Jan. 5, 1963
HYDROLYSIS OF
METHYL 2,6-DIMETHYLBENZOATES
37
[CONTRIBUTION FROM THE DEPARTMENTS OF CHEMISTRY, NORTHWESTERN UNIVERSITY, EVANSTON, ILL., AND ILLINOIS INSTITUTE OF TECHNOLOGY, CHICAGO 16, ILL.]
Acylium Ion Formation in the Reactions of Carboxylic Acid Derivatives. IV. The Acidcatalyzed Hydrolysis of Methyl 4-Substituted-2,6-dimethylbenzoates' BY MYRONL. BENDER^
AND
MARKC. CHEN
RECEIVED JULY 11, 1962 The kinetics of hydrolysis of four methyl 4-substituted-2,6-dimethylbenzoates in 9.70 M sulfuric acid were determined. Electron-donating 4-substituents accelerate the hydrolysis. The Hammett p-constant for the hydrolysis is -3.22, obtained from a plot employing u+-constants. The substituent effect is considered to be mainly operative in the rate-determining heterolysis of the protonated ester. In conjunction with other evidence, the substituent effects in this hydrolysis strongly suggest a mechanism involving an acylium ion intermediate. Comparison of the Hammett p-values of a series of hydrolytic reactions and the relative rates of a series of reactions of benzoic acid and mesitoic acid derivatives indicates that hindered benzoic acid derivatives may react uiu two distinct pathways: (1) a bimolecular pathway which shows considerable steric hindrance to reaction and is facilitated by electron-withdrawing substituents and (2) a unimolecular pathway which is facilitated by steric hindrance and by electron-donating substituents. with stirring, to an ice-cooled solutioti coritainirig a 30% excess Introduction of anhydrous methanol (Baker, reagent grade) and a few drops of The hydrolysis of methyl mesitoate in concentrated pyridine (Baker, reagent grade, stored over potassium hydroxide). sulfuric acid solution is the classical example of a mechAfter refluxing for half an hour, pyridine, methanol and the gaseous by-products were removed under vacuum. The residue, the anism involving an acylium ion intermediate. A methyl ester, was dissolved in methylene chloride (Matheson, number of different experimental approaches gives a Coleman and Bell), washed with a 5y0 sodium carbonate solution consistent picture of this mechanism. The cryoscopic and dried overnight over anhydrous sodium sulfate. Methyl 2,6behavior of methyl mesitoate in 100% sulfuric acid,3 dimethylbenzoate was distilled under vacuum; b.p. 52' (2 mm.): lit? b.p. 109" (19 mm.). Methyl mesitoate distilled a t 113-114 the proportionality between the rate constant of hydrolysis and ho in moderately concentrated sulfuric acid,4 (11 mm.), n32.6~.1.5045; lit.7 b.p. 113-113.5" (11 mm.), nzoD 1.5085.7 Methyl 4-methoxy-2,6-dirnethylbetizoate was recrystalthe positive entropy of activation5 and the lack of lized from aqueous methanol, m.p. 56.5'. oxygen exchange6 all indicate that the reaction proceeds Anal. Calcd. for CllH1403: C, 68.0; H, 7.22. Found: c, by a unimolecular heterolysis. In the previous paper 67.95; H, 7.11. in this series,6a different criterion was developed for the Methyl 4-bromo-2,6-dimethylbenzoate was recrystallized from aqueous methanol; m.p. 56", lit.'m.p. 54'. delineation of a mechanism involving the formation of Kinetic Measurements.-The spectrophotometric method for an acylium ion intermediate, namely, the use of subthe determination of the kinetics of hydrolysis has been described stituent effects in 4-substituted-2,6-dimethylbenzoic in the previous paper.6 The hydrolysis of the hindered benzoate acid derivatives. The applicability of this mechanistic esters in 9.70 M sulfuric acid is in some instances followed by the acid-catalyzed decarboxylation of the corresponding benzoic acid criterion is tested here by investigating the effect of produced in the reaction. The spectrophotometric measuresubstituents on the rates of hydrolysis of methyl 4substituted-2,6-dimethylbenzoatesin 9.70 M