Heterodiazocines: Synthesis and Photochromic Properties, Trans to Cis Switching within the Bio-optical Window

Article abstract of DOI:10.1021/jacs.6b05846

Diazocines, bridged azobenzenes, exhibit superior photophysical properties compared to parent azobenzenes such as high switching efficiencies, quantum yields, and particularly switching wavelengths in the visible range. Synthesis, however, proceeds with l

Full text of DOI:10.1021/jacs.6b05846

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Communication
Heterodiazocines: Synthesis and Photochromic Properties,
Trans to Cis Switching within the Bio-optical Window
Melanie Hammerich, Christian Schütt, Cosima Staehler, Fynn
Roehricht, Pascal Lentes, Ronja Höppner, and Rainer Herges
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Sep 2016
Downloaded from http://pubs.acs.org on September 29, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 4
Journal of the American Chemical Society
1
2
3
4
5
6
Heterodiazocines: Synthesis and Photochromic Properties,
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Trans to Cis Switching within the Bio-optical Window
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
†
†
†
†
Melanie Hammerich, Christian Schütt, Cosima Stähler, Pascal Lentes, Fynn Röhricht, Ronja
#
†
Höppner, and Rainer Herges *
†
Otto Diels-Institute of Organic Chemistry, Christian Albrechts University Kiel, Otto Hahn Platz 4, 24118 Kiel, Germa-
ny. E-mail: rherges@.uni-kiel.de
#
Institute for Physical Chemistry, Christian Albrechts University Kiel, Max-Eyth-Str. 2, 24118 Kiel, Germany
Supporting Information Placeholder
of considerable advantage in optopharmacological applica-
tions. Most photochemically switchable drugs and inhibitors
ABSTRACT: Diazocines, bridged azobenzenes, exhibit supe-
rior photophysical properties compared to parent azoben-
are active in their stretched and slender trans configurations,
zenes such as high switching efficiencies, quantum yields,
and particularly switching wavelengths in the visible range.
Synthesis, however, proceeds with low yields, and derivatives
are difficult to prepare. We now present two heterodiazo-
cines which are easier to synthesize, and the general proce-
dures should also provide facile access to derivatives. Moreo-
ver, both compounds can be switched with light in the far-
red (650 nm). Accessibility and photophysical properties
make them ideal candidates for applications such as pho-
toswitchable drugs and functional materials.
14-17
and inactive in their bulgy cis forms.
Mechanistic bio-
chemical studies as well as in vivo applications require that
switching to the inactive state is complete, because even
remaining traces of the active form can reduce the switching
efficiency, whereas an incomplete conversion to the active
state can be compensated by an increase of the concentra-
18
tion. In this regard diazocines are superior because they can
be quantitatively switched to the inactive cis state. Their
excellent photophysical properties notwithstanding, applica-
tions of diazocines so far have been rather limited. Main
obstacles are the notoriously low yields in the final ring clos-
ing azo formation and the lack of reproducibility of the syn-
1
9-22
thesis.
Functionalization of the parent system using
Azobenzenes are probably the most frequently used pho-
tochromic compounds in applications ranging from molecu-
standard aromatic substitution reactions is difficult, and the
preparation of unsymmetrically substituted diazocines
which are important for most applications is even more
problematic because all steps are based on homo couplings.
We now present two hetero diazocines which are accessible
by reliable procedures in reasonable yields. Moreover, both
compounds switch efficiently (>99%) from the trans to the
cis isomer upon irradiation with light in the far-red
23
1
-4
lar motors and machines to photoswitchable drugs. They
are easily accessible and their photochromic functions gen-
erally are quite reliable. Usually, the stretched trans isomer is
the most stable configuration. Upon irradiation with UV
light the bent cis isomer is formed which returns back to the
trans isomer either upon irradiation with visible light or
24
5
thermochemically. Aiming at in vivo applications, there have
(
650 nm).
been several attempts to shift the switching wavelengths
TD-DFT calculations (see Supporting Information) predict
6,7
towards the far-red (λ>650 nm). Within the so-called bio-
optical window (650-1100 nm) blood supported tissue is
transparent (penetration depth ~ 20 mm). Ortho substitution
of the azobenzene unit has been successful towards this end,
as shown by Woolley et al. (R=OMe, λ(E/Z)=550/450nm) and
that the nπ* transitions of the cis and the trans isomers in
both hetero diazocines 2, and 3 are separated by more than
100 nm. Therefore, we expected that efficient photo isomeri-
zation with two wavelengths should be possible. However,
the trans isomer can adopt two different conformations
(twist and chair see Figure 1) with markedly different UV-vis
spectra. In the parent diazocine 1 and the O-diazocine 2, the
8
-10
Hecht et al. (R=F, λ(E/Z)=500/410 nm).
presented BF2 bridged azobenzenes with λ(E)=710 nm.
