The Journal of Physical Chemistry B
Article
DMSO solutions of the ligands at concentrations, depending
on solubility, in the range 100 μM to 1 mM. All spectra were
processed and analyzed with the aid of MestRec (version
2.3a).40 1H spectra were recorded in the range 0−10 ppm (24K
data points) and processed using π/3-shifted squared sine-bell
and zero-filling up to 32K data points prior to Fourier
transformation. 13C spectra, recorded with broadband proton
decoupling in the range 0−200 ppm and 32K data points, were
processed using Lorenzian filtering, resulting in 15 Hz
resonance broadening followed by a π/2-shifted squared sine-
bell. The DMSO signal (1H quintuplet at 2.50 ppm, 13C
septuplet at 29.43 ppm) was used as the internal reference.
(dd, 1H, J = 0.73 Hz, 7.08 Hz, H-7); 7.48 (dd 1H J = 8.79 Hz,
7.08 Hz, H-6).
4-Bromobenzotriazole (3c, 4-BrBt). A 150 mg portion (0.7
mmol) of 4-bromo-2,1,3-benzothiadiazole (3a) was ground in a
mortar with 660 mg (3.48 mmol) of SnCl2. and added gradually
to 10 mL of conc. HCl. The mixture was stirred for 2 h at room
temperature, and the resulting white solid was filtered off and
suspended in 25% aqueous NaOH. Ether extraction (2 ×
50 mL), drying the ether layer over anhydrous Na2SO4, and
concentration in vacuo afforded 105 mg (81%) of 3-bromo-o-
1
phenylenediamine (3b). H NMR 500 MHz (DMSO-d6): δ
[ppm]: 10 (s, ext. br, NH2 × 2), 7.43 (dd, 1H, J = 1.3 Hz, J =
7.9 Hz, H-5), 7.28 (dd, 1H, J = 1.3 Hz, J = 7.9 Hz, H-7), 6.62
(t, 1H, J = 7.9 Hz, H-6):
(a) A solution of 80 mg (0.43 mmol) of 3-bromo-o-
phenylenediamine (3b) in 1 mL of AcOH and 0.4 mL of H2O
was cooled to 0 °C, followed by addition of 48.9 mg (0.71
mmol) of sodium nitrite in 0.3 mL of water. The mixture was
stirred for 1 h at room temperature, and the resulting
precipitate collected by filtration and recrystallized from dilute
ethanol to give 70 mg (83%) of pure product 3c.
1
Assignments for H resonances were done on the basis of line
splitting patterns caused by homonuclear scalar coupling, while
13C resonance assignments were supported by GIAO-derived
NMR shielding parameters (cf. Figure 1 in the Supporting
Information for general correlation)
UV-Monitored Titration. Titration of the ligands in the
pH range 2−12 was followed at 298 K on a Specord 200 UV−
vis spectrometer equipped with a thermostatted cell holder.
Changes in absorption were globally analyzed using the
Henderson−Hasselbach formula:
(b) A 0.5 g portion (1.9 mmol) of the dihydrochloride of
3-bromo-o-phenylenediamine (3b) was dissolved in 10 mL of
water, 0.5 mL of conc. HCl, and 5 mL of EtOH. The solution
was cooled to 0 °C, and 220 mg (3.1 mmol) sodium nitrite in
2 mL of water was added all at once. The mixture was stirred for
1 h at room temperature, and the resulting precipitate collected
by filtration and recrystallized from dilute ethanol to give
240 mg (63%) of pure product 3c: mp 183.5−185.5 °C; Rf (A)
0.63, (B) 0.69; UV λmax (ε): (pH 2) 267.5 nm (8465); (pH 7)
εn(λ)·10pH + εa(λ)·10pK
a
ε(λ, pH) =
10pH + 10pK
a
where ε(λ, pH) is the spectrum recorded at a given pH and
εn(λ) and εa(λ) are the reference spectra for the neutral and
dissociated forms. The pKa values were then estimated using
the Marquardt−Levenberg algorithm41 implemented in the
Gnuplot program.42
Solubility. Aqueous solubilities of benzotriazole analogues
were determined in buffered solution at pH 7.5. The
suspensions were shaken at 25 °C in a shaker (Eppendorf
Termomixer Comfort) for 96 h and then centrifuged. The
concentration of clear supernatant was estimated from the
spectra recorded in the range 220−300 nm.
