Theoretical Estimation of OctanolâWater Partition Coefficient for

Chapter 4

Theoretical Estimation of Octanol—Water Partition Coefficient for Organophosphorus Pesticides 1

Downloaded by EAST CAROLINA UNIV on March 23, 2016 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0606.ch004

Toshiyuki Katagi , Masakazu Miyakado, Chiyozo Takayama, and Shizuya Tanaka Agricultural Chemicals Research Laboratory, Sumitomo Chemical Company, Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665, Japan A wide range of logP values for 67 organophosphorus pesticides possessing the various chemical structures were theoretically estimated by using parameters derived from their molecular geometries and electronic properties calculated with the MNDO-PM3 semiempirical SCF method. The multiple regression analysis showed that the logP values were satisfactorily expressed by van der Waals volume, total number of hydrogen bonding sites, and the LUMO energy. The equation correlated very well the logP values measured. Although the accuracy of the prediction is slightly lower than that of the CLOGP procedure, our method can estimate the logΡ values for the pesticides which could not be calculated by CLOGP because of the lack of the related fragment values. The octanol/water partition coefficient (logP) of pesticides is one of the most basic physicochemical properties governing their biological activity as well as their environmental behavior in connection with the transport through various biological membranes and environmental phases (7). The most familiar technique for experimentally determining log Ρ is the shake-flask method, and chromatography using the reverse-phase T L C or HPLC has been recently utilized as a convenient analytical method to avoid the intrinsic problem of the shake-flask method due to the formation of emulsions (2,3). With the accumulation of experimental data, the fragment constant approaches represented by C L O G P have been successfully introduced (4-6) and their extensive applicability has made them a powerful tool estimating the log Ρ value of a new compound. However, the following problems for complex molecules are now recognized: the way of dividing a structure into fragments, the lack of some fragment parameters, and the estimation caused by the ambiguous corrections for conformational and electronic effects. In order to solve these problems, various computational approaches have been undertaken by using quantum-chemical methods. One of them is based on the relation between logP and the molecular properties such 1

Current address: Planning and Coordination Office, Sumitomo Chemical Company, Ltd., 27-1 Shinkawa 2-Chome, Chuo-ku, Tokyo 104, Japan 0097-6156/95/0606-0048$12.00/0 © 1995 American Chemical Society Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.


4.

KATAGI ET AL.

Octanol—Water Partition Coefficient

49

as a solvent-accessible surface area (7-9), electronic properties (10-13), and solvatochromic parameters (14,15). The others treat the partition as a thermodynamical process and directly calculate the corresponding free-energy change considering the solvation with the aid of molecular orbital (MO) methods (16-20). These approaches exhibit their usefulness in estimating the logP values of small molecules. Incidentally, the specific programs developed by individual researchers are usually needed for these approaches and their applicability to complex molecules such as pesticides has not been studied extensively. It is considered attractive to most chemists to obtain the log Ρ value of molecules from the descriptors easily obtained from chemical structures by using the popular M O programs. Based on these considerations, organophosphorus pesticides, most widely used in agriculture, possessing various chemical structures with a wide range of logP were taken for our investigation as to whether simple M O calculations and descriptors familiar to chemists well afford theoretically logP values. Most organophosphorus pesticides dealt with here are the esters possessing the pentacovalent phosphorus and classified into the 17 classes from the atoms adjacent to phosphorus. Tables 1-1 to 1-6 summarize the classification of 67 compounds used in the analysis of the logP values. Calculations The molecular geometry in lower-energy states together with the electronic properties was estimated by the MNDO-PM3 semiempirical SCF method (21). MNDO-PM3 is known to afford quite satisfactory results in the chemistry of the hypervalent phosphorus compounds (22). A l l calculations reported here were performed with the standard version of MNDO-PM3 in the M O P A C package (v. 6.0) of programs (QCPE 455). Geometries for stationary points were identified by minimization of the energy with respect to the geometric parameters using the BFGS algorithm (23) included in the MOPAC package. In order to calculate the solvent-accessible surface area (SA) and volume (VA), the program developed by Tomasi and his colleagues (24) (QCPE 554) was used for the PM3-optimized geometries. The radius of a sphere tracing out the surface was adjusted to 1.5Â as previously reported (7,17). Furthermore, the PM3-SM3 calculation developed by Cramer and Truhlar (25) in the A M S O L program (QCPE 606, v. 3.0.1) was used to estimate the molecular properties of hydrated pesticides. Unless otherwise noted, the experimentally measured logP value was taken from the logP file in the C-QSAR system 1.87 package (1994) developed by Hansch and Leo (26). The multiple regression analyses were done by using the QSAR program included in the A C A C S system (27). In all analyses reported here, each term and equation are justified above 99.5% level by F and Student's t test. Molecular Geometries of Organophosphorus Pesticides Although geometries and some electronic properties of small molecules are reported to be well reproduced by MNDO-PM3 calculation (21), its applicability to complex molecules such as pesticides is not clear. Therefore, we first examined whether the MNDO-PM3 is appropriate for our purpose by comparing the estimated geometries

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

50

CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

Table I-L Structure and LogP Value of Organophosphorus Compounds (Classes 1 and 2).


