Keto-enol/enolate equilibria in the N-acetylamino-p-methylacetophenone system. Effect of a β-nitrogen substituent

Article abstract of DOI:10.1021/ja0107529

The cis-enol of N-acetylamino-p-methylacetophenone was generated flash photolytically and its rates of ketonization in aqueous HClO₄ and NaOH solutions as well as in HCO₂H, CH₃CO₂H, H₂PO₄^-, (CH₂OH)₃CNH₃⁺, and NH₄⁺ buffers were measured. Rates of enolization of N-acetylamino-p-methylacetophenone to the cis-enol were also measured by hydrogen exchange of its methylene protons, and combination of the enolization and ketonization data gave the keto - enol equilibrium constant pK_E = 5.33, the acidity constant of the enol ionizing as an oxygen acid pQ_a^E = 9.12, and the acidity constant of the ketone ionizing as a carbon acid pQ_a^K = 14.45. Comparison of these results with corresponding values for p-methylacetophenone itself shows that the N-acetylamino substituent raises all three of these equilibrium constants: K_E by 3 orders of magnitude, Q_a^E by 1 order of magnitude, and Q_a^K by 4 orders of magnitude. This substituent also retards the rate of H⁺ catalyzed enol ketonization by 4 orders of magnitude. The origins of these substituent effects are discussed.

Full text of DOI:10.1021/ja0107529

J. Am. Chem. Soc. 2001, 123, 8979-8984
8979
Keto-Enol/Enolate Equilibria in the
N-Acetylamino-p-methylacetophenone System. Effect of a â-Nitrogen
Substituent
Y. Chiang,† A. G. Griesbeck,‡ H. Heckroth,‡ B. Hellrung,§ A. J. Kresge,*,† Q. Meng,†
A. C. O’Donoghue,| J. P. Richard,| and J. Wirz§
Contribution from the Department of Chemistry, UniVersity of Toronto, Toronto, Ontario M5S 3H6,
Canada, Institut fu¨r Organische Chemie der UniVersita¨t zu Ko¨ln, D-50939 Ko¨ln, Germany, Institut fu¨r
Physikalische Chemie der UniVersita¨t Basel, CH-4056 Basel, Switzerland, and Department of Chemistry,
UniVersity at Buffalo, SUNY, Buffalo, New York 14260-3000
ReceiVed March 21, 2001
Abstract: The cis-enol of N-acetylamino-p-methylacetophenone was generated flash photolytically and its
-
rates of ketonization in aqueous HClO4 and NaOH solutions as well as in HCO2H, CH3CO2H, H2PO4
,
(CH2OH)3CNH3+, and NH4 buffers were measured. Rates of enolization of N-acetylamino-p-methylaceto-
phenone to the cis-enol were also measured by hydrogen exchange of its methylene protons, and combination
of the enolization and ketonization data gave the keto-enol equilibrium constant pKE ) 5.33, the acidity
constant of the enol ionizing as an oxygen acid pQEa ) 9.12, and the acidity constant of the ketone ionizing
as a carbon acid pQKa ) 14.45. Comparison of these results with corresponding values for p-methylaceto-
phenone itself shows that the N-acetylamino substituent raises all three of these equilibrium constants: KE by
3 orders of magnitude, QEa by 1 order of magnitude, and QKa by 4 orders of magnitude. This substituent also
retards the rate of H+ catalyzed enol ketonization by 4 orders of magnitude. The origins of these substituent
effects are discussed.
+
There has recently been a remarkable revival of interest in
the chemistry of enol isomers of simple aldehydes and ketones,
fueled largely by the development of methods for generating
these unstable substances in solution in greater than equilibrium
amount under conditions where they can be observed directly
and rate and equilibrium constants of their reactions can be
measured accurately. As a result, much new information is now
available on the chemistry of the enol isomers of simple
aldehydes and ketones where enol is the only functional group
present in the molecule.1 Considerably less is known about the
effect of heteroatom substituents on this chemistry, and we have
consequently undertaken a program of research designed to
supply some of the missing information. In this paper we report
the results of our study of the N-acetylamino-p-methylaceto-
phenone keto-enol (1-2) system, eq 1 (Tol ) p-CH3C6H4).
Keto-enol equilibria of carbonyl compounds with a single
substituent in the â-position are complicated by the fact that
the enol can usually exist in cis and trans isomeric forms. In
such situations there are really two keto-enol equilibria, one
producing the cis enol and another producing the trans enol.
