TEMPERATURE DEPENDENCE OF THE IONIZATION CONSTANTS AND pH VALUES OF AQUEOUS SOLUTIONS OF 3-HYDROXYPYRIDINE V. P. Lezina, L. V. Shirokova, M. M. Borunov, A. U. Stepanyants, and L. D. Smirnov
UDC 541.12.036:541.124.7:541.132.3: 547.823-145.2
In recent years, derivatives of 3-hydroxypyridine (3-HP) have been arousing ever greater interest because of their biological activity [I]. In view of this, it appeared Qf interest to study the reactivity of various positions of the ring with the aid of the method of hydrogen isotope exchange. We have previously [2] studied the kinetic laws of H/D exchange of the hydrogen of 3-HP by the PMR method at 161~ for the pD range of 2.0-11.0 without taking into account the temperature dependence of the pH of the aqueous solutions of 3-HP studied. The 3-HP molecule exists in four equilibrium forms: neutral (N), bipolar (B), cationic (C), and anionic (A) because of the possibility of the ionization of the OH group or of the protonation of the N atom of the ring [3]. We studied the temperature dependence of the ionization constants pK~ (protonationof the N atom) and pK~ (splitting off of a proton) and of the pH values of aqueous solutions of 3-HP. The change in the pH values of aqueous solutions of 3-HP was studied in the pH range of 2.0-10.0 and the values of the ionization constants pK~ and pK~ in the range of 26-90 ~ . The PMR method was used to evaluate the ionization constants of the 3-HP [4]. EXPERIMENTAL 3-Hydroxypyridine (3-HP) was synthesized and purified as described previously [5]. The samples for investigating the influence of the temperature on the pH were prepared in the form of solutions with an ionic strength I = 0.08 M in double-distilled water containing no C02 or in D20. The acidity was varied in the pH range of 2.0-10.0 by the addition of a small amount of 98% H~S04 (D2SO4) or 1 N NaOH (NaOD) to the flask containing the sample. The pH values of the solution were measured on a pH-340 pH-meter, using anESL-63-07 glass electrode, with an accuracy of • The vessel with the solution under investigation (25-30 ml) was placed in a water bath. The temperature (up to 100~ was maintained with an accuracy of •176 Standard buffer solutions were used to adjust the pH-meter at the temperature established (every 10~ in the interval of 26-90~ The pH of the selected buffer solution differed from the pH of the solution being analyzed by not more than two pH units. The pH measurements of the 3-HP solutions were repeated not less than twice for each temperature. Our main attention was directed to preventing the evaporation of water from the solution under investigation. The nature of the t@mperature dependences of the pH of the 3-HP solutions was practically unchanged on passing from H20 to D=O or with a change in the ionic strength of the solution from 0.07 to 0.i M. The samples for measuring the PMR spectra were prepared in the form of solutions with an ionic strength I = 0.08 M in D=O. The spectra were recorded on a Varian HA-100 spectrometer in the range of 26-90~ (6 scale, tert-butanol as internal standard). The method of calculating the ionization constants for the dependence of the chemical shifts of the protons of the 3-HP ring on the pH of the medium has been given previously [4]. The accuracy of the evaluation of the ionization constants by the method described above in the interval of 26-90~ was not worse than • pK a unit. DISCUSSION OF RESULTS The temperature changes of the pH values of solutions of 3-HP in the pH range of 2.0i0.0 and the temperature range of 26-90~ are described satisfactorily by the equation
pH (T) ~ A / T ~ B
(1)
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow. Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 753-758, April, 1981. Original article submitted June 30, 1980.
540
0568-5230/81/3004-0540507.50
9 1981 Plenum Publishing Corporation
TABLE i. pH Values of a Solution of 3-Hydroxypyridine at 26 and 160~ and the Parameters A and B in the Expression pH = A/T + B DH (26~
lO,O0 9,75 9,50 9,15 9,10 8,50 8,20 7,95 7,50 7,05 6,80 6,50 6,00 5,60 4,40 4,00 3,35 3,00 2,65 2,55 230
AptI (26--90 ~
0,72 0,69 0,72 0,62 0,58 0,62 0,59 0,60 0,57 0,52 0,55 0,53 0,44 3,42 0,42 0,41 0,41 -0,62 -O,6i -0,61 -0,60
pI-I (160~
8,72 8,55 8,26 8,05 8,04 7,4i 7,i7 6,91 6,50 6,13 5,82 5,57 5,25 4,84 3,68 3,26 2,64 4,07 3,73 3,78 3,i6
A. iO -a
B
1,2365 1,t595 1,2290 t,0531 t,0017 1,053i 0,989i t,0t84 0,9633 0,892i 0,9303 0,8946 0,76i5 0,7207 0,7029 0,7032 0,697i -1,0452 - t,0404
-i,0449 -l,0t0i
5,8745 5,875i 5,4i85 5,6248 5,7284 4,9840 4,8883 4,5359 4,2820 5,0668 3,6688 3,5i17 3,490i 3,1840 2,0577 1,6437 i,0309 6,4860 6,i359 5,9591 5,4925
The constants A and B (Table I) were determined by the method of polynomial approximation. The maximum error in the determination of the pH from Eq. (I) did not exceed • pH unit. At 26~ the pH is determined by the equation
pH(26 ~ - A/299.15 ~ B The combination of Eqs.
