Visual enantiomeric recognition of amino acid derivatives in protic solvents

Article abstract of DOI:10.1021/jo050387u

Various types of chiral host molecules 2-7 based on a phenolphthalein skeleton and two crown ethers were prepared for use in visual enantiomeric recognition, and we examined their enantioselective coloration in complexation with chiral amino acid derivatives 9-22 in methanol solution. Methyl-substituted host (S,S,S,S)-S showed particularly prominent enantiomer selectivity for the alanine amide derivatives 11 and 12. A combination of methyl-substituted host (S,S,S,S)-S with guest (R)-11 or (R)-12 developed a purple color, whereas no color development was observed with (S)-11 or (S)-12. On the other hand, phenyl-substituted host (S,S,S,S)-6 showed deeper coloration with a wide range of (S)-β-amino alcohols compared to that seen with host (S,S,S,S)-6 and the corresponding (R)-β-amino alcohols at 0°C. Furthermore, absorbance inversion temperatures (AIT) were observed within the range of 0-50°C in many cases.

Full text of DOI:10.1021/jo050387u

Visual Enantiomeric Recognition of Amino Acid Derivatives in
Protic Solvents1,†
Kazunori Tsubaki,*,‡ Daisuke Tanima,‡ Mohammad Nuruzzaman,‡ Tomokazu Kusumoto,‡
Kaoru Fuji,§ and Takeo Kawabata‡
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan, and Faculty of
Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan
tsubaki@fos.kuicr.kyoto-u.ac.jp
Received March 1, 2005
Various types of chiral host molecules 2-7 based on a phenolphthalein skeleton and two crown
ethers were prepared for use in visual enantiomeric recognition, and we examined their enantio-
selective coloration in complexation with chiral amino acid derivatives 9-22 in methanol solution.
Methyl-substituted host (S,S,S,S)-3 showed particularly prominent enantiomer selectivity for the
alanine amide derivatives 11 and 12. A combination of methyl-substituted host (S,S,S,S)-3 with
guest (R)-11 or (R)-12 developed a purple color, whereas no color development was observed with
(S)-11 or (S)-12. On the other hand, phenyl-substituted host (S,S,S,S)-6 showed deeper coloration
with a wide range of (S)-â-amino alcohols compared to that seen with host (S,S,S,S)-6 and the
corresponding (R)-â-amino alcohols at 0 °C. Furthermore, absorbance inversion temperatures (AIT)
were observed within the range of 0-50 °C in many cases.
Introduction
Molecular recognition in protic solvents, especially in
aqueous media, is another attractive topic since non-
covalent forces derived from electrostatic interaction are
weakened according to the dielectric constant (ꢀ) of the
solvent. In addition, the designed formation of hydrogen
bonds between two molecules is especially difficult in
protic solvent since a large number of solvent molecules
can act as a hydrogen donor and/or acceptor.5
We have been investigating whether ditopic receptors
consisting of phenolphthalein (one of the most popular
pH indicators) and two crown ethers could be used to
recognize the length of guest diamine or triamine mol-
ecules and indicate this information through the develop-
ment of a purple color.6 The mechanism of color devel-
opment by phenolphthalein in the aqueous alkaline
Since the enantiomeric recognition of chiral compounds
was pioneered by Cram and co-workers in the early
1970s,2 much attention has been focused on this topic of
chemically and biologically important guests, and various
kinds of host molecules have been synthesized.3 Some of
these host molecules can discriminate enantiomers on the
basis of a color change; therefore, such molecules might
be useful as rapid sensors for determining the absolute
configurations of asymmetric guest compounds.4
† This paper is dedicated to the memory of the late Professor Kiyoshi
Tanaka.
‡ Kyoto University.
§ Hiroshima International University.
(1) A preliminary communication of part of this work has pub-
lished: Tsubaki, K.; Nuruzzaman, M.; Kusumoto, T.; Hayashi, N.;
Wang, B.-G.; Fuji, K. Org. Lett. 2001, 3, 4071-4073.
(2) (a) Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D.
J. J. Am. Chem. Soc. 1973, 95, 2692-2693. (b) Cram, D. J.; Cram, J.
M. Science 1974, 183, 803-809.
(3) For recent reviews, see: (a) Peczuh, M. W.; Hamilton, A. D.
Chem. Rev. 2000, 100, 2479-2494. (b) Mart´ınez-Ma´n˜ez, R.; Sanceno´n,
F. Chem. Rev. 2003, 103, 4419-4476. (c) Gokel, G. W.; Leevy, W. M.;
Weber, M. E. Chem. Rev. 2004, 104, 2723-2750. (d) Wright, A. T.;
Anslyn, E. V. Org. Lett. 2004, 6, 1341-1344.