Aprahamian et al.
1
1,12
Diazocines (ortho ethylene bridged azobenzenes) are partic-
-1
twist conformations are about 3 kcal mol more stable than
ularly interesting visible light switchable compounds
the chair forms, and hence the concentrations of the chair
conformers in equilibrium should be very small. Twist and
chair conformations in the S-diazocine 3, however, are al-
most isoenergetic, and therefore the UV-vis spectrum of
trans-3 is a linear combination of the spectra of both con-
formations.
13
(
λ(E/Z)=500/400nm). Bridging of the phenyl groups pre-
vents their rotation, and the rigid molecular framework
should improve power transmission of the photomechanical
movement onto the environment. This is important in bio-
chemical applications if an efficient detachment from the
active site of a protein must be achieved, or if the molecular
switching has to be translated into a macroscopic effect in
functional materials. Moreover, as opposed to azobenzenes,
diazocines are more stable in the cis form (Figure 1). This is
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1.
Calculated (B3LYP/6-31G*) strain energies
Scheme 1. Synthesis of the dinitro precursors for the di-
azocine synthesis. (TBAB: tetrabutylammonium bromide)
(
Estrain) of the cis isomers of diazocine 1 and hetero deriva-
tives 2 and 3, and energies (E ) of trans isomers (twist and
chair conformations) of 1, 2 and 3 relative to the correspond-
ing cis isomers in kcal mol . Distances are given between the
C atoms in para position to the azo group.
rel
-
1
The oxygen and sulfur bridged diazocines 2 and 3 were ob-
tained by a three step synthesis. In the first synthetic step the
bridging unit was formed. This was accomplished for the
oxygen system via Williamson ether synthesis with potassi-
um phosphate as base in water with 93 % yield (Scheme
25,26
1).
The thioether precursor 8 was formed by reduction of
the disulfide 7 with sodium borohydride and in situ reaction
with 2-nitrobenzylbromide 4 in 45 % yield.
The main problem hampering the synthesis of diazocines
are the low and unreliable yields in the subsequent reductive
ring closure of the dinitro precursors. According to our cal-
culations (Figure 1) the ring strains of the parent diazocine 1,
Scheme 2. Reaction conditions: i) Pb, NEt /formic ac-
3
id/MeOH/H O, pH = 9.5, ultrasound; ii) PPh , MoO Cl , iii)
2
3
2
2
Pb, ball mill, 40 Hz, 4 h.
and its hetero derivatives
2
and 3 amount from 16 to almost
-
1
The reduction of the oxygen bridged azoxy compounds
a/b to the corresponding diazocine 2 was achieved applying
2
0 kcal mol (details see SI). Polymer formation, therefore, is
9
the main reaction pathway. Moreover, most reduction meth-
ods require strongly basic reaction conditions which lead to
deprotonation of the benzylic positions, and consequently
the literature method with triphenylphosphine and a molyb-
22,29
denum catalyst (Scheme 2) (see Supporting Information).
27
However, the method was unsuccessful in case of the sulfur
bridged analogon 10a/b. Reduction of the latter azoxy com-
pound was achieved with lead granules in a ball mill.
cyclization, oxidation and polymer formation. Upon reduc-
tion of the corresponding dinitro precursors the O- and S-
diazocine 6 and 8 with Zn under basic conditions no traces of
the diazocine products could be isolated. Cleavage of the
benzyl(thio)ether was observed. To avoid deprotonation at
the benzylic positions, and to favour ring closure, heteroge-
27
28
neous reaction conditions under moderately basic pH were
applied. A corresponding procedure was published by Yan et
21,22
al..
They achieved the reductive ring closure of
2,2’dinitrodibenzyl to the cyclic azoxy compound with lead
powder under basic conditions, and subsequently reduced
the azoxy compound with trivalent phosphorous to the di-
azocine. As the reaction time is relatively long with two days,
and the solubility of our starting material in methanol was
quite low, we improved the synthesis by using high power
ultrasound. As main products the azoxy compounds 9a/b
(
44%, mainly 9b) or 10a/b (32%) were formed, concomitant
with small amounts of the desired diazocines 2 and 3.
Figure 2. UV spectra of O-diazocine 2 (THF, T = -80°C,
left) and S-diazocine 3 (acetonitrile, right), the cis spectrum
is plotted in black, the spectrum of the trans isomer in red,
below: solution of S-diazocine 3 before and after irradiation
in acetone.
