Feb. 5 , 1960
toxy-A6-bisnorcholenate, 0.1 ml. of absolute ethanol and 0.1 ml. of liquid ammonia was sealed and then heated a t 68" for two hours. The tube was opened and the volatiles removed t o give 48 mg. (looyo)of the amide,'* m.p. 221226"; 5.77, 6.02, and 6.09 p ( K B r ) . Crystallization of 6 mg. from methanol a t 5' gave 5 mg. (SOY0),m.p. 226-227'. Attempts t o prepare the diethylamide were unsuccessful. The reaction was incomplete after heating the ester with diethylamine for two hours at 140' in a sealed tube; after 12 hours, no ester remained but ammonolysis of the acetate group seemed to have occurred to a considerable extent. 1-Methoxyvinyl p-Nitrobenzoate. With Hg ++.-+Sitrobenzoic acid (167 mg., 1 mmole), 0.3 mg. (0.001 mmole) of mercuric acetate and 2.8 mmoles of inethoxyacetylene in 2 ml. of methylene chloride were stirred together a t room temperature for one hour. The acid is not verj soluble in the solvent and the end of the reaction was evident when the solution clarified. Removal of the volatiles gave 215 mg. (96%) of crude 1-methoxyvinyl p-nitrobenzoate, m.p. 6772", containing a little anhydride, 5.54 p (CH2C12). The crude ester (130 mg.) was dissolved in 4 ml. of hot ethanol and the solution cooled rapidly and allowed to stand a t room temperature for five minutes, after which it was centrifuged from the small amount of deposited solid. The clear filtrate was stored a t -20" and gave 89 mg. (66y0)of long, pale yellow needles, m.p. 75-78', 5.72 and 5.94 p ( K B r ) . A further crystallization from ethanol gave analytical material, m.p. 76.5-78". Anal. Calcd. for CloHsNOs: C, 53.81; H, 4.06; S , 6.28. Found: C, 53.72; H, 4.28; S , 6.36. p-Nitr0benzamide.-A tube containing 3T.8 mg. (0.17 mmole) of 1-methoxyvinyl p-nitrobenzoate, m.p. 75-78", 0.2 ml. of absolute ethanol and 0.2 ml. of liquid ammonia was sealed, heated momentarily to dissolve the solid, and then left a t room temperature for 10 minutes. Removal of the volatiles gave 28.2 mg. (looyo)of crude amide, m.p. 192-199'. Crystallization of 5.4 mg. from 0.5 ml. of water a t 5" gave 4.6 mg. (85Y0), m.p. 19&202", raised to 201202.5' by a further crystallization; 6.01 p ( K B r ) . 1-Methoxyvinyl 3,S-Dinitrobenzoate.-A suspension of 217 mg. (1.02 mmoles) of 3,5-dinitrobenzoic acid in 1.8 ml. of methylene chloride, containing 0.9 mg. (0.0028 mmole) of mercuric acetate and 2.5 mmoles of methoxyacetylene, was stirred at room temperature. The reaction was complete in 12 minutes (evident from the clearing of the solution). Removal of the volatiles gave 267 mg. (97yo) of crystalline 1-methoxyvinyl 3,5-dinitrobenzoate, m.p. 93.595.5", containing only small amounts of anhydride, ca. 5.5 (12) W. Cole and P . L. Julian, THIS JOURNAL, 67,1369 (1945).
