7
The acidity and tautomerism of P-diketones in aqueous solution John W. Bunting, James P. Kanter, Raymond Nelander, and Zhennan Wu Abstract: The acidity and ket-no1 tautomerism of a series of symmetrical P-diketones (RCOCH2COR (1): R = methyl (a), phenyl (b), 3-pyridinyl (c), 4-pyridinyl(4, 3-(N-methy1)pyridinio (e), and 4-(N- rnethy1)pyridinio (f)) and two series of unsymmetrical P-diketones (RCOCH2COCH, (7a-7fi and RCOCH,COC6H5 ( 8 a 4 f )) have been investigated in aqueous solution at 25°C and ionic strength 0.1. Values of p K 2 were measured spectrophotometrically, and the acidities of the enols ( pm were obtained from the analysis of the pH dependence of the buffer catalysis for the general acid-catalyzed protonation of the enolate conjugate bases. These data in tum allowed the calculation of the acidities of the keto tautorners (p@) and the equilibrium constants for enolization (K, = [Enoll/[Keto]). In general, KEis greater for the symmetrical ketones (1) than for the corresponding R-substituted unsymmetrical ketones (7 and 8). K, is much more sensitive to the nature of the R substituent in these three series of P-diketones than in the corresponding series of P-keto esters and amides. Correlations between for 8 and 7 combined with the known acidities of the corresponding P-keto esters and arnides provide the first accurate estimates of the acidities of dirnethyl malonate (pKa = 13.0) and malonarnide (pKa = 12.5) in aqueous solution. Key words: acidity, tautomerisrn, P-diketones. RCsum6 : OpCrant en solutions aqueuses, a 25°C et B une force ionique de 0,1, on a CtudiC l'aciditb et llisomCrie cCtdnolique d'une sCrie de P-dicktones symCtriques (RCOCH2COR (1) : R = mCthyl (a), phCnyl (b), 3-pyridyle (c), 4-pyridyle ( 4 , 3-(N-mCthy1)pyridinio(e) et 4-(N-mCthy1)pyridinio (n) et de deux series de P-dicetones non symCtriques (RCOCH2CORCH3 (7a-7f) et RCOCH2COC6H5 (8a4f)). On a rnesuri les pKaq spectrophotomCtriquement et on a dCterminC les acidids des Cnols ( p e ) par une analyse de la relation entre la dCpendance sur le pH de la catalyse du tampon sur la protonation par catalyse acide gCnCrale des bases conjuguCes Cnolates. Ces donnCes permettent ensuite de calculer les aciditCs des cCto-tautomtres et les constantes d9Cquilibre de 1'Cnolisation (KE = [Bnol:~/[~~tone]). En gCnCral, la valeur de KEest plus grande pour les cCtones symCtriques (1) que pour les cCtones non symttriques correspondantes substituies pardes groupes R (7 et 8). La valeur de KE est beaucoup plus sensible la nature du substituant R dans ces trois sCries de P-dicttones que dans les sCries correspondantes de P-cCtoamides. Des corrClations entre les valeurs des des composCs 7 et 8 cornbinCes avec les aciditCs connues des p-cktoesters et P-cCtoamides correspondants foumissent les prernisres Cvaluations prCcises des aciditks du malonate de dimCthyle (pKa = 13,O) et du malonarnide (pKa = 12,5) en solution aqueuse. Mots clis : aciditC, tautomCrie, P-dicCtones. [Traduit par la redaction] Introduction [I] K,eq = [H'] [E-]/([KH] + [EH)] In aqueous solution, P-diketones (1 = KH) exist in equilibrium with their keto-enol isomers (2 = EH) and the corresponding enolate anion (3 = E-) as described in Scheme 1. Titration of the equilibrium mixture of KH and EH gives an apparent acid ionization constant, K : q (eq. [I]),. which may be described by the ionization constant of either tautomer and the equilibrium ratio of the en01 and keto tautomers, KE = [EH:]/[KH:], as shown in eqs. [2] and [3]. I Received August 16, 1994. J.W. ~ u n t i n ~ , ' J.P. Kanter, R. Nelander, and Z. Wu. Department of Chemistry, University of Toronto, Toronto, ON M5S 1A 1, Canada ' Deceased February 20, 1995. p c q is usually readily determined by spectrophotomeric titration in aqueous solutions buffered at various pH values. In principle, the measurement of any one of p ~ f , p~r, or KE then allows the evaluation of all equilibrium constants in Scheme 1 using eqs. [2] and [3]. Aqueous solutions of acetyl- acetone (1: R = CH,) have been examined a number of times (1-lo), and there is general agreement that at equilibrium approximately 20% of this diketone exists in the form of the en01 (2: R = CH,) near room temperature. However, there have been relatively few studies of other P-diketones in aque- ous solution (4, 7, 11-13), and thus there is little information Can. J. Chem. 73: 1305-131 1 (1995). Printed in Canada1Imprim6 au Canada Can. J. Chem. Downloaded from www.nrcresearchpress.com by 219.64.186.115 on 06/04/11 For personal use only.

