Synthesis of photochromic compounds for aqueous solutions and focusable light

Article abstract of DOI:10.1002/ejoc.201100166

Photochromic compounds with improved performance in pure water have been prepared and characterized. They possess an asymmetrical and extended conjugation system with a 1,2-bis(3-thienyl)perfluorocyclopentene core, additional thiophene rings connected with sulfonic acid residues, as well as terminal pyrid-4-yl and 4-alkoxyphenyl groups. A multistep synthetic route to a key compound with an amino group required for further derivatization has been developed. The complete photocyclization reaction of the initial "open ring" compound (with absorption maximum at 340 nm in MeOH or water) can be performed with a diode laser in pure water or aqueous buffer solutions (without added or-ganic solvents) under irradiation at 366-375 nm, and the reverse ring-opening reaction of the colored "closed ring" compound (λ_max = 628 or 624 nm in MeOH or water) takes place under irradiation with visible green or red light (>500 nm). Building block 57, with a secondary amino group, can further be used in the synthesis of practically important, reversibly switchable, fluorescent compounds in which the fluorescent dye (donor) is attached to a photochromic unit (acceptor), and the resonant energy transfer from a donor to the colored form of an acceptor provides a reversible quenching of the fluorescence signal in aqueous solutions.

Full text of DOI:10.1002/ejoc.201100166

FULL PAPER
DOI: 10.1002/ejoc.201100166
Synthesis of Photochromic Compounds for Aqueous Solutions and Focusable
Light
Svetlana M. Polyakova,[a,b] Vladimir N. Belov,*[a] Mariano L. Bossi,[a] and Stefan W. Hell*[a]
Keywords: Cyclization / Heterocycles / Molecular devices / Photochromism / Solvent effects
Photochromic compounds with improved performance in
pure water have been prepared and characterized. They pos-
sess an asymmetrical and extended conjugation system with
ganic solvents) under irradiation at 366–375 nm, and the re-
verse ring-opening reaction of the colored “closed ring”
compound (λmax = 628 or 624 nm in MeOH or water) takes
place under irradiation with visible green or red light
(Ͼ500 nm). Building block 57, with a secondary amino group,
can further be used in the synthesis of practically important,
reversibly switchable, fluorescent compounds in which the
fluorescent dye (donor) is attached to a photochromic unit
(acceptor), and the resonant energy transfer from a donor to
the colored form of an acceptor provides a reversible quench-
ing of the fluorescence signal in aqueous solutions.
a
1,2-bis(3-thienyl)perfluorocyclopentene core, additional
thiophene rings connected with sulfonic acid residues, as
well as terminal pyrid-4-yl and 4-alkoxyphenyl groups. A
multistep synthetic route to a key compound with an amino
group required for further derivatization has been devel-
oped. The complete photocyclization reaction of the initial
“open ring” compound (with absorption maximum at 340 nm
in MeOH or water) can be performed with a diode laser in
pure water or aqueous buffer solutions (without added or-
that hundreds or thousands of such cycles can be performed
without considerable loss of contrast (caused by photo-
bleaching). An advantage of the fluorescent photochromic
compounds is that the light intensity required for switching
are much lower than those commonly used in other far-
field nanoscopy techniques[6] (e.g., stimulated emission de-
pletion[7] or ground state depletion with individual molecu-
lar return[8]). Therefore, the drastic reduction in the applied
light intensities would be highly beneficial to avoid photod-
amage to live cells and other biological objects.
Modern microscopy techniques demand photochromic
compounds that can be reversibly switched between color-
less and colored states by irradiation with focused light. The
technique also requires the application of high-quality op-
tics that are available for visible and near-UV light. How-
ever, aberration-corrected lenses with large numerical aper-
tures (1.35–1.45) exist only for wavelengths greater than
360 nm. Thus, the compact and relatively inexpensive, com-
mercially available diode lasers, which typically operate at
375 nm, are convenient and provide one of the shortest
wavelengths available for optical switching in life sciences.
Among the different families of photochromic com-
pounds, diarylethenes that contain a perfluorocyclopentene
unit, are regarded as the most promising, particularly for
photoswitching applications in optical nanoscopy, pcRET,
and data storage. Key features of these compounds are bi-
stability (absence of thermal reactions competing with pho-
tochromic transformations) and a large fatigue resistance
(photostability). Despite the large number of known di-
arylethenes,[9] only a few can be switched at wavelengths
Introduction
Photochromic compounds can be reversibly converted by
light between two states with different spectroscopic prop-
erties.[1] Moreover, various secondary functions of photo-
chromic compounds and their adducts (e.g., fluorescence
quantum yields, dipole moments, oxidation potentials, acid-
ity constants, etc.) can be switched by light. A reversible
modulation of the fluorescence signal can be achieved,[2] for
example, if the photochromic unit is attached to a fluores-
cent dye, and a photochromic resonant energy transfer
(pcRET) takes place.[3] For efficient energy transfer, the
emission band of the fluorescence dye (RET donor) must
overlap with an absorption band of the colored state of the
photochromic unit (RET acceptor). It was proposed that
reversible switching of fluorescent markers between the flu-
orescent and non-fluorescent state may be used for the ac-
quisition of optical images with diffraction-unlimited reso-
lution.[4] For that, the fluorescence signal of the labeled ob-
ject must be switched on and off reversibly by converting
the photochromic unit from a colorless into a colored
form.[5] The optical resolution can be improved, provided
[a] Department of NanoBiophotonics, Max Planck Institute for
Biophysical Chemistry,
Am Fassberg 11, 37077 Göttingen, Germany
Fax: +49-551-2012505
E-mail: vbelov@gwdg.de, shell@gwdg.de
[b] Present address: Institute of Organic Chemistry and
Biochemistry AS CR, v.v.i., Flemingovo n. 2, 16610 Prague 6,
Czech Republic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100166.
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longer than 360 nm. In 2006, we described the synthesis found to be photochromic; after irradiation at 313 nm, the
and properties of photoswitchable compounds with a high initial colorless solution turned red, and new absorption
degree of fluorescence modulation (up to 96% in methanol bands appeared at 358 and 529 nm; the reverse reaction was
or ethanol) under irradiation with light of 375 nm (off- driven by irradiation with visible light (Ͼ480 nm).
switching) and 660 nm (on-switching).[10] One of these pho-
A series of reports described photochromic diarylethenes
tochromic fluorescent compounds was incorporated into with amphiphilic side chains. The photochromic core was
30 nm silica gel beads, and it was shown that the optical always based on 1,2-bis(2-methyl-5-phenylthiophen-3-yl)-
resolution (along one axis) could be significantly improved perfluorocyclopentene. In the first study,[14] diarylethenes
by switching “on” and “off“ the fluorescence signal of sin- with hexa(ethylene glycol) units attached to phenyl rings
gle nanoparticles for 30 full cycles (two beads at a distance were prepared and their photochromic properties and self-
of 230 nm were resolved).[11] This study showed that the assembling behavior were studied. These compounds
bleaching of the photochromic unit allowed only about 100 showed excellent photochromic performance in organic sol-
cycles to be performed without considerable photofatigue vents and even in aqueous media, in which levels of pho-
effects, although the 1,2-bis(3-thienyl)perfluorocyclopent- toconversion under irradiation with 313 nm light reached
enes (Scheme 1) used in this work belong to one of the 86–91%. The absorption maxima of the colorless open-ring
most photostable classes of photochromic compounds.[9a] isomers in aqueous solution were observed at 289–294 nm,
An important limiting factor is that we could not perform and the absorption maxima of the closed-ring isomers were
even one complete switching cycle in water with these lipo- found to be at 573–583 nm. However, due to hydrophobic
philic diarylethenes, even when they were decorated with interactions, these molecules were found to be self-associ-
a long oligo-ethylene glycol chain to provide solubility in ated (nanodomains of around 100 nm in size in water at
aqueous media.[12]
room temperature), and their solutions became cloudy
upon heating. In general, self-association is undesirable for
fluorescent probes because this may lead to fluorescence
quenching after aggregation. In 2008, the same group re-
ported a similar bis-hexa(ethylene glycol)diarylethene hy-
brid structure with an amide group near the aromatic
core.[15] The colorless open form of this compound ab-
sorbed at around 310 nm, and the absorption maximum of
the closed-ring isomer was located at 598 nm in water. Re-
cently, a number of diarylethene derivatives with various
oligo(ethylene glycol) side chains have been prepared.[16]
The size of the aggregates and the self-assembling behavior
depended on the lengths of the amphiphilic side chains.
