S.Agharkar and S. Lindenbaum
2060 try", Vol. 1, Part IV, A. Weissberger and 6. Rossiter, Ed., Wiley, New York. k Y . , 1972,Chapter IV, pp 207-349. (5)L. J.'Gostlng and H. Fujita, J. Am. Chem. SOC.,79, 1359 (1957). (6)J. M. Creeth, J. Am. Chem. Soc., 77, 6428 (1955). (7)The Rayleigh analysis is equally applicable to all integral fringe patterns, including those from Jamin, Mach-Zender, and holographic interferometers. (8) H. S. HarneQand 6.6.Owen, "The Physical Chemistry of Electrolytic Solutions", 3rd ed, Reinhold, New York, N.Y., 1958. (9)L. Onsager and R. Fuoss, J. Phys. Chem., 36,3689 (1932). (IO)J. M. Creethand 6.E. Peter, J. Phys. Chem., 64, 1502 (1960). (11)0.W. Edwards and E. 0. Huffman, J. Phys. Chem., 63, 1830 (1959). (12)J. D. Hatfield, 0. W. Edwards, and J. L. Dunn, J. Phys. Chem., 70, 2555
(1966).
(13)R. H. Stokes, Trans. Faraday Soc., 46, 887 (1952). (14)E. Krucke and H. Ley, 2. Phys. Chem. (Frankfurt am Main), 26, 187 (1960). (15)E. Krucke, 2.Phys. Chem. (Frankfurtam Maln), 26, 202 (1960). (16)For example, the analogy with the K terms of eq 34 and 35, plus the definitions of R and T (ref 6), indicate that the next term In eq 35 will be 3\k6/24(d\ko/dz), although Creeth did not carry his.analysis this far. ~ dPo/dz are both even, this term will cancel out of eq 36. Since \ k and (17)N. Madsen and R. Sincovec, ACM Trans. Math. Software, in press. (18)Creethio suggested the point z' 0.6 based on his analytical conslderations for the linear dependence. Our more exact analytical result is z' = 0.57.Although the analytical basis is unsatjsfactory, nonetheless the points z* = 0.6 and z' = 0.57 will yield a D in error by less than 0.1% for all A more positive than -0.4 and -0.2, respectively.
Enthalpy of Dilution of Aqueous Solutions of Some Bis Quaternary Ammonium Ganglionic and Neuromuscular Blocking Agents' S. Agharkar and S. Lindenbaum* Pharmaceutical Chemistry Department, McCollumLaboratorles, The Universityof Kansas, Lawrence, Kansas 66045 (Received May 7, 1975)
Heats of dilution are reported for aqueous solutions of bis quaternary ammonium chloride, bromide, aceThe heat of dilution, AHD,for the chlotate, and butyrate salts of the type (CH3)3Nf-(CH2),-+N(CH3)3. ride and bromide salts increases with increasing n until a maximum is reached at n = 5 and then drops with increasing n. The ganglionic blocking activity of these compounds also has a maximum value at n = 5. These results suggest that the biological activity of these compounds may be determined by their properties in aqueous solution.
Introduction The polymethylene a,w-bis(trimethy1ammonium) salts (CH3)3N(CH2)nN(CH3)3X2 (X = univalent anion) are of great interest because of their ganglionic and neuromuscudeal of work has been publar blocking a ~ t i v i t y . ~A-great ~ lished in which the effect of the distance between the quaternary nitrogen atoms on pharmacological activity is exp10red."~ The maximum ganglionic blocking activity for this series of compounds occurs for pentamethonium ( n = 5) and hexamethonium ( n = 6). The maximum neuromuscular blocking activity is obtained for decamethonium ( n = 10). On the basis of these results it has been suggested4s5that the N+-N+ distances corresponding to the length of five or six methylene groups correspond closely to the distances between anionic acetylcholine receptor sites of the ganglionic receptor, and that the receptor sites of the muscle end plate receptor are separated by a distance corresponding to ten methylene groups. This correlation is however not entirely consistent, and some potent blocking agents, fiat members of the "polymethonium" series do not have their positive charge sites separated by distances corresponding to those of pentamethonium or decamethonium.6 For this reason, the validity of this two point contact hypothesis has been questioned by several investigators.6-10 It has been suggested that the biological activity might be determined by the lipophilicity of these compounds,6 rather than by a specific fit to a two point contact receptor. The Journal of Physical Chemistry, Vol. 79, No. 19, 1975
The results of a study of the thermodynamics of binding of a series of alkyltrimethylammonium salts to acetylcholinesterase have led BelleauQ to suggest that water is the determinant of the binding properties of these compounds. Belleau suggests that the binding of the quaternary ammonium ion to acetylcholinesterase (or the receptor) is facilitated by the formation of a hydrophobic bond between the quaternary ammonium ion and the receptor. The driving force for this interaction is taken to be the increase in entropy which accompanies the loss of a hydrophobic solute from the aqueous environment.11J2 On the basis of this suggestion, it might be expected that the relative affinities of these bis quaternary ammonium salts for the receptor will be determined largely by their properties in aqueous solution. The present program of study was undertakeh in order to determine the thermodynamic properties of these bis quaternary ammonium salts in aqueous solution, and to correlate these properties with their biological activity. The first of these properties reported here is the heat of dilution in aqueous solution at 2 5 O . Previous studies of tetraalkylammonium halides13-16 have suggested that the apparent molal heat content, +I,,is a measure of the hydrophobic nature, or water structuremaking property of these solutes. If, as suggested, the biological activity, i.e., the binding of these compounds to a receptor, is determined by the hydrophobic bonding phenomenon, then a correlation between 41,and biological activity might be expected.
2069
Enthalpy of Dilution of Bis Quarternary Ammonium
