Colorimetric recognition of the length of α,ω-diamines in water

Article abstract of DOI:10.1016/j.tetlet.2007.01.099

Two types of host molecules based on phenolphthalein and two crown ethers have been constructed. These hosts made it possible to recognize the length of α,ω-diamines and transformed the binding events into detectable changes in color in an aqueous buffer

Full text of DOI:10.1016/j.tetlet.2007.01.099

Tetrahedron Letters 48 (2007) 2135–2138
Colorimetric recognition of the length of a,x-diamines in water
Kazunori Tsubaki,* Daisuke Tanima,ꢀ Takahiro Sasamori,
Norihiro Tokitoh and Takeo Kawabata
Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan
Received 13 December 2006; revised 17 January 2007; accepted 19 January 2007
Available online 24 January 2007
Abstract—Two types of host molecules based on phenolphthalein and two crown ethers have been constructed. These hosts made it
possible to recognize the length of a,x-diamines and transformed the binding events into detectable changes in color in an aqueous
buffer solution.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Many supramolecular chemists have exerted consider-
able effort to establish useful methodologies for molecu-
lar recognition in water. In some cases, hydrophobic
interaction as well as desolvation effect have been used
as a driving force in the complexation of the desired
molecules. Cyclodextrin derivatives1 and rigid cages
composed of aromatic rings2 are examples of this ap-
proach. Recently, many functional host molecules based
on coordinative interaction as a main driving force have
been reported.3 In contrast, it has generally been difficult
to develop host molecules using hydrogen bonding,
since the surrounding water molecules can act as hydro-
gen donors and/or acceptors and disturb the desired
hydrogen bonding between two molecules. Further-
more, non-covalent forces derived from electrostatic
interaction, such as coulomb force and ion–dipole inter-
action, are also weakened according to the dielectric
constant (e) of the solvent.4 For all of these reasons,
more effective systems for molecular recognition in
water which use a combination of hydrogen bonding
and some other attractive interactions have been consid-
ered.5 We focused on the combination of convergent
multiple hydrogen bonds, which provide a clear direc-
tionality between target molecules, and long-range but
non-directional coulomb force between the two charges
to construct a molecular recognition system in water.
Specifically, we have been investigating whether phenol-
phthalein derivatives possessing two crown ethers could
be used to recognize the length of guest a,x-diamines
and reflect this information through the development
of a purple color in MeOH.6 In the present Letter, we
report the colorimetric recognition of the length of
a,x-diamines using polymer-supported host 1 and
water-soluble host 2 in a completely aqueous medium
(Fig. 1).
The synthetic route to polymer-supported host 1 and
water-soluble host 2 is outlined in Scheme 1. Two
carboxylic groups and a phenolic hydroxy group of
4-hydroxy phthalic acid (3) were protected by methoxy-
methyl (MOM) to give 4 in 93% yield. Two MOM esters
of 4 were selectively hydrolyzed and treated with acetic
anhydride to afford the phthalic anhydride 5 in 86%
overall yield in two steps. Crown ether 6 was treated
with t-BuLi and allowed to react with the phthalic anhy-
dride 5 to afford 7 with a small amount of its regio-
isomer in 90% yield. The phenolic MOM group was
removed by trimethylsilyl bromide in the presence of
˚
molecular sieves 4 A to afford the key intermediate 8
in 94% yield.7 To synthesize host 1, a methoxycarbon-
ylmethyl group was introduced to the phenolic hydroxy
O
O
O
O
O
O
O
O
I
OH O
OH O
Me3N
NH
O
O
O
O
O
O
O
O
O
O
OH
O
OH
O
O
O
O
O
O
*
Corresponding author. Tel.: +81 774 38 3191; fax: +81 774 38
3197; e-mail: tsubaki@fos.kuicr.kyoto-u.ac.jp
Host 1
Host 2
ꢀ JSPS research fellow.
Figure 1. Structures of hosts 1 and 2.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.099