This complication can be handled,2 but the method is laborious,
and it is easier to study a system where formation of one enol
is prevented by some structural constraint. Such a structural
constraint operates in the reaction that we used to produce the
present enol.
We generated the present enol by flash photolytic Norrish
type II photoelimination of suitably constructed p-methylac-
etophenone derivatives, 3. Irradiation of ketones such as this
gives an excited state in which the carbonyl oxygen atom
becomes a good hydrogen atom acceptor. Hydrogen transfer
from a carbon-hydrogen bond in the γ-position then takes place
producing a 1,4-diradical, 4, which can either cyclize to a
cyclobutanol derivative, 5, or fragment to an enol, 6, plus an
olefin, 7, eq 2. These transformations have recently been found
to be quite regioselective.3 For example, irradiation of the
derivative related to isoleucine, 3 with R1 ) R3 ) Me and R2
) R4 ) H, gives only fragmentation, whereas irradiation of
that related to norleucine, 3 with R1 ) Et and R2 ) R3 ) R4 )
H, gives equal amounts of fragmentation and cyclization; the
cyclized product, moreover, is produced as a single diastereo-
meric form. We performed flash photolysis on both the
isoleucine and norleucine derivatives and in each case observed
In addition to its bearing on enol chemistry, this system is of
biological interest in that its carbonyl-â-acylamino structure is
not unlike the amide linkage in peptides and proteins, whose
racemization very probably involves enol formation.
* To whom correspondence should be directed: (phone) (416) 978-7259,
(fax) (416) 978-7259, (e-mail) akresge@chem.utoronto.ca.
† University of Toronto.
‡ Institut fu¨r Organische Chemie der Universita¨t zu Ko¨ln.
§ Institut fu¨r Physikalische Chemie der Universita¨t Basel.
| University at Buffalo.
(2) Chiang, Y.; Kresge, A. J.; Walsh, P. A.; Yin, Y. J. Chem. Soc., Chem.
Commun. 1989, 869-871.
(3) Griesbeck, A. G.; Heckroth, H.; Lex, J. Chem. Commun. 1999, 1109-
1110. Griesbeck, A. G.; Heckroth, H. Res. Chem. Intermed. 1999, 25, 599-
608.
(1) See, for example: The Chemistry of Enols; Rappoport, Z., Ed.;
Wiley: New York, 1990.
10.1021/ja0107529 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

8980 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Chiang et al.
however, were too slow to be measured in this way, and in this case
the enols were generated by a single flash in the flash photolysis
apparatus, and the reacting solutions were then quickly transferred to
the cell compartment of a Cary 2200 spectrometer. Reactions were
monitored by following the decay of enol absorbance at λ ) 275-300
nm. Substrate concentrations were ca. 5 × 10-4 M, and the temperature
of the reacting solutions was controlled at 25.0 ( 0.05 °C. The data
obtained conformed to the first-order rate law, and observed first-order
rate constants were obtained by least-squares fitting of an exponential
function.
Enolization Rate Measurements. Rates of enolization of N-
acetylamino-p-methylacetophenone were measured by hydrogen ex-
1
change in D2O solution using H NMR to monitor conversion of the
methylene group CH2 singlet at δ 4.740 ppm into a CHD triplet at δ
4.714 ppm. A Varian Unity Inova 500 spectrometer was used; the
resolution of this instrument was sufficient to give baseline separation
of the CH2 and CHD signals.
a transient species with the strong styrene-type of UV absor-
bance expected of enol 6. The amount of transient formed from
the isoleucine derivative, moreover, was considerably greater
than that from the norleucine derivative, in keeping with the
regiochemical results.
The regioselectivity of this photoreaction can be understood
in terms of the size of the R-group substituents of the substrate
and the additional requirement that the diradical intermediate
be stabilized by formation of an intramolecular hydrogen bond
between its hydroxyl group and the acetyl carbonyl group, 8.
Reactions were initiated by making an 80-fold dilution of a solution
2-
of substrate in CD3CN into 5-7 mL of DCO3-/CO3 buffer at pD
10-11, to give a final substrate concentration of 0.0035-0.005 M. At
timed intervals, 1.0 mL aliquots were removed and exchange was
quenched by adjusting these aliquots to pD 2-3 with DCl (35%/D2O).