10.1021/jo050387u CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/13/2005
J. Org. Chem. 2005, 70, 4609-4616
4609

Tsubaki et al.
SCHEME 1. Mechanism of Color Development of
Phenolphthalein in the Aqueous Alkaline Region7
subunits (S,S)-24-28 were prepared from (S)-ethyl lac-
tate or (S)-mandelic acid.9 Ring-closing reactions were
carried out on 2910 with chiral tetraethylene glycol
subunits (S,S)-24-28 under sodium hydride and potas-
sium tetrafluoroborate to give the corresponding crown
ethers (S,S)-30-34 in moderate yields. Crown ethers
30-34 were treated with t-BuLi and allowed to react with
phthalic anhydride at -78 °C to afford (S,S,S,S)-35-39
in moderate to good yields (40-92%). Finally, reductive
deprotection of the allyl groups proceeded smoothly using
either 10% palladium on carbon and p-toluenesulfonic
acid in ethanol-water11 or sodium borohydride and a
catalytic amount of tetrakis(triphenylphosphine)pal-
ladium in methanol12 to afford (S,S,S,S)-2-5 and 7 in
excellent yields (91-100%).
Synthesis of the Chiral Host (S,S,S,S)-6. The
synthetic pathway for the chiral host (S,S,S,S)-6 is shown
in Scheme 3. The key intermediate (S,S)-42 was con-
structed on the basis of the known procedure.9c,13 Thus,
(S)-40 derived from (S)-(+)-mandelic acid as a diastereo
mixture was condensed with benzyl chloride 2910 in the
presence of sodium hydride in DMF, and this was
followed by deprotection of the THP groups under acidic
conditions to afford (S,S)-41 in 82% overall yield in two
steps. Treatment of (S,S)-41 with diethylene glycol di-
tosylate under sodium hydride and potassium tetrafluoro-
borate gave the corresponding crown ether (S,S)-42 in
49% yield, which was converted into the host (S,S,S,S)-6
via a route similar to those for the chiral hosts (S,S,S,S)-
2-5 and 7 in 95% overall yield in two steps.
Visual Enantiomeric Recognition by Chiral Hosts
(S,S,S,S)-2-5. A preceding paper proposed that a colored
complex between host 1 and triamine 8 developed
because both terminal amino groups of triamine 8
bridged the two phenolic crown rings of host 1 and the
inner amino group was captured as a countercation of
the carboxylate, based on ring opening of the γ-lactone
of host 1.6b Thus, a definite chain length is required for
the visualization of R,ω-diamines or linear triamines
using the achiral host 1. Derivatization of chiral guests
is indispensable for meeting the above requirement.
Therefore, two types of amino acid derivatives 9 and 10-
14 were prepared.14 Before investigating the possibility
of enantiomeric recognition between chiral hosts 2-5 and
chiral amines 9-14, we examined the interaction be-
tween chiral hosts and achiral triamine 8. When triamine
8 was added to a solution of host in methanol at 25 °C,
region, as revealed by Tamura et al.,7 is as follows:
(i) monoanion of phenolphthalein is colorless, (ii) two
types of dianion (colored carboxylate form and colorless
lactone form)8 are present, and (iii) in the strong alkaline
region, Michael addition of hydroxide takes place to give
the corresponding colorless trianion (Scheme 1). In the
present paper, we report the visual enantiomeric recogni-
tion of amino acid derivatives using chiral hosts 2-7 in
methanol media as well as changes in this phenomenon
with a change in the temperature (Figure 1).
Results and Discussion
Syntheses of Chiral Host Molecules (S,S,S,S)-2-5
and 7. The chiral hosts 2-5 and 7, containing two methyl
or phenyl groups in each crown ether, were synthesized
according to Scheme 2. Key chiral tetraethylene glycol
(4) (a) Kaneda, T.; Hirose, K.; Misumi, S. J. Am. Chem. Soc. 1989,
111, 742-743. (b) Vo¨gtle, F.; Knops, P. Angew. Chem., Int. Ed. Engl.
1991, 30, 958-960. (c) Naemura, K.; Tobe, Y.; Kaneda, T. Coord. Chem.
Rev. 1996, 148, 199-219. (d) Kubo, Y.; Maeda, S.; Tokita, S.; Kubo,
M. Nature 1996, 382, 522-524. (e) Zhang, X. X.; Bradshaw, J. S.; Izatt,
R. M. Chem. Rev. 1997, 97, 3313-3361. (f) Kim, S.-G.; Kim, K.-H.;
Jung, J.; Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2002, 124, 591-
596. (g) Tsukube, H.; Shinoda, S. Chem. Rev. 2002, 102, 2389-2404.
