Water-soluble zinc porphyrins as receptors for amino carboxylates

Article abstract of DOI:10.1246/cl.2001.688

Water-soluble zinc porphyrins bearing an ammonium group and a phenyl or tertiary butyl group above each porphyrin plane were designed and synthesized. Binding data for amino carboxylates in aqueous solution suggested that these porphyrins recognize the carboxylates on the basis of coordinative, Coulomb, and hydrophobic interactions and that a chiral recognition phenomenon for glycyl-tryptophan anion is derived from the cooperation of these interactions.

Full text of DOI:10.1246/cl.2001.688

688
Chemistry Letters 2001
Water-Soluble Zinc Porphyrins as Receptors for Amino Carboxylates
Hiroyasu Imai,* Kensuke Misawa, Hiroki Munakata, and Yoshio Uemori
Faculty of Pharmaceutical Sciences, Hokuriku University, 3 Ho Kanagawa-Machi, Kanazawa 920-1181
(Received April 16, 2001; CL-010339)
CH2Cl2 (800 cm3) was added dropwise a solution of triphenyl-
methyl bromide (2.08 g, 6.44 mmol) in CH2Cl2 (400 cm3). The
reaction mixture containing some kinds of partly amino-protected
porphyrins was evaporated to dryness and the solid was chro-
matographed on a silica-gel column (benzene, 4 × 30 cm). The
third and forth bands were separated where these were 5α,15β-
bis(2-(triphenylmethylamino)phenyl)-10α ,20β-bis(2-
aminophenyl)porphyrin and the racemic mixture of 5α,20β- and
10α,15β-bis(amino-protected) isomers, respectively. After dry-
ing the solution of the third band, the solid was dissolved in
CH2Cl2 (80 cm3) containing triethylamine (1.1 cm3). To the
solution, benzoyl chloride (0.35 cm3, 3.00 mmol) was added then
stirred for 12 h at room temperature. The reaction mixture was
treated with a mixture of dilute HCl (3 mol dm–3, 10 cm3) and
CH3COOH (10 cm3) for 1 h at room temperature, deprotecting
the two amino groups. After neutralization with aqueous ammo-
nia, the organic layer was dried over anhydrous Na2SO4 then
evaporated to dryness. The solid of 5α,15β-bis(2-benzoyl-
aminophenyl)-10α,20β-bis(2-aminophenyl)porphyrin was puri-
fied by silica-gel column chromatography (CHCl3, 2.5 × 30 cm),
yield 0.249 g (9.6%).
Water-soluble zinc porphyrins bearing an ammonium
group and a phenyl or tertiary butyl group above each por-
phyrin plane were designed and synthesized. Binding data for
amino carboxylates in aqueous solution suggested that these
porphyrins recognize the carboxylates on the basis of coordina-
tive, Coulomb, and hydrophobic interactions and that a chiral
recognition phenomenon for glycyl-tryptophan anion is derived
from the cooperation of these interactions.
Recognition of biomolecules such as amino acids by recep-
tors plays critical roles in living organisms. To understand the
recognition mechanisms in aqueous solution, a variety of artifi-
cial receptors have been designed and studied. A class of useful
model receptors for amino acids and peptides is zinc por-
phyrins,1,2 but not so many studies in aqueous solution3–5 have
been reported due to the lipophilic nature of porphyrins. In this
work we have designed and synthesized a new type of water-sol-
uble zinc porphyrin receptors that are capable of revealing three-
point recognition for amino carboxylates on the basis of coordi-
native, Coulomb, and hydrophobic interactions.
Treatment of the porphyrin (0.500 g, 0.566 mmol) with
ZnCl2 (1.00 g, 7.34 mmol) in tetrahydrofuran (100 cm3) contain-
ing 2,6-lutidine (0.50 cm3) for 4 h at room temperature afforded
the corresponding zinc porphyrin, yield 0.291 g (54.3%).
To a solution of the above zinc porphyrin (0.250 g, 0.276
mmol) and triethylamine (10 cm3, 72 mmol) in CH2Cl2 (100
cm3) in an ice bath was added dropwise a solution of N,N-
dimethylaminoacetyl chloride (0.871 g, 7.16 mmol) in CH2Cl2
(100 cm3). After stirring for 6 h at room temperature, the mix-
ture was washed twice with water. The organic layer was dried
over anhydrous Na2SO4 then evaporated to dryness. The solid
of 5α,15β-bis(2-benzoylaminophenyl)-10α,20β-bis(2-(N,N-
dimethylaminomethylcarbonylamino)phenyl)porphyrinato-
zinc(II) was purified by a silica-gel column (CHCl3, 2.5 × 20
cm), yield 0.0894 g (30.3%).
To a solution of the above zinc porphyrin (0.0800 g, 0.0716
mmol) in N,N-dimethylformamide (10 cm3) was added methyl
iodide (0.800 cm3, 10.3 mmol) with stirring at room temperature.