sulfuric ki kz ester ----f acid -3 hydrocarbon (1) acid. Substituent effects in the alkaline hydrolysis of this set of compounds had previously been determined.7 ments will lead to the rate constant for hydrolysis only if k2 is much smaller than kl. In the hydrolysis of methyl mesitoate, Therefore, i t was possible in this investigation to comkz is 30-fold less than kl in 5.78 M sulfuric acid, and 70-fold less in pare substituent effects on the rates of acid-catalyzed 11.7 M sulfuric acid.4 Furthermore, in 9.70 M sulfuric acid, 2,6ester hydrolysis with those of the base-catalyzed ester dimethylbenzoic acid and 4-bromo-2,6-dirnethylbenzoic acid hydrolysis which has been shown to proceed through a have been shown to be stable during the time necessary for the mechanism involving a tetrahedral i n t e r n ~ e d i a t e ~ , ~determination of the kinetics of hydrolysis of the corresponding esters. Typical kinetic runs are shown in Fig. 1. However, 4and with those of neutral and acid-catalyzed hydrolysis methoxy-2,6-dimethylbenzoic acid is not stable during the time of the corresponding acid chlorides which have been necessary for measurement of the kinetics of hydrolysis. In this shown to proceed through a mechanism involving an case the rate constant of the decarboxylation reaction, kz, was determined independently starting with the acid itself, and the acylium ion intermediate.6 This comparison should rate constant of the hydrolysis was obtained in the following way. provide a good test for the validity of the acylium ion The system in eq. 1 consists of two consecutive first-order reacmechanism in the acid-catalyzed hydrolysis of hindered tions. From the expression for the concentrations of ester (A), esters, and should secondarily provide a test for the acid (B) and hydrocarbon (C),Qand the fact that the absorbance of the system must be the sum of the absorbances of the three applicability of the mechanistic criterion of substituent species, it may be shown that effects in the reactions of hindered substrates.
Experimental Materials.-The sulfuric acid solutions of desired molarity were diluted from commercial concentrated sulfuric acid (B. and A. quality, C.P. reagent grade). Diluted aliquots of the stock solutions were standardized by titration with standard sodium hydroxide. The methyl 4-substituted-2,6-dimethylbenzoates were prepared from the 4-substituted-2,6-dimethylbenzoylchlorides whose preparation was described in the previous paper,6 in the following manner. The acid chloride was added dropwise, (1) This research was supported by grants from Lhe National Science Foundation and the U . S. Atomic Energy Commission. (2) Alfred P. Sloan Foundation Research Fellow; present address, Northwestern University. (3) M. S.Newman, H. G. K d v i l a and A. B . Garrett, J . A m . Chem. SOC., 67, 704 (1945), and references cited therein. (4) C. T. Chmiel and F . A. Long, i b i d . , 78, 3320 (1956). (5) M. L. Bender, H. Ladenheim and M. C.Chen, ibid., 83, 123 (1961). (6) M. L. Bender and M. C. Chen, ibid., 85, 30 (1963). (7) H. L. Goering, T. Rubin and M. S. Newman, ibid., 76, 787 (1954). ( 8 ) M. L. Bender and R. S. Dewey, ibid., 78, 317 (1956).
where e., Bb, %, are the molar absorptivities of A, B and c, and Dt is the absorbance a t time t . Here e,Aois the absorbance a t zero time and ecAo is the absorbance a t infinite time. If the term containing ebAo is eliminated in the conventional way from two simultaneous equations employing Dl a t time tl and DZa t time 1 2 , then D can be expressed as an exponential equation involving kl, kz, 11, t z , e.Ao and EJO. In this equation all quantities but kl are known. Therefore kl can be obtained analytically from the exponential equation, knowing kz and the numerical values of D a t time t , at zero time and a t infinite time.
