Tunable chiral reaction media based on two-component liquid crystals: Regio-, diastereo-, and enantiocontrolled photodimerization of anthracenecarboxylic acids

Article abstract of DOI:10.1021/ja105221u

Three kinds of enantiopure amphiphilic amino alcohols (1a-c) were newly synthesized, of which the stereochemistry of the stereogenic carbons adjacent to the amino (C2) and hydroxy (C1) groups was systematically varied. By using these amino alcohols and fo

Full text of DOI:10.1021/ja105221u

Published on Web 11/22/2010
Tunable Chiral Reaction Media Based on Two-Component
Liquid Crystals: Regio-, Diastereo-, and Enantiocontrolled
Photodimerization of Anthracenecarboxylic Acids
Yasuhiro Ishida,*,†,§ Ammathnadu S. Achalkumar,† Shun-ya Kato,‡ Yukiko Kai,‡
Aya Misawa,‡ Yumi Hayashi,‡ Kuniyo Yamada,† Yuki Matsuoka,§ Motoo Shiro,⊥ and
Kazuhiko Saigo‡,¶
RIKEN, AdVanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Department of
Chemistry and Biotechnology, Graduate School of Engineering, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-8656, Japan, PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho,
Kawaguchi, Saitama 332-0012, Japan, Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima,
Tokyo 196-8666, Japan, and School of EnVironmental Science and Engineering, Kochi UniVersity of
Technology, Miyanokuchi, Tosayamada-cho, Kami, Kochi 782-8502, Japan
Received June 17, 2010; E-mail: y-ishida@riken.jp
Abstract: Three kinds of enantiopure amphiphilic amino alcohols (1a-c) were newly synthesized, of which
the stereochemistry of the stereogenic carbons adjacent to the amino (C2) and hydroxy (C1) groups was
systematically varied. By using these amino alcohols and four photoreactive carboxylic acids, 12 kinds of
salts were prepared. The structure and thermal behavior of the salts were thoroughly investigated by various
techniques, which revealed that the stereochemistry of the amino alcohol unit has significant effects on the
properties of the salts; the salts of 1a with (1R,2S)-configuration did not exhibit any liquid crystal (LC)
phase but showed high crystallinity, whereas 1b and 1c with (1S,2S)- and (1S)-configurations, respectively,
generally afforded stable LC salts with smectic structure(s). Within the matrix of these amphiphilic salts,
the in situ photodimerizations of 2-anthracenecarboxylic acid (2c) and 1-anthracenecarboxylic acid (2d)
were conducted by the irradiation with UV/vis light (500 W, a high-pressure mercury arc lamp, >380 nm).
Concerning reactivity and regio-/diastereo-/enantioselectivities, the LC phases were found to be superior
to isotropic and crystalline phases. For the two substrates 2c and 2d, every LC phase promoted the
photodimerization with unprecedentedly high head-to-head selectivity. Particularly in the case of 2c,
diastereoselecitivity (synHH vs antiHH) could be rationally controlled by the choice of the amino alcohol unit
and mesophase (synHH:antiHH ) 61:37 to 26:72). Moreover, one of the LC phases exhibited by 1b·2c
afforded the antiHH-dimer of 2c with excellent enantioselectivity (up to 86% ee). On the basis of the hypothesis
that the present photochemical outcome arises from the preorientation of the substrates, a preliminary
structural model of these LCs was proposed.
1. Introduction
products. Despite such significance, however, the idea of
medium-controlled reactions has an inherent limitation, a “trade-
off” between selectivity and reactivity. As represented by
crystalline reaction systems, extremely ordered media occasion-
ally realize almost perfect reaction control, but in most cases,
severe restriction on molecular motions fatally reduces the
probability of reactions.1,2 Contrary to crystals, supramolecular
aggregates such as micelles,6 physical gels,7 bilayers,8 etc. are
There has been increasing interest in controlling the course
of chemical reactions by using ordered media.1-6 To date, a
number of ordered reaction media have been explored, such as
crystals,1 coordination polymers,2 zeolites,3 clays,4 discrete hosts
in homogeneous solutions,5 etc. These constrained reaction
environments have attracted continuous attention as one of the
simplest models of biological reaction systems. In addition,
medium-controlled reactions might establish a practically useful
methodology, which play a significant role complementary to
traditional organic synthesis in homogeneous media. Particularly,
precise stereocontrol of photochemical reactions has remained
as an unexplored issue in the framework of homogeneous
systems. For this purpose, ordered reaction media would offer
great promise in preorganizing substrates to yield well-controlled
(1) (a) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025–1074. (b) Braga,
D.; Grepioni, F. Angew. Chem., Int. Ed. 2004, 43, 4002–4011. (c)
Matsumoto, A. Top. Curr. Chem. 2005, 254, 263–305.
(2) (a) Kitagawa, S.; Kitaura, R.; Noro, S. Angew. Chem., Int. Ed. 2004,
43, 2334–2375. (b) Georgiev, I. G.; MacGillivray, L. R. Chem. Soc.
ReV. 2007, 36, 1239–1248.
(3) (a) Joy, A.; Ramamurthy, V. Chem.sEur. J. 2000, 6, 1287–1293. (b)
Tung, C.-H.; Wu, L.-Z.; Zhang, L.-P.; Chen, B. Acc. Chem. Res. 2003,
36, 39–47. (c) MacGillivray, L. R.; Papaefstathiou, G. S.; Friscic, T.;
Varshney, D. B.; Hamilton, T. D. Top. Curr. Chem. 2004, 248, 297–
310. (d) Kaupp, G. Top. Curr. Chem. 2005, 254, 95–183.
(4) (a) Varma, R. S. Tetrahedron 2002, 58, 1235–1255. (b) Georgakilas,
V.; Gournis, D.; Bourlinos, A. B.; Karakassides, M. A.; Petridis, D.
Chem.sEur. J. 2003, 9, 3904–3908.
† RIKEN, Advanced Science Institute.
‡ The University of Tokyo.
§ PRESTO, Japan Science and Technology Agency.
⊥ Rigaku Corporation.
¶ Kochi University of Technology.
9
10.1021/ja105221u  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 17435–17446 17435

A R T I C L E S
Ishida et al.
Scheme 1. Schematic Representation of the Photoreaction within
Liquid Crystalline Media
generally unable to realize ideal selectivity, although their
relatively loose structures are promising to promote in situ
reactions.
To solve the problem as described above, several groups have
employed liquid crystals (LCs) as media to control chemical
reactions.6a,9 Among supramolecular aggregates, thermotropic
LCs are regarded as one of the most structurally ordered classes,
which should be advantageous for the control of organic
transformations. Particularly, cholesteric LCs have been exten-
sively studied as media for asymmetric reactions in the 1970’s.10
Nevertheless, most of the previous attempts have resulted in
unsatisfactory selectivity, especially in terms of enantioselec-
tivity, probably due to the following reasons: (1) the environ-
ment of photoreactive substrates is not necessarily “monoclonal”
in these LC media, because the substrates are just mixed with
chiral mesogenic components to weakly interact with them, and
(2) in the attempts of enantiocontrol by cholesteric LC media,
their helical structures (from 100 nm to µm pitch) seems to be
too huge to bring a significant effect on events at a molecular
level.11
On the other hand, our recent studies revealed that the salts
of amphiphilic carboxylic acids with amines/amino alcohols
have a high propensity to exist as thermotropic LCs in wide
thermal ranges.12 The promising results led us to expect that
the opposite combinations, i.e. the salts of amphiphilic amino
alcohols with carboxylic acids would have a similar tendency.
