July 20, 1964
IODINATION OF PYRAZOLE AND IMIDAZOLE
Cnfortunately, our results do not shed any new light on the nature of the rearranging species. As we have indicated in Fig. 2 , rearrangement may occur a t various stages; the rates k2 and k2' may apply equally well to rearrangement of propyl chloride-aluminum chloride complex, r-complex, or cr-complex without changing the interpretation of the experimental results. We do feel that our results draw new attention to the importance of steric factors in Friedel-Crafts alkylations, and to the practical effects evidenced by the re-
[CONTRIBUTION FROM
THE
2857
orientations induced in polyalkylbenzenes to relieve steric strains. Acknowledgment.-We wish t o thank Dr. Jeff C. Davis, Jr., for help with the nuclear magnetic resonance spectrometric analysis. Financial assistance from the National Science Foundation and the Robert A. Welch Foundation is also gratefully acknowledged. D. S. wishes to thank the Department of State, Agency for International Development, for financial aid.
DEPARTMENTS OF CHEMISTRY OF THE UXIVERSITY OF HAWAII,HOSOLULU, HAWAII,A K D VIRGINIAPOLYTECHNIC INSTITUTE, BLACKSBURG, VA ]
Kinetics and Mechanism of Iodination of Pyrazole. Comparative Reactivities of Pyrazole and Imidazole BY JOHN D. VAUGHAN, DONG. LAMBERT, AND VIRGINIA L. VAUGHAN RECEIVEDFEBRUARY 24, 1964 The kinetics of iodination of pyrazole in aqueous solution has been studied. T h e rate was found to be separable into parallel "uncatalyzed" and buffer-catalyzed reactions. A mechanism involving attack of t h e conjugate base of pyrazole by iodine was given. The relative reactivities of pyrazole and imidazole in their "uncatalyzed" reactions were found t o be comparable in magnitude and were discussed in mechanistic and theoretical terms.
The kinetics of iodination of aromatic nitrogen heterocycles has been reported for trisubstituted pyrroles, imidazole, and histidine. The observed more rapid rate of iodination of 1-substituted pyrroles relative to pyrrole indicates that iodination probably occurs through the neutral pyrrole molecule rather than through the pyrrole anion.5 In contrast, the nonreactivity of 1-substituted imidazoles suggests that the anion of imidazole undergoes iodination rather than the undissociated m o l e c ~ l e . ~Similarly, ~,~ the iodinations of phenola and 4-nitrophenols seem to involve attack of the anion. Pyrazole and most substituted pyrazoles undergo iodination in the four p o ~ i t i o n . ~Since l-methylpyrazole also undergoes iodination (in the four p o ~ i t i o n ) ~ De La Mare and Ridd5 suggested that iodination occurs through the neutral pyrazole molecule rather than through the pyrazole anion. Brown's'O molecular orbital calculations of localization energies of the pyrazole molecule and of the anion showed that the anion should be markedly more reactive to electrophilic reagents than the neutral molecule. The purpose of the present investigation was to determine the detailed kinetics of iodination of pyrazole, and to compare the relative rates of iodination of pyrazole and imidazole under similar conditions. To provide similar conditions, it was desirable to re-examine the iodination of imidazole at higher temperatures and ionic strength than the previous study.3a This in(1) T a k e n in part from t h e M s. thesis of D. G . Lambert, V . P I., 1962. K . W. Doak and A. H . Corwin, J . A m . Chem. S O L ,71, 159 (1949). ( a ) J H . R i d d , J Chem. S O L . 1238 , (1955); (b) A. Grimison and J. H. i b i d . , 3019 (1959). C H Li, J . A m . Chem. SOL.,6 6 , 225 (1944). ( 5 ) P . B D . De La M a r e a n d J . H . Ridd, "Aromatic Substitution: Nitration and Halogenation," Butterworths Scientific Publications, London, 1959, pp. 200-202. ( 6 ) B. S. Painter and F. G . Soper. J . Chem. SOL.,342 (1947). ( 7 ) E. Berliner, J . A m . Chem. SOL.,79, 4307 (19511. (8) E. Grovenstein, J r , and N. S Aprahamian, i l i d , 84, 212 (1962). (9) R . Htittel, 0. Schafer, a n d P. Jochum, A n n . , 698, 200 (1955). (IO) R . D . Brown. Australian J . C h e m . , 8, 100 (1955). (2) (3) Ridd, (4)
