Revisiting secondary interactions in neighboring group participation, exemplified by reactivity changes of iminylium intermediates

Article abstract of DOI:10.1039/c6ob02719a

Neighboring group participation is defined as the action of a substituent to stabilize a transition state or an intermediate by forming a bond or a partial bond with the reaction center. In addition to the primary interaction with the nearest neighboring group, secondary interactions involving another neighboring group(s) could also occur in principle. Here, we revisit this issue by examining the influence of secondary interactions on the stability and reactivity of the putative iminylium cation intermediates, formed by N-O bond cleavage of 1-tetralone oxime systems. A direct observation of a peri-bromo-iminylium intermediate in solution supported the involvement of iminylium cations and the stabilizing effect of secondary interactions arising from a distal tandem substituent. Both experimental and computational findings support the idea that secondary interactions of a tandem-neighboring group on the primary peri-heteroatom (Br, Cl, and O(Me))-iminylium bonding interaction, i.e., a weak halogen bonding interaction (ester (nitro) oxygen-halogen bonding) and an unprecedented hydrogen bonding interaction between a nitro oxygen atom and a CH₃O hydrogen atom, are crucial determinants of the reaction pathway, leading to either overwhelmingly selective syn-migration of the oxime functionality or covalent bond formation under acid-catalyzed Beckmann rearrangement conditions.

Full text of DOI:10.1039/c6ob02719a

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Revisiting Secondary Interactions in Neighboring Group Participation,
Exemplified by Reactivity Changes of Iminylium Intermediates
1
1
1
1
2
Yingtang Ning, Tomoya Fukuda, Hirotaka Ikeda, Yuko Otani, Masatoshi Kawahata,
2
*1
Kentaro Yamaguchi Tomohiko Ohwada
1
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
2
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University,
1
314-1 Shido, Sanuki, Kagawa 769-2193, Japan

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Abstract
Neighboring group participation is defined as the action of a substituent to stabilize a
transition state or intermediate by forming a bond or partial bond to the reaction center.
In addition to the primary interaction with the nearest neighboring group, secondary
interactions involving another neighboring group(s) could also occur in principle. Here,
we revisit this issue by examining the influence of secondary interactions on the
stability and reactivity of the putative iminylium cation intermediates, formed by N-O
bond cleavage of 1-tetralone oxime systems. Direct observation of the
peri-bromo-iminylium intermediate in solution supported the involvement of iminylium
cations and the stabilizing effect of secondary interactions arising from a distal tandem
substituent. Both experimental and computational findings support the idea that
secondary interactions of a tandem-neighboring group on the primary peri-heteroatom
(Br, Cl, and O(Me))-iminylium bonding interaction, i.e., weak halogen bonding
interaction (ester (nitro) oxygen - halogen bonding) and unprecedented hydrogen
bonding interaction between nitro oxygen atom and CH O hydrogen atom, are a crucial
3
determinant of the reaction pathway, leading to either overwhelmingly selective
syn-migration of the oxime functionality or covalent bond formation under
acid-catalyzed Beckmann rearrangement conditions.
Keywords: neighboring group participation, iminylium ions, oximes, tandem ionic
interaction, halogen bonding, hydrogen bonding

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Introduction
The action of a substituent to stabilize a transition state or intermediate by forming a
bond or a partial bond to the reaction center has been referred to as neighboring group
1
, 2
participation. In particular, temporary stabilizing interactions of an electron-deficient
reaction center with π electrons, σ electrons and non-bonding (n) electrons of an
adjacent substituent have been widely studied, and indeed, are frequently utilized in
1
-4
organic synthesis. Participation of heteroatoms in the reaction center constitutes a
primary interaction, resulting in transient formation of onium ion intermediates (Figure
+
1
(a)). Such onium ion intermediates (in general [Y-X] ) involve stabilization of the
cationic center (X, usually a carbocation) by electron donation from a single heteroatom
Y) (Figure 1(a), top, 1a↔1b). For example, the oxonium cation (Figure 1(a): 1: X=C,
(
Y=O) participates in accelerated solvolysis of acetylated chloro-sugars with retention of
5
stereochemistry. In halolactonization reaction, an intermediate bromonium ion (Figure
1
(a): 1: X=C, Y=Br) is trapped intramolecularly by the carboxylic acid group to give a
6
, 7
halolactone stereoselectively.
But, in addition to the primary interaction between the reaction center and the
nearest neighboring group, secondary interaction with another neighboring group could
also exist in principle (we refer to this situation as tandem neighboring group
participation). As shown in Figure 1(a) (middle, 2a↔2b↔2c), the onium cation
+
(
[Y-X] ) might be further stabilized by interaction with another heteroatom (Z). On the
other hand, the secondary interaction can potentially disrupt bonding effect of the
primary interaction (as shown in the resonance structure 2c, Figure 1(a)), which may
influence chemoselectivities. Although the existence and effects of such secondary
interactions can be an important issue in classical organic reactions, they have not been

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extensively explored. In this paper, we revisit the tandem participation of neighboring
groups (i.e., participation of both the nearest neighbor and another group), focusing on
the putative iminylium ion systems (X = N) of 1-tetralone oximes (A and B, Figure
1
(b)). Selection of this reaction system was inspired by the reported observation of
unprecedented reactivities, such as contamination of syn-rearrangement reaction of
8
oximes (Y = Br and Cl) under Brønsted acid-catalyzed conditions in contrast to the
9
general anti-selectivity of Beckmann rearrangement.
X= N
Y= Br, Cl
Z= CO Me
(a)
Y
X+
a
+Y
X
1
1b
2
primary interaction
NO2
OMe
X+
+Y
2b
+Z
Y+
2c
-
Z
Y
Z
X
X
2
a
secondary interaction
+
+
+
Y
Z
Y
X
Z
Y
X
Z
X
2
e
+
2
d
2
f
two ionic bondis
two covalent bonds
Y
Z
X
(
hypervalent)
2
e'
one covalent bond (
)
)
+
one ionic bond
(
-
-
halogen bonding
-
(b)
OTs
OTs
OTs
+
N
+
Y
+
Z
-
+
Y
OTs
Z
Y
N
Z
Y
Z
N
N
H+
CF CO H
3
2
B1
B2
three-atom interaction
B3
A
Figure 1. (a) Neighboring group participation: primary interaction (top) and
secondary interaction of tandem neighboring groups (middle). The latter can be
represented in terms of two covalent bonds (2d), one covalent bond and one ionic

