1975
`
`1357
`
`Acid Catalysed Hydrolysis of Substituted Acetanilides. Part Ill
`By 6. Janet Giffney and Charmian J. O'Connor, Chemistry Department, University of Auckland, Private Bag,
`Auckland, New Zealand
`The rate constants of hydrolysis of 12 para-substituted acetanilides have been measured in 5-98%
`(w/w) H2S04
`(<65% w/w) the data are reasonably well fitted by the Yates r and Bunnett-OIsen criteria
`a t 100.1". In H,SO,
`for an A-2 mechanism, and correlate well with Hammett 0. Acetanilides with electron-donating substituents in
`the 4-positi0n.i.e. OH, Me, MeO, and EtO are sulphonated in >70% (w/w) H2S04 and these substituted inter-
`mediates and the other acetanilides studied are hydrolysed in concentrated (>70% w/w) H & 0 4 by an A-1
`mechanism.
`
`THE rate constants of hydrolysis of acetanilide have
`previously been measured over a wide range of acidities
`in HCI, H,SO,, and HC10, at 25.0 and 80.0", those of
`N-acetylsulphanilic acid over a wide range of acidities
`(H,SO,) and temperatures, and those for seven substi-
`in >50% (w/w) H,SO, at 100".
`tuted acetanilides
`K-Substituted amides hydrolyse by either an A-2 or an
`A-1 mechanism depending on the medium acidity.
`Evidence for a changeover in mechanism has been found
`for substituted ace t anilides .l* 3-6
`
`We have now extended the studies on hydrolysis of
`substituted acetanilides to include 12 acetanilides over a
`wide range of acidities in H,SO,.
`
`RESULTS AND DISCUSSION
`Basicity Constants.-The
`ionisation ratios I = CBH+/
`CB have been previously reporteds and plots of logl,l
`against -HA were linear with slopes (ma) near unity.
`= WZAHA4, where HA,* is thevalue of HA at
`Values of ~ K B ~ +
`half protonation, are given in Table 1. We have used
`
`TABLE 1
`Rate constants for the hydrolysis of 4-X-acetanilides in H,S04 at 100.1'
`103k~ls-l
`NH,
`Me
`2.37*
`1.28*
`1.75
`1.06
`3.58
`2.14
`5.49
`2.89
`3.20
`3.74
`3.91
`4.00
`3.97
`3.81
`3.50
`3.21
`
`F
`1.70*
`1.21
`2.38
`3.30
`4.00
`4.31
`4.70
`4.78
`4.84
`4.82
`4.62
`4.42
`4.04
`3.65
`
`c1
`1.88'
`
`2.92
`4.94
`5.60
`6.22
`6.93
`7.45
`7.81
`7.69
`7.28
`6.84
`6.38
`5.58
`
`Br
`2.01*
`
`I
`2.07*
`
`3.07
`5.50
`6.11
`7.12
`7.50
`7.98
`8.02
`7.84
`7.48
`7.23
`6.68
`6.00
`
`2.51
`4.74
`5.26
`6.08
`6.72
`7.37
`7.49
`7.46
`6.99
`6.58
`5.99
`5.24
`
`2.44
`1.44
`0.70
`0.25
`0.098
`
`4.30
`2.48
`1.24
`0.46
`0.20
`
`4.64
`2.61
`1.33
`0.51
`0.20
`
`4.47
`2.49
`1.31
`0.51
`0.24
`
`0.0038 0.0068 0.0065 0.016
`
`Me0
`1.27*
`0.93
`1.67
`2.41
`2.69
`2.88
`3.02
`3.06
`2.99
`2.92
`2.76
`2.54
`
`EtO
`1.22*
`0.93
`1.77
`2.43
`2.80
`2.95
`3.09
`3.22
`3.14
`2.99
`2.83
`2.61
`
`OH
`1.02*
`1.13
`1.68
`2.38
`
`2.70
`
`2.77
`
`2.65
`
`2.31
`
`2.42
`
`1.80
`
`1.18
`1.58
`0.70
`0.97
`0.32
`0.42
