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M. J. Harris, T. Higuchi, andJ. H. Rytting
Thermodynamic Group Contributions from Ion Pair Extraction Equilibria for Use in the Prediction of Partition Coefficients. Correlation of Surface Area with Group Contri butionsl Sister M a r i e Joan Harris,2 Takeru Higuchi.* and J. Howard Rytting Departments of Chemistry and Pharmaceuticai Chemistry, University of Kansas, Lawrence, Kansas 66044 (Received February 5 , 1973; Revised Manuscript Received July 16, 1973)
The ion pair extraction constants for 26 alkyl sulfates have been determined a t a minimum of nine temperatures from which the free energy, enthalpy, and entropy of transfer data were calculated for 18 different organic groups. The trends in the free-energy data are interpreted in terms of interfacial interactions, water structuring, and specific solvation in the aqueous phase. From correlations between the free energies of transfer for the hydrocarbon groups investigated and their respective van der Waals volumes and relative surface areas, it is demonstrated that interfacial solute-solvent interactions in the aqueous phase, as reflected by the relative surface areas, are of greater significance than the volume of the solute in determining the solution behavior of organic molecules. A simple method for measuring surface areas with molecular models is described and evaluated, and the areas thus determined are shown to correlate closely with free energies of transfer of saturated hydrocarbon groupings from water to a nonpolar phase. From the extraction data for a homologous series of alkyl sulfates, it was found that the transfer process was a n entropy controlled one below 25” for the larger anions. It was also shown that, at 30°, there was a constant increment of -916 cal/mol in the free energy, -378 cal/mol in the enthalpy, and 1.77 eu in the entropy of transfer for each additional methylene group for those anions containing five or more carbons. The importance of the specific solvation of polar groups in the organic phase was evaluated for the halogen substituents and the ether group. Although the results indicated t h a t the increase in the average solvation number is not large, the absolute magnitude of the thermodynamic data should be affected by the additional 0.25 and 0.50 molecules of chloroform found to be solvating the ion pairs containing the halide and ether groups, respectively.
Introduction One of the major goals of research in the field of solution thermodynamics has been the development of a priori methods for the prediction of solution behavior and the utilization of these methods in various physical and biological studies. However, rigorous attempts to predict how a given solute will behave in a given solvent simply from the physical properties of the pure components have been limited almost entirely to mixtures of nonpolar specie^.^ The semiempirical group contribution approach is, however, an a priori method which has achieved a relative degree of success. In this approach a molecule is considered to be composed of groups which are associated with certain thermodynamic properties. Consequently, the activity coefficient, free energy, or partition coefficient can be found from the sum of the values for the different groups comprising the molecule. In contrast to the more theoretical approaches, this method is derived solely from an analysis of empirical data. However, the results frequently assume a form similar t o those mathematically derived from statistical mechanics. This concept was first introduced by Langmuir4 as the “principle of independent surface action,” and was verified and refined by Butler in his papers on the thermodynamics of h y d r a t i ~ n . ~ ? ~ Since that time many investigators have applied the group contribution approach to the transfer of a whole molecule from one phase to another. Nevertheless, the application of this concept has been limited largely through lack of accurate data. At this time we wish to report some of the necessary data and also a relatively simple predictive approach which seems to yield numerical values for The Journal ofPhysical Chemistry, Vol. 77, No. 22, 1973
free energies of such phase transfers from water to nonpolar solvents for various hydrocarbon groupings. The approach used permits accurate and ready estimation of partition coefficient values for these systems and also provides an additional insight into the nature of solute-solvent interactions in both aqueous and nonaqueous systems. Various types of experimental data have been used to obtain values for the transfer of functional groups between phase^.^ Measured partition coefficients have been particularly useful. However, the limited solubility of many organic molecules in water often presents difficulties in measuring partition coefficients. Thus, the use of ion pairs to facilitate the measurement of partition coefficients was considered. The feasibility of such an approach is supported by correlations reported by Schill and his coworkers7.8 between measured extraction constants and carbon number, and by the previous thermodynamic data obtained from the studies of ion pair extraction equilibria in this l a b ~ r a t o r y . ~ In this study, the protonated form of dextromethorphan, d-3-methoxy-N-methylmorphinan(I), was chosen as the extracting cation to be paired with several inorganic anions and a series of alkyl sulfates. The organic phase consisted of chloroform or chloroform-carbon tetrachloride mixtures where the chloroform acted as a solvating agent to aid in the extraction process. A detailed investigation of the effects of such factors as pH, anion concentration, ion pair dissociation, and extraction procedures on the observed ion pair extraction constants was conducted also.lO In addition, a correlation was made between the corre-
Correlation of Surface Area with Group Contributions
sponding free-energy differences attributable to alkyl substituents and their effective surface areas. These differences were found to be essentially determined by the effective surface areas exposed by the hydrocarbon groups in the aqueous phase, and to a lesser degree by the surface interactions of the same solute groupings in the organic phase.
Experimental Section
Ion Pair Extraction Studies. Equipment and Reagents All absorbance readings were made using a Cary Model 16 spectrophotometer and complete spectra were recorded on a Cary Model 15 spectrophotometer. Shaking was carried out on a Burrell Wrist-Action shaker and all pH measurements were determined with a Corning Model 12 research pH meter. Dextromethorphan, obtained through the courtesy of Vick Divisions Research of the Vick Chemical Co., was found to be 99.55% pure by a nonaqueous titration.ll All other chemicals used in the study were Analytical Reagent grade. Solutions were prepared with water which had been distilled a second time from acid permanganate in an all glass apparatus. Reagent grade chloroform was shaken three times with distilled water to remove its preservative, dried over phosphorus pentoxide, and distilled immediately prior to its use. Reagent grade carbon tetrachloride was also distilled before use. Phosphate buffers were prepared to contain 0.1 M NaH2P04 and sufficient H3P04 to adjust the p H to the desired value. A p H of 2.40 was most commonly employed. The buffer solutions were saturated with the organic phase prior to use. Chloroform-carbon tetrachloride mixtures were prepared on a per cent volume basis and all organic phases were saturated with water prior to use. Preparation of the Sodium Alkyl Sulfates Equimolar amounts of the respective alcohol and concentrated sulfuric acid were mixed in a n ice bath and allowed to react a t room temperature for 48 hr. The mixture was diluted with water and was neutralized with sodium carbonate. After evaporating to dryness, at room temperature, the residue was extracted with hot methanol and the solution was again evaporated. This residue was recrystallized twice from hot methanol-2-propanol mixtures and the product was dried in a vacuum oven for 3 hr. Procedure. Ten milliliters of the aqueous phase was placed with 10 ml of the organic phase in a sealed 25-ml volumetric flask. Twenty-five-ml flasks were used to reduce the amount of vaporization of the organic phase. The two phases were shaken for 2 hr in water baths held a t constant temperatures controlled to *0.05”. A determination of extraction constants as a function of shaking time indicated t h a t equilibrium is reached within 15 min. The shaker was stopped and the flasks were allowed to equili-
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brate for a t least 10 min. The contents of the flasks were transferred to separatory funnels equilibrated to the same temperature as the solutions. The two phases were separated with the aqueous phase being filtered through a small plug of glass wool. If readings were to be made on the organic phase, the ion pair was converted t o the free base by shaking the organic phase in a volumetric flask a t room temperature for 45 min with about 10 ml of 0.1 M NaOH which had been saturated with the respective organic phase. The contents were transferred t o a separatory funnel and the organic phase was collected. Using data given in ref 10, the concentrations of dextromethorphan in the aqueous XaOH phase both in the protonated and free base form was found to be negligible (
