4097
BENZENE AND DIOXANE ELECTRIC MOMENTS OF NICOTINAWIDES
while obviously important, are probably not so large as to make this trend meaningless. That the C=C bonds of the fluoroethylenes should be shorter than the ethylene values, while those for cis-dichloroethylene and its bromine analog are longer, is interesting and has prompted us to initiate structural studies of the other dichloroethylenes. Acknowledgments. The equipment, used in this in-
vestigation, was built with financial assistance from the Graduate School of The University of Texas. A great deal of credit for its construction must go to Dr. D. M. Cowan. The research was sponsored by the Robert A. Welch Foundation of Houston, Texas. We wish to express our gratitude to Mr. Bobby Turman for his help in the collection of the experimental data and to Mr. David Loyd for his part in the construction of the equipment.
Benzene and 'Dioxane Electric Moments of N-Alkyl-Substituted Nicotinamides
from Measurements in Mixed BenzeneDioxane Solutions'
by William P. Purcell and Judith A. Singer Department of Pharmaceutical and Medicinal Chemistry, University of Tennessee College of Pharmacy, Memphis, Tennessee (Received May 10, 1966)
Dielectric constants and refractive indices of dilute mixed benzene-dioxane and pure dioxane solutions of pyridine, nicotinamide, N-methylnicotinamide, N-ethylnicotinamide, N,X-dimethylnicotinamide, N,N-diethylnicotinamide, and N,N-di-n-propylnicotinamide and also of dilute benzene solutions of N,N-di-n-propylnicotinamide were measured at 25". The dipole moments were calculated from Smith's modification of the Guggenheim equation. The mixed-solvent moments are virtually the same as those calculated from pure-solvent measurements, and the results are consistent with the electron-releasing effect of alkyl group substitution. Differences between benzene and dioxane moments for a given compound are interpreted in terms of the expected effect of the amide substituents on the solvating dioxane molecules.
Introduction We found the benzene solution moment of isonicotinamide2 to be 0.68 D. lower when it was measured in pure benzene than when it was measured by a mixed benzene-dioxane technique.3--6 This deviation was interpreted in terms of the formation of isonicotinamide dimers with zero moment when pure benzene is the solvent.2 The apparent solute-solute association problems encountered in the measurement of amides in pure benzene17coupled with our results for isonicotinamide and our interest in correlating polarities with
cholinesterase inhibitory properties,8 prompted us to apply the mixed benzene-dioxane solvent technique3-e (1) This research is being supported by the National Science Found& tion (B-15989). Computer facilities were provided through U. S. Publio Health Service Grant HE-09495. (2) W. P. Purcell and J. A. Singer, J. Phys. Chem., 69, 691 (1965). (3) G. K.Eatok and C. H.Stembridge, J . Am. Chem. Soc., 76, 4316 (1954). G. K. Estok and S. P. Sood, J . Phys. Chem., 61, 1445 (1957). (5) G. K. Estok, S. P. Sood, and C. H.Stembridge, ibid., 62, 1464 (1958). (6) G. K. Estok and S. P. Sood, ibid., 66, 1372 (1962).
(4)
Volume 69, Number 18 December 1066
WILLIAMP. PURCELL AND JUDITH A. SINGER
4098
~~~
~
~~~
Table I: Dielectric Constants Measured a t 25' in Dioxane and in Mixtures of Dioxane and Benzene Solution" and the Corresponding Slopes, Q: ( e vs. tu2) Solvent oomposition, mole 76 dioxane
108wa
100.00
0.0000 2.7850 a = 8.82 5.0817 9.2200 10.363 10.772 61.13 a = 7.70
100.00 a = 12.6
59.64 a = 11.5
38.93 a = 10.5
100.00 Q:
=
12.6
61.31 a=
11.3
100.00
0.0000 2.0398 3.6465 4.4439 6.6386 6.7425
c
Solvent composition, mole % dioxane
