658 J . Org. Chem., Vol. 58,No.
4, 1973
ZOLTEWICZ AND HELMICK
06-1 ; 3e, 37528-68-0; 4, 1713-37-7 ; 6 , 16618-72-7 ; 7, 37488-35-0; 8a, 37488-36-1; 8b, 37488-37-2; 8c, 37488-38-3; 10, 37500-24-6; 11, 37488-39-4; isopropylamine hydrobromide, 29552-58-7 ; benzylamine hydrobromide, 37488-40-7.
Acknowledgment.-This work was supported in part by Grant CA-02931 from the Yational Cancer Institute of the U. S. Public Health Service and by a grant from the Damon Runyon Memorial Fund for Cancer Research.
Ionization in Liquid Ammonia of Methyl and Amino Groups Bonded to Pyridine and Pyrazine. A Method of Determining Their PI(,Values' JOHNA. ZOLTEWICZ*~ AND LARRY 8. HELMICK Department of Chemistry, University of Florida, Gainesville, Florida 51601 Received September 1 1 , 19?'?2 Proton magnetic resonance spectra of ionized 2-methyl and 2-amino derivatives of pyridine and pyrazine along with spectra of 2-pyridone and 2-pyrazinone in liquid ammonia are reported. Changes in chemical shifts produced by ionization of the pyridines are linearly related to those for the pyrazines. Competition experiments show that 2-methyl- is less acidic than 4-methylpyridine; estimates of the pK, values for these two acids are given. It is suggested that the results provide a basis for determining the equilibrium acidities of weak heterocyclic acids.
The acidities of heterocyclic molecules containing carbon or nitrogen side chains having pK, values >20 are largely ~ n d e t c r m i n e d . ~Liquid ,~ ammonia is an attractive solvent for the determination of pKa values of these weak acids. Ammonia has long been used to study the kinetic acidities of weak acids, both carbocyclic and hetero~yclic.~,~ Its vcry low self-ionization constant (pK = 32.5 at -33')s allows high concentrations of the conjugate bases of the u-eak acids to be formed. The recent determination of pKa values for a few carbocyclic nitrogen and carbon acids in ammonia by means of potentiometry, nmr, and ultraviolet spectroscopyg encouraged US to study weak heterocyclic acids. We have found nmr to be a useful way to study the ionization of pyridines and pyrazines in ammonia and report results dealing with the ionization of methyl and amino groups bonded to these heterocyclic rings. That simple ionization takes place in the presence of amide ion was established by consideration of nrnr spectra and by a correlation involving changes in chemical shifts resulting from the deprotonation of these weak acids and the more readily ionizable compounds 2-pyridonc and 2-pyrazinone. lo Our results pave the (1) Presented in p a r t a t the Gordon Conference on Heterocyclic Chemistry, K e w Hampton, N . H . , June 26-30, 1972. (2) T o whom correspondence should be addressed. (3) K . K~ Zatsepina, .4. V. Kirova, and I. F. Tnpitsyn, Org. Reactiu. ( U S S R ) , 6, 70 (1968). (4) I n marked contrast, considerable effort has been applied to the determination of pK, values for weakly acidic aromatic hydrocarbons.6,s ( 5 ) D. J. Cram, "Fondamentals of Carbanion Chemistry," Academic Press, X e w York, N. Y . , 1965; A . Streitmieser, Jr., and J. H. Harnmons, P T o g r . Phgs. Org. Chem., 3, 41 (1965). (6) H. Fischer and D. Rewicki, Progr. Org. Chem., 7, 116 (1967). (7) A . I. Shatenshtein and I. 0. Shapiro, Rusa. Chem. Rev., 37, 845 (1968); A . I. Shatenshtein, Aduan. Phys. O m . Chem., 1, 156 (1963); Tetrahedron, 18, 95 (1962); K. K. Zatsepina, I. F. Tupitsyn, A . V. Kirova, and A . I. Relyashova, Org. Reactiu. ( U S S R ) , 8, 787 (1971). (8) L. V. Coulter, J. R . Sinclair, A. G. Cole, and G. C. Roper, J . Amer. Chem. Soc., 81, 2986 (1959). (9) J. J. Lagowski, P u r e Appl. Chem., %E, 429 (1971). (10) Anions of the type considered here can be trapped by electrophiles in ammonia; the reactions are of preparative value.">'2 (11) H. C. Brown and W. A. Murphy, J . Amer. Chem. Soc., 78, 3308 (1951). (12) W. Schwaiger and 3 . P. Ward, Recl. Trau. Chim. Pays-Bas, 90, 513 (1971); S.V. Kannan and H. Pines, J . Org. Chem., 36, 2304 (1971); G. W. H. Cheeseman and E. S. G . Werstiuk, Aduan. Heterocgcl. Chem., 14, 99 (1972).
