Generation of the enol of methyl mandelate by flash photolysis of methyl phenyldiazoacetate in aqueous solution and study of rates of ketonization of this enol in that medium

Article abstract of DOI:10.1021/jo991707a

Flash photolysis of methyl phenyldiazoacetate in aqueous solution produced phenylcarbomethoxycarbene, whose hydration generated a short-lived transient species that was identified as the enol isomer of methyl mandelate. This assignment is supported by the shape of the rate profile for decay of the enol transient, through ketonization to its carbonyl isomer, as well as by solvent isotope effects and the form of acid-base catalysis of the ketonization reaction. Comparison of the present results with previously published information on the enol of mandelic acid shows some interesting and readily understandable similarities and differences.

Full text of DOI:10.1021/jo991707a

J . Org. Chem. 2000, 65, 1175-1180
1175
Gen er a tion of th e En ol of Meth yl Ma n d ela te by F la sh P h otolysis of
Meth yl P h en yld ia zoa ceta te in Aqu eou s Solu tion a n d Stu d y of
Ra tes of Keton iza tion of Th is En ol in Th a t Med iu m
Y. Chiang, A. J . Kresge,* N. P. Schepp, and R.-Q. Xie
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
Received November 1, 1999
Flash photolysis of methyl phenyldiazoacetate in aqueous solution produced phenylcarbomethoxy-
carbene, whose hydration generated a short-lived transient species that was identified as the enol
isomer of methyl mandelate. This assignment is supported by the shape of the rate profile for
decay of the enol transient, through ketonization to its carbonyl isomer, as well as by solvent isotope
effects and the form of acid-base catalysis of the ketonization reaction. Comparison of the present
results with previously published information on the enol of mandelic acid shows some interesting
and readily understandable similarities and differences.
Enols and enolate ions derived from carboxylic acid
esters are essential intermediates in many chemical and
biological reactions, and yet little direct information on
their chemistry in aqueous solution is available. This is
undoubtedly because the concentration of enol at equi-
librium with its keto isomer is very low: interaction of
the carbonyl group of esters with the adjacent ether
oxygen atom stabilizes the keto form markedly, and that
increases the free energy difference between keto and
enol isomers by a substantial amount over what it is in
the case of simple aldehydes and ketones,1 where enol
contents are already quite low.2 For example, the keto-
enol equilibrium constant for ethyl acetate, though not
yet determined directly, has been reliably estimated as
pKE ) 19;3 this makes that equilibrium constant more
than 10 orders of magnitude smaller than the constant
for acetaldehyde or acetone, for which pKE ) 6.234 and
8.33,5 respectively.
enols has also been performed using fast reaction tech-
niques, notably flash photolysis,12 and we have employed
such a method here.
We have found that flash photolytic dediazotization of
methyl phenyldiazoacetate, 1, in aqueous solution pro-
duces methyl mandelate, 4, through the well-known O-H
insertion reaction13 of the R-carbonylcarbene, 2, so gener-
ated, eq 1. This transformation is accompanied by the
Enols can be stabilized by bulky substituents that block
access to their â-carbon atoms, through whose protona-
tion conversion of the enol to its keto tautomer must
occur.6 This technique has produced a number of remark-
ably stable enols of simple aldehydes and ketones,7 and
it has also been applied to enols of carboxylic acids,8,9
esters,8a,c,10 and amides.11 Examination of less-stable
formation and decay of a short-lived transient intermedi-
ate which we have identified as the enol, 3, of methyl
mandelate.14
Exp er im en ta l Section
Ma ter ia ls. Methyl phenyldiazoacatate was prepared by
lead tetraacetate oxidation of the hydrazone of methyl ben-
zoylformate.15 Methyl O-acetylmandelate was prepared by
acetylating methyl mandelate using acetyl chloride; its 1H and
13C NMR spectra were consistent with literature values.16 All
other materials were the best available commercial grades.
Kin etics. Rates of reaction were measured using conven-
tional (flash lamp)4 and laser (λ ) 248 nm)17 flash photolysis
* To whom correspondence should be addressed.
(1) Hegarty, A. F.; O’Neill, P. In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley: New York, 1990; Chapter 10.