Compounds with six hexa(ethylene glycol) side chains and
enhanced solubility were shown to give molecularly dis-
persed solutions in water, whereas the solubility of com-
pounds with shorter side chains in water was very poor.
However, none of these symmetric photochromic com-
pounds possess an additional functional group necessary
for attaching them to fluorescent dyes. More critically, their
absorbance at 375 nm is too low, and thus cannot be used
for effective switching.
Scheme 1. Photochromism of 1,2-bis(thiophen-3-yl)cyclopentenes.
However, good performance in water or aqueous buffer
is ultimately required for molecular markers and labels that
are suitable for use in life sciences. Therefore, the goal of
the present work was the synthesis and characterization of
hydrophilic photochromic compounds with good perform-
ance in pure water (or aqueous buffer) in the course of irra-
diation with focusable light at wavelengths longer than
360 nm.
Results and Discussion
1. Background: Photochromic Diarylperfluorocyclopentenes
with Improved Solubility in Aqueous Media
In 2007, Irie and co-workers attempted to use the new
perfluorocyclopentene derivative as a fluorescence switch-
Most molecular probes for use in biology and life sci- ing agent for the labeling of proteins. They synthesized a
ences are applied in water or aqueous buffers (as free sub- derivative of 1,2-bis(2,4-dimethyl-5-phenylthiophen-3-yl)-
stances or bioconjugates). Even a low content of organic perfluorocyclopentene attached to fluoresceine as a fluores-
solvent may cause protein denaturation or cell death. It was cent dye.[17] Reversible fluorescence switching was observed
anticipated that the poor performance of photochromic along with the photochromic reaction. Irradiation at
compounds in aqueous solutions may be improved by syn- 365 nm produced the closed-ring isomer with absorption at
thesizing their hydrophilic derivatives. 1,2-Bis(hetaryl)per- 580 nm, and the fluorescence intensity decreased. After ir-
fluorocyclopentenes are excellent photochromic com- radiation with visible light (λ Ͼ 550 nm), both absorption
pounds that can be switched many times, and their colorless and fluorescence spectra returned to their original state.
and colored forms are chemically and thermally stable.[9a] Modulation of the fluorescence was found to be 60% due
In 1997, Irie’s group reported the preparation of water-solu- to the moderate conversion between the open and closed
ble 1,2-bis(2-methyl-1-benzo[b]thiophene-3-yl)perfluorocy- forms in the photostationary state (PSS). After deprotec-
clopentenes with two sulfonic acid groups attached to the tion of the carboxy group attached to phenyl ring, the fluo-
benzene rings.[13] In aqueous media, this compound was rescent photochromic compound was decorated with a suc-
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Synthesis of Photochromic Compounds
cinimidyl ester group and attached to a protein. The ab- minated to afford the colorless crystalline bromide 6, which
sorption and fluorescence spectral changes of the labeled was transformed into boronic acid 7 in good yield.
protein were reported for the solution in PBS buffer con-
taining 30% EtOH. However, because the high content of
ethanol as an organic solvent is inappropriate for life sci-
ence applications, hydrophilic photochromic compounds
with considerable absorption in the near-UV region and
with the ability to switch reliably in pure water or buffer
solutions need to be developed.
2. Attachment of the Sulfonic Acid Residues to the
Lipophilic Photochromic Units with Extended Conjugated
Systems
2.1. Attempted Modifications of the Thiophene Rings
Attached to the Perfluorocyclopentane Core
In 2006, we described the synthesis and properties of
apolar photochromic compounds that undergo ring-closing
and ring-opening reactions under irradiation with 375 and
Scheme 2. Synthesis of the boronic acid 7 and its precursor 6 with
a protected hydroxy group.
660 nm light.[10] According to HPLC analysis, the pho-
toconversion in ethanol or methanol was nearly complete.
We planned to increase the water-solubility of this photo-
chromic unit (Figure 1) by introducing sulfonic acid groups.
Hydrophilic residues (with linkers) can be connected to the
carbon atoms (C-4) adjacent to the perfluorocyclopentene
fragment (priority 1 modification), or they may be attached
to the central 3,4-unsubstituted thiophenes (priority 2
modification) (Figure 1). After deprotection, the amino
group was expected to react with a fluorescent dye. The
whole synthetic scheme was designed in such a way that an
additional O-protected 3-hydroxypropyl residue (R) could
be attached to the amino group. Later, this moiety could be
used to link the whole molecule with an object, provided
that the deprotected alcohol could be converted into the O-
succinimydyl carbonate.
The Suzuki coupling of iodide 8 with boronic acid 7 gave
compound 9 in low yield. To reduce the number of steps,
the coupling reaction was performed with the zinc-deriva-
tive of compound 6 (Scheme 3). Towards this end, selective
lithiation of dibromide 6 followed by addition of ZnCl2 was
performed, and the reaction mixture was added into the
flask containing iodide 8 and a palladium catalyst. The cou-
pling product – the “left hand” precursor 9 – was isolated
in good yield. The dehalogenated derivative 10, which was
obtained as a side-product by hydrolysis of the zinc deriva-
tive, was also isolated and successively rebrominated to sub-
strate 6. Unfortunately, the required heptafluorocyclopent-
ene derivative 11 could not be obtained from iodide 9 and
Figure 1. Photochromic compounds[10] for decoration with hydro-
philic groups according to priority 1 and priority 2 modifications.
2-Methylthiophene (1) was used as the starting material
to implement the priority 1 modifications. It was bromi-
nated with N-bromosuccinimide (NBS) in the presence of
HClO4,[18] and then bromide 2 was smoothly transformed
into 4-bromo-2-methylthiophene (3) in the course of a
“halogen dance” (Scheme 2). The latter compound was sub-
jected to bromine–lithium exchange, and the lithio-deriva-
tive was treated with oxirane.[19] The hydroxy group in com-
pound 4 was protected with a tert-butyldiphenylsilyl
(TBDPS) residue, which was stable to hydrolysis during the
Scheme 3. Synthesis of the “left hand” precursor 8 of the photo-
subsequent synthetic procedures. The thiophene 5 was bro- chromic unit.
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perfluorocyclopentene (probably due to the cleavage or mi-
gration of the TBDPS protecting group).
Synthesis of the precursor of the “right hand” part of
the photochromic unit is depicted in Scheme 4. The
phenoxyethylamine derivative 12 was alkylated with allyl
bromide, and the terminal double bond of 13 was subjected
to hydroboration with 9-borabicyclo[3.3.1]nonane (9-BBN)
followed by oxidation.[20] Alcohol 14 was protected with a
TBDPS group, and compound 15 was iodinated with bis-
(trifluoroacetoxy)iodobenzene. Iodide 16 was coupled with
thiophene-2-boronic acid (17), and compound 18 was fur-
ther iodinated with ICl in acetic acid to afford 19 in good
yield (Scheme 5). At this stage, the hydroxy function was
deblocked in order to change the protecting group and pu-
rify the solid intermediate substance.
Scheme 6. Generating the heptafluorocyclopentene derivative 23 –
the “right hand” precursor of the photochromic compound.
Scheme 7. Photochromic compound 25 with protected hydroxy
groups.
Scheme 4. Generating the diprotected aryl iodide 16.
conditions, a fluorine atom was substituted by the adjacent
hydroxy group, and the seven-membered ring compound 27
was formed.
Scheme 5. Generating the “right hand” precursor of the photochro-
mic unit.
The hydroxy group in compound 20 was protected with
p-methoxybenzyl chloride, and biaryl 21 was coupled with
the Zn derivative of 6 in the presence of the palladium cata-
lyst [Pd(dba)2]. The triaryl compound 22 was isolated in
good yield (Scheme 6). Unfortunately, after lithiation of 22
and its interaction with an excess of perfluorocyclopentene,
Scheme 8. Deprotection of the hydroxy groups near the perfluo-
rocyclopentane ring under basic conditions.
Simultaneously, due to the presence of water in Bu4NF,
the required heptafluorocyclopentene 23 was obtained as diketone 28 was produced. Clearly, compounds 27 and 28
an inseparable mixture with the dehalogenated derivative were formed during the base-catalyzed nucleophilic ad-
24. The reaction of the lithiated derivative of 9 with this dition of ROH (R = alkyl, H) to the extremely electron-
mixture gave the required photochromic compound 25 in poor C=C bond, followed by elimination of one or several
low yield (Scheme 7).