HO

\==>Si

RO

Class 1 Class # 1 (1) 2 3 4 5 6 7 8 9 10 11 12 13 14

Name

\=^X Class 2

R

Obsd.a Caleb C L O G P

X

Fenitrothion 3.30 3.380 3.209 3-CH3-4-N0 CH3 Tolclofos-methyl CH3 2,6-Cl -4-CH3 4.56 4.220 4.854 Cyanophos 2.75 2.734 2.505 4-CN CH3 Methyl Parathion CH3 2.86 2.949 2.790 4-N0 Bromophos CH3 5.21 4.557 4.951 4-Br-2,5-Cl Chlorthion 3.45 3.398 3.345 CH3 3-C1-4-N02 Fenchlorphos 5.07 4.553 4.961 CH3 2,4,5-Cl Iodofenphos CH3 5.51 4.924 5.491 2,5-Cl -4-I Fenthion 3-CH3-4-SCH 4.09 4.066 3.907 CH3 3.58 3.469 3.545 Dicapthon CH3 2-Cl-4-N0 DEPPSc 3.46 3.471 3.425 H C H Parathion 3.83 3.762 3.468 C H 4-NO2 5.14 4.636 5.033 Dichlofenthion C H 2,4-Cl Fensulfothion 2.23 2.965 2.244 4-SOCH C H 1.337 1.223 1.22 (2) 15 DMPPc CH3 H 16 Oxonof (1) 1.798 1.799 1.69 CH3 3-CH3-4~N0 17 Oxonof(2) CH3 2,6-Cl -4-CH3 2.66d 2.785 3.444 0.84d 1.360 1.095 18 Oxonof (3) CH3 4-CN 19 Oxonof (4) 1.380 1.553 1.33 CH3 4-NO2 20 Oxon of (6) 2.234 1.935 1.83 CH3 3-C1-4-N02 21 DEPPc 1.64 1.805 2.015 H C H 22 Oxon of (12) 2.058 1.98 2.328 4-NO2 23 Propaphos 3.67 3.457 3.354 n - C H 4-SCH aRepresentative logP value in the C L O G P file. ^Calculated by Eq. 5. cDEPP: Ο,Ο- diethyl phosphate, DMPP:0,0-dimethyl phosphate, DEPPSrO.O-diethyl phosphorothioate. ^Determined by the shake-flask method in our laboratory. 2

2

2

2

3

2

3

2

2

5

2

5

2

5

2

5

2

3

2

2

2

5

C2H5 3

7

3


51


4. KATAGI ET AL.

Table 1-2. Structure and LogP Value of Organophosphorus Compounds (Classes 3 and 4). RO

RO

S ' p - . Q - ^ Hetero j

RO

Ρ — Q -—^Hetero) FX)'

/

Class 3

Class #

Class 4

Name

Hetero

R

(3) 24

Chloropyrifos-methyl C H Pirimiphos-methyl CH 26 Chlorpyrifos C H 27 Diazinon C2H5 28 Triazophos C H (4) 29 Oxon of (2 7) C H a.bSee footnotes of Table Ï-1. cStructures 3

25


0

3

2

CI

5

2

5

2

5

Hie

4.31

3.762

3.764

H2c

4.20

3.383

3.199 4.442

Hie

5.27

4.362

H3c

3.81

3.565

3.502

H4c

3.55

4.054

3.114

H3c 2.07 2.023 are shown below.

2.092

N(C Hik

CH(CH3)

2

CI

CH

Obsd.a Caleb CLOGP

CH

3

2

3

with those determined by X-ray crystallography from the Cambridge structural database (28) with some additional compounds the crystallographic structure of which is known. Compounds used for these comparisons are shown in Table II. The initial structure of pesticides was generated from the typical geometries by using A C A C S . The most extended form was taken for each moiety of the molecule. The optical isomerism around phosphorus and carbon atoms, if present, was defined to be identical with that observed in the crystallographic structure. To seek out the stable conformers, the conformational analysis was first conducted for each set of the two Table 1-3.

Structure and LogP Value of Organophosphorus Compounds (Class 5). „ Ο v

TO

Class # Name (5)30

Stirofos

R

Ri

C H 2,4.5Cl -Ph 31 Dicrotophos C H C H 32 Crotoxyphos C H C H 33 Dichiovos CH Η >bSee footnotes of Table I-1. 3

II

R2 R3

Obsd aÇalc.b CLOGP

Cl H

4.31 3.762 3.764

3

3

3

3

3

3

H C(=0)N(CH ) 0.00 0.246 0.215 H COOCH(CH )Ph 3.30 3.171 3.057 C l Cl 1.43 1.002 1.809 3

2

3

a


52

CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

Table 1-4. Structure and LogP Value of Organophosphorus Compounds (Classes 6 - 9 ) .