`0.13
`0.13
`0.047
`0.044
`0.0050 0.010
`
`1.90
`
`1.27
`0.71
`0.32
`0.14
`0.043
`0.010
`
`1.74
`
`0.99
`0.66
`0.34
`0.12
`0.053
`0.012
`
`7.02
`
`7.89
`8.64
`9.00
`9.40
`9.59
`9.37
`8.94
`8.00
`7.45
`4.71
`2.92
`1.27
`0.39
`0.035
`
`C02H
`2.20*
`2.64
`5.48
`8.13
`
`NO,
`2.59*
`5.14
`6.99
`11.6
`
`10.4
`
`13.8
`
`16.6
`
`17.2
`
`15.9
`
`11.5
`8.85
`6.70
`2.67
`1.04
`0.22
`
`15.7
`
`20.8
`
`24.6
`
`26.2
`
`25.3
`
`23.1
`18.7
`13.0
`6.89
`3.12
`0.66
`
`1.62
`3.49
`12.7
`
`H
`1.58*
`1.38
`2.84
`4.16
`
`5.13
`
`5.85
`
`5.70
`
`4.91
`
`3.67
`
`2.67
`1.50
`0.69
`0.25
`0.091
`
`Concentration
`(M)
`
`0.55
`1.09
`1.68
`2.00
`2.35
`2.70
`3.07
`3.40
`3.76
`4.13
`4.52
`4.92
`6.33
`5.78
`6.21
`7.10
`8.05
`9.16
`10.30
`12.75
`14.07
`15.40
`16.65
`18.3
`
`0.033
`1.24
`0.0054 0.0066 0.0057 0.0049
`0.0018 0.0044 0.0045 0.037
`0.049
`3.88
`0.014
`0.012
`0.014
`0.013
`0.0072 0.013
`0.011
`0.141
`0.079
`0.036
`0.065
`0.058
`0.055 25.5
`* Value of -pPKBx+.
`these values in our calculations of
`cc (the fraction of
`protonated substrate) = hA/(K,,+ + hA) which were
`necessary for analysing the rate data.
`Kinetic Data.-The
`rate constants of hydrolysis, K,, of a
`series of $am-substituted acetanilides (4-OH, -Me,
`
`3-Hydroxy- and 4-methyl-acetanilide and acetanil-
`ide are sulphonated in concentrated H,SO, and it is the
`sulphonated intermediates (3-hydroxy-ksulpho- and 4-
`met hyl-2-sulpho-acet anilide
`and N-acet ylsulphanilic
`acid) which undergo subsequent hydrolysis .
`Part I, J. W. Barnett and C. J. O'Connor, J.C.S. Perkin II,
`1972, 2378.
`2 J. W. Barnett and C. J. O'Connor, J.C.S. Perkin 11, 1973,
`220.
`3 J. A. Duffyand J. A. Leisten, J . Chem. Soc., 1960, 853.
`4 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, Russ. J . Phys. Chem.,
`1967, 41, 947.
`
`l Y 6
`
`6 J. W. Barnett and C. J. O'Connor, Tetrahedron Letters, 1971,
`2161.
`J. W. Barnett and C. J. O'Connor, Chew. and Ind., 1970,
`1.172.
`* C. J. Giffney and C. J. O'Connor, J.C.S. Perkin 11, 1975,
`$06.
`K. Yates, J. B. Stevens, and A. R. Katritzky, Canad. J .
`Chem., 1964, 42, 1957.
`
`Downloaded by University of Oxford on 04 July 2012
`
`Published on 01 January 1975 on http://pubs.rsc.org | doi:10.1039/P29750001357
`
`View Online
`
` / Journal Homepage
`
` / Table of Contents for this issue
`
`SENJU EXHIBIT 2070
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`Page 1 of 4
`
`

`
`1358
`-MeO, -EtO, -H, -F, -C1, -Br, -I, -NH,, -NO,, and
`(w/w) H,SO, at
`-CO,H) have been measured in 5-98%
`100.1'. The data are given in Table 1. The hydrolysis
`of acetanilide was also carried out in water at 100.1" and
`the rate constant obtained (k, = 6.82 x lO-'s-l)
`indi-
`cates that this hydrolysis is enhanced by a factor of lo4
`by acid solutions.
