THE DISTRIBUTION RATIOS OF SOME ORGANIC ACIDS BETWEEK WATER AKD ORGANIC LIQUIDS* BY HOMER W. SMITH AND T. A . WHITE
Sumerous investigators have called attention to an apparently close correlation between the distribution coefficients of organic substances between water and various organic liquids and the velocity with which these substances penetrate living cells. This is particularly true of the organic acids, where the penetration of definite quantity of acid can be detected by changes in the color of the intracellular pigments, artificial indicators, or by other criteria, The literature dealing with these phenomena has been recently reviewed by Jacobs,' Gellhorn,* and Taylor.3 One difficulty which prevents a more exact analysis of this problem is the absence of data on the true distribution ratios of the various substances used. I t was long ago pointed by Nernstl that the distribution law would apply only to such molecular species as were common to both solvents. If the solute is associated in one solvent (as is the case with most organic acids in organic solvents) or dissociated in the other (as happens with all acids in water) the gross distribution ratio tends to change with changing concentration of solute, and the division of the solute between the two solvents is only indirectly related to the distribution ratio of the simple molecules of solute. This latter value can in such a case be determined only when the degree of association in the organic layer or the degree of dissociation in the water are known. The general theory of the distribution of a substance between two imniiscible liquids has been reviewed by Hill," and only certain aspects of this theory need be mentioned here. If it is assumed that association in the organic layer proceeds to the formation of .dimeric molecules, and that the equilibrium between these dimeric molecules and the simple molecules present is governed by the mass law, it is possible by simultaneous equations derived from the mass law and by knowledge of the degree of dissociation in water to calculate from the gross distribution at two concentrations both the distribution ratio for the simple molecules and the association constant governing the process of association in the organic layer. The success of this method depends on the assumption, which is broadly established for the organic acids, that the solute is not significantly dissociated in organic liquids nor polymerized in water. * From the Department of Physiology a n d the Department of Chemistry, University of Virginia. L "General Cvtologv" (1924). "Das P e r m ~ a b i l i t ~ t s p r o b l e m (1929). " .i J. Gen. Physiol., 11, 207 (1927-28). Z. physik. Chem., 8, I I O (1891). j "Treatise on Physical Chemistry" ( 1 9 z j ) .
'
I954
HOMER W. SMITH AND T . A . WHITE
Equations of this type were derived by Hendrixson’ and applied to the distribution of benzoic acid and salicyclic acid between water and benzene and between water and chloroform. With a view to adding to our knowledge of the behavior of the organic acids in heterogeneous systems, we have determined the distribution ratios and association constants of a number of these substances in the systems water:toluene, aater:benzene and water :chloroform. I t is thought that these data may also be of some interest to students of molecular physics.
Methods Glass-stoppered bottles containing mixtures of water, the organic solvent and solute were suspended in a water bath maintained at z j°C. = t o .j o . Nixing was effected by regularly remoling the bottles and shaking. Samples were removed by pipetting out known amounts from each layer, after which equivalent amounts of each solvent were replaced and the bottle again brought to temperature and shaken. The samples were titrated in some cases with XaOH, in others with dilute Ba(OH)2protected from CO?. Titrations were carried out with phenol red and phenolphthalein as indicators. I n some instances the concentration in the organic layer was determined by difference, but usually the organic liquid was titrated directly after the addition of a little water. The solvents were redistilled before use, the first and final fraction being discarded. Some of the aromatic acids were purified by recrystallization, but the aliphatic acids were used without attempt at repurification. All the acids were highest grade, C.P. products. The calculation of the distribution ratio, P, and of the association constant, K, were made as follows: CI = concentration in aqueous layer in millimols per liter. C z = concentration in organic layer in millimols per liter. Q = degree of dissociation of single molecules into ions in aqueous layer. p = -concentration of single molecules in organic layer concentration of single molecules in aqueous layer K = association constant in organic layer of double into single molecules. Assuming that the process of association in the organic layer follows the mass law, then for any two concentrations
If we write Where I - a is calculated from Ostwald’s dilution law using the dissociation constants given by Scudder? for the substances under investigation, and solve equation ( I ) for P, the following expression is obtained ‘2.anorg: Chem., 12, 73 (1897). “ T h e Electrical Conductivity and Ionization Constants of Organic Compounds” (1914).
DISTRIBUTION RATIOS OF SOME ORGANIC ACIDS
P =
'955
C2n2- G'NZ (n
(4)
- N)nN
The association constant, K, in the organic layer is obtained by substituting determined values of P in equation (I). It is apparent from (4) that C2/N2 should bear a linear relation to I/K, the slope of the curve being equal to P. By plotting the experimentally determined values of Cz/Ii2and I/", it is possible to eliminate those values of C,/Y2 which are aberrant, and t o choose a value of C ? i S 2consonant with the majority to serve as a basic term of the series from which to calculate the successive values of P. I n view of the fact that in many instances the higher terms of C1 and CZ approach concentrated solutions in which the simple partition law is not valid, this preliminary graphical treatment is a necessary precaution, otherwise a whole series of relatively accurate values may be thrown into error by the unadvised choice of a basal aberrant term.'
Results The results of our determinations are collected in the following tables. Tables I, 11, and I11 deal respectively with the water:toluene, water:benzene, and the water:chloroform systems. C 1 , Cp, P, and K have the significance already given to them. TABLE I Toluene Acetylsalicyclic Acid
C1
C2
15.80 14 .oo 11.22
10.10 8.18 5.81
10.40
5.12
9.37 8.45
4.36 3.70 3.10
7.52
Mean Anisic Acid
.72 1.58 1.45 I .32 1.19 I ,056 0.924 I
Mean
9.50 8.18 7 .oo 6.07 5.28
4.49
P 0.320
0.330 0.313 0.319 0.318 0.325
I< X
103
3,33 3.40 3.26
0.320
3.32 3.30 3.32 3.33 3.32
3.24 3.38
6.j
34 7 3 .;o 3.55 3.40
7 0 7.' 6.8 6 .o
3.46
6.9 6.6
3.70
6.2
' We are indebted to Carlotta Greeiie Smith for assistance in a large p a r t of this work.
HOMER W. SMITH AND T. A. WHITE
1956
TABLEI (Continued) C1
Bensilic Acid
3.85 3.74 3.63 3.40 3.23 2.84 2.38
Mean Benzoic Acid
13.5 I2 .o
10.8 10.5
9.6 8.1 7 .2 5 7
Toluene P CZ I .96 5.50 I .98 5.28 5 .oo 2 .OI 4.62 I .99 2 .oo 4.36 2.02 3.63 2.90 I .99 162.o 128.4 105.6 100.6 82 .5 62 . 4 50.4 33.6
Mean Bromoacetic ilcid
2.2j
1.43 0,970
0,805 0.660 0.535 0.358 0.260
Mean
2.35 2.40
o ,0262 o ,0285 0.0261 0.0268 0.0264 o.02jo 0.0260
x
103
35.2 36.5 40 5 '
37.6 38.1 38.4 37.5 37.7 6.33 6.26 6.31 6.27 6.49 6,32 6.38 6.29 6.33
Fo
g 5 VI
0 0
0
o ,0265
42.Ij 31.90 23.86 19.64 17.37
14.69 12 ,90
11.38 8.87
1Iean
2.24 2.29 2.26 2 .30
2.29 92.90 63.15 42.85 38.49 30.90 24.43 17.95 13.56
a-Bromo-n-butyric Acid
2.23
I