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bond (2e and 2e’) and two ionic bonds (2f) (bottom). (X: cationic reaction center
atom (X = N), Y and Z: heteroatoms). (b) Tandem neighboring group participation
involving three-atom interaction (B1, B2 and B3) in 1-tetralone oxime systems with
Y = Br and Cl.
+
Y
+
W
V
Z
Y
X
W
V
Z
X
2
h
2
g
primary interaction
+
+
W
W
V
Z
Y
X
V
Z
Y
X
2
i
2j
secondary interaction
Z
CH2
V
Z
CH2
V
H
H
hydrogen bonding
X=N
Y=O(-CH3)
Z=CH (-O)
V=H
+
O
O
N
W
+
O
O
N
W
Y
X
Y
X
N
+
2
-
N
+
O
-
O
W=NO2
C1
C2
five-atom interaction
Figure 2. Interaction over five atoms in 7-nitro-peri-MeO tetralone oxime
A three-atom interaction could be represented in terms of various types of bonding,
as shown in Figure 1(a), bottom: two covalent (hypervalent) interactions (2d), one
covalent and one ionic bonding interactions (2e and 2e’) and two ionic bonding
1
0-14
interactions (2f).
This system can be extended to a functional group (Figure 2, 2g,
(
V-Z-Y is a functional group such as H-CH -O).
2
Computational examination of neighboring group participation in this work
suggested involvement of dual nonequivalent ionic bonding interactions in this system;
the weak secondary interaction, such as halogen bonding (Figure 1 (b) B3) and

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hydrogen bonding interaction (Figure 2, C2) between the two tandem neighboring
groups strengthens the primary ionic bonding interactions between the nitrogen cationic
center and the nearest neighboring heteroatom group, resulting in stabilizing the
1
intermediate cation (B1) sufficiently to allow its direct observation by H-NMR
spectroscopy and changing the reaction pathway leading to overwhelmingly selective
syn-migration of the oxime functionality and N-O bond formation.
Results and Discussion
Direct observation of bromonium-nitrogen cationic intermediate
We examined the effects of several substituents at the aromatic 7-position on the
acid-catalyzed rearrangement of peri(8)-bromotetralone oximes (Figure 1(b), A, B
(Y=Br)) and Table 1 and Table S1). The parent peri-Br tetralone oxime derivative (3a)
showed an intrinsic preference for alkyl migration (alkyl: benzene=89:11) (Figure
9
3
(a)). Alkyl migration involves transfer of the σ bond on the same (syn) side as the
N-O(-Ts) bond to the nitrogen atom, affording an inverted lactam (4a). Benzene
migration (Beckmann rearrangement reaction) also proceeds competitively, affording
the anti-migrated lactam (5a). The geometry of the oxime functionality of the starting
1
-tetralone was assigned as anti with respect to the benzene ring, and we confirmed that
９
isomerization of the oxime did not occur under the present reaction conditions. The
presence of a substituent at the 7-position, i.e., ester (3b, 7-CO Me), amide (3c,
2
7
-CO NHi-Pr), or nitro (3d, 7-NO ) had a clear impact on the regioselectivity and
2 2
reaction rates (Table 1, see Figure S1): these compounds afforded exclusively the
corresponding alkyl migration product (alkyl: benzene = 100:0) (Figure 3(b)).

Page 7 of 34
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The alkyl migration has been proposed to be induced through nucleophilic interaction of
the peri-Br atom with the oxime N atom upon N-OTs bond cleavage to produce the
Br-iminylium intermediate (such as 3b-IM) (Figure 3c). From the intermediate, the
C-C bond anti with respect to the putative Br-N bond migrate onto the iminylium N
atom, leading to the overall alkyl (syn-) migration product.
Table 1. Rearrangement of 8-Br tetralone oximes.
OTs
Br O
Br
N
Br
H
N
O
TFA
NH
R
R
+
R
2
0 ºC
0
.1 M
Alkyl Migration Benzene Migration
a-k
5a-k
3a-k
4
Reaction
Time
Isolated Ratio[a]
Alkyl : Benzene)
Isolated
Yield (%)
Reaction
Time
Isolated Ratio[a]
(Alkyl : Benzene)
Isolated
Yield (%)
Tosylated Oxime
OTs
Tosylated Oxime
(
8Br
N
Br O
Br
H
O
NH
N
90
1
1
h
h
+
OTs
OTs
Br
N
N
Br O
Br
H
O
MeO
MeO
MeO
N
NH
+
3
a
4a
8
9 : 11
NH
100 : 0
5a
7
95
1
h
OTs
OTs
O
Br
N
Br
4g 93 :
Br O
7
3
g
5g
MeOOC
MeO C
2
—
96
7
Br
Br
H
O
N
NH
4
b
1 h
1 h
3
b
+
92
O
Br O
5
O
Br
N
OMe
OMe
5h
OMe
4h 93 :
iPrHN
NH
100 : 0
NH
100 :
iPrHN
1 h
—
—
3h
7
92
88
OTs
Br
N
Br O
Br
H
O
4
c
N
3
Br
c
N
NH
+
OTs
94
85
Br O
7
O N
MeO
TfO
6
MeO
MeO
9 : 51
O N
2
2
3i
Br
5i
4i
4
1
3
h
h
OTs
OTs
4d
0
N
Br O
Br
H
N
O
O
3
d
NH
OTs
+
Br
N
Br O
4
h
h
TfO
TfO
100 :
NH
3
j
4j
0
5j
—
—
9
6
5
Br
N
Br O
COOMe
COOMe
Br
H
N
NH
3
e
4e
100 :
0
0
+
1
8
3
OTs
Br O
NH
Br
N
5
OTf
OTf
4k
OTf
5k
92
100 : 0
8
h
3k
5
NO2
NO2
1
00 :
3
f
4f

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OTs
Br
N
N
Br O
Br
H
N
(a)
O
H+
NH
+
CF CO H
1
3
2
4a
0 %
5a
3
a
hr, 20°C
9
(alkyl: benzene=89:11)
OTs
(b)
Br
Br O
Br
O
O
O
H
N
O
8
H+
NH
MeO
MeO
MeO
7
+
CF CO H
3
2
3
b
4b
5b
1
hr, 20°C
9
6 % (alkyl: benzene=100:0)
(
c)
OTs
O
Br
N
O
Br
N
O
Br
H+
work-up
Me
Me
Me
N
O
O
O
4b
CF CO H
3
2
migration
3
b
3b-IM
Cl
Substitution
Cl-
OH
OTs
H
+
Br
(d)
OH Br
N
Br
N
OH Br
N
O
N
TsCl
HO
6
7
8
9
N
0
°C, 15 min
78 %
Figure 3. (a) Intrinsic preference of alkyl migration from peri-Br oxime 3a (b)
Selective formation of the alkyl migration product (4b) from peri-Br oxime 3b. (c)
Plausible reaction mechanism: (oxygen)-(bromide)-(iminylium-nitrogen) bonding
interactions stabilize the putative cationic system (3b-IM), resulting in exclusive
+
formation of the alkyl migration product 4b from 3b (d) Role of O-----Br -----N
interaction in the formation of 7 from 6 (8) (see text).
When the rearrangement of 7-CO Me-8-Br tetralone oxime (3b) was monitored in
2
1
d-TFA-CD Cl by means of H-NMR spectroscopy at -12 °C, we detected a newly
2
2
emerging species concomitantly with cleavage of the N–OTs bond (i.e., release of
TsOH), in which the aromatic protons were deshielded as compared with those of the
starting material 3b (Figure 4). This suggests a decrease in the electron density of the

