Calderon-Kawasaki et al.
red color and turned basic beyond pH 8, as indicated by pH paper,
CH2Cl2 (50 mL) was added, and the solution was stirred overnight.
The organic layer was separated from the aqueous layer, and any
salts in the organic layer were filtered using a Celite pad. The
filtered organic solution was dried over sodium sulfate, and the
solvent was removed under reduced pressure. The crude product
was purified by silica gel column chromatography (eluted with 1%
isopropylamine in CH2Cl2) to furnish the mixture of atropisomers
R,R-diaminoporphyrin 10a and R,â-diaminoporphyrin 10b (0.32
anion binding. Because of its potential importance to the
understanding of biological systems in general, and drug design
in particular, we are currently doing research to determine how
well this ordered solvent sphere translates to water-bound anion
receptors.
Experimental Section
NMR Titrations. NMR titrations of tetrabutylammonium acetate
and porphyrin 3 were done as previously reported.19 Variable
temperature experiments for van’t Hoff analysis were run with a
1
g, 0.5 mmol, 70% yield). H NMR (CDCl3, 400 MHz): δ -2.72
(br s, 2H), 3.52 (br s, 4H), 7.08 (d, 2H, J ) 4.1 Hz), 7.15 (t, 2H,
J ) 7.4 Hz), 7.58 (t, 2H, J ) 7.8 Hz), 7.72-7.77 (m, 6H), 7.86 (d,
2H, J ) 4.4 Hz), 8.19 (t, 4H, J ) 3.9 Hz), 8.87 (q, 8H, J ) 11.5
Hz); 13C NMR (CDCl3, 100 MHz): δ 115.2, 115.2, 115.4, 115.4,
117.5, 120.5, 126.7, 120.5, 126.7, 127, 127.8, 129.6, 134.8, 142,
146.8; ESMS: m/z (relative intensity): 645.5 (100, M + 1).
1
300 MHz HNMR. Stock solutions of porphyrin 3 (0.01169 M)
and tetrabutylammonium salts of chloride (0.1225M) were carefully
measured with a microgram scale and mixed in a volumetric flask
(2 mL). Samples were made with DMSO-d6, and all spectra were
referenced to DMSO-d6 (2.50 ppm). The NMR samples were
prepared by mixing porphyrin 3 with the tetrabutylammonium salt
at 1:6 equivalence ratios. The temperature of the sample was varied
from 30 to 100 °C, and a spectrum was recorded at each 10 °C
increment. ∆H and ∆S of binding were determined as previously
reported.19,25
5,10-Bis-(2-nitrophenyl)-15,20-diphenylporphyrin (9). (a) Step
I: Reduction of Diacyldipyrromethane 8. Diacyldipyrromethane
8 (1 equiv, 1.0 mmol, 0.48 g) was dissolved in a solution of THF/
methanol (40 mL THF/4 mL methanol), and NaBH4 (20 equiv, 20
mmol, 0.76 g) was added to the solution in 0.25-g portions. After
40 min, the reaction solution was poured into the solution of CH2-
Cl2 (110 mL) and NH4Cl (55 mL). While the solution was being
poured, the mixture was vigorously stirred with a glass rod to
prevent the solution from bumping because of the exothermic
quench. The organic phase was washed with water two times and
dried over Na2SO4. The organic solvent was removed under reduced
pressure to furnish the crude diol as an amorphous pale yellow
solid.
r,r-5,10-Bis-(2-(4-fluorophenyl)phenylurea)-15,20-diphenylpor-
phyrin (3). (a) Step I: Isomerization of Atropisomer Mixture
of 10a and 10b. A 500-mL three-neck flask was set up with the
following: an overhead stirrer, a condenser fitted with septum and
needle to release pressure, and a septum fitted with cannulation
needle to deliver nitrogen saturated with benzene from a separate
flask that contained benzene and a gas dispersion tube. Silica gel
(72 g) was mixed with benzene (160 mL) in the three-neck round-
bottom flask and stirred for 2 h at 74 °C. A mixture of R,R- and
R,â-diaminoporphyrin 10 (0.31 mol, 2 g) was added to the silica
gel slurry, which was stirred for 24 h at the same temperature. The
apparatus was checked periodically to adjust nitrogen flow, benzene
level, and the temperature. Once the slurry cooled, the porphyrin
was removed from the silica using acetone. The solvent was
removed under reduced pressure at room temperature to preserve
the R,R configuration. The R,R-aminoporphyrin 10a was separated
from the R,â-aminoporphyrin 10b using silica gel chromatography
(eluting with CH2Cl2/IPA, 99/1) to furnish the R,R-aminoporphyrin
10a (1.6 g, 0.25 mmol, 81% yield) as dark purple crystals.