2136
K. Tsubaki et al. / Tetrahedron Letters 48 (2007) 2135–2138
HO
CO2H
CO2H
MOMO
CO2MOM
(b,c)
(a)
CO2MOM
3
4
O
O
O
O
O
OR2
O
MOMO
(d)
O
Figure 2. Structure of host 2 (stereo view). Unconcerned hydrogen
atoms and a water molecule were omitted for clarity.
O
O
O
5
O
R1O
OR2
O
O
O
O
and DMAP. The effective introduction of sufficient 11
on amino groups of the resin was judged by (1) negative
ninhydrin test and (2) clear and homogeneous purple
coloration against aqueous sodium hydroxide solution.
To construct host 2, the introduction of a dimethyl-
amino side chain to the phenolic hydroxy group of the
key intermediate 8 furnished 12 (90%), and the deprotec-
tion of two allyl groups gave 13 in 80% yield. Finally,
methylation of an amino group of 13 gave the water-
soluble quaternary ammonium host 2 in 68% yield.
The water-solubility of host 2 was approximately
1 · 10À1 M.
O
O
O
O
O
O
7: R1 = MOM, R2 = allyl
8: R1 = H, R2 = allyl
9: R1 = CH2CO2Me, R2 = allyl
10: R1 = CH2CO2Me, R2 = H
11: R1 = CH2CO2H, R2 = H
Host 1
12: R1 = (CH2)3N(Me)2, R2 = allyl
13: R1 = (CH2)3N(Me)2, R2 = H
Host 2
(e)
(f)
(g)
(h)
(j)
Br
(i)
6
(k)
(l)
Colorless crystals of host 2 were precipitated from meth-
anol-d4 in hydrated form and the structure of host 2 was
determined by X-ray analysis (Fig. 2). Interestingly,
iodide anion is located among three aromatic rings, a
methylene group in the crown ether, and a methyl group
of the ammonium group (see Supplementary data). The
distances from the iodide anion to CH in these moieties
Scheme 1. Synthesis of hosts 1 and 2. Reagents and conditions: (a)
MOMCl, K2CO3, 93%; (b) LiOH, 87%; (c) Ac2O, 99%; (d) 6, t-BuLi,
90% (e) TMSBr, MS 4 A, 94%; (f) BrCH2CO2Me, K2CO3, 99%; (g)
Pd(PPh3)4, NaBH4, 86%; (h) KOH, quant.; (i) amino PEGA resin,
WSCÆHCl, DMAP; (j) MsO(CH2)3NMe2ÆHCl,2e K2CO3, 90%; (k)
Pd(PPh3)4, NaBH4, 80%; (l) MeI, 68%.
˚
˚
are within 3.36 A, which is comparable to the sum of the
group of 8 to afford 9 in quantitative yield. After the
deprotection of allyl groups under Pd(PPh3)4 and
sodium borohydride (86%),8 methyl ester 10 was hydro-
lyzed by KOH to afford 11. The deprotected skeleton 11
was smoothly loaded on amino PEGA resin (amino
polyethylene glycol polyacrylamide resin, 0.3–0.4 mmol/g
resin, 50–100 mesh, Novabiochem) under WSCÆHCl
˚
van der Waals radii of hydrogen (1.2 A) and iodine
˚
(2.15 A). Thus, the iodide anion is captured by attractive
CH–I interactions.9
The coloration of polymer-supported host 1 in the pres-
ence of a,x-diamines of various lengths was investigated
Figure 3. The coloration of polymer supported host 1 against a,x-diamines (n = 6 and 9). Reagents and conditions: (a–c) MeOH, [a,x-
diamine] = 2.0 · 10À3 M, (a) blank, (b) n = 6, (c) n = 9; (d–f) HEPES buffer (pH 8.0, 0.6 M, titrant = NaOH), [a,x-diamine] = 2.0 · 10À2 M, (d)
blank, (e) n = 6, (f) n = 9.

K. Tsubaki et al. / Tetrahedron Letters 48 (2007) 2135–2138
2137
(Fig. 3).10 When a,x-diamines with 7–10 (7 6 n 6 10)
5
Abs570/Abs390
n
methylene chains were added to host 1 in methanol solu-
tion, monotonous purple coloration was observed on
the beads (Fig. 3c). In contrast, for a,x-diamines
(n 6 6), no coloration was detected (Fig. 3b). Thus,
polymer-supported host 1 maintained its ability to dis-
criminate the length of a,x-diamines and reflected this
information as a change in color. However, the degree
of coloration is slight and there is only a small difference
in coloration among a,x-diamines (7 6 n 6 10). In
aqueous HEPES buffer, host 1 showed almost no color-
ation under the same guest concentration, and nearly
identical colorations were observed with a 10-fold higher
concentration (Fig. 3c vs f). These results indicated that
(even though the local concentration of host 1 on the
bead surface should be high)11 the side chains of amino
PEGA resin may prevent complexation between the
binding sites of host 1 and guests of diamines, in addi-
tion to the inherent difficulties, that is, molecular recog-
nition using hydrogen bonding in water.
4
3
2
pH = 7.9
5
6
1.83
2.08
2.83
3.92
4.75
4.06
7
8
9
1
10
5
6
7
8
9
10
NH2-(CH2)n-NH2
Figure 5. The ratio of the absorbance at 570 and 390 nm.
bance at 570 nm (kmax) and 390 nm at pH 7.9 (Fig. 5).
This measurement showed that host 2 had greater affin-
ity towards diamine (n = 9) than for those of other
lengths.
In conclusion, we have developed two types of phenol-
phthalein-based hosts for molecular recognition in
water. While the sensitivity was not satisfactory, these
molecules, especially water-soluble host 2, could be used
to recognize the length of a,x-diamines and transformed
binding events into detectable changes in color in a buf-
fered aqueous solution. Thus, even in a completely aque-
ous medium, a molecular recognition system that uses
both hydrogen bonding and coulomb force could be
constructed. We are currently developing more sensitive
and/or fluorescent functional molecules for use in a
completely aqueous medium.
Next, we evaluated the performance of water-soluble
host 2 in aqueous HEPPSO buffer at two pHs. Figures
4a and b show UV–vis spectra of host 2 with diamines
of various lengths (5 6 n 6 10) at pH 7.7 and pH 7.9,
respectively. While host 2 slightly responded to the pH
of the solution in the absence of guest diamines, host 2
unambiguously recognized the length of diamines with
a change in color that depended on the length of the di-
amine. Color development with host 2 and diamines was
the deepest with the guest diamine of n = 9, and the de-
gree of coloration was much less with both longer and
shorter molecules. These phenomena could be detected
by the naked eye (Fig. 4c).
Acknowledgments
The authors are sincerely grateful to Professor Hideaki
Hioki (Tokushima Bunri University) for useful sugges-
tions regarding solid-phase synthesis and Dr. Valluru
Krishna Reddy for reading the manuscript. This study
was partly supported by Grants-in-Aid for Scientific Re-
search (No. 18390003) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, and
from the Foundation for Pharmaceutical Sciences,
Japan.
To quantify the change in color development,12 a ratio-
metric measurement13 was carried out using the absor-
1.5
1.5
n = 10
n = 9
n = 8
n = 7
n = 6
n = 5
Host 2
n = 10
n = 9
n = 8
n = 7
n = 6
n = 5
Host 2
Supplementary data
0.5
0
0.5
0
Full experimental details and crystallographic informa-
tion file (CIF) of host 2 (CCDC 624293). Supplementary
data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2007.01.099.
400
500
600
400
500
600
wavelength (nm)
wavelength (nm)
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