New N-aryloxy-phthalimide derivatives. synthesis, physico-chemical properties, and QSPR studies

Article abstract of DOI:10.2478/s11532-010-0063-6

Starting from N-hydroxyphthalimide 1 and the reactive fluoro- or chloro-nitroaryl derivatives 2, 3 and 4a-e (2-chloro-3,5-dinitropyridine; 3, NBD-chloride; 4a, 1-fluoro-2,4-dinitrobenzene; 4b, picryl chloride; 4c, 4-chloro-3,5-dinitrobenzotrifluoride; 4d,

Full text of DOI:10.2478/s11532-010-0063-6

Cent. Eur. J. Chem. • 8(4) • 2010 • 789–796
DOI: 10.2478/s11532-010-0063-6
Central European Journal of Chemistry
New N-aryloxy-phthalimide derivatives.
Synthesis, physico-chemical properties,
and QSPR studies
Research Article
Madalina Tudosea, Florin D. Badeab, Miron T. Caproiuc, Adrian Beteringhea, Maria Maganuc,
Petre Ionitaa,d, Titus Constantinescua, Alexandru T. Balabane*
a Institute of Physical Chemistry, 202 Splaiul Independentei,
Bucharest 060021, Romania
b Organic Chemistry Department, University Politehnica Bucharest,
Bucharest 011061, Romania
c Center of Organic Chemistry, 202 Splaiul Independentei,
Bucharest 060023, Romania
d Organic Chemistry Department, University of Bucharest,
Bucharest 050663, Romania
e Texas A&M University at Galveston,
Galveston TX 77551, U.S.A.
Received 03 February 2010; Accepted 17 April 2010
Abstract: Starting from N-hydroxyphthalimide 1 and the reactive fluoro- or chloro-nitroaryl derivatives 2, 3 and 4a–e (2-chloro-3,5-dinitropyridine;
3, NBD-chloride; 4a, 1-fluoro-2,4-dinitrobenzene; 4b, picryl chloride; 4c, 4-chloro-3,5-dinitrobenzotrifluoride; 4d, 2-chloro-3,5-
dinitrobenzotrifluoride; 4e, 4-chloro-3,5-dinitrobenzoic acid) the corresponding N-(2-nitroaryloxy)-phthalimide derivatives 5a–e, or 6
and 7 were obtained and characterized by IR, UV-Vis 1H-NMR and 13C-NMR spectroscopy. The TLC behavior and the hydrophobicity
of these derivatives have been experimentally evaluated by RM0 parameters (using RP-TLC). The experimental RM0 parameters were
compared with the calculated partition coefficient, log P. A QSPR study was also performed to establish possible correlations between
the structure and physical properties (λmax and RM0) of compounds 5a–e, 6, and 7.
Keywords: N-aryloxy-phthalimide derivatives • UV-Vis • TLC • RP-TLC • QSPR
© Versita Sp. z o.o.
1. Introduction
animals against ionizing radiations [15,16]. Such types
of compounds are not easily synthesized, because direct
N-Hydroxy-phthalimide 1 (known also as NHPI), is alkylations of the hydroxyl group of the hydroxylamine
a commercially available compound that is easily usually leads to N-substituted derivatives. Thus, for
synthesized from phthalic anhydride and hydroxylamine obtaining the O-substituted derivatives, the first step
[1] (obtained for the first time by Cohn [2] in 1880). This consists in protecting the amino group. The current
compound is a weak acid (pKa = 6.1) [3,4] and has a way to obtain such derivatives starts from 1, which is
variety of practical uses. Recently, it has been used as a derivatized with a reactive reagent (i.e., an activated
catalyst in oxidation processes, via the phthalimide N-oxyl haloderivative), and the resulting compound is treated
radical [5] (known as PINO). The PINO radical can be with acid, hydrazine or hydroxylamine to prepare the
obtained in several ways [5-7], and has an important role expected O-substituted hydroxylamine, possibly followed
in the oxidation of a large variety of compounds, including by deprotection [15,19].
aliphatic hydrocarbons [7,8], alkylbenzenes [9,10],
Starting from compounds 1, 2, 3 and 4a-e, we
alcohols and aliphatic amines [11,12], benzylamines [13], report the synthesis of seven nitro-substituted N-(2-
N-alkylamides [14], etc. O-Substituted hydroxylamines nitroaryloxy)-phthalimide derivatives 5a–e, or 6 and 7
have found applications in medicinal chemistry, having (Fig.1), where compounds 5a,b were known [15,19].
antihistaminic and bactericidal properties, as well as All the synthesized compounds were characterized by
being used as prophylactic chemicals in protecting IR, NMR, UV-Vis and TLC to confirm their structure.