If a photoreactive species is used as the carboxylic acid unit,
its transformation is expected to readily proceed within the LC
matrix, just by irradiating the two-component LC. Compared
with traditional LC media, such a system seems to have obvious
advantages in the following aspects; (1) the relative orientation
of the substrate (carboxylic acid) molecules is considered to be
well-defined because the substrate itself is the component of
the LC, (2) every photoreactive molecule intimately interacts
with a chiral source amino alcohol by hydrogen-bonding
interaction and salt-pair formation, and (3) owing to the
availability of various photoreactive carboxylic acids, as well
as the noncovalency of interaction between the two components,
such amino alcohol units would offer special environments to
various substrates/reactions.
For such a conceptually new approach, we have recently
reported preliminary results on the application of a two-
component LC as a reaction medium (Scheme 1), in which the
photodimerization of 2-anthracenecarboxylic acids proceeded
in satisfactory yield with unprecedented high enantioselectiv-
ity.13 In order to expand the scope of this methodology, variation
of the amphiphilic amino alcohol unit, having been limited to
only one example up to now, should be increased. For the initial
stage of our ongoing study, we focused on the variation in
stereochemistry of the amino alcohol unit. Here we report, in
detail, the design, synthesis, and reaction-controlling ability of
three amphiphilic amino alcohols (1a-c), the sizes and shapes
of which are similar, but the stereochemistries of the stereogenic
carbons adjacent to the amino (C2) and hydroxy (C1) groups
are systematically varied (the stereochemistry of C1/C2: 1a R/S,
1b S/S, and 1c S/achiral).
(5) (a) Lehn, J.-M. Science 1985, 227, 849–856. (b) Conn, M. M.; Rebek,
J. Chem. ReV. 1997, 97, 1647–1668. (c) Rebek, J. Angew. Chem., Int.
Ed. 2005, 44, 2068–2078. (d) Yoshizawa, M.; Fujita, M. Pure Appl.
Chem. 2005, 77, 1107–1112.
(6) (a) Muthuramu, K.; Ramamurthy, V. J. Org. Chem. 1982, 47, 3976–
3979. (b) Wolff, T.; Mu¨ller, N.; von Bu¨nau, G. J. Photochem. 1983,
22, 61–70. (c) Lv, F.-F.; Chen, B.; Wu, L.-Z.; Zhang, L.-P.; Tung,
C.-H. Org. Lett. 2008, 10, 3473–3476.
(7) (a) Lin, Y. C.; Weiss, R. G. Macromolecules 1987, 20, 414–417. (b)
Bhat, S.; Maitra, U. Molecules 2007, 12, 2181–2189. (c) Dawn, A.;
Fijita, N.; Haraguchi, S.; Sato, H.; Sada, K.; Shinkai, S. Chem.
Commun. 2009, 2100–2102.
(8) (a) Imae, T.; Tsubota, T.; Okamura, H.; Mori, O.; Takagi, K.; Itoh,
M.; Sawaki, Y. J. Phys. Chem. 1995, 99, 6046–6053. (b) Li, H. R.;
Wu, L. Z.; Tung, C. H. J. Am. Chem. Soc. 2000, 122, 2446–2451.
(9) For examples of organic transformations in liquid crystalline reaction
media, see the following reviews and references cited therein: (a)
Weiss, R. G. In Photochemistry in Organized and Constrained Media;
Ramamurthy, V., Ed.; VCH: New York, 1991, Chapter 14. (b) Leigh,
W. J.; Workentin, M. S. In Liquid Crystals as SolVents for Spectro-
scopic, Chemical Reaction, and Gas Chromatographic Applications;
Handbook of Liquid Crystals; Demun, D., Ed. Wiley-VCH: Weinheim,
1998; pp 839-895.
(10) (a) Saeva, F. D.; Sharpe, P. E.; Oline, G. R. J. Am. Chem. Soc. 1975,
97, 204–205. (b) Verbit, L.; Halbert, T. R.; Patterson, R. B. J. Org.
Chem. 1975, 40, 1649–1650. (c) Pirkle, W. H.; Rinaldi, P. L. J. Am.
Chem. Soc. 1977, 99, 3510–3511. (d) Eskenazi, C.; Nicoud, J. F.;
Kagan, H. B. J. Org. Chem. 1979, 44, 995–999.
(11) For selected examples of recent attempts to apply LC media to the
fabrication of meso-scaled supramoelcualr architectures, see: (a) Akagi,
K.; Piao, G.; Kaneko, S.; Sakamaki, K.; Shirakawa, H.; Kyotani, M.
Science 1998, 282, 1683–1686. (b) Kitamura, T.; Nakaso, S.; Mi-
zoshita, N.; Tochigi, Y.; Shimomura, T.; Moriyama, M.; Ito, K.; Kato,
T. J. Am. Chem. Soc. 2005, 127, 14769–14775. (c) Dobbs, W.; Suisse,
J.-M.; Douce, L.; Welter, R. Angew. Chem., Int. Ed. 2006, 45, 4179–
4182.
2. Results and Discussion
2.1. Design of the Amphiphilic Amino Alcohols 1a-c. We
have recently found that the salt of (-)-norephedrine with an
achiral amphiphilic carboxylic acid exhibited a very stable LC
phase.12 On the basis of the result, in the present study we at
first designed the chiral amphiphilic amino alcohol 1a with an
(12) (a) Ishida, Y.; Amano, S.; Saigo, K. Chem. Commun. 2003, 2338–
2339. (b) Ishida, Y.; Amano, S.; Iwahashi, N.; Saigo, K. J. Am. Chem.
Soc. 2006, 128, 13068–13069. (c) Amano, S.; Ishida, Y. K.; Saigo,
K. Chem.sEur. J. 2007, 13, 5186–5196.
(13) Ishida, Y.; Kai, Y.; Kato, S.; Misawa, A.; Amano, S.; Matsuoka, Y.;
Saigo, K. Angew. Chem., Int. Ed. 2008, 47, 8241–8245.
9
17436 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Tunable Chiral Reaction Media
A R T I C L E S
Scheme 2. Stereocontrolled Synthesis of the Amphiphilic Amino Alcohols 1a-c
absolute configuration of (1R,2S), which is similar to that of
(-)-norephedrine. On the other hand, it is well-known that
diastereomers often show chirality-induction abilities quite
different from each other. Therefore, the epimeric amino alcohol
of 1a, the amino alcohol 1b with an absolute configuration of
(1S,2S), was designed. Moreover, in order to clarify the role
of chirality at the C1 and C2 positions in 1a/1b, the synthesis
of a simpler analogue, 1c, was also tried. Since 1c lacks a methyl
group at the C2 position, it has only one stereogenic carbon at
the C1 position.
with excellent diastereoselectivity in an anti-Cram manner to
afford the (1R,2S)-isomer ((1R,2S)-7) in a stereopure form.17
By the simple hydrogenolysis of the N-protecting group in
(1R,2S)-7, one of the target molecules (1a) was successfully
obtained (Scheme 2a, right). Its epimer, 1b, was also synthesized
from the same precursor (1R,2S)-7 via the Mitsunobu inversion
at the C1 position forming the corresponding ester (1S,2S)-8,18
followed by the successive cleavages of the O- and N-protecting
groups (Scheme 2a, left).
2.2. Stereocontrolled Synthesis of the Amphiphilic Amino
Alcohols 1a-c. The two amino alcohols bearing a C2-methyl
group, 1a and 1b, were synthesized as follows: An aryllithium,
prepared by treating the bromobenzene derivative 514 with
butyllithium, was coupled with the alanine derivative (S)-415
to form (S)-6,16 which was then reduced by applying the
Meerwein-Ponndorf-Verley method; the reduction proceeded
(14) Wu, J.; Watson, M. D.; Zhang, L.; Wang, Z.; Mu¨llen, K. J. Am. Chem.
