Lipophilicity indices of triazine herbicides

The Science of the Total Environment, 109/110 (1991) 33-40 Elsevier Science Publishers B.V., Amsterdam

33

Lipophilicity indices of triazine herbicides G.L. Biagi", M.C. Guerra ~, A.M. Barbaro a, M. Recanatini b, P.A. Borea c and A. Sapone a alstituto di Farmacologia, Universita' di Bologna, Bologna, Italy bDipartimento di Scienze Farmaceutiche, Universita' di Bologna, Bologna, Italy Clstituto di Farmaeologia, Universita' di Ferrara, Ferrara, Italy

ABSTRACT A series of triazine herbicides has been investigated in order to assess the intercorrelations of different lipophilic parameters. Chromatographic Rm and log k' values have been experimentally determined and very good correlations have been found between them. Octanol/ water partition coefficients have been taken from the literature and/or calculated by means of the CLOGP program. Again, very good correlations have been shown to exist between chromatographic indices and log P data. The present results indicate the usefulness of chromatographic parameters as supplements or complements to the classical octanol/water partition coefficients.

INTRODUCTION

Lipophilic character has long been shown to play a basic role in determining distribution phenomena, as well as in influencing the mechanisms of ecotoxicity of organic chemicals [1]. Increasing interest is being devoted to the study of the ecotoxic effects of pesticides for agricultural use. Triazines are one of the most important groups of herbicides known today. The extensive application of these compounds raises the problem of their distribution to water, soil, plants and animals. The classical procedure for the measurement of the lipophilicity of organic chemicals is based on their partitioning between octanol and water [2]. Reversed-phase TLC or HPLC techniques seem to have some advantages over the classical octanol/water partition coefficient determination [3, 4]. The purpose of the present work was to study the relationships among different lipophilicity indices of a series of triazine herbicides. EXPERIMENTAL

The test compounds (Table 1) were obtained from a commercial source. All other chemicals and solvents were of analytical-reagent or HPLC grade. The R m values were obtained using a reversed-phase TLC technique, where the 0048-9697/91/$03.50

© 1991 Elsevier Science Publishers B.V. All rights reserved

34

G.L. BIAGI ET AL.

TABLE 1 Structures of triazine herbicides

N

N R2

No.

Compound

Rj

R2

R3

1

Terbuthylazine

NHC(CH3)3 CN

C1

NHCH2 CH 3

2 3 4 5

Cyanazine Desisopropylatrazine Atrazine Simazine

NHC(CH3)2 C1 CI CI CH3

C1 NHCH2 CH3 NHCH2CH3 NHCH2CH 3

NHCH2 CH3 NH2 NHCH(CH3)2 NHCH2CH 3

6 7 8 9

Secbumeton

NHCHCH2CH3 NHC(CH3)3 NHC(CH3)3 NHCH2CH3

OCH3 OCH3 SCH3 N(CH2CH3) 2

NHCH2CH3 NHCH2CH3 NHCH2CH3 C1

I

I Terbumeton

Terbutryn Trietazine

NH

10

Anilazine

CI

11 12 13 14 15 16 17 18 19 20

Aziprotryne Propazine Ametryn Desmetryn Desethylatrazine Dipropetryn Atraton Methoprotryne Prometon Simetryn

SCH3 CI NHCH2 CH 3

NHCH3 C1 NHCH(CH3)2 NHCH2CH3 NH(CH2)3OCH3 NHCH(CH3)2 NHCH2CH 3

C1 N3 NHCH(CH3)2 NHCH(CH3)2 SCH3 NH2 SCH2CH3 NHCH(CH3)2 SCH3 OCH3 SCH3

NHCH(CH3)2 NHCH(CH3)2 SCH3 NHCH(CH3)2 NHCH(CH3)2 NHCH(CH3)2 OCH3 NHCH(CH3)2 NHCH(CH3)2 NHCH2CH3

non-polar stationary phase was a silica gel layer impregnated with a silicone oil, and the mobile phase was an aqueous buffer (sodium acetate-Veronal at pH 7.0) alone or mixed with various amounts of acetone or methanol (Table 2). The log k' values were obtained using reversed-phase HPLC, where the mobile phase was water alone or mixed with methanol in different proportions (Table 2). The column was a ~Bondapack C18 (300 × 3.9 mmi.d.) (Waters, Milford, MA, USA) packed with silica gel (particle size 10~m) with a CI8

35

LIPOPHILICITY INDICES OF TRIAZINE HERBICIDES

TABLE 2

Rm, log k' and partition coefficientsof triazines No.