Pyridine 2.2075 75.27 2.2320 2.2519 a=7.86 2.2884 2.2990 2.3026 2.2446 2.2612 2.2722 2.2780 2.2957 2.2972
45.32 a = 7.51
Nicotinamide 0.0000 2.2119 75.07 0.8136 1.1913 2,0979 2.9995 3.8800
2.2222 2.2265 2.2380 2.2496 2.2606
0.0000 0.7027 1.4447 2.0423 2.0925 2.4807
2.2463 2.2545 2.2632 2.2703 2.2706 2.2746
0.0000 0.5122 1.3292 1.4350 2.2675 2.8105 2.9995
2.2591 2.2648 2.2730 2.2747 2.2830 2.2889 2.2906
a=
11.9
53.03 a=
10.9
2.2343 2.2571 2.2685 2.2743 2.2792 2.3135
0.0000 2.6383 4.8806 5.9229 7.0507 9.5544
2.2555 2.2749 2.2914 2.3000 2.3085 2.3270
a = 11.3
62.74 a = 10.4
31.08 a = 9.84
O.OOO0 2.2332
0.0000 0.8775 1.3265 1.6741 2.6138
2.2499 2.2588 2.2637 2.2678 2.2782
100.00 a = 14.4
61.04 a = 13.6
38.88 a=
10.8
O.OOO0 2.2329 1.3097 3.1582 3.8412 4.8527
2.2480 2.2692 2.2775 2.2903
0.0000
2.2602 2.2677 2.2782 2.2827 2.2901 2.2991
0.7804 1.7496 2.1535 2.8036 3.6472
0.0000 2.2332 1.4514 2.2482
10%
e
2.7559 2.2435 5.3345 2.2721 6.1741 2.2820
O.oo00 2.2440 0.9046 2.4405 4.2791 5.4908 7.0211
2.2521 2.2680 2.2872 2.3004 2.3169
0.0000 1.2602 3.3177 4.4001 5.8815
2.2617 2.2733 2.2935 2.3042 2.3196
Solvent composition, mole % dioxane
a = 10.8
46.69 a = 9.95
10%~~
3.1072 4.3231 5.0042 5.9004
t
2.2658 2.2790 2.2868 2.2968
O.oo00 2.2561 1.4453 2.8514 3.3817 4.0758 5.3250
2.2684 2.2828 2.2888 2.2956 2.3086
0.0000 0.6859 1.9037 2.8855 3.8160 5.2065 6.4451
2.2313 2.2404 2.2573 2.2704 2.2850 2.3039 2.3217
N.N-Dimethvlnicotinamide
1.1452 2.2470 1.6010 2.2526
a = 12.6
N-Ethylnicotinamide 0.0000 2.2121 76.97 1.2002 2.2263
The Journal of Physical Chemistry
0.0000 2.8634 4.3446 5.1643 5.7637 10,049
25.49
0.0000 2.2467
2.2560 2.2717 2.2784 2.2898 2.3049
I
2.2218 2'2598 2.4240 2.2620 2.6696 2.2651
N-Met hylnicotinamide 0 . m 2.2121 78.40 0.6858 2.2213 1.5634 2.2319 Q: = 11.8 2.4693 2.2442 2.9817 2.2502 4,8949 2.2737 0.9480 2.3025 2.9377 3.8502 5.1723
lO*wn
Solvent composition, mole % dioxane
100.00 Q:
=
12.9
41.91 a = 11.8
0.0000 1.0881 1.8681 2.9544 3.7626 5.6498 5.7944
2.2133 2.2287 2.2395 2.2557 2.2665 2.2941 2.2968
O.oo00 2.2434 0.9811 2.2554 2.8008 4.6267 5.2377 5.5880
2.2558 2.2739 2.2812 2.3056 2.3148 2.3187
0.0000 0.9537 1.6198 2.2159 2.2649 2.8878 3.5829
2.2679 2.2795 2.2880 2.2951 2.2961 2.3047 2.3129
77.47 a = 14.1
41.12 a = 13.1
N,N-Diethylnicotinamide 0.0000 2.2125 56.00 0.7996 2.2233 1.4996 2.2327 a = 12.1 1.5232 2.2320 2.4149 2.2450 3.1173 2.2528 3.9768 2.2640 0.0000 0.7469 1.2587 2.3789 3.1674 3.7569 4.5058
2.2574 2.2658 2.2721 2.2853 2.2948 2.3014 2.3104
29.03 a = 11.6
O.oo00 2.2581 0.8135 1.4632 1.6124 3.0937 3.1581 4.5128
2.2686 2.2771 2.2786 2.2983 2.2997 2.3169
0.0000 1.0951 2.0963 2.1330 3.4954 4.9151 5.2657
2.2466 2.2596 2.2713 2.2726 2.2886 2.3057 2.3105
0.0000 1.1170 2.2658 2.2780 1.6351 2.3376 2.5737 3,0238 3.7188
2.2845 2.2926 2.2951 2.3009 2.3085
BENZENE AND DIOXANE ELECTRIC MOMENTS OF NICOTINAMIDES
Table I (Cmtinued) Solvent composition, mole % dioxane
100.00
10%
I
Solvent composition, mole % dioxane
0.0000 1.1451 1.6124 2.8321 3.5121 4.5109 6.4131
2.2380 2.2499 2.2544 2.2676 2.2749 2.2854 2.3063
0.0000 0.9777 1.6249 2.8739 2.9905 3.2543 4.5827
2.2536 2 2631 2.2705 2 2831 2.2837 2 2863 2 3005
0.0000 1.0911 1.6244 1.9434 2.5821 2.6353 3.2742
2.2667 2.2775 2.2821 2.2852 2.2924 2 2921 2.2982
0.0000 1.0257 1.1372 2.4910 2.7735 3.7962 3.8735
2.2770 2.2865 2.2877 2.3003 2.3027 2.3130 2!, 3136
I
~
43.84 a = 10.2
0.00 LY
= 9.46
t
N,N-Dh-propylnicotinamide 2 2082 64.87 0.7855 2 2169 1.8148 f!.2280 a = 10.7 2.5565 41 2369 3.2316 2 2440 4.2018 2 2548 4.4029 2.2573 0.0000
I
a = 11.1
10ba
21.82
e
~
a = 9.68
I
' N,N-Di-n-propylnicotinamide was also measured in pure benzene. to a series of N-alkylnicotinamides, which we had already measured in pure benzene19 and to N,N-diinpropylnicotinamide.
