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Abstract
Results from calculations of the logarithm of the octanolwater partition coecient, log P, and the aqueous solubility,
S, for a wide range of arylamine dyes and related structures are presented. Since many arylamine dyes have functional
groups that easily form ions, the logarithm of the apparent partition coecient for dissociative systems, log D, has also
been calculated as a function of pH for some of these compounds. Correlations of the observed biological behavior of
various dyes with log P and S are discussed. # 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Octanolwater partition coecient; Log P; Aqueous solubility; Aminoazobenzene dyes; Structureactivity relationships
1. Introduction
Recent advances in combinatorial chemistry [1]
have enabled large numbers of new compounds to
be synthesized rapidly in parallel, which has
increased the demand for reliable methods to assess
the potential toxicity of emerging drugs, pesticides,
dyes, surfactants, etc. Rigorous animal-based testing
of all new and existing chemicals is not economically practical [2,3]. One alternative approach that
has proved to be useful in screening broad classes
of chemicals, e.g. aromatic and heterocyclic amines
[4], for a specic toxicological problem, e.g. mutagenicity, involves the development of quantitative
structureactivity relationships (QSARs). QSARs
* Corresponding author. Tel.: +1-215-951-2876; fax: +1215-951-6812.
E-mail address: chuck@larry.philau.edu (C.W. Bock).
0143-7208/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0143-7208(01)00090-0
146
2. Computational section
A variety of methods have been developed to
calculate log P [10, 1623]. These methods generally assume that log P is an additive-constitutive
molecular property [4]. Despite this assumption,
Fig. 1. Illustration of the complex equilibria involved with compounds containing ionogenic groups.
147
148
where aoctanol
is the concentration of the ith
i
microspecies in the octanol phase, and ai H2O is
the concentration of the ith microspecies in the
aqueous phase at a given pH.
It should be noted that the ACD software
allows the user to test compounds for alternative
tautomeric forms e.g. ortho-hydroxy azobenzene
dyes (20 -OHAAB) and log D can then be calculated
for these structures as well. Since only vague
descriptions of the aqueous solubility of most azo
dyes are usually available in the literature, we have
employed the ACD/aqueous solubility suite [15] to
calculate S (g/l) at 25 C and at various values of
the pH for some of these dyes. In general, the melting point of a compound is required to accurately
predict its aqueous solubility from the ACD software. Unfortunately, melting points of many azo
dyes are not available in the literature, which leads
to less reliable estimates of their aqueous solubility.