Compound

log P

Rm Acetone

Methanol

Exptl

log k' methanol Calc. (CLOGP)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Terbuthylazine Cyanazine Desisopropylatrazine Atrazine Simazine Secbumeton Terbumeton Terbutryn Trietazine Anilazine Aziprotryne Propazine Ametryn Desmetryn Desethylatrazine Dipropetryn Atraton Methoprotryne Prometon Simetryn

1.59 0.97 0.55 1.27 1.03 1.35 1.52 2.00 1.48 1.27 1.22 1.62 1.45 1.12 0.64 1.99 1.10 1.55 1.35 1.25

1.54 0.98 0.59 1.25 1.00 1.49 1.49 1.95 1.59 1.27 1.30 1.71 1.46 1.24 0.60 2.10 1.19 1.50 1.52 1.21

2.22 2.75 2.18

3.74 3.34

2.93 2.98

3.22 1.72 1.26 2.82 2.51 3.27 3.14 3.44 2.88 3.79 1.89 3.13 3.04 2.52 1.57 3.88 2.74 2.16 3.05 2.74

3.10 1.94 1.19 2.73 1.85 2.90 3.04 3.80 3.25 2.74 2.95 2.84 2.83 2.03 1.38 3.78 2.30 2.63 2.77 2.28

chemically bonde d n o n - p o l a r stationary phase. The details o f bot h c h r o m a t o graphic techniques have been described previously [5, 6]. The octanol/water partition coefficients were either experimental or calculated values (Table 2). The experimental log P values were taken from the P o m o n a College Database [7]. The calculated CLOGP values were obtained by means o f the CLOGP p r o g r a m [8]. RESULTS In the reversed-phase T L C systems the range o f linear relationship between the R m values and the organic modifier concent rat i on in the mobile phase allowed the calculation o f extrapolated R m values at 0%. The T L C equations as well as the ranges o f m et hanol or acetone in the mobile phase are shown in Tables 3 and 4. Since the m o r e hydrophilic c o m p o u n d s migrate at 0% organic solvent in the mobile phase, the experimental R m values were correlated with the extrapolated values. The very good correlations o f Eqns (1) and (2) support

36

G.L. BIAGI ET AL.

TABLE 3 T L C equations when the mobile phase was a mixture of acetone and aqueous buffer at pH 7.0 No.

T L C equation

Rmextrap = a

Rmexp b

Acetone range

r

3

0.546

- 0.071

0.965

0.563

15

0.637

- 0.062

0.966

0.658

0-8

2

0.970

- 0.034

0.991

1.021

0-60

5 17

1.035 1.101

- 0.034 - 0.035

0.979 0.991

1.035 1.136

0-60 0-60

14

1.117

- 0.038

0.991

11

1.223

- 0.033

0.979

4-60

20

1.252

- 0.042

0.995

4-60

10

1.270

-0.037

0.993

4-60

4 6

1.273 1.348

-0.036 - 0.036

0.993 0.989

4-60 4-60

19

1.349

- 0.037

0.992

4-60

13

1.454

- 0.037

0.991

4-60

9 7

1.485 1.525

- 0.040 - 0.042

0.992 0.989

12-60 12-60

18

1.552

1 12

1.588 1.620

~

0-8

4-60

- 0.038

0.992

12-60

- 0.042 - 0.040

0.993 0.990

12-60 12-60

16

1.986

- 0.045

0.989

16-60

8

2.003

- 0.045

0.993

16-60

the validity of the extrapolation technique. Methanol (pH 7.0) Rmexp =

0.063 ( + 0 . 0 8 5 ) + 0.940 ( + 0 . 0 9 4 ) Rmextrap

(n = 5,

r = 0.985,

s = 0.050,

F=

99.44,

(1)

P < 0.005)

Acetone (pH 7.0) Rmexp = (n = 5,

0.010 ( + 0 . 0 3 8 ) + 1.017 ( + 0 . 0 4 3 ) Rmextrap r - - 0.997,

s = 0.022,

F=

549.57,

(2)

P < 0.005)

Since the Rm values were measured with either acetone or methanol in the mobile phase, it was possible to check another interesting point. If the extrapolated R~ values represented the partitioning of the compounds between the silicone oil of the stationary phase and a mobile phase constituted only by water, we would expect the same extrapolated Rm values whether the organic solvent was acetone or methanol. In fact, Eqn (3) shows a very good correlation between the R m values at 0% acetone and those at 0% methanol in the

LIPOPHILICITY INDICES OF TRIAZINE HERBICIDES

37

TABLE 4 T L C equations when the mobile phase was a mixture o f methanol and aqueous buffer at p H 7.0 T L C equation

No.

