Towards photocontrol over the helix-coil transition in foldamers: Synthesis and photoresponsive behavior of azobenzene-core amphiphilic oligo(meta-phenylene ethynylene)s

Article abstract of DOI:10.1002/chem.200501564

Introduction of photochromic azobenzene units into amphiphilic oligo(meta-phenylene ethynylene)s allowed photocontrol over the helix-coil transition in this important class of foldamers. Two design principles were followed in efforts to accommodate cis- a

Full text of DOI:10.1002/chem.200501564

DOI: 10.1002/chem.200501564
Towards Photocontrol over the Helix–Coil Transition in Foldamers: Synthesis
and Photoresponsive Behavior of Azobenzene-Core Amphiphilic
Oligo(meta-phenylene ethynylene)s
Anzar Khan and Stefan Hecht*[a]
Abstract: Introduction of photochro-
mic azobenzene units into amphiphilic
oligo(meta-phenylene ethynylene)s al-
lowed photocontrol over the helix–coil
transition in this important class of fol-
damers. Two design principles were fol-
lowed in efforts to accommodate cis-
and trans-azobenzene moieties within
the helical structure to selectively turn
the helical state on and off,respective-
ly. Several oligomer series with varying
connectivities to the central azoben-
zene chromophore were synthesized
and these photochromic oligomers
were investigated with regard to their
folding behavior in both dark and irra-
diated states. Both the foldamersꢀ chain
lengths and the electronic structures of
the azobenzene moieties had to be op-
timized to ensure folding differences
and selective excitation of the photo-
chrome. The design of such stimuli-re-
sponsive macromolecules,displaying
large structural changes upon irradia-
tion,should guide the design of future
materials in,for example,“smart” de-
livery applications.
Keywords: azo compounds · chiral-
ity · foldamers · helical structures ·
photochromism
Introduction
ture and function at the molecular level.[3] In an attempt to
utilize photochromic moieties to control helix–coil transi-
tions in various polypeptide backbones,two approaches
have been followed: the side-chain approach and the tether
approach.[4,5]
Recent years have witnessed tremendous progress in the
design of artificial backbones capable of adopting well-de-
fined secondary structures—in particular of the helix type—
in solution.[1] The helical folding process is governed by non-
covalent interactions such as hydrogen bonding,metal coor-
dination,and electrostatic and p,p-stacking interactions,
among others. The helix–coil transition is therefore most fre-
quently induced by increasing the temperature,changing the
solvent composition,or adding folding-promoting/-disrupt-
ing agents. Typical denaturation experiments provide insight
into the stability of the helical conformation and the cooper-
ativity involved in the folding process. However,methods
that use light,perhaps the most advantageous external stim-
ulus,to control helix–coil conformational transitions in fol-
damers have been limited.
Side-chain approach:[4] In this approach,photochromic units
have been introduced in the side chains of various polypep-
tide backbones. Spiropyran units,for example,have been in-
corporated as side chains in poly(l-glutamic acid).[6] Photo-
A
transition of the poly(l-glutamic acid) backbone from the
random coil to the a-helical structure. Similarly,azobenzene
units have been attached to the side chains of poly(l-gluta-
mic acid). Irradiation induces a conformational transition
from the random coil to the a-helical structure.[7] Further-
more,poly (l-lysine) appended with azobenzene chromo-
A
Photochromic molecules,[2] displaying two independently
addressable switching states,have been used to affect struc-
phores has been shown to transform from a b-sheet struc-
ture to an a-helix structure upon photoisomerization.[8] The
remarkable conformational transitions in all of these cases
were found to be strongly dependent on the polymerꢀs envi-
ronment and employed solvent mixtures and hence were at-
tributed to the changes in the polarity of the photochromic
side chains affecting the surrounding media. The side-chain
approach has also been successfully utilized to photomodu-
late the helix–coil transition in related poly(isocyanate)s
with appended azobenzene photochromes.[9]
[a] A. Khan,Dr. S. Hecht
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1,45470 Mülheim an der Ruhr (Germany)
Fax : (+49)208-306-2979
E-mail: hecht@mpi-muelheim.mpg.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
4764
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774

FULL PAPER
Tether approach:[5] In this approach,the azobenzene unit
has been used as a cross-linker between two different (cys-
teine) segments of a peptide backbone. In one case the pho-
tochromic molecule links the i and i+4 cysteine groups and
photogeneration of the cis-azobenzene favors a helical back-
bone conformation. In the opposite case,the azobenzene
unit connects the i and i+11 cysteine residues and so the
trans!cis isomerization destabilizes the helical conforma-
tion. The helix content of a peptide is thereby shown to be
controlled by the steric requirements of the azobenzene
linker,which are conveniently modulated by photoisomeri-
zation.[10]
Thus far,however,no examples of photomodulation of
the helix–coil transition within (artificial abiotic) foldamers
through incorporation of the photochromic molecules into
the main chain of the helical backbone have been reported.
We have recently disclosed the first successful design of a
photoswitchable foldamer prototype based on azobenzene-
bicity of the rather nonpolar aromatic backbone in the polar
environment,resulting in an intramolecular segregation
analogous to nanophase separation in block copolymers.