HF molecules (alcohol 29 was formed from the silylated
Deprotection of the hydroxy groups was expected to help precursor 24).
to separate the corresponding alcohols and obtain com-
When the mixture of compounds 23 and 24 was intro-
pound 26 (Scheme 8). Unfortunately, deprotection was ac- duced into the reaction with the lithiated bromide 30 (ob-
companied by the loss of one or three fluorine atoms and tained from dibromide 6 through substitution of the α-bro-
formation of a mixture of compounds 27–29. Under basic mine atom with a trimethylsilyl residue), the expected pho-
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Synthesis of Photochromic Compounds
tochromic adduct 31 was isolated, albeit in low yield
(Scheme 9). These synthetic difficulties forced us to embark
on the priority 2 modifications.
Scheme 11. The“left hand” building block 39 of the photochromic
unit.
The reaction of 37 with nBuLi in the presence of
N,N,NЈ,NЈ-tetramethylethylenediamine followed by ad-
[22]
dition of CBr4
did not lead to formation of the desired
Scheme 9. Synthesis of the model photochromic compound 31.
compound 38. Fortunately, compound 37 could be bromi-
nated with NBS, and bromide 38 was coupled with thio-
pheneboronic acid 36. The pure building block 39 was iso-
lated by chromatography on silica gel.
2.2. Attachment of the Sulfonic Acid Residues to the
“Middle” Thiophene Rings
Initially, aryl iodide 16 was coupled with bromothio-
phene 34, but the yield of product 41 was low. Therefore,
aryl iodide 40 was first transformed into compound 42 by
a Suzuki coupling with the boronic acid obtained from bro-
mothiophene 34 (Scheme 12). Compound 42 was then io-
dinated with I2 and HgO in benzene, and iodide 43 was
isolated in high yield. The latter compound was coupled
with 3-bromo-2-methylthiophene-5-boronic acid (36) to
give the “right hand” precursor 44 in very good yield.
Modifications of the second type (Figure 1) were ex-
pected to be free from the drawbacks mentioned above. The
hydroxy groups in this approach are far from the central
fluorinated part of the photochromic unit.
As a starting compound with an additional functional
group, we used 3-(2-hydroxyethyl)thiophene (32), which was
selectively brominated with NBS in the 2-position of the
thiophene ring. The hydroxy group in compound 33[21a,21b]
was then protected with a tetrahydropyranyl residue
(Scheme 10). The reverse order of reactions (protection of
hydroxy groups followed by bromination according to
known procedures[21c]) led to lower overall yields of com-
pound 34. 2-Methylthiophene (1) was used as a second
building block, which, after bromination in acetic acid and
monolithiation followed by addition of B(OiPr)3, afforded
boronic acid 36[21d,21e] in good yield.
Scheme 12. “Right hand” precursor 44 of the photochromic unit
and the products 45 and 46 isolated after its reaction with perfluo-
rocyclopentene.
Scheme 10. Thiophene bromides 34 and 36 as small building
blocks.
Bromothiophene 34 was also transformed into the corre-
Both the “right” and the “left hand” precursors 44 and
sponding boronic acid and used in the Suzuki coupling with 39 were subjected to halogen–lithium exchange followed by
4-bromopyridine (Scheme 11). Attempted iodination of the treatment with an excess of perfluorocyclopentene. In the
isolated compound 37 with iodine in the presence of either first case, heptafluorocyclopentene derivative 45 could
periodic acid in ethanol or bis(trifluoroacetoxy)iodo- not be separated from dehalogenated compound 46
benzene (in CHCl3 or 80% aq. acetic acid), was unsuccess- (Scheme 12). In the second case, the yield of the required
ful and gave either only the starting material or the depro- heptafluorocyclopentene 47 was found to be lower due to a
tected compound, respectively.
side reaction.
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A very interesting compound with a betaine structure
(48-THP) was isolated from the reaction of lithiated com-
pound 39 with perfluorocyclopentene (Scheme 13). The
highly fluorescent betaine 48-THP absorbs at 440 nm (chlo-
roform) and emits with a maximum at 502 nm (excitation
at 420 nm). The emission band is broad due to a shoulder
at 530 nm, so that the “effective” Stokes shift is more than
60 nm. The fluorescence quantum yield was found to be
0.51 (in chloroform). The optical spectra of betaine 48-THP
were reminiscent of Lucifer Yellow or Coumarine 153.[23]
A combination of a large Stokes shift with relatively high
emission efficiency is a very interesting feature. Unfortu-
nately, in polar solvents (e.g., alcohols), betaine 48 emits
poorly.
Scheme 14. Synthesis of the asymmetric photochromic compound
52 with protected hydroxy groups.
tecting groups in compound 52 with bromine and PPh3.
Unfortunately, we were unable to isolate the required dibro-
mide from the reaction mixture. Therefore, another syn-
thetic approach was used. The THP-protecting groups in
photochromic compound 52 were cleaved off under mild
conditions using pyridinium p-toluenesulfonate (PPTS) in
ethanol. The liberated hydroxy groups in compound 54
were then acylated with β-sulfopropionic anhydride (55;
Scheme 15). The latter compound was obtained by dehy-
dration of 3-sulfopropionic acid (56) with phosphorus pent-
oxide.[25] 3-Sulfopropionic acid was prepared from 3-bro-
mopropionic acid (53) by stirring with Na2SO3 in aqueous
acetone. The Boc-protecting group in compound 54 was
also removed at this step, and the target water-soluble pho-
tochromic compound 57 was isolated in good yield.
Scheme 13. Synthesis of the heptafluorocyclopentene derivative 47
and betaine 48.
The formation of betaine 48 was not observed at –78 °C.
However, when this reaction was quenched at this tempera-
ture, the same by-product was formed and detected during
the work-up or isolation procedures (unless the excess of
perfluorocyclopentene was removed completely as early as
possible). Moreover, the isolated compound 47 was found
to be unstable at temperatures higher than 0 °C. Therefore,
47 was either used immediately after isolation or kept under
argon at –18 °C. The formation of the side product 48, with
a betaine structure, may be easily explained by nucleophilic
addition of the pyridine residue to the highly reactive
double bond in perfluorocyclopentene, followed by the
step-wise hydrolytic substitution of the fluorine atoms at
the activated positions.[24]
In both reactions generating heptafluorocyclopentenes
45 (Scheme 12) and 47 (Scheme 13), symmetric photochro-
mic compounds 49 and 50 were also isolated as by-products
(for structures, see Figure S1 in the Supporting Infor-
mation).
Coupling of heptafluorocyclopentene 47 with the lithi-
ated derivative of compound 44 gave the required photo-
chromic compound 52 in good yield (Scheme 14), whereas
the reaction of heptafluorocyclopentene 45 with bromide 39
(after its lithiation) resulted in the formation of a mixture
of compound 52 and debrominated derivative 51 with very
similar Rf values.
Initially, we tried to insert sulfonic acid residues through
nucleophilic substitution of bromine atoms, which we ex-
Scheme 15. Synthesis of the target photochromic and water-soluble
pected to introduce through the reaction of the THP-pro- building block 57 with a free secondary amino group.
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Synthesis of Photochromic Compounds
3. Properties of the Water-Soluble Photochromic
Diarylethene Prepared in This Study
colored closed form with a broad absorption band around
626 nm in both methanol and water (ε = 1.9ϫ104 and
1.4ϫ104 m–1 cm–1 in MeOH and water, respectively). Irradi-
ation with green or red light (Ͼ500 nm) restores the initial
absorption spectrum of the photochromic compound (Fig-
ure 2). Several isosbestic points are observed in Figure 2
(A–C), which represent switching of compound 57 in both
directions with UV and visible light. The presence of
isosbestic points indicates the reversibility of the photo-
chromic reaction involving two isomers, and that the photo-
chemical transformations are not accompanied by the for-
mation of observable amounts of by-products with (photo)-
chemically modified chromophores.
