Reaction pathway and rate-determining step of the Schmidt rearrangement/fragmentation: A kinetic study

Article abstract of DOI:10.1021/jo300419c

The Schmidt rearrangement of substituted 3-phenyl-2-butanone with trimethylsilyl azide in 90% (v/v) aqueous TFA gave two types of product, fragmentation and rearrangement, the ratio of which depends on the substituent: more fragmentation for a more electron-donating substituent. Rate measurements by azotometry indicated the presence of an induction period, and the pseudo-first-order rate constants showed saturation kinetics with respect to the azide concentration. It was indicated that the reaction proceeds through pre-equilibrium in the formation of iminodiazonium (ID) ion and that the N ₂ liberation from the ID ion is rate-determining. Under high azide concentration conditions, where the effective reactant is the ID ion, the reaction gave a linear Hammett plot with a value of -0.50. The observed substituent effects on the rate and the product selectivity imply that path bifurcation on the way from the rate-determining TS to the product states occurs, as suggested by previous molecular dynamics simulations, in a similar manner to the analogous Beckmann rearrangement/fragmentation reactions.

Full text of DOI:10.1021/jo300419c

Article
pubs.acs.org/joc
Reaction Pathway and Rate-Determining Step of the Schmidt
Rearrangement/Fragmentation: A Kinetic Study
Ryo Akimoto, Takehiro Tokugawa, Yutaro Yamamoto, and Hiroshi Yamataka*
Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro, Toshima-ku 171-8501
Tokyo, Japan
ABSTRACT: The Schmidt rearrangement of substituted 3-
phenyl-2-butanone with trimethylsilyl azide in 90% (v/v)
aqueous TFA gave two types of product, fragmentation and
rearrangement, the ratio of which depends on the substituent:
more fragmentation for a more electron-donating substituent.
Rate measurements by azotometry indicated the presence of
an induction period, and the pseudo-first-order rate constants
showed saturation kinetics with respect to the azide
concentration. It was indicated that the reaction proceeds through pre-equilibrium in the formation of iminodiazonium (ID)
ion and that the N2 liberation from the ID ion is rate-determining. Under high azide concentration conditions, where the effective
reactant is the ID ion, the reaction gave a linear Hammett plot with a ρ value of −0.50. The observed substituent effects on the
rate and the product selectivity imply that path bifurcation on the way from the rate-determining TS to the product states occurs,
as suggested by previous molecular dynamics simulations, in a similar manner to the analogous Beckmann rearrangement/
fragmentation reactions.
with the steric bulk of R,3,4 which suggested that syn−anti
INTRODUCTION
■
isomerization in ID was slow and that a group located anti to
N2 migrated preferentially. The effect of substituent on the
product ratio for the reactions of substituted benzophenones
was reported to be small,5 and information on the rate-
determining step of the reaction is scarce. No kinetic
measurement was carried out that allows one to analyze
substituent effects. In another mechanistic aspect, the Schmidt
rearrangement of ketones and aldehydes is known to yield
fragmentation products (R1 cation + R2-CN) in addition to the
expected rearrangement products, depending on the R1 group
in eq 1,6,7 in an analogous way to the Beckmann reaction of
ketoximes.8−10 Previous computational study on the Schmidt
reaction revealed that dynamic path bifurcation may occur,
depending on the structure of the ketone, for the N2-liberation
step of ID, in which both rearrangement and fragmentation
The Schmidt and Beckmann rearrangements are well-known
rearrangement reactions at an electron-deficient nitrogen
center.1 Both reactions give a carboxylic acid amide from a
ketone. However, the reaction mechanism is much less known
for the Schmidt compared with the Beckmann rearrangement.
