An artificial receptor for dimethyl aspartate

Article abstract of DOI:10.1021/jo950567b

[trans-5,15-Bis(2,7-dihydroxy-1-naphthyl)-2,3,7,8,12,13,17,18-octaethy lporphyrinato]zinc(II) (1), a trifunctionalized porphyrin host, was prepared as a receptor for amino acid derivatives, particularly those having a hydrogen-bonding site in the side chain. The free energy changes for the binding of Leu-OMe, Asp-OMe, and Glu-OMe to 1 were -5.8 kcal/mol, -6.6 kcal/mol, and -5.9 kcal/mol, showing a selectivity for Asp-OMe. ¹H NMR titration experiments indicated that three simulteneous attractive interactions, one coordination interaction, and two hydrogen-bonding interactions, are operating in the host-guest complex. The preference for Asp-OMe over Glu-OMe was found to originate from the favorable enthalpy term for Asp-OMe. The free energy change, the enthalpy change, and the entropy change were determined and split into contributions arising from coordination interaction and from hydrogen-bonding interactions by use of reference hosts. Comparison of enthalpy and entropy changes suggests that the host-guest complex becomes more ordered as the number of recognition pairs increases.

Full text of DOI:10.1021/jo950567b

J . Org. Chem. 1996, 61, 539-548
539
An Ar tificia l Recep tor for Dim eth yl Asp a r ta te
Tadashi Mizutani,* Takeshi Murakami, Takuya Kurahashi, and Hisanobu Ogoshi*
Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-01, J apan
Received March 23, 1995 (Revised Manuscript Received August 18, 1995X)
[trans-5,15-Bis(2,7-dihydroxy-1-naphthyl)-2,3,7,8,12,13,17,18-octaethylporphyrinato]zinc(II) (1), a
trifunctionalized porphyrin host, was prepared as a receptor for amino acid derivatives, particularly
those having a hydrogen-bonding site in the side chain. The free energy changes for the binding
of Leu-OMe, Asp-OMe, and Glu-OMe to 1 were -5.8 kcal/mol, -6.6 kcal/mol, and -5.9 kcal/mol,
showing a selectivity for Asp-OMe. 1H NMR titration experiments indicated that three simultaneous
attractive interactions, one coordination interaction, and two hydrogen-bonding interactions, are
operating in the host-guest complex. The preference for Asp-OMe over Glu-OMe was found to
originate from the favorable enthalpy term for Asp-OMe. The free energy change, the enthalpy
change, and the entropy change were determined and split into contributions arising from
coordination interaction and from hydrogen-bonding interactions by use of reference hosts.
Comparison of enthalpy and entropy changes suggests that the host-guest complex becomes more
ordered as the number of recognition pairs increases.
Mechanism of selectivity of molecular recognition of
biologically active molecules, especially of flexible guest
molecules, is interesting since several factors are com-
petitively contributing to the thermodynamics of the
recognition process. Elementary processes such as at-
tractive forces between the host and the guest, confor-
mational changes in host and guest, and solvation state
changes during the host-guest complex formation all
make important contributions to the recognition process.
Entropic contribution owing to the restriction of motion
upon complexation is also important for a flexible guest.1
Evaluation of each recognition interaction by use of
reference host and guest has been proved to be helpful
in understanding multipoint host-guest complexation as
exemplified by several previous papers.2,3 Thermody-
namic parameters (∆G°, ∆H°, and ∆S°) for molecular
recognition have been studied for many host-guest
systems.4 It should be noted that the values of ∆G°, ∆H°,
and ∆S° for the overall process involve contributions from
many elementary processes, so a unifying interpretation
is difficult to make.5 By using less polar solvents, we can
reduce the solvation interaction to minimal and focus on
the host-guest interaction.6 Under these conditions, the
entropy changes (∆S°) directly reflect the changes in
motion of the host-guest molecules. We can estimate
how effectively the certain host-guest interaction in-
duces the ordered state in the host-guest complex by
monitoring entropy changes.
Intermolecular interaction within the host-guest com-
plex can be classified into two categories. The first one
is the interaction between some specific groups, which
may be called point-point interaction or point recogni-
tion. The second one is the interaction between the whole
molecules such as charge transfer interaction between
the HOMO of a molecule and the LUMO of another and
hydrophobic interaction. This can be called surface-
surface interaction. We focus on point-point interactions
in the present paper. We regard the overall host-guest
interaction as being equal to the sum of the interaction
between functional groups. The free energy changes, the
enthalpy changes, and the entropy changes of the rec-
ognition process can be split into contributions arising
from each pairing of recognition groups by assuming the
hypothetical intermediate thermodynamic states. These
changes can be experimentally determined by use of
reference host or reference guest.7
Studies of amino acid recognition have been carried
out mostly for aromatic or hydrophobic amino acid
derivatives.8 To our knowledge, studies of recognition
of amino acid derivatives with polar side chains are rare.9
For recognition of such amino acids, at least three
recognition groups are necessary. For effective interac-
tion between functional groups, internal rotational free-
dom of the amino acid derivative should be frozen.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Mizutani, T.; Ema, T.; Ogoshi, H. Tetrahedron 1995, 51, 473.
(2) (a) Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi,
H. J . Am. Chem. Soc. 1990, 112, 3145. (b) Aoyama, Y.; Asakawa, M.;
Matsui, Y.; Ogoshi, H. J . Am. Chem. Soc. 1991, 113, 6233. (c) Hayashi,
T.; Miyahara, T.; Hashizume, N.; Ogoshi, H. J . Am. Chem. Soc. 1993,
115, 2049. (d) Mizutani, T.; Ema, T.; Yoshida, T.; Kuroda, Y.; Ogoshi,
H. Inorg. Chem. 1993, 32, 2072. (e) Mizutani, T.; Ema, T.; Tomita, T.;
Kuroda, Y.; Ogoshi, H. J . Am. Chem. Soc. 1994, 116, 4240. (f) Hayashi,
T.; Miyahara, T.; Aoyama, Y.; Nonoguchi, M.; Ogoshi, H. Chem. Lett.
1994, 1749.
(3) Schneider, H.-J .; Shiestel, T.; Zimmermann, P. J . Am. Chem.
Soc. 1992, 114, 7698.
(4) (a) Canceill, J .; Lacombe, L.; Collet, A. C.R. Hebd. Seances Acad.
Sci., Ser. 2 1987, 304, 815. (b) Tabushi, I.; Mizutani, T. Tetrahedron
1987, 43, 1439. (c) Williams, K.; Askew, B.; Ballester, P.; Buhr, C.;
J eong, K. S.; J ones, S.; Rebek, J ., J r. J . Am. Chem. Soc. 1989, 111,
1090. (d) Stauffer, D. A.; Barrans, R. E., J r.; Dougherty, D. A. J . Org.
Chem. 1990, 55, 2762. (e) Harvey, N. G.; Rose, P. L.; Mirajovsky, D.;
Arnett, E. J . Am. Chem. Soc. 1990, 112, 3547. (f) Mazor, M. H.;
McCammon, J . A.; Lybrand, T. P. J . Am. Chem. Soc. 1990, 112, 4411.
(g) Adrian, J . C., J r.; Wilcox, C. S. J . Am. Chem. Soc. 1991, 113, 678.
(h) Smithrud, D. B.; Sanford, E. M.; Chao, I.; Ferguson, S. B.;
Carcanague, D. R.; Evanseck, J . D.; Houk, K. N.; Diederich, F. Pure
Appl. Chem. 1990, 62, 2227. (i) Cox, J . P. L.; Nicholls, I. A.; Williams,
D. H. J . Chem. Soc., Chem. Commun. 1991, 1295. (j) Diederich, F.;
Smithrud, D. B.; Sanford, E. M.; Wyman, T. B.; Ferguson, S. B.;
Carcanague, D. R.; Chao, I.; Houk, K. N. Acta Chem. Scand. 1992, 46,
205. (k) Inoue, Y.; Hakushi, T.; Liu, Y.; Tong, L.; Shen, B.; J in, D. J .
Am. Chem. Soc. 1993, 115, 475.
(5) Recently, interpretation of the thermodynamic data (∆G°, ∆H°,
and ∆S°) in terms of solvation term and conformational energy term
is reported, see ref 4k.
(6) For importance of solvation energy, see: (a) Adrian, J . C., J r.;
Wilcox, C. S. J . Am. Chem. Soc. 1992, 114, 1398. (b) Carcanague, D.
R.; Knobler, C. B.; Diederich, F. J . Am. Chem. Soc. 1992, 114, 1515.