vestigation revealed that pyrazole, like imidazole, appears to undergo base-catalyzed iodination through the anion, and that the relative reactivities of pyrazole and imidazole are very similar in the water-catalyzed ("uncatalyzed") reaction. Experimental Materials.-Pyrazole ( P y ) , obtained from Columbia Organio Chemicals Co., was recrystallized three times from cyclohexane; m.p. 68.5". Iniidazole ( I m ) , obtained from Aldrich Chemical Co., Inc., was recrystallized three times from benzene; m . p . 88.0". Reagent grades of K I , NaZHPOd, KHpPO4, NaKO?, a n d S H 4 N 0 3were dried a t 110' and used without further purification. Reagent grade sublimed iodine was resublimed before use. Perchloric acid stock solution prepared tram reagent grade HClO, ( i o % ) was standardized indirectly against potassium acid phthalate. Product Analysis.-The iodinated product of P y was prepared by the procedure of HL'ttel, et nL.,$ except Sa2HPO4-KHzPOI buffer was used instead of sodium acetate. Excess iodine was destroyed by S a H S 0 3 . T h e product was recrystallized twice from cyclohexane (white needles, m.p. 112"). H"tte1, el u / . , ~ reported t h a t 4-iodopyrazole is pale yellow, m.p. 108.5'. Reimfinger, et al.," prepared 8(5)-iodopyrazole, m.p. 72-73". An n.m.r. spectrum of our product was t h a t expected for 4-iodopyrazole.'* Ridd showed t h a t the product of the iodination of Im with Im in stoichiometric excess is 2,4(5)-diiodoimida~oIe,~~ with the initial substitution occurring in the 4-position .3b Kinetic Runs.--All kinetic runs were made in aqueous solutions adjusted t o a constant ionic strength of 1.00 Ai. Runs with P y substrate were buffered with either HPOd-z-H2P04- or NH3-NH4+, and runs with I m were ~elf-buffered.~;' T h e final adjustment to constant ionic strength was made by addition of aqueous Nah'Oa. Some of the runs with P y substrate were followed with a Beckman DU spectrophotometer, equipped with dual thermospacers. Data were taken a t 400 mp, where the absorbancy of 11- is large and t h a t of I2 is small.l3 Other kinetic runs with P y and I m substrates were followed by titration with thiosulfate, using the procedure of Berliner.' In all runs, the (11) 13. Reimfinger, A. van Overstraeten, and H G Viehe, C h e m B e y , 94, 1036 (1961). (12) W. Goodlett, Tennessee Eastman C o . , Kingston, Tenn , private communication. (13) A. D. Autrey a n d R E. Connick, J A m Chtm. S o c . 7 3 , 1842 (1951).
2858
D.
JOHN
VAUGHAN,
DONG . L A R I B E R T ,
ratio of [I-] t o [I3-] was at least 20, and the ratio of [substrate] t o [I3-] was also 20 or greater ( t o ensure pseudo-first-order kinetics). Kinetic runs were made at 30 and 40" for both P y and I m substrates. A411solutions were prepared at room temperature; since these solutions had uniform ionic strength, thermal expansions in volume were assumed uniform. Preliminary experiments indicated t h a t small errors in solution volume led t o essentially no error in the observed first-order rate constants. I n spectrophotometric runs, all a t 30.0", the cell temperature was measured with a calibrated double junction copper-constantan thermocouple; the cell temperature varied less than 0.05" from the bath ternperature.