149
Substituent/position
20
30
40
3.13 0.32
3.13 0.32
3.13 0.32
3.13 0.32
3.13 0.32
CH3
CF3
CN
COOH
CHO
3.59 0.32
4.98 0.42
4.07 0.42
3.78 0.40
3.67 0.42
3.59 0.32
5.12 0.43
3.44 0.41
3.46 0.39
3.56 0.42
3.59 0.32
4.10 0.40
3.37 0.41
3.61 0.38
3.36 0.41
3.59 0.32
4.50 0.41
2.74 0.38
2.87 0.35
2.61 0.38
3.59 0.32
4.10 0.39
3.07 0.39
3.18 0.35
2.92 0.38
F
Cl
Br
I
3.52 0.43
3.95 0.39
4.24 0.43
4.88 0.44
3.58 0.43
4.22 0.39
4.51 0.43
4.61 0.43
3.13 0.42
3.67 0.39
3.85 0.42
4.11 0.42
3.30 0.42
3.84 0.39
4.02 0.42
4.28 0.42
3.42 0.42
3.97 0.39
4.14 0.42
4.40 0.42
OH
OCH3
OCH2CH3
OCH2CH2CH3
OCH2CH2CH2CH3
OCH2CH2OH
2.45 0.38
3.87 0.40
4.40 0.40
4.93 0.40
5.46 0.40
2.89 0.41
2.97 0.39
3.48 0.39
4.02 0.39
4.55 0.39
5.08 0.39
2.51 0.40
2.31 0.38
3.88 0.40
4.42 0.40
4.95 0.40
5.48 0.40
2.91 0.41
2.73 0.38
3.24 0.39
3.77 0.39
4.31 0.39
4.81 0.39
2.27 0.40
2.55 0.38
2.95 0.39
3.48 0.39
4.01 0.39
4.54 0.39
1.97 0.39
NH2
N(CH2CH3)2
N(CH2CH2OH)2
NO2
1.30 0.39
5.14 0.41
2.56 0.72
4.20 0.41
2.58 0.39
4.56 0.39
1.98 0.71
4.37 0.41
1.77 0.38
5.14 0.40
2.56 0.72
3.67 0.37
2.19 0.39
4.50 0.39
1.92 0.71
3.04 0.35
2.44 0.39
4.80 0.39
2.22 0.71
3.51 0.36
SO3H
1.14 0.78
2.68 0.40
1.38 0.78
1.78 0.39
1.84 0.39
150
Table 2
Values of log P calculated using the ACD/log P suite for the positional isomers of various monosubstituted DAB compounds
Substituent/position
20
30
40
H (DAB)a
4.43 0.33
4.43 0.33
4.43 0.33
4.43 0.33
4.43 0.33
CH3
CF3
CN
COOH
CHO
4.89 0.34
6.15 0.43
5.05 0.42
5.01 0.41
4.83 0.42
4.89 0.34
6.52 0.44
4.25 0.41
3.98 0.39
3.72 0.41
4.89 0.34
5.40 0.41
4.68 0.42
4.91 0.39
4.66 0.42
4.89 0.34
5.80 0.42
4.05 0.39
4.17 0.36
3.91 0.39
4.89 0.34
5.40 0.40
4.37 0.40
4.48 0.36
4.22 0.39
F
Cl
Br
I
4.73 0.44
5.33 0.39
5.51 0.44
5.80 0.44
4.91 0.44
5.50 0.39
5.68 0.44
5.38 0.44
4.43 0.43
4.97 0.39
5.15 0.43
5.41 0.43
4.60 0.43
5.14 0.39
5.32 0.43
5.58 0.43
4.72 0.43
5.27 0.39
5.44 0.43
5.70 0.43
OH
OCH3
OCH2CH3
OCH2CH2CH3
OCH2CH2CH2CH3
OCH2CH2OH
3.58 0.39
5.34 0.41
5.87 0.41
6.40 0.41
6.93 0.41
4.37 0.41
3.82 0.39
4.44 0.40
4.98 0.40
5.51 0.40
6.04 0.40
3.47 0.41
3.61 0.39
5.19 0.41
5.72 0.41
6.25 0.41
6.78 0.41
4.21 0.41
4.03 0.39
4.54 0.39
5.08 0.39
5.61 0.39
6.14 0.39
3.57 0.40
3.85 0.39
4.25 0.39
4.78 0.39
5.31 0.39
5.84 0.39
3.27 0.40
NH2
N(CH2CH3)2
N(CH2CH2OH)2
NO2
3.07 0.39
6.54 0.41
3.96 0.72
4.54 0.39
3.55 0.39
5.35 0.40
2.77 0.72
5.65 0.41
3.07 0.39
6.44 0.41
3.86 0.72
4.97 0.39
3.49 0.39
5.80 0.40
3.22 0.72
4.34 0.36
3.74 0.39
6.10 0.40
3.52 0.72
4.81 0.37
SO3H
3.12 0.79
3.08 0.39
2.68 0.78
3.08 0.39
3.14 0.39
151
Table 3
Observed mutagenicity (rev/mmol) in the TA98 Salmonella bacterial strain, calculated log P [15], calculated aqueous solubility [15],
experimental melting point ( C), and molecular weight, of A. 3-ORAAB (R=Me, Et, Pr, Bu), B. n-OMeAAB (n=2, 3, 40 ), C. nOMeNAB, and D. n-OMeMAB, E. n-OMeDAB
Compound
A.
