Dynamic path bifurcation in the Beckmann reaction: Support from kinetic analyses

Article abstract of DOI:10.1021/jo200728t

The reactions of oximes to amides, known as the Beckmann rearrangement, may undergo fragmentation to form carbocations + nitriles when the migrating groups have reasonable stability as cations. The reactions of oxime sulfonates of 1-substituted-phenyl-2-propanone derivatives (7-X) and related substrates (8-X, 9a-X) in aqueous CH₃CN gave both rearrangement products (amides) and fragmentation products (alcohols), the ratio of which depends on the system; the reactions of 7-X gave amides predominantly, whereas 9a-X yielded alcohols as the major product. The logk-logk plots between the systems gave excellent linear correlations with slopes of near unity. The results support the occurrence of path bifurcation after the rate-determining TS of the Beckmann rearrangement/fragmentation reaction, which has previously been proposed on the basis of molecular dynamics simulations. It was concluded that path-bifurcation phenomenon could be more common than thought and that a reactivity-selectivity argument based on the traditional TS theory may not always be applicable even to a well-known textbook organic reaction.

Full text of DOI:10.1021/jo200728t

ARTICLE
pubs.acs.org/joc
Dynamic Path Bifurcation in the Beckmann Reaction: Support
from Kinetic Analyses
Yutaro Yamamoto, Hiroto Hasegawa, 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
b
ABSTRACT: The reactions of oximes to amides, known as the Beck-
mann rearrangement, may undergo fragmentation to form carbocations
þ nitriles when the migrating groups have reasonable stability as cations.
The reactions of oxime sulfonates of 1-substituted-phenyl-2-propanone
derivatives (7-X) and related substrates (8-X, 9a-X) in aqueous CH3CN
gave both rearrangement products (amides) and fragmentation products
(alcohols), the ratio of which depends on the system; the reactions of 7-X
gave amides predominantly, whereas 9a-X yielded alcohols as the major product. The logkꢀlogk plots between the systems gave
excellent linear correlations with slopes of near unity. The results support the occurrence of path bifurcation after the rate-
determining TS of the Beckmann rearrangement/fragmentation reaction, which has previously been proposed on the basis of
molecular dynamics simulations. It was concluded that path-bifurcation phenomenon could be more common than thought and that
a reactivity-selectivity argument based on the traditional TS theory may not always be applicable even to a well-known textbook
organic reaction.
’ INTRODUCTION
in 1985,10 dynamics effect has been claimed to appear in different
ways, such as nonstatistical barrier recrossing,11 nonstatistical pro-
duct distribution,12 shallow minimum skip on the intrinsic reaction
coordinate (IRC),13 non-IRC path,14 and path bifurcation.15ꢀ18 All
these results suggested that the mechanism of these reactions
could not be defined by the reaction paths on the potential energy
surface (PES) and by the traditional transition state (TS) theory.
Recent molecular orbital (MO) and MD study indicated that
the Beckmann rearrangement/fragmentation reactions of 1-sub-
stituted-phenyl-2-propanone oximes in the gas phase proceeded
through a single TS, and that the introduction of an electron-
donating substituent into the phenyl ring changed the mechan-
ism from rearrangement to fragmentation. The trajectory calcula-
tions suggested that both rearrangement/fragmentation products
were formed through path bifurcation on the way from the TS to
the product states and that the product ratio varied as a function
of substituent.17 Thus, the rate-determining TS did not contain
enough information to define the product ratio and therefore to
define the entire reaction mechanism.17,18 Under these circum-
stances, it is important to know whether the bifurcation mechan-
ism operates in solution reaction as well.
The Beckmann rearrangement is a classical textbook reaction,
in which oximes under acidic conditions or oximes with an
appropriate leaving group (Y) under solvolytic conditions give
amide via intramolecular rearrangement (path a in eq 1). The
Beckmann rearrangement proceeds via a concerted mechanism
with a higher reactivity for a more electron-donating R1 group.1,2
Oximes have also been known to give fragmentation products
when the R1 group is stabilized as a cation by an adjacent group,
such as O,3 S,4 N,5 Si,6 and CHdCHR.7 Grob and co-workers
have shown that the rearrangement of an oxime tosylate (Y =
OTs, eq 1) in 80% ethanol gave the mixture of the amide and
nitrile products and that the product ratio varied depending on
R1 and R2.8 For a series of R1, the ratio (%) of fragmentation was
reported to be 0 (i-Pr), 10 (t-Bu), and 80 (CHPh2). On the other
hand, the overall reactivity varied with the R1 group in the order
(relative reactivity), Me (1) < CHPh2 (40) < Et (60) < Ph (100)
< i-Pr (810) < t-Bu (870). The ratio of fragmentation to amide
formation was not relaþted to the overall reactivity, but increases
with the stability of R1
.
In the present study, we have carried out kinetics as well as
product-analysis experiment on the reactions of a series of
sulfonate esters of ketoximes in aqueous CH3CN to address
two important mechanistic issues; (1) whether experimental
results agree with the bifurcation mechanism that was previously
proposed on the basis of the simulation study,17 and (2) what is
It has increasingly been recognized by means of molecular
dynamics (MD) simulation studies that dynamics effect plays a
crucial role in controlling the mechanism of mechanistically
borderline reactions.9 Following a pioneer study by Carpenter
Received: April 8, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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|

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the factor which controls the overall reactivity and the relative
importance of rearrangement and fragmentation routes in the
borderline reaction systems. The results have supported the
occurrence of path bifurcation for this classical reaction.
Table 1. Pseudo First-Order Rate Constants for the Reac-
tions of 7-Xꢀ9a-X in Aqueous CH3CN at 25 °C
k/sꢀ1
X
7-Xa
8-Xb
9a-Xb,c
’ RESULTS AND DISCUSSION
p-MeO
m,p-Me2
p-Me
m-Me
H
9.79 ꢁ 10ꢀ3
3.24 ꢁ 10ꢀ3
2.41 ꢁ 10ꢀ3
1.04 ꢁ 10ꢀ3
8.15 ꢁ 10ꢀ4
2.82 ꢁ 10ꢀ4
1.01 ꢁ 10ꢀ4
4.52 ꢁ 10ꢀ5
2.63 ꢁ 10ꢀ5
1.33 ꢁ 10ꢀ5
4.27 ꢁ 10ꢀ2 d
1.80 ꢁ 10ꢀ2
1.14 ꢁ 10ꢀ2
5.01 ꢁ 10ꢀ3
4.07 ꢁ 10ꢀ3
1.54 ꢁ 10ꢀ3
5.52 ꢁ 10ꢀ4
2.46 ꢁ 10ꢀ4
1.35 ꢁ 10ꢀ4
7.63 ꢁ 10ꢀ5
1.48 ꢁ 10ꢀ2
Substituted ketones (1-X) were synthesized from corre-
sponding benzaldehydes by nitroaldol with EtNO2,19 and Fe
reduction.20 Ketones, 2-X and 3-X, were prepared from 1-X by
methylation (MeI/NaOH). Oximation with NH2OH, followed
by esterification by Tipson’s method21 gave esters, (7-Xꢀ9a-X,
eq 2). We used 2-naphthalenesulfonate esters for 7-X and most
8-X, but 4-methoxybenzenesulfonates were used for 8a-p-MeO
and 9a-X, since the 2-naphthalenesulfonates were difficult to
purify for 8-p-MeO and 9-X.
