J. Phys. Chem. 1988, 92, 5244-5255
5244
gregates. In the present photoredox system, important new information has been found: (a) Reduction of MV2+ to MV" was necessary to induce viologen leaking; MV2+did not undergo transmembrane diffusion even under irradiation when CdS colloids were used as photosensitizer. (b) Transmembrane electron transfer was observed only from CdS colloids in relatively high concentration at the outer vesicle surface to MV2+ adsorbed at the inner vesicle surface. (c) Following this transmembrane electron transfer, MV" dimer formation took place and was strongly promoted by the light irradiation; this dimer or some subsequent higher aggregate diffused much less through the DHP membrane that MV" itself. These results show that transmembrane electron transfer is possible under specific conditions. However, the complications produced by redox-induced leaking and dimer formation should be avoided if we want to achieve and observe efficient charge separation by the vesicle walls. Consequently, the intrinsic properties of the membrane or of the redox species must be modified. Membrane polymerization has been tried for this p u r p o ~ e .The ~ ~success ~ ~ ~ of this approach is subjected to a detailed (27) Fendler, J. H.; Tundo, P. Acc. Chem. Res. 1984, 17, 3.
understanding of the morphology of the polymerized bilayer membrane, which is a complex challenge.29 On the basis of the other approach, promising results have been achieved by use of more highly charged viologen derivatives, which form very little dimer and exhibit much lower redox-induced transmembrane diffusion, as will be reported elsewhere.26 The direct photostimulated diffusion of MV2+,as proposed by the authors of ref 10, cannot be formally excluded nor confirmed by the technique reported here, since the presence of Ru(bpy)32+ would preclude selective detection of MV" at the working electrode. Our results are nevertheless relevant to such vesicular systems, since they strongly support redox-induced leaking as a molecular mechanism for viologen leaking.
Acknowledgment. We thank Prof. I. Milo and C. Gitler, Department of Membrane Research, Weizmann Institute of Science, and Dr. I. Rubinstein, Department of Materials Research, Weizmann Institute of Science, for stimulating discussions. Registry No. DHP, 2197-63-9; MV2", 4685-14-7; CdS, 1306-23-6;
benzyl alcohol, 100-51-6. (28) Fendler. J. H . J . Phvs. Chem. 1985. 89. 2730 (29j Reed,W.; Guterman: L.; Tundo, P.; Fendler, J. H. J . A m . Chem. Sac. 1984, 106, 1897.
Linear Solvation Energy Relationships. 46. An Improved Equation for Correlation and Prediction of OctanoVWater Partition Coefficients of Organic Nonelectrolytes (Including Strong Hydrogen Bond Donor Solutes) Mortimer J. Kamlet,+Ruth M. Doherty, Michael H. Abraham, Yizhak Marcus, and Robert W. Taft* Advanced Technology and Research, Inc., 14900 Sweitzer Lane, Laurel, Maryland 20707, Naval Surface Weapons Center, White Oak Laboratory, Silver Spring, Maryland 20910, Department of Chemistry, University of Surrey, Guildford, Surrey GU2 5XH, United Kingdom, Department of Analytical Chemistry, The Hebrew University, Jerusalem, Israel, and Department of Chemistry, University of California, Irvine, California 72717 (Received: June 24, 1987)
Octanol/water partition coefficients of 245 non-hydrogen bonding, hydrogen bond acceptor, and weak and strong hydrogen bond donor aliphatic and aromatic solutes are well correlated by the linear solvation energy relationship log Kow = 0.35 + 5.351/,/100 - 1.04(x* - 0.356) - 3.84/3, + O.lOa, (r = 0.9959, SD = 0.131), where VIis the intrinsic (van der Waals) molar volume, x * , p,, and a, are the solvatochromicparameters that measure solute dipolarity/polarizability, hydrogen bond acceptor basicity, and hydrogen bond donor acidity, and 6 is a "polarizability correction" parameter. Parameter estimation rules are set forth that allow the accurate prediction of octanol/water partition coefficients of hundreds, perhaps thousands, of solutes whose solvatochromic parameters have not yet been measured.
In earlier papers of this series,' we have pointed out that solubilities, distribution between solvents, and other properties that depend on solute-solvent interactions are well correlated by equations that include linear combinations of dependences on up to five solute parameters. A cavity term (mV/lOO) measures the endoergic process of separating the solvent molecules to provide a suitably sized cavity for the solute. A dipolarity/polarizability term [s(x* d6)] measures the endoergic effects of solutesolvent dipole-dipole and dipole-induced dipole interactions. Hydrogen bonding terms (ua, and bp,) measure the exoergic effects of hydrogen bonding interactions involving the solute as HBD and the solvent as HBA and/or the solute as HBA and the solvent as HBD (HBD = hydrogen bond donor, HBA = hydrogen bond acceptor). Accordingly the general LSER (linear solvation energy relationship) that measures the property, X Y Z , in terms of the solute parameters is given by
+
*To whom correspondence should be addressed at the University of California. Deceased.
0022-3654/88/2092-5244$01.50/0
+
+
+
+
+
X Y Z = X Y Z o m V / 1 0 0 S(R* d6) bp, aa, (1) V in eq 2 is a measure of solute volume and may be V, the liquid molar volume, taken as the solute molecular weight divided by its liquid density at 20 OC, or VI, the intrinsic (van der Waals) molar volume, computer ~ a l c u l a t e dor~ ~estimated ~ by simple additivity methods like that of M c G ~ w a n . ~We use V/100 so (1) (a) Kamlet, M. J.; Doherty, R. M.; Abboud, J.-L. M.; Abraham, M. H.; Taft, R. W. CHEMTECH 1986,16, 566. (b) Taft, R. W.; Abboud, J.-L. M.; Kamlet, M. J.; Abraham, M. H. J . Solut. Chem. 1985, 14, 153. (c) Kamlet, M. J.; Abboud, J.-L.M.; Taft, R. W. Prog. Phys. Org. Chem. 1981, 13, 485. (d) Kamlet, M. J.; Taft, R. W. Acta Chem. Scand. Ser. B 1985,39, 611. (e) Abraham, M. H.; Doherty, R. M.; Kamlet, M. J.; Taft, R. W. Chem. Br. 1986, 22, 551. (2) The reciprocal equation that describes the XYZ in terms of solvent properties is XYZ = X Y Z , + h(6H)2/100+ S ( T * + d6) + b@, + actm,where 6" is the Hildebrand solubility parameter. (3) Leahy, D. J . Pharm. Sci. 1986, 75, 629. (4) Pearlman, R. S . In Partition Coefficient Determination and Estimation; Dunn, W . J., Block, J. H., Pearlman, R. S., Eds.; Pergamon: New York, 1986; p 3. (5) McGowan, J . C. J. Appl. Chem. Biotechnol. 1978, 28,599; 1984,34A, 3 8 . Abraham, M. H.; McGowan, J . C., to be submitted for publication.
0 1988 American Chemical Society
Linear Solvation Energy Relationships
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988 5245
that the cavity term parameter should cover roughly the same range as the other independent variables in eq 1, which makes easier the evaluation of the relative contributions of the various terms to the solubility property studied. The a* solvatochromic parameter in eq 1 is a measure of solute dipolarity/polarizability. For “select” compounds, nonpolychlorinated aliphatic compounds with a single dominant bond dipole moment, T* values are very nearly proportional to molecular dipole moments. Different blends of dipole-dipole and dipoleinduced dipole effects on the solute-solvent interaction studied are accounted for in eq 1 by use of the (a* d6) formalism, where 6 is a polarizability correction parameter equal to 0.0 for nonpolychlorinated aliphatic compounds, 0.5 for polychlorinated aliphatics, and 1 .O for aromatic solutes. We have found the d coefficient to be 0 where polarizability contributions to the property studied are near maximal and -0.40 where the polarizability contributions are near minimal. The 8, and cy, solvatochromic parameters in eq 1 measure HBA basicity and HBD acidity, respectively, i.e., the ability to accept or donate a proton in a solute-solvent hydrogen bond. The subscript m indicates that, for compounds that are capable of self-association (Le., amphi-hydrogen bonding compounds), the parameter applies to the non-self-associated “monomer” solute rather than the self-associated “oligomer” solvent. For compounds that are not capable of self-association,3(, = 8. Where differences exist, the a*,p,, and cy, values in this paper supersede earlier published values6 [When applied to solubilities (as distinct from partitions between solvents), it might be considered that eq 1 should also include another important term that measures the endoergic process of extracting the single solute molecule from the bulk liquid solute before depositing it in the solvent cavity. That we have achieved such precise correlations of aqueous solubilities as are discussed below, without introducing such a term, indicates that for the solute set studied the term must covary strongly with some linear combination of V/lOO, a*,and cy,. Hence, rather than measuring only sclute-solvent interactions, the terms in eq 1, when applied to the solution process, should be regarded as measuring the differences between solute-solute interactions disrupted and solute-solvent interactions formed.] Our most recent application of eq 1 to solubility properties was in correlations of aqueous solubilities of 185 organic nonelectrolytes.’ We found that aliphatic and aromatic solutes conformed to separate and statistically distinct aqueous solubility relationships, with the equation for aliphatic but not that for aromatic solutes showing a statistically significant exoergic dependence on a*,* and the equation for aromatics showed a 25% lesser dependence on 8 than that for the aliphatics. The correlation for 115 liquid aliphatic non-HB, HBA, and weak HBD solutes was given7 by eq 2, while the very different log S,(aliphatics) = 0.05 - 5.85V1/100 1 . 0 9 ~ * 5.258,
+
+
+
n = 115, r = 0.9944, S D = 0.153 log S,(aromatics) = 0.57 - 5.85V1/100
+ 3.858,
- 0.01 10(mp-25)
n = 70, r = 0.9917, S D = 0.216 log S,(aromatics) = 0.24 - ~ . 3 0 v 1 / 1 0 0+ 3.998, - 0.0096(mp-25)
n = 147, r = 0.9903, S D = 0.3379 LSER for 70 liquid and solid non-HB, HBA, and weak HBD
aromatic solutes with up to three fused rings was given7 by eq 3a. We have since expanded the latter data base to also include aqueous solubility results for 42 polychlorinated biphenyls up to Cl2CIl0and a further 35 polycyclic aromatic hydrocarbons with up to six fused rings; the correlation is given by eq 3b. Following Yalkowsky,’othe term in (mp-25) measures the endoergic process of converting the solid solutes to supercooled liquids at 25 “C. [For liquid solutes the term in (mp-25) is taken as nil.] It is important to subsequent discussions that pyridine, substituted pyridines, and benzopyridine derivatives fit eq 3a and 3b about as well as the other aromatic solutes. We have also employed eq 1 for the analysis of factors influencing octanol/water partition coefficients, KO,,of organic nonelectrolyte solute^.^'-'^ Our correlation used P (solute liquid molar volume) to measure the cavity term. It was based on data for 102 aromatic and aliphatic non-HB, HBA, and weak HBD solutes and was given by eq 4a. More recently, Leahy3 has treated log KO, = 0.20 2.74v/100 - 0.92(a* - 0.406)- 3.388, (4a) n = 102, r = 0.989, S D = 0.17 log KO, = 0.45 5.25V1/1OO - 1 . 2 9 ( ~ *- 0.406) -3.608, (4b) n = 103, r = 0.9915, S D = 0.16
+
+
much the same data set using computer-calculated Vrto measure the cavity term, which led to a somewhat better statistical fit and eliminated the need for some cumbersome “ground rules” that were required to estimate P b u t not VI of alicyclic and aromatic solutes. Leahy’s correlation is given by eq 4b. On the expectation that polarizability contributions to solubilities in both phases were similar, and hence canceled out, we and Leahy assumed minimal net polarizability effects on log KO,,and therefore used d = -0.40 in the (a*+ d6) formalism. When the solvatochromic parameters determined for pyridine and substituted pyridine solvents were used for the same compounds acting as solutes, eq 4a and 4b undercalculated their log KO, values by 0.6-0.8 log unit.