The water-soluble photochromic compound 57 may be
switched to the colored, closed form by irradiation with UV
or violet light (365–375 nm; Figure 2 and Table 1). The col-
orless, open-ring isomer of compound 57 has an absorption
maximum at 340 nm in MeOH (ε = 4.1ϫ104 m–1 cm–1) and
in water (ε = 2.2ϫ104 m–1 cm–1). A secondary peak is ob-
served at 258 nm (ε = 2.6ϫ104 and 1.7ϫ104 m–1 cm–1 in
MeOH and water, respectively). Irradiation with 366 or
375 nm light transforms the initial substance into the blue-
Table 1. Absorption maxima of compound 57 in methanol and
water (for spectra, see Figure S5 in the Supporting Information).
Isomer[a]
Solvent
λ [nm]
logε[b]
λ [nm]
logε[b]
57-OF
MeOH
H2O
MeOH
H2O
257
258
366
367
4.41
4.23
4.34
4.26
340
340
628
624
4.61
4.34
4.28
4.15
57-CF
[a] OF: “open form”; CF: “closed form”. [b] m–1 cm–1.
Initially, solutions of compound 57 in methanol and
water were blue (Figure 2, A and B), indicating the presence
of the “closed” isomer.
Interestingly, the amount of colored “closed” form in the
isolated compound 57 is higher (ca. 20%, according to
HPLC) than that found for the structurally similar com-
pound with additional methyl groups in positions 4 and 4Ј
of the thiophene fragments attached to the central perfluo-
rocyclopentene ring.[10] The absence of these methyl groups
(situated in close proximity to the perfluorocyclopentene
cycle) in compound 57, eliminates the repulsion forces in
the closed isomer and therefore stabilizes it.[26]
By performing the ring-opening reaction with green or
red light, the concentration of the colored, closed form may
be reduced, compared with the initial content (compare
Figure 2, C and B). In this case (Figure 2, C), we stopped
the experiment after irradiation for eight hours (ca. 20 mW/
cm2 at 550 nm). Full conversion into the open-ring isomer
was achieved in both aqueous and methanolic solutions
within a few minutes by using a halogen lamp (500 W) with
a red filter. Irradiation with larger intensities is advan-
tageous, because it allows compound 57 to be switched
faster. In future applications, the irradiation will be per-
formed with laser sources using focused light instead of a
collimated mercury lamp, as in the present experiments.
The data on the kinetics of the ring-closing reaction
upon irradiation with UV light in methanol and water are
given in Figure 3. These experiments were conducted under
identical irradiation conditions (the only difference was the
concentration of the dye: 40 μm in MeOH and 24 μm in
water). It is interesting that the cyclization of the photo-
chromic compound 57 proceeds in these solvents with very
different rates. In methanol, full conversion into the closed
form was achieved in 5 min, whereas in water the absorp-
Figure 2. Absorption spectra of compound 57 undergoing pho-
toconversion between the open- and closed-ring isomers upon irra-
diation at 366 nm in MeOH (A) and in water (B). The reverse reac-
tion upon irradiation at 550 nm in water (C). The arrows indicate
changes upon irridiation with UV (A and B) and green (or red)
light (C).
Eur. J. Org. Chem. 2011, 3301–3312
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. N. Belov, S. W. Hell et al.
FULL PAPER
tion signal at 627 nm was still increasing after irradiation (ΔΔH϶ Ͻ 0). The reverse reaction was found to be almost
for 1.5 h. We monitored the course of the photochemical independent of the solvent (MeOH or water), or at least
transformations by HPLC, which showed that the full con- affected to a far lesser extent.
versions into the ring-closed and ring-open isomers can be
achieved (see Exp. Sect. for HPLC conditions, which pro-
vided the separation of the peaks of the open- and closed-
ring isomers).
Conclusion and Outlook
The new, water-soluble photochromic compound 57 in-
troduced here can be reversibly switched in aqueous solu-
tions and in methanol with focusable light of wavelengths
longer than 360 nm. Compound 57 was obtained during a
convergent synthesis in which the longest reaction sequence
consisted of only nine steps. All steps (except for the trans-
formation 39Ǟ47, which provided only 25% yield) af-
forded good yields, so that the total yield was about 3%.
The target compound contains a secondary amino group
that may be used to attach fluorescent compounds or inter-
mediate linkers with a truncation point.[11] Further synthe-
ses with building block 57 may provide fluorescent photo-
chromic compounds, and it will be interesting to study their
switching behavior in aqueous solutions.
Figure 3. Kinetics of the cyclization reaction of compound 57 in
Experimental Section
MeOH (black dots) and water (red dots) under irradiation with
366 nm light.
General: Anhydrous THF and diethyl ether were distilled from so-
dium benzophenone ketyl. Reactions were carried out under argon
with magnetic stirring in Schlenk flasks equipped with septa or
The calculated quantum yields for the photocyclization
reaction are 0.59 and 0.028 in methanol and water, respec- reflux condensers with bubble-counters using a standard manifold
with vacuum and argon lines. Elemental analyses were carried out
in Mikroanalytisches Laboratorium des Instituts für Organische
und Biomolekulare Chemie. Routine NMR spectra were recorded
with a Varian MERCURY-300 spectrometer operating at 300.5
(1H), 75.5 (13C and APT), and 282.4 (19F) MHz. 1H and 13C NMR
spectra were also recorded with Varian INOVA 600 (600 MHz) and
Varian INOVA 500 (125.7 MHz) instruments, respectively. All
NMR spectra were referenced to tetramethylsilane as an internal
standard (δ = 0 ppm) using the signals of the residual protons of
CDCl3 (δ = 7.26 ppm) or [D6]DMSO (δ = 2.50 ppm). Multiplicities
tively.
Irradiation of the sample with monochromatic light of
550 nm allowed the quantum yield of the reverse ring-open-
ing reaction to be calculated. Similar values, within experi-
mental error, of 5.8ϫ10–4 and 2.0ϫ10–4 in methanol and
water, respectively, were obtained. A probable explanation
for the differences observed in the reaction quantum yields
can be drawn: the highly ordered structure of water, with
its long-range network of hydrogen bonds, is responsible for
the slow reaction rate of the cyclization reaction. The of signals are described as follows: s = singlet, br. s = broad singlet,
d = doublet, t = triplet, quint = quintet, m = multiplet. Low-resolu-
tion mass spectra (ESI) were obtained with LCQ and ESI-TOF
mass-spectrometers [MICROTOF (focus), Fa. Bruker]. A MICRO-
TOF spectrometer equipped with an ESI ion source Apollo and
direct injector with LC autosampler Agilent RR 1200 was used to
obtain high-resolution mass spectra (ESI-HRMS). ESI-HRMS
were also obtained with an APEX IV spectrometer (Bruker). The
HPLC system (Knauer) included a Smartline pump 1000 (2x), UV
detector 2500, column thermostat 4000 (25 °C), mixing chamber,
injection valve with 20 μL loop for the analytical column; 6-port/
“open” form of compound 57 has much more degrees of
rotational freedom and is less polar that the “closed” iso-
mer. The direct π-conjugation between the electron-ac-
ceptor (pyridine ring) and electron-donor groups (phenol
residue) is possible only in the closed-ring isomer with con-
siderable charge separation. Thus, the enthalpy of acti-
vation (from the excited state) in water is expected to be
lower than that in methanol (ΔΔH϶ Ͻ 0). However,
changes in the polarity during the transition from the initial
substance (in the excited state) to the ring-closed product 3-channel switching valve; analytical column [Eurospher-100 C18;
5 μm; 250ϫ4 mm; 1.2 mL/min; solvent A: H2O (HPLC grade) +
0.1% v/v TFA; solvent B: MeCN + 0.1% v/v TFA; detection at
254 nm and 25 °C (if not stated otherwise)]. UV/Vis absorption
spectra were recorded with a Varian Cary 4000 UV/Vis spectropho-
tometer, and fluorescence spectra with a Varian Cary Eclipse fluo-
rescence spectrophotometer. Irradiation experiments and the deter-
mination of quantum efficiencies of the isomerization reactions
were previously reported.[27] The purities of the compounds were
monitored by TLC on MERCK ready-to-use plates with silica gel
60 (F254). Column chromatography: Merck silica gel, grade 60,
may require significant restructuring of the whole shell of
hydrogen bonds and dipoles of water molecules around the
reacting species. Transition to the final state, with a lower
degree of rotational freedom and highly ordered network
of hydrogen bonds and solvent dipoles, is equivalent to the
negative change in the activation entropy (ΔΔS϶ Ͻ 0, refer-
ence reaction from the excited state in methanol), and may
result in the unfavorable change in the free activation en-
ergy in water (ΔΔG϶ = ΔΔH – TΔΔS϶ Ͼ 0); even if the
enthalpy of activation in water is lower than in methanol 0.04–0.063 mm.