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aromatic part, probably resulting from formation of the bromonium cation (3b-IM)
Figure 4 and Figures S2-S3). These changes in chemical shifts were similar to those
(
+
9
previously reported for an isolated [I-N] bonding tetralone derivative. High-resolution
mass spectra of 3b in TFA, reacted at -10 ºC for 1hr, suggested the cleavage of N-O
bond (Figure S5). Furthermore, transformation of this species (3b-IM) to the alkyl
migration product (4b or its trifluoroacetate adduct) (Figure 3(c)) was also observed
when the temperature was increased to 20 ºC (Figures S4), supporting intermediacy of
the observed species (3b-IM) in the overwhelming alkyl migration.
OTs
O
Br
N
O
Br N
CF CO D
3
2
MeO
MeO
+
TsOD
b (Ts)
CD Cl
2
2
H
H
3b (Ts)
-12ºC
H
3
H
3
3b (H)
3b (H)
b
3b-IM
3
b / CD Cl2
2
3
b / CD Cl –TFA-d
2
2
0
min
3b-IM (H)
3b-IM (H)
5
min
3b-IM (H)
3b-IM (H)
TsOD
TsOD
1
0 min
3
0 min
0 min
3b-IM (H)
3b-IM (H)
TsOD
TsOD
6
8.7
8.6
8.5
8.4
8.3
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
ppm
1
Figure 4. H-NMR monitoring of the reaction in CD Cl -CF CO D (v/v= 7:1) at -12
2
2
3
2
ºC (the expanded aromatic region is shown). Peaks due to the intermediate in the
rearrangement of 3b are indicated (see also Figures S2 and S3).

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Further indirect evidence for the stabilizing effect of a 7-heteroatom is provided by
the observation (Figure 3(d)) that tosylation of the oxime 6 (7-CMe (OH)-peri-Br) in
2
the presence of triethylamine affords the anti-N-Cl imide product 7 in 78% yield after
1
5 min at 0°C (X-ray crystallographic analysis of 7, see Figure S6). In this case the
intermediate bromonium-imidonitrogen intermediate (9, Figure 3(d)), which was
assumed to be formed through O-Ts derivative 8, was significantly stabilized by the
adjacent hydroxyl group, which was trapped by S 2-like attack of the chloride anion.
N
Overwhelming biased migration in peri-chloro-substituted tetralone oximes
We also examined the effects of several substituents at the aromatic 7-position on the
acid-catalyzed rearrangement of peri-chlorotetralone oximes (Table 2 and Table S2).
Unsubstituted 8-chlorotetralone oxime (10a) afforded a mixture of alkyl (11a) and
9
benzene (12a) migration lactams in a ratio of 66:34 (Table 2).
Table 2. Rearrangement of 8-Cl tetralone oximes.
OTs
Cl
N
Cl
O
Cl
H
N
O
8
8
'
TFA
NH
7
R
R
+
R
2
0 ºC
6
5
0.1 M
Alkyl Migration Benzene Migration
10a-f
11a-f
12a-f
Isolated Ratio[a]
(Alkyl : Benzene)
Isolated Ratio[a]
(Alkyl : Benzene)
Reaction
Time
Isolated
Yield (%)
Reaction
Time
Isolated
Yield (%)
Tosylated Oxime
Tosylated Oxime
OTs
O
OTs
O
Cl
N
Cl
Cl
H
N
O
Cl
N
Cl
Cl
H
N
O
8
O N
NH
O N
16 h
2
NH O2N
+
2
93
1
h
+
95
7
1
0a
11a
12a
11d
97 :
3
12d
1
0d
6
6 : 34
OTs
Cl O
Cl
H
OTs
Cl O
Cl
N
O
Cl
N
N
NH
MeO2C
NH
97
MeO2C
8'
+
90
—
48 h
7
1
h
5
NO2
NO2
NO2
1
0b
11b 100 : 0
11e
87 : 13
12e
1
0e
OTs
Cl
N
Cl O
Cl
H
N
O
OTs
8
'
Cl
N
Cl O
Cl
H
N
O
NH
+
MeO
MeO
NH MeO
+
3
h
9
4
1 h
7
91
5
CO2Me
CO Me
11c
CO Me
67 : 33 12c
2
2
1
0f
11f
75 : 25
12f
1
0c

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1
[
a] Isolated ratios were the same as the yield ratios calculated from the H NMR
spectra of the crude products, within the limits of experimental error (see Table
S2).
7
-Methoxycarbonyl
Group: The 7-methoxycarbonyl-substituted substrate,
7
-CO Me-peri-Cl tetralone oxime 10b, gave the alkyl migration product (11b)
2
exclusively (alkyl: benzene = 100:0) (Table 2). Kinetic studies showed that the reaction
rate of 7-CO Me 10b was 5.3 times larger than that of unsubstituted 10a at -12 °C
2
(
Table 2 and Table S3). This is probably due to the synergistic effects of the ester
carbonyl oxygen atom in facilitating Cl-N bonding interaction and stabilizing the
+
resultant putative [ Cl--N] cationic system as observed in the case of peri-bromo 3b
(
Figure 5(a)).
(
a)
OTs
OTs
O
Cl O
O
Cl
N
O
Cl
N
H+
8
'
NH
O
O
O
7
CF CO H
3
2
11b
1
0b
10b-IM
(
b)
O
H
N
H+
O
94% Recovery
CF CO H
3
2
1
hr, 20°C
10b-H
OTs
OTs
(c)
Cl
N
Cl
O
Cl
Cl
N
H+
H
N
O
8
'
NH
CF CO H
3
2
5
1
hr, 20°C
COOMe
0c
COOMe
NMR Ratio: 53
1c
COOMe
26
COOMe
21
:
:
1
1
(recovery)
1
2c