Soc. 2004, 126, 177–186.
(15) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Tetrahedron Lett.
1987, 28, 6331–6334.
(16) Davies, D. T.; O’hanlon, P. J. Synth. Commun. 1988, 18, 2273–2280.
(17) Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D., III J. Org.
Chem. 2006, 71, 840–843.
(18) Mitsunobu, O. Synthesis 1981, 1–28.
9
J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010 17437

A R T I C L E S
Ishida et al.
Figure 1. Thermotropic behavior of the salts of amphiphilic amino alcohols (1a-c) with photoreactive carboxylic acids (2a-d) in a cooling process. Iso
) isotropic phase, SmA ) smectic A phase, SmX ) smectic phase other than SmA, Meso ) unidentified mesophase, Cry ) crystalline phase.
One of the most beneficial features of the present synthetic
route is potential applicability to the synthesis of other am-
phiphilic amino alcohols; not only the alanine derivative (S)-4,
various enantiopure amino-acid derivatives are available as the
starting material, which would provide stereoregulated, am-
phiphilic amino alcohols bearing the corresponding substituent
at the C2 position.
(2c), and 1-anthracenecarboxylic acid (2d). Typically, equimolar
amounts of the amino alcohol and the carboxylic acid were
dissolved in 2-propanol, and the solvent was removed to dryness
to give the corresponding salt as a solid or waxy oil. For every
combination of the acids and bases employed here, the formation
of ammonium-carboxylate salt pair was unambiguously con-
firmed by IR spectroscopy; an absorption attributable to the
CdO vibration was observed at 1620-1650 cm-1, which was
notably shifted from the corresponding absorption of usual free
carboxylic acids (1680-1695 cm-1).
In the syntheses of 1a and 1b, one of the two stereogenic
carbons (C2) was originated from the starting amino acid, while
the stereochemistry of the other (C1) was controlled by the
neighboring effect of the stereoregulated C2. Contrary to them,
1c has only one stereogenic carbon at the C1 position, meaning
that the same strategy is not applicable to the synthesis of 1c.
Thus, a new synthetic method was developed, which involves
the enantioseparation (Scheme 2b). The aldehyde 919 was
converted into a racemic 2-amino alcohol (rac-11) via a well-
established series of reactions, the cyanohydrin formation
followed by the hydride reduction of the nitrile group.20
Fortunately, the enantiomers of 11 could be easily separated
by the diastereomer salt method by using mandelic acid as the
most suitable resolving agent. Owing to the convenience and
scalability of this method, both enantiomers of 11 were obtained
in a gram scale. The absolute configuration of 11 was deduced
from the configuration of (S)-mandelic acid already known; we
succeeded in obtaining the X-ray crystal structure of the salt of
(R)-11 with (S)-mandelic acid. The enantiopure (S)-11 thus
obtained was then derived into the target amphiphilic 2-amino
alcohol 1c through the protection of the hydroxy group, the
hydrogenolysis of the benzyl ether moieties, the protection of
the amino group, the coupling of the phenolic hydroxy groups
with dodecyl bromide, and the deprotection of the hydroxy and
amino groups.
The thermotropic behavior of these amiphiphilic salts was
investigated by using a combination of differential scanning
calorimetry (DSC), polarized optical microscopy (POM), and
X-ray diffraction analysis (XRD). Through a cooling process
from an isotropic melt, transitions into crystalline and/or LC
phase(s) were clearly monitored by POM, where characteristic
textures were generated. Transition temperatures and their
enthalpy changes were obtained by DSC operated at a scanning
rate of 5 °C min-1
.
Upon repeating heating and cooling cycles, essentially
identical DSC traces were observed in good reproducibility,
except for the first heating. These observations strongly suggest
that undesired thermal events, such as the decomposition of the
components and the cleavage of the salt pair, did not take place
within the thermal range of the DSC measurement (-50 to 160
1
°C), which was confirmed by H NMR and IR spectroscopy.
On a heating process, some salts showed complicated thermo-
tropic behaviors involving crystal-to-crystal phase transition(s),
of which the DSC peaks were overlapped with each other.
Judging from the DSC traces of the first/second heating and
cooling processes, some mesophases appeared in the cooling
processes were monotropic (Figure 1, SmA[1b · 2a],
SmX[1b · 2b], SmA[1b · 2c], Meso[1b · 2c], Smx[1c · 2c], and
SmA[1c · 2d]). Although such metastable phases may turn into
other phases, which is not favorable as reaction media, their
lifetime was confirmed to be long enough (1-20 h) for the
2.3. Thermotropic Behavior of the Salts of Amphiphilic
Amino Alcohols (1a-c) with Photo-Reactive Carboxylic
Acids (2a-d). With the three types of amphiphilic amino
alcohols (1a-c) in hand, we next prepared and characterized
their salts with four kinds of photoreactive carboxylic acids,
sorbic acid (2a), cinnamic acid (2b), 2-anthracenecarboxylic acid
(19) Zaveri, N. T. Org. Lett. 2001, 3, 843–846.
(20) Kirk, K. L.; Cantacuzene, D.; Collins, B.; Chen, G. T.; Nimit, Y.;
Creveling, C. R. J. Med. Chem. 1982, 25, 680–6844.
9
17438 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Tunable Chiral Reaction Media
A R T I C L E S
Figure 2. Polarized optical microscopy images (top), differential scanning calorimetry traces (middle), and X-ray diffraction profiles (bottom) of the amphiphilic
salts (a) 1a·2c, (b) 1b·2c, and (c) 1c·2c.
present photoreactions. In addition, these LC phases appeared
in good reproducibility when the system was cooled slower
(-2.5 °C min-1). Therefore, we focused only on a cooling
process from an isotropic melt to simplify the comparison
of the thermotropic behavior of the salts. The lattice patterns
of these phases were estimated by XRD measurements. The
phase transition behavior of the twelve salts is summarized
in Figure 1.
Contrary to our expectation based on the thermotropic
behavior of the salt of an amphiphilic carboxylic acid with (-)-
norephedrine,12 none of the salts derived from 1a, which has
an absolute configuration similar to that of (-)-norephedrine,
exhibited LC phase; a direct transition from an isotropic phase
to a crystalline phase was commonly observed. In sharp contrast,
1b and 1c showed high propensity to form LC salts with wide
thermal ranges; seven of the eight salts (1b·2a-c and 1c·2a-d)
exhibited one or two LC phase(s). Most of the mesophases
showed an XRD pattern characteristic to a smectic lattice with
a strong fundamental (001) reflection at ∼30 Å, accompanied
with a diffusive reflection around 4.5 Å (Figure 2, bottom). In
POM observation, some of these smectic LCs exhibited a focal
conical texture, strongly indicative of smectic A (SmA) phase
(Figure 2b and Figure 2c, top). Among the mesophases found
here, Meso[1b·2c] was an exception. Apparently, its XRD
pattern seems to be a smectic phase with higher order than SmA,
characterized with sharp reflections at 30 Å [(001)], 15 Å
[(002)], and 5 Å [most likely (100)], as well as a diffusive
reflection around 4.5 Å. However, the (001) reflection was
overlapped with an unknown broad reflection (Figure 2b,
bottom). Considering the hydrophobic-hydrophilic volume ratio
of these amphiphilic salts, these salts were expected to take a
bilayer-like structure, which might lead to the formation of
smectic or related structures. The observed d-spacings were
shorter than anticipated from extended molecular modeling, most
likely due to the partial interdigitation of the aliphatic tails
(Figure 3).21
As summarized in Figure 1, a subtle change in the structure
of the amino alcohol unit, regarding the substituent at and the
stereochemistry of the C2 position, brought a significant effect
(21) Such a difference between the observed and anticipated d-spacings
can be elucidated not only by the interdigitation of the alkyl chains
but also by the tilting of the bilayers. The latter case should lead to
the formation of a SmC structure. In POM observations, however, most
of the LC salts exhibited a typical focal conical texture often observed
for SmA phases, while the textures characteristic of smectic C phases,
such as broken focal conic and Schlieren textures, were not observed.