ACS Paragon Plus Environment

Page 3 of 4
Journal of the American Chemical Society
1
Photophysical properties were investigated with H NMR and
parent diazocines). In contrast to azobenzenes the cis con-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
UV/Vis spectroscopy. The UV/vis spectra of the O-diazocine
2 and S-diazocine 3 are similar to the parent system. The nπ*
bands of the cis isomers are located at 400 nm. By switching
both diazocines to the trans isomers, the nπ* excitations are
shifted bathochromically to λmax =525 nm. These bands are
broad and extend up to 700 nm. Therefore, the back isomeri-
zation to the cis isomers can be performed with red light
figurations are thermodynamically more stable than the
trans isomers. Moreover, trans-cis isomerization is very effi-
cient (>99%) even with light in the far-red (650 nm). This
would be most suitable for in vivo activation of compounds
3
0,31
that are more active in the cis state.
Fatigue or decompo-
sition was not observed over a large number of cycles under
air at room temperature. The above properties of this novel
class of photochromic compounds provide the basis for nu-
merous applications in photo pharmacology, and functional
materials.
(
660 nm) (Figure 2). In contrast to the parent diazocine 1 and
the O-diazocine 2, the S-diazocine 3 exhibits an additional
strong absorption at 380 nm which we attribute to the chair
conformation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
ASSOCIATED CONTENT
Supporting Information
Photostationary states were determined by H NMR spec-
troscopy. In both systems (2 and 3) cis-trans isomerizations
were achieved with 385 or 405 nm (2: 80%, 3: 70%) and trans-
cis switching with 530 or 660 nm (>99%) (Table 1).
1
13
DFT-calculations, experimental procedures, H- and C-
NMRs of all compounds, photoswitching experiments
Half-lives of the trans compounds were also determined by
H NMR spectroscopy (X = S, 3) and UV/Vis spectroscopy
1
1
( H-NMR and UV/Vis), web enhanced object (movie)
demonstrating the switching of the oxygen diazocine 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
X = O, 2). Compared to the parent system the oxygen
bridged system 2 exhibits a distinctly shorter half-life. Rate
constants were determined at four different temperatures
(-11, 0, 4, and 9°C) and the half-life at room temperature was
extrapolated from the Arrhenius equation (see Supporting
information) as t1/2 = 89 s (20 °C). In contrast to 2, the trans
isomer of the sulphur system 3 exhibits a high thermal stabil-
ity. With t1/2 = 3.5 d the half-life of trans-3 is considerably
longer than the half-life of the parent system 1 (t1/2 = 4.5 h).
To check the photostability of hetero diazocines 2 and 3 were
irradiated with 385 and 530 nm in an alternate sequence. No
fatigue was observed over a large number of cycles (Figure 3).
AUTHOR INFORMATION
Corresponding Author
*E-mail: rherges@oc.uni-kiel.de.
Author Contributions
Notes
The authors declare no competing financial interests.
Table 1. Photostationary states and half-lives of heterodi-
azocines 2 and 3.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support by the
Deutsche Forschungsgesellschaft (DFG) within the Sonder-
forschungsbereich 677, “Function by Switching”.
PSS385/405
PSS530/660
% cis
X =
t1/2
%
trans
a
8
9 s (20 °C)
O (2)
S (3)
80
> 99
> 99
b
70
3.5 d (27 °C)
REFERENCES
a) 385 nm, -70 °C b) 405 nm, 27 °C.
(1)
Szymanski, W.; Beierle, J. M.; Kistemaker, H. A. V.;
Velema, W. A.; Feringa, B. L. Chem. Rev. 2013, 113, 6114–6178.
(2)
Merino, E.; Ribagorda, M. Beilstein J. Org. Chem. 2012, 8,
Feringa, B. L.; Brown, W. R. In Molecular Switches; 2nd,,
1
071–1090.
(
3)
Ed.; Wiley-VCH: Weinheim, 2011.
4) Kay, E. R.; Leigh, D. A.; Zerbetto, F. Angew.Chem.Int.Ed
007, 46, 72–191.
(
2
(
5)
Hartley, G. S. Nature 1937, 140, 281–281.
(
6)
Bléger, D.; Hecht, S. Angew. Chem. Int. Ed. 2015, 54, 11338–
1
1349.
Figure 3. Left: measured absorbances of a solution of 2 at
(7)
Dong, M.; Babalhavaeji, A.; Samanta, S.; Beharry, A. A.;
4
04 nm (black zig-zag line) and 522 nm (red zig-zag line) in
Woolley, G. A. Acc. Chem. Res. 2015, 48, 2662–2670.
the photostationary states after alternating irradiation at 530
and 385 nm in repeated switching cycles. Right: absorbance
of 3 at 396 nm (black) and 523 nm (red) after irradiation at
(8) Samanta, S.; Beharry, A. A.; Sadovski, O.;
McCor-
mick, T. M.; Babalhavaeji, A.; Tropepe, V.; Woolley, G. A. J. Am.