Experimental Section Reagents. Pyridine (Spectroquality reagent, Matheson Coleman and BeU) was used without further purification; n 2 6 ~ 1.5074 (lit.lo n 2 6 ~ 1.5073). Nicotinamide (Matheson Coleman and Bell) was recrystdlized four times from benzene, m.p. 126.8-127.3" (lit.11m.p. 129-130'). N-Methylnicotinamide (reagent grade, K & K Laboratories) was recrystallized four times from benzene, m.p. 104.8-105.3" (lit.12 m.p. 104-105"). N,N-Dimethylnicotinamide (Aldrich Chemical Co.) was vacuum distilled, b.p. 97" (0.1 mm.), n 2 S ~1.5416. N-Ethylnicotinamide (reagent grade, K & K Laboratories) was vacuum distilled, b.p. 128" (0.12 mm.). N,N-Diethylnicotinamide (Aldrich Chemical Co.) was vacuum distilled, b.p. 104' (0.09 mm.), n 2 S ~1.5233. N,N-Di-n-propylnicotinamide was prepaxed by a procedure previously described13and was vacuum distilled into a receiver pro~ tected from light, b.p. 116" (0.20 mm.), n 2 6 1.5121 (lit.14b.p. 182-183" (I6 mm.)).
4099
Soluents. The compounds were measured in dilute solutions of SpectrAR benzene (Mallinckrodt) or Spectroquality benzene (Matheson Coleman and Bell), Spectroquality p-dioxane (Matheson Coleman and Bell), and in mixtures of these solvents. Apparatus. The dielectric constants of all the solutions and the refractive indices of the pure solutes were measured at 25" as previously des~ribed.~The refractive indices of the solutions were measured to 3=0.00003 at 25" with a Bausch and Lomb Precision refractometer (sodium D-line) ; the temperature of the solutions was controlled to ztO.02" by a NBe Haake constant-temperature circulator using a thermometer calibrated against a National Bureau of Standards certified thermometer. Calculations. The dipole moments in pure benzene and in pure dioxane were calculated from eq. 116 and Smith's modificati~nl~(eq. 2) of the Guggenheim p =
0.01281(TP~)"~
PM = 3Mzs[a/(e1
+ 2)2 - r/(n12+ 2121
(1) (2)
equation," where p is the dipole moment, T is the absolute temperature, PMis the orientation polarization, M is the molecular weight, u is the specific volume, E is the dielectric constant, n is the refractive index, a is the slope of e us. the weight fraction wZ,y is the slope of n2 us. WZ,and the subscripts 1 and 2 refer to the solvent and solute, respectively. The dipole moments from extrapolation of mixed-solvent a values to pure dioxane and to pure benzene solution were calculated from a modification of the method described by Estok, et al.a-s The slope, a, was calculated for each mixedsolvent series by the method of least squares; these values for a were plotted against mole per cent dioxane of the mixed solvent and extrapolated to 0% dioxane to give abensene and extrapolated to 100% dioxane to give adioxane. The slopes, y,were determined with pure benzene and pure dioxane as solvents by the method of least squares. Smith's method16 (eq. 1 and 2) (7) P. A. Geary and J. G. Miller, J. Electrochem. Soc., 97,64 (1950). (8) W. P. Purcell, J. G. Beasley, and R. P. Quintana, Biochim. Biophys. Acta, 88, 233 (1964). (9) W.P. Purcell, J. Phys. Chem., 68, 2666 (1964). (10)V. Zawidski, Chemiker-Ztg., 30,299 (1906). (11) C. F. Krewson and J. F. Couch, J. Am. Chem. SOC.,65, 2256 (1943). (12) A. Pictet and G. Suasdorff, Chem. Zentr., 69, 677 (1898). (13) J. G. Beasley, R. P. Quintana, and G. G. Nelms, J . Mecl. Chem., 7 , 698 (1964). (14) H. Fricker, French Patent 791,783 (Dec. 17, 1936). (15) C. P.Smyth, "Dielectric Behavior and Structure," McGraw-Hill Book Co., Inc., New York, N. Y., 1966,p. 221. (16) J. W. Smith, Trans. Faraday Soc., 46,394 (1960). (17) E.A. Guggenheim, ibid., 45, 714 (1949).
