Fusion of photochromic reaction and synthetic reaction: Photoassisted cyclization to highly strained chiral azobenzenophanes

Article abstract of DOI:10.1021/ol300992d

A method for synthesizing highly strained cyclic structures by combining photochromic and synthetic reactions is described. Tightly linked azobenzene-binaphthyl dyads (R)-4 and (R)-6 could not be obtained by conventional cyclization, but continuous application of photoirradiation, which induced (E)→(Z) isomerization of the azobenzene moiety, allowed the cyclization reaction to proceed, affording the desired chiral azobenzenophanes.

Full text of DOI:10.1021/ol300992d

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ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Fusion of Photochromic Reaction and
Synthetic Reaction: Photoassisted
Cyclization to Highly Strained Chiral
Azobenzenophanes
Kazuto Takaishi,*,†,‡ Masuki Kawamoto,*,† Atsuya Muranaka,†,§ and
Masanobu Uchiyama*,†,
RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Department of Materials and
Life Science, Seikei University, 3-3-1 Kichijoji-kitamachi, Musashino, Tokyo 180-8633,
Japan, Japan Science and Technology Agency (JST), PRESTO, Kawaguchi 332-0012,
Japan, and Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
takaishi@st.seikei.ac.jp; mkawamot@riken.jp; uchi_yama@riken.jp
Received April 17, 2012
ABSTRACT
A method for synthesizing highly strained cyclic structures by combining photochromic and synthetic reactions is described. Tightly linked
azobenzeneꢀbinaphthyl dyads (R)-4 and (R)-6 could not be obtained by conventional cyclization, but continuous application of photoirradiation,
which induced (E)f(Z) isomerization of the azobenzene moiety, allowed the cyclization reaction to proceed, affording the desired chiral
azobenzenophanes.
The synthesis, conformation, and optical properties of
smaller cyclophanes and nano rings are beginning to
attract attention because these molecules often have unu-
sual properties not shared by larger macrocycles and linear
analogues.1,2 Meanwhile, azobenzenes are widely used as
molecular switches because they undergo dramatic, revers-
ible, and facile photoisomerization between the (Z)- and
(E)-forms.3 In general, UV light induces (E)f(Z) isomer-
ization, whereas visible light or heat induces (Z)f(E)
isomerization. Recently, azobenzenes incorporated into
cyclic compounds, so-called azobenzenophanes, have
attracted particular interest because isomerization of
the azobenzene moiety can efficiently and dramatically
change the conformation of the whole molecule.4 We
have previously investigated the configuration and the
photoswitching of chiroptical properties of axially chiral
† RIKEN.
‡ Seikei University.
§ JST, PRESTO.
The University of Tokyo.
(1) Recent examples: (a) Kawase, T.; Nishiyama, Y.; Nakamura, T.;
Ebi, T.; Matsumoto, K.; Kurata, H.; Oda, M. Angew. Chem., Int. Ed.
2007, 46, 1086–1088. (b) Forgan, R. S.; Sauvage, J.-P.; Stoddart, J. F.
Chem. Rev. 2011, 111, 5434–5464. (c) Zhang, F.; Goetz, G.; Mena-
Osteritz, E.; Weil, M.; Sarkar, B.; Kaim, W.; Baeuerle, P. Chem. Sci.
2011, 2, 781–784. (d) Sprafke, J. K.; Kondratuk, D. V.; Wykes, M.;
Thompson, A. L.; Hoffmann, M.; Drevinskas, R.; Chen, W.-H.; Yong,
C. K.; Karnbratt, J.; Bullock, J. E.; Malfois, M.; Wasielewski, M. R.;
Albinsson, B.; Herz, L. M.; Zigmantas, D.; Beljonne, D.; Anderson,
H. L. J. Am. Chem. Soc. 2011, 133, 17262–17273.
(2) Highly strained cycloparaphenylenes were synthesized: (a) Jasti,
R.; Bhattacharjee, J.; Neaton, J. B.; Bertozzi, C. R. J. Am. Chem. Soc.
2008, 130, 17646–17647. (b) Yamago, S.; Watanabe, Y.; Iwamoto, T.
Angew. Chem., Int. Ed. 2010, 49, 757–759. (c) Sisto, T. J.; Golder, M. R.;
Hirst, E. S.; Jasti, R. J. Am. Chem. Soc. 2011, 133, 15800–15802.
