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

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Predicting Octanol-Water Partition Coefficients
(Kow) from Water Solubility and Molar
VolumesCary T. ChiouNational Cheng Kung
Univ., Tainan,TaiwanU.S. Geological Survey,
Denver, CO, USA
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Uses and Needs of Kow Values

• Kow is a general partition indicator for organic
  compounds in environmental studies
• Kow approximates Klipid-w for assessing the
  bioconcentration factors of compounds
• Kows are unavailable for many compounds
• Inconsistent Kows for given compounds
• (differing often by 1-2 orders of
  magnitude)

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Water solubilities (Sw), octanol-water
partition coefficients(Kow), and lipid
triolein-water partition coefficients (Ktw) of
organic compounds

• Compound log Sw (mol/L) log Kow log Ktw
• Benzene -1.64 2.13 2.25
• Toluene -2.25 2.69 2.77
• Ethylbenzene -2.84 3.15 3.27
• 1,3,5-Trimethylbenzene -3.09 3.42 3.56
• 1,2-Dichlorobenzene -2.98 3.38 3.51
• 1,2,4-Trichlorobenzene -3.72 4.02 4.12
• 1,2,3,5-Tetrachlorobenzene (-4.53) 4.59 4.69
• Hexachlorobutadiene -5.01 4.90 5.04
• Pentachlorobenzene (-5.18) 5.20 5.27
• Hexachlorobenzene (-5.57) 5.50 5.50
• 2-PCB (-4.57) 4.51 4.77
• 2,4-PCB (-5.28) 5.10 5.30
• 2,5,2,5-PCB - - 6.11 5.81

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Lipid triolein-water partition coefficients (Ktw)
and fish bioconcentration factors (BCF)lipid
(Laboratory Experiments)

• Compound log Ktw log (BCF)lipid log
  (BCF)lipid
• (guppies)a (rainbow trout)b
• 1,2-Dichlorobenzene 3.51 3.51-3.80
• 1,3-Dichlorobenzene 3.63 3.70-4.02
• 1,4-Dichlorobenzene 3.55 3.26 3.64-3.96
• Hexachloroethane 4.21 3.79-4.13
• 1,2,3-Trimethylbenzene 4.19 4.11 4.15-4.47
• 1,2,4-Trimethylbenzene 4.12 4.19-4.56
• 1,3,5-Trichlorobenzene 4.36 4.15 4.34-4.67
• 1,2,3,4-Tetrachlorobenzene 4.68 4.80-5.13
• 1,2,3,5-Tetrachlorobenzene 4.69 4.86
• 1,2,4,5-Tetrachlorobenzene 4.70 4.80-5.17
• Hexachlorobutadiene 5.04 4.84-5.29
• Pentachlorobenzene 5.27 5.42 5.19-5.36
• Hexachlorobenzene 5.50 5.46 5.16-5.37
• a Könemann and van Leeuwen (Chemosphere, 1980)
  b Oliver and Nimii (EST, 1983)

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Laboratory Fish BCF Experiments
Chiou (EST, 1985) with Ktw and literature
BCF data
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Current Kow 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 (Sw)
• - Polyparameter Linear Solvation Energy
• Relationships (pp-LSERs)

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Substituent Contribution to Partition Coefficient

• Fujita et al. (J. Am. Chem. Soc., 1964)
• pX log KX - log KR
• KX partition coefficient of solute with
  substituent X
• KR partition coefficient of the reference
  solute R
• Chiou et al. (J. Pharm. Sci., 1982) show
• pX ?X - log (?o)X/(?o)R
• where
• ?X log
  (Sw)R/(Sw)X

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?X, pX (octanol-water) , and pX (heptane-water)
of Functional Groups Attached to Benzene