Acidity of Beta Diketone

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Page 1: Acidity of Beta Diketone

The acidity and tautomerism of P-diketones in aqueous solution

John W. Bunting, James P. Kanter, Raymond Nelander, and Zhennan Wu

Abstract: The acidity and ket-no1 tautomerism of a series of symmetrical P-diketones (RCOCH2COR (1): R = methyl (a), phenyl (b), 3-pyridinyl (c), 4-pyridinyl(4, 3-(N-methy1)pyridinio (e), and 4-(N- rnethy1)pyridinio ( f ) ) and two series of unsymmetrical P-diketones (RCOCH2COCH, (7a-7fi and RCOCH,COC6H5 (8a4f )) have been investigated in aqueous solution at 25°C and ionic strength 0.1. Values of pK2 were measured spectrophotometrically, and the acidities of the enols ( p m were obtained from the analysis of the pH dependence of the buffer catalysis for the general acid-catalyzed protonation of the enolate conjugate bases. These data in tum allowed the calculation of the acidities of the keto tautorners (p@) and the equilibrium constants for enolization (K, = [Enoll/[Keto]). In general, KE is greater for the symmetrical ketones (1) than for the corresponding R-substituted unsymmetrical ketones (7 and 8). K, is much more sensitive to the nature of the R substituent in these three series of P-diketones than in the corresponding series of P-keto esters and amides. Correlations between for 8 and 7 combined with the known acidities of the corresponding P-keto esters and arnides provide the first accurate estimates of the acidities of dirnethyl malonate (pKa = 13.0) and malonarnide (pKa = 12.5) in aqueous solution.

Key words: acidity, tautomerisrn, P-diketones.

RCsum6 : OpCrant en solutions aqueuses, a 25°C et B une force ionique de 0,1, on a CtudiC l'aciditb et llisomCrie cCtdnolique d'une sCrie de P-dicktones symCtriques (RCOCH2COR (1) : R = mCthyl (a), phCnyl (b), 3-pyridyle (c), 4-pyridyle ( 4 , 3-(N-mCthy1)pyridinio (e) et 4-(N-mCthy1)pyridinio (n) et de deux series de P-dicetones non symCtriques (RCOCH2CORCH3 (7a-7f) et RCOCH2COC6H5 (8a4f)). On a rnesuri les pKaq spectrophotomCtriquement et on a dCterminC les acidids des Cnols ( p e ) par une analyse de la relation entre la dCpendance sur le pH de la catalyse du tampon sur la protonation par catalyse acide gCnCrale des bases conjuguCes Cnolates. Ces donnCes permettent ensuite de calculer les aciditCs des cCto-tautomtres et les constantes d9Cquilibre de 1'Cnolisation (KE = [Bnol:~/[~~tone]). En gCnCral, la valeur de KE est plus grande pour les cCtones symCtriques (1) que pour les cCtones non symttriques correspondantes substituies pardes groupes R (7 et 8). La valeur de KE est beaucoup plus sensible la nature du substituant R dans ces trois sCries de P-dicttones que dans les sCries correspondantes de P-cCtoamides. Des corrClations entre les valeurs des des composCs 7 et 8 cornbinCes avec les aciditCs connues des p-cktoesters et P-cCtoamides correspondants foumissent les prernisres Cvaluations prCcises des aciditks du malonate de dimCthyle (pKa = 13,O) et du malonarnide (pKa = 12,5) en solution aqueuse.

