March, 1961
HYDROLYSIS OF ALKYL ACETATESI N
PHOSPHBTE-BUFFERED
TABLE I1
Kx\'OaD
System
Temp.,
OC.
463
TABLE I11 HEATSOF REACTION
STABILITY CONSTANTS ( MOLAL-1) Solvent
AQUEOUSMEDIUM
KI X 10-1
KIKz X 10-2
Kz X 10-1
Agi C1-
370 5.00 8.60 1.70 3.33 1.19 436 2.80 4.72 1.34 Sa-KK03 Ag+, C1333 3.53 374 2.80 2.50 0.893 Na-KN03 A g + , B r - 376 9.33 31.1 3.33 1.84 414 7.23 13.3 Constants calculated from data of Blander, ef al.
+ + + + + +
Reaction
Solvent
-AH
(kcal./mole)
Xgf c1- = AgCl KNO," iigCl C1- = AgC12.4g+ C1- = AgCl SaNo3-KNOJ AgCl Cl- = AgC1,NaN03-KN03 Ag+ Br- = BgBr Br- = AgBrzAgBr a Heats calculated from data of Blander, et al.
7.96 4 92 4 40 7.73 5.94 13.9
as solvent to a eutectic mixture of NaN03-KN03 be further investigated as a function of the solvent as shown by the product KIKz. This trend will cation.
HYDROLYSIS OF ALKYL ACETATES I N A PHOSPHATE-BUFFERED AQUEOUS MEDIUM BYJOHN M. HOLLAND AND JOHN G. MILLER Department of Chemistry of the University of Pennsylvania, Philadelphia, Penna. Received September 8 , 1960
The hydrolyses of methyl and ethyl acetates have been studied a t 30" in aqueous medium maintained in the pH range of 6.2 to 6.9 by sodium phosphate buffer. The hydrolyses occurred a t a measurable rate; the reaction was found to be first order in both ester and phosphate dianion. The specific rate constant for ethyl acetate hydrolysis, determined a t seven different concentrations of ester and phosphate dianion, and at, a total ionic strength of 1.6, was 1.00 f 0.10 x 1. mole-' hr.-l. The rate constant extrapolated to zero ionic strength was approximately 1.8 f 0.1 x 10-3 1. mole-' hr.+. For methyl acetate the hydrolytic rate constant, determined at three different concentrations of reactants and a total ionic strength of 1.5, was 1.75 It 0.05 X 10-8 1. mole-' hr.-l. The course of the reaction was followed by titrimetric determinations of increasing concentration of phosphate monoanion. A mechanism has been proposed which includes a rate-determining nucleophilic attack by phosphate dianion on the carbonyl carbon of the ester followed by a relatively rapid hydrolytic decomposition of the intermediate acetyl phosphate monoanion into acetate and phosphate monoanions.
Several years ago during an investigation of the effects of various solvents on the alkaline hydrolysis esters, it was found in this Laboratory that phosphate-buffered hydrolyses of several formates and acetates proceeded at a measurable rate in aqueous dioxane solution and in the pH range 7.6 to 8.8.' Although the WOI k was of a semiquantitative nature, the results could be equated to a second-order rate expression involving ester and phosphate dianion concentrat ions. This present study was undertaken to demonstrate that ester hydrolysis does occur with reproducible second-order kinetics in a neutral phosphate-buffered aqueous medium, where the catalytic effects of hydronium and hydroxyl ions are minimal. The exclusion of organic solvents limited this work to those alkyl acetates with sufficient watersolubility to ensure homogeneity; ie., methyl and ethyl acetates. The hydrolyses of phenyl and pnitrophenyl acetates in phosphate buffers, but otherwise uncatalyzed, has been reported recently by several and in two of these studieszce kinetic measurements of p-nitrophenyl acetate hydrolysis in phosphate buffer have been reported. I n each case the reaction was followed by determining either the disappearance of esterzd (1) G. A. Gallagher, Dissertation, Univ. of Pa., 1954; C . A . , 48, 104136 (1954). (2) (a) T. C. Bruice and G. I,. Schmir, J . A m . Chem. Soc., 79, 1663 (1967); (b) T. C. Bruice and G. L. Schmir, z b i d . , 80, 148 (1958); (c) T C. Bruice and R Lapinski, %bad.,80, 2265 (1958); (d) W. P. Jencks and J. Carriuolo. r b d . 82, 675 (1960); (e) W. P. Jencks and J. Carriuolo, ibid , 82, 1778 (1980).
or the appearance of hydrolysis products.2a,b,C e In the investigation reported here, we have followed the course of the hydrolyses through the alteration of the phosphate buffer content.
Experimental Reagents: Ethyl Acetate.-J. T. Baker Reagent Grade ethyl acetate was treated by the method of Fieser.3 A sample of the distilled material had an nDZ5 of 1.3700 (lit. value4 ~ ~ ~ 2 61.37012). . 2 Examination of a sample by gas chromatography uncovered no im urities. Methyl Acetate.-Fisher-Certiged methyl acetate was treated by the method of Hurd and Strong: 1 2 ~ 2 6of sample, 1.3589 (best literature values are 1.358868 and 1.3593tPb). Gas chromatography indicated the presence of impurities in both reagent and redistilled materials, with reduction in peaks with the latter. An approximately 2.5 M solution of NaH2PO4mas made up and stored in a 250-ml. volumetric flask using freshly opened Mallinckrodt granular NaHzP04.€120 and freshlyboiled distilled water. Anhydrous dibasic sodium phosphate, N a z H P 0 4 ,B. R: A . Reagent Grade, and Mallinckrodt, granular, Analytical Reagent, was dried to constant weight a t 105" and weighed amounts made up in a calibrated 500-ml. volumetric flask with freshly-boiled distilled water. The molarity of this solution was calculated ( c a . 0.5 M ) . Sodium hydroxide was made up in a liter Pyrex bottle in concentrated (50 wt. %) solution with freshly-boiled distilled water to which was added a small amount of barium hydroxide. Dilute solutions (0.05 t o 0.1 N ) were pre ared periodically from this stock solution and kept in a !$rex (3) L. F. Fieser, "Experiments in Organic Chemistry," 3rd Ed., D. C. Heath and Co., Boston, Mass., 1955, p. 287. (4) Zawidski, Z . physzlc. Chem., 8 6 , 140 (1900). ( 5 ) C. D. Hurd and J. 9. Strong, Anal. Chem., 2 8 , 542 (1951). (6) (a) J. C. Munch, J . A m . Chem. Soc., 48, 994 (1926); (b) I. J. Krchma and J. W. Williams, %bid.,49, 2408 (1927).