* E-mail: balabana@tamug.edu
789

New N-aryloxy-phthalimide derivatives. Synthesis,
physico-chemical properties,and QSPR studies
Because such compounds may have some biological
activity, we studied their hydrophobicity (lipophilicity)
using different chromatographic systems. We also used
QSPR (quantitative structure-property relationships) for
studying these synthesized compounds 5a–e, 6 and 7
(Fig. 1).
2. Experimental Procedure
All the starting chemicals (N-hydroxyphthalimide 1,
2-chloro-3,5-dinitropyridine
2,
NBD-chloride
3,
1-fluoro-2,4-dinitrobenzene
4a, 4-chloro-3,5-
dinitrobenzotrifluoride 4c, 2,4-dinitro-6-trifluoromethyl-
chlorobenzene 4d, and 4-chloro-3,5-dinitrobenzoic
acid 4e) were purchased from Sigma-Aldrich and used
as received. Picryl chloride 4b was synthesized as we
described previously [20]. Preparative and analytical
silica gel TLC plates were purchased from Sigma-Aldrich
and Merck. Solvents were purchased from Chimopar or
Sigma-Aldrich and used without further purification.
UV-Vis spectra were recorded in methanol
Figure 1. Compounds 1-7.
at room temperature (22oC) using
a UVD-3500 3, and 4a-e with N-hydroxyphthalimide 1 in dry acetone
spectrophotometer. IR spectra were recorded in solid as solvent and in the presence of triethylamine. The
state (ATR) on a Bruker Vertex 70 spectrometer. 1H-NMR ratio between these reagents was 1 : 1.1 : 1.2 (halogen-
and 13C-NMR spectra were recorded on a Bruker BB300 derivative
instrument, using deuterated chloroform or deuterated exception being made for the synthesis of compound 5e,
: N-hydroxyphthalimide : triethylamine),
dimethylsulfoxide as solvent.
when a twofold excess of triethylamine has been used
to neutralize the COOH group. The reaction mixture
was stirred at room temperature for at least 2 h, then
2.1. Computational details.
The values of octanol-water partition coefficient (log P) the mixture was poured into icy water, and allowed to
for compounds 1, 5a–e, 6, and 7 were calculated by stand overnight at 4oC. Then the precipitate was filtered
means of the Hyperchem program (trial version [21]); off, washed with hexane and dried in a dessicator.
values of net atomic charges and dipole moments If the purity of the final product (as checked by TLC) was
for these compounds were calculated with the not satisfactory, the product was purified by preparative
MOPAC program (a semiempirical molecular orbital TLC on silica gel using methylene chloride as eluent.
package developed by J. J. P. Stewart [21]). For the
5a (N-(2,4-Dinitrophenyl)oxyphthalimide), yield 88%,
geometry optimization we used the semiempirical mp. 180-183°C, 1H-NMR (CDCl3, δ ppm, J Hz): 8.97 (d,
PM3 (parametric method number 3) method [21,22] 1H, H-11, 2.7); 8.44 (dd, 1H, H-13, 2.7, 9.2); 7.99 (m, 2H,
implemented in the program ArgusLab [23], because H-1, H-4); 7.91 (m, 2H, H-2, H-3); 7.46 (d, 1H, H-14, 9.2).
the MM+ [24] force field and the AM1 [25] method
13C-NMR (CDCl3, δ ppm): 162.07 (C-5, C-6); 156.50
did not lead to satisfactory results. The geometry (C-9); 143.22 (C-12); 137.31 (C-10); 135.83 (C-2, C-3);
optimizations were performed without symmetry 129.50 (C-13); 128.70 (C-5, C-6); 124.74 (C-1, C-4);
constraints applying the geometry-optimizing routine 122.65 (C-11); 115.82 (C-14).
EF (eigenvector following [26]) and were completed
Elemental analysis: calculated for C14H7N3O7:
after reaching a gradient norm of 0.01 kcal mol-1 Ǻ-1. M = 329, C, 51.08%, H, 2.14%, N, 12.76; found: C,
To obtain the energies displayed in Table 4 we used the 51.17%, H, 2.14%, N, 12.55%.
Gamess program and hybrid QM/MM force field [27].