AAB
3-OMeAAB
3-OEtAAB
3-OPrAAB
3-OBuAAB
B.
AAB
2-OMeAAB
3-OMeAAB
40 -OMeAAB
C.
NAB
2-OMeNAB
3-OMeNAB
40 -OMeNAB
D.
MAB
2-OMeMAB
3-OMeMAB
40 -OMeMAB
E.
DAB
2-OMeDAB
3-OMeDAB
20 -OMeDAB
30 -OMeDAB
40 -OMeDAB
a
b
c
d
e
f
Melting point
( C) ([Ref.])
Molecular
weight (g/mol)
0.041
0.021
0.0063
0.0022
0.0012
124125 [32]
110111 [32]
107109 [32]
9798 [32]
6365 [32]
197.236
227.262
241.289
255.315
269.342
3.13
3.87
3.48
2.95
0.041
0.0037
0.021
0.027
124125 [32]
157159 [34]
110111 [34]
155159 [34]
197.236
227.262
227.262
227.262
400 [35]
20 [35]
2250 [35]
40 [35]
4.20
5.26
4.18
4.02
0.0029
0.00054
0.0025
0.0022
132134 [36]
9091 [36]
131132 [36]
158159 [36]
227.219
257.245
257.245
257.245
183 [37]
3.79
4.34
3.88
3.61
0.018
0.0028
0.016
0.020
87.588a [37]
114115 [34]
7274 [34]
9395 [40]
211.263
241.289
241.289
241.289
140 [42]
c
d
e
f
e
4.43
5.34
4.44
5.19
4.54
4.25
0.0024
0.00035
(0.0030)b
0.00065
0.0027
0.0017
117118 [41]
104105 [34]
9091 [34]
8788 [34]
146147 [40]
225.289
255.315
255.315
255.315
255.315
255.315
TA98 rev/mmol
(+S9) ([Ref.])
ACD/log P
(neutral form)
204 [32]
77065 [32]
13802 [32]
18919 [32]
4983 [32]
3.13
3.48
4.02
4.55
5.08
204 [32]
10 [33]
77065 [32]
2300 [33]
ACD/Aqueous
solubility (g/l) pH=7
Other values of the melting point have been reported as 86 [38] and 89 [39].
Calculated without melting point data which is not available in the literature.
Noncarcinogen [42].
Carcinogen, but less so than 3-OMeAAB and 3-OMeMAB.
Mild carcinogen [42]
Severe carcinogen [42].
152
Fig. 4. Plot of aqueous solubility, S (g/l), versus pH for 2OMe, 3-OMe, and 40 -OMeAAB.
153
Table 4
Observed mutagenicity (rev/mmol) in the TA98 Salmonella bacterial strain, calculated log P [15], calculated aqueous solubility, melting
point ( C), and molecular weight, of A. 30 -RDAB (R=H, CH2OH, CHO, COOH), B. 30 -CH2OHR (R=AAB, MAB, DAB), and C.
30 -MeR (R=AAB, MAB, DAB)
Compound
A.
DAB
30 -CH2OHDAB
30 -CHODAB
30 -COOHDAB
B.
30 -CH2OHAAB
30 -CH2OHMAB
30 -CH2OHDAB
C.
30 -MeAAB
30 -MeMAB
30 -MeDAB
TA98 rev/mmol
(+S9) ([Ref.])
ACD/log P
(neutral form)
ACD/aqueous
solubility (g/l) pH=7
Melting point
( C) ([Ref.])