(3) (a) Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M.;
Sommerdijk, N. A. J. M. Chem. Rev. 2001, 101, 4039–4070. (b) Balzani,
V.; Venturi, M.; Credi, A. Molecular Devices and Machines; Wiley-VCH:
Weinheim, 2003. (c) Hoeben, F. J. M.; Jonkheijm, P.; Meijer, E. W.;
Schenning, A. P. H. J. Chem. Rev. 2005, 105, 1491–1546. (d) Caruso,
F. J.; M., M.; Davis, D. A.; Shen, Q.; Odom, S. A.; Sottos, N. R.; White,
S. R.; Moore, J. S. Chem. Rev. 2009, 109, 5755–5798. (e) Feringa, B. L.;
Browne, W. R. Molecular Switches, 2nd Completely Revised and Enlarged
ed.; Wiley-VCH: Weinheim, 2011.
r
10.1021/ol300992d
XXXX American Chemical Society

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(ꢀOꢀ), were selected as model compounds, and we ex-
amined the feasibility of using simple cyclization by means
of tandem Williamson ether synthesis to generate them
with the aid of continuous photoirradiation during the
reaction to relieve strain as required.
Synthesis of dyads (R)-3ꢀ6 was first attempted as shown
in Scheme 1. (R)-3 and (R)-5 were successfully synthesized
as follows. Compound (R)-3 was prepared in moderate
yield by coupling of 2,20-bis(bromomethyl)binaphthyl
(R)-77 and 1.0 equiv of 2,20-dihydroxyazobenzene (8).
(R)-5 was synthesized similarly, using 7,70-bis(bromo-
methyl)binaphthyl (R)-9. However, attempts to synthesize
(R)-4 and (R)-6 from 3,30-disubstituted azobenzenes 108
and 129 were unsuccessful, affording complex mixtures
including larger macromolecules. Under these conditions,
the azobenzenes 8, 10, and 12 should exist completely in
(E)-form, which is thermally stable. Therefore, it was
considered that the two hydroxy groups of (E)-10 and
the fluorinated carbons of (E)-12, i.e., the reactive points,
aretoo distantfromeachother, comparedwiththethoseof
binaphthyls (R)-7 and (R)-11.10 In the optimized structures
obtained by DFT calculation at the B3LYP/6-31G(d,p)
Figure 1. Azobenzeneꢀbinaphthyl dyads (R)-1ꢀ6.
binaphthylꢀazobenzene cyclic dyads, mainly 1, 2, and
their benzylated analogues (Figure 1).5 In most molecular
switches, including these dyads, the distance between the
stimulus-driven moiety and the effector site and the nature
of the linkers are very important. Nevertheless, the synthe-
sis of not only cyclic molecular switches but also almost all
small cyclic compounds with short linkers is difficult and
sometimes impossible because of the large molecular
strain. In fact, the shortest linkers that have so far been
successfully used to connect a binaphthyl moiety and an
azobenzene moiety consist of fouratoms,ꢀOꢀCꢀCꢀOꢀ,
as in (R)-2.5e Strained azobenzenophanes were previously
synthesized by means of NdN forming reaction of two
nitro or amino groups under stringent conditions.6 Here,
we focus on the development of a versatile, mild, and
simple method for synthesis of small cyclic compounds,
and we also investigate their conformations. Initially,
(R)-3ꢀ6, linked by two atoms (ꢀOꢀCꢀ) or one atom
˚
˚
level, the OꢀO distance is 3.9 A for (E)-8 and 9.0 A for
(E)-10, and the Csp3ꢀCsp3 distance of the bromomethyl
groups in (R)-7 is 4.1 A.11 The OꢀO distance of (Z)-10 is
˚
˚
5.9 A. Therefore, we envisioned that the coupling of (Z)-10
with (R)-7 might be a feasible route to (R)-4. In order
to drive the reaction, we decided to employ continuous
photoirradiation, inducing (E)f(Z) isomerization, throu-
ghout the reaction period.