The reaction pathway of the Schmidt rearrangement is often
written as eq 1, in which azidohydrin (AH) and iminodiazo-
products are formed through a common transition state (TS).11
In the present study, we have carried out a kinetic and
product analysis experiment to clarify important, but still
unsolved, mechanistic issues for the Schmidt rearrangement:
(1) identification of the rate-determining step of this multistep
reaction, (2) substituent effects on the reactivity and product
selectivity, (3) factors that determine the product ratio, and (4)
possible occurrence of dynamic path bifurcation on the
rearrangement/fragmentation step.
nium ion (ID) are important intermediates. Although there has
been a claim that an amide is directly formed from AH,2 ID is
commonly considered to be the precursor intermediate for the
rearrangement.3−6 The reaction of PhCHC(CH3)N3 under
acidic conditions was shown to give a mixture of PhCH2- and
CH3-migrated amides, whose ratio was the same as that
observed for the Schmidt reaction of PhCH2COCH3. The
+
results indicated that ID (PhCH2C(CH3)N3 ) was the
common intermediate of the two reactions.5
Product analysis studies for the Schmidt reactions of ketones,
ArCOR, showed that the fraction of R rearrangement increased
Received: February 28, 2012
Published: April 10, 2012
© 2012 American Chemical Society
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evolution−time plots are shown in Figure 3. Two points are
apparent in Figure 3. First, in both cases, the evolution of N2
did not start right after the reaction was allowed to occur by
mixing the ketone and TMSA and showed an induction period.
Second, the plot exhibited different patterns depending on the
substituent. The plot for X = p-CF3 was normal, in which the
infinity value of evolved N2 agreed with the theoretical one
calculated from the initial concentration of the ketone ([1-p-
CF3] = 0.05 M, 90% (v/v) TFA, 6.0 mL). The data gave good
linear pseudo-first-order kinetic plots, if the induction period
observed at the very beginning of the reaction was neglected.
On the other hand, the reaction of 1-m-Me produced more N2
than expected from the ketone concentration. Apparently,
additional N2 was generated from a secondary reaction in
addition to the Schmidt reaction of the ketone and TMSA. The
additional N2 generation became more significant when X was
more electron-donating.
It appeared reasonable to expect that fragmentation product
4-X underwent further reactions to generate N2. The reaction
of separately prepared 4-H at 0 °C in 90% (v/v) TFA indeed
generated N2 and yielded N-1-phenylethylaniline as the major
product, probably through the route in Scheme 1. The reaction
of 4-H in 90% (v/v) TFA at 25 °C exhibited the time-
dependent UV spectra (Figure 4), which were similar to those
observed for the Schmidt reaction of 1-H in Figure 1. The fact
strongly suggested that the UV spectrum observed during the
course of the Schmidt reaction was due to α-phenylethyl
cation.12,13
Pseudo-first-order kinetic analyses of the results of the
azotometry experiment were made by using data of the 1.0−2.0
mL N2-evolution period (14−28% conversion of reaction) for
each substituted derivative in order to avoid interference from
the initial induction and the secondary reactions. Although the
absolute rate constants could be in significant error because of
the arbitrary selection and the narrow range of data points used
in the kinetic analyses, the relative reactivities would be much
more reliable since the analyses were made in the same way for
all substituted derivatives.
Effect of TMSA Concentration. Rate measurements by
azotometry at different TMSA concentrations were carried out
for selected derivatives, and the results are listed in Table 2.
The rate constants did not show a linear dependence on the
TMSA concentration as required for the second-order kinetics,
but showed the sign of saturation kinetics (Figure 5). The
occurrence of saturation of the pseudo-first-order rate constants
with the concentration of TMSA reflects the multistep nature
of the Schmidt rearrangement/fragmentation reaction.