(h) Heinrichs, G.; Vial, L.; Lacour, J.; Kubik, S. Chem. Commun. 2003,
1252-1253. (i) Zhu, L.; Anslyn, E. V. J. Am. Chem. Soc. 2004, 126,
3676-3677. (j) Pu, L. Chem. Rev. 2004, 104, 1687-1716. (k) Escuder,
B.; Rowan, A. E.; Feiters, M. C.; Nolte, R. J. M. Tetrahedron 2004, 60,
291-300. (l) Shinoda, S.; Okazaki, T.; Player, T. N.; Misaki, H.; Hori,
K.; Tsukube, H. J. Org. Chem. 2005, 70, 1835-1843.
(9) For (S,S)-25: (a) Dyer, R. B.; Metcalf, D. H.; Ghirardelli, R. G.;
Palmer, R. A.; Holt, E. M. J. Am. Chem. Soc. 1986, 108, 3621-3629.
For (S,S)-27: (b) Cooper, K. D.; Walborsky, H. M. J. Org. Chem. 1981,
46, 2110-2116. For (S,S)-28: (c) Hirose, K.; Fujiwara, A.; Matsunaga,
K.; Aoki, N.; Tobe, Y. Tetrahedron: Asymmetry 2003, 14, 555-566.
(d) Hirose, K.; Ogasahara, K.; Nishioka, K.; Tobe, Y.; Naemura, K. J.
Chem. Soc., Perkin Trans. 2 2000, 1984-1993. For (S,S)-24 and (S,S)-
26, see the Supporting Information.
(10) Tsubaki, K.; Otsubo, T.; Morimoto, T.; Maruoka, H.; Furukawa,
M.; Momose, Y.; Shang, M.; Fuji, K. J. Org. Chem. 2002, 67, 8151-
8156.
(11) Boss, R.; Scheffold, R. Angew. Chem., Int. Ed. Engl. 1976, 15,
558-559.
(5) (a) Molt, O.; Ru¨beling, D.; Scha¨fer, G.; Schrader, T. Chem. Eur.
J. 2004, 10, 4225-4232. (b) Rekharsky, M.; Inoue, Y.; Tobey, S.;
Metzger, A.; Anslyn, E. J. Am. Chem. Soc. 2002, 124, 14959-14967.
(6) (a) Fuji, K.; Tsubaki, K.; Tanaka, K.; Hayashi, N.; Otsubo, T.;
Kinoshita, T. J. Am. Chem. Soc. 1999, 121, 3807-3808. (b) Tsubaki,
K.; Hayashi, N.; Nuruzzaman, M.; Kusumoto, T.; Fuji, K. Org. Lett.
2001, 3, 4067-4069. (c) Tsubaki, K.; Kusumoto, T.; Hayashi, N.;
Nuruzzaman, M.; Fuji, K. Org. Lett. 2002, 4, 2313-2316.
(12) (a) Beugelmans, R.; Bourdet, S.; Bigot, A.; Zhu, J. Tetrahedron
Lett. 1994, 35, 4349-4350. (b) Bois-Choussy, M.; Neuville, L.; Beugel-
mans, R.; Zhu, J. J. Org. Chem. 1996, 61, 9309-9322.
(13) (a) Huszthy, P.; Bradshaw, J. S.; Zhu, C. Y.; Izatt, R. M.; Lifson,
S. J. Org. Chem. 1991, 56, 3330-3336. (b) Naemura, K.; Nishikawa,
Y.; Fuji, J.; Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry 1997, 8, 873-
882.
(7) Tamura, Z.; Abe, S.; Ito, K.; Maeda, M. Anal. Sci. 1996, 12, 927-
930.
(8) Taguchi, K. J. Am. Chem. Soc. 1986, 108, 2705-2709.
(14) For the synthesis of guests, see the Supporting Information.
4610 J. Org. Chem., Vol. 70, No. 12, 2005

Visual Enantiomeric Recognition
FIGURE 1. Hosts and guests.
a color change (from colorless to purple) based on an
increase in the absorption band at around 570 nm was
observed. The association constants (K) and molar ab-
sorption coefficients (ꢀ) were determined by UV-vis
titration and analyzed by the Rose-Drago method.15 The
results are summarized in Table 1.
The data in Table 1 show that the association constants
(K) decreased dramatically when two methyl groups were
introduced into a phenolic crown ring (compare entry 1
with entries 2-5). Furthermore, K values gradually
decreased as the two methyl substituents moved from
the top (positions 8 and 10, see Figure 1) to the bottom
(positions 4 and 14) of the phenol crown ring (2 > 3 > 4
> 5). A similar tendency was observed for the molar
absorption coefficient (ꢀ). Consequently, the degree of
coloration (absorbance) caused by the product of the
molar absorption coefficient (ꢀ) and the concentration of
the host-guest complex changed dramatically depending
on the host 1-5 and guest triamine 8.
late that ꢀ reflects the position of the equilibrium between
the colored and colorless dianion of the host (Scheme 1).
