220
`
`J.C.S. Perkin I1
`
`The Acid-catalysed Hydrolysis of Acetanilide
`By J. W. Barnett and Charmian J. O'Connor,' Department of Chemistry, University of Auckland, New Zealand
`
`The rate of hydrolysis of acetanilide has been measured over a wide range of acidities in HCI, H2S04, and HCIO,.
`In H,S04 3 80% (w/w) acetanilide undergoes sulphonation in preference to hydrolysis. Application of the
`Bunnett criteria of mechanism fit the data in HCI and H2S04well, whereas the data in HCI04 are fitted by an empirical
`two-term rate equation. A revised value of the constant -pKAH+ has been determined in each acid.
`
`THE nitro-derivatives of acetanilide all show a rate
`minimum ls2 in their hydrolysis profiles between 70 and
`80% (w/w) H,SO, and this has been attributed to a
`change in mechanism from A-2 to A-1. These sub-
`stituted anilides are quite weakly basic and consequently
`this change in mechanism occurs only in very concen-
`trated acid. If this were a general phenomenon then
`acetanilide with a reported -~KAH+ value of -0.61
`hould have displayed a unimolecular mechanism in
`
`relationship (1) where Abs, AbsA, and AbsAE+ are the
`absorbances of the solute in its partially protonated,
`[AH+]/[A] = (Abs - Absa)/(Absm+ - Abs)
`(1)
`unprotonated, and fully protonated forms, respectively,
`at hmaxAn+. At the concentration of acetanilide used
`(7.4 x 1 0 - 6 ~ ) these varied from AbsA = 0.665
`to
`AbsAH+ = 0.543. Equation (1) does not take account
`of minor medium effects and impurity errors, and it is not
`
`TABLE 1
`Ionisation ratios for acetanilide (7.4 x 1 0 - 5 ~ ) in hydrochloric, sulphuric, and perchloric acids calculated using
`absorbances measured a t 238 nm
`Sulphuric acid
`CHf
`1-31
`1-62
`2.18
`2-90
`3-49
`3.98
`6-10
`
`Perchloric acid
`CH+
`0.95
`1.50
`2.07
`2.65
`3-28
`4.70
`
`log10 I
`-0.811
`- 0.487
`- 0.233
`- 0.014
`0-218
`0.791
`
`--HA
`0-325
`0-57
`0.91
`1.13
`1.36
`1-89
`
`Hydrochloric acid
`log10 1
`- 0.757
`- 0.506
`-0.165
`- 0.207
`0.201
`0.247
`0.635
`1.065
`
`CH+
`1.41
`2.00
`2.30
`2-87
`4.00
`4.45
`5.50
`7.00
`
`- H A
`0.46
`0.73
`0.84
`1.34
`1.44
`1-55
`1.86
`2.31
`
`--HA
`0.48
`0.63
`0.87
`1.18
`1.38
`1.62
`2.30
`
`log10 I
`- 1.009
`- 0.794
`- 0.354
`0.009
`0.059
`0-139
`1.006
`
`reasonably dilute acid. Although the hydrolysis of
`acetanilide does show a rate minimum in concentrated
`solutions of sulphuric acid, this is caused by preliminary
`sulphonation to N-acetylsulphanilic acid. Measurement
`of the basicity constant of acetanilide shows the literature
`value 3 to be in error.
`
`RESULTS AND DISCUSSION
`Basicity Constant.-We have determined the ionisation
`ratio I = [AH+]/[A] for acetanilide in hydrochloric,
`sulphuric, and perchloric acids (Table 1) by use of the
`1 J. A. Duffy and J. A. Leisten, J . Chem. Soc., 1960, 853.
`a M. I. Vinnik, I. M. Medvetskaya, L. R. Andreeva, and
`A. E. Tiger, Russ. J . Phys. Chem., 1967, 41, 128; M. I. Vinnik
`and I. M. Medvetskaya, ibid., p. 947.
`
`easy to specify a systematic error which could be due to
`such effects when one has very small differences between
`extinction coefficients of the two forms of an indicator.
`However, the spectra appeared very clean, reproducible,
`and reversible, and we believe that the U.V. spectro-
`photometric changes we observed represent the equili-
`brium protonation of acetanilide, and are not an artifact
`of medium effects, as was observed for the spectra of
`benzonitrile in acid soluti~n.~
`
`I. Heilbron, Dictionary of Organic Compounds,' Eyre and
`Spottiswoode, 1937, vol. 1, p. 3, as quoted by J. A. Duffy and
`J. A. Leisten (Ref. 1).
