171
Equilibration Studies. Protomeric Equilibria of 2- and 4-Hydroxypyridines, 2- and 4-Hydroxypyrimidines, 2- and 4-Mercaptopyridines, and Structurally Related Compounds in the Gas Phase Peter Beak,* Fred S. Fry, Jr., Jaekeun Lee, and Frank Steele Contributionsfrom the Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61 801. Received March 31, I975
Abstract: Ultraviolet spectroscopy reveals that 2-hydroxypyridine (3), 6-chloro-2-hydroxypyridine(1 l ) , 4-hydroxypyridine (1% 2-hydroxypyrimidine (19), 4-pyrimidone (25), 4-methyl-6-hydroxy-2,3-dihydro-7-azabenzofuran ( 2 9 ) , 2-mercaptopyridine (31), 4-mercaptopyridine ( 3 9 , 5-acridone (40), and 9-anthrone (44) are the major protomeric isomers in the vapor. Infrared spectroscopy confirms the assignments for 3, 15, 19, and 25, and the infrared results show that the isomers are monomeric in the vapor. The fact that the protomers are in equilibrium in the vapor is established by the constancy of the ratio of the absorptions of 2-hydroxypyridine (3) and 2-pyridone (4) as the intensities of the absorptions increase and decrease with temperature changes. Equilibrium constants or a limit on an equilibrium constant, are calculated for the ten systems studied. The results are discussed in terms of the relative chemical binding energies of the protomeric isomers, and it is shown that three presently used quantum mechanical predictions of relative stability of 3-4 are in error by at least 10 kcal/ mol. The large differences between the stabilities of the tautomeric forms in the vapor and in solution again reveal the dominant influence that environment can have on relative molecular stabilities. It is further shown that analysis of this difference for 3-4 in terms of the Onsager dipole interaction model is surprisingly effective in providing understanding of the environmental effect. The implications of this work for future determinations of tautomeric equilibria, for calculations of stability, and for applications of tautomeric constants to biological problems are noted.
The position of equilibrium for protomeric systems in solution has often been used to deduce general structure-stability relationships. For example, equilibria between a wide variety of iminols 1 and the corresponding amides 2 have
1
2
been shown to favor the and those results have been extended beyond the initial studies to such diverse areas as quantum mechanical calculations and theories of genetic mutation. The important role that molecular environment can play in such equilibria may be illustrated by the case of the 2hydroxypyridine (3)-2-pyridone (4). Determination that the equilibrium for 3-4 in solution lies far on the side of 4 is
vored structure in the solid." However, studies of the vapor of 3-4 by infraredi2 and mass spectrometry' and infrared investigation of material trapped from the vapor in an argon matrixi4 indicate that comparable amounts of the tautomers are present. The contrast between the relative amounts of 3 and 4 in the vapor and in solution have been attributed to a lack of equilibrium in the vapor.i0,12c We now present more specific support for our previous contention that an equilibrium of 2.5:1 is established for 3-4 in the vapor phasei5 and report extensions of these studies to ultraviolet and infrared determinations of gas phase equilibria of iminol-amide and thioiminol-thioamide functions in other six-membered heteroaromatics. These results provide fundamental information about the differences in chemical binding energies of the systems studied and demonstrate a large medium effect on these protomeric equilibria. We also show that the latter effect can be rationalized for some 2-substituted pyridines by the Onsager dipole-medium interaction model.
Results Ultraviolet Spectra in the Gas Phase. The gas phase ul3,R=H R traviolet spectra of 2-hydroxypyridine-2-pyridone (3-4) 4,R= H 5. R = CH, and of the model compounds 2-methoxypyridine (5) and 16, R = CH, methyl-2-pyridone (6) are presented in Table I.I6 one of the classic studies of tautomerism. As early as 1907 Acceptance of 5 and 6 as models and comparison of the ultraviolet spectral data were interpreted in favor of the spectra in Table I show that ultraviolet absorptions attribamide form: but it was not until 1942 that comparison of utable to both 3 and 4 are observed in the vapor at 130 and the spectra of the protomeric system with those of 2250'. The absorption bands in the spectrum of 3-4 in the methoxypyridine ( 5 ) and 1-methyl-2-pyridone (6) firmly gas phase at 135 f 3' are stable for 8 hr and a 95% recovestablished the validity of that c o n c l ~ s i o nQualitative .~ supery of material with solution ir, NMR, and uv spectra idenport for the predominance of 4 in liquid media is also protical with those of 4 was achieved after the sample had been vided by i ~ ~ f r a r e and d ~ ~nuclear .~ magnetic r e s ~ n a n c e ~ ~ heated ,~ in the gas cell for 6 hr at 120- 150'. Material used to spectral data and dipole moment although 4 is obtain spectra at 250' was recovered in 90% yield and highly dimerized in nonpolar solvents.6d$8Basicity measureshown to have the solution uv spectrum of 4. Spectra below ments of 3-4, with 5 and 6 as model compounds, have pro240' were obtained in a conventional spectrometer with a vided a quantitative estimate of the equilibrium in aqueous double windowed cell. Trial experiments showed that dousolution at 25' as ca. IO3 in favor of 4.9310Structure deterble windows were necessary to prevent condensation on the mination by x-ray crystallography also supports 4 as the fawindows. If condensation occurs, a spectrum is obtained Beak et al.