The resulting solutions were then immediately extracted with ca. 1 mL
of CDCl3, the aqueous layers were removed by Pasteur pipet, and 0.75
mL portions of the CDCl3 solutions were injected into NMR tubes.
These were stored in a desiccator at 4 °C until NMR analyses were
performed; all analyses were completed within 2-3 days of storage.
Chemical shifts were referenced to CHCl3 at δ 7.27 ppm, and spectra
(65-128 transients, 70 s relaxation delay) were obtained using a sweep
width of 6000 Hz, a 90° pulse angle, and an acquisition time of 6 s.
Integrated areas of the CH2 signals were referenced to the area of
the multiplet at δ 7.882 ppm due to two aromatic protons of
N-acetylamino-p-methylacetophenone. Disappearance of the CH2 signal
conformed to the first-order rate law well, and observed first-order rate
constants were obtained by least-squares fitting of an exponential
function.
This hydrogen bond constrains the hydroxyl and N-acetylamino
groups to lie on the same side of the bond that becomes the
enol double bond in the fragmentation process, and only the
cis enol is consequently formed.
Results
To have an unsubstituted system with which to compare the
chemistry of the N-acetylamino-p-methylacetophenone keto-
enol pair, we also examined the p-methylacetophenone keto
(9)-enol (10) system itself, eq 3. We generated this enol also
Ketonization Rates. Rates of ketonization of the enols of
N-acetylamino-p-methylacetophenone and p-methylaceto-
phenone were measured in dilute aqueous perchloric acid and
sodium hydroxide solutions, and also in aqueous HCO2H, CH3-
CO2H, H2PO4-, (CH2OH)3CNH3+, and NH4+ buffers. The data
so obtained are summarized in Tables S1-S6.6
The measurements in buffers were made in series of solutions
of constant buffer ratio and constant ionic strength (0.10 M),
and therefore constant [H+], but varying buffer concentration.
Observed first-order rate constants increased with increasing
buffer concentration and conformed to the buffer dilution
expression shown in eq 5; the data were therefore analyzed by
by flash photolytic Norrish type II photoelimination, using
p-methylisocaprophenone, 11, as the substrate, eq 4.
kobs ) ko + kcat[buffer]
(5)
linear least-squares fitting of this expression.7 The zero-buffer-
concentration intercepts, ko, so obtained were then combined
with the rate constants measured in HClO4 and NaOH solutions
to construct the rate profiles shown in Figure 1. Values of [H+]
needed for this purpose were obtained by calculation using
thermodynamic acidity constants of the buffer acids from the
literature and activity coefficients recommended by Bates.8
Experimental Section
Materials. The isoleucine and norleucine derivatives (3, R1 ) R3
) Me, R2 ) R4 ) H and 3, R1 ) Et, R2 ) R3 ) R4 ) H, respectively)
were samples that had been prepared before.3 p-Methylisocaprophenone
(11) was made by Friedel-Crafts acylation of toluene with isocaproyl
chloride.4 All other materials were best available commercial grades.
Ketonization Rate Measurements. Rates of ketonization of the
enols of N-acetylamino-p-methylacetophenone and p-methylacetophe-
none were measured for the most part using conventional (microsecond)
flash photolysis systems that have already been described.5 Some rates,
(6) Supporting Information; see paragraph at the end of this paper
regarding availability.
(7) Buffer catalysis became progressively weaker with decreasing buffer
+
acid strength, until observed rate constants measured in the most basic NH4
(4) Rae, I. D.; Woolcock, M. L. Aust. J. Chem. 1987, 40, 1023-1029.
(5) Chiang, Y.; Kresge, A J.; Wirz, J. J. Am. Chem. Soc. 1984, 106,
6392-6395. Chiang, Y.; Hojatti, M.; Keeffe, J. R.; Kresge, A J.; Schepp,
N. P.; Wirz, J. J. Am Chem. Soc. 1987, 109, 4000-4009.
buffer used for the ketonization of N-acetylamino-p-methylacetophenone
enol ([H+] ) 1.4 × 1010 M) no longer changed significantly with buffer
concentration. A simple average of observed rate constants measured in
this series of solutions was therefore used for rate profile construction.

