Sterically hindered enols of carboxylic acids and esters. the ketonisation reactions of 2,2-bis(2,4,6-trimethylphenyl)ethene-1,1-diol and 2,2-bis(pentamethylphenyl)ethene-1,1-diol

Article abstract of DOI:10.1039/a703653a

The ketonisation of two enols of carboxylic acids, 2,2-bis(2,4,6-trimethylphenyl)ethene-1,1-diol 2a and 2,2-bis(pentamethylphenyl)ethene-1,1-diol 2b have been studied at 25°C in 1:1 acetonitrile-water. The stability of these compounds arises from the inhibition of the β-carbon site to protonation, and this effect is now quantified. A pK_a of 8.18 is reported for ionisation of the first hydroxyl group Of(MeS)₂C=C(OH)₂ 2a and 8.63 for (PMP)₂C=C(OH)₂ 2b. A pH-rate profile has been determined over the full pH range for both species. General acid catalysis was detected, yielding Bronsted a values of 0.35 and 0.34 for 2a and 2b, respectively. Similarly, Bronsted a'′ values of 0.48 and 0.45 were calculated for general acid catalysis of both enolate mono-anions. Studies of the ketonisation of the enols of the corresponding methyl esters have permitted comparative studies on the reactivity of enols of carboxylic acids, esters and ketene acetals. The reactivity of MeS₂C=C(OH)(OCH₃) lies closer to the enediol, MeS₂C=C(OH)₂ 2a than to the ketene acetal, suggesting that in this case, one hydroxy group is almost as efficient as two such groups in the stabilisation of the positive charge developing at C_β as protonation occurs.

Full text of DOI:10.1039/a703653a

View Article Online / Journal Homepage / Table of Contents for this issue
Sterically hindered enols of carboxylic acids and esters. The
ketonisation reactions of 2,2-bis(2,4,6-trimethylphenyl)ethene-1,1-diol
and 2,2-bis(pentamethylphenyl)ethene-1,1-diol
Barbara M. Allen, Anthony F. Hegarty* and Pat O’Neill
Chemistry Department, University College Dublin, Dublin 4, Ireland
The ketonisation of two enols of carboxylic acids, 2,2-bis(2,4,6-trimethylphenyl)ethene-1,1-diol 2a and
2,2-bis(pentamethylphenyl)ethene-1,1-diol 2b have been studied at 25 ЊC in 1:1 acetonitrile–water. The
stability of these compounds arises from the inhibition of the â-carbon site to protonation, and this effect
is now quantified. A pK of 8.18 is reported for ionisation of the first hydroxyl group of (Mes) C᎐C(OH)
᎐
a
2
2
2a and 8.63 for (PMP) C᎐C(OH) 2b. A pH–rate profile has been determined over the full pH range for
᎐
2
2
both species. General acid catalysis was detected, yielding Brønsted á values of 0.35 and 0.34 for 2a and 2b,
respectively. Similarly, Brønsted áЈ values of 0.48 and 0.45 were calculated for general acid catalysis of
both enolate mono-anions. Studies of the ketonisation of the enols of the corresponding methyl esters
have permitted comparative studies on the reactivity of enols of carboxylic acids, esters and ketene
acetals. The reactivity of Mes C᎐C(OH)(OCH ) lies closer to the enediol, Mes C᎐C(OH) 2a than to the
᎐
᎐
2
3
2
2
ketene acetal, suggesting that in this case, one hydroxy group is almost as efficient as two such groups in
the stabilisation of the positive charge developing at Câ as protonation occurs.
Introduction
While the chemistry of enols of aldehydes and ketones has been
well studied,1 examples of observable 1,1-enediols (enols of
carboxylic acids) are rare.2–8 The problem lies in generating the
enol tautomer at concentrations greater than the very low
values pertaining at equilibrium. Recent work on the enolis-
ation of ethyl acetate9 yields a pKE value of 18.6 which is very
close to values obtained using theoretical calculations.10 There
is no general method for generating these elusive species; how-
ever, in some cases, 1,1-enediols may be generated as observ-
able intermediates in the hydration of ketenes, as shown in
Scheme 1.
