haacke, S.; Canizzo, A.; Chergui, M.; Zanirato, V.; Fusi, S.;
Santoro, F.; Basosi, R.; Ferre´, N.; Olivucci, M. Proc. Natl. Acad. Sci. U.S.A.
2008, 105, 17642–17647.
(24) Zanirato, V.; Pollini, G. P.; De Risi, C.; Valente, F.; Melloni, A.; Fusi,
S.; Barbetti, J.; Olivucci, M. Tetrahedron 2007, 63, 4975–4982.
(26) Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc.
2006, 128, 5127–5135.
J. Org. Chem. Vol. 74, No. 13, 2009 4667

Rivado-Casas et al.
SCHEME 2. Synthetic Route to NAFPs
plexes were synthesized (2a and 2e) and tested. Although both
compounds yield the same product 3b, better results were
obtained for the tungsten compound (58% from 2a and 40%
from 2e). Following the optimized protocol, a set of compounds
shown in Table 1 could be prepared in modest to good yields
in all but one entry.
In the case that chiral nonracemic fluorenone imines 1b and
1c were the substrates, a certain degree of diastereoselection
was observed, instead reacting 1d, a single diastereoisomer, was
isolated from the reaction mixture. However, we were not able
to appreciate optical activity for 3j, and chiral GC/MS analysis,
in order to evaluate its ee, revealed to be impracticable. On the
other hand, when a sample containing 3j in CDCl3 was doped27
Through the preparation of a library of N-alkylated fluorenyl-
idene-pyrroline switches (NAFPs), we show that it is possible
to achieve biomimetic light-driven switches where the absorption
maxima of an unsubstituted system has been red-shifted by >50
nm with respect to that of the NAIPs. We also show that, similar
to NAIPs, NAFPs undergo Z f E and E f Z photoisomerization
displaying a photomodulable stationary state.
Several approaches were considered for the synthesis of the
polyconjugated iminium chromophore. The main synthetic task
was an expeditious entry to a small library of compounds, the
synthetic route was required to be amenable to the preparation
of derivatives in which functional groups with different elec-
tronic nature could serve to tune the photochemical behavior.
Another goal was the production of chiral molecular switches
potentially acting as molecular rotors. With these considerations
in mind, we believed of particular usefulness the already
reported28 reaction of alkynyl Fischer carbene complexes with
fluorenone imines leading directly to compounds featuring the
pivotal chromophore embedded into a conformationally locked
structure. As shown in Scheme 2, different substituents could
be introduced with ease in almost every point of the molecule,
thus allowing the tuning of the properties of the system.
1
with Eu(hfc)3 the H NMR signals moved downfield showing
coupling but no splitting, a result suggesting a g90% ee (see
the Supporting Information for details). As far as both (possible)
enantiomers showing exactly the same displacements, further
experiments will be needed for a comprehensive exploration
of the stereochemical outcome of the Aumann’s reaction.28 As
expected, the carbomethoxy fluorenone imines gave rise to the
corresponding fluorenylidene-pyrrolines as a mixture of geo-
metric isomers. All attempts to prepare the 5-TMS derivatives
failed and only the substitution product 4 could be isolated.
Apparently, the TMS group hampers the Michael-type addition
of the imine nitrogen atom to the alkyne ꢀ carbon and, as
expected,29 the isopropylamine in the reaction medium gives
substitution at the carbene carbon atom.
Once the compounds featuring a fluorene nucleus conjugated
to the cyclic imine were prepared, what remained to do in order
to obtain biomimetic20 switches was the quaternization of the
imine nitrogen atom. Several methods were tried to alkylate
the imine moiety (Me2SO4, MeI, Et3OBF4) but best results
were obtained with methyl triflate in dry toluene. Under these
conditions, the triflate salts precipitated in pure form and the
free bases could be easily recovered from the filtrate. Alterna-
tively, iminium ions (5e, 5f) were quantitatively obtained
following protonation with HBF4 of the corresponding imines
in CDCl3 solution. Chart 2 shows the NAFP switches formed
and used in the photochemical study, while Figure 1 depicts
the structure of 5c as obtained from X-ray diffraction data.
