Mechanism of α-ketol-type rearrangement of benzoin derivatives under basic conditions

Article abstract of DOI:10.1021/jo401156h

The mechanism of base-catalyzed rearrangement of ring-substituted benzoins in aqueous methanol was examined by kinetic and product analyses. Substituent effects on the rate and equilibrium constants revealed that the kinetic process has a different electron demand compared to the equilibrium process. Reactions in deuterated solvents showed that the rate of H/D exchange of the α-hydrogen is similar to the overall rate toward the equilibrium state. A proton-inventory experiment using partially deuterated solvents showed a linear dependence of the rate on the deuterium fraction of the solvent, indicating that only one deuterium isotope effect contributes to the overall rate process. All these results point to a mechanism in which the rearrangement is initiated by the rate-determining α-hydrogen abstraction rather than a mechanism with initial hydroxyl hydrogen abstraction as in the general α-ketol rearrangement.

Full text of DOI:10.1021/jo401156h

Article
pubs.acs.org/joc
Mechanism of α‑Ketol-Type Rearrangement of Benzoin Derivatives
under Basic Conditions
Masahiro Karino, Daiki Kubouchi, Kazuki Hamaoka, Shintaro Umeyama, and Hiroshi Yamataka*
Department of Chemistry and the Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro, Toshima-ku, 171-8501
Tokyo, Japan
S
* Supporting Information
ABSTRACT: The mechanism of base-catalyzed rearrangement of ring-substituted benzoins in aqueous methanol was examined
by kinetic and product analyses. Substituent effects on the rate and equilibrium constants revealed that the kinetic process has a
different electron demand compared to the equilibrium process. Reactions in deuterated solvents showed that the rate of H/D
exchange of the α-hydrogen is similar to the overall rate toward the equilibrium state. A proton-inventory experiment using
partially deuterated solvents showed a linear dependence of the rate on the deuterium fraction of the solvent, indicating that only
one deuterium isotope effect contributes to the overall rate process. All these results point to a mechanism in which the
rearrangement is initiated by the rate-determining α-hydrogen abstraction rather than a mechanism with initial hydroxyl
hydrogen abstraction as in the general α-ketol rearrangement.
INTRODUCTION
■
α-Hydroxyketones are versatile species in synthetic chemistry
and have been used to prepare a variety of compounds via α-
ketol rearrangement (eq 1).1,2 A possible involvement of the α-
ketol rearrangement in biological reactions has also been a
matter of controversy for many years.3
RESULTS AND DISCUSSION
Rate and Equilibrium Constants. A series of benzoins (1-
■
The mechanism of the base-catalyzed α-ketol rearrangement
appears simple, in which the reaction is initiated by
deprotonation of the hydroxyl group, followed by 1,2-R3
migration and protonation. However, when R3 is hydrogen,
namely, for the reaction of acyloin or benzoin, an alternative
pathway with an initial α-hydrogen abstraction becomes
possible. The mechanism of the α-ketol rearrangement of this
type of compound is complex and has not yet been fully
X; X = p-MeO, p-Me, m-Me, p-F, p-Cl, m-F, m-Cl, p-CF3, m-
CN, p-CN) were prepared according to the literature.4,5 The
reactions of 1-X with KOH in 70% (v/v) aqueous MeOH were
carried out under N2. The reactions under O2-contaminated
conditions were deteriorated by oxidation to give benzils as side
products.
The rates of the reactions were measured photometrically,
elucidated.
and the equilibrium constants were determined by 1H NMR at
In the present study, we have carried out the reactions of
25.0 °C and are listed in Table 1. The determined rate
ring-substituted benzoins (XC6H4CHOHCOPh, 1-X) with
constants are for the rates toward the equilibrium mixtures and
KOH in 70% (v/v) aqueous MeOH and determined the
are given as keq = kf + kr. Here, kf is the forward rate constant
substituent effects on the rate and equilibrium constants. These
from 1-X to 2-X, and kr is the reverse rate constant from 2-X to
substituent effects, together with solvent isotope effects and the
result of a H/D exchange experiment, showed that the reaction
proceeds via an initial α-H abstraction (path B in eq 2) rather
Received: May 27, 2013
than via an initial hydroxyl hydrogen abstraction (path A).