/
Protomeric Equilibria of Pyridines, Pyrimidines, and Related Compounds
172 Table 1. Ultraviolet Spectra in the Vapor Phase and in Solution Compd(s)
Phase
T , “C
hmax, nm
E
3-4
Vapor Vapor Water (pI1 6Ic Ethanol Cyclohexane Melt Vapor Vapor Water (pH 7)C Ethanol Vapor Vapor Water (pH 5)C Ethanol
130 250 Ambient Ambient Ambient >lo8 Ambient 250 Ambient Ambient 55 2s 0 Ambient Ambient
297,271 299,271 293 305 300 310 271 270 269 271 305 307 297 302
a
4
5
6
b
5900 6000
1l,R = H 13,R = CH,
5700 5550
which has a, , ,A at 300 nm and corresponds to that obtained from a thin film of melted 4. Spectra taken above 240’ were obtained on a uv spectrometer modified for high temperature work. The use of methylated compounds as model chromophores for protomeric isomers is well e ~ t a b l i s h e d . ~Empir~” ical justification for the present case is based on the correspondence of the ultraviolet spectrum of anisole (7) [A, 271, 277 nm (t 2000, cyclohexane)] with that of phenol (8) ,A,[, 272, 277 nm ( t 2000, c y c l ~ h e x a n e )and ] ~ ~on the correspondence of the spectrum of 3,4-dihydrocarbostyril (9) [Amax 252 nm ( t 10000 dioxane)] with that of l-methyl3,4-dihydrocarbostyril (10) [A,, 253 nm ( e 14000 diox-
7,R=H 8. R
= CH,
15,R=H 16,R=H 17,R= CH, 18,R = CH,
3230 4450
a T h e absorbance ratio at h m a , A ( 3 ) / A ( 4 )= 2.17. b The absorbance ratio at h,,,, A ( 3 ) / A ( 4 )= 1.96. CA. I. Scott, “Interpretation of Ultraviolet Spectra of Natural Products”, Pergamon Press, New York. N.Y., 1964, pp 178--184.
8
12,R=H 14,R = CHI
19,R=H 2l,R=CHj
25,R=H 28,R=CH,
20,R=H 22,R=CHj
29.R=H 5l,R=CH,
23,R=H 26,R=CHJ
30,R=H 52,R=CH3
9.R= H
ane)].” Also included in Table I are solution spectra which show that, although shifts of A,,, do occur with changes in medium, for these cases the shifts are not large enough to affect the assignments. In fact, the spectra of 5 and 6 in Table I in the vapor phase are virtually identical with those in ethanol, with the exception of fine structure observed in the gas phase spectrum of 5 . For the present work (vide infra), this correspondence is taken to justify the comparison of ethanol spectra of the models with vapor phase spectra of the protomers. The ultraviolet spectra of a number of monocyclic, sixmembered, nitrogen-containing heteroaromatics have been obtained and are presented in Table I1 along with the spectra of the corresponding methylated isomers. The spectra in ethanol and the tautomeric assignments made therefrom are generally consistent with previous assignments for solut i o n ~ Of . ~ more interest are the vapor phase spectra. The spectra of 11-12, 13, and 14 in Table I1 show 6-chloro-2hydroxypyridine (12) to be the major form in the vapor. The same protomer is favored in ethanol but, in highly aqueous ethanolic solutions, 6-chloro-2-pyridone is preferred.?O The spectra in the table show that 4-hydroxypyridine (15) and 2-hydroxypyrimidine (19) predominate in the vapor phase, whereas 4-pyrid0ne~-”~,*land 2-pyrimidone9a,9b%22 are the only detectable forms in ethanolic solution. In the case of 4-pyrimidone, however, the amide form Journal of the American Chemical Society / 98:l
3l,R=H 33,R=CH3
S
Q I R
s
32,R=H 34,R=CH,
b& I
H)&
H
35,R=H 37,R=CHJ
36,R=H 38,R=CH3
0
10,R = CH,
24,R=H 27,R=CH3
R 40,R = H 42, R = CH,
39,R = H 41,R=CHJ 0
43,R=H 45, R = CH,
44,R = H 46, R = CHJ