Results and Discussion In this paper we report a correlation of log octanol/water partition coefficient that differs from Leahy’s and our earlier LSERs in several important regards: (a) The correlation now includes strong HBD solutes (phenols and carboxylic acids) and, to accommodate them, a term in (ICY,. (b) Rather than the d coefficient being fixed at -0.40, the 6 parameter has now been included as a floating variable, and the d coefficient is determined in the multiple linear regression analysis. (c) The data base has now been expanded to include 245 liquid and solid aliphatic and aromatic solutes, including large numbers of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) of great interest to the environmental community because of their toxicity and bioaccumulation properties. (d) In addition to parameter estimation rules for PCBs, PAHs, and other solid solutes that were used earlier in our correlations of aqueous solubilities by eq 3a,7 we have set forth a number of additional rules for estimation of VI, K*, Om,and cy, of substituted phenols, benzoic acids, and anilines. These new rules will now allow accurate estimates of log S, and log KO,of hundreds of additional solutes. Important requirements that need to be met for an LSER to correctly represent the solute-solvent interaction studied are a high correlation coefficient, r, and a low standard deviation, SD. An equally important and more rigorous test, and hence less frequently applied, is that the equation be “robust”, Le., the in-
(6) Kamlet, M. J.; Abboud, J.-L. M.; Abraham, M. H.; Taft, R. W. J . Org. Chem. 1983, 48, 2877. (7) Kamlet, M. J.; Doherty, R. M.; Abraham, M. H.; Carr, P. W.; Doherty, R. F.; Taft, R. W. J . Phys. Chem. 1987, 91, 1996.
(9) If eight data points, which most likely involve erroneous measurements, are excluded, the equation becomes log S , = 0.27 - 5.29V1/100 + 3.938 0.0096(mp-25), r = 0.9929, SD = 0.285. (10) Yalkowsky, S. H.; Valvani, S. C. J . Pharm. Sci. 1980, 69, 602. (1 I ) Kamlet, M. J.; Abraham, M. H.; Doherty, R. M.; Taft, R. W. J . A m .
(8) The different dependence on r* for the aromatics was rationalized’ on the basis that because of ‘vertical stacking” in the neat liquid aromatic solutes, the process of separating the single solute molecule from the bulk liquid solute (before depositing it in the solvent cavity) showed a larger endoergic dependence on P’ in the aromatic than in the aliphatic series.
Chem. SOC.1984, 106, 464. (12) Taft, R. W.; Abraham, M. H.; Famini, G. R.; Doherty, R. M.; Kamlet, M. J. J . Pharm. Sci. 1985, 74, 807. (13) Kamlet, M. J.; Doherty, R. M.; Carr, P. W.; Mackay, D.; Abraham, M. H.; Taft, R. W., submitted for publication in Enuiron. Sci. Technol.
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The Journal of Physical Chemistry, Vol. 92, No. 18, 1988
TABLE I: Comparison of Correlation Equations for Different Subsets of the Data
log KO, = XYZ, no.
1. 2. 3. 4. 5. 6.
data set Leahy’s correlation all solutes non-HBD aliphatics all aliphatics non-HBD aromatics all aromatics
+ rnVI/lOO + s(n* + d6) + bo, + ua, a
XYZ”
m
S
d
b
+0.45 +0.32 +0.40 +0.38 +0.15 +0.31
+5.25 +5.35 +5.41 +5.42 +5.30 +5.22
-1.29 -1.04 -1.29 -1.28 -0.69 -0.91
-0.40 -0.35 -0.33 -0.33 -0.38 -0.38
-3.60 -3.84 -3.83 -3.85 -3.78 -3.87
tercept and the coefficients of the independent variables should be reasonably similar for different subsets of the data. In this paper we shall first give the equation for the total data set and then the equations for different subsets of the data. For convenient comparison the equations using the (?r* - d6) formalism are assembled in Table I. We shall also discuss the parameter estimation rules applicable to each subset. The LSER for octanol/water partition coefficients of 245 aliphatic and aromatic non-HB, HBA, and HBD nonelectrolytes is given by eq 5; the corresponding equation using the (a* + d6) log KO, = (0.32 f 0.04) (5.35 f O.O5)V,/lOO - (1.04 f 0 . 0 4 ) ~ *+ (0.35 f 0.03)6 - (3.84 f 0.05)p, (0.10 f 0.04)am (5)
+
+
n = 245, r = 0.9959, S D = 0.131
formalism is given by eq 2 of Table I. Several features of eq 5 need to be noted: (a) The intercept and coefficients of VI/lOO, T*,and 0correspond reasonably closely to Leahy’s earlier eq 4b. (b) Despite the larger and far more variegated data set, the statistical goodness of fit is significantly better than in the earlier correlations. [If one takes (1.000 - r Z )as the amount of information not accounted for by the correlation equation, 1.7% of the information remains unaccounted for by Leahy’s eq 4b, 0.8% by our eq 5.1 (c) The term in a, is small but statistically significant at the 99.3% confidence level by Student’s t-test. (d) The d coefficient obtained by regression analysis does not differ markedly from Leahy’s and our earlier estimates. (e) As in our aqueous solubility correlations, the leading terms are seen to be the endoergic cavity term, which favors partition into the less cohesive solvent, octanol, and the exoergic solvent donor/solute acceptor hydrogen bonding term, which favors partition into the stronger HBD solvent, water. [For evaluation of the effect of octanol acting as hydrogen bond donor, the b coefficient of -3.84 in eq 5 compares with b = -5.28 for CC14/water partition. To evaluate the effect of octanol acting as hydrogen bond acceptor, the u coefficient of +0.10 compares with a = -3.17 for CCl,/water.] Non-HBD Aliphatic Solutes. The first subset of the data to be considered are for the non-HBD aliphatic solutes. Experimental log KO,,,values for 46 such compounds are assembled in Table 11, together with the solute solvatochromic parameters and log KO, values calculated through eq 5. The experimental data are from the collection assembled by Hansch and Leo.I4 With the following exceptions, the solute solvatochromic parameters in Table I1 are those published earlier for the same compounds acting as solvents.6 (a) We had previously used p = 0.10 for chloro- and polychloroalkanes and -alkenes acting as solutes in the strong HBD solvent water (while continuing to use a p value of 0.00 for the same compounds acting as solvents). We now believe that aqueous solubilities, HPLC capacity factors, and solvent/water partition coefficients can be better calculated if we “fine tune” this parameter estimation rule by using p = 0.10 for chloro- and polychloroalkanes but /3 = 0.05 for chloro- and polychloroalkenes. This accords with our observation that a p value of 0.00 allows accurate predictions of aqueous solubilities and octanol/water partition coefficients of the higher polyhalobenzenes and polychlorinated biphenyls (vide infra). (b) We use p = 0.45 for ethyl acetate and higher alkyl alkanoates and p = 0.48 for ( 1 4) Hansch, C.; Leo, A . Substituent Constantsfor Correlation Analysis in Chemistry and Biology; Wiley-Interscience: New York, 1979.
+O.lO
+0.09
+0.08
n
r
SD
103 245 46 71 71 174
0.9915 0.9959 0.9960 0.9967 0.9916 0.9944
0.17 0.131 0.132 0.1 17 0.121 0.129
acetone and higher acyclic ketones, while A* is taken as 0.55 for the C4esters and 0.67 for the C4 ketone, with 0.02 subtracted from A* for each additional methylene group. The only major change from earlier published values6 is that this parameter estimation rule assigns a T* value of 0.51 rather than 0.46 to butyl acetate. (c) Similarly, we arrive at A* = 0.84 for diethylacetamide by subtracting 0.04 from the value for dimethylacetamide. The multiple linear regression equation for this subset is given by eq 6, which corresponds to eq 3 of Table I. It is seen that log Ko,(non-HBD aliphatics) = (0.40 f 0.10) + (5.41 f 0.16)V1/100 - (1.29 f 0 . 0 5 ) ~ * (0.42 f 0.12)6 - (3.83 f 0.12)p (6)
+
n = 46, r = 0.9960, S D = 0.132
intercept and coefficients of the independent variables for the subset agree quite well with the corresponding terms for the full data set. It may be noted in Table I1 that log KO, values for n-heptane and n-octane differ from eq 5 by more than 2 standard deviations. Interestingly, these same compounds were less soluble in water than predicted by eq 2, with the -A log S, values being nearly the same as the A log KO, values. HBD Aliphatic Solutes. We have noted earlierI5 that a A* value of 0.40 for all alkanol solutes and p, values of 0.42 for methanol, 0.45 for all other primary alkanols, 0.51 for all secondary alkanols, and 0.57 for all tertiary alkanols allowed highly accurate predictions of aqueous solubilities by eq 2. [These values also accorded well with p, results determined by Abboud and co-workers16 for methanol, ethanol, isopropyl alcohol, and tertbutyl alcohol from formation constants of hydrogen-bonded complexes with 3,4-dinitrophenol.l We have similarly found that a p value of 0.45 for aliphatic carboxylic acids from Cz to Cloleads to highly accurate predictions of log KO,. We have taken a A* value of 0.60 for acetic acid from a **/dipole moment correlation for aliphatic compounds, A* = 0.03 + 0.2311, and assumed that methylene group decrements to A* for the carboxylic acids were similar to those for esters and ketones. Values of a, are relative to values of 0.33 for primary alkanols and 0.61 for phenol and were determined from equations relating solvent/water partition coefficients of HBD solutes to solvatochromic parameters of the solvents (i.e., the greater the response to solvent HBA basicity, the greater the HBD acidity of the solute). The values in this paper are to be regarded as preliminary and will undoubtedly be changed somewhat in the forthcoming definitive report on a “monomer” scale of HBD acidity of 0-H, N-H, S-H, and C-H hydrogen bond donors. However, since the dependence of log KO, on a, is small, changes in the amscale will not materially affect the results reported here. When the results in Tables I1 and 111 are combined, the LSER for non-HBD and HBD aliphatic solutes is given by eq 7, which log K,,(aliphatics) = (0.38 f 0.06) + (5.42 f O.O8)V1/100 - (1.28 f 0 . 0 7 ) ~ *+ (0.42 f 0.1 1)6 - (3.85 f 0.lO)P + (0.09f 0 . 0 7 ) ~(7) ~~ n = 71, r = 0.9967, S D = 0.117 (15) Kamlet, M. J.; Doherty, R. M.; Abboud, J.-L. M.; Abraham, M. H.; Taft. R. W. J . Pharm. Sci. 1986. 75. 338. (16) Abboud, J.-L. M.; Sraidi,’L.; Guiheneuf, G.; Kamlet, M. J.; Taft, R. W. J . Org. Chem. 1985, 50, 2870. (17) Abraham, M. H.; et al., unpublished information.