3308
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3301–3312

Synthesis of Photochromic Compounds
4-{3-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]thiophen-2-yl}pyridine pound was isolated as a yellow oil (6.35 g, 91%) by chromatog-
(37): To a solution of 34 (8.73 g, 30.0 mmol) in anhydrous THF
(150 mL), nBuLi (2.5 m in hexane, 13.2 mL, 33.0 mmol) was added
dropwise at –78 °C, and the mixture was stirred for 1 h at –78 °C.
Then B(OiPr)3 (8.46 g, 45.0 mmol) was added, and the mixture was
stirred for 1 h at –78 °C and then for 2 h at room temperature.
Water (2 mL) was added, followed by 4-bromopyridine hydrochlo-
raphy (200 g of SiO2) eluting with hexane/EtOAc (2:1Ǟ1:1); Rf =
0.11 (hexane/EtOAc, 1:1). H NMR (300 MHz, CDCl3): δ = 1.42–
1.86 (m, 6 H, 3ϫ CH2, 3/4/5-H), 2.40 (s, 3 H, CH3), 2.98 (t, J =
6.7 Hz, 2 H, CH2), 3.42–3.52 (m, 1 H, CHH-6), 3.60–3.78 (m, 2 H,
CHHO and CHH-6), 4.00 (dt, J = 6.7, 9.6 Hz, 1 H, CHHO), 4.61
(t, J = 3.3 Hz, 1 H, CHO), 7.00 (s, 1 H, CH), 7.09 (s, 1 H, CH),
1
ride (7.0 g, 36 mmol), Ph3P (315 mg, 1.2 mmol), [Pd(dba)2] 7.46 (dd, J = 1.7, 4.5 Hz, 2 H, CH), 8.62 (dd, J = 1.7, 4.5 Hz, 2 H,
(173 mg, 0.30 mmol), and 20% aq. Na2CO3 (150 mL), and the mix-
ture was heated under argon at 78 °C (bath temp.) for 18 h in a
flask equipped with a reflux condenser and a bubble counter. The
reaction mixture was diluted with EtOAc (100 mL) and the organic
layer was separated, washed with brine (50 mL), dried, and evapo-
rated under reduced pressure. The title compound was isolated by
CH) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 14.8 (CH3), 19.3
(CH2-4), 25.3 (CH2-5), 29.4 (CH2), 30.5 (CH2-3), 62.0 (CH2-6),
67.0 (CH2O), 98.7 (CHO), 109.7 (C), 123.3 (2ϫ CH), 126.2 (CH),
126.7 (CH), 133.8 (2ϫ C), 134.9 (C), 136.3 (C), 138.1 (C), 141.7
(C), 149.9 (2ϫ CH) ppm. ESI-MS (positive mode): m/z (%) = 466.0
and 464.0 (100) [M + H]+. HRMS (ESI, positive mode): calcd. for
chromatography (200 g of SiO2; hexane/EtOAc, 4:1Ǟ1:1) to yield C21H22BrNO2S2 [M + H]+ 464.0348; found 464.0358.
37 (6.1 g, 70%) as a colorless oil. Rf = 0.14 (hexane/EtOAc, 1:1).
tert-Butyl N-Methyl-N-[2-(4-{3-[2-(tetrahydro-2H-pyran-2-yloxy)-
1H NMR (300 MHz, CDCl3): δ = 1.38–1.85 (m, 6 H, 3ϫCH2, 3/
ethyl]thiophen-2-yl}phenoxy)ethyl]carbamate (42): To a solution of
4/5-H), 3.10 (t, J = 6.9 Hz, 2 H, CH2), 3.41–3.49 (m, 1 H, CHH-
34 (3.93 g, 13.5 mmol) in anhydrous THF (70 mL), nBuLi (2.5 m in
6), 3.65 (dt, J = 6.9, 9.7 Hz, 1 H, CHHO), 3.67–3.76 (m, 1 H,
hexane, 5.94 mL, 14.9 mmol) was added dropwise at –78 °C under
argon, and the mixture was stirred for 1 h at –78 °C. Then
CHH-6), 3.99 (dt, J = 6.9, 9.7 Hz, 1 H, CHHO), 4.59 (t, J = 3.3 Hz,
1 H, CHO), 7.08 (d, J = 5.2 Hz, 1 H, CH), 7.34 (d, J = 5.2 Hz, 1
B(OiPr)3 (3.81 g, 20.3 mmol) was added and the mixture was
H, CH), 7.45 (dd, J = 1.7, 4.5 Hz, 2 H, CH), 8.62 (dd, J = 1.7,
stirred for 1 h at –78 °C and for 2 h at room temperature. Water
4.5 Hz, 2 H, CH) ppm. 13C NMR (125.5 MHz, CDCl3): δ = 19.4
(0.5 mL) was added, followed by compound 40[10] (3.39 g,
(CH2-4), 25.4 (CH2-5), 29.3 (CH2), 30.5 (CH2-3), 62.0 (CH2-6),
9.00 mmol), Ph3P (189 mg, 0.72 mmol), [Pd(dba)2] (104 mg,
67.2 (CH2O), 98.6 (CHO), 123.4 (2ϫCH), 125.4 (CH), 130.2 (CH),
0.18 mmol), and 20% aq. Na2CO3 (70 mL), and the mixture was
heated at 78 °C (bath temp.) for 18 h in a flask equipped with a
reflux condenser and a bubble-counter. The mixture was diluted
with EtOAc (100 mL) and the organic phase was separated, washed
135.9 (C), 136.9 (C), 142.1 (C), 149.8 (2 ϫ CH) ppm. EI-MS (posi-
tive mode): m/z (%) = 289.2 (26) [M]+, 187.2 (100), 175.1 (72), 85
(74). C16H19NO2S (289.4): calcd. C 66.41, H 6.62, N 4.84; found
C 66.65, H 6.44, N 5.04.
with brine (50 mL), dried, and evaporated under reduced pressure.