Complete delocalization of the π system is clearly shown by
long double bond distances (CdN, 1.31 Å, central CdC, 1.37
Å) and short single bond distances (CsC between 1.45 and
1.49 Å). This will be reflected in the low-energy UV absorption
bands. Besides, the structure is not planar as the dihedral angle
between the fluorenyl and pyrroline moieties is 19.5°.
Synthesis
In the original paper,28 the nonenolizable imine partners of
the pentacarbonyl(1-ethoxy-3-phenyl-2-propyn-1-ylidene)tung-
sten were restricted to a couple of examples and no further
efforts have appeared in the literature to extend this intriguing
reactivity. A rapid entry to a small library of NAFP photo-
switches was envisaged simply by combining different alkynyl
Fischer carbene complexes with proper imines, both preparable
by conventional chemistry.
Embarking on the synthetic work we prepared imines from
fluorenone as well as from the C-2 and C-4 carbomethoxy
derivatives. Regarding the amine moiety with the required C-H
bond adjacent to the primary nitrogen atom, we used four
different substrates. Importantly, starting from commercially
available enantiopure primary amines chirality was easily
introduced in the imine reactants. Eventually, structural diversi-
ty also could be introduced at the Fischer carbene complex by
modifying the metal, the alkoxy, and alkynyl substituents (see
Chart 1).
Our next step was to optimize the reaction conditions: best
results were obtained by heating the imines at 90 °C in a toluene
solution 0.5 M in carbene complexes. The main side reactions
consisted of carbene complexes decomposition (specially for
2d) and imine hydrolysis followed by amine addition to carbene
complexes. These drawbacks could be mitigated by avoiding
higher temperatures, employing 1.5 equiv of carbene complexes
and using anhydrous conditions. The presence in the reaction
mixture of pyrrolium complexes as reported by Aumann28 was
not investigated. Both tungsten and chromium carbene com-
Spectroscopic Studies
First, we studied the effect in the UV spectrum of the imine
methylation. As stated before, previous results suggest that the
presence of a positive charge in the nitrogen atom would
contribute to an increase in the isomerization rate. Of course, a
fast activation process is a desirable feature of a molecular
switch, but the positive charge also can cause a direct effect on
the absorbance of these compounds. To check this effect, we
recorded the UV-visible spectrum for 3a and 5a shown in
Figure 2.
(28) Aumann, R.; Yu, Z.; Fro¨hlich, R.; Zippel, F. Eur. J. Inorg. Chem. 1998,
11, 1623–1629.
(29) Do¨rwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 1999.
(27) Parker, D. Chem. ReV. 1991, 91, 1441–1457.
4668 J. Org. Chem. Vol. 74, No. 13, 2009

Light-DriVen Molecular Switches
CHART 1. Imines and Carbene Complexes Used in the Synthesis of Molecular NAFP Switches
As can be seen, the main difference between both spectra is
the red-shift of the low-energy band of the salt with respect to
that of the neutral compound. Although this behavior is common
in the chemistry of iminium salts, it becomes important in this
particular case as far as the displacement of ca. 70 nm implies
that these compounds will absorb in the visible region. This
feature greatly increases the interest in these compounds as far
as no UV-light will be needed to activate the switches.
but this equilibrium should be controlled in the case of chiral
molecules behaving as molecular motors.
Photoisomerization of Neutral Compounds
We chose for this part of the study 3m and 3n, as far as they
1
are separable isomers with distinctive H NMR signals. We
started from pure samples of the two isomers 3m and 3n and
followed the photoisomerization process by 1H NMR. We used
a 125-W medium-pressure Hg lamp and pyrex filter to ensure
absorption of the low-energy band (see Figure 2). We recorded
the spectra at different times to follow the isomerization process.
Results can be seen in Figure 5.
As can be seen, fast isomerization takes places and the
photostationary state is reached within 30 min starting from 3m
(Figure 5, top) and 60 min starting from 3n. In both cases the
same equilibrium is reached (ca. 55:45) with a majority of the
mixture formed by 3n. This equilibrium remains unaltered with
further irradiation or heating. To check the photochemical nature
of the process, we carried out a comparative experiment heating
isolated isomers 3m and 3n at 50 °C in the dark. Results are
shown in Figure 6.
