Recognition of dihydroxynaphthalenes by a C2-symmetric host

Article abstract of DOI:10.1016/S0040-4039(03)00073-X

A functionalized C₂-symmetric host (2) shows high affinity and substrate selectivity for dihydroxynaphthalenes.

Full text of DOI:10.1016/S0040-4039(03)00073-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1887–1890
Recognition of dihydroxynaphthalenes by a C2-symmetric host
Hae-Jo Kim,a Dohyun Moon,b Myoung Soo Lahb and Jong-In Honga,*
aSchool of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea
bDepartment of Chemistry, College of Science, Hanyang University, Ansan, Kyunggi-Do 425-791, South Korea
Received 2 December 2002; revised 30 December 2002; accepted 8 January 2003
Abstract—A functionalized C2-symmetric host (2) shows high affinity and substrate selectivity for dihydroxynaphthalenes. © 2003
Elsevier Science Ltd. All rights reserved.
While recognition of sugars or aliphatic alcohols has
been well studied by natural and artificial receptors,1
relatively fewer examples of hosts for hydroxy-substi-
tuted aromatic guests have been reported,2 even though
hydrogen bonding and p–p interactions can be
exploited for the efficient recognition of neutral
hydroxy-substituted aromatic guests in nonaqueous sol-
vents. Herein, a synthetic host utilizing both hydrogen
bonding and p–p interactions for the recognition of
dihydroxy-substituted naphthalenes is reported.
reaction mixture, indicating that no cyclization
occurred on the elimination product.
In order to determine the guest affinity to host 2,
fluorescence titration was carried out in a reverse man-
ner because the guests were highly luminescent (Fig. 3).
When adding a solution of 2 to dihydroxynaphthalene,
while maintaining the concentration of dihydroxy-
naphthalene constant, the fluorescence intensity
decreased gradually (Fig. 4).
Synthesis of the functionalized oxazoline host (2) was
carried out in three steps according to the previously
reported synthetic method.3 Conversion of terephthalic
acid to acid chloride by treatment with oxalyl chloride,
coupling with L-serine methyl ester in the presence of
TEA and activation of the resulting alcohol with mesyl
chloride, followed by cyclization in basic condition
afforded the desired product, 2 in overall 30% yield.4
Since a hydrogen in the amino acid unit is acidic, a
b-elimination product was also obtained under the
reaction condition5 (Fig. 1).
Figure 1. Synthetic scheme of the host (2).
The structure of 2 was confirmed by X-ray diffraction
1
study6 as well as by H, 13C spectra and optical proper-
ties (Fig. 2).4
From the crystal structure, it turns out that chiral
centers on the oxazoline rings are all retained as (S,S)
configuration7 during the cyclization process even
though there is a possibility of another process, elimina-
tion followed by cyclization leading to racemization.8
No proton peaks corresponding to other stereoisomeric
1
products were observed in the H NMR spectra of the
Figure 2. ORTEP drawing of 2. Selected torsional angle (°)
,
(bond lengths [A]; bond angles [°]) of C8ꢀC6ꢀC5ꢀN1: −5.4
(1.394, 1.477, 1.268; 119.57, 125.59).
* Corresponding author. E-mail: jihong@plaza.snu.ac.kr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00073-X