(2)
(i) and (2) leads to the equation
pit(T) = pH(26 ~ + A (299.15 - -
f)/299.15T
(3)
which can be used to evaluate the pH of a selected solution of 3-HP at any temperature. The validity of Eq. (3) was checked graphically in the coordinates pH(T) versus pH(26~ for the temperatures 40, 50, 70, and 90~ The temperature changes of the pH in the 26-90~ interval showed that the magnitude of the change in the pH, ApH(26-90~ depends substantially on the pH region and the changes ApH have their greatest value in the alkaline region. For solutions of 3-HP prepared at 26~ a decrease was observed within the pH interval of 3.0-10.0, and at pH < 3.0 an increase in the pH with a rise in the temperature. The different natures of the temperature dependences are apparently due to structural features of the 3-HP molecule and to the manifestation by 3-HP of both basic and acidic properties. The concentration ionization constants pK~ and pK~ (Table 2) were determined from dependences of the chemical shifts of the protons of the 3-HP ring on the pH of the medium in the 26-90~ interval as described previously [4]. The analysis of the figures given in Table 2 showed that with a rise in the temperature 3-HP becomes a weaker base and the constant pK~ is more sensitive to a change in the temperature than pKg. TABLE 2. Ionization Constants of an Aqueous Solution of 3-Hydroxypyridine (I ~ 0.8 M) [the pK a values calculated from Eqs. (4) and (6) are given in parentheses] Concentration c o n s t a n t
T., ~ 26 42 50 60 70 80 90 t60
PK ia 5,0a (5,02) 4,97 (4,95) 4,94(4,93) 4,92(4,90) 4,88 (4,88) 4,85 (4,85) 4,82 (4,83) (4,78)
PK2a 8,60(8,62) 8,48 (8,46) 8,42 (8,40) 8,33 (8,34) 8,28(8,29) 8,26 (8,26) 8,25 (8,25) (8,45)
Thermodynamic constant (pKai)T
(PKa2)T
4,92 (4,90) 4,85 (4,84) 4,82(4,81) 4,80 (4,78) 4,76(4,75) 4,72 (4,73) 4,69 (4,70) (4,62)
8,71 (8,73) 8,60(8,57) 8,54(8,51) 8,45 (8,45) 8,40 (8,4i) 8,38 (8,38) 8,36 (8,37) (8,56)
541
TABLE 3. Thermodynamic Parameters of an Aqueous Solution of 3-Hydroxypyridine at 25~
Ionization constant
AH ~ eal/mole
(pK~l) T (1)K~2)"
t770 4740
I AS~ I cal/deg 9mole I [
ACp, cal/deg .mole -7,5 -59,0
-17 -24
The changes in the concentration ionization constants in the 26-90~ scribed satisfactorily by the equation
interval are de-
pK~ = C / T + D + E T pK,~ t = 672,17/T q - t , 7 5 0 4 pKa 2 :
-~ 0~0034tT
(4)
3075..q/r - - 8~3775 -t- 0.02246T
The constants C, D, and E were determined by the method of approximation of second-order polynomials. The maximum error in the determination of pK a from Eq. (4) does not exceed • a unit. The use of solutions with an ionic strength not exceeding 0.08 M made it possible to evaluate not only the concentration ionization constants Ka, but also the thermodynamic constants (Ka)T. To evaluate the activity coefficients in the 26-90~ interval we used Guntelberg's equation for aqueous solutions: log y• = --A~I/(I + ~ ) [6], where I is the ionic strength of the solution, and A is a function of the temperature and of the dielectric constant of the solvent. The connection between the thermodynamic and concentration ionization constants iS defined by the equations
(pK.1) T = p K . 1 @ l g y+ (pK~2)T = - p K 2 - - 1 g
y_
The calculated values of the thermodynamic ionization constants are given in Table 2. pendences of (PKa)T on the temperature are described by the equations
(pK.~) T -
628.8/T + i.9903 @ 0,0027tT
(pK~2)T = 2 9 5 0 . 6 / T - - 7 . 5 7 6 4
(5) The de-
(6)
+ 0.02153T