The N-Acetylamino-p-methylacetophenone System
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8981
Table 1. General Acid Catalytic Coefficients for the Ketonization
of N-Acetylamino-p-methylacetophenone and p-Methylacetophenone
Enolate Ionsa
kHA/M-1 s-1
catalyst
H3O+
HCO2H
TolC(OH)dCHNHAc
TolC(OH)dCH2
3.74 × 109
2.31 × 107
1.29 × 107
3.13 × 106
3.94 × 105
1.65 × 102
2.09 × 107
7.14 × 105
1.98 × 105
2.94 × 104
5.66 × 103
CH3CO2H
-
H2PO4
+
(CH2OH)3CNH3
+
NH4
H2O
5.46 × 10-1
a Aqueous solution; 25 °C; ionic strength ) 0.10 M.
squares fitting of this expression produced the following
Figure 1. Rate profiles for the ketonization of the enols of N-
acetylamino-p-methylacetophenone (4) and p-methylacetophenone (O)
in aqueous solution at 25 °C.
These rate profiles are characteristic of enol ketonization
reactions. They may be understood in terms of the accepted
mechanism for this process, which consists of rate-determining
protonation of the enol on its â-carbon atom by all available
acids.9 Since these profiles refer to reactions through solvent-
related species only, the available acids will be the hydronium
ion, written here as H+, and the solvent water itself.
The acid-catalyzed portions at the high-acidity ends of these
profiles then represent â-carbon protonation of the un-ionized
enols by H+. These portions are followed by “uncatalyzed”
regions, which could be due either to carbon protonation of un-
ionized enol by H2O, or to ionization of the enol to the very
much more reactive enolate anion10 followed by carbon proto-
nation of that by H+; this latter route produces H+ in a rapid
equilibrium step and then uses it up in the rate-determining step,
which gives an overall process independent of H+ concentration.
The first of these two alternative routes would give rate constants
for carbon protonation of un-ionized enol by H2O that are not
very much less than those for the same protonation by H+
+
results: for N-acetylamino-p-methylacetophenone enol, kH
)
(2.07 ( 0.08) × 10-1 M-1 s-1, k′H ) (2.09 ( 0.18) × 107
M-1 s-1, k′o ) (3.03 ( 0.11) × 101 s-1, QEa ) (7.59 ( 0.57) ×
10-10 M, and pQaE ) 9.12 ( 0.03,11 and for p-methylac-
+
etophenone enol, kH ) (2.15 ( 0.05) × 103 M-1 s-1, k′H
)
,
+
+
(3.74 ( 0.57) × 109 M-1 s-1, k′o ) (9.10 ( 0.38) × 103 s-1
QEa ) (4.70 ( 0.37) × 10-11, and pQEa ) 10.32 ( 0.03.11
The buffer catalytic coefficients, kcat, obtained by analyzing
the buffer data according to eq 5 were separated into their
general acid, kHA, and general base, kB, components with the
aid of eq 8, in which fA is the fraction of the buffer present in
the acidic form. Only general base catalysis was found,
kcat ) kB + (kHA - kB)fA
(8)
indicating that all of the reactions were proceeding through base-
assisted ionization of the enol followed by rate-determining
carbon protonation of the enolate ion by the conjugate acid of
the general base, eq 9. The rate law for this process, shown in
eq 10, can be rearranged to give an expression for the general
(kH ) 2.1 × 10-1 M s-1 and kH O ) 1.6 × 10-2 s-1 for
+
2
+
N-acetylamino-p-methylacetophenone enol, and kH ) 2.2 ×
103 M-1 s-1 and kH O ) 1.8 × 10-1 s-1 for p-methylaceto-
2
phenone enol), which seems unlikely for acids of such widely
different strength, and the second of these two routes is
consequently to be preferred.
At sufficiently low acidities, H+ concentrations are too small
to sustain protonation of the enolate ions on carbon by H+, and
reaction through protonation by water takes over. A proton is
now still produced in a rapid equilibrium step, but it is no longer
used up in the rate-determining step; the result is a process
whose rate is inversely proportional to [H+], giving an apparent
hydroxide ion catalysis. At even lower acidities, the enol-
enolate ion equilibrium shifts over to the side of enolate, and
the advantage of converting a less reactive (enol) to a more
reactive (enolate) species is lost; this produces the final
“uncatalyzed” low-acidity portions of the rate profiles.
The reaction scheme representing these mechanisms is shown
in eq 6, and the rate law that applies is given in eq 7. Least-
acid catalytic coefficient of the enolate ion reaction, k′HA in terms
of the known quantities, QEa , QaHA, and kB; the results so
obtained are listed in Table 1.
