Molecules 2016, 21, 707
11 of 13
´
H] calculated 399.2283 m/z, found
52.03, 50.77, 45.32, 45.20, 21.85, 10.26; HR-MS: C23H31N2O4 [M
399.2263 m/z.
´
1-(2-Fluorophenyl)-4-{2-hydroxy-3-[(4-propoxybenzoyl)oxy]propyl}piperazinediium dichloride (4b). Yield: 63%;
˝
Rf: 0.89; Rf(rev): 0.48; M.p.: 167–170 C; HPLC pur. 98.78 (254.8 nm); 1H-NMR (700.25 MHz,
DMSO-d6)
δ
: 10.87 (bs, 2H, NH+), 7.99 (d, 3J = 8.9 Hz, 2H, ArCOO), 7.19–7.09 (m, 3H, Ar-F),
7.06–7.02 (m, 3H, ArO + Ar-F), 6.00 (s, 1H, OH), 4.50–4.47 (m, 1H, CH(OH)), 4.23–4.22 (m, 2H,
COOCH2), 4.02 (t, 3J = 6.6 Hz, 2H, CH2CH2CH3), 3.74–3.23 (m, 10H, Hpip + CH2Npip), 1.77–1.72
(m, 2H, CH2CH2CH3), 0.98 (t, 3J = 7.4 Hz, 3H, CH3); 13C-NMR (176.08 MHz, DMSO-d6)
δ: 165.14,
162.69, 154.79 (d, 1JC-F = 244.5 Hz), 138.23 (d, 2JC-F = 8.5 Hz), 131.53, 124.91 (d, 3JC-F = 2.9 Hz), 123.31
2
(
d, 3JC-F = 7.8 Hz), 121.43, 119.52 (d, 4JC-F = 1.1 Hz), 116.09 (d, JC-F = 20.3 Hz), 114.30, 69.29, 66.05,
63.31, 58.29, 52.33, 51.05, 46.84, 46.69, 21.83, 10.24; HR-MS: C23H30FN2O4 [M
´
H]´ calculated
417.2190 m/z, found 417.2172 m/z.
1-(4-Fluorophenyl)-4-{2-hydroxy-3-[(4-propoxybenzoyl)oxy]propyl}piperazinediium dichloride (4c). Yield: 57%;
˝
Rf: 0.85; Rf(rev): 0.39; M.p.: 203–205 C; HPLC pur. 99.33 (254.8 nm); 1H-NMR (700.25 MHz, DMSO-d6)
: 10.80 (bs, 2H, NH+), 7.98 (d, 3J = 8.9 Hz, 2H, ArCOO), 7.11–7.09 (m, 2H, Ar-F), 7.05–7.02 (m, 4H, ArO +
Ar-F), 5.19 (s, 1H, OH), 4.50–4.47 (m, 1H, CH(OH)), 4.24–4.20 (m, 2H, COOCH2), 4.02 (t, 3J = 6.5 Hz, 2H,
CH2CH2CH3), 3.74–3.16 (m, 10H, Hpip + CH2Npip), 1.77–1.72 (m, 2H, CH2CH2CH3), 0.98 (t, 3J = 7.4 Hz
3H, CH3); 13C-NMR (176.08 MHz, DMSO-d6) : 165.15, 162.69, 156.55 (d, 1JC-F = 236.9 Hz), 146.31
d, 4JC-F = 1.5 Hz), 131.53, 121.43, 117.77 (d, 3JC-F = 7.6 Hz), 115.45 (d, 2JC-F = 22.0 Hz), 114.30, 69.29,
δ
,
δ
(
66.07, 63.34, 58.12, 52.05, 50.78, 45.97, 45.85, 21.83, 10.24; HR-MS: C23H30FN2O4 [M
417.2190 m/z, found 417.2179 m/z.