Results The kinetics of hydrolysis in 9.70 ill sulfuric acid of a series of methyl 4-substituted-2,6-dimethylbenzoates in (9) A. A. Frost and R. G. Pearson, "Kinetics and Mechanism," John Wiley and Sons, Inc., New York, N. Y.,1953, p. 153.
38
VOl. s5
MYRON L. BENDERAND MARKc). CIIEN ’Lillie, niiii. 0
50
100
13.J
200 I
- o.e
- 1.0 h
d I
6
v
-
M
- 1.5
0.5 10,000 20,000 Time, min. Fig. 1.-Kinetics of t h e hydrolysis of methyl 4-S-2,6-dimethgla t 2 5 ’ : X = CHB,0; H, A ; Br, 0. benzoates in 9.70 -11 0
0 u
or u+.
Fig. 2.-log kjko for t h e rates of hydrolysis of methyl 4-X-2,6dimethylbenzoates i n 9.70 i1f HzSO4 a t 25’ DS. u + or u: 0, u t ; A,
u.
that is a mechanism involving the rate-determining 9.70 M sulfuric acid a t 25’ are shown in Table I. Since formation of an acylium ion. This hypothesis is based the hydrolysis of methyl 4-metho~y-2~6-dimethylben-on cyroscopic measurements in 1 0 0 ~ sulfuric o acid which zoate in 9.70 M sulfuric acid does not follow simple indicate the formation of an acylium ion13on the much first-order kinetics because of the subsequent decarfaster rate of hydrolysis of methyl mesitoate than boxylation reaction, the rate constant of this hydrolysis methyl benzoate in concentrated sulfuric acid solution was calculated by means of the numerical analysis de(although the opposite is true in dilute acid ~ o l u t i o n ) , ~ scribed in the Experimental section. In 9.70 M sulfuric and on the correlation between the logarithm of the acid solution, the first-order rate constant for the dehydrolytic rate constant and HO4.The last mechanistic carboxylation of 4-methoxy-2,6-dimethylbenzoicacid argument has been subject to much criticism in recent is 4.0 X sec.-l Comparison of this value with that years and certainly cannot be used as definitive eviof the hydrolytic constant of the ester under comparable dence.12 The acylium ion mechanism for the hydrolyconditions shown in Table I indicates that the rate sis of methyl mesitoate is further supported by the obconstants of the two consecutive reactions of hydrolysis servation of positive values of the entropy of activation and decarboxylation are very similar and must be in this reaction.6 This result is considerably different treated according to eq. 2 . It is interesting to note that from the entropy of activation of an ordinary acidic while kl (hydrolysis) and kz (decarboxylation) are comhydrolysis such as that of methyl acetate, for example, parable to one another in 9.70 M sulfuric acid, kl is which exhibits an entropy of activation of -21.3 enmuch greater than kz in 11.50 M sulfuric acid, indicating tropy units.11~12 that the hydrolysis reaction is much more sensitive to The absence of carbonyl oxygen exchange of methyl sulfuric acid concentration than is the decarboxylation mesitoate during its hydrolysis in a number of sulfuric reaction. acid solutions has been reported.6 The acylium ion The Hammett plots of the logarithms of the rate mechanism explains the inability of exchange to occur. constants versus n and u + values are shown in Fig. 2. However, as mentioned previously, it is a priori imThe plot utilizing n-values yields a curved line, whereas possible to state whether this lack of exchange is due to the plot utilizing a+-values results in a straight line the formation of an acylium ion intermediate rather with a slope of -3.22. than a tetrahedral intermediate whose reversion to reactants is less than its decomposition to products. TABLE I Although all of the above pieces of experimental evi‘LHE KINETICS O F THE HYDROLYSIS O F h ~ E T I I Y 1 , 4-SUBSTITUTEDdence are self-consistent, many of the individual pieces 2,(i-DI.\lETrIPLBENZOATES IN 9.70 JW SULFURIC ACID“ of evidence are ambiguous. This is a common occurSuhstituent k X sec.-l Substituent k X sec.-l rence in mechanistic arguments. In such a situation the CH.30 5.0 H 0.033 best that can be done is to collect a large number of CHI o 3ib Br 0.01 pieces of evidence using different approaches to see if 25.0’. * 9.80 -If sulfuric acid a t 24.2’. Average of at least any piece is inconsistent with the proposed hypothesis. two runs. One aspires to obviate such difficulties by finding a Discussion definitive experiment which will prove the mechanism unequivocally. The present experiment was directed In moderately concentrated sulfuric acid solutions to this goal. At best, the present experiment can the hydrolysis of inethyl mesitoate can be reasonably assumed to proceed by way of an A A C l mechanism’O; (11) R. W. T a f t , Jr., J . A m . Cheiiz. Soc., 74, 5372 (1952); R. W. Taft, Jr., ,
‘I
(10) C. K . Ingold, “Structuie and Mechanism in Organic Chemistry,” Cornel1 Univereity Press, Ithaca, N. Y . , 19.53, p. 767.