The meta connectivity allows the molecule to fold back on
itself,enabling favorable p,p interactions between the stack-
ing electron-deficient aromatic repeat units. Starting at a
sufficient length (n>8) the enthalpic gain overcompensates
the entropic loss and therefore leading to preferential for-
mation of a helical structure,[13] in which six repeat units
constitute a turn.[14] Consistent with helix–coil theory,[15]
quantitative analysis of absorption and fluorescence data
has established a linear relationship between chain length
and helix stabilization energy for 8<nꢀ18.[13] The helix–coil
transition in OmPE-related foldamers is governed by the
nature of the solvent,[16] temperature,[17] metal complexa-
tion,[18] and acidity/basicity.[19] Thus far,however,no photo-
control over folding transitions in OmPE-based or other fol-
damers has been achieved,so we became interested in ach-
ieving this goal through the incorporation of a photochromic
azobenzene moiety into the main chain of the helical back-
bone,as illustrated in Figure 1.
core
amphiphilic
oligo(meta-phenylene
ethynylene)s
(OmPEs).[11] Here we wish to give a full account detailing
our extensive work relating to the synthesis of various azo-
benzene-containing OmPEs foldamers and investigation of
their photoresponsive behavior.
Results and Discussion
Design
Choice of the stimulus and the photochromic moiety: The
use of light as an external stimulus is particularly attractive,
due to its noninvasive nature,ease of control and dose,the
potential temporal and spatial resolution of exposure,and
the absence of generated byproducts. These advantageous
properties clearly make light the stimulus of choice,yet ne-
cessitate selection of an appropriate switchable chromo-
phore.[2] Ideally,the photochromic system should consist of
two independently addressable switching states,interconver-
sion of which is associated with large changes in the molecu-
lar geometry. The system should be robust,allowing for
many switching cycles,and the photoreaction should be con-
veniently quantifiable by means of spectroscopic methods.
Taking these requirements—together with synthetic accessi-
bility—into account,we chose the azobenzene moiety as the
“classic” photochromic unit,because it displays a very clean
and reversible trans!cis photoisomerization that proceeds
with large structural changes in the geometry of the chromo-
phore. It should be noted that alternative more quantitative-
ly switching and thermostable electrocyclization-based pho-
tochromes[2] such as dithienylethenes,fulgides,or spiropyr-
ans were not chosen because the interconversion between
their switching states is associated with much smaller rela-
tive geometrical changes.
Figure 1. Incorporation of a photoisomerizable core unit (magenta) into
a helical foldamer strand (blue) should allow for photoswitching of the
helix–coil transition through the use of light as an external noninvasive
stimulus offering potential spatial and temporal control over exposure.
Design of the foldamer system: Our working hypothesis was
based on replacement of a single internal diphenylacetylene
unit in an OmPE foldamer with differently substituted azo-
benzene chromophores (Figure 2). Both thermally stable
helices and coils should be accessible in this way,so the heli-
cal conformation could be turned off or on by use of irradia-
tion. The lengths of the oligomeric sequences attached to
the photochromic unit would have to be adjusted in such a
way that they would not be able to adopt stable helical con-
formations by themselves,but photoisomerization would
either disrupt or create a kinked connection,resulting either
in helix denaturation or in helix formation.
These two design approaches,resembling “turn-on” and
“turn-off” helices,were followed by the introduction of
kinked cis- and trans-azobenzene units,respectively,in the
folding backbone.
1) “Turn-on” helices: In this design attempt we anticipated
that incorporation of a para-substituted trans-azobenzene
core in an OmPE foldamer should furnish a random coil,
due to the linear geometry of the para linkage. The
trans!cis photoisomerization should trigger the folding
reaction as the curved geometry of the cis isomer should
Choice of the folding backbone: Amphiphilic OmPEs are
known to adopt helical conformations in polar solvents.[12]
The driving force for such folding reactions is the solvopho-
Chem. Eur. J. 2006, 12,4764 – 4774
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4765

A. Khan and S. Hecht
“Turn-on” helices
Synthesis of the oligomers: Or-
thogonally protected tetramer 1
and octamer 2 were synthesized
by
a
divergent/convergent
growth strategy.[20,21] One termi-
nus in each of these oligomers
was capped by treatment with
acetylene 3 to yield the phenyl-
terminated oligomers 4 and 5,
while the other terminus was
used for coupling to the appro-
priate bifunctional azobenzene
core (Scheme 1). Removal of
the trimethylsilyl groups in
oligomers 4 and 5,followed by
palladium-catalyzed
coupling
with the azodiiodide 8,furnish-
ed the target oligomers 10 and
11. Model compound 9 was also
synthesized by coupling acety-
lene 3 with the azodiiodide 8.
The synthesized oligomers
were thoroughly characterized
by using several analytical tools.
1H NMR spectroscopy,for ex-
ample,permitted rapid identifi-
cation of the molecular struc-
ture,as evidenced by symmetri-
cal signal sets including identifi-
able end groups. Matrix-assisted
Figure 2. Structural resemblance of para-substituted cis-azobenzene (left) and meta-substituted trans-azoben-
zene (right) chromophores to the diphenylacetylene unit of the oligo(m-phenylene ethynylene) foldamer. Side
(middle) and top (bottom) views of space-filling models of the expected helical conformation (n = 5).
in principle provide the nec-
essary kink in the structure
to allow the molecule to
fold in on itself in the ap-
propriate polar environ-
ments (Figure 2,left).