We first explored the photochemical behavior of the simplest
switch structures, i.e., 3a and 3b. Irradiation of 3a with a
medium-pressure Hg lamp at room temperature was followed
by 1H NMR. Different spectra were recorded every 90 min and
no change was noticed after 18 h of irradiation. Similar results
were obtained after irradiation of 3b. Methylated compound 5a
was also tested under the same reaction conditions and the
compound remained unaltered after irradiating for 60 h. These
values are also important because they denote the high photo-
stability of these compounds, a key feature of any potential
technological application. Although 3a and 3b, together with
other examples shown in Table 1, have the symmetrical
fluorenone moiety, they could present two different stereoiso-
mers due to steric constraints around the central double bond.
This feature has also been used before in the preparation of
molecular switches and motors.30 This was also shown in the
X-ray diffraction structure for 5c (Figure 1) where the dihedral
angle around the central double bond is 19.5°. These two
isomers were studied by means of DFT theoretical calculations
(Figure 3). The main geometrical change between both structures
is the dihedral angle connecting the fluorenyl and pyrroline
moieties. The most stable structure for 3b shows a dihedral angle
of 23.3° (close to the value of 19.5° for 5c), while the isomer
presents a dihedral angle of -26.5°. However, only a very small
energy difference was found between both isomers.
To clarify this point, a careful NMR analysis of 3c was carried
out. We chose this compound due to the absence of the phenyl
ring bonded to the imine, which simplifies the NMR spectrum
in the relevant region of aromatic hydrogen atoms. The presence
of unresolved aromatic signals at 298 K suggested the possibility-
of different isomers in fast equilibrium. To check the possibility
of equilibrium between the two stereoisomers shown in Figure
3 we registered the NMR spectrum at low temperatures.
Temperature-dependent NMR spectra enabled the measurement
of the energy barrier between isomers, by determining experi-
mentally the coalescence temperature for the signals (Figure
4). The relation between the coalescence point, the difference
in the chemical shift, and the rate constant is well-known.31
Using these data we were able to obtain a value of 11.6 kcal/
mol for the dynamic energy barrier from a coalescence tem-
perature of 253 K. It should be noted that the equilibration
between these two stereoisomers is fast at room temperature
and it will not hamper the photoactivated Z-E isomerization,
Clearly, although thermal isomerization also takes place,
heating at 50 °C for more than 18 h is needed to reach the
equilibrium. These data should be compared with the 30 min
necessary to photochemically equilibrate the mixture. Thus, the
photochemical isomerization is much faster than the thermal
one, and the latter can be completed at short times. Once we
assessed the feasibility of the fast photoisomerization process
we aimed for the effect the reaction conditions could have on
the isomerization speed. In order to do this, we carried out
similar experiments as those described above with different
solvents, switches, and light sources. To determine the perfor-
mance of the switches, we measured the initial rate constant
for the isomerization process, ki. To permit direct comparison
we carried out a series of experiments in which we varied only
one variable at a time. This will allow us to obtain precise
information on the effect of the variable, but comparison
between different runs should be taken with care. We first
1
measured by H NMR the isomerization process of neutral
compounds and these data will used as a benchmark for the
cationic species.32 Results are summarized in Table 2.33
Several conclusions can be drawn from the data presented in
Table 2. First, the solvent has some influence on the isomer-
ization ratio for both 3m and 3n. Polar solvents such as
acetonitrile contribute to a faster isomerization but the effect is
stronger in 3m (the relative ratio in CD3CN is twice that with
CDCl3) than in 3n (relative ratio 1:1.1). Comparing 3m vs. 3n
with CD3CN as solvent, faster isomerization takes place for 3m.
This could be linked to the relative stability of both compounds
as far as DFT calculations show that 3m is 1.2 kcal/mol less
stable than 3n (see the Supporting Information for details).
(30) For a recent example see: Katsonis, N.; Minoia, A.; Kudernac, T.; Mutai,
T.; Xu, H.; Uji-i, H.; Lazzaroni, R.; DeFeyter, S.; Feringa, B. L. J. Am. Chem.