E. L. Purlee, P . Riesz, and C. A. DeFazio, ibid., 7 7 , 1584 (1953). (12) PIT. C. Deno and C. Perizzolo, ibid., 79, 1345 (1957).
Jan. 5, 1963 TABLE I1 HYDROLYSIS O F SUBSTRATES
HAMMETT p-VALUES FOR THE
+ +
Reaction
Sigma
Pre-equil.
U
-0.93
Benzarnide H + (dil. sulfuric acid) H + (99yo sulfuric acid) Benzamide H + (99% sulfuric acid) Methyl benzoates Methyl-4-substd.-2,6-dimethylbenzoates H 4-Substd.-2,6 dimethylbenzoyl chlorides 4-Substd.-2,6-dimethylbenzoyl chlorides f H + 4-Substd.-2,6-dirnethylbenzoyl chlorides Me4N+OHMethyl 4-substd.-2,6-dimethylbenzoates NaOH This investigation.
+
+
+
+ +
furnish an unequivocal proof of the mechanism; otherwise it can add one further experimental criterion to the other pieces of information listed above. The rates of reaction involving the formation of carbonium ion intermediates adjacent to a benzene ring are greatly increased by electron-donating substituents in the fl-position. For example, the p of the solvolysis of m- and p-substituted phenyldimethylcarbinyl chlorides is highly negative. l 3 Furthermore ordinary u-constants would not correlate the rate data, leading to the definition of a new set of electrophilic substituent constants, u+. The a+-values reflect a higher degree of resonance interaction between the substituent and the positively charged reaction center than do U-values. Therefore two substituent effect criteria exist for a mechanism involving an acylium ion intermediate, a p which is highly negative and a correlation with a+-constants rather than u-constants. There are limitations to the use of the latter criterion, however. u+-Values differ from U-values only for highly electron-donating substituents such as pmethyl and p-methoxyl groups. In addition, some electrophilic reaction series are not adequately correlated by ~ r + - v a l u e s ~ and ~ J the ~ value may vary of the order of tenfold, depending on the reaction series.14 The present results indicate that the hydrolysis of methyl 4-substituted-2,6-dimethylbenzoates in 9.70 M sulfuric acid has a p of -3.22 and that a correlation between the logarithms of the rate constants and u+constants is found. In the hydrolysis of six ethyl 3,4,5substituted-benzoates in 99.9% sulfuric acid a t 45', although weakly electron-withdrawing substituents on the benzene nucleus retard the rate of hydrolysis, there are successive increases in rate with stronger electron-withdrawing substituent^.'^ On the other hand, electron-withdrawing substituents retard the rate of hydrolysis of similarly substituted methyl benzoates in 99.9% sulfuric acid solution. These results led to the conclusion that in 99.9% sulfuric acid all methyl esters hydrolyze with the A ~ c mechanism, l while the ethyl esters hydrolyze with either an A ~ c l or an A A L mechanism, ~ depending upon the substituent. The Hammett plots of the rates of hydrolysis of the methyl esters yields a p-value of - 3 utilizing u+, very similar to the present results. Furthermore, the hydrolysis of substituted benzamides in 98-100~o sulfuric acid yields a p-value of -1.8 to -3.4, again a value very similar to the results obtained in the prese n t experiments. An analysis of the meaning of the Hammett pconstant found in the present investigation is complicated by the fact that the acid-catalyzed hydrolysis of an ester proceeding through an acylium ion intermediate involves a pre-equilibrium protonation before (13) H. C. Brown and Y . Okamoto. J. A m . 80, 4979 (1958). (14) S . C. Deno and W. L. Evans, ibid., 79, (15) D. N. Kershaw and J. A. Leisten, Pvoc. I 1 C ) J. A. Duffy and J. A. Leisten, J . Chent.
