R. H. Cox AND A. A. BOTHNER-BY
1646
Proton Nuclear Magnetic Resonance Spectra of Monosubstituted Pyrazines
by R.
H.Cox and A. A. Bother-By
Mellon Institute, CarnegisMellon University, Pittsburgh, Pennsylvania
16213 (Received October 27, 1967)
The proton spectra of eight monosubstituted pyrazines have been analyzed in terms of chemical shifts and coupling constants. Trends in the parameters obtained for the pyraaines parallel those of the monosubstituted benzenes and pyridines. Spin-tickling experiments show the sign of the meta-coupling constant across the nitrogen atom to be negative. Evidence for the existence of 2-hydroxypyrazine in the keto form is presented.
Introduction Substituted benzenes, pyridines, and diazines [pyridazine (I),pyrimidine (11), and pyrazine (III)] form a related family of compounds of great current interest, providing abundant experimental test material for various concepts of electronic structure. Theories ranging from rule of thumb to sophisticated quantum mechanical analysis have been employed to predict such properties as basicity, ease of chemical attack, tautomeric behavior, and spectral characteristics including uv, ir, and nmr parameters.’
solids were used as received; liquids were purified by vacuum distillation. Melting points and boiling points agreed with literature values. Known procedures were
(1) A. R. Katritrky, Ed., “Physical Methods in Heterocyclic Chemistry,” Vol. 11, Academic Press Inc., New York, N. Y., 1963. (2) S. Castellano and C. Sun, J . Am. Chem. SOC.,88, 4741 (1966). (3) S. Castellano, R. Kostelnik, and C. Sun, Tetrahedron Letters, in press. (4) S. Castellano, private communication. (5) V. J. Kowalewski and D. G. de Kowalewski, j. Chem. Phys., 36, 266 (1962). (6) V. J. Kowalewski and D. G. de Kowalewski, ibid., 37, 2603 (1962). (7) V. J. Kowalewski, D. G. de Kowalewski, and E. C. Fer& J . Mol. Spectry., 20, 203 (1966). (8) W. Brtlgel, Z. Elektrochem., 66, 159 (1961). (9) S. Castellano and A. A. Bothner-By, J. Chem. Phys., 41, 3863 (1964). (10) S. Castellano, H. Gtlnther, and S. E. Ebersole, J. Phys. Chem., I 69, 4166 (1965). (11) S. Castellano, C. Sun, and R. Kostelnik, J . Chem. Phys., 46, Substituted benzenes have been the subject of a 327 (1967). recent intensive investigation by cast ell an^,^-^ while (12) J. B. Merry and J. H. Goldstein, J . A m . Chem. Soc., 88, 5560 pyridines have received attention from the Kowalew(1966). skis,5-’ Brugel,s Ca~tellano,g-~~ and Merry and Gold(13) V. M. S. Gil, Mol. Phys., 9, 443 (1965). stein.12 Among the diazines, pyrida~inesl~-~l and (14) K. Tori, M. Ogata, and H. Kano, Chem. Pharm. Bull. (Tokyo), 11, 235 (1963). pyrimidine^^^-^^ have been examined in detail. How(15) K. Tori and M. Ogata, ibid., 12, 272 (1964). ever in the case of pyrazines, investigations have been (16) A. H. Gawer and B. P. Dailey, J . Chem. Phys., 42, 2658 (1965). much more limited in scope. Several workers have (17) P. C. Lauterbur, ibid., 43, 360 (1965). reported the C13-H coupling constants in p y r a z i n e ~ l ~ ~(18) ~ ~J. N. Murre11 and V. M. S. Gil, Trans. Faraday SOC.,61, 402 (1965). and in its methyl derivatives, as well as the proton (19) A. Mathias and V. M . S. Gil, Tetrahedron Letters, 3163 (1965). shifts.16,16,18,34,a6 An analysis of the proton spectrum (20) K. Tori and T. Nakagawa, J . Phys. Chem., 68, 3163 (1964). of pyrazine, using the C1* satellite signals, has been (21) F. Declerck, R. Degroote, J. de Lannoy, R. Nnsielski-Hinkens, given;’5 and recently the spectra of a few carbonyl and J. Nasielski, Bull. SOC.Chim. Belges, 74, 119 (1965). side-chain derivatives of pyrazine have been reported.36 (22) C. D. Jardetzky and 0. Jardetsky, J . Am. Chem. SOC.,82, 222 (1960). In this paper are reported the results of a complete (23) E. 8 . Gronowitz and R. A. Hoffman, Arkiv Kemi, 16, 459 analysis of the nmr spectra of eight monosubstituted (1960). pyrazines. Values obtained for the parameters are (24) E. S. Gronowitr, B. Norrman, B. Gestblom, B. Mathiasson, compared with results obtained from the analyses of and R. A. Hoffman, ibid., 22, 65 (1964). substituted benzenes and pyridines. (25) J. P. Kokko, J. H. Goldstein, and L. Mandell, J . A m . Chem. SOC., 83, 2909 (1961). (26) G. S. Reddy, R. T. Hobgood, Jr., and J. H. Goldstein, ibid., 84, Experimental Section 237 (1962). Materials. The chloro, amino, methyl, and amide (27) R. U. Lemieux, R. K. Kullnig, H. J. Bernsteili, and W. G. Schneider, ibid., 79, 1005 (1957); 80, 6098 (1958). derivatives were of commercial origin. Crystalline
II
The Journal of Physical Chemistry
ID
PROTON NMRSPECTRA OF R~ONOSUBSTITUTED PYRAZINES
1647
Table I : Proton Nmr Parameters of Monosubstituted Pyrazines
Substituent
Solventa
88
2-OH 2-NHz 2-OCHs 2-CH3 2-c1 2-F 2-COzCHs 2-CONH2
DMSO DMSO DMSO CDCh DMSO DMSO DMSO DMSO
9 . 790d 6 . 320d 3 .95Sd 2 . 566d
...
