Predicting Octanol-Water Partition Coefficients (K ow ) from Water Solubility and Molar Volumes Cary T. Chiou National Cheng Kung Univ., Tainan,Taiwan U.S. Geological Survey, Denver, CO, USA

Uses and Needs of K ow Values  K ow is a general partition indicator for organic compounds in environmental studies  K ow approximates K lipid-w for assessing the bioconcentration factors of compounds  K ow ’s are unavailable for many compounds  Inconsistent K ow ’s for given compounds (differing often by 1-2 orders of magnitude)

Water solubilities (S w ), octanol-water partition coefficients(K ow ), and lipid triolein-water partition coefficients (K tw ) of organic compounds Compoundlog S w (mol/L)log K ow log K tw Benzene Toluene Ethylbenzene ,3,5-Trimethylbenzene ,2-Dichlorobenzene ,2,4-Trichlorobenzene ,2,3,5-Tetrachlorobenzene(-4.53) Hexachlorobutadiene Pentachlorobenzene(-5.18) Hexachlorobenzene(-5.57) PCB(-4.57) ,4’-PCB(-5.28) ,5,2’,5’-PCB

Lipid triolein-water partition coefficients (K tw ) and fish bioconcentration factors (BCF) lipid (Laboratory Experiments) Compoundlog K tw log (BCF) lipid log (BCF) lipid (guppies) a (rainbow trout) b 1,2-Dichlorobenzene ,3-Dichlorobenzene ,4-Dichlorobenzene Hexachloroethane ,2,3-Trimethylbenzene ,2,4-Trimethylbenzene ,3,5-Trichlorobenzene ,2,3,4-Tetrachlorobenzene ,2,3,5-Tetrachlorobenzene ,2,4,5-Tetrachlorobenzene Hexachlorobutadiene Pentachlorobenzene Hexachlorobenzene a Könemann and van Leeuwen (Chemosphere, 1980) ; b Oliver and Nimii (ES&T, 1983)

Laboratory Fish BCF Experiments Chiou (ES&T, 1985) with K tw and literature BCF data

Current K ow Prediction Methods Indirect Experimental Methods: - HPLC Retention Time or Volume using a chosen stationary phase Molecular Computation Models: - Fragment or Group Constants (f and  ) - Molecular Volumes or Areas - Correlations with Water Solubility (S w ) - Polyparameter Linear Solvation Energy Relationships (pp-LSERs)

Substituent Contribution to Partition Coefficient Fujita et al. (J. Am. Chem. Soc., 1964): π X = log K X - log K R K X = partition coefficient of solute with substituent X K R = partition coefficient of the reference solute R Chiou et al. (J. Pharm. Sci., 1982) show: π X =  X - log [(  o *) X /(  o *) R ] where  X = log [(S w ) R /(S w ) X ]

 X, π X (octanol-water), and π X (heptane-water) of Functional Groups Attached to Benzene CompoundGroup  X π X (oct-w) π X (hep-w) Benzene TolueneCH EthylbenzeneC 2 H o-Xylene1-CH 3 -2-CH FlurorbenzeneF ChlorobenzeneCl BromobenzeneBr m-Dichlorobenzene1-Cl-3-Cl ,2,4-Trichlorobenzene1,2,4-(Cl) AnilineNH m-Chloroaniline1-NH 2 -3-Cl BenzaldehydeCHO PhenolOH Benzoic acidCOOH Phenylacetic acidCH 2 COOH

Solvent-Water Partition Coefficients for Dilute Solutes: Using the mole fraction as the basis to express the solute activity (i.e., by Raoult’s Law), one obtains log K ow = – log S w – log V o * – log F dv log F dv = log  o * + log (  w /  w * ) S w = Solute water solubility (mol/L) V o * = Molar volume of the water-saturated solvent (e.g., octanol) (L/mol)  o *,  w,  w * are the solute activity coefficients in water-saturated solvent (octanol), pure water, and solvent-saturated water

Solute Water Solubility For solid compounds, the S w is that for the supercooled liquid: S w (supercooled liquid) = S w * (solid) (F sl ) where log (F sl ) = (  H f /2.303R) [(T m  T)/T.T m ]

Typical log K ow - log S w Correlations Chiou et al. (ES&T, 1982) for mostly substituted benzenes: log K ow = log S w Mackay et al. (Chemosphere, 1980) for substituted benzenes, PAHs, and others: log K ow = - log S w