JOHN M. HOLLAND AND JOHN G. MILLER
464
bottle equipped with a drying tube containing Ascarite. Each fresh solution was standardized with reagent grade potassium acid phthalate. Reagent grade sodium chloride was dried at about 110' for 30 minutes before weighed amounts were transferred to reaction flasks. Procedure.-The homogeneous reaction solution was made up by transferring by calibrated delivery pipets both phosphate solutions, freshly-boiled distilled water, and ester, and then distilled water to the mark of the 100-ml. volumetric flask. For each series of runs a blank solution containing all but the ester was also made up. All of these transfers were carrikd out in a thermostat which waa maintained at 30.00 & 0.1'. In those runs requiring the addition of sodium chloride to maintain the desired ionic strength, the salt was weighed into each volumetric flask before any solution was added. When transfer was completed, the flasks were shaken vigorously for about 30 seconds and returned to the bath. Ten-ml. aliquots were then withdrawn from reaction and blank solutions and the nTaH2P04 content of each determined by titration with sodium hydroxide using a Leeds & Northrup, Model 7664, pH meter. Ten-ml. aliquots of the reaction solution were then pipetted into 18 mm. Pyrex tubes partially immersed in salt-ice water. The tubes were immediately corked to prevent evaporation of ester until they were sealed. After sealing they were placed in the bath and were removed at recorded times for determination of NaH2P04 content. The blank solution was kept in the stoppered volumetric flask, and aliquots were removed from time to time during the run for determination of NaH2P04content. In no instance did this value vary by more than 0.5'%; an average of these values was used as a base point in calculating the steady increase in NaHzPOa content found in the reaction aliquots. Before each titration the pH meter was standardized with NBS phosphate buffer in the pH 6.8-6.9 region. A set of three samples was usually analyzed consecutively; the readjustment required after each was quite small, less than 0.05 pH unit. Whether the buffered reaction solution is affected to any degree by being in contact with Pyrex glass over an extended period of time (some of the samples remained in the bath for nine months) is not known. The reaction is sensitive, however, to traces of strong acid, since an almost instantaneous increase of 2 to 5y0 in phosphate monoanion content was noted in preliminary runs where volumetric flasks and delivery pipets had been cleaned with chromic acid and then rinsed a dozen times with distilled water. Subsequently, volumetric flasks were cleaned with a nonionic detergent (Triton X-100). Chromic acid rinse of delivery pipets was followed by one in alcoholic KOH and then a dozen rinses with distilled water. This revision in procedure eliminated the initial upsurge in monoanion content. The Pyrex tubes were simply rinsed about a dozen times with water. Calculations.-Equating increase in phosphate monoanion, which is measured, t o consumption of dianion and ester, the second-order rate expression has been used to plot the course of the reaction. In Table I data for Run 6 are listed.
THE
TARLE I HYDI~OLYSIS OF ETIIYL AcEram IN PHATE BUFFER AT 30'
noted that the pH values listed take into consideration the dilution effect on phosphate buffer solutions; Le., these estimated values are about 0.2 pH unit lower than those measured for 10-ml. aliquots diluted to about 100 ml. An attempt was made to measure ester hydrolysis in water alone at a neutral pH, but in the absence of buffer the medium gradually became acidic and triggered acid-catalyzed hydrolysis. It mas found, however, that during the first two weeks of this blank run only about 0.40/, of the ester had hydrolyzed; thereafter the rate accelerated rapidly.
Discussion The k values listed in Table I1 for the hydrolysis of ethyl acetate in solutions with a total ionic strength of 1.6 are constant within the range of experimental error. These constants have been obtained with varying concentrations of reactants. Equimolar amounts of each phosphate have been employed except in one case, run 13, where the ratio of di- to monoanion was 2, and the initial pH of the reaction solution was about 6.9, rather than 6.6-6.7 for the other runs. This variation in phosphate ratio had no noticeable effect on the rate. Close agreement in rate constants has been found with the three methyl acetate hydrolysis runs. The reaction mechanism which best fits these data is believed to be a two-stage one, involving (1) nucleophilic attack by phosphate dianion on the partially polarized carbonyl carbon of the ester, followed by a splitting off of alkoxide ion and the formation of the relatively stable acetyl phosphate monoanion. In the second step, acetyl phosphate monoanion is hydrolyzed with P-0 bond fissioii and the formation of acetate and monovalent phosphate anions and alcohol 0 kl
+ -O-k'-OH
k-
0 .4QUEOUS PHOS-
T'ol. 65
II
1
0
/ I
CH~-C--O-~-P--OI-I I I 0-
+ 0/ + -011 ---+ k8
\
€1 0 0 0 3 0.00072 ..... II I 54 0 .00281 0 00130 CEIa-C-OHO-P-OH HOR ( 2 ) 335 8 .01099 .00088 I 674 2 .02082 .OW89 0968. G ,02881 .o0091 assuming kl