4.09 ꢁ 10ꢀ3
1.46 ꢁ 10ꢀ3
2.22 ꢁ 10ꢀ4
p-Cl
m-Cl
p-CF3
p-CN
p-NO2
3.50 ꢁ 10ꢀ5
a In 80% (v/v) CH3CN. b In 90% (v/v) CH3CN Rate constants for
p-methoxybenzensulfonates of 6. d Calculated from the rate constant for
8a-p-MeO and the relative reactivity of the two leaving groups. See text
in detail.
c
Table 2. Product Distributions for the Reactions of 7-Xꢀ9a-
X in Aqueous CH3CN at 25 °C
7-Xa
8-Xb
9a-Xb
X
Rc
Fd F%e
Rc
Fd F%e Rc
Fd
F%e
p-MeO
77.6 27.7 26.3
9.0 9.4 40.3 57.8 58.9
90.4
7.4 7.6 46.5 50.2 51.9 0.0 100.0f 100.0
4.9 90.9 94.9 0.0 100.0f 100.0
m,p-Me2 86.6
p-Me
m-Me
H
100.0f 0.0 0.0 74.5 24.2 24.4
100.0f 0.0 0.0 77.3 20.9 21.3 5.6 95.7
100.0f 0.0 0.0 76.7 19.7 20.4
94.5
59.4
The three reaction systems were chosen in the hope that they
all would give either or both rearrangement (R) and fragmenta-
tion (F) products and that the product ratios would vary with
systems (eq 3), thus allowing us to examine the correlation
between the overall reactivity and the product selectivity. The
reactions of 7-Xꢀ9a-X were carried out in aqueous CH3CN at
25 °C in the presence of 1.1 equiv of N,N-dimethylaniline. We
chose aqueous CH3CN as the solvent system, where the product
composition was simple with only amide (rearrangement) and
alcohol (fragmentation) as each type of the product and the
reaction rates were conveniently measured by a spectroscopic
method. Pseudo first-order rate constants are summarized in
Table 1. Rate constants are averages of multiple runs with
reproducibility of (3%. The rate of 8-p-MeO could not be
measured directly, since this compound could not be purified by
recrystallization. Instead, the rate constant for 8-p-MeO was
calculated from the logkꢀlogk plot between 8-X (X = H and
p-Cl) and 8a-X (X = H (1.35 ꢁ 10ꢀ3 sꢀ1), p-Cl (4.57 ꢁ 10ꢀ4
p-Cl
m-Cl
p-CF3
p-CN
p-NO2
100.0f 0.0 0.0 95.3
100.0f 0.0 0.0 94.7
5.9 5.8 41.8 61.1
1.5 1.6
100.0f 0.0 0.0 100.0f 0.0 0.0
100.0f 0.0 0.0 100.0f 0.0 0.0 76.6 21.8
22.2
a In 80% (v/v) CH3CN. b In 90% (v/v) CH3CN. c Yield of rearrange-
ment product (%). d Yield of fragmentation product (%). e Relative
yield of fragmentation product (F/(R þ F)). f Single product was
obtained.
are the major product for 7-X, whereas 2-phenyl-2-propanols are
the major product for 9a-X. For 8-X, the relative yield of alcohol
(F%) spans in a wide range from 0 to 95%. In all cases, there is a
general trend that a more fragmentation product is formed with a
more electron-donating substituent.
The substituent effect on the reactivity was analyzed by means
of an extended Hammett equation (the Yukawa-Tsuno equation,
eq 4), in which r is a parameter to measure the relative
importance of resonance effect over inductive effect and r = 1.0
for σapp = σþ by definition and r = 0.27 for σapp = σ.22 Figure 1
shows the Yukawa-Tsuno plot for the reactions of 7-X in 80%
s
ꢀ1) and p-MeO (1.19 ꢁ 10ꢀ2 sꢀ1)).
CH3CN at 25 °C. The values of σ° and ΔσRþ are listed in the
h
Supporting Information. The observed excellent linear correla-
tion with r = 0.52 indicates that the reaction mechanism is
basically the same for all 7-X’s. The medium sized F and r values
suggest that the migrating benzyl group bears a significant
amount of positive charge on the benzylic carbon, consistent
The product compositions for these reactions were deter-
mined by NMR, and the results are listed in Table 2. It is seen that
the product ratio is different for the three systems. Acetamides
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indicated that the substituent effects gave an excellent linear
Hammett correlation, despite the fact that the intrinsic reaction
coordinate (IRC) from each respective TS led to different
products depending on the substituent; 4-X with an electron-
donating X gave the fragmentation product, whereas
4-X with an electron-withdrawing X yielded the rearrange-
ment product. Ab initio dynamics simulations gave trajec-
tories, which followed the IRC path for X = p-NH2 and p-MeO
giving fragmentation products, and almost so for X = p-NO2
giving the rearrangement products. However, in borderline
cases where X was less electron-donating than p-MeO or
less electron-withdrawing than p-NO2, the trajectories
did not follow the minimum energy path on the PES, but
gave both rearrangement and fragmentation products
directly from the single TS through path bifurcation after
the TS.17
The present experimental observations agree with these
computational results and the observed mismatch between
relative reactivity and product selectivity is best rationalized
as arising from path bifurcation occurring on the way from the
rate-determining TS to the product states (eq 5). An excellent
linear correlation was observed between 7-Xꢀ9a-X despite the
fact that the product varied depending on the system and the
substituent. Interestingly 9a-X, which gave mostly fragmenta-
tion products showed the same substituent effects as 7-X, for
which rearrangement products are the major product. These
results demonstrate that the stability of the TS, or the reactivity,
has no relevance to the identity of the product. The product
ratio could be determined by dynamics effect and is likely to be
controlled by the relative stability of the two cationic inter-
mediates (carbocation and nitrilium ion), as indicated by the
previous calculations.17 A substrate with a more electron-
donating substituent yields more fragmentation product be-
cause the barrier that separates the two product regions on the
PES is located closer to the less stable product region, in
accordance with the LefflerꢀHammond postulate23 and the
Thornton rule.24 As a result, more trajectories lead to a more
stable product region. It should be noted that the resultant
product selectivity is in line with the prediction based on the
traditional electronic theory.
Figure 1. Yukawa-Tsuno plot for the reaction of 7-X in 80% (v/v)
CH3CN at 25 °C.
Figure 2. Logkꢀlogk plot between the reactions of 8-X and 9a-X in
90% (v/v) CH3CN vs 7-X in 80% (v/v) CH3CN at 25 °C.
with previous observations.1 The Yukawa-Tsuno analyses of the
substituent effects for 8-X and 9a-X gave similar results with
F and r values of ꢀ2.15 and 0.56, and ꢀ2.00 and 0.59,
respectively. The linear free energy (logkꢀlogk) plots between
the three systems are more straightforward as shown in Figure 2.