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Figure 5. Effect of peri-chloride atom. (a) The (oxygen)-(chloride)-
iminylium-nitrogen) bonding interactions in 7-ester 10b stabilize the putative
(
cationic system (10b-IM), resulting in exclusive formation of the alkyl migration
product 11b from 10b (b) Crucial role of the peri-Cl substitution for alkyl
migration. (c) A 5-ester group retarded the reaction and lowered the
regioselectivity.
This would be consistent with the observation that the 7-CO Me-peri-H-tetralone
2
derivative 10b-H (Figure 5(b)), lacking the peri-Cl atom, did not undergo the
rearrangement: the starting material was recovered in 94% yield under similar acidic
conditions (TFA for 1 hr at 20 °C). Further indirect evidence is provided by the
observation that the regioselectivity of 10c (5-CO Me-peri-Cl) (alkyl: benzene = 67:33)
2
is similar to that of the unsubstituted substrate (10a) (Table 2). When the reaction was
quenched after 1 hr (20 °C in TFA), the starting tosylated oxime 10c, in addition to a
mixture of the two migration products (11c and 12c), was recovered (Figure 5(c)). This
indicates that the reactivity of 5-CO Me 10c is lower than that of 7-CO Me 10b. This is
2
2
consistent with involvement of the ester at the 7-position in the high migration
selectivity and reaction acceleration (the order of the reaction rates was: 7-CO Me 10b
2
>
H 10a > 5-CO Me 10c; Table S3). The 5-CO Me and 7-CO Me groups are in
2 2 2
ortho/para positions with respect to the peri-Cl group, respectively, suggesting they
would have similar electronic effects at the peri-Cl group and the aromatic 8’ position
(
meta position with respect to the ester group in both cases: see Table 2). The latter 8’
position is the reaction center for the benzene migration.

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The observation that an ortho- but not a para-ester group with respect to the
peri-chloro group changed the major reaction pathway led us to hypothesize that the
ortho (7)-CO Me group intervenes in the ionization process, generating a long-lived
2
cationic intermediate (10b-IM, Figure 5(a)), due to interaction of the chloro-iminylium
cation with the adjacent ester oxygen atom, in a similar manner to the long-lived
ester-stabilized bromonium-imidonitrogen intermediate (3b-IM, Figure 3(c)).
7
-Nitro Group: Compound (10d) bearing an electron-withdrawing nitro group at
the 7-position also showed a markedly increased preference for alkyl migration over
benzene migration at 20 °C (alkyl: benzene = 97:3, Table 2). The reaction of 10d was
very slow (reaction time: 16 hrs), as compared with that of 10a (reaction time: 1 hr)
under the same conditions.
1
0a showed first-order kinetics with respect to the starting tosylated oxime at
-
12°C, while nitro-substituted 10d and 10e (5-NO )did not react at this temperature, but
2
did react at 20°C and at 45°C (Table S3). The relative reaction rates at 45 ºC were:
unsubstituted 10a (>10, calculated at 45°C) >> 7-NO 10d (1.0) > 5-NO 10e (0.3).
2
2
Thus, it appears that the 7-nitro group (10d) increased both the alkyl migration
preference and the reaction rate compared with the 5-nitro group (10e), suggesting
involvement of interaction of the 7-nitro group with the Cl-N cationic system.
Substitution with 7-Methoxy Group The 7-MeO derivative 10f showed a slightly
increased preference for alkyl migration (alkyl: benzene = 75:25) as compared with that
of the unsubstituted 10a (alkyl: benzene = 66:34) (Table 2). This is because the
interaction of the oxygen atom of the 7-MeO group with the adjacent onium cation
system is inefficient due to the large angle strain in forming a 4-membered cyclic
interaction (other MeO-substituted substrates, see Table S2). This result confirms the

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idea that interaction of the heteroatom at the 7-position changes the migration
preference.
Rearrangement of peri-methoxytetralone oximes: Enhancement of N-O covalent
bonding
The oxime rearrangement reaction of peri-methoxytetralone oxime derivative (13a) was
studied (Table 3 and Table S4). We found that 13a predominantly yielded the alkyl
migration reverse lactam (14a) together with the benzene migration lactam (15a) in a
ratio of 91:9 (alkyl: benzene) (Table 3). This alkyl migration is considered to involve
interaction of the peri-oxygen atom with the putative electron-deficient imino-nitrogen
atom (see Figure 6). A similar ratio of alkyl/benzene migration was found in the case of
peri-ethoxy derivative (13b).
When the 7-nitro group was introduced on the aromatic ring, the compound (13c)
reacted differently from 13a and 13b: 13c gave the ring-closed compound 16c, a
1
,2-benzisoxazole, in 80 % yield, together with the alkyl migration product (14c) in 9 %
yield (Table 3 and Table S4). No benzene migration product (15c) was detected. The
structure of 16c was confirmed by X-ray crystallographic analysis (Figure S7). On the
other hand, the isomeric 5-nitro derivative 13d gave only rearrangement products (14d
and 15d), the ratio (14d: 15d =90: 10) being similar to that of unsubstituted 13a.

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Table 3. Rearrangement reactions of 8-alkoxy-tetralone oximes
OTs
MeO
O
MeO
MeO
N
H
N
O
O
N
TFA
NH
R
R
+
R
+
R
2
0 ºC
0
.1 M
Alkyl Migration Benzene Migration Bond formation
13a-d
14a-d
15a-d
16
Tosylated
Oxime
Reaction
Time
Isolated Ratio
(Alkyl : Benzene)
Isolated
Yield
entry
OTs
OTs
OTs
MeO
N
MeO
EtO
O
MeO
H
O
O
8
N
NH
1
1
4a 80%
5a 8%
1
2
+
1
h
h
1
1
3a
1
4a
9
1 : 9 15a
EtO
N
O
EtO
H
8
N
NH
1
1
4b 74%
5b 11%
+
1
3b
1
4b
8
7 :13 15b
MeO
N
O
MeO
O N
MeO
H
O
O
N
O N
8'
N
2
2
NH O N
2
O N
2
+
3
7
14c 9%
6c 80%
1
h
+
1
1
3c
14c
1
5c
1
6c
1
00 : 0
MeO
OTs
MeO
N
MeO
O
H
N
O
8
'
NH
+
4
1 h
14d 82%
15d 9%
5
NO2
NO 14d
NO 15d
2
2
9
0 : 10
1
3d
-
(
CF CO )
3 2
Nu
H
H
H
C
Me
Me
OTs
+
O
N
O
O
N
O
O
O
N
H+
O N
O2N
O N
NH
2
N
2
+
O
CF COOH
3
1
80%
6c
14c
9.3%
1
3c
13c-IM'
-
(
CF CO )
3
2
Nu
H
H
H C
O
N
+
O
N
O
13c-IM