Remarks: - Accurately predicts the log K ow for solutes similar in size to substituted benzenes - Underpredicts the log K ow for small-sized solutes (e.g., dichloromethane & TCE) - Overpredicts the log K ow for large-sized solutes (many PCBs, PAHs, & Pesticides) - Raout’s law is not generally accurate for the partition of all dilute solutes

Polyparameter LSERs for Partition Coefficients (Tafts, Abraham, Kamlet, Taylor) For Any Partition Coefficient (K): log K = c + rR 2 + sπ 2 + a  2 + b  2 + vV x R 2 = Solute excess molar refraction π 2 = Solute dipolarity  2 = Solute H-bond acidity  2 = Solute H-bond basicity V x = Solute characteristic volume

Solvent-Water Partition Coefficients for Dilute Solutes: Using the volume fraction as the basis to express the Solute activity, one obtains instead log K ow = – log S w – log V – log F dv log F dv = log  o * + log (  w /  w * ) S w = Solute water solubility (mol/L) V = Solute Molar volume (L/mol)  o *,  w,  w * are the equivalent solute activity coefficients on a volume-fraction basis

Perfect Partition Coefficients for Dilute Solutes in Any Solvent-Water Mixtures log K º sw = - log S w - log V Note: K º sw is numerically equal to the ratio of the molar concentration of a pure liquid solute (i.e., 1/V) to its molar solubility in water (S w ). K º sw or K ow shows a dependence on solute molar volume (V) rather than on solvent molar volume (V o * ).

Water solubilities (S w ), octanol-water partition coefficients(K ow ), and triolein-water partition coefficients (K tw ) of organic compounds (K ow  K tw, no dependence on the solvent size) Compoundlog S w (mol/L)log K ow log K tw Benzene Toluene Ethylbenzene ,3,5-Trimethylbenzene ,2-Dichlorobenzene ,2,4-Trichlorobenzene ,2,3,5-Tetrachlorobenzene(-4.53) Hexachlorobutadiene Pentachlorobenzene(-5.18) Hexachlorobenzene(-5.57) PCB(-4.57) ,4’-PCB(-5.28) ,5,2’,5’-PCB

Partition Coefficients in Octanol-Water Mixtures log K ow = log K º sw - log F dv or log K ow = - log S w - log V - log F dv where log F dv = log  o * + log (  w /  w * )

Log S w and Log Kº sw of Reference Solutes and Their Log F dv in Octanol-Water Mixtures Compound (n = 33)- log S w log K º sw log K ow log F dv Diethyl ether Aniline Dichloromethane Carbon tetrachloride Benzene Ethyl benzene ,3-Dichlorobenzene ,2,3,4-Tetrachlorobenz Hexene n-Octane Naphthalene (3.09) Phenanthrene (4.48) ,2’,5-PCB (5.83) ,2’,3,3’,4,4’-PCB (7.59) Chlorpyrifos (5.68) Lindane (3.62) p,p’-DDT (6.79)

- log S w log F dv log F dv = log S w

Correlation of Log K ow with Log S w and Log V Chiou et al. (ES&T, 2005) Substituting log F dv = log S w into log K ow = - log S w - log V - log F dv gives log K ow = log S w - log V

Log K ow Predictions by Volume-Fraction-Based (A) and Mole-Fraction-Based (B) Dilute-Solution Models Compound Experimental Pred. (A) Pred. (B) Small-Sized Solutes (V = L/mol) Dichloromethane ,2-dichloroethane Chloroform Trichloroethylene Substituted Benzenes (V = L/mol) Toluene ,4-Xylene ,2,3-Trichlorobenzene Large-Sized Solutes (V = L/mol) 2,2’,3,3’,5,5’,6,6’-PCB Dieldrin Ethion Leptophos Nonylphenol-4EOs (A): log K ow = log S w - log V ; (B): log K ow = log S w

Predicted Log K ow of NOCs from Log S w and Log V S w - log S w - log V Pred Expt  Compound (ppm) (mol/L) (L/mol) log K ow log K ow log K ow ALHCs Cyclohexane n-Heptane Octene Hexyne HALHCs 1,2-Dichloromethane 8.7E TCE 1.37E Bromoheptane Hexachlorobutadiene ALBZs Styrene ,3,5-Trichlorobenzene ,2,4,5-Tetrachlorobenz 3.48 (4.02) (0.795) Hexamethylbenzene (4.68) (0.704)