The observed excellent linear correlations with slopes of near
unity clearly indicate that the substituent effects for all three
systems are the same despite the fact that the product ratios are
very different.
logðk=k0Þ ¼ Ffσ° þ rðσþ ꢀ σ°Þg ¼ Ffσ° þ rΔσRþg
¼ Fσapp
ð4Þ
Alternative Interpretations. There are three alternatives that
do not invoke unfamiliar bifurcation for the fundamental organic
reaction: (1) concurrent and competitive pathways for rearran-
gement and fragmentation as in eq 1, (2) a mechanism with the
fragmentation intermediate (ArCR1R2þ) as a common precur-
sor for both rearrangement and fragmentation products (eq 6),
Path Bifurcation. Previous MO calculations showed that the
acid-catalyzed reactions of 4-X in the gas phase proceeded
through TSs, whose structures had features characteristic to the
rearrangement reactions.17 The analyses of activation energies
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and (3) a mechanism with the rearrangement intermediate as a
common precursor for the both products (eq 7).
Table 3. Product Distributions for the Reactions of Selected
Substrates with Added NMe4þOHꢀ a
NMe4þOHꢀ b
Rc
Fd
F%e
8-H
0.00
1.30
2.60
0.00
1.10
2.76
0.00
0.29
0.51
1.20
2.00
4.00
0.00
2.00
4.00
81.7
82.2
81.0
50.2
54.4
55.4
40.1
45.6
48.8
53.8
56.8
53.9
0.0
19.3
19.9
19.8
46.5
42.9
44.8
59.5
58.7
54.1
45.9
45.2
43.8
99.4
81.2
80.4
19.1
19.5
19.6
48.1
44.1
44.7
59.8
56.3
52.6
46.0
44.4
44.8
100.0
80.7
80.9
8-p-Me
9a-m-Cl
9a-p-Me
20.5
20.5
a In 90% (v/v) CH3CN at 25 °C with the reactant concentration of 2.4
mmol/L. b Molar ratio of NMe4þOHꢀ added relative to the reactant.
c Yield of rearrangement product (%). d Yield of fragmentation product
(%). e Relative yield of fragmentation product (F/(R þ F)).
eliminate the possibility, this mechanism is unlikely since it
requires that the NꢀC bond cleavage in the cationic intermedi-
ate is competitive with the attack of solvent water on the cation.
The former step is endergonic in the gas phase (20.8 and 9.0
kcal/mol for PhCH2NdCþCH318 and PhC(CH3)2NdCþCH3,
respectively, in free energy at MP2/6-31G*), whereas the latter
step is likely to be exergonic and in know to be fast in aqueous
solvent.26 The mechanism also requires that the observed fully
exclusive formation of the fragmentation products for 9a-p-Me
and 9a-p-MeO have occurred via the rearrangement intermedi-
ates, which is very unlikely. In order to further examine the
possibility, the reactions of four substrates (8-H, 8-p-Me, 9a-m-
Cl, and 9a-p-Me) were carried out in 90% aqueous CH3CN in
the presence of NMe4þOHꢀ. Under the reaction conditions, F%
would be suppressed if the fragmentation product were formed
via the rearrangement intermediate, since OHꢀ is known to be
much better nucleophile than H2O in the reaction with nitrilium
ions,26 and therefore OHꢀ should effectively trap the intermedi-
ate to give the rearrangement product. The results of the
reactions are summarized in Table 3. The reaction of 8-p-Me
showed an only slight decrease in F% by the addition of 1.1 equiv
of OHꢀ and F% stayed unchanged with a higher concentration of
OHꢀ, which suggests that a small portion of the fragmentation
product may have arisen from the rearrangement intermediate.
The reaction of 9a-m-Cl also gave a decrease in F% with an
increase of the concentration of OHꢀ, and the F% value stayed
constant at 2 equiv of OHꢀ. Thus, roughly 15% out of total 60%
fragmentation product was judged to have arisen through the
rearrangement intermediate. Similarly, 20% of the fragmentation
product was assigned to have formed through the rearrangement
intermediate for 9a-p-Me. Thus, the major part of the fragmenta-
tion product is considered to be formed via a reaction route that
does not involve the rearrangement intermediate. In summary,
the results of the product analyses and the substituent effect on
reactivities are best rationalized by the mechanism that involves
path bifurcation after the rate-determining TS.
The first alternative is unlikely, since it requires that the two
pathways have the same substituent effect although the two initial
intermediates are very different. It is also inconsistent with the
previous computational results that there is only one TS leading
to either the fragmentation or the rearrangement product for the
reactions of 4-X.
The second mechanism with the fragmentation intermediate
as a common precursor requires the fragmentation step being
rate-determining (eq 6). Since the intermediate cation is much
more stable for 9a-H (PhCMe2þ) than for 8a-H (PhCHMeþ),
the rate constant should be much larger for 9a-H than for 8a-H,
which is not consistent with the observations: k = 1.35 ꢁ 10ꢀ3
s
ꢀ1 for 8a-H and 1.46 ꢁ 10ꢀ3 sꢀ1 for 9a-H. Similarly, the R-Me
rate-acceleration effect for 8-X/7-X is ca. 5, which is much smaller
than that (∼103ꢀ105) known for carbocation-formation reac-
tions in aqueous solvent.25 To further examine the second
possibility, the reaction of 8-p-Me was carried out in 90%
aqueous CD3CN and deuterium content of the product
p-MeC6H4CHCH3NHCOCH3 was determined. If the benzylic
cation is the common intermediate for the rearrangement and
the fragmentation product, the amide product for the reaction in
CD3CN solvent should contain deuterium in the acetyl methyl
group. It was found that the F% for the reaction in aqueous
CD3CN was 53.3%, which was similar to 51.9% in aqueous
CH3CN. The NMR analysis of the product revealed that the
H-content in the acetyl CH3 group of the amide was 99.1 ( 1.3%.
The result eliminates a possible involvement of p-MeC6H4CHCH3
cation as a precursor of the rearrangement product.
In the third interpretation, the reaction goes through a TS to
give the rearrangement intermediate, which may afford CH3CN
þ benzylic cation upon NꢀC bond cleavage in addition to the
amide formation (eq 7). Although it is difficult to completely
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1-p-Methoxyphenyl-2-propanone Oxime (4-p-MeO). The
procedure is the same as for 4-H. Yield: 64%. Mp 73ꢀ75 °C. 1H NMR
(CDCl3, 400 MHz) δ 8.56 (bs, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.84 (d, J =
8.6 Hz, 2H), 3.79 (s, 3H), 3.43 (s, 2H), 1.81 (s, 3H).
1-m,p-Dimethylphenyl-2-propanone Oxime (4-m,p-Me2).
The procedure is the same as for 4-H. Yield: 67%. Mp 60ꢀ61 °C. 1H
NMR (CDCl3, 400 MHz) δ 8.81 (bs, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.98
(s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.42 (s, 2H), 2.240 (s, 3H), 2.236 (s,
3H), 1.81 (s, 3H).
1-p-Methylphenyl-2-propanone Oxime (4-p-Me). The pro-
1
cedure is the same as for 4-H. Yield: 53%. Mp 79ꢀ81 °C. H NMR
(CDCl3, 400 MHz) δ 8.77 (bs, 1H), 7.11 (s, 4H), 3.45 (s, 2H), 2.32 (s,
3H), 1.81 (s, 3H).