2) “Turn-off” helices: In our
second design,we expected
that
trans-azobenzene
structurally
a
meta-substituted
should
a
resemble
single tolane unit of the
OmPE foldamer. In its trans
state
the
chromophore
should provide the necessa-
ry curvature in the structure
to form a helix in polar sol-
vents,while
irradiation
should result in disruption
of the helical conformation
by breaking the aromatic
contacts due to the nonpla-
narity and incorrect curva-
ture of the cis-azobenzene
(Figure 2,right).
Scheme 1. Synthesis of the para-linked azobenzene-core oligomers 9–11. TEA = triethylamine,DIPA = di-
isopropylamine.
4766
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774

Photoresponsive Helices
FULL PAPER
laser desorption/ionization time-of-flight (MALDI-TOF)
mass spectrometry (MS) measurements corroborated the
NMR results by showing the expected [M+Na]+ signals.
Each oligomer exhibited a single,symmetrical peak in gel
permeation chromatograms. The purities of the oligomers
were determined to be greater than 99% by using gel-per-
meation chromatography (GPC).[20]
band and an increase in the absorption in the backbone
chromophore range at l = 290 nm (Figure 4). This increase
is related to the contribution of the cis isomer of the azo-
The central azobenzene chromophore common to oligom-
ers 9, 10,and 11 is attached to oligomer segments with
lengths of one,five,and nine repeat units,respectively,so
the oligomeric arms on each side of the photochrome
should not be able to fold in isolation. Moreover,communi-
cation between the two oligomeric arms of one chromo-
phore is not possible because of the linear structure of the
trans-azobenzene. However,photoisomerization should gen-
erate a curved structure associated with cis-azobenzene.
This curvature should in principle allow communication be-
tween the two oligomeric arms through p,p-stacking interac-
tions between the aromatic repeat units,so we expected that
stable helices of 12 and 20 repeats units,respectively,should
be formed from oligomers 10 and 11 upon irradiation in a
helix-promoting solvent.
Photoisomerization studies: The absorption spectra of
oligomers 10 and 11 each exhibit two bands,associated with
the backbone and the photochrome units. The absorption
maximum at l = 380 nm (Figure 3) corresponds to the p–
Figure 4. UV/Vis absorption spectra of oligomer 10 in CHCl3 (top) and
CH3CN (bottom),showing thermal relaxation at 25 8C after irradiation at
395 nm ([10cis
]
U
]
G
benzene core to this absorption band (that is,the hypso-
chromically shifted p–p* band). Two well-developed iso-
sbestic points can be detected at l = 339 and 448 nm,con-
firming clean interconversion between two species. The pho-
togenerated 10cis present in the photostationary state
(PSS)[22] slowly reverts back to the 10trans in the dark at room
temperature confirming the reversibility of the isomeriza-
tion.
Figure 3. UV/Vis absorption spectra of oligomers 9 (g), 10 (a),and
11 (c) in CHCl3 (258C).
Oligomer 11 was also exposed to 395 nm light for the
same period of time. Similar changes to those seen in the
case of oligomer 10 could be observed in the absorption
spectrum,with two clear isosbestic points at l = 339 and
448 nm. Figure 5 shows the thermal cis!trans isomerization
of oligomer 11 in chloroform and acetonitrile.
p* transition of the trans-azobenzene chromophore,while
the absorption band at l = 290 nm belongs to the phenyl-
ene ethynylene backbone. The strong bathochromic shift of
the azobenzene core in oligomers 9–11 in relation to the
native chromophore (lmax ꢁ320 nm) is a result of the extend-
ed p conjugation due to para substitution with the phenyla-
cetylene unit.
Irradiation of oligomer 10trans with 395 nm light for 2 min
resulted in rapid conversion into the corresponding 10cis
isomer. The photoisomerization event could easily be moni-
tored with the aid of UV-visible spectroscopy: irradiation
causes a decrease in the absorption of the p–p* (380 nm)
Kinetics of thermal cis!trans isomerization: Because of the
anticipated conformational changes accompanying both
photochemical and thermal isomerization,we were interest-
ed in studying the kinetics to reveal potential effects on the
rates of interconversion. In view of the convenient time
frames of the thermal cis!trans isomerizations,with half-
lives of the order of hours,thermal reversal of solutions in
Chem. Eur. J. 2006, 12,4764 – 4774
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4767

A. Khan and S. Hecht
sion from individual cross-conjugated,and hence isolated,
repeat units is observed,due to the absence of a folded con-
formation. In polar solvents such as acetonitrile,however,
the helical conformation prevails,so excimer-like emission
arising from the p-stacked aromatic rings is seen.[13] As fluo-
rescence spectroscopy is a rather sensitive technique,the
presence of the non-emissive but potentially emission-
quenching azobenzene chromophore could complicate anal-
ysis. In the case of oligomer 10 (Figure 6,top),fluorescence
Figure 5. UV/Vis absorption spectra of oligomer 11 in CHCl3 (top) and
CH3CN (bottom),showing thermal relaxation at 25 8C after irradiation at
l
=
395 nm ([11cis
]
U
]
G
the photostationary state (PSS) was investigated as a func-
tion of chain length and solvent. In all these experiments
the temperature was kept constant at 258C. We were ex-
pecting that the rates of cis!trans isomerization of oligomer
9 should be similar in two different solvents as it is too short
to form a stable helix. In contrast,oligomers 10 and 11—if
they adopted stable helical conformations upon isomeriza-
tion—should undergo slower back reactions in the helix-pro-
moting solvent,as favorable p,p-stacking interactions would
have to be broken in order to reach the trans configuration.