Rmextrap = a

Rmexp

b

Methanol range

r

3

0.588

-- 0.026

0.999

0.563

0-8

15

0.599

-- 0.021

0.987

0.658

0-70

2

0.985

-- 0.026

0.998

1.021

0-70

5

1.003

-- 0.026

0.995

1.035

0-70

17

1.188

- 0.025

0.991

1.136

20

1.210

- 0.026

0.987

4-70

14 4

1.239 1.252

- 0.026 - 0.027

0.996 0.995

12-70 4-70

10

1.268

- 0.025

0.987

20-70

11

1.301

- 0.023

0.989

12-70

13

1.465

- 0.027

0.994

12-70

7 6

1.491 1.495

- 0.027 - 0.029

0.998 0.997

20-70 16-70

18

1.498

- 0.029

0.999

20-70

19

1.522

- 0.029

0.996

20-70

1

1.540

- 0.028

0.998

20-70

9

1.595

- 0.027

0.993

20-70

12

1.711

- 0.031

0.994

28-70

8

1.950

- 0.027

0.989

20-70

16

2.1 O0

-- 0.030

0.996

24-70

0-70

mobile phase. RmmethanoI

=

0.023 ( + 0.064) + 1.008 ( ± 0.047) Rmacetone

(n = 20,

r = 0.981,

s = 0.075,

F=

460.60,

(3)

P < 0.005)

The slope and intercept of Eqn (3), close to 1 and 0 respectively, show the overlapping of the R m values extrapolated from the two solvent systems. As for TLC, the reversed-phase HPLC technique provided for each compound a range of linear relationship between log k' and organic modifier concentration in the mobile phase. The log U values at 0% methanol are shown in Table 2. Their correlations with the R m values are described by Eqns (4) and (5). Rmrnethanol

=

(n = 20,

r = 0.948,

Rmacetone

=

- 0 . 0 1 1 (+0.111) + 0.520 (+0.041) log U s = 0.124,

F=

107.12,

(4)

P < 0.005)

--0.005 (___0.110) + 0.505 (___0.041) log k'

(5)

38

G.L. BIAGI ET AL.

(n = 20,

r = 0.946,

s = 0.123,

F=

152.86,

P < 0.005)

The two equations are quite similar, as expected from the results of Eqn (3). Finally, the chromatographic parameters were correlated with the partition coefficients. Since the octanol/water partition coefficients were not measured for all compounds, we started with Eqns (6)-(8), which were calculated for the seven derivatives for which experimental log P values were available (Table 2). Rmmetha,o~ =

--0"329 (__+0.284) ÷ 0.608 (____0.097) log P

(n = 7,

r = 0.942,

Rmacetone

----

(n = 7,

r = 0.940,

log k'

s = 0.134,

F=

39.28,

P < 0.005)

- 0 . 3 0 1 (+0.281) + 0.592 (+0.096) log P

=

s = 0.132,

F=

38.06,

r = 0.995,

s = 0.074,

F=

508.41,

(7)

P < 0.005)

- 0.742 (_+ 0.157) + 1.231 (_+ 0.054) log P

(n = 7,

(6)

(8)

P < 0.005)

Because of the lack of experimental log P values for the remaining 13 compounds of Table 2, we turned our attention to the use of calculated partition coefficients. The CLOGP program seems to be the most reliable tool for such calculations. Equation (9) describes the relationships between experimental and calculated partition coefficients for the above seven compounds. CLOGP

0.466 (+0.726) + 0.808 (+0.248) log P

----

(n = 7,

r = 0.824,

s = 0.343,

F=

10.60,

(9)

P < 0.025)

Despite the fact that the correlation coefficient of Eqn (9) is rather low, Eqns (10)-(12) were calculated using the available experimental log P values and the CLOGP values for the remaining compounds. Rmmethano

I

=

(n = 20, Rmacetone

0.154 (-t-0.202) + 0.431 (___0.071) log P

r = 0.821, =

s = 0.222,

F=

37.19,

P < 0.005)