1-m-Methylphenyl-2-propanone Oxime (4-m-Me). The
procedure is the same as for 4-H. The crude product was purified by
column chromatography (Hexane/AcOEt = 4:1). Yield: 82%. 1H NMR
(CDCl3, 400 MHz) δ 9.59 (bs, 1H), 7.25ꢀ7.01 (m, 4H), 3.47 (s, 2H),
2.32 (s, 3H), 1.82 (s, 3H).
1-p-Chlorophenyl-2-propanone Oxime (4-p-Cl). The proce-
1
dure is the same as for 4-H. Yield: 44%. Mp 91ꢀ92 °C. H NMR
Figure 3. Schematic 3D energy surface and the mode of bifurcation for
the Beckmann reaction.
(CDCl3, 400 MHz) δ 8.13 (bs, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.15 (d, J =
8.2 Hz, 2H), 3.46 (s, 2H), 1.80 (s, 3H).
1-m-Chlorophenyl-2-propanone Oxime (4-m-Cl). The pro-
cedure is the same as for 4-H. The crude product was purified by column
chromatography (Hexane/AcOEt = 4:1). Yield: 93%. 1H NMR (CDCl3,
400 MHz) δ 9.60 (bs, 1H), 7.23ꢀ7.21 (m, 3H), 7.12 (s, 1H), 3.48 (s,
2H), 1.83 (s, 3H).
1-p-Trifluoromethyl-2-propanone Oxime (4-p-CF3). The
procedure is the same as for 4-H. Yield: 38%. Mp 83ꢀ85 °C. 1H
NMR (CDCl3, 400 MHz) δ 9.18 (bs, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.34
(d, J = 7.8 Hz, 2H), 3.56 (s, 2H), 1.83 (s, 3H).
1-p-Cyano-2-propanone Oxime (4-p-CN). The procedure is
the same as for 4-H. Yield: 9%. Mp 70ꢀ72 °C. 1H NMR (CDCl3, 400
MHz) δ 8.59 (bs, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H),
3.56 (s, 2H), 1.83 (s, 3H).
1-p-nitro-2-propanone oxime (4-p-NO2). The procedure is
the same as for 4-H. Yield: 48%. Mp 143ꢀ144 °C. 1H NMR (CDCl3,
400 MHz) δ 8.19 (d, J = 8.4 Hz, 2H), 7.64 (bs, 1H), 7.39 (d, J = 8.4 Hz,
2H), 3.60 (s, 2H), 1.83 (s, 3H).
3-p-Methoxyphenyl-2-butanone Oxime (5-p-MeO). The
procedure is the same as for 4-H. Recrystallized from ethanol. Yield:
35%. Mp 121 °C. 1H NMR (CDCl3, 400 MHz) δ 9.36 (bs, 1H), 7.16 (d,
J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 3.79 (s, 3H), 3.61 (q, J = 7.0 Hz,
1H), 1.73 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H).
3-m,p-Dimethylphenyl-2-butanone Oxime (5-m,p-Me2).
The procedure is the same as for 4-H. Yield: 49%. Mp 78ꢀ80 °C. 1H
NMR (CDCl3, 400 MHz) δ 8.69 (bs, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00
(s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 3.58 (q, J = 7.2 Hz, 1H), 2.25 (s, 3H),
2.24 (s, 3H), 1.74 (s, 3H), 1.42 (d, J = 7.2 Hz, 3H).
’ CONCLUDING REMARKS
The previous computational study has predicted that the
reactions of 4-X proceed via a single TS for each substituted
compound, but gave both rearrangement and fragmentation
products from the single TS through path bifurcation after the
TS.17 Extensive kinetic and product analysis results presented
here for the reactions of 7-Xꢀ9a-X are consistent with the
occurrence of bifurcation after the TS for the Beckmann reac-
tions. In Figure 3 is shown a schematic presentation of 3D energy
surface, in which the main TS is located on the center of the top
edge and the two product regions are separated by the second TS
(TS0). Reacting molecule coming down from the main TS lead to
either of the two product regions, and the ratio of the two
products depends on the location of TS’. The present result that
more fragmentation product was obtained for 9-X than 7-X and
with a more electron-donating substituent is explained by the
shift of TS0 in a manner consistent with the Leffler-Hammond
principle23 and the Thornton rule.24 It is thus concluded that TSs
may not always have information about what product they would
give and that a conventional reactivity-selectivity argument and
mechanistic assignment based on the TS theory may not always
be applicable even to well-known organic reactions.
’ EXPERIMENTAL SECTION
3-p-Methylphenyl-2-butanone Oxime (5-p-Me). The proce-
Materials. Acetonitrile was distilled over CaH2. Substituted phenyl-
propanones (1-X) were synthesized from corresponding benzaldehydes
by nitroaldol with EtNO2,19 and Fe reduction.20 2-Phenylbutanones
(2-X) and 2-methyl-2-phenylbutanones (3-X) were prepared from 1-
X by methylation (MeI/NaOH). Oximation with NH2OH, followed by
esterification by Tipson’s method21 gave esters, (7-Xꢀ9a-X).
1
dure is the same as for 4-H. Yield: 37%. Mp 73ꢀ75 °C. H NMR
(CDCl3, 400 MHz) δ 9.52 (bs, 1H), 7.13 (s, 4H), 3.62 (q, J = 7.0 Hz,
1H), 2.32 (s, 3H), 1.74 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H).
3-m-Methylphenyl-2-butanone Oxime (5-m-Me). The pro-
cedure is the same as for 4-H. Yield: 82%. 1H NMR (CDCl3, 400 MHz)
δ 9.63 (bs, 1H), 7.23ꢀ7.04 (m, 4H), 3.62 (q, J = 7.0 Hz, 1H), 2.33 (s,
3H), 1.75 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H).
1-Phenyl-2-propanone oxime (4-H). To 1-phenyl-2-propa-
none (1-H) (12.2 g, 91.1 mmol) were added aqueous NaOH (20 mL,
3-Phenyl-2-butanone Oxime (5-H). The procedure is the same
as for 4-H. Yield: 27%. Mp 57 °C. 1H NMR (CDCl3, 400 MHz) δ 8.36
(bs, 1H), 7.34ꢀ7.22 (m, 5H), 3.65 (q, J = 7.2 Hz, 1H), 1.74 (s, 3H), 1.45
(d, J = 7.2 Hz, 3H).
3-p-Chlorophenyl-2-butanone Oxime (5-p-Cl). The proce-
dure is the same as for 4-H. Recrystallized from ethanol. Yield: 44%. Mp
91ꢀ92 °C. 1H NMR (CDCl3, 400 MHz) δ 9.33 (bs, 1H), 7.29 (d, J = 8.5
154 mmol) and aqueous NH2OH HCl (30 mL, 205 mmol), and then
3
ethanol to obtain a clear solution. The solution was refluxed for 1 h,
mixed with water, extracted with ether, and the ether layer was dried over
MgSO4. Evaporation of the solvent gave oily material, which solidified
on cooling. Recrystallization from hexane 4-H (2.4 g, 16.1 mmol, 18%).
Mp 87ꢀ88 °C. 1H NMR (CDCl3, 400 MHz): δ 8.31 (bs, 1H),
7.33ꢀ7.21 (m, 5H), 3.50 (s, 2H), 1.82 (s, 3H).
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ARTICLE
1
Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 3.64 (q, J = 7.2 Hz, 1H), 1.73 (s, 3H),
1.43 (d, J = 7.2 Hz, 3H).