AND V I R G I N I A
[HPOd-] X 102
[PYI
x
2 6 9 13 16 20
103,
TABLE I RATEOF IODINATION OF PYRAZOLE WITH PYRAZOLE COSCENTRATION (30')
THE
M
kl
636 640 296 48 15 22
x IO4,set.-' 1 18 3 4 6 7 9
M, M
ki X 102 , I . mole - 1 sec. -1 [Pyl
4 4 4 4 4 4
08 27 13 47 58
48 64 59 55 65 73
0 0 1 1 3 3 5 5
TABLE I1 VARIATION OF THE RATEOF IODISATION OF PYRAZOLE WITH THE IODIDE CONCEXTRATION (30") HPO4-Z, H2PO4-buffer; in all runs, [XazHPO4] = 6.203 X lo-' M , [ K a H z P 0 4 ]= 5.00 X lo-' Ai, [Py] = 1.348 X lo-' M [ I - ] x 103 ki X 104' k i [ I - ] 2 X 108' 3.91 31.7 4.85 5.48 16.4 4.92 7.82 9.03 5.52 9.65 6.13 5.71 9.78 5.94 5.68 18.08 1.77 5.79 23.72 0.955 5.36 .4v. 5 . 4 0 i 0 . 4 4
x
10-2
10 00 12.00
kl
klII-12
X
2.11 2 .08 2.01 2.02 1.26 1.31 0.84 0.92 Av.
0
Sec. - l .
x
2 56
2 14
1 24
4 42
0 50
10 96
2 585
[P;HI'I/[XHI]
[ H I ] X 108
10'0
3 54 5 07 6 31 8 05 9 91 11 64 1 84 3 52 3 59 5 06 4 84 6 8; 6 89 8 42 1 275 2 29 4 4; 6 28 7 76 9 33 10 03 1 15 1 69 2 29 8 8 15 15 29 29 45 44
74 60 0 0 1 0 2 3
[I -12/[Py
x
I
1 0 5 ~
At 30"
8 85
0 485 485 970 970 1 455 1 455 1 940 1 940 0 485 0 970 1 455 1 940
lOGb
the buffer concentration, the hydrogen ion concentration, and the temperature are observed in Table I11 : [ P y ] and [I-] dependences were removed by multiplying kl by [I-]? [Py] Hydrogen ion concentrations
1 83
kl
1.35 1.33 1.29 1.29 1.26 1.31 1.21 1.33 1 . 2 9 i0 . 0 3
Set.-' moleZ1. -'.
3 00
2 13
98 98 97 97 93 93 90 90
["JI
XH3, S H 4 +buffer; in all runs, [NHB]= 9.70 X 10- M , [XH,N03] = 9.55 X lo-.' M , [Py] = 2.00 X lo-' hf 8.00
x
At 40"
I n Table 11, the reciprocal second-order dependence of k1 of pyrazole upon [I-] is evident for phosphate- and ammonia-buffered systems, plots of log kl us log [I-] gave slopes of - 2 for both systems The effects of
[I-]
[Pvl
kl[I-l'
[ H - ] X 10'
At 30"
Table I, the first-order dependence of the rate of iodination of pyrazole upon the concentration of pyrazole is seen.
I n all runs, [Iz] = 5.32 X lo-' M , [ K I ] = 9.648 X [ X a 2 H P 0 4 ]= 6.203 X lo-' M , [ S ~ H Z P O I=] 5.000 X
[HP04-21/ [HzPOd-I
2 15 3 00 4 00 5 00 6 00 7 00 1 06 2 12 2 12 3 18 3 18 4 24 4 24 5 31 1 55 3 02 6 20 8 00 10 00 12 00 12 41 4 00 6 00 8 00
The Rate Laws.-In
THE
Vol. 86
TABLE I11 DEPENDESCE OF THE RATEOF IODISATION OF PYRAZOLE UPON THE BUFFERA N D HYDROGEN 10sCOSCENTRATIOXS
Results
VARIATION OF
I . VAUGHXN
4 68
14 8
7 83
4 4 6 6 8 8 10 10 2 4 5 6
87 92 75 64 55 70 13 07 94 32 06 12
10 10 13 13 16 16 19 19
31 31 46 50 00 50 26 40
At 40"
0
0 44 44 88 88 1 33 1 33 1 77 1 77 Sec --I mole 1
10 35
6 48
-l
were calculated from the appropriate buffer equilibrium expression
K,
=
[ H P O ~ - 2 ] [ H f ] / ~ H ~ P=O 5.48 ~-] X
IODINATION OF PYRAZOLE AND IMIDAZOLE
July 20, 1964
2859
or
Kb
=
[NH4+]10-14/[NH3][H+]= 1.89 X l o p 5