...
3.991d 7 .900d 8. 280d
68
7.922 7.941d 8.309 8.568 8.714 8.726 9.222 9.253
66
6s
7.296 7.705 8.219 8.376 8.599 8.696 8.933 8.896
7.398 7.899 8.224 8.453 8.463 8.423 8.859 8.756
JasC
-0.047 -0.277 -0.354 -0.199 -0.395 -0.462 -0.296 -0.012
Jas
JSS
1.338 1.541 1.394 1.479 1.432 1.331 1.487 1.509
3.914 2.771 2.857 2.555 2.606 2.667 2.426 2.494
* I n ppm downfield from internal tetramethylsilane. a DMSO = dimethyl sulfoxide. methyl protons a t the given numbered position. used to prepare the flu0~0,~' m e t h o ~ y and , ~ ~ methyl es ter39 derivatives. Hydroxypyrazine was prepared by acidifying the commercially available sodium salt of pyr azinol and working up the reaction mixture according to a procedure given by Erick~on.~ONo impurity peaks could be observed in any of the recorded spectra. Samples were made up gravimetrically to 10 mole % (except for the amide, which was 5 mole %) of a sohtion containing 2% tetramethylsilane as an internal reference and lock signal source. All samples were degassed and sealed under vacuum. Spectra. Proton nmr spectra were obtained using a Varian Associates HA-100 spectrometer. Frequencysweep spin-tickling and spin-decoupling experiments were performed using a Hewlett-Packard 201 CR audiooscillator monitered by a Varian V-4315 frequency counter. Calibration of the spectra was by the usual side-band method. Line positions were obtained by averaging the results of two upfield and two downfield scans. A scan width of 50 Hz was employed with sweep times of either 1000 or 2500 sec.
Results Spectra were analyzed in terms of chemical shifts and coupling constants using the computer program LAOCN 3.4i Results obtained from the analyses are given in Table I. Data are reported to three decimal places as obtained from the output of the computer. Calculated probable errors for the parameters were less than 0.03 He. Although proton signals in the spectra of the monosubstituted pyrazines are broadened somewhat owing to residual coupling with the nitrogen atoms, resolution was sufficient to observe the expected lines. A typical spectrum is that of 2-chloropyrazine, shown in Figure 1. Spin-tickling experime~its~~ were carried out on 2chloro- and 2-fluoropyrazine in order to establish the
n
Jir
J26
J20
...
,..
... ...
... .., f0.21d
...
-8.172
... ,
I n hertz.
8
Ho
.
I
... ...
.,.
~ k 0 . 4 5 ~ f0.70d
...
4.723
... ...
...
-1.433
...
...
Shift or coupling constant of
A,
-
Figure 1. Proton nmr spectrum of 2-chloropyraxine in DMSO solution a t 100 MHz.