R2

\ = X

0

X

R2

Class 6


Class

#

V=A R*O

0

\=>X

X

Class 7

Class 8 R2

Ri

(6) 34 35

Butamifos Isofenphos

5-C4H9 C H /-C3H7 C H

(7) 36 37 38 39 (8) 40 41 42 43

Oxonof (34) Crufornate Fenamiphos ET-15d

2

2

5

5

N=*X

Class 9 Obsd a Cale b CLOGP

X

Name

tfo

3-CH3-6-NO2 2-COO-;-C h 3

7

4.62 4.12 2.73c 3.42 3.23 2.53 4.29 3.85 6.31 5.23 2.44c

4.103 3.865 4.683 4.046

2.754 2.325 5-C4H9 C H 3-CH3-6-NO2 2.925 3.326 CH 2-CI-4-/-C4H9 CH 2.604 3.220 i - C H C H 3-CH -4-SCH 1.973 2.545 Η CH 2,4,5-Cl 4.152 4.283 Cyanofenphos Ph C H 4-CN 4.534 4.568 EPN Ph C H 4-NO2 5.846 6.390 Leptophos Ph CH 4-Br-2,5-Cl 4.835 4.939 Trichloronate C H C H 2,4,5-Cl (9) 44 Oxonof (40) Ph 3.095 2.473 C H 4-CN 45 Oxonof (42) Ph 4.58 4.502 4.580 CH 4-Br-2,5-Cl a,bSee footnotes of Table 1-1. ^Determined by the shake-flask method in our laboratory. dET-15:0-methyl 0-(2,4,5-trichlorophenyl) phosphoramidate. 2

5

3

3

3

7

2

5

3

3

3

3

2

5

2

5

3

2

5

2

2

5

2

3

5

3

2

single P-B (Β: Ο, N H , S or C) bonds by stepwise changing of the torsional angles. In the case of dimethyl phenyl phosphorothioate, which is the basic structure of class (1) compounds listed in Table 1-1, the three lower-energy state conformers were found through the conformational analysis followed by full optimization of the geometry. The two conformers in which one of the two methyl groups is in the trans position to sulfur and the other is in the gauche position exhibited an energy about 1 2 kcal mol-i lower than the other possessing both methyl groups in the gauche position. In each case, the phenyl group was in the gauche position. These conformations are found typically for the crystall structure of phosphorothionates (28). Similar stable conformations were expected for pesticides used here and the lowest-energy conformer with the extended structure was chosen for analysis. The computational results are briefly summarized in Table III. The X-ray crystallographic structure of phosphorothioates and trisubstituted phosphates (I and II) were satisfactorily reproduced. The P-0 bond length was slightly overestimated by 0.12 - 0.14À but the deviations for the other bonds were less than 0.05Â. The mean unsigned error for bond angles was within 5°. The torsional angles determining the orientation of alkyl and aryl substituents were not predicted so precisely as the above geometric parameters and the mean unsigned error was less than 20». The bond


4.

53


KATAGI ET AL.

lengths in phosphoramidothioates (III, not shown), phosphoramidates (IV), and phosphonothioates (V, not shown) were estimated with a precision similar to those in phosphorothioates. The mean unsigned errors of bond and torsional angles were less than 4° and 17°, respectively. In the case of phosphorodithioates (VI), the P-S-C bond angles were overestimated by 15.6±0.9° (mean unsigned error, not shown) but the other geometric parameters were well reproduced. The S-P=S moiety has not Table 1-5. Structure and LogP Value of Organophosphorus Compound (Classes 10 - 13).


1

1

P-O-R

P-SR

R2Q

Class 10

.PS

RO R2

Ri

(10)46 Methamidophos H 47 DMPATc CH 48 Acephate COCH3 (11)49 MDMPc CH 50 Fosetyl H 51 Glyphosate H 3

WO

2

R

Class 13

Obsd.aCalc.b C L O G P

R

CH CH CH

3

CH CH

3

CH3

3

VR R 2

Class 12

Class 11

Class # Name

R Q°

\\\

-0.66 -0.408 -0.868 -0.07 -0.062 -0.172 -0.85 -0.648 -0.892

3

3

-0.66 -0.900 -0.662 -2.70 -2.623 N.E.d C H N H C H - -3.60 -4.085 N.E.d COOH 52 Trichlorfon CH(OH)CCl 0.51 0.737 0.299 CH CH 0.78 0.733 0.752 (12)53 Dimethoate H CONHCH3 CH Hie 2.75 2.564 2.685 H 54 Azinphos-methyl C H 3 H2e 2.78 1.983 2.813 55 Phosmet H CH 3.56 3.813 3.465 56 Phorate C2H5 H SC2H5 H CON(CH3)CHO 1.48 1.103 1.507 57 Formothion CH H3e 2.42 2.373 2.409 58 Methidathion H CH 3.69 4.755 3.580 Ph 59 Phenthoate COOC2H5 CH 4.48 4.487 4.173 S-/-C4H9 H 60 Terbufos C H Hle 0.78 1.358 1.406 H (13)61 Oxon of (5 4) CH 2.07 2.512 1.986 62 Oxonof (56) H SC2H5 C H a,bSee footnotes of Table I-1. cDMPAT: 0,S-dimethyl methyl phosphoramidothioate, MDMP:0,0-dimethyl methyl phosphonate.

Theoretical Estimation of OctanolâWater Partition Coefficient for

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