This variable ꢀ makes visual recognition unique and
complicated, as described later.
Next, the enantiomeric recognition of hosts 1-5 with
phenylalanine derivatives 9 was examined. The associa-
tion constants (K) and molar absorption coefficients (ꢀ)
are listed in Table 2. In entry 1, the achiral host 1 was
investigated to guarantee the purity of the chiral guests
and the titration procedure. Small association constants
were observed for the complexation of hosts 2-4 with
enantiomeric pairs of 9, indicating weak host-guest
interaction. Almost no enantioselective recognition was
observed for hosts 2-4. The binding ability of host 5 was
too low to determine the association constant.
During these investigations, a fundamental host-guest
relationship was revealed: (i) unexpectedly large steric
repulsion was observed between even the smallest methyl
substituents on the phenol crown ring and the terminal
primary amino group in the guest molecule, and (ii) the
small differences between the association constants for
achiral triamine 8 and chiral triamine 9 for each host
molecule indicated that there were no additional interac-
tions between methyl substituents on the host molecule
and a chiral moiety introduced into the inner amino
group of the guest molecule.
Although the molar absorption coefficient (ꢀ) is sup-
posed to be constant for each host-guest complex, its
value is critically attributable to the structure of the host
compound. While we do not have a clear explanation for
the fluctuating molar absorption coefficient (ꢀ), we specu-
(15) (a) Rose, N. J.; Drago, R. S. J. Am. Chem. Soc. 1959, 81, 6138-
6141. (b) Rose, N. J.; Drago, R. S. J. Am. Chem. Soc. 1959, 81, 6141-
6145. (c) Hirose, K. J. Inclusion Phenom. Macrocycl. Chem. 2001, 39,
193-209.
Taking this information into consideration, we next
examined the visual enantiomeric recognition of chiral
J. Org. Chem, Vol. 70, No. 12, 2005 4611

Tsubaki et al.
SCHEME 2. Synthetic Pathway for Chiral Hosts
SCHEME 3. Synthetic Pathway for Chiral Host
(S,S,S,S)-2-5 and 7a
(S,S,S,S)-6a
a Key: (a) NaH; (b) H+; (c) diethylene glycol ditosylate, NaH,
KBF4; (d) t-BuLi, phthalic anhydride; (e) Pd(PPh3)4, NaBH4.12
TABLE 1. Association Constants (K) and Molar
Absorption Coefficients (E) of Complexes of Hosts 1-5
with Triamine 8a
entry
host
K (M-1
)
ꢀ
1
2
3
4
5
1
2270 ( 30
274 ( 3
208 ( 4
96 ( 2
5080 ( 20
5900 ( 32
1525 ( 18
1724 ( 30
806 ( 22
(S,S,S,S)-2
(S,S,S,S)-3
(S,S,S,S)-4
(S,S,S,S)-5
a Key: (a) NaH, KBF4; (b) t-BuLi, phthalic anhydride; (c) 10%
47 ( 2
Pd/C, TsOH11 or Pd(PPh3)4, NaBH4.12
a Conditions: [host 1]0 ) 5.0 × 10-3 M; [host 2]0 ) 5.0 × 10-4
M; [hosts 3-5]0 ) 1.0 × 10-3 M; 25.0 °C, MeOH.
guests 10-14,16 amides of R-amino acid and linear
diamine, by chiral hosts (S,S,S,S)-2-5. In this stage,
guest molecules bear chiral substituents near the termi-
nal amino group. Since relatively small association
constants might be expected from the data in Tables 1
and 2, UV-vis titration experiments were carried out at
15 °C in the presence of a large excess of N-ethylpiperi-
dine (NEP). In previous studies, we found that protonated
N-ethylpiperidine (NEPH+) served only as a counter-
cation for the carboxylate anion derived from ring-
opening of the benzolactone of host 1 without any
interaction with the phenol crown of host 1.6a The
apparent association constants (K′) and molar absorption
coefficients (ꢀ) for 11 and 12 are summarized in Table 3.
The positions of the methyl groups on phenolic
18-crown-6 crucially affected the enantiomeric recogni-
tion toward (R)- and (S)-alanine derivatives 11 and 12.