The Journal of Physical Chemistry, Vol. 92, No. 18. 1988 5247
Linear Solvation Energy Relationships
TABLE 11: Octanol/Water Partition Coefficients of Non-HBD Aliphatic Solutes 1%
solute
no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. c
VI/ 100
n*
0.553 0.648 0.745 0.842 0.500 0.598 0.428 0.336 0.427 0.514 0.455 0.406 0.578 0.492 0.519 0.442 0.617 0.700 0.450 0.548 0.433 0.704 0.985 0.505 0.699 0.699 0.424 0.521 0.622 0.716 0.622 0.521 0.27 1 0.369 0.380 0.477 0.574 0.670 0.767 0.619 0.480 0.674 0.466 0.543 0.444 0.737
-0.08 -0.04 -0.02 0.01 -0.01 0 0.08 0.82 0.58 0.28 (0.22)C 0.44 0.28 0.53 0.49 0.8 1 0.95 0.62 0.39 0.39 0.16 0.14 0.14 0.27 0.27 0.27 0.60 0.55 0.53 0.51 0.53 0.60 0.75 0.70 0.71 0.67 0.65 0.63 0.61 0.76 0.63 0.63 1.oo 0.88 0.88 0.84
corresponds to eq 4 of Table I. It is seen that the equation is quite "robust" (Le,, negligible change from eq 6 ) and that the term in a,,,, although not statistically significant at the 95% confidence level for this subset, agrees quite well with eq 5. We must admit that we had expected the HBD subset to be more difficult to fit to the partition equations. This is because these amphi-hydrogen bonding compounds are subject to type AB hydrogen bonding, wherein the solute acts simultaneously as HB Jo..mH\O-solvent
\
**
0--"
type A B
0 0 0 0 0 0 0 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Kow
P
am
exptl
eq 5
difPSb
0 0 0 0 0 0 0.07 0.10 0.10 0.10 0.10 0.05c 0.05' 0.05' 0.10
0 0 0 0 0 0 0 0.13 0.20 0 0 0 0 0 0 0
3.39 3.90 4.66 5.18 3.00 3.44 2.40 1.15 1.94 2.63 2.53 2.09 2.88 2.35 2.49 1.48 2.39 3.05 2.04 2.64 0.22 1.36 2.79 0.89 2.03 2.03 0.18 0.73 1.24 1.82 1.21 0.83 -0.34 0.10 -0.24 0.29 0.91 1.38 1.98 0.81 0.88 1.78 -1.35 -0.77 -1.01 0.34
3.33 3.80 4.30 4.79 2.98 3.50 2.23 1.07 1.80 2.55 2.29 2.00 3.08 2.21 2.36 1.63 2.43 3.20 1.93 2.46 -0.06 1.18 2.77 0.91 1.99 1.95 0.34 0.80 1.36 1.88 1.36 1.02 -0.18 0.37 -0.23 0.33 0.87 1.40 1.94 0.81 0.65 1.69 -1.20 -0.61 -0.87 0.39
+0.06 +0.10 +0.36** +0.39** +0.02 -0.05 +0.17* +0.08 +0.14* +0.08 +0.24* +0.09 -0.20* -0.02 +O. 13 -0.15* -0.04 -0.15* +0.11 +0.18* +0.28** +0.18* +0.02 -0.02 +0.04 +0.08 -0.16* -0.07 -0.12 -0.06 -0.15* -0.19* -0.16* -0.27' -0.01 -0.04 +0.04 -0.02 +0.04 0.00 +0.23* +0.09 -0.15* -0.16* -0.14* -0.05
0.10 0.10 0.10 0.10 0.10 0.65 0.71 0.69 0.47 0.46 0.47 0.42 0.45 0.45 0.45 0.45 0.38 0.31 0.31 0.48 0.48 0.48 0.48 0.48 0.53 0.41 0.41 0.76 0.76 0.69 0.78
0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0.09 0 0.04 0.03 0 0 0 0 0 0 0 0 0 0
asterisk denotes a difference by more than 1 standard deviation; two asterisks, two standard deviations.
Experimental minus calculated. See tdxt .
CHa-C
6
hydrogen bonding of carboxylic acid
donor and H B acceptor in a probably cyclic H B complex. We had expected that free energies of type AB hydrogen bonding would differ significantly from summations of type A effects (solvent donor/solute acceptor) and type B effects (solute donor/solvent acceptor). All of the above notwithstanding, however, the alcohols and carboxylic acids fit eq 5 quite well. The average difference between observed and calculated log K , values for the compounds of Table 111 is 0.124 log unit, and the largest difference is 0.19 log unit.
We would not be surprised if these results proved to be fortuitous consequences of compensating errors. Aromatic Non-HBD Solutes. Data and parameters for 12 non-HBD aromatic solutes are assembled in Table IV. 1/1/100 values for most of the monosubstituted benzene derivatives are computer-calculated results of Leahy? with simple additivity rules giving VI/ 100 for the polysubstituted benzenes. The most useful of these rules is to add 0.098 to VI/lOO for replacement of H by CH3 or insertion of CH2 into a side chain, 0.090 for replacement of H by C1, 0.133 for Br, and 0.140 for NO2. Additional parameter estimation rules for the compounds of Table IV are as follows: (a) For most of the monosubstituted benzene derivatives, the solute n* values are the same as those reported earlier6 for the same compounds acting as solvents. (b) For replacement of H by C H 3 on a ring, subtract 0.04 from n*; for replacement on a side chain, subtract 0.02. (c) For first through third C H 3 on a ring add 0.01 to @; for fourth through sixth, add 0.02; add 0.01 to @ for first methyl ethyl, but nothing for further side-chain enlargement. (d) For two dipolar ortho substituents, add 0.10 to the higher n* of monosubstituted derivatives; for two meta substituents, add 0.05 to n*; for para substituents, add 0.00 to n*,e.g., ?r* of 4-chlorophenol is the same as that for phenol, and 4-bromophenol is the same as that for
-
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The Journal of Physical Chemistry, Vol. 92, No. 18, 1988
Kamlet et al.
TABLE 111: Octanol/Water Partition Coefficients of Aliphatic Hydrogen Bond Donor Solutes
solute
no. 1. 2. 3.