relative signs of coupling constants. When line 12 (see Figure 1) of the C part of the spectrum of 2-chloropyrazine was irradiated with a weak radiofrequency (28) It. U.Lemieux, It. K. Kullnig, and R. T.Moir, J . Am. Chem. SOC.,80, 2237 (1958). (29) J. B. Leane and R. E. Richards, Trans. Faraday Soc., 55, 518 (1959). (30) H. T. Miles, R. B. Brsdley, and E. D. Becker, Science, 142, 1569 (1963). (31) B. W. Roberts, J. B. Lambert, and J. D. Roberts, J . Am. Chem. Soc., 87, 5439 (1965). (32) L. Bauer, G.E. Wright, B. A. Mikrut, and C. L. Bell, J . Hetero"ycl. Chem., 2, 447 (1965). (33) D. Herbison-Evans and R. E. Richards, Mol. Phys., 8, 19 (1964). (34) H.Kamei, J . Phys. Chem., 69, 2791 (1965). (35) J. C. N Ma and E. W. Warnhoff, Can. J . Chem., 43, 1849 (1965). (36) S. K. Chakrabartty and R. L. Levine, J . Heterocycl. Chem., 4, 109 (1967). (37) H. Rutner and P. E. Spoerri, ibid., 492 (1965). (38) A. Albert and J. N. Phillips, J . Chem. Soc., 1294 (1956). (39) 6. A. Hall and P . E. Spoerri, J . Am. Chem. Soc., 62, 664 (1940). (40) A. E.Erickson and P. E. Spoerri, ibid., 68, 401 (1946). (41) A more efficient version of the program LAOCOON 11, described by Castellano and Bothner-By.9 (42) R . H. Cox and S. L. Smith, J . Phys. Chem., 71, 1809 (1967). Volume 72, Number 6 Moy 1968
1648 field, lines 5 and 7 of the B region and lines 1 and 3 in the A portion of the spectrum were affected. Similarly when line 9 was irradiated, lines 6 and 8 of the B region and lines 2 and 4 of the A portion of the spectrum were affected. These results d e m o n ~ t r a t ethat ~ ~ J35must be opposite in sign from J 3 6 and J56. Making the usual assumption that vicinal H-H couplings are positive,4*~45 the absolute sign of J 3 5 in Table I is given as being negative. Spin-tickling experiments carried out on 2-fluoropyrazine establish the following in relation to signs of the various couplings: J35 opposite to J56; J35 opposite to J36; J 2 e opposite to J Z B and ; J 2 0 same as J24. As before, JaS is deduced to be negative, and Jaeand J 5 6 are deduced to be positive. Relative signs of the H-F couplings cannot be related to the H-H couplings from these experiments. However, relative sign determinations of the H-F couplings in various 2-fluoropyridines46have shown J 2 3 to be negative. Therefore, it seems reasonable to assume J 2 3 to be negative in 2-fluoropyrazine1 whence J 2 6 is negative and J 2 5 is positive. Parameters were obtained for the ring protons of 2-methylpyrazine by recording the spectrum while irradiating the methyl signal, thereby reducing the spectrum to a three-spin case. Values given in Table I for couplings to the methyl protons were obtained from a first-order analysis of the methyl signals, and no signs were determined.
R. H. Cox AND A. A. BOTHNEIZ-BY
7.6
.
“5
E
,
a
.-c
m”
-
,, ,
,
I,“
,
2 ;1
,
,
,;a
I
,
,
,
I
I
6.4
0 3
c .-
.-” E r“ u
7.4 --
PARA
ea
0
7.0
-
4
-
6
3
I
6.6
co
0
-
0
I
,
I
,
1
,
I
,
,
,
I
,
I
,
l
,
I
,
,
Discussion Chemical Shijts. The effect of substituents on chemical shifts is roughly parallel to that in monosubstituted benzenes. Comparison of shifts in the 3, 5 , and 6 positions of 2-substituted pyrazines, with oTtho, meta, and para proton shifts in monosubstituted benz e n e ~ , ~shows - ~ similar behavior (Figure 2) with the protons of the pyrazines occurring -1.4 ppm to low field of the corresponding protons in the benzenes. When the chemical shifts of 2-substituted pyrazines are compared with those of 2-substituted pyridines,6+-10 the comparison is not as linear as that found between monosubstituted benzenes. Nevertheless, similar trends are observed. As is the case with benzenes, there is a general, somewhat parallel movement of the chemical shifts of all three protons to lower field as conjugative electron donation (CH,O, ”2) gives way to conjugative electron withdrawal (CONH2, COZCH,). For the 5 and 6 protons, the chemical shifts cross over each other at this point: 65 < 66 (CH30, NHz, CH3) and 65 > 66 (Cl, F, COzCH3, CONH2). A deviation to the above parallelism of chemical shifts between benzenes and pyrazines is shown by 2-hydroxypyrazine. The signals for protons 5 and 6 (Table I) of 2-hydroxypyrazine are shifted upfield by 0.4 and 0.5 ppm, respectively, u-hen compared to the same protons of 2-aminopyrazine and by 0.92 and 0.83 The Journal of Physical Chemistry
ppm, respectively, when compared to 2-methoxypyrazine. Extensive ir47148 and uv49,50 studies on 2-hydroxyand 2-aminopyrazine have been interpreted in terms of the tautomeric structure V for 2-hydroxypyrazine in neutral solution, while structure VI predominates for 2-aminop yrazine, This upfield shift of protons 5 and 6 supports the conclusion that 2-hydroxypyrazine exists as V and that 2-aminopyrazine exists as VI. Since it is known that 2-hydroxypyridine exists in the keto form and 2-aminopyridine exists in the amino formlS1data supporting (43) J. W. Emsley, J. Feeney, and L. H . Sutcliffe, “High-resolution Nuclear Magnetic Resonance Spectroscopy,” Pergamon Press Inc., New York, N. Y., 1965, p 466. (44) M. Karplus, J . A m . Chem. Soc., 84, 2458 (1962). (45) P. C. Lauterbur and R. J. Kurland, ibid., 84, 3405 (1962). (46) J. C. Deck, Ph.D. Thesis, University of Illinois, 1966. (47) S. F. Mason, J . Chem. SOC.,4874 (1960). (48) Y. N. Sheinker and Y . I. Pomerontsev, Zh. Fit. Khim., 30, 79 (1956). (49) S. F. Mason, J . Chem. Soc., 5010 (1957). (50) G. W. H. Cheeseman, ibid., 242 (1960). (51) A . R. Katritzky and J. M. Lagowski, Advan. Heterocycl. Chem., 1, 339 (1963).