After 7 h, addition of ether to the mixture precipitated a solid of
the iodide of 1. The iodide was converted to the corresponding
chloride by ion-exchange column chromatography (CH3OH, 3 ×
30 cm (Amberlyst A-21)), yield 0.0323 g (37.0%).6
5α,15β-Bis(2-(t-butylcarbonylamino)phenyl)-10α,20β-bis-
(2-(trimethylammoniomethylcarbonylamino)phenyl)porphyri-
natozinc(II) (2) (chloride) was similarly prepared by using
pivaloyl chloride instead of benzoyl chloride. 5α,20β-Bis(2-
benzoylaminophenyl)-10α , 15β -bis(2-(trimethyl-
ammoniomethylcarbonylamino)phenyl)porphyrinatozinc(II) (3)
(chloride) was similarly prepared as the racemic mixture from
the mixture of 5α,20β-bis(2-(triphenylmethylamino)phenyl)-
10α,15β-bis(2-aminophenyl)porphyrin and its enantiomer.
The synthesis of 5α ,15β-bis(2-benzoylaminophenyl)-
10α ,20β-bis(2-(trimethylammoniomethylcarbonylamino)-
phenyl)porphyrinatozinc(II) (1) (chloride) is as follows. To an
ice-cold solution of 5α,10α,15β,20β-tetrakis(2-aminophenyl)-
porphyrin (2.00 g, 2.96 mmol) and triethylamine (5.0 cm3) in
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
689
In aqueous solution a nitrogenous axial ligand (L) such as
amino carboxylates can substitute the coordinated water on a
zinc porphyrin (ZnP) and this reaction is explained as follows:
racemic mixture, chiral recognition for the enantiomers of the
amino carboxylates was expected. Our binding data on amino
acids, however, do not show chiral recognition evidence; no
difference in K is observed between DL- and L-Trp. Contrary to
this, a slight but certain difference in K for 3 was obtained
between Gly–DL-Trp and Gly–L-Trp.10 This can be reasonably
explained in terms of the relative magnitude of the two
hydrophobic interactions produced by the indole group of the
amino carboxylates with the porphyrin plane and with the
phenyl group of the porphyrin. In the bound Trp the former
interaction must be strong to eclipse the latter interaction,
whereas in the bound Gly–Trp the relatively decreased former
interaction by elongating the separation of the indole group
from the porphyrin plane might lead to the appearance of the
chiral recognition.
where the N atom of L coordinates to the zinc ion.7 Since the
pKa values of the coordinated H2O of these zinc porphyrins
were estimated to be larger than 12 and the pKa values of amino
+
acids (–NH3 ) are smaller than 9.6, the binding experiments
were carried out at a pH value between them. Binding con-
stants (K = [ZnP·L]/[ZnP·H2O][L]) for the equilibrium were
determined spectrophotometrically by a usual method.8
References and Notes
1
T. Mizutani, T. Ema, T. Tomita, Y. Kuroda, and H. Ogoshi, J. Am.
Chem. Soc., 116, 4240 (1994); Y. Kuroda, Y. Kato, T. Higashioji, J.
Hasegawa, S. Kawanami, M. Takahashi, N. Shiraishi, K. Tanabe, and
H. Ogoshi, J. Am. Chem. Soc., 117, 10950 (1995).
2
3
K. Konishi, K. Yahara, H. Toshishige, T. Aida, and S. Inoue, J. Am.
Chem. Soc., 116, 1337 (1994).
E. Mikros, A. Gaudemer, and R. Pasternack, Inorg. Chim. Acta, 153,
199 (1988); C. Verchére-Bèaur, E. Mikros, M. Perrèe-Fauvet, and A.
Gaudemer, J. Inorg. Biochem., 40, 127 (1990).
4
5
6
T. Mizutani, K. Wada, and S. Kitagawa, J. Am. Chem. Soc., 121, 11425
(1999).
T. Mizutani, K. Wada, and S. Kitagawa, J. Org. Chem., 65, 6097
(2000).
Selected data: Compound 1 (chloride): 1H NMR (400 MHz, DMSO-
d6) δ 2.25 (s, 18H, N(CH3)3), 6.61 (d, 4H, CO–ph), 6.67 (t, 4H,
CO–ph), 6.95 (t, 2H, CO–ph), 7.66 (m, 4H, ph), 7.88 (m, 6H, ph),
7.99 (d, 2H, ph), 8.02 (d, 2H, ph), 8.33 (d, 2H, ph), 8.60 (d, 2H, pyr-
role), 8.63 (d, 2H, pyrrole), 8.72 (s, 2H, pyrrole), 8.73 (s, 2H, pyrrole),
8.98 (s, 4H, NHCO), 9.17 (s, 4H, NHCO); vis (H2O/NaHCO3–Na2CO3,
pH 10.4) λmax (log ε) 424 (5.44), 557 (4.18), 596 (3.61) nm; Anal.
Table 1 lists binding data of amino carboxylates and butyl-
amine to zinc porphyrins. It is appeared that amino carboxy-
lates bind more tightly to the zinc porphyrins than butylamine
and that the K values for Asp are greater than those for Gly,
suggesting that Coulomb interaction between an –N+(CH3)3
group of the porphyrins and the –COO– group(s) of the coordi-
nated carboxylates enhances the binding. This was supported
.