R
R
OH
R
H
OH
k1
k2
β
α
C
C
O
C
C
C
C
Fig. 1 pH–log rate profiles for the ketonisation of enediols 2a (᭿) and
2b (᭹) in 50% aqueous acetonitrile at 25 ЊC
R
R
OH
R
O
1
2
3
confirms their identity but also provides basic data on the rates
and equilibria for the ketonisation of these thermodynamically
very unstable enols and of the enols of the corresponding
methyl esters which are formed on the addition of methanol to
the ketenes 1.
a R = 2,4,6-Me3C6H2- (Mes)
b R = 2,3,4,5,6-Me5C6- (PMP)
Scheme 1
1,1-Enediols are observed when k1 > k2, i.e., when water
attack is not rate determining. The enediol intermediate sub-
sequently tautomerises to give the more stable carboxylic acid
product. Electron-withdrawing substituents increase the rate of
hydration but, conversely, decrease the relative rate of ketonis-
ation, so that observation of the enediol intermediate is
favoured.11 Because the trajectory of approach of the nucleo-
philic water is in the plane of the ketene, some bulky sub-
stituents show a marked effect on the rate of hydration of
ketenes.12 However, in certain cases the enediol intermediate 2
may be observed, since the subsequent ketonisation to the acid
3 may be even more sensitive to steric substitution.2,3,8
Results and discussion
Rate profiles
The pH–log rate profiles shown in Fig. 1 were obtained in 1:1
water–acetonitrile and were constructed using experimental pH
values (see Experimental). The ene-1,1-diols were preformed at
low buffer concentration at pH ca. 4 ( where the subsequent
ketonisation is slowest) and the solution were ‘aged’ until the
hydration was essentially complete. The pH was then changed
by the addition of a more concentrated buffer solution which
also defined the final solvent composition. A mixed organic
solvent with water was used rather than water alone for solu-
bility reasons.
Previously, we reported the observation of remarkably stable
carboxylic acid enols, formed as observable intermediates in the
hydration of the mesityl (Mes) and pentamethyl (PMP) ketenes,
(Mes) C᎐C᎐O 1a and (PMP) C᎐C᎐O 1b in aqueous aceto-
The profiles show a well defined acid catalysed region, a pH
independent region, a base catalysed region which levels off,
and finally at higher base concentrations a second base cata-
lysed region is evident but without rate saturation. The terms
᎐ ᎐
᎐ ᎐
2
2
nitrile.2,3 This has now permitted the direct measurement, using
conventional techniques, of pH–rate profiles for ketonisation
(formation of carboxylic acids) of these species; this not only
J. Chem. Soc., Perkin Trans. 2, 1997
2733

View Article Online
Table 1 Summary of rate and equilibrium constants for reactions
associated with the ketonisation of enediols 2a and 2b in 50% aqueous
acetonitrile at 25 ЊC
Rate constanta
Species
R = Mes
R = PMP
(R)2C᎐C(OH)2
kHϩ = 0.15
kHϩ = 4.0 × 10Ϫ2
pK1 = 8.63
᎐
pK1 = 8.18
(R)2C᎐C(OH)OϪ
kЈHϩ = 2.38 × 105
kЈHϩ = 9.18 × 104
᎐
kH O = 7.84 × 10Ϫ2
kH O = 0.21
2
2
(R)2C᎐C(OϪ)2
—
kЈH OK2/Kw = 0.50
᎐
2
a dm3 molϪ1 sϪ1
.
representing the rate constants for protonation of the neutral
enol by hydronium ion, the mono-enolate by hydronium, and
the mono-enolate and di-enolate by water are each denoted by
kHϩ, kЈHϩ, k
and kЈH O, respectively. The equilibrium con-
H2O
Fig. 2 First-order rate constants for the ketonisation reactions of 2a
2
stants for successive ionisations of the enediol are denoted K1
and K2. The experimental data fits well to eqn. (1) yielding
values for each of the terms which are listed in Table 1.