Mots clis : aciditC, tautomCrie, P-dicCtones.

[Traduit par la redaction]

Introduction [I] K,eq = [H'] [E-]/([KH] + [EH)]

In aqueous solution, P-diketones (1 = KH) exist in equilibrium with their keto-enol isomers (2 = EH) and the corresponding enolate anion (3 = E-) as described in Scheme 1. Titration of the equilibrium mixture of KH and EH gives an apparent acid ionization constant, K:q (eq. [I]),. which may be described by the ionization constant of either tautomer and the equilibrium ratio of the en01 and keto tautomers, KE = [EH:]/[KH:], as shown in eqs. [2] and [3].

I Received August 16, 1994.

J.W. ~ u n t i n ~ , ' J.P. Kanter, R. Nelander, and Z. Wu. Department of Chemistry, University of Toronto, Toronto, ON M5S 1A 1, Canada

' Deceased February 20, 1995.

p c q is usually readily determined by spectrophotomeric titration in aqueous solutions buffered at various pH values. In principle, the measurement of any one of p ~ f , p ~ r , or KE then allows the evaluation of all equilibrium constants in Scheme 1 using eqs. [2] and [3]. Aqueous solutions of acetyl- acetone (1: R = CH,) have been examined a number of times (1-lo), and there is general agreement that at equilibrium approximately 20% of this diketone exists in the form of the en01 (2: R = CH,) near room temperature. However, there have been relatively few studies of other P-diketones in aque- ous solution (4, 7, 11-13), and thus there is little information

Can. J. Chem. 73: 1305-131 1 (1995). Printed in Canada1 Imprim6 au Canada

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Can. J. Chem. Vol. 73, 1995

0 0 0 OH II I1 II I

R-C-CH2-C-R . R-C-CH-C-R

Scheme 1.

available on the dependence of each of the three equilibrium constants of Scheme 1 upon the nature of the R substituents in 1, which represents symmetrical P-diketones, or upon R' and

I R2 in 4, which represents unsymmetrical species (R' # R2).

The study of unsymmetrical P-diketones introduces an additional complication, which is not relevant for symmetrical P-diketones, and is of no significance for P-keto esters or amides that we have recently examined (14). Unsymmetrical P-diketones (4) can enolize to give a pair of en01 structural iso- mers (5 and 6). Thus the generation of enols by 0-protonation of the enolate ion derived from 4 will in general give a mixture of these two en01 species, and so the p ~ F and KE defined in terms of Scheme 1 will contain a contribution from the equi- librium ratio of 5: 6. This limitation will com licate the inter- 2 pretation of the structural dependences of pK, and KE and also relationships between pe and p ~ f such as those which were developed (14) for P-keto esters and arnides.

The current work reports an investigation of the equilibria for the deprotonation and tautomerism of 15 P-diketones in

I aqueous solution. These species include six symmetrical , ketones (la-lf; see Table l), six P-keto methyl ketones (7a- I 7f; see Tables 1 and 2; note that l a = 7a), and six P-keto phe-

nyl ketones (8a-8f; note that 8a = 76 and 8b = 16). Useful lin- ear free energy relationships are established between values for the various classes of P-diketones and the corre- sponding P-keto esters and arnides (14). We have also found that the en01 contents of P-keto esters and amides are not, in

0 0 0 0 I1 I1 I I II

CH3 - C - CH2- C-R CsH5-C-CH2-C-R

general, a reasonable basis for the confident prediction of the en01 contents of similarly substituted P-diketones.

