+
Zn
2
and Acetic Acid as Catalysts of Enolization
A R T I C L E S
been several studies of metal ion catalysis of the deprotonation
Scheme 2
of relatively acidic carbon acids such as 1, which are activated
in D
2
O at 25 °C and I ) 1.0 (KCl) was determined by assuming that
-
the concentration of this complex is equal to the decrease in [AcO ]
that can be calculated from the observed decrease in the pD of acetate
buffers upon addition of known amounts of Zn2 , using pK
+
) 5.06
a
2
for acetic acid in D O.
for proton transfer by a second substituent (e.g., a phenyl group)
Solutions of acetate buffer in D O at pD 5.70 and I ) 1.0 (KCl)
2
1
6-19
and contain a basic site for chelation the metal ion.
By
containing Zn2+ were prepared by mixing KOAc, KCl, and ZnCl2
comparison, there are only limited data for metal ion catalysis
of the slower deprotonation of weakly acidic R-carbonyl carbon
acids that are relevant models for enzyme-catalyzed deproto-
followed by the addition of DCl to give a final pD of 5.70. The required
amount of DCl was calculated from pK
a
) 5.06 for acetic acid and
-
1
+
Kassoc ) 7.0 M for formation of the (AcO‚Zn) complex in D
2
O (see
nation of keto sugars.1
4,20
above). Small adjustments of the initial pD of these solutions (<0.10
The lack of model studies of metal
unit) were made, as needed, to bring the final pD to 5.70.
ion catalysis of proton transfer from simple carbon acids has
impeded discussions of the relative advantages of Brønsted acid
and metal ion catalysis by enzymes.1
1
1
H NMR Analyses. H NMR spectra at 500 MHz were recorded in
O at 25 °C using a Varian Unity Inova 500 spectrometer. Values of
) 6 and 7 s, respectively, were determined for the R-CH OD and
R-CH protons of hydroxyacetone using a solution of 5 mM substrate
in D O at I ) 1.0 M (KCl). These are similar to T ) 6 s reported for
the R-CH protons of acetone determined in chloroform. Spectra were
D
2
,6
T
1
2
Both hydroxyacetone and acetone are ideal substrates for
studies of metal ion catalysis of the deprotonation of ketones:
3
2
1
21,22
(1) There are literature data
for catalysis of the deprotonation
25
3
of acetone by Brønsted acids that may be used in combination
with new data for metal ion catalysis to obtain the relative
stabilization of the transition state for proton transfer by
interaction with these different electrophiles. (2) A comparison
of metal ion catalysis of deprotonation of acetone and hydroxy-
acetone will provide a simple estimate of the contribution to
catalysis available from chelation of the metal ion by the
substrate. (3) Additional insight into organic reactivity and
reaction mechanism can be obtained from a comparison of
kinetic data for deprotonation of the R-CH3 and R-CH2OH
groups of hydroxyacetone.23
recorded with a sweep width of 6000 Hz, a 90° pulse angle, and an
acquisition time of 6 s. The relaxation delay between pulses was at
least 10-fold greater than the longest T for the protons of interest.
1
Chemical shifts are reported relative to HOD at 4.67 ppm. Baselines
were subjected to a first-order drift correction before determination of
integrated peak areas.
Small signals of around 1% the area of those for the methyl and
methylene protons of the keto form of hydroxyacetone were observed
in the region expected for the signals of the methyl and methylene
protons of hydroxyacetone hydrate.
Deuterium Exchange Reactions. All reactions were carried out at
pD 5.70 in D O at 25 °C and I ) 1.0 (KCl). Reactions were initiated
2
by the addition of a small volume of a solution of acetone or
hydroxyacetone in D O to the reaction mixture to give a final substrate
2
Experimental Section
Materials. Hydroxyacetone (Fluka), acetone (Mallinckrodt), ZnCl
Baker), potassium acetate (Aldrich), and all other inorganic salts were
2
concentration of 15 mM.
(
3
The exchange for deuterium of the R-CH protons of acetone and
reagent grade or better and were used without further purification.
Deuterium oxide (99.9% D) and deuterium chloride (35% w/w, 99.5%
D) were purchased from Cambridge Isotope Laboratories. Potassium
deuterioxide (40wt %, 98+% D) was purchased from Aldrich.
of hydroxyacetone was followed by 1H NMR by monitoring the
disappearance of the singlets at 2.202 and 2.058 ppm, respectively,
due to the R-CH
(JHD ) 2.5 Hz) shifted upfield by 0.016 and 0.018 ppm, respectively,
due to the R-CH D groups of the products. The exchange for deuterium
of the R-CH OD protons of hydroxyacetone was followed by H NMR
by monitoring the disappearance of the singlet at 4.282 ppm due to
the R-CH OD group of the substrate and the appearance of the triplet
3
group of the substrate and the appearance of triplets
2+
Preparation of Acetate Buffers Containing Zn . Solution pD was
determined at 25 °C using an Orion Model 720A pH meter equipped
with a Radiometer GK2321C combination electrode that was standard-
ized at pH 7.00 and 4.00. Values of pD were obtained by adding 0.4
2
1
2
2
2
4
to the observed reading of the pH meter.
(JHD ) 2.5 Hz) shifted upfield by 0.023 ppm due to the R-CHDOD
group of the product. These deuterium isotope effects on H chemical
2
+
1
The addition of Zn to acetate buffers leads to the formation of a
complex between Zn2 and acetate anion that results in a decrease in
the ratio of the concentrations of the basic and acidic forms of the
+
shifts and H-D coupling constants are similar to those for related
carbon acids that were reported in our earlier work.1
4,25-31
-
buffer, [AcO ]/[AcOD], and a decrease in solution pD (Scheme 2).
Values of R, which is a measure of the progress of the deuterium
exchange reaction,3 were calculated according to eq 1 for the reaction
2,33
An apparent value of pK
a
2
) 5.06 for acetic acid in D O at 25 °C and
I ) 1.0 (KCl) was determined from the measured pD of acetate buffers
of R-CH
hydroxyacetone. In these equations, ACH3 and ACH2 are the integrated
areas of the singlets due to the R-CH and R-CH OD groups of the
3
2
groups or eq 2 for the reaction of the R-CH OD group of
2
+
-1
prepared in the absence of Zn . A value of Kassoc ) 7.0 M for
+
2+
formation of the (AcO‚Zn) complex between acetate anion and Zn
3
2
(
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