2770
J. D. REINHEIMER, J. T. GERIG,R. GARSTAND U. SCHRIER [CONTRIBUTION FROM SEVERENCE CHEMICAL LABORATORY, THECOLLEGE O F WOOSTER, WOOSTER,
VOl. s4 OHIO]
An Acid-catalyzed Aromatic Nucleophilic Substitution Reaction BY JOHN D. REINHEIMER,~ JOHN T. GERIG,ROGER GARSTAND BRUCESCHRIER RECEIVEDSEPTEMBER 18, 1961 The rate of displacement of the halogen in 2-halo-5-nitropyridines by water in 5-10 M sulfuric acid, acetic acid-water and dioxane-water has been investigated. The rate decreased with increasing acid concentration in aqueous sulfuric acid and was found to be proportional to the 4th power on ~ E O Hand to the fraction of the halopyridine protonated. The reaction rates were determined in D20 with DnSOa catalyst and an isotope effect of 2.36 was obtained. The pK, of the 2-halo-5nitropyridines were determined. A mechanism for the reaction is suggested.
The nucleophilic substitution of halogen substituents by basic reagents has been known for a long time. However, the fact that protonation of the heterocyclic nitrogen results in an increased rate of substitution o d y recently has been recognized. Banks2 showed that the rate of replacement of "active C1" on heterocyclic bases was increased if acid were present. He used about 10 heterocyclic compounds and 40 aromatic amines to demonstrate the generality of the reaction. Bunnett3 and Merte14 have reviewed the literature and have given a number of examples of the scope and usefulness of this reaction. Chapman and Kees5 were concerned with the autocatalytic reaction in which the HC1 liberated in the reactions of chloronitropyridines with aniline protonated the aromatic substrate. Dummel and Mosher6 have observed the acid-catalyzed displacement of the nitro group of 2-nitropyridine-5-carboxylic acid by the OH or C1 group. The present research was initiated in the expectation of obtaining some quantitative data on these acid-catalyzed reactions.
Experimental Materials.-Sulfuric acid, d u Pont reagent grade, was used without further purification. The acid was standardized by a potentiometric titration with NaOH. The density was also determined; the value was within the inanufacturer's specifications and corresponded exactly t i , the composition given in the l i t e r a t ~ r e . ~ Deuterium sulfate was prepared k v the method of Schubert m d Burkett.8 The greaseon the -$ joints of the apparatus turned dark on practice runs, but the use of Teflon sleeves elitninated this difficulty. The product was analyzed by titration of a weighed amount of the acid as above. Deuterium oxide was obtained from Isotopes Specialties Co. of Pasadena, Calif., and was labeled 99.5%. 2-Chloro-5-nitropy~idine, hereinafter abbreviated 2C5TP, was obtained from Aldrich Chemical Co., Inc. It was purified by recq-stallization from benzene or benzenepetroleum ether and had a melting point of 107-108", iit.9 108~. "-Iodo-3-niti-[)pyritline, abbreviated 215NP, was synthesized by t h e replacement o f C1 by I - in a n acid-catalyzed reactioti. One-half mole o f SLiI was refluxed for 1.5 hr. nit11 0.1 mole of 2CcjSP i n 300 i d . of glacial acetic acid. The product was isolated by pouring the reaction mixture ( 1 ) This research was supported by a grant ( N o . DA-ORD-1) from the Office of Ordnance Research, U. S . Army. ( 2 ) C . Kenneth Banks. J Anz. Chem. Soc., 6 6 , 1127 (1944). (a) J . F. Bunnett and R. Zahler, Chent. Reus., 49, 331 (1951). (4) H. E. Mertel. "In the Chemistry of Heterocyclic Compounds," A . Weissberger, Editor, Interscience Publishers, Inc., New York, S Y , Part 11, I Y l i l , C h V I I,->) S R C h a p m a n anrl C . \V. Kee.;, .I ( ' ~ P I I I . .Yo(., 1190 (19.74). ( l i ) I< J Ilumrnel anrl H . S Rlosher. J O r g . h he?)^., 24, 1007 (1969). r i ) "International Critical Tables," Val. 111, p . 57. 18) \V. I1 Schubert and H . Burkett, J . A m . Chem. Soc., 7 8 , 6: (lg.-)Ii). , ICjSC (l(J42). (9) \\'. '1'. Caldivcll a n d Ii C .Kornfcld, f f ~ i d . 64,