4-{5-Bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]thiophen-2-
yl}pyridine (38): To a solution of 37 (5.78 g, 20.0 mmol) in anhy-
drous DMF (20 mL), a solution of NBS (4.27 g, 24.0 mmol) in an-
hydrous DMF (20 mL) was added dropwise, and the mixture was
stirred at room temperature for 24 h in the dark. The mixture was
then poured into crushed ice, extracted with CHCl3 (2 ϫ 200 mL),
washed with 10% aq. KOH (2ϫ 100 mL), water (3ϫ 100 mL), and
dried with MgSO4. The solvents were evaporated under reduced
pressure and the residue was filtered through SiO2 (200 mL) eluting
with hexane/EtOAc (1:1) to give the title compound (Rf = 0.12) as
a yellow oil; yield 5.2 g (76%; according to HPLC analysis, ca. 7%
Chromatography (150 g of SiO2) with hexane/EtOAc (8:1Ǟ4:1) af-
forded the title compound (3.7 g, 90%) as a colorless oil; Rf = 0.12
(hexane/EtOAc, 4:1). HPLC [70Ǟ 100 % A (30 Ǟ0 % B) for 0–
1
20 min]: tR = 10.9 min. H NMR (300 MHz, CDCl3): δ = 1.46 (s,
9 H, tBu), 1.48–1.89 (m, 6 H, 3 ϫ CH2, 3/4/5-H), 2.93 (t, J =
7.0 Hz, 2 H, CH2CH2O), 2.99 (s, 3 H, CH3N), 3.40–3.49 (m, 1 H,
CHH-6), 3.54–3.67 (m, 3 H, OCH2CH2N and CH2CHHO), 3.70–
3.79 (m, 1 H, CHH-6), 3.94 (dt, J = 7.0, 9.6 Hz, 1 H, CH2CHHO),
4.06–4.17 (m, 2 H, OCH2CH2N), 4.58 (t, J = 3.3 Hz, 1 H, CHO),
6.88–6.96 (m, 2 H, 2ϫ CH), 7.02 (d, J = 5.2 Hz, 1 H, CH), 7.18
(d, J = 5.2 Hz, 1 H, CH), 7.36–7.43 (m, 2 H, CH) ppm. 13C NMR
(125.5 MHz, CDCl3): δ (2 rotamers) = 19.5 (CH2-4), 25.5 (CH2-5),
28.5 (3ϫ CH3), 29.1 (CH2), 30.6 (CH2-3), 35.4/36.3 (CH3N), 48.3
1
of the initial substance remained). H NMR (300 MHz, CDCl3): δ
= 1.43–1.84 (m, 6 H, 3ϫ CH2, 3/4/5-H), 2.94 (t, J = 6.6 Hz, 2 H,
CH2), 3.42–3.51 (m, 1 H, CHH-6), 3.61 (dt, J = 6.7, 9.7 Hz, 1 H, (CH2N), 62.0 (CH2-6), 66.1/66.9 (OCH2), 67.6 (CH2OTHP), 79.7
CHHO), 3.67–3.76 (m, 1 H, CHH-6), 3.96 (dt, J = 6.7, 9.7 Hz, 1
H, CHHO), 4.58 (t, J = 3.2 Hz, 1 H, CHO), 7.05 (s, 1 H, CH),
(C), 98.5 (CHO), 114.3 (2ϫ CH), 123.0 (CH), 126.9 (C), 129.5 (2ϫ
CH), 130.6 (CH), 134.2 (C), 138.8 (C), 155.4/155.7 (CO), 157.9/
7.39 (dd, J = 1.7, 4.5 Hz, 2 H, CH), 8.62 (dd, J = 1.7, 4.5 Hz, 2 H, 158.1 (CO) ppm. ESI-MS (positive mode): m/z (%) = 484.2 (100)
CH) ppm. 13C NMR (125.5 MHz, CDCl3): δ = 19.4 (CH2-4), 25.4
(CH2-5), 29.2 (CH2), 30.5 (CH2-3), 62.1 (CH2-6), 67.0 (CH2O), 98.7
(CHO), 112.5 (C-Br), 123.2 (2ϫ CH), 132.9 (CH), 137.4 (C), 137.7
(C), 141.0 (C), 149.9 (2ϫ CH) ppm. CI-MS (NH3, positive mode):
m/z (%) = 370.3 and 368.3 (100) [M + H]+. HRMS (ESI, positive
mode): calcd. for C16H18BrNO2S [M + H]+ 368.0314; found
368.0315;
[M + Na]+, 462.2 (6) [M + H]+. C25H35NO5S (461.6) calcd. C
65.05, H 7.64, N 3.03; found C 65.33, H 7.39, N 2.90.
tert-Butyl N-[2-(4-{5-Iodo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-
thiophen-2-yl}phenoxy)ethyl]-N-methyl Carbamate (43): To a solu-
tion of 42 (3.55 g, 7.7 mmol) in benzene (30 mL), HgO (2.0 g,
9.2 mmol) and iodine (2.37 g, 9.2 mmol) were added alternately in
small portions. The mixture was stirred at room temperature for
4 h, and then filtered through a Celite pad, washing with toluene
(100 mL). The combined organic solutions were washed with sat.
aq. Na2S2O3 (2 ϫ 50 mL), water (3ϫ 50 mL), and dried. After
evaporation of the solvents under reduced pressure, the residue was
filtered through SiO2 (100 g) eluting with hexane/EtOAc (4:1) to
give the title compound (4.19 g, 92%) as a yellowish oil; Rf = 0.09.
4-{4Ј-Bromo-5Ј-methyl-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-
[2,2Ј]bithiophen-5-yl}pyridine (39): Bromide 38 (5.52 g, 15.0 mmol),
[Pd(dba)2] (173 mg, 0.3 mmol), Ph3P (315 mg, 1.2 mmol), and bo-
ronic acid 36[21d,21e] (3.65 g, 16.5 mmol) were loaded into a Schlenk
flask fitted with a reflux condenser and a bubble-counter. The flask
was evacuated and flushed with argon several times. THF (75 mL)
and 20% aq. Na2CO3 (75 mL) were added and the mixture was HPLC [70Ǟ100% A (30Ǟ0% B) for 0–20 min]: tR = 15.5 min.
heated to reflux (bath temp. 78 °C) for 18 h. After dilution with
1H NMR (300 MHz, CDCl3): δ = 1.47 (s, 9 H, tBu), 1.49–1.86 (m,
EtOAc (75 mL), the organic layer was separated, washed with 6 H, 3ϫ CH2, 3/4/5-H), 2.87 (t, J = 6.9 Hz, 2 H, CH2CH2O), 2.99
brine, dried, and evaporated under reduced pressure. The title com- (s, 3 H, CH3N), 3.42–3.50 (m, 1 H, CHH-6), 3.52–3.60 (m, 1 H,
Eur. J. Org. Chem. 2011, 3301–3312
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V. N. Belov, S. W. Hell et al.
FULL PAPER
CH2CHHO), 3.62 (t, J = 5.0 Hz, 3 H, OCH2CH2N), 3.69–3.78 (m,
= 578.1 (100) [M + H]+. HRMS (ESI, positive mode): calcd. for
1 H, CHH-6), 3.90 (dt, J = 6.9, 9.7 Hz, 1 H, CH2CHHO), 4.07– C26H22F7NO2S2 [M + H]+ 578.1058; found 578.1063.
4.17 (m, 2 H, OCH2CH2N), 4.57 (t, J = 3.4 Hz, 1 H, CHO), 6.90–
Photochromic Compound 52: To a solution of bromide 44 (0.64 g,
6.95 (m, 2 H, 2ϫ CH), 7.17 (s, 1 H, CH), 7.31–7.36 (m, 2 H,
1.0 mmol) in anhydrous THF (15 mL), nBuLi (2.5 m in hexane,
CH) ppm. 13C NMR (125.5 MHz, CDCl3): δ (2 rotamers) = 19.4
0.4 mL, 1.0 mmol) was added dropwise at –78 °C, and the mixture
was stirred for 1 h at –78 °C. A solution of heptafluorocyclopen-
tene 47 (0.29 g, 0.5 mmol) in THF (9 mL) was added and the mix-
ture was stirred for 2 h at –78 °C and for 1 h at room temperature,
(CH2-4), 25.5 (CH2-5), 28.5 (3ϫ CH3), 28.7 (CH2), 30.6 (CH2-3),
35.4/36.2 (CH3N), 48.3 (CH2N), 62.0 (CH2-6), 66.1/66.8 (OCH2),
67.3 (CH2OTHP), 70.6 (C-I), 79.6 (C), 98.5 (CHO), 114.4 (2 ϫ
CH), 125.8 (C), 130.5 (2ϫ CH), 136.4 (C), 139.3 (CH), 145.0 (C),
followed by addition of brine (1 mL). The organic layer was sepa-
155.3/155.6 (CO), 158.2/158.4 (CO) ppm. ESI-MS (positive mode):
rated, dried with Na2SO4, and evaporated under reduced pressure.
m/z (%) = 610.1 (100) [M + Na]+. HRMS (ESI, positive mode):
The title compound was isolated by chromatography (100 g of
SiO2) with hexane/EtOAc (1:1Ǟ1:3) as eluent to give 52 (0.35 g,
calcd. for C25H34INO5S [M + Na]+ 610.1100; found 610.1095.