• Compound Group ?X pX (oct-w) pX (hep-w)
• Benzene - - 0 0 0
• Toluene CH3 0.60 0.56 0.59
• Ethylbenzene C2H5 1.20 1.02 1.17
• o-Xylene 1-CH3-2-CH3 1.08 0.99 1.13
• Flurorbenzene F 0.16 0.14 0.19
• Chlorobenzene Cl 0.72 0.71 0.69
• Bromobenzene Br 0.91 0.86 0.84
• m-Dichlorobenzene 1-Cl-3-Cl 1.40 1.25 1.28
• 1,2,4-Trichlorobenzene 1,2,4-(Cl)3 1.93
  1.89 1.89
• Aniline NH2 - 1.24 -
  1.23 - 2.22
• m-Chloroaniline 1-NH2-3-Cl - 0.27
  - 0.25 - 1.55
• Benzaldehyde CHO - 0.23
  - 0.65 - 1.21
• Phenol OH - 1.70 -
  0.67 - 3.18
• Benzoic acid COOH - 0.73
  - 0.28 - 2.98
• Phenylacetic acid CH2COOH - 1.15
  - 0.83 - 3.33

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• Solvent-Water Partition Coefficients for Dilute
  Solutes
• Using the mole fraction as the basis to express
  the
• solute activity (i.e., by Raoults Law), one
  obtains
• log Kow log Sw log Vo log Fdv
• log Fdv log ?o log (?w/ ?w)
• Sw Solute water solubility (mol/L)
• Vo 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

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Solute Water Solubility
For solid compounds, the Sw is that for the
supercooled liquid Sw (supercooled liquid)
Sw (solid) (Fsl) where log
(Fsl) (?Hf/2.303R) (Tm ? T)/T.Tm
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Typical log Kow - log Sw Correlations Chiou
et al. (EST, 1982) for mostly
substituted benzenes log Kow -
0.862 log Sw - 0.710 Mackay et al.
(Chemosphere, 1980) for substituted benzenes,
PAHs, and others log Kow - log Sw
0.254
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Remarks - Accurately predicts
the log Kow for solutes similar in size to
substituted benzenes - Underpredicts the
log Kow for small-sized solutes (e.g.,
dichloromethane TCE) - Overpredicts the
log Kow for large-sized solutes (many PCBs,
PAHs, Pesticides) - Raouts law is not
generally accurate for the partition of all
dilute solutes
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Polyparameter LSERs for Partition
Coefficients(Tafts, Abraham, Kamlet, Taylor)

• For Any Partition Coefficient (K)
• log K c rR2 sp2 a?2 b?2 vVx
• R2 Solute excess molar refraction
• p2 Solute dipolarity
• ?2 Solute H-bond acidity
• ?2 Solute H-bond basicity
• Vx Solute characteristic volume

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• Solvent-Water Partition Coefficients for Dilute
  Solutes
• Using the volume fraction as the basis to express
  the
• Solute activity, one obtains instead
• log Kow log Sw log V log Fdv
• log Fdv log ?o log (?w/ ?w)
• Sw 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

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Perfect Partition Coefficients for Dilute Solutes
in Any Solvent-Water Mixtures

• log Kºsw - log Sw - log V
  
• Note
• Kºsw 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
  (Sw).
• Kºsw or Kow shows a dependence on solute
  molar volume (V) rather than on solvent molar
  volume (Vo).

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Water solubilities (Sw), octanol-water
partition coefficients(Kow), and
triolein-water partition coefficients (Ktw) of
organic compounds(Kow ? Ktw, no dependence on
the solvent size)

• Compound log Sw (mol/L) log Kow log Ktw
• Benzene -1.64 2.13 2.25
• Toluene -2.25 2.69 2.77
• Ethylbenzene -2.84 3.15 3.27
• 1,3,5-Trimethylbenzene -3.09 3.42 3.56
• 1,2-Dichlorobenzene -2.98 3.38 3.51
• 1,2,4-Trichlorobenzene -3.72 4.02 4.12
• 1,2,3,5-Tetrachlorobenzene (-4.53) 4.59 4.69
• Hexachlorobutadiene -5.01 4.90 5.04
• Pentachlorobenzene (-5.18) 5.20 5.27
• Hexachlorobenzene (-5.57) 5.50 5.50
• 2-PCB (-4.57) 4.51 4.77
• 2,4-PCB (-5.28) 5.10 5.30
• 2,5,2,5-PCB - - 6.11 5.81