[CONTRIBUTION FROM
665
AMINOLYSIS OF ESTERS
THE
(CH2CI2). Attempts to crystallize the ester led to extensive decomposition. Analytical material was obtained in another run, using 106 mg. (0.5 mmole) of acid and 7 mmoles of methoxyacetylene in 5 ml. of methylene chloride (no mercuric salt was added). The reaction was complete in 15 minutes. Removal of the vo1a:iles gave 135 mg. (lOlyO) of crystalline ester, 93.5-95.5 , 5.71 and 5.94 p (KBr). Anal. Calcd. for C10H~N207: C, 43.78; H , 3.01; Pi, 10.45. Found: C,45.03; H,3.24; K, 10.29. 1-Methoxyvinyl p-Phenylazobenzoate. With Hg ++.A suspension of 41 mg. (0.18 mmole) of p-phenylazobenzoic acid in 3 ml. of methylenechloride, containing 0.8 mmole of methoxyacetylene, was stirred a t room temperature for 12 hours. The infrared spectrum of the filtered solution showed that the acid was sparingly soluble in the solvent and negligible reaction had occurred. After the addition of 2.7 mg. (0.0085 mmole) of mercuric acetate, the reaction proceeded rapidly and was complete in half an hour (evident from the clearing of the solution). Removal of the volatiles gave 51 mg. (96%) of crude 1-methoxyvinyl p-phenylazobenzoate, m.p. 76-80". With rapid heating and cooling of the solution, 32 mg. was crystallized from ethanol a t 5" to give 26.5 mg. (8070) of pure ester, 5.72 and 5.97 p (KBr). If heated slowly from i o " , a transition with partial melting, followed by solidification, occurred a t 81", m.p. (sharp) 94.595.5". If immersed in the oil-bath a t 85", the ester melted completely before solidifying and finally remelting a t 94.595.5'. Anal. Calcd. for C X H ~ ~ N Z OC, ~ : 68.07; H, 5.00; N, 9.92. Found: C, 68.03; H, 5.U9; N, 9.94. p-Pheny1azobenzamide.-A tube containing 6.0 mg. (0.021 mmole) of 1-methoxyvinyl p-phenylazobenzoate, 0.2 ml. of ethanol and 0.1 ml. of liquid ammonia was sealed and left a t room temperature for 10 minutes. Removal the volatiles gave 4.9 mg. ( 1OOyo) of amide, m.p. 226-227 , unchanged after crystallization from ethanol; 6.04 p ( K B r ) . 1-Methoxyvinyl 3&Hydroxy-As-cholenate. Without Hg++.-A suspension of 53 mg. (0.14 mmole) of 3 8 - h ~ droxy-A5-cholenic acid in 5 ml. of methylene chloride was stirred overnight with 0.4 ml. (5.7 mmoles) of methoxyacetylene. Removal of the volatiles gave 61 mg. ( 1 0 0 ~ o ) of crude ester, m.p. 125-12i0 (capillary tube inserted a t 120°), 5.70 and 5.96 p (KBr). An attempt to crystallize the crude material from methanol resulted in crystals melting less sharply below 110'. The crude product was not further characterized. NEW HAVEX,COSN.
p
tf
DEPARTMENTS OF CHEMISTRY OF THE UNIVERSITY OF SORTH CAROLIXA ASD UNIVERSITY]
OF
BROWN
The Mechanism of Aminolysis of Esters1f2 BY J. F. BUNNETTAND GEORGE T. DAVIS RECEIVED MAY11, 1959 T h e reaction of ethyl formate with n-butylamine in ethanol solution t o form n-butylformamide is general base catalyzed. The rate law contains terms second order in amine (representing amine catalysis) and 3 / 2 order in amine (representing alkoxide ion catalysis) but no detectable term first order in amine. Addition of n-butylammonium chloride affects the rate law and the rate in a fashion consistent with this interpretation. The results are best represented by the mechanism of equations 23-25. The mechanism of equations 1-4, formerly generally accepted, is untenable. This work constitutes additional evidence for the intermediate complex mechanism as a general mechanism for substitution a t carbonyl carbon.
The reactions of carboxylic esters with amines to form carboxamides have been extensively studied. 3,4 Careful kinetic researches5e6have revealed that such reactions are susceptible to base catalysis. (1) T h e portion of this work performed a t the University of North Carolina was supported in part by the Office of Ordnance Research, U. S. Army, and t h e portion performed a t Brown University by t h e National Science Foundation (Grant No. N.S.F. GB210). (2) Preliminary results of this research were presented t o t h e KekulC Symposium OD Theoretical Organic Chemistry, London, September, 1958; J. F. Bunnett, Proceedings of the KekuM Symposium, p. 144.