Calcd for C68H60N10O4Zn. Cl2 6H2O: C, 61.61; H, 5.47; N, 10.57%.
Found: C, 61.36; H, 5.38; N, 10.03%; MS m/z 1181 (M+), M+ calcd
for C68H60N10O4ZnCl, 1180. Compound 2 (chloride): 1H NMR (400
MHz, DMSO-d6) δ 0.07 (s, 18H, C(CH3) 3), 2.30 (s, 18H, N(CH3)3),
7.58 (t, 2H, ph), 7.61 (s, 2H, NHCO), 7.71 (t, 2H, ph), 7.81 (t, 2H, ph),
7.86 (t, 2H, ph), 7.97 (m, 6H, ph), 8.40 (d, 2H, ph), 8.58 (s, 4H, pyr-
role), 8.64 (s, 4H, pyrrole), 9.01 (s, 2H, NHCO); vis
(H2O/NaHCO3–Na2CO3, pH 10.4) λmax (log ε) 424 (5.65), 557 (4.25),
596 (3.63) nm; Anal. Calcd for C64H68N10O4Zn.Cl2 .5H2O: C, 60.71;
H, 6.02; N, 11.06%. Found: C, 60.69; H, 5.83; N, 11.01%; MS m/z
1141(M+), M+ calcd for C64H68N10O4ZnCl, 1140. Compound 3
(chloride): 1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 18H, N(CH3)3),
6.67 (m, 8H, CO–ph), 6.96 (m, 2H, CO–ph), 7.66 (m, 4H, ph), 7.88
(m, 6H, ph), 7.99 (m, 4H, ph), 8.32 (d, 2H, ph), 8.52 (s, 2H, pyrrole),
8.62 (d, 2H, pyrrole), 8.75 (d, 2H, pyrrole), 8.84 (s, 2H, pyrrole), 9.02
(s, 2H, NHCO), 9.29 (s, 2H, NHCO); vis (H2O/NaHCO3–Na2CO3,
pH 10.4) λmax (log ε) 424 (5.18), 557 (4.20), 596 (3.66) nm; Anal.
from examining the dependence of K on ionic strength I where
–
slope for plotting log K versus √I can correlate to the magnitude
of Coulomb interaction.4,9 The slope on the binding of butyl-
amine to 2 was found to be 0.09 while those of L-Trp and DL-
Asp were –1.26 and –1.63, respectively, indicating that
Coulomb interaction strengthens the binding.
On the binding of amino carboxylates to 5,10,15,20-tetra-
kis(N-methyl-4-pyridyl)porphyrinatozinc(II) in aqueous solu-
tion, the K values for Phe and Trp anions were increased in
terms of hydrophobic interactions between the hydrophobic
side chains of the carboxylates and the porphyrin plane.3 This
effect cannot be expected for the amino carboxylates with no
hydrophobic side chain such as Gly and Asp. For the zinc por-
phyrins prepared, similar increments in K are also observed for
the binding of Phe and Trp compared to Gly, suggesting the
presence of hydrophobic interaction with the porphyrin plane.
Another hydrophobic interaction is also possible between the
side chain of Phe or Trp and the t-butyl or phenyl group of the
zinc porphyrins prepared. This can be correlated to the fact that
the K values for 1 and 3 with the amines except Asp are appar-
ently larger than those for 2. This result might be reasonably
ascribed to the increased hydrophobic area of the phenyl group
compared to the t-butyl group.
.
Calcd for C68H60N10O4Zn.Cl2 3H2O.2CH3OH: C, 62.95; H, 5.58; N,
10.49%. Found: C, 63.23; H, 5.21; N, 10.06%; MS m/z 1181(M+), M+
calcd for C68H60N10O4ZnCl, 1180.
7
8
H. Imai, H. Munakata, A. Takahashi, S. Nakagawa, and Y. Uemori,
Chem. Lett., 1997, 819; H. Imai, H. Munakata, A. Takahashi, S.
Nakagawa, Y. Ihara, and Y. Uemori, J. Chem. Soc., Perkin Trans. 2,
1999, 2565.
A plot of [L] versus [L]/∆A gave a straight line with intercept –K–1,
where ∆A is the difference between the absorbance at 424 nm of the
solution of ZnP without L and that with a given concentration of free L;
J. P. Collman, J. I. Brauman, K. M. Doxsee, T. R. Halbert, S. E. Hayes,
and K. S. Suslick, J. Am. Chem. Soc., 100, 2761 (1978).
9
M. A. Hossain and H.-J. Schneider, Chem. Eur. J., 5, 1284 (1999).
10 The K values of 3 with chiral amines were estimated from the formation
of the Zn–N bond (reference 8) where the two diastereomeric conforma-
tions of the amine adducts can not be distinguishable. Therefore chiral
recognition of the amines by 3 results a decrease in K for L- (or D-) body
of the amines compared with the DL- racemic mixture in terms of a
decreased amount of a preferred diastereomeric conformation.
Thus, compounds 1 and 3 can recognize amino carboxy-
lates on the basis of coordination, Coulomb interaction, and
two-point hydrophobic interactions. Since 3 exists as the