(2) Toullec, J . In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley:
New York, 1990; Chapter 6.
(3) Amyes, T. L.; Richard, J . P. J . Am. Chem. Soc. 1996, 118, 3129-
3141.
(4) Chiang, Y.; Hojatti, M.; Keeffe, J . R.; Kresge, A. J .; Schepp, N.
P.; Wirz, J . J . Am. Chem. Soc. 1987, 109, 4000-4009.
(5) Chiang, Y.; Kresge, A. J .; Schepp, N. P. J . Am. Chem. Soc. 1989,
111, 3977-3980.
(6) Keeffe, J . R.; Kresge, A. J . In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley: New York, 1990; Chapter 7.
(11) Frey, J .; Rappoport, Z. J . Am. Chem. Soc. 1996, 118, 3994-
3995. Rappoport, Z.; Frey, J .; Sigalov, M.; Rochlin, E. Pure Appl. Chem.
1997, 69, 1933-1940.
(7) Hart, H.; Rappoport, Z.; Biali, S. E. In The Chemistry of Enols;
Rappoport, Z., Ed.; Wiley: New York, 1990; Chapter 8.
(8) (a) Hegarty, A. F.; O’Neill, P. J . Chem. Soc., Chem. Commun.
1987, 744-745. (b) Allen, B. M.; Hegarty, A. F.; O’Neill, P.; Nguyen,
M. T. J . Chem. Soc., Perkin Trans. 2 1992, 927-934. (c) Allen, B. M.;
Hegarty, A. F.; O’Neill, P. J . Chem. Soc., Perkin Trans. 2 1997, 2733-
2736.
(12) Kresge, A. J . Chem. Soc. Rev. 1996, 25, 275-280.
(13) Kirmse, W. Carbene Chemistry, 2nd ed.; Academic Press: New
York, 1971; pp 423-430. In Advances in Carbene Chemistry, Brinker,
U. H., Ed.; J AI Press: Greenwich, CT, 1994; pp 1-51.
(14) Part of this work was published in preliminary form: Chiang,
Y.; Kresge, A. J .; Pruszynski, P.; Schepp, N. P.; Wirz, J . Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1366-1368.
(15) Ciganek, E. J . Org. Chem. 1970, 35, 862-863.
(16) Basavaiah, D.; Krishna, P. D. Tetrahedron 1995, 51, 2403-
2416.
(9) Frey, J .; Rappoport, Z. J . Am. Chem. Soc. 1996, 118, 5169-5181;
5182-5191.
(10) O’Neill, P.; Hegarty, A. F. J . Org. Chem. 1987, 52, 2113-2114.
10.1021/jo991707a CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/14/2000

1176 J . Org. Chem., Vol. 65, No. 4, 2000
Chiang et al.
systems that have already been described. The temperature
of all solutions upon which rate measurements were made was
controlled at 25.0 ( 0.05 °C. Two successive reactions were
observed. When the rates of these were sufficiently different,
each reaction was monitored in separate experiments, and the
data were analyzed by least-squares fitting of single-exponen-
tial functions. When the rates were too similar to allow such
separation, both reactions were monitored in the same experi-
ment, and the data were analyzed by least-squares fitting of
double exponential functions.
P r od u ct An a lysis. Wholly aqueous solutions of methyl
phenyldiazoacetate were photolyzed with 254 or 313 nm light
from a low pressure mercury lamp for about 10 min until no
absorption due to the diazo compound remained. Some of these
solutions were then subjected directly to GC analysis; others
were extracted with CHCl3, and the extracts were subjected
to GC-MS analysis; and still others were extracted with diethyl
ether, the ether was removed, and the residues were subjected
Further support for the assignment of the rise and
decay of the λ ) 280/310 nm transient absorbance to the
formation and ketonization of the enol of methyl man-
delate is provided by solvent isotope effects and the form
of acid-base catalysis in buffer solutions (vide infra).
The enol of methyl mandelate can exist in two stere-
oisomeric forms, as (Z)-2-hydroxy-1-methoxy-2-phenyle-
thenol, 9, or (E)-2-hydroxy-1-methoxy-2-phenylethenol,
10. The two isomers might be expected to ketonize at
1
to H NMR analysis.