`When 4-hydroxy-, 4-niethyl-, 4-methoxy-, and 4-
`ethoxy-acetanilides were hydrolysed in > 70% (w/w)
`H,SO, the positions of A,,,.
`underwent a bathochromic
`shift (Table 2) followed by a decrease in absolute ab-
`TABLE 2
`the sulphonation of
`Positions of Anla,. before a and after
`acetanilides having electropositive substituents (X) on
`the benzene ring
`X
`4-Et0
`4-Me0
`4-Me
`4-OH
`241.5
`244.0
`244.0
`244.0
`AInax/nm;
`248.5
`248.0
`246.0
`247.0
`~ m a x l n m
`sorbance. Similar shifts have previously been observed
`and interpreted in terms of formation of sulphonated
`intermediates19 By analogy, the final hydrolysis pro-
`ducts in the four cases above are assumed to be 2-amino-
`5-hydroxy-, 2-amino-5-methyl-, 2-amino-5-methoxy-,
`arid 2-amino-5-ethoxy-benzenesulphonic acids.
`
`4
`
`3
`
`2
`
`8
`41
`Cn 0 -
`'
`*
`-3-
`0
`cn
`
`+
`C?
`
`1
`
`
`
`c
`
`-1
`
`0.0
`
`0
`
`0.2
`
`0.4
`
`0.6
`
`0.8
`
`log ,@ Qw
`FIGURE 1 Typical plots of Yates Y function l1 for
`4-X-acetanilides in H,SO, at 100.1"
`
`The rate profiles of all the acetanilides studied have a
`minimum in the observed rate constants in concentrated
`10 K. Yates, Accounts Chenz. Res., 1971, 4, 136.
`l1 I<. Yates and J. B. Stevens, Canad. J . Chem., 1965, 43, 529.
`1, J. F. Bunnett and F. P. Olsen, Canad. J . Chew., 1966, 44,
`1917.
`
`J.C.S. Perkiii II
`acid solutions, followed by an increase in rate with fur-
`ther increase in acid concentration. Minima in the rate
`profiles of other acetanilides 19395s6
`and of esters lo have
`previously been observed and have been attributed to a
`
`0
`
`1
`
`2
`
`b
`
`3
`
`4
`
`FIGURE 2 Typical plots of Bunnett-Olsen linear free
`eaergy relationship 1, for 4-X-acetanilides in H,SO, at 100.1'
`
`changeover from an A-2 to an A-1 mechanism and a
`similar explanation is proposed here.
`The kinetic data for the hydrolysis of the 4-X-acetanil-
`(w/w) H,SO, has been analysed according
`ides in 5-65%
`t o the standard criteria of mechanism. Typical plots of
`Yates Y function l1 (log k, - log CY) against logloaw, cor-
`relation coefficients 0.97-0.99,
`slopes (Y) 2.5-3.5
`relationship l2 (loglok, - logl0a) against (logloCn: +- Ho),
`(+0.2), and of the Bunnett-Olsen linear free energy
`correlation coefficients 0.995-0.999,
`slopes (+) 0.19--0.91
`(k0.02) are given in Figures 1 and 2 respectively and
`show slight curvature. As we found previously for
`the fit of these criteria involving only a
`acetanilides
`one term mechanistic pathway is quite good; indeed the
`values of Y obtained indicate that water is involved as a
`nucleophile in the rate-determining step 1 1 9 1 3 and suggest
`that there are three water molecules involved in going
`from the ground to the transition state in this acid-
`catalysed hydrolysis. This is similar to the results
`obtained by Yates and Stevens l4 and by Moodie ct n1.l5
`J. F. Bunnctt, J . Amev. Chem. SOC., 1961, 83, 4956, 4968,
`4973, 4978.
`l4 K. Yates and J. B. Stevens, Canad. J . Cheutz., 1965, 43, 529.
`R. B. Moodie, P. D. Wale, and T. J. Whaite, J . Chem. Soc.,
`1963, 4273.