`K. Yates and J, B. Stevens, Canad. J. Chem., 1965, 43, 529.
`6 C. J. Hyland and C . J. O'Connor, J.C.S. Perkin 11, following
`paper.
`
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`Page 1 of 3
`
`SENJU EXHIBIT 2075
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`

`
`1973
`Table 2 shows the results of plotting log,, I against
`Only values of log,, I within the range &l were
`-HA.6
`substituted in these plots. The slopes are close to unity,
`and thus the values of - ~ K A H + = - H A at log,, I = 0
`can be regarded as valid functions within the limitations
`of the basic uncertainties discussed above. The limits
`on -PKAH+ given in Table 2 were obtained from least-
`squares plots, but bearing in mind the small difference
`
`TABLE 2
`Values of - p K a ~ + of acetanilide in hydrochloric, sulphuric,
`and perchloric acids a t 25.0 "C
`Slope of log,, I
`- pKm+
`VS. -HA
`0-97 f 0.04
`1.23 & 0.02
`1-04 f 0.07
`1-32 & 0.02
`1-00 f 0-03
`1-12 -J= 0.01
`
`Correln.
`coefft.
`0.993
`0.989
`0.998
`
`Acid
`HC1
`H W *
`HC10,
`
`in absorbance and the limitation of the spectrophoto-
`meter (&0.002 absorbance units), more realistic error
`
`221
`(H, + log,, c,+)
`free-energy
`linear
`(Bunnett-Olsen
`relationship) .9 Both these criteria of mechanism give
`good correlations for the data in HCl and H,SO,. The
`values of w generally lie in the range 1.2-3-3 said to be
`characteristic of water acting as a nucleophile in the
`r.d.s., but the values of 4 are all >,0.58, and therefore
`fall in the region indicative of water acting as a proton-
`transfer agent. It would seem that the limits of
`Bunnett's original classifications will have to be extended
`as more experimental data becomes available.
`The data in HC10, do not correlate well with these
`criteria of mechanism. We have previously found a
`similar lack of correlation for rates of hydrolysis of
`benzamide, N-methylbenzamide, and NN-dimethyl-
`benzamide in HC1, H,SO,,
`and HC10,.7 We have
`found, however, that all these data correlate very well
`with a rate equation7310 which allows the acid hydro-
`lysis of amides to proceed by two distinct mechanistic
`paths involving both oxygen- and nitrogen-protonated
`
`Hydrochloric acid
`26.0 "C
`105k4p
`cH+
`1.42
`0.416
`2.74
`0.880
`4.46
`0.961
`6-05
`0-672
`7.67
`0.270
`9.45
`0.129
`
`TABLE 3
`Hydrolysis of acetanilide in concentrated solutions of mineral acids
`Hydrochloric acid
`Sulphuric acid
`Sulphuric acid
`Perchloric acid
`26.0 "C
`80.0 "C
`80.0 "C
`26.0 "C
`Iosk?kg/s-l
`losh$!l/s-l
`10Skg/s-l
`CHS 105kgp
`CH+
`CH+
`CH+
`1.06
`1-40
`70.3
`1-10
`0.394
`1.48
`82.2
`0.287
`1.18
`1.72
`0.669
`2.13
`97.7
`93.3
`1.62
`0.403
`2-33
`0.746
`2.96
`126
`2.40
`112
`2.23
`0.440
`3.76
`147
`3.02
`0.781
`3.16
`117
`2.88
`0.431
`3.72
`0-735
`4-61
`138
`3-83
`116
`3-58
`0.368
`4.51
`0.694
`6-26
`118
`4.63
`106
`4.34
`0-266
`6-05
`101
`5-32
`0.343
`6-26
`6-16
`0.210
`60.8
`7.70
`79-6
`6-19
`0-203
`7.1 1
`31.6
`10.1
`18.4
`9.16
`9-16
`
`Perchloric acid
`80.0 "C
`Ca+ 105k+p
`26.8
`0.50
`1.06
`48.3
`2-25
`80.7
`3-60
`59.3
`6-20
`36.6
`7-10
`17.2
`
`TABLE 4
`Analysis of rate data for hydrolysis of acetanilide by use of
`Bunnett w and Bunnett-Olsen 1.f.e.r. relationships
`1.f.e.r.