Resu lts
P r od u ct An a lysis. GC analysis of reaction mixtures
after complete photodecomposition of methyl phenyldia-
zoacetate in aqueous solution showed that only one
product was formed throughout the acidity range used
in the present work ([H+] ) 0.1 to 10-12 M), and
comparison of MS and 1H NMR spectra of this single
product with those of an authentic sample identified this
substance as methyl mandelate.
different rates, and the fact that the ketonization rate
data collected here confirmed well to a simple first-order
rate law suggests that only one isomer was formed in
the carbene hydration reaction. We have no information,
however, that allows us to decide which isomer that is.
Kin etics: Ca r ben e Hyd r a tion . Rates of hydration
of phenylcarbomethoxycarbene were measured in aque-
ous sodium hydroxide solutions and in aqueous acetic
acid, biphosphate ion, and ammonium ion buffers. For
each kind of solution, a range of concentrations was
employed and replicate measurements were made at each
concentration; the ionic strength was maintained con-
stant at 0.10 M. These data are summarized in Tables
S1 and S2.21
The measurements in buffers were done in series of
solutions of constant buffer ratio and constant ionic
strength but varying buffer concentration. As Figure 1
illustrates, observed rate constants within a given series
increase linearly with buffer concentration, and the data
were therefore analyzed by least-squares fitting of the
buffer dilution expression shown in eq 3. The zero-buffer-
Tr a n sien t Id en tifica tion . Flash photolysis of methyl
phenyldiazoacetate in weakly basic aqueous solution
([NaOH] ) 10-4 M) produced a transient absorbance with
λmax = 275 nm immediately after the laser pulse; this
transient then decayed over a period of ca. 1 µs while
another transient absorbance, with λmax = 310 nm, grew
in and then also decayed. The rate of decay at λ ) 275
nm was the same as the rate of rise at λ ) 310 nm,
indicating that the 310 nm species is formed from the
275 nm species. The absorbance at λ ) 275 nm did not
change its wavelength with changes in the acidity of the
medium, but the absorbance at λ ) 310 shifted to λ =
280 in acidic solutions.
This is the behavior expected for photolysis of methyl
phenyldiazoacetate, 1, to phenylcarbomethoxycarbene, 2,
hydration of this carbene to methyl mandelate enol 3,
and ketonzation of the enol to methyl mandelate 4, as
shown in eq 1. The styrene-type chromophore of this enol
can be expected to have a strong absorption band in the
region about λ ) 280 nmsâ,â-dimethoxystyrene, for
kobs ) ko + kbuff[buffer]
(3)
example, has λ
) 268 nm18sand this band will shift
max
to longer wavelengths as the enol is converted to enolate
ion in basic solution.19 The R-carbonylcarbene, on the
other hand, having no acidic or basic groups, will have
an acidity-independent absorption spectrum. These ab-
sorption changes, moreover, are similar to those produced
by flash photolysis of phenyldiazoacetic acid, 5, which
were attributed to formation of phenylcarboxycarbene,
6, hydration of that to mandelic acid enol, 7, and
ketonization of the enol to mandelic acid, 8, eq 2.20
concentration intercepts, ko, obtained in this way, to-
gether with the rate constants measured in sodium
hydroxide solutions, are displayed as the upper rate
profile of Figure 2. Hydronium ion concentrations of the
buffer solutions needed to construct this profile were
obtained by calculation using literature values of the
buffer acidity constants and activity coefficients recom-
mended by Bates.22
Kin etics: En ol Keton iza tion . Rates of ketonization
of methyl mandelate enol were measured in aqueous
perchloric acid and sodium hydroxide solutions and in
formic acid, acetic acid, cacodylic acid, biphosphate ion,
(17) Andraos, J .; Chiang, Y.; Huang, C.-G.; Kresge, A. J .; Scaiano,
J . C. J . Am. Chem. Soc. 1993, 115, 10605-10610.
(18) Okuyama, T.; Kawao, S.; Fueno, T. J . Org. Chem. 1981, 46,
4372-4375.
(19) Haspra, P.; Sutter, A.; Wirz, J . Angew. Chem., Int. Ed. Engl.