© XXXX American Chemical Society
A
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Table 1. Rate and Equilibrium Constants for the Reactions of 1-X with KOH in 70% (v/v) MeOH at 25.0 °C
X
102keq/s−1 M−1
K
102kf/s−1 M−1
102kr/s−1 M−1
p-MeO
p-Me
m-Me
p-F
3.21 0.07
7.84 0.02
2.58 0.01
2.85 0.06
0.36 0.01
4.34 0.04
3.13 0.03
1.21 0.02
6.65 0.30
1.10 0.02
3.48 0.16
3.17 0.14
a
1.24 0.02
a
a
p-Cl
13.4 0.3
0.675 0.005
0.370 0.011
0.337 0.014
0.157 0.001
0.130 0.005
0.081 0.004
5.4 0.1
8.0 0.2
m-F
a
a
a
m-Cl
p-CF3
m-CN
p-CN
30.5 7.1
7.7 1.8
22.8 5.3
49.6 1.1
6.7 0.1
42.9 1.0
a
a
a
a
a
a
a
Not determined.
1-X. The reaction rates for the F-substituted derivatives could
not be measured due to extremely small absorbance changes
during the reactions, and those for the CN-substituted
derivatives could not be determined with acceptable accuracy
due to side reactions. The rate constants of the forward and
reverse reactions were calculated from the second-order rate
constants (keq = kf + kr) and the equilibrium constants (K = kf/
kr).
Substituent Effect. Substituent effects on the equilibrium
constant (K) and the forward (kf) and reverse (kr) rate
constants were analyzed by means of an extended Hammett
equation (the Yukawa−Tsuno equation, eq 3), in which r is a
parameter to measure the relative importance of the resonance
effect over the inductive effect and r = 1.0 for σapp = σ+ by
definition and r = 0.27 for σapp = σ.6 The Hammett plots for the
equilibrium, the forward and reverse reactions, are illustrated in
Figures 1 and 2.
product 2-X is stabilized by substituent X both inductively and
resonatively in its intramolecularly hydrogen-bonded structure
(Chart 1). (2) The Hammett plot for the forward reaction gave
a small positive ρ value, in spite of the fact that the
corresponding equilibrium gave a negative ρ value. This
indicates that the charge type on the benzylic carbon of 1-X
is different at the rate-determining transition state (TS) and the
product state. The result is thus consistent with an enolate-
forming TS in mechanism B. At the TS, the benzylic carbon
bears a partial negative charge, and hence, the ρ value for the
forward rate is small positive. The zero r value is reasonable for
the mechanism, since the electron-donating resonance effect is
absent at the TS. (3) The substituent effect on the reverse
reaction, on the other hand, gave a relatively large positive slope
with a significant size of the r value. These values are in line
with an initial state (2-X), stabilized by an electron-donating
substituent both inductively and resonatively, and the enolate-
forming TS, stabilized by an electron-withdrawing substituent.
It should be noted, however, that these substituent effects are
also in line with mechanism A, in which the hydride migration
step is rate determining.
log(k/k0) = ρ{σ° + r(σ+ − σ°)}
+
= ρ(σ° + rΔσR
)
̅
Isotope Exchange Experiment. To gain information on
the role of the α-H abstraction in the reaction mechanism, the
reaction of 1-m-Me with KOH was carried out in 70% (v/v)
= ρσ
app
(3)
1
D2O−CD3OD. The reaction was followed with H NMR by
measuring the changes of the intensities of the Me signals (δ
2.31 and 2.35) of 1-m-Me and 2-m-Me and the α-H signals (δ
5.91 and 5.94) of 1-m-Me and 2-m-Me with respect to the
internal standard (PhOCH3). The signal intensities (I) were
normalized by the number of hydrogens on the groups. The
initial intensities of 1-m-Me at t = 0 could not be determined
due to the delay of sampling time in the NMR measurement.
The OH signals of 1-m-Me disappeared right after the reaction
was started (t = 0). At t = 5000 s, the two Me signals gave the
intensities expected for the equilibrium mixture, and the α-H
signal disappeared due to H/D exchange. The α-H signal of 2-
m-Me could not be detected. The time dependence of the
signal intensities in Figure 3 indicates that the Me and α-H
signals of 1-m-Me decreased and the Me signal of 2-m-Me
increased at similar rates. In particular, it is important to point
out that the pseudo-first-order rate constants for the decay of
the Me and α-H signals of 1-m-Me were calculated to be 9.76 ×
10−4 and 9.73 × 10−4 s−1, respectively, under the reaction
conditions, showing that the α-H abstraction and the benzoin
rearrangement occur at nearly the same rates.