Synthetic Procedures. 2,1,3-Benzothiadiazole (2). To a
suspension of 30 g (0.28 mol) of o-phenylenediamine (1) in
dry toluene (300 mL) was added 90 mL (1.23 mol) of thionyl
chloride. The mixture was heated under reflux for 3 h, followed
by addition of 65 mL of thionyl chloride and 6 mL of dry
pyridine in three portions of 2 mL each. Heating was continued
for an additional 19 h. Distillation at 150 °C removed toluene
and excess thionyl chloride. The fraction boiling at 200−220 °C
was collected and, on cooling, the distillate of 2,1,3-
benzothiadiazole solidified. The product was dissolved in ethanol,
reprecipitated with water, collected, and washed with water
to yield 31.2 g (82%) of 2: mp 43.2−44.1 °C [lit. 44 °C37];
Rf (C) 0.74; 1H NMR: δ [ppm]: 8.01 (dd, 2H, J = 3.4, 6.8 Hz,
H-4, H-7); 7.6 (dd, 2H, J = 2.9 Hz, 6.8 Hz, H-5, H-6).
4-Bromo-2,1,3-benzothiadiazole (3a). A 5 g portion (37
mmol) of 2,1,3-benzothiadiazole (2) was suspended in 10 mL
of 47% HBr. The mixture was heated to reflux with stirring, and
1.9 mL (37 mmol) of Br2 was added portionwise for 2 h.
Heating was continued for 1 h. The mixture was cooled and
poured into ice water, and the resulting precipitate was
collected by filtration. The crude product included small
amounts of starting material and 4,7-dibromo-2,1,3-benzothia-
diazole (4a), which were removed by steam-distillation.
Crystallization from EtOH gave 4.34 g (55%) of pure product
3a: mp 80.1−81.7 °C [lit. 80−81 °C37]; Rf (C) 0.80; 1H NMR:
δ [ppm]: 7.98 (dd, 1H, J = 0.73 Hz, 8.79 Hz, H-5); 7.85
1
272 nm (8660); (pH 12) 280 nm (10350); H NMR δ: 16.13
(br s, 1H-NH), 7.89 (br s, 1H, H-5), 7.67 (d, 1H, J = 6.6 Hz,
H-7), 7.4 (t, 1H, J = 7.7 Hz, H-6); 13C NMR δ: 140.79, 138.03,
128. 30, 128.45, 113.88, 109.13; MS for C6H5Br1N3 [M+H]+:
found, 197.96629; calcd, 197.96668.
4,7-Dibromo-2,1,3-benzothiadiazole (4a). A 5 g portion
(37 mmol) of 2,1,3-benzothiadiazole (2) was suspended in
15 mL of 47% HBr. The mixture was heated under reflux with
stirring, and 5.65 mL (110 mmol) of Br2 was added dropwise
very slowly (∼3 h). The mixture was then heated for another
2 h and the residue collected by filtration. Recrystallization from
AcOH with addition of EtOH, and then from EtOH, gave 7.02 g
(65%) of pure product 4a: mp 188.4−189.5 °C [lit. 188−189 °C37];
1
Rf (C) 0.85; H NMR: δ [ppm]: 7.73 (s, 2H, H-5, H-6).
4,7-Dibromobenzotriazole (4c, 4,7-Br2Bt). A 2 g portion
(6.83 mmol) of 4,7-dibromo-2,1,3-benzothiadiazole (4a) was
dissolved in 108 mL of THF and 40 mL of EtOH. The mixture
was cooled to 0 °C, and 4.4 g (116 mmol) cooled NaBH4 was
added portionwise. The mixture was then stirred for 20 h.
Following removal of solvent, H2O was added and the mixture
extracted with diethyl ether. The organic phase was washed
with brine and dried over Na2SO4. Evaporation in vacuo gave
80% yield of the diamine 4b: 1H NMR 500 MHz (DMSO-d6):
δ [ppm]: 6.64 (s, 2H), 5.00 (s, 4H, NH2), which was then used
to obtain 4,7-dibromobenzotriazole (4c) by the same
procedure as for 4-bromobenzotriazole (3c, see above), in
75% yield: mp 255.5−257.1 (dec.); Rf (A) 0.6, (B) 0.82; UV
λmax (ε): (pH 2) 275 nm (9140), 292 nm (8260); (pH 7) 286
1
nm (11810); (pH 12) 285 nm (12621); H NMR δ: 16.64
(br s, NH), 7.63 (s, 2H, H-5, H-6); 13C NMR δ: 139.80,
129.93, 107.26; MS for C6H4Br2N3 [M+H]+: found, 277.87412;
calcd, 277.87515.
7261
dx.doi.org/10.1021/jp301561x | J. Phys. Chem. B 2012, 116, 7259−7268