Collot et al.
reagent. Anhydrous cadmium chloride was a GPR reagent, as was
copper(II) chloride dihydrate
weak acid catalysis of tautomerization and correspondingly large
advantage of metal ions over protons as catalysts. The com-
parison of proton and metal ion catalysis of enolization (strictly
formation of the enolate anion) provides an “ideal” example
for analysis in terms of binding of the catalysts to reactants,
products, and transition states of a reaction. The close relation-
ship of this analysis to that based on rate-equilibrium relation-
ships and the kinetic effect of thermodynamic driving force is
emphasised.
Equilibrium Measurements. Equilibrium and kinetic measure-
ments were performed at 25 °C in aqueous solution. Ionic strengths
were usually 0.1 M unless indicated otherwise. Measurements of
pKa values were based on spectrophotometric measurements,
described in the Supporting Information, or proton NMR.
The NMR measurements of the protonation of phenylacetylpyra-
zine and acetylpyrazine were made in solutions of DCl in D2O in
the concentration range 0 - 4.2 M, and pKa values in D2O were
obtained from extrapolations based on eq 33 in which X is Cox
and Yates’s free energy/acidity parameter for correlating medium
effects on acid-base equilibria in DCl-D2O,20 m* is the slope of
the plot of pKa against X, Ka ) [B][D+]/[BD+] at the indicated
acid concentration and pKa(D2O) is the intercept at X ) 0 (for pure
D2O).
Experimental Section
Synthesis and Materials. A sample of 9-phenylacetylpyrazine
was prepared from pyrazine carboxylic acid using a modification
of the method employed by Bunting and Stefanidis for the
corresponding phenylacetylpyridine.7 The carboxylic acid was
converted to its methyl ester by Fischer esterification and condensed
with ethyl phenylacetate to give the R-carbethoxy ester of phenyl-
acetylpyrazine (15) as shown in eq 29. The ester was then
hydrolyzed and decarboxylated to phenylacetyl pyrazine.
pKa ) pKa(D2O) + m*X
(33)
Values of Ka were evaluated from eq 34 below in which δ is the
chemical shift of the 5-hydrogen atom of the acylpyrazine at the
indicated concentration of D3O+, and δP and δD are the limiting
chemical shifts at high and low acid concentrations for the
protonated and unprotonated heterocycles. Chemical shifts are listed
in Tables S1and S2 (Supporting Information), and the data are
plotted as δ against pH - Xo in Figures 1 and S1 (Supporting
Information). The line through the points in Figure 1 represents a
best fit of calculated to experimental chemical shifts for optimized
values of δD, δP, m*, and pKa.
2-Phenyl-2-carbethoxy-1-pyrazinylethanone 15. Phenyl-
ethylacetate (5.49 g, 0.033 mol) and methyl pyrazinoate (4.0 g 0.027
mol) in dry THF (30 mL) were added dropwise with stirring to a
freshly prepared solution of sodium ethoxide (0.75 g sodium, 0.033
mol) in 12 mL of ethanol. The solution turned orange and then
dark red during the course of the addition. It was heated to reflux
for 3 h and after cooling poured into water (200 mL). Unreacted
starting material was extracted with chloroform and the solution
acidified with concentrated sulfuric acid to give a brown semi-
solid which was extracted with chloroform (3 × 100 mL). The
product was dried (Na2SO4) and evaporated to give a brown oil
which solidified on standing (4.05 g, 60%). A portion of the product
(2.5 g) was purified by flash chromatography on silica. Elution with
10:2 hexane/ethyl acetate gave 1.1 g of white solid. 1H NMR (270
MHz, CDCl3) δ: 9.24 (d, 1H, J ) 1.5 Hz), 8.76 (d, 1H, J )2.4
Hz), 8.68 (dd, 1H, J ) 1.4, 2.4 Hz), 7.26-7.45 (m, 5H), 6.06 (s,
1H), 4.13 -4.29 (m, 2H, J ) 7.15 Hz), 1.21 (3H, t, J ) 7.15 Hz).