Figure 1. Hammett plots for the equilibrium constant for the reaction
of 1-X and KOH in 70% (v/v) aqueous MeOH at 25.0 °C.
Since the number of substituents is small for the analyses
with the dual-parameter equation, the calculated parameters,
especially the r values, should not be taken quantitatively.
Nevertheless, important information could be extracted from
the plots. (1) The plot for the equilibrium gave a negative slope
with a significant size of the r value. This indicates that the
The result, at first glance, appears to be consistent with
mechanism A with the rate-determining 1,2-H shift. However,
since the intensity of the α-H signal of 2-m-Me was absent, this
B
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Figure 2. Hammett plots for the (A) forward and (B) reverse rate constants for the reaction of 1-X and KOH in 70% (v/v) aqueous MeOH at 25.0
°C.
p-MeO to 2-p-MeO, the mechanism requires that the rate
toward the equilibrium mixture is only slightly smaller than the
rate of α-H abstraction (see the Supporting Information).
The same kinetic experiments were carried out for the
reverse process with 2-m-Me as the starting material, and the
results are illustrated in Figure 4. Two important points are
Chart 1
1
Figure 4. Time dependence of H NMR intensities of Me and α-H
signals of 2-m-Me and 1-m-Me and pseudo-first-order kinetic plots. [2-
m-Me] = 11 mM, [KOH] = ca.19 mM, and CD3OD:D2O = 7:3 (v/v).
1
Figure 3. Time dependence of H NMR intensities of Me and α-H
signals of 1-m-Me and 2-m-Me and pseudo-first-order kinetic plots. [1-
m-Me] = 10 mM, [KOH] = ca. 21 mM, and CD3OD:D2O = 7:3 (v/v).
apparent in the plots. First, the rate of disappearance of the α-H
signal of 2-m-Me is similar to the rate of the rearrangement
measured by intensity changes of the Me signals of 1-m-Me and
2-m-Me. Second, the α-H signal of 1-m-Me did not show up in
the NMR spectrum. Similar experiments were performed for 1-
p-MeO, 2-p-MeO, 1-p-Me, and 2-p-Me in duplicate. The time
dependence plots are shown in the Supporting Information,
and the calculated rate constants are summarized in Table 2. In
these measurements, the reaction temperature and the base
concentration were not strictly controlled, and hence,
comparison of the obtained rate constants is allowed only
within each run. Nevertheless, the data in Table 2 clearly show
that the pseudo-first-order rates of disappearance of 1-X and
the rates of appearance of 2-X are the same, which are the rates
of reaction toward the equilibrium states (kobsd). Furthermore,
mechanism requires much faster α-H/D exchange in 2-m-Me
than in 1-m-Me, which is very unlikely. Alternatively, the
reaction may proceed through the rate-limiting α-H abstraction
in mechanism B to give a quasi-symmetrical enolate
intermediate. The intermediate gives 2-m-Me by the fractiona-
tion factor k2/(k2 + k−1), and thus, kf is given as k1k2/(k2 + k−1).
Similarly, kr is given as k−1k−2/(k2 + k−1). The fact that the H/D
exchange rate in 1-m-Me and the rate of the equilibrium
mixture formation are essentially the same is consistent with
mechanism B, since the latter rate constant is given by kf + kr,
and hence, if the equilibrium constant K is near unity, then kf +
kr becomes similar to k1 in eq 2b. When the reaction is downhill
and K is larger than unity as in the case of the reaction from 1-
C
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fractionation factors have been experimentally determined and
Table 2. Pseudo-First-Order Rate Constants Determined by
NMR for the Reactions of 1-X and 2-X in Deuterated
Aqueous 70% (v/v) MeOH
used to estimate the size of the solvent isotope effects.7
(4)
SH + ROD ⇌ SD + ROH
X
104k1/s−1
104kobsd(1-X)/s−1
104kobsd(2-X)/s−1
[SD]/[ROH]
[SD]/[ROH]
[SD]/[SH]
[ROH]/[ROD]
K =
=
= ϕ
1-p-MeO
10.9
11.0
3.86
5.14
9.77
7.12
6.64
7.22
9.73
7.98
9.47
9.00
9.82
9.70
4.66
7.77
9.34
6.27
7.29
6.89
9.76
9.25
9.73
9.54
9.88
9.70
4.75
7.54
9.02
6.37
7.54
7.96
10.1
9.67
9.53
9.58
(5)
2-p-MeO
1-p-Me
2-p-Me
1-m-Me
2-m-Me
In the present reaction, the equilibrium isotope effect (KH/
KD) for the proton-abstraction step from 1-p-MeO and OH−/
OD− is given by eqs 6 and 7. Since the isotopic fractionation
3
factor for a Csp −H bond is around unity, the deuterium
equilibrium isotope effect (KH/KD) is calculated to be 0.5.
