373
Dielectric Constanrs of Amide-Water Systems
Dielectric Constants of Amide-Water Systems Peter Rohdewald" and Manfred Moldner hstrtut f u r pharmazeufische Chemie, Westfalfsche Wiihelms-Un/vers/fat, 44 Munsfer, Germany
(Received June 27, 1972)
Dielectric constant measurements were carried out on mixtures of unsubstituted, N-monoalkylated, and N,N.dialkylated aliphatic amides with water over the whole concentration range. The formamide-water and acetamide-water systems show positive deviations from ideal behavior of mixtures, while in mixtures of N-monoalkylated and N,N-dialkylated amides the deviations are negative. The positive deviations of A € are qualitatively attributed to a "build-in" of the components of the mixture in the structure of the respective solvent. The decreasing values of A€ in the amide-rich region of the aqueous mixtures of the alkylated amides are explained by an interstitial solvation of water into the structure of the amides, whereas in the water-rich region the decrease in A6 should result from the breaking of amide aggregates and the hydrophobic solvation of the alkyl moieties.
Introduction Extending Hildebrarid's solubility parameter theory1 to semipolar and polar systems and observing an empirical equation whiich links the dielectric constant t and the sol0.26, Paruta and coworkers2 ubility parameter 6, 6 = 7.5 ipostulated that "a maximum solubility of a given solute should occur within a particular narrow dielectric constant range, regardless of whether this dielectric constant is that of a pure solvent or that of an appropriate mixture of two solvents. '' Experimentally this hypothesis proved to be a t first partieulary successful,2-4 but later the same author concluded that the observed dependence of peak solubility on the dielectric constants of binary mixtures is restricted to the given solvent system and not independent of the solvent system used.5 The influence of the dielectric const ant of binary or tertiary mixtures on the solubility of drugs was studied with the aid o€ an "approximated dielectric constant" (ADC). Assuming that the DC of a mixture of two or more solvents is directly proportional to the concentration of the individual solvents, Moore5 calculated the ADC as follows ADC
zz
[2(%solventl)(tl) C (70s o l v e n t a ) ( ~+ ) . . . (% solventx)(tx)]/lOO
Although the results of Moore6 first indicated the usefulness of the ADC to predict the solubilities of drugs in solvent mixtures, a recent paper showed that ADC had only a very limited ability to predict the solubilities.7 The aliphatic amides cover a very wide range of dielectric constants (frorn 20 to 190), therefore these substances seem to be an optimal class of water-miscible solvents for use in an extended study of the interrelations between the solubility of drugs and the dielectric constants of the pure amides and also of their aqueous mixtures. A knowledge of the dielectric constants of aqueous amide mixtures is not only important for the possible elucidation of the importance of the DC in solubility problems but also in the use of aqueous amide systems as electrolytic solvents or as polar solvents €or kinetic investigations. As far as we know, the dielectric constants of binary aqueous amide systems have not been the subject of a systematic investigation. Only the dielectric constants for and Nthe systems N,N-dimethylformamide-water~~9 butylacetamide-water9 have been reported.
In our investigations we have included the unsubstituted amides formamide (FA), acetamide (AA), and propionamide (PA). In the series of FA and AA derivatives the length of the N-alkyl groups was changed for both the mono- and the dialkylated derivatives. The influence of the acid alkyl groups was investigated in the series of Nmonomethylated amides going from N-methylformamide (NMF) to N-methylpropionamide (NMP). The dependence of the dielectric constants of the binary systems on the nature of the amide substituents should give some indications of the liquid structure of the amidewater systems.
Experimental Section N-Isopropylformamide (NIPF) was prepared from isopropylamine and methyl formate. The other commercially available liquid amides were treated with powdered CaO for 5-6 days, further dried by passage through a column of molecular sieve (4 A, previously heated at 400"), and distilled under vacuum in an atmosphere of dry nitrogen. The middle fraction comprising 60% was retained. N-Methylacetamide (NMA) was azeotroped with toluol. AA was recrystallized twice from absolute ethanol and once from CHC1,; mp 81". PA was recrystallized twice from benzene; mp 80.5". Purified water with a conductivity of 1-2 Kohms cm-1 was obtained after deionization and double quartz distillation. Refractive index measurements were made with an Abbe refractometer at 25 f 0.05'; the densities were obtained using specific gravity bottles, capacity 25 ml at 25 f 0.01". The amide-water mixtures were prepared volumetrically using the Multidosimat F 415 from Methrom A.G., accuracy *10-2ml. (1) J. H. Hildebrand and R. L. Scott, "The Solubility of Nonelectrolytes," 3rd ed, Dover Publications, New York, N. Y . , 1964,p 150. (2) A. N. Paruta, B. J. Sciarrone, and N. G. Lordi, J. Pharm. Sci., 53,
1349 (1964).
(3) A. N. Paruta, 8. J. Sciarrone, and N. G. Lordi, J. Pharm. Sci., 54, 838 (1965).