´
H]´ calculated
1-{2-Hydroxy-3-[(4-propoxybenzoyl)oxy]propyl}-4-(2-methoxyphenyl)piperazinediium dichloride (4d). Yield:
1
56%; Rf: 0.77; Rf(rev): 0.51; M.p.: 127–130 ˝C; HPLC pur. 94.78 (254.8 nm); H-NMR (700.25 MHz,
DMSO-d6) δ
: 10.71 (bs, 2H, NH+), 7.99 (d, 3J = 9.0 Hz, 2H, ArCOO), 7.04 (d, 3J = 8.9 Hz, 2H, ArO),
7.03–7.02 (m, 1H, Ar), 6.99–6.98 (m, 1H, Ar), 6.96–6.95 (m, 1H, Ar), 6.92–6.90 (m, 1H, Ar), 5.11 (s, 1H,
OH), 4.49–4.46 (m, 1H, CH(OH)), 4.24–4.21 (m, 2H, COOCH2), 4.02 (t, 3J = 6.6 Hz, 2H, CH2CH2CH3),
3.80 (s, 3H, OCH3), 3.71–3.11 (m, 10H, Hpip + CH2Npip), 1.78–1.73 (m, 2H, CH2CH2CH3), 0.98
(
t, 3J = 7.4 Hz, 3H, CH3); 13C-NMR (176.08 MHz, DMSO-d6)
δ: 165.14, 162.69, 151.78, 139.19, 131.53,
123.49, 121.43, 120.79, 118.24, 114.30, 111.97, 69.29, 66.03, 63.27, 58.30, 55.36, 52.58, 51.20, 46.76, 46.62,
´
21.82, 10.24; HR-MS: C24H33N2O5 [M ´ H] calculated 429.2389 m/z, found 429.2361 m/z.
1-{2-Hydroxy-3-[(4-propoxybenzoyl)oxy]propyl}-4-(4-methoxyphenyl)piperazinediium dichloride (5e). Yield:
63%; Rf: 0.81; Rf(rev): 0.49; M.p.: 191–194 ˝C; HPLC pur. 98.70 (254.8 nm); 1H-NMR: (700.25 MHz,
3
DMSO-d6)
(
δ
: 10.85 (bs, 2H, NH+), 7.99 (d, J = 7.9 Hz, 2H, ArCOO), 7.05–7.03 (m, 4H, Ar), 6.89
d, 3J = 8.2 Hz, 2H, NAr), 5.05 (s, 1H, OH), 4.49–4.47 (m, 1H, CH(OH)), 4.25–4.20 (m, 2H, COOCH2),
4.02 (t, 3J = 6.5 Hz, 2H, CH2CH2CH3), 3.76–3.21 (m, 10H, Hpip + CH2Npip), 3.71 (s, 3H, OCH3), 1.77–1.72
(m, 2H, CH2CH2CH3), 0.98 (t, J = 7.4 Hz, 3H, CH3); 13C-NMR (176.08 MHz, DMSO-d6)
δ
: 165.16,
3
162.69, 154.27, 142.65, 131.54, 121.43, 118.40, 114.46, 114.30, 69.30, 66.07, 63.38, 58.09, 55.24, 51.94, 50.70,
´
46.95, 46.86, 21.83, 10.24; HR-MS: C24H33N2O5 [M
´
H] calculated 429.2389 m/z, found 429.2364 m/z.
3.3. Quantum Chemical Calculations
The models of the complexes were prepared using interactive computer graphics, and their
structures were optimized as follows. First, the harmonic vibrational frequencies were calculated
employing the density functional theory (DFT)-based B3LYP/6-311G** method to assess the curvature
of the potential-energy surface (PES). This served as an input for the gradient-based geometrical
optimization at the same level of the quantum chemical theory. The resulting stationary points
of the PES were then verified to be minima by calculating the harmonic vibrational frequencies
again. The geometries thus obtained were used for the predictions of the NMR chemical shielding
by combining the GIAO strategy [21,22] with the B3LYP/6-311G** method. This approach, further