Soc. 2008, 130, 386–387.
(31) Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic
Chemistry; 4th ed.; McGraw-Hill: New York, 1984.
(32) A typical experiment was carried out with a concentration of 0.010 M,
but concentrations between 0.004 and 0.15 M were also tested with similar results.
(33) Several experiments were performed for each entry. Data shown
correspond with the mean value and error was determined to be <8%.
J. Org. Chem. Vol. 74, No. 13, 2009 4669

Rivado-Casas et al.
CHART 2. NAFP Molecular Switches Used in the
TABLE 1. Fluorenylidene-pyrroline Derivatives
Photochemical Study
Photoisomerization of Biomimetic Switches
Methylated Compounds. The next step was to study the
photoisomerization of switches 5c and 5d. In this case, one more
factor should be taken into account as far as these compounds
also absorb in the visible. So, the light source could also affect
the isomerization rate. The results obtained in this series of
experiments are shown in Table 3.
As can be seen, the solvent used has little influence on the
rate of isomerization, at least in the cases studied. The only
exception was 5d in CDCN, which gave a mixture of 5c and
5d from the very beginning avoiding the measurement of the
isomerization rate. However, methylated analogues 5c and 5d
are more soluble in polar solvents like acetonitrile and concen-
tration in less polar solvents like chloroform or toluene always
must be lower to avoid precipitation. When both cationic
compounds are compared, little difference in the photoisomer-
ization rate is observed (1:1.1). However, it should be noted
that 5d isomerizes slightly faster than 5c. This result is opposed
to the one found for the neutral compounds, but also in this
case the difference in the relative stability can explain these
rates. Our DFT calculations show that 5d is less stable than 5c
by 0.5 kcal/mol. As expected, nitrogen atom methylation
contributes not only to simulate the retinal chromophore, but
also to speed up the isomerization process. In the case of 5c,
a Two separable diastereoisomers were obtained in a 6:1 ratio. b One
only diastereoisomer was found in the reaction crude. c As an inseparable
mixture of two isomers. d As a separable mixture of two isomers.
FIGURE 1. X-ray diffraction structure for NAFP switch 5c.
4670 J. Org. Chem. Vol. 74, No. 13, 2009

Light-DriVen Molecular Switches
FIGURE 2. UV-visible spectrum in CH3CN for compounds 3a (neutral, 7.25 × 10-5 M) and 5a (methylated, 4.84 × 10-5 M).
FIGURE 3. BP86/6-31G* structures and absolute and relative energies for the two stereoisomers available for 3b.
FIGURE 4. 1H NMR spectra for 3c in d8-toluene at the temperatures shown.
photoisomerization takes place almost four times faster than for
Finally, the effect of the light source was assessed. For both
3m, while 5d isomerizes almost three times faster than 3n.
switches 5c and 5d, higher relative rates were found when using
J. Org. Chem. Vol. 74, No. 13, 2009 4671

Rivado-Casas et al.
FIGURE 5. Photoisomerization process for 3m and 3n with use of pyrex-filtered UV light.
the medium-pressure Hg lamp compared to ambient light. This
effect is clearly due to the different intensities of the light
sources. However, the small differences in the reaction rates
indicate the usefulness of these switches as far as no UV light
is needed to trigger the photoisomerization. This fact, far from
being trivial, constitutes an important feature of these switches
and constitutes an improvement over the majority of switches
based in overcrowded alkenes15 which usually need UV light
to rotate. The use of low-energy light in the presence of a
complex matrix and sunlight exploitation are important features
for technological applications of molecular switches. To further
explore the effect of the light source, we explored the
wavelength dependence in the photoisomerization of 5c. Using
monochromatic light, we followed the photoisomerization
process at 330 and 433 nm. We chose those wavelengths
because they have the same extinction coefficient (ε ) 1060)
at both sides of the absorption band (see Figure 2 for the UV
spectrum of a related compound). Under these conditions,
solutions of the same concentration (0.02 M) will absorb exactly
the same amount of light. We found the same kinetic constants
and composition of the photostationary state (57% of 5c and
43% of 5d) for the irradiation at these two wavelengths for 6 h.