62%) as a green foam. HPLC [30Ǟ100% A (70Ǟ0% B) in
tert-Butyl N-[2-(4-{4Ј-Bromo-5Ј-methyl-4-[2-(tetrahydro-2H-pyran-
25 min]: tR (OF) = 13.9 min. 1H NMR (600 MHz, CDCl3): δ (open
2-yloxy)ethyl]-(2,2Ј)bithiophen-5-yl}phenoxy)ethyl]-N-methyl carb-
form, mixture of rotamers) = 1.47 (s, 9 H, tBu), 1.49–1.86 (m, 12
amate (44): According to the procedure described for the synthesis
H, 6ϫ CH2), 1.95 (s, 3 H, CH3), 1.97 (s, 3 H, CH3), 2.91 (t, J =
of 39, iodide 43 (4.0 g, 6.8 mmol), [Pd(dba)2] (78 mg, 0.14 mmol),
6.9 Hz, 2 H, CH2), 2.99 (t, J = 6.8 Hz, 2 H, CH2), 3.00 (s, 3 H,
Ph3P (142 mg, 0.54 mmol), and boronic acid 36[21d,21e] (1.8 g,
CH3N), 3.44–3.50 (m, 2 H, 2ϫ CHH-6), 3.59–3.65 (m, 3 H, CH2N
8.2 mmol) gave the title compound (4.15 g, 96%) as a yellow oil
and CHHOTHP), 3.65–3.69 (m, 1 H, CHHOTHP), 3.72–3.80 (m,
after chromatography (150 g of SiO2) eluting with hexane/EtOAc
2 H, 2ϫ CHH-6), 3.95 (dt, J = 6.9, 9.5 Hz, 1 H, CHHOTHP), 4.01
(4:1); Rf = 0.12. HPLC [70Ǟ100% A (30Ǟ0% B) for 0–20 min,
(dt, J = 6.8, 9.6 Hz, 1 H, CHHOTHP), 4.08–4.17 (m, 2 H, CH2O),
100 % A for 20–25 min]: tR = 22.9 min. 1H NMR (300 MHz,
4.59–4.64 (m, 2 H, 2ϫ CHO), 6.91–6.95 (m, 2 H, 2ϫ CH), 7.09
CDCl3): δ = 1.47 (s, 9 H, tBu), 1.49–1.87 (m, 6 H, 3ϫ CH2, 3/4/5-
(s, 1 H, CH), 7.10 (s, 1 H, CH), 7.14 (s, 1 H, CH), 7.16 (s, 1 H,
H), 2.39 (s, 3 H, CH3), 2.90 (t, J = 6.9 Hz, 2 H, CH2CH2O), 3.00
CH), 7.34–7.42 (m, 2 H, 2ϫ CH), 7.45 (dd, J = 1.5, 4.5 Hz, 2 H,
(s, 3 H, CH3N), 3.42–3.52 (m, 1 H, CHH-6), 3.56–3.66 (m, 3 H,
CH), 8.63 (dd, J = 1.5, 4.5 Hz, 2 H, CH) ppm. 13C NMR
OCH2CH2N, CH2CHHO), 3.70–3.80 (m, 1 H, CHH-6), 3.95 (dt, J
(125.7 MHz, CDCl3): δ (open form, mixture of rotamers) = 14.2
= 7.0, 9.6 Hz, 1 H, CH2CHHO), 4.06–4.17 (m, 2 H, OCH2CH2N),
(CH3), 14.5/14.6 (CH3), 19.5 (2ϫ CH2-4), 25.4/25.5 (2ϫ CH2-5),
4.60 (t, J = 3.3 Hz, 1 H, CHO), 6.89–6.96 (m, 2 H, CH), 6.93 (s, 1
29.2/29.4 (2ϫ CH2), 30.6 (2ϫ CH2-3), 35.4/36.3 (CH3N), 48.3
H, CH), 7.05 (s, 1 H, CH), 7.38–7.43 (m, 2 H, CH) ppm. 13C NMR
(CH2N), 62.1 (2ϫ CH2-6), 66.2/66.9 (OCH2), 67.1 (CH2OTHP),
(125.5 MHz, CDCl3): δ (2 rotamers) = 14.8 (CH3), 19.5 (CH2-4),
67.4 (CH2OTHP), 79.7 (C), 98.6/98.7 (2ϫ CHO), 114.0 (C), 114.5
25.5 (CH2-5), 28.5 (3ϫ CH3), 29.2 (CH2), 30.6 (CH2-3), 35.4/36.2
(2ϫ CH), 122.0 (CH), 123.0 (CH), 123.2 (3ϫ CH), 125.4 (C), 125.6
(CH3N), 48.3 (CH2N), 62.0 (CH2-6), 66.1/66.9 (OCH2), 67.3
(C), 126.7/127.1 (2ϫ CH), 130.4 (2ϫ CH), 133.3 (C), 134.8 (C),
(CH2OTHP), 79.7 (C), 98.5 (CHO), 109.4 (C-Br), 114.5 (2ϫ CH),
135.2 (2ϫ C), 135.8 (C), 135.9 (C), 138.0 (2ϫ C), 138.6 (C), 139.1
125.3 (CH), 126.2 (CH), 130.4 (2ϫ CH), 132.7 (C), 133.6 (C), 134.5
(CH), 140.3 (C), 141.2 (C), 141.5 (C), 149.9 (2ϫ CH), 155.4/155.7
(C), 135.1 (C), 137.7 (C), 138.3 (C), 155.4/155.7 (CO), 158.1/158.2
(CO), 158.2/158.3 (CO) ppm. 19F NMR (282 MHz, CDCl3): δ =
(CO) ppm. ESI-MS (positive mode): m/z (%) = 660.1 and 658.1
–110.04 (m, 2 F), –110.14 (m, 2 F), –131.82 (quint, J = 5.7 Hz, 2
(100) [M + Na]+. HRMS (ESI, positive mode): calcd. for
F) ppm. ESI-MS (positive mode): m/z (%)
[M
H]+. HRMS (ESI, positive mode): calcd. for
C56H60F6N2O7S4 [M + H]+ 1115.3260; found 1115.3259.
= 1115.3 (100)
C
30H38BrNO5S2 [M + Na]+ 658.1267 and 660.1248; found
658.1268 and 660.1246.
+
4-{5Ј-Methyl-4Ј-(heptafluorocyclopent-1-enyl)-4-[2-(tetrahydro- Photochromic Compound 54: A solution of 52 (0.22 g, 0.20 mmol)
2H-pyran-2-yloxy)ethyl]-2,2Ј-bithiophen-5-yl}pyridine (47): To a vig-
orously stirred mixture of bromide 39 (0.93 g, 2.0 mmol) in anhy-
drous THF (20 mL), nBuLi (2.5 m in hexane, 0.88 mL, 2.2 mmol)
and PPTS (10 mg, 0.04 mmol) in EtOH (10 mL) was stirred at
55 °C for 7 d under argon. After evaporation of the solvent, the
title compound was isolated as a blue foam by chromatography
was added dropwise at –78 °C, and the mixture was stirred for 1 h (100 g of SiO2) with CH2Cl2/MeOH (10:1) as eluent. Yield 0.165 g
at –78 °C. Cooled perfluorocyclopentene (2.7 mL, 20.0 mmol) was
quickly added and the mixture was stirred for 1 h at –78 °C and
then quenched with brine. The reaction mixture was diluted with
EtOAc (15 mL), dried, and evaporated under reduced pressure.
Chromatography (100 g of SiO2) with hexane/EtOAc (1:1) afforded
the title compound (0.30 g, 25%) as a yellowish oil; Rf = 0.13.
HPLC [30Ǟ100% A (70Ǟ0% B) for 0–25 min]: tR = 19.4 min.
1H NMR (300 MHz, CDCl3): δ = 1.42–1.86 (m, 6 H, 3ϫ CH2, 3/
(87%). 1H NMR (300 MHz, CDCl3): δ (open form, mixture of rot-
amers) = 1.47 (s, 9 H, tBu), 1.97 (s, 3 H, CH3), 1.98 (s, 3 H, CH3),
2.88 (t, J = 6.5 Hz, 2 H, CH2), 2.97 (t, J = 6.5 Hz, 2 H, CH2), 2.99
(s, 3 H, CH3N), 3.58–3.66 (m, 2 H, CH2N), 3.85 (t, J = 6.5 Hz, 2
H, CH2OH), 3.93 (t, J = 6.5 Hz, 2 H, CH2OH), 4.07–4.17 (m, 2
H, CH2O), 6.90–6.97 (m, 2 H, 2ϫ CH), 7.05 (s, 1 H, CH), 7.09 (s,
1 H, CH), 7.11 (s, 1 H, CH), 7.15 (s, 1 H, CH), 7.35–7.41 (m, 2 H,
2ϫ CH), 7.41–7.45 (m, 2 H, CH), 8.56–8.68 (m, 2 H, CH) ppm.