Experimental

2,4-Pentanedione (acetylacetone la), 1-phenyl-1,3-butanedi- one (benzoylacetone 7b), and 1,3-diphenyl-l,3-propanedione (dibenzoylmethane lb) are commercially available. All other neutral P-diketones were prepared by the condensation of the enolate anion of 3- or 4-acetylpyridine with the appropriate methyl ester. A detailed synthesis of l c is described below. Each pyridyl P-diketone was methylated by treatment with methyl bromide in acetone solution in a pressure bottle at room temperature for 24 h. All products were characterized by 'H NMR spectroscopy in CD3SOCD3; in general these spectra indicated the presence of a mixture of the keto and en01 tau- tomers in this solvent (13).

1,3-Di-3-pyridinyl-l,3-propanedione (lc) Methyl nicotinate (2.5 g) was dissolved in 3-acetylpyridine (10 mL). An 80% dispersion of sodium hydride in mineral oil (0.6 g) was added to this solution, with constant stirring, over a period of 30 min. The mixture was stirred and refluxed for a further 2.5 h during which time the solution became bright yellow. The product solution was cooled to room temperature, diluted with diethyl ether (40 mL), and neutralized with a few drops of concentrated HC1. A saturated aqueous solution of sodium chloride (20 mL) was added, and the product was col- lected by exhaustive extraction with methylene chloride. These extracts were dried over magnesium sulfate, and the solvent was removed on the rotary evaporatory. The resulting oil was treated with a 1: 1 mixture of diethyl ether and hexane (10 mL). After refrigeration overnight, large pale-yellow crys- tals of l c were obtained, and recrystallized from 2-propanol in 78% overall yield; mp 198-200°C (lit. (15) mp 199-201°C; (16) mp 198°C).

The following P-diketones were similarly prepared: Id, mp 152-154°C; 7c, mp 81-83°C (lit. (17) 81-82°C); 7d, mp 66- 67°C (lit. (18) mp 6647°C); 8c, mp 119-121°C; 8d, mp 83- 84°C (lit. (18) mp 8344°C).

The following bromide salts were also obtained: le.(Br-)2, mp 243°C (dec.); lf(Br-),, mp '248°C (dec.); 7e.Br-, mp 142°C (dec.); 7fBr-, mp 152°C (dec.); 8e.Br-, mp 210- 212°C; 8fBr-, mp 255-257°C.

pK, measurements The spectro hotometric measurements of pK,eq and the evalu- R ation of pK, in pH-jump experiments by stopped-flow spec- trophotometry closely followed the methods described in detail in our recent work (14). All experimental data are for aqueous solutions of ionic strength of 0.1 (KC1 + buffer) at 25"C, with the exception of data for dibenzoylmethane (lb) for which limited aqueous solubility required the addition of 10% acetonitrile to all aqueous solutions.

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Bunting et al.

Fig. 1. The pH dependence of the absorption spectrum of 7e (0.101 rnM) in aqueous solution. Spectra are at pH 4.00 (spectrum l), 6.03, 6.23,7.02, and 8.50 (spectrum 5).

WAVELENGTH (nm)

Fig. 2. The pH dependence of the absorption spectrum of l e (0.0454 mM) in aqueous solution. Spectra are at pH 2.08 (spectrum 1), 3.47,4.00,4.51,5.04,5.52, and 7.04 (spectrum 7).

Results

Figures 1 and 2 display the pH-dependence of the electronic absorption spectra of two of the ketones examined in this study. These two examples, which are typical of the spectral observations for all diketones in the current study, are chosen to demonstrate pH-dependent spectra for a P-diketone (7e) that predominates over its en01 tautomer, and a diketone ( le) that exists mainly as the en01 isomer. In basic solution, each enolate conjugate base displays an intense long-wavelength absorption maximum. These A,,, are listed in Tables 1 and 2, and vary systematically in the order: methyl < phenyl < 3- pyridyl < 4-pyridyl < 3-(N-methyl pyridinio) < 4-(N-methyl pyridinio) for the enolates; i.e., systematically from a-f for the conjugate bases from each of 1 ,7 , and 8. The same ordering of A,,, values was also observed (14) for the enolate conjugate bases of the corresponding P-keto esters and amides. All sym- metrical enolate ions (3) have longer wavelength absorption maxima (Table 1) than do the corresponding unsymmetrical enolate ions from each of 7 and 8 (Table 2). The corresponding en01 (2J) has A,,, = 353 nm.