IR (ATR, cm-1): 3101, 1798, 1732, 1603, 1526, 1476,
1418, 1347, 1266, 1227, 1184, 1112, 1069, 967, 913,
870, 831, 784, 737, 690, 586, 509.
2.2. Synthesis of compounds 5a–e, 6, and 7.
The synthesis of these compounds has been performed
according to literature data (available for compounds 50%, mp. 185-188°C, H-NMR (CDCl3, δ ppm, J Hz):
5a,b) [15,19]. The general procedure involves the 8.89 (s, 2H, H-11, H-13); 7.96÷7.81 (m, 4H, H1, H-2,
reaction of the reactive chloro- or fluoro-derivatives 2, H-3, H-4).
5b (N-(2,4,6-Trinitrophenyl)oxyphthalimide), yield
1
790

M. Tudose, et al.
13C-NMR (CDCl3, δ ppm): 161.99 (C-7, C-8); 144.33
(C-9); 134.38 (C-12); 131.26 (C-10, C-14); 134.97 (C-1, 60%, mp. 185-190°C, H-NMR (CDCl3, δ ppm, J Hz):
C-4); 128.95 (C-5, C-6); 124.15 (C-2, C-3); 124.00 (C-11, 9.31(d, 1H, H-13, 2.4); 9.15 (d, 1H, H-11, 2.4); 7.97 (m,
6
(N-(2,4-Dinitropyridine)oxyphthalimide), yield
1
C-13).
Elemental analysis: calculated for C14H6N4O9: M =
2H, H-1, H-4); 7.88 (m, 2H, H-2, H-3).
13C-NMR (CDCl3, δ ppm): 161.29 (C-7, C-8); 157.10
374, C, 44.93%, H, 1.62%, N, 14.97; found: C, 45.05%, (C-9); 147.34 (C-13); 141.62 (C-12q); 135.29 (C-1,
H, 1.68%, N, 14.67%. C-4); 132.52 (C-11); 131.71 (C-10); 128.66 (C-5, C-6);
IR (ATR, cm-1): 3436, 3323, 3084, 2922, 2853, 1795, 124.45 (C-2, C-3).
1740, 1534, 1340, 1279, 1225, 1178, 1077, 931, 872,
693, 516.
Elemental analysis: calculated for C13H6N4O7 : M =
330, C, 47.29%, H, 1.83%, N, 16.97; found: C,47.15 %,
5c (N-(2,6-Dinitro-4-trifluoromethylphenyl) H, 1.88%, N,14.71 %.
1
oxyphthalimide), yield 40%, mp. 155-160°C, H-NMR
IR (ATR, cm-1): 3094, 3059, 1828, 1737, 1527, 1465,
(CDCl3, δ ppm, J Hz): 8.30 (s, 2H, H-11, H-13); 7.92÷7.86 1334, 1243, 1183, 1080, 994, 948, 895, 871, 694, 594, 516.
(m, 4H, H-1, H-2, H-3, H-4).
7 (N-[4-(7-Nitrobenzofurazan)]oxyphthalimide), yield
13C-NMR (CDCl3, δ ppm): 161.89 (C-7, C-8); 152.87 54%, mp.195-198°C, 1H-NMR (CDCl3, δ ppm, J Hz):
(C-9); 142.74 (C-10, C-14); 135.93 (C-1, C-4); 128.58 8.52 (d, 1H, H-13, 8.4); 8.01 (m, 2H, H-1, H-4); 7.91 (m,
(q, C-12, J(F-C)= 35.7 Hz); 128.35 (C-5, C-6); 126.14 2H, H-2, H-3); 7.16 (d, 1H, H-14, 8.4).
(q, C-11, C-13, 3J(F-C)=3.7 Hz); 124.79 (C-2, C-3);
120.61 (q, CF3, J(F-C)=272.8 Hz).
13C-NMR (CDCl3, δ ppm): 161.69 (C-7, C-8); 154.83
(Cq); 152.85 (C-9); 145. 31 (Cq); 144.14 (Cq); 142.67
Elemental analysis: calculated for C15H6F3N3O7: M = (Cq); 135.74 (C-1, C-4); 132.16 (C-13); 128.64 (C-5,
397, C, 45.36%, H, 1.52%, N, 14.35; found: C, 45.35%, C-6); 108.14 (C-14).
H, 1.55%, N, 14.14%.
Elemental analysis: calculated for C14H6N4O6 :
IR (ATR, cm-1): 3081, 2922, 1801, 1745, 1624, 1544, M = 326, C, 51.55%, H, 1.85%, N, 17.17%; found:C,
1347, 1318, 1133, 1057, 918, 869, 787, 699, 663, 589, 51.76%, H, 1.89%, N, 16.94%.