Thus, the binding ability of host 2 is superior to those of
other chiral hosts, but enantiomeric recognition was
hardly observed. Among the hosts examined, host 3,
which possesses two methyl groups at positions 7 and
11 of the phenolic 18-crown-6 ring, shows prominent
enantiomeric selectivity. Interestingly, Hirose and Tobe
reported that the substituents at positions 5 and 13 of
azo-phenolic 18-crown-6 play crucial roles in visual chiral
recognition.9c-d,17 A difference in coloration is seen in
Figure 2 as well as in the UV-vis absorption spectra
(Figure 3). In Figure 2, the combination of host 3 with
guest (R)-11 or (R)-12 led to color development, while
almost no color development was observed with (S)-11
or (S)-12. Thus, it was easy to discriminate between
enantiomers.
Furthermore, when guest 12 with different optical
purities was added to the host 3 solution, a linear
relationship was observed between the absorbance
(λmax, 574 nm) and the enantiomeric excess (ee) of guest
12. This result clearly shows that host 3 can read the
chirality of the guest and turn such molecular interac-
tions into visual information (Figure 4).
With hosts 1-5 and diamine 10, no color development
was observed even under these conditions, and therefore,
(16) The guests 10-14 were used as 2HCl salts, which would deliver
free amine in the presence of large excess NEP.
(17) Ogasahara, K.; Hirose, K.; Tobe, Y.; Naemura, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 3227-3236.
4612 J. Org. Chem., Vol. 70, No. 12, 2005

Visual Enantiomeric Recognition
TABLE 2. Association Constants (K) and Molar Absorption Coefficients (E) of Complexes of Hosts 1-4 with Triamine 9a
b
b
entry
host
KR (M-1
)
ꢀR
KS (M-1
)
ꢀS
KR/KS
ꢀR/ꢀS
1
2
3
4
1
1658 ( 65
169 ( 6
87 ( 3
1987 ( 14
2702 ( 55
938 ( 36
780 ( 20
1645 ( 42
155 ( 2
62 ( 7
1940 ( 9
2303 ( 15
850 ( 30
800 ( 25
(S,S,S,S)-2
(S,S,S,S)-3
(S,S,S,S)-4
1.1
1.4
1.1
1.2
1.1
1.0
56 ( 4
49 ( 5
a Conditions: [host 1-2]0 ) 5.0 × 10-4 M; [host 3-4]0 ) 1.0 × 10-3 M; [guest 9]0 ) 1.0 × 10-1 M; 25.0 °C, methanol. a KR and KS
denote association constants for (R)- and (S)-guests, respectively.
TABLE 3. Apparent Association Constants (K′) of Complexes of Hosts 1-5 with Alanine Derivatives 11-12 in
Methanola
entry
host
guest
K′ d,e
ꢀR
K′ d,e
ꢀS
K′ /K′
ꢀR/ꢀS
R
S
R
S
1a
2b
3c
1
2
3
4
5
1
2
3
4
5
11
11
11
11
11
12
12
12
12
12
1766 ( 106
2334 ( 121
378 ( 15
148 ( 14
262 ( 29
1647 ( 55
2224 ( 94
366 ( 10
251 ( 10
208 ( 14
4568 ( 123
890 ( 35
895 ( 17
349 ( 29
320 ( 19
6732 ( 113
1596 ( 30
1610 ( 21
410 ( 9
1762 ( 68
1554 ( 107
62 ( 13
328 ( 20
214 ( 17
1625 ( 62
1437 ( 78
65 ( 7
296 ( 11
245 ( 18
4584 ( 102
718 ( 24
630 ( 96
584 ( 20
341 ( 13
6900 ( 123
1549 ( 41
850 ( 30
781 ( 18
398 ( 13
1.5
6.1
0.45
1.2
1.2
1.4
0.60
1.1
4c
5c
6a
7b
8c
1.5
5.6
0.85
0.85
1.0
1.9
0.52
0.93
9c
10c
371 ( 15
a Conditions: (a) [host]0 ) 5.0 × 10-4 M; [NEP] ) 5.0 × 10-2 M; 25.0 ( 0.1 °C; (b) [host]0 ) 5.0 × 10-4 M; [NEP] ) 5.0 × 10-2 M; 15.0
( 0.1 °C; (c) [host]0 ) 2.0 × 10-3 M; [NEP] ) 5.0 × 10-1 M; 15.0 ( 0.1 °C. d K′ and K′ denote apparent association constants for
R
(R)- and (S)-guests, respectively. e The apparent association constants (K′) were determinSed in the following manner. K ) [complex]/
[host][guest][NEP] where [NEP] . [host] and [guest]. Thus, [NEP] can be adequately approximated to constant K′ ) K [NEP] ) [complex]/
[host][guest].
FIGURE 4. Linear relationship between the absorbance and
the enantiomeric excess of guest 12. Conditions: [host 3] )
2.0 × 10-3 M, [guest 12]total ) 2.0 × 10-3 M, [NEP] ) 5.0 ×
10-1 M, MeOH, 15.0 ( 0.1 °C.