(c) Bonar-Law, R. P.; Sanders, J . K. M. J . Am. Chem. Soc. 1995, 117,
259. (d) Mizutani, T.; Murakami, T.; Matsumi, N.; Kurahashi, T.;
Ogoshi, H. J . Chem. Soc., Chem. Commun. 1995, 1257.
(7) Ogoshi, H.; Ema, T.; Kato, Y.; Mizutani, T.; Kuroda, Y. Supramol.
Chem. 1995, 6, 115.
0022-3263/96/1961-0539$12.00/0 © 1996 American Chemical Society

540 J . Org. Chem., Vol. 61, No. 2, 1996
Mizutani et al.
Ch a r t 1
Compensation of ∆H and ∆S is expected for such a
process. Rizzarelli and co-workers9a reported that his-
tidine forms a more stable complex than does histamine
with Cu2+ with an additional AlaO- ligand in water. The
stronger binding of histidine over histamine is entropy
driven. Because the complexation experiments of Riz-
zarelli were carried out in water, the enthalpy term and
the entropy term should be much affected by the solva-
tion state changes. Other interactions such as conforma-
tion energy, hydrogen-bonding energy, and coordination
energy are thus in some cases difficult to observe in
water. To probe these interactions, use of organic solvent
is advantageous.
In the present paper, we report the preparation of a
trifunctional porphyrin host as a model receptor for
dimethyl aspartate and the comparative studies of the
binding of amino acid derivatives by the trifunctional as
well as difunctional and monofunctional porphyrin hosts.
The binding studies were performed in chloroform to
minimize the contribution from solvation effects to the
thermodynamic parameters.
Resu lts
P r ep a r a tion of Tr ifu n ction a l P or p h yr in Host 1.
[trans-5,15-Bis(2,7-dihydroxy-1-naphthyl)-2,3,7,8,12,13,-
17,18-octaethylporphyrinato]zinc(II) (1) (Chart 1) was
prepared by condensation of 3,3′,4,4′-tetraethyl-2,2′-
dipyrrylmethane with 2-hydroxy-7-methoxy-1-naphthal-
dehyde (Scheme 1). The precursor aldehyde 12 was
prepared from 2,7-dihydroxynaphthalene, by protecting
the two hydroxyl groups with methyl iodide, followed by
formylation by Vilsmeier reaction and the selective
deprotection of the 2-hydroxyl group with BBr3. As a
direct approach, 2,7-dihydroxy-1-naphthaldehyde was
first condensed with the dipyrrylmethane to give 5,15-
bis(2,7-dihydroxy-1-naphthyl)-2,3,7,8,12,13,17,18-octa-
ethylporphyrin (15 and cis isomer of 15). Separation of
the trans isomer from the cis isomer, however, was
unsuccessful with this compound. Therefore we prepared
5,15-bis(2-hydroxy-7-methoxy-1-naphthyl)-2,3,7,8,12,13,-
17,18-octaethylporphyrin (13 and 14) first. With these
porphyrins, the trans isomer was easily separated from
the cis isomer by column chromatography. The methoxy
group was then deprotected by BBr3, and zinc was
inserted in a usual manner to yield 1. The structure of
the cis isomer 13 was confirmed by reacting it with 1,8-
dibromooctane in K2CO3/acetone to yield the bridged
porphyrin 16 (Scheme 2). The bridged porphyrin 16 was
rins,10 we expect that host 1 shows only one binding
constant. Host 3 is a reference host, which lacks a pair
of 7-hydroxyl groups on the naphthyl rings. The cis
isomers of these hosts, host 4 and host 5, also serve as
trifunctional hosts. Lack of the symmetry, however,
results in the two different coordination sites, and we
expect to obtain two binding constants for 4 and 5.
Deter m in a tion of th e Bin d in g Con sta n ts betw een
r-Am in o Acid Ester s a n d P or p h yr in Hosts. The
binding constants between amino acid esters and host 1
were determined by following the absorbance changes in
the Soret band of 1 upon the addition of the guest
molecules. The guest molecules used were leucine meth-
yl ester (Leu-OMe), valine methyl ester (Val-OMe),
alanine methyl ester (Ala-OMe), tryptophan methyl ester
(Trp-OMe), aspartic acid dimethyl ester (Asp-OMe),
glutamic acid dimethyl ester (Glu-OMe), proline methyl
ester (Pro-OMe), cysteine methyl ester (Cys-OMe), and
methionine methyl ester (Met-OMe). All these amino
1
identified by the H-1H COSY and FAB-mass spectros-
copy.
Host 1 has C2h symmetry, and owing to this symmetry,
two identical coordination sites exist. Host 1 has a zinc
ion and two hydroxyl groups in a binding pocket. Be-
cause only 1:1 complexation is known for zinc porphy-
(8) (a) Rebek, J ., J r.; Nemeth, D. J . Am. Chem. Soc. 1985, 107, 6738.
(b) Nakagawa, T.; Shibukawa, A.; Kaihara, A.; Itamochi, T.; Tanaka,
H. J . Chromatogr. 1986, 353, 399. (c) Pirkle, W. H.; Pochapsky, T. C.
J . Am. Chem. Soc. 1987, 109, 5975. (d) Andersson, L. I.; O’Shannessy,
D. J .; Mosbach, K. J . Chromatogr. 1990, 513, 167. (e) Murakami, Y.;
Ohno, T.; Hayashida, O.; Hisaeda, Y. J . Chem. Soc., Chem. Commun.
1991, 950. (f) Galan, A.; Andreu, D.; Echavarren, A. M.; Prados, P.; de
Mendoza, J . J . Am. Chem. Soc. 1992, 114, 1511. (g) Kuroda, Y.; Kato,
Y.; Higashioji, T.; Ogoshi, H. Angew. Chem. 1993, 105, 774.
(9) (a) Borghesani, G.; Pulidori, F.; Remelli, M.; Purrello, R.;
Rizzarelli, E. J . Chem. Soc., Dalton Trans. 1990, 2095. (b) Ikeura, Y.;
Kurihara, K.; Kunitake, T. J . Am. Chem. Soc. 1991, 113, 7342. (c)
Heath, J . G.; Arnett, E. M. J . Am. Chem. Soc. 1992, 114, 4500. (d)
Liu, R.; Still, W. C. Tetrahedron Lett. 1993, 34, 2573.
(10) (a) Miller, J . R.; Dorough, G. D. J . Am. Chem. Soc. 1952, 74,
3977. (b) Kirksey, C. H.; Hambright, P.; Storm, C. B. Inorg. Chem.
1969, 8, 2141.

Artificial Receptor for Dimethyl Aspartate
J . Org. Chem., Vol. 61, No. 2, 1996 541
Sch em e 1
acid esters were L-isomers. The titration was carried out
at 25 °C in CHCl3 containing either 1% ethanol or, 0.1%
amylene as a stabilizer or containing no stabilizer. Even
a small amount of ethanol present in chloroform results
in a reduced binding constant. This reduction in the
binding constant is due to the interaction between
ethanol and the recognition groups (Zn, CdO, and OH).
UV-vis titration experiments were carried out both in
1%EtOH-CHCl3 and in EtOH-free CHCl3. 1H NMR and
variable-temperature UV-vis titration experiments were
carried out in EtOH-free CHCl3 or CDCl3. The binding
constants in amylene-containing chloroform agreed with
those in pure chloroform within experimental errors.
In the UV-vis titration experiment, the absorbance at
414 nm increased and that at 428 nm decreased isos-
bestically as the guest was added. The binding constants
were determined by curve fitting to the absorbance
changes at 414 and 428 nm on the assumption of a 1:1
complexation. The standard deviation of the binding
constant was within 5%. The binding constants for host
3 were similarly determined. Host 6 is a mixture of cis
and trans atropisomers, and the spectral changes upon
guest addition were more complicated. At least three
configurations are possible for this host: one configura-
tion of a complex of trans-6 and guest and two configura-
tions of a complex of cis-6 and guest depending on the
coordination site occupied by the guest (Figure 1).
Therefore only the absorbance change at 428 nm was
used to determine a single binding constant, and the
binding constant obtained should be regarded as a sum
for those configurations. The binding constants are
summarized in Table 1.
Sch em e 2
F igu r e 1. Binding site of porphyrin hosts. The trans isomer
has only one kind of binding pocket, while the cis isomer has
two binding pockets.

542 J . Org. Chem., Vol. 61, No. 2, 1996
Mizutani et al.