515.
IR (ATR, cm-1): 3081, 1796, 1740, 1600, 1547, 1340,
5d (N-2,4-Dinitro-6-trifluoromethylphenyl) 1221, 1182, 1132, 1077, 969, 942, 872, 828, 692, 537,
oxyphthalimide), yield 40%,mp.165-170°C,1H-NMR 512.
(CDCl3, δ ppm, J Hz): 8.78 (d, 1H, H-11, 2.5); 8.72 (d,
1H, H-13, 2.5); 7.93÷7.86 (m, 4H, H-1, H-2, H-3, H-4).
3. Results and Discussion
13C-NMR (CDCl3, δ ppm): 161.48 (C-7, C-8);
152.54 (C-9); 143.12 (Cq); 140.62 (Cq); 135.93 (C-1,
3.1. Synthesis of compounds 5a–e, 6, and 7.
3
C-4); 128.25 (C-5, C-6); 126.10 (q, C-13, J(F-C)=5.1
Hz); 124.82(C-2, C-3); 124.54(C-11); 124.07 (q, C-14,
3J(F-C)=34.4 Hz); 120.85 (q, CF3, J(F-C)=273.2 Hz).
Elemental analysis: calculated for C15H6F3N3O7:
Compounds 5a–e, 6, and 7 (Fig. 1), are easily obtained
starting from 1 and the fluoro- or chloro-nitroaryl
derivatives, namely 2-chloro-3,5-dinitropyridine 2;
4-chloro-7-nitrobenzofurazan (or 4-chloro-7-nitrobenz-
M = 397, C, 45.36%, H, 1.52%, N, 14.35%; found: C, 2-oxa-1,3-diazole, NBD chloride) 3; 1-fluoro-2,4-
45.50%, H, 1.59%, N, 14.23%.
dinitrobenzene 4a; picryl chloride (or 1-chloro-2,4,6-
IR (ATR, cm-1): 3083, 2854, 1802, 1746, 1545, 1470, trinitrobenzene) 4b; 4-chloro-3,5-dinitrobenzotrifluoride
1319, 1134, 1058, 939, 918, 871, 817, 700, 665, 590, 516. 4c; 2-chloro-3,5-dinitro-benzotrifluoride 4d; and
5e(N-(4-Carboxy-2,6-dinitrophenyl)oxyphthalimide), 4-chloro-3,5-dinitrobenzoic acid 4e.
1
yield 50%, mp. 155-160°C, H-NMR (CDCl3, δ ppm, J
The reaction was conducted in dry acetone, in the
Hz): 8.87 (s, 2H, H-11, H-13); 7.93 (m, 2H, H-1, H-4); presence of a slight excess of triethylamine as base, to
7.83 (m, 2H, H-2, H-3).
obtain in the first step the corresponding anion from 1
13C-NMR (CDCl3, δ ppm): 161.95 (C-7, C-8); 160.49 and in the next step an S
NAr process via Meisenheimer
σ-anion complexes [28,29]. The expected products
were obtained with yields varying from 40% to 95%,
depending on the structure and reactivity of the nitroaryl
derivatives 2, 3 and 4a-e. The reaction conditions
(COOH); 149.63 (C-9); 141.22 (C-10, C-14); 134.98 (C-
1, C-4); 132.92 (C-11, C-13); 128.94 (C-5, C-6); 125.73
(C-12); 124.19 (C-2, C-3).
Elemental analysis: calculated for C15H7N3O9: M =
373, C, 48.27%, H, 1.89%, N, 11.26%; found:C ,48.29%, were similar to those described in the literature [15,19]
H, 1.79%, N, 11.04%.
(acetone as solvent, triethylamine as base, room
temperature), due to the fact that other conditions
[16-18,30] (i.e., potassium hydroxide as base, DMF as
solvent, or ultrasound condition) do not work properly.
IR (ATR, cm-1): 3215, 3083, 2524, 1779, 1735, 1705,
1538, 1420, 1356, 1246, 1185, 1116, 1013, 974, 917,
873, 693, 517.