on 400 g. of crushed ice and filtering. The crude yield was 23 g., 9079. It was recrystallized from benzenepetroleum ether to give a melting point of 163-164". The infrared spectra was similar to that of the known 2C5NP. Analysis was for %I of a sample hydrolyzed in acid solution: calcd. 50.78y0, found 50.51,50.587,. 2-Hydroxy-3-bromo-5-nitropyridine was prepared by the diazotization of the corresponding amino compound. The melting point of 204-205" was obtained after recrystallization from acetone. Dioxane was purified by the method given in Weissbergerlo; i.e., acid hydrolysis followed by reflux over Na metal. Glacial acetic acid, Fisher reagent grade, was partially frozen and the liquid discarded. Procedure.-Pipets, burets and thermometers were calibrated. The halopyridine, 0.5-0.6 g., was weighed accurately on a tared aluminum pan and transferred to a volumetric flask. The sample was dissolved in concentrated sulfuric acid, and ice-cold water was added to the flask in an ice-bath to obtain the desired concentration. Final dilution was performed after the solution had warmed to room temperature. Eight samples were pipetted into tubes and these were sealed by fusing their elongated necks. The reactions were run in a bath in which the temperature variation was = t 0 . l o or less. The reaction was stopped by plunging the sample tube in ice. Immediately after the sample tube was opened and rinsed, the C1- or I- was titrated with AgN03. The electrode system was Agcalomel with an ammonium nitrate or KNOBsalt bridge to eliminate C1- leakage from the calomel electrode. A Beckman Zeromatic p H meter was used as a potentiometer. Plots of log ( Vm - V )os. time were prepared and the pseudofirst-order rate constants determined from the slope. Some oxidation of I - was observed, so that the reaction mixture was outgassed with nitrogen by means of a sintered glass filter stick. In addition, the sample tubes were flushed with nitrogen before filling. In spite of these precautions, some IZ color developed in samples removed toward the end of a run. The samples were treated with 5 ml. of water saturated with SOP to reduce the 1 2 . The product of the reaction, 2-hydroxy-5-nitropyridine, 2H5NP, did not iodinate under reaction conditions. p K , Values.-The pK, of BCBNP, 215XP and 2H5XP were determined by the method of David akd Geissman." The wave lengths used were 2800 and 2650 A . for 2C5r\'P, 3220 and 3030 for 215NP, and 2550 and 2400 for 2H5NP. The temperature dependence of the pK, of 2C5NP was obtained by filling the cells at a given temperature and quickly reading the absorbance before the temperature changed. The uncertainty in the temperature was estimated by placing a thermometer in the cell and timing the operations. This gives an estimate of the temperture change, which is given in the results. Isolation of the Reaction Products.-Dilution of the dioxane-water reaction mixture with a large amount of water gave a yellow material identical with 2H5NP by its melting point of 182-183", lit.'* 184'. Other reaction mixtures were made basic after 10 half-lives and the ultraviolet spectra compared to that of an authentic sample of 2H5XP. Other reaction mixtures were brominated to give a sample melting a t 201-205". The mixed melting point with an authentic .- ..
~
(111) A Wei5sberger. '"lechnique of Organic Cherniqtry," Inlersci-
rnce Puhlishers, Inc., New York, N . Y . ,2nd Edition, Vol. X'III, p 372. (11) C . Ilavis and G. Geissman. J . A m . Chenz. Soc., 7 6 , 3507 (Ig54). (12) Brilstein s "Handbuch Der Organischen Chemie," Julius Springer, Berlin, 1935, 4th Edit on, 1st Supplement, Vc~l X S I . I,. 202.
July 20, 1962
AROMATIC NUCLEOPHILIC SUBSTITUTIONS
sample of 2-liydroxy-3-broiiio-5-iiitropyridiiiegave no depression.
277 1
99.1 45.3,46.4 25.0 0.0169 (calcd.) 72.0 3.20 Results 76.8 4.79 The k4, the first-order rate constants, are given 82.1 8.26 in Tables I, V and VI. The activation energies 89.1 14.6 are also given in the same tables, and indicate 32.1 (22.9) 98.0 TABLE I 6.39 25,O 0,0115(calcd.) 72. 0 2.55 I