The pH dependence of the absorbance at constant wave- length in the vicinity of A,,, of the enolate was used to evalu- ate pK:4 for the equilibrated tautomeric mixtures from each of 1 ,7 , and 8. Values of p K 2 are listed in Tables 1 and 2.

The acidities of the enols ( p ~ f ) were calculated form the pH dependence of buffer catalysis of the ketonization reac- tions in pH-jump experiments in which a solution of the eno- late conjugate base was rapidly acidified in the stopped-flow spectrophotometer. This technique, and the algebraic treat-

ment of the kinetic data that allows the calculation of p ~ F , have recently been described (14) in some detail. Values of p ~ F are included in Tables 1 and 2. These tables also include KE calculated from eq. [3], and p e , which was subsequently calculated from eq. [2].

For l e and If there was no observable time-dependent absorbance change upon acidification of the enolate species. This implies that the conjugate acid species is predominantly the en01 tautomer in these two cases and that pK,eq = For 8d and Sf, the time-dependent absorbance changes upon acid- ification of the enolate were quite small. In these two cases, values of p ~ : were still measurable; however, these en01 acidities are within experimental error of pK24, and so accu- rate values of KE and PK: are not directly accessible by the current experimental method. The estimates of p ~ F in Tables 1 and 2 for these two species are based upon the linear free energy relationships that are developed below.

Discussion

The data in Tables 1 and 2 represent the most extensive set of data that are currently available for the structural dependence of the equilibrium constants defined in Scheme 1 for P-di- ketones in aqueous solution. Before discussing the trends in these data it is important to appreciate a limitation that is inherent in the current experimental method for the evaluation of KE and p ~ f . The calculation of these two parameters requires a significant difference between pKaq and pe. If KE (= [Enol]/[Keto]) < 1, this difference is large and accurate val- ues of KE and p ~ f are obtained. However, ~ K F = pKzq for those species for which the tautomeric ratio lies heavily in favour of the en01 tautomer, and accurate numerical values of KE are not accessible. Our experience from both the current study and our earlier work (14) is that KE should be less than 5 for the quantitative analysis of structural effects upon KE and p ~ F . This limit will be adopted in the correlation analyses of equilibrium constants that are presented below, although we will also show that the linear free energy relationships that we have developed do allow an alternative route to the estimation of p ~ f (and consequently K,) when this equilibrium constant is not directly accessible experimentally.

Acidities of keto and en01 tautomers A well-defined relationship between the acidities of the P-keto methyl ketones (7) and the structurally related P-keto phenyl ketones (8) is shown in Fig. 3. This figure includes data points for the methyl esters and amides of acetoacetic and benzoyl- acetic acids in addition to the P-diketones of the current study. The correlation line in Fig. 3 is defined by eq. [4], which in turn allows the estimation of p e for 8 d and 8f (Table 2).

Similar linear correlations can be demonstrated between ~ K F values for P-keto methyl ketones (7) and P-keto methyl esters (9) (eq. [51), P-keto phenyl ketones (8) and P-keto methyl esters (9) (eq. [6]), P-keto methyl ketones (7) and P- keto amides (10) (eq. [7]), and P-keto phenyl ketones (8) and P-keto amides (10) (eq. [7]). The slope parameters in eqs. [51-

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1308 Can. J. Chern. Vol. 73, 1995

Table 1. Equilibrium constants for deprotonation and tautomerization of symmetrical P-diketones (1) and their enols (2)."

