2666
WILLIAMPAULPURCELL
Electric Moment Measurement of N-Alkyl-Substituted Nicotinamides and Calculation of Aromatic Amide Group Moments'
by William Paul Purcell Department of Pharmaceutical and Medicinal Chemistry, College of Pharmacy, University of Tennessee, Memphis, Tennessee (Receiaed M a y 6 , 1964)
Dielectric constants, refractive indices, and densities of dilute benzene solutions of pyridine, nicotinamide, ?;-methylnicotinamide, N,N-dimethylnicotinamide, K-ethylnicotinamide) and N,N-diethylnicotinamide were measured at 25'. The dipole moments were calculated according to the equations of Halverstadt and Kumler, Guggenheim, and Smith. The moments are consistent with the evidence that alkyl group substituents have an electronreleasing effect. hromatic amide group moments were calculated from the observed data using (1) a free-rotation and (2) a restricted-rotation treatment. The amide group moments increase with alkyl group substitution.
Introduction The amide group contributes significantly to the function of many physiologically active compounds. In human plasma "pseudo"-cholinesterase systems, for example, its activity has been found2to be sensitive to minor substitutional changes of the groups bonded to the nitrogen atom. It is felt that substitution of an alkyl group for a hydrogen atom on the nitrogen affects the polarity of the carbonyl group in the amide, and that the resulting change in electron distribution contributes to the striking change in biochemical response.2 Electric moment measurement and analysis should yield quantitative inforination regarding the polarity of the amide group as the nitrogen substituents are changed. We chose the nicotinamide series for study because of the implication of these organic compounds in biochemical and pharmacodynamic processes; for example, nicotinamide (niacinamide) is a vitamin and N,X-diethylnicotinainide (nikethamide, Coramine@) is a respiratory and cardiac stimulant.a The molecules in this series, however, are structurally simple enough to be analyzed in terms of molecular geometry and niolecular and group moments, and should serve as a bridge to the measurement and interpretation of more complicated molecules which have been biochemically evaluated2 and which are presently under study in our department. The Journal of Physical Chemistry
Experimental Reagents. Pyridine (Spectroquality reagent, Matheson Coleman and Bell) was used without further purification; n Z 51.5074 ~ (lit.4n Z 51.5073). ~ Nicotinamide (Matheson Coleman and Bell) was recrystallized four times from benzene; m.p. 128.1-128.6° ( l k 5 m.p. 129-130'). N-Methylnicotinamide (reagent grade, K and K Laboratories) was recrystallized four times from benzene; m.p. 101.8-102.4° (lit.6 m.p. 104-105'). N,K-Dimethylnicotinamide (Aldrich Chemical Co.) was vacuum distilled; b.p. 97' (0.01 mm.). K-Ethylnicotinamide (reagent grade, K and K Laboratories) was vacuum distilled; b.p. 128' (0.12 mm.). N,NDiethylnicotinamide (Aldrich Chemical Co.) was vacuum distilled; b.p. 114' (0.15 min.), n Z 51.5214. ~
(1) This investigation is being supported by U. S. Public Health Service Grant MH-04379 and by cl grant from the Geschickter Fund for Medical Research, Inc. Computer facilities were provided in part through U. S. Public Health Grant FR-1. (2) A. Lasslo, J. G. Beasley, G. G. Xelms, and G. J. Epperson, J . Med. Chem., 6 , 811 (1963). (3) L. S. Goodman and A. Gilman, "The Pharmacological Basis of Therapeutics," 2nd Ed., The Macrnillan Co., New York, N. Y., 1955, p. 330. (4) V. Zawidski, Chemiker Ztg., 30, 299 (1906). (5) C. F. Krewson and J. F. Couch, J . Am. Chem. Soc., 65, 2256 (1943). (6) A. Pictet and G. Sussdorff, Chem. Zentr., 69, 677 (1898).
2667
ELECTRIC MOMENT MEASUREMENT OF i\I-ALKYL-SUBSTITUTED NICOTINAMIDES
Solvents. The compounds were measured in dilute benzene solution using Spectroquality benzene (Eastman Organic Chemicals) without further purification. The following solvents were used in the calibration of the Dipolemeter and cell. Benzene (Spectroquality reagent, Matheson Coleman and Bell) was refluxed over sodium ribbon and distilled twice through a 1.5-xi. coluinn packed with glass helices. The middle onethird fraction was retained each time, and the solvent was measured immediately after the second distillation. Cyclohexane (Spectrograde, Eastman Organic Chemicals) was treated the same as benzene. Carbon tetrachloride (Spectranalyzed, Fisher Scientific Co.) was treated the same as benzene with the exception that sodium was not used. Apparatus. The dielectric constants were measured at 25" with the Dipolemeter DM 01 (Wissenschaft-, lich-Technische Werkstatten) which employs the heterodyne beat method.' The 20-ml. jacketed gold-. plated DFL 1 cell was calibrated with benzene, carbon tetrachloride, and cyclohexane a t 20' using dielectric constant valuess of 2.2832, 2.2368, and 2.0230, respectively. Refractive indices were measured a t 25" using a Bausch and Lomb Abbe-3L refractometer. The densities were also measured a t 25" with a 20-ml. modified Ostwald pycnometer. All temperatures were measured with thermometers calibrated against an N.B.S. certified thermometer and controlled to =k0.02" by a Type NBe Haake constant temperature circulator for dielectric constant and refractive index measurements, and by a Sargent Thermonitor controlled water bath for density measurements. The dielectric constants, refractive indices, and densities of the dilute solutions are given in Table I. Calculations. The dipole moments were calculated from the equations and methods described by Halverstadt and Kumler, lo Guggenheim,l' and Smith.12 No correction was made for the atomic polarization, i.e., the molar refraction, RD, was assumed equal to the sum of the atomic and electronic polarizations. A program was written for the IBM 1620 computer which applies least-squares lines to the solution data plotted against the weight fraction, w2, of the solute,10and to Guggenheini's A against moles of polar solute per cc. of so1ution.l' The original data, Table I, were processed directly. The program includes the three methods of calculation, and the corresponding values, p H K , p a , ps, were printed out. The standard error in p was calculated from the equation used by E