Chem. Soc. 2013, 135, 9777–9784.
5
30 and 405 nm.
(9)
Beharry, A. A.; Sadovski, O.; Woolley, G. A. J. Am. Chem.
Soc. 2011, 133, 19684–19687.
In summary, we synthesized two novel photochromic com-
pounds, and investigated their photophysical properties.
They are structurally quite simple, and can be viewed as
ortho (O-CH and S-CH ) bridged azobenzenes. Synthesis is
(10)
Bléger, D.; Schwarz, J.; Brouwer, A. M.; Hecht, S. J. Am.
Chem. Soc. 2012, 134, 20597–20600.
(
11)
Yang, Y.; Hughes, R. P.; Aprahamian, I. J. Am. Chem. Soc.
2
2
2012, 134, 15221–15224.
short (two or three steps) and reliable (as compared to the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 4
(
12)
2014, 136, 13190–13193.
(13) Siewertsen, R.;
Herges, R.; Näther, C.; Renth, F.; Temps, F. J. Am. Chem. Soc. 2009,
31, 15594–15595.
14) Broichhagen, J.; Frank, J. A.; Trauner, D. Acc. Chem. Res.
015, 48, 1947–1960.
15) Velema, W. A.; Szymanski, W.; Feringa, B. L. J. Am. Chem.
Soc. 2014, 136, 2178–2191.
16) Pittolo, S.; Gómez-Santacana, X.; Eckelt, K.; Rovira, X.;
Yang, Y.; Hughes, R. P.; Aprahamian, I. J. Am. Chem. Soc.
(22)
Joshi, D. K.; Mitchell, M. J.; Bruce, D.; Lough, A. J.; Yan, H.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Tetrahedron 2012, 68, 8670–8676.
Neumann, H.;
Buchheim-Stehn, B.;
(23)
(24)
Reisser, A.; Crämer, K. Chem. Ber. 1928, 61, 2555–2566.
Tellkamp, T.; Shen, J.; Okamoto, Y.; Herges, R. Eur. J. Org.
1
Chem. 2014, 2014, 5456–5461.
(25) Lellmann, E.; Mayer, N. Chem. Ber. 1892, 25, 3583–3586.
26) Wang, H.; Ma, Y.; Tian, H.; Yu, A.; Chang, J.; Wu, Y.
Tetrahedron 2014, 70, 2669–2673.
(
2
(
(
(27)
Machin, J.; Mackie, R. K.; McNab, H.; Reed, G. A.; Sagar, A.
(
J. G.; Smith, D. M. J. Chem. Soc., Perkin Trans. 1 1976, 394–399.
daltonalton, J.; Goudet, C.; Pin, J.-P.; Llobet, A.; Giraldo, J.; Llebar-
ia, A.; Gorostiza, P. Nat. Chem. Biol. 2014, 10, 813–815.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(28)
Asghari, J. Chem. Eur. J. 2010, 16, 13236–13242.
(29) Sanz, R.; Escribano, J.; Fernández, Y.; Aguado, R.; Ped-
rosa, M. R.; Arnáiz, J., Francisco Synlett 2005, 1389–1392.
(30) Velema, W. A.; van der Berg, J. P.; Hansen, M. J.;
Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 2013, 5,
24–928.
31)
Thorwirth, R.; Bernhardt, F.; Stolle, A.; Ondruschka, B.;
(
17)
Stein, M.;
Middendorp, S. J.;
Carta, V.;
Pejo, E.;
Raines, D. E.; Forman, S. A.; Sigel, E.; Trauner, D. Angew. Chem.
2012, 124, 10652–10656.
(
18)
Tuczek, F.; Herges, R. Chem. Eur. J. 2012, 18, 16358–16368.
(19) Samanta, S.; Qin, C.; Lough, A. J.; Woolley, G. A. Angew.
Chem. 2012, 124, 6452–6455.
Thies, S.; Sell, H.; Bornholdt, C.; Schütt, C.; Köhler, F.;
9
(
Borowiak, M.; Nahaboo, W.; Reynders, M.; Nekolla, K.;
Jalinot, P.; Hasserodt, J.; Rehberg, M.; Delattre, M.; Zahler, S.;
Vollmar, A.; Trauner, D.; Thorn-Seshold, O. Cell 2015, 162, 403–411.
(20)
9, 1–7.
Sell, H.; Näther, C.; Herges, R. Beilstein J. Org. Chem. 2013,
(21)
Eljabu, F.; Dhruval, J.; Yan, H. Bioorg. Med. Chem. Lett.
2015, 25, 5594–5596.
TOC graphic
ACS Paragon Plus Environment