(b) Step II: 2 + 2 Synthesis of Porphyrin Macrocycle. A
solution of dry CH3CN (400 mL) and freshly purified 2-nitrodipyr-
romethane 5b (1 equiv, 1 mmol, 0.27 g) was added to the flask
containing the crude diol. The solution was stirred vigorously for
5 min to allow the formation of a homogeneous mixture. Then TFA
(0.92 mL, 12 mmol) was added dropwise rapidly, and after 3.5
min, DDQ (3 equiv, 3 mmol, 0.68 g) was added to the reaction
mixture to oxidize the intermediate porphyrinogen macrocycle. TEA
(1.7 mL, 12 mmol) was added after 1 h, and the crude reaction
was passed through an alumina gel column (eluted with CH2Cl2)
until no color remained in the eluent. The solvent was removed
under reduced pressure, and the crude product was purified by silica
gel column chromatography (eluted with CH2Cl2). The solvent from
the collected porphyrin solution was removed under reduced
pressure, and the product was recrystallized from ethanol, yielding
a purple solid as a mixture of atropisomers (0.15 g, 0.2 mmol, 21%
yield over steps I and II). 1H NMR (DMSO, 400 MHz): δ -2.86
(br s, 2H), 7.80-7.88 (m, 6H), 8.14-8.20 (m, 6H), 8.28 (t, 2H, J
) 7.7 Hz), 8.34-8.36 (m, 1H), 8.49 (q, 1H, J ) 4.4 Hz), 8.55 (q,
1H, J ) 4.9 Hz), 8.57-8.59 (m, 2H), 8.73 (br d, 4H, J ) 5.5 Hz),
8.82-8.84 (m, 4H); 13C NMR (DMSO, 100 MHz): δ 114.4, 114.4,
120.8, 124, 124.1, 126.8, 128.0, 130.4, 131.8, 134, 134.6, 134.7,
136.5, 136.5, 140.8, 151.2, 151.2, 151.4, 151.4; ESMS: m/z (relative
intensity): 705.4 (100, M + 1).
5,10-Bis-(2-aminophenyl)-15,20-diphenylporphyrin (10). Dini-
troporphyrin 9 (1 equiv, 0.71 mmol, 0.5 g) was dissolved in
hydrochloric acid (30 mL) and stirred at room temperature under
nitrogen. After the porphyrin had dissolved, an excess amount of
SnCl2‚H2O (1.2 g) was added, and the reaction mixture was stirred
for 2 h. Then over a 15 min period, the mixture was brought to
65-70 °C and held for 25 min at that temperature. The reaction
mixture was cooled to room temperature and was cautiously
quenched with concentrated NH4OH to avoid excess heat evolution
by the neutralization reaction. Once the reaction mixture gained a
(b) Step II: Formation of Urea Picket Porphyrin. The R,R-
aminoporphyrin 10a (1 equiv, 0.51 mmol, 0.33 g) was dried in a
vacuum desiccator over P2O5 for 48 h. Porphyrin 10a was carefully
transferred to a dried 100-mL round-bottom flask from the
desiccator inside a nitrogen bag. While in the bag, a dried addition
funnel closed with rubber septum was attached to the flask. Once
the apparatus was taken out of the bag and fixed with a nitrogen
line, dry CHCl3 (26 mL) was added to dissolve the porphyrin. A
solution of dry CHCl3 (9 mL) and 4-fluorophenylisocyanate (4
equiv, 2.1 mmol, 0.23 mL) was syringed into the addition funnel,
and the isocyanate solution was added dropwise to the stirring
porphyrin solution. The reaction was quenched after 25 h by adding
water, and the aqueous layer was extracted with CHCl3. The solvent
was removed under reduced pressure, and the crude reaction mixture
was purified by silica gel chromatography (eluting with a stepwise
gradient of solvents: 99/1 mixture of CH2Cl2/ethyl acetate was used
until the elution of a UV absorbing band, upon which time the
solvent was changed to a 95/5 mixture of CH2Cl2/ethyl acetate).
Porphyrin 3 was collected and recrystallized from a mixture of ether
and petroleum ether to furnish 0.15 g (0.16 mmol, 32% yield) and
0.18 g (0.19 mmol, 38% yield), respectively, over two reactions of
the above scale. Mp: 232-234 °C; UV/visible (CH2Cl2): λ nm
(ꢀ, cm-1 M-1, ×103) 644 (2.53), 589 (5.06), 550 (5.50), 515 (15.9),
1
419 (271.2); H NMR (CDCl3, 400 MHz): δ -2.72 (br s, 2H),
6.77 (t, 4H, J ) 4.5 Hz), 6.91 (q, 4H, J ) 6 Hz), 7.41 (t, 2H, J )
7.4 Hz), 7.48 (s, 2H), 7.77-7.88 (m, 10H), 8.12-8.22 (m, 6H),
8.43 (d, 2H, J ) 4.4 Hz), 8.76-8.85 (m, 8H); 13C NMR (CDCl3,
100 MHz): δ 114.8, 115.1, 119.3, 120.3, 121.6, 127, 128.2, 129.2,
131.3, 134, 134.3, 135.2, 135.4, 139.1, 141, 152.5, 155.4, 158.5;
ESMS: m/z (relative intensity): 919.5 (100, M + 1); Anal. Calcd
for C58H40F2N8O2: C, 75.80; H, 4.39; N, 12.19. Found: C, 75.58;
H, 4.28; N, 11.95.
9086 J. Org. Chem., Vol. 72, No. 24, 2007