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Figure 6. Formation of cyclization product. Possible reaction mechanism of 7-nitro
compound (13c) to afford ring-closed 1,2-benzisoxazole 16c and reverse lactam 14c
through an analogous intermediate 13c-IM’ or a different bonding intermediate
1
3c-IM.
The relative experimental reaction rates was estimated to be in the order H 13a >
-NO 13c > 5-NO 13d, based on the rates of consumption of the starting material
7
2
2
(
Figure S8). This acceleration of the reaction of 7-NO 13c over that of isomeric 5-NO
2 2
1
3d is consistent with tandem neighboring group participation of the 7-NO group in the
2
reaction of 13c (Figure 6).
Because of the presence of the effect of the 7-substituent, an intermediacy of a similar
chemical species 13c-IM’ is assumed to participate, involving O - - O - - N bonding
interactions.
Alkyl migration from the intermediate 13c-IM’ can occur, but would be slow, and the
stabilized intermediate would be susceptible to nucleophilic attack of anionic species
such as trifluoroacetate anion at the positively charged methyl group of the methyl
+
oxonium cation (see Figure 6), leading to cleavage of the Me-O bond, and
consequently a N-O covalent bond is formed to give the aromatic 1,2-benzisoxazole
(
16c). Later, the computational study suggested that the bonding net work is not
3c-IM’, but 13c-IM (see Figure 8).
1
Computational study of the impact of the 7-substituent on intermediate stability

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In density functional theory (DFT) calculations of substrates and transition state
structures (TSs), and resulting cation intermediates of the migration reactions, we used
tetralone derivatives substituted with O-mesylate (Ms) as a leaving group, which is
9
similar to the experiment, with hydrogen chloride as the acid in simulated HCO H
2
solution to minimize diversity in orientation of molecules. In the calculations TS
2
structures for substitution of peri-heteroatom onto oxime sp -nitrogen atom, and the
resultant peri-heteroatom-iminylium N intermaediates (such as 3b-IM) can be identified
(
Figure 7).
Change of rate-determining step Overall alkyl migration reaction involves
substitution of the peri-heteroatom onto oxime nitrogen atom and subsequent migration
of the alkyl group, anti with respect to the temporary peri-heteroatom -- iminylium
9
nitrogen bonding interaction (see Figure 3(c)). For 7-substituted peri-Cl- and
peri-MeO-substituted compounds, the calculations suggested that the substitution step
(elimination step) is rate-determining, rather than the migration process, in the overall
alkyl migration reaction (Tables S5 and S6). In the case of the 7-substituted peri-Br
compound, the rate-determining step is migration rather than substitution (Table S7,
9
Figure S9). Thus, the rate-determining step was shifted to the migration process from
the substitution step when a 7-CO Me or 7-nitro substituent was introduced into the
2
peri-Br compound. In the peri-Cl case, the calculated energy barrier of the substitution
step decreased in the order of 10c-Ms (5-CO Me) > 10a-Ms (5-H) > 10b-Ms
2
(
(
7-CO Me) (Table S5), and this is consistent with the results of the kinetic study of 10b
2
Table S3), which showed acceleration of the reaction and high selectivity for alkyl
migration as compared with the 7-unsubstituted 10a (Table 1). Similarly, the
substitution intermediate 7-CO Me-peri-Br 3b-IM was kinetically stabilized (Figure
2

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S9), because the migration process is more energy-demanding than the substitution
process. These calculation results are consistent with the fact that the intermediate
7
-CO Me- peri-Br 3b-IM was directly observed by NMR spectroscopy (Figure 4).
2
peri-Br
Br
+0.13)
Br
(+0.50)
N
-0.14)
N
Br
(+0.85) (-0.44)
N
(
(
(-0.20)
O1
-0.61)
(
O1
-0.63)
(
O1
(
-0.59)
-135.9º
-1.1º
-0.3º
(
Br-N: 2.369 Å)
(
Br-N: 3.096 Å)
(Br-N: 1.981 Å)
3b-IM
3b-Ms
3b-Ms-TS-S
peri-Cl
Cl
N
Cl
Cl
N
O1 (+0.68)
(-0.62)
O1
-0.61)
(-0.34)
(+0.04)
N
-0.17)
(+0.49)
(-0.17)
(
O1
(
(-0.61)
B
A
-1.6
-1.9º
-42.2º
(Cl-N: 1.878 Å)
(Cl-N: 2.115 Å)
(
Cl-N: 2.962 Å)
1
0b-IM
1
0b-Ms-TS-S
10b-Ms
(
CH3)
H
+0.23)
O2
-0.38)
(
(+0.51)
peri-OMe
(
CH3)
(
N
N
O1
(-0.40)
(+0.47)
(-0.09)
O1
-0.39)
(-0.01)
O1
O1
-0.38)
O2
(
(-0.59)
(
(
-0.31)
N
(-0.18)
-33.5º
-8.5
-13.1
(
O1-N: 1.599 Å)
(
O1-N: 2.720 Å)
(O1-N: 1.871 Å)
13c-Ms-TS-S
13c-IM
13c-Ms
Figure 7. Calculated structures of the reactant, TS of the substitution process, and
the resultant intermediate in the substitution of 7-CO Me-peri-Br compound
2
(
3b-Ms, top), 7-CO Me-peri-Cl compound (10b-Ms, middle), and 7-NO -peri-MeO
2
2
compound (13c-Ms, bottom). Distances between peri-heteroatom (Y)-N atom are

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shown in parentheses. Charges of selected atoms, obtained by natural population
analysis (NPA), are also shown in parentheses.
Geometrical changes: The distance between the oxygen atom (O1) of the 7-ester
and the Br atom, and that between the Br atom and the oxime N atom are decreased
from those of the starting material (3b-Ms (7-CO Me): O---Br: 3.081 Å and Br---N:
2
3
2
.096 Å) in the TS structure (3b-Ms-TS-S (7-CO Me)): O---Br: 2.891 Å and Br---N:
2
.369 Å. They are further decreased in the intermediate (3b-IM, O---Br: 2.883 Å and
Br---N: 1.981 Å) as compared with the TS (3b-Ms-TS-S) structure. The former
1
5
(
(
O---Br) is still larger than the sum of the covalent radii (1.86Å), while the latter
1
5
Br---N) is only marginally larger than the sum of the covalent radii (1.91Å). The
Br---N distance was shorter than the corresponding distance of the intermediate of the
-CO Me substituted analogue (3e-IM: 2.001 Å) (see Figure S10 and Table S8). This
5
2
implied that strong bonding is formed between Br and N atoms, while the bonding
between the ester oxygen atom and the bromide should be weak. Similar structural
changes are also found in the TS and the intermediate in the case of 7-NO substituted
2
peri-Br-oxime (3d-Ms) (see Supporting Table S8 and Figure S11). The nature of the
bonding interaction between the two distal atoms is ambiguous, and will be further
discussed below.
In the case of the peri-Cl, geometrical features of the calculated TS and the
intermediate for the substitution process of the peri-Cl-7-CO Me derivative (10d-Ms)
2
(
Figure S12) are similar to those in the corresponding structures of the peri-Br