This fact emphasizes the usefulness of these compounds under
low-energy irradiation.
We also checked the thermal isomerization of these com-
pounds. An equivalent experiment as the one shown in Figure
6 was carried out for 5c and 5d, with similar results. After 22 h
at 50 °C an equilibrium formed by 59% 5c and 41% 5d was
reached. Interestingly, the main isomer in this case (5c) is the
opposite of the one mainly obtained when the neutral compounds
are used (3n). This means that methylation causes a change in
the relative stabilities of the different isomers. This is confirmed
by the DFT calculations carried out for both pairs of compounds
as discussed above (see the Supporting Information for details).
Protonated Compounds. Finally, we decided to explore the
effect of protonation instead of methylation in the nitrogen atom.
This was first carried out with HBF4 to generate the cationic
species 5e and 5f. A series of experiments was then performed
to determine how this modification affects the isomerization
outcome. Results are shown in Table 4.
Although protonation in the nitrogen atom also contributes
to faster photoisomerization rates, the accelerating effect is
smaller than that in the methylated analogues. However, light
absorption takes place also in the visible and preparation of the
4672 J. Org. Chem. Vol. 74, No. 13, 2009

Light-DriVen Molecular Switches
FIGURE 6. Thermal isomerization process for 3m and 3n.
TABLE 2. Photochemical Isomerization of 3m and 3n
anhydrous CH3OH (179 µL) was added in the dark and at
room temperature to a solution of 3n (8 mg (0.018 mmol) in
1.5 mL of CD3OD). The solution was divided into two equal
compd
solvent
kia
3m
3m
3n
3n
3m
3n
CDCl3
CD3CN
CDCl3
CD3CN
CD3CN
CD3CN
1
1.9
1
1.1
1.8
1
1
parts and transferred into two NMR tubes and the H NMR
spectra was recorded immediately. One NMR tube is kept
in the dark, while the other is irradiated at 420 nm with a
monochromator. The progress of the isomerization, both
thermal and photochemical, was monitored by 1H NMR
spectroscopy, recording different spectra at different times.
The results are reported in Table 5.
a Relative rate constants.
protonated compounds 5e and 5f can be obtained in situ in
quantitative yields. Thus, these compounds could also be useful
in practical applications. It should also be noted that the
counterion is different in pairs 5c-5d and 5e-5f and it is known
that the counterion affects the reaction rate in related photoi-
somerizations.34
Again, isomerization can be easily achieved by in situ
formation of the protonated switches and using an ambient light
source. As in previous experiments, it can be seen that the
photoisomerization proceeds much faster than the thermal one.
Protonation can also be carried out with HCl. Here 4.6
µL of a solution containing HCl obtained with CH3COCl in
(34) Cembran, A.; Bernardi, F.; Olivucci, M.; Garavelli, M. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 6255–6260.
J. Org. Chem. Vol. 74, No. 13, 2009 4673

Rivado-Casas et al.
TABLE 3.
Photochemical Isomerization of 5c and 5d
somers available. Thermal and photochemical stability have been
checked to validate the use of these compounds as useful
switches. Kinetic measures of the photoisomerization allow
quantitative exploration the effect of the modifications in the
basic structure. Fast photochemical isomerization can be
achieved through irradiation of pure samples of neutral or
cationic forms. The effect of substitution, solvent, methylation,
and light source has been investigated in order to control the
switch behavior prior to its use in practical applications. In
contrast with most of switches based in overcrowded alkenes,
NAFP switches presented here can use visible light to rotate.
This constitutes a clear improvement over previous results and
makes retinal-based molecular switches interesting candidates
for technological applications.
compd
solvent
light source
kia
5c
5c
5d
5d
5c
5d
3m
5c
3n
5d
5c
5c
5d
5d
5c
5d
CDCl3
CD3CN
CDCl3
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
UV
UV
UV
UV
UV
UV
UV
UV
UV
UV
UV
visible
UV
visible
visible
visible
1
1.01
1
b
-
1
1.1
1
3.9
1
2.8
1.61
1
1.92
1
Experimental Section
Typical Procedure for the Synthesis of Fluorenylidene-Pir-
roline Derivatives. To a pentacarbonyl(ethoxyalkynylcarbene)tungsten
complex (2a) (482 mg, 1.00 mmol) solution in dried and degassed
toluene (2 mL) was added (fluoren-9-ylidene)isopropilamine (1a)
(221 mg, 1.00 mmol) under Ar at room temperature. The reaction
mixture was stirred for 36 h at 90 °C until the complex disappeared.
