BASESTRENGTHS OF CYANOAMINES
Nov. 20, 1958
TABLE V DISSOCIATIONCONSTANTS OF 3-sUBSTITUTED-3-METHYLACRYLIC ACIDS Substituent COzEt Et Me
c1 H
106K 553 7 , la 7.6= 36 95
Method of evaluation Conductimetric Conductimetric Conductimetric
Ref. 25 11 11 12 12
Acid 3-Carboxyethyl-3-methylacrylic 3-Methyl-2-pentenoic 3-Methyl-2-butenoic 3-Chloro-2-butenoic Isocrotonic
All data in water a t 25”. The configuration in these acids is such that the methyl group is cis t o the carboxyl group. The dissociation constants are non-thermodynamic unless otherwise stated. a Thermodynamic constant.
From these correlations, it can be seen that the Hammett equation is directly applicable to the trans-olefinic systems. Other reaction series are now under consideration. Acknowledgment.-The‘ helpful advice and discussion of Professor H. Nechamkin, Pratt Institute,
[ CONTRIBUTIOE FROM
THE
5943
TABLE VI DISSOCIATIONCONSTANTS O F 3-STJBSTITUTED-3-CARBOXYACRYLIC ACIDS(SUBSTITUTED MALEICACIDS) Substituent
106K
Method of evaluation
Ref.
Acid
H Me Et C1 Br OH
14.2 5.14 2.30 10.0 35.0 2.505
From gH From PH Conductimetric From pH From p H Conductimetric
26 26 27 26 26 28
Maleic Citraconic Ethylmaleic Chloromaleic Bromomaleic Hydroxymaleic
is gratefully acknowledged. The authors wish also to acknowledge the suggestion of one of the reviewers regarding the use of the substituent constants proposed by McDaniel and Brown,20thereby making unnecessary the use in some cases of upvalues. (27) K. Von Auwers and 0. Ungenach, Aizn., 611, 152 (1934). (28) A. Wohl a n d P. Clausner. Ber., 40, 2308 (1907).
BROOKLYN, N. Y.
DEPARTMEST OF PHARMACOLOGY AND TOXICOLOGY, UNIVERSITY OF CALIFORNIA AT Los ANGELES MEDICAL SCHOOL]
Base Strengths of Cyanoamines] BY GEORGEW. STEVENSON AND DALLAS WILLIAMSON RECEIVED JUNE 2, 1958 Substitution of aliphatic amines with cyano groups lowers their basicities. The iY-cyano, a-cyano, 0, 7,6 and e-cyanoamines are weaker by approx. 13, 5.7, 3.1, 1.6, 0.8 and 0.4 pK units, respectively. The ApK, of n cyanosubstituted amines = approx. n (single AgK). The lowered basicity appears due to the large inductive field effect of the cyano group. A spectrophotometric method was developed t o determine the p&’s of the very weak bases. Because of the wide range of pK,’s of the cyanoamines, their ease of preparation, and stability, aliphatic cyanoamines should be useful.
During the course of conversion of secondary to tertiary bases by cyanoethylation it was found that the tertiary cyanoethylamines were considerably weaker bases than the secondary amines and about 3 pK units weaker than the corresponding tertiary ethylamines. That the highly electron-withdrawing cyano group should exert a base-weakening effect was to be anticipated but its magnitude was surprising. Despite the large number of cyanoamines which have been synthesized, only one paper dealing with the base strengths of the cyanoamines, by Marxer,2ahas appeared.2b Mamer found that the formation of cyanomethyl tertiary amines from several secondary amines resulted in an average decrease in pKa of 6.5 pK units.2a However, i t was shown that the pKa of a-piperidine-isobutyronitrile was less than that of piperidine by only 2.0 pK units. It has been found in this investigation that the (1) T h i s investigation was supported by Research G r a n t B-1106 from t h e National Institute of Neurological Diseases and Blindness of the National Institutes of Health, U. S. Public Health Service. Presented in part a t t h e 133rd National Meeting of t h e American Chemical Society, San Francisco, Calif., April 13-18, 1958. (2) (a) A . Marxer, Hels. C h i m . Acta, 37, 166 (1954). (b) Since t h e completion of this work another paper dealing with t h e PK,’s of Ncyano-, a-cyano- and B-cyanoamines has been published: S. Soloway and A. Lipschitz, J . O v g . C h e m . , 23, 613 (1958). T h e pK,’5 of 11 compounds are given, 5 of which are included also in this study. T h e pK.’s are in reasonable agreement except for t h a t of diethylcyanamide which is reported by the above authors as 1.2; see footnote 7b.