Substituent Effect. The observations of the saturation
kinetics and the induction period suggested that the Schmidt
RESULTS AND DISCUSSION
■
Product Analysis. Reactions of ring-substituted-3-phenyl-
2-butanones, 1-X (X = p-MeO, p-Me, m-Me, H, p-Cl, m-Cl, p-
NO2), with trimethylsilyl azide (TMSA) were carried out in
90% (v/v) aqueous TFA (eq 2). Since it became clear that the
initial fragmentation product, 4-X, underwent secondary
reactions (vide infra), the product yields and the material
balance were examined by analyzing the product distribution at
less than 50% conversion of reaction. The products were
identified and the yields were determined by 1H NMR, and the
results are listed in Table 1. The observed material balance was
acceptable despite possible disturbance due to secondary
reactions. It is clear that the product distribution depends
strongly on the electronic nature of the substituent. The major
product was the rearrangement product, 2-X for X = m-Cl and
p-CF3, but the fragmentation product, 4-X, became a major
product for 1-X with an electron-donating X. Another
fragmentation product, 6-X, could not be detected. It was
considered to be possible that the nitrilium ion (R2−C+N−
−
R1) intermediate is trapped by N3 and subsequent R2
rearrangement and hydrolysis give the dialkylurea derivative
(R2NHCONHR1). Actually, however, this type of product was
not obtained.
Rate Measurement. UV Spectrometry. Attempted
measurements of rate constants of the Schmidt reactions of
1-X were carried out photometrically in 90% (v/v) TFA at 30
°C. For 1-H, the absorbance at 299 nm increased monotoni-
cally up to 24 min, and then started to decrease, as illustrated in
Figure 1. The time dependence of the UV absorbance for p-Me,
H, and p-CF3 derivatives (Figure 2) suggested the formation
and decomposition of some kind of intermediate during the
course of the reaction, especially for X = p-Me and H. The time
course of the absorbance did not allow the measurement of the
rate constants of these reactions by the UV method.
Azotometry. The rate of N2 evolution from the reaction
mixture was monitored by using a gas buret for the reactions of
1-X (X = p-MeO, p-Me, m-Me, H, p-Cl, m-Cl, and p-CF3) with
TMSA in 90% (v/v) TFA at 0 °C. Two representative N2
a
Table 1. Product Yields for the Reaction of 1-X and TMSA in 90% (v/v) TFA at 0 °C
b
X
2-X
3-X
4-X
95
5-X
F/(R + F)
material balance (%)
p-MeO
p-Me
m-Me
H
0
0
3
0
5
5
5
7
3
8
1
1
1
1
1
5
1
100
95
92
85
77
10
0
98
100
95
1
94
87
79
67
8
1
1
1
3
1
1
1
1
1
1
5
10
16
87
92
3
1
1
1
6
92
p-Cl
10
2
1
98
m-Cl
p-CF3
1
1
91
0
0
99
a
Initial concentration: [1-X] = 0.05 M, [TMSA] = 0.50−1.0 M. Yields are relative yields in percentage, and material balance is based on the amount
b
of remaining reactant and the absolute yields of the products. Percentage of the fragmentation products over the total products.
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Figure 1. Time dependence of UV spectra for the reaction of 1-H and TMSA in 90% (v/v) TFA at 30 °C. [1-H] = 0.75 mM, [TMSA] = 150 mM.
Scheme 1
Figure 2. Time dependence of the absorbance at 299 nm for 1-X (X =
p-Me, H, p-CF3) at 30 °C. [1-H] = 0.75 mM, [TMSA] = 150 nM in
90% (v/v) TFA.
rearrangement obeys pre-equilibrium kinetics. The reaction is
−
initiated by carbonyl addition of N3 to give AH. Dehydration
from AH to ID is expected to be fast in TFA, and hence the
kinetic scheme is expressed by eq 3 and the kinetic equation is
given by eq 4. According to this mechanism, the observed rate
constant is first-order with respect to the azide concentration at
low [TMSA] and zero-order at high [TMSA]. Under high azide
concentration conditions, where the reaction gives the zero-
order kinetics with respect to [TMSA], the ID ion acts as the
effective reactant since the equilibrium in eq 3a lies on the ID
side, and the N2-liberation step becomes rate-determining. The
pseudo-first-order rate constants at a [TMSA] of 1.50 M were
then measured for all substituted derivatives and are listed in
Table 3. The Hammett plot gave a ρ value of −0.50 (Figure 6).