791

New N-aryloxy-phthalimide derivatives. Synthesis,
physico-chemical properties,and QSPR studies
3.2. Spectral data
on the nitroaryl moiety, the Rf values decrease in the
The IR spectra of all compounds 5a–e, 6 and 7 following order: 5c = 5d > 5a > 6 > 7> 5b > 5e > 1; (ii)
confirm the presence of carbonyl groups, with a very the supplementary NO2 or CF3 groups increase the Rf
intense peak around 1700-1750 cm-1; the aromatic values through their hydrophobicity (compounds 5b–d),
hydrogen stretching bands appear around 3100 cm-1. while OH or COOH groups decrease the Rf values,
For compounds 5a–e, 6, and 7, which contain nitro due to the strong bonds formed with the stationary
group(s), two characteristic IR bands are noticed at phase (compounds 1 and 5e ); (iii) Rf for 5a and Rf for
around 1550 cm-1 and 1350 cm-1. The N-aryloxy bond is 6 are explained by the nitrogen atom present in the
characterized by a band at around 900 cm-1.
2,4-dinitropyridine moiety of the compound 6, which is
1H-NMR and 13C-NMR spectra confirm the structure less basic; (iv) the Rf value for the isomeric pair 5c,d is
1
the compounds 5a–e, 6 and 7; thus, in H-NMR the the same; and (v) the comparative Rf values of 5a and 7
aromatic phthalimide hydrogens appear at around (ΔRf = 0.12) prove the lower interaction with stationary
8 ppm as a multiplet; hydrogens from the nitroaryl group phase of 2,4-dinitrobenzene moiety, comparatively with
come out as singlets or doublets, depending on the the 4-nitrobenzofurazan moiety (NBD).
structure, around 8.5-9 ppm. For the fluoro-derivatives 3.3.2 RP-TLC
5c,d supplementary splittings are noticed in 13C-NMR Reversed phase thin layer chromatography (RP-TLC)
(due to the 19F atoms).
is often used to evaluate the organic–water partitioning
In solid state, compounds 1, 5a–e, 6 and 7 have properties of solutes [33-36]. The correlation between
different colors, from almost white to yellow or red. The structure and activity plays an important role in the
UV-Vis spectra recorded in methanol (Table 1) showed study of biological interactions. Among the molecular
that with two exceptions (5a and 5d), the synthesized properties the lipophilicity is important because the
compounds have two absorption maxima, one of which biological activity is correlated in QSAR (Quantitative
appears at 350–410 nm. Table 1 presents also calculated Structure-Activity Relationship) studies with their
[21,31] values (see Experimental Procedure) for log P, capacity to cross the lipophilic cell membrane [37].Along
net atomic charges and dipole moments of compounds with classical methods of hydrophobicity (lipophilicity)
1, 5a–e, 6, and 7. Compound 7 is not fluorescent in determination by partitioning the compound between
solution or solid state (at 366 nm) although it contains a polar and a non-polar solvent pair (usually, n-octanol
the NBD moiety. This behavior is analogous to other and water [22,37]), RP-TLC is widely used owing to the
NBD-OAr derivatives [32].
simplicity and the rapidity of this method. For RP-TLC,
this method uses the measurement of Rf values obtained
using a non-polar stationary phase [18,33-36](silica gel
3.3. TLC investigations
Thin layer chromatography (TLC) is a fast and reliable impregnated with paraffin oil, silanized silica gel, C18
method for checking compound purity, for the evaluation derivatized silica gel, etc.) and two miscible solvents,
of hydrophobic/lipophilic properties, and also for the one of which is water (i.e., alcohol–water, acetone-water,
preparative isolation of pure compounds.
acetonitrile-water, etc.). The RM values necessary for the
3.3.1 TLC behavior
determination of the hydrophobicity/lipophilicity of the
The TLC behavior of compounds 5a–e, 6 and 7 leads compounds are obtained as shown by Eq. 1 [18,33-36].
to the following observations (Table 1): (i) depending To measure the specific hydrophobic surface area, the
Table 1. Experimental (Rf and λmax in nm) and calculated [21,31] values for logP, net atomic charges and dipole moments of compounds 1, 5a–e,
6, and 7.
Net atomic charges
Dipole moment
Comp.