where K , was computed from the measured pH value of 6.67 for the buffer ratio [ H P 0 4 - 2 ] / [ H 2 P 0 4 - ]= 2.56, and Kb from the pH value of 8.33 and the buffer ratio [NH4+]/ [NH3] = 8.85. K , and Kb so computed are not correct thermodynamic dissociation constants for these buffers a t an ionic strength of 1.000 M , but permit accurate calculations of relative values of [ H + ] corresponding to different buffer ratios a t this fixed ionic strength.3a In the ammonia-buffered system, the reciprocal first-order dependence of k1 on [ H + ]is shown in Fig. 1, where kl[I-lZ[H+]/[Py] vs. [NHs] for runs a t 30’ is seen to be linear. The slopes and intercepts shown in Fig. 1 for runs a t 30 and 40’ reveal “uncatalyzed” and base-catalyzed reactions, respectively. Figure 2 indicates the similar behavior of the phosphate-buffered system. The intercepts were less clearly defined by the points of Fig. 2 than those of Fig. 1; we therefore based the intercepts shown in Fig. 2 upon those obtained in Fig. 1. Figure 3 indicates the buffer dependence of the rate of iodination of imidazole (Im) a t 30 and 40’ a t pH 7.10. Here Im serves the dual role of substrate and buffer.14 Following Ridd,3a the buffer ratio was controlled by measured addition of perchloric acid. The experimental rate law found for the iodination of pyrazole and applicable also for the iodination of imidazole3”is given by -d [Is-]/dt = kz [Is-]
0
2
1 [“a]
Fig. 1.-Dependence
X 102.
of the rate of iodination of pyrazole upon the buffer concentration.
[SI
where
Here ko is the rate constant for the “uncatalyzed” iodination of substrate (S), and kcat is the rate constant for the base (B) catalyzed iodination of S. For pyrazole substrate, B = H P 0 4 - 2 or NH3, and for imidazole substrateB = Im. ko and kcat values for Py and Im obtained from the slopes and intercepts of Fig. 1 and 2 and Fig. 3, respectively, are given in Table IV.
/’
6
TABLE IV UNCATALYZED AND CATALYZED IODINATIONS OF PYRAZOLE A N D IMIDAZOLE
RATECONSTANTS FOR
THE
ko X 10l’a
1, o c
koat X
101lb
Pyrazole 1 . 5 f 0.2‘ 4.0 f 0.2
0
Pyrazole 3.8 f 0.5 10.5 f 0 . 7
) “Uncat.”
1.* mole-* set.-'. mated graphically.
* 1.
mole-’ set.-'.
12
IHPO,-*l X 102.
1.7 f0.2 3.7 f .3 2 . 9 f .3 18.2 f .5 30 40
8
4
e
2.9 f 0.3 8.7 f0.5 Uncertainties esti-
~-
(14) Pyrazole may not serve a s i t s own buffer in a similar m a n n e r to t h a t of imidazole, because its basicity is a b o u t 10-4 t h a t of imidazole.
Fig. 2.-Dependence
of the rate of iodination of pyrazole upon the buffer concentration.
Experimental activation energies and experimental frequency factors calculated from the results in’Table I V are given in Table V.
Discussion Mechanism.-Several mechanisms are possible for these base-catalyzed reactions. A recent study of the iodination of 4-nitrophenol by Grovenstein and Aprahamian8 showed that iodination by I + could not account for the observed kinetics, but that iodination
JOHN
D. VAUGHAN, DON G. LAMBERT, AND VIRGINIAL. VAUGHAN
i 1’
/
/I
ka
HzO --+ SI-
S‘
\
Vol. 86
+ HaOf
(4)
H I
40’
8
/
where B is NH3 or HP04 when S is Py, or B is I m when SisIm. ForPy
a
SI-
+ H~O+,SI
+ H?O
(6)
For Im fast + 12 + SI2- + I- + H f SI2- + H a O ’ S SI, + HzO
SI-
(7) (8)
If we assume that (4) and ( 5 ) are rate determining, and assume that ka
> kr
the steady state approximation gives 0
2
4
[ I m l X 102.
Fig. 3.-Depc:ndence
of the rate of iodination of imidazole upon the buffer concentration.