59%. Mp 73ꢀ75 °C. H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H),
8.02ꢀ7.92 (m, 4H), 7.72ꢀ7.63 (m, 2H), 6.91 (d, J = 7.1 Hz, 2H), 6.82
(d, J = 7.1 Hz, 2H), 3.40 (s, 2H), 2.25 (s, 3H), 1.85 (s, 3H).
3-m-Chlorophenyl-2-butanone Oxime (5-m-Cl). The proce-
dure is the same as for 4-H. The crude product was purified by column
chromatography (Hexane/AcOEt = 4:1). Yield: 84%. 1H NMR (CDCl3,
400 MHz) δ 9.71 (bs, 1H), 7.25ꢀ7.13 (m, 4H), 3.65 (q, J = 7.3 Hz, 1H),
1.76 (s, 3H), 1.44 (d, J = 7.3 Hz, 3H).
3-p-Trifluoromethylphenyl-2-butanone Oxime (5-p-CF3).
The procedure is the same as for 4-H. Yield: 10%. Mp 59ꢀ60 °C. 1H
NMR (CDCl3, 400 MHz) δ 9.24 (bs, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.37
(d, J = 7.8 Hz, 2H), 3.73 (q, J = 7.2 Hz, 1H), 1.75 (s, 3H), 1.47 (d, J = 7.2
Hz, 3H).
1-m-Methylphenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-m-Me). The procedure is the same as for 7-H. Yield:
1
49%. Mp 69ꢀ70 °C. H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H),
8.03ꢀ7.93 (m, 4H), 7.71ꢀ7.62 (m, 2H), 7.02ꢀ6.73 (m, 4H), 3.41 (s,
2H), 2.13 (s, 3H), 1.86 (s, 3H).
1-p-Chlorophenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-p-Cl). The procedure is the same as for 7-H. Yield:
43%. Mp 138ꢀ141 °C. 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H),
8.01ꢀ7.89 (m, 4H), 7.73ꢀ7.64 (m, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.86
(d, J = 8.1 Hz, 2H), 3.42 (s, 2H), 1.86 (s, 3H).
3-p-Cyanophenyl-2-butanone Oxime (5-p-CN). The proce-
1
dure is the same as for 4-H. Yield: 26%. Mp 84ꢀ86 °C. H NMR
1-m-Chlorophenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-m-Cl). The procedure is the same as for 7-H. Yield:
(CDCl3, 400 MHz) δ 8.38 (bs, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.36
(d, J = 8.0 Hz, 2H), 3.71 (q, J = 7.2 Hz, 1H), 1.74 (s, 3H), 1.46 (d, J = 7.2
Hz, 3H).
1
43%. Mp 69ꢀ71 °C. H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H),
8.00ꢀ7.93 (m, 4H), 7.70ꢀ7.65 (m, 2H), 7.17ꢀ6.82 (m, 4H), 3.44 (s,
2H), 1.88 (s, 3H).
3-p-Nitrophenyl-2-butanone Oxime (5-p-NO2). The proce-
1
dure is the same as for 4-H. Yield: 60%. Mp 108ꢀ110 °C. H NMR
1-p-Trifluoromethylphenyl-2-propanone Oxime 2-Naph-
thalenesulfonate (7-p-CF3). The procedure is the same as for 7-H.
Yield: 47%. Mp 111ꢀ112 °C. 1H NMR (CDCl3, 400 MHz) δ 8.57 (s,
1H), 8.01ꢀ7.88 (m, 4H), 7.72ꢀ7.66 (m, 2H), 7.33 (d, J = 7.6 Hz, 2H),
7.04 (d, J = 7.6 Hz, 2H), 3.52 (s, 2H), 1.89 (s, 3H).
1-p-Cyanophenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-p-CN). The procedure is the same as for 7-H. Yield:
51%. Mp 100 °C. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H),
8.01ꢀ7.87 (m, 4H), 7.76ꢀ7.66 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.04 (d, J = 8.0 Hz, 2H), 3.52 (s, 2H), 1.90 (s, 3H).
1-p-Nitrophenyl-2-propanone Oxime 2-Naphthalenesul-
fonate (7-p-NO2). The procedure is the same as for 7-H. Yield: 28%.
Mp 112ꢀ113 °C. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, 1H),
7.99ꢀ7.87 (m, 6H), 7.76ꢀ7.65 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H),
3.57 (s, 2H), 1.92 (s, 3H).
3-p-Methoxyphenyl-2-butanone Oxime p-Methxybenze-
nesulfonate (8a-p-MeO). The procedure is the same as for 7-H.
p-Methoxybenzenesulfonyl chloride was used in place of 2-naphthalene-
sulfonyl chloride. Yield: 24%. Mp 45ꢀ46 °C (dec.). 1H NMR (CDCl3, 400
MHz) δ 7.94 (d, J = 8.45 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.45
Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 3.91 (s, 3H), 3.78 (s, 3H), 3.61 (q, J = 7.0
Hz, 1H), 1.73 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H).
3-m,p-Dimethylphenyl-2-butanone Oxime 2-Naphthale-
nesulfonate (8-m,p-Me2). The procedure is the same as for 7-H.
Yield: 17%. Mp 45ꢀ46 °C (dec.). 1H NMR (CDCl3, 400 MHz) δ 8.62
(s, 1H), 8.03ꢀ7.95 (m, 4H), 7.70ꢀ7.63 (m, 2H), 6.86 (d, J = 8.0 Hz,
1H), 6.69ꢀ6.67 (m, 2H), 3.56 (q, J = 8.0 Hz, 1H), 2.15 (s, 3H), 2.01 (s,
3H), 1.75 (s, 3H), 1.33 (d, J = 8.0 Hz, 3H).
3-p-Methylphenyl-2-butanone Oxime 2-Naphthalenesul-
fonate (8-p-Me). The procedure is the same as for 7-H. Yield: 44%.
Mp 50 °C (dec.) 1H NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H),
8.02ꢀ7.95 (m, 4H), 7.71ꢀ7.62 (m, 2H), 6.89 (d, J = 7.8 Hz, 2H),
6.82 (d, J = 7.8 Hz, 2H), 3.58 (q, J = 6.9 Hz, 1H), 2.24 (s, 3H), 1.74 (s,
3H), 1.33 (d, J = 6.9 Hz, 3H).
(CDCl3, 400 MHz) δ 8.19 (d, J = 8.8 Hz, 2H), 8.09 (bs, 1H), 7.42 (d, J =
8.8 Hz, 2H), 3.76 (q, J = 7.2 Hz, 1H), 1.75 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H).
3-Methyl-3-p-methoxyphenyl-2-butanone Oxime (6-p-
MeO). The procedure is the same as for 4-H. Yield: 55%. Mp
165ꢀ166 °C. 1H NMR (CDCl3, 400 MHz) δ 8.77 (bs, 1H), 7.20 (d,
J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 1.64 (s, 3H), 1.47
(s, 6H).
3-Methyl-3-p-methylphenyl-2-butanone Oxime (6-p-Me).
The procedure is the same as for 4-H. Yield: 34%. Mp 89ꢀ91 °C. 1H
NMR (CDCl3, 400 MHz) δ 8.70 (bs, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.13
(d, J = 8.0 Hz, 2H), 2.33 (s, 3H), 1.65 (s, 3H), 1.48 (s, 6H).