The experimental results[20] (Table 1) revealed that the rates
were strongly dependent on solvent,but no chain-length de-
pendence,as anticipated in the case of helical folding,was
found.
Figure 6. Fluorescence spectra of oligomer 10 (top) before irradiation
(a) and after irradiation (c) in CHCl3 and before irradiation (g)
and after irradiation (d) in CH3CN,and of oligomer 11 (bottom),
before irradiation (a) and after irradiation (c) in CHCl3 and before
irradiation (g) and after irradiation (d) in CH3CN at an excitation
wavelength of 290 nm (258C).
spectra in chloroform show a band at l = 350 nm before
and after irradiation. In acetonitrile,the presence of a heli-
cal secondary structure before irradiation is unlikely,be-
cause the attached oligomers on both sides of the azoben-
zene core are not long enough to fold into stable individual
helices. Hence,only the monomer emission was observed in
acetonitrile before irradiation. However,irradiation of
oligomer 10 in acetonitrile at l = 395 nm causes no change
in the shape of the emission spectrum,suggesting that there
is no conformational change associated with the photoiso-
merization. Interestingly,the azobenzene moiety does not
seem to influence the emission characteristics notably,per-
haps as a result of its p conjugation to the neighboring phe-
nylacetylene units.
Table 1. Rates of thermal back reaction for oligomers 9–11 in chloroform
and acetonitrile at 258C.
Oligomer
krev in chloroform [sꢂ1
]
krev in acetonitrile [sꢂ1
]
9 (n = 1)
10 (n = 5)
11 (n = 9)
k = 7.89ꢃ0.04”10ꢂ5
k = 8.90ꢃ0.08”10ꢂ5
k = 9.09ꢃ0.47”10ꢂ5
k = 3.51ꢃ0.05”10ꢂ5
k = 1.26ꢃ0.09”10ꢂ5
k = 1.62ꢃ0.19”10ꢂ5
Fluorescence spectroscopy: Fluorescence spectroscopy is a
valuable tool for study of conformational changes of OmPE
foldamers. In denaturing solvents such as chloroform,emis-
4768
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774

Photoresponsive Helices
FULL PAPER
Solutions of the longer oligomer 11 in chloroform dis-
played the expected monomer emission at l = 350 nm both
before and after irradiation. In acetonitrile before irradia-
tion,however,the 350 nm band shows unexpected partial
quenching of monomer emission and the appearance of a
redshifted,broad featureless band centered at 425 nm. This
band can be attributed to p-stacked aromatic chromophores
and indicates that there is partial population of folded
oligomers in solution before irradiation (Figure 6,bottom).
Most probably,the electron-deficient azobenzene core en-
gages in stronger p,p-stacking interactions,resulting in more
pronounced stabilization of the helical conformation and
hence folding at shorter lengths than observed with the
parent amphiphilic OmPEs.[12] After trans!cis photoisome-
rization a similar spectrum is observed,indicating no signifi-
cant conformational change in the folding backbone before
and after irradiation. The nonplanarity of the cis-azoben-
zene core most probably destabilizes the helical conforma-
tion by disturbing the p,p-stacking interactions,as indicated
by molecular modeling (Figure 2),and hence prevents for-
mation of a stable helix. The photochromic behavior of azo-
benzene is caused by the nonplanar structure of the cis
isomer,allowing for the necessary spectral differences be-
tween trans and cis isomers.[2] We therefore abandoned the
turn-on helix design and focused on efforts to introduce the
planar trans isomer into the helical backbone: that is,turn-
off helices.
model compound 16 and oligomer 17,respectively. The
structural integrities and purities of these oligomers were
verified by several analytical tools,including 1H NMR spec-
[21]
troscopy,MALDI-TOF MS,and GPC.
Folding studies in the dark state: The absorption spectrum of
the phenylacetylene chromophore shows two absorption
maxima at l = 288 and 303 nm. These two peaks can be re-
garded as two vibronic bands belonging to the cisoid and
transoid conformations of the phenylene ethynylene back-
bone. Conformational change of the OmPEs results in hypo-
chromism of the 303 nm band.[12]
To investigate the folding properties of oligomer 17,UV-
visible spectra were recorded in a series of solvent mixtures
ranging from pure chloroform to pure acetonitrile. Addition
of acetonitrile causes a decrease in the 303 nm band and in
pure acetonitrile this band vanishes completely. Plotting of
the absorbance ratio (A303 nm/A288 nm) as a function of the sol-
vent composition yielded a titration curve that revealed a
sigmoidal shape,indicating the cooperative nature of the
folding process (Figure 7).
From solvent denaturation data,the helix stabilization
energy in pure acetonitrile was calculated to be DG
(CH3CN) = ꢂ1.6 kcalmolꢂ1.[21] While these results already
show the folding of oligomer 17,fluorescence spectroscopy
did not aid conformational analysis,due to the presence of
several unassigned emission bands (Figure 8),most probably
caused by the presence of the meta-linked azobenzene core.