(4) A. N. Paruta, B. J. Sciarrone, and N. G. Lordi, J. F'harm. Sci., 54, 1325 (1965). (5) A. N. ParutaandS. Irani, J. Pharm. Sci., 56, 1565 (1967). (6) W. E. Moore, J. Amer. Pharm. Ass., Sci. Ed., 47,855(1958). (7) C. Sunwoo and H. Eisen, J. Pharm. Sci., 60,238(1971). (8) G. Douheret and M. Morenas, C. R. Acad Sci.. Ser. C, 264, 729 (1967). (9) R. Reynand, C.R. Acad. Sci., Ser. C, 266,489 (1968). The Journal of Physical Chemistry, Vol. 77, No. 3, 1973
Peter Rohdewald and Manfred Moldner
374 TABLE I: Physicochemical Dale of Some Aliphatic Amides
-
. _ _ . I -
Amide
1-Cliloro-N, N-dimeth ylacetamide N,N-Diethylformamide (DEF)
n25D
1.4753 1.4320 1.4352a
N,N-Diethylacetamide (DEA)
1.4370 1.4396b
1-Chlot o-Ai, N-diethylacetamide
1.4675 1.4694d I ,4685 1.4316 1.4371e 1.4416 1.4411e 1.4305 1.4310f 1.4289 1.4320 1.4274 1.4289h
N,N-Diethylacetoacetamide (DEDEA) N,N-Diisopropylformamide (DIPF)
N,N-Dioropylacetamide(DPA) N- Metl. ylforrnamide ( N M F )
N-Ethyiformamide (NEF) N-lsopt opylforrnamide (NIPF)
~ 4 2 5g ,
cm-3
K25.
cm-i ohm-'
x 10-5
1.1746
2
0.901 7
4.8 x
0.9057b 0.906lC o.9oao 0.9045b 0.908OC 1.0848 0.9905 0.8978 0.8844 o.8agic 0.9985 0.9976f 0.9451 0.9447 0.9081 0.9115h
€25
49.4 28.4 29.eC
10-7
7.5 x 10.-7
30.4 32.Ic
5 x 10-6
39.2
9
x
10-7
40.8 24.2
1.7 x 10-5
4 x 10-7 7 x 10-6 5 x 10-5 2 x 10-5
f
1.7 x 10-5 8.5 x 10-7h
23.2 24.5r 186.9 182.4 f 101.5 102.7 g 65.7 6%.3h
Bohme and F. Soldan, Chem. Ber., 94, 3109 (1961). B. V. Joffe, Zh. Obsch. Khim., 25, 902 (1955). values at 20'. Reference 13. M. Neemann, Chem. Sot., 2525 (1955). e J . H. Robson and G. Reinhart, J. Amer. Chem. SOC., 77, 498 (1955), values at 20'. [Reference 15. gReference 12. D. Wagner, Dissertation, 1948, Stuttgart. values at 30". O.H.
J
The dielectric constants were measured using the cells
MF1z-MFLII, volume 50 ml, together with the Multidekameter from WTW. Measurements were made at 10 mHz and 25 $: 0.02". The cells used were calibrated with purified NMA, water, N,N-dimethylformamide (DMF), acetone, benzyl alcohol, and ethylenechloride as standard liquids. The accuracy of the dielectric constants is *0.30.5%. To avoid air bubbles in the mixtures the measurements were carried out 5 hr after mixing; freshly distilled liquids were used. Precautions were observed at all times to minimize *he atmospheric contamination of the amides.
Results and ~ ~ s c u s s ~ ~ n The dielectric constants of amides used in our investigations are listed in Table I together with their refractive indices, deiisifies, and conductivities. Some comparisons with literature data are given only in cases of (small) deviations from literature data or for differences in the temperature used by other authors. For NMA we obtained a DC value of 179 in agreement with the value of Dawson, et al., of 178.9 10 for 30". The further purification by zone refining seems to be unnecessary in view of the instability of the highly purified NMA, DC 191.3,11 in the presence of moisture, considering the following irivestigation of amide-water mixtures. The dielectric constants for the other amides used were in perfect agreement with the literature data. From Table X it will be seen that the introduction of chloro atoms or the CH&O group into the dialkylated amides causes an increase of the DC of about 10 units as would be expected from the higher polarity of these amides. In contrast the monoalkylated amide N-methyl-2chloroacetainide pobsesses a very low DC of 92.3 1 2 when compared to the value for NMA cited previously. The steric hinderance to chain association seems to be responsible for the lowering of the DC in the monosubstituted amides12 whereas the dialkylated amides are only slightly associatedl3J& and thewfore an increase in the dipole moThe Journal of Phy:sica/ Chemisfry, Vol. 77, No. 3, 7973
ment contributes to the increase in the DC. The results of the DC measurements on the amidewater systems are expressed as the excess in the DC. A t = €obsd - ejd, where €id = ~ 1 x 1 f 6 2 x 2 , X is the mole fraction of the component. All amide-water mixtures deviate widely from the behavior of ideal mixtures (Figures 1-4). The dielectric constant curves for mixtures of the unsubstituted amide and water (Figure 1) show a certain parallelism. The curve of AA is extrapolated to t = 74 for pure AA, obtained from mixtures of AA and FA.15 The less soluble PA seems to exhibit a deviation from linearity toward lower DC values like the other two amides, although the DC of pure