Ta ble 1. Bin d in g Con sta n ts (K, M-1) betw een Hosts 1-3
a n d Am in o Acid Ester s in CHCl3 (Eith er Con ta in in g 1%
Eth a n ol or No Ad d itive) a t 25 °C
Ta ble 3. Com p lexa tion -In d u ced Sh ift Obser ved in Host
1a
∆δ (ppm)
K(1) K(2) K(3) K(1)/K(3) K(2)/K(3) solventa
Leu-OMe
Asp-OMe
Glu-OMe
Leu-OMe
Val-OMe
Ala-OMe
Trp-OMe 18200 4140
Asp-OMe 20900
Glu-OMe 7820
Leu-OMe 17800
Asp-OMe 69800
Glu-OMe 24000
Pro-OMe 69000
Cys-OMe
Met-OMe
7620 3310
7800 2460
4010 1080
6010
4490
1490
5720
1560
890
13200
2850
2420
1.27
1.74
2.69
3.18
13.4
8.77
1.35
0.55
0.55
0.72
0.72
0.62
0.54
a
a
a
a
a
a
b
b
b
a
a
a
2-OH
7-OH
naphthyl 8-H
0.57
0.40
-0.05
0.95
0.97
-0.16
0.67
0.98
-0.09
a
500 MHz 1H NMR was obtained in CDCl3 at either 30 °C (Asp-
OMe and Glu-OMe) or 40 °C (Leu-OMe), [1] ) 5.37 × 10-5 to 1.86
× 10-4 M, [guest] ) 0 - (2.57 × 10-3) M.
960
480
24.5
9.92
hydrogens bonding in this binding pocket because the
geometry of the guest does not fit to the binding pocket.
The difference between binding pockets of 7OH-7OH-
Zn and 7OH-2OH-Zn is not clear. It may be attribut-
able to the conformational energy of the bound guest.
1H NMR Stu d ies of th e Bin d in g. The 1H NMR
spectral changes of host 1 upon addition of Leu-OMe,
Asp-OMe, and Glu-OMe were recorded in CDCl3. The
hydroxyl protons of host 1 gave two resolved signals at
5.20 and 4.17 ppm in CDCl3. Both signals were shifted
downfield and the naphthyl H-8 proton shifted upfield
by adding the guest. These complexation-induced shifts
(CIS) are shown in Figure 2 and Table 3. The curves in
Figure 2 are drawn by a least-squares curve fitting to
the following equation:
6470
6340
a
a, CHCl3 containing 1% ethanol; b, CHCl3 free from ethanol.
Ta ble 2. Com p a r ison of Bin d in g Con sta n ts (K, M-1) of
Asp -OMe by Th r ee-P oin t Recogn ition Hosts in CHCl3
Con ta in in g 1% Eth a n ol a t 25 °Ca
binding sites
K(7OH,7OH,Zn)
K(7OH,2OH,Zn)
K(2OH,2OH,Zn)
17 600
10 450
4300
a
The binding constants for each binding site were calculated
from the following equations: K(7OH,7OH,Zn) ) K(4-Asp-OMe)
-
K(2OH,2OH,Zn), where K(4-Asp-OMe) ) 21 900 and
K(2OH,2OH,Zn) ) 4300 M-1. K(7OH,2OH,Zn) ) K(1-Asp-OMe)/
2, where K(1-Asp-OMe) ) 20 900 M-1
.
The value of K(1-Asp-
δ0 δ1
-δ0g0 + δ1g0 + δ0h0 + δ1h0 -
2h0
+
OMe) was divided by two, because host 1 has two identical binding
sites. K(2OH,2OH,Zn) ) K(5-Asp-OMe) - K(6-Asp-OMe)/2,
K
K
δ )
+
where K(6-Asp-OMe) ) 310 M-1
.
Host 1 shows large binding constants for Pro-OMe,
Asp-OMe, and Trp-OMe. The large binding constant
observed for Pro-OMe can be ascribed to a strong basicity
of the secondary amino group of Pro-OMe. The binding
constants determined in ethanol-free chloroform were 2.3
to 3.3 times larger than those in 1% EtOH-CHCl3. We
expect that, in 1% EtOH-CHCl3, the interaction of
ethanol with the recognition groups (Zn, OH, and CdO)
partly blocks the binding pocket. These ethanol mol-
ecules must be released to accommodate the guest. This
energetically unfavorable process can account for the
reduced binding constants observed in 1% EtOH-CHCl3.
For comparison, the ratios of the binding constants
K(1)/K(3) and K(2)/K(3) are also listed in Table 1. These
ratios represent the effects of the 7-hydroxyl group of host
1 and the 7-methoxy group of host 2 on the binding,
respectively. The binding constants of 1 are 24.5-fold and
9.9-fold larger than those of 3 for dimethyl aspartate
(Asp-OMe) and dimethyl glutamate (Glu-OMe) guests,
respectively, in ethanol-free chloroform, which can be
ascribed to the effect of the 7-hydroxyl group. These
results indicate that the hydrogen bonding to the 7-hy-
droxyl group results in the high selectivity of host 1
toward Asp-OMe and Glu-OMe. On the other hand, the
7-methoxy group acts as a repulsive site for all the guests
as seen from the smaller ratio of K(2)/K(3) than one.
The selectivity for Asp-OMe was compared between
three-point recognition hosts 1, 4, and 5, which have the
hydroxyl groups at different distances from the porphyrin
plane. The binding constants for each recognition site
are summarized in Table 2. The binding constant was
largest for the binding site having two distant OH groups
(7-OH) and was smallest for that having two proximal
OH (2-OH). The small binding constant for the 2OH-
2OH-Zn binding pocket can be understood by the mo-
lecular modeling investigation. It was difficult to build
a complex having simultaneous coordination and two
δ
1 + 2g K + 2h K + g2K2 - 2g h K2 + h2K2
ox
0
0
0
0
0
0
-
2h0K
δ
1 + 2g K + 2h K + g2K2 - 2g h K2 + h2K2
1x
0
0
0
0
0
0
2h0K
where δ is the chemical shift in the presence of g0
M
guest, δ1 is the saturated value of the chemical shift at a
high concentration of guest, h0 is the concentration of the
host, and K is the binding constant. The hydroxyl
protons appearing at the lower field were assigned to the
2-OH proton, and those appearing at the higher field
were assigned to the 7-OH proton, based on the fact that
the chemical shift observed for the OH proton of host 2
is close to that which appears at the lower field in the
spectra of 1. This assignment was also supported by the
isoshielding map prepared for the magnetic field pro-
duced by the ring current of a porphyrin ring. The
isoshielding map predicts that the proton of 2-OH shows
-1.5 to 0.8 ppm of anisotropic chemical shift according
to the geometry of molecular modeling.11 The uncertainty
of the shift arises from free rotation along the C2-O2
bond. The proton of 7-OH shows 0.3 to 2.0 ppm chemical
shift displacements. From the difference in the averages
of these values, we predict that the 7-OH proton appears
1.5 ppm upfield relative to the 2-OH proton, in reasonable
agreement with observation. The binding constants
determined by the complexation-induced shifts are Leu-
OMe K ) 14 900 (2-OH), 14 100 (7-OH), 17 700 (naph-
thyl, 8-H) at 40 °C, Asp-OMe K ) 27 000 (2-OH), 28 100
(7-OH), 33 300 (naphthyl, 8-H) at 30 °C, and Glu-OMe
K ) 19 000 (2-OH), 13 400 (7-OH), 12 100 (naphthyl, 8-H)
(11) (a) J ohnson, C. E. J .; Bovey, F. A. J . Chem. Phys. 1958, 29,
1012. (b) Ogoshi, H.; Setsune, J .; Omura, T.; Yoshida, Z. J . Am. Chem.
Soc. 1975, 97, 6461.

Artificial Receptor for Dimethyl Aspartate
J . Org. Chem., Vol. 61, No. 2, 1996 543
Cir cu la r Dich r oism Stu d ies of th e Bin d in g. The
induced CD spectra were recorded under the conditions
that more than 90% of the host is complexed with a guest.
The split type induced CD was observed for all the amino
acid esters examined, including Leu-OMe, Asp-OMe, and
Glu-OMe (Table 5, Figure 3). It should be noted that the
intensities of the induced CD (ICD) are slightly smaller
than those observed for host 3 except for Asp-OMe. This
reduction in intensity may be explained by the assump-
tion, suggested by the 1H NMR titration, that at least
two configurations are possible in the host-guest com-
plex, one has hydrogen bonding between (guest)1O‚‚‚2-
HO(host) and the other has hydrogen bonding between
(guest)1O‚‚‚7-HO(host). Alternatively, the longer dis-
tance of the distant carbonyl chromophore (hydrogen
bonded to 7-OH) from the porphyrin chromophore than
the proximal carbonyl group (hydrogen bonded to 2-OH)
may result in the ineffective coupling between the
chromophores, leading to diminished contribution from
the distant carbonyl group to the induced CD. This can
also account for the present induced CD.