4. 5. 6. I. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
CH,OH C~H~OH n-CSH70H 2-CSH70H n-CdH90H 2-CH3-1-C3H,0H 2-CdH90H (CH~)SCOH n-CSHIIOH 2-CH3-1-C4H90H 3-CH3-1-C,H90H 2-CSHIiOH 3-CSHllOH CH$H*C(CH3)20H 1-C6H130H l-Ci2HzsOH
cyclohexanol CH2=CH-CH20H HCOOH CH3COOH CZHSCOOH n-CjH7COOH wC~H~COOH n-CSHilCOOH n-CgHl9COOH
V I /100
K*
6
P
0.205 0.305 0.402 0.402 0.499 0.499 0.500 0.499 0.593 0.593 0.593 0.593 0.593 0.593 0.690 1.278 0.636 0.372 0.224 0.323 0.421 0.519 0.617 0.7 15 1.107
0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.42 0.45 0.40 0.65 0.60 0.58 0.56 0.54 0.52 0.42
0 0 0 0 0 0 0 0 0 0
0.42 0.45 0.45 0.51 0.45 0.45 0.5 1 0.57 0.45 0.45 0.45 0.5 1 0.51 0.57 0.45 0.45 0.51 0.43 0.38 0.45 0.45 0.45 0.45 0.45 0.45
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
%l
0.35 0.33 0.33 0.31 0.33 0.33 0.31 0.32 0.33 0.33 0.33 0.31 0.3 1 0.32 0.33 0.33 0.31 0.33 0.65 0.56 0.56 0.56 0.56 0.55 0.55
1% exptl -0.70 -0.25 0.28 0.13 0.75 0.75 0.7 1 0.36 1.40 1.29 1.42 1.34 1.29 0.93 2.03 5.13 1.23 0.17 -0.54 -0.24 0.30 0.79 1.39 1.90 4.09
KO,
eq 5 -0.58 -0.16 0.36 0.12 0.88 0.88 0.64 0.41 1.36 1.38 1.38 1.15 1.15 0.91 1.90 5.13 1.33 0.28 -0.47 -0.21 0.32 0.86 1.41 1.95 4.15
diffa-b -0.12 -0.09 -0.08 +0.01 -0.13 -0.13 +0.07 -0.05 +0.04 -0.09 +0.04 +0.19* +0.15* +0.02 +O. 13 0.00 -0.10 -0.1 1 -0.07 -0.03 -0.02 -0.07 -0.02 -0.05 -0.06
",*Sameas in Table 11. bromobenzene. (e) For substituents that are strong a-electron donors to the ring (NMe2, NH2, OH, OCHJ, assume multiple hydrogen bonding effects at substituent and ring and add 0.10 to the solvent @ value for additional hydrogen bonding to ring, e.g., p = 0.33 for dimethylaniline solvent but 0.43 for dimethylaniline solute. (f) For addition of chlorine or bromine to halobenzene, alkylbenzene, or a benzene ring containing an electron-withdrawing substituent, subtract 0.04 from @; for addition of fluorine, subtract 0.02. (8) For addition of chlorine or bromine to a ring containing a strong electron-donor substituent or where the ring had been a second site of hydrogen bonding, subtract 0.10 from 0;for addition of fluorine, subtract 0.05. (h) For biphenyl derivatives and for benzyl benzoate, calculate a* and p separately for each ring and use Ea*,Cb, and C/3. It should be noted that these parameter estimation rules were not set forth specifically to calculate log KO, values but have served for the correlation and prediction of aqueous solubility (by eq 2), a large amount of HPLC data, and other solvent/water partition coefficients. An important monosubstituted benzene whose solvatochromic parameters have not been reported earlier is aniline. We have estimated a* = 0.73 from the **/dipole moment relationship for aromatic compounds, a * = 0.56 + 0 . 1 1 ~ . The 0 value was back-calculated from a large number of HPLC correlations involving a variety of stationary phases and methanol/water, acetonitrile/water, and tetrahydrofuran/water mobile phases. At high water concentrations, these correlations showed important dependences on 0 and easily calculable VI/ 100 and only minor dependences on r* and a,, so that uncertainties in the estimates of the latter parameters did not materially influence the backcalculated & values, which were averaged to obtain p = 0.50 for aniline (for hydrogen bonding to amine and the ring). This value, with the parameter estimation rules, gave us access to results for 14 aminobenzene and aminobiphenyl derivatives (compounds 59-72 of Table IV), which are seen to fit eq 5 quite well. The multiple linear regression equation for the 72 data points in Table VI is given by eq 8 (eq 5 of Table I), which is seen to
+
log S,(non-HBD aromatics) = (0.15 -+ 0.10) (5.30 & O . ~ ~ ) V ' I / ~ O- O (0.69 f 0 . 1 0 ) ~ *+ (0.26 f 0.1O)b - (3.78 f 0 . l l ) p (8) n = 72, r = 0.9916, S D = 0.121
agree quite well with eq 6 and 7 insofar as the coefficients of VI/100 and /3 are concerned but somewhat less well insofar as the coefficient of a * is concerned. Compounds with Aliphatic and Aromatic Moieties. The next group of data to be examined is for compounds wherein the main HBA site is on an aliphatic side chain and is separated from the ring by one or more methylene groups or oxygen. Here the parameter estimation rule is to estimate a* and /3 separately for the ring and side chain (Le., the ring where H replaces the side chain and the side chain where H replaces the ring) and use E a * , 6 = 1.00, and C/3 in the correlation. Thus, for example, for phenylacetonitrile, we add a* = 0.75 and p = 0.31 for acetonitrile to a * = 0.59, 6 = 1.00, and p = 0.10 for benzene. For ethyl 3-phenylpropionate, we add a* = 0.53 and j3 = 0.45 for ethyl propionate to a* = 0.59, b = 1.00, and 0 = 0.10 for benzene. We do not use the increment of 0.10 to 0 for hydrogen bonding to the ring if the ring is a third hydrogen bonding site. Thus, for N,N-dimethylphenoxyacetamide,we add a* = 0.88 and /3 = 0.76 for N,N-dimethylacetamide to a* = 0.72, 6 = 1.OO, and /3 = 0.23 (not 0.33) for phenol. The data for this subset are assembled in Table V, where it is seen that these simple parameter estimation rules accommodate the experimental results about as well as was observed for the less complex solutes. Aromatic HBD Solutes. The next subset of the,data to be considered are for the aromatic hydrogen bond donor solutes. Results for 32 derivatives of phenol, benzoic acid, phenylalkanoic acids, and phenylalkanols are assembled in Table VI. The a * values of phenol and benzoic acid were estimated from the a*/ dipole moment relationship; the 6 values were back-calculated from HPLC correlation equations (which gave a phenol value similar to that for anisole and a benzoic acid value similar to that for methyl benzoate, as earlier they had given an acetic acid value similar to that for ethyl acetate); the a, values were estimated from solvent/water partition coefficients, as will be discussed in detail in future papers. The a* and /3 values of benzyl alcohol are summations of those for benzene and methanol; the values for phenylacetic acid are summations of those for benzene and acetic acid, and in both series 0.02 is subtracted from a* for each side-chain methylene group. For substitution by chlorine or bromine, 0.10 is subtracted from fl of the phenols, phenylalkanols, and phenylacetic acids (since of the parent compounds had included increments of 0.10 for hydrogen bonding to the rings), and 0.04 is subtracted for the benzoic acid derivatives.
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988 5249
Linear Solvation Energy Relationships
TABLE I V Octanol/Water Partition Coefficients of Non-HBD Aromatic Solutes
no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.
compound
v,/100
T*
d
P
0.491 0.592 0.668 0.668 0.668 0.668 0.769 0.769 0.769 0.867 0.867 0.867 0.867 0.867 0.867 0.965 1.063 0.690 0.606 0.631 0.639 0.727 0.824 0.834 0.736 0.590 0.520 0.581 0.624 0.671 0.775 1.139 0.721 0.721 0.721 0.764 0.764 0.764 0.729 0.720 0.728 0.728 0.728 0.780 0.780 0.824 0.721 0.788 0.788 0.679 0.679 0.679 0.834 0.562 0.758 0.752 0.948 0.850 0.660 0.660 0.660 0.652 0.652 0.653 0.695 0.659 0.659 0.591 0.591 0.591 0.99 1 1.062
0.59 0.55 0.51 0.51 0.51 0.53 0.47 0.51 0.5 1 0.43 0.43 0.43 0.49 0.49 0.47 0.39 0.35 0.90 0.92 1.01 0.73 0.69 0.67 0.74 0.75 0.90 0.62 0.71 0.79 0.81 0.88 1.32‘ 1.11 1.06 1.01 1.06 1.01 0.97 0.97 0.73 0.69 0.69 0.69 0.95 0.90 0.90 0.90 0.86 0.88 0.67 0.67 0.67 0.71 0.73 0.82 0.90 0.86 0.86 0.69 0.69 0.69 0.83 0.78 0.73 0.89 0.84 0.79 0.83 0.78 0.73 1.32‘ 1.4@
1.oo 1.oo 1 .oo 1 .oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 2.00e 1.oo 1.oo 1 .oo 1.oo 1 .oo 1 .oo 1.oo 1 .oo 1.oo 1 .oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1.oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1.oo 1 .oo I .oo 1 .oo 1 .oo 1.oo 1.oo
0.10 0.11 0.12 0.12 0.12 0.12 0.13 0.12 0.12 0.1 SC 0.1 5c 0.15c 0.12 0.12 0.13 0.1 7c 0.19c 0.49 0.44 0.30 0.32d 0.30d 0.30d 0.41 0.39 0.37 0.07 0.07 0.06 0.05 0.49 0.50d 0.26 0.26 0.26 0.26 0.26 0.3 1 0.3 1 0.22 0.33 0.33 0.33 0.45 0.45 0.45 0.47 0.50 0.49 0.08 0.08 0.08 0.40 0.50d 0.47d 0.43d 0.43d 0.44d 0Sld 0.51d 0.51d 0.40 0.40 0.40 0.40 0.40 0.40 0.45 0.45 0.45 0.60d
1 .oo
1.oo 1.oo 1 .oo 1 .oo 2.00‘ 2.00e
1 .OOd
exptl
eq 5
difPVb
0 0 0 0.06 0.06 0.06 0.06 0 0 0 0 0 0 0.26 0.17 0 0 0 0 0 0 0.25 0.3 1 0.3 1 0.25
2.13 2.69 3.12 3.20 3.15 3.15 3.84 3.66 3.68 4.11 4.17 4.00 4.26 4.1 1 4.10 4.56 5.1 1 1.58 1.48 1.85 2.1 1 2.51 3.18 2.64 2.16 1.56 2.27 2.84 2.99 3.25 2.20 3.97 2.24 2.46 2.41 2.64 2.55 2.45 2.45 2.82 2.74 2.66 2.66 2.51 2.35 2.43 1.72 2.19 2.20 3.42 3.28 3.33 2.75 0.90 2.16 2.28 3.31 2.61 1.35 1.41 1.40 1.91 1.99 1.83 2.11
-0.15* -0.13 -0.10 -0.02 -0.07 -0.06 +0.07 -0.11 -0.09 -0.15 -0.08 -0.26* -0.06 -0.21* -0.20* -0.19* -0.13 +0.04 +0.23* +0.01 +0.08 -0.16* -0.03 -0.13 -0.23* +0.10 -0.25 +0.07 +0.04 +0.03 +0.19* +0.16* -0.13 +0.03 -0.07 -0.02 -0.16* +0.08 +0.08 -0.02 +0.18* +0.10 +0.10 +0.40** +0.18* +0.02 -0.06 +0.03 +o. 12 +0.14 0.00 +0.05 -0.09 -0.08 +0.10 +O. 19* +0.12 -0.01 -0.16* -0.10 -0.11 +0.15* +0.18* -0.03 +O. 18
0.31
2.10
0.31 0.28 0.28 0.28 0.26 0.62e
2.05 1.26 1.30 1.15 2.84 1.34
2.28 2.82 3.22 3.22 3.22 3.21 3.77 3.77 3.77 4.26 4.26 4.26 4.32 4.32 4.30 4.75 5.24 1.54 1.25 1.84 2.03 2.67 3.21 2.77 2.39 1.46 2.52 2.77 2.95 3.22 2.01 3.81 2.37 2.43 2.48 2.66 2.71 2.37 2.37 2.84 2.56 2.56 2.56 2.11 2.17 2.41 1.78 2.06 2.08 3.28 3.28 3.28 2.84 0.98 2.06 2.09 3.19 2.62 1.51 1.51 1.51 1.76 1.81 1.86 1.93 1.98 2.03 1.23 1.28 1.33 2.64 1.34
urn
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0.04 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
+o. 12
+0.02 +0.03 +0.02 -0.18* +0.20* 0.00
“VbSameas in Table 11. ‘New parameter estimation rule: add 0.02 to p for third, fourth, fifth, and sixth CH3 group on ring. dIncludes increment of 0.10 for second hydrogen bond to aromatic ring. eThese are ET*, E&and Camvalues.