PA is not known. In the systems FA-H20 and AA-W20 nearly the same positive deviations from ideal behavior appear, with a well-marked maximum between 45 and 50 mol % amide (Figure 2). In Figures 3 and 4 the negative deviations, Ac, for the mono- and dialkylated amides are shown. The minima grow more pronounced with increasing chain lengths of the N-alkyl groups of the disubstituted amides, whereas for the monosubstituted amides no simple correlation between chain lengths and A t could be observed. The results are summarized in Table 11. It is obvious that the magnitude of the minima in Ac is related to the chain length of the N-alkyl and the acyl groups of the amides, except for the differences between the N-methyl and N-ethyl groups. The Ac values of the formamides are generally lower than those of the corresponding acetamides, (IO) L. R . Dawson, P. G. Sears, and R. H. Graves, J. Amer. Chem. Soc., 7 7 , 1986 (1955). (11) 0. D. Bonnerand G. B. Woolsey, J. Phys. Chem., 75,2879 (1971). (12) P. G. Sears and W. C. O'Brien, J. Chem. Eng. Data, 13, 112 (1968). (13) M. Steffen, Ber. Bunsengesell. Phys. Chem., 74, 505 (1970). (14) S. J . Bass, W. I. Nathan, R . M. Maighan, and R . ti. Cole, J. Phys. Chem., 68,509 (1964). (15) G. R. Leader and J. F. Gormley, J. Amer. Chem. Soc., 73, 5731 (1951).
375
Dielectric Constants of Amide--Water Systems uo UJ
a+ 110
io
5
90
80
AMIDE i ~ t r x i )
50
loo
Figure 2. Positive A < values of the unalkylated amides as a function of t h e amide concentration. TABLE II: Positions of the Maxima of Ac and the Per Cent Deviation between the Observed DC and the ADC
----c---+-+
!
50
’ AMIDE (Mol%)
100
Figure 1. Dielectric constants of t h e amide-water systems for the unalkylated amides, as a function of the amide concentration. The dielectric constant curve for acetamide is extrapolated to t h e value of 74 for pure AA;15 AA and PA are not completely soluble in water
The position of the minima i n Ac is nearly independent of the length of the acyl or N-alkyl groups of the Nmonoalkylated amides; only in the case of NIPF-H20 is the minimuin markedly shifted to a lower amide concentration, corresponding to a molar ratio of 1amide:2 H2O. For the dialkylated amides the molar ratio at the minimum is changed regularly with each additional CH2 group from 1:1for 13MA-HzO to X :3 for DPA-HzO. The results demonstrate clearly that the use of “approximated9’ dielectric constants of amide-water mixtures will lead to erroneous results especially for amides with larger alkyl groups; in this case the deviation from additivity in the minima is between 20 and 40% (Table II). The remarkable contrast between the unalkylated amides with positive Ac values on the one hand and the mono- and dialkylated amides with negative A< values on the other hand requires some reflection. Accepting the existence of a large number of cyclic associates in the pure unalkylated amides,l6 the +Ac values could be interpreted as a “breaking-up” of cyclic amide associates through the formation of water-amide bonds. The diminuition of the number of cyclic associates where the dipoles me more or less antiparallel should lead to an increase in the dielectric constant of the amide-water systems. The high dielectric constant of FA is in disagreement with a preferential cyclic association and its low electric
AA FA
NMF NMA NMP NEF NlPF N EA DMF DEF DMA DEA AEDEA DPA
45
$13.9
$14.9
46 60 50 57 60
4-14.5
+ia.s
-11.8
-5.1
-18.4
-14.1 -25.2 -5.2
-33.5
50
-4.8 -8.5 -16.4
46
-8.8
33 44 33 33
- 16.5
30
25
-9.8
-10.1 -16.0
- 14.8 -26.6
-16.3
-14.8
-23.5
-13.5
-20.5 -40.7
-26.4
moments. Starting from the crystal structure of AA16 it is possible to construct highly polar double chains of the unalkylated amide with a parallel ordering of the individual dipoles. Such chain associated unalkylated amides are in agreement with the high dielectric constant of FA and with the results of Tyuzyol’ from measurements of the enthalpy of vaporization. Following the interpretation of b y n a n d 9 that the “break-up” of the associated chains of the N-monoalkylated amides is responsible for the minimum in Ac, one must expect minima also in the aqueous mixtures of FA and AA. For the pure disubstituted amides dipolar head-to-tail (16) M. Davies and H. E. Hallam, Trans. Faraday SOC.. 47, 1170 (1951). (17) K. Tyuzyo, Bull. Chem. SOC.Jap., 30, 851 (1957) The Journal of Physical Chemistry, Vol. 77, No. 3, 1973
Peter Rohdewald and Manfred Moldner
376 UJ