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Partition Coefficients in Octanol-Water Mixtures

• log Kow log Kºsw - log Fdv
• or
• log Kow - log Sw - log V - log Fdv
• where
• log Fdv log ?o log (?w/?w)

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Log Sw and Log Kºsw of Reference Solutes and
Their Log Fdv in Octanol-Water Mixtures

• Compound (n 33) - log Sw log Kºsw log Kow
  log Fdv
• Diethyl ether 0.0899 1.07 0.83 0.24
• Aniline 0.410 1.45 1.09 0.36
• Dichloromethane 0.641 1.83 1.51 0.32
• Carbon tetrachloride 2.28 3.30 2.73 0.57
• Benzene 1.64 2.69 2.13 0.56 Ethyl
  benzene 2.82 3.74 3.15 0.59
  1,3-Dichlorobenzene 3.07 4.01 3.44 0.57
  1,2,3,4-Tetrachlorobenz 4.59 5.43 4.60 0.83
• 1-Hexene 3.08 3.98 3.39 0.59
• n-Octane 5.24 6.02 5.18 0.84
• Naphthalene (3.09) 3.99 3.36 0.63
• Phenanthrene (4.48) 5.25 4.46 0.79
  2,2,5-PCB (5.83) 6.48 5.60 0.88
  2,2,3,3,4,4-PCB (7.59) 8.12 6.98 1.14
  Chlorpyrifos (5.68) 6.29 5.27 1.02 Lindane
  (3.62) 4.39 3.72 0.67
• p,p-DDT (6.79) 7.40 6.36 1.04

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log Fdv - 0.116 log Sw 0.268
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Correlation of Log Kow with Log Sw and Log V
Chiou et al. (EST, 2005)

• Substituting
• log Fdv - 0.116 log Sw 0.268
• into
• log Kow - log Sw - log V - log Fdv
• gives
• log Kow - 0.884 log Sw - log V - 0.268

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Log Kow Predictions by Volume-Fraction-Based (A)
and Mole-Fraction-Based (B) Dilute-Solution Models

• Compound
  Experimental Pred. (A) Pred. (B)
• Small-Sized Solutes (V 0.064 - 0.090 L/mol)
• Dichloromethane 1.51 1.49 1.26
• 1,2-dichloroethane 1.76 1.77 1.62
• Chloroform 1.90 1.90 1.76
• Trichloroethylene 2.53 2.53 2.42
• Substituted Benzenes (V 0.10 - 0.14 L/mol)
• Toluene 2.69 2.69 2.65
• 1,4-Xylene 3.18 3.14 3.15
• 1,2,3-Trichlorobenzene 4.04 3.98 3.98
• Large-Sized Solutes (V 0.27 - 0.39 L/mol)
• 2,2,3,3,5,5,6,6-PCB 7.11 7.11 7.42
• Dieldrin 4.55 4.53 4.79
• Ethion 5.07 5.13 5.49
• Leptophos 6.31 6.34 6.60
• Nonylphenol-4EOs 4.24 4.31 4.77

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Predicted Log Kow of NOCs from Log Sw and Log V