way for the determination of pK, values for these and many more weakly acidic heterocyclic molecules in ammonia. They also provide the first reliable estimates of the pKa values for 2- and 4-methylpyridines. Results and Discussion Pyridines. --Addition of 2-methylpyridine to an excess of KNH2 in ammonia gives a highly colored solution. I t s nmr spect,rum shows at -40" no evidence of unreacted starting material or any other component in addition to ionized substrate. Chemical shifts and coupling constants are given in Table I. The ring protons of the anion are shielded by 1.6, 1.7, 2.3, and 1.3 ppm for the 3, 4, 5, and 6 positions, respectively, relative to t'he starting carbon acid in ammonia. The methylene group shows a clear AB pair of doublet's a t -40°, T 7.4 and 7.55 ( J = 3.2 He). These shifts are very similar to that of the methyl group, T 7.5. No change in the spectrum could be detected after the sample stood for 1 week at room temperature, indicating a surprising stability. The large shielding values and the nonequivalent methylene prot'ons indicate that a largely ionic compound is formed;13 charge delocalization into the ring leads to double-bond character and restricted rotation about the met'hylene-ring bond. When the carbon acid is incompletely neutralized, signals for both the acid and its conjugate base are present. There is no evidence of signal averaging. This is to be expected. The nmr spectrum of this 2-pyridylmethylpotassium in ammonia is very similar to that of 2-pyridylmethyllithium in tetrahydr~furan.'~The shielding of ring and methylene prot'ons of the sample in ammonia is no greater than 12 Hz; coupling constants for ring protons (13) I t is expected t h a t ion pairing will be important in ammonia for this and the other compounds Considered here.g$'"*'b Hence, pKa values are ion-pair values.' (14) M. Fisher and M. Szwarc, Macromolecules,3, 23 (1970); M. Sohlosser, Angew. Chem., Int. Ed. Engl., 3, 287 (1964); "Ions and Ion Pairs in Organic Reactions," Val. 1, M. Szwarc, E d . , Wiley-Interscience, New York, N. Y., 1972. (15) J. H. Takemoto a n d J . J. Lagowski, J . Amer. Chem. Soc., 91, 3785 (1969). (16) T . Birchall and K.L. Jolly, i b i d . , 87, 3007 (1965). (17) K. Konishi, K . Takahashi, and R. Asami. B u l l . Chem. Soc. J a p . , 44, 2281 (1971).
IONIZED PYRIDINE AND PYRAZINE DERIVATIVES
J. Org. Chem., Vol. 38, No. 4, 1973
659
TABLE I CHEMICAL SHIFTS AND COUPLINQ CONSTANTS FOR IONIZED 2-SUBSTITUTED PYRIDINES IN
AMMONIA
J , Hz
-
X
3
4
5
6
3,4
3,5
3,6
4,5
4,6
5,6
I, CH2 "
4.61 4.24 3.98
3.93 3.34 2.89
5.23 4.54 4.03
3.00 2.55 2.26
9.0 8.5 8.5
1.3 1.5 1.2
1.0 1.0 1.0
6.0 6.5 6.5
2.0 2.0 2.5
4.8 5.0 5.0
0
differ by less than 0.7 Hz. (The methylene group was said to be br0ad.I') Because the material in ammonia is largely ionic and because the spectra of the tq70 salts in the two solvents are so similar, it seems likely that the lithium compound also is largely ionic. The nmr spectra of ionized 2-aminopyridine and 2pyridone in ammonia also were obtained. Since 2methylpyridine is completely ionized by an excess of amide ions, the more acidic amino and oxy compounds also must undergo total ionization in the presence of excess amide ions. Again, deprotonation brings about shielding of the ring protons but shielding factors are smaller than those for methyl group ionization, being in the range 0.3-1.1 ppm. Unlike the carbon acid just considered, separate signals for these acids and their conjugate bases are not expected, owing to rapid proton exchange.lO Comparison of the three isoelectronic conjugate bases, Table I, reveals that coupling constants are virtually identical. Chemical shifts vary in an understandable way. As more negative charge resides on the side chain in the order expected from atom electronegativity considerations, i e . , X = CH2, n",and 0, respectively, in I, smaller shielding factors result for the ring protons. Indeed, the spectral similarities firmly support the idea that the three pyridines only undergo simple ionization in the presence of amide ions to give charge-delocalized ion I. 4
I, X = CH2,NH, 0
The nmr spectrum of the anion of 2-pyridone in D20 has been reported.18 Comparison of the spectra obtained from ammoniacal and aqueous solutions indicates that there are only minor differences in coupling constants (29. That this acid is completely ionized by amide ion means pK, < 33.2. I n other words the pKa is >29 but