catalysed by acetic acid at 25 ЊC versus total buffer concentration at
different buffer ratios (AcOH/AcOϪ); 1.78 (᭿), 1.00 (᭹), 0.33 (᭡)
given for the reaction of 2a in acetic acid buffers in Fig. 2. From
the dependences, the buffer acid and base component kAH and
kAϪ have been deduced using eqn. (2), where KAH is the dis-
kobs = kHϩ[Hϩ] ϩ {(kH O ϩ kЈHϩ[Hϩ])/(1 ϩ [Hϩ]/K1)} ϩ
2
kЈH O/(1 ϩ [Hϩ]/K2) (1)
2
kobs = k0 ϩ {(kHA[Hϩ]/KAH) ϩ kAϪ}[AϪ]
(2)
Acid catalysis is interpreted in terms of protonation of the
neutral enediol by hydronium ion. The pH independent region
may be interpreted in terms of pre-equilibrium formation of
the enolate monoanion followed by rate-determining proton-
ation by hydronium ion. The alternative mechanism, whereby
the neutral enol undergoes protonation by solvent water, would
be expected to yield a much lower rate constant when compared
with the rate of reaction of H3Oϩ with the neutral enediol. The
well defined base-catalysed region of the pH profile is explained
using a similar argument, but where solvent water is the domin-
ant protonating species. At high pH values rate saturation is
observed at pH = pK1, where ionisation of the first hydroxyl
group is complete. At more basic pH values, where ionisation of
the second hydroxyl group is important, base catalysis is again
observed. However, the pKa for formation of the dianion (pK2)
could not be determined satisfactorily. These processes are
summarised in Scheme 2.
sociation constant of the buffering species. In most cases both
buffer acid and buffer base catalysis were observed. Where the
contribution for general acid catalysis was small, eqn. (3) was
kobs = k0 ϩ {kHA ϩ (kAKAH)/[Hϩ]}[AH]
(3)
used. Finally, the general acid catalysis of the enolate anion
R C᎐C(OH)OϪ can be determined from the overall general
᎐
2
base catalysis, using the function of the substrate present in
the enolate form, K1/([Hϩ] ϩ K1), where under the experimental
conditions, [Hϩ] ӷ K1 so that eqn. (4) may be used to calculate
kЈAH
.
kЈAH = (kA Ϫ KAH)/K1
(4)
These values in turn may be used to construct Brønsted plots,
yielding α values of 0.35 and 0.34 for 2a and 2b, respectively. A
further Brønsted exponent, corresponding to general acid cata-
lysis of the enolate mono-anion, αЈ, was obtained from plots of
kЈHA versus pKa, yielding Brønsted values of 0.48 and 0.45 for
both species. The low α values obtained for the ketonisation of
both enediols reflects their reactivity, indicating an early transi-
R
R
OH
OH
R
O–
R
R
O–
+
O–
K1
K2
+
H+
+
2H+
3H+
C
C
C
C
C
C
R
OH
+
+
+
+
kH [H ]
k′H [H ]
k
k′
H2O
H2O
tion state. The ketonisation reactions of (Mes) C᎐C(OH) 2a
᎐
2
2
and (PMP) C᎐C(OH) 2b showed both general acid and general
᎐
2
2
R
R
OH
C
R
OH
R
R
O–
base catalysis. This is the expected behaviour, in as much as
ketonisation can occur either through direct rate-determining
proton transfer from an acid to the β-carbon of the enediol,
producing general acid catalysis, or by prior ionisation of the
enediol to the monoenolate followed by proton transfer from
the acid to that species, which is equivalent to general base
catalysis.