Although the KIE should be somewhere between 0.5 and 1.0
depending on the position of the TS along the reaction
coordinate, the observed KIE of 0.46 is qualitatively consistent
with the mechanism assuming the rate-determining α-proton
abstraction by OH−/OD− as discussed above.
−
SH + OL ⇌ S− + HOL
(6)
ϕOL−ϕCL(sp3)
KH
KD
0.5 × 1.0
=
=
= 0.5
the rates of α-H abstraction (k1) are similar to kobsd. These
results clearly indicate that the rearrangement proceeds via
mechanism B.
ϕHOL
1.0
(7)
In Figure 5 is shown the plot of the rate constant (keq) vs the
Solvent Deuterium Kinetic Isotope Effect. To obtain
information on the role of the solvent, in particular a possible
involvement of a proton-transfer relay mechanism, in the
reaction, a proton-inventory experiment was carried out for 1-p-
MeO in aqueous methanol with different molar fractions of
deuterated solvent.7,8 The chemical meaning of keq in
deuterated solvent is a little complex, since keq = kf + kr, and
here kf at the initial stage of the reaction is the rate constant of
the reaction of nondeuterated 1-p-MeO, whereas kf at a later
stage corresponds to the forward rate constant of α-deuterated
1-p-MeO. Furthermore, kr is the rate constant of the reaction of
α-deuterated 2-p-MeO in deuterated solvent. However, since kf
is large enough compared to kr for 1-p-MeO (Table 1), the size
of the solvent deuterium kinetic isotope effects (KIEs) should
primarily reflect the size of the isotope effect on the kf step if
the kinetic analyses were made only with the first half-life
kinetic data. The equilibrium constant determined independ-
ently in the fully deuterated solvent was 7.84, which is identical
with the constant in the nondeuterated solvent. By assuming
that the equilibrium constant in a partly deuterated solvent is
the same, the forward rate constant (kf) could be calculated.
The rate constants thus obtained are listed in Table 3.
fraction of deuterium in the solvent system. The linear proton-
Figure 5. Proton-inventory plot for the reaction of 1-p-MeO with
KOH in 70% (v/v) aqueous MeOH at 25.0 °C.
inventory plot suggests that only one type of isotope effect
contributes to the overall KIE, eliminating multiple active
participation of solvent molecules.8
In conclusion, all these results point to the mechanism in
which the rearrangement is initiated with the rate-determining
α-hydrogen abstraction rather than the mechanism with initial
hydroxyl hydrogen abstraction as in the general α-ketol
rearrangement.
The observed solvent KIE (kH/kD) was determined to be
0.43 (=2.85/6.58) for fully deuterated solvent. The magnitude
of the solvent deuterium isotope effects is conveniently
interpreted with isotopic fractionation factors, ϕ, which are
given as the equilibrium constant in eq 4.7 As shown in eq 4, ϕ
is the preference for deuterium over protium in SL (L = H or
D) relative to that in hydroxylic solvent, ROL. A number of
Table 3. Rate Constants for Equilibration of 1-p-MeO with KOH in 70% (v/v) Aqueous MeOH at 25.0 °C with Variable D
Content
a
a
n
102keq/s−1 M−1
102kf/s−1 M−1
n
102keq/s−1 M−1
102kf/s−1 M−1
0
3.21 0.07
3.79 0.10
4.15 0.12
4.50 0.11
5.11 0.06
2.85 0.06
3.37 0.09
3.68 0.11
3.99 0.09
4.54 0.05
0.657
0.750
0.875
1.00
5.55 0.15
6.09 0.12
6.77 0.10
7.42 0.10
4.93 0.13
5.41 0.11
6.01 0.09
6.58 0.09
0.125
0.250
0.375
0.500
a
Fraction of deuterated solvent.