25 predominates in both s o l u t i ~ nand , ~the ~ gas ~ ~ phase, ~ ~ ~ ~ although absorption due to a t least one other protomer, either 23 or 24, is also observed in the vapor phase. Those spectra are shown in Figure 1, where the spectrum of 27 is reported a t 150’ because a t higher temperatures rearrangement to 28 occurs. The vapor phase spectra of 4-methyl-6-hydroxy-2,3-dihydro-7-azabenzofuran recorded in Table I1 shows both tautomers can be observed and that the hydroxy form predominates. The tautomer 29 is also the major form (60%) in ethanol, whereas the amide 30 predominates in highly aqueous e t h a n ~ l . ” ~ .The * ~ report of Levin and Rodionova,12c that a change in the ratio of the protomers 29-30 is observed on heating in the vapor phase, prompted us to study the vapor spectra as a function of temperature.’2c We found that a t 180’ the absorbances of 29 and 30 both decreased. Examination of the material in the cell after cooling indicated that thermal decomposition had occurred and heating to higher temperatures gave only more decomposition. The earlier worklZcwas carried out a t 345-360°, a temperature a t which decomposition of this compound could be extensive. The spectra of the 2- and 4-thio-substituted pyridine rings suggest that the 2-mercapto and 4-mercapto forms 31
/ January 7, 1976
173 Table 11. Ultraviolet Spectra in the Vapor Phase and in Solution Compd( s)
Phase
T,"C
11-12
Vapor Ethanol0 Aqueous AqueousQ Aqueousa Vapor Ethanol Vapor Ethanol Vapor Ethanol Vapor Ethanol Ethanol Ethanol Vapor Ethan61 Vapor Ethanol Vapor Ethanol Vapor Ethanol Vapor Ethanole Ethanole Ethanole Vapor Ethanol Vapor Ethanol Vapor Ethanol Vapor Ethanol Vapro Ethanol Vapor Ethanol Vapor
100 i 3 Ambient Ambient Ambient Ambient 25 0 Ambient 160 Ambient 175 Ambient 220 Ambient Ambient Ambient 220 Ambient 170 Ambient 150 Ambient 190 Ambient 175 Ambient Ambient Ambient 175 Ambient 35 Ambient 110 Ambient 150 Ambient 35 Ambient 190 Ambient 270
Ethanol
Ambient
12 13 14 15 16 17 18 19 20 21 22 23-25 25 26 27 28 29-30 51 52 31 32 33 34 35
36 37 38 40
41
Vapor Ethanol
42
44 45
Ambient
Vapor
230
Ethanol
Ambient
Vapor Ethanol
220 Ambient
Vapor Ethanol
46
200
100 Ambient
Vapor Ethanol
150 Ambient
Xrnaxp nm 285,300 277, 305 304 308 276 24 0 25 7 240 218,235 (sh) 258 265 25 8b 298 264 302 255,275 218,270 24 8 248 254 24 2 275 218,275 287, 325 295,326 290 326 233,284,380 287,362 248,290 248,291 245,293, 368 287, 357 235, 257 (sh) 230,342 248, 262 (sh) 26 3 235, 350 231, 348 371, 363 (sh), 353 295 (sh), 268, 238 398,368, 363 (sh) 344 (sh), 307, 294 268 (sh), 265 (sh), 255 368 (sh), 353, 338 242,238 385 (sh), 370 (sh), 354 348 (sh), 337,323 (sh) 25 3 377, 368,353 295,277,239 400, 383, 365 (sh) 305, 293, 223 (sh) 263 (sh), 256 298,286,250 305,290 (sh), 268 (sh) 260,248 (sh) 376,372,357 353, 340, 325 310,250 388,368,249 333,318,256 248 302,296,290 25 7 268, 290 (sh), 300 (sh)
E
5130,1240 7000 7400 5400 14700 10200,2200 30000 4710 4780 5400 C
12000,3850 3150 16000 7590, 3710 d 7250 9550
f
10200,4860 g
10400,4080 h 12900,6370
i 5920,14300
i 11800 k 6520,25000 1
8870,8410,4670 1860,1400,2330 117100, 36000, 53700
m 3500,5700,8770 7190,5260,2630 156000 n 8180,7720,3630 1360,2630,15900 30900,48600 0
2920,3850,135 00 26000, 13500 P 6400,7300,4600 2100,820, 188000 95000 4
15600,6000,4220
References 20 and 21g. b Shoulders at 252,263 nm. C Ratio of absorbances is 9: 10. d Ratio of absorbances is 1: 10. e References 17a and 12c. fRatio of absorbances is 10:4:0.5.8 Ratio of absorbances is 10:3. h Ratio of absorbances at 293 and 268 nm is 10:2. The absorbance at 245 nm is three sharp absorbances. i Ratio of absorbances i s 10:4. /'Ratio of absorbances is 10:4. k Ratio of absorbances is 10:6. I Ratio of absorbances is 1.6:1.3:1.4:0.8:4.3:10. m Ratio of absorbances is 0.2:0.5:0.4:10:8.5. Ratio of absorbances is 2.5:1.5:1.5:0.8:3.6:10. Ratio of absorbances is 1.4:1.4:10. P Ratio of absorbances is 1.5:1.3:1.6:10.4 Ratio of absorbances is9 .8:6.2:10:7.8:6.8:3.6:1.6. (2
and 35 are dominant in the vapor. Again, these results are in contrast to the solution s t ~ d i e s . ~ ~ , ~ ' ~ , ~ ~ The results of the vapor phase ultraviolet studies of 5acridone and 9-anthrone and their derivatives compiled in Beak et al.