These enols were the first reported examples of observable
1,1-enediols.2 Their unusual kinetic stability is attributed
entirely due to steric effects in the proton transfer to the β
carbon. A recent paper by Rappoport and co-workers reports
the observation of similarly stable enols.9 Ditipyl ketene
(tipyl = 2,4,6-triisopropylphenyl) undergoes hydration to yield,
to date, the longest lived 1,1-enediol 2 generated in solution. It
showed remarkable kinetic stability, undergoing ketonisation in
42:5:3 [2H7]DMF–[2H8]THF–H2O with a half life of ca. 95
min at 30 ЊC, which allowed for complete spectral characteris-
ation. This compares with the half lives for ketonisation of ca. 8
and 90 min for 2a and 2b, respectively, in 1:1 acetonitrile–water
at 25 ЊC.
+
H+
+
2H+
CH
CH
R
C
CH
C
OH
O
O
Scheme 2
Brønsted exponents
Ketonisation rate constants were measured in several buffer
solutions. The extrapolated buffer-independent rate constants
were, however, unsuitable for use in the pH–log rate profile due
to the large uncertainties in their values. For this reason, rate
constants at various pH values were measured using a potentio-
stat. Other buffers were found to be unsuitable due to low solu-
bility in the chosen solvent medium. The oxidative formation of
a stable free radical was promoted by phosphate buffers, and
borax buffers were found to complex with the substrate mak-
ing them unsuitable for this study.
Rate constants for the ketonisation of 1,1-enediols were
measured in dichloroacetic, chloroacetic, glycolic and acetic
acid buffer solutions. Buffer catalysis was observed in all cases
yielding straight line plots. A typical example of such a plot is
2734
J. Chem. Soc., Perkin Trans. 2, 1997

View Article Online
Table 2 Summary of the second-order rate constants for general acid
catalysed ketonisation of enediols 2a and 2b in 50% aqueous
acetonitrile at 25 ЊC
kAH/dm3 molϪ1 sϪ1
(Mes)2C᎐
C(OH)2
(Mes)2C᎐
(PMP)2C᎐
C(OH)2
(PMP)2C᎐
᎐
᎐
᎐
᎐
Species
C(OH)OϪ
C(OH)OϪ
Cl2CHCO2H
ClCH2CO2H
HOCH2CO2H 0.074
CH3CO2H
0.550
0.155
—
0.112
—
5.75 × 103
1.70 × 103
5.03 × 102
0.041
5.30 × 102
78.1
7.9 × 10Ϫ3
0.011
—
3.44
obtained by electronic integration with a Waters 745 Data
Module.
Fig. 3 pH–log rate profile for the ketonisation of the enol of the ester
4 in 50% aqueous acetonitrile at 25 ЊC
Materials
Inorganic materials used for kinetic measurements were
AnalaRTM grade, where possible. The salts employed, e.g.
sodium acetate and sodium chloride, were finely ground and
dried at 120 ЊC for 2 h before use. Water was doubly distilled
using an Exelo Water Still. Dissolved carbon dioxide was
removed by vigorous boiling, followed by cooling while
attached to a soda lime trap.
Solution of sodium hydroxide and hydrochloric acid were
prepared by dilution of Rhône Poulenc Volucon ampoules. The
sodium hydroxide solution was standardised by titration with
potassium hydrogen phthalate, with Bromophenol Blue as indi-
cator. HPLC grade organic solvents were used where possible
for kinetic solutions. Both ketenes were synthesised as described
in earlier papers.2,3
Reactivity of enols of esters
The corresponding enol of the methyl ester, (Mes) C᎐C-
᎐
2
(OH)(OCH3), shows very similar reactivity when compared
with 2. This enol undergoes ketonisation to yield the more
stable tautomer, i.e. the ester (Mes)2CHCO2CH3. The pH–log
rate profile (Fig. 3) shows the characteristic behaviour of an
enol reaction. Fitting the experimental data to a modified form
of eqn. (1), where the term for reaction of the dianion is omit-
ted, yields values kHϩ = 0.11 dm3 molϪ1 Ϫ1, kЈHϩ = 1.53 × 106
s
dm3 molϪ1 sϪ1, kH O = 3.09 dm3 molϪ1 sϪ1 and pKa = 8.92 which
2
are quite close to the values obtained for the enediol 2a.