2-Phenyl-1-pyrazinylethanone (phenylacetylpyrazine). 2-Phenyl-
2-carbethoxy-1-pyrazinylethanone (1.0 g) in 60% aqueous ethanol
(100 mL) containing concentrated HCl (1.5 mL) was heated under
reflux at 100 °C overnight. Completion of the reaction was checked
by TLC after a “mini-workup”. Saturated aqueous sodium bicar-
bonate was added to the reaction mixture which was then extracted
with dichloromethane (3 × 100 mL), washed with brine, dried
(Na2SO4), and evaporated to give a brown oil which solidified on
cooling (∼700 mg). The product was purified by flash chromatog-
raphy on silica using 90:10 hexane/ethyl acetate to give white
crystals (∼500 mg). Anal. Calcd for C12H10N2O: C, 72.72; H, 5.09;
Ka ) [D+](δ-δD)/(δP-δ)
(34)
For phenylacetylpyrazine, pKa ) -0.42 ( 0.07 and m* ) 1.0
( 0.25 and for acetylpyrazine pKa ) -0.57 ( 0.07 and m* ) 1.4
( 0.25. The large uncertainty in the m* values reflects the low
acid concentrations studied and thus small deviation of pKa values
from those in water.
Kinetic Measurements. Kinetic measurements were carried out
using UV-vis spectra to monitor reactions. Directly measured rate
constants are generally subject to random errors of (5%. However,
values dissected from combinations with equilibrium constants,
from pH profiles or kinetic saturation plots, may be subject to a
greater uncertainty, usually noted in the text, and were used to
construct the log kobs - pH profiles in Figures 2 and 3 from the
inflections of which pKa values for mono- and di-protonation of
the enol were inferred.
First-order rate constants for ketonization of the enol tautomer
of phenylacetylpyrazine, kobs, were measured in HClO4, HCl and
DCl as described in the Results and Supporting Information. The
values are listed in Tables S6 and S9 (Supporting Information) and
are plotted as log k against pH or pH - Xo in Figures 2 and 3. The
plot against pH - Xo (i.e., for Xo * 0) refers to concentrated
solutions of the acids and is based on modification of eq 9 so that
kAHH3O+, KaEH2+ and KaEH3++ are multiplied by the term 10m*Xo
,
where m* is the slope of a plot of log k or pKa against Xo.22 As
noted above, spectrophotometric evaluation of m* for the equilib-
rium constants gives values close to 1.0. Likewise, the near
independence of acid concentration of the value of log kobs at high
acid concentrations (Figure 2, pH - Xo < -2) implies that m3* for
kAH is close to 1.0. The lines drawn through the data points in
Figures 2 and 3 are calculated on this basis and correspond to
1
N, 14.15. Found: 72.16; H, 5.08; N 14.15. H NMR (270 MHz,
CDCl3) δ: 9.3 (m, 1 H), 8.8 (m, 1H), 8.7 (m, 1H,), 7.2 - 7.5 (m,
5H), 4.5 (s, 2H). 13C NMR (68 MHz, CDCl3) δ: 198.5, 147.8, 147.3,
144.2, 143.5, 133.8, 129.9, 129.9, 128.6, 127.0, 44.2. MS m/z: 198
(M+, 54), 169 (31), 107 (36), 91(100), 65 (40), 52 (32), 39 (18).
Other organic materials were used without purification, including
2-pyrazinecarboxylic acid and 2-acetylpyrazine. Inorganic reagents
used for kinetic or equilibrium measurements were generally AR
grade (NaCl, NaBr, KI, nickel(II) chloride hexahydrate, and
copper(II) nitrate trihydrate). Iodine was GPR grade (resublimed),
and bromine was Aristar grade. Zinc(II) nitrate tetrahydrate was a
“proanalysi” reagent and Cobalt(II) nitrate trihydrate was a “reinst”
replacing [H+] in eq 9 by 10(pH-Xo)
.
It is noteworthy that the pKa values derived from Figures 2 and
3 have lower values than those determined spectrophotometrically
from intial absorbances of the enol or protonated enol from
quenching the enolate anion in acid media. For pKaEH2+ and
pKaEH3++ in HClO4 the spectrophotometric values are, respectively,
0.45 (0.42 in HCl) and -4.8 compared with kinetic values of -0.58
(-0.41 in HCl) and -7.9. The discrepancy for pKaEH3+2 reflects
3368 J. Org. Chem. Vol. 74, No. 9, 2009