PROTON NMRSPECTRA OF MONOSUBSTITUTED PYRAZINES
1649
4.0
04
1 . OH
2. OMe 3. NHz 4. CH,
5. CI 6.F 7. CONH, 8. C0,CH3
Ip
PI structures V and VI are found in the chemical shifts of the hydroxyl and amine protons (9.79 and 6.32 ppm, respectively) when compared to the corresponding shifts of 2-hydroxy- and 2-aminopyridine protons (11.43 and 6.21 ppm, respectively). Coupzing Constants. The effect of substituents on coupling constants in 2-substituted pyrazines is likewise similar to that found for monosubstituted ben~ e n e s , 2 -pyridine~,5-~0 ~ and pyrimidine^.^^^^^ Neglecting the substituentwhichgives rise to a tautomeric structure ( k e . , hydroxy), the range of observed values of J ~ G is -0.012 to -0.462 Hz; that of J36, +1.331 to +1.541 He; and that of J56, +2.426 to +2.557. I n identically substituted benzenes, the corresponding ranges are: J,, 7.32-7.66 Hz; J,, 1.10-1.62 Hz; and J,, 0.40-0.77 Hz. The similarity between substituent effects on coupling constants in 2-substituted pyridines and 2-substituted pyrazines is shown in Figure 3. For 2-hydroxypyrazine, JG6 is larger by -1.4 Hz than JS6 in other monosubstituted pyrazines. 111 2-hydroxypyridine, Jb6 is -7.0 Hz, an increase of ~ other 2-substituted pyridines. -2.0 Hz over J B for Thus, this increase in Jj6indicates some double-bond fixation, reflecting the existence of 2-hydroxypyrazine as V. The small and normal value of J66 in 2-aminopyrazine as compared with J Min other monosubstituted pyrazines confirms that 2-aminopyrazine exists in the amino form (VI).
1 .o
4.0
I
I
5.0 ,J,
I
I
6.0
I
I
I
7.0
in Hz for Monosubstituted Pyridines
Figure 3. Plot of Jjg in monosubstituted pyraeines us. J M in monosubstituted pyridines.
Introduction of two nitrogen atoms paTa into a sixmembered ring (pyrazine) causes a lowering of the vicinal coupling constant about twice that found for the introduction of one nitrogen atom (pyridine). The vicinal coupling constant in benzene is 7.56 H Z ,and ~ ~in pyridine, the vicinal constant corresponding to JG6 is 4.56 a difference of 2.70 Hz. In the monosubstituted pyrazines, J5a is -2.5 Hz, a difference of -2.4 Hz‘from J56 of pyridine. The negative sign found for J 3 5is not surprising in view of recent reports. A negative sign for the H-H coupling across nitrogen has been reported for pyridine” and 3-acetylpyridine.’ Signs of the H-F couplings in 2-fluoropyrazine are identical with those of similar couplings in various 2-fluoropyridines. 46
Acknowledgiizent. This research was performed with support from the National Institutes of Health under Grant FR-00292. We are grateful for technical assistance by Mr. R. H. Obenauf and wish to thank Dr. S. Castellano for many helpful discussions. (52) J. M. Read, Jr., R. E. Mayo, and J. H. Goldstein, J. M o l . Spectry., 22, 419 (1967).
Volume 73, Number 6
M a y 1968