5250
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988
Kamlet et ai.
TABLE V: Octanol/Water Partition Coefficients of Compounds with Aliphatic and Aromatic HBA Sites log K,,
no. 1. 2. 3. 4. 5.
compound CnH,CH,CN C,H;CH;CH,CN C~HSCH~-CO-CH~ C6HsCH2-O-CO-CH3 C6HSCH2CH2-O-CO-CH3 C~HSCH~CH~CH~-O-CO-CH~ C~HSCH~CO-OCH~ C6HSCH2CH2CO-OC2HS C~HSCH~CH~CHZ-CO-CH~ C~HSCH~CH~CH~OCH~ C~HSOCH~COOC~HS C~HSOCH~CON(CH~)~ C~HSCH~N(CH~)~ C~HS-O-CO-CH, 2-CH3C6H4-O-CO-CH3 ~-CHSC~H~-O-CO-CH~ 4-C H 3C6H4-O-CO-C H 3 2-C1C6H4-O-CO-CH3 3-CIC6H4-O-CO-CH3 4-C1C6H4-O-CO-CH3 4-FC6H4-O-CO-CH3 2-BrC6H4-O-CO-CH3
6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22
osbSameas
in
Table 11. CTheseare
)37r*
and
v1j10o
7r*c
0.688 0.786 0.788 0.826 0.918 1.016 0.826 1.039 0.984 0.914 0.864 1.027 0.855 0.736 0.834 0.834 0.834 0.826 0.826 0.826 0.767 0.869
1.34 1.29 1.30 1.19 1.14 1.12 1.19 1.12 1.22 0.86 1.21 1.60 0.75 1.14 1.10 1.10 1.10 1.24 1.19 1.14 1.14 1.24
6 1.00
1.oo 1 .oo 1 .oo 1 .oo
1.oo 1 .oo 1 .oo 1 .oo 1 .oo 1.oo 1 .oo 1.oo 1 .oo 1.oo 1.oo 1 .oo
I .oo 1 .oo
1 .oo 1 .oo
1 .00
p’
am
0.41 0.41 0.58 0.52 0.55 0.55 0.52 0.55 0.58 0.56 0.68 0.99 0.67 0.52 0.53 0.53 0.53 0.42 0.42 0.42 0.47 0.42
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
exptl 1.56 1.69 1.44 1.92 2.30 2.57 1.83 2.73 2.42 2.70 1.41 0.77 1.91 1.49 1.93 2.09 2.11 2.18 2.32 2.01 1.74 2.20
eq 5 1.39 1.97 1.32 1.86 2.28 2.83 1.86 2.95 2.44 2.50 1.39 0.70 1.87 1.50 1.95 1.95 1.95 2.19 2.24 2.29 1.78 2.42
diffatb +0.17* -0.28** +o. 12 +0.06 +0.02 -0.26* -0.03 -0.22 -0.02 +0.20* +0.02 +0.07 +0.04 -0.01 -0.02 -0.14* -0.16* -0.01 +0.08 -0.28** -0.04 -0.22*
eq 5 1.59 2.44 2.47 2.58 2.63 2.11 2.11 1.93 2.46 2.46 2.53 2.58 2.71 2.76 1.42 1.94 2.16 2.16 2.31 2.31 1.72 1.72 1.72 1.96 2.51 1.08 1.60 1.60 1.81 1.81 1.51
diffaib -0.10 +0.05 -0.02 +0.05 -0.04 -0.15* -0.17* +0.02 -0.09 -0.19* +0.15 +0.07 +0.16*
2.05
-0.17.
ZP values.
TABLE VI: Octanol/Water Partition Coefficients of Aromatic Hydrogen Bond Donor Solutes no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
compound
V,jlOO 0.536 0.626 0.626 0.669 0.669 0.634 0.634 0.650 0.748 0.748 0.740 0.740 0.783 0.783 0.748 0.846 0.838 0.838 0.881 0.881 0.777 0.777 0.777 0.846 0.944 0.634 0.732 0.732 0.724 0.724 0.732 0.830
OBbSarne as in Table 11. ‘These and following are
E a * and
7r*
6
P
am
0.72 0.77 0.72 0.84 0.79 0.68 0.68 0.74 0.70 0.70 0.79 0.74 0.84 0.79 1.19c 1.15 1.31 1.31 1.39 1.39 1.22 1.22 1.22 1.17 1.15 0.99 0.95 0.93 1.11 1.11 0.97 0.95
1.oo
0.33 0.23 0.23 0.23 0.23 0.34 0.34 0.40 0.4 1 0.41 0.36 0.36 0.36 0.36 0.55‘ 0.56 0.45 0.45 0.45 0.45 0.50 0.50 0.50 0.55 0.55 0.52 0.53 0.53 0.42 0.42 0.55 0.55
0.61 0.69 0.67 0.69 0.67 0.58 0.58 0.59 0.59 0.59 0.64 0.63 0.63 0.63 0.60 0.60 0.62 0.62 0.62 0.62 0.62 0.62 0.62 0.55 0.55 0.39 0.39 0.39 0.40 0.40 0.33 0.33
I .oo 1 .oo 1 .oo 1 .oo 1 .oo
I .oo
1.oo 1 .oo
1 .oo
1 .oo 1 .oo I .oo 1
.oo
1 .oo 1.oo 1.oo 1 .oo 1 .oo 1.oo 1 .oo 1
.oo
1 .oo 1 .oo 1 .oo 1 .oo 1.00 1 .oo 1 .oo 1 .oo 1 .oo 1 .00
1% exptl 1.49 2.49 2.45 2.63 2.59 1.96 1.94 1.95 2.37 2.27 2.68 2.65 2.87 2.86 1.46 1.86 2.09 2.12 2.37 2.31 1.50 1.55 1.65 1.84 2.42 1.08 1.58 1.59 1.94 1.96 1.36 1.88
Kow
+0.10
+0.04 -0.12 -0.07 -0.04 +0.06 0.00 -0.22* -0.17* -0.07 -0.12 -0.09 0.00 -0.02 -0.01 +O. 13 +0.15* -0.15*
values
It is seen in T a b l e VI t h a t as with t h e earlier series, these parameter estimation rules accommodate t h e experimental results quite well. Experimentally determined solvatochromic parameters for benzene, methanol, acetic acid, phenol, and benzoic acid, taken with t h e p a r a m e t e r estimation rules, allow t h e successful correlation of all 32 sets of d a t a . Polyhalobenzene and Polychlorinated Biphenyls. W e next direct our attention t o a number of polyhalobenzenes a n d polychlorinated biphenyls (PCBs), which have been of considerable interest t o t h e environmental communitv because of their bioaccumulation a n d toxicity properties. Because of uncertainties
resulting from t h e extreme difficulty of measuring octanol/water partition coefficients higher t h a n 6.0, we have restricted o u r correlations to compounds with reported log KOwvalues lower than 6.0. D a t a for 13 polyhalobenzenes, biphenyl, 10 PCBs, a n d bibenzyl a r e assembled in T a b l e VII. T h e polyhalobenzene results are those reported by Miller and co-workers,Is and the PCB results a r e t h e “selected” experimental values reported by S h i u a n d Mackay.I9 (18) Miller, M. M.; Wasik, S. P.; Huang, G.-L.; Shiu, W.-Y.; Mackay, D. Enuiron Sci. Technol. 1985, 19, 522.
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988 5251
Linear Solvation Energy Relationships
TABLE VII: Octanol/Water Partition Coefficients of Polyhalobenzenes and Polychlorinated Biphenyls
no.
compound
VI/ 100 0.67 1 0.67 1 0.67 1 0.761 0.761 0.761 0.851 0.851 0.851 0.941 1.03 1 0.758 0.758 0.920 1.010 1.100 1.100 1.190 1.190 1.280 1.280 1.116
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
ff*
0.80 0.75 0.70 0.85 0.75 0.70 0.80 0.80 0.70 0.75 0.70 0.89 0.79 1.18 1.30 1.30 1.35 1.34 1.29 1.39 1.46 1.10
6 1.oo 1 .oo 1 .oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00
P 0.03 0.03 0.03 0 0 0 0 0 0 0 0 0.02 0.02 0.20 0.17 0.13 0.13 0.10 0.10 0.10 0.07 0.22
am
exptl
0
3.28 3.48 3.38 4.04 3.98 4.02 4.55 4.65 4.5 1 5.03 5.31 3.75 3.64 3.90 4.30 5.10 5.00 5.60 5.50 5.91 5.99 4.80
0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
eq 5 3.30 3.35 3.40 3.85 3.95 4.00 4.39 4.39 4.49 4.92 5.45 3.72 3.82 3.94 4.41 5.05 5.00 5.61 5.66 6.04 6.09 4.99
difP*b -0.02 +O. 13 -0.02 +0.19 +0.03 +0.02 +0.16 +0.26* +0.02 +0.11 -0.08 +0.03 -0.18* -0.04 -0.11 +0.05 0.00 -0.01 -0.16* -0.13 -0.10 -0.19*
‘VbSarne as in Table 11.