Ester aminolyses are in the category of nucleophilic substitutions a t unsaturated carbon. An( 3 ) (a) P . K. Glasoe, L. D. Scott and L. F. Audrieth, THISJOURNAL, 61, 2387 (19391, and preceding papers; (b) R. N. Washburne, J. G. Miller and A. R. Day, ibid., 80, 5963 (195S), and preceding papers; ( c ) G. H . Grant and C. N. Hinshelwood, J. Chem. Soc., 1351 (1933); (d) N. T. Vartak, N. L. Phalnikar and B. V. Bhide, J. Indian Chem. Soc., 24, 131A (1047); (e) P. J. Hawkins and I. Piscalnikow, THIS JOURNAL, 77, 2771 (1955). (4) R. Baltzly, I. M. Berger and A. A. Rothstein, ibid., 72, 4149 (1950). ( 5 ) R. L. Betts and L. P . Hammett, ibid., 59, 1568 (1937). (ti) W. H. Watanabe and L. R. DeFonso, ibid., 78, 4542 (195b)
J . F. BUNNETT AND GEORGE T. DAVIS
666
Vol. 82
other aminolysis reaction within this category, that Watanabe and DeFonsoa studied the kinetics of of N-methylaniline with 2,4-dinitrofluorobenzene reaction of n-butylamine with ethyl formate in to form N-methyl-2,4-dinitrodiphenylamine,is ethanol solution and in ca. 4 M ethylene glycol in also sensitive to base catalysis, and a study7 dioxane. Kinetics first order in ester and approxof the catalysis phenomenon indicated a mechanism imately 3 / 2 order in amine were observed. Howsubstantially different from that which had been ever, the over-all 5/2 order rate coefficients were advanced to explain base catalysis of ester amin- not constant throughout any run and the data olysis. A re-examination of the latter effect was were treated in terms of limiting values a t zero therefore undertaken. time. When n-butylamine hydrochloride was Betts and Hammett,5on the basis of their kinetic present in constant amount, the kinetics in any run study of ester aminolysis, proposed the mechanism were accurately third-order over-all (first order in ester, second order in amine). When n-bu tylamine RNHz RKH2 RXH3+ + R X H - K A (1) ~ hydrochloride concentration was varied but total RNHz + R’OH RNH3+ + R’OKg ( 2 ) salt concentration was kept constant by compensation with lithium chloride, the rate coefficient R”C0OR’ R S H z +R ” C 0 X H R + R’OH k, (3) decreased about threefold with change of [RNH3R”C0OR’ R N H - --+ R ” C 0 N H R f R‘O- k b (4) Cl] from 0.005 to 0.100 M . Strong catalysis (in They were careful to point out that this mechanism ethanol) by added sodium ethoxide also was noted. was not the only one consistent with their data,* These observations are similar to those of Betts but this mechanism was clearly favored by them. and Hammett and were interpreted in terms of the It has come to be generally accepted. same mechanism. Watanabe and DeFonso emThe experiments of Betts and Hanimett con- phasized, however, that the mechanism of Betts cerned the reactions of ammonia (R = H) with and Hammett was not uniquely required by their methyl esters (R’ = CH3) of phenylacetic acid and data. some of its ring-substituted derivatives. The The results of the foregoing author^^,^ are also observations which called for the above mechanism compatible with this type of mechanism or a mathematically equivalent one were: (a) ki the reactions were approximately 3 / 2 order in R ” C 0 O R ’ + RXHz R”COOR’,RA-Hz ( 9 ) ammonia as well as first order in ester, (b) the k- 1 reactions were accelerated by added sodium methk2 oxide, and (c) the reactions were retarded by R”COOR’.RNH, ----f R ” C 0 S H R + R’OH (10) added RNH3C1 in such a way that a plot of the apparent second-order rate coefficient (first order k3 in ester and first order in ammonia) against R”COOR‘.RNHz f B + R “ C 0 S H R + R’OH + B (11) 1/[RNH3+] was linear. I t will now be shovm how these observations To our knowledge, this type of mechanism for ester were reconciled with the mechanism of equations aminolysis was first suggested by Hawkins and 1-4. The over-all rate (from equations 3 and 4) Tarbellg as an interpretation of the base catalysis should be of thiolester aminolysis which they observed. The kinetic expression for this type of mechanism,’ rate = k,[E] [ R S H ? ] f kl,[E] [ R S H - ] (5) derived with reliance on the steady state assumpFrom equation 1 tion, is