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counterpart 3b-Ms (peri-Br-7-CO Me) in terms of the through-space distances between
2
the peri-Cl atom and the nitrogen atom, and between the peri-Cl atom and the oxygen
atom of the 7-ester group. The distance between the Cl – N atoms (1.878 Å) of the
intermediate of peri-Cl-7-CO Me derivative (10b-IM) is close to the sum of the
2
1
5
covalent radii (Cl---N: 1.73 Å) ; in contrast, the O – Cl distance (2.829 Å) in the
intermediate of the peri-Cl-7-CO Me derivative (10b-IM) is much larger than the sum
2
1
5
of the covalent radii (O---Cl: 1.68 Å) (Table S8).
In the peri-MeO-7-NO (13c-Ms) case, the geometrical features of the calculated
2
TS and the intermediate for the substitution process are similar, but differ slightly from
those of the peri-Br and peri-Cl 7-NO -analogues: the distance between the peri-O(Me)
2
and N atoms of the intermediate (13c-IM) (1.599 Å) is slightly larger than that of the
7
-unsubstituted analogue (13a-IM) (1.580 Å), both being larger than the sum of the
1
5
covalent radii (O---N: 1.37 Å) (Table S8). The distance between the peri-O(Me) and
7
-nitro oxygen atom of the intermediate (13c-IM) (2.871 Å) is much larger than the
sum of the covalent radii (O---O: 1.32 Å). Intriguingly, the bond length in the case of
peri-O-CH is elongated in the TS (1.493 Å) and intermediate (13c-IM) (1.520 Å) as
3
compared with the initial bond length (1.441 Å) found in the starting material (13c-Ms)
(
Table S8). Elongation of Me-O bond of the intermediate (13c-IM) (1.520 Å) is greater
than that found in the corresponding intermediate of the 7-unsubstituted analogue
13a-IM) (1.505 Å).
(

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Furthermore, geometrical changes in passing through the TS also support
tandem neighboring group participation (Figure 7 and Figures S10-S13). The
calculated TS (TS-S, Figure 7) for the putative attack of the peri-Br, peri-Cl and
2
peri-OMe atom on the sp N(-OMs) group, with the MsOH group leaving, involves a
planar alignment of the peri-heteroatom, oxime N and O(Ms) atoms, resembling the
1
6
TSs of S 2 reactions. Synchronous rotation of the 7-subsituent was also observed in
N
the TS of the 7-substituted compounds (Figure 7, Table S9), involving a planar
alignment of the ester or nitro oxygen atom (O1) at the 7-position, peri-Br/Cl/(CH )O
3
atom (Y), and oxime N atom; the dihedral angles, ∠O1-C10-C7-C8; ∠Y-C8-C9-C1;
N-C1-C9-C8 in the TS structure are as follows: (Y=Br: 3b-Ms-TS-S (7-CO Me): -1.1°;
2
1
.1°; -3.1°; Y=Cl: 10b-Ms-TS-S (7-CO Me): -1.9°; 0.3°; 0.7°; Y=(Me)O: 13c-Ms-TS-S
2
(
7-NO ): -13.1°; -4.1°; 0.9°) and in the starting structure: (Y=Br: 3b-Ms (7-CO Me):
2 2
-
135.9°; -11.5°; -42.5°; Y=Cl: 10b-Ms (7-CO Me): -42.2°; -4.5°; -37.8°; Y=(Me)O:
2
1
3c-Ms (7-NO ): -33.5°; -7.3°; -31.7°) (Table S9). The leaving mesyl oxygen atom is
2
also located on the same plane as the ester carbonyl or nitro oxygen atom (O1) at the
-position, the peri-Y atom, and the oxime N atom. The dihedral angle of the oxygen
atom of the leaving Ms group in the TS (3b-Ms-TS-S (peri-Br-7-CO Me),
7
2
∠
O1-Br-N-O(Ms) =-176.7°; 10b-Ms-TS-S (peri-Cl-7-CO Me), ∠O1-Cl-N-O(Ms)
2
=
144.3°; 13c-Ms-TS-S (peri-MeO-7-NO ), ∠O1-O(Me)-N-O(Ms)=-173.2°) indicates a
2
1
7
linear arrangement similar to that of an S 2 substitution reaction.
N
Charge Redistribution: Natural population analysis (NPA) suggested a highly
polarized nature of the putative O-Cl bonding as compared to the putative Cl-N bonding
in the TS (10b-Ms-TS-S (7-CO Me-peri-Cl)) and the intermediate (10b-IM
2

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(
7-CO Me-peri -Cl)) (Figure 7 middle): the Cl-N and O-Cl bonding of the TS
2
(
10b-Ms-TS-S: (C=)O: -0.61, Cl: +0.49, N: -0.17) became more polarized (charge
alternation) in the intermediate (10b-IM, (C=)O: -0.62, Cl: +0.68, N: -0.34). Therefore,
+
the three aligned atoms, O(Z) ---- Cl(Y) -----N(X) in the intermediate (10b-IM)
+
enhanced the nature of ionic interaction of O(Z)----Cl(Y) and stabilized the whole
system. Similar charge distributions are also found in the cases of peri-bromo
substrates: the incipient Br-N bond has a bromonium cation character both in the TS
(
(
3b-Ms-TS-S (7-CO Me-peri-Br)) and in the resultant cationic intermediate (3b-IM
2
7-CO Me-peri-Br)), which are stabilized by the negatively charged 7-carbonyl oxygen
2
atom, indicating enhancement of ionic interaction between the peri-Br atom and the
-carbonyl oxygen atom (Figure 7 top). In the case of the 7-NO -peri-MeO
7
2
intermediate 13c-IM, the interactions can be represented in terms of ionic interactions
of the positively charged hydrogen atom (+0.23) of the MeO group with negatively
charged nitro oxygen (-0.40) atom. Because of the highly polarized nature of the C-O σ
bond in the MeO group, the methoxy O – N bonding is slightly polarized (O: -0.31; N:
-
0.09) (Figure 7, see also Figure 2, C2). Other types of charge calculations gave
similar results (Figures S14-S15 and Table S10).
These trends are consistent with the bonding nature found in the following quantum
theory of atoms-in-molecules (QTAIM) analysis.
Quantum theory of atoms-in-molecules (QTAIM) analysis
1
8, 19, 20
Molecular graphs of quantum theory of atoms-in-molecules (QTAIM) analysis
of
the iminylium intermediates indicate the presence of dual nonequivalent bonding