General acid catalytic coefficients for rate-determining proton-
transfer reactions such as enolate ketonizations are expected to
parallel the acid strength of the catalysts. The Bronsted relations
of Figure 2 show that this is so for both of the present systems,
despite the fact that these correlations are based upon a rather
mixed bag of catalysts of different charge types and also include
the solvent-related species H+ and H2O. The Bronsted exponents
obtained by least-squares analysis of all of the data moreover,
(8) Bates, R. G. Determination of pH Theory and Practice; Wiley: New
York, 1973; p 49.
(9) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley: New York, 1990; Chapter 7.
(10) Pruszynski, P.; Chiang, Y.; Kresge, A J.; Schepp, N. P.; Walsh, P.
A. J. Phys. Chem. 1986, 90, 3760-3766. Chiang, Y.; Kresge, A. J.;
Santabella, J. A.; Wirz, J. J. Am. Chem. Soc. 1988, 110, 5506-5510.
(11) This is a concentration quotient applicable at the ionic strength of
its determination, 0.10 M.

8982 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Chiang et al.
Figure 2. Bronsted plots for the ketonization of the enols of
N-acetylamino-p-methylacetophenone (4) and p-methylacetophenone
(O) in aqueous solution at 25 °C.
Figure 3. Data for the hydrogen exchange (enolization) of N-
2-
acetylamino-p-methylacetophenone in aqueous (D2O) DCO3-/CO3
buffer solutions at 25 °C plotted according to eq 12: (4) [DCO3-]/
[CO32-] ) 9 and (O) [DCO3-]/[CO32-] ) 1.
R ) 0.44 ( 0.04 for the enolate ion of N-acetylamino-p-
methylacetophenone and R ) 0.42 ( 0.04 for the enolate ion
of p-methylacetophenone, are small, in keeping with the rapid
nature of these reactions.
Enolization Rates. Rates of enolization of N-acetylamino-
p-methylacetophenone, monitored by following loss of its CH2
nent,14 which, for the enolization of carbonyl compounds,
-
-
generally amounts to about 40%. For example, kDO /kHO
)
)
1.37 for the enolization of acetaldeheyde,15 and kDO /kHO
-
-
1.46 for the enolization of acetone and 1.39 for the enolization
of mandelate ion.16 Use of the rounded average value 1.4 then
gives kHO ) (6.85 ( 0.81) × M-1 s-1 for the enolization of
N-acetylamino-p-methylacetophenone in H2O solution.
-
group 1NMR signal in D2O solution, were measured in DCO3
/
2-
CO3 buffers, using a series of solutions of constant buffer
ratio and constant ionic strength, and therefore constant [D+],
but varying buffer concentration. Two different buffer ratios,
[DCO3-]/[CO32-] ) 9 and [DCO3-]/[CO32-] ) 1, were used.
The data so obtained are summarized in Table S7.6
Equilibrium Constants. An enol-forming reaction such as
that used here to measure rates of enolization of N-acetylamino-
p-methylacetophenone can in principle produce both cis and
trans enols. It is likely, however, that in the present case there
was a considerable bias favoring cis-enol formation. This follows
from consideration of the substrate conformations shown in the
Newman projection formulas 12 and 13, which lead to the cis
and trans enols, respectively. Structure 13 will be disfavored
because it places the large tolyl and N-acetylamino groups
together, whereas structure 12 juxtaposes each of these large
groups with the smaller hydrogen and carbonyl-oxygen sub-
stituents. Structure 12 will also be favored by an electrostatic
Enolization of ketones is a rate-determining hydron transfer
process and is therefore subject to general base catalysis. The
rate law that applies in the presently used basic buffers
consequently contains a term representing reaction through the
carbonate anion in addition to that for hydroxide ion, eq 11.