FIGURE 2. Color development by host 3. Conditions: [host
3] ) 1.0 × 10-3 M, [guests 11-12] ) 1.0 × 10-2 M, [NEP] )
5.0 × 10-1 M, MeOH, 15.0 ( 0.1 °C.
groups. The seven atoms including the amide bond are
slightly shorter and more rigid than simple 1,7-diamino-
heptane. This could explain why color development was
not observed with diamine 10.
An increase in the size of the substituents at the chiral
center in guest molecules usually increases the extent
of enantiomeric selectivity. However, no color develop-
ment was observed with guest molecules 13 and 14 with
larger substituents (R ) Et, i-Pr). Only host (S,S,S,S)-2
binds vaguely to guest 13 as measured by UV-vis
titration and analyzed by the Benesi-Hildebrand
method.18 The apparent association constants and molar
absorption coefficients were determined in the presence
of NEP (5.0 × 10-1 M) by adding guest solutions (5.0 ×
10-2 M) to 1.0 × 10-2 M of host 2 in methanol at 25 °C to
FIGURE 3. UV-vis spectra of host 3 with guests 11-12.
Conditions: [host 3] ) 1.8 × 10-3 M, [guests 11-12] ) 1.8 ×
10-3 M, [NEP] ) 5.0 × 10-1 M, MeOH, 15.0 ( 0.1 °C.
give the following values: for (R)-13, K′ ) 40 M-1
,
the association constants for 10 were too small to
measure. Judging from the previous results with
R,ω-diamines,6 diamine 10 may develop color only weakly,
since there are seven atoms between the two amino
ꢀ ) 1145; for (S)-13, K′ ) 30 M-1, ꢀ ) 708. These results
(18) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71,
2703-2707.
J. Org. Chem, Vol. 70, No. 12, 2005 4613

Tsubaki et al.
FIGURE 5. Proposed three-component colored complex.
indicated that even an ethyl or isopropyl group on the
guest molecules was too bulky to form a complex under
these conditions.
To explain this enantiomeric recognition, we considered
steric repulsion between host 3 and guest 12, since host
3 can strictly recognize the bulkiness of substituents at
the R position of a terminal amino group of guests, as
mentioned above. We assume that the three-component
colored complex shown in Figure 5 should be generated.
Thus, terminal amino groups of guest 12 bridge two
phenolic crown rings of host 3 and NEPH+ serves as a
countercation of the carboxylate. Taking into account the
steric repulsion between the methyl group at C-7 of the
phenolic 18-crown-6 ring of 3 and the R1 substituent of
guest 12, the complex between 3 and (R)-12 is more
stable than its diastereomeric complex. Thus, host 3 can
discriminate between hydrogen and a methyl group of
the guest molecule. Furthermore, this assumption can
also be applied to the reverse selectivity between host 4
and guest 11 or 12 (Table 3, entries 3 vs 4 and 8 vs 9).
Visual Enantiomeric Recognition of â-Amino Al-
cohols. Although this visual recognition was accompa-
nied by a sharp and drastic color change, the types of
guest molecules were too restricted. Therefore, we next
explored its broader application to other amino acid
derivatives (i.e., â-amino alcohols). First, the visual
enantiomeric recognition of chiral â-amino alcohols
15-22 with chiral hosts (S,S,S,S)-2-5 was screened.
Since these guest molecules lack two primary amino
groups and the proper distance to bridge the two phenol
crown rings of the hosts, feeble interaction and coloration
might be expected. Therefore, screening of guests was
carried out at low temperature (0 °C) under very highly
concentrated conditions. Under these conditions, colora-
tion based on host-guest interaction was certainly
observed (Figure 6). Clear coloration gradually increased
as the two methyl substituents were separated from the
phenolic rings in the crown part. A similar tendency was
observed in the visual enantiomeric recognition of alanine
amide with 1,6-hexamethylenediamine 12 (mentioned
above). However, at the point of chiral recognition,
negligible differences could be perceived between enan-
tiomeric pairs of guests by the human eye.
FIGURE 6. Color development by the hosts 2-5 with various
â-amino alcohols. [hosts] ) 5.0 × 10-3 M, (a) host 2, (b) host
3, (c) host 4, (d) host 5. [guests 15-22] ) 1.0 × 10-1 M in
MeOH/CHCl3 ) 9/1 at 0 °C. Red label on the lid denotes
(R)-configuration of guest. Key: 15, 2-amino-2-phenylethanol;
16, 2-amino-1-propanol; 17, 2-amino-1-butanol; 18, 2-amino-
2-phenylethanol; 19, 2-amino-3-methyl-1-butanol; 20, 2-amino-
4-methyl-1-pentanol; 21, erythro-R-(1-aminoethyl)benzyl alco-
hol; 22, cis-1-amino-2-indanol.