Predicted Log K ow of NOCs from Log S w and Log V S w - log S w - log V Pred Expt  Compound (ppm) (mol/L) (L/mol) log K ow log K ow log K ow Anilines 3-Toluidine 1.50E N,N-Dimethylaniline 1.11E Ethers MTBE5.16E Anisole Diphenyl ether 18 (3.95) (0.800) Esters Ethyl acetate8.04E Ethyl benzoate Di-butyl phthalate Di-octyl phthalate4.6E

Predicted Log K ow of NOCs from Log S w and Log V S w - log S w - log V Pred Expt  Compound (ppm) (mol/L) (L/mol) log K ow log K ow log K ow HABZs Fluorobenzene Iodobenzene ,4-Dichlorobenzene 73 (3.03) (0.828) ,2,3-Trichlorobenzene 16.3 (3.79) (0.903) ,2,4,5-Tetrachlorobenzene 0.29 (4.70) (0.848) Hexachlorobenzene 5.0E-3 (5.71) (0.741) PAHs Acenaphthene 3.93 (3.89) (0.830) Fluorene 1.90 (4.14) (0.814) Phenanthrene 1.29 (4.48) (0.773) ,4,5-Trimethylnaphthalene Pyrene (4.92) (0.753) Benzo(a)anthracene (5.89) (0.694)

Predicted Log K ow of NOCs from Log S w and Log V S w - log S w - log V Pred Expt  Compound (ppm) (mol/L) (L/mol) log K ow log K ow log K ow PCBs 2,4’-PCB (5.34) (0.674) ,2’,5,5’-PCB (6.19) (0.615) ,2’,4,4’,6,6’-PCB 4.1E-4 (8.24) (0.526) ,2’,3,3’,5,5’,6,6’-PCB 3.93E-4 (7.78) (0.499) ,2’,3,3’,4,5,5’,6,6’-PCB 1.8E-5 (9.04) (0.467) DXDBFs 2,8-Dichlorodibenzofuran (5.67) (0.739) ,2,3,4-Tetrachlorodioxin6.3E-4 (6.75) (0.668) Heterocyclics Carbazole 1.03 (3.00) (0.830) Benzo(b)thiophene 130 (2.94) (0.933)

Predicted Log K ow of Pesticides from Log S w and Log V S w - log S w - log V Pred Expt  Compound (ppm) (mol/L) (L/mol) log K ow log K ow log K ow OGCLs Dieldrin (4.73) (0.616) Heptachlor (6.05) (0.645) p,p’-DDE (6.15) (0.627) OGPPs Chlorfenvinphos (0.578) Ethion Leptophos (6.83) (0.570) Carbamates Oxamyl 2.83E5 (-0.87) (0.646) Aldicarb 6.02E3 (0.59) (0.798) Carbaryl 104 (2.09) (0.742) AUTZs Alachlor 240 (2.89) (0.623) Linuron 75 (2.57) (0.701) Atrazine 30 (2.37) (0.741)

 Log K ow for Classes of NOCs and Pesticides Class No.  log K ow ALHCs HALHCs ALBZs HABZs Anilines Ethers Esters PAHs PCBs DXDBFs Heterocyclics OGCLs OGPPs Carbamates AUTZs Total 194 Ave

Predicted Log K ow from Log S w and Log V for Phenols and Alcohols S w Pred Expt  Compound (ppm) - log S w - log V log K ow log K ow log K ow Phenols Phenol7.65E4 (-0.01) (1.051) ,4,6-Trimethylphenol1.01E3 (1.67) (0.907) Chlorophenol1.15E4 (1.05) (0.990) ,4,5-Tichlorophenol 649 (2.09) (0.881) Octylphenol12.6(4.05) (0.685) Nonylphenol-4EOs7.65(4.71) (0.411) Alcohols n-Hexanol5.84E4 (1.24) (0.903) n-Heptanol1.68E3(1.84) (0.849) n-Octanol495(2.42) (0.801) Benzyl alcohol3.8E4(0.45) (0.983)

Prediction of Octanol-Water Partition Coefficients (K ow ) by pp-LSERs (Abraham et al., J. Pharm. Sci., 1994) log K ow = R  2 H  2 H  2 H V x with n = 613 and SD = Note: No pesticides and complex molecules