9
J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010 17439

A R T I C L E S
Ishida et al.
Figure 3. Schematic representation of the structures of (a) the amiphiphilic amino alcohol 1c, (b) the photoreactive carboxylic acids 2a-d, and (c) the
self-assembled bilayer.
on the thermotropic behavior of their salts, although the
substituent at this position contributes less than 2% of the total
molecular weight of an amphiphilic salt.22 This observation
might reveal the risk of our preconception that the self-
organization of amphiphilic molecules can be simply elucidated
on the basis of a hydrophilic-hydrophobic volume ratio. Among
these three amino alcohols, 1c had the strongest propensity to
form LC salts with a wide thermal window; all of the four salts
derived from 1c exhibited one or two kinds of LC phase(s).
Moreover, in the case of 1b, three of the four salts showed LC
phase(s), and their clearing temperatures were generally lower
than those of the corresponding salts composed of 1c. In sharp
contrast, all of the salts derived from 1a exhibited no LC phase;
a direct transition from an isotropic phase to a crystalline phase
was commonly observed.
To elucidate the effect of the state of the salts (isotropic, LC,
or crystalline) on an in situ reaction (efficiency and selectivity),
the salts of 1a, which showed exceptionally high crystallinity,
would provide some insights. At an appropriate temperature,
the salts of 1b and/or 1c exhibit LC phases, while the
corresponding salt of 1a exists as a crystal. Therefore, photo-
reactions can be conducted at the same temperature in these
crystalline and LC states, which would enable us to directly
compare the results of the photoreactions, free from the effect
of the reaction temperature.
the amphiphilic salt matrices. Our strategy is principally
applicable to the reactions of all carboxylic acids (2a-d), which
is undoubtedly the ultimate goal of our ongoing study. However,
at first we planned to carry out the photodimerization of
anthracene derivatives (2c, 2-anthracenecarboxylic acid; 2d,
1-anthracenecarboxylic acid), because its simplicity seemed to
be advantageous to clarify the effect of the stereochemistry of
the amino alcohol units. The photodimerization of anthracene
derivatives is a well-established, simple [4 + 4] cycloaddition,
which hardly involves complicated side reactions such as the
isomerization of the monomeric unit.23 In addition, it still
remains as a challenge to control the regio- and stereochemistries
of the photodimerization of laterally substituted anthracene
derivatives; the photodimerization of dissymmetric anthracene
derivatives like 2c and 2d principally gives rise to no less than
four configurational isomers (head-to-head/head-to-tail isomers
with syn/anti isomerism, denoted as synHH, antiHH, synHT, and
antiHT), two isomers of which consist of a pair of C2-
enantiomers, respectively ((R)/(S)-antiHH and (R)/(S)-synHT).
To date, the environment-directed photodimerization of
2-anthracenecarboxylic acid (2c) have been extensively studied,
by using various hosts including cyclodextrins, modified cy-
clodextrins,proteins,aminereceptors,andorganogelmatrices.24-26
Owing to a wealth of data having been reported on regio-/
diastereo-/enantiocontrols, the photodimerization of 2c has
become a ‘benchmark’ reaction to evaluate the ability of
2.4. General Aspects of the Photodimerization of
Anthracenecarboxylic Acids. In the next stage, we conducted
the photoinduced transformation of carboxylic acid units within
(23) For general aspects of the photodimerization of anthracenes, see: (a)
Bouas-Laurent, H.; Desvergne, J.-P.; Castellan, A.; Lapouyade, R.
Chem. Soc. ReV. 2000, 29, 43–55. (b) Bouas-Laurent, H.; Desvergne,
J.-P.; Castellan, A.; Lapouyade, R. Chem. Soc. ReV. 2001, 30, 248–
263.
(22) Percec, V.; Dulcey, A. E.; Peterca, M.; Adelman, P.; Samant, R.;
Balagurusamy, V. S. K.; Heiney, P. A. J. Am. Chem. Soc. 2007, 129,
5992–6002.
9
17440 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Tunable Chiral Reaction Media
A R T I C L E S
supramolecular systems to derive a controlled reaction. Nev-
ertheless, successful examples have been surprisingly limited,
especially in terms of enantiocontrol. In a recent noticeable
achievement, Inoue and co-workers have reported a highly
enantioselective photodimerization of 2c within hydrophobic
cavities of human serum albumin to afford the synHT- and antiHH
-
dimers with excellent enantiomeric excesses (up to 82 and 90%
ee, respectively). Unfortunately, the net overall yields of these
isomers were at an unsatisfactory level (5.9 and 1.0% net overall
yield, respectively) due to the problems in regio-/diastereose-
lectivities and conversion.24e More recently, the same research
group has succeeded in the highly regio-/diastereo-/enantiose-
lective formation of the synHT-dimer in excellent yield (up to
91% ee, >65% net overall yield); in this work, a derivative of
2c covalently modified with R-cyclodextrin was used as a
substrate, while γ-cyclodextrin was used as a host molecule.25c
On the other hand, the photodimerization of 2d has not been
extensively investigated thus far. However, the reaction should
be another attractive target, considering its simple reaction
course and complicated regio-/stereochemistries, are similar to
those of 2c.27
2.5. Photodimerization of 2-Anthracenecarboxylic Acid
(2c) in the Amphiphilic Salts. The in situ photodimerization of
2-anthracenecarboxylic acid (2c) was conducted by irradiating
the salt (1a·2c, 1b·2c, or 1c·2c) with UV/vis light (500 W, a
high-pressure mercury arc lamp, >380 nm) under argon
atmosphere. The photoirradiated sample was then treated with
an excess amount of trimethylsilyldiazomethane to esterify the
carboxyl groups in the system, and volatiles were removed under
reduced pressure. The resultant mixture was applied to 1H NMR
spectroscopy (CDCl3) to estimate the yield of the photodimer-
ization. From the mixture, the esterified photodimers were
isolated by preparative silica gel TLC, and the isomer distribu-
tion was evaluated by a two-stage normal-phase HPLC analysis
(Figure 4).28 Because the methylation proceeded quantitatively,
the yield and isomer distribution of the photodimer diesters 3c
should be essentially identical to those of the original photo-
dimers. The results are summarized in Table 1.
Figure 4. (a) Estimation of the isomer distribution by achiral HPLC. An
authentic mixture of the four isomers of 3c (top) and a mixture obtained
from photoirradiated 1b·2c (bottom). (b) Estimation of the enantiomeric
ratio of antiHH-3c by chiral HPLC. An authentic racemate of antiHH-3c (top)
and antiHH-3c obtained from photoirradiated 1b·2c (bottom).