Chefit. Soc., 79, 1913 (1957); 5804 (1957). Chem. Soc., 84 (1960) Soc., 853 (1960).
U+ U+
u+
.... ....
0 to - 0 . 9
U+
,...
U+
...
U U
I
.... ....
p-Valiie---------Rate-determ. Over-all
1.05 -1.8 to - 3 . 4 -3 - 2 . 3 to - 3 . 2 -3.85 -3.B 1.20 1.2G
Ref.
17 16 15
0.12 -1.8 to - 3 . 4 -3 -3.22 -3.85 -3.73 1.20 1.2
6 6 6 7
the rate-determining step. A substituent can affect both the pre-equilibrium and the rate-determining step, and therefore the question arises as to what the Haminett p-constant means in such an instance. Leisten" Q+H +/OCH, C
x
X
-
X products
(3)
encountered this problem when analyzing substituent effects in the hydrolysis of substituted benzamides in moderately concentrated acid. He was successful in separating the substituent effects of the two steps according to the equation Pover-all = Ppre-equil.
f Prate-determ. step
(4)
In the benzamide system it is possible to determine each p independently, pover-all from reaction in dilute sulfuric acid, Prate determ. step from reactions in moderately concentrated sulfuric acid and ppre-equil. from measurements of the P K a ' s of the benzamides. All the p's thus found were completely consistent with eq. 4. In 1 0 0 ~ osulfuric acid, substituted benzamides and methyl benzoates are fully protonated and one therefore measures the p of the rate-determining step. The question may, however, be asked as to what step the p determined in the present investigation pertains. The basicity constants of substituted benzoic acids, substituted benzaldehydes and substituted acetophenones have been determined by Stewart and coworkers.1E-20 Their data yield values of p of -2.7, -1.85 and -0.9 for the protonation of acetophenones, benzaldehydes and benzoic acids, respectively, using a+-constants in the correlation. The protonation of the hindered benzoate esters used in this study are probably less susceptible to substituent effects than are the closest analogs above, the benzoic acids, because of steric inhibition of resonance. Therefore we shall assume that the p of the pre-equilibrium step in the present reaction is less than -0.9 and possibly very close to zero. On this basis, the p of the ratedetermining step of the reaction is -3.22 to -2.3. The comparison of the p's of a number of acid-catalyzed hydrolyses is shown in Table 11. The Hammett p-values for the rate-determining steps of the reactions in Table I1 can be grossly divided into those which have a value of +1 and those which have a value of - 3 to -4. The former values are characteristic of nucleophilic attack a t a carboxylic acid derivative. The latter values are characteristic (17) J. A. Leisten, ibid., 1572 (19.56). (18) R. Stewart and K. Yates, J . A m . Chem. Soc., 80, 6355 (1958) (19) R. Stewart and K. Yates, ibid.,82, 4059 (1960). (20) K. Yates and R . Stewart, C a n . J . Chem., 37, 664 (1959).