The point for p-MeO deviates downward from the correlation
line, partly because of a decreased electron-donating ability of
p-MeO in the highly acidic medium and because of an exalted
resonance stabilization of ID compared to that in the TS (Chart
1, vide infra). It is interesting to note here that the ρ value is
much smaller than that for the Beckmann rearrangement,
despite the fact that the N2- or H2O-liberation step is
considered rate-determining in both cases.
kobs = Kk[N3−]/(1 + K[N3−])
(4)
Figure 3. Time dependence of N2 evolution for the reaction of 1-X
(0.05 M) and TMSA (0.50 M) at 0 °C. Closed circle for X = m-Me
Previous computational studies on the Schmidt and the
and open circle for X = p-CF3.
Beckmann rearrangement of ketone 1-X showed that the ρ
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Figure 4. Time dependence of UV spectra for the reaction of 4-H in 90% (v/v) TFA at 25 °C. [4-H] = 0.75 mM.
Table 2. Pseudo-First-Order Rate Constant (104kobs/s−1) Determined by Azotometry for the Reaction of 1-X at Different TMSA
a
Concentrations in 90% (v/v) TFA at 0 °C
b
b
b
b
b
b
b
X
0.20
0.375
0.50
0.75
1.00
1.20
1.50
p-MeO
1.92 0.14
1.75 0.14
3.16 0.33
2.40 0.46
3.68 0.19
2.69 0.37
3.95 0.21
3.44 0.30
3.93 0.36
3.58 0.15
4.34 0.06
3.77 0.07
4.37 0.26
3.79 0.31
H
a
b
Initial concentration of [1-X] is 0.05 M. Rate constants are the average of 4-7 measurements, and errors are standard deviations. Concentration of
TMSA in M.
Figure 5. Concentration dependence of the pseudo-first-order rate constants for the Schmidt reactions of (A) 1-p-OMe and (B) 1-H in 90% (v/v)
TFA at 0 °C. The initial concentration of 1-X = 0.05 M.
Table 3. Pseudo-First-Order Rate Constant (104kobs/s−1) Determined by Azotometry for the Reaction of 1-X at [TMSA] = 1.50
a
M in 90% (v/v) TFA at 0 °C
p-MeO
p-Me
m-Me
H
p-Cl
m-Cl
p-CF3
104kobs/s−1
4.37 0.26
4.86 0.44
4.04 0.27
3.79 0.31
2.95 0.29
2.62 0.28
2.11 0.22
a
Initial concentration of [1-X] is 0.05 M. Rate constants are the average of 4−7 measurements, and errors are standard deviations.
values for N2 liberation from ID (Schmidt) and H2O liberation
from oxime (Beckmann) are large (−7.1) for the Beckmann9
and near zero for the Schmidt reaction.11 The experimental ρ
value for Beckmann was −2.2.10 Thus, the present small ρ value
is in line with the computational prediction. The reason for the
small ρ value for the Schmidt rearrangement step is that the
unit positive charge on the ID ion is delocalized into the phenyl
ring, as shown in Chart 1, which makes the stability of the ID
ion substituent-dependent. The significant substituent effect in
the effective reactant masked the substituent effect on the TS
stability, and hence the Hammett ρ value on the process from
ID to TS became small, as observed. The rationale was
supported by previous MO calculations.11
It should be noted that the Hammett plots in Figure 6 gave a
reasonably good straight line. This indicates that the reaction
mechanism is the same for all substituted derivatives, whereas
the product distribution (rearrangement vs fragmentation) is
different with substituent. If the two products are formed via
independent and concurrent paths, a change of relative
importance of the two paths should have given V-shaped
Hammett plots, which were not observed. To further examine
the possibility of the concurrent mechanism, the observed rate
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apparent discrepancy between substituent effects on the rate
and the product selectivity could arise from path bifurcation
occurring on the way from the TS to the products.9
Experimental results on the Beckmann reaction agreed with
the MO predictions on the substituent effects on the rate and
the product selectivity and gave support for the computational
predictions of path bifurcation.10
In the Schmidt reaction, MO calculations gave a small ρ
value for the N2-liberation step and MD simulations indicated
path bifurcation occurring on the way from the TS to the
products,11 in a similar manner to the Beckmann reaction. The
present experimental results on the Schmidt reaction agreed
with the MO calculations on the substituent effects on the rate
and the product selectivity, and thus it is likely that a path
bifurcation on the way from the TS to product states occurs for
the Schmidt reaction of 1-X as well in a similar manner to the
Beckmann reaction.