2.5.1. Reactivity. In all phases of the amphiphilic salts, the
photodimerization underwent cleanly to afford a mixture of the
photodimers, where only the formation of 2-anthraquinonecar-
boxylic acid was a detectable side reaction (<1%). When the
photodimerization was conducted in the isotropic phases,
excellent yields were realized after 1-h irradiation, without
depending on the amino alcohol unit (entries 3, 11, and 16,
Iso[1a·2c], Iso[1b·2c], and Iso[1c·2c], 83-91% yield). As was
expected, the LC phases also showed acceptable to good
reactivity (entries 4-8, Meso[1b · 2c]; entries 9 and 10,
SmA[1b·2c]; entries 12 and 13, SmX[1c·2c]; entries 14 and 15,
SmA[1c·2c]). Although the reaction rate in the LC phases was
lower than that in the isotropic phases, all of the LC reaction
systems attained satisfactory yields after enough irradiation
(entries 5, 8, 9, 13 and 15, 58-85% yield). Among them, the
two LC phases of 1c·2c realized yields almost comparable to
those in the isotropic phases (entry 13, SmX[1c·2c], 85% yield;
entry 15, SmA[1c·2c], 81% yield). Contrary to 1c·2c, the
crystalline phase of 1a·2c (Cry[1a·2c]) afforded a mixture of
the photodimers in unsatisfactory yield, even after adequate
irradiation at higher temperatures (entries 1 and 2, Cry[1a·2c],
(24) For selected examples of the photodimerization of 2-anthracenecar-
boxylic acid, see: (a) Tamaki, T.; Kokubu, T.; Ichimura, K. Tetrahe-
dron 1987, 43, 1485–1494. (b) Ito, Y.; Olovsson, G. J. Chem. Soc.,
Perkin Trans. 1 1997, 127–133. (c) Nakamura, A.; Inoue, Y. J. Am.
Chem. Soc. 2003, 125, 966–972. (d) Ikeda, H.; Nihei, T.; Ueno, A. J.
Org. Chem. 2005, 70, 1237–1242. (e) Nishijima, M.; Wada, T.; Mori,
T.; Pace, T. C. S.; Bohne, C.; Inoue, Y. J. Am. Chem. Soc. 2007, 129,
3478–3479. (f) Reference 7c. (g) Reference 12. (h) Kawanami, Y.;
Pace, T. C. S.; Mizoguchi, J.; Yanagi, T.; Nishijima, M.; Mori, T.;
Wada, T.; Bohne, C.; Inoue, Y. J. Org. Chem. 2009, 74, 7908–7921.
(i) Ke, C.; Yang, C.; Mori, T.; Wada, T.; Liu, Y.; Inoue, Y. Angew.
Chem., Int. Ed. 2009, 48, 6675–6677.
(25) For the photodimerization of 2-anthracenecarboxylic acid esters/amides,
see: (a) de Schryver, F. C.; de Brackeleire, M.; Toppet, S.; van Schoor,
M. Tetrahedron Lett. 1973, 15, 1253–1256. (b) Hiraga, H.; Morozumi,
T.; Nakamura, H. Eur. J. Org. Chem. 2004, 4680–4687. (c) Yang,
C.; Mori, T.; Origane, Y.; Ko, Y. H.; Selvapalam, N.; Kim, K.; Inoue,
Y. J. Am. Chem. Soc. 2008, 130, 8574–8575. (d) Dawn, A.; Shiraki,
T.; Haraguchi, S.; Sato, H.; Sada, K.; Shinkai, S. Chem.sEur. J. 2010,
16, 3676–3689.
(28) As an established method to estimate the isomer distribution of the
photodimer of 2c, an HPLC analysis based on tandem reversed-phase
columns (Inertsil ODS-2 and Chiralcel OJ-R) has been widely used
(ref 24c). However, this method does not seem to be optimal for the
reaction systems containing hydrophobic components; for HPLC
injection, samples should be pre-treated to remove the hydrophobic
component, which has a risk of biasing the distribution of isomers. In
addition, due to the inherent hydrophobicity of the photodimer of 2c,
retention times of the isomers were relatively long, which is
problematic for the accurate estimation of the peak area. Therefore,
we developed an alternative method, based on the esterification of
carboxyl groups in the system, followed by two-stage normal-phase
HPLC (see Supporting Information).
(26) For the photodimerization of anthracenes in liquid crystals, see: (a)
Me´ry, S.; Haristoy, D.; Nicoud, J.-F.; Guillon, D.; Monobe, H.;
Shimizu, Y. J. Mater. Chem. 2003, 13, 1622–1630. (b) Takaguchi,
Y.; Tajima, T.; Yanagimoto, Y.; Tsuboi, S.; Ohta, K.; Motoyosiya,
J.; Aoyama, H. Org. Lett. 2003, 5, 1677–1679.
(27) For the photodimerization of 1-anthracenecarboxylic acid and its esters/
amides, see: (a) Reference 24a. (b) Ueno, A.; Moriwaki, F.; Iwama,
Y.; Suzuki, I.; Osa, T.; Ohta, T.; Nozoe, S. J. Am. Chem. Soc. 1991,
113, 7034–7036. (c) Becker, H.-D.; Becker, H.-C.; Langer, V. J.
Photochem. Photobiol. A 1996, 97, 25–32. (d) Reference 24b.
9
J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010 17441

A R T I C L E S
Ishida et al.
Table 1. Photodimerization of 2-Anthracenecarboxylic Acid (2c)a
product ratio (%)e
antiHH synHT
entry
medium
phase
temp. (°C)
time (h)
yield (%)d
synHH
antiHT
ee (%)f antiHH
1
2
3
4
5
6
7
8
1a
Cry
Cry
Iso
40
80
160
35
35
45
45
45
80
80
110
40
40
105
105
160
25
15
15
1
3
15
1
3
15
1
3
1
3
15
1
3
1
10
23
89
23
58
24
48
68
72
66
83
42
85
64
81
91
88
96
57
52
50
26
27
27
28
34
46
48
52
56
56
61
61
56
7
41
44
36
72
71
71
70
64
52
49
45
42
43
37
37
41
14
7
1
2
4
1
1
1
1
1
1
2
2
1
1
1
1
2
36
22
1
2
10
1
1
1
1
1
1
1
1
1
1
1
1
1
43
32
-15
-16
-14
+78
+74
+86
+81
+67
+45
+26
+18
+31
+32
+14
+16
+13
n.d.
1b
Meso
Meso
Meso
Meso
Meso
SmA
SmA
Iso
SmX
SmX
SmA
SmA
Iso
9
10
11
12
13
14
15
1c
16
b
H2O
CH2Cl2
Sol
Sol
1
2
c
25
21
n.d.
a Irradiated at λ ) >380 nm under argon. b Irradiated at λ ) >320 nm under argon in a phosphate buffer solution (pH 7.0). See ref 24e. c Irradiated at
λ ) >320 nm under argon in dichloromethane. See ref 24h. d Determined by 1H NMR. e Isomer distribution of 3c estimated by achiral HPLC.
f Enantiomeric excess of antiHH-3c estimated by chiral HPLC. The signs + and - represent that the major product was the first- and second-eluted
enantiomer in the chiral HPLC analysis, respectively.
10 and 23% yield). Taking account of the reaction temperatures
employed here, such a large difference in reaction efficiency
between the LC and crystalline phases is not attributable to the
difference in reaction temperature, but to the difference in
molecular mobility.
of the molecular alignment even after the transition from a
crystalline/LC phase to an isotropic phase.29
2.5.3. syn/anti Selectivity. As described above, main products
in the present reaction systems were the synHH- and antiHH
-
dimers, while the synHT- and antiHT-dimers were formed in
negligible yields. Therefore, the discussion in this section
focuses on the effect of the reaction systems on synHH/antiHH
ratios.
2.5.2. HH/HT Selectivity. Regardless of the choice of the
amino alcohol unit or phase, almost all of the present reaction
systems showed surprisingly high HH/HT selectivities (HH:
HT ) 97:3-98:2). The only exception was the isotropic phase
of 1a·2c (entry 3, Iso[1a·2c], HH:HT ) 86:14); even in this
case, the HH/HT selectivity was still superior to those of most
of conventional supramolecular reaction systems designed for
the control of this reaction. As far as we are aware of, the HH/
HT ratios achieved here are at the highest level in the
photodimerization of 2c. In the absence of environmental
constraint, the photodimerization of 2c generally gives the HT-
dimers as main products, because of the steric and/or electro-
static repulsion between the carboxylate moieties (Table 1, refs.).