Discu ssion
UV-Vis a n d NMR Stu d ies of Bin d in g. UV-vis
titration of host 1 with amino acid esters indicates that
the Soret band of 1 shifted to a long wavelength with
several isosbestic points, suggesting a 1:1 complexation
with the amino group coordinating to zinc.13 1H NMR
titration also indicates that amino acid esters are close
to the central metal of porphyrin host 1 in the complex.
For a guest bearing one hydrogen-bonding site, Leu-OMe,
both hydroxyl protons of host 1, 2-OH and 7-OH, shifted
downfield (Figure 2a). This observation suggests that
both hydroxyl groups, 2-OH and 7-OH, participate in the
hydrogen bonding to the guest (Figure 4). The complex-
ation-induced shift (CIS) of the 2-OH proton is larger
than that of the 7-OH proton by 43%. For complexation
between host 1 and Asp-OMe, where three pairs of
interactions are possible, the CIS values of the hydroxyl
groups are approximately twice as large as those induced
by Leu-OMe (Figure 2b). The CIS values of the 2-OH
proton and the 7-OH proton are almost the same. These
observations are consistent with the formation of two
hydrogen bonds between 1 and Asp-OMe (Figure 5). The
CIS value of the 7-OH signal observed for Glu-OMe is
similar to that observed for Asp-OMe, while the CIS
value of the 2-OH signal for Glu-OMe is smaller than
that for Asp-OMe. This result indicates that Glu-OMe
is hydrogen bonded to the 7-OH group of host 1 normally
and to the 2-OH group in a somewhat distorted fashion.
The upfield shift of the naphthyl proton is tentatively
ascribed to the shielding effects of the guest carbonyl
group because the molecular model indicates that the
naphthyl H-8 proton is close to the shielding region of
the guest carbonyl group in the host-guest complex.
In d u ced CD of Am in o Acid E st er -P or p h yr in
Com p lex. The complex between host 1 and most of the
amino acid esters (Table 5) exhibited split type induced
CD (ICD) in the Soret region. This characteristic ICD is
similar to those observed for the complex between host
3 and amino acid esters, suggesting that these two hosts
bind amino acid esters with a similar binding mode. The
rotational strengths of the host 1-amino acid ester
complexes are smaller than those of the host 3-amino
acid esters complexes except for Asp-OMe. In previous
F igu r e 2. Chemical shift of host 1 induced by complexation
with Leu-OMe (a) and Asp-OMe (b) in CDCl3. See also footnote
of Table 3.
at 30 °C. In parentheses is shown the proton used for
the determination of the binding constants.
En th a lp y a n d En tr op y Ch a n ges in th e Tw o-P oin t
a n d Th r ee-P oin t Recogn ition Host-Gu est System s.
Standard enthalpy (∆H°) and standard entropy (∆S°)
changes of the binding were determined from the vari-
able-temperature UV-vis titration experiments.12 The
values of ∆H° and ∆S° are summarized in Table 4. The
experiments were carried out in amylene-containing
chloroform. Binding constants in amylene-containing
chloroform were identical to those in ethanol-free chlo-
roform. The two-point recognition host 3 shows similar
values of ∆H° and ∆S° for Leu-OMe, Asp-OMe, and Glu-
OMe. In contrast to this, the values of ∆H° and ∆S° for
three-point recognition host 1 change sensitively as the
guest structures change. Asp-OMe selectivity observed
for host 1 is achieved by the more negative enthalpy
change for this guest.
(12) Wilcox et al.4g pointed out that a small amount of water in
chloroform has a dramatic effect on the values of ∆H and ∆S of
association process through hydrogen bonding. The amount of water
in amylene-containing chloroform used in our experiments was less
than 2 mM as estimated by NMR integration, indicating that the
chloroform is “dry” as compared to their CHCl3.
(13) Nardo, J . V.; Dawson, J . H. Inorg. Chim. Acta 1986, 123, 9.

544 J . Org. Chem., Vol. 61, No. 2, 1996
Mizutani et al.
Ta ble 4. En th a lp y a n d En tr op y Ch a n ges of th e Bin d in g of Am in o Acid Ester s to Hosts 1, 3 a n d 6a
1
3
6
∆H°
(kcal/mol)
∆S°
(cal/K/mol)
∆H°
(kcal/mol)
∆S°
(cal/K/mol)
∆H°
(kcal/mol)
∆S°
(cal/K/mol)
Leu-OMe
Asp-OMe
Glu-OMe
-12.5 ( 0.4
-14.6 ( 0.5
-13.3 ( 0.5
-22.7 ( 1.4
-26.8 ( 1.6
-24.8 ( 1.3
-12.4 ( 0.4
-11.2 ( 0.5
-11.0 ( 0.4
-22.7 ( 1.2
-21.7 ( 1.5
-21.7 ( 1.3
-8.3 ( 0.3
-15.4 ( 1.0
a
Determined from the following equation: R ln K ) -∆H°/T + ∆S°, where the binding constants (K) were determined by the variable-
temperature UV-vis titration experiments between 10 and 40 °C in CHCl3 containing 0.1% amylene. The plot of R ln K against 1/T was
linear, indicating that the differential heat capacity ∆Cp is negligibly small. It was confirmed that the binding constants in amylene-
containing CHCl3 were almost the same as those in ethanol-free CHCl3. Ten to fourteen determinations of K were used for the calculation
of ∆H° and ∆S°.
Ta ble 5. Rota tion a l Str en gth (R, 10-40 cgs) of CD of Hosts 1 a n d 3 In d u ced by Com p lexa tion w ith Am in o Acid Ester sa
1b
3c
λ1 (nm)
R1
λ2 (nm)
R2
λ1 (nm)
R1
λ2 (nm)
R2
Leu-OMe
Val-OMe
Ala-OMe
Phe-OMe
Trp-OMe
Pro-OMe
Glu-OMe
Asp-OMe
Glu-OMed
Asp-OMed
Cys-OMe
Met-OMe
422.2
422.3
422.8
422.1
423.2
422.3
422.4
420.2
421.1
421.1
421.7
422.7
25.5
20.8
6.4
427.7
427.9
431.9
428.5
427.9
430.7
430.2
427.3
425.7
426.2
428.9
429.5
-25.4
-22.0
-7.5
422.2
424.5
424.5
422.6
423.0
422.3
422.9
424.0
32.3
31.5
19.2
19.0
38.2
17.6
16.1
20.6
427.2
430.2
429.3
429.3
429.1
428.1
429.9
429.6
-36.5
-30.2
-18.0
-29.9
-51.4
-14.2
-12.5
-20.3
8.4
-15.0
-41.4
-8.9
32.3
10.5
10.4
22.9
11.0
24.0
6.6
-9.0
-23.3
-13.7
-26.9
-9.3
10.8
-9.6
422.1
10.9
428.1
-13.4
a
b
d
In CHCl3 containing 1% ethanol otherwise noted. At 25 °C. c At 15 °C. In CHCl3 free from ethanol.
of the guest participate in the hydrogen bonding. There
are two other conformations, in which the anti lone pair
electrons are hydrogen bonded. In Figure 4, only the
complexes in which the hydroxyl group is hydrogen
bonded to the syn lone pair electrons of the carbonyl
group are shown. If we consider only the two conforma-
tions shown in Figure 4, the transition moments of the
carbonyl groups (indicated by arrows in Figure 4) are
located in the similar fashion relative to the porphyrin
chromophore in both conformations. Therefore ICD
should remain unchanged according to the carbonyl-
porphyrin coupling mechanism. The observed ICD is
slightly reduced in intensity. This observation is con-
sistent with the carbonyl-porphyrin coupling mechanism
but suggests that at least one conformation in addition
to those shown in Figure 4 also contributes to the present
ICD.
F igu r e 3. Induced circular dichroism of a complex prepared
from host 1 (3.9 × 10-6 M) and dimethyl aspartate (6.34 ×
10-4 M) in chloroform (ethanol free) at 25 °C.
The ICD observed for the Asp-OMe-1 complex is
difficult to explain. If we consider the conformation of
the Asp-OMe-host 1 complex shown in Figure 6, the
transition moments of the two carbonyl groups cancel out;
thus a reduced ICD is predicted with respect to that of
Leu-OMe-1 complex. The observed ICD was slightly
less intense than that of the Asp-OMe-3 complex. This
may suggest that one or more additional conformations
contribute to the ICD of the Asp-OMe-1 complex. For
example, a conformation in which the carbonyl group is
almost perpendicular to the porphyrin plane is possible.