• Sw - log Sw - log V Pred
  Expt ?
• Compound (ppm) (mol/L) (L/mol) log Kow
  log Kow log Kow
• ALHCs
• Cyclohexane 55.8 3.18 0.963 3.51 3.44 -0.07
• n-Heptane 2.93 4.53 0.832 4.57 4.66 0.09
• 1-Octene 2.70 4.62 0.802 4.62 4.57 -0.05
• 1-Hexyne 360 2.36 0.937 2.75 2.73 -0.02
• HALHCs
• 1,2-Dichloromethane 8.7E3 1.06 1.104 1.77 1.76 -
  0.01
• TCE 1.37E3 1.98 1.045 2.53 2.53 0
• 1-Bromoheptane 6.65 4.43 0.804 4.45 4.36 -0.09
• Hexachlorobutadiene 2.55 5.01 0.810 4.97 4.90 -0
  .07
• ALBZs
• Styrene 300 2.54 0.936 2.91 2.95 0.04
• 1,3,5-Trichlorobenzene 69.2 3.24 0.865 3.46 3.42
  -0.04
• 1,2,4,5-Tetrachlorobenz 3.48 (4.02)
  (0.795) 4.08 4.10 0.02
• Hexamethylbenzene 0.235 (4.68)
  (0.704) 4.57 4.61 0.04

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Predicted Log Kow of NOCs from Log Sw and Log V

• Sw - log Sw - log V Pred
  Expt ?
• Compound (ppm) (mol/L) (L/mol) log Kow
  log Kow log Kow
• Anilines
• 3-Toluidine
  1.50E4 0.85 0.965 1.45 1.42 -0.03
• N,N-Dimethylaniline
  1.11E3 2.04 0.895 2.43 2.31 -0.12
• Ethers
• MTBE 5.16E4 0.23 0.925 0.86 0.94 0.08
• Anisole 2030 1.73 0.964 2.22 2.11 -0.11
  Diphenyl ether 18 (3.95)
  (0.800) 4.02 4.08 0.06
• Esters
• Ethyl acetate 8.04E4 0.040 1.010 0.78 0.73 -0.05
• Ethyl benzoate 720 2.32 0.845 2.63 2.64 0.01
• Di-butyl phthalate 13.0 4.33 0.575 4.14 4.08 -0
  .06
• Di-octyl phthalate 4.6E-4 8.93 0.399 8.02 8.10 0
  .08

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Predicted Log Kow of NOCs from Log Sw and Log V

• Sw - log Sw - log V Pred Expt
  ?
• Compound (ppm) (mol/L) (L/mol) log Kow
  log Kow log Kow
• HABZs
• Fluorobenzene 1550 1.79 1.027 2.34 2.27 -0.07
• Iodobenzene 229 2.95 0.951 3.29 3.28 -0.01
• 1,4-Dichlorobenzene 73 (3.03)
  (0.828) 3.34 3.37 0.03
• 1,2,3-Trichlorobenzene 16.3 (3.79)
  (0.903) 3.98 4.04 0.06
• 1,2,4,5-Tetrachlorobenzene 0.29 (4.70)
  (0.848) 4.73 4.70 -0.03
• Hexachlorobenzene 5.0E-3
  (5.71) (0.741) 5.52 5.50 -0.02
• PAHs
• Acenaphthene 3.93 (3.89)
  (0.830) 4.00 3.92 -0.08
• Fluorene 1.90 (4.14)
  (0.814) 4.21 4.18 -0.03
• Phenanthrene 1.29 (4.48)
  (0.773) 4.46 4.46 0
• 1,4,5-Trimethylnaphthalene 2.1 4.91
  0.760 4.83 4.87 0.04
• Pyrene 0.135 (4.92) (0.753) 4.83 4.88 0
  .05
• Benzo(a)anthracene 0.014 (5.89)
  (0.694) 5.63 5.61 -0.02

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Predicted Log Kow of NOCs from Log Sw and Log V

• Sw - log Sw - log V Pred
  Expt ?
• Compound (ppm) (mol/L) (L/mol) log Kow
  log Kow log Kow
• PCBs
• 2,4-PCB 0.637 (5.34)
  (0.674) 5.13 5.10 -0.03
• 2,2,5,5-PCB 0.046 (6.19)
  (0.615) 5.82 5.81 -0.01
• 2,2,4,4,6,6-PCB 4.1E-4 (8.24)
  (0.526) 7.54 7.55 0.01
• 2,2,3,3,5,5,6,6-PCB 3.93E-4
  (7.78) (0.499) 7.11 7.11 0
• 2,2,3,3,4,5,5,6,6-PCB 1.8E-5 (9.04)
  (0.467) 8.19 8.16 -0.03
• DXDBFs
• 2,8-Dichlorodibenzofuran 0.0145 (5.67)
  (0.739) 5.48 5.44 -0.04
• 1,2,3,4-Tetrachlorodioxin 6.3E-4 (6.75)
  (0.668) 6.37 6.20 -0.17
• Heterocyclics
• Carbazole 1.03 (3.00)
  (0.830) 3.21 3.29 0.08 Benzo(b)thiophene 130
  (2.94) (0.933) 3.26 3.26 0