Therefore, the present exclusive HH-dimer formation is un-
doubtedly attributable to capability of the reaction media, which
overcame the intrinsic reaction course. In the cases of the
crystalline and LC phases, such a strong preference to HH-dimer
formation is reasonably elucidated, assuming that (1) the
matrices take a bilayer-like structure, and that (2) an intralayer
dimerization is a much favorable process than an inter-layer
dimerization (see Figure 3c). Noteworthy, all of the isotropic
phases also afforded the HH-dimers in unexpectedly good
selectivities (entries 3, 11, and 16, Iso[1a·2c], Iso[1b·2c], and
Iso[1c·2c], HH:HT ) 86:14-97:3), which is in contrary to a
generally conceived notion that molecules take random arrange-
ment in an isotropic phase. Because the present salts are regarded
as ionic LC materials, strong interactions are likely to work
between the components, which would lead to partial retention
As summarized in Table 1, the synHH/antiHH ratio notably
varied, depending on the amino alcohol unit as well as the phase.
For most of the present reaction systems, slight synHH-selectivity
(synHH:antiHH ) 52:45-56:41) was observed, including all of
the isotropic phases (entry 3, Iso[1a·2c]; entry 11, Iso[1b·2c];
entry 16, Iso[1c·2c]), the LC phase (entries 12 and 13,
SmX[1c·2c]), and the crystalline phase (entries 1 and 2,
Cry[1a · 2c]). In contrast, the following three LC phases
(Meso[1b·2c], SmA[1b·2c], and SmA[1c·2c]) interestingly
showed selectivities distinguishable from the others. Among
them, SmA[1c·2c] showed prominent synHH-selectivity (entries
14 and 15, SmA[1c·2c], synHH:antiHH ) 61:37). On the other
hand, the two LC phases of 1b·2c showed the opposite
selectivity, i.e. the preferential formation of the antiHH-dimer
was observed (entries 4-8, Meso[1b·2c], 28:70-26:72; entries
9 and 10, SmA[1b·2c], 48:49-46:52). Noteworthy, the synHH
/
antiHH ratio of the photodimerization product could be rationally
controlled in the present reaction system, by choosing an
(29) For selected examples of multicomponent ionic liquid crystals, see:
(a) Yoshio, M.; Mukai, T.; Ohno, H.; Kato, T. J. Am. Chem. Soc.
2004, 126, 994–995. (b) Cook, A. G.; Baumeister, U.; Tschierske, C.
J. Mater. Chem. 2005, 15, 1708–1721. (c) Kouwer, P. H. J.; Swager,
T. M. J. Am. Chem. Soc. 2007, 129, 14042–14052. (d) Kishikawa,
K.; Hirai, A.; Kohmoto, S. Chem. Mater. 2008, 20, 1931–1935. (e)
Olivier, J.-H.; Camerel, F.; Barbera´, J.; Retailleau, P.; Ziessel, R.
Chem.sEur. J. 2009, 15, 8163–8174.
9
17442 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Tunable Chiral Reaction Media
A R T I C L E S
appropriate amino alcohol unit and phase. Although a number
of reaction systems have been reported to control the photo-
dimerization of 2c, a detailed study on the control of a syn/anti
ratio has been very limited, as far as we know.
2.5.4. Enantioselectivity. Among the major products provided
in the present reaction systems, the antiHH-dimer has a C2
symmetric chirality, whereas the synHH-dimer is achiral. Quite
interestingly, one of the two LC phases of 1b·2c (Meso[1b·2c])
afforded the antiHH-dimer with unexpectedly high enantiose-
lectivity (Table 1, entries 4-8, Meso[1b·2c], +67 to +86%
ee). Even in the other LC phase of 1b·2c at a higher thermal
region (SmA[1b·2c]), the enantiocontrol was also at an ap-
preciable level, although the control was inferior to that of
Meso[1b·2c] (entries 6 and 7, SmA[1b·2c], +26 and +48%
ee). As far as we know, the enantiocontrol achieved in
Meso[1b·2c] is the second highest in the asymmetric photo-
dimerizations of 2c having been reported to date.24e The present
outstanding selectivity was not a simple chirality transfer within
the discrete salt pair, but was a result driven by the framework
of the chiral supramolecular architecture, because the isotropic
phase attained only insufficient selectivity (entry 11, Iso[1b·2c],
+18% ee). In the case of 1c·2c, the LC phase at a lower thermal
region (SmX[1c·2c]) showed relatively good enantioselectivity
(entries 12 and 13, SmX[1c·2c], ∼30% ee), while the other LC
phase (SmA[1c·2c]) afforded the antiHH-dimer with moderate
enantioselectivity (entries 14 and 15, SmA[1c·2c], ∼+15% ee),
comparable to that of the isotropic phase (entry 16, Iso[1c·2c],
13% ee). Contrary to our expectation, the crystalline phase of
1a·2c showed unsatisfactory enantioselectivity (entries 1 and
2, Cry[1a·2c], ∼-15% ee); most likely, the photodimerization
proceeded mainly at defects in the crystal, so that the selectivity
would not necessarily reflect the highly ordered structure in the
crystal.
Figure 5. (a) Estimation of the isomer distribution by 1H NMR. An
authentic mixture of the four isomers of 3d (top) and a mixture obtained
from photoirradiated 1a·2d (bottom). (b) Estimation of the enantiomeric
ratio of antiHH-3d by chiral HPLC. An authentic racemate of antiHH-3d (top)
and antiHH-3d obtained from photoirradiated 1a·2d (bottom).
Concerning the preference of the stereochemical outcomes,
worth noting is that the stereochemistry of the major enantiomer
was perfectly correlated with that of the stereogenic carbon
adjacent to the hydroxy group (C1) in the amino alcohol unit;
1b (C1: S) and 1c (C1: S) afforded the (+)-antiHH-dimer,
whereas 1a (C1: R) gave the (-)-antiHH-dimer. In other words,
Even in the isotropic phases, the photodimerization proceeded
only at a moderate level to achieve 57-77% yield (entries 2,
4, and 7, Iso[1a·2d], Iso[1b·2d], and Iso[1c·2d]). These results
indicate that the reactivity of 2d in the salts with 1a-c is a
little lower than that of 2c in its salts. On the other hand, the
crystalline phases of 1a·2d and 1b·2d surprisingly achieved
acceptable yields (entry 1, Cry[1a·2d], 55% yield; entry 3,
Cry[1b·2d], 39% yield), which were comparable to that of the
LC phase of 1c·2d (entries 5 and 6, SmA[1c·2d], up to 43%
yield).
the absolute configuration of the preferentially produced antiHH
-
dimer might be ‘predictable’ from the C1 stereochemistry of
the amino alcohol unit.
2.6. Photodimerization of 1-Anthracenecarboxylic Acid
(2d) in the Amphiphilic Salts. We next performed the in situ
photodimerization of 1-anthracenecarboxylic acid (2d) in the
reaction systems composed of the salts with 1a-c. The
photodimerization and product analyses were carried out by
using procedures similar to those of 2c; the photoirradiated
sample was subjected to thorough esterification, and the yield,
isomer distribution, and enantiomeric ratio of the photodimer
2.6.2. HH/HT Selectivity. In all of the present reaction
systems, the photodimerization of 2d commonly proceeded in
a highly HH-selective manner (HH:HT ) 81:19-99:1). Most
likely, the same mechanism, as was considered for the reaction
of 2c, worked in the photodimerization of 2d; within a bilayer-
like structure, an intra-layer dimerization proceeded much faster
than an inter-layer dimerization. Worth noting is that the LC
phase of 1c·2d (SmA[1c·2d]) showed extremely high HH-
diesters 3d were evaluated. The ratio of the four isomers (synHH
,
antiHH, synHT, and antiHT-isomers) was determined by 1H NMR
without resorting to a HPLC analysis; 1H NMR signals
attributable to the bridge-head methyne protons of the four
isomers were observed separately from each other (Figure 5a).