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H.-J. Kim et al. / Tetrahedron Letters 44 (2003) 1887–1890
This highly selective binding affinity toward 2,7-dihy-
droxynaphthalene is thought to originate from the
structure of the guest appropriate for aromatic stacking
and hydrogen bonding interactions with the host. As
suggested by the computational modeling (Fig. 6),10 the
naphthalene ring of the guest perfectly matches the
phenyl ring of the host with an interplane distance
Figure 3. Guest structures.
,
3.378 A for the maximum p–p stacking interaction. In
addition, the two hydrogen bonds between OH of the
guest and ester CꢁO of the host are rather linearly
,
arranged (DꢀH···A angle/distance=173°/1.780 A and
,
154°/1.802 A). However, the hydrogen bonds with 1,5-
and 2,6-dihydroxynaphthalenes (DꢀH···A angle/dis-
tance=144°/1.904 A and 144°/1.904 A, 167°/1.771 A
and 146°/1.833 A) are more deviated from the linearity.
Further, only half of the naphthyl group of 2,6-dihy-
droxynaphthalene matches the phenyl ring of 2, thus
presumably reducing the extent of p–p stacking
interaction.
,
,
,
,
In order to verify the aromatic stacking interaction
between host and guests, 1,5-dihydroxy-1,2,3,4-tetra-
hydronaphthalene instead of 1,5-dihydroxynaphthalene
was used as the guest. Its binding affinity was in the
range of millimolar concentration (Kd=2.1( 0.25)×10−3
M), which corresponds to 16-fold decrease in the bind-
ing affinity.11 Thus, it is concluded that there are sub-
stantial p–p stacking interactions between host and
Figure 4. Typical emission spectra (uex=347 nm, 0.20 mM in
CHCl3) of Naph-2,6-diOH at 298 K upon addition of 2.
1
naphthalene guests during the binding events. H NMR
titration revealed that the OH protons of the guest were
Table 1. Dissociation constants (Kd) between 2 and guests
a
in CHCl3
Entry
Guestb
Kd (M)
1
2
3
Naph-1,5-diOH
Naph-2,6-diOH
Naph-2,7-diOH
1.29(90.17)×10−4
1.09(90.45)×10−4
5.01(93.10)×10−6
a Reverse fluorescence titration at 298 K, [guest]=0.20 mM, [2]o=15
mM.
b uex=298 nm and uem=450 nm for Naph-1,5-diOH. uex=347 nm
and uem=375 nm for Naph-2,6-diOH. uex=284 nm and uem=346
nm for Naph-2,7-diOH.
Figure 5. Fluorescence titration of dihydroxynaphthalenes
(Naph-diOH) with 2 at 298 K, [Naph-diOH]=0.20 mM,
[2]o=15 mM. (Open circle) Naph-1,5-diOH; (filled circle)
Naph-2,6-diOH; (open rectangle) Napht-2,7-diOH.
Normalized fluorescence intensity (DF/F0) versus [2]
was analyzed by the nonlinear regression method
implemented in Sigma Plot 4.0.9 The results are shown
in Fig. 5.
Observed dissociation constants for 1,5- and 2,6-dihy-
droxynaphthalenes are in the range of submillimolar
affinity; however, they are in the range of micromolar
affinity (more than 20-fold increase) in the case of
2,7-dihydroxynaphthalene, as summarized in Table 1.
Figure 6. Energy-minimized structure for the complex
between 2 and 2,7-dihydroxynaphthalene in chloroform sol-
vation model.