In this conformation, the coupling between the transition
moment of the perpendicular carbonyl group and that of
the porphyrin should be very ineffective, and this car-
bonyl group would then make much less contribution to
the ICD. The distance between the carbonyl chro-
mophore and the porphyrin chromophore may be an
important factor. Because the carbonyl group hydrogen
bonded to the 7-OH group is distant from the porphyrin
plane, the coupling between the chromophores is reduced
and the contribution to the ICD may be diminished.
Alternatively, the three-point fixation may cause the
studies,2d,14 we reported that the ICD originates from the
coupling between the transition moment of the carbonyl
chromophore and that of the porphyrin chromophore.
From this mechanism, it is predicted that if the two
carbonyl groups of Asp-OMe and Glu-OMe are fixed
effectively, then the ICD can be doubled or canceled
depending on the relative orientation of the carbonyl
groups. To discuss the ICD, detailed analysis of the
distribution of conformers of host-guest complexes will
be necessary.
First, we consider the ICD of the Leu-OMe-1 complex.
Four configurations of the hydrogen-bonding complexes
are possible for this complex. For this complex, hydrogen
bonding to the 2-OH group (Figure 4, left) and the 7-OH
group (Figure 4, right) are the two conformations in
which the syn lone pair electrons of the carbonyl group
(14) Mizutani, T.; Ema, T.; Yoshida, T.; Renne´, T.; Ogoshi, H. Inorg.
Chem. 1994, 33, 3558.

Artificial Receptor for Dimethyl Aspartate
J . Org. Chem., Vol. 61, No. 2, 1996 545
F igu r e 4. Schematic representation of two conformers of the 1-Leu-OMe complex. Arrows indicate the direction of the transition
dipole moment of the carbonyl group.
F igu r e 5. Schematic representation of three-point adduct
between 1 and Asp-OMe.
F igu r e 7. Thermodynamic intermediate states of three-point
molecular recognition process. Reference hosts are used to
approximate these intermediate states. The reference host-
guest complexes are shown in parentheses. A1: hypothetical
F igu r e 6. Transition moments of the carbonyl groups in one
of possible conformers of the 1-Asp-OMe complex.
one-point adduct. A2: hypothetical two-point adduct. A3:
three-point adduct. Thermodynamic quantities (∆G°i, ∆H°i,
and ∆S°i, where i ) 1-3) are determined by reference host or
guest.
strain in porphyrin framework, resulting in the ICD.
Detailed information of the conformation of the host-
guest complexes is required to discuss the observed ICD
in detail.
cates that interactions other than the point-point inter-
action make a significant contribution to the enthalpy
term. In the following discussion, we compare only the
complexes consisting of the same guest and different
hosts. Enthalpy changes between the complexes consist-
ing of the same guest and different hosts can be reason-
ably explained in terms of the point-point interaction.
The three-point recognition process was assumed to
proceed through a hypothetical one-point adduct and two-
point adduct thermodynamic state (Figure 7). The first
process (Figure 7, top) is driven by the coordination
interaction between the amino group and the zinc ion.
In the second process (Figure 7, middle), one hydrogen
Th er m od yn a m ic P a r a m eter s of Mu ltip oin t Rec-
ogn ition . The enthalpy and entropy values of the
complexation process indicate that the complexation is
enthalpy driven. Table 4 shows that the enthalpy change
(-∆H°) increases as the number of recognition pairs
increases except for the difference in the enthalpy
changes between the 3-Leu-OMe complex and the
3-Asp-OMe complex. Although both of these complexes
can have one coordination and one hydrogen-bonding
pair, the 3-Leu-OMe complex is more stable than the
3-Asp-OMe complex by 1.2 kcal/mol. This result indi-

546 J . Org. Chem., Vol. 61, No. 2, 1996
Mizutani et al.
Ta ble 6. Coor d in a tion a n d Hyd r ogen -Bon d in g F r ee En er gy, En th a lp y, a n d En tr op y in P or p h yr in -Am in o Acid
Mu ltip oin t Ad d u ctsa
free energy,b
∆G°, kcal/mol
enthalpy,
∆H°, kcal/mol
entropy,
∆S°, cal/K/mol
compensation
temp,c °C
coordination (∆G°1, ∆H°1, ∆S°1)
hydrogen bond (O1-HO, ∆G°2, ∆H°2, ∆S°2)
hydrogen bond (O4-HO, ∆G°3, ∆H°3, ∆S°3)
-3.7
-1.9
-1.5
-8.3
-4.1
-3.4
-15.4
-7.3
-5.1
266
562
666
a
Coordination terms were calculated from the thermodynamic data for complexation of Leu-OMe and host 6. Hydrogen-bonding (O1-
HO) terms were calculated from the difference in thermodynamic data between 3-Leu-OMe complexation and 6-Leu-OMe complexation.
Hydrogen-bonding (O4-HO) terms were calculated from the difference in thermodynamic data between 1-Asp-OMe complexation and
b
c
3-Asp-OMe complexation. Free energy was calculated from ∆G°i ) ∆H °i - T∆S°i at 25 °C. The compensation temperature, Tc, was
calculated from Tc ) ∆H°i /∆S°i (i ) 1-3).
bond forms within the one-point adduct (A1). In the third
process (Figure 7, bottom), another hydrogen bond forms
to yield the three-point adduct (A3). The values of ∆H°1
and ∆S°1 involve the stabilization owing to the coordina-
tion interaction and the resulting motional changes (the
translational freedom and part of the rotational freedom
of guest are lost), respectively. The values of ∆H°2 and
∆S°2 involve the stabilization owing to the hydrogen-
bonding interaction and the resulting motional changes
(the rotational freedom of guest is lost), respectively. The
values of ∆H°3 and ∆S°3 involve the stabilization owing
to the second hydrogen-bonding interaction and the
resulting motional changes (the internal rotational free-
dom of guest is lost), respectively. Thermodynamic
quantities of these two hypothetical states were deter-
mined by use of reference host 3 and reference host 6.
The values of ∆G°, ∆H°, and ∆S° for the equilibrium
between A0 and A1 and the equilibrium between A1 and
A2 are obtained from the thermodynamic parameters
determined for Leu-OMe and the following equations.
OH group and the CdO group upon binding. Therefore
the decrease of entropy owing to the restriction of internal
rotation by the second hydrogen bond can be estimated
to be larger than 5.1 cal/K/mol. This value is close to
the internal rotational entropy along a single bond
calculated for Ala-OMe and Val-OMe.1 The negative
enthalpy change owing to one hydrogen bond (∆H3°) is
3.4 kcal/mol. This value is also a compensated value by
the positive enthalpy change owing to the desolvation of
the OH group and the CdO group, namely the stripping
of CHCl3 from these groups. It also involves the changes
in conformational energy of guest. Therefore the hydro-
gen-bonding enthalpy is approximately equal to -3.4
kcal/mol. The hydrogen-bonding energy is reported to
be -3.5 to -6.0 kcal/mol for the water dimer in vacuo
and the carboxylic acid dimer in a liquid state.15 The
observed hydrogen-bonding enthalpy listed in Table 6 is
close to this range.
The compensation temperature16 for each interaction
is also listed in Table 6. The physical meaning of the
compensation temperature is as follows. If the temper-
ature of the binding experiment is raised up to the
compensation temperature, the attractive interaction will
disappear owing to the thermal motion of the molecules.
The compensation temperature increases as the number
of recognition pairs increases as shown in Table 6.
Although the first interaction between zinc and the amino
group has large negative ∆H° value, the compensation
temperature is not so high. This can be ascribed to the
large entropy loss from the restriction of the translational
and rotational motion. In contrast, the third interaction,
hydrogen bonding between (guest)O4‚‚‚HO(host), has a
much higher compensation temperature of 666 °C. This
reflects that the host-guest system is already in an
ordered state before the third interaction operates. This
trend that the compensation temperature increases as
the number of the recognition pairs increases may be the
general one in the multipoint molecular recognition.
The selectivity of Asp-OMe over Glu-OMe observed for
host 1 is ascribed to the enthalpy change. The enthalpy
difference ∆∆H° was 1.3 kcal/mol. To examine the origin
of this enthalpy difference, the conformational energy of
these guests in the complexed state and the free state
was calculated by molecular orbital calculations (the PM3
method).17 For both of these guests, the coordinates of
the host-guest complex were generated so that the
coordination interaction and the two hydrogen bonds take
place in the complex. The enthalpy change of Asp-OMe
from the free form to the complexed form was -0.07 kcal/
mol and that of Glu-OMe was +1.6 kcal/mol. Therefore
∆G°1 ) ∆G°(6-Leu-OMe)
∆H°1 ) ∆H°(6-Leu-OMe)
∆S°1 ) ∆S°(6-Leu-OMe)
∆G°2 ) ∆G°(3-Leu-OMe) - ∆G°(6-Leu-OMe)
∆H°2 ) ∆H°(3-Leu-OMe) - ∆H°(6-Leu-OMe)
∆S°2 ) ∆S°(3-Leu-OMe) - ∆S°(6-Leu-OMe)
Similarly, ∆G°3, ∆H°3, and ∆S°3 are obtained from the
thermodynamic parameters determined for Asp-OMe and
the following equations.