No. R La, (1% E ) ~ P C q PKF PC KE

l a = 7a CH3 292 (4.41) 8.79 8.03 8.71 0.21 l b = 86' c8, 347 (4.17) 8.7 1 8.64 =7.9 =6 IC 3-C5H,N 350 (4.04) 7.23 7.04 6.78 1.8 Id 4-C5H4N 356 (4.05) 5.51 5.45 4 . 6 5 =6 l e 3-(C5H4NCH,') 362 (4.17) 4.82 4.82 (3 .2)d 40 If 4-(C5H4NCH,') 403 (3.99) 3.07 3.07 (0.7)d 200

"In aqueous solution, ionic strength 0.1, at 25°C. K, is calculated from eq. [3] for la-ld, and from eq. [2] for l e and If. bLongest wavelength absorption maximum in the spectrum of the enolate conjugate base. 'All data are for aqueous solutions containing 10% acetonitrile. dAverage of the values calculated from eqs. [9] and [lo].

Table 2. Equilibrium constants for deprotonation and tautomerization of unsymmetrical P-diketones (7 and 8 ) and their enols."

No. R Amax (log E ) ~ PK? PKf PC KE

76 = 8a C,H5 320 (4.09) 8.77 8.39 8.53 0.72 7c 3-C5H4N 322 (3.75) 7.64 7.15 7.47 0.48 7d 4-C5H4N 327 (4.13) 7.39 7.16 7.00 1.4 7e 3-(C5H4NCH3+) 329 (3.93) 6.24 5.53 6.15 0.24 7 f 4-(C5H4NCH3+) 377 (3.79) 5.97 5.92 4 . 0 =8 8c 3-C5H4N 347 (4.14) 7.62 7.37 7.26 1.3 8d 4-C5H4N 350 (4.22) 7.30 7.27(7.18)' (6.7)d 3 8e 3-(C5H4NCH3+) 354 (4.12) 6.15 5.84 5.86 0.97 Sf 4-(C5H4NCH3') 388 (3.96) 5.92 5.89 (4.7)d 16

"In aqueous solution, ionic strength 0.1, at 25°C. K, was calculated from eq. [3] in all cases excepting 8d and Sf for which eq. [2] was used (see text).

b n g e s t wavelength absorption maximum in the spectrum of the enolate base. 'Calculated from eq. [3] for K, = 3. dCalculated from eq. [4].

[8] demonstrate that P-diketones are somewhat less sensitive to variation in the R substituent of the acyl functional group than are the less acidic P-keto esters and amides

Interpolation in these correlation equations can be used to predict pK: for some related species. Equation [5] and pKF= 10.60 for methyl acetoacetate (7: R = OCH,) (14) predicts pK: = 12.9 for dimethyl malonate (9: R = OCH,). Equation [6] and P K ~ = 10.28 for methyl benzoylacetate (8: R = OCH,) (14) lead to pKF = 13.0 for this same malonate diester. These predictions are similar to the pK, = 13.3 for diethyl malonate (19) that is the only experimental value we have been able to locate for the acidity of a malonate diester in aqueous solution, although the experimental basis of this value is unclear.

A similar analysis using p ~ r = 10.41 for acetoacetamide and pK: = 10.04 for benzoylacetamide (14) leads to pK: = 12.5 for malonamide (10: R = NH,) from both eqs. [7] and [8]. We have been unable to find a literature value for the acidity of this diamide in aqueous solution. Williams and Xia (20) have recently estimated KE = 4 x lo-'' for the enolization of malonamide. These values of p ~ f and KE then allow the cal-

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Fig. 3. Correlation between pKf for 8 and pK: for 7 (a-e as defined in Table 2), including data for methyl esters (9 = E) and amides (10 = A) of acetoacetic and benzoylacetic acids. The correlation line is defined by eq. [4].

culation of p e = 3.1 for the en01 of malonamide using Scheme 1.

Figure 4 shows a linear relationship (eq. [9]) between p ~ f for symmetrical P-diketones (1) and p ~ f for the correspond- ing unsymmetrical P-keto methyl ketones (7). A similar linear relationship (eq. [lo]) also exists between p ~ F for 1 and p ~ $ for the unsymmetrical P-keto phenyl ketones (8). The pKt data estimated above for the diester and diamide of malonic acid appear to be consistent with these relationships. Equa- tions [9] and [lo] can be used to estimate for l e and If (see Table 1) for which we have been unable to demonstrate any 6- diketone tautomer upon acidification of solutions of the eno- late conjugate bases in pH-jump experiments. The calculated KE ratios then confirm the predominance of the en01 tautomers in these two cases.