The rate-limiting step in both reactions is proton transfer to
the double bond. It has been demonstrated that the acid cata-
lysed enol ether hydrolysis13 is significantly slower when com-
pared to the analogous enol ketonisation14 reactions in acid.
This is thought to be due to stabilisation of the developing
positive charge through solvation of the hydroxyl group which
undergoes hydrogen bonding. Surprisingly, our results seem to
indicate that the presence of the second hydroxy group in the
enediol 2 is not important until relatively high pH values. This
contrasts with the results obtained for the acid catalysed
hydrolysis of the corresponding dimethyl acetal,15 (Mes) C᎐C-
Kinetics
Due to interference from free radical formation, solutions were
deoxygenated before use. Dissolved CO2 was removed from
water by boiling. Solvents and solutions were deoxygenated by
bubbling oxygen free nitrogen through them. Nitrogen was
passed through a chain of reagents, including Fiesers solution
to remove oxygen, saturated lead() tetraacetate to remove
sulfur dioxide, soda lime to remove CO2 and calcium chloride
and silica gel to remove moisture. A system with two reservoirs
in series was used—bubbling a gas through a solution may
cause changes in concentration due to loss of the volatile
solvent, thus the loss of solvent from the second reservoir was
compensated for by the gain from the first.
᎐
2
(OCH3)2, kHϩ = 2.215 × 10Ϫ4 dm3 molϪ1
s
Ϫ1, which shows a
marked decrease in reactivity on replacement of the second
hydroxy group by a methoxy group.
Kinetics were monitored spectrophotometrically using a
Cary 210 at appropriate wavelengths in the ultraviolet region, or
using a Hitech Stopped Flow. In all cases the rates were studied
under pseudo-first order conditions for a final substrate concen-
Experimental
pH was measured using a Radiometer pH meter 26 and a
Metrohm combined pH glass electrode. The pH control of
unbuffered solutions was achieved using an autoburette, Radi-
ometer ABU12 and a Radiometer Titrator 11 where necessary.
However, during our kinetic experiments the pH did not vary
significantly and the addition of acid/base was often minimal.
A thermostatted glass cell was fitted with quartz windows, the
longer path length (5 cm) permitting the use of more dilute
solutions. UV spectra were obtained from a Cary 210 equipped
with a thermostatted cell compartment. Temperature control
was achieved using a Techne TE8D Tempette water bath and
pump and a Techne RB12 Refrigerated Bath and are within
0.5 ЊC. Stopped-flow experiments were carried out using a
Hitech support unit SF-3L connected to a Hitech Timer-Delay
Unit TDU-43. A Thorn EMI power supply unit type PM28B
was used with the photomultiplier. Kinetic analysis was carried
out by direct link through an ADC to a BBC microcomputer.
HPLC analysis was performed by injection onto either a C18
bondapak column or a Waters Associates reverse phase Radial-
PAK cartridge, which was pressurised inside a Waters Radial
Compression Module. Mobile phase was pumped through the
system using a Waters 501 LC pump. Detection was achieved by
a Waters LC spectrophotometer model 455. Peak areas were
tration of ca. 10Ϫ4 mol dmϪ3
.
Pseudo-first order rate constants were calculated from data
covering several half lives and using experimental infinity
values. Plots of log (At Ϫ Ainfin) versus t, where At is the absorb-
ance of the solution at any time t, and Ainfin is the experimental
absorbance of the solution under kinetic conditions of t = infin,
gave straight lines of slope equal to kobs/2.303. In certain cases,
where the infinity value was not well defined, e.g. due to a
consecutive slower reaction, the Guggenheim or Swinbourne
methods of calculation were used. Rates were reproducible to
within 4% of the mean value.