+
+ +
[RSH-]
and theref ore rate
=
k,[E][RSH,I
k’.\,[RSHz] ‘j [RSHa+]
=
+ kbK,r,,[E] [Rr\TH2]z/[RKHz+] ( 6 )
In the absence of added KSH3i-,the concentrations of RNH3+ and R’O are equal (equation 2) and hence [R‘O-]
=
KB1iz[RXH2]’/2
(3
Equation 6 is then transformed into rate
=
k,[E] [RSHz]
if k-l greatly exceeds both kz and k3[B], the denominator simplifies to k l . Then, taking account of the presence of three bases in an alcoholic solution of an amine-the alcohol, the amine and the alkoxide ion-one may write rate = [E][RSHs]
klk3‘ - + kLl ~
[R‘O-] 4kik3”
+ kbK2trn[E][ R S H z I a / ? / K ~ ‘ / 2( 8 )
Equation 8 was said to explain observation (a) and equation 6 to explain (c). The accelerating effect of added sodium methoxide was interpreted as due to a shift of equation 2 to the left and a resulting shift of equation 1 to the right, causing an increase in [RNH-1. (7) J . F. Bunnett and J. J. R a n d d l , THISJOURXAI., 8 0 , 6020 (19.58). (8) Betts and H a m m t t t s said, “ T h e obvious mechanism for such a [base] catalysis would involve amide ion as t h e actual reactant, and we shall discuss it in terms of this mechanism. T h e same conclusions can, however. be obtained f r o m other mechanisms. Thus t h e reaction might be a truly termolecular one involving ester, ammonia and methylate ion, or t h e initial equilibrium might involve the ester and methylate ion.”
k--i
[RXH,]]
(13)
Letting kRto- stand for klk3’/k-l and k R N H 2 for k l k 3 ” / k - 1 , we may rewrite this equation as rate
( k i k ~ / k - - ~ ) / [[RSHzI E] k ~ ’ o - [ E [RSHz] ] [R’O-]
=
f
+ ~ R X E ~[RNH?12 [E] (14)
When no RNH3+ salt is present this equation becomes (see equation 7)
+
rate = (klkp/k-~)[E][RSHg] (151 ~ R ’ o - K B ’ / ~ [RXH2l3/2 [E] f ~ x x R ~ [[RSH?]’ E]
And when RNHa+ salt is present, equation 14 (9) P J (1953)
Hawklns and D
S
Tarbell. THIS JOURNAL. 75. 2982
becomes (see equation 2) rate
=
(klke/k-~)[EI[RNHzl [RNHB']
667
AMINOLYSISOF ESTERS
Feb. 5, 1960
+ ~ R ' O - K B [ E[RKHp12/ ] + ~ R N H ~[RNHz]' [E]
(16)
Equation 15 contains terms in which the kinetic order in amine is one, 3 / 2 and two, respectively. Hence ester aminolysis might be any of these three orders in amine, or a mixture of orders, depending on the relative magnitudes of the three terms. If alkoxide catalysis were dominant, the second term which is 3 / 2 order in amine would account for most of the reaction. The observation of approximately 3 / 2 order in amine is thus understandable. If an RNH3+ salt were present, equation 16 would obtain and a t any fixed RNH3+ concentration the second and third terms would merge as a term second order in amine. Thus the mechanism of equations 9-11 gives an adequate account of the observations of kinetic order reported by Betts and Hammett and by Watanabe and DeFonso. Acceleration by alkoxide ion, as observed, is obviously called for by equation 14. When two chemically different mechanisms are both compatible with a set of kinetic data, a means of distinguishing them experimentally is desirable. In the present case, further kinetic tests can be applied. Foremost is determination of the type of base catalysis which prevails. The mechanism of equations 1-4 requires specific lyate ion catalysis whereas that of equations 9-11 demands general base catalysis.1°
mate in ethanol solution. T h e kinetic effects of varying concentrations of n-butylamine, of n-butylammonium chloride, of lithium chloride and of sodium ethoxide, in various combinations, were studied. Because of the specillcity of salt effects in ethanol solutions, owing largely t o the prevalence of ion pairing, the ionic strength is not in itself a n adequate representation of salt effects in this solvent. Therefore no effort was made to maintain constant ionic strength, and salt effects were studied separately.