∆G°3 ) ∆G°(1-Asp-OMe) - ∆G°(3-Asp-OMe)
∆H°3 ) ∆H°(1-Asp-OMe) - ∆H°(3-Asp-OMe)
∆S°3 ) ∆S°(1-Asp-OMe) - ∆S°(3-Asp-OMe)
These thermodynamic values are listed in Table 6. As
the number of recognition pairs increases from one to
three, the magnitudes of both ∆H° and ∆S° decrease.
This may reflect that the multipoint adduct becomes
more ordered as the number of recognition pairs in-
creases.
We can ascribe the ∆S°3 term primarily to entropy loss
owing to the freezing of internal rotation of the guest and
the host. The internal rotation along the C2-C3 bond
and the C3-C4 bond of Asp-OMe should be restricted
together with the C7-O7 bond of the naphthyl group of
host. The ∆S°3 term may also involve a contribution from
positive entropy change owing to the desolvation of the
(15) J effrey, G. A.; Saenger, W. Hydrogen bonding in biological
structures; Springer-Verlag: New York, 1991.
(16) Gelb, R. I.; Schwartz, L. M.; Cardelino, B.; Fuhrman, H. S.;
J ohnson, R. F.; Laufer, D. A. J . Am. Chem. Soc. 1981, 103, 1750.
(17) MOPAC Version 5 and Version 6, Stewart, J . J . P. QCPE Bull.
1989, 9, 10.

Artificial Receptor for Dimethyl Aspartate
J . Org. Chem., Vol. 61, No. 2, 1996 547
P r epar ation of 3,3′,4,4′-Tetr aeth yl-2,2′-dipyr r ylm eth en e
Hyd r obr om id e (8). To a solution of 3,4-diethylpyrrole (5.34
g, 0.433 mmol) and 3,4-diethyl-2-formylpyrrole (7) in ethanol
(35 mL, 6.50 g, 0.430 mmol) was added aqueous HBr (47%,
5.5 mL) dropwise at 0 °C. When the reaction mixture turned
pale red and precipitates appeared, additional ethanol (10 mL)
was added and the solution was stirred well. After 1 h, the
solvent was evaporated, and the residue was recrystallized
from ethanol to yield 3,3′,4,4′-tetraethyl-2,2′-dipyrrylmethene
hydrobromide (7.47 g, 42%): 1H NMR (500 MHz, CDCl3) 13.24
(br s, 2H), 7.72 (d, J ) 3.7 Hz, 2H), 7.27 (s, 1H), 2.70 (q, J )
7.7 Hz, 4H), 2.48 (q, J ) 7.7 Hz, 4H), 1.204 (t, J ) 7.7 Hz,
6H), 1.200 (t, J ) 7.7 Hz, 6H); FAB MS (3-nitrobenzyl alcohol)
m/ z 257 (M+ - Br).
Asp-OMe is bound to host 1 via a three-point fixation
mode in a stable conformation while Glu-OMe is bound
to host 1 in a distorted and unstable conformation. The
conformational enthalpy difference can account for the
experimentally observed enthalpy difference ∆∆H° of 1.3
kcal/mol.
Exp er im en ta l Section
Gen er a l. Dichloromethane, 1,2-dichloroethane, and N,N-
dimethylformamide were distilled from CaH2. CHCl3 used in
UV-vis titrations was prepared in one of the following three
ways. (1) CHCl3 free from ethanol: CHCl3 containing ethanol
as a stabilizer (spectrophotometric grade, 99% stabilized with
ethanol, Dojindo Laboratories) was washed with distilled water
of the same volume three times, dried over anhydrous potas-
sium carbonate, and distilled from CaH2 under N2. This CHCl3
free from ethanol was used for UV-vis titrations within 12 h
after distillation. (2) CHCl3 containing ethanol as a stabi-
lizer: the above spectrophotometric grade CHCl3 was used as
received. (3) CHCl3 containing amylene as a stabilizer: A.C.S.
HPLC grade (99.9% stabilized with amylene, Aldrich) was used
as received. Amino acid methyl ester hydrochlorides were
commercially available. After neutralization and extraction
with dichloromethane, all amino acid esters were freshly
distilled just before use for UV-vis titration except for Trp-
OMe. Unless otherwise noted, other materials were obtained
from commercial sources and used without further purification.
Hosts 3 and 6 were prepared by the reported procedure.
Because the cis and trans atropisomers of 6 could not be
separated, the mixture was used for the binding constant
determination.
Va r ia b le-Tem p er a t u r e UV-Vis Sp ect r op h ot om et r ic
Titr a tion . To (3.8 × 10-6)-(7.1 × 10-6) M 1, 2, 3, or 6 in
chloroform was added a stock solution of R-amino acid ester
in chloroform over the temperature range 10 to 40 °C, and
changes in absorbance at 414-416 and 428-430 nm of the
Soret band were monitored at eight different concentrations
of the guest molecules. The binding constants were calculated
assuming 1:1 complexation by use of a computer-assisted
nonlinear least-squares method. The concentration of R-amino
acid ester was (7 × 10-6)-(2 × 10-3) M for host 1, (3 × 10-5)-
(7 × 10-3) M for host 2, (9 × 10-6)-(4 × 10-3) M for host 3,
and (6 × 10-4)-(1.1 × 10-2) M for host 6.
P r ep a r a tion of 2,7-Dim eth oxyn a p h th a len e (10).
A
solution of 2,7-dihydroxynaphthalene (500 mg, 3.12 mmol), K2-
CO3 (1.72 g, 12.5 mmol), and CH3I (0.97 mL, 15.6 mmol) in
DMF (3 mL) was heated at 50-60 °C for 3.5 h under N2. After
the reaction mixture was cooled, water was added and the
product was extracted with ether. The organic layer was
washed subsequently with water and saturated aqueous NaCl,
dried over K2CO3, filtered, and evaporated to dryness. The
residue was recrystallized from ether to yield 10 (270 mg, 46%
1
yield): mp 138 °C; H NMR (500 MHz, CDCl3) δ 7.65 (d, J )
8.9 Hz, 2H), 7.05 (d, J ) 2.5 Hz, 2H), 6.99 (dd, J ) 2.5, 9.2 Hz,
2H), 3.90 (s, 6H).
P r ep a r a tion of 2,7-Dim eth oxy-1-n a p h th a ld eh yd e (11).
To a solution of 10 (100 mg, 0.531 mmol) in 1,2-dichloroethane
(2 mL) were added N-methylformanilide (87 µL, 0.701 mmol)
and POCl3 (65 µL, 0.701 mmol). The solution was heated at
100 °C for 11 h. After the mixture was cooled, it was poured
into an ice-water mixture. The product was extracted with
ether, and the organic layer was washed with 2 M aqueous
HCl, dried over Na2SO4, filtered, and evaporated. The residue
was chromatographed on silica gel column (hexane:ether ) 3:1
to 2:1) to obtain 11 (95.4 mg, 83%): mp 101 °C; 1H NMR (500
MHz, CDCl3) δ 10.88 (s, 1H), 8.83 (d, J ) 2.8 Hz, 1H), 7.97 (d,
J ) 8.9 Hz, 1H), 7.65 (d, J ) 8.9 Hz, 1H), 7.10 (d, J ) 8.9 Hz,
1H), 7.05 (dd, J ) 2.6, 9.0 Hz, 1H), 4.03 (s, 3H), 3.96 (s, 3H);
IR (KBr) νCO 1665 cm-1. Anal. Calcd for C13H12O3: H, 5.59;
C 72.21. Found: H, 5.75; C, 72.02.
P r ep a r a tion of 2-Hyd r oxy-7-m eth oxy-1-n a p h th a ld e-
h yd e (12). To a solution of 11 (1.20 g, 5.55 mmol) in CH2Cl2
(50 mL) cooled to -55 °C was gradually added a solution of
BBr3 in CH2Cl2 (1 M, 8.0 mL, 8.0 mmol) under N2. The
reaction mixture was warmed up to room temperature. After
4.5 h, aqueous HCl was added at 0 °C until orange precipitates
were dissolved. The product was extracted with ether, and
the organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane:ether ) 4:1 to 1:1) to obtain 12 (0.91 g, 81%): mp 130
The induced CD of the host 1-amino acid esters was
obtained under the conditions that more than 90% of the host
is complexed with amino acid esters. The rotational strengths
were calculated by fitting the circular dichroism spectra of the
350 to 500 nm region to Gaussian functions: a1 exp(-((λ -
λ1)/σ1)2) - a2 exp(-((λ - λ2)/σ2)2) or a1 exp(-((λ - λ1)/σ1)2) where
a1, a2, λ1, λ2, σ1, and σ2 are parameters to be determined. The
rotational strength (R1, R2) was calculated from these param-
eters. The curve fitting was carried out by use of Igor,
WaveMetrics, Inc.