`
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`
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`
`View Online
`
`Page 2 of 4
`
`

`
`1975
`for the hydrolysis of a variety of amides.
`In addition a
`value of r ca. 3.0 was obtained for nine acetanilides and
`nicotinamides studied by Hashmi in H2S04 at 25 O C , 1 6
`his data being analysed using values of pKBa+ measured
`in this laboratory,g (where applicable), or those calculated
`from his ionisation data l6 using the amide acidity scale,
`HA, and the value of mAHa*.
`The rate data obtained in this study has also been
`analysed according to the two term rate equation (1) of
`
`k, = kN(1 - a)CH+a, -+ KOCXG
`(1)
`Bunton et ~ 1 . ~ 7 which allows hydrolysis to occur con-
`currently by two distinct paths, involving both N- and
`0-protonated cations, but the results were unsatisfactory.
`Equation (1) has previously been found to be applicable
`only to aromatic amides.18
`Hainmett Plots.-The
`rates of hydrolysis of the un-
`sulphonated acetanilides in 90% (w/w) H2S04 have been
`applied to the Hamrnett e q ~ a t i 0 n . l ~ The correlation of
`log,,kp (where kp = k, as all the acetanilides will be fully
`protonated in this concentrated acid), with both (J 2o
`(correlation coefficient = 0.867) and Q+ 21 (correlation
`coefficient = 0.893) is only reasonable, but the values of
`p obtained (5.08 and 4.39 respectively) indicate that the
`reaction is very definitely favoured by electron-withdraw-
`ing groups.
`Indeed, electronegative substituents on the
`benzene ring attached to the nitrogen would be expected
`to assist in the unimolecular fission of the carbonyl-
`nitrogen bond, this being the mechanism previously pro-
`posed for the hydrolysis of other acetanilides in concen-
`trated acid.3 The positive values of p indicate that the
`positive charge has decreased on the nitrogen atom in the
`transition state, and are consistent with an A-1 reaction
`occurring through the 0-protonated form, and not the
`minor N-protonated form. Amides are fully O-proton-
`ated in 100% H2S04,22923 and although the concentration
`of ,V-protonated amide is related to the fraction, a, of the
`amide that is protonated on oxygen, when the fraction of
`unprotonated substrate becomes < 0.1 the stability of the
`X-protonated cation is markedly reduced and the proton-
`ation equilibria shift to favour formation of the 0-
`protonated cation.24
`The Hammett equation has also been applied to the
`kinetic data obtained in 20 and 50% (w/w) H,S04, the
`observed rate constants being corrected for the degree of
`protonation of the substrate (kp = k~/ct) and the values
`of log,kp being plotted against CJ and G+. The results are
`given in Table 3. The plots of log,,K, against Q are shown
`in Figure 3.
`The A-2 reaction mechanism at moderate acidities is
`
`l6 11. S. Hashmi, Ph.D. Thesis, University of East Anglia, 1973.
`l7 ( a ) C. A. Bunton, C. J . O’Connor, and T. A. Turney, Cbzem.
`and Tnd., 1967, 1385; (b) C. A. Bunton, S. J. Farber, A. J. G.
`JIilbank, C. J. O’Connor, and T. A. Turney, J.C.S. Pevkin 11,
`1972, 1869.
`J. W. Barnett, C. J. Hyland, and C. J. O’Connor, J.C.S.
`Chein. Cornm., 1972, 720.
`l9 L. P. Hammett (a) J . Awzev. Chewz. SOG., 1937, 59, 96; (b)
`Tvans. Faraday SOC., 1938, 34, 156.
`2o D. H. McDaniel and H. C. Brown, J . Ovg. Chern., 1958, 23,
`420.