H.-J. Kim et al. / Tetrahedron Letters 44 (2003) 1887–1890
1889
1306; (c) Aoyama, Y.; Tanaka, Y.; Sugara, S. J. Am.
Chem. Soc. 1989, 111, 5397–5404; (d) Tsukagoshi, K.;
Shinkai, S. J. Org. Chem. 1991, 56, 4089–4091; (e) Inoue,
M.; Takahashi, K.; Nakazumi, H. J. Am. Chem. Soc.
1999, 121, 341–345; (f) Davis, A. P.; Wareham, R. S.
Angew. Chem., Int. Ed. Engl. 1999, 38, 2978–2996; (g)
Rusin, O.; Kral, V. Chem. Commun. 1999, 2367–2368; (h)
Schrader, T. J. Am. Chem. Soc. 1998, 120, 11816–11817;
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N.; Ogoshi, H. J. Am. Chem. Soc. 1997, 119, 8991–9001;
(j) Kim, Y.-H.; Hong, J.-I. Angew. Chem., Int. Ed. Engl.
2002, 41, 2947–2950.
2. (a) Sheridan, R. E.; Whitlock, H. W., Jr. J. Am. Chem.
Soc. 1988, 110, 4071–4073; (b) Whitlock, B. J.; Whitlock,
H. W. J. Am. Chem. Soc. 1990, 110, 3910–3915; (c)
Sijbesma, R. P.; Kentgens, A. P. M.; Lutz, E. T. G.; van
der Maas, J. H.; Nolte, R. J. M. J. Am. Chem. Soc. 1993,
115, 8999–9005; (d) Gieling, G. T. W.; Scheeren, H. W.;
Israel, R.; Nolte, R. J. M. Chem. Commun. 1996, 241–
243.
3. (a) Kim, H.-J.; Kim, Y.-H.; Hong, J.-I. Tetrahedron Lett.
2001, 42, 5049–5052; (b) Lee, S.-H.; Yoon, J.; Nakamura,
K.; Lee, Y.-S. Org. Lett. 2000, 2, 1243–1246.
4. Typical experimental and characterizations for 2 are as
follows;
Figure 7. Job’s plot between 2 and dihydroxynaphthalenes at
298 K in CHCl3, [G]+[H]=0.20 mM. (Open rectangle) Naph-
2,7-diOH; (filled circle) Naph-2,6-diOH.
broadened upon the addition of the host, indicating the
participation of OHs in H-bond interactions with the
host. Furthermore, 1H NMR titrations showed the
upfield shifts (Dl=−0.017 to −0.031 ppm) of the aro-
matic protons of dihydroxynaphthalenes upon addition
of 2, suggesting that the aromatic groups of 2 and
dihydroxynaphthalenes are in vicinity to each other
upon complexation
To a solution of 144.6 mg (0.393 mmol) of 1 and 0.30 mL
of TEA (4 equiv.) in 10 mL of dichloromethane was
added dropwise 2 equiv. of methanesulfonyl chloride (100
mL, 1.29 mmol) in 5 mL of dichloromethane at 0°C under
nitrogen. Resulting white suspension was stirred for addi-
tional 24 h under nitrogen. All volatiles were removed
under reduced pressure. Column chromatography on a
silica gel (CH2Cl2:MeOH=20:1, Rf=0.48) afforded the
desired product as a white solid in 30% yield. Recrystal-
lization was carried out by slow evaporation of the
solution (EtOAc:CH2Cl2=3:1) at 0°C.
The stoichiometry between host and guest was deter-
mined by a continuous variation plot obtained by
taking traces of fluorescent intensity (Fig. 7).12 It was
evidently shown that a 1:1 complex between host and
guest was formed.
In conclusion, a functionalized C2-symmetric oxazoline
host (2) was shown to bind dihydroxynaphthalenes with
high affinity and high selectivity. Comparing with pre-
vious hosts possessing rigidly defined cavities and con-
cave H-bond acceptors capable of binding
hydroxy-substituted aromatic guests,2 the high affinity
for dihydroxynaphthalenes and high selectivity for 2,7-
dihydroxylnaphthalene by the oxazoline host (2) are
remarkable in that 2 is acyclic and has only two rather
weak H-bond acceptors and phenyl rings for the aro-
matic stacking interaction. The high affinity and selec-
tivity are due to the rigid host structure, appropriately
arranged H-bond accepting ester functionality and
phenyl ring of the oxazoline host.
1H NMR (300 MHz, CDCl3): l 8.07 (s, 4H of aromatic
H), 5.00 (dd, J=11 Hz, 8.0 Hz, 2H of C*H), 4.76 (dd,
J=11 Hz, 8.8 Hz, 2H of CH2O), 4.66 (dd, J=11 Hz, 8.8
Hz, 2H of CH2O), 3.86 (s, 6H of CO2CH3). Assignments
based on HMQC.
13C NMR (75 MHz, CDCl3): l 171.8, 166.0 (carbonyl
and oxazoline), 130.3, 129.0 (aromatic), 70.2 (CH2O),
69.0 (C*H), 53.3 (CO2CH3). Assignments based on
DEPT32, DEPT45, DEPT135 and HMQC.
[h]2D3 +151.8 (c 0.485, CH2Cl2); Mass (FAB+, m-NBA):
m/z 333 ([M+H]).
5. The ratio of a cyclization product to an elimination
product was 10:7 based on 1H NMR spectrum after
filtration of the reaction mixture through a short plug of
silica gel.
Acknowledgements
6. Crystal data: C16H16N2O6, Mr=332.31, orthorhombic
Financial support from the CMDS (KOSEF) is grate-
fully acknowledged. We are also grateful to Dr. H. S.
Park in the Hamilton group for helpful discussions on
fluorescence titration. H.J.K. thanks the Ministry of
Education for the award of a BK 21 fellowship.
,
C2221, a=4.4516(10), b=10.888(2), c=31.971(7) A, V=
3
1549.6(6) A , F(000)=696, Z=4, v=0.111 mm−1, Dc=
,
1.424 Mg/m3, 4811 reflection measured, 1857 unique(Rint
0.0211) with I>2|(I). Final R1 and wR2 are 0.0391 and
0.1036 with absolute structure parameter of −0.5(1).
7. Flack x parameter=−0.4774 for (S,S), whereas it is
1.4588 for (R,R)-configuration in X-ray crystallography,
which led to the conclusion of the resulting structure as
(S,S)-configuration. For retention of the configuration
during the functionalized oxazoline syntheses, see: (a)
Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J.
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in M.
10. We obtained two global minimum structures by compu-
tational calculation, MacroModel 7.0; one is a S-shaped
structure like the X-ray crystal structure, the other is
U-shaped. Although the host itself shows the S-shaped
structure, the complex form of the host is supposed to
have U-shaped structure because the rotational barrier
between U- and S-shaped structure of the host is less
than 5 kcal/mol in chloroform.
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9. Modified fluorescence titration equation from the 1:1
NMR titration equation was used.
Fobs−Fo
F
−F ([H] +[G] +K )−ꢂ([H] +[G] +K )2−4[H] [G]
ꢀ ꢁ
HG
o
o
o
d
o
o
d
o
o
11. 1H NMR titration was carried out because the guest was
nonfluorescent, Kd=2.1( 0.25)×10−3 M, [H]=1.0 mM,
[G]o=20 mM in CDCl3 at 298 K.
12. Job, P. Ann. Chim. 1928, 9, 113–203. The complex con-
centration, [HG] was calculated by the equation, [HG]=
DF/F0×[H].
=
Fo
Fo
2[H]o
where Fo is initial fluorescence intensity, Fobs is observed
fluorescence intensity as a dependent variable (H=dihy-
droxynaphthalenes, G=2), [H]o is host concentration
which is constant, [G]o is guest concentration as an