Figure 6. Hammett plot for the Schmidt reaction of 1-X in 90% (v/v)
TFA at 0 °C. The initial concentration of [1-X] = 0.05 M, and
[TMSA] = 1.50 M.
SUMMARY AND CONCLUDING REMARKS
■
Analysis of the Schmidt rearrangement of 1-X was complicated
by the secondary reaction of initially formed fragmentation
products. Nevertheless, kinetic measurements by means of
azotometry revealed two important features: the presence of an
induction period, and saturation kinetics with respect to azide
concentrations. It was indicated that the reaction proceeds
through pre-equilibrium in the formation of the ID ion and that
the N2 liberation from the ID ion could be rate-determining.
The effective reactant is the ID ion under high azide
concentration conditions. The reaction gave linear Hammett
plots with a ρ value of −0.50. The small ρ value is consistent
with the mechanism. The reaction gave two types of products,
fragmentation and rearrangement, the ratio of which depends
on the substituent: more fragmentation for a more electron-
donating substituent. The analysis of the observed substituent
effects on the rate and the product selectivity eliminates the
mechanism of concurrent reaction pathways. A plausible
mechanism is that path bifurcation on the way from the rate-
determining TS to the product states occurs in the Schmidt
rearrangement, as suggested by previous MD simulations in a
similar manner to the analogous Beckmann rearrangement. It
should be noted that such bifurcation was observed for a
specially designed system, which reacts in a borderline
mechanism and gives two products in different ratios
depending on substituent. Thus, the present results do not
necessarily suggest the occurrence of bifurcation for commonly
used substrates, but it is sure that the possibility of path
bifurcation should be taken into consideration when a reaction
mechanism and a product selectivity are in question.
Chart 1
constants were divided into individual rate constants, kr and kf,
for the rearrangement and fragmentation steps, respectively,
under the assumption that the two types of products were
formed from ID directly and independently. The calculated kr
and kf were then used to construct Hammett plots in Figure 7.
Figure 7. Hammett plots for the rearrangement (filled circle) and
fragmentation (open circle) steps of the Schmidt reaction of 1-X in
90% (v/v) TFA at 0 °C. Rate constants for each step were derived
under the assumption that the rearrangement and fragmentation steps
are independent and concurrent pathways. The initial concentration of
[1-X] = 0.05 M, and [TMSA] = 1.50 M.
EXPERIMENTAL METHODS
■
Materials. 1-Substituted-phenyl-2-propanones were synthesized
from corresponding benzaldehydes by nitroaldol with EtNO2,14 and
Fe reduction.15 3-Substituted-phenyl-2-butanones (1-X) were pre-
pared from 1-substituted-phenyl-2-propanones by methylation (MeI/
NaOH) and purified by using 2,4-dinitrophenylhydrazine. Hydrolyses
of hydrazones gave nearly pure 1-X, which were further purified by
distillation, and column chromatography (hexane/AcOEt = 4:1).
Reaction solvents were purified by distillation. Trimethylsilyl azide was
used as received.
Apparently, both Hammett plots showed poor correlation
against the standard σ constants. Furthermore, the plot for the
rearrangement gave a positive slope, which is inconsistent with
the step. Thus, the Hammett plots in Figure 6 strongly argued
the concurrent product formation mechanism unlikely.
In the Beckmann reaction, MO calculations gave a linear
Hammett plot for the H2O-liberation step together with a
strong substituent dependence on the product distribution.