the table are consistent with the predominance of the carbonyl tautomers 40 and 44 for both compounds and, in these cases, the carbonyl forms are predominant in solut i ~ as n well. ~ ~
/ Protomeric Equilibria of Pyridines, Pyrimidines, and Related Compounds
Table 111. Infrared Spectra of the Vapor Compd( s)
T, "C
3-4 15 19 23-25
225 270 280 280
OHst,,cm-'
NHst,,cm-'
3600 3650 3550 3590
3450 3440
Table IV. Variable Temperature Gas Phase Ultraviolet Spectra of 2-Hydroxypyridine (3)-2-&ridone (4)
T, "C 120k 3 132 f 3 139 * 3
A(3P 0.65 1.27 1.67
0.02 0.21 f 0.14 f
f
A (4)Q
A(3)/A(4IQ
0.31 k 0.01 0.59 t 0.12 0.76 f 0.14
2.08 2.17 2.19 ~
k f k
0.04 0.12 0.12
~~~
a The error limit is the range observed on successive measurements in both heating and cooling cycles.
250
Table V. Vapor and Solution Equilibrium Constants. KT = INHI/IOHl
300
Compd(s) Figure 1. Gas phase ultraviolet spectra: (23-25) 4-Hydroxypyrimidine4-pyrimidone (-, 255'); (28) 3-methyl-4-pyrimidone (- - -, 21 8'); (27) 1 -methyl-4-pyrimidone (. 150'); (26) 4-methoxypyrimidone (- * -, 170').
.
T, "C
3 -4
130
11-12 15-16 19-20 23-25 29-30 31-32 35-36 39-40 43-44
120 25 0 220 220 175 170 150 270 220
a,
Infrared Spectra in the Gas Phase. The first indication that the composition of 3-4 in the vapor is different from that in solution was provided by the infrared investigations of Levin and Rodionova. Subsequent work by them has shown that a number of hydroxypyridine-pyridone systems have different compositions in the vapor from that in solution. For example, the Russian workers have reported 6chloro-2-hydroxypyridine and 4-methyl-6-hydroxy-2,3-dihydro-7-azabenzofuran to be the dominant protomers in the vapor.'* The vapor phase infrared spectra summarized in Table 111 were obtained in the present study and support the tautomer assignments made to 3-4 on the basis of the ultraviolet studies (vide supra). The assignments of O H and NH stretching frequencies are in agreement with previous work.'2*26Both bands in the case of 3-4 are sharp doublets, an effect which could be attributed to unresolved rotational states or Fermi r e s o n a n ~ e . ' ~ In. ~the ~ case of the 4-pyrimidone, the ir spectrum allows a choice for the minor tautomer to be made in favor of the hydroxy compound 23. Equilibrium in the Gas Phase. It has been suggested on the basis of the change observed in the intensities of the N H and OH absorptions for 29-30 at 345-360' that the composition of such protomeric systems in the gas phase could be controlled by the relative rates of vaporization of the protomers and not by their relative stabilities.1°~12cHowever, the enol of acetone has been shown to equilibrate with its keto tautomer in the gas phase by wall collisions at substantially lower temperatures under conditions6*28aotherwise comparable to the present work. Moreover, the similarity of the ratio of absorbances for 3-4 at 130 and 250' of 2.17 and 1.96 (Table I) might be regarded as surprising if dependence on the relative rates of vaporization were significant. In order to establish whether the relative rates of vaporization determine the relative amounts of 3 and 4 in the vapor, the changes in absorption for these isomers were studied as a function of temperature from 120 to 139' (Table IV). Although the absorbances attributed to each protomer change by a factor of ca. 2.5 over this range the averaged ratios of the absorbances vary by a factor of less than 0.12. The values in Table IV are averages of four to ten measurements and were made on both cooling and heating cycles. Clearly there are no apparent rate differences Journal of the American Chemical Society
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98:l
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KT(wpor)
0.4 k 0.25 (uv) 0.5 k 0.3 (ir) 0.05, 0.03C