cyano group is more effective than all others in lowering basicity, possibly excluding some in which the electronegative group is attached directly to the nitrogen. Published pK values for some other types of amines are given below. Groups also can be compared using 6*-values as shown below. Taft has compiled a list of 6 * - v a l ~ e s . ~ The pKa’s of N-chlorodimethylamine and Nchlorodiethylamine have been reported as 0.46 and 1.02 by Weil and Morris.4 A series of pchloroethylamines has been titrated by Cohen, et aL5 The weakest of these was tri-b-chloroethylamine with a pK, of 4.39. This is a much stronger base than the corresponding cyano compound which has a PK, of 1.1. The effect of the fluoro group is comparable with that of the chloro. The hydroxyl has a considerably smaller effect, the $Ka of hydroxylamine being 5.976 and that of triethanolamine, 7 . 7 7 . I a (3) R. W. T a f t , J r . . in M . S. Newman’s “Steric Effects in Organic Chemistry,” John Wiley and Sons, Inc., New York, N. Y . ,1956, p. 619. (4) I. Weil and J. C. Morris, THISJOURNAL, 71, 3123 (1949). (5) B. Cohen, E. R . Van Artsdalen and J. Harris, ibid., T O , 282 (1948). (6) T. C. Bissot, R. W. Parry and D. H. Campbell, ibid., 79, 799 (1957). (7) (a) N. F. Hall and M. R. Sprinkle, ibid., 64, 3473 (1932). (b) I n addition t o t h e value for t h e p K , of this compound, -2.0 as determined by the spectrophotometric method, two additional observations indicate the p K , of this compound must be less than zero. When diethylcyanamide (either Eastman No. 6320 01 t h a t prepared for this study) was dissolved in water a t room temp., about 1.3 ml. saturated
Considering the wide range of pK,'s of the cyanoamines, their ease of preparation and their relative stability, these compounds are unique and potentially useful aliphatic amines. I n order to explore preparation of these compounds, and to determine the relation between the structure of cyanoalkyl amines and their basicities, the cyanodiethylamines from diethylcyanamide to diethylaminocapronitrile and various multi-cyano substituted amines were prepared and their pK's measured. I n Table I a.re listed the pK,'s of the various cyanoamines, their ApK's with the compounds in which -CN has been replaced with -H, and their ApK's with the unsubstituted starting amine, either ammonia, or a primary or secondary amine. The N-cyano compound has only slight basicity with a pKa of -2.0,ib whereas the longest-chained compound in the series, diethylaminocapronitrile, has a pKa of 10.46, only 0.44 pK unit weaker a base than the corresponding alkylamine. The rate of decrease of ApK per additional methylene group between the amino and cyano groups appears to indicate that there is little or no difference in the pK's of the longer chained cyano- and alkylamines, although this has not yet been experimentally demonstrated. ,Multi-substitution by cyanoalkyl groups on amines produces approximately equivalent decrements in the pK's in the cases of two cyanomethyl substituents or either two or three cyanoethyl substituents. The base-weakening effect of the cyano group is probably due either to inductive, field effects, or to a direct interaction of the cyano group with the amine by quasi-ring formation or intermolecular complexing. That the base-weakening is not due to direct interaction is shown by the facts that the cyanomethylamine's are weak bases but could not form quasi-rings, by the equivalent