Table 1 shows the results of the photoassisted synthesis
of (R)-4, conducted as illustrated in Figure 2. The half-life,
T
1/2, of (Z)-10 was 21 min at 80 °C (rate constant k = 5.6 ꢁ
10ꢀ4 sꢀ1, DMF, 1 ꢁ 10ꢀ5 M). This is sufficiently long to be
applicable for the synthesis because (E)f(Z) photoisome-
rization occurs at the picosecond or subpicosecond time
(7) (a) Bergmann, E. D.; Szmuszkovicz, J. J. Am. Chem. Soc. 1951,
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Chem. 2007, 72, 679–682. (b) Shen, Y.-T.; Guan, L.; Zhu, X.-Y.; Zeng,
Q.-D.; Wang, C. J. Am. Chem. Soc. 2009, 131, 6174–6180. (c) Mathews,
M.; Tamaoki, N. Chem. Commun. 2009, 3609–3611. (d) Basheer, M. C.;
Oka, Y.; Mathews, M.; Tamaoki, N. Chem. ;Eur. J. 2010, 16, 3489–
3496. (e) Tanaka, K.; Fukuoka, S.; Miyanishi, H.; Takahashi, H.
Tetrahedron Lett. 2010, 51, 2693–2696. (f) Mathews, M.; Zola, R. S.;
Hurley, S.; Yang, D. ꢀK.; White, T. J.; Bunning, T. J.; Li, Q. J. Am.
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X.; Zhang, M.; Zheng, B.; Hu, X.; Shao, S.; Huang, F. Org. Lett. 2010,
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(5) (a) Kawamoto, M.; Aoki, T.; Wada, T. Chem. Commun. 2007,
930–932. (b) Takaishi, K.; Kawamoto, M.; Tsubaki, K.; Wada, T.
J. Org. Chem. 2009, 74, 5723–5726. (c) Kawamoto, M.; Shiga, N.;
Takaishi, K.; Yamashita, T. Chem. Commun. 2010, 46, 8344–8346.
(d) Takaishi, K.; Kawamoto, M.; Tsubaki, K.; Furuyama, T.; Muranaka,
A.; Uchiyama, M. Chem.;Eur. J 2011, 17, 1778–1782. (e) Takaishi, K.;
Muranaka, A.; Kawamoto, M.; Uchiyama, M. J. Org. Chem. 2011, 76,
7623–7628. (f) Takaishi, K.; Muranaka, A.; Kawamoto, M.; Uchiyama,
M. Org. Lett. 2012, 14, 276–279.
(11) Several conformations of 7ꢀ12 were also calculated; see Figure
S7 in the Supporting Information. Calculations were performed Gaus-
sian 09, Revision B.01. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone,
V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg,
J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd,
J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox,
J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
(6) Thermally stable (Z)-azobenzenes have been reported; see:
(a) Norikane, Y.; Katoh, R.; Tamaoki, N. Chem. Commun. 2008,
1898–1900. (b) Siewertsen, R.; Neumann, H.; BuchheimꢀStehn, B.;
€
Herges, R.; Nather, C.; Renth, F.; Temps, F. J. Am. Chem. Soc. 2009,
€
131, 15594–15595. (c) Reuter, R.; Wegner, H. A. Chem.;Eur. J. 2011,
17, 2987–2995.
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian, Inc., Wallingford CT, 2009.
B
Org. Lett., Vol. XX, No. XX, XXXX

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Scheme 1. Reactions of Binaphthyls and Azobenzenesa
a Conditions: 22.7 mM for 7ꢀ12 and 227 mM for K2CO3.
Table 1. Synthesis of (R)-4 under Photoirradiation at 365 nma
Figure 2. Photograph of the apparatus and schematic illustra-
tion of photoassisted cyclization. Irradiation conditions:
365 nm, 10 mW/cm2 using a 120 W high-pressure mercury lamp
(Asahi Spectra REX-120). The reaction was conducted under an
atmosphere of N2 and the apparatus was surrounded by a
blackout curtain.
entry
temp (°C)
conc of (R)-7 (mM)
light
yieldb (%)
1
2
3
4
5
6
80
20
80
50
20
80
22.7
22.7
2.27
2.27
2.27
2.27
ON
ON
ON
ON
ON
OFF
8
0
20
14
0
0
heat, and the use of the highest feasible dilution. The
application of photoirradiation increased the yield from
0% (entry 6) to 20%. Similarly, in the synthesis of (R)-6
from (R)-11 and 12, photoirradiation increased the yield
from 0% to 10% (for details, see the Supporting
Information). The cyclization using (R)-7 and 4,40-dihy-
droxyazobenzene was also examined, but we could not
obtain the 1:1 reaction product even when the azobenzene
was in the (Z)-form.