Rfa
logP
λ
(log e)
max
(Debyes)
N
O
C
1
0.11
0.69
0.76
0.77
0.76
0
294 (3.12)
276 (4.05)
1.23
2.85
2.80
3.73
3.73
2.55
2.70
2.62
-0.207
-0.233
-0.274
-0.244
-0.245
-0.246
-0.242
-0.232
-0.197
-0.042
-0.239
-0.066
-0.227
-0.228
-0.245
-0.237
–
1.47
2.23
1.40
1.76
0.74
0.99
2.77
4.86
5a
5b
5c
5d
5e
6
0.171
0.215
0.243
0.207
0.209
0.212
0.170
313 (3.83), 403 (3.60)
302 (3.55), 407 (3.27)
351 (3.52)
293 (4.09), 403 (3.49)
289 (3.96), 351 (3.50)
265 (4.08), 352 (3.85)
0.67
0.57
7
a Rf values on analytical TLC plates silica gel with fluorescent indicator (Sigma) stationary phase and dichloromethane mobile phase (detection at
254 nm).
792

M. Tudose, et al.
From the data presented in Table 2 and Table 3, one
can notice that the lowest RM0 values have been recorded
in the case of compounds 1 and 5e as expected, and
the highest values for RM0 have been recorded in the
case of the fluoro-derivatives 5c,d (again as expected,
it being well known that the trifluoromethyl group has a
high hydrophobicity [37]) and the NBD-derivative 7.
Satisfactory correlations of the calculated [31] logP
(as in Table 1) with measured RM0 values are obtained:
for Table 2, the coefficient of determination is R2 = 0.853,
thestandarddeviation is SD=0.751, and cross-validated
RCV2 =0.751;forTable3,thecoefficientofdeterminationis
R2 = 0.867, SD = 0.667, and cross-validated RCV2 = 0.801.
Between the two sets of RM0 values, a better correlation
exists, namely RM0 (Table 3) = 0.7945 × RM0 (Table 2) +
1.247, with R2 = 0.933.
linear correlation between the RM values of compounds
1, 5a–e, 6, and 7 and the concentration of the organic
solvent in the eluent (C) were calculated by Eq. 2 [18,33-
36]. The intercept RM0 (molecular hydrophobicity) is the
RM value of a compound extrapolated to zero organic
phase concentration in the eluent, and the slope b is
the change of lipophilicity caused by unit concentration
change of the organic phase. These values (RM0 and b)
are the best indicators of the lipophilicity and the specific
hydrophobic surface area of the compounds [18,33-36].
(1)
(2)
For the data presented in Table 2:
We used two analytical systems to measure the
hydrophobicity; in the first one, we used silanized silica
gel as the stationary phase (Table 2).
In the second one, C18-derivatized silica was used
(Table 3).
For both systems (Table 2 and Table 3), the eluent
was a mixture of acetone with water in different
proportions (50–85% acetone).
R
M0 =1.611 × logP – 2.108
For the data presented in Table 2:
M0 =1.336 × logP – 0.583
For the data presented in Table 3:
M0,exp =1.029RM0,calc − 0.052
For the data presented in Table 3:
M0,exp = RM0,calc
(3)
(4)
(5)
(6)
R
R
R
Table 2. Experimental data for RM0 and b using silanized silica as the stationary phase a
RM
Comp.
RM0
b
R
SD
A
B
C
D
1
-0.41
0.95
0.57
1.38
1.38
-0.10
0.90
0.86
-0.43
0.50
0.26
0.72
0.72
-0.41
0.50
0.52
-0.57
0
-0.54
-0.19
-0.28
-0.12
-0.12
-0.78
-0.19
-0.19
-0.13
2.88
2.05
3.84
3.83
0.99
2.77
2.68
-0.5619
-3.9461
-2.9816
-5.1056
-5.0699
-2.2704
-3.7900
-3.6512
0.88
0.99
0.99
0.98
0.99
0.99
0.99
0.99
0.05
0.11
0.07
0.15
0.14
0.05
0.09
0.07
5a
5b
5c
5d
5e
6
-0.12
0.12
0.15
-0.62
0.01
0.05
7
a A, B, C, and D are the RM values obtained for 50%, 60%, 70% and 80% acetone–water ratios in eluent, respectively.
Table 3. Experimental data for RM0 and b using a C18-derivatized silica gel stationary phase a
RM
Comp.
RM0
b
R
SD
A
B
C
D
1
-0.45
0.82
0.55
0.90
0.90
0
-0.36
0.68
-0.66
0.09
-0.052
0.18
0.18
-0.69
0.05
0
-1.00
-0.39
1.08
4.00
2.60
4.36
4.36
2.37
3.12
3.11
-0.0234
-0.0510
-0.0352
-0.0548
-0.0548
-0.0401
-0.0414
-0.0409
0.86
0.95
0.98
0.93
0.93
0.99
0.98
0.98
0.17
0.20
0.08
0.27
0.27
0.05
0.07
0.07
5a
5b
5c
5d
5e
6
0.048
0.86
-0.347
-0.39
0.86
-0.39
-0.47
0.147
0.147
-1.00
0.70
0.70
-0.347
-0.347
7
a A, B, C, and D are the RM values obtained for 50%, 60%, 70% and 80% acetone–water ratios in the eluents, respectively.