In accordance with earlier experimentally determined solvatochromic parameters and the parameter estimation rule for solutes containing two dipolar substituents, a* is 0.59 for benzene, 0.7 1 for chlorobenzene, 0.80 for 1,2-dichlorobenzene, 0.75 for 1,3dichlorobenzene, and 0.70 for 1,4-dichIorobenzene. For the higher polychlorobenzenes, we add 0.05 to a* if the next substituent increases the dipole moment and subtract 0.05 if it decreases the dipole moment. This gives us the following x* values: 1,2,3CsH3C13, 0.85; 1,2,4-C6HjC13, 0.75; 1,3,5-C6H3C13, 0.70; 1,2,3,4-C6H2C14, 0.80; 1,2,3,5-C6HzCld, 0.80; 1,2,4,5-C6HzC14, 0.70; C6HC15,0.75; c6c16,0.70. Values of are 0.10 for benzene, 0.07 for chlorobenzene, 0.03 for the dichlorobenzenes, and nil for higher polychlorobenzenes. The parameter estimation rules for the PCBs are quite simple. Use VI/lOO = 0.920 for biphenyl and add 0.090 for each chlorine. Calculate a* and for each ring and use Ea*,E6 = 2.00, and E/3(the same rule was applied to amino- and diaminobiphenyl in Table IV). As will be demonstrated in this and subsequent papers, this explicit and quite simple set of approximations allows us to predict the partition and solubility properties and many of the toxicity properties of all 209 possible PCBs, as well as large numbers of other substituted biphenyl derivatives (vide infra for comparison of observed with calculated log K, values of the higher PCBs). Note that these rules do not lead to the same /3 values when the halogens are on the same ring or distributed between the two rings. Thus, 0 = 0.10 for 2,3,4,5-C12H6C14,0.07 for the 2,2’,4,5 isomer, and 0.06 for the 3,3’,4,4’ isomer. Note also that there are decrements to /3 on addition of the first, second, and third halogens to the ring but not for the fourth, fifth, and sixth. This may be one of the reasons why other types of estimates based on simple additivity rules have broken down for the higher PCBS.~O Polycyclic Aromatic Hydrocarbons. The final subset of the data is for the polycyclic aromatic hydrocarbons (PAHs), also of considerable environmental interest because of their bioaccumulation properties. Here, as with the PCBs, we have included only the compounds with reported log KO,values lower than 6.0. Results for 26 such PAHs are assembled in Table VIII. Parameter estimation rules are as follows: (a) For fused rings, add 0.0655 to VI/lOO for each ring-CH and 0.0815 for ring-CH2. naphthalene, 0.373 for Hence we add 0.262 for benzene pyrene, and 0.163 for naphthalene acenaphthalene
-
-
-
(19) Shiu, W.-Y.;Mackay, D. J . Phys. Chem. Ref. Data 1986, 15, 911. (20) As an example, the Hansch-Leo C log P rnethodl4 usually overcah culates the octanol/water partition coefficients of the higher PCBs.
naphthene. (b) For naphthalene, x* = 0.70, and 6 = 0.15. For each additional fused ring, and 0.10 to a* and 0.05 to /3. Thus, for naphthalene dibenzanthracene, AT* = 0.30, and A0 = 0.15. (d) We use 6 = 1.OO for the entire PAH system but 6 = 2.00 for fluorene, which may be considered a biphenyl derivative. (d) For chloro and alkyl PAH derivatives, use the same increments and decrements as for the corresponding benzenes. (e) For HBA substituent on PAH, start with correspondingly substituted benzene; add 0.10 to x * , nothing to 0 for first additional fused ring, 0.10 to a*,and 0.05 to 0for further fused rings. Thus, for 1-nitroanthracene, a* = 1.21, and 0 = 0.35. As with the other subsets, it may be seen in Table VI11 that these parameter estimation rules accommodate the experimental results quite well. Those who are knowledgeable about such measurements will recognize that the precision of the calculation is better than the usual error in the measurement. The chemometricians have coined a term, “level of exhaustive fit“, which they define as the condition where the standard deviation of the correlation equation is better than the usual reproducibility of the measurement between data sources.2’ We believe that for the PAHs and PCBs in Tables VI1 and VIII, as for the other subsets in Tables 11-VI, we have reached the “level of exhaustive fit” in the prediction of octanol/water partition coefficients. As a final test of the correlations, we have carried out a further calculation for the subset comprising all mono- and polycyclic non-HB, HBA, and HBD compounds in Tables IV-VIII. The multiple linear regression equation for the 174 aromatic solutes is given by eq 9, which corresponds to eq 6 of Table I. The quite
-
log K,,(aromatics) = (0.31 f 0.06) (5.22 f 0.08)V1/100 - (0.91 f 0.06)a* (0.35 f 0.05)S - (3.87 f 0.07)p (0.08 f 0 . 0 4 ) ~(9) ~~
+
+
+
n = 174, r = 0.9944, S D = 0.129 good agreement between eq 7 for the 71 aliphatic solutes, eq 9 for the 174 aromatics, and eq 5 for the total data set indicates that we have achieved an equation for prediction of log K,,, which not only is precise and likely to be correct but also is “robust” (Le., additional data points are not likely to cause more than minimal changes). The minor differences in the s and d coefficients in eq 7 and 9 (eq 4 and 6 of Table I) are not surprising in light of the fact that d i n eq 7 is based on 6 = 0.50 for polychlorinated versus 0.00 for nonpolychlorinated aliphatics, whereas d i n eq 9 (21) Wold, S.; Sjostrom, M . Acfa Chem. Scand. Ser. B 1986, 40, 270.
5252 The Journal of Physical Chemistry, Vol. 92, No. 18, 1988
Kamlet et al.
TABLE VIII: Octanol/Water Partition Coefficients of Polvcvclic Aromatic ComDounds
no. 1. 2. 3. 4.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
compound naphthalene 1-methylnaphthalene 2-methylnaphthalene 1,3-dimethylnaphthalene 1,4-dimethyInaphthalene 1,5-dimethylnaphthalene 2,3-dimethylnaphthalene 2,6-dimethylnaphthalene 1-ethylnaphthalene
V,/lOO 0.753 0.851 0.851 0.949 0.949 0.949 0.949 0.949 0.949 1.047 0.960 0.916 1.015 1.015 1.058 1.156 1.418 1.105 1.277 1.113 0.893 0.9 12 0.798 0.978 0.824 0.824
1,4,5-trimethylnaphthalene fluorene acenaphthene phenanthrene anthracene I-methylfluorene pyrene 3,4-benzopyrene 2-chlorophenan threne benz[a]anthracene 2-methylphenanthrene 1-nitronaphthalene 1-naphthalenecarboxylic acid I-naphthol 2-naphthol 1-naphthylamine 2-naphthylamine
T*
6
R
am
0.70 0.66 0.66 0.62 0.62 0.62 0.62 0.62 0.64 0.58 1.18 0.66 0.80 0.80 1.14 0.90 1 .oo 0.91 0.90 0.76 1.11 0.84 0.82 0.82 0.83 0.83
1 1 1 .oo 1.oo
.oo .oo
0.15
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.59 0.61 0.61 0.3 1 0.35
1 .oo
.oo
1 1 .oo 1.oo 1.oo 1.oo
2.00 1.oo
.oo
1 1.oo
2.00
1.oo
1 .oo 1.00 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1 .oo
0.16 0.16 0.17 0.17 0.17 0.17 0.17 0.17 0.18 0.22 0.17 0.20 0.20 0.23 0.25 0.30 0.16 0.25 0.21 0.30 0.40 0.33 0.33 0.50 0.50
log KO, exDtl ea 5 3.35 3.87 3.86 4.42 4.37 4.38 4.40 4.31 4.39 4.90 4.18 3.92 4.57 4.54 4.97 5.18 5.98 5.16 5.61 4.86 3.19 3.10 2.91 2.81 2.24 2.28
3.38 3.91 3.91 4.43 4.43 4.43 4.43 4.43 4.41 4.96 4.07 4.22 4.49 4.49 4.60 4.96 6.07 5.02 5.61 5.02 3.14 3.24 2.90 2.90 2.28 2.28
difP,b -0.03 -0.04 -0.05 -0.01 -0.06 -0.05 -0.03 -0.12 -0.02 -0.06 +0.11 -0.30** +0.08 +0.05 +0.37** +0.22* -0.09 +O. 14* 0.00 -0.16* +0.05 -0.14* +O.lO -0.09 -0.04 0.00
a'bSame as in Table I1
TABLE IX: ,9, Values Back-Calculated from Solubilities and Solvent/Water Partition Coefficients of Pyridine Derivatives solvent solute pyridine 3-methylpyridine 4-methylpyridine quinoline isoquinoline 3-methylisoquinoline
Vl/lOO 0.470 0.568 0.568 0.732 0.732 0.830
aq solubility"
T*
6 value
0.87 0.84 0.84 0.92 0.92 0.88
0.64 0.67 0.67 0.64 0.64 0.65
pi
log S 0.47 -0.04
0.65 0.66
-1.30 -1.45 -2.19
0.58 0.55 0.61
diff +O.Ol -0.01
octanol/H20b log K 6, diff 0.65 0.42 -0.22 1.20 0.42 -0.25 1.22 0.42 -0.25
-0.06 -0.09 -0.04 av -0.038
log K 1.37 1.89 1.96
CHC13/H20C 6, diff 0.47 -0.17 0.48 -0.19 0.50 -0.17
-0.240
benzene/H20d
-0.177
CCIq'H2O'
solute
log K
6,
diff
log K
P,
pyridine 3-methylpyridine 4-methylpyridine
0.44 1.08 1.03
0.53 0.53 0.54
-0.1 1 -0.14 -0.13 av -0.127
0.33
0.44
-0.20
0.84
0.46
-0.21 -0.205
diff
+
"Equation 5. bEquation 3a. 'log K(CHCI,/H20) = 0.01 6.13V1/100 + 0 . 2 7 ~ *- 0.066 - 3.636 - 3.27am,n = 48, r = 0.9944, SD = 0.156. "log K(C,H,/H,O) = -0.01 6.23V1/100 - 0.18n* 0.246 - 4.796 - 2.73a,, n = 43, r = 0.9959, SD = 0.124. 'log K(CC14/H20) = 0.46 + 6.25V1/100 - 0 . 7 5 ~ . - 0.1 16 - 5.288 - 3.18am,n = 54, r = 0.9949, SD = 0.142.
+
+
is based on 6 = 2.00 for t h e PCBs versus 1.00 for t h e other a r o m a t i c solutes.
Solubilities and Solvent/ Water Partition Coefficients of Pyridine Derivatives. An i m p o r t a n t problem t h a t w e have not been a b l e t o resolve involves the pyridine and benzopyridine derivatives. As has been mentioned, the 0 values determined earlier6 for these compounds acting a s solvents serve reasonably well with eq 3a t o predict aqueous solubilities. However, these same p values lead t o serious underprediction of octanol/water a n d o t h e r solvent/water partition coefficients. O u r q u a n d a r y is illustrated in T a b l e IX, where w e have listed log aqueous solubilities and log octanol/water, chloroform/water, benzene/water, a n d c a r b o n tetrachloride/water partition coefficients for a n u m b e r of these compounds. T h e (preliminary) correlation equations for t h e other solvent/water partition coefficients a r e given in t h e footnotes t o T a b l e IX. F r o m e q 3a, e q 5 , a n d these o t h e r solvent/water partition equations, we have back-calculated a n d included in t h e table t h e individual pi values that would best accommodate these solubility and partition results. I t is seen t h a t t h e pyridine solvent p values accommodate t h e aqueous solubilities of t h e pyridine solutes reasonably well b u t
that significantly lower /3 values are required t o correctly predict t h e various solvent/water partition coefficients. I t is evident t h a t some solutesolvent interaction, which we have so far been unable t o identify, increases t h e free energies of transfer of t h e pyridine solutes from the organic solvents to water by the following amounts (in kcal/mol): octanol, 1.3; chloroform, 0.9; benzene, 0.8; carbon tetrachloride, 1.5. T h e good fit of t h e aqueous solubility results would a p p e a r t o suggest t h a t this additional solute-solvent interaction m u s t be in t h e organic phase, b u t we cannot exclude t h e possibility that compensating errors a r e giving us the ''correct'! aqueous solubility results. T h e octanol/water partition coefficients of t h e pyridine solutes c a n b e calculated by eq 5 if w e include t h e following among t h e parameter estimation rules: (a) Values of 0 for pyridine solutes a r e 0.20 unit less than corresponding values for pyridine solvents.22 (b) A d d 0.10 t o T * but nil to 0 for a n aromatic ring fused directly (22) This parameter estimation rule applies only to solvent/water partition properties and not to aqueous solubilities. Because we have been able to find good physicochemical justification for the other estimation rules but not for these dual solute R values, we are particularly uncomfortable with this rule.