1
°C; H NMR (500 MHz, CDCl3) δ 13.17 (s, 1H), 10.75 (s, 1H),
7.89 (d, J ) 8.9 Hz, 1H), 7.70 (d, J ) 8.9 Hz, 1H), 7.67 (d, J )
2.5 Hz, 1H), 7.08 (dd, J ) 8.9, 2.5 Hz, 1H), 6.98 (d, J ) 8.9 Hz,
1H), 3.96 (s, 3H); IR (KBr) νCO 1624 cm-1
. Anal. Calcd for
P r ep a r a tion of 3,4-Dieth yl-2-for m ylp yr r ole (7). To
DMF (3.96 mL, 5.11 mmol) was added POCl3 (4.86 mL, 5.21
mmol) dropwise at 0 °C under N2. After the ice bath was
removed, 1,2-dichloroethane (10 mL) was added and the
solution was stirred for 20 min. A solution of freshly distilled
3,4-diethylpyrrole18 (5.9 g, 4.87 mmol) in 1,2-dichloroethane
(10 mL) was added, and the resulting solution was heated at
50 °C for 1.5 h. To the brown reaction mixture was added a
solution of sodium acetate (5.06 g) in water (39 mL); the
reaction mixture was heated again at 80 °C for 40 min. The
cooled reaction mixture was extracted with ether, and the
organic layer was washed with saturated aqueous Na2CO3,
water, and saturated aqueous NaCl, dried over anhydrous Na2-
CO3, and evaporated. The residue was recrystallized from
hexane to yield 3,4-diethyl-2-formylpyrrole (6.67 g, 90.6%): 1H
NMR (500 MHz, CDCl3) δ 9.59 (s, 1H), 9.02 (br s, 1H), 6.84 (d,
J ) 2.8 Hz, 1H), 2.72 (q, J ) 7.7 Hz, 2H), 2.45 (q, J ) 7.7 Hz,
2H), 1.21 (t, J ) 7.7 Hz, 3H), 1.19 (t, J ) 7.7 Hz, 3H); MS m/ z
151 (M+).
C12H10O3: H, 4.98; C, 71.28. Found: H, 4.98; C, 71.22.
P r ep a r a tion of tr a n s- a n d cis-5,15-Bis(2-h yd r oxy-7-
m eth oxy-1-n aph th yl)-2,3,7,8,12,13,17,18-octaeth ylpor ph y-
r in . To a solution of 3,3′,4,4′-tetraethyl-2,2′-dipyrrylmethene
hydrobromide (2.70 g, 8.00 mmol) in ethanol (50 mL) was
slowly added under N2 a solution of NaBH4 (426 mg, 11.26
mmol) in ethanol (15 mL) until the reaction mixture turned
from dark brown to pale brown. After stirring for 1 h at room
temperature, the solvent was evaporated and to the residue
was added ether. The precipitate was filtered off and the
filtrate was evaporated to quantitatively yield 3,3′,4,4′-tetra-
ethyl-2,2′-dipyrrylmethane (9). The dipyrrylmethane was
dissolved in methanol (20 mL, degassed by N2 bubbling for 1
h), and a solution of 12 (1.60 g, 7.91 mmol) and p-toluene-
sulfonic acid monohydrate (0.39 g, 2.08 mmol) in methanol (105
mL) was added dropwise. After the addition the reaction
mixture was stirred for 15 h in the dark. The solvent was
evaporated, and the residue was dissolved in THF (168 mL),
followed by the addition of chloranil (446 mg, 1.81 mmol). The
solution was stirred for 3 h. After the solvent was evaporated,
the residue was chromatographed on silica gel column (CHCl3:
(18) Whitlock, H. W.; Hanauer, R. J . Org. Chem. 1968, 33, 2169.

548 J . Org. Chem., Vol. 61, No. 2, 1996
Mizutani et al.
AcOEt ) 20:1) to separate the trans and the cis isomers. Both
isomers were recrystallized from CHCl3-hexane: Trans iso-
mer. Rf ) 0.59 (CHCl3:AcOEt ) 20:1); cis isomer, Rf ) 0.21
(CHCl3:AcOEt ) 20:1). Since the trans isomer was contami-
nated with an impurity having the same Rf value, it was
converted to a zinc complex and purified by silica gel column
chromatography (CHCl3) and recrystallized from CHCl3-
hexane.
chromatography (CHCl3:AcOEt ) 10:1) and recrystallized from
CHCl3-hexane to yield 1 in quantitative yield: mp > 300 °C
dec; UV-vis (CHCl3 containing amylene) λmax (log ꢀ) 416 (5.45),
542 (4.28), 578 (4.23); 1H NMR (500 MHz, CDCl3) 10.22 (s,
2H), 8.19 (d, J ) 9.1 Hz, 2H), 7.94 (d, J ) 9.1 Hz, 2H), 7.46 (d,
J ) 8.8 Hz, 2H), 6.95 (dd, J ) 8.8, 2.4 Hz, 2H), 5.94 (d, J )
2.4 Hz, 2H), 5.20 (s, 2H), 4.17 (s, 2H), 4.03-3.91 (m, 8H), 2.91-
2.83 (m, 4H), 2.64-2.55 (m, 4H), 1.84 (t, J ) 7.7 Hz, 12H),
0.94 (t, J ) 7.5 Hz, 12H); HRMS calcd for C56H56O4N4Zn
912.359, found 912.368.
Tr a n s Isom er Zin c Com p lex 2. To the crude trans isomer
(400 mg) dissolved in CHCl3 (150 mL) was added methanol
saturated with zinc acetate (30 mL), and the solution was
refluxed for 2 h. Water was added to the reaction mixture,
the organic layer was separated, and the aqueous layer was
extracted with CHCl3. The combined organic layer was dried
over Na2SO4 and evaporated in vacuo. The residue was
purified by silica gel column chromatography (CHCl3). Further
purification by recrystallization from CHCl3-hexane afforded
pure 2 (red purple powder; 172 mg, first crop) followed by a
second crop of 234 mg (total yield 406 mg, 10.9% based on
dipyrrylmethene): reddish purple powder, mp > 300 °C dec;
UV-vis (CHCl3 containing amylene) λmax (log ꢀ) 416 (5.47), 542
P r ep a r a tion of cis-5,15-Bis(2,7-d ih yd r oxy-1-n a p h th yl)-
2,3,7,8,12,13,17,18-octa eth ylp or p h yr in (17). The methoxy
groups of 13 (37.7 mg, 40.0 µmol) were deprotected to hydroxy
groups by using the same procedure as that for 15. The cis
isomer was purified by silica gel column chromatography
(CHCl3: AcOEt ) 10:1) and recrystallized from CHCl3-hexane
to obtain 17 (28.3mg, 83%, purple powder): mp >300 °C dec;
UV-vis (CHCl3 containing amylene) λmax (log ꢀ) 414 (5.23), 510
1
(4.20), 546 (3.88), 576 (3.87), 628 (3.58); H NMR (500 MHz,
CDCl3) 10.30 (s, 2H), 8.18 (d, J ) 8.8 Hz, 2H), 7.95 (d, J ) 9.1
Hz, 2H), 7.45 (d, J ) 9.0 Hz, 2H), 6.96 (dd, J ) 8.9, 2.5 Hz,
2H), 5.97 (d, J ) 2.1 Hz, 2H), 5.24 (br, 2H), 4.21 (br, 2H), 4.05-
4.10 (m, 8H), 2.96-2.86 (m, 4H), 2.64-2.60 (m, 4H), 1.84 (t, J
) 7.7 Hz, 12H), 0.98 (t, J ) 7.5 Hz, 12H), NH (not observed
for broadening); HRMS calcd for C56H58O4N4 850.446, found
850.451.