3-Methyl-3-phenyl-2-butanone Oxime (6-H). The procedure
is the same as for 4-H. Yield: 28%. Mp 104ꢀ106 °C. 1H NMR (CDCl3,
400 MHz) δ 8.46 (bs, 1H), 7.35ꢀ7.21 (m, 5H), 1.65 (s, 3H), 1.50 (s, 6H).
3-Methyl-3-m-chlorophenyl-2-butanone oxime (6-m-Cl).
The procedure is the same as for 4-H. Yield: 25%. Mp 107ꢀ109 °C. 1H
NMR (CDCl3, 400 MHz) δ 9.03 (bs, 1H), 7.28ꢀ7.16 (m, 4H), 1.66 (s,
3H), 1.49 (s, 6H).
3-Methyl-3-p-nitrophenyl-2-butanone Oxime (6-p-NO2).
The procedure is the same as for 4-H. Recrystallized from ether-hexane.
Yield: 46%. Mp 157ꢀ159 °C. 1H NMR (CDCl3, 400 MHz) δ 8.19 (d,
J = 8.8 Hz, 2H), 7.65 (bs, 1H), 7.46 (d, J = 8.8 Hz, 2H), 1.65(s, 3H), 1.53
(s, 6H).
1-Phenyl-2-propanone Oxime 2-Naphthalenesulfonate
(7-H). To an ice-cooled dry pyridine solution (20 mL) of 1-phenyl-2-
propanone oxime (4-H) (1.63 g, 10.0 mmol) was added 2-naphthale-
nesulfonyl chloride (2.51 g, 11.1 mmol), which requires 1 h. The
solution was allowed to react for additional 1 h at the same tempera-
ture, and was poured onto iceꢀwater (200 mL). The resulted
precipitates were collected by suction and recrystallized from ether-
hexane. Yield: 59%. Mp 57 °C. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s,
1H), 8.02ꢀ7.92 (m, 4H), 7.72ꢀ7.63 (m, 2H), 7.19ꢀ6.92 (m, 5H),
3.45 (s, 2H), 1.86 (s, 3H).
1-p-Methoxyphenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-p-MeO). The procedure is the same as for 7-H. Yield:
20%. Mp 127ꢀ128 °C. 1H NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H),
7.89ꢀ7.85 (m, 4H), 7.59ꢀ7.52 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.80
(d, J = 8.0 Hz, 2H), 4.40 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H).
1-m,p-Dimethylphenyl-2-propanone Oxime 2-Naphtha-
lenesulfonate (7-m,p-Me2). The procedure is the same as for 7-H.
Yield: 34%. Mp 81ꢀ82 °C. 1H NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H),
8.03ꢀ7.93 (m, 4H), 7.72ꢀ7.63 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H),
6.70ꢀ6.67 (m, 2H), 3.38 (s, 2H), 2.16 (s, 3H), 2.04 (s, 3H), 1.85 (s, 3H).
1-p-Methylphenyl-2-propanone Oxime 2-Naphthalene-
sulfonate (7-p-Me). The procedure is the same as for 7-H. Yield:
3-p-Methylphenyl-2-butanone Oxime p-Methxybenzene-
sulfonate (8a-p-Me). The procedure is the same as for 8a-p-MeO.
Yield: 42%. Mp 53ꢀ54 °C. 1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J =
8.8, 2H), 7.06 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.0
Hz, 2H), 3.91 (s, 3H), 3.62 (q, J = 7.2 Hz, 1H), 2.31 (s, 3H), 1.73 (s, 3H),
1.36 (d, J = 7.2 Hz, 3H).
3-m-Methylphenyl-2-butanone Oxime 2-Naphthalene-
sulfonate (8-m-Me). The procedure is the same as for 7-H. Yield:
1
49%. Mp 46ꢀ47 °C. H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H),
8.03ꢀ7.95 (m, 4H), 7.72ꢀ7.63 (m, 2H), 7.01ꢀ6.97 (m, 2H), 6.74ꢀ6.73
(m, 2H), 3.59 (q, J = 8.0 Hz, 2H), 2.13 (s, 3H), 1.75 (s, 3H), 1.34 (d, J = 8.0
Hz, 3H).
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3-Phenyl-2-butanone Oxime 2-Naphthalenesulfonate (8-H).
The procedure is the same as for 7-H. Yield: 59%. Mp 57 °C. 1H NMR
(CDCl3, 400 MHz) δ 8.62 (s, 1H), 8.03ꢀ7.95 (m, 4H), 7.73ꢀ7.63 (m,
2H), 7.17ꢀ6.92 (m, 5H), 3.63 (q, J = 7.0 Hz, 1H), 1.75 (s, 3H), 1.36 (d,
J = 7.0 Hz, 3H).
(t, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 1.68 (s, 3H),
1.39 (s, 6H).
3-Methyl-3-m-chlorophenyl-2-butanone Oxime p-Meth-
xybenzenesulfonate (9a-m-Cl). The procedure is the same as for
8a-p-MeO. Yield: 6%. Mp 66ꢀ67 °C. 1H NMR (CDCl3, 400 MHz) δ
7.96 (d, J = 8.8 Hz, 2H), 7.20ꢀ7.18 (m, 2H), 7.05ꢀ6.92 (m, 4H), 3.91
(s, 3H), 1.67 (s, 3H), 1.42 (s, 6H).
3-Methyl-3-p-nitrophenyl-2-butanone Oxime 2-Naphtha-
lenesulfonate (9-p-NO2). The procedure is the same as for 7-H.
Yield: 46%. Mp 70ꢀ72 °C. 1H NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H),
8.04ꢀ7.91 (m, 6H), 7.77ꢀ7.66 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 1.70
(s, 3H), 1.45 (s, 6H).
3-Phenyl-2-butanone Oxime p-Methxybenzenesulfonate
(8a-H). The procedure is the same as for 8a-p-MeO. Yield: 12%. Mp
1
60ꢀ62 °C. H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 7.1 Hz, 2H),
7.28ꢀ7.23 (m, 2H), 7.05ꢀ7.01(m, 4H), 3.91 (s, 3H), 3.66 (q, J = 7.3 Hz,
1H), 1.74(s, 3H), 1.39 (d, J = 7.3 Hz, 3H).
3-p-Chlorophenyl-2-butanone Oxime 2-Naphthalenesul-
fonate (8-p-Cl). The procedure is the same as for 7-H. Yield: 32%. Mp
68ꢀ69 °C. 1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.02ꢀ7.93 (m,
4H), 7.74ꢀ7.64 (m, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.2 Hz,
2H), 3.60 (q, J = 7.0 Hz, 1H), 1.75 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H).
3-p-Chlorophenyl-2-butanone Oxime p-Methxybenzene-
sulfonate (8a-p-Cl). The procedure is the same as for 8a-p-MeO.
Yield: 40%. Mp 74ꢀ75 °C. 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J =
7.05 Hz, 2H), 7.23 (d, J = 6.6 Hz, 2H), 7.01 (d, J = 7.05 Hz, 2H), 6.98 (d,
J = 6.6 Hz, 2H), 3.92 (s, 3H), 3.63 (q, J = 7.05 Hz, 1H), 1.75 (s, 3H), 1.37
(d, J = 7.05 Hz, 3H).