Linear Solvation Energy Relationships
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988 5253
TABLE X Octanol/Water Partition Coefficients of Some Pyridine Derivatives
lop, K,, no. 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13.
solute pyridine 3-chloropyridine 4-chloropyridine 3-bromopyridine 4- bromopyridine 3-methylpyridine 4-methylpyridine quinoline isoquinoline 6-methylquinoline 7-methylquinoline 8-methylquinoline acridine
v*/100
lr*
6
0.470 0.560 0.560 0.603 0.603 0.568 0.568 0.732 0.732 0.830 0.830 0.830 0.994
0.87 0.92 0.87 0.92 0.87 0.84 0.84 0.92 0.92 0.88 0.88 0.88 1.02
1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo 1.oo
diffasb 0.44 0.53 0.53 0.51 0.51 0.47 0.47 0.44 0.44 0.45 0.45 0.45 0.44
0 0 0 0 0 0 0 0 0 0 0 0 0
0.65 1.33 1.28 1.60 1.54 1.20 1.22 2.03 2.08 2.57 2.47 2.60 3.40
0.58 1.43 1.48 1.74 1.78 1.02 1.02 1.92 1.92 2.45 2.45 2.45 3.22
+0.07 -0.10 -0.20* -0.14* -0.28* +0.18* +0.20* +0.11 +0.16* +0.12 +0.02 +0.15* +0.18*
'qbSame as in Table 11. CTheseare solvent 0 values minus 0.20. TABLE XI: Aqueous Solubilities and Solvent/Water Partition Coefficients of Some Primary and Secondary Amines octanol/H20a aq solubility* CHC13/H20C solute V~/100 A* 0 log K calcd diff log S calcd diff log K calcd diff C2HS"2 0.335 0.32 0.70 -0.13 -0.90 +0.77 2.06 2.10 -0.04 -0.35 -0.38 +0.03 n-CaH7NH2 0.433 0.31 0.69 0.48 -0.34 +0.82 1.52 1.47 +0.05 0.26 0.25 +0.01 n-CIHgNH2 0.535 0.31 0.69 0.86 0.21 +0.65 0.96 0.87 +0.09 0.99 0.87 +0.12 n-C5HIINH2 0.633 0.31 0.69 1.49 0.74 +0.75 0.27 0.27 0.00 n-CbHI3NH2 0.729 0.31 0.69 2.04 1.25 +0.79 -0.25 -0.28 +0.03 av +0.76 +0.03 +0.05
(C2H5)2NH (n-C3H7)2NH (n-CdHg)zNH
0.535 0.729 0.923
solute C,H,NH, n-C3H7~H2 n-CIHgNH2
0.25 0.25 0.25
0.70 0.70 0.70
log K
0.50 1.70 2.75
0.23 1.27 2.31
benzene/HzOd calcd
0.03
-0.04
+0.27 +0.43 +0.44 av +0.38
diff
+0.17
1.03 -0.54 -1.44
0.86 -0.28 -1.41
log K -1.27 -0.59 0.04
+0.17 -0.26 -0.03 -0.04
0.85
0.03
+0.03 +0.03
CCl,/H20' calcd -1.38 -0.7 1 -0.07
diff +0.11 +0.12 +0.11 +0.11
-0.09
+0.12
av +O. 17 +0.05 -0.10 av -0.03
0.82
+o. 12
"Equation 5. *Equation 2. e-eSameas in Table IX. to a pyridine ring. log KO, values calculated from these and earlier estimation rules and eq 5 are compared in Table X. Primary and Secondary Aliphatic Amines. A Special Case. Unlike aromatic amines, which fit eq 5 quite well (Table IV), primary and secondary aliphatic amines comprise another family of compounds whose octanol/water partition coefficients are not correctly predicted by eq 5 if we use earlier determined6 solvatochromic parameters. Here, however, it is possible to identify the additional effect as one that is due to a specific type of solute-solvent interaction in the octanol phase. Observed and calculated log KO,values for some R N H z and R2NH compounds are compared in Table XI, together with corresponding observed and calculated aqueous solubilities and CHC13/H20,C6H6/H20,and CC14/H20partition coefficients. It is seen that the experimental aqueous solubilities and the other solvent/water partition coefficients agree quite well with the calculations. Average differences between observed and calculated values for the primary and secondary amines were as follows: log S,, +0.03, -0.04; log K(CHC13/H20), +0.05, -0.03; log K(C6H,j/H20), +0.17, -0.03; log K(CCl,/H20), +O.1 I , +O.12. By way of contrast, the observed log KO, values are on the average 0.76 log units higher than calculated for the primary amines and 0.38 log unit higher than calculated for the secondary amines. This means that some specific solute-solvent interaction in octanol but not in the other organic solvents favors free energy of transfer from water by 1.O kcal/mol for the RNH, compounds and 0.5 kcal/mol for the R z N H compounds. We suggest that
this interaction involves type AB hydrogen bonding between the aliphatic amines and octanol as represented here: pc t
\O C t type AB hydrogen bonding between aliphatic amine and octanol We also suggest that, for amphi-hydrogen bonding compounds to participate in type AB hydrogen bonding, they must fall within certain ranges of H B acidity and basicity and possibly have a certain type of hybridization on the amine nitrogen. It may be that aliphatic but not aromatic amines fit these requirements, and hence we see the effect in Table XI but not in Table IV. In the literature there are hundreds of correlations of log KO, with aqueous solubilities, HPLC capacity factors with all sorts of stationary and mobile phases, bioaccumulation and soil/water partition, and toxicities to many different kinds of organisms. If our equations, reasoning, and conclusions are correct, it must necessarily follow that these correlations will break down for the primary and secondary amines. Additional Out-of-Line Compounds. Octanol/water partition coefficients and aqueous solubility data for several additional compounds that do not fit eq 5 are assembled in Table XII. Considering first the nitroalkanes, it is seen that observed log KO, values are lower than predicted by an average of 0.60 log unit
5254
Kamlet et al.
The Journal of Physical Chemistry, Vol. 92, No. 18, 1988
TABLE XII: Some Additional Solutes Whose Octanol/Water Partition Coefficients Do Not Fit Eq 5 octanol/HzO calcd diff log K V*/lOO P no. solute a* 0.34 -0.68 0.25 -0.34 0.348 0.85 1. CHtNO, 0.18 0.90 -0.72 0.25 0.445 0.80 2. C2H5Nd, 0.87 1.43 -0.56 0.78 0.25 3. n-C,H,N02 0.543 1.47 1.99 -0.52 0.76 0.25 4. ~C4HgN02 0.641 2.01 2.51 -0.50 0.25 0.739 0.74 5. n-CSHIIN02 av -0.60 0.46 0.03 +0.43 0.58 0.55 6. tetrahydrofuran 0.455 0.51 0.54 7. tetrahydropyran 0.553
but that aqueous solubilities agree reasonably well with values calculated by eq 2. One of us, who spent many years as an explosives chemist (M.J.K.), is conditioned to attribute any aberrant behavior of nitromethane to the normal to aci tautomerism, and this may provide the explanation here:
Another compound that is out of line by more than 3 standard deviations of eq 2 is tetrahydrofuran, whose partition into water is less by 0.43 log unit than predicted by eq 5. This compound is also less soluble in water by about the same amount and has also been out of line in a number of HPLC and toxicological correlations. Here, we think either that our solvent p value may be incorrect or that the solvent 3( value does not, for some reason, apply to the solute. An important aspect of the types of correlations reported here and in earlier papers is that they often tell us more about the outliers than they do about the compounds that fit. The fact that we see similar aberrant behavior for five primary amines, three secondary amines, and five nitro compounds as concerns octanollwater partition and regular patterns of behavior in the other solvents is almost certain evidence that different types of solute-solvent interactions are taking place. We offer no apology for excluding the compounds of Tables XI and XI1 from the correlations of log KO, and caution the reader to be alert to the possibility of aberrant behavior of these compounds in other type correlations. Wold and Sjostrom have suggested that because we occasionally exclude outliers from our correlations, the LSERs should be regarded as “local empirical models of similarity” rather than fundamental laws of chemistry.*I We assert, on the other hand, that the ability to identify and (for good and sufficient reasons) exclude outliers from the correlations is a strength, rather than weakness, of our methodology. Concluding Comments Regarding the Parameter Estimation Rules. A perceptive referee has pointed out the following: “Using a rather complex set of (apparently empirical) rules, this paper proposes that when unmeasured solvatochromic parameters are encountered, they can be calculated from the original measured set. With so many “degrees of freedom” now at their disposal, it is small wonder that their calculations now appear more reliable than the data on which they are based. If a reasonable number of these “back-calculated’’ solvatochromic parameters are not verified by independent measurements, workers in this field may lose confidence in their validity”. On the expectation that the rarely encountered measures of goodness of fit in this, our other solvent/water partition, our aqueous solubility, and our HPLC correlations might cause other readers to share this opinion, we now feel it necessary to detail how the parameter estimation rules were arrived at. (a) The original set of solvatochromic parameters was mainly for liquid compounds and was derived mainly from solvent effect studies.6 (b) When it was found that the same parameters and methodology could be used to correlate solubilities and other properties of solutes, we began to assemble a data base of parameters for solid solutes. (c) We assembled a preliminary a , scale by correlating solvent/water partition coefficients (e.g. benzene/water, cyclohexane/water, diethyl ether/water, butyl acetate/water) for single solutes like phenol or benzoic acid ac-
aq solubility log S 0.20 -0.29 -0.80 -1.46
calcd 0.25 -0.37 -0.96 -1.55
0.48 -0.1 1
0.90 0.20
diff -0.05
+o. 12 +0.16 +0.09 av +0.10 -0.42 -0.31
TABLE XI11 4-NO2-C6H4-OH 4-NO2-CsH4-NHZ 4-HzN-C,H.+-COOCHp 4-HO-C,H,-COOH
V,/lOO
a*
0.676 0.702 0.807 0.695
1.15 1.25 1.00 1.00
a,
a,
0.32 0.82 0.48 0.42 0.58 0.25 0.58 (1.19)“
exDtl calcd 1.92 1.99 1.39 1.33 1.96 1.75 1.26 1.29
“This value is particularly uncertain, but since the a, term has so little influence on log KO,,it introduces only relatively minor uncertainties in the calculation.