The thermodynamic constants calculated from Eq. (6), (pK~) T = 4.93 and (pK~) T = 8.80, coincide, within the limits of accuracy of our method, with the corresponding ionization constants (4.86 and 8.72) determined at 20~ by the potentiometeric titration method [3]. The temperature dependence of the thermodynamic ionization constant of an aqueous solution of 3-HP makes it possible to estimate the enthalpy of ionization AH ~ In our case, (PKa) T = C'/T + D' + E'T, i.e., in(Ka) T = --2.303(C'/T + D' + E'T). Making use of the Van't Hoff equation d in Ka/dT = AH~ 2, we find that 5H ~ = 2.303R(C' -- E'T2). The entropy of ionization can be evaluated from the equation AS ~ = d(RT in Ka)/dT , whence AS ~ = --2.303R' (D' + 2E'T). The change in the heat content of the ionization of 3-HP is determined as ACp = dAH~ = --4.606RE'T. The thermodynmmic characteristics of 3-HP so obtained are given in Table 3. The accuracies of the estimates of the enthalpy and entropy of ionization for 25~ with an error in the determination of pK a of • amount to • cal/mole and • cal/deg" mole, respectively. In a previous study [2], the pH (pD) values of the 3-HP solutions investigated were measured at 29~ while the hydrogen isotope exchange reaction was carried out at 161~ As was shown above, the pH depends strongly on the temperature, and therefore, the necessity arose for making a correction for the temperature changes of the pD values of aqueous solutions of 3-HP in the pD interval of 2.0-10.0. The validity of the equations describing the t e m p e r a ture changes in pH (see Table i) has been shown experimentally only up to 90~ However, it may be assumed, as was done in estimating the temperature changes of the ionization constant of water [6], that these equations will also be valid at higher temperatures. The pll values of 3-HP solutions at 160~ calculated from these equations are given in Table i. Figure
542
Fig. i. Dependence of the effective rate constant of the deuterium exchange of 3-hydroxypyridine on the pD of the medium for the ring protons H 2 (i), H 6 (2), and H 4 (3) at 161~ The full line represents the change in k eff for H 2 from [2], and the dashed lines the changes in k eff calculated theoretically for the H 2 proton in the cases of the A and N forms.
-log kelf, s e c t
t"~I-
-..-
"%.1
,i /A
{
I
I
e
4
6
8
l
lop5
i shows a graph of the dependence of log k eff for each of the reacting ring protons (previous results [2]) on the pD at 161~ The values obtained from the H/D exchange of the H 2 proton without taking the temperature changes in pD into account are given for comparison. It can be seen that the introduction of the correction scarcely changes the nature of the dependence and only shifts it in the direction of lower pH values. The rate constants from the exchange of the protons of 3-HP in form A (KA) and also the ratio between the ionization constants of the C, N, and B forms (Kc, KN, and K B) at 161~ in DIO and the rate of isotopic exchange of the H 2 proton in the N form (k~) were calculated with the aid of a method which has been described in detail previously [2] (Table 4). Analysis of the results of the H/D exchange of 3-HP taking ApD (29-160~ into account showed that exchange of the H 2 proton takes place both for the A form (which predominates at pD > 6.0) and for the N form (this Predominates at pD < 3.5), while the exchange of the H 6 and H 4 protons can by measured by the method used in the investigation only for the A form. The ratios between the ionization and the protonation constants of the various forms of 3-HP (Kc, KN, and K B) are known only at 20~ [3]. Since there is no information in the literature on the ratio between them at various temperatures, the calculations were performed on the assumption of an invariability of these ratios in the range of 20-160~ The assumption that inDlO (K~) D ~ (K~) D ~ 2(K~) D, and (K~)D ~ (K~)D/2 [3] made it possible to evaluate the rate constant of the exchange of ~he H proton~ (kl) _f~ the N form, and also the averaged protonatlcm. . and ionization constants (K~) u and (K~) D. Making use of the figures of Table 4, k~ = 8.0 liters/ sec'mole; (K~) D ~ 8.4"i0 -6 M (pK~ = 5.1); (K~) D = 6.0" i0 -~~ M (pK~ = 9.2) for a solution of 3-HP in DaO. The change in k~ ff for the H 2 proton over the whole pD range of 2.0-10.0 is satisfactorily described by Eq. (5) from [2]
~;1A [DaO+] @
elf
[DaO+]~