Division of this expression by [DO-] then gives a relationship,
2-
kobs ) kDO-[DO-] + k [CO
]
(11)
B
3
eq 12, that requires kobs/[DO-] to be a linear function of the
kobs/[DO-] ) kDO- + k [CO 2-]/[DO-]
(12)
B
3
concentration ratio [CO32-]/[DO-], with kDO as the zero
intercept. Figure 3 shows that the present data conform to this
relationship well, and least-squares analysis gives the result
-
interaction between the partial positive charge on the N-
acetylamino nitrogen atom and the negative charge being
generated on the erstwhile carbonyl oxygen atom in the
transition state of this base-catalyzed enolate ion forming
enolization reaction. It seems quite likely, therefore, that this
enolization reaction produced mostly cis-enol, and that combi-
nation of the rate constant for this process with rates of
ketonization measured flash photolytically, which also refer to
the cis-enol, will provide an equilibrium constant for the keto-
cis-enol reaction shown in eq 1.
kDO ) (9.59 ( 0.90) M-1 s-1. Values of [DO-] needed for
-
this purpose were obtained by calculation using literature values
- 12
of thermodynamic acidity constants for DCO3
and D2O13
plus activity coefficients recommended by Bates.8
This hydroxide ion catalytic coefficient for the enolization
of N-acetylamino-p-methylacetophenone can be combined with
ketonization rate measurements to estimate the keto-enol
equilibrium constant for this system (vide infra), but it must
first be converted from D2O to a value for the H2O medium in
which the ketonization rate measurements were made. Solvent
isotope effects on hydroxide ion catalyzed reactions have no
primary component, but there is an inverse secondary compo-
This keto-enol equilibrium may be formulated as shown in
eq 13, and evaluation of the expression for its equilibrium
constant, KE ) (kHO/k′o)(Qw/QE), gives KE ) (4.72 ( 0.68) ×
a
(14) Gold, V.; Grist, S. J. Chem. Soc., Perkin Trans. 2 1972, 89-95.
Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F. In Isotopes in Organic
Chemistry; Buncel, E., Lee, C. C., Eds.; Elsevier: New York 1987; Vol. 7,
Chapter 4.
(15) Keeffe, J. R.; Kresge, A J. Can. J. Chem. 1988, 66, 2440-2442.
(16) Pocker, Y. Chem. Ind. (London) 1958, 1117-1118.
(12) Paabo, M.; Bates, R. G. J. Phys. Chem. 1969, 73, 3014-3017.
(13) Covington, A. K.; Robinson, R. A.; Bates, R. G. J. Phys. Chem.
1966, 70, 3820-3824. Gold, V.; Lowe, B. M. J. Chem. Soc. A 1967, 936-
943.

The N-Acetylamino-p-methylacetophenone System
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8983
Table 2. Summary of Rate and Equilibrium Constantsa
constant, KE, by 3 orders of magnitude, giving a substituent
effect of δR∆G° ) 4.1 kcal mol-1. This sizable effect can be
attributed to destabilization of the keto isomer plus stabilization
of the enol isomer. The keto isomer is destabilized by the
unfavorable interaction of the partial positive charge on its
carbonyl carbon atom with the partial positive charge on the
amide nitrogen atom of its N-acetylamino group, as shown by
the ionic resonance forms given in eq 14. The enol, on the other
hand, is stabilized by the favorable interaction of this positively
charged amide nitrogen with the partial negative charge on the
enol â-carbon; this is also illustrated by eq 14. Both of these
effects operate to decrease the energy difference between keto
and enol forms, and they thus serve to increase KE.
The N-acetylamino group also raises the acidity constant of
the enol, QEa , but by a much smaller amountsonly 1 order of
magnitudesthan its influence on KE; the substituent effect here
amounts to just δR∆G° ) 1.6 kcal mol-1. This effect is so much
smaller than that on KE because the enol rather than the keto
isomer is the initial state for this acid ionization process, and
destabilization of the keto form, which contributed to the
substituent effect on KE, is no longer a factor. Only stabilization
of the partial negative charge on the system’s â-carbon operates
here, and since this charge is greater in the enolate ion than in
the enol, the stabilization of enolate is greater than that of enol
and the result is an increase in QEa .
a Aqueous solution; 25 °C; ionic strength ) 0.10 M.
10-6 and pKE ) 5.33 ( 0.06. The first part of the relationship
of eq 13 includes the ionization of N-acetylamino-p-methyl-
The substituent effect of N-acetylamino on the acidity constant
of the keto isomer ionizing as a carbon acid, QKa , is greatest of
all: it amounts to 4 orders of magnitude, which makes for
δR∆G° ) 5.8 kcal mol-1. This, of course, is because the keto
form is the initial state of this process, and both keto-form
destabilization and enolate ion stabilization contribute to this
substituent effect.