Next, we analyzed fundamental optical properties and
conformations of the synthesized dyads, especially (R)-3
and (R)-4. Figure 3a,b shows absorption spectra obtained
after photoirradiation. In both (R)-3 and (R)-4, judging
from the absorption at over 300 nm which is derived from
azobenzene,3 photoirradiation at 365 nm induced (E)f(Z)
isomerization, whereas photoirradiation at 436 nm led to
(Z)f(E) isomerization. Photoisomerization ratios after
irradiation at 365 nm were 0.86 and 0.78 for (R,Z)-3 and
(R,Z)-4, respectively, and those after irradiation at 436 nm
were 0.80 and 0.58 for (R,E)-3 and (R,E)-4, respectively.
We also examined thermal isomerization of these com-
pounds. In the case of (R)-3, the (Z)-form showed a typical
pattern of change into the (E)-form (Figure 3c). Intrigu-
ingly, however, (R,E)-4 thermally isomerized to (R,Z)-4
(Figure 3d).14 This is consistent with the fact that synthesis
of (R)-4required photoirradiation, as described above. In addi-
tion, thermal isomerizations of both (R)-3 and 4 were
a Conditions: a DMF solution of compound 10 was pre-photoirra-
diated for 1 h, except in the case of entry 6. Reaction time was 24 h.
Reaction mixtures were photoirradiated throughout the reaction period;
365 nm, 10 mW/cm2. Molar ratio of (R)-7/10/K2CO3 = 1:1:10.
b Isolated yield. No detectable starting materials remained at the end
of the reaction.
scale.12 Underthe conditions showninScheme 1, including
photoirradiation, the reaction afforded (R)-4, although in
low yield (8% yield, entry 1). A high dilution condition
promoted the intramolecular second etherification (20%
yield, entry 3). The side products were complex mixtures
including cyclic and acyclic macromolecules. The use of
lower temperatures gave a larger proportion of polymer-
ized macromolecules, even though the (Z)f(E) thermal
isomerization of 10 is suppressed (entries 2, 4, and 5). We
cannot yet explain this phenomenon. However, one possi-
bility is that the reaction is one of the CurtinꢀHammet
controlled reactions,13 being linked to the (Z)ꢀ(E) equili-
brium and ΔΔGq. This would be consistent with the fact
thatsynthesisof (R)-4 requires photoirradiation at 365 nm,
(12) (a) Lednev, I. K.; Ye, T.-Q.; Hester, R. E.; Moore, J. N. J. Phys.
Chem. 1996, 100, 13338. (b) Fujino, T.; Tahara, T. J. Phys. Chem. A
2000, 104, 4203. (c) Diau, E. W.-G. J. Phys. Chem. A 2004, 108, 950.
(d) Chang, C.-W.; Lu, Y.-C.; Wang, T.-T.; Diau, E. W.-G. J. Am. Chem.
Soc. 2004, 126, 10109.
(13) Seeman, J. I. Chem. Rev. 1983, 83, 83–134.
Org. Lett., Vol. XX, No. XX, XXXX
C

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with heterogeneous isomerization depending on the com-
pounds. (R)-5 showed the same tendency as (R)-3. Mean-
while, in the case of (R,Z)-6, neither photo- nor thermal
isomerization occurred, and only degradation was ob-
served. Unisomerizable (Z)-azobenzenes are limited largely
to 5,6-diazaphenanthrene structures,15 and (R,Z)-6 is struc-
turally quite different from them. Therefore, 4 as well as 6
should be useful in studies on (Z)-azobenzene structure.
To compare the conformations and stability, optimized
structures of (R)-3 and (R)-4 were calculated (Figure S8,
Supporting Information).16 (R,E)-3 was significantly more
stable than (R,Z)-3, while in contrast, (R,Z)-4 was more
stable than (R,E)-4, in accordance with the experimental
results. The (E)-azobenzene moiety of (R,E)-4 was strained
in the direction of the linkers owing to the limited move-
ment of the binaphthyl. In fact, the dihedral angles of
CꢀNꢀNꢀC were 176° for (R,E)-3 and 157° for (R,E)-4,
whereas 180° is expected for the unstrained structure.