I + [DaO+]/KN ~- [DaO+I/KB + [DaO+]Z/KN K C on the assumption that only the N and A forms are reactive in the H/D exchange reaction. The dashed lines in Fig. 1 show the dependence of the effective rate constant of the isotopic exchange of the H 2 hydrogen for the pD range in which either the A or the N form makes the main contribution to the overall rate constant k~ ff. In the calculation we used the values of k~, (K~)D, and (K~)D obtained above. To recalculate the values of the ionization constants of 3-HP in DIO to the w{lues in HIO we made use of an equation from the literature [7], (pKa) D = 1.018(pK a) + 0.43, whence
pKa = 0.982 (pK~) D -- 0,42
(7)
On substituting the values of (pK~) D and (pK~) D for a solution of 3-HP in DIO at 160~ in Eq. (7) we obtain the value of the ionization constants of 3-HP in HIO at 160~ pK~ = 4.6; pK~ = 8.6. TABLE 4. Rate Constant of the Isotope Exchange of the Protons of the 3-Hydroxypyridine and the Equilibrium Constants at 161~ in DIO
Proton IkA 4 under- | "I0" , gang ex-~liter/moIe 9 change | see
1 kN/K N 910-9, kNKc 9i0151 KNK C 9i0I~, sec"I lliter-z 9 rnqleZ sec_t
liter/mole
I
H~
H6 H~
23,0
3,3 t,0
1,7 2,0 2,0
t
6,7
3,4__ I
5,0__ 543
The values of pKadeterminedfrom Eqs. (4) and (6) and from the results of H/D exchange atl60~ proved to be close, which indicates the correctness of the assumed mechanism of the electrophilic substitution reaction upon which the treatment of the results of the isotopic exchange of hydrogen was based [2]. SUMMARY i. The influence of the temperature on the pH of solutions of 3-hydroxypyridine has been studied in the pH range of 2.0-10.0 and the temperature interval of 26-90~ and equations have been derived describing the dependence of the ionization constants on the temperature. 2. The rate constants of exchange characterizing the contribution of the neutral and ionic forms of 3-hydroxypyridine in the deuterium exchange reactions of the H 2, H 6, and H 4 prO{ons have been obtained with corrections for the temperature changes in the pH values of the solutions. LITERATURE CITED i. 2.
5. 6.
K . M . Dyumaev and L. D. Smirnov, Usp. Khim., 44, 1788 (1975). V . P . Lezina, A. U. Stepanyants, L. D. Smirnov, and M; I. Vinnik, Izv. Akad. Nauk SSSR~ Ser. Khim., 317 (1978). A. Albert and J. N. Phillips, J. Chem. Soc., 1294 (1956). V . P . Lezina, A, U. Stepanyants, N. I. Golovkina, and L. D. Smirnov, Izv. Akad. Nauk SSSR, Ser. Khim., 98 (1980). Preparative Organic Chemistry [in Russian], Goskhimizdat, Moscow (1959), p. 446. R . A . Robinson and R. H. Stokes, Electrolyte Solutions, 2nd ed., Butterworth, London
7.
H.J.
3. 4.
(1959). 928
C. Yeh, K. L. Kirk, L. A. Cohen, and J. S. Cohen, J. Chem. Soc. Perkin Trans.
2,
(1975).
PMR INVESTIGATION OF INTERNAL INHIBITED ROTATION IN NI,NI-DIMETHYL-N 2TRIFLUORO[CHLORO]ACETYLAMIDINES OF PICOLINIC AND NICOTINIC ACIDS B. A. Arbuzov, A. V. Aganov, N. N. Zobova, and V. V. Klochkov
UDC 543.422.25:541.67:547.82
Continuing an investigation of rotation around CNMe2 bonds in acylamidines by the PMR method [i, 2], we have studied the N~,N~-dimethyl-N2-trifluoro[chloro]acetylamidines of picolinic and nicotinic acids (I-III) in order to determine the dependence of the barrier to internal rotation on solvation, steric, and electronic effects. C X ~ C ( O ) N = C(R) - - N M e 2
(0
-
(m)
R = CsH~N-a; X = F(I); t/ = CsH4N-?, R - - CsH4N-D, X = C1 ( I I I )
X = F(II);
Compound (I) was obtained as described previously [3] and compound (II) by two methods: a) by the same method as [3] in low yield because of the competing reaction of betaine formation, and b) as described by King [4]. In the first case, the S-syn isomer is formed, since the IR spectrum has bands at 1680 cm-1(C=O) and 1620 cm-1(C=N) which are characteristic for conjugated bonds, and in case b) predominantly the S-anti isomer, to which correspond bands at 1720 cm-1(C=O) and 1640 cm -I (C=N) of nonconjugated bonds
V. I. Ul'yanov-Lenin Kazan State University. Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 758-762, April, 1981. Original article submitted June 24, 1980. 544
0568-5230/81/3004-0544507.50
9 1981 Plenum Publishing Corporation