Experimental
The classic experiment for distinguishing general base catalysis from specific lyate ion catalysis involves determining the reaction rate in a series of buffers of constant buffer ratio but varying absolute buffer concentration, and a t constant ionic strength.1° n'ater is customarily the solvent for such a study. In this research, water was eschewed in order to avoid possible hydrolysis complications. An amphoteric solvent, in the Bronsted sense, was desired; the obvious choice was the alcohol represented in the alkyl group of the ester. If any other alcohol were used, Umesterung would be a possible complication, as Watanabe and DeFonso have pointed out. Bearing in mind the possibility that general base catalysis might be confused with nucleophilic catalysis," we wanted a catalyzing base unable to effect nucleophilic displacement of ester alkoxy groups or which, if it did displace the alkoxy group, would not complicate the over-all reaction. The special bases which meet the latter requirement are the amine reactant itself and the alkoxide ion corresponding to the alkoxy group. These special bases were in fact the only ones studied in this work. In order that the progress of the reaction in any run should not disturb the buffer ratio, it was desired to have the amine and buffer components in large excess over the ester. This meant that the ester need be a t very low concentration and therefore that a sensitive analytical method be used. Photometric analysis in the ultraviolet, depending on the difference in absorptivity between ester and amide functions, was found to be feasible. Several ester-amine combinations were found to lack sufficient reactivity to be useful for our purposes. These included aniline-ethyl acetate, piperidine-ethyl acetate, aniline-ethyl benzoate, aniline-ethyl pnitrobenzoate, nbutylamine-ethyl benzoate and n-butylamine-ethyl acetate. Eventually we settled on the system studied by Watanabe and DeFonso, the reaction of n-butylamine with ethyl for-
Materials.-Absolute ethanol was prepared by distillation of 95yo ethanol from calcium oxide and then distillation from magnesium ethoxide.la This method was found to give ethanol of highest optical purity for measurements a t 220 mp. Commercial butylamine was precipitated as the hydrochloride, m.p. 213-213.5", from ether.6 After three reprecipitations from ethanol by addition of ether, the free amine was liberated with excess strong base. After ether extraction and separation, the material was distilled (b.p. 77.377.8") several times from solid potassium hydroxide and stored in a desiccator over solid sodium hydroxide. Butylamine hydrochloride was prepared as described above and stored over Drierite and paraffin chips. Weighings of the hygroscopic hydrochloride were conducted in a dry-box. Stock solutions of lithium chloride in ethanol were prepared from reagent grade material redried in vacuo over phosphorus pentoxide and weighed in a dry-box. The solutions were standardized by potentiometric chloride determination. Ethyl formate was dried, distilled (b.p. 54.0-54.6') and stored over phosphorus pentoxide. n-Butylformamide was prepared from chloral and butylamine13 in 247, yield, b.p. 121-122" (21 mm.) (uncor.), n Z E ~ 1.4387 (lit.13 b.p. 122-123' (16 mm.), n z 6 1.4385). ~ This material was employed in initial spectral studies, and in preparation of mock infinity solutions. A sample of n-butylamine was purified through the o-chlorobenzoyl derivative, m.p. 79-80'. Anal. Calcd. for C11H14ClNO: C, 62.40; H, 6.67. Found14: C, 62.62; H, 6.33. n-Butylamine liberated from this material by basic hydrolysis was kinetically indistinguishable from amine purified through the hydrochloride. Sodium ethoxide solutions were prepared by dissolving clean, freshly cut sodium in absolute ethanol, and standardizing the solution against standard acid. Methanol was treated with magnesium metal and distilled from magnesium methoxide. The methyl benzoate used was a commercial product, redistilled, b.p. 197.8-199 3'. N-n-Butylbenzamide was prepared from benzoyl chloride and n-butylamine by the Schotten-Baumann reaction, b.p. 194-195' (25 mm.). After solidification in a n ice-chest, the material was recrystallized three times from ethanol with seeding, m.p. 40-42' (lit.'sB b.p. 182-184" (12 mm.), 68-70", r n . ~ . 41-42'). '~~ This material was used for spectral studies and preparation of infinity solutions. Spectral studies of formic acid were made on solutions containing weighed quantities of sodium formate in acidified aqueous alcoholic media. Methods.-The aminolysis reaction solutions were prepared from pipetted aliquots of standard stock solutions which were mixed and diluted a t the reaction temperature. At appropriate time intervals, 10-ml. aliquots were quenched in 25-m1. volumetric flasks containing excess cold alcoholic hydrochloric acid (0.2-1.5 M ) . The samples then were diluted t o the mark and measured a t 220 mp. Slow decrease in absorption on standing required photometric measurements t o be made without delay. Measurements were made on a Beckman DU spectrophotometer in matched 1-cm. quartz cells against a blank of quenching solution. Care was taken to use the same quenching medium
(10) L. P. Hammett, "Physical Organic Chemistry," McGraw-Hill Book Co., Inc., New York, 1;.Y., 1940, p , 215. (11) M. L. Bender and B. W. Turnquest, THIS J O U R N A L , 79, 1G52, 1656 (1957); M. L. Bender, Y.-L. Chow and F. Chloupek, ibid., 80, 5380 (19.58); T C. Rruice and R. Lapinski, ibid., 80, 2265 (1958); E. R. O i r r e t t t b i 1 , 7 9 , 320G (19,571.