Since the experimentally measured pe values contain con- tributions from more than one en01 tautomer of 7 and 8, we did not expect to find simple relationshi s for pe that are analo- k' gous to those reported above for pK, . However, Figs. 5 and 6 show that some approximate relationships involving p ~ F do exist. Thus, there appears to be a linear relationship between the p ~ F values for the enols of 7 and 8 (Fig. 5 and eq. [ l I I) although 6-keto esters and arnides, which give a single enol, deviate somewhat from the relationship for the P-diketones. Figure 6

Fig. 4. Correlations between pKf for 1 and 7 (a-e as defined in Tables 1 and 2), including data for dimethyl malonate (A) and malonamide (E) evaluated from eq. [4] as examples of 1. The correlation line is defined by eq. [9].

Mtd

% 8

demonstrates the dependence of pKf upon pK: for 1,7, and 8. The correlation line in Fig. 6 corresponds to eq. [12], which is defined for the symmetrical P-diketones (1). The data for the unsymmetrical ketones, apart from the 3-(N-methyl pyridinio) derivatives (7e and 8e), are also consistent with eq. [12].

Structural effects upon KE It is apparent from Table 2 that KE is smaller for P-keto methyl ketones (7) than for the corresponding P-keto phenyl ketones (8) bearing the same R substituent. This enhanced en01 content for phenyl ketones over methyl ketones is dramatized by the 30-fold greater KE for dibenzoylmethane (lb) than for acetyl- acetone (la); this is presumably attributable to the styrene-like conjugation that is present in the enols of phenyl ketones. For the symmetrical P-diketones (1) en01 content increases in the order: methyl < 3-pyridyl c phenyl = 4-pyridyl<< 3- and 4- (N-methyl puridinio). With the exception of R = 3-(N-methyl pyridinio), this same order is essentially preserved for 7 and 8, although the en01 content is clearly smaller for R = phenyl than for R = 4-pyridyl in these two series of unsymmetrical ketones. For 7e and 8e, the en01 content is unusually small in comparison with the high en01 content of the symmetrical 3- (N-methyl pyridinio) diketone (le). For both 7e and 8e, KE is of similar magnitude to that found for 7a and 8a and more than 10-fold smaller than for the isomeric 4-(N-methyl pyridinio) species (7f and 8f). We have no simple explanation for the unique effects from the 3-(N-methyl pyridinio) substituents in symmetrical and unsymmetrical P-diketones, other than to suggest that the predominant enol, for reasons unknown, may be that which enolizes on the side of the acetyl and benzoyl groups, respectively (i.e., 5: R~ = CH3 or C6H5), rather than

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Can. J. Chem. Vol. 73,1995

Fig. 5. Correlation between p ~ $ for the enols of 8 and 7 (a-e as defined in Table 2). The correlation line is defined by eq. [I I]. The data for methyl esters (9 = E) and amides (10 = A) of acetoacetic and benzoylacetic acids are not included in this relationship.

I rather than towards the 3-pyridinio carbonyl group (i.e., 6: R' I = 3-(C,H,NCH,+)). I The strong dependence of KE upon R for P-diketones in I

1 Tables 1 and 2 is in marked contrast with the relative insensi- tivity of KE to the same six R substituents in P-keto esters and amides (9 and 10 with R substituents a-f as defined in Tables 1 and 2) (14). All of these P-keto esters and amides predominate over their en01 tautomers (en01 contents in the range 622%) in aqueous solution, with KE for each of 9 and 10 being smaller than for the corresponding R-substituted diketone in Table 2. For each of 9 and 10, KE varies less than 4-fold, with little dif- ference between the en01 contents for R = methyl and R = phe- nyl. For both 9 and 10, KE is largest for R = 4-pyridyl, with approximately a 2-fold decrease in en01 content upon N-meth- ylation of either the 3- or 4-pyridyl derivatives. This latter observation is in marked contrast to the dramatic increase in KE that is indicated in Tables 1 and 2 upon methylation of lc, Id, 7d, and 8d.