793

New N-aryloxy-phthalimide derivatives. Synthesis,
physico-chemical properties,and QSPR studies
for NBD-derivative (7). No satisfactory correlation for
experimental λmax (Table 1) vs. calculated λmax was
obtained using dipole moments plus net atomic charges
(Table 1), but Eq. 7 allowed a fairly good correlation in
terms of dipole moments D plus the average information
content atomic index of order 0 (AIC0) [39-42]; the
3.4. Theoretical studies
3.4.1. Geometries of the compounds 1, 5a–e, 6, and 7
For more information about the relationship between the
structure of the compounds 1, 5a–e, 6, and 7 and their
physical-chemical properties, we performed computational
studies. For geometry optimization we used programs
[22,23,26,31] (see Experimental Procedure). As seen in average information content is defined on the basis of
Fig. 2, steric hindrance causes marked deviations from the Shannon information theory and is calculated as in
planarity in compounds 5b–e and 7.
formula I [41,42]. This is understandable because the
Calculations using the GAMESS software package dipole moment integrates information about the whole
[27,38] were used for total energies of compounds 1, molecule, whereas net atomic charges on a single atom
5a–e, 6, and 7 (Table 4).
cannot provide such information.
λmax = 72.67(±28.23)AIC0 – 13.41(±3.966)D + 169.8 (7)
The total energy calculated for the compounds
1, 5a–e, 6 and 7 decreases in the following order:
5b>6>7>5e>5c>5d>5a>1 (see the comment at the end
of this paragraph justifying the comparison between
non-isomeric compounds); these total energies are the
ni
n
ni
n
k IC = −
log2
Formula I
∑
i
where ni is the number of atoms in the i-th class, and
sum of the seven types of energies displayed in Table 4. n is the total number of atoms in the molecule.
It is interesting to note that the planar structures (1 and
5a) with no steric strain have the lowest energies.
3.4.2. QSPR studies
Because in physical-chemical properties of compounds
1, 5a–e, 6 and 7 the bonds that play the main role
involve phthalimidic heteroatoms and their adjacent
carbon atoms (N–O for 1, and N–O–C for 5a–e, 6 and
7), we have calculated the net atomic charges on these
atoms (Table 1) [21]. Also we have calculated dipole
moments of compounds 1, 5a–e, 6 and 7 (Table 1) using
the MOPAC program [21].
The results presented in Table 1 lead to the following
observations: (i) the most negative net atomic charges
on the hydroxyphthalimidic (NHPI) nitrogen atom
are recorded for compounds with three nitro groups
(5b), trifluoromethyl group (5c,d) or carboxyl groups
(5e); (ii) the most net negative atomic charges on the
NHPI oxygen atom are recorded for 2,4-dinitropyridine
(6), picryl (5b) and NBD (7) derivatives; (iii) the most
positive net atomic charge on the N–O–C carbon
atom are recorded for the trifluoromethyl derivative
(5c); and (iv) the highest dipole moment is recorded
Figure 2.Optimized geometries of compounds 1, 5a–e, 6, and 7.
Table 4. Calculated energies [26,27] (kcal mol-1) of compounds 1, 5a–e, 6, and 7
Stretch-
Bend
energy
Stretch
energy
Bend
energy
Torsion
energy
Non-1,4
VDW energy
1,4 VDW
energy
Dipole-dipole
Energy
Total
energy
Comp.
1
0.331
1.798
2.297
2.049
2.044
2.482
1.649
1.383
10.650
27.258
36.643
28.129
28.887
30.221
28.161
28.945
-0.117
-0.521
-0.654
-0.485
-0.291
-0.517
-0.414
-0.329
-2.259
-7.796
-7.779
-3.918
-3.629
-6.032
-2.105
-7.769
-3.344
-10.882
-5.496
-4.992
-2.991
-9.210
-4.427
-4.096
5.985
15.880
14.615
15.109
14.721
17.029
14.940
14.112
7.661
14.375
12.977
11.394
3.075
18.907
40.112
52.603
47.286
41.816
49.314
50.877
49.801
5a
5b
5c
5d
5e
6
15.341
13.073
17.555
7
794

M. Tudose, et al.
Asatisfactory correlation (Eq. 9) was found according
to Eqs. 7 and 8:
λmax, exp = λmax, calc – 0.221
N = 8; R2 = 0.800; SD = 12.56; RCV2 = 0.767
Mh
M
Formula III
HLB = 20
(8)
where Mh is the molecular mass of the hydrophilic
AQSPR study has been conducted on the RM0 values portion of the molecule, and M is the molecular mass of
of compounds 1, 5a–e, 6 and 7 in terms of the average the whole molecule, giving a result on an arbitrary scale
nucleophilic reactivity index for carbon (ANRIC) [39,43] of 0 to 20.