1979, 18, 617-619.
(20) Chiang, Y.; Kresge, A. J .; Popik, V. V.; Schepp, N. P. J . Am.
Chem. Soc. 1997, 119, 10203-10212.
(21) Supporting Information: see paragraph at the end of this paper
regarding availability.
(22) Bates, R. G. Determination of pH Theory and Practice; Wiley:
New York, 1973; p 49.

Generation of the Enol of Methyl Mandelate
J . Org. Chem., Vol. 65, No. 4, 2000 1177
F igu r e 3. Relationship between buffer concentration and
observed rate constants for the ketonization of methyl man-
delate enol in aqueous acetic acid buffer solutions at 25 °C;
[CH3CO2H]/[CH3CO2-] ) 0.55.
F igu r e 1. Relationship between buffer concentration and
observed rate constants for the hydration of phenylcar-
bomethoxycarbene in aqueous acetic acid buffer solutions at
25 °C; [CH3CO2H]/[CH3CO2-] ) 0.28.
cates that this reaction is subject to catalysis by hydro-
nium and hydroxide ions, and that there is also a region
of no catalysis by solvent-related species. The detailed
mechanisms of these reactions are at present unknown,
but the data may nevertheless be analyzed using the
general rate law given in eq 4.
kobs ) kH+[H+] + k + k
[HO-]
HO-
(4)
o
+
Least-squares fitting of this expression gave kH ) (3.53
( 0.60) × 1010 M-1 s-1, ko ) (3.09 ( 0.40) × 105 s-1, and
kHO ) (6.64 ( 0.32) × 109 M-1 s-1
.
-
These results are quite similar to those obtained for
the closely analogous hydration of phenylcarboxycar-
bene,20 shown in eq 2. The lifetime of the present carbene
in the central “uncatalyzed” region of its hydration rate
profile, τ ) 3 µs, is considerably longer than the ca. 1 ns
lifetimes recently reported for other R-carbonylcarbenes.23
Those lifetimes, however, refer to reactions performed in
nonpolar organic solvents, unlike the wholly aqueous
medium used here. The previous substrates were also
different from the present carbene in that they lacked a
phenyl substituent next to the carbenic center. Such a
phenyl group might be expected to stabilize the carbene,
and microsecond lifetimes have in fact been reported for
phenylcarbomethoxycarbene and 2-naphthylcarbomethox-
ycarbene in organic solvents.24
En ol Keton iza tion : Ra te P r ofile. The ketonization
of enols is known to occur by rate-determining proton
transfer from any available acid to the â-carbon atom of
the enol or its enolate ion.6 The present rate profile for
ketonization of methyl mandelate enol by solvent-related
species in aqueous solution, shown in Figure 2, may
consequently be interpreted in terms of the reaction
scheme of eq 5, in which water and the hydronium ion,
written here as H+, are the proton donors.
F igu r e 2. Rate profiles for the hydration of phenylcar-
bomethoxycarbene in H2O solution (∆, solid line) and the
ketonization of methyl mandelate enol in H2O (O, solid line)
and D2O (∆, broken line) solution at 25 °C.
and ammonium ion buffers. Again, a range of concentra-
tions was employed, replicate measurements were made,
and ionic strength was maintained at 0.10 M. These data
are summarized in Tables S3-S5.21
The rate measurements in buffers were performed in
series of solutions of constant buffer ratio but varying
buffer concentration, and, as Figure 3 shows, observed
rate constants once again increase linearly with buffer
concentration. These data were therefore also analyzed
using eq 3. The zero-buffer-concentration intercepts, plus
the rate constants measured in perchloric acid and
sodium hydroxide solutions, are displayed as the middle
rate profile shown in Figure 2.
Some ketonization rate measurements were also made
in D2O solutions of perchloric acid, sodium hydroxide, and
acetic acid buffers. These data are summarized in Tables
S6-S8,21 and the rate profile they provide is shown as
the bottom curve of Figure 2.
(23) Toscano, J . P.; Platz, M. S.; Nikolaev, V.; Popik, V. V. J . Am.
Chem. Soc. 1994, 116, 8146-8151. Toscano, J . P.; Platz, M. S. J . Am.