The foregoing comparisons make it clear that, in general, substituent effects upon KE from the acyl groups in P-keto esters and arnides cannot be used as a general guide to the effects of these same acyl groups upon the en01 contents of P- diketones. While this result may initially appear somewhat surprising, in fact there should be significant differences between the roles of substituent effects upon en01 stability for P-keto esters (and amides), symmetrical P-diketones, and unsymmetrical P-diketones. For 9 and 10, enolization is only expected towards the ketone, and not towards the formal car- bony1 group of the ester or amide unit. In these cases, the dependence of KE upon R gives a direct indication of the influ- ence of R upon the relative stabilities of ketones and their iso- meric enols. For symmetrical diketones, two R groups are changed simultaneously and, while there is only one en01 spe-

Fig. 6. The relationship between p ~ f and p ~ F for 1 (filled circles), 7 (empty circles), and 8 (filled triangles). The correlation line is eq. [I21 defined for symmetrical ketones (1) only.

cies, the effects of the two R groups upon the stability of 2 will probably be quite different. For unsymmetrical P-diketones, there is the additional problem that the experimentally deter- mined KE contains contributions from two structurally iso- meric enols (5 and 6) and the likelihood that the equilibrium ratio of [5]/[6] will also be dependent upon R' and R'.

Acknowledgement We appreciate the support of this work by the Natural Sci- ences and Engineering Research Council of Canada.

References I. G. Schwarzenbach and E. Felder. Helv. Chim. Acta, 27, 1044

(1944); 27, 1701 (1944). 2. M.L. Eidenhoff. J. Am. Chem. Soc. 67,2073 (1945). 3. B. Eistert, E. Merkel, and W. Reiss. Chem. Ber. 87, 1513

(1954). 4. P. Rurnpf and R. La Rivitre. C. R. Hebd. Seances Acad. Sci.

244, 1501 (1957). 5. A.S.N. Murthy, A. Balasubrarnanian, C.N.R. Rao, and T.R.

Kasturi. Can. J. Chem. 40,2267 (1962). 6. M.L. Ahrens, M. Eigen, W. Kruse, and G. Maass. Ber. Bunsen-

ges. Phys. Chem. 74,380 (1970). 7. P. Alcais and R. Brouillard. J. Chern. Soc. Perkin Trans. 2, 1214

(1972). 8. C.F. Bernasconi and R.D. Bunnell. Isr. J. Chern. 26,420 (1985). 9. M. Moriyasu, A. Kato, and Y. Hashirnoto. J. Chern. Soc. Perkin

Trans. 2,515 (1986). 10. J. Ernsley and N.J. Freeman. J. Mol. Stmct. 161, 193 (1987). 11. J.-P. Calrnon and P. Maroni. Bull. Soc. Chim. Fr.,2532 (1965). 12. S. ForsCn and M. Nilsson. In The chemistry of the carbonyl

group. Vol. 2. Edited by J. Zabicky. Interscience, London. 1970. Chap. 3.

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

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sear

chpr

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Bunting et al. 131 1

14. J.W. Bunting and J.P. Kanter. J. Am. Chem. Soc. 115, 11 705 18. E. Belgodere, R. Bossio, F. De Sio, S. Maraccini, and R. (1993). Repino. Heterocycles, 20,504 (1983).

15. M. Ferles, S. Kafka, A.S. Ankava, and M. Sputova. Collect. 19. R.G. Pearson and J.M. Mills. J. Am. Chem. Soc. 72, 1692 Czech. Chem. Commun. 46, 1169 (1981). (1950).

16. A. Babska, L. Bielski, L. Kuczynski, S. Respond, and H. Witek. 20. D.L.H. Williams and L. Xia. J. Chem. Soc. Chem. Commun. Pol. J. Pharmacol. Pharm. 25, 175 (1973). 985 (1992); J. Chem. Soc. Perkin Trans. 2, 1429 (1993).

17. L.F. Kuick and H.J. Adkins. J. Am. Chem. Soc. 57, 143 (1 935).

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. J. C

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