cording to the equation: log K(solvent/water) = XYZo + sa* bp. The b Coefficientswere proportional to solute HBD acidity, and relative b values were used to set up a preliminary a, scale anchored at a, = 1.OO for 4-nitrophenol (this value has since been changed to 0.82). (d) pK, versus a, correlations were then used to expand the a , scale.23 (e) Values of s* for a number of solid solutes were arrived at from the following T* versus dipole moment relationships: r*(aliphatics) = 0.03 0.2311; **(polychlorinated ; = 0.56 + 0.1 lp. (f) aliphatics) = 0.27 0 . 3 5 ~**(aromatics) A number of p, values were estimated on the assumptions, later shown to be correct, that carboxylic acid HBA basicities were near to those of the corresponding esters, and phenol HBA basicities were near to those of the corresponding alkyl ethers. (These assumptions were based on our earlier observations that alcohol p, values are close to those of the corresponding dialkyl ethers.) (g) Using the parameters thus determined and those earlier available, we carried out correlations of aqueous solubility, octanol/water partition coefficients, 5 other sets of solvent/water partition coefficients, and about 20 sets of HPLC capacity factors using different mobile and stationary phases. (h) From these we back-calculated p, values for about 30 compounds, which allowed us to establish certain regularities, e.g., 4-chloro- and 4-bromophenol versus phenol, 4-chloro- and 4-bromoaniline versus aniline, 4-chloro- and 4-bromobenzoic acid versus benzoic acid, 4chloronitrobenzene versus nitrobenzene, phenanthrene versus anthracene versus naphthalene versus benzene, polychlorinated biphenyls versus polychlorobenzenes. (i) From these regularities and from the admittedly nonquantitative property, chemical instinct (which is, after all, the distillation of large numbers of structure-property relationships considered over the years), we constructed the parameter estimation rules used in the present paper. We wish to emphasize that these parameter estimation rules for more than 150 compounds have served not only in the present correlation of octanollwater partition coefficients but also in the correlation of aqueous solubilities,’Jiue other sets of soluentlwater partition coefjiicient~,~~ and about 50 sets of HPLC capacity factors (most of which will be reported in future papers). The correlation coefficients for these LSERs were always greater than 0.990, usually greater than 0.993, and frequently greater than 0.995. I t is also useful to set forth some of the reasoning used in our parameter estimation rules. We assumed that for conformationally
+
+
+
(23) Unpublished information. (24) We have mentioned that d is near 0 when polarizability effects are maximal and near -0.40 when they are near minimal. Hence the d6 term opposes the S?T* term. If we used 6 = 1.0 for the biphenyls, we would be opposing the ST* term of only one ring rather than the SET*terms of the two
rings.
J . Phys. Chem. 1988, 92, 5255-5257 mobile molecules with multiple HBA sites (e.g., arylalkyl compounds, biphenyls) separate solvent clusters would hydrogen bond to each site and undergo separate nonspecific dielectric interactions a t each site; hence we use Eo,,, and ET* for the compounds of Table V and the biphenyl derivatives. For compounds that are not conformationally mobile, such as the polycyclic aromatic hydrocarbons, the same solvent cluster may hydrogen bond at multiple sites; hence we use increments to K* and 0, rather than summations. The use of 6 = 2.0 for the biphenyl derivatives was for similar reasons and for c o n ~ i s t e n c y . ~ ~ The most important class of compounds for which we have not
5255
yet constructed parameter estimation rules are those wherein there is resonance delocalization of electron density, Le., those with an electron-donor substituent para to a mesomeric electron-acceptor substituent. Since the submission of this paper we have determined solvatochromic parameters for a number of such compounds from back-calculations of HPLC data. Their experimental log KO, values compare with values calculated through eq 5 as in Table XIII. We have also not constructed parameter estimation rules for compounds where there is intramolecular hydrogen bonding. Registry No. Octanol, 111-87-5
New Electronegativity Scale for the Correlation of Heats of Formation. 1. Alkyl Derivatives Yu-Ran Luo and Sidney W. Benson* Donald P. and Katherine B. Loker Hydrocarbon Research Institute, University of Southern California. University Park, Los Angeles, California 90089- 1661 (Received: February 12, 1988)
We report a quantitative linear relation between the differences in standard heats of formation [AfHo(RX)- AfHo(CH3X)] AAfHo(RX/CH3X) and V,, the unshielded core potential of X: AAfHo(RX/CH3X) = I,,, + S,V, (eq 4). Here R is CH3-,,,(CH3),,,, which are taken to be ethyl, isopropyl, and tert-butyl when m = 1, 2, and 3, respectively. X is a halogen atom, OH, SH, NH,, H, or CH3, and V, = nx/rx,where n, is the number of valence electrons in the bonding atom in X and rx (angstroms) is its covalent radius. V, was first proposed by Yuan as a measure of electronegativity of the elements. The slope S,and intercept ICin this relation can be related to m; I,,, (kcal/mol) = 0.9 - 1.5m(m - 1) (eq 6); S, (kcal A/mol) = -rn/(0.67 i 0.21m) (eq 7). For the 23 compounds available average deviations are 0.3 kcal/rnol with one maximum deviation of 1.9 kcal/mol. In all cases the experimental uncertainties exceed the deviations. The relation can be used to estimate values of AfHofor other elements and groups where data on AfHo(MeX) are known. With AfHO(MeF) = 55.9 f 0.5 kcal/mol, values are estimated for AfHoof EtF, i-PrF, and t-BuF.
Introduction which has been so surprisingly The law of group successful in estimating the heats of formation, AfHo, of homologous families of compounds, provides direct evidence that chemical forces are short range. However, it has been clear for some time that there are important exceptions to group additivity in compounds such as the fluorocarbons and chlorocarbons with many, very polar bonds. Benson and Shaw4 showed that on comparing AfHo(RX) for alkyl derivatives RX, there were systematic changes in the differences of [AfHo(RX)- AfHo(R'X)] = AAfHo(RX/R'X), where R CH3 and R' Et, i-Pr, or t-Bu, with the polarity of the C-X bond. AAfHO(MeX/t-BuX) changed monotonically from a maximum of 27 kcal for CH30H/t-BuOH to a minimum of 14 kcal for CH4/i-C4HI0. Efforts to find a quantitative correlation of AAfHo with dipole moments or other measures of the polarity of the C-X bond were unsucce~sful.~ A recent study of the thermochemistry of metal organic compounds6 has shown that AAfHo(MH,/MMe,,,) and AAfHO(MMe,,,/MEt,,,) show semiquantitative correlation (f2 kcal) with the electronegativities of M by using Pauling's scale for'electronegativity.' In the present paper we shall make use of a different (1) Buss, J. H.; Benson, S. W. J . Chem. Phys. 1958, 29, 546. (2) Cruikshank, F. R.; Golden, D. M.; Haugen, G. R.; O'Neal, H. E.; Rodgers, A. S.; Shaw, R.; Walsh, R.; Benson, S. W. Chem. Rev. 1969, 69, 279. (3) Eigenmann, H. K.; Golden, D. M.; Benson, S. W. J . Phys. Chem. 1973, 77, 1687. (4) Shaw, R.; Benson, S. W. Adu. Chem. Series, 1968, No. 75, 288. (5) Benson, S. W. Angew. Chem., Int. Ed. Engl. 1978, 17, 812. (6) Benson, S. W.; Tsotsis, T. T.; Francis, J. T., submitted for publication. (7) Pauling, L. J . Am. Chem. SOC.1947, 69, 542.
0022-3654/88/2092-5255$01.50/0
TABLE I: AfHo(RX) of a Number of Alkyl Derivatives'
CHq F OH C1 2"
Br
SH I CH3 H
-55.96 -48.2 f 0.1 -19.6 f 0.1 -5.5 f 0.1 -8.5 f 0.3 -5.5 f 0.2 3.5 f 0.3 -20.0 f 0.1 -17.8 f 0.1
CpH, -56.3 -26.8 -11.3 -14.8 -11.1 -1.8 -25.0 -20.0
f 0.1 f 0.3 f 0.2 f 0.4 f 0.2 f 0.4 f 0.1 f 0.1
i-C,H, -70.1' -65.1 -34.6 -20.0 -23.8 -18.2 -9.6 -32.1 -25.0
f 0.1 f 0.3 f 0.2 f 0.6 f 0.2 f 0.9 f 0.2 f 0.1
t-CaHs -74.7 f 0.2 -43.6 f 0.5 -28.9 f 0.2 -3 1.6 f 0.4 -26.2 f 0.2 -17.2 f 0.8 -40.2 f 0.2 -32.1 f 0.2
All values are in kcal/mol. Uncertainties listed are experimental precision, not accuracy. We estimate that in general AfHo of carbon compounds are not known to better than fO.ln kcal/mol, where n = number of carbon atoms. bReference11. CThevalue may be incorrect (see text).
electronegativity scale first proposed by Yuan* and show that it yields a quantitative correlation of AAfHo(RX/R'X) with the unshielded core potential, V,. There have been a number of reviews of the data on AfHoof organic compounds in the last 2 decades, and some of the experimental values have undergone "analytical" revision by small We shall adopt amounts, generally less than 0.5 kcal/m01.*~~J~ (8) Yuan, H. C. Acta Chim. Sin. 1964, 30, 341. (9) Pedley, J. B.; Naylor, R. D.; Kirby, S. P. Thermochemical Data of Organic Compounds, 2nd ed.; Chapman and Hall: London, 1986. (10) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and MetalsOrganic Compounds; Academic: London, 1970. (1 1) Kudchader, S. A,; Kudchader, A. P. J. Phys. Chem. ReJ Data 1978, 7, 1285.
0 1988 American Chemical Society