Chem. Soc. 1995, 117, 4712-4713. Wang, J .-L.; Toscano, J . P.; Platz,
M. S.; Nikolaev, V.; Popik, V. V. J . Am. Chem. Soc. 1995, 117, 5477-
5483. Toscano, J . P.; Platz, M. S.; Nikolaev, V.; Cao, Y.; Zimmt, M. B.
J . Am. Chem. Soc. 1996, 118, 3527-3528.
(24) Fujiwara, Y.; Tanimoto, Y.; Itoh, M.; Hirai, K.; Tomioka, H. J .
Am. Chem. Soc. 1987, 109, 1942-1946. Wang, Y.; Yuzawa, T.;
Hamaguchi, H.; Toscano, J . P. J . Am. Chem. Soc. 1999, 121, 2875-
2882. Wang, J .-L.; Likhotvorik, I.; Platz, M. S. J . Am. Chem. Soc. 1999,
121, 2883-2890.
Discu ssion
Ca r ben e Hyd r a tion . The rate profile for hydration
of phenylcarbomethoxyketene shown in Figure 2 indi-

1178 J . Org. Chem., Vol. 65, No. 4, 2000
Chiang et al.
substrate,27 and the present bend may be attributed to
ionization of the enolic hydroxyl group. At acidities lower
than [H+] ) 10-7 M, ionized enol is then the substrate
form in the initial state of the ketonization reaction; the
advantage of converting less reactive enol to more reac-
tive enolization is consequently lost and the apparent
hydroxide ion catalysis becomes saturated. This produces
the plateau seen at the low acidity end of the rate profile,
which represents simple carbon protonation of enolate
ion by H2O.
The present rate profile shows no acid catalysis. This
means that carbon protonation of the un-ionized enol by
H+, with the rate constant kHK+, takes place to a signifi-
cant extent only at acidities greater than the most acidic
solution examined, [H+] ) 0.1 M. In more acidic solutions,
however, the flash photolytic substrate, methyl phenyl-
diazoacetate, undergoes rapid acid-catalyzed hydrolysis,25
and the region above [H+] ) 0.1 M could therefore not
be investigated.
The rate law that applies to this reaction scheme is
shown in eq 6,
kobs ) (kH′K+ [H+] + k′K) {QE/(QE + [H+])}
(6)
o
a
a
whose rate and equilibrium constants are defined by eq
5. Least-squares fitting of this expression using the data
obtained in H2O solution gave k′K+ ) (1.85 ( 0.10) × 109
H
M-1 s-1, (k′K)H ) (4.20 ( 0.09) 105 s-1, and QEa ) (2.83
The horizontal plateau at the high acidity end of the
present profile has two possible interpretations: it could
be due to carbon protonation of the un-ionized enol by
2O
( 0.12) ×o10-7 M, pQEa ) 6.55 ( 0.02,28 and similar
treatment of the data obtained in D2O solution gave k′K
+
D
H2O, with rate constant kK, or it could be caused by
) (1.63 ( 0.17) × 109 M-1 s-1, (k′K)D O ) (5.42 ( 0.26) ×
o
2
o
equilibrium ionization of the enol to enolate ion followed
by carbon protonation of enolate by H+, with rate
constant k′HK+. The latter process produces H+ in its
initial equilibrium, and then uses it up in the rate-
determining step, to give an overall reaction whose rate
is independent of [H+]. Enolate ions, moreover, are many
orders of magnitude more reactive than the correspond-
ing enols,26 and reaction via the enolate can be a
favorable process even when the enolate concentration
is quite low.
A choice between these two alternatives may be made
on the basis of the fact that enol ketonization obeys the
Brφnsted relation, and the rate of reaction effected by
proton transfer from an acid as strong as H+ can be
expected to be many orders of magnitude greater than
that effected by proton transfer from an acid as weak as
H2O.26 Assignment of the high acidity profile plateau to
protonation of un-ionized enol by H2O, however, coupled
with the nonappearance of protonation of un-ionized enol
by H+ at acidities as high as [H+] ) 0.1 M, makes the
rate of reaction effected by H+ at least comparable to, if
not less than, the rate of reaction effected by H2O. This
is contrary to expectation, and this molecular interpreta-
tion of this part of the rate profile may therefore be
rejected; the alternative explanationsionization of the
enol followed by carbon protonation of enolate ion by H+s
may consequently be accepted.