π-donor in complex with acidic hydrogen atoms of the
guest molecules.
Clear coloration was observed with host 6 and â-amino
alcohols (Figure 7a), whereas almost no coloration was
detected using host 7 (Figure 7b). The coloration of host
These data suggest that the methyl subunits on the
crown ether were too sterically small to discriminate the
chirality of â-amino alcohols. Therefore, we synthesized
phenyl-substituted hosts 6 and 7, where the phenyl group
was expected to be an effective chiral barrier or attractive
4614 J. Org. Chem., Vol. 70, No. 12, 2005

Visual Enantiomeric Recognition
FIGURE 9. Proposed four-component colored complexes.
FIGURE 10. Proposed proton transfer through surrounding
methanol. Crown ether parts have been omitted for clarity.
FIGURE 7. Color development by the hosts 6-7 with various
â-amino alcohols. [hosts] ) 5.0 × 10-3 M, host 6 for a, host 7
for b, [guests 15-22] ) 1.0 × 10-1 M in MeOH/CHCl3 ) 9/1,
0 °C. Red label on the lid denotes (R)-configuration of guest.
plot (red line b) shifted to 0.66. This behavior indicates
that a four-component colored complex (in case a, host
6/guest ) 1:3, in case b, host 6/NEP:guest ) 1:1:2) should
be generated in this solution (Figure 9). In Figure 9, these
complexes are shown as canonical structures. Therefore,
there may be some irrational interaction between the
quinoid form of the phenolic crown ether of the host (right
side) and the neutral amino group of the guest. We can
interpret the actual complexes as follows (Figure 10):
(i) the guest amines react with free host 6 to generate
two kinds of dianions (see Scheme 1), (ii) with regard to
“colored” complexes, a negative charge preferentially
locates on the carboxylate, and another charge spreads
over the two phenolic rings, and (iii) proton transfer takes
place from the ammonium ion bound to the phenoxide
form of the crown ether to the neutral amine bound to
the quinoid form through intervention of the bulk solvent
(methanol). Thus, both amines acquire a positive charge,
depending on the time-scale of the above equilibrium. It
should be pointed out, in this respect, that no coloration
was observed in aprotic polar solvents such as CHCl3,
DMSO, and DMF.
FIGURE 8. Job’s plots of host 6 with (S)-16 (a) in the absence
of NEP (blue line) and (b) in the presence of NEP (red line).
Conditions: (a) [host 6] + [(S)-16] ) 2.0 × 10-2 M, 570 nm;
(b) [host 6] + [(S)-16] ) 2.0 × 10-2 M, [NEP] ) 5.0 × 10-1 M,
569.5 nm, MeOH/CHCl3 ) 9/1, 10 °C.
6 (which has large phenyl groups at C-5 and C-13) with
amines was generally deeper than that with the corre-
sponding methyl-substituted host 4 (Figure 6c vs Figure
7a). Host 6 was selected for further investigations of
enhanced functions. Figure 7a shows that coloration is
sensitive to bulkiness around the amino group of the
guest molecule (18 vs 16 and 17). Based on observation
with the naked eye, the development of color between
host 6 and (S)-guests is stronger than that between host
6 and (R)-guests in all cases.
Next, the stoichiometry of the colored complex formed
by host 6 and guest (S)-16 was determined by a Job’s
plot (Figure 8). The Job’s plot exhibited a peak at
approximately 0.7 and suggested that the host-guest
ratio was 1:2 or 1:3 (Figure 8, blue line a). To clarify the
stoichiometry of complex formation, the Job’s plot was
measured in the presence of a large excess of NEP. Figure
8 shows that under these conditions, the peak of the Job’s
We also found that the response of host 6 and (S)-16
to temperature was completely different from that of host
6 and (R)-16.19 Therefore, the relationship between color
development and temperature was investigated. The
temperature of the mixture of host 6 and guest was
increased gradually from 0 °C to 50 °C over 50 min
(1 °C/min), and wavelengths of absorption maxima (λmax
)
were measured by UV-vis spectroscopy.20 Some ex-
amples are shown in Figure 11a-h.
(19) For a recent review for temperature effect on the selectivity,
see: (a) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew.
Chem., Int. Ed. Engl. 1991, 30, 477-515. (b) Cainelli, G.; Giacomini,
D.; Galletti, P.; Marini, A. Angew. Chem., Int. Ed. Engl. 1997, 35,
2849-2852.
(20) The actual variable-temperature UV spectra for a pair of
diastereomeric complexes of host 6 and 15 are shown in Figure SI-1
(Supporting Information).
J. Org. Chem, Vol. 70, No. 12, 2005 4615

Tsubaki et al.