Molecular
weight (g/mol)
140 [42]
601 [38]
383 [38]
201 [38]
4.43
3.25
3.91
4.17
0.0024
0.023
0.0087
0.30
117118 [41]
122123 [45]
9799 [45]
212213 [45]
225.289
255.315
253.299
269.299
596 [38]
503 [38]
601 [38]
1.94
2.60
3.25
0.59
0.10
0.023
107109 [45]
119121 [45]
122123 [45]
227.262
241.289
255.315
240 [38]
445 [38]
356 [38]
3.59
4.25
4.89
0.027
0.0042
0.00031
8991 [41]
109109.5 [41]
168170 [40]
211.263
225.289
239.316
Table 5
Observed mutagenicity (rev/mmol) in the TA98 Salmonella bacterial strain, calculated log P, aqueous solubility, melting point ( C),
and molecular weight of MAB, 30 -MeMAB, 40 -MeMAB, and some of their possible metabolites
Compound
A.
MAB
30 -MeMAB
40 -MeMAB
B.
NOHMAB
NOH30 -MeMAB
NOH40 -MeMAB
C.
NOAcMAB
NOAc30 -MeMAB
NOAc40 -MeMAB
D.
NOBzMAB
NOBz30 -MeMAB
NOBz40 -MeMAB
a
b
c
Melting point
( C) ([Ref.])
Molecular
weight (g/mol)
0.018
0.0042
0.0045
87.588 [37]
109109.5 [46]
105105.5 [46]
211.263
225.289
225.289
2.74
3.20
3.20
0.032
(0.040)c
(0.040)c
171174b [46]
227.262
241.289
241.289
26,000a [46]
28,000a [46]
55,000a [46]
2.94
3.40
3.40
0.098
0.027
0.021
7476 [47]
85.586.5 [46]
9899 [46]
269.999
283.325
283.325
32,000a [46]
52,000a [46]
38,095a [46]
4.69
5.15
5.15
0.0011
0.00032
0.00034
8991 [46]
9697 [46]
9596 [46]
331.368
345.395
345.395
TA98 rev/mmol
(+S9) ([Ref.])
ACD/log P
(neutral form)
183 [37]
233 [46]
283 [46]
3.79
4.25
4.25
650 [47]
1000 [46]
1132 [46]
ACD/aqueous
solubility (g/l) pH=7
These results were recorded in the absence of a mammalian microsomal activation system (S9).
A much lower value for the melting point of NOHMAB, 45 , was given in reference [48].
Calculated without melting point data. This is expected to reduce the reliability of the calculated aqueous solubility.
154
Table 6
Values of log P and S (g/l) calculated using the ACD/log P suite [15] for selected arylamine dyes from the color index [14]
CI number
Class
ACD/log P
(neutral form)
ACD/aqueous
solubility pH=7 S (g/l)a
Melting point
( C)
Molecular
weight (g/mol)
11000
CI Solvent Yellow
(Aniline Yellow, AAB)
CI Disperse Orange 3
CI Solvent Orange 9
CI Disperse Orange 3:1
Disperse Dye
CI Solvent Yellow 2 (DAB)
CI Solvent Yellow 56
CI Disperse Black 3
Disperse Dye
CI Disperse Black 7
CI Disperse Red 41
Disperse Dye
Disperse Dye
CI Disperse Blue 165
CI Disperse Blue 183
CI Disperse Red 210
CI Disperse Orange 5
CI Disperse Red 1
CI Disperse Red 8
CI Disperse Red 72
CI Disperse Red 13
CI Disperse Red 73
CI Disperse Red 90
CI Disperse Red 2
CI Disperse Orange 30
CI Disperse Violet 12
CI Disperse Orange 52
Solvent Dye
CI Solvent 58
CI Disperse Red 19
CI Disperse Red 82
CI Disperse Orange 138
CI Disperse Red 7
CI Disperse Brown 1
CI Disperse Brown 1:1
CI Solvent Yellow 3
Disperse Dye
CI Disperse Red 32
CI Disperse Red 98
CI Solvent Red 116
3.130.32
8.9102 [3.9102]
127.5
197.236
3.510.36
3.970.36
2.980.46
4.430.33
5.490.33
3.740.39
3.880.36
4.560.40
5.870.42
6.350.42
6.930.42
4.960.54
5.680.35
4.270.48
5.340.61
4.580.59
5.060.62
4.140.50
5.220.60
4.710.47
4.100.50
3.770.60
5.390.46
6.120.62
5.270.66
6.280.60
2.910.71
3.290.72