(12) H. Lund and J. Bjerrum, Ber., 64, 210 (1931). (13) F. F. Blicke and Chi Jung Lu, THISJOURNAL, 74, 3933 (1952). (14) Analysis by Micro-Tech Laboratories, Skokie, Ill. 115) (a) J. v. Braun and J. Weismantel, Bcr., 65, 3170 (1922); (b) H. W. Grimmel, A. Guenther and I. F. Morean. Tnis J O U R N A L , 68, 83'3 (1946).
Choice of Experimental Conditions
J. F.BUNNETT rlND
668
throughout a given run, as variations in solvent absorbances were found t o be appreciable at 220 mfi. Yields based on the infinity absorbances for the unbuffered runs appeared t o vary considerably and in an irregular manner. Undoubtedly, this contributed t o the low precision of these runs. I n the most rapid runs containing added sodium ethoxide, special techniques were used to follow the reaction. The reactants were prepared to known volumes and concentrations in separate flasks and mixed by rapid introduction into a glass-stoppered erlenmeyer flask. Samples were withdrawn by means of a rapid-delivery syringe having a metal stop over the plunger. By this technique, i t was possible to obtain samples at intervals of five seconds. T h e runs involving methyl benzoate were followed by increase in absorption at 250 m r due to production of N-butylbenzamide; 1-cc. aliquots were taken from reaction solutions containing 0.0100 A1 initial ester. These were quenched in 0.100 iM 50% aqueous ethanolic hydrochloric acid. Plots of log (O.D. - O.D.) uerSuS time gave good straight lines (cf. Fig. 1). The slope of such a line, selected by eye, was multiplied by 2.303 to give the total pseudo-first-order rdte coefficient, k$.
I
I
TABLE I BUFFEREDREACTION O F BUTYLAMISE WITH ETHYL FORMliTE Iius IN ABSOLUTE ETHANOL AT 24.6". A REPRESENTATIVE Initial concentrations: RNH,, 0.200 M ; RSHaCI, 1.00 JI; HCOOEt, 0.0100 M Time, min.
Optical density (O.D.)
0 5 35 0 67 0 105 0 140 0 168.0 200.5 237.5 1200
0.422 ,477 ,530 ,588 ,624 ,652
0
0.4
0
I
I
I 100 Time, niin.
0 Fig. 1.-Representative
O.D.)
-
0.452 ,397 ,344 ,286 ,250 ,222 ,194 ,164
,680 ,710
kinetic run. Table I.
I 200
+
1 lug (O.l).m O.D.)
0.655 .599 ,537 .456 ,398 ,346 .288 ,213
,874 TABLE
11
REPRODUCIBILITY OF USBUFFERED R c s s . BUTYLAMIKOLYSIS OF ETHYL FORMATE AT 24.60' Initial concentration of ethyl formate: 0,0100 M kd X 104,
Yield of aminolysis product,' %
SCC. - 1
73 88 104 96 104 XG
T A I 3 L E I11 BUFFEREDI