Molecular dynamics (MD) simulations indicated that the
3-p-Methoxyphenyl-2-butanone 2,4-Dinitrophenylhydro-
1
zone: H NMR (CDCl3, 400 MHz) δ 11.1 (s, 1H), 9.15 (d, J = 2.9
Hz, 1H), 8.35 (dd, J = 9.6, 2.9 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.16
(d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.76 (q, J =
7.2 Hz, 1H), 1.90 (s, 3H), 1.54 (d, J = 7.2 Hz, 3H). mp 129−134 °C.
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3-p-Methylphenyl-2-butanone 2,4-Dinitrophenylhydro-
by comparing proton intensities of the products and the internal
standard.
1
zone: H NMR (CDCl3, 400 MHz) δ 11.1 (s, NH), 9.15 (d, J =
2.4 Hz, 1H), 8.35 (dd, J = 9.6, 2.4 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H),
7.12−7.18 (m, 4H), 3.78 (q, J = 7.0 Hz, 1H), 1.91 (s, 3H), 1.54 (d, J =
7.0 Hz, 3H). mp 129−134 °C.
Rate Measurements. Azotometry. A 90% (v/v) TFA solution of
1-X (1.00 mmol, 10.0 mL) and a solution of TMSA (10.00 mol, 10.0
mL) were separately prepared at 0.0 0.5 °C. Two solutions (3.0 mL
each) were mixed by means of a hypodermic syringe in a two-neck
flask connected to a gas buret, and the amount of gas evolved was
measured volumetrically. After some induction period, gas evolution
started, but for all 1-X, except X = p-CF3, the amount of N2 evolved
exceeded the theoretical value (7.3 mL) due to secondary reactions of
fragmentation products. To avoid disturbance by the induction period
and the secondary reactions, pseudo-first-order kinetics was analyzed
by using a 1.0−2.0 mL range of N2 evolution, which corresponds to
the conversion of reaction of 14%−28%. Although the absolute rate
constants could be in significant error because of the arbitrary selection
and the narrow range of data used in the kinetic analyses, the relative
reactivities would be much more reliable since the analyses were made
in the same way for all substituted derivatives.
3-m-Methylphenyl-2-butanone 2,4-Dinitrophenylhydro-
1
zone: H NMR (CDCl3, 400 MHz) δ 11.1 (s, NH), 9.16 (d, J =
2.8 Hz, 1H), 8.36 (dd, J = 9.6, 2.8 Hz, 1H), 8.08 (d, J = 9.6 Hz, 1H),
7.04−7.25 (m, 4H), 3.77 (q, J = 7.3 Hz, 1H), 2.35 (s, 3H), 1.91 (s,
3H), 1.55 (d, J = 7.3 Hz, 3H). mp 146−147 °C.
1
3-Phenyl-2-butanone 2,4-Dinitrophenylhydrozone: H NMR
(CDCl3, 400 MHz) δ 11.1 (s, NH), 9.15 (d, J = 2.9 Hz, 1H), 8.35 (dd,
J = 9.6, 2.9 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.24−7.35 (m, 5H), 3.82
(q, J = 6.9 Hz, 1H), 1.92 (s, 3H), 1.57 (d, J = 6.9 Hz, 3H). mp 169−
171 °C.
3-p-Chlorophenyl-2-butanone 2,4-Dinitrophenylhydrozone:
1H NMR (CDCl3, 400 MHz) δ 11.1 (s, NH), 9.15 (d, J = 2.3 Hz, 1H),
8.36 (dd, J = 9.6, 2.3 Hz, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 8.6
Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 3.79 (q, J = 6.9 Hz, 1H), 1.91 (s,
3H), 1.55 (d, J = 6.9 Hz, 3H). mp 114−116 °C.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yamataka@rikkyo.ac.jp.
■
3-m-Chlorophenyl-2-butanone 2,4-Dinitrophenylhydro-
1
zone: H NMR (CDCl3, 400 MHz) δ 11.1 (s, NH), 9.16 (d, J =
2.4 Hz, 1H), 8.36 (dd, J = 9.6, 2.4 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H),
7.13−7.31 (m, 4H), 3.79 (q, J = 7.0 Hz, 1H), 1.92 (s, 3H), 1.56 (d, J =
7.0 Hz, 3H). mp 130−134 °C.
Notes
The authors declare no competing financial interest.