3-m-Chlorophenyl-2-butanone Oxime 2-Naphthalenesul-
fonate (8-m-Cl). The procedure is the same as for 7-H. Yield: 46%. Mp
73ꢀ75 °C. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.02ꢀ7.94 (m,
4H), 7.72ꢀ7.62 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 7.8 Hz,
1H), 6.96 (s, 1H), 6.81 (d, J = 7.8 Hz, 1H), 3.60 (q, J = 7.0 Hz, 1H), 1.77
(s, 3H), 1.34 (d, J = 7.0 Hz, 3H).
3-p-Trifluoromethylphenyl-2-butanone Oxime 2-Naph-
thalenesulfonate (8-p-CF3). The procedure is the same as for 7-H.
Yield: 41%. Mp 93ꢀ94 °C. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H),
8.01ꢀ7.93 (m, 4H), 7.73ꢀ7.64 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.04
(d, J = 8.2 Hz, 2H), 3.69 (q, J = 7.2 Hz, 1H), 1.77 (s, 3H), 1.3 (d, J = 7.2
Hz, 3H).
3-p-Cyanophenyl-2-butanone Oxime 2-Naphthalenesul-
fonate (8-p-CN). The procedure is the same as for 7-H. Yield: 23%.
Mp 79ꢀ80 °C. 1H NMR (CDCl3, 400 MHz) δ 8.58 (s, 1H), 8.02ꢀ7.91
(m, 4H), 7.76ꢀ7.66 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0
Hz, 2H), 3.68 (q, J = 8.0 Hz, 1H), 1.78 (s, 3H), 1.38 (d, J = 8.0 Hz, 3H).
3-p-Nitrophenyl-2-butanone Oxime 2-Naphthalenesulfo-
nate (8-p-NO2). The procedure is the same as for 7-H. Yield: 25%. Mp
82 °C. 1H NMR (CDCl3, 400 MHz) δ 8.58 (s, 1H), 8.01ꢀ7.97 (m, 3H),
7.94ꢀ7.91 (m, 3H), 7.77ꢀ7.66 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H), 3.74
(q, J = 7.1 Hz, 1H), 1.80 (s, 3H), 1.41 (d, J = 7.1 Hz, 3H).
3-Methyl-3-p-nitrophenyl-2-butanone Oxime p-Meth-
xybenzenesulfonate (9a-p-NO2). The procedure is the same
as for 8a-p-MeO. Yield: 38%. Mp 83ꢀ84 °C. 1H NMR (CDCl3, 400
MHz) δ 8.12 (d, J = 9.2, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.24 (d, J =
9.2 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.93 (s, 3H), 1.69 (s, 3H), 1.48
(s, 6H).
1
N-p-Methoxybenzylacetamide. H NMR (CDCl3, 400 MHz)
δ 7.19 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.07 (bs, 1H), 4.32
(d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 1.98 (s, 3H). Mp 97 °C.
N-m,p-Dimethylbenzylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.10 (d, J = 7.6 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J = 7.6 Hz,
1H), 5.63 (bs, 1H), 4.36 (d, J = 5.6 Hz, 2H), 2.25 (s, 3H), 2.25 (s, 3H),
2.01 (s, 3H). Mp 87ꢀ88 °C.
1
N-p-Methylbenzylacetamide. H NMR (CDCl3, 400 MHz) δ
7.17 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 5.82 (bs, 1H), 4.37 (d,
J = 6.0 Hz, 2H), 2.33 (s, 3H), 2.00 (s, 3H). Mp 112ꢀ113 °C.
N-m-Methylbenzylacetamide. 1H NMR (CDCl3, 400 MHz) δ
7.21ꢀ7.03 (m, 4H), 6.50 (bs, 1H), 4.32 (d, J = 5.5 Hz, 2H), 2.31 (s, 3H),
1.96 (s, 3H).
N-p-Benzylacetamide. 1H NMR (CDCl3, 400 MHz) δ 7.35ꢀ7.26
(m, 5H), 6.05 (bs, 1H), 4.40 (d, J = 6.0 Hz, 2H), 1.99 (s, 3H). Mp
56ꢀ57 °C.
1
N-p-Chlorobenzylacetamide. H NMR (CDCl3, 400 MHz) δ
7.29 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 5.91 (bs, 1H), 4.39 (d,
J = 5.5 Hz, 2H), 2.02 (s, 3H). Mp 107ꢀ108 °C.
N-m-Chlorobenzylacetamide. 1H NMR (CDCl3, 400 MHz) δ
7.32 (s, 1H), 7.21ꢀ7.18 (m, 3H), 7.09ꢀ7.07 (m, 1H), 4.27 (d, J = 6.0
Hz, 2H), 1.92 (s, 3H).
N-p-Trifluoromethylbenzylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.57 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.03 (bs, 1H),
4.48 (d, J = 6.0 Hz, 2H), 2.04 (s, 3H). Mp 103ꢀ104 °C.
1
N-p-Cyanobenzylacetamide. H NMR (CDCl3, 400 MHz) δ
3-Methyl-3-p-methoxyphenyl-2-butanone Oxime p-Meth-
xybenzenesulfonate (9a-p-MeO). The procedure is the same as
7.63 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 5.85 (bs, 1H), 4.50 (d,
J = 6.0 Hz, 2H), 2.07 (s, 3H). Mp 145ꢀ147 °C.
1
for 8a-p-MeO. Yield: 44%. Mp 41ꢀ43 °C (dec.). H NMR (CDCl3,
400 MHz) δ 7.97 (d, J = 9.2 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 6.96
(d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H), 3.78 (s, 3H),
1.64 (s, 3H), 1.40 (s, 6H).
N-p-Nitrobenzylacetamide. 1H NMR (CDCl3, 400 MHz) δ
8.19 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.96 (bs, 1H), 4.55 (d,
J = 6.0 Hz, 2H), 2.08 (s, 3H). Mp 128ꢀ130 °C.
1
N-p-Methoxyphenylethylacetamide. H NMR (CDCl3, 400
3-Methyl-3-p-methylphenyl-2-butanone Oxime p-Meth-
xybenzenesulfonate (9a-p-Me). The procedure is the same as
for 8a-p-MeO. Yield: 20%. Mp 45ꢀ46 °C (dec.). 1H NMR (CDCl3, 400
MHz) δ 7.97 (d, J = 9.2, 2H), 7.06 (d, J = 8.24 Hz, 2H), 7.03 (d, J = 9.2
Hz, 2H), 6.93 (d, J = 8.24 Hz, 2H), 3.92 (s, 3H), 2.30 (s, 3H), 1.65 (s,
3H), 1.41 (s, 6H).
3-Methyl-3-phenyl-2-butanone Oxime p-Methxybenze-
nesulfonate (9a-H). The procedure is the same as for 8a-p-MeO.
Yield: 26%. Mp 47ꢀ48 °C. 1H NMR (CDCl3, 400 MHz) δ 7.97 (d, J =
8.8 Hz, 2H), 7.28ꢀ7.18 (m, 3H), 7.06ꢀ7.01 (m, 4H), 3.91 (s, 3H), 1.65
(s, 3H), 1.43 (s, 6H).
3-Methyl-3-m-chlorophenyl-2-butanone Oxime 2-Naph-
thalenesulfonate (9-m-Cl). The procedure is the same as for 7-H.