`
`1359
`also favoured by electron withdrawal (p > + 1 .O) but it is
`significant that the mechanism in highly acidic media is
`much more dependent on electron withdrawal and this
`supports the identification as A-1. A central issue in
`amide hydrolysis is whether the actual hydrolyses pro-
`ceed via the N- or the 0-protonated conjugate acid. We
`
`/
`
`(J
`/’
`
`3r
`
`P *
`s1
`ln
`d +
`m
`
`- 0.4
`0.0
`0.8
`0.4
`U
`FIGURE 3 Hammett plot of 3 + loglOk, against 0 for the
`hydrolysis of 4-X-acetanilides in 20% (w/w) H2S04; a, and
`in 50% (wlw) H2S04, 0
`TABLE 3
`Analysis of rate data of 4-X-acetanilides in 20% (w/w)
`H,SO, a and in 50% (w/w) H,SO,
`by the Hammett
`equation
`
`o Values
`7 - 7
`Ordinate of correln.
`coefft.
`of plot
`
`log,ok, ; 0.993
`
`log,,k,
`
`0.982
`
`(r+ Values
`r--
`correln.
`coeff t.
`0.956
`0.917
`
`P
`1.18 -+ 0.12
`0.96 & 0.14
`
`7
`
`P
`1.87 f 0.07
`1.60 f 0.09
`
`have shown (see above and ref. 18) that the postulate of a
`two-term mechanistic pathway is not viable for acetanil-
`ides. Comparison of these present data with those for
`hydrolysis of 4-chlorobenzamides 25 under comparable
`conditions leads us to favour an A-2 reaction mechanism
`in which water attacks the N-protonated conjugate acid
`in the rate determining step. Both Moodie et aZ.26 and
`Smith and Yates 27 have considered the possibility that
`21 H. C. Brown and Y . Okamoto, J . Amer. Chem. SOC., 1958,80,
`4979.
`z2 R. J. Gillespie and T. Eirchall, Canad. J . Chem., 1963, 41
`( ( I ) 148; (a) 2642.
`23 M. Liler, J.C.S. Perkin I1 (a) 1972, 816; (b) 1974, 71.
`24 C. J. Giffney and C. J . O’Connor, unpublished results.
`25 C. J. Giffney and C. J. O’Connor, J.C.S. Perkin 11, 1975,
`1203.
`2 6 V. C. Armstrong, D. W. Farlow, and R. B. Moodie, J . Chem.
`SOC. ( B ) , 1968, 1099.
`27 C. R. Smith and K. Yates, J . Amer. Chem. SOC., 1971, 93,
`6578.
`
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`
`View Online
`
`Page 3 of 4
`
`

`
`1360
`hydrolysis takes place via the AND2 (acid catalysed, bi-
`molecular, N-protonated cation, direct displacement)
`mechanism.
`
`EXPERIMENTAL
`
`Materials.-Concentrated AnalaR sulphuric acid was
`standardised against sodium hydroxide, and diluted with
`distilled water by weighing to give solutions of the required
`molarity.
`Preparation, purification, and m.p.s of the acetanilides
`have been previously des~ribed.l7~
`Measurement of Reaction Rates.-The
`acetanilides were
`hydrolysed using the method previously described.'? The
`error in estimate of K , is generally within 4 2 % . For the
`slower runs the accuracy decreased to f5% and these rates
`are quoted to only two significant figures in Table 1.
`As the reaction proceeded the absorbance maximum of the
`
`J.C.S. Perkin
`
`carbonyl peak for acetanilide and the 4-Me, 4-F, and
`4-NH2 derivatives tended towards zero, while the position of
`remained unaltered. For the other acetanilides
`AWx
`(aniline), the product, differed from that of
`studied A,,
`Lx (acetanilide) and a constant isosbestic point was noted
`throughout a kinetic run.
`The hydrolysis of substituted acetanilides, in dilute and
`moderately concentrated acid, yields the corresponding
`anilines and these were identified by U.V. spectroscopy.
`The other product in the hydrolysis of these acetanilides is
`acetic acid.
`Least-squares analyses were carried out on a Burroughs
`B6700 computer.
`
`We express our gratitude to Dr. C. D. Johnson for permis-
`sion to use the unpublished data from Dr. M. S. Hashmi's
`Ph.D. thesis.
`
`[4/2687 Received, 23rd December, 19743
`
`0 Copyright 1976 by The Chemical Societj
`
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`
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`
`Page 4 of 4