104 s-1, and (QE)D O ) (6.51 ( 0.66) × 10-8 M, (pQE)D O
)
2
2
a
a
7.19 ( 0.04.28
En ol Keton iza tion : Isotop e Effects. These results
provide isotope effects that offer good support for the
molecular interpretation of the rate profile given
above. Primary isotope effects are known to vary in
magnitude with transition state structure, passing through
a maximum value for symmetrical transition states in
which the atom in flight is half-transferred, and falling
off from this maximum for reactant-like and product-like
transition states.29 Because carbon protonation of the
enolate ion by H+ is such a fast processsits rate constant,
k′HK ) 1.85 × 109 M-1 s-1, shows it to be a nearly dif-
+
fusion-controlled processsit can be expected to have a
very reactant-like transition state30 and consequently
to give only a weak isotope effect. The value provided by
the present data, k′HK+/k′K ) 1.14 ( 0.13 is entirely
+
D
consistent with this expectation; the present result is
also similar to k′HK+/k′K ) 1.00 ( 0.21 determined for
+
D
the carbon protonation of isobutyrophenone enolate
ion by H+,31 which is also a very fast reaction with k′HK
)
+
3.0 × 108 M-1 s-1 26
.
The process identified as carbon
protonation of the enolate ion by H2O, on the other hand,
is a much slower reaction with k′oK ) 4.20 × 105 s-1, and
its isotope effect is correspondingly stronger: (k′K)H
/
2O
o
(k′K)D O ) 7.74 ( 0.40. This isotope effect is also aug-
2
o
mented by the fact that proton transfer from H2O
produces a hydroxide ion, and that provides a secondary
isotope effect component in the normal direction, kH/kD
> 1,32 in addition to the primary isotope effect. The
This part of the rate profile is followed by a rising
portion of slope ) +1 that extends from [H+] = 10-4
M
to [H+] = 10-7 M. This section may be attributed to
ionization of the enol to enolate ion followed by carbon
protonation of the ion by H2O. Since the H+ produced in
the prior equilibrium is not used up in the rate-determin-
ing step, the overall reaction rate will be inversely
proportional to [H+] or directly proportional to [HO-], for
an apparent hydroxide ion catalysis.
(27) Loudon, G. M. J . Chem. Educ. 1991, 68, 973-984.
(28) This is a concentration acid dissociation constant that applies
at the ionic strength, 0.10 M, at which it was determined.
(29) Melander, L. Isotope Effects on Reaction Rates; Ronald Press:
New York, 1960; pp 24-32. Westheimer, F. Chem. Rev. 1961, 61, 265-
273. Bigeleisen, J . Pure Appl. Chem. 1964, 8, 217-223. Kresge, A. J .
In Isotope Effects on Enzyme Catalyzed Reactions; Cleland, W. W.,
O’Leary, M. H., Northrop, D. B., Eds.; University Park Press: Balti-
more, MD, 1977; pp 37-63.
(30) Hammond, G. S. J . Am. Chem. Soc. 1955, 77, 334-338.
(31) Chiang, Y.; Kresge, A. J .; Walsh, P. A. Z. Naturforsch. 1988,
44a, 406-412.
(32) Kresge, A. J .; More O’Ferrall, R. A.; Powell, M. F. In Isotopes
in Organic Chemistry; Buncel, E., Lee, C. C., Eds.; Elsevier: Amster-
dam, 1987; Vol. 7, pp 177-273.
Downward bends in rate profiles such as that seen here
at [H+] = 10-7 M are commonly caused by a change in
the state of ionization of acidic or basic groups in the
(25) J ones, J ., J r.; Kresge, A. J . J . Org. Chem. 1993, 58, 2658-2662.
(26) 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 .;
Santaballa, J . A.; Wirz, J . J . Am. Chem. Soc. 1988, 110, 5506-5510.