4.760.51
4.020.60
4.190.75
5.480.77
5.360.81
4.050.33
3.850.59
5.800.61
2.2102
7.4103
1.5102
4.9103
4.2104
1.5102
5.8103
1.8103
9.6105
1.9105
7.9106
9.7105
9.7106
2.7104
8.7105
9.0104
1.7104
4.6104
1.5104
4.1104
4.6104
2.6103
2.0105
1.4105
5.4105
1.2105
3.6102
8.3103
8.0105
2.4103
8.3104
2.2105
1.3105
1.0102
4.6103
2.8105
[2.7103]
210212
[2.5103]
115
[2.6103]
186187
[4.1104]
160
[7.5103]
100
242.234
256.260
330.256
225.289
253.342
240.304
282.340
274.749
300.313
343.337
328.366
405.410
459.297
422.930
367.186
314.339
359.337
406.395
348.784
348.359
406.395
344.365
450.275
387.390
404.914
376.837
285.341
330.339
439.422
320.731
364.783
433.673
478.124
225.289
300.313
383.229
5.560.65
2.9105
407.262
5.180.74
6.580.62
6.910.68
6.920.70
3.750.72
7.5105
4.6106
6.4107
Insoluble
2.7103
395.904
401.417
480.313
510.339
344.365
4.390.75
5.220.51
4.5104
2.6105
378.810
453.448
11005
11005:1
11015
11020
11021
11025
11030
11035
11040
11060
11070
11077
11078
11079
11100
11110
11113
11114
11115
11116
11117
11118
11119
11120
11121
11125
11129
11130
11140
11145
11150
11152
11152:1
11160
11180
11190
11191
11192
11195
11200
11205
11210
11215
11218
155
Class
ACD/log P
(neutral form)
ACD/aqueous
solubility pH=7 S (g/l)a
11220
11225
11227
11228
11230
11232
11239
11240
11245
11250
11255
11260
11275
11282
11285
11290
11300
11310
11330
11335
11337
11343
11345
11350
11360
11365
11370
11380
11385
11390
11395
11405
11406
11420
11430
13020
13056
13058
13379
13430
13710
CI Disperse Black
CI Disperse Red 16
CI Disperse Orange 25
CI Disperse Red 65
Disperse Dye
CI Disperse Red 97
CI Disperse Orange 62
CI Disperse Orange 7
Disperse Dye
CI Disperse Red 31
CI Disperse Black 2
CI Disperse Blue 11
Oxidation Dye
CI Disperse Red 63
CI Solvent Brown 1
CI Mordant Brown 12
CI Mordant Brown 48
Disperse Dye
CI Solvent Brown 2
CI Mordant Brown 4
CI Disperse Blue 337
CI Disperse Blue 90
CI Disperse Blue 79
CI Solvent Yellow 4
CI Solvent Brown 3
CI Disperse Black 1
CI Disperse Blue 85
CI Solvent Yellow 5
CI Solvent Red 5
CI Solvent Yellow 6
CI Mordant Green 24
CI Disperse Blue 338
CI Disperse Blue 335
Disperse Dye
CI Disperse Blue 38
CI Acid Red 2
CI Disperse Orange 10
CI Pigment Red 100
CI Disperse Red 6
Pigment
CI Acid Black 180
3.420.76
3.650.76
4.680.41
5.770.42
3.850.60
3.870.63
7.410.46
4.430.37
3.150.41
4.330.41
3.250.40
4.690.44
0.600.40
1.680.40
2.530.39
1.090.42
2.410.44
3.480.46
2.990.39
1.550.42
4.300.61
4.210.71
5.300.60
4.360.32
5.590.33
3.670.39
5.930.64
3.690.31
4.070.35
4.150.31
3.490.41
7.190.59
7.700.60
5.060.49
4.441.08
4.910.39
2.770.58
3.390.72
2.810.58
2.421.06
4.990.57
5.2103
5.3103
6.5104
3.6105
2.0103
1.1103
Insoluble
2.4103
2.8102
2.3103
2.9102
8.9104
7.31
5.9101
1.1101
9.26102
4.28101
9.2103
3.5102 [2.1102]
3.05102
7.6105
9.2105
8.6107
4.0103 [2.2103]
1.7104
1.2102 [4.4103]
7.6106
1.4102 [1.3102]
3.4103 [9104]
4.8103 [2.9103]
5.20
Insoluble
Insoluble
5.5105
3.0104
1.82
1.17102
1.16101
1.1102
2.23103
8.4105
Melting point
( C)
148
123
159160
104
185.5
126
Molecular
weight (g/mol)
344.408
360.365
323.349
371.821
353.375
384.346
512.344