Referring to the experimental rate law, we see that ko
TABLE ‘I’ EXPERIMENTAL .kCTIvATIOV ENERGIES AND EXPERIMEYTaL LOGFREQUENCY FACTORS log
“Cncatalyzed” Catalyzed ( SHa) Catalyzed (HPOa -)
AexP
EeexP, kcal /moleb
Py r a z o1e 0 51 -0 31 14 33
18 5 14 7 34 5
Iniidazole Cncatalyzed 1 42 (1 12)“ 19 2 Catalyzed ( I m ) 1 90 ( 4 60)” 20 7 e ‘I’alues in parentheses correspond to rnonoiodination, given by log A e y p - log 2 b f - 2 kcal /mole
by Iz could do so. Accordingly, we assume that I2 is the iodinating reagent for pyrazole and imidazole. The mechanism of Grovenstein and Aprahamian adapted to these substrates follows I t - Z I 2 +IS
+ H2O s S- + H3OC
H
H
A
H
KI
(1)
Kz
(2)
=
(ki/k--l)k3KiKz [HzOI
(9)
and koat = ( k l
%l)k4K,KZ
Since we have made the usual assumption that water serves as base catalyst for the “uncatalyzed” reaction for Py and Im,3a315 we expect the efficiencies of the various catalysts to depend upon their relative basicities. This relation clearly exists for the uncharged bases, i.e., water and ammonia for pyrazole substrate and water and imidazole for imidazole substrate I n the case of HP04’2 and NH3 catalysts, we note that kcatxH3 < kCatHPo‘-despiteKB“’ > KBHPo4-’at30 and 40’. This latter result suggests that the role of HP04-2 in base catalysis is significantly different from that of NH3. In addition, the markedly higher experimental activation energy and experimental frequency factor for HP04-2 catalysis compared with HzO and NH3 catalysis (and Im catalysis) also points to a different role; the nature of this difference is not clear from the kinetic data. Base catalysis of the iodination of Py by a number of charged and’ uncharged bases is presently being studied and will be presented in a later paper. Reactivities of Pyrazole and Imidazole.-To compare the reactivities of these substrates in iodination reactions, one must compare the “uncatalyzed” (watercatalyzed) reactions, rather than the base-catalyzed reactions, since the same buffer was not used for the two substrates. From eq. 9, we may write
where the factor I / z corrects the rate constant for the diiodination of imidazole to mon~iodination~” ; this ratio is -1.3 a t 30 and 40’ (Table IV), to indicate (1.5) E. Berliner, J . A m . Chem. Soc., 71. 4003 (1950)
July 20, 1964
HYDROXY-1 ,2,5-THIADIAZOLES
2861
the very similar reactivities of the two substrates. The to $1. Hamano and Hameka" calculated accurate acid ionization constants (K,) are reported to be 10-14 dipole moments for Py and I m by a simple molecular and 10-14.5for Py and Im, respectively,16 indicating orbital method, using h = 2.70 for the pyrrole-type that the equilibrium concentrations of anions availN and h = 0.38 for the pyridine-type N . I n the anion, able for iodination is of the same order of magnitude both nitrogen atoms are pyridine types; hence a comfor Py and Im in solutions of the same stoichiometric mon h-value is applicable. Because of the accuracy concentration. The other two factors, kllk-1 and k ~ , of the Hamano and Hameka calculations for the cannot be separated. However, we note t h a t the molecules of Py and Im, we assume h = 0.38 for the ratio Izrlk-1 will determine the steady-state concentratwo pyridine-type atoms of the anion. Brown's atom localization energies for h = 0.38 are 2.1 ( - p ) for H imidazole and 2.13 ( - p ) for pyrazole. If we assume / tion of the Wheland intermediate (S' ) ; the formathat the entropies of formation of the U'heland inter\ mediate for imidazole and pyrazole are comparable 1 in magnitude, then these nearly identical atom localition of this intermediate involves localization of two zation energies suggest that the free energy of formaelectrons to form a u-bond between C and I. Theretion of the intermediates of Py and Im will likewise be fore, the atom localization energy a t the 4-position of comparable, and therefore that kllk-1 of the two subPy and Im should provide a t least a semiquantitative strates will have nearly the same value. We may concomparison of the relative values of k l / L l for the two clude therefore that the rate-determining rate consubstrates. stants ( k ~ of ) Py and I m must also have nearly the Brownlo calculated atom localization energies for same value. The comparable values of the experithe 4-positions of Py and Im by the simple molecular mental activation energies of .the "uncatalyzed" reorbital method (neglecting overlap) and made no disactions of Py and Im support this argument, since tinction between the pyridine-type nitrogen ( > N :) and any significant difference in the energy barriers of the the pyrrole-type nitrogen (N-H) ; that is, he assigned rate-determining reactions would be reflected by a a common inductive parameter h for the coulomb difference in the experimental activation energies.I8 integral CXN = CYC hp for the two N atoms. Here Acknowledgment.-We wish to thank, Dr. D . E . uN is the coulomb integral for nitrogen, CYC that for Boswell of Socony-Mobile Oil Co., Inc., for helpful carbon, and /3 is the resonance integral. Brown gave suggestions. localization energies for values of h ranging from -1 T
+
(16) A . Albert, "Heterocyclic Chemistry," Essential Books, Fair Lawn, N . J., 1959, p. 143.