0.168 (+0.202) + 0.415 ( + 0 . 0 7 1 ) l o g P

(n = 20,

r = 0.810,

log k'

0.400 (-t-0.356) + 0.800 (___0.124) log P

=

(n = 20,

r = 0.834,

s = 0.222,

s = 0.391,

F=

F=

34.41,

41.21,

(10)

(11)

P < 0.005) (12)

P < 0.005)

The correlation coefficients of Eqns (10)-(12) are rather low because of the deviations of three data points (compounds 10, 11 and 18). Their exclusion from the analysis yielded Eqns (13)-(15) with much higher correlation coefficients.

39

LIPOPHILICITY INDICES OF TRIAZINE HERBICIDES

Rmmethano~ = (n = 17, Rmacetone (n = 17, log k ' = (n = 17,

--0.253 (+0.115) + 0.572 (+0.040) log P

r = 0.965,

s = 0.110,

F=

205.22,

P < 0.005)

- 0 . 2 2 1 (+0.125) + 0.548 (+0.043) log P

=

r = 0.956,

s = 0.120,

F--- 158.58,

s = 0.166,

F=

308.53,

(14)

P < 0.005)

- 0 . 3 6 0 (+0.173) + 1.055 (+0.060) log P r = 0.976,

(13)

(15)

P < 0.005)

It should be noted that, in Eqns (10)-(15), both the calculated and the experimental partition coefficients are given as log P. DISCUSSION

In the present paper we have reported some data aimed at characterizing R m and log k' values as lipophilicity indices of triazine herbicides for QSAR studies. The very good correlations between experimental and extrapolated R m values at 0% organic solvent in the mobile phase allows one to be confident also in the extrapolated values for more lipophilic compounds. It has also been shown that the extrapolation technique yields very similar Rm values when using two different organic solvents in the mobile phase. This is further evidence that the extrapolated Rm values can be considered a measure of the partitioning between water and silicone oil. Equations (4)-(8) and (10)-(15), showing very good intercorrelations between Rm, log k' and log P, indicate the reliability of the chromatographic parameters as supplements or complements to classical octanol/water partition coefficients. As regards Eqns (13)-(15), the exclusion of three data points deserves some comment. It can be seen that all three compounds fit well the equations correlating R m and log k ' values. The fact that they do not fit Eqns (10)-(12) can be attributed to structural effects operating in the chromatographic systems and not accounted for by the calculated CLO~P values. The same factors could explain the low correlation of Eqn (9). The experimental determination of their log P values will certainly contribute to the explanation of this discrepancy. As a final remark, some advantages of the chromatographic parameters over the classical partition coefficients can be outlined: (a) the chromatographic method is simple and rapid; (b) it requires little material, which is important with compounds that are expensive and/or difficult to synthesize; (c) the material does not need to be very pure. REFERENCES 1 G.D. Veith and D. De Foe, Structure-activity relationships for screening organic chemicals for potential ecotoxicity effects, Drug Metab. Rev., 15 (1984-85) 1295-1303.

40

G.L. BIAGI ET AL.

2 A. Leo, C. Hansch and D. Elkins, Partition coefficients and their uses, Chem. Rev., 71 (1971) 525-616. 3 C.B.C. Boyce and B.V. Milborrow, A simple assessment of partition data for correlating structure and biological activity using thin-layer chromatography, Nature, 208 (1965) 537-539. 4 R. Kaliszan, Quantitative Structure-Chromatographic Retention Relationships, John Wiley, New York, 1987. 5 G.L. Biagi, A.M. Barbaro, M.F. Gamba and M.C. Guerra, Partition data of penicillins determined by means of reversed-phase thin-layer chromatography, J. Chromatogr., 41 (1969) 371-379. 6 M.C. Guerra, A.M. Barbaro, G. Cantelli Forti, M.C. Pietrogrande, P.A. Borea and G.L. Biagi, Determination of lipophilic character of a series of dermorphin-related oligopeptides by means of reversed-phase HPLC, J. Liq. Chromatogr., 7 (1984) 1495-1500. 7 Pomona College Medicinal Chemistry Project Data Base, Pomona College, Claremont, CA, 1986. 8 Pomona College Medicinal Chemistry Project, CLOGP Program, Version 3.42, Pomona College, Claremont, CA, 1986.