Volume 69,Number 18 December 1966
4100
WILLIAMP. PURCELL AND JUDITH A. SINGER
and the Values for CYbensene, ybenzene, Odioxane, and were then used to calculate the corresponding moments. All least-squares calculations were carried out on the IBM 1620 computer, using a modification of t,he program TIPS, which prints slopes, intercepts, and deviations of the experimental points from the corresponding points on the least-squares line. Ydioxsne
Table LU: Refractive Indices Measured at 25’ in Dioxane and in Benzene Solution and the Corresponding Slopes, y (nDz vs. WB) -Dioxan108wr
Benzen-
The dielectric constants of the solutions are given in Table I. With the exception of N,N-di-n-propylnicotinamide, the dielectric constants of solutions of these molecules in pure benzene have already been r e p ~ r t e dand, , ~ therefore, we measured only the mixed benzene-dioxane and pure dioxane solutions. Table I also gives the slopes, a, for each series of solutions of solute at a particular solvent composition. The mixedsolvent cr value (Table I) were extrapolated as described under Calculations to obtain Obensene and adioxane for each compound (Table 11).
2.7850 5.0817 8.2146 9.2!200 10.363 10.772 y
0.0000 1.5110 2.6915 4.0051 y
0.0000
Table 11: Slopes, a ( E us. WZ),Extrapolated to Pure-Solvent from Mixed-Solvent Data Compound
abensene
Wioxane
Pyridine Nicotinamide N-Methylnicotinamide N-Ethylnicotinamide N,N-Dimethylnicotinamide N,N-Diethylnicotinamide N,N-Di-n-propylnicotinamide
6.99 8.87 9.69 9.08 12.0 11.0 9.20
8.15 13.0 12.4 11.2 14.7 13.0 11.5
RD
Pyridine 0.0000
Results and Discussion
loa,,
nD
1.1492 3,1346 4.2557 y
0.0000 2.9454 5.7851 8.2078 y
1.41990 1.42008 1.42027 1.42058 1.42068 1.42074 1.42077 = 0.240
0.0000
1* 49777
1.4148 2.5790 3.4973
1.49788 1.49799 1.49810
y = 0.028
Nicotinamide 0 * 0000
1.41986 1.42015 1.42037 1.42049 = 0.456
1.49782 1.49782 1.49788 1.49791 y = 0.172
0.5108 1.0765 1.7357
N-Methylnicotinamide 0.0000
1.41990 1.41999 1.42030 1.42046 = 0.386
1.49771 1.49779 1.49791 1.49805 y = 0.220
0.8271 2.1858 4.5752
N-Ethylnicotinamide 0.0000
1.41996 1.42027 1.42061 1.42092 = 0.333
6.8431 6.9379 15.275 y
1,49771 1.49802 1.49807 1.49849 = 0.153
N,N-Dimethylnicotinamide 0.0000 1.41990 o.ooO0 1.49771 Tablc I11 gives the refractive indices for the solu5.0358 1.42049 6.6566 1.49805 tions of each compound in pure benzene and pure di6.8435 1.42071 9.7393 1.49821 oxane and the corresponding slopes, y. 15.934 1.42177 18.534 1,49861 The electric moments are reported in Table IV. y = 0.145 y = 0.334 The moments measured in pure benzene solutione N ,N-Diethylnicotinamide are repeated for comparison although the benzene mo0.000 1.41990 0.0000 1.49777 ment for N,N-di-n-propylnicotinamide, 4.22, is new. 10.155 1.49805 1.42127 13.575 The value is 0.07 D. larger than that for N,N-diethyl22.558 1.49841 1.42177 18.624 nicotinamide, which is consisttent with the electron re41 .669 1.49891 1* 42202 20.995 leasingla effect of alkyl groups and the trends prey = 0.082 y = 0.286 viously reported.9 The N,N-di-n-propylamide group N,N-Di-n-propylnicotinamide moment, calculated from the ‘‘75% trans” m e t h ~ d , ~ 0.0000 1.49779 1.41993 0.0000 is 5.12. 4.0546 1.42033 4.1752 1.49788 Comparing the differences between the benzene and 9.5375 1.49799 1.42049 5.5491 1.49810 dioxane moments measured in the pure solvents, one 10.368 1.42093 15.368 y = 0.060 y = 0.274 finds an interesting trend. Nicotinamide shows the greatest difference, 0.37, and has two amide hydrogen atoms available for hydrogen bonding to the oxygen atoms in dioxane, thus inducing moments and in(18)C. A. Coulson, “Valence,” 2nd Ed., Oxford University Prese, creasing the observed moment in dioxane. N-MethylLondon, 1961, pp. 356-365.