The results are summarized in Table 2.
1
2.6.1. Reactivity. In all of the reaction systems, the photo-
dimerization of 2d proceeded cleanly to give a mixture of the
photodimers in acceptable to good yields (Table 2, entries 1-7,
36-77% yield). The only detectable side reaction was the
formation of an anthraquinone derivative, which was similar to
the case of the systems containing 2c. Overall, the yields of the
photodimers of 2d were lower than those of 2c to some extent.
selectivity, where the HT-dimer was not detected at all by H
NMR (entries 5 and 6, SmA[1c·2d], HH:HT ) >99:1). The HH/
HT selectivity achieved here was the highest in the present study,
including the photodimerization of 2c. Unexpectedly, the
isotropic phases (Iso[1a·2d], Iso[1b·2d], and Iso[1c·2d]) again
showed relatively high HH-selectivity, probably because the
isotropic phases partially retained a structural order similar to
9
J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010 17443

A R T I C L E S
Ishida et al.
Table 2. Photodimerization of 1-Anthracenecarboxylic Acid (2d)a
product ratio (%)c
antiHH synHT
entry
medium
phase
temp. (°C)
time (h)
yield (%)b
synHH
antiHT
ee (%)d antiHH
1
2
3
4
5
6
7
1a
Cry
Iso
Cry
Iso
SmA
SmA
Iso
25
100
25
90
65
15
3
15
3
3
15
3
55
72
39
57
36
43
77
75
69
47
50
67
66
57
22
24
40
30
33
34
34
2
4
2
4
3
-13
10
-6
-8
-9
-5
1b
1c
10
11
<1
<1
5
8
<1
<1
5
65
120
n.d.
b
a Irradiated at λ ) >380 nm under argon. Determined by H NMR. c Isomer distribution of 3d estimated by achiral HPLC. d Enantiomeric excess of
antiHH-3d estimated by chiral HPLC. The signs + and - represent that the major product was the first- and second-eluted enantiomer in the chiral
HPLC analysis, respectively.
1
those of the LC/crystalline phases (entries 2, 4, 7, Iso[1a·2d],
Iso[1b·2d], and Iso[1c·2d], HH:HT ) 81:19-92:8).
Cry[1a·2d]). Overall, the enantiocontrol of the antiHH-dimer
formation of 2d was at an unsatisfactory level, compared with
that of the reaction of 2c. Because of a relatively large distance
between the two carboxylate groups in the antiHH-dimer of 2d,
we may need to design another amino alcohol unit for the
improvement of the enantioselectivity.
Taking into account of the results of the photodimerizations
of the two substrates 2c and 2d, we can clearly conclude that
the present amphiphilic salts generally promote HH-dimer
formation; in both cases, the reaction media strongly directed
the reaction course to exclusively afford the HH-dimers, in spite
of their thermodynamically disadvantageous structures.
2.6.3. syn/anti Selectivity. Without depending on the amino
alcohol unit or the phase, the synHH-dimer was generally afforded
as a predominant product. Although similar synHH-selectivity
was also observed in the case of the reactions of 2c, the
photodimerization of 2d showed this tendency more markedly.
2.7. Mechanistic Aspect I: Stereochemistry and Conforma-
tional Preference of the Amino Alcohols. The results mentioned
above clearly show that the stereochemistry of the amino alcohol
unit brought significant effects on the properties of their salts,
such as the thermal behavior, self-assembled structure, and
capability of controlling the in situ photoreaction. Worth noting
is that such a subtle modification around the C1/C2 positions
was a determinant for these properties. For further sophisticated
design of an amino alcohol unit, it might be important to
elucidate the relationship between the substitution pattern and
the three-dimensional structure of the amino alcohol units. Thus,
we examined the Cambridge Structure Database (CSD) for the
salts of analogous amino alcohols with acids. We searched for
structures containing the fundamental skeleton of erythro-2-
amino-1-phenyl-1-propanol (type a), threo-2-amino-1-phenyl-
1-propanol (type b), and 2-amino-1-phenylethanol (type c), as
the analogues of 1a, 1b, and 1c, respectively (Figure 6a), to
give a total of 22 structures (type a, 10 structures; type b, 2
structures; type c, 10 structures).30
In principle, three kinds of rotamers are possible for the
present amino alcohols (AG, GG, and GA); the first and second
indices (G, gauche; A, anti) represent the arrangement of the
C(Ar)-C1-C2-N and O-C1-C2-N chains, respectively
(Figure 6b).31c Among the 22 structures retrieved from CSD,
20 structures were found to take an AG conformation. Therefore,
we can conclude that the present amino alcohols have a strong
tendency to take an AG conformation.31 In order to simplify
Particularly, the crystalline phase of 1a·2d realized a synHH
/
antiHH ratio of no less than 75:22. Such a strong synHH preference
in the photodimerization of 2d probably originated from a self-
assembled structure based on a hydrogen-bonding network
together with the characteristic structures of the photodimers
of 2d. In the amphiphilic salts, a one-dimensional hydrogen-
bonding network of the functional groups (carboxylate, am-
monium, and hydroxy) is considered to be formed, which would
force carboxylate groups to be located near each other. Since
such a ground-state orientation should be reflected on its excited-
state orientation, the formation of the antiHH-dimer of 2d, of
which the two carboxylate groups are located apart from each
other, is considered to be unfavorable, compared with that of
the synHH-dimer.
2.6.4. Enantioselectivity. Among the photodimers of 2d, the
antiHH- and synHT-dimers have a C2 symmetric chirality, while
the other two dimers are achiral. Due to the perfect HH
selectivity of the present reaction systems, we focused on the
antiHH-dimer as a target product in the context of enantiocontrol.
Unfortunately, however, all of the amphiphilic salts afforded
the antiHH-dimer as the second major product. In addition, the
ee value of the antiHH-dimer generated here was encouraging,
but far from an ideal level (up to -13% ee). For the preference
of the stereochemical outcomes, the configuration of the C1 in
the amino alcohol unit was again found to be a determinant
factor; in general, the amino alcohols with (S)-configuration at
the C1 position generated the (-)-antiHH-dimer, although the
only exceptional result was obtained when the reaction was
carried out in the crystalline phase of 1a · 2d (entry 3,
(30) Crystal structures with the following CSD entry codes were used. Type
a: amagaw, jastus, mixpeac, nephcl, qawsuc, ugeyua, Vejqeg. Type
b: geVneb, jasVaa. Type c: cektuh, cimkeo, hpetac, jammal, nadren,
nadrhc, octopc, yiVcem, yVciq, yiVcow.
(31) For the conformational behavior of norephedrine and derivatives, see:
(a) Pullman, B.; Coubeils, J. L.; Courriere, P.; Gervois, J. P. J. Med.
Chem. 1972, 15, 17–23. (b) Tsai, H.; Roberts, J. D. Magn. Reson.
Chem. 1992, 30, 828–830. (c) Alonso, J. L.; Sanz, M. E.; Lo´pez, J. C.;
Cortijo, V. J. Am. Chem. Soc. 2009, 131, 4320–4326.
9
17444 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Tunable Chiral Reaction Media
A R T I C L E S
modification of the amino alcohol unit, such as the replacement
of the methyl group in 1a or 1b with a bulkier substituent, would
be attractive.