`Bunnett w
`+
`Correln.
`coefft.
`0.990
`0.996
`0.987
`0.989
`0.892
`0.971
`
`log,, K O ,
`-2.17
`0.58
`-4.32
`0.66
`-2.00
`0.67
`-4.14
`0.71
`0.68 -2.33
`0.70
`-4.62
`
`Correln.
`coeff t.
`0.991
`0-997
`0.998
`0.996
`0.963
`0.992
`
`Acid
`HC1
`H,SO,
`
`HCIO,
`
`t/"C
`w
`80.0 2.46
`26.0
`2.88
`80.0 2.67
`26.0
`3.96
`80.0
`2.86
`26.0
`4.37
`
`-PKAH+ would be approximately
`limits of
`-j=O.1.
`However, it does seem that the values of - p K a ~ +
`obtained differ for the three mineral acids, as do the
`basicity constants of benzamide, N-methylbenzamide,
`and NN-dimet h ylbenzamide .'
`Table 3 summarises the results obtained for the
`hydrolysis of acetanilide in acid solutions. The pseudo-
`first-order rate constants of hydrolysis, k4, must be
`corrected for the fraction, a, of protonated substrate
`before an attempt at kinetic analysis is made. Equations
`
`a = [AHf]/([AHt] + [A]) == hA/(KAH+ + hA)
`
`applicable to hydrolysis of moderately basic substrates
`have been used in the application of the data in Table 3
`to the criteria of mechanism which follow. Where the
`data are available, values of H,, and a, appropriate to the
`temperature of the rate measurements have been sub-
`stitGted into the equations of criteria of mechanism.
`This method has been described previ~usly.~
`Table 4 shows the results of plotting (log,, k* - log,, a )
`and against
`against loglo a, (Bunnett w function)
`
`(a) K. Yates, J. B. Stevens, and A. R. Katritzky, Canad. J .
`Chem., 1964, 42, 1967; (b) K. Yates and J. C. Riordan, ibid.,
`1966, 43, 2328; (c) K. Yates, personal communication.
`7 C. A. Bunton, S. J. Farber, A. J. G. Milbank, C. J. O'Connor,
`and T. A. Turnev. T.C.S. Perkin II. 1972. 1869.
`
`transition states. Table 5 shows the fit of this equation
`(2) for the hydrolysis data of acetanilide. We have
`kg = kN(1 - a)cH+aw + hoaa,
`plotted the data in two forms
`k,Jaa, = kNcB+(l - a ) / a + ko
`k*/cH+(l - a)a, = kN + kga/cH+(l - a)
`
`(2)
`
`(3)
`
`(4)
`J. F. Bunnett, J. Amer. Chem. Soc., 1961, 83, 4956, 4968,
`4973, 4978.
`J. F. Bunnett and F. P. Olsen, Canad. J . Chem., 1966, 44,
`1899.
`10 C. A. Bunton, C. J. O'Connor, and T. A. Turney, Chein. and
`Ind.. 1967. 43. 1386.
`
`and
`
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`
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`
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`
`

`
`222
`where equation (3) gives a more reliable value of kN (the
`rate constant for hydrolysis by the N protonated path)
`and equation (4) a more reliable value of ko (the rate
`constant for hydrolysis by the 0 protonated pathway).
`
`J.C.S. Perkin I1
`
`Acid
`HC1
`
`H2S04
`
`TABLE 6
`Analysis of rate data for hydrolysis of acetanilide by use
`of a two-term rate equation
`Equation (3)
`Equation (4)
`10%~/ Correln.
`Correln.
`105ko/s-l coefft.
`1 mol-l s-1
`coefft.
`t/"C
`0.960
`62-3
`0.914
`80-0 47.6
`0.321
`0-341
`0.976
`0.929
`26-0
`62.1
`0.982
`33.3
`0.923
`80.0
`0.403
`0.982
`0-177 0.738
`25.0
`0.998
`46.3
`0.994
`60.1
`80-0
`0.310
`0.999
`0.172
`0.992
`26.0
`
`hydrochloric, sulphuric, and perchloric acids at 25.0 "C
`were measured on a Shimadzu QV.50 spectrophotometer at
`238 nm. The value of AbsA was taken as the value in water
`obtained in solutions > 25% (w/w) hydrochloric acid,
`and the value of AbsAH+ was the constant absorbance value
`2 6 0 % (w/w) sulphuric acid and in solutions of 2 5 5 %
`= 238 nm log,, &A = 3-95
`(w/w) perchloric acid. At
`and log,, &AH+ = 3.86. It should be noted that the
`extinction coefficient of protonated acetanilide is less than
`that for acetanilide. This is opposite from the normal
`behaviour of amides, but similar behaviour has been found
`with ureas.16 However, the measurements relate to a true
`equilibrium situation since 1 ml samples of stock solution
`(7.4 x 1 0 - 4 ~ ) in water and 70% (w/w) HClO, gave identical
`spectra when diluted to 10 ml of 20% (w/w) HClO, with
`acid and water respectively.