D
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EXPERIMENTAL SECTION
AUTHOR INFORMATION
Corresponding Author
*E-mail: yamataka@rikkyo.ac.jp.
Notes
■
■
Materials. Asymmetrically substituted benzoins 1-X and 2-X were
synthesized either by the reaction of XC6H4CHO (X = H for
preparation of 2-X) with SiMe3CN4a followed by the Grignard
reaction with XC6H4MgBr (X = H for 1-X)4b or by the reaction of
PhCHO with (EtO)3P and Me3SiCl followed by the reactions with
LDA and then with XC6H4CHO.4b
Reactions. Methanol and water were fractionally distilled and
degassed by bubbling N2 gas for 1 h before use. The concentration of
KOH solution was determined titrimetrically before use. All reactions
were carried out strictly under N2 conditions; otherwise, the reaction
was deteriorated by oxidative side reactions.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was in part supported by SFR aid by Rikkyo
University and a Grant-in-Aid for Scientific Research (No.
22350023) from the Ministry of Education, Science, Sports,
Culture and Technology, Japan.
Equilibrium Constants. As a typical example, a 70% (v/v)
aqueous MeOH solution of 1-p-Me (10 mM) and KOH of known
concentration was allowed to react at 25.0 0.1 °C for 10−20 half-
lives. The reaction solution was poured into ice−water and extracted
with ether. The 1H NMR analysis of the intensities of the Me signals of
1-p-Me and 2-p-Me allowed one to calculate the relative abundance of
1-p-Me and 2-p-Me. The same measurement was carried out four
times, two starting from 1-p-Me and two from 2-p-Me and with
different KOH concentrations (8.79 and 19.1 mM). For p-MeO- and
m-Me substituted-compounds, the Me signals were used, and for F-,
Cl-, and CF3-substituted compounds, the α-CH signals were used to
calculate the relative abundance of 1-X and 2-X. Standard deviations
for multiple measurements of the equilibrium constants are listed in
Table 1.
Rate Measurements. The rates of the reactions were measured
photometrically at 25.0 0.1 °C in aqueous 70% (v/v) MeOH. As an
example, a reaction solution of 1-p-MeO (7.3 mM) and KOH (19.3
mM) was placed in a tightly sealed constant-temperature UV cell. Both
the substrate and base solutions were fully bubbled with N2 before
mixing. The rate was measured by following the absorbance at 283 nm,
at which the change of absorbance is largest during the reaction. A
good linear first-order rate plot was obtained up to 2 half-lives with a
correlation coefficient of better than 0.999. The experimental
absorbance after enough reaction time (infinity absorbance) agreed
well with that calculated from the extinction coefficients of 1-p-MeO
and 2-p-MeO and the equilibrium constant measured separately.
However, in some cases, these experimental and calculated infinity
absorbances disagreed due to the occurrence of a side reaction
(oxidation to benzil). In those cases, the calculated infinity absorbance
was used to obtain pseudo-first-order rate constants. The effect of the
base concentration on the rate was examined with 1-p-Me, for which
the rate constants showed a linear dependence on [KOH] with a near
zero intercept.
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Isotope Exchange Experiment. Reactions were carried out in
deuterated 70% (v/v) D2O−CD3OD in an NMR tube at room
temperature. For the reactions of 1-p-MeO and 2-p-MeO, the changes
of the 1H intensity of the MeO signals and α-H signals were followed
with time with respect to the internal standard (PhMe). For the
reactions of 1-p-Me, 1-m-Me, 2-p-Me, and 2-m-Me, PhOMe was used
as the internal standard. The intensities of the signals of the starting
materials relative to the internal standard at t = 0 could not be
measured due to the elapsed time for measurement setting, and thus,
data acquisition could be started only several minutes after mixing.
Due to the H/D exchange of the α-H during the reaction, the kinetic
analyses were made with data for the first half-life.
Solvent Isotope Effect. Reactions in deuterated solvent were
carried out in either fully deuterated CD3OD:D2O = 7:3 (v/v) or in a
preset mixture of CD3OD:D2O = 7:3 (v/v) and CH3OH:H2O = 7:3
(v/v) and were followed photometrically as described above.
Reactions were followed for the first half-life.
ASSOCIATED CONTENT
■
S
* Supporting Information
Results of isotope exchange experiments (Figures S1−S4) and
kinetic equations. This material is available free of charge via
the Internet at http://pubs.acs.org.
E
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