Generation of the Enol of Methyl Mandelate
J . Org. Chem., Vol. 65, No. 4, 2000 1179
present result is also consistent with (k′K)H O/(k′K)D O
)
Ta ble 1. Gen er a l Acid Ca ta lytic Coefficien ts for th e
Keton iza tion of Meth yl Ma n d ela te En ola te Ion a
2
2
o
o
6.9 determined for the same reaction of the closely related
′K
HA
mandelic acid enol.20
acid
HCO2H
pKa
k
/107 M-1 s-1
The ionization of oxygen acids, such as the present
enol, gives solvent isotope effects in the normal direction,
and the value obtained from the present results
3.75
4.76
6.27
7.20
9.25
9.22
11.3
9.33
2.50
0.281
CH3CO2H
(CH3)2AsO2H
-
(QEa )H O/(QEa )D O ) 4.34 ( 0.48, is of the magnitude
H2PO4
NH4
+
2
expec2ted for an acid with the strength of the present
a
enol.33 This value also agrees well with (QEa )H O/(QaE)D O
Aqueous solution, 25 °C, ionic strength ) 0.10 M.
2
2
) 4.5 determined for the ionization of mandelic acid
Ta ble 2. Su m m a r y of Ra te a n d Equ ilibr iu m Con sta n tsa
enol.20
En ol Keton iza tion : Bu ffer Ca ta lysis. Further sup-
port for the molecular interpretation of the ketonization
rate profile given above comes from the form of acid-
base catalysis in buffer solutions. The slopes, kbuff, of the
buffer dilution expression of eq 3 used to analyze the
buffer rate data, may be separated into their general acid,
kHA, and general base, kB, components with the aid of eq
7, in which fA is the fraction of buffer present in the acid
kbuff ) kB + (kHA - kB) fA
(7)
form in a given buffer solution series. Least-squares
fitting of this expression showed general base catalysis
in formic acid, acetic acid, and cacodylic acid buffers and
general acid catalysis in biphosphate ion and ammonium
ion buffers.
The buffer-catalyzed component of the present enol
ketonization reaction may be formulated as shown in eq
8. Its rate-determining step, being a proton transfer from
a
Aqueous solution, 25 °C, ionic strength ) 0.10 M.
catalyzing acid to substrate, will show general acid
catalysis. In solutions where the substrate exists as un-
ionized enol, however, the prior conversion of enol to
enolate will transform the general acid catalysis of the
rate-determining step into overall general base catalysis.
The measurements in formic, acetic, and cacodyoic acid
buffers were done in solutions where the enol was largely
in its un-ionized form, and the data therefore showed
general base catalysis, whereas the measurements in
biphosphate and ammonium ion buffers were done in
solutions where the enol was largely ionized, and these
data consequently showed general acid catalysis.
It follows from the reaction scheme of eq 8 that the
general base, kKB, and general acid, kH′KA, catalytic coef-
ficients are related through the acid ionization constant
of the enol, and the acid ionization constant of the buffer
acid, as shown in eq 9.
decreasing acid strength of the catalyst, as expected.
Although the catalysts are of mixed charge type, they
nevertheless give a reasonable Brφnsted correlation with
R ) 0.35 ( 0.08. The low value of this exponent is
consistent with the great speed of these reactions and
their consequently expected early transition states.30
Treatment of the data obtained in D2O solutions of
acetic acid in the manner described above for H2O
solutions, using the appropriate acidity constants for the
enol and acetic acid34 in D2O, gave a catalytic coefficient,
which when combined with its H2O counterpart, pro-
duced the isotope effect k′HKA/k′K ) 3.02 ( 0.47. This is a
DA
rather weak isotope effect, though not as weak as that
on carbon protonation of the enolate ion by H+ described
above. This difference, of course, is consistent with the
fact that the acetic acid-catalyzed reaction, though fast,
is nevertheless, not as fast as that promoted by H+, and
it should consequently have a less reactant-like and more
symmetrical transition state and thus show a stronger
isotope effect.