1
(4.29), 578 (4.24); H NMR (500 MHz, CDCl3) 10.23 (s, 2H),
8.20 (d, J ) 9.0 Hz, 2H), 7.95 (d, J ) 9.2 Hz, 2H), 7.46 (d, J )
9.0 Hz, 2H), 7.01 (dd, J ) 9.0, 2.6 Hz, 2H), 6.05 (d, J ) 2.6 Hz,
2H), 5.14 (s, 2H), 4.00-3.93 (m, 4H), 2.86-2.78 (m, 4H), 2.78
(s, 6H), 2.60-2.52 (m, 4H), 1.85 (t, J ) 7.7 Hz, 12H), 0.93 (t,
J ) 7.6 Hz, 12H); HRMS calcd for C58H60O4N4Zn 940.391,
found 940.391.
P r epar ation of [cis-5,15-Bis(2,7-dih ydr oxy-1-n aph th yl)-
2,3,7,8,12,13,17,18-octaeth ylpor ph yr in ato]zin c(II) (4). Zinc
was inserted to 17 (18.7 mg, 22.0 µmol) by using the same
procedure as that used for 2. The zinc complex was purified
by silica gel column chromatography (CHCl3:AcOEt ) 5:1) and
recrystallized from CHCl3-hexane to obtain 4 (14.0 mg, 70%,
reddish purple powder): mp > 300 °C dec; UV-vis (CHCl3
containing amylene) λmax (log ꢀ) 416 (5.47), 542 (4.27), 578
Cis isom er fr ee ba se 13: yield 214 mg, 6.1%; purple
crystal, mp > 300 °C dec; UV-vis (CHCl3 containing amylene)
λmax (log ꢀ) 414 (5.21), 512 (4.00), 544 (3.79), 578 (3.77), 628
1
(3.44); H NMR (500 MHz, CDCl3) 10.33 (s, 2H), 8.19 (d, J )
8.9 Hz, 2H), 7.96 (d, J ) 9.2 Hz, 2H), 7.45 (d, J ) 9.2 Hz, 2H),
7.04 (dd, J ) 8.9, 2.8 Hz, 2H), 6.22 (d, J ) 2.5 Hz, 2H), 5.15
(s, 2H), 4.00-3.94 (m, 8H), 2.90-2.82 (m, 4H), 2.85 (s, 6H),
2.70-2.62 (m, 4H), 1.85 (t, J ) 7.6 Hz, 12H), 0.97 (t, J ) 7.5
Hz, 12H), -1.70 (br, 2H); HRMS calcd for C58H62O4N4 878.477,
found 878.481.
1
(4.23); H NMR (500 MHz, CDCl3) 10.22 (s, 2H), 8.19 (d, J )
8.9 Hz, 2H), 7.95 (d, J ) 8.8 Hz, 2H), 7.47 (d, J ) 9.2 Hz, 2H),
6.94 (dd, J ) 8.9, 2.7 Hz, 2H), 5.86 (d, J ) 2.5 Hz, 2H), 5.27
(s, 2H), 4.12 (s, 2H), 4.02-3.88 (m, 8H), 2.80-2.91 (m, 4H),
2.50-2.62 (m, 4H), 1.84 (t, J ) 7.7 Hz, 12H), 0.95 (t, J ) 7.5
Hz, 12H); HRMS calcd for C56H56N4O4Zn 912.359, found
912.354.
P r ep a r a tion of tr a n s-5,15-bis(2-h yd r oxy-7-m eth oxy-1-
n aph th yl)-2,3,7,8,12,13,17,18-octaeth ylpor ph yr in (14): mp
> 300 °C dec; UV-vis (CHCl3 containing amylene) λmax (log ꢀ)
414 (5.22), 512 (4.19), 544 (3.83), 578 (3.82), 628 (3.53); 1H
NMR (500 MHz, CDCl3) 10.32 (s, 2H), 8.19 (d, J ) 8.9 Hz,
2H), 7.95 (d, J ) 8.9 Hz, 2H), 7.45 (d, J ) 8.9 Hz, 2H), 7.02
(dd, J ) 9.2, 2.5 Hz, 2H), 6.12 (d, J ) 2.5 Hz, 2H), 5.10 (s,
2H), 4.14-3.92 (m, 8H), 2.92-2.82 (m, 4H), 2.79 (s, 6H), 2.70-
2.60 (m, 4H), 1.83 (t, J ) 7.6 Hz, 12H), 0.97 (t, J ) 7.5 Hz,
12H), -1.83 (br, 2H); HRMS calcd for C58H62O4N4 878.477,
found 878.482.
P r ep a r a tion of Br id ged P or p h yr in 16. To a solution of
cis-5,15-bis(2-hydroxy-7-methoxy-1-naphthyl)-2,3,7,8,12,13,17,-
18-octaethylporphyrin (13) (30 mg, 34.1 µmol) in acetone (120
mL) was added 1,8-dibromooctane (9.28 mg, 34.1 µmol), and
the solution was refluxed for 1 week. After the solvent was
removed by evaporation, water was added to the residue and
the mixture was extracted with ether. Purification by chro-
matography on silica gel (hexane:AcOEt ) 20:1) and recrys-
tallization from CHCl3-hexane afforded the bridged porphyrin
16 (6.0 mg, 18.1%, purple crystal): mp > 300 °C dec; UV-vis
P r ep a r a tion of tr a n s-5,15-Bis(2,7-d ih yd r oxy-1-n a p h -
th yl)-2,3,7,8,12,13,17,18-octa eth ylp or p h yr in (15). Since 2
is nearly insoluble in CH2Cl2, 2 (22.9 mg, 24.3 µmol) was
demetalated by the addition of 3 M aqueous HCl followed by
the treatment with saturated aqueous NaHCO3 to obtain the
free base. To the free base dissolved in CH2Cl2 (15 mL) and
cooled to -70 °C was added a solution of BBr3 in CH2Cl2 (1
M, 0.58 mL) slowly. After the reaction mixture was allowed
to warm to room temperature over 3 h, excess BBr3 was
decomposed by the addition of MeOH. To the solution was
added saturated aqueous NaHCO3, the resultant mixture was
extracted with CH2Cl2, dried over Na2SO4, and filtered, and
the solvent was evaporated. The residue was purified by
column chromatography on silica gel (CHCl3:AcOEt ) 10:1),
and recrystallized from hexane-CHCl3 to obtain the free base
of 1 (7.3 mg, 35%, purple powder): mp > 300 °C dec; UV-vis
(CHCl3 containing amylene) λmax (log ꢀ) 414 (5.31), 512 (4.30),
1
(CHCl3 containing amylene) λmax 418, 513, 546, 582, 635; H
NMR (500 MHz, CDCl3) 10.16 (s, 2H), 8.15 (d, J ) 8.9 Hz,
2H), 8.03 (d, J ) 9.2 Hz, 2H), 7.62 (d, J ) 2.1 Hz, 2H), 7.23-
7.19 (m, 2H), 4.00-3.90 (m, 4H), 3.34 (s, 6H), 3.24 (t, J ) 5.5
Hz, 4H), 2.85-2.76 (m, 4H), 2.65-2.55 (m, 4H), 1.83 (t, J )
7.6 Hz, 12H), 0.83 (t, J ) 7.5 Hz, 12H), -0.39 to -0.47 (m,
4H), -1.60 (br, 2H), -1.68 to -1.76 (m, 4H), -2.25 to -2.32
(m, 4H); HRMS calcd for C66H76O4N4 988.587, found 988.595.
Ack n ow led gm en t. We thank T. Kobatake for his
kind help in the mass spectroscopy measurements. This
work was supported by a Grant-in Aid for Scientific
Research (No. 06650980, No. 04101003) from the Min-
istry of Education, Science, and Culture of J apan.
1
546 (3.99), 578 (3.95), 628 (3.70); H NMR (500 MHz, CDCl3)
10.31 (s, 2H), 8.18 (d, J ) 8.9 Hz, 2H), 7.95 (d, J ) 8.9 Hz,
2H), 7.46 (d, J ) 8.9 Hz, 2H), 6.96 (dd, J ) 8.9, 2.5 Hz, 2H),
5.97 (d, J ) 2.5 Hz, 2H), 5.22 (s, 2H), 4.83 (br, 2H), 4.03-3.93
(m, 8H), 2.95-2.86 (m, 4H), 2.68-2.59 (m, 4H), 1.84 (t, J )
7.7 Hz, 12H), 0.99 (t, J ) 7.5 Hz, 12H), -1.81 (br, 2H); HRMS
calcd for C56H58O4N4 850.446, found 850.453.
P r ep a r a tion of [tr a n s-5,15-Bis(2,7-d ih yd r oxy-1-n a p h -
th yl)-2,3,7,8,12,13,17,18-octaeth ylpor ph yr in ato]zin c(II) (1).
Zinc was inserted by using the same procedure as that used
for 2. The zinc complex was purified by silica gel column
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1, 2, 4, 7, 8, 13, 15, 16, and 17 (9 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
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J O950567B