(17) H. H a m a n o and H. F. Hameka, Tetrahedron, 18, 985 (1962). (18) A. A. Frost and R. G. Pearson, "Kinetics and Mechanism," J o h n Wiley and Sons, I n c . , New York. N. Y.,1953, p. 209 ff.
ELECTROCHEMICALS DEPARTMENT AND THE CENTRAL RESEARCH DEPARTMEKT, DU P O N T DE NEMOURS AND C O . , INC.,m'ILMIKGTOK 98, D E L . ]
[JOINT CONTRIBUTION FROM THE
E. I.
Hydroxy-l,2,5-thiadiazoles. I. A Novel Route from Potassium Cyanide and Sulfur Dioxide BY JOHN M. ROSS' AND WILLIAMC. SMITH* RECEIVED OCTOBER 7, 1963
3-Cyan0-4-hydroxy-1.2,Bthiadiazolehas been obtained from the reaction of potassium cyanide and sulfur dioxide a t 25-85' in the absence of hydroxylic solvents. The structure was elucidated by degradation to diethylaminoacetamide and to N-sulfamoyloxamic acid dipotassium salt, and by independent synthesis from isonitrosocyanoacetamide and sulfur dichloride. Various 3-hydroxy-1,2,5-thiadiazole derivatives were prepared including several potassium acid salts involving symmetrical hydrogen bonding of the acidic 3-hydroxyl proton.
The reaction of potassium cyanide and sulfur dioxide in aqueous solution has been known since Etard3 obtained a crystalline product by passing sulfur dioxide through 407, aqueous potassium cyanide. The identity of this product as dipotassium aminomethanedisulfonate (I) was more clearly elucidated by von Pechmann and M a n ~ k . ~ Reactions under other conditions have received only cursory examination. The formation of potassium cyanosulfinate (11) was postulated by Jander and coSOaK H*KCH< 1 SO3K
OK
o=s < I1
CN
(1) Organic Chemicals Department, Jackson Laboratory, E. I. d u P o n t d e Nemours a n d Co., Wilmington 99, Del. ( 2 ) Fabrics and Finishes Department, Experimental Station, E. I. du P o n t d e Nemours and Co., Wilmington 98, Del. (3) A . E t a r d , Compt. r e n d . , 88, 649 (1879). (4) H . von Pechmann and P h . Manck, Bey., 28, 2374 (1895).
workers5 to account for the break in the potentiometric titration of potassium cyanide with sulfur dioxide dissolved in liquid hydrogen cyanide, but no reaction product was characterized. More recently Seel and Muller6 reinvestigated the work of Jander and co-workers and showed that the precipitate formed by addition of sulfur dioxide t o a solution of potassium cyanide in liquid hydrogen cyanide was potassium pyrosulfite. They further studied the product obtained by prolonged exposure of potassium cyanide to liquid sulfur dioxide a t room temperature and concluded that the over-all reaction could be described by the equation lOKCN
+ 1OSOz ---+ 2KzS205
+ K&Oe + K2SOa + 2KSCS + 8CX
(5) G. Jander, B. Griittner, a n d G . Scholz, i b i d . , 80, 279 (1947) (6) F. Seel and E . Muller, i b i d . , 88, 1747 (1955).