The properties of these dyads indicate that they would
make excellent chiroptical photoswitches; for example,
ΔΔε of CD at 227 nm of (R)-4 was 165 and Δ[R]D of
(R)-3 was 1226 (Table S1, Supporting Information).
In conclusion, we have developed a method for synthe-
sizing highly strained cyclic structures by combining a
photochromic reaction with the synthetic reaction. Thus,
we were able to synthesize azobenzeneꢀbinaphthyl dyads
with extremely short linkers by means of photoassisted
cyclization, making use of the photoinduced (E)f(Z)
isomerization of the azobenzene moiety, which allows
the cyclization reaction to proceed. This novel syn-
thetic method should provide convenient access to a
variety of strained functionalized molecules that have
previously been inaccessible or very difficult to synthe-
size. Studies on optimization and work to establish the
range of application of this photoassisted synthesis are
continuing.
Figure 3. (a,b) Absorption spectra of (R)-3 and (R)-4 after
irradiation at 365 nm (blue, rich in (Z)-form) and after irradia-
tion at 436 nm (red, rich in (E)-form) at 20 °C. Inset: expanded
version of part of the spectra. (c) Time-dependent change of
absorption spectra of (R)-3 after irradiation at 365 nm at 65 °C.
(d) Time-dependent change of absorption spectra of (R)-4 after
irradiation at 436 nm at 35 °C. Common conditions: 1,4-
dioxane, 1.0 ꢁ 10ꢀ5 M, light path length = 10 mm, irradiation
at 10 mW/cm2 for 100 s).
Acknowledgment. We thank Dr. D. Hashizume and
members of the molecular characterization team at
RIKEN for single-crystal X-ray analysis and the spectral
measurements. The calculations were performed using the
RIKEN Integrated Cluster of Clusters (RICC).
Supporting Information Available. Synthesis, spectra,
computational details, and thermodynamic parameters
of novel compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
first-order reactions, and the entropies of activation, ΔSq,
were ꢀ19.7 cal/mol K for (R)-3 and þ5.2 cal/mol K for
3
3
(R)-4. The apparent ΔSq difference would be consistent
(16) The (Z)-forms have helical chirality, (P) or (M); the calculated
energy values suggested that (R,Z,M)-3 and (R,Z,P)-4 were preferred
over the opposite helical isomers (Table S3, Supporting Information).
Judging the helicity of (Z)-azobenzenes from CD spectra is difficult
because of the influence of induced CD related to the binaphthyl moiety
and residual (Z)-form. (a) Kobayashi, N.; Higashi, R.; Titeca, B. C.;
Lamote, F.; Ceulemans, A. J. Am. Chem. Soc. 1999, 121, 12018–12028.
(b) Ma, X.; Wang, Q.; Qu, D.; Xu, Y.; Ji, F.; Tian, H. Adv. Funct. Mater.
2007, 17, 829–837. (c) Helical (Z)-azobenzenes were reported; see: ref 5d
and: Haberhauer, G.; Kallweit, C. Angew. Chem., Int. Ed. 2010, 49,
2418–2421.
(14) According to time-dependent 1H NMR spectra, the (E)f(Z)
thermal isomerization of (R)-4 was completed within 96 h at 20 °C, and
the stationary state included no (E)-form (Figure S10, Supporting
Information). Stationary states of (R)-3 and (R)-5 were the (E)-form
and that of (R)-6 was the (Z)-form; see the NMR spectra in the
Supporting Information.
(15) Recent examples: (a) Caronna, T.; Fontana, F.; Mele, A.; Sora,
I. N.; Panzeri, W.; Vigano, L. Synthesis 2008, 3, 413–416. (b) Yang, Y.;
Seidlits, S. K.; Adams, M. M.; Lynch, V. M.; Schmidt, C. E.; Anslyn,
E. V.; Shear, J. B. J. Am. Chem. Soc. 2010, 132, 13114–13116.
(c) Vinogradova, O. V.; Balova, I. A.; Popik, V. V. J. Org. Chem.
2011, 76, 6937–6941.
The authors declare no competing financial interest.
D
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