2.8. Mechanistic Aspect II: “Topotacticity” of the Two-
Component LC Reaction System. The present photoreactions of
two-component LCs generally showed unprecedentedly high
HH/HT selectivity even after achieving high conversion (HH:
HT ) 97:3 to 99:1), regardless of the choice of amino alcohol
and carboxylic acid units. Such generality, i.e. the tolerance
toward variation in the shape of components, might be one of
the most outstanding benefits, compared with that of the
reactions in the crystalline state. Within the framework of
traditional crystalline-state reaction systems, “topotacticity” is
a determinant factor for the reactivity and selectivity. In the
case of topochemical systems, the difference between substrates
and products is so small that the original three-dimensional order
is preserved with relatively small adjustments in the unit cell.
On the other hand, solid-to-solid reconstructive systems involve
sufficiently large molecular movement, which leads to the
complicated changes of crystalline lattice. Therefore, it is
worthwhile to investigate the structural changes during the
present reactions, which would give a clue to elucidate the origin
of the general versatility of our LC reaction system.
As a model system, we chose the SmX phase of 1c·2c
(SmX[1c·2c]), because of its simple XRD pattern, as well as
its wide thermal window ranging over rt. The salt 1c·2c was
irradiated at 20 °C for 15 h (∼80% conversion of 2c into the
photodimers), and the changes before and after irradiation were
investigated by XRD, POM, and DSC. As depicted in Figure
7a, 15-h irradiation caused no distinct change in the XRD
pattern, where a strong reflection was observed at a small-angle
region assignable to (001), accompanied with a diffusive
reflection at a wide-angle region due to the loose packing of
the paraffin moiety. A closer comparison of these XRD patterns
revealed that the d-spacing calculated from the (001) reflection
increased from 30 to 33 Å. In POM observation, the focal
conical texture of the original state was retained throughout the
photoreaction, which also indicates that a drastic phase transition
was not likely to happen during the in situ photoreaction.
Moreover, DSC and variable-temperature POM revealed that
the irradiated sample acted as a thermotropic LC; through the
scanning between -50 and 150 °C, the irradiated salt exhibited
a LC phase in both of the cooling and heating processes.32
These observations strongly suggest that (1) the fundamental
structure of the smectic LC was retained through the photo-
dimerization, and (2) the photodimerization induced a remark-
able change in the layer distance (∼10% increase). Supposing
that density of the salt is essentially unchanged during the
photoreaction-induced transformation, the increase in d(001) might
be elucidated as follows; because the photodimerization should
decrease the averaged distance between the carboxylate groups,
the structural unit would shrink in the z-axis direction. As
compensation, the unit would expand in the x-axis direction by
reducing the degree of interdigitation of the tail parts, in order
to avoid the congestion of the alkyl chains (Figure 7b). Most
likely, such a flexible nature enabled the present LC system to
suppress the collapse of the original smectic structure. As a
result, the high HH selectivity would be achieved even at the
Figure 6. (a) Three types of amino alcohols as analogues of 1a-c. Sub
represents the substituent(s) on the aromatic ring. (b) Newman projections
of the possible conformers of the present amino alcohols. (c) Definition of
the dihedral angle θ. (d) Superimposition of structures retrieved from CSD.
Hydrogen atoms, C2-methyl groups, and substituent(s) on the aromatic ring
are omitted for clarity.
comparison, only the structures taking an AG conformation were
adopted in the following discussion.
In the cases of amino alcohols bearing a C2-methyl group
(type a and type b), an AG conformation should cause
considerable steric hindrance between the methyl and aromatic
groups. As a result, the aromatic group is anticipated to tilt in
the direction opposite the methyl group. On the other hand, the
aromatic group in type c amino alcohols seems to be able to
take various orientations. To confirm the anticipation, the
dihedral angle θ, as defined in Figure 6c, was calculated on the
basis of the structures obtained from CSD. As might be expected
from the orientation of the C2-methyl group, the dihedral angles
of type-b amino alcohols (θ ) 61.6 and 78.2°, Figure 6d,
middle) were obviously smaller than those of type-a amino
alcohols (θ ) 96.8-155.4°, Figure 6d, left). Meanwhile, type-c
amino alcohols were found to take a wide range of θ
(78.3-120.0°, Figure 6d, right), most likely because this type
of amino alcohols has almost no steric hindrance. For further
confirmation, theoretical calculations at the HF/6-31G level were
conducted for these three types of amino alcohols, which showed
a tendency similar to that of the CSD studies; the dihedral angles
θ of the optimized structures were 90.0, 70.8, and 73.2° for
type a, b, and c, respectively. Since the dihedral angle θ directly
reflects the relative orientation of the amino/hydroxy groups and
the aromatic ring, it is quite reasonable that the salts of 1a-c
showed different characteristics as described above. Thus, the
stereochemistry at C1 and the substituent at C2 of the am-
phiphilic amino alcohols play a very important role to determine
their characteristics, although it is generally accepted that the
self-organization of amphiphilic molecules can be simply
elucidated on the basis of a hydrophilic-hydrophobic volume
ratio. Although there are still some unclear points, further
(32) Generaly, the photodimers of anthracene derivatives are known to
undergo thermal cleavage to afford the monomer when extensively
heated. In the case of the present LC salt obtained by the irradiation
of 1c·2c, however, the cleavage of the photodimer 3c did not proceed
at a detectable level through the present DSC measurement.
9
J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010 17445

A R T I C L E S
Ishida et al.
Figure 7. (a) XRD pattern of 1c·2c before (top) and after (bottom) photoirradiation (λ ) >380 nm under argon, at 20 °C for 15 h). (b) Schematic representation
of the plausible structural changes of 1c·2c through the photodimerization of 2c. Blank arrows represent the transformation of the lattice.
last stage of this photoreaction, where most of the starting
materials had been converted.
words, these three amino alcohols might play a complementary
role to each other, and therefore, the present work has certainly
expanded the scope of this method. As far as we are aware of,
the present LC system is one of the most advantageous reaction
media to direct the photodimerization of anthracenecarboxylic
acids, from the viewpoints of generality, simplicity, reactivity,
regio-/diastereo-/enantioselectivities, and tunability. By using
the synthetic method established here, various amphiphilic
amino alcohols would be available in stereopure forms, which
would further expand the scope of the present methodology.
3. Conclusion
We have demonstrated that two-component liquid crystals,
composed of the salts of enantiopure amphiphilic amino alcohols
with anthracenecarboxylic acids (2c: 2-anthracenecarboxylic
acid, 2d: 1-anthracenecarboxylic acid) generally offer a unique
reaction environment for the photodimerization of the carboxylic
acid unit. Three types of amino alcohols were developed, of
which the stereochemistry around the amino and hydroxy groups
was systematically varied (stereochemistry of C1/C2: 1a R/S,
1b S/S, and 1c S/achiral). On a cooling process from an isotropic
melt, some combinations exhibited one or two kinds of LC
phases (1b·2c, 1c·2c, and 1c·2d), while the other (1a·2c,
1a·2d, and 1b·2d) showed direct transition into a crystalline
phase. In every LC phase obtained here, the photodimerization
of the carboxylic acid unit proceeded efficiently with excellent
selectivity, which strongly suggests the general utility of the
two-component liquid crystal method. Moreover, the choice of
the amino alcohol unit and the phase brought a notable effect
on the isomer distribution of the photoreaction product. In other
Acknowledgment. We acknowledge Dr. Toshimi Shimizu and
Dr. Hiroyuki Minamikawa (AIST), for XRD measurements.
Supporting Information Available: Synthesis and character-
ization of the amphiphilic amino alcohols 1a-c, preparation
and thermal behavior of the 12 kinds of salts 1·2, experimental
details for the photodimerization of the anthracenecarboxylic
acids 2c and 2d, and X-ray crystallographic data for the salt of
(R)-11 with (S)-mandelic acid. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA105221U
9
17446 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010