The solvent was removed and the solid residue was disolved in
ethyl acetate and solution was filtered through a Buchner funnel.
Solvents were then removed with a rotary evaporator, and the
products were separated by column chromatography. Elution with
hexane/ethyl acetate affords a brown fraction with compound 3b
(Rf 0.3, in hexane/ethyl acetate, 4:1, 220 mg, 58%).
1
1.01
a Relative rate constants. b A mixture of compounds 5c and 5d was
obtained from the beginning.
TABLE 4. Photochemical Isomerization of 5e and 5f
compd
solvent
kia
3-Ethoxy-4-(9H-fluoren-9-ylidene)-3,4-dihydro-2,2-dimethyl-
1
5-phenyl-2H-pyrrole (3b): brown oil; yield 220.10 mg, 58%; H
5e
5f
3m
5e
3n
5f
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
1.6
1
1
1.3
1
1.2
NMR (300 MHz, CDCl3) δ 8.31-8.25 (m, 1H), 7.84-7.70 (m,
1H), 7.66 (dd, J ) 6.58, 1.70 Hz, 1H), 7.57 (d, J ) 7.50 Hz, 1H),
7.45-7.27 (m, 6H), 7.13 (t, J ) 7.45, 7.45 Hz, 1H), 6.75-6.64
(m, 1H), 6.55 (d, J ) 7.93 Hz, 1H), 5.07 (s, 1H), 3.66 (td, J )
13.85, 6.94, 6.94 Hz, 1H), 3.54-3.43 (m, 1H), 1.61 (s, 3H), 1.25
(d, J ) 4.99 Hz, 3H), 1.20 (d, J ) 6.91 Hz, 3H) ppm; 13C NMR
(300 MHz, CDCl3) δ 171.1, 141.6, 141.5, 139.0, 135.3, 130.8,
129.9, 129.1, 128.9, 128.7, 128.6, 127.9, 126.4, 126.3, 119.6, 119.3,
90.1, 62.2, 27.7, 22.0, 15.5 ppm; UV-vis λ 224 (ε 29 922 M-1
cm-1), λ 257 (ε 24 457 M-1 cm-1), λ 339 (ε 7981 M-1 cm-1);
exact mass (C27H25NO + H) calcd 380.2009, found 380.2000.
a Relative kinetic constants.
TABLE 5. Photochemical and Thermal Isomerization after
Protonation of 3n with HCl
a
time (min)
hνa
∆
30
60
90
1/0.52
1/0.73
1/0.73
1/0.40
1/0.52
1/0.56
Acknowledgment. We thank the Spanish MEC (CTQ2007-
64197) for financial support. D.S. is financed by the Ramo´n y
Cajal program from the MEC. L.R. thanks the Comunidad
Autonoma de La Rioja for his fellowship. M.O., V.Z. and S.F.
are grateful to MIUR for the Grant PRIN 2006 In silico design,
synthesis and photochemical reactivity of cyclic phototunable
peptidomimetics containing the RGD sequence.
a E/Z ratio.
Conclusions
Fischer carbene complexes have been used to synthesize a
new family of photochemical switches based in the retinal
chromophore (NAFP switches). Optimization of the overall yield
allows the synthesis of a set of compounds acting as photoac-
tivated molecular switches. The synthetic route has been
explored to allow the formation of compounds with a different
substitution pattern. Chosen compounds have been used to
determine the structure and characterize the different stereoi-
Supporting Information Available: Experimental proce-
dures, characterization data for new compounds, X-ray structure
details for compound 5c in CIF format, and Cartesian coordi-
nates for the calculated geometries. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO802792J
4674 J. Org. Chem. Vol. 74, No. 13, 2009