MYRONL. BENDERAND MARKC. CHEN
40 b N
o 11
m
CQ
of reactions involving a transition state which has a high degree of cationic character. These reactions which include the reaction studied in the present investigation possess p-values which are quite similar to those of many carbonium ion reactionsz1 and are thus reasonably described as reactions involving acylium ion intermediates. The structural reasons leading to this mechanism have been discussed in detail pre-
d,
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A comparison of the reactivity of sterically hindered and unhindered benzoic acid derivatives, as reprev i % I sented by mesitoic and benzoic acid derivatives, is i a j Y shown in Table 111. In Table I11 two distinct patp& I 1 \fi 1 - 1 '>$$ terns emerge. Reactions 1-10 include processes in A>?$.$ 5,-.vipvi ?v i v+i v ;i which the benzoic acid derivative reacts considerably more rapidly than the mesitoic acid derivative. Rei Ud ri Ob; 'i ,7;. y o 0 5 -J,--. + actions 12-17, on the other hand, show exactly the u u + 4 2 2 & 2 v2 ud u x x 2 -. x x x k? $ x x x x x 3 opposite behavior. Two separate mechanisms may * O0 % d E k0 io *- . w. + N m 0 0 0 o d 3 mv3 ffi m 0% be assigned to these two categories of behavior, the 2 N' 2 2 z z z *I h A b A 1 0 e E two mechanisms being bimolecular and unimolecular, 2 respectively, In dilute acid or alkaline solution, the .c.l rate of reaction of the mesitoic acid derivatives is Li d v c c i ci p w v i vui vui vi always much slower than that of the benzoic acid a" aiaiaijj d derivatives, with the exception of the acid chloride c - - - e 2 . 0 0 0 0 ; 7 3 I l l reactions. Apparently steric hindrance occurs in all 4 cicid 2 .K > > \ > 8 $ vi vi g ? -OJ g p $ reactions of mesitoic acid derivatives in dilute acid 2 ; 1 I 1 T T T 7 o* or alkaline solutions which proceed by a bimolecular I ?>I 6 Z P ~ 0 0 0 0 0 0 0 E O 0 0 1 0 ci mechanism. The anomalous behavior of the reaction "+ 8 of mesitoyl chloride (KB/KM is much less than one) implies that this compound reacts via a different mech8 u.*m-NbrT,mm -$qq+?N? A t2 < "aNc? .? '1? *, ,d& N $W anism which is not adversely affected by steric hinM m b N ,g2 a u drance. The fact that k B / k M decreases with an inij -0 C ' $ E! crease in the concentration of perchloric acid in the U Y ? acid-catalyzed hydrolysis of methyl benzoate and ;; : 3 f f i m o o ~ o m z $ m m m o m m i n m ~ ~ j 0.1 2 w N m fi OJ 8 c.1 0.1 N N c.1 c.1 o mesitoate (reaction 6) is presumably due to the in2 creasing incursion of the unimolecular mechanism. *5 k 65 o- s This presumption is further supported by the results 82 of the hydrolysis in 100% sulfuric acid (reaction 14), in which methyl mesitoate hydrolyzes much faster E? u * than methyl benzoate by a mechanism involving ac" 0 " 6.c < w f5g 2 yliumionformation. aJw 6 G 0 C oooy; 9 Thus the comparison of the Hammett p-values of a E 8% 0 d. e5 ed . s 8 d ,z series of hydrolytic reactions in Table I1 and the rela5 % d h h h C I O J tive rates of the series of reactions of benzoic acid 04 5 40 + $ +. 2s .-4 and mesitoic acid derivatives in Table I11 indicates x O 0 E $ < $ r n a &&.E ---&$ that hindered benzoic acid derivatives may react via &? 8 two distinct pathways: (1) a bimolecular pathway 2 0; 51 b2 b 2u o It which shows considerable steric hindrance to reaction L, m . and is facilitated by electron-withdrawing substituents I + $1x. and ( 2 ) a unimolecular pathway which is facilitated . P 2 ~48 by steric hindrance and by electron-donating substitm 2.uents. 2 Acknowledgment. -The authors gratefully acknowlb g,e Ex:$ a* -d edge valuable discussions with Dr. H. Ladenheim. 1 % 0 '-d i d 0
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