The Hitech Stopped Flow was equipped with a premix
chamber, so that aged solutions of the enediol could be gener-
ated from the ketene. A third syringe was used to generate solu-
tions of the enediol in the required buffer solution. The rates
were determined at each concentration at least eight times and a
mean value calculated. The reproducibility under these condi-
tions was reasonable, ca. 8%.
For kinetic experiments involving the enol of the ester, the
ketene, (Mes) C᎐C᎐O, was incubated with HPLC grade meth-
᎐ ᎐
2
anol for 120 s, and the preformed enolester was studied in the
same manner as the enediols.
J. Chem. Soc., Perkin Trans. 2, 1997
2735

View Article Online
8 J. Frey and Z. Rappoport, J. Am. Chem. Soc., 1996, 118, 5169.
In all cases, the identity of the final product was confirmed
using HPLC analysis and UV spectrophotometry, by com-
parison with an authentic sample of the product.
9 T. L. Amyes and J. P. Richard, J. Am. Chem. Soc., 1996, 118, 3129.
10 (a) J. Andraos, A. J. Kresge, M. R. Peterson and I. G. Csizmadia,
J. Mol. Struct., 1991, 232, 155; (b) J. P. Guthrie, Can. J. Chem., 1993,
71, 2123; (c) J. P. Guthrie and Z. Liu, Can. J. Chem., 1995, 73, 1395.
11 T. T. Tidwell, Ketenes, Wiley, New York, 1995.
References
12 (a) A. D. Allen and T. T. Tidwell, J. Am. Chem. Soc., 1987, 109, 2774;
(b) A. D. Allen, A. J. Kresge, N. P. Schepp and T. T. Tidwell, Can. J.
Chem., 1987, 65, 1719.
1 Z. Rappoport, The Chemistry of Enols, John Wiley, 1990.
2 P. O’Neill and A. F. Hegarty, J. Chem. Soc., Chem. Commun., 1987,
744.
3 B. M. Allen, A. F. Hegarty, P. O’Neill and M. T. Nguyen, J. Chem.
Soc., Perkin Trans. 2, 1992, 927.
4 B. Urwyler and J. Wirz, Angew. Chem., Int. Ed. Engl., 1990, 29(7),
790.
5 Y. Chiang, A. J. Kresge, P. Pruszynki, N. P. Schepp and J. Wirz,
Angew. Chem., Int. Ed. Engl., 1990, 29, 792.
6 (a) J. Andraos, Y. Chiang, C. G. Huang, A. J. Kresge and J. C.
Scaiano, J. Am. Chem. Soc., 1993, 115, 10 605; (b) J. K. Almstead,
B. Urwyler and J. Wirz, J. Am. Chem. Soc., 1993, 116, 954;
(c) J. Andraos, A. J. Kresge and V. V. Popik, J. Am. Chem. Soc.,
1994, 116, 961.
13 (a) A. J. Kresge, H. L. Chen, Y. Chiang, E. Murill, M. A. Payne and
D. S. Sagatys, J. Am. Chem. Soc., 1971, 93, 413; (b) A. J. Kresge,
D. S. Sagatys and H. L. Chen, J. Am. Chem. Soc., 1977, 99, 7228.
14 (a) Y. Chiang, A. J. Kresge and J. Wirz, J. Am. Chem. Soc., 1984,
106, 6392; (b) Y. Chiang, M. Hojatti, J. R. Keefe, A. J. Kresge,
N. P. Schepp and J. Wirz, J. Am. Chem. Soc., 1987, 109, 4000;
(c) J. R. Keefe, A. J. Kresge and N. P. Schepp, J. Am. Chem. Soc.,
1988, 110, 1993.
15 F. Kelleher, PhD Thesis, National University of Ireland, 1992.
Paper 7/03653A
Received 27th May 1997
Accepted 29th July 1997
7 J. Andraos, Y. Chiang, A. J. Kresge, I. G. Pojarlieff, N. P. Schepp
and J. Wirz, J. Am. Chem. Soc., 1994, 116, 73.
2736
J. Chem. Soc., Perkin Trans. 2, 1997