To gain additional insight into the prevailing solution con-
formation,CD spectroscopy was employed to study oligo-
“Turn-off” helices
Synthesis of the oligomers: The synthesis of the azobenzene
core molecule 15 was accom-
plished in three linear steps
Scheme 2). Methyl 3-nitroben-
zoate was brominated,with
A
subsequent treatment with zinc
under basic conditions to yield
the desired azobenzene bis-acid
13,which was then converted
into the corresponding acid
chloride in thionyl chloride at
reflux. The crude bis-acid chlor-
ide was treated with the chiral
alcohol 14 to furnish the de-
sired azobenzene core 15. The
introduction of chiral alcohol
14 was deliberate,to allow
study of the conformational
changes of the synthesized
oligomers with the help of cir-
cular dichroism (CD) spectro-
scopy. Finally,both bromine
functionalities in the azoben-
zene core molecule 15 were
coupled to acetylene-terminat-
ed oligomers 3 and 6,carrying
Scheme 2. Synthesis of the meta-linked azobenzene-core oligomers 16 and 17. DIB = dibromoisocyanuric
achiral side chains,to yield
acid.
Chem. Eur. J. 2006, 12,4764 – 4774
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4769

A. Khan and S. Hecht
Figure 7. UV/Vis absorption spectra of oligomer 17 in CHCl3 with in-
creasing CH3CN content (100% CHCl3!100% CH3CN). The spectra,
measured at approximately the same concentration,have been normal-
ized with respect to their maximum intensity. The inset shows a plot of
the UV/Vis absorbance ratio (A303 nm/A290 nm) as a function of the volume
percent chloroform in acetonitrile (258C).
Figure 9. CD spectra of oligomer 17 in chloroform (g),acetonitrile
(a),and 40 vol% water in acetonitrile ( c) (258C).
for folding. As a result of the larger overall helix content,
and hence absolute excess of one helical twist sense,a more
intense CD signal was observed (Figure 9). The positive
Cotton effect arising from excitonic coupling of the aromatic
repeat units indicates a P-helical twist sense.[23] Interestingly,
side chains with b-methyl instead of a-methyl substitution
show inverse helicity and point to “odd–even effects” in
these and related oligomers.[24,25]
Irradiation studies: The photoisomerization of oligomers 16
and 17 was unsuccessful,as irradiation at l = 320 nm result-
ed in irreversible changes in the absorption spectra. This be-
havior can be understood in the following way. In the case
of the turn-on oligomers 10 and 11 the azobenzene chromo-
phore is extended due to conjugation with both neighboring
phenylacetylene units,so the p–p* absorption maximum of
the photochromic moiety is centered at 380 nm. The lack of
conjugation in the cases of oligomers 16 and 17,due to the
meta connectivity,results in a blueshifted p–p* absorption
maximum at 320 nm. Because the backbone absorption
dominates at this wavelength,selective excitation of the azo-
benzene photochrome is not possible and the light is mainly
absorbed by the phenylene ethynylene units,resulting in as
yet unidentified irreversible photochemistry.[26]
Figure 8. Fluorescence spectra of oligomer 17 in CHCl3 (c) and
CH3CN (a) at an excitation wavelength of l = 290 nm (258C).
chains. Incorporation of these enantiomerically pure side
chains caused efficient chirality transfer to the backbone,re-
sulting in a twist sense bias due to the presence of a non-
equivalent ratio of right- and left-handed diastereomeric
helices. The generated excess helicity can conveniently be
detected by using CD spectroscopy.
As expected,oligomer 17 showed no CD signal in chloro-
form,independently verifying the absence of any helical sec-
ondary structure in solution (Figure 9). In acetonitrile,how-
ever,a CD signal could be detected in the absorption region
of the backbone (l = 250–350 nm),confirming the ability
of oligomer 17 to adopt a helical conformation in acetoni-
trile,as shown above by the UV-visible spectroscopy data.
The observed CD signal was rather weak,however,suggest-
ing inefficient chirality transfer,associated with the rather
small energy difference separating the two diastereomeric
helices,resulting in only a mediocre twist sense bias. The
population of the helical conformation could further be atte-
nuated by the addition of water to the sample solution in
acetonitrile,making the environment significantly more
polar and thereby increasing the solvophobic driving force
Selective excitation of the azobenzene chromophore: In
order to allow selective excitation of the photochromic
moiety,the p–p* absorption maximum has to be shifted
bathochromically. One way to achieve redshifts of p–p*
bands is based on the use of donor–acceptor-substituted azo-
benzene chromophores,but the short lifetimes of their cis
forms present a severe limitation to our studies. Alternative-
ly the introduction of two donor substituents into the azo-
benzene chromophore also gives a considerable redshift. For
synthetic reasons we chose symmetrical disubstitution of the
azobenzene moiety by two (4,4’) methoxy groups. The ex-
perimental results confirmed that the absorption band of
the non-methoxy azobenzene core compound 15 (lmax
ꢁ320 nm) could be shifted to longer wavelengths (lmax
ꢁ350 nm) in this manner (Figure 10),so selective excitation
4770
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774

Photoresponsive Helices
FULL PAPER
creased number of p,p-stacking contacts,so the synthesis of
oligomer 24 was carried out (Scheme 3).