and the molecular weight-adjusted hydrophilic-lipophilic
Values for the calculated [39,40] RM0 in terms of
balance (HLB) [44,45]; ANRIC is the extreme (maximum ANRIC and HLB were obtained by Eq. 9:
and minimum) or average value of the simplified RM0 = – 632.29 (±128.98) ANRIC – 0.557 (±0.118)HLB + 12.11 (9)
nucleophilic (N’A) reactivity indices for a given atomic N = 8; R2 = 0.889; SD = 0.536; RCV2 = 0.791
species in the molecule, defined by formula II [43].
Satisfactory correlations [39,40] (Eqs. 10 and 11)
were found for RM0:
2
for Table 5, RM0,exp = 1.029RM0,calc − 0.052
for Table 6, RM0,exp = RM0,calc
The correlations between experimental values and
(10)
(11)
N ' =
c
iHOMO
∑
A
Formula II
i∈A
where the summation is performed over all atomic those calculated according to Eqs. 10 and 11 are as
orbitals at the given atom, and ciHOMO denotes the i-th follows. For Table 5, the coefficient of determination is
AO coefficient on the highest occupied molecular orbital R2 = 0.927, the standard deviation is SD = 0.155, and
2
(HOMO).
cross-validated RCV = 0.907; for Table 6 the coefficient
The hydrophilic/lipophilic balance HLB was of determination is R2 = 0.983, SD = 0.449, and cross-
calculated using formula III [44,45]:
validated RCV2 = 0.874.
Table 5. Values obtained for correlation between experimental and calculated RM0 for silanized silica as stationary phase.
RM0
Comp.
ANRIC
HLB
a
b
Experimental
Calculated
Residuals
1
9.003×10-3
4.523×10-3
5.590×10-3
5.988×10-3
5.240×10-3
5.229×10-3
3.861×10-3
4.317×10-3
11.777
10.312
11.980
8.798
-0.13
2.88
2.05
3.84
3.83
0.99
2.77
2.68
-0.142
3.300
1.902
3.423
3.874
1.733
2.399
2.279
0.012
-0.420
0.148
0.417
-0.044
-0.743
0.371
0.401
5a
5b
5c
5d
5e
6
8.837
12.694
13.050
12.749
7
a As in Table 2. b Calculations according to [27,28]
Table 6. Values obtained for correlation between experimental and calculated RM0 for C18-derivatized silica gel stationary phase.
RM0
Comp.
ANRIC
HLB
a
b
Experimental
Calculated
Residuals
1
9.003×10-3
4.523×10-3
5.590×10-3
5.988×10-3
5.240×10-3
5.229×10-3
3.861×10-3
4.317×10-3
11.777
10.312
11.980
8.798
1.08
4.00
2.60
4.36
4.36
2.37
3.12
3.11
1.064
4.102
2.699
4.135
4.497
2.516
3.030
2.952
0.016
-0.102
-0.099
0.225
-0.137
-0.146
0.090
0.158
5a
5b
5c
5d
5e
6
8.837
12.694
13.050
12.749
7
a As in Table 3. b Calculations according to [27,28]
795

New N-aryloxy-phthalimide derivatives. Synthesis,
physico-chemical properties,and QSPR studies
and UV-Vis spectra, TLC behavior and experimental
hydrophobicity (lipophilicity) measurements were used
to characterize all compounds, and computational
4. Conclusions
Starting from N-hydroxyphthalimide 1 and reactive calculations were performed to correlate them. The
nitroaryl derivatives 2, 3 and 4a-e, compounds 5a–e, 6, QSPR study correlated structures with electronic
and 7 were obtained, from which five are new (namely spectra and the hydrophilic/hydrophobic balance for
compounds 5c–e, 6, and 7). The IR, 1H-NMR, 13C-NMR, compounds 1, 5a–e, 6 and 7.
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