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interactions (Figure 8). The electron densities at the relevant bond paths and the
Laplacians of electron density are summarized in Table S11. Examination of the dual
bonding interactions in the TS structures also confirms the existence of primary and
secondary interactions of neighboring groups. The unsymmetrical bonding interactions
in the TS structures are maintained in the intermediate structures.
Peri-bromo-7-ester Derivative The QTAIM analysis of the TS and the putative
intermediate 3b-IM identified the presence of secondary interaction of the third
neighboring group (Figure 8(a) and Table S11), i.e., bond paths and bond critical
points (bcps) were found between the peri-bromo atom and the nitrogen atom (bcp1),
and also between the peri-bromo atom and the ester oxygen atom (bcp2) in the
intermediate 3b-IM, indicating that adjacent three heteroatoms (O, Br and N) are
interacting simultaneously in the TS and the intermediate (Figure 1(b), B2). There are
also two ring critical points in the virtual fused two five-membered rings. The
interactions in the O -- Br -- N system are nonequivalent: a larger electron density
3
ρ(r) value (0.130 e/bohr ) at the former bcp1 (Br -- N) and a small ρ(r) value (0.018
b
b
3
e/bohr ) at the latter bcp2 (O – Br) were calculated (Figure 8 and Table S11), the
former bonding (i.e., the primary interaction) being stronger than the latter (i.e., the
secondary bonding). The former bcp1 (Br -- N) of 3b-IM has larger electron density
3
3
(
0.130 e/bohr ) than that of the 7-unsubstituted 3a-IM (ρ(r) value (0.122 e/bohr ))
b
(Table S11), indicative of enhancing the bonding nature of Br – N arising from another
neighboring group (the 7-ester group). Small positive values of the Laplacians of the
2
5
5
electron density (ꢀ ρ(r)) (+0.046 e/bohr (Br – N) and +0.058 e/bohr (O – Br)) at the
relevant bond critical points of 3b-IM were found, providing a sharp contrast to the

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2
5
negative values of covalent σ bonding (C-Br: ꢀ ρ(r): -0.0813 e/bohr ; ρ(r) value:
b
3
0
.1407 e/bohr , see Table S11). This suggested that the electron density is not
2
1
concentrated, but rather is slightly depleted in these interacting regions. The bonding
nature of O --- Br, that is, a small electron density and a positive small Laplacian of the
electron density, is consistent with that of ionic bonding, being similar to halogen
2
2, 23
bonding.
Therefore, cleavable non-covalent bonding of the Br – N, i. e., electrostatic
interaction would lead to acceleration of the alkyl migration.
Br
O
C
bcp2
Cl
(a)
bcp2
bcp1
(b)
bcp1
O
N
N
CH3
C
O
O
CO CH3
2
CO CH
2
3
3
b-IM
10b-IM
(
bcp1) (bcp2)
Br-N a O-Bra
(bcp1) (bcp2)
Cl-N a O-Cl a
0.147 0.017
(CH3)
C
ρ(r)b
0.130 0.018
2ρ(r)b +0.046 +0.058
ρ(r)b
b
b
H
b
b
2ρ(r)b +0.060 +0.063
(c)
bcp2
N
bcp1
O
O
N
(
NO2)
O
(
bcp1) (bcp2)
O-N a H-O a
0.182 0.018
ρ(r)b
2ρ(r)b +0.151 +0.068
b
b
13c-IM
Figure 8. Molecular graph of the putative intermediate 3b-IM (7-CO Me-peri-Br),
2
1
0b-IM (7-CO Me-peri-Cl) and 13c-IM (7-NO -peri-MeO). Grey balls: atom
2 2
critical points; red balls: bond critical points; green balls: ring critical points.
Colored lines show bond paths. bcp=bond critical point. Electron density(ρ(r)b)
2
and the Laplacians of the electron density (
ꢀ
ρ(r)) at the bond critical points 1 and
3
5
2
were shown (for detail: see Table S11). a: in (e/bohr ); b: in (e/bohr ).

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Peri-chloro-7-ester Derivative In a similar manner to the peri-Br case, QTAIM
analysis again identified the presence of secondary interaction involving the third
neighboring group (7-ester), i.e., bcp1 between the peri-chloride atom and the nitrogen
atom and bcp2 between the peri-chloride atom and the ester oxygen atom in TS and
intermediate 10b-IM (Figure 8(b)), indicating that the three adjacent heteroatoms (O,
Cl and N) are interacting simultaneously in the TS and the intermediate (Figure 1(b),
B2; see also Table 3). The bonding nature of O --- Cl, that is, a small electron density
and a positive small Laplacian of the electron density, is consistent with that of halogen
2
2
bonding, in a similar manner to the peri-Br case (3b-IM) (Table S11 and Figure S16).
Therefore, substitution of the 7-ester group increased the electron density between the
peri-halogen and N atoms, which will lead to lower activation energies and stabilization
of the subsequent intermediates. This cannot be simply described in terms of the
resonance structures shown in Figure 1.
Peri-methoxy-7-nitro Derivative At first, we thought that the oxygen atom of the
ortho(7)-NO group would interact with the adjacent oxygen atom of the peri-OMe
2
group, forming an oxygen-oxygen bond in the intermediate 13c-IM in a similar manner
to the peri-Br and peri-Cl cases (Figure 6). However, QTAIM analysis identified the
presence of bond paths and bond critical points (bcps) between the methoxy oxygen
atom and the imino nitrogen atom (bcp1), and also between the nitro oxygen atom and
O-CH proton (bcp2) as in 13c-IM, instead of the nitro oxygen atom and the O-CH
3
3
oxygen atom (as 13c-IM’) (Figure 8 (c)). Ring critical points were also found in the
virtual seven-membered ring, C-H-O-N-C-C-O and five-membered ring, O-C-C-C-N.
This is consistent with the long distance between the nitro oxygen and peri-O(Me)