Azobenzene core 18 was extended by palladium-catalyzed
coupling with trimethylsilylacetylene (TMSA) to furnish
compound 20,which was deprotected by treatment with tet-
rabutylammonium fluoride (TBAF) to give bis-acetylene 21.
The free acetylene groups in 21 were subjected to a tenfold
excess of diiodide 22 under Sonogashira–Hagihara coupling
conditions at room temperature to yield compound 23. Use
of the excess of diiodide 22 allowed undesired side reactions
such as oligomerization and polymerization to be avoided.
Coupling of the diiodide 23 with acetylene-terminated
oligomer 6 gave the desired oligomer 24. This overall exten-
sion of the sterically hindered dibromide 18 to the more re-
Figure 10. UV/Vis absorption spectra of compound 15 (c) and 18
(g) in chloroform (258C).
of the photochromic unit can
be—at least partially—achieved
without interfering with the
phenylene ethynylene back-
bone.
Synthesis of donor-substituted
azobenzene core foldamers: The
methoxy-substituted
azoben-
zene-core oligomer 19 was ob-
tained by palladium-catalyzed
coupling of azobenzene dibro-
mide 18[11] with pentamer acety-
lene 6 in 9% yield (Scheme 3).
The low yields of the coupling
reactions are presumably the
result of the more difficult oxi-
dative addition to the ortho-me-
thoxy-substituted aryl bromide.
Solvent titration studies involv-
ing UV-visible and CD spectro-
scopy revealed that oligomer 19
did not adopt a stable helical
conformation in acetonitrile.
Apparently the introduction of
the methoxy groups significant-
ly changes the electronics of the
azobenzene moiety—an effect
desired in terms of shifting the
absorption maximum—but p,p-
stacking interactions between
the aromatic units are conse-
quently weakened.[27] We ex-
pected that lengthening the oli-
gomeric segment should com-
pensate for this effect and
might perhaps result in the for-
mation of a more stable helical
conformation due to an in- Scheme 3. Synthesis of the meta-linked methoxy-substituted azobenzene-core oligomers 19 and 24.
Chem. Eur. J. 2006, 12,4764 – 4774
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4771

A. Khan and S. Hecht
active elongated diiodide 23 resulted in significantly higher
coupling efficiency for the formation of 24. Several analyti-
cal tools such as 1H NMR spectroscopy,electrospray
ionization(ESI) MS,and GPC were used to characterize
G
oligomer 24 extensively.[11]
Folding studies in the dark state: The folding behavior of
azobenzene-core oligomer 24 was investigated by means of
typical solvent denaturation experiments with use of UV-
visible absorption to monitor the conformational transition
(Figure 11). The sigmoidal shape of the obtained titration
Figure 12. CD spectra of oligomer 24 in chloroform (g,not visible—on
baseline) and in 60 vol% water in acetonitrile (c) (258C). q = elliptic-
ity.
into the corresponding cis isomer as monitored by using
UV-visible absorption spectroscopy (Figure 13). The ob-
served absorbance changes—decreasing p–p* (350–400 nm),
Figure 11. UV/Vis absorption spectra of oligomer 24 in CHCl3 with in-
creasing CH3CN content (100% CHCl3!100% CH3CN). The spectra,
measured at approximately the same concentration,have been normal-
ized with respect to their maximum intensity. The inset shows a plot of
the UV/Vis absorbance ratio (A303 nm/A290 nm) as a function of the volume
percentage chloroform in acetonitrile (258C).
curve indicates the cooperative nature of the folding proc-
ess.
Analysis of the data obtained by the UV-visible titration
experiments reveals a helix stabilization energy in pure ace-
Figure 13. UV/Vis absorption spectra obtained during photochemical
trans!cis isomerization of oligomer 24 caused by l = 365 nm irradiation
in acetonitrile at 258C (t = 0,1,3,7,15,31,63 s). The inset shows a
magnification of the characteristic p–p* band of the azobenzene core.
tonitrile of DG
A
ment of the central tolane unit in the parent tetradecam-
er[12,13] by the azobenzene core thus gives rise to only slight
helix destabilization. The destabilization effect can be attrib-
uted to the weaker p,p-stacking interactions due to the pres-
ence of the electron-donating methoxy substituents.[27]
CD spectroscopy in pure acetonitrile did not reveal a
large Cotton effect,so addition of water was again utilized
to increase the driving force for helical structure formation.
In 60 vol% water in acetonitrile the induced CD signal is of
significant intensity and the positive Cotton effect indicates
the presence of an excess of the P-helical conformation
(Figure 12),as observed in the case of oligomer 17. These
experiments complement the independently obtained UV-
visible spectroscopic evidence for helix formation in the
case of trans-azobenzene oligomer 24.
weakly increasing n–p* (400–450 nm),and increasing p–p*
(<265 nm) absorptions,as well as the presence of two well-
defined isobestic points at l = 265 nm and 418 nm—are in-
dicative of the trans!cis photoisomerization process. While
the photochemical trans!cis conversion is achieved within
irradiation times of seconds,the thermal cis!trans reversion
occurs over the time frame of several hours at room temper-
ature.