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Predicted Log Kow of Pesticides from Log Sw and
Log V

• Sw - log Sw - log V Pred
  Expt ?
• Compound (ppm) (mol/L) (L/mol) log Kow
  log Kow log Kow
• OGCLs
• Dieldrin 0.465 (4.73)
  (0.616) 4.53 4.55 0.02
• Heptachlor 0.056 (6.05)
  (0.645) 5.73 5.73 0
• p,p-DDE 0.040 (6.15)
  (0.627) 5.80 5.77 -0.03
• OGPPs
• Chlorfenvinphos 145 3.39
  (0.578) 3.31 3.23 -0.08
• Ethion 1.1 5.54 0.501 5.13 5.07 -0.06
• Leptophos 0.021 (6.83)
  (0.570) 6.34 6.31 -0.03
• Carbamates
• Oxamyl 2.83E5 (-0.87) (0.646) - 0.39
  - 0.43 -0.04
• Aldicarb 6.02E3 (0.59)
  (0.798) 1.05 1.13 0.08 Carbaryl 104
  (2.09) (0.742) 2.32 2.31 -0.01
• AUTZs
• Alachlor 240 (2.89)
  (0.623) 2.91 2.92 0.01
• Linuron 75 (2.57)
  (0.701) 2.70 2.76 -0.06
• Atrazine 30 (2.37)
  (0.741) 2.57 2.64 0.07

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? Log Kow for Classes of NOCs and Pesticides

• Class
  No. ? log Kow
• ALHCs 14 0.07
• HALHCs 22 0.07
• ALBZs 15 0.06
• HABZs 14 0.04
• Anilines 6 0.06
• Ethers 7 0.09
• Esters 11 0.06
• PAHs 23 0.07
• PCBs 26 0.07

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Predicted Log Kow from Log Sw and Log V for
Phenols and Alcohols

• Sw Pred Expt ?
• Compound (ppm) - log Sw - log V log
  Kow log Kow log Kow
• Phenols
• Phenol 7.65E4 (-0.01) (1.051) 0.78 1.45
  0.67
• 2,4,6-Trimethylphenol 1.01E3 (1.67)
  (0.907) 2.11 2.73 0.72
• 2-Chlorophenol 1.15E4 (1.05)
  (0.990) 1.65 2.15 0.50
• 2,4,5-Tichlorophenol 649 (2.09)
  (0.881) 2.46 3.72 1.26
• 4-Octylphenol 12.6 (4.05) (0.685) 3.99 4.12
  0.13 Nonylphenol-4EOs 7.65 (4.71)
  (0.411) 4.31 4.24 -0.07
• Alcohols
• n-Hexanol 5.84E4 (1.24)
  (0.903) 1.73 2.03 0.30
• n-Heptanol 1.68E3 (1.84) (0.849) 2.21 2.57
  0.36
• n-Octanol 495 (2.42) (0.801) 2.67 3.15 0.48
• Benzyl alcohol 3.8E4 (0.45)
  (0.983) 1.12 1.10 -0.02

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Prediction of Octanol-Water Partition
Coefficients (Kow) by pp-LSERs(Abraham et al.,
J. Pharm. Sci., 1994)

• log Kow 0.088 0.562 R2 - 1.054
  ?2H 0.034 ?2H -
  3.460 ?2H 3.814Vx
• with
• n 613 and SD 0.116
• Note No pesticides and complex molecules