Yield: 23%. Mp 58ꢀ60 °C. 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H),
8.03ꢀ7.96 (m, 4H), 7.73ꢀ7.63 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.00
MHz) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.78 (bs, 1H),
5.08 (quin, J = 6.9 Hz, 1H), 3.79 (s, 3H), 1.96 (s, 3H), 1.46 (d, J = 6.9 Hz,
3H). Mp 68ꢀ69 °C.
N-m,p-Dimethylphenylethylacetamide. 1H NMR (CDCl3,
400 MHz) δ 7.12ꢀ7.04 (m, 3H), 5.62 (bs, 1H), 5.07 (quin, J = 6.8
Hz, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 1.97 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H).
Mp 89ꢀ91 °C.
N-p-Methylphenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.20 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.97 (bs,
1H), 5.08 (quin, J = 6.9 Hz, 1H), 2.32 (s, 3H), 1.95 (s, 3H), 1.46 (d, J =
6.9 Hz, 3H). Mp 73ꢀ75 °C.
N-m-Methylphenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.23ꢀ7.05 (m, 4H), 6.23 (bs, 1H), 5.09ꢀ5.02 (m, 1H), 2.33
(s, 3H), 1.94 (s, 3H), 1.43 (d, J = 7.3 Hz, 3H).
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dx.doi.org/10.1021/jo200728t |J. Org. Chem. 2011, 76, 4652–4660

The Journal of Organic Chemistry
ARTICLE
1
N-Phenylethylacetamide. 1H NMR (CDCl3, 400 MHz) δ
7.35ꢀ7.23 (m, 5H), 6.09 (bs, 1H), 5.10 (quin, J = 69 Hz, 1H), 1.95
(s, 3H), 1.47 (d, J = 6.9 Hz, 3H). Mp 76 °C.
2-p-Methylphenyl-2-propyl Alcohol. H NMR (CDCl3, 400
MHz) δ 7.38 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H),
1.75 (bs, 1H), 1.57 (s, 6H).
1
N-p-Chlorophenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.10 (bs,
1H), 5.06 (quin, J = 6.9 Hz, 1H), 1.96 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H).
Mp 98ꢀ99 °C.
2-Phenyl-2-propyl Alcohol. H NMR (CDCl3, 400 MHz) δ
7.51ꢀ7.26 (m, 5H), 1.75 (bs, 1H), 1.59 (s, 6H).
1
2-m-Chlorophenyl-2-propyl Alcohol. H NMR (CDCl3, 400
MHz) δ 7.50 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H),
7.22 (d, J = 8.0 Hz, 1H), 1.75 (bs, 1H), 1.57 (s, 6H).
N-m-Chlorophenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.23ꢀ7.14 (m, 4H), 5.01 (quin, J = 6.9 Hz,1H), 1.92 (s, 3H),
1.39 (d, J = 6.9 Hz, 3H).
Kinetics. The rates of the reactions were studied photometrically at
25.0 ( 0.1 °C with the substrate concentration of 2.0 mmol/L in the
presence of 1.1 equiv of N,N-dimethylaniline in aqueous CH3CN (80%
(v/v) for 7-X and 90% (v/v) for 8-X, 8a-X and 9a-X). The decay of
absorbance of the esters at 327 nm for 7-X and 8-X and the decay of
absorbance of N,N-dimethylaniline at 300 nm for 8a-X and 9a-X were
followed. Excellent first-order rate plots (R2 > 0.9997) were obtained
with reproducibility within 3%.
Product Analysis. The authentic samples of the reaction products
were either isolated from the reaction mixture or synthesized separately.
Product distributions were measured by running the reaction with the
substrate concentration of 2.4 mmol/L for 10 half-lives and analyzing the
reaction mixture by means of NMR by using dibenzyl ether as an internal
standard.
N-p-Trifluoromethylphenylethylacetamide. 1H NMR
(CDCl3, 400 MHz) δ 7.58 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz,
2H), 6.01 (bs, 1H), 5.17ꢀ5.10 (m, 1H), 1.99 (s, 3H), 1.48 (d, J = 7.3 Hz,
3H). Mp 105ꢀ106 °C.
N-p-Cyanophenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 7.63 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.68 (bs,
1H), 5.14 (m, 1H), 2.02 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H). Mp
156ꢀ158 °C.
N-p-Nitrophenylethylacetamide. 1H NMR (CDCl3, 400
MHz) δ 8.19 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 5.74 (bs,
1H), 5.18 (quin, J = 6.9 Hz, 1H), 2.03 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H).
Mp 119ꢀ121 °C.
1
N-2-p-Methylphenyl-2-propylacetamide. H NMR (CDCl3,
400 MHz) δ 7.28 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.69
(bs, 1H), 2.32 (s, 3H), 1.96 (s, 3H), 1.69 (s, 6H). Mp 140ꢀ141 °C.
N-2-Phenyl-2-propylacetamide. 1H NMR (CDCl3, 400 MHz)
δ 7.40ꢀ7.21 (m, 5H), 5.74 (bs, 1H), 1.97 (s, 3H), 1.70 (s, 6H). Mp
95ꢀ96 °C.
’ ASSOCIATED CONTENT
S
Supporting Information.
Hammett σ values and free
b
energies and geometrical coordinates of the species discussed in
this paper. This material is available free of charge via the Internet
at http://pubs.acs.org.
N-2-m-Chlorophenyl-2-propylacetamide. 1H NMR (CDCl3,
400 MHz) δ 7.34ꢀ7.18 (m, 4H), 5.73 (bs, 1H), 1.98 (s, 3H), 1.66
(s, 6H). Mp 112ꢀ113 °C.
’ AUTHOR INFORMATION
N-2-p-Nitrophenyl-2-propylacetamide. 1H NMR (CDCl3,
400 MHz) δ 8.18 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 5.82
(bs, 1H), 2.00 (s, 3H), 1.69 (s, 6H). Mp 122ꢀ124 °C.
Corresponding Author
*yamataka@rikkyo.ac.jp
p-Methoxybenzyl Alcohol. 1H NMR (CDCl3, 400 MHz) δ 7.29
(d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.61 (s, 2H), 3.81 (s, 3H).
m,p-Dimethylbenzyl Alcohol. 1H NMR (CDCl3, 400 MHz) δ
7.15ꢀ7.09 (m, 3H), 4.63 (s, 2H), 2.07 (s, 3H), 2.06 (s, 3H).
’ ACKNOWLEDGMENT
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 Technology,
Japan.
1
p-Methylbenzyl Alcohol. H NMR (CDCl3, 400 MHz) δ 7.26
(d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 4.64 (s, 2H), 2.35 (s, 3H).
p-Methoxyphenylethyl Alcohol. 1H NMR (CDCl3, 400 MHz)
δ 7.25 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.76 (q, J = 6.4 Hz,
1H), 3.74 (s, 3H), 2.64 (bs, 1H), 1.41 (d, J = 6.4 Hz, 3H).
m,p-Dimethylphenylethyl Alcohol. 1H NMR (CDCl3, 400
MHz) δ 7.15ꢀ7.09 (m, 3H), 4.84 (q, J = 6.4 Hz, 1H), 2.27 (s, 3H),
2.25 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H).
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