Conformational change during photoisomerization as moni-
tored by using CD: In order to monitor the conformational
changes during both forward and backward isomerization
processes,CD spectra of oligomer 24trans in folding-promot-
ing solvent mixtures were recorded. Irradiation of the heli-
cally folded oligomer 24trans at 365 nm resulted in a rapid de-
Photoisomerization studies: Irradiation of the oligomer
24trans with use of 365 nm light to excite the central azoben-
zene chromophore selectively resulted in rapid conversion
4772
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774

Photoresponsive Helices
FULL PAPER
crease in the CD signal,indicating depopulation of the heli-
cal conformation,while thermal reversion resulted in com-
plete recovery of the initial CD signal intensity,indicating
that the original complete population of the helical back-
bone conformation had been reinstated. The presence of a
well-developed isodichroic point at 295 nm suggested a
clean conversion between both conformations (Figure 14).
The composition of the mixture in the 24cis/24trans PSS (
ꢁ40%) can be directly deduced from the ratio of the CD
signals.[11] Kinetic analysis of the data at 258C provides the
Experimental Section
For details of the general methods,optical spectroscopy,irradiation ex-
periments,derivation of the rate constants for thermal cis!trans isomeri-
zation,and syntheses,please see the Supporting Information.
Acknowledgements
rate of the thermal cis!trans isomerization kcis!trans ꢁ3.8”
Christian Kaiser is greatly acknowledged for synthesizing the chiral side
chains. The authors thank Dr. Eckhard Bill (MPI for Bioinorganic Chem-
istry,Mülheim/Ruhr) for the extensive use of the CD spectrometer. Gen-
erous support by the Sofja Kovalevskaja Program of the Alexander von
Humboldt Foundation sponsored by the Federal Ministry of Education
and Research and the Program for Investment in the Future (ZIP) of the
German Government,the German Research Foundation (DFG: SFB
448,HE 3675/2-1),and the Max Planck Society (MPG) is gratefully ac-
knowledged.
ꢂ1
10ꢂ5 s ,corresponding to a half-life of t = ꢁ5 h and an acti-
1
2
vation energy of DG° ꢁ23.5 kcalmolꢂ1,typical for azoben-
zene-cored macromolecules in solution.[28]
[1] D. G. Hill,M. J. Mio,R. B. Prince,T. S. Hughes,J. S. Moore,
Chem.
Rev. 2001, 101,3893–4012.
[2] a) Photochromism—Molecules and Systems (Eds.: H. Dürr,H.
Bouas-Laurent),Elsevier,Amsterdam, 2003; b) Molecular Switches
(Ed.: B. L. Feringa),Wiley-VCH,Weinheim, 2001; c) special Issue:
“Photochromism: Memories and Switches”, Chem. Rev. 2000, 100,
1683–1890; d) Organic Photochromic and Thermochromic Com-
pounds (Eds.: J. C. Crano,R. J. Guglielmetti),Kluwer Academic/
Plenum Publishers,New York, 1999; e) Organic Photochromes (Ed.:
A. V. El’tsov),Consultants Bureau,New York, 1990.
[3] a) V. Balzani,A. Credi,M. Venturi,
Molecular Devices and Ma-
chines: Journey into the Nanoworld,Wiley-VCH,Weinheim,
A
2003; b) S. Hecht, Small 2005, 1,26–29.
[4] O. Pieroni,A. Fissi,N. Angelini,F. Lenci, Acc. Chem. Res. 2001, 34,
9–17.
Figure 14. CD spectra obtained during thermal cis!trans isomerization
of 24 in H2O in CH3CN (60 vol%,9.5”10 ꢂ6 m) at 228C (starting at PSS: t
= 0,1.5,3,4.5,7.5,10,48,53,72 h).
[5] G. A. Woolley, Acc. Chem. Res. 2005, 38,486–493.
[6] a) F. Ciardelli,D. Fabbri,O. Pieroni,A. Fissi,
J. Am. Chem. Soc.
1989, 111,3470–3472; b) for a very recent example of a photo- and
thermoresponsive spiropyran-appended peptide tetradecamer,see:
Conclusion
K. Fujimoto,M. Amano,Y. Horibe,M. Inouye,
285–287.
Org. Lett. 2006, 8,
Through a rigorous synthetic effort involving several design
cycles,we have been able to demonstrate the feasibility of
using light as an external stimulus to control helix–coil tran-
sitions in helically folding amphiphilic OmPEs. Although
our initial approach targeting turn-on helices,based on in-
corporation of para-connected azobenzene within the core
of the helix,was not successful,introduction of a meta-con-
nected trans-azobenzene chromophore proved viable and re-
sulted in the formation of stable turn-off helices. Photochro-
mic trans!cis isomerization of the central azobenzene chro-
mophore disrupts the helix while thermal cis!trans rever-
sion restores the original helical conformation. Such light-
triggered systems can potentially function as photorespon-
sive dynamic receptors and hence promise applications in
the field of “smart” delivery devices.
[7] F. Ciardelli,O. Pieroni,A. Fissi,J. L. Houben, Biopolymers 1984, 23,
1423–1437.
[8] O. Pieroni,A. Fissi,F. Ciardelli, Biopolymers 1987, 26,1993–2007.
[9] S. Mayer,R. Zentel, Prog. Polym. Sci. 2001, 26,1973–2013.
[10] D. J. Flint,J. R. Kumita,O. S. Smart,G. A. Woolley,
Chem. Biol.
2002, 9,391–397.
[11] a) A. Khan,C. Kaiser,S. Hecht, Angew. Chem. 2006, 118,1912–
1915; Angew. Chem. Int. Ed. 2006, 45,1878–1881; b) A. Khan,S.