4/5-H), 2.46/2.47 (s, 3 H, CH3), 2.99 (t, J = 6.6 Hz, 2 H, CH2), 13C NMR (125.7 MHz, CDCl3): δ = 14.5 (CH3), 14.6 (CH3), 28.5
3.42–3.52 (m, 1 H, CHH-6), 3.62–3.78 (m, 2 H, CHHO and CHH- (3ϫ CH3), 31.9 (CH3N), 32.1 (2ϫ CH2), 48.3 (CH2N), 62.5 (2ϫ
6), 4.01 (dt, J = 6.6, 9.6 Hz, 1 H, CHHO), 4.62 (t, J = 3.2 Hz, 1
H, CHO), 7.13 (s, 1 H, CH), 7.15 (s, 1 H, CH), 7.44 (dd, J = 1.7,
4.6 Hz, 2 H, CH), 8.63 (dd, J = 1.7, 4.6 Hz, 2 H, CH) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 14.6/14.7 (CH3), 19.3 (CH2-4), 25.4
(CH2-5), 29.4 (CH2), 30.5 (CH2-3), 62.1 (CH2-6), 67.7 (CH2O), 98.7
CH2OH), 62.8 (CH2O), 79.8 (C), 114.6 (2ϫ CH), 122.3 (CH),
123.3 (3ϫ CH), 125.4 (C), 125.6 (C), 126.2 (CH), 126.7 (CH), 130.5
(2ϫ CH), 133.8 (C), 134.6 (2ϫ C), 134.7 (C), 135.4 (C), 135.5 (C),
136.4 (2ϫ C), 137.6 (2ϫ C), 139.1 (C), 140.5 (C), 141.4 (C), 141.6
(C), 149.8 (2ϫ CH), 158.3 (C=O), 158.4 (C) ppm. 19F NMR
(CHO), 120.4 (C), 122.9 (CH), 123.3 (2ϫ CH), 127.5 (CH), 135.1 (282 MHz, CDCl3): δ = –109.96 (m, 2 F), –110.04 (m, 2 F), –131.79
(C), 135.5 (C), 135.6 (C), 138.1 (C), 141.5 (C), 143.0 (C), 150.1 (2ϫ (t, J = 5.2 Hz, 2 F) ppm. ESI-MS (positive mode): m/z (%) = 947.1
CH) ppm; Due to low intensities, the split signals of the fluorinated
carbon atoms were not detected. ESI-MS (positive mode): m/z (%)
(100) [M
+
H]+. HRMS (ESI, positive mode): calcd. for
C46H44F6N2O5S4 [M + H]+ 947.2110; found 947.2114.
3310
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3301–3312

Synthesis of Photochromic Compounds
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Photochromic Compound 57: Compound 54 (14 mg, 15 μmol) was
stirred with β-sulfopropionic acid anhydride (55; 4 mg, 30 μmol)
under argon in anhydrous THF at room temperature for 12 h. The
solvent was evaporated under reduced pressure and the residue was
purified by chromatography (20 g of SiO2) eluting with CH2Cl2/
MeOH (2:1) to afford the title compound (15 mg, 83%) as a green
foam. HPLC [30Ǟ100% A (70Ǟ0% B) in 25 min; detection at
the isosbestic point (362 nm)]: tR (OF) = 12.4 min (78%), tR (CF)
= 12.7 min (22%).
[5]
[6]
For recent reviews of various nanoscopy techniques and their
applications, see: a) S. W. Hell, Far-Field Optical Nanoscopy in
Single Molecule Spectroscopy in Chemistry, Physics and Biology
(Eds.: A. Gräslund, R. Rigler, J. Widengren), Springer, Berlin,
2009, pp. 365–398; b) S. W. Hell, Science 2007, 316, 1153–1158;
c) L. Schermellech, R. Heintzmann, H. Leonhardt, J. Cell Biol.
2010, 190, 165–175; d) J. Vogelsang, C. Steinhauer, C.
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Chapman & Hall/CRC, Boca Raton, 2010, pp. 1–13; b) S. W.
Hell, Nat. Methods 2009, 6, 24–32; c) S. W. Hell, J. Wichmann,
Opt. Lett. 1994, 19, 780–782; d) R. Schmidt, C. A. Wurm, A.
Punge, A. Egner, S. Jakobs, S. W. Hell, Nano Lett. 2009, 9,
2508–2510; e) J. Hotta, E. Fron, P. Dedecker, D. P. F. Janssen,
C. Li, K. Müllen, B. Harke, J. Bückers, S. W. Hell, J. Hofkens,
J. Am. Chem. Soc. 2010, 132, 5021–5023; f) R. Kasper, B.
Harke, C. Forthmann, P. Tinnefeld, S. W. Hell, M. Sauer, Small
2010, 6, 1379–1384; g) G. Y. Mitronova, V. N. Belov, M. L.
Bossi, C. A. Wurm, L. Meyer, R. Medda, G. Moneron, S.
Bretschneider, C. Eggeling, S. Jakobs, S. W. Hell, Chem. Eur. J.
2010, 16, 4477–4488; h) K. Kolmakov, V. N. Belov, C. A.
Wurm, B. Harke, M. Leutenegger, C. Eggeling, S. W. Hell, Eur.
J. Org. Chem. 2010, 3593–3610.
57-OF: 1H NMR (300 MHz, CD3OD): δ = 2.03 (2 s, 6 H, CH3),
2.59–2.87 (m, 4 H, CH2CO), 2.71 (s, 3 H, CH3N), 2.95–3.14 (m, 6
H, 2ϫ CH2, CH2N), 3.45–3.50 (m, 4 H, 2ϫ CH2S), 4.16–4.26 (m,
2 H, CH2O), 4.27–4.40 (m, 4 H, CH2OCO), 7.03–7.16 (m, 4 H,
CH), 7.22 (s, 1 H, CH), 7.25 (s, 1 H, CH), 7.34–7.50 (m, 2 H, CH),
7.53–7.63 (m, 2 H, CH), 8.52–8.68 (m, 2 H, CH) ppm. ESI-MS
(negative mode): m/z (%) = 1117.2 (100) [M – H]–, 558.1 (91) [M –
2H]2–. HRMS (ESI, negative mode): calcd. for C47H44F6N2O11S6
[M – 2H]2– 558.0514; found: 558.0520
[7]
Compound 57-CF: Isolated after irradiation of the methanolic solu-
tion containing compound 57-OF with a UV-lamp (365 nm) fol-
lowed by evaporation in vacuo, column chromatography on SiO2
(CHCl3/MeOH/H2O, 75:25:3) and lyophilization. 1H NMR
(600 MHz, CD3OD): δ = 2.18 (s, 6 H, CH3), 2.49 (m, 2 H,
CH2CO), 2.71 (s, 3 H, CH3N), 2.72 (t, J = 7 Hz, 2 H, CH2CO),
2.86 (m, 2 H, CH2S), 3.02 t (J = 7 Hz, 2 H, CH2S), 3.07 (t, J =
6 Hz, 2 H, CH2CAr), 3.12 (t, J = 7 Hz, 2 H, CH2CAr), 3.34 (t, J =
6 Hz, 2 H, CH2N), 4.24 (t, J = 6 Hz, 2 H, CH2O), 4.30 [t, J =
6 Hz, 2 H, (NCH2)CH2O], 4.35 (t, J = 7 Hz, 2 H, CH2O), 6.57 (s,
1 H, CH=), 6.64 (s, 1 H, CH=), 7.12 (d, J = 8 Hz, 2 H, ArH), 7.40
(s, 1 H, ArH), 7.48 (s, 1 H, ArH), 7.49 (d, J = 8 Hz, 2 H, ArH), 7.62
(m, 2 H, 3-H in 4-pyridyl), 8.64 (m, 2 H, 2-H in 4-pyridyl) ppm.
19F NMR (282 MHz, CD3OD): δ = –135.0 (m, 2 F), –114.0 (m, 4
F) ppm.
[8]
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Acknowledgments
This work was supported by the Leibniz Prize fund of the Deutsche
Forschungsgemeinschaft (DFG) (to S. W. H.) and by the Max-
Planck-Gesellschaft. The authors are indebted to Masahiro Irie for
his generous gift of perfluorocyclopentene. The authors are grateful
to Reinhard Machinek, Holm Frauendorf and their co-workers for
recording numerous NMR and mass spectra at the Institut für Or-
ganische und Biomolekulare Chemie (Georg-August-Universität
Göttingen), as well as to Jay Jethwa for critical reading of the ma-
nuscript.
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Eur. J. Org. Chem. 2011, 3301–3312
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3311

V. N. Belov, S. W. Hell et al.
FULL PAPER
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Received: February 4, 2011
Published Online: May 4, 2011
3312
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Eur. J. Org. Chem. 2011, 3301–3312