decrements of pk' of additional cyanoalkyl groups and by the regular decrease of the base-weakening effect with 10 nil. of distilled water, whereas about 1.4 mi. saturated 10 ml. of 1 hf EICI. T h e p H of this latter saturated solution was within 0.02 p H t i n i t of th.rt of pure 1 AI HCt, though t h e mole ratio of diethylcyanamirle"HC1 was greater t h a n 1. Both t h e failure of significant increase i n the solubility or g H in t h e 1 JI HCI solution indicates t h a t salt furmation did not take place t o any significant extent ecen in 1 A!! HCI. T h e PK. of diethylcyanamide therefore cannot he measured u i i n s t h e experimental method described by Soloway and Lipschitz. T h a t the p R s value - 2 . 0 refers to protonation of t h e EtlN-nitrogen is nut certain, since protonation of the cyano nitrogen is also possible. Some additional observations are peitinent. When t h e compound was c!:,soivcd in 1 8 ,if HCI there was a rapid but gradual increase in t h e rirbancr a t 210 or 212 mfi up t o appron. 20 X the initial absorbance l i i n 1 hour. After dilution t o 0.9 h ' acid there was a slower decrease in absorbance (to 33yG in 20 min.). I n 1.8 M HzSO4 no appreciatrle increase in absorbance occurred. I n t h e higher concenlratiirns of II?SOa necessary for rneasurement of the P K , , absorbance did increase with time making necessary rapid measurement of absorbance and back extrapolation of t h e values t o obtain t h e initial decrease in absorbance probalilp due t o salt formation. The most re;i.;onal,le explanation of these results is t h a t a n intermediate in t h e Iiydrol)-iis of these compounds is formed reversibly and more readily with HCl t h a n with H2S0,. T h e reaction m a y be (CHsCHz)%ZNC=SRII S q (CHaCHi)zSCR=SH. T h e protonation of this latter type of compound is proposed a s t h e rtite-determining step in t h e hydrolysis of cyanamides by S. Ohishi and 1%.Takamnra, l i d Chcni. SOC.J Q ~ ~2'7, z 41G-421 , (19.54). I t is most likely t h a t (CHaCHz)zI\'C= +KH is only a transitory intermediate in formation of the imino chloride or imino bisulfate whereas ( C H 3 C H ~ ) ~ ' X H C r Nis the salt in the proton, base, salt equilibrium.
+
pK,'s
AND
TABLE I ApK.'s OF THE CYANOAMINES~ --npKa-----.
RCN
EtzSCN EtzXCHzCX Et*N(CHz)zCN EtzS( CHz)sCN Etzh'( CHJ4CN Et?N(CHz)6CX EtzXC(CH3)zCS
$Ka
Cyanodiethylamines - 2 . 0 =t0 . 3 13.C" 4.55 5 7Ab 7.65 3 , If) 9.2'3 1.56 10.08 0.82 10.46 0.44 0.13
Multi-cyano substituted HK(CHzCS)t 0.2 E t N (C H Z C K ) ~ -0.6 + HS(CHZCH,CK), 5.26 EtS(CHzCH2CK) 2 4.55 N(CHzCHzCT*;)a 1.1 k
*
-
(-RH) -(>NH) (-KCXI (>.URCN)
13.0"
6.43" :j . :j:ju
1.69" 0 , 9(1°
0.5Y 1.85"
aniincs . I 1 0 . 4 ~ D.O" . 1 10.6' 11.3' 5.72" 3.96" 6.20 6.120 .1 9 . 6 8.1'
Other cyanoamines HzSCHzCS 5.34 5.2P 3 8F,* K-Piperidine-CHXX 4.55c 5.53' 6.67i" S-Piperidine-C(CHJ*CS 9.22' 2 . ODk 3.;-Amphetamine-(CH*)*C Y 7.23 2.92" 2.65" S-hlethamphetamine(CHz) 2CKp 6 '35 3.13 S-T\'nrcodeine-(CHz)nCS 5 . 68 3.41 " of diethylamine =: 10.98; Hall and Sprinkle, ref. 7a.'$>K, of methyldiethylamine = 10.29; J. Hansson, Svensk. Kem. Tidskrift, 67, 256(1955). Eastman No. P7164, rec:ystallized from ethanol, m.p. 75-76" (Kofl.), m.p. 75-77 , H. S.Mosher, J. Cornell, Jr., 0. L. Stafford and T. Roe, Jr., T H I SJOURSAL,75, 4953 (1953). p?. of dimethylamine = 10.64; ref. 7n. e pK, of ammonia = 9.22; D. H. Everett and IV. F. K. lyynne-Jones, Proc. Roy. SOC.(London), A169, 190 (1938). PI