270.287
272.303
286.286
256.303
302.286
227.265
257.248
262.309
318.245
352.690
302.246
276.336
332.272
493.515
493.268
639.410
247.295
297.353
262.309
445.813
247.295
292.292
261.321
353.289
493.515
347.402
427.252
398.800
269.299
348.421
329.351
370.427
371.368
429.881
Values in [ ] were calculated using the melting point in the next column.
156
Fig. 6. Plot of aqueous solubility, S (g/l), versus pH for MAB, NOHMAB, and NOAcMAB.
157
the predicted aqueous solubility of the dye signicantly, e.g. for CI Disperse Orange 3 the predicted solubility is 0.0027 g/l at all values of pH
from 5 to 9; the solubility of some dyes, e.g. CI
Mordant Dye 24, are more sensitive to changes in
the pH: 0.76 g/l at pH=5 to 5.53 g/l at pH=9.
Most of the compounds in Table 6 are solvent
and/or disperse dyes, although a few are mordant
or acid dyes. Log P varies over a broad range of
values (0.607.70) for the arylamine dyes in
Table 6: from 2.98 to 6.93, 2.91 to 6.28, and 1.09
to 3.49 for disperse, solvent, and mordant dyes,
respectively. (The value of log P is 0.60 for the one
oxidation dye in the table, CI number 11275; the
values of log P for the two acid dyes are 4.91 and
4.99, CI numbers 13020 and 13710 respectively.)
Aqueous solubilities for the solvent and disperse
dyes in the table are generally quite low, although
Fig. 7. Distribution of log P values for (a) all, (b) the disperse,
and (c) the solvent arylamine dyes in Table 6.
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4. Conclusions
Log P has proved to be a valuable descriptor in
understanding the biological behavior of various
classes of compounds [4,24]. It is often used in conjunction with other molecular descriptors, e.g. the
energy of the highest occupied molecular orbital,
HOMO, or lowest unoccupied molecular orbital,
LUMO, refractive index, etc., in developing predictive QSARs. Log P has an important advantage
as a molecular descriptorit can be calculated
quickly. Currently, the expected accuracy is about
0.5 log units. The accuracy of the calculations,
however, is improving and additional conformational information, including stereochemistry, is
being incorporated into the algorithms [15]. Progress is also being made in estimating the aqueous
solubility of a compound, particularly when its
melting point is known [15].
It now appears that log P and S may be valuable descriptors in understanding the biological
behavior of dyes. This nding may eventually
enable us to devise safer dyes. We have shown that
for the series of 2-, 3-, and 40 -methoxy substituted
AAB, MAB, DAB, and NAB dyes, the compound
with the highest log P, or the lowest aqueous
Acknowledgements
Dr. Krishna Bhat would like to thank the
National Textile Center (Grant No. COO-PO1) for
nancial support of this work. The authors would
also like to acknowledge Dr. Nancy Howard of
Philadelphia University for helpful discussions.
References
[1] Akerblom EB. Mol Diversity 1999;4:53.
[2] SCRIP World Pharmaceutical News, 9 January, 1996,
PJB Publications, Ltd.
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