Hecht, Polym. Prepr. Am. Chem. Soc. Div. Polym. Chem. 2004, 45,
743–744.
[12] a) J. C. Nelson,J. G. Saven,J. S. Moore,P. G. Wolynes, Science 1997,
277,1793–1796; b) C. R. Ray,J. S. Moore, Adv. Polym. Sci. 2005,
177,91–149; c) M. T. Stone,J. M. Heemstra,J. S. Moore,
Chem. Res. 2006, 39,11–20.
Acc.
[13] R. B. Prince,J. G. Saven,P. G. Wolynes,J. S. Moore,
J. Am. Chem.
Soc. 1999, 121,3114–3121.
[14] K. Matsuda,M. T. Stone,J. S. Moore, J. Am. Chem. Soc. 2002, 124,
11836–11837.
Ongoing work in our laboratory is concerned with the
design of polymeric analogues featuring better spectral sepa-
ration of photoisomerizable unit and the helical backbone in
order to achieve more quantitative switching between com-
pact helical and extended coil structures.
[15] B. H. Zimm,J. K. Bragg, J. Chem. Phys. 1959, 31,526–535.
[16] D. J. Hill,J. S. Moore, Proc. Natl. Acad. Sci. USA 2002, 99,5053–
5057.
[17] R. B. Prince,PhD thesis,University of Illinois at Urbana-Cham-
paign,Urbana,IL, 2000.
[18] R. B. Prince,T. Okada,J. S. Moore, Angew. Chem. 1999, 111,245–
248; Angew. Chem. Int. Ed. 1999, 38,233–236.
Chem. Eur. J. 2006, 12,4764 – 4774
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4773

A. Khan and S. Hecht
[19] H. Abe,N. Masuda,M. Waki,M. Inouye,
127,16189–16196.
[20] a) E. Igner,O. I. Peynter,D. J. Simmonds,M. C. Whiting,
J. Am. Chem. Soc. 2005,
J. Chem.
[24] For the use of (S)-b-methyltri(ethyleneglycol) side chains,see:
a) R. B. Prince,L. Brunsveld,E. W. Meijer,J. S. Moore,
Angew.
Chem. 2000, 112,234–236; Angew. Chem. Int. Ed. 2000, 39,228–
230; b) R. B. Prince,J. S. Moore,L. Brunsveld,E. W. Meijer, Chem.
Eur. J. 2001, 7,4150–4154.
Soc. Perkin Trans. 1 1987,2447–2454; b) J. Zhang,J. S. Moore,Z.
Xu,R. A. Aguirre, J. Am. Chem. Soc. 1992, 114,2273–2274; for a
review,see: c) R. E. Martin,F. Diederich, Angew. Chem. 1999, 111,
1440–1469; Angew. Chem. Int. Ed. 1999, 38,1350–1377; d) J. S.
Moore,R. B. Prince in Synthesis of Polymers (Ed.: A. D. Schlüter),
Wiley-VCH,New York, 1999,pp. 11–36.
[25] So called “odd–even effects” have been observed in the self-assem-
bly of p-conjugated oligothiophenes bearing various chiral oligo(e-
thyleneglycol) side chains: E. R. Lermo,B. M. W. Langeveld-Voss,
R. A. J. Janssen,E. W. Meijer, Chem. Commun. 1999,791–792. In-
terestingly,a related helical oligothiophene did not give rise to a CD
signal: J. R. Matthews,F. Goldoni,A. P. H. J. Schenning,E. W.
Meijer, Chem. Commun. 2005,5503.
[26] The nature of the products arising from the irreversible photochemi-
cal processes,most likely cycloaddition and isomerization products,
has not yet been deduced.
[21] See the Supporting Information.
[22] The cis content present in the PSS can be roughly estimated by
using UV/Vis absorption from the formula [cis]PSS = [trans]0ꢂ(APSS
/
etrans),in which e is the molar ellipticity and A is the absorbance,
though the data are associated with a certain error due to residual
absorption of the cis isomer. Alternative techniques have been em-
ployed to determine the compositions of the PSSs,yet 1H NMR
spectroscopy was only applicable in the cases of compounds 9–11,
due to limited spectral resolution,and HPLC or GPC separation
were unsuccessful.
[27] For the most prominent examples,consult: a) S. Lahiri,J. L. Thomp-
son,J. S. Moore, J. Am. Chem. Soc. 2000, 122,11315–11319; b) H.
Goto,J. M. Heemstra,D. J. Hill,J. S. Moore, Org. Lett. 2004, 6,889–
892.
[23] a) N. Berova,K. Nakanishi in Circular Dichroism Principles and Ap-
plications (Eds.: N. Berova,K. Nakanishi,R. B. Woody),Wiley-
[28] For example,see: L.-X. Liao,F. Stellacci,D. V. McGrath,
J. Am.
Chem. Soc. 2004, 126,2181–2185.
VCH, 2000,pp. 337–376; b) D. A. Lightner,J. E. Gurst,
Organic
Conformational Analysis and Stereochemistry from Circular Dichro-
Received: December 14,2005
ism Spectroscopy,Wiley-VCH, 2000,pp. 423–454.
Published online: March 10,2006
4774
www.chemeurj.org
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2006, 12,4764 – 4774