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DOI: 10.1039/C6OB02719A
3
oxygen atoms (see Table S8). A small electron density at bcp2 (ρ(r) , 0.018 e/bohr ) of
b
3
the H---O(NO ) and a larger electron density (ρ(r) : 0.182 e/bohr ) at the bcp1 of the
2
b
O(CH )---N bond path suggested that the interactions are nonequivalent, the latter
3
bonding being stronger than the former, and in fact as strong as conventional σ bonding
3
(
e.g., C(H )-O in 13c-IM): ρ(r) = 0.181 e/bohr ). The Laplacians of the electron
3
b
2
densities (ꢀ ρ(r)) in these interacting regions were calculated to be positive and small
5
2
(
+0.068 and +0.151 e/bohr ), in contrast to a negative ꢀ ρ(r) value of conventional σ
2
5
bonding, such as C(H )-O in 13c-IM (ꢀ ρ(r)= -0.159 e/bohr ) (see also Table S11). The
3
electron-density properties of the O – H(C) bonding are consistent with those of
2
4
hydrogen bonding. Therefore, in the case of the combination of 7-NO and peri-MeO
2
substituents, the primary and secondary bonding interactions of neighboring group
participation occurred over five atoms (O-H-C-O-N), still involving dual nonequivalent
bonding interactions: unprecedented hydrogen bonding interaction between O (nitro)
and H (peri-OMe) and strong ionic bonding interaction between the oxygen atom
(
peri-OMe) and the putative iminylium nitrogen atom (13c-IM, Figures 6 and 8 (c), see
also Figure 2, C2). The dual bonding interactions appear to be relayed through the
intervening C-O σ bond. Finally accumulation of electron density in the region
3
between (Me)O -- N of 13c-IM (0.182 e/bohr ) as compared with that of the
3
7
-unsubstituted peri-MeO derivative (13a-IM: (ρ(r) , 0.179 e/bohr )) would lead to
b
N-O covalent bond formation (Table S11). Furthermore, QTAIM analysis also
suggested reduction of electron density of the H C-O σ bond in the intermediate
2
(
13c-IM) as compared with that of the 7-unsubstituted intermediate (13a-IM) (Table
S11), which is consistent with the geometrical elongation of H C-O σ bond length. This
2

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DOI: 10.1039/C6OB02719A
redistribution of electron density would enhance the secondary interaction, i.e, ionic
interaction (hydrogen bonding) between the CH O hydrogen and nitro oxygen atoms,
3
and also facilitate cleavage of the H C-O σ bond leading to the final N-O bond
3
formation (see Figure 6).
Aromaticity: The intermediate peri-Cl-7-CO Me 10b-IM has temporary
2
five-membered cyclic systems through three-atom bonding interaction, i.e., ring A
(Cl-N-C-C-C) and ring B (O-Cl-C-C-C) (10b-IM) in Figure 7). NICS
2
5
(
nucleus-independent chemical shifts) calculations gave NICS(1) values of ring A
ZZ
and ring B of -11.0 and +2.7, respectively, suggesting strong aromaticity (for ring A)
and non-aromaticity (for ring B). The former feature may be one of the driving forces
for bonding interaction.
Conclusion
A tandem-neighboring group proved to be a crucial determinant of the reaction
pathway, leading to either overwhelmingly selective syn-migration of the oxime
functionality or covalent bond formation under acid-catalyzed Beckmann rearrangement
conditions. The tandem participation of neighboring groups at the present putative
iminylium ions involves dual bonding interaction among three heteroatoms (B2, Figure
1
7
1
(b)), i.e., the two heteroatoms at the peri- and the 7-positions interacting with the
putative iminylium nitrogen cation in the cases of peri-Br and peri-Cl substituents.
Further, in the the case of peri-MeO substituent, the dual bonding interaction can be
relayed by a polarized σ bond (i.e., a polarizable functional group), involving a

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five-atom interaction (Figure 2, C1), in the compound bearing 7-nitro and peri-MeO
groups on the tetralone oxime, wherein unprecedented hydrogen bonding between
7
-NO oxygen and peri-MeO hydrogen atoms is involved. The bonding nature of these
2
stabilizing interactions can be regarded as acyclic interactions in a D (donor, Z)-D
+
(
donor, Y)-A (acceptor, N ) system (Figure 1 (a)) or D(W)-D(CH , (Z))-D(O,
3
+
(
Y))-A(N ) system, in which HOMO-HOMO interaction between D’s (Z and Y) in the
2
6
D-D-A system or in the extended D-D-D-A system contribute to stabilization. Indeed,
we could directly observe the imino-bromonium cation (3b-IM), which is the reactive
intermediate of the subsequent migration, by NMR spectroscopy. We consider that
tandem participation of neighboring groups contributes to proper alignment of multiple
functional groups for the transition state of substitution. While the generality of the
present work remains to be examined, there is potential for contributions of such
tandem interactions in general to stabilize the intermediate, accelerate the reaction and
also induce high chemoselectivity in finite (D) -A systems.
n

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Experimental Sections
General Methods:
All reactions were carried out under argon atmosphere in oven-dried glasswares. All
commercially available compounds and solvents were used as received unless otherwise
mentioned. N-Bromosuccinimide (NBS) was recrystallized from hot water. NaH was
washed with hexane before use and measured under argon atmosphere. Triethylamine
was purified by distillation over CaH.
Open column chromatography was carried out using Kanto chemical silica gel (silica
gel 60 N (100-210 μm)). Melting points were determined with a Yanaco micro
1
13
melting point apparatus without correction. H- (400 MHz) and C- (100 MHz) NMR
spectra were recorded on a Bruker Avance 400. Chemical shifts were calibrated with
tetramethylsilane and solvent as an internal standard or with the solvent peak, and are
shown in ppm (δ) values, and coupling constants are shown in hertz (Hz). The
following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd =
double doublet, dt = double triplet, dq = double quartet, h = hextet, m = multiplet, brs =
broad singlet, br = broad signal. Temperature was calibrated using methanol according
2
7
to the reported method. Electron spray ionization time-of-flight mass spectra
ESI-TOF MS) were recorded on a Bruker micrOTOF-05 to give high-resolution mass
(
spectra (HRMS). The combustion analyses were carried out in the microanalytical
laboratory of this department.
Synthesis and Reactions:
The detail of synthesis and reactions are described in ESI.
Kinetic measurements
General Procedure A (peri-Cl compounds)
Each substrate Ts-O-oxime (0.30 mmol) was dissolved in TFA (3.0 mL) at -15 ºC in dry
flasks under argon atmosphere and stirred until concentration is 0.1 M. The solution
was divided and transferred into 3 NMR tubes filled with argon, and monitored with
NMR. The NMR spectrum was recorded at regular intervals, at a specified temperature.
Magnetic field locking was not used, but the shimming was maximized with using
1
CDCl . The H-NMR spectra were obtained at -12 °C (10a, 10b, 10g and 10f) and 45 ºC
3
(
10d and 10e). The peak of TFA was used as an internal standard of the integration. The
integration value of separated signals of the substrate, as compared with that of TFA,
was obtained and concentrations of the remaining starting material are calculated. The
ratios (in logarithm) of disappearance of the starting substrate against the initial amount