The Journal of Physical Chemistry
BENZENE AND DIOXANE ELECTRIC MOMENTS OF NICOTINAMIDES
Table IV : Electric Moments, D. lrdiorsne
&benzene
Compound
Pyridine Nicotinamide N-Methylnicotinamide N-Ethylnicot inamide N,N-Dimethylnicotinamide N,N-Diethylnicctinamide N,N-Di-n-propylnicotinamide
from extrapfrom extrapolation olation of mixedof mixedlrdiorane solvent Pbencene solvent from data to from data to pure 100% pure 100% solvent dioxane solvent" benzene
2.27 3.07 3.42
2.25 3.13 3.44
2.33 3.44 3.65
2.24 3.50 3.63
3.44
3.51
3.63
3.62
3.99
4.04
4.11
4.16
4.15
4.23
4.25
4.26
4.22
4.16
4.24
4.30
Electric moments in benzene at 25' of all compounds, exclusive of N,N-di-n-propylnicotinamide, previously reported: W. P. Purcell, J . Phys. Chem., 68, 2666 (1964).
nicotinamide, which has only one amide hydrogen a.vailable for bonding, has a smaller difference, 0.23, and the difference for N-ethylnicotinamide, 0.19, is still a little smaller, probably because the bulkier ethyl group interferes sterically with the solvating molecule(s). The disubstituted derivatives have even smaller differences which decrease with increasing size of the substituent groups--i.e., N,N-dimethylnicotinamide, 0.12; N,Ndiethylnicotinamide, 0.10; N,Ndi-n-propylnicotinamide, 0.02. Comparing the benzene moments measured in pure benzene with those calculated from mixed-solvent measurements, one sees very little difference; the greatest difference is between the two moments of diethylnicotinamide, 4.15 and 4.23, which is larger than the experimental error for this compound. Similarly,
4101
the differences between the dioxane moments measured in pure dioxane and those calculated from mixedsolvent measurements are small, the largest difference being 0.09 D. One might conclude, therefore, that the mixed-solvent technique apparently offers little advantage (for these hmologs) since virtually the same moments are obtained from pure-solvent measurements, and considerably less experimental work is required in the latter technique. We wish to add, however, that the dimers formed from these 3-pyridine derivatives would generally have moments not equal to zero, and, therefore, the fact that the pure-benzene moments and the benzene moments from mixed solvents are the same would not necessarily indicate that there is no solutesolute association in pure benzene. Furthermore, the benzene and dioxane mixed-solvent moments and the pure-dioxane moments increase in the same direction as the pure-benzene moments, so the application of this technique does have the advantage of corroborating our earlier discussion.@ There are three exceptions, however: the benzene moment of N,Ndiethylnicotinamide measured by the mixed-solvent technique is larger than the corresponding N,Ndi-npropylnicotinamide moment by 0.07 D.; the dioxane moment of N-methylnicotinamide measured by mixed solvents is larger than the corresponding N-ethylnicotinamide moment by 0.01 D. ; and the dioxane moment of N,N-diethylnicotinamide measured by mixed solvents is larger than t'he corresponding N,N-di-npropylnicotinamide moment by 0.01 D. The first exception has a moment difference which does seem somewhat large, but the second and third are certainly within the experimental error.
Aclcnowbdgment. The authors wish to thank Dr. R. P. Quintana for synthesizing and supplying a sample of N,Ndi-n-propylnicotinamide and Dr. C. W. Sheppard and Mrs. A. B. McEachran of the University of Tennessee Medical Units Computer Center for their help in processing the data.
Velum 69,Number 12 December 1966