`Measurement of Reaction Rates.-Hydrolysis
`reactions at
`80.0 f 0.1 "C were carried out in an oil-bath maintained at
`the required temperature by using a Gallenkamp contact
`Only the data in HC10, give good correlations of these
`thermometer, Klaxon stirrer, and a heating element. The
`plots.
`hydrolysis reactions at 25.0 f 0.1 "C were carried out in a
`We have recently shownll that, generally, rate
`water-bath fitted with a Tecam (Techne, Cambridge)
`constants for acid hydrolysis of amides which do not
`temperature unit.
`Acetanilide (ca. 7 x L O - 4 ~ ) was dissolved in 10 ml of
`fit the well accepted criteria of reaction m e c h a n i ~ m ~ , ~
`the appropriate acid. 1 ml aliquots, sealed in ampoules,
`seem to fit this empirical two-term rate equation. We
`were removed a t time intervals and were diluted 10 times
`do not, however, suggest that equation (2) should be
`before spectrophotometric analysis of the decrease in ab-
`applied to all acid-catalysed amide hydrolysis data.
`sorbance between 235 and 245 nm. Values of A$, calculated
`SuZphonation.-In H,S04 > 70% (wlw) ( 1 1 . 5 ~ ) the
`a t several wavelengths from slopes of plots of log,, (Abs, -
`position of maximum absorbance shifted rapidly from
`Abs,) against t (where Abs, and Abs, are the absorbances of
`238 to 252 nm to form an intermediate identified as
`the aliquots at time t and at infinite time respectively)
`N-acetylsulphanilic acid, which then hydrolysed to
`agreed within
`2%.
`4-aminobenzenesulphonic acid. Details of this sulphon-
`Product A rtaZysis.-On
`hydrolysis, acetanilide produces
`= 7500) and acetic
`= 204 nm (
`the anilinium ion, A,,
`ation reaction l2 and a report on the acid-catalysed
`E
`~
`~
`
`acid, A,,
`= 204 nm (cmx = 60). Under the conditions
`hydrolysis of the intermediate 133 l4 have been published.
`of the hydrolysis reactions, it was not possible to identify
`the products. Therefore solutions of acetanilide ten times
`more concentrated than under the kinetic conditions were
`heated for the time required for complete hydrolysis in
`(wlw) J , perchloric
`solutions of hydrochloric acid [6-35y0
`acid [10-70~0 (w/w)], and sulphuric acid [10-75%
`(wlw)].
`Peaks were then observed at 260.5,254.6, 248-7, and 249 nm
`and these agreed well with the spectrum of pure aniline.
`It was not possible to identify acetic acid under these
`conditions.
`
`HC10,
`
`EXPERIMENTAL
`(B.D.H.) was recrystallised from
`Materials.-Acetanilide
`hot water (m.p. 113.5-114-0 "C).
`Concentrated AnalaR hydrochloric, sulphuric, and per-
`chloric acids were standardised against sodium hydroxide,
`and were diluted with deionised water by weighing to give
`solutions of the required molarity.
`UZtmviobt Sfiectra.-The
`changes in the spectrum of
`acetanilide, 7.4 x 10-6~, in increasing concentrations of
`l1 J. W. Barnett, C. J. Hyland, and C. J. O'Connor, Cham.
`Comm., 1972, 720.
`la J. W. Barnett and C. J. O'Connor, Chew. and Ind., 1970,88,
`1172.
`
`121446 Received, 6th April, 19721
`la J. W. Barnett and C. J. O'Connor, J.C.S. Perkin 11, 1972,
`2378.
`l4 J. W. Barnett and C. J. O'Connor, Tetrahedron Letters, 1971,
`2164.
`l6 J. W. Barnett and C. J. O'Connor, unpublished results.
`
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