3-p-Trifluoromethylphenyl-2-butanone 2,4-Dinitrophenyl-
1
hydrozone: H NMR (CDCl3, 400 MHz) δ 11.1 (s, NH), 9.15 (d,
ACKNOWLEDGMENTS
■
J = 2.8 Hz, 1H), 8.36 (dd, J = 9.8, 2.8 Hz, 1H), 8.04 (d, J = 9.8 Hz,
1H), 7.61 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 3.89 (q, J = 6.8
Hz, 1H), 1.93 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). The melting point was
not measured since the sample was contaminated by the hydrazone of
dimethylated ketone.
The study was, in part, supported by the SFR aid by Rikkyo
University, and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, Culture and Technol-
ogy, Japan.
Substituted 3-phenyl-2-butanone (1-X) purified via hydrazone,
distillation, and column chromatography showed >99% purity with
GC, and their NMR spectra were consistent with those in the
literature.16
REFERENCES
■
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Wiley: New York, 1963; Vol. 1, Chapter 8.
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6.9 Hz, 3H). bp 100−101 °C/0.7 Torr.
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(d) Rodríguez, C.; de Gonzalo, G.; Pazmino, D. E. T.; Fraaije, M. W.;
Gotor, V. Tetrahedron: Asymmetry 2009, 20, 1168 (1-m-Me, 1-m-Cl).
3-p-Methylphenyl-2-butanone (1-p-Me): 1H NMR (CDCl3,
400 MHz) δ 7.15 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.70
(q, J = 7.0 Hz, 1H), 2.33 (s, 3H), 2.04 (s, 3H), 1.37 (d, J = 7.0 Hz,
3H). bp 70 °C/0.5 Torr.
1
3-m-Methylphenyl-2-butanone (1-m-Me): H NMR (CDCl3,
́
enyi, J. Helv.
400 MHz) δ 7.00−7.24 (m, 4H), 3.70 (q, J = 7.2 Hz, 1H), 2.34 (s,
3H), 2.05 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H). bp 173−74 °C/0.5 Torr.
3-Phenyl-2-butanone (1-H): 1H NMR (CDCl3, 400 MHz) δ
7.21−7.36 (m, 5H), 3.74 (q, J = 7.0 Hz, 1H), 2.05 (s, 3H), 1.39 (d, J =
7.0 Hz, 3H). bp 65−66 °C/0.5 Torr.
1
3-p-Chlorophenyl-2-butanone (1-p-Cl): H NMR (CDCl3, 400
MHz) δ 7.31 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 3.73 (q, J =
7.1 Hz, 1H), 2.06 (s, 3H), 1.38 (d, J = 7.1 Hz, 3H). bp 80−85 °C/0.7
Torr.
3-m-Chlorophenyl-2-butanone (1-m-Cl): 1H NMR (CDCl3,
400 MHz) δ 7.09−7.28 (m, 4H), 3.72 (q, J = 7.0 Hz, 1H), 2.07 (s,
3H), 1.39 (d, J = 7.0 Hz, 3H). bp 73−74 °C/0.4 Torr.
̈
3-p-Trifluoromethylphenyl-2-butanone (1-p-CF3): 1H NMR
(CDCl3, 400 MHz) δ 7.60 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz,
2H), 3.83 (q, J = 6.8 Hz, 1H), 2.08 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H).
bp 75 °C/0.4 Torr.
Product Analysis. Material balance and product distribution were
determined by analyzing the reaction mixture by NMR. A mixture of
1-X (0.05 M), TMSA (0.50 M), and a small amount of dibenzyl ether
as an internal standard for NMR measurement was allowed to react at
0.0 0.5 °C for a preset time. The reaction solution was poured into
cold benzene, and the solvent was evaporated. The remaining material
was dissolved in CDCl3, and the NMR spectrum was recorded. The
products were identified by comparing the spectra with those of
separately prepared authentic samples, and the yields were determined
(1-H, 1-p-Cl).
̃
4078
dx.doi.org/10.1021/jo300419c | J. Org. Chem. 2012, 77, 4073−4078