TABLE 4. Wavelength of Maximal Absorption (λmax),
Visual Enantiomeric Discrimination Values (VED), and
Absorbance Inversion Temperature (AIT)a
guest
λmax (S) (nm)
λmax (R) (nm)
VED
AIT (°C)
15
16
17
18
19
20
21
22
23
571.5
571.0
571.0
571.0
571.0
571.0
571.0
572.0
571.5
569.5
569.0
569.5
569.5
569.0
569.5
570.0
569.5
572.0
3.86
2.77
2.88
1.78
1.92
2.64
3.83
1.92
0.78
19.9
44.5
21.6
20.3
29.2
8.7
a Conditions: [host 6] ) 5.0 × 10-3 M, [guest] ) 1.0 × 10-1 M,
MeOH/CHCl3 ) 9/1.
is not 0), actual observations were uncommon. We defined
visual enantiomeric discrimination (VED) values to
conveniently reflect the enantiomeric discrimination abil-
ity as follows:
VED ) abs(host 6 - (S)-guest)/abs(host 6 - (R)-guest)
([host 6] ) 5.0 × 10-3 M, [guest] )
1.0 × 10-1, MeOH/CHCl3 ) 9/1, λmax, 0 °C)
The VED values, λmax, and AIT are listed in Table 4.
The VED values are approximately 1.8-3.8, and the
discrimination of enantiomers could be easily determined
by the naked eye.22 In addition, the λmax value of complex
of host 6 with (R)-23 is larger than those of host 6 with
â-amino alcohols. This phenomenon presumably suggests
that hydrogen bonding between the oxygen atom of host
6 and the -OH hydrogen of the guest stabilized the
ground state of the colored complex.
In conclusion, we have developed phenolphthalein-
based hosts with methyl- or phenyl-substituted crown
ethers. Host (S,S,S,S)-3 can discriminate the chirality of
alanine amides by a color change that is discernible by
the naked eye. Host (S,S,S,S)-6 could be widely applicable
as a chiral indicator for â-amino alcohols. We also
observed that the strength of color development with host
6, and (S)- or (R)-guest was reversed at the absorbance
inversion temperature. Furthermore, this molecular rec-
ognition based on hydrogen bonding, Coulomb force, and
ion-dipole interaction in a protic solvent is a challenging
subject in supramolecular chemistry. We are currently
extending this system to an aqueous medium.
FIGURE 11. Temperature dependence of the absorbance of
host 6 and guests. Conditions: [host 6] ) 5.0 × 10-3 M, [guest]
) 1.0 × 10-1, MeOH/CHCl3 ) 9/1, λmaxs of the UV absorbance
are plotted on the vertical axes (see Table 4).
As expected, the differences in color development with
host 6 and (R or S)-amino alcohols 15-21 were enhanced
as the temperature decreased. In contrast, simple amine
23 showed relatively small differences in color develop-
ment. These data indicate that the hydroxy group
adjacent to the amino group plays a crucial role in chiral
recognition. We found absorbance inversion temperatures
(AIT) in the range of 0-50 °C in many cases.21 For
example, Figure 11a shows that the absorption between
host 6 and (S)-15 is greater than that with (R)-15 below
19.9 °C. In contrast, color development with host 6 and
(R)-15 is deeper above this temperature. Although this
phenomenon should theoretically exist for any diaster-
eomeric combination of a host and a guest (if their ∆∆S
Acknowledgment. This study was partly supported
by Grants-in-Aid for Scientific Research (C), Grants-in
Aid for JSPS Fellows, the 21st Century COE Program
on Kyoto University Alliance for Chemistry from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan, and a BANYU Award in Synthetic
Organic Chemistry, Japan.
(21) Temperature-dependent reversal of the enantiomer selectivity
was reported. Naemura, K.; Fuji, J.; Ogasahara, K.; Hirose, K.; Tobe,
Y. Chem. Commun. 1996, 2749-2750.
(22) Because we cannot estimate the proportion of colorless complex
(see Scheme 1 and ref 6b), the association constants of the colored
complex between host 6 and (R)- and (S)-guests have not been
determined yet. In fact, a curious relationship was observed between
the absorbance (λmax, 570 nm) and the enantiomeric excess of guest
15 (Figure SI-2, Supporting Information). We suppose these phenom-
ena may be caused by the complicated equilibrium among colored
6-(S)-15, colored 6-(R)-15, colorless 6-(S)-15, and colorless 6-(R)-
15.
Supporting Information Available: Full experimental
details, variable-temperature UV spectra for a pair of diaster-
eomeric complexes of host 6 and 15, and the relationship
between the absorbance and the enantiomeric excess of guest
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO050387U
4616 J. Org. Chem., Vol. 70, No. 12, 2005