Com p a r ison w ith Oth er System s. It was pointed
out above that hydronium-ion catalysis of the ketoniza-
tion of the presently examined enol could not be detected
because its diazo compound precursor is not stable in
kKB ) k′K QEa /QHa A
(9)
HA
Since these acid ionization constants are known, the
general base catalytic coefficients may be converted into
general acid values. The results, summarized in Table
1, show a trend of generally decreasing values with
(33) Laughton, P. M.; Robertson, R. E. In Solute-Solvent Interac-
tions; Coetzee, J . F., Ritchie, C. D., Eds.; M. Dekker: New York, 1969;
Chapter 7.
(34) Gary, R.; Bates, R. G.; Robinson, R. A. J Phys. Chem. 1965, 69,
2750-2753. Gold, V.; Lowe, B. M. J . Chem. Soc. (A) 1968, 1923-1932.

1180 J . Org. Chem., Vol. 65, No. 4, 2000
Chiang et al.
sufficiently acidic solutions. An upper limit for the
hydronium-ion catalytic coefficient may nevertheless be
estimated on the basis of the reasonable assumption that
an acid-catalyzed reaction 10% above the “uncatalyzed”
enolate ion, for which the now somewhat greater rate
constants are k′ ) 18.5 × 108 M-1 s-1 and k′ ) 4.2 ×
+
H
o
105 s-1. In these enolate ion reactions, of course, the
partial positive charge being transferred to the substrate
in the rate-determining step is neutralized by the full
negative charge already there, and the better positive-
charge-stabilizing ability of OH does not come into play.
In situations such as this involving net negative charge,
the relevant substituent property would seem rather to
be the electron-withdrawing inductive or field effect,
which is stronger for OH than for OCH3, as judged by F
) 0.33 for OH and F ) 0.29 for OCH3.37 The enolate ion
initial state of these negative-charge-destroying reactions
is consequently stabilized more in the mandelic acid
system than in the methyl mandelate system, making
the former less reactive than the latter.
plateau at the high acidity end of the rate profile shown
+
in Figure 2 would have been detected. The result, kH
<
5 × 102 M-1 s-1, makes this reaction at least 20 times
slower than the hydronium-ion-catalyzed ketonization of
3
-1
+
the enol of mandelic acid, for which kH ) 9.0 × 10 M
s-1 20
.
The present enol may, of course, be regarded as the
monomethyl ether of the enol of mandelic acid, and this
+
difference in kH is therefore consistent with the decrease
in reactivity, by 1 or 2 orders of magnitude, generally
found in going from enols of simple aldehydes and
ketones to their methyl enol ethers.6
This difference between enols and methyl enol ethers
has been attributed to the better ability of an OH group
to effect conjugative stabilization of an adjacent positive
charge, such as that being generated on the substrate in
the rate-determining step of these reactions, which in
both cases involves protonation of the enolic double bond.
This is evidenced, for example, by the stronger value of
the σ+ substituent constant for OH, σ+ ) -0.92,35 than
that for OCH3, σ+ ) -0.78.36 It is significant, therefore,
that this difference in reactivity is reversed when the enol
becomes ionized and the comparison changes to one
between protonation of a double bond bearing OH and
This difference between OH and OCH3 substituent
effects is also apparent in the difference between the
acidity constants of mandelic acid and methyl mandelate
enols ionizing as oxygen acids: pQEa ) 6.39 for mandelic
acid enol20 and pQEa ) 6.55 for methyl mandelate enol.
These ionizations are negative-charge-generating reac-
tions, and the greater ability of OH to stabilize such a
charge makes mandelic acid enol the stronger acid.
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
and the United States National Institutes of Health for
financial support of this work.
O
- groups on one hand and OCH3 and O- groups on the
other hand: the former situation is represented by
ketonization of mandelic acid enolate ion, for which k′
+
H
Su p p or tin g In for m a tion Ava ila ble: Tables S1-S8 of
rate data. This material is available free of charge via the
Internet at http://pubs.acs.org.
) 8.6 × 108 M-1 s-1 and k′ ) 1.7 × 105 s-1 20
,
and the
o
latter situation is represented by the methyl mandelate
J O991707A
(35) Clementi, S.; Linda, P. J . Chem. Soc., Perkin Trans. 2 1973,
1887-1888.
(36) Brown, H. C.; Okamoto, Y. J . Am. Chem. Soc. 1958, 80, 4979-
(37) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195.
4987.