Carbon-acid acidity constants for the ionization of the
â-carbon-hydrogen bonds of methyl ammonioacetate, 14, and
methyl trimethylammonioacetate, 15, have recently been de-
termined,19 and comparison of the results with the acidity
constant of ethyl acetate, 16,20 gives substituent effects of δR∆G°
acetophenone as a carbon acid, and the equilibrium constant
for this ionization may be evaluated as QKa ) (kHO/k′o)Qw
(3.59 ( 0.36) × 10-15 M and pQKa ) 14.45 ( 0.04.11
)
The keto-enol equilibrium constant for the other system
examined here, that of p-methylacetophenone, has been deter-
mined before.17 Its value, pKE ) 8.34, when combined with
pQEa ) 10.33 obtained here from the rate profile for ketoniza-
tion of the enol of this ketone, gives pQKa ) 18.67 as the
acidity constant of p-methylacetophenone ionizing as a carbon
acid. The p-methyl group of this system is unlikely to exert
much influence on these equilibrium constants, and it is
significant therefore that the present results are quite similar to
corresponding values for acetophenone itself, pKE ) 7.96, pQE
a
) 10.40, and pQKa ) 18.36.18
Discussion
) 6.3 kcal mol-1 for NH3+ and δR∆G° ) 10.4 kcal mol-1 for
NMe3+. These effects are in the same direction and of roughly
similar magnitude as that found here for the NHAc group, and
they may be attributed to the same causes. They are, however,
somewhat greater than the presently determined effects, which
is consistent with the fact that these substituents bear full positive
Equilibria. The present results, summarized in Table 2, show
that introduction of an N-acetylamino group into the â-position
of p-methylacetophenone raises the keto-enol equilibrium
(17) Hochstrasser, R.; Kresge, A. J.; Schepp, N. P.; Wirz, J. J. Am. Chem.
Soc. 1988, 110, 7875-7876.
(18) Jefferson, E. A.; Keeffe, J. R.; Kresge, A. J. J. Chem. Soc., Perkin
Trans. 2 1995, 2041-2046. Keeffe, J. R.; Kresge, A. J.; Toullec, J. Can J.
Chem. 1986, 64, 1224-1227. Chiang, Y.; Kresge, A. J.; Wirz, J. J. Am.
Chem. Soc. 1984, 106, 6392-6395.
(19) Rios, A.; Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 2000,
122, 9373-9385.
(20) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1996, 118, 3129-
3141.

8984 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Chiang et al.
charges whereas the amide nitrogen atom of the N-acetylamino
group possesses only a partial positive charge.
) 5.5 kcal mol-1, inasmuch as the positive charge has been
removed from the substrate in the final state of the overall
process and the additional transition state interaction is no longer
a factor. Further reinforcement of this explanation comes from
ketonization of the enolate ion effected by H+, eq 16, where
Kinetics. The considerable vertical displacement from one
another of the rate profiles given in Figure 1 shows that the
N-acetylamino group also has a strong influence on rates of
ketonization. Ketonization of un-ionized enol catalyzed by H+,
for example, is slowed by 4 orders of magnitude, giving the
substituent effect δR∆Gq ) 5.5 kcal mol-1. This retardation must
be due in part to stabilization of the enol initial state by the
N-acetaylamino group, but another contributing factor is pro-
vided by the two-step nature of the acid-catalyzed ketonization
of un-ionized enols, which involves a positively charged
carbonyl-oxygen-protonated intermediate, eq 15.9 The unfavor-
the substituent effect on the rate, δR∆Gq ) 3.1 kcal mol-1, is
less than that on the overall reaction, δR∆G° ) 5.8 kcal mol-1
.
This process is a one-step reaction with no intermediate9 and,
since the starting material is negatively charged, there is no
generation of positive charge on the substrate.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada, The Deutsche
Forschungsgemeinschaft, the Swiss National Science Founda-
tion, and the United States National Institutes of Health for
financial support of this work.
able interaction between this positive charge and the partially
positively charged N-acetylamino nitrogen then raises the energy
of the protonation transition state, and that lowers the rate of
reaction. This explanation is supported by the fact that the
substituent effect on the overall conversion of enol to keto forms,
δR∆G° ) 4.1 kcal mol-1, is less than that on the rate, δR∆Gq
Supporting Information Available: Tables S1-S7 of rate
data (14 pages, print/PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0107529